Chemokine receptor binding heterocyclic compounds with enhanced efficacy

专利摘要:
The present invention relates to a heterocyclic compound consisting of a core nitrogen atom surrounded by three side chain groups, wherein two of the three side chain groups are preferably benzimidazolyl methyl and tetrahydroquinolyl, and the third side chain group N and, optionally, further rings). The compound binds to chemokine receptors, including CXCR4 and CCR5, and has the effect of protecting target cells from being infected by human immunodeficiency virus (HIV).
公开号:KR20040068339A
申请号:KR10-2004-7009919
申请日:2002-12-23
公开日:2004-07-30
发明作者:브릿저게리제이.；스컬즈리네이토티.；칼러알；하윅커티스；보우거키데이빗；윌슨트레버；크로포드제이슨；맥이천어네스트제이.；앗스마벰；난쓰차오；저우위안시；숄스도미니크；스미스크리스토퍼데니스；디플루리로사리아마리아
申请人:아노르메드 인코포레이티드；
IPC主号:

专利说明:

Chemokine receptor binding heterocyclic compounds with enhanced efficacy}
[1] Cross Reference to Related Application
[2] The present application is directed to 35 U.S.C. Claims priority on US Provisional Application No. 60 / 342,716, filed December 21, 2001, and US Provisional Application No. 60 / 350,822, filed January 17, 2002, under Section 119 (e). The contents of these applications are incorporated herein by reference.
[4] At least in part, about 40 human chemokines have been described that function by regulating a complex and overlapping series of biological activities critical for lymphoid cell migration and leukocyte outflow and tissue penetration into stimulants [eg, See P. Ponath, Exp. Opin. Invest. Drugs , 7: 1-18, 1998]. These chemotactic cytokines or chemokines constitute a protein system that is about 8-10 kDa in size. Chemokines appear to share a common structural motif consisting of four conserved cysteines involved in maintaining the quaternary structure. There are two main chemokine subsystems: "CC" or β-chemokine and "CXC" or α-chemokine. These chemokine receptors are classified based on chemokines that make up the natural ligands of the receptor. The receptor of β-chemokine is designated "CCR", while the α-chemokine is designated "CXCR".
[5] Chemokines are believed to be major mediators in the initiation and maintenance of infections. Chemokines in Disease published by Humana Press (1999), Edited by C. Herbert; Murdoch et al. Blood 95, 3032-3043 (2000). More specifically, chemokines have been shown to play an important role in the regulation of endothelial cell function, including proliferation, migration and differentiation during angiogenesis and endothelial cell proliferation following injury . Gupta et al. , J. Biolog. Chem. , 7: 4282-4287, 1998]. Two specific chemokines have been implicated in the pathogenesis of infection with human immunodeficiency virus (HIV).
[6] In most cases, HIV initially binds to the target cell's CD4 receptor through its gp120 envelope protein. Morphological changes appear to occur at gp120 and subsequently bind to chemokine receptors such as CCR-5 (Wyatt et al ., Science , 280: 1884-1888 (1998)). HIV-1 isolates that subsequently occur in infection bind to the CXCR-4 chemokine receptor. In view of the fact that another related retrovirus, the feline immunodeficiency virus, binds to the chemokine receptor without first binding to the CD4 receptor, it is suggested that the chemokine receptor may be a prototypical absolute receptor for immunodeficiency retroviruses.
[7] After HIV initially binds to CD4, it is a different member that acts as a fusion cofactor for the macrophage- and T-tropic isolates of HIV-1 to members of the chemokine receptor system. Mediated virus-cell fusion occurs (see Carroll et al., Science , 276: 273-276 1997; Feng et al. Science 272, 872-877 (1996); Bleul et al. Nature 382, 829-833 (1996); Oberlin et al. Nature 382, 833-835 (1996); Cocchi et al. Science 270, 1811-1815 (1995); Dragic et al. Nature 381, 667-673 (1996); Deng et al. Nature 381, 661-666 (1996); Alkhatib et al. Science 272, 1955-1958, 1996]. During infection in patients many HIV particles appear to migrate from M-stimulatory to more aggressive pathogenic T-stimulatory virus phenotypes . Miedema et al. , Immune. Rev. , 140: 35 (1994); Blaak et al. Proc. Natl. Acad. Sci . 97, 1269-1274 (2000); Simmonds et al. J. Virol . 70, 8355-8360 (1996); Tersmette et al. J. Virol . 62, 2026-2032, 1988); Connor, RI, Ho, DD J. Virol . 68, 4400-4408 (1994); Schuitemaker et al. J. Virol . 66, 1354-1360 (1992). The M-stimulatory virus phenotype correlates with the ability of the virus to enter the cell and bind to the CCR-5 receptor, while the T-stimulatory virus phenotype is associated with the fact that the virus enters the cell and then binds to and binds to the CXCR-4 receptor. Correlated. Clinical observations suggest that patients with genetic mutations of CCR-5 or CXCR-4 appear to be resistant or less susceptible to HIV infection. Liu et al. Cell 86, 367-377 (1996); Samson et al. Nature 382, 722-725 (1996); Michael et al. Nature Med . 3, 338-340 (1997); Michael et al. J. Virol . 72, 6040-6047 (1998); Obrien et al. Lancet 349, 1219 (1997); Zhang et al. AIDS Res. Hum. Retroviruses 13, 1357-1366 (1997); Rana et al. J. Virol . 71, 3219-3227 (1997); Theodorou et al. Lancet 349, 1219-1220 (1997). Although the reported number of chemokine receptors for HIV mediates entry into cells, it appears that CCR5 and CXCR4 are only physiologically related co-receptors used by a wide variety of major clinical HIV-1 strains. Zhang et al. al. J. Virol . 72, 9307-9312 (1998); Zhang et al. J. Virol . 73, 3443-3448 (1999); Simmonds et al. J. Virol . 72, 8453-8457 (1988). Fusion and entry of T-stimulatory virus using CXCR4 is inhibited by native CXC-chemokine stromal cell induced factor-1, whereas fusion and entry of M-stimulatory virus using CCR5 is native CC-chemokine, ie It is inhibited by regulation on expressed and secreted activated normal T-cells (RANTES) and macrophage inflammatory proteins (MIP-1 alpha and beta).
[8] However, the binding of chemokine receptors to their natural ligands plays a more evolutionary and central role than just as a vehicle for HIV infection. The binding of the natural ligand, pre-B-cell growth stimulating factor / stromal cell induced factor (PBSF / SDF-1) to CXCR4 provides an important signaling mechanism: CXCR4 or SDF-1 knock-out mice are cerebellum, heart And gastrointestinal abnormalities . Zou et al. , Nature , 393: 591-594 (1998); Tachibana et al. , Nature , 393: 591-594 (1998); Nagasawa et al. Nature 382,635-638 (1996). CXCR4 deficient mice also exhibit hematopoietic deficiency [Nagasawa et al. Nature 382, 635-638 (1996); Migration of CXCR4 expressing leukocytes and hematopoietic progenitor cells to SDF-1 has been shown to be important for maintaining B-cell lineage and localization of CD34 ⁺ progenitor cells in bone marrow. Bleul et al. J. Exp. Med . 187, 753-762 (1998); Viardot et al. Ann. Hematol . 77, 195-197 (1998); Auiti et al. J. Exp. Med . 185, 111-120 (1997); Peled et al. Science 283, 845-848 (1999); Qing et al. Immunity 10, 463-471 (1999); Lataillade et al. Blood 95, 756-768 (1999); Ishii et al. J. Immunol . 163, 3612-3620 (1999); Maekawa et al. Internal Medicine 39, 90-100 (2000); Fedyk et al . J. Leukocyte Biol. 66, 667-673 (1999); Peled et al. Blood 95, 3289-3296 (2000).
[9] Signals provided by SDF-1 for binding to CXCR4 may play an important role in the regulation of tumor cell proliferation and angiogenesis associated with tumor growth ( Chemokines and Cancer published by Humana Press (1999); Edited by BJ Rollins; Arenburg et al. J. Leukocyte Biol . 62, 554-562 (1997); Moore et al. J. Invest. Med . 46, 113-120 (1998); Moore et al. Trends cardiovasc. Med. 8, 51-58 (1998); Seghal et al. J. Surg. Oncol. 69, 99-104 (1998); Known angiogenic growth factors VEG-F and bFGF, upregulate the levels of CXCR4 in endothelial cells, and SDF-1 can induce neovascularization in vivo [Salcedo et al. Am. J. Pathol . 154, 1125-1135 (1999); Leukemia cells expressing CXCR4 migrate and attach to lymph nodes and bone marrow stromal cells expressing SDF-1. Burger et al. Blood 94, 3658-3667 (1999); Arai et al. Eur. J. Haematol . 64, 323-332 (2000); Bradstock et al. Leukemia 14, 882-888 (2000)].
[10] The binding of SDF-1 to CXCR4 may also be responsible for the pathogenesis of atherosclerosis [Abi-Younes et al. Circ. Res . 86, 131-138 (2000)], rejection of renal allograft [Eitner et al. Transplantation 66, 1551-1557 (1998)], asthma and allergic airway inflammation [Yssel et al. Clinical and Experimental Allergy 28, 104-109 (1998 ); J. Immunol. 164, 5935-5943 (2000); Gonzalo et al. J. Immunol . 165, 499-508 (2000)], Alzheimer's disease [Xia et al. J. Neurovirology 5, 32-41 (1999)] and arthritis [Nanki et al. J. Immunol . 164, 5010-5014 (2000).
[11] In an attempt to better understand the relationship between chemokines and their receptors, recent experiments to block the fusion, entry, and replication of HIV through the CXCR4 chemokine receptor have suggested a useful therapeutic method for monoclonal antibodies or small molecules. It was carried out through the use of Schols et al. , J. Exp. Med. 186: 1383-1388 (1997); Schols et al. , Antiviral Research 35: 147-156 (1997); Bridger et al. J. Med. Chem . 42, 3971-3981 (1999); Bridger et al. "Bicyclam Derivatives as HIV Inhibitors in Advances in Antiviral Drug Design Volume 3, p161-229; Published by JAI press (1999); Edited by E. De Clercq). Small molecules such as bicyclam are specific to CXCR4 and not CCR5. (Donzella et al. , Nature Medicine , 4: 72-77 (1998)) These experiments have shown interference of membrane entry and HIV fusion to target cells in vivo. Cyclam has also been shown to inhibit the fusion and replication of feline immunodeficiency virus (FIV) using CXCR4 for entry (Egberink et al. J. Virol . 73, 6346-6352 (1999)).
[12] Further experiments showed that dose-independent bicyclam for SDF-1 inhibited the binding and signal transduction of 125I labeled SDF-1 to CXCR4 (indicated by increased intracellular calcium). Thus, bicyclam also served as an antagonist to signal transduction resulting from the binding of epilepsy-induced factors or natural chemokines to SDF-1α, CXCR4. Bicyclam also inhibited HIV gp120 (enveloped) induced apoptosis of non-HIV infected cells. Blanco et al. Antimicrobial Agents and Chemother . 44, 51-56 (2000).
[13] US Pat. Nos. 5,583,131, 5,698,546, 5,817,807, 5,021,409, and 6,001,826, which are incorporated herein by reference, describe cyclic compounds that are active against HIV-1 and HIV-2 in in vitro tests. . It is subsequently found that these compounds bind to chemokine receptor CXCR4 expressed on the surface of certain cells of the immune system and exhibit anti-HIV activity and are further described in PCT WO 02/34745. This competitive binding thus protects these target cells from infection by HIV using the CXCR4 receptor for entry. In addition, these compounds antagonize the binding, transduction, and chemotactic effects of natural ligands on CXCR4, chemokine stromal cell induced factor 1α (SDF-1). We further found that these novel compounds exhibit a protective effect against HIV infection of target cells by in vitro binding to the CCR5 receptor.
[14] In addition, the inventors have found that such cyclic polyamine antiviral agents described in the patents / patents mentioned above not only exhibit antiviral properties but also act to enhance the production of leukocyte cells. Thus, these agents are useful for controlling the side effects of chemotaxis, enhancing the success of bone marrow transplantation, enhancing wound healing and burn healing, and eliminating bacterial infection of leukemia.
[15] More recently, the inventors have expressed the expression of certain cells in the immune system in PCT WO 00/56729, PCT WO 02/22600, PCT WO 02/22599, and PCT WO 02/34745. A series of heterocyclic compounds was found that bind chemokine receptors CXCR4 and CCR5 and exhibit anti-HIV activity. This competitive binding thus protects these target cells from infection by HIV using CXCR4 or CCR5 receptors for entry. In addition, these compounds antagonize the binding, transduction, and chemotactic effects of CXCR4, chemokine stromal cell induced factor 1α (SDF-1) and / or natural ligands to CCR5, natural ligands to chemokine RANTES.
[16] The chemokine receptor, CXCR-4, can be used for vascularization of the gastrointestinal tract (Tachibana, et al., Nature (1998) 393: 591-594) and hematopoietic and cerebellar development (Zou, et al., Nature (1998) 393: 591-594. Interfering with any of these important functions acted by the binding of pre-B-cell growth stimulating factor / epilepsy-induced factor (PBSF / SDF-1) to the CXCR-4 chemokine receptor may result in vascular development, hematopoiesis and cardiomyocytes Results in a fatal deficiency of development. Similarly, the cerebellar development of the fetus appears to depend on the tongue function of CXCR-4 in neuronal cell migration and the patterning of the central nervous system. These G-protein coupled chemokine receptors appear to play a critical role in ensuring the required pattern of migration of granular cells of the cerebellar primitive.
[17] Herein, the inventors have identified compounds that make a unique chemical contribution and exhibit a protective effect against HIV infection of target cells by binding to chemokine receptor CXCR4 or CCR5 in a manner similar to previously disclosed macrocyclic compounds. In addition, these compounds antagonize the binding, transduction, and chemotactic effects of natural ligands for CXCR4, chemokine stromal cell induced factor 1α (SDF-1) and / or natural ligands for chemokines (CHEMOCAIN RANTES).
[18] Citations to the above documents are not intended to permit any of the preceding descriptions to be appropriate prior art. All statements to date or the content of these documents are based on the information available in the application and do not constitute a permit for the accuracy of the date or content of these documents. In addition, all references cited throughout this application are hereby incorporated by reference in their entirety.
[3] The present invention relates to novel compounds, pharmaceutical compositions and their use. More specifically, the present invention relates to novel heterocyclic compounds that bind to chemokine receptors, including CXCR4 and CCR4, and exhibit a protective effect against infection of target cells by human immunodeficiency virus (HIV).
[19] The present invention provides novel compounds that bind chemokine receptors and interfere with their binding to natural ligands. The compounds of the present invention are useful as agents that exhibit a protective effect on target cells from HIV infection, and are useful for the treatment of tumulic arthritis. Embodiments of the present invention are directed to agents capable of reconstituting the immune system by increasing the level of CD4 ⁺ , antagonists of apoptosis of immune cells, such as CD8 ⁺ cells and neurons, of human bone marrow B lineage cells against epilepsy-induced factor 1 Compounds that act as antagonists or agonists for chemokine receptors, useful as antagonists of migration, and other biologically active antagonists of these compounds' ability to inhibit chemokine binding to their receptors.
[20] More specifically, the present invention relates to macrocyclic compounds generally found to consist of "core" nitrogen atoms surrounded by three pendant groups, wherein two of the three pendant groups are benzimidazolyl methyl and tetrahydroquinoli And the third is a pendant group containing additional nitrogen).
[21] In one embodiment, the invention relates to compounds of formula (I).
[22]
[23] In Formula I above,
[24] X and Y are independently N or CR ¹ ,
[25] Z is S, O, NR ¹ or CR ¹ ₂ ,
[26] R ¹ to R ⁶ are independently H or non-interfering substituents,
[27] n1 is 0 to 4,
[28] n2 is 0-1 (where * indicates that C≡C may be substituted by CR ⁵ = CR ⁵ ),
[29] n3 is 0 to 4,
[30] n1 + n2 + n3 is 2 or more,
[31] b is 0 to 2,
[32] R ² + R ² , one R ² + R ³ , R ³ + one R ⁴ , R ⁴ + R ⁴ , one R ⁵ + another R ⁵ , one R ⁵ + one R ⁶ and R ⁶ The combination of the R groups of + R ⁶ may be cuffed to give rise to a ring which may be saturated or unsaturated,
[33] The ring may not be aromatic when the participants of the ring formation are two R ⁵ ,
[34] When n2 is 1, n1 and n3 cannot be zero.
[35] It should be noted that two R ⁵ on the same atom (and two R ² or R ⁶ on the same atom) may form a bridge.
[36] Six-membered rings are preferred for ring B, with preferred combinations of rings A and B being tetrahydroquinolinyl.
[37] Suitable non-interfering substituents include alkyl (C _1-10 ), alkenyl (C _2-10 ), alkynyl (C _2-10 ), aryl ("C" _5-12 ), arylalkyl, arylalkenyl or aryl Alkynyl is included, each of which may optionally contain one or more heteroatoms selected from O, S and N, each of which may be further substituted, or acyl, arylacyl, alkyl-, alkenyl-, alkoxy Optionally substituted forms of nilsulfonyl or arylsulfonyl and their forms containing heteroatoms in alkyl, alkenyl, alkynyl or aryl moieties. Other non-interfering substituents include OR, SR, NR ₂ , COOR, CONR ₂ , where R is H or alkyl, alkenyl, alkynyl or aryl as defined above. When the substituted atom is C, the substituents may include, in addition to the substituents described above, halo, OOCR, NROCR, wherein R is H or the substituents described above, or may be = 0.
[38] In general, "non-interfering substituents" are substituents which, when present, do not destroy the ability of the compound of formula (I) to behave as a chemokine. In particular, the presence of substituents does not destroy the efficacy of the compound. Since the compounds of the present invention have been shown to inhibit HIV replication, in particular with the CXCR4 receptor, the compounds of the present invention appear to be effective under processing conditions that need to modulate CXCR4 and CCR5-mediated activity.
[39] In another aspect, the present invention relates to pharmaceutical compositions containing one or more compounds of Formula (I) and to methods for improving conditions regulated by the CXCR4 receptor or CCR5 receptor. Such conditions include HIV infection, inflammation related diseases, immunosuppression and diseases associated with certain tumors.
[40] Form of carrying out the invention
[41] The present invention provides a compound as described above of Formula I which is a chemokine and thus a regulator of chemokine receptors.
[42] More specifically, the compounds bind chemokine receptors and interfere with the binding of natural ligands to them, and exhibit protective action against target cells from HIV infection. The compound is also an antagonist or agonist of chemokine receptors, an antagonist of apoptosis of immune cells such as CD8 ⁺ cells and neurons, migration of human bone marrow B lineage cells to epilepsy-induced factor 1 and chemokine receptors thereof It is useful as an antagonist of other biological activities on the ability of these compounds to inhibit binding to and thus can increase the level of CD4 ⁺ cells to reconstruct the immune system.
[43] Chemokine antagonists that interfere with the binding of chemokines to their receptors are useful for reconstructing the immune system by increasing levels of CD4 + cells (Biard-Piechaczyk, et al., Immunol. Lett. , 70: 1-3 1999; As an antagonist of apoptosis of immune cells such as CD8 ⁺ cells [Hergin, et al., Nature 395: 189-193, 1998] and as an antagonist of apoptosis of neurons [Ohagen et al., J. of Virol. 73: 897-906, 1999; and Hesselgesser, et al., Curr. Biol. 8: 595-598, 1998]. Chemokine receptor antagonists also inhibit the migration of human bone marrow B lineage cells to epilepsy-induced factor 1 (see, for example, E. Fedyk, et al., J of Leukocyte Biol., 66: 667-783, 1999].
[44] The present invention includes pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) and one or more excipients and methods of treating diseases of the human or other mammal's body with such compositions. The present invention provides a method for blocking or preventing binding of a chemokine receptor to its natural ligand, including contacting the chemokine receptor with an effective amount of a compound of formula (I). In addition, methods of protecting target cells with chemokine receptors that, when administered, result in disease or pathology by the inventive agent, including administering to a mammalian subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I This includes. The present invention includes the use of a compound of formula (I) in the manufacture of a medicament for the treatment of diseases in which it is advantageous to block or interfere with the chemokine receptor's binding to its natural ligand. The compound is formulated into the composition in an amount corresponding to a therapeutically effective amount of the compound of formula (I).
[45] Compound of the Invention
[46] Compounds of the present invention are generally represented by Formula I, reproduced below for this discussion.
[47] Formula I
[48]
[49] In one embodiment, the compounds of the present invention are in formula (II) or salts and prodrug forms thereof.
[50]
[51] In Formula II above,
[52] b is 1,
[53] X is CR ¹ ,
[54] Y is N,
[55] Z is CR ¹ ₂ ,
[56] R ¹ to R ⁶ and n1 to n3 are as defined in formula (I).
[57] In this subgenus, preferred tetrahydroquinolinyl and imidazole / benzimidazolyl methyl groups are bonded to the core nitrogen.
[58] In one embodiment, no ring is formed in the portion of the molecule containing bicore nitrogen (two R ⁶ coupled). In another embodiment, any two R ^{5 s} containing two R ^{5 s} in the same C, two R ⁶ or one R ⁵ and one R ⁶ are joined together through a 1-6 membered binder to form a ring can do. Also contemplated are the rings formed by two R ² , one R ² and R ^3, and R ³ and one R ⁴ . Examples of such rings are, in particular, cycloalkyl, cycloalkenyl, saturated or partially saturated heterocycles (piperidine, piperazine, pyrrolidine, pyrroline, pyrazolidine, imidazoline, morpholine, thiomorpholine, tetra Hydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dihydropyran, tetrahydropyran and the like). However, a ring formed from two R ⁵ from the same C may not be aromatic.
[59] Thus, in another alternative, the invention relates to compounds of formula IIIa to formula IIIe wherein in particular R ⁶ is H or one R ⁶ is H and the other comprises an aryl moiety or two R ⁶ form a ring Its salt or prodrug form is provided.
[60]
[61]
[62]
[63]
[64]
[65] In Formula IIIa to Formula IIIe,
[66] d is 0 to 3,
[67] n4 is 2-6.
[68] The compound may be supplied as a “prodrug”, ie in a protected form that releases the compound after administration to a patient. For example, a compound may include a protecting group that is isolated by hydrolysis in body fluids, such as the blood stream to release the active compound, or is oxidized or reduced in body fluid to release the compound. A discussion of prodrugs can be found in Smith and Williams Introduction to the Principles of Drug Design, H.J. Smith, Wright, Second Edition, London 1988.
[69] The compounds may also be supplied as salts with nontoxic organic or inorganic acids or bases. In the present sense, "non-toxic" should be considered in the diagnosis of untreated infected patients. Examples of inorganic bases include alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (eg, calcium, magnesium, etc.) and hydroxides such as aluminum, ammonium, and the like. Examples of organic bases include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like. Examples of inorganic acids include hydrochloric acid, bromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Examples of organic acids include formic acid, oxalic acid, acetic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Also included are salts with basic amino acids such as arginine, lysine, ornithine and acidic amino acids such as aspartic acid and glutamic acid.
[70] All compounds of the present invention contain one or more chiral centers. The present invention includes mixtures of stereoisomers, respective stereoisomers, enantiomeric mixtures and mixtures of multiple stereoisomers. In short, the mixture may be supplied in any desired level of chiral purity.
[71] As described above, the basic structures of the compounds of the invention are defined in formula (I), and in particular exemplary embodiments are shown in formulas (I) to (III). Further definitions of the compounds of the present invention depend on what the non-interfering substituents are.
[72] Preferred embodiments of R ¹ include H, halo, alkyl, alkoxy, CF ₃ and the like. Preferably, all R ¹ is H or one R ¹ is not H and the other two R ¹ are H.
[73] Preferred embodiments of R ² include H, alkyl and alkenyl, in particular H and methyl.
[74] Preferred embodiments of R ³ include H, alkyl, alkenyl, arylalkyl and aryl.
[75] Preferred embodiments of R ⁴ include those in which H, alkyl, alkenyl, in particular two R ⁴ are bridged to form an aromatic ring, wherein the substituent on the core nitrogen is benzimidazolylmethyl, further comprising a heteroatom containing form Include.
[76] Preferred embodiments of R ⁵ include H, alkyl and alkenyl, each optionally substituted, wherein the alkyl or alkynyl substituent on a single carbon or adjacent or non-adjacent carbon forms a saturated or unsaturated ring. The ring may not be aromatic. Alternative embodiments for R ⁵ include oximes, alkylated oxime hydroxylamines, alkylated hydroxylamines, halo, and the like.
[77] Preferred embodiments of R ⁶ include H, arylalkyl, arylsulfonyl and include one or more nitrogen atoms present in the ring and condensed ring aryl groups such as indolyl. Also preferred are R ⁶ heteroatom containing groups such as guanidyl groups, carboxyl and carbamino groups, amides, arylsulfonic acids and aryl acyl substituents, aryl groups containing one or more nitrogens, alkenyl, It is also preferred to include cycloalkyl, carboxyl and optional substituents, alkyl and alkenyl moieties, and substituted by alcohols or amines. Two R ⁶ may form a saturated, unsaturated or aromatic ring optionally containing one or more N, O and / or S. R ⁵ and R ⁶ or two R ⁶ may also constitute a covalent alkylene or alkenylene crosslinking to obtain saturated or unsaturated rings which may be aromatic. In all cases (R ⁵ + R ⁵ or R ⁵ + R ⁶ or R ⁶ + R ⁶ ), the covalent alkylene or alkenylene substituents may comprise one or more heteroatoms such as N, S or O.
[78] It is preferred that one to three, preferably one or two R ⁵ groups are not hydrogen. In one embodiment, all R ⁵ are hydrogen, and in another embodiment, a pair of R ⁵ is such moiety comprising a covalent alkylene, alkenylene or heteroatom.
[79] Examples of optionally substituted alkyl groups include methyl, ethyl, propyl, and the like, and include cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and examples of optionally substituted alkenyl groups are allyl , Crotyl, 2-pentenyl, 3-hexenyl, 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, and the like, and C _1-6 alkyl and Alkenyl is preferred.
[80] Examples of halogen include fluorine, chlorine, bromine, iodine and the like, with fluorine and chlorine being preferred.
[81] Examples of optionally substituted hydroxyl and thiol groups include optionally substituted alkyloxy or alkylthio (such as C _1-10 alkyl), for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl Tertiary butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, and optionally substituted arylalkyloxy or arylalkylthio such as phenyl-C _1-4 alkyl such as benzyl , Phenethyl and the like). If two adjacent hydroxyl or thiol substituents are present, the heteroatoms can be linked through an alkylene group such as O (CH ₂ ) _n O and S (CH ₂ ) _n S, where n is 1 to 5 have. Examples include methylenedioxy, ethylenedioxy and the like. Oxides of thio-ether groups such as sulfoxides and sulfones are also envisaged.
[82] Examples of optionally substituted hydroxyl groups also include optionally substituted C _2-4 alkanoyl (eg acetyl, propionyl, butyryl, isobutyryl, etc.), C _1-4 alkylsulfonyl (eg methanesulfonyl, Ethanesulfonyl and the like) and optionally substituted aromatic and heterocyclic carbonyl groups such as benzoyl, pyridinecarbonyl and the like.
[83] Substituents of an optionally substituted amino group may be bonded to each other to form a cyclic amino group (e.g., 5-6 membered cyclic amino, etc., for example, tetrahydropyrrole, piperazine, piperidine, pyrrolidine, morpholine, Thiomorpholine, pyrrole, imidazole, and the like). Cyclic amino groups may have substituents, examples of the substituents being halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy groups, thiol groups, amino groups, carboxyl groups, optionally halogenated C _1-4 alkyl (eg trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (eg methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C _2-4 alkanoyl (eg acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg methanesulfonyl, ethanesulfonyl, etc.), and the preferred number of substituents is 1-3.
[84] Amino groups are optionally substituted alkyl groups, including C _1-10 alkyl (eg methyl, ethyl, propyl, etc.), optionally substituted alkenyl groups such as allyl, crotyl, 2-pentenyl, 3- Hexenyl and the like or optionally substituted cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl may be substituted once or twice with groups (secondary or tertiary amine formation) . In this case, C _1-6 alkyl, alkenyl and cycloalkyl are preferred. The amine group may also be an aromatic or heterocyclic group, aralkyl (eg phenyl C _1-4 alkyl) or heteroalkyl, for example phenyl, pyridine, phenylmethyl (benzyl), phenethyl, pyridylmethyl, pyridinyl Optionally substituted with ethyl or the like. The heterocyclic group may be a 5 or 6 membered ring containing 1 to 4 heteroatoms.
[85] The amino group may be optionally substituted C _2-4 alkanoyl such as acetyl, propionyl, butyryl, isobutyryl, etc. or C _1-4 alkylsulfonyl (eg methanesulfonyl, ethanesulfonyl, etc.) or Carbonyl or sulfonyl substituted aromatic or heterocyclic rings such as benzenesulfonyl, benzoyl, pyridinesulfonyl, pyridinecarbonyl and the like.
[86] Uses and Administration
[87] The present invention relates to compounds of formula (I) which modulate chemokine receptor activity. Chemokine receptors include, but are not limited to, CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CXCR-3 and CXCR-4.
[88] In one embodiment, the present invention provides a chemical formula that specifically binds to chemokine receptors and thus has a protective effect on target cells from HIV infection by affecting natural ligand binding to CCR-5 and / or CXCR-4 of the target cell. Provides compounds of I.
[89] In another embodiment, the compounds of the present invention are chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CXCR-3 and CXCR-4, for which a number of inflammatory and immune When correlated as important mediators of regulatory diseases, they are useful as agents affecting these chemokine receptors.
[90] Other diseases also related to chemokines as mediators include angiogenesis and tumorigenesis such as brain and breast tumors. Thus, compounds that modulate the activity of such chemokine receptors are useful for the treatment or prevention of such diseases.
[91] The term "modulator" as used herein is intended to include antagonists, agonists, partial antagonists or partial agonists, ie inhibitors and activators. In one embodiment of the invention, the compound of formula (I) exhibits protective action against HIV infection by inhibiting HIV from binding to chemokine receptors such as CCR-5 and / or CXCR-4 in target cells. Such regulation is obtained by a method comprising contacting a target cell with an amount of a compound useful for inhibiting the binding of the virus to the chemokine receptor.
[92] Compounds that inhibit chemokine receptor activity and function include, but are not limited to, inflammatory or allergic diseases such as asthma, allergic rhinitis, irritable lung disease, irritable pneumonia, eosinophilic pneumonia, delayed-type hypersensitivity, interstitial Pulmonary disease (ILD) (eg, ILD in idiopathic pulmonary fibrosis or rheumatoid arthritis, systematic sclerosis, Schegrin's syndrome, multiple myositis or dermatitis); Systematic or hypersensitivity reactions, drug allergies, pest bite allergy; Autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myasthenia gravis, childhood onset diabetes; Transplant rejection or graft-versus-host disease including glomerulonephritis, autoimmune throiditis, allograft rejection; Inflammatory bowel disease such as Crohn's disease and ulcerative colitis; Spondyloarthropathy; Scleroderma; Psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; Vasculitis (eg, necrotic, dermatological and irritable vasculitis); It can be used for the treatment of diseases associated with inflammation, including eosinophilic myotis, eosinophilic fasciitis and cancer.
[93] In addition, compounds that activate or promote chemokine receptor function include diseases associated with immunosuppression, such as chemotherapy, radiation therapy, enhanced wound treatment and chemical therapy for individuals, therapy for autoimmune diseases or other drug therapies. Combinations of conventional drugs used in the treatment of autoimmune diseases and graft / graft rejection (eg, corticosteroid therapy) or which cause immunosuppression; Immunosuppression due to innate deficiency of receptor function or other causes; And infectious diseases such as, but not limited to, parasitic diseases, including enteroparasitic infections such as nematodes (roundworms); Wormworms, nematodes, roundworms, duodenum, nematodes, trichinosis, pilaremia; Insect repellents; Visceral worms, visceral larval transitions (eg toxocara), eosinophilic gastroenteritis (eg, Anisaki spp., Pocanema spp.), Skin larvae transition (Ancylostona braziliense, Ancylostoma caninum); Malaria caused by malaria, human cytomegalovirus, herpesvirus saimiri, Kaposi's sarcoma herpesvirus, also known as human herpesvirus 8, and poxvirus Moluscum contagiosum.
[94] The compounds of the present invention can be used in combination with any other active agent or pharmaceutical composition, wherein such combination therapies are useful for modulating chemokine receptor activity, which is useful for preventing and treating inflammatory and immunomodulatory diseases.
[95] The compound may further be used in combination with one or more agents useful for the prevention or treatment of HIV. Examples of such agents include:
[96] (1) nucleotide reverse transcription inhibitors, such as tenofovir disoproxil fumarate; Lamivudine / zidovudine; Abacavir / lamivudin / dojivudine (abacavir / lamivudine / zidovudine); Emtricitabine; Amdoxovir; Allovudine; DPC-817; SPD-756; SPD-754; GS7340; ACH-126,443 (beta) -L-FVd4C; Didanosine, zalcitabine, stavudine, adefovir, adefovir dipivoxil, fozivudine todoxil and the like;
[97] (2) nonnucleotide reverse transcription inhibitors (including agents having antioxidant activity, such as immunological, oltipraz, etc.), for example nevirapine, delavirdine, epavirens (efavirenz), lobbyiride, immunocal, oltipraz, TMC-125; DPC-083; Capavarine; Calanolide A; SJ-3366 series and the like;
[98] (3) protease inhibitors such as saquinavir, lopinavir / ritonavir, atazanavir, fosamprenavir, tipranavir TMC-114, DPC-684, indinavir, nelfinavir, amprenavir, palinavir, palinavir, lasinavir and the like;
[99] (4) entry inhibitors such as T-20; T-1249; PRO-542; PRO-140; TNX-355; BMS-806 series; And 5-helix;
[100] (5) CCR5-receptor inhibitors such as Sch-C (or SCH351125); Sch-D and SCH350634; TAK779; UK # 427,857 and TAK # 449;
[101] (6) integrase inhibitors such as L-870,810; GW-810781 (S-1360); And
[102] (7) sprouting inhibitors such as PA-344; And PA-457.
[103] The combination of a compound of the present invention with an HIV agent is not limited to (1), (2) and / or (3), but includes any combination with any agent useful for the treatment of HIV. Combinations of compounds of the invention with other HIV agents can be administered separately or together. One agent may be administered before, simultaneously with, or after the other agent (s).
[104] The compounds according to the invention can be administered by oral, intramuscular, intraperitoneal, intravenous, intracisternal injection or infusion, subcutaneous injection, transdermal or intramucosal administration or transplantation.
[105] Compounds of the invention are used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats, and monkeys. In addition, the compounds of the present invention are effective for use in humans.
[106] The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of formula (I). The compounds may be administered orally or parenterally, alone or in admixture with a pharmaceutically acceptable carrier (e.g., solid formulations such as tablets, capsules, granules, powders, liquid formulations such as syrups, injections). Examples of parenteral formulations include injections, drops, suppositories, pessaries.
[107] In the treatment or prophylaxis of a condition requiring chemokine receptor modulation, suitable dosage levels are generally from about 0.01 to 500 mg / kg of patient body weight per day, which can be administered in single or multiple doses. Preferably the dose level is about 0.1 to about 250 mg / kg per day. Certain dosage levels and frequency of administration may vary for any particular patient, which indicates the activity, metabolic stability, and duration of activity of the particular compound used, age, weight, general health, sex, diet, dosage form and time, excretion rate. , The formulation of the drug, the severity of the particular condition and the therapy applied to the patient.
[108] Intermediates 8-hydroxy-5,6,7,8-tetrahydroquinoline and 8-amino-5,6,7,8-tetrahydroquinoline are disclosed in PCT Patent Application WO 00/56729 (Bridger et al.). Prepared according to the described process. Intermediate N '(1H-benzimidazol-2-ylmethyl) -N' (5,6,7,8-tetrahydro-8-quinolinyl) -1,4-benzenedimethanamine Prepared as described in 60 / 232,891 and 60 / 234,510 to Bridger et al. Intermediate 1-N-tert-butoxycarbonyl-2-chloromethylbenzimidazole is described by An, H .; Wang, T .; Mohan, V .; Griffey, R. H .; Cook, P.D. Tetrahedron 1998, 54, 3999-4012.
[109] General Synthetic Process:
[110] Of (1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine with mesylate or alkyl chloride N-alkylation
[111] (1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinoline-8- in CH ₃ CN (concentration ˜0.1-0.2 M) Mesylate or alkyl chloride (e.g., in a solution of yl) -amine (or amine) (1 to 1.4 equivalents), N, N-diisopropylethylamine (or K ₂ CO ₃ ) and KI (0.05 to 0.16 equivalents) : 1-N-tert-butoxycarbonyl-2-chloromethylbenzimidazole) (1 to 1.4 equiv) was added and the mixture was monitored by analytical thin layer chromatography with stirring at 50 to 70 ° C. for 3 to 25 hours. . The reaction mixture was cooled down and diluted with CH ₂ Cl ₂ (10 mL / mmol amine) and diluted with aqueous NaHCO ₃ or brine (10 mL / mmol alcohol). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 10 mL / mmol amine). The conjugated organic phase was dried (Na ₂ SO ₄ or mgSO ₄ ) and concentrated under reduced pressure. The crude material was purified by chromatography to give the N-alkylated product.
[112] General Process A: NaBH ₃Direct Reduction Amination with CN
[113] A carbonyl compound (˜1-2 equivalents) was added at a time to a stirred solution of amine (1 equivalent) in anhydrous methanol (concentration ˜0.1 M) at room temperature. Once carbonyl was dissolved (˜5 min), NaBH ₃ CN (˜2 to 4 equiv) was added in one portion and the resulting solution was stirred at room temperature. The solvent was removed under reduced pressure and CH ₂ Cl ₂ (20 mL / amine 1 mmol) and brine or 1.0 M aqueous NaOH (10 mL / amine 1 mmol) were added to the residue. The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 10 mL / amine 1 mmol). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude material was purified by chromatography.
[114] General Process B: NaBH (OAc) ₃Or NaBH ₄Direct Reductive Amination Using
[115] To a stirred solution of amine (1 equivalent) in CH ₂ Cl ₂ (concentration ˜0.2 M) at room temperature a carbonyl compound (˜1 to 2 equivalents), glacial acetic acid (0 to 2 equivalents) and NaBH (OAc) ₃ (˜1.5 to 3 equivalents) was added and the resulting solution was stirred at room temperature. The reaction mixture was charged with saturated aqueous NaHCO ₃ or 1.0 M aqueous NaOH (10 mL / amine 1 mmol). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 10 mL / amine 1 mmol). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude material was purified by chromatography.
[116] Similarly, carbonyl compound (1 equiv) was added to a stirred solution of amine (1 equiv) in anhydrous MeOH (concentration ˜0.1 M) at room temperature. The resulting solution was stirred at room temperature or heated to reflux for 4 to 24 hours. NaBH ₄ (1-2 equivalents) was added and the resulting mixture was stirred for ˜20 minutes at room temperature. The reaction mixture was concentrated, dissolved in CH ₂ Cl ₂ and washed successively with saturated aqueous NaHCO ₃ and NaCl. The aqueous layer was extracted with CH ₂ Cl ₂ (2 ×) and the combined organic extracts were dried (MgSO ₄ ) and concentrated.
[117] General Process C: Reaction of Alcohol with Methanesulfonyl Chloride
[118] Methanesulfonyl chloride (˜1.5 equiv) was added to a stirred solution of alcohol (1 equiv) and Et ₃ N (1.5-2 equiv) in CH ₂ Cl ₂ (or THF) at room temperature (concentration ˜0.1 M) and the reaction was allowed to Stir at 0.5 to 1 h. The reaction mixture was introduced into saturated aqueous NaHCO ₃ or saturated NH ₄ Cl (10 mL / alcohol 1 mmol). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 10 mL / amine 1 mmol). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude material was purified by chromatography and used without further purification in the N-alkylation step.
[119] General process D: salt formation using saturated HBr (g) in acetic acid
[120] To a free base solution in glacial acetic acid (2 mL) was added a saturated solution of HBr (g) in acetic acid (2 mL). Subsequently, a large amount of ether (25 mL) was added to precipitate the solid, which was allowed to settle on the base of the flask and the supernatant was decanted. The solids were decanted with ether (3 × 25 mL) and the remaining traces of solvent were removed in vacuo. For further purification, the solid was dissolved in methanol and reprecipitated with a large amount of ether. The solid was washed off with ether, and then the solid was dried under vacuum (0.1 Torr) to afford the desired compound.
[121] Intermediate
[122] Preparation of 4-hydroxymethylbenzaldehyde
[123] Terephthaldicarboxaldehyde (30.02 g, 224 mmol), methanol (200 mL), palladium on activated carbon (10%, 3.02 g) and 2- (aminomethyl) pyridine (2.3 mL, 22 mol, 0.01 mol equivalent) were combined in a hydrogenation tube and The reaction mixture was shaken for 2.5 h at 40 psi hydrogen in a Parr hydrogenator. The mixture was filtered through celite and the cake was washed with methanol and the solvent from the eluate was removed in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc / hexanes, 1: 1) to afford the title compound (23.8 g, 78%) as a white solid. ¹ H NMR (CDCl ₃ ) δ 4.80 (s, 2H), 7.53 (d, 2H, J = 9 Hz), 7.87 (d, 2H, J = 9 Hz), 10.00 (s, 1H).
[124] Preparation of 6,7-dihydro-5H-quinolin-8-one:
[125]
[126] To a stirred solution of 8-hydroxy-5,6,7,8-tetrahydroquinoline (13.96 g, 93.6 mmol) in anhydrous CH ₂ Cl ₂ (400 mL) was added active manganese dioxide (purity 85%, 82.22 g, 804 mmol). Was added. The resulting heterogeneous mixture was stirred for 18 hours, at which point the black slurry was filtered through a celite cake and washed with CH ₂ Cl ₂ (3 × 50 mL). The combined washes were concentrated to give 11.27 g (82%) of the title compound as a pale yellow solid, which was used for the subsequent reaction without further purification. ¹ H NMR (CDCl ₃ ) δ 2.17-2.25 (m, 2H), 2.82 (t, 2H, J = 7 Hz), 3.04 (t, 2H, J = 6 Hz), 7.37 (dd, 1H, J = 9, 6 Hz ), 7.66 (dd, 1H, J = 9, 1 Hz), 8.71 (dd, 1H, J = 6, 1 Hz); ¹³ C NMR (CDCl ₃ ) δ 22.2, 28.6, 39.2, 126.6, 137.3, 140.5, 147.6, 148.6, 196.5. ES-MS m / z 148 (M + H).
[127] Preparation of (1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine:
[128]
[129] Using the N-alkylation general process: 1-N-tert-butoxycarbonyl in 8-amino-5,6,7,8-tetrahydroquinoline (7.34 g, 49.6 mmol) in anhydrous CH ₃ CN (250 mL) 2-chloromethylbenzimidazole (13.22g, 49.6mmol), N, N-diisopropylethylamine (15.5ml, 89.2mmol) and potassium iodide (0.41g, 8.2mmol) were added and the mixture was 3.5 at 60 ° C. Stir for hours. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 99: 1 followed by 97: 3 and 96: 4) gave intermediate amine (6.38 g, 34%) as an orange sticky oil. ¹ H NMR (CDCl ₃ ) δ 1.76 (s, 9H), 1.81-2.10 (m, 2H), 2.25-2.37 (m, 1H), 2.72-2.89 (m, 2H), 3.77-3.84 (m, 1H) , 4.39 (d, 1H, J = 15.0 Hz), 4.56 (d, 1H, J = 15.0 Hz), 7.00-7.06 (m, 1H), 7.27-7.37 (m, 1H), 7.64-7.74 (m, 1H ), 7.90-7.96 (d, 2H, J = 8.1 Hz), 8.34 (d, 1H, J = 3.0 Hz); ¹³ C NMR (CDCl ₃ ) δ 20.13, 28.48, 29.00, 29.20,47.15, 56.89, 86.20, 115.32, 120.28, 122.06, 124.43, 124.85, 132.77, 133.74, 137.01, 142.44, 147.10, 149.22, 154.90, 157.7 ES-MS m / z 279 (M + H-boc).
[130] Preparation of (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine:
[131]
[132] To a stirred solution of (2-aminomethyl) benzimidazole dihydrochloride hydrate (5.96 g, 27.1 mmol) in anhydrous MeOH (225 mL) 6,7-dihydro-5H-quinolin-8-one (3.99 g, 27.1 mmol) was added and stirred at room temperature for 69 hours. Sodium borohydride (2.06 g, 54.2 mmol) was added to the obtained solution in two portions, and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated in vacuo and diluted with CH ₂ Cl ₂ (150 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (200 mL), the aqueous layer was extracted with CH ₂ Cl ₂ (2 × 50 mL), the combined organic phases were dried (Na ₂ SO ₄ ), filtered and vacuum Concentrated under. Purification by chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 99: 1, followed by 98: 2 and 96: 4) yielded the intermediate amine (3.59 g, 50%) as a yellow foam. ¹ H NMR (CDCl ₃ ) δ 1.66-1.90 (m, 3H), 1.91-2.00 (m, 1H), 2.00-2.17 (m, 1H), 2.33-2.69 (br m, 1H), 3.88-3.96 (m , 1H), 4.37 (d, 1H, J = 3.0 Hz), 7.18-7.26 (m, 4H), 7.48 (d, 1H, J = 6.0 Hz), 7.58-7.78 (br m, 1H), 8.55-8.58 (m, 1 H); ¹³ C NMR (CDCl ₃ ) δ 19.66, 29.12, 30.24, 46.62, 57.28, 122.21, 122.83, 133.55, 138.07, 146.98, 156.17, 157.73.
[133] Preparation of 1- (2-trimethylsilylethoxymethyl) -2-formyl-benzimidazole:
[134]
[135] To a stirred solution of 2-hydroxymethylbenzimidazole (31.94, 0.216 mol) in anhydrous DMF (450 mL) was added N, N-diisopropylethylamine (90 mL, 0.52 mol), followed by 2- (trimethylsilyl ) Ethoxymethyl chloride (75% in pentane, 55 g, 0.25 mol) was added and the mixture was heated to 60 ° C. for 2 hours. The mixture was cooled to rt, concentrated under reduced pressure and partitioned between EtoAc (400 mL) and distilled water (700 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with brine (1 × 400 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purify the crude oil by column chromatography on silica gel (4% MeOH / CH ₂ Cl ₂ ) to afford the desired 1- (2-trimethylsilylethoxymethyl) -2-hydroxymethylbenzimidazole (26.28 g, 44% ) Was obtained as a yellow oil. ¹ H NMR (CDCl ₃ ) δ -0.04 (s, 9H), 0.89 (t, 2H, J = 9 Hz), 1.75 (br s, 1H), 3.55 (t, 2H, J = 9 Hz), 4.94 (s, 2H), 5.58 (s, 2H), 7.26-7.30 (m, 2H), 7.43-7.45 (m, 1H), 7.70-7.72 (m, 1H).
[136] To a stirred solution of alcohol (26.58 g, 0.096 mol) in anhydrous CH ₂ Cl ₂ (450 mL) from above was added activated MnO ₂ (<5 μ, 85%, 93 g, 0.91 mol) and the suspension was stirred at rt overnight. Celite mixture Filter through (175 g) and wash the cake with CH ₂ Cl ₂ . The solvent was removed from the eluent under reduced pressure and the residue obtained was purified by column chromatography on silica gel (3% MeOH / CH ₂ Cl ₂ ) to give the title aldehyde (14.41 g, 55%) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ -0.07 (s, 9H), 0.90 (t, 2H, J = 9 Hz), 3.56 (t, 2H, J = 9 Hz), 6.04 (s, 2H), 7.43-7.51 (m , 2H), 7.66 (d, 1H, J = 9 Hz), 7.95 (d, 1H, J = 9 Hz), 10.13 (s, 1H); ¹³ C NMR (CD ₃ OD) δ −1.19, 17.94, 66.62, 73.30, 112.22, 122.51, 124.64, 127.43, 136.62, 143.11, 146.39, 185.10; ES-MS m / z (M + H);
[137] Preparation of [1- (2-trimethylsilylethoxymethyl) -1H-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine:
[138]
[139] To a stirred solution of 1- (2-trimethylsilylethoxymethyl) -2-formyl-benzimidazole (4.26 g, 15.4 mmol) in anhydrous MeOH (50 mL) 8-amino-5 in anhydrous MeOH (20 mL) A 6,7,8-tetrahydroquinoline (2.20 g, 14.8 mmol) solution was added and the mixture was stirred at room temperature under an argon atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was analyzed by ¹ H NMR to confirm imine formation. The residue was redissolved in anhydrous MeOH (80 mL) and the resulting solution was added to sodium borohydride (1.17 g, 30.8 mmol). The mixture was stirred for 5 h, concentrated in vacuo, diluted with CH ₂ Cl ₂ (100 mL) and diluted with saturated aqueous NaHCO ₃ (125 mL). The phases were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 × 75 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified through a plug of silica gel (CH ₂ Cl ₂ / MeOH 96: 4) to afford the desired amine (5.91 g, 98%) as an orange oil. ¹ H NMR (CDCl ₃ ) δ -0.07 (s, 9H), 0.90 (t, 2H, J = 9 Hz), 1.72-1.83 (m, 2H), 1.95-2.01 (m, 1H), 2.76-2.85 (m , 2H), 3.54 (t, 2H, J = 9 Hz), 4.33 (m, 2H), 5.68 (d, 1H, J = 12 Hz), 5.75 (d, 1H, J = 12 Hz), 7.05-7.09 (m, 1H), 7.25-7.30 (m, 2H), 7.38 (d, 1H, J = 9 Hz), 7.44-7.46 (m, 1H), 7.71-7.73 (m, 1H), 8.36-8.38 (m, 1H).
[140] N ^One-(5,6,7,8-tetrahydro-quinolin-8-yl) -N ^OnePreparation of-[1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-ylmethyl] -butane-1,4-diamine:
[141]
[142] (5,6,7,8-tetrahydro-quinolin-8-yl)-[1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole-2- in CH ₃ CN (75 mL) Ilmethyl] -amine (2.86 g, 6.93 mmol), bromobutyronitrile (1.4 mL, 14.1 mmol) and DIPEA (3.0 mL, 17.2 mmol) solutions were stirred at 80 ° C. for 2 days. KI (54 mg, 0.33 mmol) was added and the resulting mixture was stirred at 80 ° C. for 20 h. The mixture was concentrated under reduced pressure, diluted with CH ₂ Cl ₂ (100 mL) and washed with aqueous NaCl. The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 50 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 80: 1) afforded the desired nitrile (1.19 g, 36%) as an orange syrup. ¹ H NMR (CDCl ₃ ) δ -0.09 (s, 9H), 0.81-0.87 (m, 2H), 1.56-1.75 (m, 2H), 1.87-2.07 (m, 2H), 2.01-2.26 (m, 1H ), 2.29-2.53 (m, 2H), 2.62-2.86 (m, 4H), 3.35-3.48 (m, 2H), 3.95-4.01 (m, 1H), 4.16 (d, 1H, J = 13.8 Hz), 4.26 (d, 1H, J = 13.5 Hz), 5.76 (d, 1H, J = 11.1 Hz), 6.17 (d, 1H, J = 11.0 Hz), 7.04 (dd, 1H, J = 7.5, 4.5 Hz), 7.22-7.28 (m, 2H), 7.32 (d, 1H, J = 7.5 Hz), 7.43-7.46 (m, 1H), 7.69-7.73 (m, 1H), 8.46 (dd, 1H, J = 4.8, 1.3 Hz).
[143] 4-{(5,6,7,8-tetrahydro-quinolin-8-yl)-[1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-ylmethyl] -amino } -Butyronitrile (840 mg, 1.75 mmol) was dissolved in NH ₃ saturated MeOH (15 mL), treated with Raney nickel (excess), and placed on a Parr shaker for 16 h under 45 psi H ₂ . The mixture was diluted with MeOH and filtered through celite. The cake was washed with MeOH and the combined filtrates were concentrated under reduced pressure. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 50: 2: 1) afforded the desired amine (560 mg, 66%) as an orange syrup. ¹ H NMR (CDCl ₃ ) δ -0.10 (s, 9H), 0.81 (t, 2H, J = 9.0 Hz), 1.43-1.50 (m, 4H), 1.59-1.76 (m, 1H), 1.86-2.09 ( m, 2H), 2.08-2.23 (m, 1H), 2.56-2.71 (m, 4H), 2.76-2.85 (m, 2H), 2.41 (t, 2H, J = 8.1 Hz), 4.07-4.12 (m, 3H), 5.71 (d, 1H, J = 11.1 Hz), 7.37 (d, 1H, J = 11.1 Hz), 7.05 (dd, 1H, J = 7.5, 4.5 Hz), 7.21-7.29 (m, 2H), 7.34 (d, 1H, J = 6.6 Hz), 7.40-7.45 (m, 1H), 7.71-7.76 (m, 1H), 8.58 (d, 1H, J = 3.6 Hz).
[144] N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,4-diamine:
[145]
[146] Preparation of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine (Smith, J .; Liras, JL; Schneider, SE; Anslyn, E J. Org. Chem. 1996, 61, 8811-8818 ):
[147] CHCl ₃ (230㎖) of trans-1,4-cyclohexane diamine, di -tert- butyl dicarbonate (7.67g, 35.1mmol) a syringe pump a solution of _{(8.01g, 70.1mmol) CHCl 3 (} 50㎖) To a solution Was added over 6 hours. The resulting white suspension was stirred for an additional 10 hours at room temperature, then concentrated in vacuo and diluted with CH ₂ Cl ₂ (100 mL) and saturated aqueous Na ₂ CO ₃ (100 mL). The layers were separated and the organic layer was washed with saturated aqueous Na ₂ CO ₃ (2 × 30 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound as a white solid (5.30 g, 71% based on Boc ₂ O).
[148] According to the general procedure for reductive amination with NaBH (OAc) ₃ : 6,7-dihydro-5H-quinolin-8-one (3.04 g, 20.65 mmol) and N-tert in dry THF (100 mL) To a stirred solution of butoxycarbonyl-trans-1,4-cyclohexanediamine (4.42 g, 20.65 mmol) was added AcOH (3 mL) and NaBH (OAc) ₃ (5.69 g, 26.85 mmol) and the mixture was at room temperature. Stir overnight. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 96: 4: 0 then 94: 5: 1) gave the desired amine as a white solid (3.79 g, 53%).
[149] Example 1
[150]
[151] Compound 1: (1H-benzimidazol-2-ylmethyl) -piperidin-3-ylmethyl- (5,6,7,8-tetrahydro-quinolin-8-yl) -amine (hydrobromide salt) Manufacture
[152] Preparation of 3-formyl-N-tert-butoxycarbonyl-piperidine:
[153]
[154] To a solution of 3-piperidinmethanol (0.544 g, 4.72 mmol) in THF (20 mL) was added di-tert-butyl dicarbonate (1.01 g, 4.63 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the crude product obtained was used in the next reaction without further purification.
[155] 4-methylmorpholine N-oxide (0.672 g, 5.74 mmol) and tetrapropylammonium perlute in a suspension of alcohol from the stomach (~ 4.7 mmol) and 3 'molecular sieves (1.17 g) in CH ₂ Cl ₂ (10 mL) Nate (0.084 g, 0.24 mmol) was added and the mixture was stirred overnight. The reaction was concentrated under reduced pressure and purified by column chromatography through a plug of silica gel (ethyl acetate / hexane, 1: 2) to afford the title compound (0.429 g, 43% over two steps) as a clear oil. ¹ H NMR (CDCl ₃ ) δ 1.46 (br s, 9H), 1.48-1.55 (m, 1H), 1.65-1.73 (m, 2H), 1.91-1.99 (m, 1H), 2.40-2.44 (m, 1H ), 3.04-3.13 (m, 1H), 3.32 (dd, 1H, J = 15, 9 Hz), 3.60-3.65 (m, 1H), 3.89-3.94 (m, 1H), 9.70 (s, 1H).
[156] General process B use: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (159 mg in CH ₂ Cl ₂ (5 mL) , 0.57 mmol) and a mixture obtained by adding NaBH (OAc) ₃ (157 mg, 0.74 mmol) to a stirred solution of 3-formyl-N-tert-butoxycarbonyl-piperidine (125 mg, 0.59 mmol). Was stirred at room temperature for 2.5 hours. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 96: 4) afforded the alkylation product (185 mg, 68%) as a mixture of diastereomers.
[157] Yellow foam (185 mg, 0.39 mmol) oil from above was dissolved in CH ₂ Cl ₂ / TFA (1: 1, 2 mL) and the mixture was stirred overnight. The reaction was then concentrated and diluted with CH ₂ Cl ₂ (30 mL) and 1N NaOH (30 mL). The aqueous layer was washed with CH ₂ Cl ₂ (2 × 10 mL) and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give Boc-deprotection material as a mixture of diastereomers. Purified and separated by silica gel radial chromatography (1 mm plate, 50: 1: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give the less polar diastereomer (25 mg, 17%) at the top and the bottom More polar diastereomers (20 mg, 14%) were obtained, both of which are transparent foams.
[158] Use General Process D: Compound 1 (34 mg, 97%) by converting the more polar lower diastereomer (20 mg, 0.05 mmol) from the stomach into a hydrobromide salt and then reprecipitating the intermediate solid from methanol / ether Was obtained as a white solid. ¹ H NMR (D ₂ O) δ 0.97-1.09 (m, 1H), 1.44-1.57 (m, 1H), 1.72-1.88 (m, 2H), 1.90-2.07 (m, 2H), 2.13-2.36 (m , 4H), 2.53 (br t, 1H, J = 12 Hz), 2.74-2.90 (m, 2H), 2.98-3.00 (m, 2H), 3.27-3.32 (m, 2H), 4.38 (d, 1H J = 16.5 Hz), 4.48 (d, 1H J = 16.5 Hz), 4.50-4.55 (m, 1H), 7.62 (dd, 2H, J = 6.3, 3.3 Hz), 7.81 (dd, 2H, J = 6.3, 3.3 Hz ), 7.89 (dd, 1H, J = 7.8, 6 Hz), 8.37 (d, 1H, J = 8.1 Hz), 8.67 (d, 1H, J = 5.6 Hz); ¹³ C NMR (D ₂ O) δ 19.89, 20.27, 21.58, 26.64, 27.79, 31.91, 44.57, 47.09, 48.00, 54.69, 59.91, 114.34, 126.18, 127.09, 131.14, 139.59, 141.23, 148.32, 150.59, 150.76. ES-MS mlz 376 (M + H). Calcd for C ₂₃ H ₂₉ N ₅ .3.0HBr.2.2H ₂ O: C, 41.99; H, 5.58; N, 10.65; Br, 36.44. Found: C, 42.05; H, 5. 44; N, 10.50; Br, 36.40.
[159] Example 2
[160]
[161] Compound 2: (1H-benzimidazol-2-ylmethyl) -piperidin-3-ylmethyl- (5,6,7,8-tetrahydro-quinolin-8-yl) -amine (hydrobromide salt) Manufacture
[162] Use General Process D: Convert the less polar diastereoisomer from the stomach (see Compound 1) to the hydrobromide salt and then reprecipitate the intermediate solid from methanol / ether to give Compound 2 (39 mg, 88%). Obtained as a white solid. ¹ H NMR (D ₂ O) δ 1.07-1.19 (m, 1H), 1.54-1.68 (m, 1H), 1.74-1.90 (m, 3H), 1.97-2.07 (m, 2H), 2.13-2.22 (m , 1H), 2.30-2.43 (m, 2H), 2.52 (br t, 1H, J = 12 Hz), 2.80 (td, 1H, J = 13.2, 2.4 Hz), 2.92 (dd, 1H, J = 13.8, 4.5 Hz), 2.98-3.00 (m, 2H), 3.32-3.36 (m, 1H), 3.61-3.65 (m, 1H), 4.38 (d, 1H J = 16.5 Hz), 4.46 (d, 1H J = 16.5 Hz ), 4.52 (dd, 1H, J = 10.5, 5.7 Hz), 7.63 (dd, 2H, J = 6.3, 3.3 Hz), 7.82 (dd, 2H, J = 6.3, 3.3 Hz), 7.90 (dd, 1H, J = 7.5, 6.3 Hz), 8.37 (d, 1H, J = 7.8 Hz), 8.68 (d, 1H, J = 6 Hz); ¹³ C NMR (D ₂ O) δ 18.97, 19.39, 21.05, 26.03, 26.91, 31.14, 43.69, 46.67, 47.04, 54.41, 58.71, 113.46, 125.31, 126.27, 130.15, 138.77, 140.30, 147.54, 149.50, 149.74. ES-MS mlz 376 (M + H). Calcd for C ₂₃ H ₂₉ N ₅ .3.0HBr.2.6H ₂ O: C, 41.54; H, 5. 64; N, 10.53; Br, 36.04. Found: C, 41.47; H, 5.41; N, 10.22; Br, 36.19.
[163] Example 3
[164]
[165] Compound 3: (1H-benzimidazol-2-ylmethyl) -piperidin-2-ylmethyl- (5,6,7,8-tetrahydro-quinolin-8-yl) -amine (hydrobromide salt) Manufacture
[166] Preparation of 2-formyl-piperidine-1-carboxylic acid tert-butyl ester:
[167] To 2-piperidinmethanol (561 mg, 4.9 mmol) in dry THF (10 mL) was added di-tert-butyl dicarbonate (1.14 g, 5.2 mmol) and the mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo to give a colorless oil which was used in the next step without further purification.
[168] To a stirred solution of 2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.737 g, 3.4 mmol) in anhydrous CH ₂ Cl ₂ (10 mL) 3-molecular seed (1.03 g), N-methylmor Pauline N-oxide (0.644 g, 5.5 mmol) and tetrapropylammonium perruthenate (72 mg, 0.21 mmol) were added and the mixture was stirred at rt for 3 h. The reaction mixture was purified through a silica gel plug (hexane / EtOAc, 70:30 then 100: 0) to give the title aldehyde (0.500 g, 70%) as pale yellow oil.
[169] General process B use: To a stirred solution of 1-carboxylic acid tert-butyl ester (0.163 g, 0.76 mmol) in anhydrous CH ₂ Cl ₂ (3.5 mL) (1H-benzimidazol-2-ylmethyl)-(5,6 , 7,8-tetrahydroquinolin-8-yl) -amine (0.210 g, 0.76 mmol) and sodium triacetoxyborohydride (0.240 g, 1.1 mmol) were added and the mixture was stirred at rt overnight. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 96: 4 after 98: 2) gave a pale yellow foam (0.305 g) containing a mixture of diastereomers.
[170] To a stirred solution of diastereomer (0.305 g) in anhydrous CH ₂ Cl ₂ (2 mL) was added dropwise trifluoroacetic acid (1 mL) and the mixture was stirred at rt for 3.5 h. The reaction mixture was diluted with CH ₂ Cl ₂ (10 mL) and then concentrated in vacuo. The concentrate was diluted with CH ₂ Cl ₂ (20 mL) and extracted with 1N NaOH (30 mL). The aqueous layer was washed with CH ₂ Cl ₂ (2 × 15 mL), then the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purified by radial chromatography on 1 mm TLC grade silica gel plate (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 50: 1: 1 after 100: 1: 1), separating the two diastereomers, both of which are colorless oils, Less polar diastereomers (63 mg, 22%) and more polar diastereomers (22 mg, 8%) (stereochemistry not known) were obtained.
[171] General Process D Use: The less polar diastereomers (63 mg, 0.17 mmol) from the stomach were converted to hydrobromide salts to give compound 3 (83 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.34-1.68 (m, 3H), 1.73-1.93 (m, 3H), 1.93-2.08 (m, 2H), 2.08-2.23 (m, 1H), 2.24-2.38 (m , 1H), 2.79 (dd, 1H, J = 14.7, 9.9 Hz), 2.94-3.07 (m, 3H), 3.27 (dd, 1H, J = 14.7, 9.9 Hz), 3.38-3.56 (m, 2H), 4.33 (s, 2H), 4.57 (dd, 1H, J = 9.9, 5.7 Hz), 7.56-7.62 (m, 2H), 7.70-7.83 (m, 3H), 8.28 (d, 1H, J = 7.8 Hz) , 8.57 (d, 1 H, J = 4.8 Hz); ¹³ C NMR (D ₂ O) δ 19.84, 20.28, 21.76, 22.16, 26.99, 27.83, 45.34, 47.01, 54.30, 54.82, 58.86, 114.55, 125.99, 127.08, 131.59, 140.23, 141.046, 147.96, 149.03, 149.84; ES-MS m / z 376 (M + H); Calcd for C ₂₃ H ₂₉ N ₅ .3.0HBr.1.2H ₂ 0.0.3C ₄ H ₁₀ O: C, 43.90; H, 5.69; N, 10.58; Br, 36.20. Found: C, 43.78; H, 5.47; N, 10.54; Br, 36.41.
[172] Example 4
[173]
[174] Compound 4: (1H-benzimidazol-2-ylmethyl) -piperidin-2-ylmethyl- (5,6,7,8-tetrahydro-quinolin-8-yl) -amine (hydrobromide salt) Manufacture
[175] General Process D Use: The more polar diastereomers (22 mg, 0.059 mmol) from above (see Compound 3) were converted to hydrobromide salts to afford Compound 4 (35 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.22-1.39 (m, 1H), 1.39-1.68 (m, 2H), 1.71-1.93 (m, 3H), 2.03-2.24 (m, 3H), 2.31-2.42 (m , 1H), 2.79-2.89 (m, 1H), 2.91-3.07 (m, 3H), 3.16 (dd, 1H, J = 13.8, 6.0 Hz), 3.32-3.49 (m, 2H), 4.34 (d, 1H , J = 15.9 Hz), 4.43 (d, 1H, J = 16.2 Hz), 4.53 (dd, 1H, J = 10.2, 6.0 Hz), 7.54-7.61 (m, 2H), 7.65-7.77 (m, 3H) , 8.25 (d, 1H, J = 7.8 Hz), 8.49 (d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 20.04, 20.25, 21.54, 22.23, 27.04, 27.75, 45.22, 46.43, 54.61, 55.98, 60.69, 114.46, 125.90, 127.01, 131.66, 139.70, 140.96, 148.03, 149.70; ES-MS m / z 376 (M + H); Calcd for C ₂₃ H ₂₉ N ₅ .3.0HBr.2.2H ₂ O: C, 41.99; H, 5.58; N, 10.65; Br, 36.44. Found: C, 42.22; H, 5. 46; N, 10.47; Br, 36.23.
[176] Example 5
[177]
[178] Compound 5: (1H-benzimidazol-2-ylmethyl)-(S) -1-pyrrolidin-2-ylmethyl- (5,6,7,8-tetrahydro-quinolin-8-yl)- Preparation of amines (hydrobromide salts)
[179] General process B use: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (148 mg) in CH ₂ Cl ₂ (5 mL). , 0.53 mmol) and NaBH (OAc) ₃ (146 mg, 0.69 mmol) were added to a stirred solution of N-tert-butoxycarbonyl-L-prolinal (110 mg, 0.55 mmol). Stir overnight. The crude material was purified by silica gel radial chromatography (2 mm plate, 50: 1: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH followed by 10: 1: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give the desired amine. (73 mg, 30%) was obtained as a yellow oil.
[180] Use General Process D: Convert oil (40 mg, 0.11 mmol) from above into hydrobromide salt and then reprecipitate intermediate solid from methanol / ether to give compound 5 (53 mg, 73%) as beige solid It was. ¹ H NMR (D ₂ O) δ 1.22-1.28 (m, 1H), 1.61-1.74 (m, 1H), 1.75-1.89 (m, 1H), 1.99-2.09 (m, 3H), 2.16-2.31 (m , 1H), 2.33-2.39 (m, 1H), 2.92 (dd, 1H, J = 14.4, 9.3 Hz), 2.97-3.03 (m, 1H), 3.25 (q, 1H, J = 7.2 Hz), 3.33- 3.41 (m, 1H), 3.35 (td, 2H, J = 7.5, 2.4 Hz), 3.86-3.96 (m, 1H), 4.34 (d, 1H, J = 16.2 Hz), 4.42 (d, 1H, J = 16.2 Hz), 4.59 (dd, 1H, J = 10.2, 6 Hz), 7.59 (dd, 2H, J = 6.3, 3.3 Hz), 7.78 (dd, 2H, J = 6.3, 3.3 Hz), 7.79-7.83 (m , 1H), 8.31 (d, 1H, J = 8.7 Hz), 8.60 (d, 1H, J = 5.1 Hz); ¹³ C NMR (D ₂ O) δ 19.91, 20.29, 22.88, 27.80, 28.46, 45.88, 47.28, 52.97, 58.23, 58.77, 114.47, 126.02, 127.00, 131.50, 140.22, 141.00, 147.99, 149.62, 149.98. ES-MS mlz 362 (M + H). Calcd for C ₂₂ H ₂₇ N ₅ ³ HBr ₂ H ₂ O 0.2 C ₄ H ₁₀ O: C, 41.80; H, 5.54; N, 10.69; Br, 36.59. Found: C, 41.66; H, 5. 45; N, 10.65; Br, 36.93.
[181] Example 6
[182]
[183] Compound 6: (1H-benzimidazol-2-ylmethyl) -piperidin-4-ylmethyl- (5,6,7,8-tetrahydro-quinolin-8-yl) -amine (hydrobromide salt) Manufacture
[184] Preparation of 1- (tert-butoxycarbonyl) -piperidine-4-carboxaldehyde
[185] Water (1 mL) was added to ethyl isonipekotate (0.750 g, 4.77 mmol) in THF (24 mL), then di-tert-butyl dicarbonate (1.09 g, 5.00 mmol) was added and the resulting mixture was allowed to come to room temperature. Stirred for 1 h. The mixture was diluted with ethyl acetate (50 mL) and the organic phase washed with brine (3 x 20 mL), dried (MgSO ₄ ) and concentrated to 1- (tert-butoxycarbonyl) -4- (carbo 1.20 g (98%) of ethoxy) -piperidine was obtained as a colorless oil.
[186] Diisobutylaluminum hydride (1.0M in THF, 15 mL, 15 mmol) was added to a cold (-78 ° C.) stirred solution of oil (1.20 g, 4.67 mmol) from above in anhydrous THF (46 mL). After 30 minutes, the reaction mixture was allowed to warm to room temperature and stirred for a further 20 minutes. Saturated aqueous NH ₄ Cl (5 mL) was added and the resulting white slurry was stirred at room temperature for 45 minutes. Solid MgSO ₄ (5 g) was added and the mixture was florisil Filtration through. The column was washed with ethyl acetate (200 mL). The combined eluates were concentrated under reduced pressure to afford 1.01 g (97%) of 1- (tert-butoxycarbonyl) -4- (hydroxymethyl) -piperidine as a white solid.
[187] To a solution of the above alcohol (0.437 g, 2.03 mmol) in CH ₂ Cl ₂ (10 mL) at 3 ° C. molecular sieve (1.07 g), N-methylmorpholine N-oxide (0.365 g, 3.11 mmol) and tetrapropyl Ammonium perruthenate (70 mg, 0.20 mmol) was added continuously. After 1 hour, the mixture was filtered through a short column of silica gel and the cake washed with ethyl acetate. The solvent was removed from the filtrate under reduced pressure. The crude material was column chromatography on silica gel (4: 1 hexane = ethyl acetate) to give 90 mg (20%) of 1- (tert-butoxycarbonyl) -piperidine-4-carboxaldehyde as a colorless oil. . ¹ H NMR (CDCl ₃ ) δ 1.46 (s, 9H), 1.51-1.62 (m, 2H), 1.85-1.93 (m, 2H), 2.37-2.46 (m, 1H), 2.88-2.97 (m, 2H) , 3.94-4.00 (m, 2H), 9.66 (s, 1H).
[188] General process B use: 1- (tert-butoxycarbonyl) -piperidine-4-carboxaldehyde (0.090 g, 0.42 mmol) and (1H-benzimidazol-2-ylmethyl)-(5,6 , 7,8-tetrahydro-quinolin-8-yl) -amine (0.110 g, 0.40 mmol) was reacted with NaBH (OAc) ₃ (0.223 g, 1.05 mmol) in CH ₂ Cl ₂ (5 mL) for 20 hours. The crude material was then column chromatography on silica gel (50: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 0.120 g (63%) of an off-white solid.
[189] General Process D Use: The BOC-protecting group was simultaneously removed while converting the off-white solid (120 mg) to the hydrobromide salt and then reprecipitating the intermediate solid from methanol / ether to give compound 6 (98 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.13-1.28 (m, 2H), 1.80-2.36 (m, 8H), 2.81-3.00 (m, 5H), 3.35-3.43 (m, 2H), 4.38 (d, 1H) , J = 16.5 Hz), 4.46 (d, 1H, J = 16.5 Hz), 4.52 (dd, 1H, J = 10.5, 6.0 Hz), 7.59-7.65 (m, 2H), 7.78-7.85 (m, 2H) , 7.89 (dd, 1H, J = 7.8, 6.0 Hz), 8.37 (d, 1H, J = 8.1 Hz), 8.67 (d, 1H, J = 5.7 Hz); ¹³ C NMR (D ₂ O) δ 17.72, 18.24, 24.98 (2 carbons), 25.71, 29.64, 41.94, 42.05, 45.79, 54.96, 57.53, 112.25, 124.08, 125.04, 128.97, 137.47, 139.09, 146.24, 148.75 (2 carbons); ES-MS mlz 376 (M + H). Calcd for C ₂₃ H ₂₉ N ₅ .3.1 HBr.1.8 H ₂ O: C, 41.93; H, 5. 46; N, 10.63; Br, 37.60. Found: C, 42.07; H, 5.55; N, 10.28; Br, 37.43.
[190] Example 7
[191]
[192] Compound 7: (1H-benzimidazol-2-ylmethyl) -piperidin-4-yl- (5,6,7,8-tetrahydro-quinolin-8-yl) -amine (hydrobromide salt)
[193] Preparation of 4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -piperidine-1-carboxylic acid tert-butyl ester:
[194]
[195] General process B use: Boc-4-piperidone (641 mg, 3.22 mmol), 5,6,7,8-tetrahydro-quinolin-8-ylamine (476 mg, 3.22 mmol) in THF (25 mL), Sodium triacetoxyborohydride (1.36 g, 6.44 mmol) and acetic acid (0.25 mmol) were reacted at room temperature under N ₂ for 20 minutes to afford the title compound (1.05 g, 98%) as a yellow oil.
[196] 4- (5,6,7,8-Tetrahydro-quinolin-8-ylamino) -piperidine-1-carboxylic acid tert-butyl ester (240 mg, 0.72 mmol), 2-chloromethyl-benzimidazole- 1-carboxylic acid tert-butyl ester (212 mg, 0.79 mmol), DIPEA (0.20 mmol, 1.58 mmol) and KI (6 mg, 0.036 mmol) were heated to 60 ° C. under N ₂ in CH ₃ CN (7 mmol). The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, washed with NH ₄ Cl (aq), NaCl (aq) and dried (MgSO ₄ ). The solvent was evaporated and the residue was purified by flash chromatography on silica gel (CH ₂ Cl ₂ -MeOH-NH ₄ OH 98: 1: 1) to afford the title compound (331 mg, 82%) as a white foam.
[197] General Process D Use: The foam from the stomach (100 mg, 0.18 mmol) was converted to a hydrobromide salt using acetic acid / HBr solution and then reprecipitated salt from diethyl ether to give compound 7 as a white solid. ¹ H NMR (CD ₃ OD) isomer mixture δ 1.94-2.15 (m, 3H), 2.19-2.26 (m, 2H), 2.41-2.51 (m, 2H), 2.60-2.65 (m, 1H), 3.03-3.14 (m, 4H), 3.18-3.28 (m, 1H), 3.41-3.52 (m, 2H), 4.61 (d, 2H, J = 3.9 Hz), 4.67-4.72 (m, 1H), 7.58-7.63 (m , 2H), 7.86-7.94 (m, 3H), 8.37 (d, 1H, J = 8.1 Hz), 8.91 (d, 1H, J = 5.7 Hz); ¹³ C NMR (CD ₃ OD) isomer mixture δ 25.71, 29.19, 31.67, 32.47, 33.30, 48.62, 48.76, 48.93, 60.93, 63.27, 118.96, 130.51, 131.51, 136.12, 144.91, 145.36, 152.51, 156.45, 156.63 ES-MS m / z 362.3 (M + H); (C ₂₂ H ₂₇ N ₅ ). 3.0 (HBr). 1.8 (H ₂ O). 0.4 (C ₄ H ₁₀ O) Calcd for: C, 42.54; H, 5.69; N, 10.51; Br, 35.98. Found: C, C, 42.61; H, 5.47; N, 10.46; Br, 35.93.
[198] Example 8
[199]
[200] Compound 8: Preparation of (1H-benzimidazol-2-ylmethyl) -piperidin-3-yl- (5,6,7,8-tetrahydroquinolin-8-yl) amine (hydrobromide salt)
[201] Preparation of tert-butyl 3-hydroxy-1-piperidinecarboxylate:
[202] To a 0 ° C. solution of 3-hydroxypiperidine (2.12 g, 21.0 mmol) in EtOH (20 mL) was added NEt ₃ (5.6 mL, 40.2 mmol), followed by (Boc) ₂ O in EtOH (20 mL). 5.03 g, 23.0 mmol) solution was added. The reaction was stirred at rt for 1 h and then the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 10% citric acid (50 mL), water (50 mL) (50 mL) and brine (50 mL). The organic solution was dried (MgSO ₄ ), filtered and evaporated under reduced pressure to afford the crude product as a white solid (3.55 g, 17.6 mmol, 84%). ¹ H NMR (CDCl ₃ ) δ 1.45 (s, 9H), 1.48-1.52 (m, 2H), 1.72-1.78 (m, 1H), 1.84-1.94 (m, 1H), 2.12 (br. S, 1H) , 3.01-3.12 (m, 2H), 3.46-3.59 (m, 1H), 3.65-3.78 (m, 2H).
[203] Preparation of tert-butyl 3-oxo-1-piperidinecarboxylate:
[204] 3 'molecular sieves (5.26 g), 4-methylmorpholine-N-oxide (1.76 g, 15.0 mmol) and tetrapulverized in a 0 ° C. solution of alcohol (2.01 g, 10.0 mmol) in CH ₂ Cl ₂ (50 mL) Propylammonium perruthenate (357 mg, 1.02 mmol) was added. The resulting black solution was stirred at 0 ° C. for 20 minutes and then at room temperature for another 1 hour. The mixture was filtered through a plug of silica, rinsed with EtoAc, and the concentrated filtrate was flash chromatography on silica gel (EtOAc / hexanes, 1: 1) to give the ketone as a yellow liquid (1.49 g, 7.48 mmol, 75%). ¹ H NMR (CDCl ₃ ) δ 1.46 (s, 9H), 1.98 (ddd, 2H, J = 12.3, 6.5, 6.0 Hz), 2.47 (t, 2H, J = 6.5 Hz), 3.58 (t, 2H, J = 6.0 Hz), 4.00 (s, 2H).
[205] Preparation of tert-butyl 3- (5,6,7,8-tetrahydroquinolin-8-ylamino) -piperidine-1-carboxylate:
[206] To a solution of 8-amino-5,6,7,8-tetrahydroquinoline (1.00 g, 6.75 mmol) in MeOH (30 mL) was added a solution of ketone (1.40 g, 7.03 mmol) in MeOH (20 mL). The reaction was stirred at rt for 16 h. NaBH ₄ (848 mg, 22.4 mmol) was added and the mixture was stirred for an additional 45 minutes. The solvent was evaporated under reduced pressure and the residue was dissolved in CH ₂ Cl ₂ (50 mL) and washed with saturated aqueous NaHCO ₃ (10 mL) and brine (10 mL). The organic solution was dried (MgSO ₄ ), filtered and evaporated under reduced pressure. Purification by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 9: 1: 0.5) gave a brown oil, which was then purified _second (CH ₂ Cl ₂ / MeOH, 97: 3). The amine was obtained as a yellow oil (638 mg, 1.92 mmol, 28%). ¹ H NMR (CDCl ₃ ) δ 1.22-1.40 (m, 2H), 1.47 (s, 9H), 1.65-1.81 (m, 3H), 1.91-2.04 (m, 2H), 2.11-2.25 (m, 2H) , 2.44-2.65 (m, 1H), 2.65-2.90 (m, 4H), 3.88-4.05 (m, 2H), 4.05-4.31 (m, 1H), 7.06 (dd, 1H, J = 7.7, 4.7 Hz) , 7.36 (d, 1H, J = 7.8 Hz), 8.37 (d, 1H, J = 4.3 Hz).
[207] Preparation of Compound 8:
[208] Amine (247 mg, 0.75 mmol) in CH ₃ CN (4 mL), tert-butyl 2-chloromethyl-benzimidazole-1-carboxylate (238 mg, 0.89 mmol), DIPEA (0.20 mL, 1.2 mmol) and A mixture of KI (14 mg, 0.08 mmol) was heated to 60 ° C. for 20 hours. After cooling, the reaction was diluted with saturated aqueous NaHCO ₃ (10 mL) and extracted with CH ₂ Cl ₂ (25 mL × 3). The organic solution was dried (MgSO ₄ ), filtered and evaporated under reduced pressure. The dark red oil obtained was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 9: 1) to give an orange foam. Second purification (CH ₂ Cl ₂ / MeOH, 19: 1) afforded a tertiary amine as an orange solid (83 mg, 20%).
[209] The material was stirred in TFA (1.5 mL) at room temperature for 2 hours, then excess solvent was removed under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (20 mL) and washed with saturated aqueous NaHCO ₃ (10 mL). The aqueous solution was extracted with CH ₂ Cl ₂ (20 mL × 2) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 89: 10: 1) yielded an about 2: 1 mixture of diastereomers of the free amine as a yellow foam (21 mg, 0.06 mmol, 41 Obtained as%). To a solution of this material (20 mg, 0.055 mmol) in ice HOAc (1 mL) was added saturated HBr (0.5 mL) in HOAc. The reaction was stirred at rt for 40 min. Et ₂ O (2 mL) was added, the suspension was stirred and the solvent was decanted. The precipitate was washed with Et ₂ O (1 mL × 5) and then dried under reduced pressure to afford compound 8 as a yellow solid (26 mg, 0.038 mmol, 70%). ¹ H NMR (D ₂ O) δ 1.61-1.94 (m, 3H), 1.98-2.11 (m, 1H), 2.11-2.17 (m, 2H), 2.17-2.49 (m, 1H), 2.80-2.92 (m , 1H), 2.93-3.01 (m, 2H), 3.09-3.25 (m, 2H), 3.31-3.40 (m, 1H), 3.82-3.90 (m, 1H), 4.43 (d, 1H, J = 16.5 Hz ), 4.55 (d, 1H, J = 16.5 Hz), 4.55-4.65 (m, 1H), 7.53-7.60 (m, 2H), 7.67-7.77 (m, 3H), 8.20 (d, 0.67H, J = 7.8 Hz), 8.23 (d, 0.33 H, J = 7.8 Hz), 8.51 (d, 0.67 H, J = 5.7 Hz), 8.55 (d, 0.33 H, J = 5.7 Hz). ¹³ C NMR (D ₂ O) δ 20.5 and 20.6, 21.9 and 22.1, 24.2 and 24.5, 26.8 and 27.5, 28.0, 43.2, 44.0, 46.2 and 47.0, 58.5 and 59.2, 114.4, 125.8, 126.8, 131.7, 139.5, 140.5 And 141.6, 147.7 and 147.8, 150.6 and 151.2. ES-MS mlz 362 (M + H). Calcd for C ₂₂ H ₂₇ N ₅ .3.1 HBr.1.8H ₂ O.0.3C ₄ H ₁₀ O: C, 41.78; H, 5.55; N, 10.50; Br, 37.14. Found: C, 41.48; H, 5. 44; N, 10.44; Br, 37.50.
[210] Example 9
[211]
[212] Compound 9: Preparation of (1H-benzimidazol-2-ylmethyl) -piperidin-3-yl- (5,6,7,8-tetrahydroquinolin-8-yl) amine (hydrobromide salt)
[213] The free base was prepared by N-alkylation and TFA deprotection as described above (see compound 8). The crude material was purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 9: 1: 0.1) to give a yellow foam as a yellow foam with 18 mg (0.05 mmol, 5%) of a single diastereomer as a brown foam. 51 mg (0.14 mmol, 14%) of a mixture of diastereomers were obtained.
[214] Single diastereomers (18 mg, 0.05 mol) were dissolved in HOAc (1 mL) and saturated HBr in HOAc (0.5 mL). The solution was stirred at rt for 40 min. Et ₂ O (2 mL) was added, the mixture was stirred and the solvent was decanted. The precipitate was washed with Et ₂ O (1 mL × 5) and dried at 90 ° C. under reduced pressure to give diastereomeric compound 9 as a yellow powder (22 mg, 0.03 mmol, 67%). ¹ H NMR (D ₂ O) δ 1.57-1.74 (m, 1H), 1.75-1.90 (m, 2H), 2.03-2.12 (m, 1H), 2.12-2.24 (m, 2H), 2.31-2.47 (m , 2H), 2.80-2.92 (m, 1H), 2.92-3.00 (m, 2H), 3.06-3.20 (m, 2H), 3.29-3.38 (m, 1H), 3.47-3.57 (m, 1H), 4.43 -4.53 (m, 1H), 4.48 (d, 1H, J = 16.4 Hz), 4.57 (d, 1H, J = 16.4 Hz), 7.51-7.58 (m, 2H), 7.68-7.76 (m, 3H), 8.20 (d, 1H, J = 7.5 Hz), 8.53 (d, 1H, J = 5.7 Hz). ¹³ C NMR (D ₂ O) δ 20.5, 21.9, 24.2, 26.8, 27.5, 43.4, 43.9, 47.0, 55.5, 59.2, 114.4, 125.8, 126.6, 132.0, 139.7, 140.5, 147.6, 150.9, 151.1. ES-MS mlz 362 (M + H). Calcd for C ₂₂ H ₂₇ N ₅ .3.0HBr. 1.8 H ₂ O.0.3C ₄ H ₁₀ O: C, 42.29; H, 5. 60; N, 10.63; Br, 36.38. Found: C, 42.27; H, 5. 60; N, 10.62; Br, 36.42.
[215] Example 10
[216]
[217] Compound 10: N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -ethane-1,2-diamine (hydrobromide salt)
[218] General process B use: N- (tert-butoxycarbonyl) -2-amino-acetaldehyde (0.112 g, 0.71 mmol) and (1-tert-butoxycarbonyl-1H in CH ₂ Cl ₂ (5 mL) -Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (0.189 g, 0.50 mmol) with NaBH (OAc) ₃ (0.215 g, 1.01 mmol) ) Was reacted for 18 hours, and then the crude material was purified by radial chromatography on silica gel (2 mm plate, 100: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to obtain a white solid (0.167 g, 64%). ) Was obtained.
[219] General Process D Use: The white solid (167 mg) was converted to the hydrobromide salt while at the same time removing the BOC-protecting group, followed by reprecipitation of the intermediate solid from methanol / ether to give compound 10 (173 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.75-1.89 (m, 1H), 1.98-2.11 (m, 1H), 2.15-2.22 (m, 1H), 2.38-2.43 (m, 1H), 2.91-3.02 ( m, 3H), 3.16-3.31 (m, 3H), 4.40 (d, 1H, J = 16.5 Hz), 4.52-4.67 (m, 2H), 7.58-7.63 (m, 2H), 7.76-7.84 (m, 3H), 8.32 (d, 1H, J = 7.8 Hz), 8.59 (d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 20.30, 20.44, 27.68, 37.75, 47.12, 49.11, 60.07, 114.40, 126.08, 127.11, 131.17, 139.78, 140.92, 148.23, 150.09, 150.17; ES-MS m / z 322 (M + H). Calcd for C ₁₉ H ₂₃ N ₅ .3.0 HBr .1.1 H ₂ O: C, 39.08; H, 4.87; N, 11.99; Br, 41.05. Found: C, 39.19; H, 4.98; N, 11.76; Br, 40.89.
[220] Example 11
[221]
[222] Compound 11: n ^One-(1H-benzimidazol-2-ylmethyl) -N ²-(5-nitro-pyridin-2-yl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -ethane-1,2-diamine (hydrobromide salt)
[223] General procedure B use: 2- (2-aminoethylamino) -5-nitropyridine (368 mg) in a solution of 6,7-dihydro-5H-quinolin-8-one (294 mg, 2 mmol) in MeOH (6 mL). , 2.02 mmol) was added, and the resulting solution was stirred at room temperature for 3 hours. Solid NaBH ₄ (168 mg, 4.44 mmol) was added to the solution and the mixture was stirred for an additional 45 minutes at room temperature. The crude yellow foam obtained (639 mg) was used in the next step without further purification.
[224] General process use for N-alkylation: substance from stomach (639 mg), potassium iodide (5 mg, 0.030 mmol) and N, N-diisopropylethylamine (0.70 mL, 4.0 in CH ₃ CN (10 mL) mmol) in a solution of N- (tert-butoxycarbonyl) -2-chloromethylbenzimidazole [An, H .; Wang, T .; Mohan, V .; Griffey, RH; Cook, PD (527 mg, 1.98 mmol) was added as described in Tetrahedron 1998, 54, 3999-4012) and the reaction was stirred at 60 ° C. for 6.5 h. The crude brown foam was purified by flash chromatography on silica gel (99: 1 CH ₂ Cl ₂ / MeOH then 98: 2) to give the alkylation product, 2-{[[2- (5-nitro-pyridin-2-ylamino)- Ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester (645 mg, 60%) as a yellow foam Obtained.
[225] Use General Process D: Convert the free base (84 mg, 0.16 mmol) from the stomach into a hydrobromide salt and then reprecipitate the intermediate solid from methanol / ether to give compound 11 (87 mg, 78%) as a yellow solid. It was. ¹ H NMR (D ₂ O) δ1.81-1.88 (m, 1H), 2.06-2.17 (m, 2H), 2.38-2.43 (m, 1H), 2.88-2.96 (m, 1H), 3.01-3.03 ( m, 2H), 3.14-3.21 (m, 1H), 3.39-3.57 (m, 2H), 4.37 (d, 1H, J = 16.8 Hz), 4.57 (d, 1H, J = 16.8 Hz), 4.61-4.66 (m, 1H), 6.49 (d, 1H, J = 9.6 Hz), 7.42 (dd, 2H, J = 6, 3 Hz), 7.57 (dd, 2H, J = 6, 3 Hz), 7.86-7.93 (m, 2H), 8.33 (br s, 1H), 8.37 (d, 1H, J = 7.8 Hz), 8.70 (d, 1H, J = 6.6 Hz); ¹³ C NMR (D ₂ O) δ 20.41, 20.79, 27.80, 41.02,49.30, 50.55, 62.07, 110.03, 110.77, 114.22, 126.02, 126.66, 130.60, 133.75, 135.36, 139.77, 140.95, 143.67, 148.28, 150.42, 151.28, 179.57; ES-MS m / z 444 (M + H). Calcd for C ₂₄ H ₂₅ N ₇ 0 ₂ 2.9 HBr 2.4 H ₂ 0: C, 39.96; H, 4.57; N, 13.59; Br, 32.12. Found: C, 40.17; H, 4. 47; N, 13.20; Br, 32.03.
[226] Example 12
[227]
[228] Compound 12: (1H-benzimidazol-2-ylmethyl)-(2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine Produce.
[229] Preparation of toluene-4-sulfonic acid 2-tert-butoxycarbonylamino-ethyl ester .
[230]
[231] Tosyl chloride (1.50 g, 7.87 mmol) was dissolved in (2-hydroxy-ethyl) -carbamic acid tert-butyl ester (0.84 g, 5.2 mmol) in CH ₂ Cl ₂ (26 mL) and Et ₃ N (1.23 mL, 8.82 mmol) solution. The solution was washed with H ₂ O (15 mL) and the aqueous phase was extracted with CH ₂ Cl ₂ (10 mL). The combined organic phases were dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (20% EtOAc / hexanes) to give yellow crystals (1.29 g, 79%). ¹ H NMR (CDCl ₃ ) δ1.41 (s, 9H), 2.45 (s, 3H), 3.38 (m, 2H), 4.07 (m, 2H), 4.82 (br s, 1H), 7.35 (d, 2H , J = 8.1 Hz), 7.79 (d, 2H, J = 8.1 Hz).
[232] (2-imidazol-1-yl-ethyl) -carbamic acid tert-butyl ester .
[233]
[234] A solution of imidazole (253 mg, 3.72 mmol) in DMF (2 mL) was added to a suspension of NaH (60% in mineral oil, 164 mg, 4.10 mmol) in DMF (8 mL), and the mixture was stirred at room temperature for 45 minutes. . A solution of toluene-4-sulfonic acid 2-tert-butoxycarbonylamino-ethyl ester (1.29 g, 4.09 mmol) in DMF (6 mL) was added and the mixture was stirred at rt for 16 h and then concentrated in vacuo. . The residue was partitioned between H ₂ O (25 mL) and EtOAc (25 mL) and the aqueous phase was extracted with EtOAc (25 mL). The combined organic phases were dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (200: 5: 1-100: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give a colorless oil (224 mg, 29%). ¹ H NMR (CDCl ₃ ) δ 1.44 (s, 9H), 3.43 (m, 2H), 4.08 (m, 2H), 4.64 (br s, 1H), 6.92 (s, 1H), 7.09 (s, 1H ), 7.46 (s, 1 H).
[235] (2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine
[236]
[237] A solution of (2-imidazol-1-yl-ethyl) -carbamic acid tert-butyl ester (224 mg, 1.06 mmol) in 1: 1 TFA / CH ₂ Cl ₂ (4 mL) was stirred at room temperature for 1 hour. , Concentrated in vacuo. The residue was dissolved in 1N NaOH (aq) (10 mL), then saturated with sodium chloride and extracted with CHCl ₃ (5 × 15 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to give a yellow oil (55 mg).
[238] General Process B Use: Amine (55 mg), 6,7-dihydro-5H-quinolin-8-one (73 mg, 0.50 mmol) and AcOH (0.030 mL, 0.52 mmol) from the stomach in THF (5 mL) NaBH (OAc) ₃ (315 mg, 1.49 mmol) was added to the stirred solution of, and the mixture was stirred at room temperature for 2 hours. The crude material was dissolved in saturated HBr / AcOH (2 mL) and stirred at room temperature for 15 minutes. The solution was made basic with 10N NaOH (aq) and extracted with CH ₂ Cl ₂ (3 × 15 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (200: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give a yellow oil (92 mg, 77%). ¹ H NMR (CDCl ₃ ) δ 1.73 (m, 2H), 1.91-2.13 (m, 2H), 2.76 (m, 2H), 3.12 (m, 2H), 3.78 (m, 1H), 4.11 (m, 2H), 7.01 (s, 1H), 7.08 (m, 2H), 7.38 (d, 1H, J = 7.5 Hz), 7.56 (s, 1H), 8.37 (d, 1H, J = 3.9 Hz).
[239] 2-{[(2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert -Butyl ester.
[240]
[241] (2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (92 mg, 0.37 mmol), 2- in acetonitrile (4 mL) Of chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (101 mg, 0.379 mmol), potassium iodide (3 mg, 0.02 mmol), and N, N-diisopropylethylamine (0.10 mL, 0.57 mmol) The mixture was heated at 60 ° C. for 15 h. Saturated NaHCO ₃ (aq) (15 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 × 15 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (250: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give a yellow oil (21 mg, 12%). ¹ H NMR (CDCl ₃ ) δ 1.45 (m, 1H), 1.66 (m, 10H), 1.91 (m, 2H), 2.69 (m, 2H), 2.92 (m, 1H), 3.18 (m, 1H) , 3.67 (m, 2H), 4.20 (dd, 1H, J = 10, 5.6 Hz), 4.67 (d, 1H, J = 15 Hz), 4.80 (d, 1H, J = 15 Hz), 6.74 (s, 1H) , 6.90 (s, 1H), 7.01 (dd, 1H, J = 7.7, 4.7 Hz), 7.33 (m, 4H), 7.73 (m, 1H), 7.86 (m, 1H), 8.38 (d, 1H, J) = 3.3 Hz).
[242] (1H-benzimidazol-2-ylmethyl)-(2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (Compound 12) .
[243] 2-{[(2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-in 3: 1 TFA / CH ₂ Cl ₂ (4 mL)- A solution of amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester (21 mg, 0.044 mmol) was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was partitioned between CH ₂ Cl ₂ (20 mL) and 1N NaOH (aq) (10 mL) and the aqueous phase was extracted with CH ₂ Cl ₂ (10 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to afford compound 12 as a yellow foam (15 mg, 83%). ¹ H NMR (CDCl ₃ ) δ 1.73 (m, 2H), 1.99 (m, 1H), 2.20 (m, 1H), 2.69-2.88 (m, 2H), 2.92-3.08 (m, 2H), 3.82- 3.98 (m, 2H), 4.04 (d, 1H, J = 17 Hz), 4.09 (m, 1H), 4.19 (d, 1H, J = 17 Hz), 6.70 (s, 1H), 6.93 (s, 1H), 7.18 (m, 3H), 7.42 (m, 2H), 7.57 (br s, 2H), 8.51 (d, 1H, J = 3.9 Hz); ¹³ C NMR (CDCl ₃ ) δ 21.55, 25.06, 29.36, 46.03, 50.34, 52.23, 62.59, 119.32, 122.26, 122.82, 129.55, 134.97, 137.93, 147.26, 155.42, 156.77. ES-MS m / z 373 (M + H). Calcd for C ₂₂ H ₂₄ N ₆ .0.2CH ₂ Cl ₂ .0.8CH ₄ O: C, 66.55; H, 6. 70; N, 20.25. Found: C, 66.64; H, 6. 40; N, 20.06.
[244] Example 13
[245]
[246] Compound 13: (1H-Benzimidazol-2-ylmethyl)-[3- (1H-imidazol-2-yl) -propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine Manufacture
[247] Preparation of 1-trityl-1H-imidazole-2-carbaldehyde
[248]
[249] To a suspension of imidazole-2-carboxaldehyde (1.00 g, 10.4 mmol) in DMF (16 mL) was added N, N-diisopropylethylamine (4.0 mL, 23.0 mmol) and then in DMF (10 mL). A solution of trityl chloride (3.19 g, 11.4 mmol) was added and the mixture was stirred at 30 ° C. for 21 h. The mixture was concentrated in vacuo and then dissolved in EtOAc (60 mL). The solution was washed with saturated NaHCO ₃ (aq) (2 × 30 mL) and brine (15 mL), then dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (20% EtOAc / hexanes) to give a yellow solid (1.63 g, 46%). ¹ H NMR (CDCl ₃ ) δ 7.03 (s, 1H), 7.12 (m, 6H), 7.32 (m, 10H), 9.23 (s, 1H).
[250] (E) -3- (1-trityl-1H-imidazol-2-yl) -acrylic acid ethyl ester
[251]
[252] Triethyl phosphonoacetate (1.24 mL, 6.25 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 212 mg, 5.30 mmol) in DME (5 mL) and stirred at room temperature for 30 minutes. The solution was added to a suspension of 1-trityl-1H-imidazole-2-carbaldehyde (1.63 g, 4.82 mmol) in DME (7 mL), the mixture was heated to reflux for 15 minutes and then at 60 ° C. for 1 hour. Was stirred. The reaction mixture was quenched with H ₂ O (30 mL) and extracted with CH ₂ Cl ₂ (3 × 15 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (25% EtOAc / hexanes) to give a yellow solid (1.32 g, 67%). ¹ H NMR (CDCl ₃ ) δ 1.13 (t, 3H, J = 7.1 Hz), 4.00 (q, 2H, J = 7.1 Hz), 6.52 (d, 1H, J = 15 Hz), 6.70 (d, 1H, J = 15 Hz), 6.87 (d, 1H, J = 1.2 Hz), 7.13 (m, 7H), 7.33 (m, 9H).
[253] 3- (1-trityl-1H-imidazol-2-yl) -propan-1-ol
[254]
[255] A solution of (E) -3- (1-trityl-1H-imidazol-2-yl) -acrylic acid ethyl ester (1.32 g, 3.23 mmol) in 4: 1 MeOH / EtOAc (20 mL) was added with 10% Pd / C. Stir with suspension of (132 mg, 0.124 mmol) for 20 h at room temperature under hydrogen atmosphere (1 atm). The catalyst was filtered off and the filtrate was concentrated in vacuo to yield yellow crystals (1.49 g). To a solution of crude ester (1.49 g) from above in THF (7 mL) was added LiAlH ₄ (1.0 M / THF, 7.0 mL, 7.0 mmol) at ° C and the mixture was stirred at rt for 1 h. Methanol (5 mL) was added followed by 1N NaOH (aq) (40 mL) and the mixture was extracted with CH ₂ Cl ₂ (2 × 25 mL). The combined organic extracts were dried (MgSO ₄ , concentrated in vacuo.) ¹ H NMR (CDCl ₃ ) δ 1.37 (m, 2H), 2.09 (m, 2H), 3.51 (m, 2H), 6.68 (d, 1H) , J = 1.5 Hz), 6.92 (d, 1H, J = 1.5 Hz), 7.13 (m, 6H), 7.33 (m, 9H).
[256] 3- (1-trityl-1H-imidazol-2-yl) -propionaldehyde
[257]
[258] Dess-Martin in a solution of 3- (1-trityl-1H-imidazol-2-yl) -propan-1-ol (201 mg, 0.545 mmol) in CH ₂ Cl ₂ (6 mL) Periodinan (278 mg, 0.655 mmol) was added at room temperature. After stirring for 1 h at rt, the mixture was diluted with EtOAc (30 mL), washed with 1N NaOH (aq) (2 × 10 mL) and brine (10 mL), then dried (MgSO ₄ ) and vacuum Concentration under afforded a tan foam (178 mg, 89%). ¹ H NMR (CDCl ₃ ) δ 2.19 (m, 2H), 2.37 (m, 2H), 6.75 (d, 1H, J = 1.5 Hz), 6.93 (d, 1H, J = 1.5 Hz), 7.13 (m , 6H), 7.34 (m, 9H), 9.54 (s, 1H).
[259] (1H-Benzimidazol-2-ylmethyl)-[3- (1H-imidazol-2-yl) -propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (Compound 13)
[260] General process B use: 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -benzoimidazole-1-carboxylic acid tert-butyl ester (184 in THF (5 mL) Mg, 0.486 mmol) and NaBH (OAc) ₃ (206 mg, 0.972 mmol) in a stirred solution of 3- (1-trityl-1H-imidazol-2-yl) -propionaldehyde (178 mg, 0.486 mmol). Was added and the mixture was stirred at rt for 3.5 h. The crude material was purified by column chromatography on silica gel (200: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give 2-({(5,6,7,8-tetrahydro-quinoline by ¹ H NMR). -8-yl)-[3- (1-trityl-1H-imidazol-2-yl) -propyl] -amino} -methyl) -benzimidazole-1-carboxylic acid tert-butyl ester with 3- (1 A yellow oil (168 mg) was obtained, which was determined to be a mixture of -trityl-1H-imidazol-2-yl) -propan-1-ol, which was used in the next step without further purification.
[261] The crude amine solution from above in saturated HBr / AcOH (3 mL) was stirred at RT for 1 h, then basified with 10N NaOH (aq) and extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (300: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give (1H-benzimidazol-2-ylmethyl)-(5,6,7,8- Tetrahydro-quinolin-8-yl)-[3- (1-trityl-1H-imidazol-2-yl) -propyl] -amine was obtained as a yellow oil (101 mg, 33% over two steps). .
[262] (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-[3- (1-trityl-) in CH ₂ Cl ₂ (1.6 mL) To a solution of 1H-imidazol-2-yl) -propyl] -amine (101 mg, 0.161 mmol) was added triethylsilane (0.38 mL, 2.4 mmol), then TFA (1.9 mL, 25 mmol) was added and the solution was added. After stirring for 21 h at rt, it was concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (15 mL) and washed with 1N NaOH (aq) (10 mL). The aqueous phase was extracted with CH ₂ Cl ₂ (2 × 10 mL) and the combined organic phases were dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (150: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to afford compound 13 as a colorless foam (47 mg, 69%). ¹ H NMR (CDCl ₃ ) δ1.62-1.93 (m, 4H), 2.02 (m, 1H), 2.16 (m, 1H), 2.58-2.88 (m, 6H), 3.91 (d, 1H, J = 16Hz ), 3.98 (d, 1H, J = 16 Hz), 4.02 (m, 1H), 6.86 (s, 2H), 7.18 (m, 3H), 7.43 (d, 1H, J = 7.2 Hz), 7.55 (m, 2H), 8.55 (d, 1H, J = 3.6 Hz); ¹³ C NMR (CDCl ₃ ) δ 21.52, 23.71, 25.96, 26.67, 29.43, 49.21, 51.07, 62.23, 115.28, 120.75, 122.41, 122.81, 135.47, 138.23, 138.86, 146.68, 148.71, 155.28, 157.49. ES-MS mlz 387 (M + H). Calcd for C ₂₃ H ₂₆ N ₆ .0.21H ₂ O.0.36CH ₂ Cl ₂ : C, 66.67; H, 6. 50; N, 19.97. Found: C, 66.77; H, 6.65; N, 19.69.
[263] Example 14
[264]
[265] Compound 14: N- (6-2-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -ethylamino} -pyridine-3 Preparation of -yl) -acetamide
[266] 2-{[[2- (5-nitro-pyridin-2-ylamino) -ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] in AcOH (4 mL) To a -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester solution (see compound 11) iron powder (172 mg, 3.08 mmol) was added and the reaction heated to reflux for 2 hours. The mixture was cooled to rt, diluted with water (5 mL) and extracted with CH ₂ Cl ₂ (3 × 25 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), concentrated in vacuo, and subjected to radial chromatography on silica gel (1 mm plate, 100: 1: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH then 50: 1: 1). Purification gave the desired product (96 mg, 30%) as a clear oil.
[267] General Process D Use: The free base (25 mg, 0.055 mmol) was converted to the hydrobromide salt and then reprecipitated the intermediate solid from methanol / ether to give compound 14 (36 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.83-1.90 (m, 1H), 2.05-2.20 (m, 2H), 2.14 (s, 3H), 2.39-2.43 (m, 1H), 2.86-2.94 (m, 1H), 3.01-3.03 (m, 2H), 3.18-3.25 (m, 1H), 3.39-3.49 (m, 2H), 4.38 (d, 1H, J = 16.5 Hz), 4.58 (d, 1H, J = 16.5 Hz), 4.62-4.68 (m, 1H), 6.75 (d, 1H, J = 9.6 Hz), 7.47 (dd, 2H, J = 6, 3 Hz), 7.49 (s, 1H), 7.60 (dd, 2H , J = 6, 3 Hz), 7.83 (s, 1H), 7.89 (t, 1H, J = 6.6 Hz), 8.38 (d, 1H, J = 7.8 Hz), 8.71 (d, 1H, J = 6.6 Hz) ; ¹³ C NMR (D ₂ O) δ 20.39, 20.84, 23.07, 27.83, 41.24, 49.13, 50.29, 62.01, 113.37, 114.24, 125.70, 125.82, 126.11, 126.96, 130.58, 138.24, 139.94, 141.08, 148.39, 149.47 150.18, 151.32, 172.99; ES-MS m / z 456 (M + H). Calcd for C ₂₆ H ₂₉ N ₇ O.3.2 HBr. 2.4 H ₂ O: C, 41.21; H, 4.92; N, 12.94; Br, 33.75. Found: C, 41.12; H, 4.98; N, 12.77; Br, 34.06.
[268] Example 15
[269]
[270] Compound 15: N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -propane-1,3-diamine (hydrobromide salt)
[271] Preparation of N- (tert-butoxycarbonyl) -3-amino-propionaldehyde:
[272] To a solution of tert-butyl N- (3-hydroxypropyl) carbamate (0.177 g, 1.01 mmol) in CH ₂ Cl ₂ (5 mL) was added Dess-Martin Periodinan (0.545 g, 1.28 mmol) and obtained. One mixture was stirred at rt for 2.5 h. The mixture was diluted with ether (20 mL) and treated with 20% aqueous Na ₂ S ₂ O ₃ (5 mL) and saturated aqueous NaHCO ₃ (5 mL). After 10 minutes the mixture became clear and colorless, and the phases were separated. The aqueous phase was extracted with ether (3 × 10 mL). The combined organic extracts were washed successively with 20% aqueous Na ₂ S ₂ O ₃ (10 mL), saturated aqueous NaHCO ₃ (10 mL) and brine (10 mL), dried (MgSO ₄ ) and concentrated to N- ( 0.127 g (96%) of tert-butoxycarbonyl) -3-amino-propionaldehyde was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.43 (s, 9H), 2.71 (t, 2H, J = 6.0 Hz), 3.42 (m, 2H), 4.89 (br s, 1H), 9.81 (s, 1H).
[273] General process B use: N- (tert-butoxycarbonyl) -2-amino-propionaldehyde (0.127 g, 0.73 mmol) and (1H-benzimidazol-2-ylmethyl)-(5,6,7, 8-tetrahydro-quinolin-8-yl) -amine (0.152 g, 0.55 mmol) and NaBH (OAc) ₃ (0.262 g, 1.24 mmol) in CH ₂ Cl ₂ (5 mL) were reacted for 18 hours, The crude material was purified by silica gel radial chromatography (2 mm plate, 50: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to yield 0.169 g of a yellow foam. The foam was dissolved in CH ₂ Cl ₂ (2 mL) and treated with trifluoroacetic acid (1 mL). The resulting solution was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (10 mL) and treated with NaOH (10 M, ˜2 mL) until the aqueous phase became basic (pH 14). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 5 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel radial chromatography (1 mm plate, 10: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 57 mg of white foam.
[274] General Process D Use: The free base (57 mg) was converted to the hydrobromide salt and then reprecipitated intermediate solids from methanol / ether to give compound 15 (75 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.77-2.09 (m, 4H), 2.18-2.22 (m, 1H), 2.38-2.42 (m, 1H), 2.60-2.70 (m, 1H), 2.87-2.97 ( m, 3H), 3.01-3.04 (m, 2H), 4.42 (d, 1H, J = 16.8 Hz), 4.51-4.49 (m, 2H), 7.60-7.63 (m, 2H), 7.79-7.90 (m, 3H), 8.36 (d, 1H, J = 7.8 Hz), 8.65 (d, 1H, J = 5.7 Hz); ¹³ C NMR (D ₂ O) δ 20.41 (2 carbons), 26.38, 27.66, 37.69, 47.94, 49.13, 60.39, 114.32, 126.02, 126.98, 131.10, 139.50, 140.73, 148.18, 150.96, 151.36; ES-MS m / z 336 (M + H). Calcd for C ₂₀ H ₂₅ N ₅ .3.0 HBr.1.6 H ₂ O: C, 39.57; H, 5. 18; N, 11.54; Br, 39.49. Found: C, 39.85; H, 5. 10; N, 11.45; Br, 39.15.
[275] Example 16
[276]
[277] Compound 16: N ^One-(1H-benzimidazol-2-ylmethyl) -N ²-Pyridin-2-ylmethyl-N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -ethane-1,2-diamine (hydrobromide salt)
[278] N ^1- (1H-benzimidazol-2-ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -ethane-1 in H ₂ O (2 mL), To a solution of 2-diamine hydrobromide salt [Compound 10] (98 mg, 0.168 mmol) was added NaOH (10M, 2 mL). The resulting solution was extracted with CH ₂ Cl ₂ (4 × 5 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), concentrated and 53 mg free base was obtained. Pyridine-2-carboxaldehyde (20 mL, 0.210 mmol) was added to a solution of free base (53 mg, 0.165 mmol) from the stomach in methanol (2 mL), and the resulting solution was stirred at room temperature for 2 hours. NaBH ₄ (36 mg, 0.95 mmol) was added and the mixture was stirred for 15 minutes. The mixture was concentrated and the residue was partitioned between CH ₂ Cl ₂ (10 mL) and brine (5 mL). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 5 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel radial chromatography (1 mm plate, 25: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 34 mg (45%) of the free base of the title compound.
[279] General Process D Use: The free base (34 mg) was converted to the hydrobromide salt and then reprecipitated the intermediate solid from methanol / ether to give compound 16 (57 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.78-1.90 (m, 1H), 1.98-2.11 (m, 1H), 2.17-2.22 (m, 1H), 2.39-2.43 (m, 1H), 2.97-3.09 ( m, 3H), 3.25-3.37 (m, 3H), 4.39 (d, 1H, J = 16.5 Hz), 4.47 (d, 2H, J = 2.4 Hz), 4.54-4.59 (m, 2H), 7.57-7.65 (m, 4H), 7.77-7.88 (m, 3H), 8.04 (dt, 1H, J = 1.5, 7.5 Hz), 8.35 (d, 1H, J = 7.8 Hz), 8.50 (d, 1H, J = 4.8 Hz), 8.61 (d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 20.27, 20.54, 27.67, 45.45, 47.48, 48.12, 50.32, 60.32, 114.42, 125.85, 126.11, 126.19, 127.27, 130.98, 139.83, 141.03, 141.70, 147.87, 148.39 (2 carbons ), 149.85, 150.06; ES-MS m / z 413 (M + H). Calcd for C ₂₅ H ₂₈ N ₆ .4.1 HBr 2.0 H ₂ O: C, 38.48; H, 4. 66; N, 10.77; Br, 41.98. Found: C, 38.69; H, 4.78; N, 10.60; Br, 41.70.
[280] Example 17
[281]
[282] Compound 17: N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt)
[283] (1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine in CH ₃ CN (5 mL) To a solution of (0.169 g, 0.451 mmol) was added N, N-diisopropylethylamine (0.25 mL, 1.44 mmol), followed by 4-bromobutyronitrile (0.10 mL, 1.01 mmol). The resulting mixture was heated to 80 ° C. for 5 hours and then cooled to room temperature. The mixture was cooled and the residue was partitioned between CH ₂ Cl ₂ (20 mL) and brine (10 mL). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (30: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 108 mg (54%) of a yellow foam.
[284] Intermediate from the stomach (108 mg, 0.24 mmol) was dissolved in NH ₃ saturated methanol (4 mL), treated with Raney nickel (100 mg) and placed under 50 psi H ₂ for 24 h on a Parr shaker. Celite mixture Filter through and wash the cake with methanol. The eluate was concentrated under reduced pressure. The crude material was purified by silica gel radial chromatography (1 mm plate, 20: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 33 mg (39%) of the free base of the title compound as a white foam. .
[285] General Process D Use: The white foam (33 mg) was converted to a hydrobromide salt, followed by reprecipitation of the intermediate solid from methanol / ether to give compound 17 (40 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.52 (br s, 4H), 1.74-1.88 (m, 1H), 1.95-2.08 (m, 1H), 2.15-2.21 (m, 1H), 2.34-2.39 (m , 1H), 2.50-2.61 (m, 1H), 2.79-2.86 (m, 3H), 2.99-3.02 (m, 2H), 4.38 (d, 1H, J = 16.8 Hz), 4.47-4.56 (m, 2H ), 7.58-7.63 (m, 2H), 7.76-7.88 (m, 3H), 8.34 (d, 1H, J = 7.8 Hz), 8.62 (d, 1H, J = 5.7 Hz); ¹³ C NMR (D ₂ O) δ 20.42 (2 carbons), 25.03, 25.42, 27.64, 39.50, 48.20, 51.71, 60.64, 114.26, 125.93, 126.93, 131.05, 139.32, 140.62, 148.09, 150.31, 151.82; ES-MS m / z 350 (M + H). Calcd for C ₂₁ H ₂₇ N ₅ .2.9 HBr.2.2 H ₂ O: C, 40.44; H, 5.54; N, 11.23; Br, 37.15. Found: C, 40.38; H, 5. 42; N, 10.85; Br, 37.42.
[286] Example 18
[287]
[288] Compound 18: N '(1H-benzimidazol-2-ylmethyl) -N' (S) -5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine (hydro Chloride salt)
[289] Preparation of 4-phthalamido-butyraldehyde:
[290] A solution of 4-amino-1-butanol (5.0 g, 56 mmol) and phthalic anhydride (8.3 g, 56 mmol) in 20% MeOH / CHCl ₃ (140 mL) was stirred at reflux for 66 h. The mixture was cooled to rt and washed successively with water (3 × 75 mL) and 1N NaOH (3 × 50 mL). The separated organic phase was dried (MgSO ₄ ), concentrated and purified by flash chromatography (5 cm id., Eluted with 120 g of silica gel, 2% MeOH / CH ₂ Cl ₂ ) to afford the desired alcohol as a white solid ( 4.21 g, 34%).
[291] CH ₂ Cl ₂ (100㎖) of TPAP (340㎎, 0.96mmol), NMO (3.4g, 29mmol) and the alcohol from the top of 3Å molecular CH ₂ Cl ₂ (50㎖) To a stirred slurry of ssibeu (10g) A solution of (4.2 g, 19 mmol) was added over 30 minutes. After addition, the black slurry was stirred for 30 minutes under N ₂ , concentrated in vacuo and purified by flash chromatography (5 cm id., 80 g silica gel, eluted with EtOAc) to afford the pure title compound as a gray solid (3.30 g). , 80%). ¹ H NMR (CDCl ₃ ) δ 1.97-2.07 (m, 2H), 2.54 (t, 2H, J = 7.2 Hz), 3.74 (t, 2H, J = 6.8 Hz), 7.71-7.75 (m, 2H) , 7.82-7.88 (m, 2 H), 9.77 (s, 1 H).
[292] General process B use: 4-phthalamido-butyraldehyde (3.21 g, 14.8 mmol) from the stomach was added with S- (5,6,7,8-tetrahydroquinolin-8-yl in dichloromethane (150 mL). ) -Amine (2.40 g, 16.3 mmol) and NaBH (OAc) ₃ (9.54 g, 45.0 mmol). Flash chromatography (5 cm id., Eluted with 200 g of silica gel, 5% MeOH / CH ₂ Cl ₂ ) gave pure 2 ° amine as a white effervescent solid (2.48 g, 48%).
[293] To a solution of amine (2.5 g, 7.1 mmol) from the stomach in acetonitrile (70 mL), diisopropylethylamine (1.9 mL, 10.7 mmol), 1-boc-2-chloromethylbenzimidazole (2.3 g, 8.6 mmol) and potassium iodide (115 mg, 0.70 mmol) were added. The mixture was stirred at 60 ° C. for 15 h under N ₂ atmosphere, cooled to rt and concentrated in vacuo. The residue was partitioned between chloroform (150 mL) and water (100 mL). The separated organic phase is dried (MgSO ₄ ), concentrated and flash chromatography (5 cm id, 120 g of silica gel, CH ₂ Cl ₂ to remove unreacted chloride) followed by 2% MeOH / CH to remove the desired product. Eluted with ₂ Cl ₂ ) to afford the desired amine as a pale yellow effervescent solid (3.50 g, 85%).
[294] Amine (3.33 g, 5.7 mmol) from the stomach in ethanol (30 mL) was treated with hydrazine monohydrate (1.80 g, 36 mmol) and stirred for 3 hours. The mixture was then concentrated in vacuo and purified by flash chromatography (5 cm id., 80 g silica gel, eluted with 5% MeOH / CH ₂ Cl ₂ ) to convert the unprotected amine into a pale yellow foamy solid (1.70 g, 86). Obtained as%).
[295] Amine (1.70 g, 4.86 mmol) from above was dissolved in glacial acetic acid (5 mL) and treated with HCl saturated acetic acid (5 mL). The solution was stirred at room temperature for 5 minutes and then slowly added dropwise with diethyl ether (400 mL) with vigorous stirring. The resulting slurry was suction filtered through a glass frit funnel, the filter cake was washed with diethyl ether (3 × 100 mL) and dried in a vacuum oven at 40 ° C. for 16 hours to give compound 18 as a white solid (2.34 g, 94%). ¹ H NMR (D ₂ O) δ 1.46-1.63 (m, 4H), 1.70-1.87 (m, 1H), 1.97-2.07 (m, 1H), 2.10-2.21 (m, 1H), 2.28-2.38 ( m, 1H), 2.55-2.65 (m, 1H), 2.81-2.90 (m, 3H), 2.91-3.00 (m, 2H), 4.30 (d, 1H, J = 16.3 Hz), 4.41 (d, 1H, J = 16.3 Hz), 4.42-4.48 (m, 1H), 7.48-7.51 (m, 2H), 7.70-7.75 (m, 3H), 8.20 (d, 1H, J = 8.2 Hz), 8.53 (d, 1H , J = 4.5 Hz); ¹³ C NMR (D ₂ O) δ 20.36, 20.43, 21.67, 24.99, 25.24, 27.60, 39.51, 48.29, 51.78, 60.54, 114.46 (2 carbons), 125.63, 126.10 (2 carbons), 132.53, 139.58, 140.16, 147.34, 151.41, 151.81. ES-MS m / z 350 (M + H). Calcd for C ₂₁ H ₂₇ N ₅ .2.5HCl. 2.0H ₂ O. 0.6CH ₃ COOH: C, 52.01; H, 7.06; N, 13.66; Cl, 17.29. Found: C, 52.15; H, 7.09; N, 13.40; Cl, 17.56.
[296] Enantiomeric purity of compound 18 was determined to be 96.7% by chiral HPLC using the following conditions: Instrument: Hewlett Packard 1100 HPLC (VWD1); Column: Chiralpak OD, 0.46 cm × 25 cm; Mobile phase: A: 90:10 hexanes / isopropanol (0.1% DEA), B: isopropanol; Isocratic: 90% A, 10% B; Total running time: 20 minutes; Flow rate: 0.5 ml / min; Temperature: 10 ° C .; Detector: UV @ 270 nm; Injection volume: 20 ml.
[297] Retention time for the S enantiomer = 16.3 min.
[298] Retention time for R enantiomers = 21.9 min.
[299] Example 19
[300]
[301] Compound 19: N ^One-(1-methyl-1H-benzoimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt)
[302] 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione was prepared following the process for compound 18. 2- {4-[(1-Methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -isoindole -1,3-dione was prepared according to the general procedure for reductive amination.
[303] 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione (0.2011 g, 0.58 mmol) in dichloromethane (5.8 mL) To the solution of 1-methyl-1H-benzoimidazole-2-carbaldehyde (0.1844 g, 1.15 mmol) and NaBH (OAc) ₃ (0.2462 g, 1.16 mmol) was added and stirred at room temperature for 4 hours. The organic phase was washed with NaHCO ₃ (2 × 10 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by column chromatography on silica gel (47: 2: 1 CH ₂ Cl ₂ -MeOH-NH ₄ OH) to give 2- {4-[(1-methyl-1H-benzoimidazol-2-ylmethyl) 103 mg (36%) of-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -isoindole-1,3-dione were obtained. ¹ H NMR (CDCl ₃ ) δ 1.30-1.44 (m, 2H), 1.48-1.63 (m, 3H), 1.84-1.96 (m, 2H), 2.03-2.07 (m, 1H), 2.54-2.81 (m , 4H), 3.51 (t, 2H, J = 7.2 Hz), 3.95 (s, 3H), 3.99-4.06 (m, 2H), 4.19 (d, 1H, J = 13.5 Hz), 6.94-6.98 (m, 1H), 7.13-7.21 (m, 2H), 7.24-7.29 (m, 2H), 7.63-7.68 (m, 3H), 7.74-7.78 (m, 2H), 8.40 (d, 1H, J = 3.6 Hz) .
[304] 2- {4-[(1-methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] in ethanol (1 mL) To a solution of -butyl} -isoindole-1,3-dione (0.1030 g, 0.21 mmol) was added hydrazine monohydrate (0.51 mL, 10.5 mmol) and the reaction mixture was stirred at rt for 18 h. The mixture was concentrated and first purified by column chromatography on silica gel (91: 12: 1 CH ₂ Cl ₂ -MeOH-NH ₄ OH), then radial chromatography on silica (18: 1: 1 CH ₂ Cl ₂ -MeOH- purified by NH ₄ OH) to N ¹ - (1- methyl -1H- benzoimidazol-2-ylmethyl) -N ¹ - (5,6,7,8- tetrahydro-quinolin-8-yl) -butane 0.0246 g (32%) of -1,4-diamine were obtained. ¹ H NMR (CDCl ₃ ) δ1.32-1.42 (m, 5H), 1.91-2.02 (m, 2H), 2.05-2.11 (m, 1H), 2.55 (t, 2H, J = 6.9 Hz), 2.60- 2.64 (m, 3H), 2.76-2.86 (m, 1H), 3.98 (s, 3H), 4.04-4.17 (m, 3H), 7.00-7.04 (m, 1H), 7.21-7.27 (m, 2H), 7.30-7.33 (m, 2H), 7.68-7.72 (m, 1H), 8.47 (d, 1H, J = 3.3 Hz).
[305] According to general process D, N ¹ - (1- methyl -1H- benzo imidazole ylmethyl -2-) -N ¹ - (5,6,7,8- tetrahydro-quinolin-8-yl) -butane- 1,4-diamine was chlorided. (1-methyl -1H- benzoimidazol-2-ylmethyl) -N ¹ - - ethyl N ¹ in (0.8㎖) (5,6,7,8- tetrahydro-quinolin-8-yl) -butane- HBr / AcOH (1 mL) is added to a 1,4-diamine (0.0246 g, 0.068 mmol) solution, followed by diethyl ether (50 mL), from which the salt is precipitated. The ether was decanted and the remaining solid was washed with diethyl ether (2 x 50 mL). The remaining diethyl ether was removed in vacuo and methanol (1 mL) was added to the solid. Again diethyl ether (50 mL) was added and the salt was washed with diethyl ether (3 × 50 mL) to afford compound 19 (23 mg, 76%) as a white solid. ¹ H NMR (D ₂ O) δ 1.52-1.53 (m, 4H), 1.73-1.87 (m, 1H), 1.99-2.11 (m, 1H), 2.15-2.19 (m, 1H), 2.40-2.43 ( m, 1H), 2.51-2.58 (m, 1H), 2.78-2.84 (m, 3H), 2.97-2.99 (m, 2H), 3.96 (s, 3H), 4.38 (d, 1H, J = 17.7 Hz) , 4.48-4.54 (m, 1H), 4.59 (d, 1H, J = 17.7 Hz), 7.58-7.61 (m, 2H), 7.75-7.84 (m, 3H), 8.30 (d, 1H, J = 7.8 Hz ), 8.58 (d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) 20.44 (2H), 25.03, 25.44, 27.69,31.52, 39.47, 47.70, 52.18, 60.88, 112.80, 114.22, 125.88, 126.73, 127.12, 130.08, 133.45, 139.32, 140.64, 148.09, 151.13 , 151.68. ES-MS m / z 364 (M + H). Anal. Calcd. for C ₂₂ H ₂₉ N ₅ ^. 3.2HBr ^. 2.2H ₂ 0: C, 39.91; H, 5.57; N, 10.58; Br, 38.62. Found: C, 39.97; H, 5. 44; N, 10.37; Br, 38.49.
[306] Example 20
[307]
[308] Compound 20: N ^One-[5- (4-Fluoro-phenyl) -1 H-imidazol-2-ylmethyl] -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine
[309] 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione was prepared according to General Process B for Reductive Amination. . 5,6,7,8-tetrahydro-quinolin-8-ylamine (1.0609 g, 7.1 mmol) and 4- (1,3-dioxo-1,3-dihydro-iso in methylene chloride (64 mL) To a solution of indol-2-yl) -butyraldehyde (1.4079 g, 6.8 mmol) (prepared according to the process for compound 18) was added NaBH (OAc) ₃ (4.07 g, 19.2 mmol) and 2 h at room temperature. Was stirred. The reaction was quenched with 1N NaOH (45 mL), extracted with methylene chloride (2 × 55 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by column chromatography on silica gel (40: 1: 1 CH- ₂ Cl ₂ -MeOH-NH ₄ OH) to give 2- [4- (5,6,7,8-tetrahydro-quinoline-8- 1.16 g (52%) of monoamino) -butyl] -isoindole-1,3-dione were obtained. ¹ H NMR (CDCl ₃ ) δ 1.57-1.66 (m, 3H), 1.69-1.84 (m, 4H), 1.93-2.03 (m, 1H), 2.07-2.13 (m, 1H), 2.69-2.86 (m , 4H), 3.70-3.77 (m, 3H), 7.03-7.07 (m, 1H), 7.35 (d, 1H, J = 7.2 Hz), 7.67-7.73 (m, 2H), 7.80-7.85 (m, 2H ), 8.37 (d, 1H, J = 3 Hz).
[310] To a solution of 4- (4-fluoro-phenyl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbaldehyde (0.2301 g, 0.72 mmol) in methylene chloride (7.2 mL) 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione (0.3030 g, 0.87 mmol) followed by NaBH (OAc) ₃ (0.3060 g, 1.44 mmol) was added and the reaction mixture was stirred at rt for 4 days. The reaction was quenched with saturated NaHCO ₃ (6 mL), extracted with CH ₂ Cl ₂ (2 × 25 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (50: 1: 1 CH- ₂ Cl ₂ -MeOH-NH ₄ OH) to give 2- {4-[[5- (4-fluoro-phenyl) -1- ( 2-trimethylsilanyl-ethoxymethyl) -1H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -isoindole- 0.3125 g (66%) of 1,3-dione were obtained. ¹ H NMR (CDCl ₃ ) δ 0.82-0.87 (m, 2H), 1.25-1.37 (m, 2H), 1.48-1.69 (m, 10H), 1.88-2.08 (m, 3H), 2.56-2.82 (m , 4H), 3.38-3.44 (m, 2H), 3.53 (t, 2H, J = 7.2 Hz), 3.96 (s, 2H), 4.01-4.04 (m, 1H), 5.56 (d, 1H, 10.8 Hz) , 5.79 (d, 1H, J = 10.5 Hz), 6.97-7.03 (m, 3H), 7.12 (s, 1H), 7.30 (d, 1H, J = 7.5 Hz), 7.61-7.70 (m, 4H), 7.75-7.79 (m, 2 H), 8.44 (d, 1 H, J = 4.5 Hz).
[311] 2- {4-[[5- (4-fluoro-phenyl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazol-2-ylmethyl]-in ethanol (5 mL) Hydrazine monohydrate (0.12 ml) in a (5,6,7,8-tetrahydro-quinolin-8-yl) -amino]-butyl} -isoindole-1,3-dione (0.3125 g, 0.48 mmol) solution Was added and the reaction mixture was stirred at rt for 17 h. The reaction mixture was concentrated and purified by column chromatography on silica gel (20: 1: 1 CH ₂ Cl ₂ -MeOH-NH ₄ OH) to give N ^1- [5- (4-fluoro-phenyl) -1- ( 2-trimethylsilanyl-ethoxymethyl) -1H-imidazol-2-ylmethyl] -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4- 0.1838 g (73%) of diamine was obtained. ¹ H NMR (CDCl ₃ ) δ 0.85 (t, 2H, J = 8.1 Hz), 1.25-1.34 (m, 7H), 1.61-1.72 (m, 1H), 1.89-2.05 (m, 4H), 2.54- 2.82 (m, 8H), 3.35-3.47 (m, 3H), 3.93 (s, 2H), 4.06 (t, 1H, J = 8.1 Hz), 5.53 (d, 2H, J = 10.5 Hz), 5.78 (d , 2H, J = 10.8 Hz), 6.99-7.04 (m, 3H), 7.15 (s, 1H), 7.31 (d, 1H, J = 7.5 Hz), 7.66-7.70 (m, 2H), 8.47 (d, 1H, J = 3.6 Hz).
[312] N ^1- [5- (4-fluorophenyl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazol-2-ylmethyl] -N1- (5 in methylene chloride (5 mL) TFA (5 mL) was added to 6,7,8-tetrahydro-quinoline-8-l) -butane-1,4-diamine (0.1838 g, 0.35 mmol) and stirred at room temperature for 3 days. The mixture was concentrated, dissolved in CH ₂ C1 ₂ and neutralized with 10N NaOH. The aqueous phase was extracted with CH ₂ C1 ₂ (4 times) and the combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by column chromatography on silica gel (15: 1: 1 CH ₂ C1 ₂ MeOH-NH ₄ OH) followed by radial chromatography on silica (15: 1: 1 CH ₂ C1 ₂ MeOH-NH ₄ OH) gave compound 20 (0.0421 g, 31%) as an orange oil. ¹ H NMR (CDC1 ₃ ) δ1,25-1.43 (m, 4H), 1.62-1.75 (m, 1H), 1.84-1.92 (m, 1H), 1.96-2.05 (m, 1H), 2.13-2.15 (m , 1H), 2.44-2.50 (m, 3H), 2.63-2.73 (m, 2H), 2.79-2.89 (m, 1H), 3.87 (s, 1H), 3.99-4.04 (m, 2H), 7.04 (t , 2H, J = 9Hz), 7.10-7.14 (m, 1H), 7.23 (s, 1H), 740 (d, 1H, J = 7.5Hz), 7.65-7.70 (m, 2H), 8.50 (d, 1H , J = 4.2 Hz); ¹³ C NMR (CDC1 ₃ ) δ 21.70, 23.02, 26.37, 29.57, 30.17, 41.44, 49.02, 50.72, 61.70, 115.83 (d, 2C, J = 14.34 Hz), 122.49, 126.43 (d, 2C, J = 5.18 Hz), 130.26, 135.01, 137.74, 147.14 (2C), 149.64, 157.77, 160.34, 163.58. ES-MS m / z 394 (M + H). Calcd for C ₂₃ H ₂₈ N ₅ F.1.3CH ₂ Cl ₂ : C, 70.20; H, 7. 17; N, 17.80. Found: C, 58.09; H, 6. 23; N, 13.59.
[313] Example 21
[314]
[315] Compound 21: N '(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -N-benzyl-1,4-butanediamine (hydrobromide salt Manufacturing
[316] N '(1- (2-trimethylsilyl) -ethane-1yloxymethyl) -benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8 in methanol (4 mL) To a solution of -yl) -1,4-butanediamine (70 mg, 0.15 mmol) was added benzaldehyde (0.015 mL, 0.15 mmol). The mixture was stirred at rt overnight and then cooled to 0 ° C. Then sodium borohydride (38 mg, 1.0 mmol) was added, the reaction was stirred for 1 h and gradually warmed to room temperature. Then the solution was concentrated. The residue was dissolved in dichloromethane, washed with 1N sodium hydroxide (3 mL), dried over anhydrous sodium sulfate, concentrated and purified by chromatography on silica gel (10: 1 dichloromethane: methanol) to N '(1--1). (2-trimethylsilyl) -ethan-1yloxymethyl) -benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -N-benzyl-1,4-butane Diamine (39 mg, 49%) was obtained. ¹ H NMR (CDCl ₃ ) δ0.10 (s, 9H), 0.80 (t, 2H, J = 7.0 Hz), 1.41 (m, 3H), 1.76-2.21 (m, 5H), 2.44 (m, 2H) , 2.46-2.26 (m, 2H), 3.35 (t, 2H, J = 7.0 Hz), 3.67 (s, 2H), 4.06 (m, 1H), 4.08 (d, 1H, J = 15.8 Hz), 4.22 ( d, 1H, J = 15.8 Hz, 5.80 (d, 1H, J = 14.6 Hz), 6.02 (d, 1H, J = 14.6 Hz), 7.00 (m, 1H), 7.27 (m, 8H), 7.42 ( m, 1H), 7.80 (m, 1H), 8.44 (d, 1H, J = 4.8 Hz).
[317] A saturated solution of HBr in acetic acid (1 mL) was added while dissolved in acetic acid (1 mL). The mixture was then stirred, precipitated and separated as in process D to give compound 21 as a white crystalline solid (26 mg). ¹ H NMR (D ₂ O). δ 1.52 (m, 4H), 1.88 (m, 1H), 2.01 (m, 1H), 2.08 (m, 1H), 2.31 (m, 1H), 2.44 (m, 1H), 2.88 (m, 1H) , 3.00 (t, 2H, J = 6.9 Hz), 3.03 (m, 2H), 4.13 (s, 1H), 4.31 (d, 1H, J = 16.1 Hz), 4.47 (m, 1H), 4.49 (d, 1H, J = 16.1 Hz), 7.36 (m, 5H), 7.60 (m, 2H), 7.77 (m, 2H), 7.83 (m, 1H), 8.26 (d, 1H, J = 7.8 Hz), 8.68 ( d, 1H, J = 4.9 Hz). ¹³ C NMR (D ₂ O) δ 20.41, 23.68, 25.45, 27.63, 46.86, 48.24, 51.34, 51.57, 60.63, 114.25, 125.93, 126.95, 129.66, 130.08, 130.17, 130.98, 139.30, 140.60, 148.10, 151, 24, 151.77. ES-MS m / z 440 (M + H); Calcd for (C ₂₈ H ₃₃ N ₅ x 3.1 HBr x 1.4 H ₂ O): C, 46.99; H, 5. 48; N, 9.79; Br 34.61. Found: C, 47.00; H, 5. 44; N, 9.54; Br, 34.57.
[318] Example 22
[319]
[320] Compound 22: N ^One-(1H-benzimidazol-2-ylmethyl) -N ⁴-Pyridin-2-ylmethyl-N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt)
[321] Using General process B (step 2 reductive amination): N ¹ - (ethoxy-methyl-1- (2- (trimethylsilyl)) -1H- benzimidazol-2-ylmethyl) -N ¹ - (5,6 , 7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (101 mg, 0.21 mmol) was pyridine-2-carboxaldehyde (30 mL, 0.32) in CH ₃ OH (4 mL). mmol) for 6 h, NaBH ₄ (35 mg, 0.92 mmol) for 40 min, and then the crude material was subjected to radial chromatography on silica gel (1 mm plate, 20: 1: 1 CH ₂ Cl ₂ -CH _3). OH-NH ₄ OH) afforded 84 mg (70%) of a colorless oil. Oil from the stomach (84 mg, 0.15 mmol) was dissolved in 6N HCl (2 mL), heated at 50 ° C. for 4.5 h and cooled to room temperature. The solution was treated with 10N NaOH (2 mL) and extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel radial chromatography (1 mm plate, 10: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 41 mg (63%) of the free base of the title compound as a colorless oil. .
[322] General Process D Use: Oil (41 mg, 0.092 mmol) from the stomach was converted to a hydrobromide salt and then reprecipitated intermediate solids from methanol / ether to give compound 22 (72 mg, 93%) as a white solid. . ¹ H NMR (D ₂ O) δ 1.50-1.66 (m, 4H), 1.79-1.89 (m, 1H), 1.96-2.08 (m, 1H), 2.15-2.20 (m, 1H), 2.35-2.39 ( m, 1H), 2.50-2.60 (m, 1H), 2.80-2.88 (m, 1H), 3.00-3.10 (m, 4H), 4.36-4.56 (m, 5H), 7.58-7.63 (m, 2H), 7.72-7.88 (m, 5H), 8.22 (dt, 1H, J = 1.5, 7.8 Hz), 8.35 (d, 1H, J = 8.1 Hz), 8.62 (d, 1H, J = 5.7 Hz), 8.66 (d , 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 20.43 (2 carbons), 23.77, 25.43, 27.65, 47.86, 48.23, 49.66, 51.64, 60.64, 114.26, 125.94, 126.42, 126.54, 126.95, 130.97, 139.33, 140.62, 143.16, 146.99, 148.09, 148.11, 151.23, 151.76. ES-MS m / z 441 (M + H). Calcd for C ₂₇ H ₃₂ N ₆ .4.0HBr.3.7H ₂ O: C, 39.03; H, 5. 26; N, 10.11; Br, 38.47. Found: C, 39.04; H, 5. 22; N, 10.04; Br, 38.52.
[323] Example 23
[324]
[325] Compound 23: N ^One-(1H-benzimidazol-2-ylmethyl) -N ⁴-(1H-indol-3-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (free base).
[326] CH ₂ Cl ₂ (2㎖) of N ¹ - (ethoxy-methyl-1- (2- (trimethylsilyl)) -1H- benzimidazol-2-ylmethyl) -N ¹ - (5,6,7,8 Trifluoroacetic acid (4 mL) was added to a solution of -tetrahydro-quinolin-8-yl) -butane-1,4-diamine (73 mg, 0.16 mmol), and the resulting solution was stirred at room temperature overnight, Concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (10 mL) and (5 mL) and treated with NaOH (10 M, ˜2 mL) until the aqueous phase became basic (pH 14). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel radial chromatography (1 mm plate, 15: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give N ^1- (1H-benzimidazol-2-ylmethyl) -N ¹ to give the butane-1,4-diamine as a white foam 37㎎ - (5,6,7,8-tetrahydro-quinolin-8-yl).
[327] Use General Process B (2-Step Reductive Amination): N ^1- (1H-benzimidazol-2-ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) Butane-1,4-diamine (86 mg, 0.25 mmol) was reacted with indole-3-carboxaldehyde (55 mg, 0.38 mmol) in CH ₃ OH (2.5 mL) for 30 minutes, and then the crude material was silica. Purification by gel phase chromatography (1 mm plate, 50: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) gave 74 mg (60%) of compound 23 as a white solid. ¹ HNMR (CDCl ₃ ) δ 1.38-1.52 (m, 4H), 1.64-1.73 (m, 1H), 1.83-1.95 (m, 1H), 2.00-2.05 (m, 1H), 2.15-2.21 (m, 1H), 2.49-2.56 (m, 3H), 2.67-2.89 (m, 3H), 3.88 (s, 2H), 3.96-4.10 (m, 3H), 7.03 (br s, 1H), 7.07-7.13 (m , 2H), 7.16-7.22 (m, 3H), 7.35 (dd, 1H, J = 7.8, 1.0 Hz), 7.40 (d, 1H, J = 7.8 Hz), 7.58-7.60 (m, 3H), 8.17 ( br s, 1 H), 8.55 (d, 1 H, J = 4.5 Hz); ¹³ C NMR (CDCl ₃ ) δ 21.79, 23.58, 26.53, 27.64, 29.64, 44.94, 49.34, 49.88, 50.59, 61.83, 111.66, 114.88, 118.99, 119.72, 121.96, 122.29, 122.51, 123.13, 127.42, 135.05,136. , 137.72, 147.10, 156.87, 157.83. ES-MS m / z 479 (M + H). Calcd for C ₃₀ H ₃₄ N ₆ .1.3 H ₂ O: C, 71.77; H, 7. 35; N, 16.74. Found: C, 71.69; H, 7.14; N, 16.59.
[328] Example 24
[329]
[330] Compound 24: (1H-benzimidazol-2-ylmethyl)-(3-piperidin-2-yl-propyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (hydrobromide Salts).
[331] Paring a mixture of 3- (2-pyridyl) -1-propanol (0.75 mL, 5.83 mmol), PtO ₂ (60 mg, 0.26 mmol) and concentrated HCl (0.48 mL, 5.86 mmol) in ethanol (3.1 mL) Hydrogenated at room temperature for 20 hours (50 psi). The mixture was filtered through celite and the cake was washed with methanol. The solvent was removed from the filtrate under reduced pressure to yield 1.34 g of a white slush solid. Solid (1.34 g) was dissolved in THF (30 mL) and water (1 mL), N, N-diisopropylethylamine (2.0 mL, 11.42 mmol) and di-tert-butyl dicarbonate (2.16 g, 9.89 mmol) and the resulting mixture was stirred at rt overnight. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 60 mL). The combined organic extracts were washed with brine (2 × 20 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (2: 1 hexane-ethyl acetate) to give 1.38 g (3- (N-tert-butoxycarbonyl-3-piperidin-2-yl-propan-1-ol) 97%) from 2-pyridyl) -1-propanol was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ1.40-2.04 (m, 20H), 2.75 (t, 1H, J = 12 Hz), 3.66-3.69 (m, 1H), 3.94-3.96 (m, 1H), 4.25 (br s, 1 H).
[332] Into a solution of N-tert-butoxycarbonyl-3-piperidin-2-yl-propan-1-ol (0.372 g, 1.53 mmol) in CH ₂ Cl ₂ (7.5 mL) at room temperature 3 μg molecular seeds (0.814 g) ), N-methylmorpholine N-oxide (0.278 g, 2.37 mmol) and tetrapropylammonium perruthenate (56 mg, 0.16 mmol) were added successively. After 90 minutes, the mixture was filtered through a short column of silica gel and the cake washed with ethyl acetate. The solvent was removed from the filtrate under reduced pressure to yield 0.32 g (86%) of N-tert-butoxycarbonyl-3-piperidin-2-yl-propionaldehyde as a green oil, which was used without further purification. .
[333] General process B use: N-tert-butoxycarbonyl-3-piperidin-2-yl-propionaldehyde (0.32 g, 1.33 mmol) and (1H-benzimidazol-2-ylmethyl)-(5, 6,7,8-tetrahydro-quinolin-8-yl) -amine (0.307 g, 1.10 mmol) was added to NaBH (OAc) ₃ (0.448 g, 2.11 mmol) in CH ₂ Cl ₂ (10 mL) for 16 h. After the reaction, the crude material was purified by column chromatography on silica gel (30: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 0.285 g of a yellow foam. The foam (0.285 g) was dissolved in THF (10 mL), treated with 3N HCl (10 mL) and the resulting solution was stirred at room temperature for 75 minutes. The pH of the solution was adjusted to ˜14 with 10N NaOH (˜4 mL). The solution was extracted with CH ₂ Cl ₂ (4 × 30 mL) and the combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (25: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 0.176 g (40%) of the free base of the title compound as a white foam.
[334] General Process D Use: The foam from the stomach (69 mg, 0.17 mmol) was converted to a hydrobromide salt and then reprecipitated the intermediate solid from methanol / ether to give compound 24 (79 mg, 67%) as a white solid. . NMR and HPLC analysis showed a ˜1: 1 mixture of diastereomers. ¹ H NMR (D ₂ O) δ 1.18-1.53 (m, 7H), 1.78-1.84 (m, 4H), 1.96-2.08 (m, 1H), 2.15-2.20 (m, 1H), 2.35-2.40 ( m, 1H), 2.49-2.56 (m, 1H), 2.81-3.00 (m, 5H), 3.28-3.32 (m, 1H), 4.35-4.56 (m, 3H), 7.59-7.62 (m, 2H), 7.79-7.89 (m, 3H), 8.34 (br d, 1H, J = 7.8 Hz), 8.63 (br d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 20.42 (2 carbons), 21.82, 22.22, 24.03, 27.64, 28.23, 31.02 & 31.11, 45.11, 48.13 & 48.24, 51.76 & 51.88, 56.76 & 56.83, 60.59 & 60.71, 114.25, 125.94, 126.97, 130.99, 139.31, 140.65, 148.11, 151.26, 151.75. ES-MS m / z 404 (M + H). Calcd for C ₂₅ H ₃₃ N ₅ 3.0HBr 3.2H ₂ O: C, 42.66; H, 6.07; N, 9.95; Br, 34.05. Found: C, 42.47; H, 5. 82; N, 9.78; Br, 34.43.
[335] Example 25
[336]
[337] Compound 25: 4-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyraldehyde aminoguanidine hydrazone ( Hydrobromide salts)
[338] General process B use: 4-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino]-in anhydrous MeOH (4 mL) To a stirred solution of butyraldehyde (see Compound 32 for preparation) (0.2182 g, 0.63 mmol) and aminoguanidine hydrochloride (69 mg, 0.63 mmol) was added AcOH (75 mL, 1.26 mmol) and the mixture was allowed to stand at room temperature. Stir for 3 hours. The reaction was concentrated and the residue was partitioned between CH ₂ Cl ₂ (20 mL) and saturated aqueous NaHCO ₃ (30 mL), the phases separated and the aqueous layer extracted with CH ₂ Cl ₂ (2 × 15 mL). . The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude material was purified by silica gel radial chromatography (1 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, 20: 1: 1 and then 10: 1: 1) to afford the desired aminoguanidine hydrazone (69 mg, 30 %) Was obtained as a pale yellow foam.
[339] Use General Process D: Convert foam (69 mg, 0.17 mmol) from above into hydrobromide salt and then reprecipitate intermediate solid from methanol / ether to make compound 25 (93 mg, 76%) as a beige solid Obtained. ¹ H NMR (D ₂ O) δ1.54-1.77 (m, 2H), 1.78-1.94 (m, 1H), 1.95-2.11 (m, 1H), 2.12-2.31 (m, 3H), 2.32-2.44 ( m, 1H), 2.45-2.62 (m, 1H), 2.79-2.91 (m, 1H), 2.96-3.08 (m, 2H), 4.35 (d, 1H, J = 16.5 Hz), 4.50 (d, 1H, J = 16.5 Hz), 4.51-4.59 (m, 1H), 7.32 (t, 1H, J = 5.1 Hz), 7.58-7.64 (m, 2H), 7.77-7.81 (m, 2H), 7.88 (dd, 1H) , J = 7.8, 5.7 Hz), 8.36 (d, 1H, J = 7.8 Hz), 8.65 (d, 1H, J = 9.6 Hz); ¹³ C NMR (D ₂ O) δ 20.40, 23.75, 27.69, 29.09, 48.45, 50.79, 60.42, 114.20, 125.88, 126.99, 130.98, 139.35, 140.72, 148.06, 151.35, 151.79, 152.94. ES-MS m / z 405 (M + H). Calcd for C ₂₂ H ₂₈ N ₈ .3.1HBr.1.4H ₂ O.0.4C ₄ H ₁₀ O: C, 39.91; H, 5. 38; N, 15.78; Br, 34.88. Found: C, 39.89; H, 5.29; N, 15.84; Br, 34.94.
[340] Example 26
[341]
[342] Compound 26: 1-N '[4- (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -aminobutane-N, N-dimethylform Preparation of amidine (hydrobromide salt)
[343] L. 2-pyridinesulfonyl chloride (56 mg) in DMF (1 mL) using the process of L. Cai (Y. Han and L. Cai Tetrahedron Lett. 1997, 38 (31), 5423-5426). , 0.32 mmol) was stirred at room temperature for 10 minutes. N '(1H-benzimidazol-2-ylmethyl) -N ^' (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (73 mg, 0.21 mmol) was added and the mixture was stirred at rt for 2 h. The DMF was then removed in vacuo and the residue dissolved in dichloromethane and washed successively with saturated aqueous sodium carbonate solution followed by distilled water. The organic fractions were then dried over anhydrous sodium sulfate and concentrated. The residue was then purified by silica gel flash chromatography to give two products: 1-N '[4- (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro Quinolin-8-yl) -amino] -aminobutane-N, N-dimethylformamidine (51 mg, 59%) and N ^' (1H-benzimidazol-2-ylmethyl) -N ^' (5,6 , 7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine-N- (2-pyridinyl) -sulfonamide (31 mg, 29%). The spectral data for formamidine are as follows: ¹ H NMR (CDCl ₃ ) δ 1.38-1.44 (m, 4H), 1.68 (m, 1H), 2.00 (m, 1H), 2.15 (m, 1H) , 2.35 (m, 1H), 2.66-3.01 (m, 4H), 3.01 (s, 6H), 3.16 (t, 2H, J = 6.9 Hz), 4.05 (s, 2H), 4.12 (m, 1H), 7.18 (m, 2H), 7.46 (m, 1H), 7.58 (m, 2H), 8.53 (m, 1H). Since sulfonamides show excessive expansion of resonance in the ¹ H NMR spectrum (CDCl ₃ ), they are not fully characterized at this stage and instead are transferred directly to the chlorination reaction.
[344] 1-N '[4- (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -aminobutane-N, N-dimethylform Amidine (49 mg, 0.120 mmol) was dissolved in acetic acid (1 mL), and thereto was added a saturated HBr solution in acetic acid (1 mL). The mixture was then stirred, precipitated and separated for process D to afford compound 26 as a white crystalline solid (52 mg). ¹ H NMR (D ₂ O). δ 1.39 (m, 4H), 1.85 (m, 1H), 2.01 (m, 1H), 2.15 (m, 1H), 2.36 (m, 1H), 2.53 (m, 1H), 2.78 (m, 1H) , 2.85 (s, 3H), 3.00 (m, 2H), 3.07 (s, 3H), 3.25 (t, 2H, J = 6.9 Hz), 4.46 (d, 1H, J = 16.8 Hz), 4.51 (m, 1H), 4.52 (d, 1H, J = 16.8 Hz), 7.60 (m, 2H), 7.65 (s, 1H), 7.80 (m, 2H), 7.87 (dd, 1H, J = 7.8, 5.8 Hz), 8.35 (d, 1H, J = 7.8 Hz), 8.63 (d, 1H, J = 5.8 Hz). ¹³ CNMR (D ₂ O) δ 22.89, 23.27, 27.81, 30.10, 38.38, 45.57, 49.52, 51.21, 54.51, 63.61, 116.70, 128.35, 129.43, 133.35, 141.73, 143.03, 150.53, 153.75, 154.54, 158.63. ES-MS m / z 405 (M + H); Calcd for (C ₂₄ H ₃₂ N ₆ x 3.3 HBr x 1.8 H ₂ O): C, 40.95; H, 5.57; N, 11.94; Br 37.46. Found: C, 40.77; H, 5.59; N, 11.78; Br, 37.72.
[345] Example 27
[346]
[347] Compound 27: N- {4-[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -guanidine (hydrobromide salt) Manufacture
[348] THF (0.2㎖) of N ¹ - (5,6,7,8- tetrahydro-quinolin-8-yl) -N ¹ - [1- (2- trimethylsilanyl-ethoxymethyl) -1H- benzoimidazol Dazol-2-ylmethyl] -butane-1,4-diamine (170 mg, 0.35 mmol), 1-H-pyrazole-1-carboxamidine hydrochloride (51 mg, 0.35 mmol) and DIPEA (61 mL) , 0.35 mmol) was stirred at room temperature for 3 hours. Ether (1 × 10 mL and 3 × 5 mL) was added and decanted. The syrup obtained was dried under vacuum to give a white foam (150 mg) which was used for the next reaction without further purification.
[349] Guanidine (150 mg) solution from the stomach in 6N HCl (5 mL) was heated to 50 ° C. for 4 h. The reaction mixture was cooled to rt, H ₂ O (5 mL) was added, the mixture was neutralized with NaHCO ₃ (s) and saturated with NaCl (s). The aqueous layer was extracted with CHCl ₃ (3 × 50 mL) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 20: 2: 1) gave the desired guanidine as a light yellow foam (63 mg, 46% over two steps).
[350] General Process D Use: The foam from above was converted to the hydrobromide salt to give compound 27 as a light beige solid. ¹ H NMR (D ₂ O) δ 1.40 (br s, 4H), 1.81-1.90 (m, 1H), 1.98-2.10 (m, 2H), 2.34-2.38 (m, 1H), 2.48-2.54 (m , 1H), 2.74-2.83 (m, 1H), 2.99-3.03 (m, 4H), 4.44 (d, 1H, J = 10.8 Hz), 4.51-4.63 (m, 2H), 7.57-7.63 (m, 2H ), 7.77-7.82 (m, 2H), 7.87 (dd, 1H, J = 7.8, 6.0 Hz), 8.35 (d, 1H, J = 8.1 Hz), 8.64 (d, 1H, J = 5.5 Hz); ¹³ C NMR (D ₂ O) δ 20.45, 25.52, 26.10, 27.66, 41.01, 48.97, 51.89, 61.17, 114.27, 125.92, 126.92, 131.04, 139.29, 140.50, 148.04, 151.41, 152.03, 156.91. ES-MS mlz 392.3 (M + H). Calcd for C ₂₂ H ₂₉ N ₇ .3.1HBr.1.2H ₂ O.0.3C ₄ H ₁₀ O: C, 40.61; H, 5.51; N, 14.29; Br, 36.10. Found: C, 40.92; H, 5. 31; N, 14.28; Br, 35.70.
[351] Example 28
[352]
[353] Compound 28: N '(1H-benzimidazol-2-ylmethyl) -N' (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine-N- ( Preparation of 2-pyridinyl) -sulfonamide (hydrobromide salt)
[354] N '(1H-benzimidazol-2-ylmethyl) -N' (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine-N- (2-pyri Dinyl) -sulfonamide (from the above reaction, 31 mg, 0.063 mmol) was dissolved in acetic acid (1 mL), and a saturated solution of HBr in acetic acid (1 mL) was added. The mixture was then stirred, precipitated and separated for process D to afford compound 28 as a white crystalline solid (52 mg). ¹ H NMR (D ₂ O) δ 1.30 (m, 4H), 1.81 (m, 1H), 1.91 (m, 1H), 2.05 (m, 1H), 2.31 (m, 1H), 2.43 (m, 1H ), 2.79 (m, 1H), 2.83 (t, 2H, J = 6.9 Hz), 3.00 (m, 2H), 4.31 (d, 1H, J = 16.3 Hz), 4.49 (m, 1H), 4.51 (d , 1H, J = 16.3 Hz, 7.57 (m, 2H), 7.86 (m, 2H), 7.83 (m, 2H), 8.00 (t, 2H, J = 7.8 Hz), 8.32 (d, 1H, J = 7.8 Hz), 8.56 (d, 1H, J = 4.9 Hz), 8.68 (d, 1H, J = 5.4 Hz). ¹³ C NMR (D ₂ O) δ 20.43, 20.81, 24.95, 26.54, 27.64, 42.44, 48.80, 51.47, 60.94, 114.26, 122.86, 125.92, 126.91, 128.36, 130.97, 139.30, 140.08,140.48, 140.06, 150.22, 151.40, 152.00. ES-MS m / z 491 (M + H); Calcd for (C ₂₆ H ₃₀ N ₆ 0 ₂ S x 3.1 HBr x 1.7 H ₂ O x 0.9 HOAc): C, 40.42; H, 4.89; N, 10.17; Br 29.98. Found: C, 40.31; H, 4.98; N, 10.13; Br, 30.22.
[355] Example 29
[356]
[357] Compound 29: N- (1H-benzoimidazol-2-ylmethyl) -N'pyrimidin-2-ylmethyl-N- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane Preparation of -1,4-diamine (hydrobromide salt).
[358] Pyrimidine-2-carbaldehyde was added to compound 68 using pyrimidine-2-carboxylic acid methyl ester (255 mg, 1.85 mmol), THF (18 mL) and LiAlH ₄ (1.0 M / THF, 0.55 mL, 0.55 mmol). It was prepared as described for. The crude material (332 mg) was determined to be a mixture of pyrimidine-2-carbaldehyde, pyrimidine-2-carboxylic acid methyl ester and THF (1.0: 12.6: 6.0, respectively) by ¹ H NMR, which was further purified It was used in the next step without.
[359] General Process B Use: Crude aldehyde (332 mg) and N '(1H-benzoimidazol-2-ylmethyl) -N' (5,6,7,8-tetrahydro- from stomach in THF (2 mL) To a solution of quinolin-8-yl) -butane-1,4-diamine (49 mg, 0.14 mmol) was added NaBH (OAc) ₃ (89 mg, 0.42 mmol) and the mixture was stirred at rt for 1.5 h. The crude material was dissolved in saturated HBr / AcOH (2 mL) and stirred at room temperature for 5 minutes. The solution was made basic with 10N NaOH (aq) and extracted with CH ₂ Cl ₂ (3 × 15 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo The crude was purified by column chromatography on silica gel (200: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give a yellow oil (44 mg). Obtained.
[360] General Process D Use: The oil from the stomach (44 mg, 0.10 mmol) was converted to a hydrobromide salt and then reprecipitated the intermediate solid from methanol / ether to give compound 29 (68 mg, 84%) as a colorless solid. . ¹ H NMR (D ₂ O) δ 1.64-1.93 (m, 5H), 2.07 (m, 1H), 2.22 (m, 1H), 2.42 (m, 1H), 2.61 (m, 1H), 2.89 (m , 1H), 3.04 (m, 2H), 3.15 (m, 2H), 4.41-4.61 (m, 5H), 7.53 (t, 1H, J = 5.1 Hz), 7.63 (m, 2H), 7.87 (m, 3H), 8.38 (d, 1H, J = 8.1 Hz), 8.67 (d, 1H, J = 5.7 Hz), 8.80 (d, 2H, J = 5.1 Hz); ¹³ C NMR (D ₂ O) δ 20.44, 23.80, 25.46, 27.66, 47.61, 48.30, 51.00, 51.68, 60.67, 114.27, 121.65, 125.94, 126.94, 130.95, 139.35, 140.62, 148.12, 151.24, 151.78, 158.37, 160.71. ES-MS m / z 442 (M + H). Calcd for C ₂₆ H ₃₁ N ₇ .4.0HBr. 3.2H ₂ O: C, 37.95; H, 5.07; N, 11.92; Br, 38.84. Found: C, 38.20; H, 5.04; N, 11.77; Br, 38.61.
[361] Example 30
[362]
[363] Compound 30: N- (1H-benzoimidazol-2-ylmethyl) -N '(1H-imidazol-2-yl) -N- (5,6,7,8-tetrahydro-quinolin-8-yl Preparation of) -butane-1,4-diamine.
[364] To a partially dissolved solution of 2-aminoimidazole sulfate (200 mg, 1.51 mmol) in MeOH (2 mL) was added NaOH (s) (65 mg, 1.59 mmol) and the mixture was stirred at rt overnight. The mixture was diluted with CH ₂ Cl ₂ (20 mL), dried (MgSO ₄ ) and filtered through celite. The cake was washed with CH ₂ Cl ₂ / MeOH (10: 1) and the filtrate was concentrated under reduced pressure to give brown syrup (115 mg) which was used in the next reaction without further purification.
[365] Amine (39 mg, 0.47 mmol) from the stomach in MeOH (1.5 mL) and 4-{[1- (tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5, A solution of 6,7,8-tetrahydro-quinolin-8-yl) -amino} butyraldehyde (see Compound 32 for preparation) (100 mg, 0.22 mmol) was stirred at 40 ° C. for 3 days. NaBH ₄ (17 mg, 0.44 mmol) was added and the resulting mixture was stirred for an additional 15 minutes. The reaction mixture was diluted with CH ₂ Cl ₂ , filtered through celite and the cake washed with CH ₂ Cl ₂ . The combined filtrates were concentrated under reduced pressure. The crude orange foam was purified by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 50: 2: 1) followed by radial chromatography on silica gel (1 mm plate, EtOAc / MeOH / NH ₄ OH, 100). : 3: 1) to give compound 30 (32 mg, 35%) as a light purple foam. ¹ H NMR (CDCl ₃ ) δ1.32-1.75 (m, 5H), 1.83-1.95 (m, 1H), 2.02-2.10 (m, 1H), 2.17-2.21 (m, 1H), 2.51-2.91 (m , 4H), 3.05-3.09 (m, 2H), 3.98-4.11 (m, 3H), 4.31 (br s, 1H), 6.61 (s, 2H), 7.12-7.16 (m, 1H), 7.18-7.23 ( m, 2H), 7.43 (d, 1H, J = 7.2 Hz), 7.56 (br s, 2H), 8.52 (d, 1H, J = 3.3 Hz); ¹³ C NMR (CDCl ₃ ) δ 21.12, 23.92, 25.24, 27.29, 29.14, 43.55, 49.17, 50.22, 62.13, 114.93, 117.27, 121.89, 122.34, 134.91, 137.65, 146.48, 150.88, 156.09, 157.26. ES-MS mlz 416.3 (M + H). Calcd for C ₂₄ H ₂₉ N ₇ .0.9H ₂ O.0.3C ₄ H ₈ O ₂ : C, 66.06; H, 7. 30; N, 21.40. Found: C, 66.12; H, 7. 32; N, 21.34.
[366] Example 31
[367]
[368] Compound 31: N ^One-(1H-benzimidazol-2-ylmethyl) -N ⁴-(1H-indol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine
[369] Indole-2-carboxaldehyde (prepared as described for compound 65) (31 mg, 0.21 mmol) and N ^1- (1H-benzimidazol-2-ylmethyl) -N in MeOH (1.8 mL) ^{A solution of 1-} (5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine (see compound 17) (51 mg, 0.15 mmol) was stirred at room temperature under nitrogen for 23 hours. It was. NaBH ₄ (14 mg, 0.37 mmol) was added and the reaction stirred for an additional 15 minutes, then the solvent was evaporated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (25 mL) and washed with saturated aqueous NaHCO ₃ (5 mL) and brine (5 mL). The organic solution was dried (MgSO ₄ ), filtered and evaporated under reduced pressure. The yellow residue was purified by column chromatography on flash silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 19: 1: 0.1) to give compound 31 as a white solid (37 mg, 0.077 mmol, 53%). ¹ H NMR (CDCl ₃ ) δ 1.35-1.49 (m, 4H), 1.60-1.76 (m, 1H), 1.81-1.96 (m, 1H), 1.96-2.08 (m, 1H), 2.11-2.22 (m , 1H), 2.45 (t, 2H, J = 6.5 Hz), 2.50-2.60 (m, 1H), 2.66-2.76 (m, 2H), 2.76-2.90 (m, 1H), 3.83 (s, 2H), 3.93-4.10 (m, 3H), 6.27 (s, 1H), 7.02-7.16 (m, 3H), 7.16-7.24 (m, 2H), 7.32 (d, 1H, J = 7.8 Hz), 7.41 (d, 1H, J = 7.8 Hz, 7.53 (d, 1H, J = 7.8 Hz), 7.55-7.62 (m, 2H), 8.56 (d, 1H, J = 3.6 Hz), 9.01 (br. S, 1H). ¹³ C NMR (CDCl ₃ ) δ 21.6, 23.8, 26.2, 27.5, 29.6, 47.2, 48.9, 49.8, 50.8, 62.3, 100.6, 111.2, 119.8, 120.4, 121.7, 122.0, 122.6, 128.8, 135.1, 136.5, 137.8 , 147.1, 156.9, 157.8. ES-MS m / z 479 (M + H). Calcd for C ₃₀ H ₃₄ N ₆ .0.5CH ₂ Cl ₂ .0.2C ₄ H ₁₀ O: C, 70.15; H, 6.96; N, 15.68. Found: C, 70.16; H, 6.97; N, 15.73.
[370] Example 32
[371]
[372] Compound 32: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(N, N-dimethyl-4-amino-but-1-yl ) -Amine (hydrobromide salt)
[373] [1- (tert-Butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-(4-hydroxy- Preparation of but-1-yl) -amine:
[374]
[375] To a stirred suspension of NaH (95%, 0.81 g, 33.8 mmol) in THF (68 mL) was added 1,4-butanediol (3.0 mL, 33.9 mmol) at room temperature. After 1.5 h, tert-butyldimethylsilyl chloride (5.14 g, 34.1 mmol) was added. After stirring for an additional 2.5 hours, the reaction was diluted with diethyl ether (250 mL). The organic phase was washed with saturated aqueous NaHCO ₃ (2 × 75 mL) and brine (1 × 75 mL). The combined aqueous phases were extracted with ether (1 × 75 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a colorless solution (6.40 g, 92%).
[376] To a stirred solution of oxalyl chloride (6.0 mL, 68.8 mmol) in CH ₂ Cl ₂ (450 mL) was added DMSO (6.5 mL, 91.6 mmol) at −78 ° C. After 2 hours, alcohol from the stomach (6.40 g, 31.3 mmol) was added to the solution in CH ₂ Cl ₂ (90 mL). Triethylamine (32 mL, 230 mmol) was added after 20 minutes, and the bang bath was removed. After 1 hour, the reaction was washed with water (1 × 200 mL). The aqueous phase was extracted with CH ₂ Cl ₂ (3 × 100 mL). The combined organic phases were washed with 1N HCl (1 × 200 mL), saturated aqueous NaHCO ₃ (1 × 200 mL) and brine (1 × 200 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 6.36 g (quantitative) of a yellow liquid.
[377] General process B use: aldehyde (3.085 g, 15.2 mmol) from the stomach in CH ₂ Cl ₂ (90 mL) and (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro To a stirred solution of quinolin-8-yl) -amine (3.67 g, 13.2 mmol) was added NaBH (OAc) ₃ (6.33 g, 29.9 mmol) and the mixture was stirred for 16 h. The resulting yellow foam (8.06 g) was dissolved in THF (20 mL) and treated with 3N HCl (80 mL). After 2 hours, the reaction was basified with saturated aqueous NaHCO ₃ . The phases were separated and the aqueous phase was dried over diethyl ether (4 × 150 mL) and CH ₂ Cl ₂ (2 × 150 mL) and concentrated under reduced pressure to give an orange oil (4.44 g, 72%).
[378] To a stirred solution of protected alcohol (5.01 g, 10.8 mmol) from the stomach in THF (50 mL) was added hydrogen fluoride-pyridine (-5 mL, 175 mmol) at 0 ° C. After 75 minutes, an additional 1 ml of HF-pyridine was added. After an additional 20 minutes, the pH of the solution was raised to pH 13 with 1N NaOH followed by 10N NaOH. The mixture was extracted with CH ₂ Cl ₂ (5 × 40 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give crude oil (4.22 g). The oil was purified by column chromatography (4 cm OD, silica 100 g, 30: 1 CH ₂ Cl ₂ : CH ₃ OH) to give the deprotected alcohol as a yellow foam (2.92 g, 77%).
[379] Di-tert-butyl di-carbonate (1.96 g, 8.98 mmol) at 0 ° C. in a stirred solution of deprotection alcohol (2.92 g, 8.33 mmol) and diisopropylethyl amine (15 drops) from ethanol in THF (40 mL). ) Was added. After stirring for 17 hours, during which the reaction was allowed to warm to room temperature, and the reaction was concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (100 mL) and washed with brine (3 × 50 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give N-protected material as a crude yellow foam (3.79 g, quantitative). ¹ H NMR (CDCl ₃ ) δ 1.48-1.71 (m, 14H), 1.93-2.05 (m, 2H), 2.15-2.25 (m, 1H), 2.57-2.67 (m, 1H), 2.71-2.94 (m , 3H), 2.53-2.59 (m, 2H), 4.32 (dd, 1H, J = 9.7, 6.5 Hz), 4.49 (d, 1H, J = 15.8 Hz), 4.61 (d, 1H, J = 15.8 Hz) , 6.93 (dd, 1H, J = 7.7, 4.6 Hz), 7.20-7.30 (m, 3H), 7.68-7.72 (m, 1H), 7.78-7.83 (m, 1H), 8.33 (d, 1H, J = 3.7 Hz).
[380] 4-{[1- (tert-Butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino} Preparation of Butyraldehyde:
[381]
[382] To a stirred solution of oxalyl chloride (4.5 mL, 9.0 mmol) in CH ₂ Cl ₂ (40 mL) was added DMSO (0.86 mL, 12.1 mmol) at −78 ° C. After 30 minutes, [1- (tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-(4 -Hydroxy-but-1-yl) -amine (3.66 g, 8.13 mmol) was added as a solution in CH ₂ Cl ₂ (7.5 mL). After another 20 minutes, triethylamine (70 mL, 71.7 mmol) was added and the ice bath was removed. The reaction was stirred for a further 75 minutes and then concentrated under reduced pressure. The residue was taken up in ethyl acetate and filtered through celite to give crude yellow oil (3.88 g). The oil was purified by column chromatography on silica gel (solvent = 35: 1: 1 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) to afford the desired pure aldehyde (1.25 g, 39%). ¹ H NMR (CDCl ₃ ) δ 1.52-1.72 (m, 13H), 1.74-1.88 (m, 1H), 1.90-2.00 (m, 1H), 2.06-2.17 (m, 1H), 2.36 (t, 2H , J = 6.6 Hz), 2.53-2.74 (m, 2H), 2.79-2.88 (m, 1H), 4.22 (dd, 1H, J = 9.7, 6.3 Hz), 4.48 (d, 1H, J = 15.4 Hz) , 4.66 (d, 1H, J = 15.2 Hz), 6.93 (dd, 1H, J = 7.6, 4.7 Hz), 7.19-7.28 (m, 4H), 7.65-7.70 (m, 1H), 7.73-7.82 (m , 1H), 8.33 (d, 1H, J = 3.6 Hz), 9.56 (s, 1H).
[383] General process B use: 4-{[1- (tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetra in THF (5 mL) NaBH (OAc) ₃ (84 mg, 0.396) in a stirred solution of hydro-quinolin-8-yl) -amino} butyraldehyde (119 mg, 0.265 mmol) and dimethyl amine (2.0 M in THF, 0.145 mL, 0.290 mmol) mmol) was added and the mixture was stirred for 17 h. The crude orange oil (116 mg) was purified by silica gel radial chromatography (75: 1: 1 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) to prepare the N-protected intermediate (69 mg, 55%). Obtained.
[384] General Process D Use for Simultaneous Deprotection and HBr Chloride: N-protected material (69 mg) from the stomach was converted to a hydrobromide salt to give a white solid (80 mg). The solid was diluted with 10N NaOH (3 mL) and extracted with CH ₂ Cl ₂ (5 × 3 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The yellow oil obtained by silica chromatography on silica gel (60: 1: 1 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) was purified to give pure free base as a colorless oil (19 mg, 35%).
[385] General Process D Use: The free base from the stomach (19 mg) was converted to the hydrobromide salt to give compound 32 as a white solid (24 mg, 71%). ¹ H NMR (D ₂ O) δ 1.46-1.64 (m, 4H), 1.77-1.90 (m, 1H), 1.95-2.09 (m, 1H), 2.13-2.23 (m, 1H), 2.33-242 ( m, 1H), 2.51-2.62 (m, 1H), 2.74-2.89 (m, 7H) containing 2.81 (s, 6H), 2.96-3.03 (m, 4H), 4.39 (d, 1H, J = 16.6 Hz) , 4.48-4.58 (m, 2H) containing 4.53 (d, 1H, J = 17.1 Hz), 7.61 (dd, 2H, J = 6.2, 3.1 Hz), 7.81 (dd, 2H, J = 6.2, 3.2 Hz), 7.87 (dd, 1H, J = 6.7, 6.9 Hz), 8.35 (d, 1H, J = 7.9 Hz), 8.63 (d, 1H, J = 5.4 Hz). ¹³ C NMR (D ₂ O) δ 20.43 (2 carbons), 22.27, 25.33, 27.63, 43.02 (2 carbons), 48.23, 51.66, 57.62, 60.70, 114.25 (2 carbons), 125.93, 126.93 (2 carbons), 131.01, 139.31, 140.60, 148.10, 151.24, 151.76. ES-MS m / z 378 (M + H) Anal Calc. for C ₂₃ H ₃₁ N ₅ .3.0HBr .1H ₂ O: C, 40.86; H, 5.99; N, 10.36; Br, 35.45. Found: C, 40.74; H, 5.91; N, 10.22; Br, 35.71.
[386] Example 33
[387]
[388] Compound 33: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(N-allyl-4-amino-but-1-yl)- Amine
[389] 4-Bromo-butan-1-ol (1.30 mL, 11.8 mmol) was added dropwise to reflux allylamine (2.05 g, 35.9 mmol) and the mixture was stirred at 65 ° C. for 23 h. The orange solution was diluted with 10N NaOH (15 mL) and diethyl ether (30 mL). The aqueous phase was subsequently extracted with ether (2 x 30 mL). The organic phase was dried, filtered and concentrated under reduced pressure to give a yellow oil (841 mg, 55%).
[390] To a stirred solution of secondary amine (841 mg, 6.51 mmol) from above in THF was added di-tert-butyl di-carbonate (1.449 g, 6.64 mmol) at 0 ° C. and the reaction was stirred at 0 ° C. for 2 hours. . The reaction was concentrated under reduced pressure. Yellow oil (1.645 g) was purified by column chromatography (4 cm OD, 35 g silica, EtOAc) to give N-protected alcohol (1.246 g, 84%).
[391] TPAP (37 mg, 0.106) in a suspension of N-protected alcohol (236 mg, 1.03 mmol), NMO (187 mg, 1.59 mmol) and 3 ′ molecular sieves (537 mg) from the stomach in CH ₂ Cl ₂ (5 mL). mmol) was added and the mixture was stirred at rt for 2 h. The mixture was filtered through a silica gel plug containing ethyl acetate. The filtrate was concentrated under reduced pressure. Yellow oil (197 mg) was purified by column chromatography (silica 12 g, 10: 1 hexanes: ethyl acetate) to yield N-protected aldehyde (112 mg, 48%).
[392] General process B use: N-protected aldehyde (112 mg, 0.49 mmol) and [1- (tert-butyloxycarbonyl)-(1H-benzimidazole-2 from the stomach in CH ₂ Cl ₂ (5 mL) To a stirred solution of -ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl) -amine (187 mg, 0.49 mmol) was added NaBH (OAc) ₃ (208 mg, .98 mmol). The mixture was stirred for 17 hours. Crude yellow oil (286 mg) was purified by flash chromatography (silica 12 g, 50: 1: 1 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) to give N-protected tertiary amine (172 mg, 59%). Obtained.
[393] General Process D Use: N-protected amine (172 mg, 0.308 mmol) from the stomach was converted to compound 33 (145 mg, 70%) as a white solid. ¹ H NMR (D ₂ O) δ 1.53 (br s, 4H), 1.77-1.90 (m, 1H), 1.95-2.03 (m, 1H), 2.13-2.23 (m, 1H), 2.32-2.42 (m , 1H), 2.50-2.60 (m, 1H), 2.77-2.86 (m, 1H), 2.88-2.95 (m, 2H), 2.97-3.03 (m, 2H), 3.56 (d, 2H, J = 6.5 Hz ), 4.38 (d, 1H, J = 16.7 Hz), 4.47-4.56 (m, 2H) containing 4.53 (d, 1H, J = 17.0 Hz), 5.39 (s, 1H), 5.44 (d, 1H, J = 4.8 Hz), 5.74-5.89 (m, 1H), 7.60 (dd, 2H, J = 6.1, 3.0 Hz), 7.80 (dd, 2H, J = 6.4, 3.4 Hz), 7.86 (dd, 1H, J = 7.9 , 5.8 Hz), 8.34 (d, 1H, J = 7.9 Hz), 8.62 (d, 1H, J = 5.3 Hz). ¹³ C NMR (D ₂ O) δ 19.81 (2 carbons), 20.42, 23.79, 25.47, 27.28, 27.63, 46.75, 48.23, 49.80, 51.65, 50.65, 114.25 (2 carbons), 124.01, 125.93, 126.94 (2 carbons) ), 127.70, 130.98, 139.31, 140.61, 148.10, 151.26, 151.78. ES-MS mlz 390 (M + H) Calcd for C ₂₁ H ₂₅ N ₅ O.3.2HBr.9H ₂ O: C, 38.41; H, 4.91; N, 10.67; Br, 38.94. Found: C, 38.53; H, 5.02; N, 10.42; Br, 38.79.
[394] Example 34
[395]
[396] Compound 34: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(N-methyl-4-amino-but-1-yl)- Amine
[397] To a stirred solution of 4- (methylamino) -butyric acid hydrochloride (303 mg, 1.97 mmol) and dioxane (2 mL) in saturated aqueous NaHCO ₃ (2 mL) di-tert-butyl di-carbonate (523 mg, 2.40 mmol) was added and the mixture was stirred at 0 ° C. for 20 minutes and then at room temperature for 22 hours. The reaction was concentrated under reduced pressure and the residue was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (2 x 15 mL). The aqueous phase was treated with 5% w / v aqueous citric acid until pH 4 was obtained. The aqueous phase was then extracted again with ethyl acetate (4 x 15 mL). The combined organic phases were dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give a colorless oil (300 mg, 70%).
[398] To a stirred solution of N-protected acid (143 mg, 0.659 mmol) from the stomach in THF (5 mL) was added BH ₃ · THF (1.0 M in THF, 2.5 mmol) and the mixture was stirred at 50 ° C. for 64 h. It was. Anhydrous CH ₃ OH (5 mL) was added and the mixture was stirred at 70 ° C. for 1 h. The reaction was concentrated under reduced pressure. Crude yellow oil (148 mg) was purified by column chromatography (2 cm OD, silica 20 g, 1: 1 EtOAc: hexane) to give N-protected alcohol (71 mg, 53%).
[399] TPAP (13 mg, 0.04) in a suspension of N-protected alcohol (71 mg, 0.35 mmol), NMO (65 mg, 0.56 mmol) and 3 ′ molecular seed (186 mg) from the stomach in CH ₂ Cl ₂ (2.55 mL). mmol) was added and the mixture was stirred at rt for 1 h. The mixture was filtered through a silica gel plug containing ethyl acetate. The filtrate was concentrated under reduced pressure to give a yellow oil (46 mg, 65%).
[400] General process B use: N-protected aldehyde from above in CH ₂ Cl ₂ (2.55 mL) and [1- (tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-( To a stirred solution of 5,6,7,8-tetrahydroquinolin-8-yl) -amine (89 mg, 0.229 mmol) was added NaBH (OAc) ₃ (100 mg, 0.47 mmol) and the mixture was stirred for 19 h. It was. Crude yellow oil (126 mg) was purified by flash chromatography (silica 12 g, 50: 1: 1 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) to give N-protected amine (80 mg, 62%). It was.
[401] General Process D Use: N-protected tertiary amine (76 mg, 0.135 mmol) from the stomach was converted to compound 34 (71 mg, 75%) as a white solid. ¹ H NMR (D ₂ O) δ 1.54 (br s, 4H), 1.74-1.90 (m, 1H), 1.95-2.09 (m, 1H), 2.13-2.23 (m, 1H), 2.32-2.42 (m , 1H), 2.50-2.64 (m, 4H) [containing 2.61 (s, 3H)], 2.77-2.94 (m, 3H), 2.97-3.04 (m, 2H), 4.39 (d, 1H, J = 17.1 Hz ), 4.47-4.60 (m, 2H) [containing 4.53 (d, 1H, J = 17.2 Hz)], 7.60 (dd, 2H, J = 6.1, 3.0 Hz), 7.80 (dd, 2H, J = 6.1, 3.0) Hz), 7.86 (dd, 1H, J = 7.9, 6.2 Hz), 8.34 (d, 1H, J = 7.9 Hz), 8.62 (d, 1H, J = 5.0 Hz). ¹³ C NMR (D ₂ O) δ 20.42 (2 carbons), 23.69, 25.40, 27.64, 33.05, 48.23, 49.00, 51.68, 60.66, 114.25 (2 carbons), 125.93, 126.93 (2 carbons), 130.97, 139.31, 140.61, 148.10, 151.25, 151.77. ES-MS m / z 364 (M + H). Calcd for C ₂₁ H ₂₅ N ₅ O. 3.2HBr. 1.9H ₂ O: C, 38.41; H, 4.91; N, 10.67; Br, 38.94. Found: C, 38.53; H, 5.02; N, 10.42; Br, 38.79.
[402] Example 35
[403]
[404] Compound 35: (1H-benzimidazol-2-ylmethyl)-[3- (2H-pyrazol-3-yl) -propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl ) -Amine (hydrobromide salt)
[405] Preparation of (cyanomethyl) triphenylphosphonium bromide:
[406] BrCH ₂ CN (0.42 mL, 6.0 mmol) was added to a solution of PPh ₃ (1.57 g, 5.99 mmol) in Et ₂ O (30 mL). The reaction was stirred at reflux for 17 h. The solvent was removed under reduced pressure and the residue was suction filtered from a small amount of ice-cold Et ₂ O, washed with a small amount of Et ₂ O, to give the phosphonium product as a white powder (1.05g, 2.74mmol, 46%) . ¹ H NMR (CDCl ₃ ) δ6.39 (d, 2H, J = 15.3 Hz), 7.69-7.76 (m, 6H), 7.82-7.87 (m, 3H), 7.96-8.03 (m, 6H).
[407] Preparation of 3- (2H-pyrazol-3-yl) -acrylonitrile:
[408] To a suspension of phosphonium salt (900 mg, 2.35 mmol) in THF (10 mL) was added NaH (60% in mineral oil, 99 mg, 2.5 mmol) in one portion. The suspension was stirred at room temperature for 10 minutes and then pyrazole-3-carboxaldehyde (211 mg, 2.20 mmol) was added in one portion as a solid. The reaction was heated to reflux for 30 minutes, then cooled to room temperature and saturated aqueous NH ₄ Cl (10 mL) was added. The mixture was extracted with CH ₂ Cl ₂ (25 mL × 3) and the combined organic solutions were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica yielded an alkane (white solid) as an about 1.5: 1 mixture of E; Z isomers (232 mg, 1.95 mmol, 89%).
[409] Data for E-isomers: ¹ H NMR (CDCl ₃ ) δ5.92 (d, 1H, J = 16.5 Hz), 6.54 (d, 1H, J = 2.4 Hz), 7.43 (d, 1H, J = 16.8 Hz ), 7.60 (d, 1H, J = 2.4 Hz).
[410] Data for Z-Isomer: ¹ H NMR (CDCl ₃ ) δ5.46 (d, 1H, J = 12.0 Hz), 6.98 (d, 1H, J = 2.4 Hz), 7.24 (d, 1H, J = 12.3 Hz ), 7.66 (d, 1H, J = 2.4 Hz).
[411] Preparation of 3- (2H-pyrazol-3-yl) -propylamine:
[412] α, β-unsaturated nitrile (isomer mixture, 250 mg, 2.10 mmol) was hydrogenated (45 psi) with Raney-nickel in MeOH saturated with NH ₃ (15 mL) for 15.5 hours. The mixture was suction filtered through celite and washed with MeOH. The filtrate was concentrated under reduced pressure to give a brown oil. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 5.6: 1: 0.07) afforded saturated primary amine as a yellow oil (197 mg, 1.57 mmol, 75%). ¹ H NMR (CDCl ₃ ) δ1.82 (quint, 2H, J = 7.1 Hz), 2.76 (apparent q, 4H, J = 6.8 Hz), 4.46 (br. S, 3H), 6.07 (d, 1H, J = 2.1 Hz), 7.47 (d, 1H, J = 1.8 Hz).
[413] Preparation of [3- (2H-pyrazol-3-yl) -propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine:
[414] A solution of primary amine (190 mg, 1.52 mmol) and 8-oxo-5,6,7,8-tetrahydroquinoline (270 mg, 1.83 mmol) in MeOH (4 mL) was stirred at room temperature for 6 hours. NaBH ₄ (75 mg, 2.0 mmol) was added and the reaction was stirred for an additional 15 minutes, then the solvent was evaporated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (20 mL) and washed with saturated aqueous NaHCO _{3 (} 5 mL) and brine (5 mL). The organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 19: 1: 0.1, then MeOH) afforded secondary amine as a yellow oil (100 mg, 0.39 mmol, 26%). ¹ H NMR (CDCl ₃ ) δ 1.67-1.87 (m, 2H), 1.90-2.03 (m, 3H), 2.11-2.23 (m, 1H), 2.67-2.89 (m, 6H), 3.84 (dd, 1H , J = 7.7, 5.3 Hz), 6.03 (d, 1H, J = 1.8 Hz), 7.09 (dd, 1H, J = 7.7, 4.7 Hz), 7.39 (d, 1H, J = 7.6 Hz), 7.41 (d , 1H, J = 1.8 Hz), 8.42 (d, 1H, J = 3.9 Hz).
[415] 2-{[[3- (2H-pyrazol-3-yl) -propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzimidazole- Preparation of 1-carboxylic acid tert-butyl ester:
[416] Amine in CH ₃ CN (2.5 mL) (100 mg, 0.39 mmol), tert-butyl 2-chloromethyl-benzimidazole-1-carboxylate (107 mg, 0.40 mmol), DIPEA (0.10 mL, 0.57 mmol) and A solution of KI (about 10 mg) was heated to 60 ° C. for 18.5 hours under nitrogen. Once cooled to room temperature, saturated aqueous NaHCO ₃ (10 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (15 mL × 3). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Three attempts were made by purification by flash column chromatography on silica, the first eluting with CH ₂ Cl ₂ / MeOH / NH ₄ OH, 19: 1: 0.1, and the second with CH ₂ Cl ₂ / MeOH / NH ₄ Eluted with OH, 49: 1: 0.25, progressively 19: 1: 0.1, third eluted with CH ₂ Cl ₂ / MeOH / NH ₄ OH, 49: 1: 0.25, yielding tertiary amine as a white foam (70.6 Mg, 0.15 mmol, 37% ¹ ). ¹ H NMR (CDCl ₃ ) δ 1.64 (s, 9H), 1.64-1.80 (m, 2H), 1.90-2.12 (m, 3H), 2.19-2.33 (m, 1H), 2.41-2.51 (m, 1H ), 2.60-2.86 (m, 4H), 3.06-3.15 (m, 1H), 3.23-3.37 (m, 1H), 4.04 (dd, 1H, J = 10.4, 6.8 Hz), 4.19 (d, 1H, J) = 15.0 Hz), 4.53 (d, 1H, J = 15.0 Hz), 6.00 (d, 1H, J = 1.5 Hz), 6.72 (dd, 1H, J = 7.5, 4.8 Hz), 6.89 (d, 1H, J = 7.5 Hz), 7.14-7.29 (m, 2H), 7.45 (d, 1H, J = 1.5 Hz), 7.63 (dd, 1H, J = 7.9, 1.5 Hz), 7.73 (dd, 1H, J = 7.9, 1.5 Hz), 8.35 (d, 1H, J = 3.6 Hz).
[417] Preparation of Compound 35:
[418] To a solution of tertiary amine (30.8 mg, 0.063 mmol) in ice HOAc (1.0 mL) was added a saturated solution of HBr in HOAc (0.5 mL). The mixture was stirred at rt for 1 h and then diluted with Et ₂ O (5 mL). The solvent was decanted and the precipitate was washed with Et ₂ O (1 mL × 5) and dried at 90 ° C. under reduced pressure to give compound 35 as a yellow solid (35.5 mg, 0.049 mmol, 78%). ¹ H NMR (D ₂ O) δ 1.68-2.00 (m, 4H), 2.07-2.19 (m, 1H), 2.27-2.49 (m, 2H), 2.66 (t, 1H, J = 7.4 Hz), 2.73 -2.85 (m, 1H), 2.92-3.01 (m, 2H), 4.32 (d, 1H, J = 16.8 Hz), 4.47 (d, 1H, J = 16.8 Hz), 4.49 (dd, 1H, J = 10.7 , 5.9 Hz), 6.32 (d, 1H, J = 2.7 Hz), 7.54-7.61 (m, 2H), 7.71-7.79 (m, 3H), 7.83 (dd, 1H, J = 8.1, 5.4 Hz), 8.32 (d, 1H, J = 7.8 Hz), 8.59 (d, 1H, J = 5.7 Hz). ¹³ C NMR (D ₂ O) δ 20.4, 20.5, 22.8, 27.1, 27.6, 48.1, 50.9, 60.5, 106.2, 114.2, 125.9, 127.0, 130.9, 134.4, 139.3, 140.7, 148.1, 149.0, 151.1, 151.5. ES-MS mlz 387 (M + H). Calcd for C ₂₃ H ₂₆ N ₆ .3.3HBr. 1.9H ₂ 0.0.9C ₄ H ₁₀ O: C, 40.85; H, 5. 10; N, 11.53; Br, 36.16. Found: C, 41.02; H, 5.05; N, 11.56; Br, 35.98.
[419] Example 36
[420]
[421] Compound 36: N '(1H-imidazol-2-ylmethyl) -N' (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt)
[422] Preparation of 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione:
[423] 4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyraldehyde (617 mg, 2.84 mmol), 6,7-di in CH ₂ Cl ₂ (25 mL) Hydro-5H-quinolin-8-one (463 mg, 3.13 mmol), and sodium triacetoxyborohydride (1.81 g, 8.53 mmol) were stirred at room temperature for 2 hours. It was then quenched with 1N NaOH (20 mL) and the mixture was washed with CH ₂ Cl ₂ (2 × 25 mL). The organic layer was dried (MgSO ₄ ), filtered, concentrated and dried under vacuum to give a brown oil. Purification by flash column chromatography on silica gel using CH ₃ OH / CH ₂ Cl ₂ (5:95) gave the pure product as a yellow oil (506 mg, 51%). ¹ H NMR (CDCl _-3- ) δ 1.59-1.83 (m, 6H), 1.98-2.00 (m, 1H), 2.14-2.16 (m, 1H), 2.73-2.81 (m, 4H), 3.70-3.76 (m, 3H), 7.06 (dd, 1H, J = 6.0, 3.0 Hz), 7.36 (d, 1H, J = 6.0 Hz), 7.68-7.71 (m, 2H), 7.82-7.84 (m, 2H), 8.36 (d, 1 H, J = 6.0 Hz).
[424] Preparation of N '(1H-imidazol-2-ylmethyl) -N- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine:
[425] Stomach amine (215 mg, 0.62 mmol), 2-imidazolcarboxaldehyde (118 mg, 1.23 mmol), and sodium cyanoborohydride (114 mg, 1.85 mmol) were stirred in methanol (5 mL) overnight. . The resulting mixture was then dissolved with CH ₂ Cl ₂ (15 mL) and extracted with saturated NaHCO ₃ (3 × 10 mL). The aqueous layer was washed with CH ₂ Cl ₂ (2 × 20 mL). The combined organic extracts were dried (MgSO ₄ ), filtered, concentrated and dried under vacuum to give a yellow foam. The partially purified product was purified by silica gel radial chromatography (2 mm plate, using NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ ; 1: 1: 100 → 1: 3: 100) to give a yellow foam (179 mg, 67). Obtained as%). ¹ H NMR (CDCl ₃ ) δ 1.36-1.41 (m, 3H), 1.55-1.63 (m, 3H), 2.00-2.04 (m, 2H), 2.52-2.76 (m, 4H), 3.46-3.79 (m , 2H), 3.83 (q, 2H, J = 18 Hz), 4.18 (m, 1H), 3.96 (s, 1H), 7.03-7.10 (m, 1H), 7.05 (s, 1H), 7.45-7.49 (m , 1H), 7.67-7.71 (m, 2H), 7.79-7.81 (m, 2H), 8.48 (d, 3.0 Hz).
[426] To a solution of the above amine (179 mg, 0.42 mmol) in ethanol (4 mL) was added hydrazine hydrate (0.12 mL, 2.49 mmol). The reaction mixture was stirred at rt for 3 days. The solvent was then removed under reduced pressure, and the residue was dissolved in CH ₂ Cl ₂ and filtered. The filtrate was concentrated to dryness to afford a yellow oil. Purification by silica gel radial chromatography (2 mm plate, using NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ ; 1: 5: 100 → 1: 10: 100) gave the product as a yellow oil (66.1 mg, 53%). Obtained. ¹ H NMR (CDCl ₃ ) δ 1.31-1.38 (m, 4H), 1.61-1.65 (m, 1H), 1.79-1.83 (m, 1H), 1.96-2.02 (m, 1H), 2.11-2.15 (m , 1H), 2.32-2.39 (m, 1H), 2.46-2.55 (m, 2H), 2.61-2.70 (m, 2H), 2.74-2.80 (m, 1H), 3.78 (q, 2H, J = 15.3 Hz ), 3.95 (dd, 1H, J = 9.3, 6.3 Hz), 6.93 (s, 2H), 7.09 (dd, 1H, J = 7.7, 4.5 Hz), 7.39 (d, 1H, J = 7.5 Hz), 8.42 (d, 1H, J = 3.9 Hz).
[427] Preparation of N '(1H-imidazol-2-ylmethyl) -N' (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt):
[428] A bromic acid saturated acetic acid (0.5 mL) was added to a solution of the above amine (66 mg, 0.22 mmol) in acetic acid (1 mL). The reaction mixture was stirred for 30 minutes, then diethyl ether was added until a precipitate of compound 36 was obtained as orange oil (22 mg, 33%). ¹ H NMR (D ₂ O) δ 1.47-1.50 (m, 4H), 1.81-1.94 (m, 2H), 2.12-2.16 (m, 1H), 2.25-2.29 (m, 1H), 2.46-2.50 ( m, 1H), 2.71-2.75 (m, 1H), 2.84-2.86 (m, 2H), 2.97-3.00 (m, 2H), 4.19 (q, 2H, J = 19.8 Hz), 4.33-4.38 (m, 1H), 7.40 (s, 2H), 7.83 (t, 1H, J = 6.3 Hz), 8.31 (d, 1H, J = 8.1 Hz), 8.55 (d, 1H, J = 6.0 Hz). ¹³ C NMR (D ₂ O) δ 20.19, 20.41, 25.02, 25.29, 27.57, 39.53, 47.09, 49.29, 51.20, 60.10, 119.54, 125.82, 139.22, 140.45, 145.32, 147.96, 151.46. ES-MS m / z 300 [M + H] ⁺ . Calcd for C ₁₇ H ₂₅ N ₅ .3.6HBr.1.4H ₂ 0.0.4C ₂ H ₄ O ₂ : C, 33.41; H, 5. 12; N, 10.84; Br, 44.76. Found: C, 33.41; H, 5. 12; N, 10.84; Br, 44.76.
[429] Example 37
[430]
[431] Compound 37: N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-yl) -butane-1,4-diamine
[432]
[433] Preparation of 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-ylamine
[434] To a stirred solution of 2,3-cycloheptenopyridine (42.94 g, 0.292 mol) in glacial acetic acid (160 mL) was added 30% H ₂ O ₂ (30 mL) at room temperature and the resulting solution was heated to 70 ° C. After 6 hours, the reaction mixture was cooled to room temperature, additional H ₂ O ₂ (30 mL) was added and the solution was heated at 70 ° C. overnight. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in CHCl ₃ (200 mL) and treated with solid Na ₂ CO ₃ (100 g). After 1 hour, the supernatant was decanted and the residue washed with warm CHCl ₃ (3 × 200 mL). The combined supernatants were filtered and concentrated to give 60 g of 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine 1-oxide as a yellow oil. ¹ H NMR (CDCl ₃ ) δ1.63-1.73 (m, 4H), 1.82-1.91 (m, 2H), 2.77-2.83 (m, 2H), 3.36-3.42 (m, 2H), 6.94-7.05 (m , 2H), 8.17 (d, 1H, J = 6.1 Hz).
[435] N-oxide was dissolved in acetic anhydride (222 mL) and heated at 90 ° C. overnight. The mixture was cooled to rt and concentrated. The resulting oil was distilled (Kugelrohr, bp 110-140 ° C. @ 1 Torr) to give 53.26 g of acetic acid 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-yl ester.
[436] K ₂ CO ₃ (72.98 g, mol) in a solution of acetic acid 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-yl ester (53.26 g, 0.259 mol) in methanol (350 mL) Was added and the resulting mixture was stirred at rt overnight. The mixture was poured into water (350 mL) and extracted with CHCl ₃ (3 × 300 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated to yield 41.70 g of 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-ol.
[437] To a stirred solution of 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-ol (41.70 g, 0.255 mol) in CH ₂ Cl ₂ (300 mL) at 0 ° C. triethylamine ( 72 mL, 0.517 mol) was added followed by methanesulfonyl chloride (30 mL, 0.388 mol). The resulting mixture was stirred at rt overnight. The mixture was poured into water (200 mL) and the phases separated. The organic phase was washed with brine (2 × 150 mL), dried (Na ₂ SO ₄ ) and concentrated to crude methanesulfonic acid 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine-9 50.87 g of -yl ester were obtained.
[438] The ester was dissolved in DMF (420 mL), treated with sodium azide (33.40 g, 0.514 mol) and heated at 60 ° C. overnight. The mixture was cooled to rt and concentrated. The resulting slurry was poured into brine (500 mL) and extracted with ether (4 x 500 mL). The combined organic extracts were washed with brine (2 × 100 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was filtered through a short plug of silica gel (eluent CH ₂ Cl ₂ ) to give 23.18 g of 9-azido-6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine (2, 42%) from 3-cycloheptenopyridine was obtained as a red oil. ¹ H NMR (CDCl ₃ ) δ 1.53-1.66 (m, 1H), 1.73-2.14 (m, 5H), 2.63-2.72 (m, 1H), 2.99-3.09 (m, 1H), 4.93 (dd, 1H) , J = 7.8, 1.7 Hz), 7.13 (dd, 1H, J = 7.9, 4.8 Hz), 7.44 (d, 1H, J = 5.7 Hz), 8.39 (dd, 1H, J = 4.8, 1.9 Hz).
[439] To a solution of azide (23.18 g, 0.123 mol) in methanol (150 mL) was added 10 wt% palladium (1.95 g) on activated carbon and the resulting mixture was hydrogenated at 40 psi on a Parr shaker. The mixture was vacuum filtered through celite and the cake was washed with methanol. The solvent was removed from the filtrate under reduced pressure and the oil obtained was distilled (Kugelrohr, bp 105-140 ° C. @ 0.2 Torr) 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-yl 17.56 g (88%) of amine were obtained as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ1.23-1.37 (m, 1H), 1.43-1.57 (m, 1H), 1.78-2.10 (m, 6H) including 2.04 (s, 2H), 2.71-2.85 (m, 2H ), 4.19 (dd, 1H, J = 10.0, 1.5), 7.05 (dd, 1H, J = 7.4, 4.9 Hz), 7.36 (d, 1H, J = 5.9 Hz), 8.38 (d, 1H, J = 4.9 Hz).
[440] 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-ylamine (0.235 g, 1.45 mmol) and NaBH (OAc) _{3 from the} stomach in anhydrous CH ₂ Cl ₂ (8 mL) (0.461 g, 2.18 mmol) in 4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyraldehyde in anhydrous CH ₂ Cl ₂ (4 mL) 0.263 g, 1.21 mmol) was added dropwise. The resulting mixture was stirred at rt for 3 h, diluted with CH ₂ Cl ₂ (25 mL) and quenched with saturated aqueous NaHCO _{3 (} 15 mL). The two phases were stirred together for 1 hour and then separated. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel (30: 1 CH ₂ Cl ₂ / MeOH then 20: 1 CH ₂ Cl ₂ / MeOH) to give 0.34 g (65%) of amine as a colorless oil.
[441] 2- [4- (6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-9-ylamino) -butyl] -isoindole-1 from the stomach in CH ₃ CN (5 mL) In a stirred solution of, 3-dione (0.34 g, 0.94 mmol), N, N-diisopropylethylamine (0.30 mL, 1.7 mmol), KI (7.8 mg, 0.047 mmol) and 1- (tert-butoxycarbonyl ) -2- (chloromethyl) benzimidazole (0.302 g, 1.13 mmol) was added. The resulting mixture was stirred at 60 ° C. overnight, cooled and concentrated under reduced pressure. The residue was partitioned between CH ₂ Cl ₂ (25 mL) and saturated aqueous NaHCO ₃ (15 mL). The aqueous phase was extracted with CH ₂ Cl ₂ (2 × 10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (50: 1 CH ₂ Cl ₂ / MeOH) afforded the desired alkylated amine (0.33 g, 60%) as a white foam.
[442] 2-{[[4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyl]-(6,7,8,9-tetrahydro in EtOH (4 mL) Anhydrous hydrazine (0.090 mL, 2.8) in a stirred solution of -5H-cyclohepta [b] pyridin-9-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester (0.33 g, 0.56 mmol) mmol) was added and the resulting mixture was stirred at rt for 16 h. The mixture was filtered and concentrated under reduced pressure. The crude material was purified by silica gel radial chromatography (TLC grade 2 mm plate, 50: 1: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH followed by 40: 1: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH). 0.13 g (62%) of free base of the compound was obtained as a white foam. ¹ H NMR (CDCl ₃ ) δ 1.30-1.85 (m, 7H), 1.90-2.00 (m, 2H), 2.10-2.24 (m, 1H), 2.40-2.52 (m, 1H), 2.57-2.78 (m , 4H), 3.15-3.27 (m, 1H), 3.77-3.86 (m, 1H), 4.00 (d, 1H, J = 18 Hz), 4.15 (t, 1H, J = 6 Hz), 7.16 (dd, 1H, J = 2.7, 7.5 Hz), 7.20-7.26 (m, 4H), 7.48 (dd, 1H, J = 1.5, 7.5 Hz), 7.56-7.69 (m, 2H), 8.48 (dd, 1H, J = 1.5, 4.8 Hz); ¹³ C NMR (CDCl ₃ ) δ 25.04, 27.46, 27.85, 28.85, 31.63, 34.58, 42.25, 48.21, 51.26, 67.12, 122.18, 122.76, 138.74, 145.95, 163.11. ES-MS m / z 364 (M + H). Calcd for C ₂₂ H ₂₉ N ₅ .0.3CH ₂ Cl ₂ : C, 68.86; H, 7.67; N, 18.00. Found: C, 68.99; H, 7. 84; N, 17.63.
[443] Example 38
[444]
[445] Compound 38: (1H-benzoimidazol-2-ylmethyl)-[3- (1H-imidazol-4-yl) -propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl ) -Amine Preparation
[446] Preparation of 3- (1H-imidazol-4-yl) -propionic acid:
[447]
[448] A suspension of urokanoic acid (2.00 g, 14.5 mmol) in H ₂ O (40 mL) was shaken at room temperature with 10% Pd / C (200 mg, 0.19 mmol) under oxygen atmosphere (30 psi) for 2 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to give a colorless solid (1.95 g, 96%). ¹ H NMR (D ₂ O) δ 2.52 (t, 2H, J = 7.2 Hz), 2.92 (t, 2H, J = 7.2 Hz), 7.16 (s, 1H), 8.49 (s, 1H).
[449] Preparation of 3- (1H-imidazol-4-yl) -propionic acid methyl ester:
[450]
[451] A solution of 3- (1H-imidazol-4-yl) -propionic acid (1.95 g, 13.9 mmol) and H ₂ SO ₄ (catalytic) in MeOH (30 mL) was heated at reflux for 15 hours and then vacuum Concentrated under. The residue was dissolved in CH ₂ Cl ₂ (40 mL) and washed with saturated NaHCO ₃ (aq) (30 mL). The aqueous phase was saturated with sodium chloride and extracted with EtOAc (4 × 25 mL). The combined organic phases were dried (MgSO ₄ ) and concentrated in vacuo to give a yellow oil (1.93 g, 90%). ¹ H NMR (CDCl ₃ ) δ 2.68 (t, 2H, J = 7.2 Hz), 2.93 (t, 2H, J = 7.2 Hz), 3.69 (s, 3H), 6.81 (s, 1H), 7.55 (s , 1H).
[452] Preparation of 4- (3-hydroxy-propyl) -imidazole-1-carboxylic acid tert-butyl ester :
[453]
[454] To a solution of 3- (1H-imidazol-4-yl) -propionic acid methyl ester (1.92 g, 12.5 mmol) in THF (25 mL) was charged LiAlH ₄ (1.0 M / THF, 12.5 mL, 12.5 mmol) at 0 ° C. Was added and the mixture was stirred at 0 ° C. for 15 minutes. H ₂ O (0.50 mL) was added to the mixture, followed by 15% NaOH (aq) (0.50 mL) and H ₂ O (1.5 mL). The mixture was allowed to warm to rt, then filtered and concentrated in vacuo to give a colorless oil (930 mg).
[455] To a crude alcohol (930 mg) solution from above in THF (25 mL) was added di-t-butyl dicarbonate (2.40 g, 11.0 mmol) and the solution was stirred at room temperature for 3 days. The solution was concentrated in vacuo and the crude was purified by column chromatography on silica gel (200: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give colorless crystals (1.04 g, 37%). ¹ H NMR (CDCl ₃ ) δ1.61 (s, 9H), 1.89 (m, 2H), 2.69 (t, 2H, J = 6.9 Hz), 2.98 (t, 1H, J = 5.7 Hz), 3.73 (dd , 2H, J = 12, 5.7 Hz), 7.10 (s, 1H), 7.99 (s, 1H).
[456] Preparation of 4- (3-oxo-propyl) -imidazole-1-carboxylic acid tert-butyl ester:
[457]
[458] To a solution of 4- (3-hydroxy-propyl) -imidazole-1-carboxylic acid tert-butyl ester (95 mg, 0.42 mmol) in CH ₂ Cl ₂ (4 mL) at room temperature, des-martin perododonan (214). Mg, 0.505 mmol) was added. After stirring for 1 h at rt, the mixture was diluted with EtOAc (20 mL), washed with 1N NaOH (aq) (2 × 10 mL) and brine (10 mL), dried (MgSO ₄ ) and in vacuo. Concentration gave a colorless oil (86 mg, 91%). ¹ H NMR (CDCl ₃ ) δ1.61 (s, 9H), 2.86 (m, 4H), 7.11 (s, 1H), 7.99 (s, 1H), 9.84 (s, 1H).
[459] General Process B Use: 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -benzoimidazole-1-carboxylic acid tert-butyl ester (145) in THF (4 mL) Mg, 0.383 mmol) and NaBH (OAc) ₃ (244 mg, 1.15 mmol) in a stirred solution of 4- (3-oxo-propyl) -imidazole-1-carboxylic acid tert-butyl ester (86 mg, 0.38 mmol). Was added and the mixture was stirred at rt for 16 h. The crude material was purified by column chromatography on silica gel (200: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give a colorless oil (39 mg, 17%). ¹ H NMR (CDCl ₃ ) δ 1.64 (m, 20H), 1.92 (m, 2H), 2.14 (m, 1H), 2.44 (m, 2H), 2.60-2.92 (m, 5H), 4.26 (dd, 1H, J = 9.5, 5.9 Hz), 4.52 (d, 1H, J = 16 Hz), 4.66 (d, 1H, J = 16 Hz), 6.85 (d, 1H, J = 0.9 Hz), 6.95 (dd, 1H, J = 7.5, 4.8 Hz, 7.27 (m, 3H), 7.69 (m, 1H), 7.80 (m, 1H), 7.88 (d, 1H, J = 1.2 Hz), 8.37 (dd, 1H, J = 4.5 , 1.2 Hz).
[460] 2-{[[3- (1-tert-butoxycarbonyl-1H-imidazol-4-yl) -propyl]-(5,6,7 in 3: 1 TFA / CH ₂ Cl ₂ (4 mL) A solution of, 8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester (39 mg, 0.066 mmol) was stirred at room temperature for 30 minutes and then vacuum Concentrated under. The residue was partitioned between CH ₂ Cl ₂ (15 mL) and 1N NaOH (aq) (10 mL) and the aqueous phase was extracted with CH ₂ Cl ₂ (15 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to afford compound 38 as a yellow foam (24 mg, 80%). ¹ H NMR (CDCl ₃ ) δ 1.67 (m, 3H), 1.86 (m, 1H), 2.00 (m, 1H), 2.16 (m, 1H), 2.42-2.87 (m, 6H), 4.01 (m, 3H), 6.51 (s, 1H), 7.15 (m, 3H), 7.42 (m, 2H), 7.53 (m, 2H), 8.54 (d, 1H, J = 3.6 Hz); ¹³ C NMR (CDCl ₃ ) δ 21.66, 23.85, 24.01, 28.39, 29.50, 49.64, 50.78, 62.36, 115.22, 118.74, 122.23, 122.74, 134.47, 135.25, 135.58, 138.03, 139.02, 146.88, 156.37, 157.69 ES-MS mlz 387 (M + H). Calcd for C ₂₃ H ₂₆ N ₆ .0.4CH ₂ Cl ₂ .0.9CH ₄ O: C, 64.96; H, 6. 82; N, 18.70. Found: C, 65.13; H, 6.93; N, 18.91.
[461] Example 39
[462]
[463] Compound 39: (1H-Benzoimidazol-2-ylmethyl)-(3-pyridin-2-yl-propyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (hydro Bromide salts)
[464] Preparation of 3-pyridin-2-yl-propionaldehyde:
[465] TPAP (256 mg, 0.73 mmol) in a stirred suspension of 2-pyridinepropanol (1.00 g, 7.29 mmol), NMO (1.281 g, 10.94 mmol) and 3 molecular sieves (3.645 g) in CH ₂ Cl ₂ (37 mL). Was added. The resulting black mixture was stirred at rt overnight. The mixture was concentrated and filtered through a silica gel plug. Purification by column chromatography on silica gel (EtOAc, 100%) gave the desired aldehyde (111 mg, 11%) as a yellow syrup. ¹ H NMR (CDCl ₃ ) δ 2.90-2.95 (m, 2H), 3.11 (t, 2H, J = 7.0 Hz), 7.09 (dd, 1H, J = 7.0, 4.8 Hz), 7.17 (d, 1H, J = 7.8 Hz), 7.54-7.63 (m, 1 H), 8.48 (d, 1 H, J = 4.2 Hz), 9.86 (s, 1H).
[466] Aldehyde (67.6 mg, 0.50 mmol) and 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -benzoimidazole-1- from stomach in THF (5 mL) NaBH (OAc) ₃ was added to a stirred solution of carboxylic acid tert-butyl ester (200 mg, 0.50 mmol) and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, diluted with CH ₂ Cl ₂ (75 mL) and washed successively with H ₂ O (5 mL), saturated aqueous NaHCO ₃ (7 mL) and saturated aqueous NaCl (7 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (20 mL) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 1: 1) affords the desired compound (172 mg) as an orange syrup, which is used in the next step without further purification. It was.
[467] To a solution of amine (172 mg, 0.35 mmol) from the stomach in CH ₂ Cl ₂ (2 mL) was added TFA (2 mL) and the resulting mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and the syrup was dissolved in a minimum amount of H ₂ O and basified with 1N NaOH (pH 10). CHCl ₃ (75 mL was added, the phases were separated and the aqueous layer was extracted with CHCl ₃ (2 × 75 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Crude yellow syrup Was purified by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 1: 1) and then by silica gel radial chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 1: 1). To give the desired compound (97 mg, 70%) as a yellow syrup.
[468] General Process D Use: The yellow syrup from the stomach was converted to a hydrobromide salt to give compound 39 as a white solid. ¹ H NMR (D ₂ O) δ1.82-2.06 (m, 4H), 2.14-2.19 (m, 1H), 2.35-2.38 (m, 1H), 2.51-2.61 (m, 1H), 2.85-3.01 ( m, 5H), 4.36 (d, 1H, J = 16.8 Hz), 4.47-4.56 (m, 2H), 7.56-7.61 (m, 2H), 7.72-7.79 (m, 4H), 7.85 (dd, 1H, J = 7.8, 6.0 Hz), 8.30-8.35 (m, 2H), 8.48-8.51 (m, 1H), 8.62 (d, 1H, J = 4.8 Hz); ¹³ C NMR (D ₂ O) δ 20.41, 20.58, 27.61, 27.65, 30.85, 47.99, 51.00, 60.39, 114.31, 125.32, 126.00, 127.00, 127.36, 130.96, 139.44, 140.71, 141.08, 147.26, 148.16, 151.05 151.41, 156.22. ES-MS mlz 398.3 (M + H). Calcd for C ₂₅ H ₂₇ N ₅ .3.2HBr. 1.2H ₂ O: C, 44.28; H, 4. 85; N, 10.33; Br, 37.71. Found: C, 44.31; H, 5.06; N, 10.19; Br, 37.71.
[469] Example 40
[470]
[471] Compound 40: N- {4-[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -benzenesulfonamide Manufacture
[472] N ^1- (1H-benzoimidazol-2-ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl in CH ₂ Cl ₂ (1.0 mL) cooled to 0 ° C. PhSO ₂ Cl (45 mL, 0.35 mmol) was added to a solution of) -butane-1,4-diamine (56 mg, 0.16 mmol) and DIPEA (33 mL, 0.19 mmol). The resulting mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure, diluted with CH ₂ Cl ₂ (75 mL) and washed successively with H ₂ O (5 mL), saturated aqueous NaHCO ₃ (7 mL) and saturated aqueous NaCl (7 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (20 mL) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The disulfonamide obtained (98 mg) was used for the next step without further purification.
[473] Disulfonamide (98 mg, 0.16 mmol) from above was stirred in saturated HBr (g) in AcOH solution (1.5 mL) for 3 hours. The mixture was concentrated in vacuo and a suspension of the resulting yellow syrup and K ₂ CO ₃ (excess) powder in MeOH was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, diluted with CH ₂ Cl ₂ and filtered through celite. The cake was washed with CH ₂ Cl ₂ and the combined filtrates were concentrated under reduced pressure. The crude yellow foam was subjected to column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 1: 1) followed by radial chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 1: Purification with 1) gave compound 40 (50 mg, 64% over 2 steps). ¹ H NMR (CDCl ₃ ) δ1.42-1.46 (m, 3H), 1.61-1.75 (m, 1H), 1.81-1.99 (m, 1H), 2.00-2.09 (m, 1H), 2.14-2.21 (m , 1H), 2.46-2.55 (m, 1H), 2.67-2.90 (m, 6H), 3.91 (d, 1H, J = 16.2 Hz), 3.98-4.05 (m, 2H), 5.80 (br s, 1H) , 7.12-7.21 (m, 3H), 7.39-7.44 (m, 3H), 7.48-7.57 (m, 3H), 7.75-7.79 (m, 2H), 8.53-8.55 (m, 1H); ¹³ C NMR (CDCl ₃ ) δ 21.21, 23.06, 25.25, 27.47, 29.10, 42.81, 49.38, 50.21, 61.41, 121.73, 122.29, 126.92, 128.97, 132.37, 134.72, 137.51, 140.22, 146.71, 155.65, 157.25. ES-MS mlz 490.3 (M + H). Calcd for C ₂₇ H ₃₁ N ₅ 0 ₂ S.1.0H ₂ 0: C, 63.88; H, 6.55; N, 13.80; S, 6.32. Found: C, 63.91; H, 6. 32; N, 13.46; S, 6.33.
[474] Example 41
[475]
[476] Compound 41: (2S) -2-Amino-5-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -pentanoic acid (hydrobromide Salts)
[477] 6,7 in a solution of (2S) -5-amino-2- (tert-butoxycarbonylamino) -pentanoic acid tert-butyl ester (free base) (0.905 g, 3.11 mmol) in CH ₃ OH (15 mL) -Dihydro-5H-quinolin-8-one (0.504 g, 3.43 mmol) was added and the resulting solution was stirred at room temperature for 5 hours. NaBH ₄ powder (0.379 g, 9.98 mmol) was added and the mixture was stirred at rt for 25 min and then concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (100 mL) and brine (20 mL). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (20: 1 CH ₂ Cl ₂ -CH ₃ OH) to give (2S) -2-tert-butoxycarbonylamino-5- (5,6,7,8-tetra 0.700 g (54%) of hydroquinolin-8-ylamino) -pentanoic acid tert-butyl ester was obtained as a yellow oil.
[478] General process use for N-alkylation: (2S) -2- (tert-butoxycarbonylamino) -5- (5,6,7,8-tetrahydroquinoline-8- in CH ₃ CN (16 mL) Monoamino) -pentanoic acid tert-butyl ester (0.700 g, 1.67 mmol), 1- (tert-butoxycarbonyl) -2- (chloromethyl) -benzimidazole (0.690 g, 2.59 mmol) and N, N The diisopropylethylamine (0.60 mL, 3.44 mmol) solution was heated at 60 ° C. for 24 h. The crude material was purified by column chromatography on silica gel (50: 1 CH ₂ Cl ₂ -MeOH) to give 2-{[(4-tert-butoxycarbonyl-4-tert-butoxycarbonylamino-butyl)-( 0.830 g (77%) of 5,6,7,8-tetrahydroquinolin-8-yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester were obtained as a tan foam.
[479] General process D: 2-{[(4-tert-butoxycarbonyl-4-tert-butoxycarbonylamino-butyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino ] -Methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester (139 mg) is converted to the hydrobromide salt, while the BOC-protecting group is removed and the tert-butyl ester is hydrolyzed and then methanol / ether Reprecipitation of the intermediate solid from gave compound 41 (116 mg, 81%) as a tan solid (mixture of two diastereomers). ¹ H NMR (D ₂ O) δ1.54-1.84 (m, 5H), 1.96-2.06 (m, 1H), 2.15-2.2.19 (m, 1H), 2.34-2.38 (m, 1H), 2.53- 2.60 (m, 1H), 2.80-2.87 (m, 1H), 2.99-3.01 (m, 2H), 3.82 (t, 1H, J = 6.3 Hz), 4.38 (d, 1H, J = 16.8 Hz), 4.50 -4.55 (m, 2H), 7.57-7.62 (m, 2H), 7.76-7.88 (m, 3H), 8.33 (br d, 1H, J = 5.1 Hz), 8.62 (br d, 1H, J = 6.0 Hz ); ¹³ C NMR (D ₂ O) δ 20.32, 20.40, 23.87, 24.12, 27.63, 27.93, 28.04, 48.16, 51.34, 51.51, 53.41, 53.54, 60.48, 60.58, 114.24, 125.92, 126.92, 130.98, 139.36, 140.60, 148.08, 151.18, 151.61, 173.06; ES-MS m / z 394 (M + H). Calcd for C ₂₂ H ₂₇ N ₅ 0 ₂ 2.9HBr2.1H ₂ 0: C, 39.68; H, 5. 16; N, 10.52; Br, 34.79. Found: C, 39.81; H, 5. 19; N, 10.14; Br, 34.70.
[480] Example 42
[481]
[482] Compound 42: N ^One-(1H-benzimidazol-2-ylmethyl) -N ⁴-Cyclopropyl-N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (HBr salt).
[483] 1,4-butanediol (0.90 mL, 10.16 mmol) was added to a stirred suspension of NaH (246 mg, 10.25 mmol) in THF (20 mL) at room temperature and stirred for 30 minutes. Acetyl chloride (0.70 mL, 9.84 mmol) was then added to the viscous white slurry. After stirring for 45 minutes, the solution was diluted with diethyl ether (30 mL) and 10 ^w / _v % K ₂ CO _{3 (aq)} . The phases were separated and the organic phase was washed with 10% K ₂ CO ₃ (1 × 15 mL) and brine (1 × 15 mL). The combined aqueous phases were extracted with diethyl ether (1 x 30 mL). The organic phase was dried (MgSO ₄ ) and concentrated to give 933 mg of crude product as a colorless liquid. Purification by column chromatography (25 g silica, 2: 1 hexanes: ethyl acetate) gave 686 mg of acetic acid 4-hydroxy-butyl ester (51%). ¹ H NMR (CDCl ₃ ) δ 1.58-1.77 (m, 4H), 2.05 (s, 3H), 3.68 (t, 2H, J = 6.1 Hz), 4.10 (t, 2H, J = 6.4 Hz).
[484] Tetrapropylammonium perruthenate (195 mg, 0.555 mmol) was monoprotected diol (715 mg, 5.41 mmol) from the stomach in CH ₂ Cl ₂ (27 mL), ground and dried 3 ′ molecular sieves (2.71 g, 5.42 mmol) and NMO (953 mg, 8.13 mmol) and the mixture was stirred for 75 minutes. The suspension was filtered through a plug of silica containing ethyl acetate to give 0.48 g of acetic acid 4-oxo-butyl ester as a colorless oil (68%). ¹ H NMR (CDCl ₃ ) δ 1.98 (pent, 4H, J = 6.6 Hz), 2.05 (s, 3H), 2.55 (t, 2H, J = 7.4 Hz), 4.10 (t, 2H, J = 6.4 Hz ), 9.80 (s, 1 H).
[485] General process B use: cyclopropylamine (0.51 mL, 7.36 mmol) and mono-protected aldehyde (480 mg, 3.69 mmol) from the stomach were added NaBH (OAc) ₃ (1.573 g, 7.42) in CH ₂ Cl ₂ (18 mL). mmol) for 19 hours to give the crude product. The crude product was purified by column chromatography on silica gel (20 g silica, 50: 1 → 25: 1 CH ₂ Cl ₂ : CH ₃ OH) to give 293 mg (46%) of acetic acid 4-cyclopropylamino-butyl ester. ¹ H NMR (CDCl ₃ ) δ 0.29-0.45 (m, 4H), 1.49-1.71 (m, 4H), 2.04 (s, 3H), 2.07-2.14 (m, 1H), 2.70 (t, 2H, J = 6.9 Hz), 4.07 (t, 2H, J = 6.7 Hz).
[486] Di-tert-butyl-dicarbonate (399 mg, 1.83 mmol) was added to a solution of amine (293 mg, 1.71 mmol) from above in THF (8.5 mL), the solution was stirred for 75 minutes, and the solution was then vacuumed. Concentrated. The residue was diluted with CH ₂ Cl ₂ (30 mL) and brine (20 mL). The combined aqueous phases were extracted with CH ₂ Cl ₂ (2 × 20 mL). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to contain acetic acid 4- (tert-butoxycarbonyl-cyclopropyl-amino) -butyl ester and excess di-tert-butyl-dicarbonate 622 mg of colorless liquid was obtained.
[487] Potassium carbonate (2.53 g, 18.3 mmol) was added to a solution of ester (622 mg, 1.71 mmol) from above in methanol (10 mL) at room temperature and the suspension was stirred for 80 minutes. The solution was then diluted with distilled water (20 mL). The mixture was extracted with CHCl ₃ (4 × 20 mL). The organic phase was dried (Na ₂ SO ₄ ) and concentrated to give 399 mg (100% over 2 steps) of crude cyclopropyl- (4-hydroxy-butyl) -carbamic acid tert-butyl ester as a colorless oil.
[488] Tetrapropylammonium perruthenate (65 mg, 0.185 mmol) with alcohol from the stomach (399 mg, 1.74 mmol), NMO (305 mg, 2.60 mmol) and 3 ′ molecular sieves (861) in anhydrous CH ₂ Cl ₂ (8.5 mL). Mg, 1.72 mmol) was added at room temperature and the mixture was stirred for 1 hour. The suspension was then filtered through silica gel with ethyl acetate. The filtrate was concentrated under reduced pressure to give 545 mg of crude product. The crude was purified by column chromatography (28 g silica, 10: 1 →: 1 hexanes: ethyl acetate) to give 63 mg (16%) of pure cyclopropyl- (4-oxo-butyl) -carbamic acid tert-butyl ester and 434 mg of impurity was obtained. ¹ H NMR (CDCl ₃ ) δ0.56-0.62 (m, 2H), 0.71-0.78 (m, 2H), 1.45 (s, 9H), 1.62 (s, 1H), 1.87 (pent, 2H, J = 7.3 Hz), 2.45 (t, 2H, J = 6.6 Hz), 3.24 (t, 2H, J = 7.2 Hz), 9.79 (s, 1H).
[489] General process B use: N-protected aldehyde (63 mg, 0.277 mmol) from the stomach in CH ₂ Cl ₂ (2.5 mL) and [1- (tert-butyloxycarbonyl)-(1H-benzimidazole-2 To a stirred solution of -ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl) -amine (103 mg, 0.273 mmol) was added NaBH (OAc) ₃ (86 mg, 0.406 mmol). The mixture was stirred for 19 h. Crude yellow oil (165 mg) was purified by radial chromatography (2 mm plate, 150: 1: 1 CH ₂ Cl ₂ : CH ₃ OH: NH _4- OH) to give 2-{[[4- (tert-butoxycarbo). Ylmg-cyclopropyl-amino) -butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester 116 mg ( 72%) was obtained.
[490] General Process D Use: The double protective tertiary amine (116 mg, 0.197 mmol) from the stomach was converted to compound 42 (99 mg, 70%) as a white solid. ¹ H NMR (D ₂ O) δ 0.76-0.79 (m, 4H), 1.54 (br s, 4H), 1.81-1.85 (m, 1H), 1.95-2.07 (m, 1H), 2.15-2.19 (m, 1H), 2.34-2.38 (m, 1H), 2.55-2.61 (m, 2H), 2.79-2.84 (m, 1H), 3.01 (br s, 4H), 4.38 (d, 1H, J = 17.4 Hz), 4.50-4.56 (m, 2H), 7.57-7.59 (m, 2H), 7.77-7.79 (m, 2H), 7.83 (t, 1H, J = 6.6 Hz), 8.33 (d, 1H, J = 7.8 Hz) , 8.62 (d, 1H, J = 5.4 Hz). ¹³ C NMR (D ₂ O) δ 3.35, 20.45, 23.69, 25.57, 27.67, 30.32, 48.12, 48.32, 51.71, 60.70, 114.28, 125.95, 126.94, 130.97, 139.34, 140.62, 148.12, 151.26, 151.79. ES-MS m / z 390 (M + H). Calcd for C ₂₄ H ₃₁ N ₅ .3.4HBr.3.0H ₂ O: C, 40.11; H, 5.67; N, 9.74; Br, 37.80. Found: C, 40.33; H, 5.57; N, 9. 60; Br, 37.63.
[491] Example 43
[492]
[493] Compound 43: (cis-2-aminomethyl-cyclopropylmethyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine ( Hydrobromide salts)
[494] Preparation of (cis-2-hydroxymethyl-cyclopropyl) -methanol:
[495] To a 0 ° C. solution of dimethyl cis-1,2-cyclopropanedicarboxylate (3.03 g, 19.1 mmol) in THF (25 mL) was added LiAlH ₄ (1.0 M in hexane, 25 mL) slowly under nitrogen. After stirring for 1.5 h the resultant mixture at room temperature and then carefully quenched by addition, H ₂ O (1㎖), out for 15% NaOH (1㎖) and H ₂ O (3㎖). The precipitate was removed by suction filtration, washed with EtOAc and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH, 19: 1) afforded the diol as a colorless liquid (1.79 g, 17.5 mmol, 92%). ¹ H NMR (CDCl ₃ ) δ 0.21 (dd, 1H, J = 10.5, 5.4 Hz), 0.80 (td, 1H, J = 8.3, 5.1 Hz), 1.24-1.38 (m, 2H), 3.16-3.29 ( m, 4H), 4.02-4.14 (m, 2H).
[496] Preparation of [cis-2- (tert-butyl-dimethyl-silanyloxymethyl) -cyclopropyl] -methanol:
[497] To a 0 ° C. suspension of NaH (60% in mineral oil, 733 mg, 18.3 mmol) in THF (25 mL) was added a solution of diol (1.78 g, 17.4 mmol) in THF (10 mL) under nitrogen. The mixture was stirred for 10 minutes. Then, t-BDMSCl (2.73 g, 18.1 mmol) was added in one portion as a solid The reaction was stirred at room temperature for 25 minutes, then saturated aqueous NaHCO ₃ (35 mL) was added, the layers were separated and the aqueous solution was CH Extracted with ₂ Cl ₂ (25 mL × 2) The combined organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure by flash column chromatography on silica (hexanes / EtOAc, 4: 1). Purification gave silane as a pale yellow liquid (3.12 g, 14.4 mmol, 83%) ¹ H NMR (CDCl ₃ ) δ0.09 (s, 3H), 0.11 (s, 3H), 0.19 (dd, 1H, J = 10.5, 4.5 Hz), 0.76 (td, 1H, J = 7.5, 6.0 Hz), 0.91 (s, 9H), 1.17-1.29 (m, 1H), 1.30-1.43 (m, 1H), 3.19-3.32 (m, 3H), 3.96 (td, 1H, J = 11.5, 5.3 Hz), 4.14 (dd, 1H, J = 11.7, 5.4 Hz).
[498] Preparation of tert-butyl- (cis-2-chloromethyl-cyclopropylmethoxy) -dimethyl-silane:
[499] To a solution of alcohol (3.11 g, 14.4 mmol) and NEt ₃ (3.0 mL, 21.5 mmol) in CH ₂ Cl ₂ (45 mL) was added MsCl (1.65 mL, 21.3 mmol) under nitrogen. The reaction was heated to reflux for 17 hours. Once cooled to room temperature, saturated aqueous NaHCO ₃ (45 mL was added, the layers separated and the aqueous solution extracted with CH ₂ Cl ₂ (25 mL). The combined organic solutions were dried (MgSO ₄ ), filtered and depressurized Purification by flash column chromatography on silica (hexanes / EtOAc, 9: 1) gave the chloride as a light yellow liquid (1.52 g, 6.46 mmol, 45%) ¹ H NMR (CDCl ₃ ) δ0. 06 (s, 3H), 0.07 (s, 3H), 0.40 (dd, 1H, J = 10.5, 4.6 Hz), 0.84-0.93 (m, 10H), 1.23-1.42 (m, 2H), 3.57-3.72 ( m, 3H), 3.81 (dd, 1H, J = 11.6, 5.7 Hz).
[500] Preparation of N- (cis-2-hydroxymethyl-cyclopropylmethyl) -phthalimide:
[501] A mixture of chloride (1.51 g, 6.43 mmol) and potassium phthalimide (1.31 g, 7.07 mmol) in DMF (25 mL) was heated to 80 ° C. for 3.5 h. Once cooled to room temperature, H ₂ O (25 mL) was added and the mixture was extracted with CH ₂ Cl _{2 (} 25 mL × 3). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure to afford crude phthalimide as a yellow oil.
[502] To a solution of this material in THF (15 mL) was added 1M HCl solution (15 mL) and the reaction stirred at room temperature for 30 minutes. THF was evaporated under reduced pressure and the aqueous solution was extracted with CH ₂ Cl ₂ (25 mL × 3). The organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (EtOAc / hexanes, 1.5: 1) afforded the alcohol as a white solid (880 mg, 3.80 mmol, 59%). ¹ H NMR (CDCl ₃ ) δ 0.18 (dd, 1H, J = 12.5, 5.0 Hz), 0.79 (td, 1H, J = 8.8, 5.2 Hz), 1.18-1.34 (m, 2H), 2.93 (br. s, 1H), 3.50-3.60 (m, 2H), 3.92-4.01 (m, 2H), 7.71-7.75 (m, 2H), 7.83-7.87 (m, 2H).
[503] Preparation of cis- [2- (phthalimidomethyl) -1-cyclopropyl] methyl methanesulfonate:
[504] MsCl (0.22 mL, 2.8 mmol) in CH ₂ Cl ₂ (0.8 mL) under nitrogen in a 0 ° C. solution of alcohol (443 mg, 1.92 mmol) and NEt ₃ (0.40 mL, 2.9 mmol) in CH ₂ Cl ₂ (7 mL). ) Solution was added. The reaction was stirred at 0 ° C. for 15 minutes, then saturated aqueous NaHCO ₃ (10 mL) was added. The layers were separated and the aqueous solution was extracted with CH ₂ Cl ₂ (15 mL × 2). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (EtOAc / hexanes, 1: 1) afforded mesylate as a white solid (513 mg, 1.66 mmol, 86%). ¹ H NMR (CDCl ₃ ) δ 0.52 (dd, 1H, J = 11.4, 5.7 Hz), 1.89 (td, 1H, J = 8.4, 5.4 Hz), 1.32-1.45 (m, 1H), 1.53-1.66 ( m, 1H), 3.01 (s, 3H), 3.71 (dd, 1H, J = 14.4, 7.8 Hz), 3.79 (dd, 1H, J = 14.4, 7.8 Hz), 4.23 (dd, 1H, J = 11.0, 8.9 Hz), 4.57 (dd, 1H, J = 11.1, 6.9 Hz), 7.70-7.75 (m, 2H), 7.83-7.88 (m, 2H).
[505] Preparation of (cis-2-aminomethyl-cyclopropylmethyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine:
[506] Mesylate (371 mg, 1.20 mmol) in CH ₃ CN (7 mL), (1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetra A solution of hydroquinolin-8-yl) -amine (379 mg, 1.00 mmol), DIPEA (0.26 mL, 1.5 mmol) and KI (19 mg, 0.11 mmol) was heated to 60 ° C. for 19 hours under nitrogen. The combined organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 19: 1: 0.1) yielded a tertiary amine (yellow foam) of about 1: 3 mixture of diastereomers (432 mg, 73%) Obtained.
[507] The material (432 mg, 73%) and hydrazine monohydrate (0.35 mL, 7.2 mmol) in EtOH (9 mL) were heated to reflux under nitrogen for 1 h. Once cooled, the solvent was evaporated under reduced pressure. The residue was dissolved in saturated aqueous NaHCO ₃ (10 mL) and extracted with CH ₂ Cl ₂ (25 mL × 3). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 9: 1: 0.05 after 19: 1: 0.1) gave the fully deprotected amine as a white foam (147 mg, 0.41 mmol, 58%). Obtained as. ¹ H NMR (CDCl ₃ ) δ 0.15-0.02 (m, 1H), 0.49-0.59 (m, 1H), 0.72-0.92 (m, 2H), 1.64-1.81 (m, 1H), 1.86-1.98 (m , 1H), 1.99-2.11 (m, 2H), 2.15-2.32 (m, 2H), 2.47-2.61 (m, 1H), 2.66-2.90 (m, 3H), 2.96-3.13 (m, 1H), 3.89 (2 × d, 0.3H, J = 15.1 Hz), 4.06 (s, 0.7 H), 4.13 (dd, 0.7 H, J = 10.1, 5.9 Hz), 4.40 (2 × d, 0.3H, J = 6.2 Hz ), 7.02-7.09 (m, 1H), 7.15-7.20 (m, 2H), 7.37 (d, 1H, J = 7.5 Hz), 7.52-7.62 (m, 2H), 8.51 (d, 1H, J = 3.3 Hz).
[508] Preparation of Compound 43:
[509] To a solution of amine (75 mg, 0.21 mmol) in ice HOAc (1.0 mL) was added a saturated solution of HBr in HOAc (0.5 mL). The solution was stirred at rt for 25 min, then Et ₂ O (5 mL) was added. The precipitate was washed with Et ₂ O (1 mL × 5) and dried at 90 ° C. under reduced pressure to give compound 43 as a yellow solid (131 mg, 0.19 mmol, 91%). ¹ H NMR (MeOH-d ₄ ) δ0.23-0.32 (m, 0.7H), 0.36-0.45 (m, 0.3H), 0.51-0.69 (m, 1H), 1.01-1.20 (m, 1H), 1.33 -1.57 (m, 1H), 1.87-2.04 (m, 1H), 2.06-2.31 (m, 2H), 2.37-2.60 (m, 1H), 2.63-2.88 (m, 2H), 2.99-3.27 (m, 4H), 4.52-4.83 (m, 3H), 7.57-7.67 (m, 2H), 7.86-8.02 (m, 3H), 8.38-8.46 (m, 1H), 8.87-8.95 (m, 1H). ¹³ C NMR (D ₂ O) δ 10.0 and 10.9, 12.4 and 13.6, 15.5, 20.4 and 20.6, 20.7, 27.7, 39.8, 48.6, 51.7 and 52.6, 61.3 and 62.0, 114.2, 125.9, 126.9, 130.9, 139.3 and 139.4, 140.5 and 140.6, 148.1, 151.0 and 151.2, 151.9 and 152.6. ES-MS mlz 362 (M + H). Calcd for C ₂₂ H ₂₇ N ₅ .3.2HBr.2.4H ₂ 0.0.3C ₄ H ₁₀ O: C, 40.63; H, 5.58; N, 10.21; Br, 37.28.
[510] Found: C, 40.61; H, 5. 45; N, 10.10; Br, 37.19.
[511] Example 44
[512]
[513] Compound 44: (trans-2-aminomethyl-cyclopropylmethyl)-(1H-benz-imidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydroquinolin-8-yl Preparation of amines (hydrochloride salts).
[514] Preparation of trans-1,2-cyclopropanedimethanol:
[515] To a solution of diethyl trans-1,2-cyclopropanedicarboxylate (14.9 g, 80 mmol) in THF (50 mL) cooled to 0 ° C. under nitrogen was added a 1.0 M LAH solution in THF (107 mL, 107 mmol). The resulting mixture was heated to reflux for 2 hours, then cooled to room temperature and stirred for 16 hours. The crude was cooled to 0 ° C. and quenched by the slow addition of deionized water (4 mL), followed by 15% NaOH solution (4 mL) and more deionized water (12 mL). The mixture was stirred at rt for 20 min. The thick slurry was diluted with diethyl ether (100 mL), dried over MgSO ₄ , filtered with a glass sinter funnel and concentrated in vacuo to afford the title compound as a colorless oil (6.30 g, 78%). ¹ H NMR (CDCl ₃ ) δ 0.43 (t, 2H, J = 6.8 Hz), 0.96-1.07 (m, 2H), 3.05 (dd, 2H, J = 11.4, 8.7 Hz), 3.13 (br. S, 2H), 3.83 (dd, 2H, J = 11.4, 4.7 Hz).
[516] Preparation of trans-1-hydroxymethyl-2- (tert-butyl-dimethyl-silanyloxymethyl) -cyclopropane (McDougal, PG; Rico, JG; Oh, Y .; Condon, BDJ Org. Chem. 1986, 51, 3388-3390):
[517] To a cooled (0 ° C.) stirred solution of trans-1,2-cyclopropanedimethanol (2.0 g, 20 mmol) in THF (40 mL) was slowly added NaH (60% in oil dispersion, 0.80 g, 20 mmol). Stirring was continued at 0 ° C. for 10 minutes and tert-butyldimethylchlorosilane (3.0 g, 20 mmol) was added. The thick white slurry was warmed to room temperature and stirred for 10 minutes. The obtained mixture was poured into diethyl ether (400 mL), washed with 10% K ₂ CO ₃ (100 mL), and then again with brine (100 mL). The separated organic layer was dried over Na ₂ SO ₄ and concentrated. The crude material was purified by flash column chromatography (5 cm id., Eluted with 100 g of silica, 5: 1 hexanes / ethyl acetate) to give the mono-protected desired product as a clear oil (2.8 g, 65%). ¹ H NMR (CDCl ₃ ) δ0.05 (s, 6H), 0.41-0.53 (m, 2H), 0.89 (s, 9H), 0.89-1.04 (m, 2H), 1.41 (t, 1H, J = 5.8 Hz), 3.41-3.50 (m, 3H), 3.60 (dd, 1H, J = 11.2, 5.8 Hz).
[518] Preparation of trans-N-{[2- (hydroxymethyl) cyclopropyl] methyl} phthalimide:
[519] Trans-1-hydroxymethyl-2- (tert-butyl-dimethyl-silanyloxymethyl) -cyclopropane (4.7 g, 22 mmol) and triethylamine (9.2 mL, 65 mmol) in CH ₂ Cl ₂ (75 mL). To a stirred solution of methanesulfonyl chloride (3.7 mL, 48 mmol) was added dropwise. The mixture was stirred at reflux for 16 h and then cooled to rt. Deionized water (50 mL) was added to the red solution and the layers were separated. The organic layer was washed with brine (50 mL), dried over MgSO ₄ and concentrated to a red oil. The crude material was purified by flash column chromatography (5 cm id., 140 g silica gel, eluted with 5% EtOAc / hexanes) to afford chloride as a yellow oil (4.0 g, 78%).
[520] Chloride (4.0 g, 17 mmol) and potassium phthalimide (4.8 g, 26 mmol) from above were stirred in anhydrous DMF (115 mL) at 100 ° C. under nitrogen atmosphere for 3 hours. The mixture was concentrated to remove DMF. The obtained residue was diluted with CH ₂ Cl ₂ (200 mL), washed with brine (50 mL), dried over MgSO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (5 cm id., 160 g silica gel, eluted with 10: 1 hexanes / ethyl acetate) to give phthalimide as pale yellow oil (5.4 g, 92%).
[521] Phthalimide (5.3 g, 15 mmol) from above was stirred in a mixture of THF (40 mL) and 1N HCl (40 mL) for 1.5 h. THF was removed in vacuo and the solution extracted with CH ₂ Cl ₂ (3 × 50 mL). The separated organic layers were combined, dried over MgSO ₄ and concentrated. The crude material was purified by flash column chromatography (5 cm id., 120 g silica gel, 1: 1 hexanes / ethyl acetate) to afford the title compound as a white solid (3.5 g, 97%). ¹ H NMR (CDCl ₃ ) δ0.50 (ddd, 1H, J = 8.4, 5.1, 5.1 Hz), 0.66 (ddd, 1H, J = 8.4, 5.1, 5.1 Hz), 1.13-1.25 (m, 2H), 1.50 (br. S, 1H), 3.33-3.43 (m, 1H), 3.45-3.53 (m, 1H), 3.60 (dd, 2H, J = 6.9, 5.1 Hz), 7.69-7.74 (m, 2H), 7.82-7. 86 (m, 2 H).
[522] 2-[(trans-2-phthalimidomethyl-cyclopropylmethyl)-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl) -aminomethyl] -benzimidazole-1- Preparation of carboxylic acid tert-butyl esters:
[523] 0 ° C. solution of trans-N-{[2- (hydroxymethyl) cyclopropyl] methyl} phthalimide (3.4 g, 15 mmol) and triethylamine (8.4 mL, 60 mmol) in CH ₂ Cl ₂ (50 mL) To methanesulfonylchloride (2.9 mL, 37 mmol) was added dropwise. The mixture was heated to reflux for 18 h, cooled to rt, washed with deionized water (100 mL) followed by NaHCO ₃ (100 mL) and finally with brine (100 mL). The separated organic layer was dried over MgSO ₄ and concentrated to a tan solid. The crude solid was purified by flash column chromatography (5 cm id., 100 g silica gel, eluted with 9: 1 hexanes / ethyl acetate) to afford chloride as an off-white solid (3.2 g, 85%).
[524] Sodium iodide (12 g, 80 mmol) was added to the chloride from the stomach (2.0 g, 8.0 mmol) in acetone (40 mL). The mixture was vigorously stirred at reflux for 68 hours, then cooled to room temperature and concentrated. The residue was partitioned between deionized water (100 mL) and CH ₂ Cl ₂ (100 mL). The separated organic layer was dried over MgSO ₄ and concentrated to an orange solid (3.2 g). The material was used without further purification.
[525] A solution of iodide (2.7 g, 8.0 mmol) from the stomach (2.9 g, 7.6 mmol) and DIPEA (2.1 mL, 12 mmol) in CH ₃ CN (40 mL) were heated to 60 ° C. under nitrogen for 15.5 h. Once cooled to room temperature, the mixture was concentrated. Saturated aqueous NaHCO ₃ (100 mL) was added and the aqueous layer was extracted with CHCl ₃ (3 × 100 mL). The combined organic fractions were dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give a brown foam. Purification by flash column chromatography on silica (5 cm id., 170 g silica gel, eluted with 2% MeOH / CH ₂ Cl ₂ ), then the product containing material was subjected to second column chromatography (5 cm id., 150 g). Purification by silica gel, eluting with 5% NH ₄ OH / EtOAc) gave a 1: 1 mixture of the two diastereomers of the title compound as a pale yellow foam (2.7 g, 59%). ¹ H NMR (CDCl ₃ ) δ 0.17-0.27 (m, 1H), 0.42-0.51 (m, 1H), 0.89-1.11 (m, 2H), 1.69 and 1.70 (2 × s, 9H), 1.79-2.02 (m, 3H), 2.08-2.20 (m, 1H), 2.52-2.83 (m, 4H), 3.16 (dd, 0.5H, J = 14.2, 7.7 Hz), 3.34 (dd, 0.5H, J = 14.2, 7.7 Hz), 3.50-3.58 (m, 1H), 4.24-4.34 (m, 1H), 4.40-4.52 (m, 1H), 4.62 (d, 1H, J = 16.5 Hz), 6.88-6.94 (m, 1H ), 7.18-7.29 (m, 4H), 7.57-7.64 (m, 2H), 7.67-7.76 (m, 2H), 7.78-7.83 (m, 1H), 8.28-8.33 (m, 1H).
[526] Preparation of (trans-2-aminomethyl-cyclopropylmethyl)-(1H-benzimidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydroquinolin-8-yl-amine :
[527] 2-[(trans-2-phthalimidomethyl-cyclopropylmethyl)-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl) -aminomethyl]-in EtOH (27 mL)- A solution of benzimidazole-1-carboxylic acid tert-butyl ester (3.5 g, 5.9 mmol) and hydrazine hydrate (1.76 mL, 35 mmol) was stirred at room temperature under nitrogen for 2 hours. The white slurry was diluted with diethyl ether, filtered and the filtrate was concentrated. The crude material was purified by flash column chromatography (5 cm id., 80 g silica gel, eluted with 2% NH ₄ OH / 2% MeOH / CH ₂ Cl ₂ ) to give the pure title compound as a pale yellow effervescent solid (1.8 g, 83). %). ¹ H NMR (CDCl ₃ ) δ 0.15-0.31 (m, 2H), 0.58-0.74 (m, 2H), 1.59-1.76 (m, 1H), 1.79-1.92 (m, 1H), 1.96-2.07 (m , 1H), 2.15-2.91 (m, 7H), 4.06-4.16 (m, 2H), 4.21 (2 × d, 1H, J = 14.6 Hz), 7.10-7.22 (m, 3H), 7.41 (d, 1H) , J = 7.5 Hz), 7.54-7.62 (m, 2H), 8.57 (d, 1H, J = 4.5 Hz).
[528] (Trans-2-aminomethyl-cyclopropylmethyl)-(1H-benz-imidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydroquinolin-8-yl-amine ( Hydrochloride salt) (Compound 44):
[529] (Trans-2-aminomethyl-cyclopropylmethyl)-(1H-benz-imidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydroquiniline- in glacial acetic acid (10 mL) A stirred solution of 8-yl-amine (1.7 g, 4.8 mmol) was treated with a saturated solution of HCl _(g) in glacial acetic acid (10 mL). The resulting solution was added dropwise to diethyl ether (300 mL) with vigorous stirring. Once the addition was complete, the white precipitate was settled and the clear liquid was drained off. The solid was washed repeatedly with ether (4 x 300 mL) and decanted each time. The solids were then recovered with a sintered glass funnel, rinsed with diethyl ether (3 × 50 mL) and dried in a vacuum oven at 40 ° C. for 60 hours to give compound 44 as a white solid (2.1 g, 88%, diastereomer). 1: 1 mixture). ¹ H NMR (D ₂ O) δ 0.11-0.18 (m, 0.5H), 0.30-0.41 (m, 1H), 0.44-0.50 (m, 0.5H), 0.69-0.87 (m, 2H), 1.71- 1.86 (m, 1H), 1.91-2.52 (m, 5H), 2.70 (ddd, 1H, J = 27.0, 13.2, 6.0 Hz), 2.90-2.99 (m, 3H), 4.33-4.61 (m, 3H), 7.51-7.55 (m, 2H), 7.72-7.83 (m, 3H), 8.26 (t, 1H, J = 7.6 Hz), 8.59 (t, 1H, J = 7.6 Hz); ¹³ C NMR (D ₂ O) δ 10.12, 11.19, 13.71, 15.45, 16.88, 17.04, 20.42, 20.56, 20.63, 27.62,43.20, 43.31, 48.93, 49.64, 55.43, 55.73, 61.58, 61.89, 114.38, 125.71, 126.38, 126.43, 131.75, 132.04, 139.54, 140.30, 147.54, 147.64, 151.27, 152.28. ES-MS mlz 362 (M + H). Calcd for C ₂₂ H ₂₇ N ₅ .2.9HCl.1.7H ₂ O: C, 53.08. H, 6. 74; N, 14.07; Cl, 20.65. Found: C, 52.91; H, 6. 90; N, 14.20; Cl, 20.90.
[530] Enantiomeric purity of Compound 44 was determined to be 100% by chiral HPLC using the following conditions: Instrument: Hewlett Packard 1100 HPLC (VWD2); Column: chiralcel OD, 0.46 cm × 25 cm; Mobile phase: A = 90:10 hexane / alcohol reagent (0.1% TFA), B = hexane; Isocratic: 50% A, 50% B; Total running time: 30 minutes; Flow rate: 1.0 ml / min; Temperature: 40 ° C .; Detector: UV @ 270 nm; Injection volume: 20 μl.
[531] Retention time of the S enantiomer = 13.0 minutes.
[532] Retention time of R enantiomers = 16.7 minutes.
[533] Example 45
[534]
[535] Compound 45: N '(1H-benzimidazol-2-ylmethyl) -3-methyl-3-phenyl-N' (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1 Preparation of 4-diamine
[536]
[537] Preparation of 2-methyl-2-phenyl-pent-4-enal, see Ciganek, E .; Read, J. M .; Calabrese, J.C. J. Org. Chem. 1995, 60, 5795-5802]:
[538] A solution of 2-phenylpropionaldehyde (9.90 mL, 74.5 mmol), allyl alcohol (20.4 mL, 300 mmol) and p-toluene sulfonic acid (0.8560 g, 4.5 mmol) in benzene (37 mL) was heated at reflux for 19 hours. And water formed using a Dean-Stark trap. The mixture was cooled to rt and saturated aqueous NaHCO ₃ (5 mL) and H ₂ O (5 mL) were added. The phases were separated and the organic layer was washed twice with saturated aqueous NaHCO ₃ (5 mL) and H ₂ O (5 mL). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting yellow residue of p-xylene was heated to reflux for 24 hours. The solution was cooled to rt and concentrated under reduced pressure. The obtained aldehyde (13.0 g) was used without further purification in the next reaction.
[539] Preparation of acetic acid 2-methyl-2-phenyl-pent-4-enyl ester:
[540] To a solution of 2-methyl-2-phenyl-pent-4-enal (1.23 g, 7.02 mmol) in ethanol (20 mL) was added sodium borohydride (0.80 g, 21.15 mmol) and the resulting suspension was stirred at room temperature for 3 hours. Stirred. The mixture was concentrated under reduced pressure, diluted with saturated NaHCO ₃ (10 mL), filtered, concentrated and dried under vacuum to give a yellow oil (1.04 g) which was used in the next step without further purification.
[541] Acetic anhydride in a solution of crude alcohol (360 mg, 2.03 mmol), 4-dimethylaminopyridine (24.4 mg, 0.20 mmol) and triethylamine (340 mL, 2.44 mmol) from the stomach in CH ₂ Cl ₂ (10 mL). (230 mL) was added and the resulting mixture was stirred at rt overnight. The mixture was then stirred at rt overnight. The aqueous layer was washed with CH ₂ Cl ₂ (2 × 20 mL). The combined organic extracts were then washed with saturated NaHCO ₃ (2 × 30 mL), dried (MgSO ₄ ), filtered, concentrated and dried under vacuum to give a yellow oil. Purification by column chromatography on silica gel (CH ₃ OH / CH ₂ Cl ₂ , 1: 9) afforded the title compound (400 mg, 70% over 2 steps). ¹ H NMR (CDCl- _3- ) δ 1.36 (s, 3H), 2.01 (s, 3H), 2.45 (qd, 2H, J = 29.1, 16.2, 7.1 Hz), 4.19 (q, 2H, J = 11.1 , 7.8 Hz), 4.97-5.05 (m, 2H), 5.48-5.54 (m, 1H), 7.21-7.44 (m, 5H).
[542] Preparation of acetic acid 2-methyl-5-oxo-2-phenyl-pentyl ester:
[543] Osmium tetraoxide (2.5% in t-butanol) in a solution of acetate (400 mg, 1.82 mmol) and 4-methylmorpholine N-oxide (427 mg, 3.65 mmol) from the stomach in CH ₂ Cl ₂ (10 mL). (680 mL, 0.06 mmol) was added and the mixture was stirred at rt overnight. The mixture was then diluted with ethyl acetate and filtered through a celite bed. The filtrate was concentrated under reduced pressure and dried under vacuum to give an orange oil. Column chromatography on silica gel (CH ₃ OH / NH ₄ OH / CH ₂ Cl ₂ , 4: 1: 95), followed by silica gel radial chromatography (2 mm plate, CH ₃ OH / CH ₂ Cl ₂ , 0: 100 and then 2 : 98) to give diol (198 mg) as a yellow oil which was used in the next step without further purification.
[544] Crude diol (198 mg, 0.82 mmol) from above in THF (5 mL) and H ₂ O (1 mL) was stirred at room temperature for 2 hours. The mixture was diluted with CH ₂ Cl ₂ (15 mL) and washed with saturated NaCl (15 mL). The aqueous layer was washed with CH ₂ Cl ₂ (15 mL). The combined organic extracts were then dried (MgSO ₄ ), filtered, concentrated and dried in vacuo to give the product as a pale yellow oil (146 mg, 36% over 2 steps). ¹ H NMR (CDCl _-3- ) δ 1.53 (s, 3H), 2.03 (s, 3H), 2.81 (ABqd, 2H, J = 49.2, 15.9, 2.7 Hz), 3.75 (t, 1H, J = 6.3 Hz), 4.23 (ABq, 2H, J = 20.4, 11.1 Hz), 7.24-7.34 (m, 4H), 7.38 (d, 1H, J = 3.0 Hz), 9.54 (t, 1H, J = 3.0 Hz).
[545] Preparation of 4- [1H-benzoimidazol-2-ylmethyl)-(5.6.7.8-tetrahydro-quinolin-8-yl) -amino] -2-methyl-2-phenyl-butan-1-ol:
[546] 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -benzimidazole-1-carboxylic acid tert-butyl ester in CH ₂ Cl ₂ (4 mL) (299 mg, 0.79 mmol) and sodium triacetoxyborohydride (251 mg, 1.18 mmol) were added to the above aldehyde (146 mg, 0.66 mmol) solution, and the mixture was stirred at room temperature for 3 days. The mixture was diluted with CH ₂ Cl ₂ (10 mL) and extracted with NaOH (1N, 2 × 10 mL) and brine (2 × 10 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered, concentrated and dried in vacuo to give a dark yellow oil. Chromatography on silica gel (2 mm plate, CH ₃ OH / NH ₄ OH / CH ₂ Cl ₂ , 3: 1: 96 after 0: 1: 99), and (2 mm plate, NH ₄ OH / CH ₂ Cl ₂ , 0 Partial purification with: 100 after 1:99) afforded the compound as a yellow oil (198 mg), which was used without further purification.
[547] Potassium carbonate (84 mg, 0.61 mmol) was added to the crude amine (198 mg, 0.34 mmol) from the stomach in methanol (3.5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure and dissolved in CH ₂ Cl ₂ . The mixture was filtered to remove inorganic salts, the filtrate was concentrated and dried in vacuo to give a yellow oil. Purification by silica gel radial chromatography (1 mm plate, CH ₃ OH / NH ₄ OH / CH ₂ Cl ₂ , 3: 1: 96 after 1: 1: 98) gave the product as a pale yellow foam (85 mg, over two steps). 24%). ¹ H NMR (CDCl ₃ ) δ 1.20 and 1.26 (s, 3H total), 1.65-1.68 (m, 2H), 1.93-2.01 (m, 3H), 2.13-2.16 (m, 1H), 2.53-2.74 ( m, 3H), 3.53-3.76 (m, 2H), 3.91-4.01 (m, 3H), 7.00-7.09 (m, 3H), 7.17-7.19 (m, 3H), 7.26-7.29 (m, 2H), 7.41 (t, 2H, J = 7.8 Hz), 7.64-7.67 (br m, 1H), 8.43 and 8.47 (d, 1H total, J = 3.5 Hz).
[548] To a solution of alcohol (80 mg, 0.15 mmol) from the stomach in CH ₂ Cl ₂ (1.5 mL) was added Dess-Martin reagent (75 mg, 0.18 mmol) and the mixture was stirred at room temperature for 20 minutes. Saturated NaHCO ₃ (1 mL) and aqueous sodium dithionate (20%, 1 mL) were added to the mixture and stirred until the layers separated. The mixture was diluted with CH ₂ Cl ₂ (5 mL) and the phases were separated. The aqueous layer was diluted with CH ₂ Cl ₂ (5 mL) and the phases were separated. The aqueous layer was washed with CH ₂ Cl ₂ (3 × 10 mL). The combined organic extracts were then dried (Na ₂ SO ₄ ), filtered, concentrated and dried under vacuum to give a yellow foam (91 mg) which was used without further purification.
[549] N '(1H-benzimidazol-2-ylmethyl) -3-methyl-3-phenyl-N' (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4- Preparation of Diamine
[550] To a solution of crude aldehyde (90 mg, 0.17 mmol) from above in methanol (1.5 mL) was added hydroxyamine hydrochloride salt (23 mg, 0.33 mmol) and the mixture was stirred at room temperature for 40 minutes. The mixture was concentrated under reduced pressure and the residue was dissolved in CH ₂ Cl ₂ (5 mL). The residue was basified to pH 9 with NaHCO ₃ and the phases were separated. The aqueous layer was separated by CH ₂ Cl ₂ (2 × 10 mL). The combined organic extracts were then dried (Na ₂ SO ₄ ), filtered, concentrated and dried under vacuum to give a pale yellow foam (72 mg) which was used without further purification.
[551] To a crude oxime solution (285 mg, 0.63 mmol) from above in methanol (20 mL) was added a slurry of Raney-Nickel (about 30 mg) in water. The mixture was purged with ammonia gas and then hydrogenated overnight at 35 psi. The mixture was then filtered through a layer of celite and the filtrate was concentrated and dried in vacuo to give a yellow oil. Silica gel radial chromatography (2 mm plate, CH ₃ OH / NH ₄ OH / CH ₂ Cl ₂ , 1: 1: 98 after 0: 1: 99), (2 mm plate, CH ₃ OH / NH ₄ OH / CH ₂ Cl ₂ , 1: 1: 98 3: 1: 96), (1 mm plate, CH ₃ OH / NH ₄ OH / CH ₂ Cl ₂ , 1: 1: 98 after 2: 1: 97) 45 was obtained yellow foam (16 mg, 4% over 3 steps). ¹ H NMR (CDCl ₃ ) δ1.21 and 1.25 (s, total 3H), 1.62-2.05 (m, 6H), 2.25-2.80 (m, 7H), 3.48 (q, 1H, J = 6.9 Hz), 3.89 -4.15 (m, 3H), 7.00-7.26 (m, 8H), 7.36-7.38 (m, 1H), 7.58 (br s, 2H), 8.58 (br m, 1H). ¹³ C NMR (CDCl ₃ ) δ 21.70, 23.07, 23.71, 29.36, 30.09, 38.19, 38.57, 46.76, 49.87, 49.96, 62.02, 62.20, 122.10, 122.44, 126.34, 126.49, 126.56, 128.68, 128.97, 134.87, 137. , 147.11, 147.20. ES-MS m / z 440 [M + H] ⁺ . Calcd for C- ₂₈ H ₃₃ N ₅ .0.2CH ₂ Cl ₂ .0.6C ₄ H ₁₀ O: C, 73.35; H, 7.93; N, 13.98. Found: C, 72.97; H, 7.87; N, 13.78.
[552] Example 46
[553]
[554] Compound 46 (R), Compound 46 (S): (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-phenyl-1 Preparation of Aminobut-4-yl) -amine (hydrobromide salt)
[555] Note: Proceeding from (R)-(N-t-butoxycarbonyl) -2-phenylglycinol the synthesis of Compound 46 (R) is described below. The synthesis of compound 46 (S) proceeds the same from the (S) -isomer.
[556] A solution of DMSO (2.13 mL, 30 mmol) in dichloromethane (100 mL) was cooled to -60 ° C under nitrogen. Oxalyl chloride (15 mL of 2.0 M solution in dichloromethane, 30 mmol) was added to this stirred solution over 5 minutes. The mixture was stirred at -60 [deg.] C. for 10 minutes, then a solution of (R)-(Nt-butoxycarbonyl) -2-phenylglycinol (5.3 g, 20 mmol) in dichloromethane (40 mL) was added for 10 minutes. Added over. The mixture was stirred at −60 ° C. for 20 minutes, then triethylamine (8.35 mL, 60 mmol) was added. The mixture was gradually warmed to room temperature with stirring over 60 minutes. Then a saturated aqueous solution of ammonium chloride (75 mL) was added. The aqueous and organic layers were separated and the aqueous layer was washed twice with dichloromethane. The combined organic fractions are then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford (R)-(Nt-butoxycarbonyl) -2-phenylglycine as a unstable yellow oil, which is not purified further. Immediately used in the next reaction (assuming 100 conversion). ¹ H NMR (CDCl ₃ ) δ1.43 (s, 9H), 5.31 (m, 1H), 5.75 (br s, 1H (NH)), 7.30-7.41 (m, 5H), 9.55 (s, 1H).
[557] The aldehyde was dissolved in benzene (150 mL) and methyl (triphenylphosphoranilidene) acetate (6.96 g, 20 mmol) was added. The mixture was then stirred at rt overnight. The suspension was then concentrated in vacuo and weighted directly with a silica gel column (1: 1 hexanes: ethyl acetate). The (E) -methyl 4-[(t-butoxycarbonyl) -amino] -4-phenylbut-2-enoate product was recovered as a colorless oil in a yield of 3.17 g (52%). s, 9H), 3.71 (s, 3H), 4.95 (m, 1H), 5.56 (br s, 1H (NH)), 5.96 (dd, 1H, J = 15.2, 2.9 Hz), 7.05 (dd, 1H, J = 15.2, 4.1 Hz), 7.27-7.49 (m, 5H).
[558] Palladium on carbon (250 mg (10% by weight, Pd)) in a solution of methyl 4-[(t-butoxycarbonyl) -amino] -4-phenylbut-2-enoate (3.17 g) in methanol (100 mL) ) Was added. The mixture was then placed under 50 psig hydrogen gas and shaken for 2 hours in a Parr hydrogenator. The mixture was then filtered through celite, concentrated in vacuo and purified by silica gel flash chromatography (3: 1 hexanes: ethyl acetate) to give methyl 4-[(t-butoxycarbonyl) -amino] -4- Phenylbutanoate was obtained as a pale yellow oil in a yield of 2.61 g (82%). ¹ H NMR (CDCl ₃ ) δ 1.45 (s, 9H), 2.07 (m, 2H), 2.36 (m, 2H), 3.69 (s, 3H), 4.59 (m, 1H), 5.15 (br s, 1H ( NH)), 7.21-7.34 (m, 5H).
[559] To a 0 ° C. solution of methyl 4-[(t-butoxycarbonyl) -amino] -4-phenylbutanoate (293 mg, 1.0 mmol) in dichloromethane (25 mL) dival-H (1.0 M in dichloromethane) 3 ml of solution, 3.0 mmol) was added. The mixture was then heated at 0 ° C. for 2 hours and then quenched with saturated aqueous sodium potassium tartrate solution (10 mL). The dibasic mixture was then stirred rapidly for about 45 minutes until the aqueous and organic layers separated. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a pale yellow residue which was purified by silica gel flash chromatography (1: 1 hexanes: ethyl acetate) to give 4-[(t-butoxy). Carbonyl) -amino] -4-phenylbutanol was obtained as a colorless oil in a yield of 138 mg (52%). ¹ H NMR (CDCl ₃ ) δ 1.43 (s, 9H), 1.45 (m, 2H), 1.56 (m 2H), 2.71 (br s, 1H (OH)), 3.54 (t, 2H, J = 6.9 Hz) , 4.56 (m, 1 H), 5.22 (br s, 1 H (NH)), 7.16-7.26 (m, 5H).
[560] Triethylamine (0.140 mL, 1.0 mmol) was added to a 0 ° C. solution of 4-[(t-butoxycarbonyl) -amino] -4-phenylbutanol (133 mg, 0.5 mmol) in dichloromethane (8 mL). Methanesulfonyl chloride (0.057 mL, 0.75 mmol) was then added. The solution was then stirred at 0 ° C. for 15 minutes and then quenched with aqueous ammonium chloride solution (2 mL). The aqueous and organic layers are then separated, the aqueous layer is extracted twice with dichloromethane and the combined organic fractions are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 4-[(t-butoxycarbonyl) -Amino] -4-phenylbutanol mesylate was obtained as a yellow oil which was used immediately in the next half without further purification. ¹ H NMR (CDCl ₃ ) δ 1.43 (s, 9H), 1.67-2.00 (m, 4H), 2.95 (s, 3H), 4.18 (t, 2H, J = 7.1 Hz), 4.20 (m, 1H), 4.92 (br s, 1 H (NH)), 7.21-7.33 (m, 5 H).
[561] Sodium azide (130 mg, 2 mmol) was added to a solution of mesylate (0.5 mmol, assuming 100% conversion from the previous step) in dimethylformamide (5 mL). The mixture was then heated at 70 ° C. for 2 hours under nitrogen. After cooling, the reaction was diluted with 40 mL of ethyl acetate and extracted repeatedly with distillation. The organic fractions were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1: 1 hexanes: ethyl acetate) to give 100 mg (69% from alcohol) of 4-[(t-butoxycarbonyl) -amino] -4-phenylbutyl azide. Obtained in yield. ¹ H NMR (CDCl ₃ ) δ 1.38 (s, 9H), 1.47-1.61 (m, 2H), 1.78 (m, 2H), 3.25 (t, 2H, J = 6.8 Hz), 4.58 (m, 1H), 4.97 (m, 1 H (NH)), 7.20-7.33 (m, 5 H).
[562] To a solution of azide (100 mg, 0.34 mmol) in methanol (20 mL) was added a Lindler catalyst (5% Pd over CaCO ₃ , contaminated with lead (15 mg)). The mixture was placed under 1 atmosphere H ₂ and stirred overnight. The mixture was then filtered through celite, concentrated in vacuo and purified by silica gel flash chromatography (15% methanol, 1% NH ₄ OH in dichloromethane) to 4-amino-1-phenyl-1- (t Butoxycarbonyl) -amine was obtained in a yield of 65 mg (72%). ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H), 1.77 (m, 2H), 2.29 (m, 2H), 2.70 (t, 2H, J = 7.8 Hz), 4.58 (m, 1H), 5.11 ( m, 1H (NH)), 7.20-7.33 (m, 5H).
[563] 5,6,7,8-tetrahydroquinolin-8-one (40 mg, 0.271 mmol) and 4-amino-1-phenyl-1- (t-butoxycarbonyl) -amine in dichloromethane (8 mL) To a solution of (65 mg, 0.246 mmol) was added sodium triacetoxyborohydride (115 mg, 0.542 mmol). The reaction was then stirred overnight at room temperature. Saturated sodium carbonate solution (5 mL) was added and the aqueous and organic layers were separated. The aqueous layer was extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography to give 4-[(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -1-phenyl-1- (t-butoxycarbonyl) -amine Was obtained in a yield of 65 mg (61%). ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H), 1.61-1.85 (m, 6H), 1.94 (m, 1H), 2.04 (m, 1H), 2.74 (m, 4H), 3.78 (m, 1H ), 4.91 (m, 1H), 5.35 (m, 1H (NH)), 7.07 (dd, 1H, J = 8.1, 4.9 Hz), 7.24-7.28 (m, 5H), 7.36 (d, 1H, J = 8.1 Hz), 8.36 (d, 1H, J = 4.9 Hz). -fix 1H
[564] (Nt-butoxycarbonyl) -2-chloromethylbenzimidazole (53 mg, 0.20 mmol), 4-[(5,6,7,8-tetrahydroquinolin-8-yl in acetonitrile (5 mL) ) -Amino] -1-phenyl-1- (t-butoxycarbonyl) -amine (65 mg, 0.165 mmol) and diisopropylethylamine (0.043 mL, 0.25 mmol) were stirred at 70 ° C. for 16 h. It was. After cooling, the mixture was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate solution (5 mL). The aqueous and organic layers were then separated and the aqueous layer was washed twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography to give N-[(t-butoxycarbonyl) -benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl )-(1-phenyl-1-aminobut-4-yl)-(t-butoxycarbonyl) -amine was obtained as a pale foam in a yield of 73 mg (71%). ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H), 1.63 (s, 9H), 1.71-2.11 (m, 8H), 2.58-2.79 (m, 4H), 4.16 (dd, 1H, J = 10.9, 8.1 Hz), 4.43 (m, 3H), 5.05 (m, 1H (NH)), 6.96 (m, 1H), 7.15-7.31 (m, 8H), 7.75 (m, 1H), 7.83 (m, 1H) , 8.30 (m, 1 H).
[565] Using General Process D: Compound 46 (R) (58 mg, 70%) was beige by converting the foam from the stomach (72 mg, 0.117 mmol) into a hydrobromide salt and then reprecipitating the intermediate solid from methanol / ether. Obtained as a solid. ¹ H NMR (D ₂ O) δ 0.83 (m, 1H), 1.84 (m, 5H), 2.06-2.20 (m, 2H), 2.30-2.55 (m, 2H), 2.90 (m, 2H), 4.05 ( m, 1H), 4.22 (d, 1H, J = 15.8 Hz), 4.45 (m, 1H), 4.48 (d, 1H, J = 15.8 Hz), 7.07-7.18 (m, 5H), 7.62 (m, 2H ), 7.73 (m, 2H), 7.87 (dd, 1H, J = 13.2, 5.7 Hz), 8.28 and 8.31 (d, 1H total, J = 5.7 Hz (double line for diastereomers respectively)), 8.54 (d , 1H, J = 5.4 Hz); 13C NMR (D 2 O) δ 20.59, 25.10, 25.23, 27.59, 30.46, 30.56, 49.59, 55.04, 55.50, 61.15, 61.98, 114.29, 125.92, 126.94, 127.28, 127.39,129.47, 129.61, 129.84, 129.92 139.23, 140.41, 148.13, 151.72. ES-MS m / z 426 (M + H). Calcd for C ₂₇ H ₃₁ N ₅ .3.0HBr.2.6H ₂ O: C, 45.35; H, 5.52; N, 9.79; Br, 33.52. Found: C, 45.72; H, 5. 34; N, 9.43; Br, 33.34.
[566] N-[(t-butoxycarbonyl) -benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-(using the same process described above 49 mg (58%) of hydrobromide salt were obtained from 73 mg (0.117 mmol) of 1-phenyl-1-aminobut-4-yl)-(t-butoxycarbonyl) -amine as a white solid to obtain Compound 46 (S). Prepared. ¹ H, ¹³ C and MS data are the same as for Compound 46 (R). Calcd for C ₂₇ H ₃₁ N ₅ .3.0HBr.2.7H ₂ O: C, 45.23; H, 5.54; N, 9.77; Br, 33.43. Found: C, 45.52; H, 5.49; N, 9.39; Br, 33.45.
[567] Example 47
[568]
[569] Compound 47: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-aminobutan-3-ol-4-yl)- Preparation of Amine
[570] To a solution of 3-butene-1-ol (10 g, 138 mmol) in dichloromethane (150 mL) was added acetic anhydride (13 mL, 138 mmol) and 4-dimethylaminopyridine (244 mg, 2 mmol). The mixture was then stirred at rt for 8 h. The reaction mixture was then introduced into saturated aqueous sodium bicarbonate solution (100 mL). After separating the aqueous layer and the organic layer, the aqueous layer was extracted twice with 100 ml of dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-buten-1-yl acetate as a colorless oil in 12.9 g (82%) yield. ¹ H NMR (CDCl ₃ ) δ 2.04 (s, 3H), 2.38 (m, 2H), 4.11 (t, 3H, J = 7.1 Hz), 5.04 (d, 1H, J = 9.1 Hz), 5.08 (d, 1H, J = 15.3 Hz), 5.77 (m, 1H).
[571] To a solution of 3-buten-1-yl acetate (5.7 g, 50 mmol) in dichloromethane (200 mL) was added m-chloroperoxybenzoic acid (12.9 g, 75 mmol). The reaction was then stirred at rt for 3 h. The reaction mixture was then filtered through celite and concentrated in vacuo. The residue was purified by silica gel flash chromatography (4: 1 hexanes: ethyl acetate) to give 3,4-epoxybutan-1-yl acetate as a colorless oil in a yield of 3.8 g (58%). ¹ H NMR (CDCl ₃ ) δ 1.78-1.88 (m, 2H), 2.03 (s, 3H), 2.47 (m, 1H), 2.75 (m, 1H), 2.99 (m, 1H), 4.18 (t, 1H , J = 6.6 Hz).
[572] To a solution of 3,4-epoxybutan-1-yl acetate (3.9 g, 29 mmol) in DMF (50 mL) was added potassium phthalimide (6.47 g, 35 mmol). The stirred mixture was then heated to 90 ° C. for 16 hours. After cooling, the mixture was diluted with ethyl acetate (200 mL) and extracted repeatedly with water. The organic fractions were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1: 1 hexanes: ethyl acetate) to give 1.65 g (20%) of N- (3-hydroxybutan-4-yl-1-acetate) -phthalimide as pale yellow oil. Obtained in the yield). ¹ H NMR (CDCl ₃ ) δ 1.69-1.88 (m, 2H), 2.04 (s, 3H), 2.90 (m, 1H (OH)), 3.79 (d, 2H, J = 5.7 Hz), 4.03 (m, 1H), 4.21-4.31 (m, 2H), 7.70 (m, 2H), 7.83 (m, 2H). MS m / z 300 (M + Na).
[573] Imidazole (150 mg, 2.2 mmol) and t-butyl in a solution of N- (3-hydroxybutan-4-yl-1-acetate) -phthalimide (554 mg, 2.0 mmol) in acetonitrile (15 mL) Dimethylsilyl chloride (310 mg, 2.05 mmol) was added. The mixture was then stirred at rt overnight. Dichloromethane (50 mL) was then added to the reaction and the mixture was extracted with saturated ammonium chloride solution. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated to leave a yellow oily residue which was purified by silica gel flash chromatography (3: 1 hexanes: ethyl acetate) to give N- (3-t-butyldimethylsiloxy Butan-4-yl-1-acetate) -phthalimide was obtained in a yield of 570 mg (73%). ¹ H NMR (CDCl ₃ ) δ -0.04 (s, 3H), -0.01 (s, 3H), 0.84 (s, 9H), 1.78 (m, 2H), 3.68 (dd, 1H, J = 8.1, 6.5Hz ), 3.73 (dd, 1H, J = 8.1, 6.2 Hz), 4.15 (m, 3H), 7.71 (m, 2H), 7.85 (m, 2H).
[574] To a stirred solution of -78 ° C in N- (3-t-butyldimethylsiloxybutan-4-yl-1-acetate) -phthalimide (670 mg, 1.71 mmol) in THF (20 mL) was used. 5.1 ml solution of 1.0 M in hexane, 5.1 mmol) was added. The reaction was stirred at −78 ° C. for 45 minutes and then saturated solution of ammonium chloride (5 mL) was added. The mixture was allowed to warm to room temperature, then ethyl acetate (20 mL) and 1N HCl (2 mL) were added. The mixture was then shaken separately in the funnel to accelerate the rate of fractionation of the layers and then the organic and aqueous layers were separated. The aqueous layer was extracted twice with ethyl acetate, then the combined organic fractions were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1: 1 hexanes: ethyl acetate) to give 465 mg of N- (3-t-butyldimethylsiloxybutan-1-ol-4-yl) -phthalimide as a colorless oil. Obtained in the yield (78%). ¹ H NMR (CDCl 3) δ -0.02 (s, 3H), 0.09 (s, 3H), 0.86 (s, 9H), 1.71-1.82 (m, 2H), 2.11 (m, 1H (OH)), 3.76 ( m, 4H), 4.28 (m, 1H), 7.73 (m, 2H), 7.85 (m, 2H).
[575] Dess-Martin Periodinan (212 mg) in a solution of N- (3-t-butyldimethylsiloxybutan-1-ol-4-yl) -phthalimide (160 mg, 0.4 mmol) in dichloromethane (10 mL) , 0.5 mmol) was added. The mixture was then stirred at rt for 30 min. A 5% solution of sodium thiosulfate (10 mL) and saturated sodium bicarbonate solution (10 mL) were added along with another 20 mL of dichloromethane. The mixture was then stirred rapidly for 20 minutes and the aqueous and organic layers were separated. The aqueous layer was extracted twice with dichloromethane, the combined organic fractions were extracted twice with anhydrous sodium sulfate, the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give N- (3-t-butyldimethyl Siloxybutan-1-al-4-yl) -phthalimide was obtained as a yellow oil which was used immediately in the next reaction without further purification. ¹ H NMR (CDCl ₃ ) δ -0.02 (s, 3H), 0.05 (s, 3H), 0.81 (s, 9H), 2.61 (m, 2H), 3.74 (m, 2H), 4.51 (m, 1H) , 7.71 (m, 2H), 7.85 (m, 2H), 9.81 (m, 1H).
[576] (5,6,7,8-tetrahydroquinoline) in a solution of N- (3-t-butyldimethylsiloxybutan-1-al-4-yl) -phthalimide (0.4 mmol) in dichloromethane (15 mL) -8-yl)-[(Nt-butoxycarbonyl) -benzimidazol-2-yl) methyl] -amine (151 mg, 0.4 mmol) was added. The mixture is stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (170 mg, 0.8 mmol) is added and the reaction is allowed to stir for 16 hours. Saturated sodium bicarbonate solution (10 ml) was added and the aqueous and organic layers were separated. The organic layer was then extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by silica gel flash chromatography (3% methanol in dichloromethane) to [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetra 224 mg (79%) of hydro-quinolin-8-yl)-(1- (N-phthalimidyl) -butan-3- (t-butyldimethylsiloxy) -4-yl) -amine as a pale yellow foam Obtained in the yield. ¹ H NMR (CDCl ₃ ) δ -0.25 (s, 3H), -0.23 (s, 3H), 0.69 (s, 9H), 1.44-1.63 (m, 4H), 1.68 (s, 9H), 2.00 (m , 2H), 2.16 (m, 1H), 2.65-2.74 (m, 3H), 3.48-3.62 (m, 2H), 3.94 (m, 1H), 4.23 (m, 1H), 4.44 (d, 1H, J = 15.3 Hz), 4.72 (m, 1H, J = 15.3 Hz), 6.95 (m, 1H), 7.20 (m, 3H), 7.67 (m, 3H), 7.77 (m, 3H), 8.44 (m, 1H ).
[577] [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1- (N in THF (8 mL)) 1N HCl (2 mL) was added to phthalimidyl) -butan-3- (t-butyldimethylsiloxy) -4-yl) -amine (170 mg, 0.24 mmol). The mixture is then heated to 50 ° C. for 2 hours. After cooling, dichloromethane (50 mL) was added and the mixture was shaken with saturated sodium bicarbonate solution (20 mL). After separating the aqueous and organic layers, the aqueous layer was extracted twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield an effervescent residue which was purified by silica gel flash chromatography (5% methanol in dichloromethane) (1-H-benzimidazole). 2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1- (N-phthalimyl) -butan-3-ol-4-yl) -amine Obtained as a white foam in a yield of 73 mg (49%). ¹ H NMR (CDCl ₃ ) δ 1.50-1.59 (m, 2H), 1.70-2.07 (m, 5H), 2.21 (m, 1H), 2.75-3.00 (m, 4H), 3.78-3.94 (m, 2H) , 4.00-4.22 (m, 2H), 7.04 (m, 1H), 7.16 (m, 2H), 7.24 (d, 1H, J = 5.8 Hz), 7.68 (br s, 1H (NH)), 7.71 (m , 3H), 7.81 (m, 3H), 8.21 and 8.42 (d, 1H total, J = 4.9, 5.1 Hz respectively).
[578] (1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1- (N-phthalimidyl) in modified ethanol (5 mL) To a solution of) -butan-3-ol-4-yl) -amine (73 mg, 0.147 mmol) was added hydrazine hydrate (0.07 mL, 1.5 mmol). The mixture was then heated to reflux for 6 minutes. After cooling, the reaction was concentrated in vacuo, dissolved in dichloromethane (20 mL) and washed with aqueous sodium carbonate solution (5 mL). The aqueous layer was then extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated to give an effervescent residue, which was subjected to silica gel flash chromatography (10% methanol, 0.5% in dichloromethane). Purification with ammonium hydroxide) (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-aminobutan-3-ol- 4-yl) -amine (Compound 47-diastereomer mixture) was obtained as a white foam in a yield of 22 mg (41%). ¹ H NMR (CDCl ₃ ) δ 1.35 (m, 1H), 1.70-1.82 (m, 2H), 2.06 (m, 1H), 2.26 (m, 1H), 2.54-2.99 (m, 5H), 3.57 and 3.84 (m, total of 1H), 3.94 (d, 1H, J = 15.3 Hz), 4.01 (m, 1H), 4.13 (s, 1H), 4.13 (d, 1H, J = 15.3 Hz), 7.14-7.21 ( m, 3H), 7.42 (d, 1H, J = 7.5 Hz), 7.57 (m, 2H), 8.46 and 8.56 (d, 1H total, J = 3.6, 3.6 Hz respectively); ¹³ C NMR (CDCl ₃ ) δ 21.57, 22.25, 29.33, 31.52, 32.30, 46.46, 47.69, 48.69, 49.91, 62.15, 62.67, 70.11, 74.23, 122.33, 122.67, 122.99, 135.61, 138.21, 146.93, 147.29, 141.15 154.89. ES-MS m / z 366 (M + H). Calcd for C ₂₁ H ₂₇ N ₅ O.0.4CH ₂ Cl ₂ : C, 64.35; H, 7.01; N, 17.53. Found: C, 64.16; H, 7. 20; N, 17.22.
[579] Example 48
[580]
[581] Compound 48: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-3-fluoro-butan-4-yl ) -Amine Preparation
[582] (1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1- (N- in dichloromethane (5 ml) in polyethylene test tubes To a 0 ° C. solution of phthalimidyl) -butan-3-ol-4-yl) -amine (81 mg, 0.163 mmol (preparation method described above)), diethylaminosulfur trifluoride (0.065 mL, 0.5 mmol) was added. The mixture was stirred and gradually warmed to room temperature for 2 hours. The mixture was poured into saturated sodium bicarbonate solution (10 mL). The aqueous charge and organic layer were then separated and the aqueous layer was extracted twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (5% methanol in dichloromethane) to give (1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl )-(1- (N-phthalimidyl) -3-fluoro-butan-4-yl) -amine was obtained as a white foam in a yield of 55 mg (67%). ¹ H NMR (CDCl ₃ ) δ 1.69 (m, 2H), 1.86-2.04 (m, 4H), 2.75-2.88 (m, 4H), 3.99 (m, 1H), 4.02-4.20 (m, 4H), 5.01 And 5.08 (m, total of 1H), 7.13 (m, 4H), 7.26 (m, 1H), 7.59-7.73 (m, 4H), 7.89 (m, 1H), 8.78 (m, 1H).
[583] (1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1- (N-phthalimidyl) in modified ethanol (5 mL) To a solution of) -3-fluoro-butan-4-yl) -amine (55 mg, 0.110 mmol) was added hydrazine hydrate (0.07 mL, 1.5 mmol). The mixture was then heated to reflux for 60 minutes. After cooling, the reaction was concentrated in vacuo, dissolved in dichloromethane (20 mL) and washed with aqueous sodium carbonate solution (5 mL). The aqueous layer was then extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated to give an effervescent residue, which was subjected to silica gel flash chromatography (10% methanol, 0.5% in dichloromethane). Purification with Ammonium Hydroxide) (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-3-fluorobutane -4-yl) -amine (compound 48-diastereomer mixture) was obtained as a white foam in a yield of 16 mg (40%). ¹ H NMR (CDCl ₃ ) δ 1.73 (m, 2H), 1.91-2.04 (m, 2H), 2.23 (m, 1H), 2.61-2.86 (m, 6H), 4.00 (d, 1H, J = 16.5Hz ), 4.05 (s, 1H), 4.07 (m, 1H), 4.15 (m, 1H), 4.17 (d, 1H, J = 16.5 Hz), 4.47 and 4.53 (m, 1H total), 7.14-7.22 (m , 4H), 7.42 (d, 1H, J = 8.1 Hz), 7.57 (m, 1H), 7.58 (br s, 1H (NH), 8.58 (d, 1H, J = 4.5 Hz); ¹³ C NMR (CDCl3 ) δ 21.73 and 23.83 (d, 1 C total, J _CF = 23 Hz), 29.30, 29.54, 30.73, 39.09, 45.92 and 46.60 (total of 1 C), 47.35, 50.10 and 62.23 (d, 1 C total, J _CF = 27 Hz) , 92.65 and 95.11 (d, total of 1H, JC-F = 167 Hz), 115.38, 122.08, 122.73, 129.19, 131.29, 135.07, 137.82, 137.98, 146.99, 147.11, 156.49, 157.65.ES-MS m / z 368 ( M + H) Calcd for C ₂₁ H ₂₆ N ₅ F.0.1CH ₂ Cl ₂ .0.2C ₆ H ₁₂ : C, 68.19; H, 7.34; N, 17.83 Found: C, 67.82; H, 7.14; N, 17.66.
[584] Example 49
[585]
[586] Compound 49: [3- (1-Amino-cyclopropyl) -propyl]-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)- Preparation of amines (hydrobromide salts)
[587] Preparation of 1-tert-butoxycarbonylamino-cyclopropane carboxylic acid ethyl ester (Wentland, M.P .; Perni, R.B .; Dorff, P.H .; Rake, J.B. J. Med. Chem. 1988, 31, 1694-1697.):
[588] To a suspension of 1-aminocyclopropanecarboxylic acid (998 mg, 9.87 mmol) in EtOH (25 mL) cooled to 0 ° C. was added dropwise SOCl ₂ (2.0 mL, 27 mmol) for 10 minutes. The resulting solution was heated to reflux under nitrogen for 2 hours and then evaporated under reduced pressure to yield the ester as a light brown oil.
[589] The material was dissolved in EtOAc (25 mL) and a solution of KHCO ₃ (1.51 g, 15.1 mmol) in H ₂ O (9 mL) was added dropwise. The resulting solution was cooled to 0 ° C. and a solution of Boc ₂ O (2.97 g, 13.6 mmol) in EtOAc (10 mL) was added. The reaction was stirred at rt for 16 h, the layers separated and the aqueous solution extracted with EtOAc (25 mL). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (EtOAc / hexanes, 1: 3) afforded the protective amine as a light brown solid (1.27 g, 5.54 mmol, 56%). ¹ H NMR (CDCl ₃ ) δ 1.08-1.18 (m, 2H), 1.23 (t, 3H, J = 7.2 Hz), 1.44 (s, 9H), 1.46-1.53 (m, 2H), 4.14 (q, 2H , J = 7.2 Hz), 5.13 (br. S, 1H).
[590] Preparation of (1-hydroxymethyl-cyclopropyl) -carbamic acid tert-butyl ester:
[591] To a solution of ester (1.18 g, 5.15 mL) in THF (10 mL) was added dropwise for 10 minutes LiBH ₄ (200 mg, 9.2 mmol) in THF (10 mL) under nitrogen. The reaction was stirred at rt for 17.5 h and then cooled to 0 ° C. A solution of 50% HOAc was added until gas evolution ceased (about 8 mL). The white suspension obtained was diluted with H ₂ O (15 mL) and extracted with Et ₂ O (30 mL). The organic solution was washed with 15% aqueous NaHCO ₃ (15 mL) and brine (15 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (EtOAc / hexanes, 1: 1) afforded the alcohol as a white solid (592 mg, 3.16 mmol, 61%) ² . ¹ H NMR (CDCl ₃ ) δ 0.81 (s, 4H), 1.43 (s, 9H), 3.52 (br. S, 1H), 3.58 (s, 2H), 5.12 (br. S, 1H).
[592] Preparation of (1-formyl-cyclopropyl) -carbamic acid tert-butyl ester:
[593] Trimolecular seeds (1.05 g), NMO (382 mg, 3.26 mmol) and TPAP (76 mg, ground) in a solution of alcohol (389 mg, 2.08 mmol) in CH ₂ Cl ₂ (11 mL) cooled to 0 ° C. 0.22 mmol) was added. The black mixture was stirred at 0 ° C. for 30 minutes and at room temperature for another 30 minutes. The mixture was diluted with EtOAc (20 mL), flushed through a short silica column and rinsed with EtOAc. The product containing the material was concentrated under reduced pressure to give aldehyde as a white solid (345 mg, 1.86 mmol, 90%). ¹ H NMR (CDCl ₃ ) δ 1.27-1.37 (m, 2H), 1.40-1.52 (m, 2H), 1.46 (s, 9H), 5.22 (br. S, 1H), 9.16 (s, 1H).
[594] Preparation of (E) -3- (1-tert-butoxycarbonylamino-cyclopropyl) -acrylic acid ethyl ester:
[595] Triethyl phosphoacetate (0.62 mL, 3.13 mmol) was added dropwise to a suspension of 60% NaH (120 mg, 3.00 mmol) in mineral oil in THF (5 mL). The resulting solution was stirred at room temperature for 10 minutes and then added dropwise to a solution of aldehyde (463 mg, 2.50 mmol) in THF (5 mL). The reaction was stirred at 0 ° C. for 15 minutes and then heated to reflux for 1 hour. Once cooled to room temperature, saturated aqueous NH ₄ Cl (10 mL) was added, the layers were separated and the aqueous solution was extracted with CH ₂ Cl ₂ (10 mL × 2). The organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (EtOAc / hexanes, 1: 1) afforded the saturated ester as a pale yellow solid (539 mg, 2.11 mmol, 84%). ¹ H NMR (CDCl ₃ ) δ 1.11-1.18 (m, 2H), 1.24-1.29 (m, 5H), 1.44 (s, 9H), 4.17 (q, 2H, J = 7.1 Hz), 5.02 (br.s , 1H), 5.84 (d, 1H, J = 15.3 Hz), 6.47 (d, 1H, J = 15.6 Hz).
[596] Preparation of 3- (1-tert-butoxycarbonylamino-cyclopropyl) -propionic acid ethyl ester:
[597] A solution of saturated ester (495 mg, 1.94 mmol) in EtOAc (10 mL) was hydrogenated (H ₂ balloon) with 10% Pd / C (25 mg, 0.023 mmol) at room temperature for 3 hours. The mixture was suction filtered through celite, washed with EtOAc and the filtrate was evaporated under reduced pressure to give saturated ester as a colorless oil (500 mg, 1.94 mmol, 100%). ¹ H NMR (CDCl 3) δ 0.61-0.65 (m, 1H), 0.73-0.78 (m, 1H), 0.91 (t, 2H, J = 7.4 Hz), 1.25 (td, 3H, J = 7.1, 1.4 Hz) , 1.43 (s, 9H), 1.78-1.90 (m, 2H), 2.36 (t, 1H, J = 7.7 Hz), 2.44 (t, 1H, J = 7.5 Hz), 4.12 (q, 2H, J = 7.1 Hz).
[598] Preparation of [1- (3-hydroxy-propyl) -cyclopropyl] -carbamic acid tert-butyl ester:
[599] LiBH ₄ (70 mg, 3.2 mmol) was added to a solution of ester (500 mg, 1.94 mmol) in THF (8 mL). The reaction was stirred at room temperature under nitrogen for 18 hours and then quenched by dropwise addition of 50% aqueous HOAc (about 2 mL) until gas evolution ceased. The suspension was diluted with H ₂ O (10 mL) and extracted with Et ₂ O (15 mL). The organic solution was washed with saturated aqueous NaHCO ₃ (10 mL) and brine (10 mL), dried, filtered (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification by flash column chromatography on silica (hexane / EtOAc, 2: 1; increased to 1: 1) afforded the alcohol as a colorless oil (164 mg, 0.77 mmol, 40%). ¹ H NMR (CDCl 3) δ 0.55-0.62 (m, 2H), 0.69-0.75 (m, 2H), 1.40 (s, 9H), 1.52-1.72 (m, 4H), 2.10 (br. S, 1H), 3.64 (t, 2H, J = 6.3 Hz), 4.96 (br. S, 1H).
[600] Preparation of {1- [3- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -propyl] -cyclopropyl} -carbamic acid tert-butyl ester:
[601] Trimolecular seeds (374 mg), NMO (125 mg, 1.07 mmol) and TPAP (26 mg, ground) in a solution of alcohol (160 mg, 0.74 mmol) in CH ₂ Cl ₂ (4 mL) cooled to 0 ° C. 0.07 mmol) was added. The reaction was stirred at 0 ° C. for 25 minutes and then at room temperature for an additional 15 minutes. The reaction was diluted with EtOAc (8 mL) and the mixture was flushed through a short silica column eluting EtOAc. Removal of solvent under reduced pressure gave aldehyde as a pale yellow oil (123 mg, 78%).
[602] A solution of this material (120 mg, 0.56 mmol) and 8-amino-5,6,7,8-tetrahydroquinoline (90 mg, 0.61 mmol) in MeOH (1.5 mL) was stirred at room temperature under nitrogen for 17 hours. . NaBH ₄ (35 mg, 0.93 mmol) was added and the reaction stirred for an additional 15 minutes. The solvent was evaporated under reduced pressure and the residue was dissolved in CH ₂ Cl ₂ (20 mL) and washed with saturated aqueous NaHCO ₃ (5 mL) and brine (5 mL). The organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 19: 1: 0.1) gave the primary amine as an orange oil (51 mg, 0.15 mmol, 26%). ¹ H NMR (CDCl ₃ ) δ 0.57-0.63 (m, 2H), 0.69-0.76 (m, 2H), 1.42 (s, 9H), 1.56-1.80 (m, 5H), 1.80-2.06 (m, 3H) , 2.09-2.20 (m, 1H), 2.68-2.87 (m, 4H), 3.77 (t, 1H, J = 6.3 Hz), 5.16 (br.s, 1H), 7.06 (dd, 1H, J = 7.7, 4.7 Hz), 7.37 (d, 1H, J = 7.5 Hz), 8.38 (d, 1H, J = 4.2 Hz).
[603] 2-{[[3- (1-tert-butoxycarbonylamino-cyclopropyl) -propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl}- Preparation of benzimidazole-1-carboxylic acid tert-butyl ester:
[604] Secondary amine (51 mg, 0.147 mmol) in CH ₃ CN (0.8 mL), tert-butyl 2-chloro-methylbenzimidazole-1-carboxylate (47 mg, 0.18 mmol), DIPEA (0.04 mL, 0.2 mmol) ) And KI (5 mg, 0.03 mmol) were stirred at 60 ° C. under nitrogen for 18 hours. Once cooled to room temperature, saturated aqueous NaHCO ₃ (5 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (10 mL × 3). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH 4 OH, 19: 1: 0.1) afforded tertiary amine as a pale orange foam (60 mg, 0.104 mmol, 71%). ¹ H NMR (CDCl ₃ ) δ 0.30-0.46 (m, 2H), 0.48-0.63 (m, 2H), 1.29-1.50 (m, 11H), 1.60-1.76 (m, 12H), 1.79-1.90 (m, 1H), 1.95-2.05 (m, 1H), 2.08-2.19 (m, 1H), 2.59-2.70 (m, 2H), 2.72-2.87 (m, 2H), 4.26 (dd, 1H, J = 9.5, 6.5 Hz), 4.50 (d, 1H, J = 15.6 Hz), 4.63 (d, 1H, J = 15.0 Hz), 5.10 (br.s, 1H), 6.98 (dd, 1H, J = 7.7, 4.7 Hz), 7.26-7.32 (m, 3H), 7.72 (dd, 1H, J = 6.2, 3.2 Hz), 7.83 (dd, 1H, J = 6.0, 3.0 Hz), 8.37 (d, 1H, J = 3.0 Hz).
[605] Preparation of Compound 49:
[606] To a solution of tertiary amine (57.6 mg, 0.100 mmol) in ice HOAc (1.0 mL) was added a saturated solution of HBr in HOAc (0.5 mL). The reaction was stirred at rt for 1 h and Et ₂ O (5 mL) was added. Washing the resulting viscous solid with Et ₂ O (1㎖ × ₂₎ was ground to a next, Et ₂ O (~ 2㎖) Spa under tyulreo. The precipitate obtained was washed with Et ₂ O (1 mL × 2) and then dried under reduced pressure to give compound 49 as an orange powder (65.7 mg, 0.091 mmol, 91%). ¹ H NMR (D ₂ O) δ 0.63-0.68 (m, 2H), 0.81-0.86 (m, 2H), 1.46-1.67 (m, 4H), 1.76-1.90 (m, 1H), 1.93-2.06 (m , 1H), 2.12-2.22 (m, 1H), 2.31-2.41 (m, 1H), 2.48-2.58 (m, 1H), 2.77-2.87 (m, 1H), 2.96-3.02 (m, 2H), 4.39 (d, 1H, J = 16.8 Hz), 4.47-4.56 (m, 2H), 7.59 (dd, 2H, J = 6.2, 3.2 Hz), 7.79 (dd, 2H, J = 6.2, 3.2 Hz), 7.85 ( dd, 1H, J = 7.8, 6.0 Hz, 8.33 (d, 1H, J = 7.8 Hz), 8.62 (d, 1H, J = 5.4 Hz). 13 C NMR (D 2 O) δ 9.6, 20.4, 24.3, 27.6, 31.8, 34.3, 48.0, 51.8, 60.5, 114.3, 125.9, 126.9, 131.0, 139.3, 140.6, 148.1, 151.2, 151.7. ES-MS mlz 376 (M + H). C ₂₃ H ₂₉ N ₅ .3.1 HBr. Calcd for 1.5C ₂ H ₄ O ₂ .0.2H ₂ O: C, 43.37; H, 5.39; N, 9.73; Br, 34.40. Found: C, 43.26; H, 5.67; N, 9.64; Br, 34.68.
[607] Example 50
[608]
[609] Compound 50: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(5-amino-pent-1-yl) -amine (hydrobromide salt)
[610] [1- (2- (trimethylsilyl) ethoxymethyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl in CH ₃ CN To a stirred solution of) -amine (188 mg, 0.455 mmol) and diisopropylethyl amine (0.26 mL <1.49 mmol) was added 5-bromovalenotyryl (0.12 mL, 1.03 mmol). The mixture was heated at 80 ° C. for 47 h and then the reaction was cooled to rt. After removing the volatiles under reduced pressure, the residue was dissolved in CH ₂ Cl ₂ (20 mL). The solution was washed with brine (3 x 15 mL). The aqueous phase was extracted with CH ₂ Cl ₂ (1 × 15 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give crude orange oil (306 mg). The oil was purified by column chromatography (1.75 cm OD, silica 14 g, 40: 1 CH ₂ Cl ₂ : CH ₃ OH) to give purified tertiary amine (110 mg, 50%).
[611] The amine from the stomach (110 mg) was dissolved in ammonia saturated CH ₃ OH (12 mL) and treated with Raney-nickel (410 mg). The mixture was shaken for 20 hours at 50 psi H ₂ in a Parr hydrogenator, then the mixture was filtered through celite and concentrated to give a crude yellow-orange oil (124 mg).
[612] Amine (124 mg) from the stomach was dissolved in 4N HCl (2 mL) and heated at 50 ° C. for 6 hours. The mixture was then cooled to rt and basified with 10N NaOH (final pH> 13). The aqueous phase was extracted with CH ₂ Cl ₂ (4 × 10 mL). The organic phase was then dried (Na ₂ SO ₄ ), filtered and concentrated to give crude brown foam (83 mg). The foam was purified by silica gel radial chromatography (40: 1: 1 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) to give pure free base (38 mg, 46% over two steps).
[613] General Process D Use: The free base (38 mg) from the stomach was converted to a hydrobromide salt to give compound 50 as a white solid (53 mg, 76%). ¹ H NMR (D ₂ O) δ 1.14-1.28 (m, 2H), 1.39-1.57 (m, 4H), 1.77-1.90 (m, 1H), 1.96-2.10 (m, 1H), 2.13-2.23 (m , 1H), 2.31-241 (m, 1H), 2.46-2.57 (m, 1H), 2.73-2.90 (m, 3H), 2.96-3.03 (m, 2H), 4.38 (d, 1H, J = 16.7 Hz ), 4.47-4.57 (m, 2H), 7.60 (dd, 2H, J = 6.3, 3.3 Hz), 7.80 (dd, 2H, J = 6.2, 3.1 Hz), 7.86 (dd, 1H, J = 7.9, 6.0 Hz), 8.31 (d, 1H, J = 7.0 Hz), 8.62 (d, 1H, J = 4.7 Hz). ¹³ C NMR (D ₂ O) δ 20.40, 23.88, 26.92, 27.63, 27.87, 39.68, 48.51, 52.09, 60.86, 114.26 (2 carbons), 125.85, 126.83 (2carbons), 131.17, 139.29, 140.47, 147.92 (2 carbons) ), 151.48, 152.00. ES-MS m / z 364 (M + H). Calcd for C ₂₂ H ₂₉ N ₅ .3.1HBr.2.6H ₂ O: C, 39.97; H, 5.69; N, 10.59; Br, 37.46. Found: C, 39.96; H, 5. 64; N, 10.62; Br, 37.36.
[614] Example 51
[615]
[616] Compound 51: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(6-amino-hex-1-yl) -amine (hydrobromide salt)
[617] Preparation of N- (tert-butoxycarbonyl) -6-amino-1-hexanal:
[618]
[619] Di-tert-butyl-dicarbonate (1.155 g, 5.29 mmol) was added to a solution of 6-amino-1-hexanol (541 mg, 4.62 mmol) and diisopropylethyl amine (0.25 mL) in THF (10 mL). Was added. After the mixture was stirred at ambient temperature for 18 hours, the volatiles were removed under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (30 mL) and washed with brine (3 × 20 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and removed in rotochet to give a crude yellow oil (1.090 g).
[620] A portion of the oil (220 mg, 1.01 mmol) obtained above was dissolved in CH ₂ Cl ₂ (5 mL) and treated with des-martin periodinan (455 mg, 1.07 mmol). After 2 hours, the reaction was diluted with diethyl ether (20 mL) and treated with 20% w / v Na ₂ S ₂ O ₃ (aq). The phases were separated after 10 minutes and the aqueous phase was extracted with ether (3 × 10 mL). The combined organic phases were washed with 20% w / v Na ₂ S ₂ O ₃ (1 × 12 mL), saturated aqueous NaHCO ₃ (1 × 12 mL) and brine (1 × 12 mL). The organic phase was dried (MgSO ₄ ), filtered and removed under reduced pressure to give crude colorless oil (172 mg). The oil was purified by column chromatography (1.75 cm OD, silica 14 g, 4: 1 hexanes: ethyl acetate) to give 31 mg of the desired intermediate (14%). ¹ H NMR (CDCl ₃ ) δ 1.29-1.50 (m, .13H), 1.63 (quintet, 2H, J = 7.4 Hz), 2.42 (td, 2H, J = 7.2, 1.6 Hz), 3.06-3.12 (m , 2H), 4.57 (br s, 1 H), 9.74 (s, 1 H).
[621] General process B use: [1- (2- (trimethylsilyl) ethoxymethyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7, in CH ₂ Cl ₂ (2.5 mL) Stirred solution of 8-tetrahydro-quinolin-8-yl) -amine (62 mg, 0.150 mmol) and N- (tert-butoxycarbonyl) -6-amino-1-hexanal (31 mg, 0.144 mmol) To NaBH (OAc) ₃ (66 mg, 0.311 mmol) was added and the mixture was stirred for 24 hours to give crude yellow oil (91 mg).
[622] Oil (91 mg) was dissolved in 4N HCl (2 mL) and heated to 50 ° C. After 4 hours the reaction was cooled. The reaction was basified with 10N NaOH (final pH> 13) and the aqueous phase extracted with CH ₂ Cl ₂ (8 × 7 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and removed from the roto snake to give 52 mg of crude yellow oil free base. The oil was purified by silica gel radial chromatography (40: 1: 1 CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH) to give 36 mg (66% over 2 steps) of a yellow film.
[623] General Process D Use: The free base (36 mg) from the stomach was converted to a hydrobromide salt to give compound 51 as a white solid (53 mg, 84%).
[624] ¹ H NMR (D ₂ O) δ 1.13-1.23 (m, 4H), 1.31-1.56 (m, 4H), 1.75-1.90 (m, 1H), 1.96-2.10 (m, 1H), 2.13-2.23 (m , 1H), 2.31-241 (m, 1H), 2.44-2.55 (m, 1H), 2.71-2.81 (m, 1H), 2.85 (t, 2H, J = 7.8 Hz), 2.97-3.04 (m, 2H ), 4.38 (d, 1H, J = 17.0 Hz), 4.48-4.59 (m, 2H), 7.61 (dd, 2H, J = 6.1, 3.1 Hz), 7.80 (dd, 2H, J = 6.1, 3.0 Hz) , 7.86 (dd, 1H, J = 7.7, 5.9 Hz), 8.34 (d, 1H, J = 8.3 Hz), 8.62 (d, 1H, J = 5.7 Hz). ¹³ C NMR (D ₂ O) δ 20.39, 20.45, 25.81, 26.41, 27.07, 27.64, 28.14, 39.74, 48.67, 52.22, 60.95, 114.24 (2 carbon), 125.86, 126.88 (2 carbon), 131.01, 139.21, 140.49 , 147.99, 151.55, 152.12. ES-MS m / z 378 ( M + H) calcd for _{C 23 H 31 N 5 · 3.1HBr} · 1.9H 2 O: C, 41.69; H, 5.77; N, 10.57; Br, 37.38. Found: C, 41.77; H, 5. 60; N, 10.60; Br, 37.36.
[625] Example 52
[626]
[627] Compound 52: N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-cis-1,4-diamine (hydrobromide salt)
[628] Preparation of 4- [N- (tert-butyloxycarbonyl)] amino-cyclohexanone:
[629] A solution of trans-4-aminocyclohexanol hydrochloride (2.67 g, 1.14 mol) in 1N NaOH (40 mL) was diluted with CHCl ₃ (40 mL), CH ₂ Cl ₂ (2 × 30 mL), and EtOAc (4 × 30 mL). )). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford the desired free base (0.43 g) as a white solid. To a suspension of trans-4-aminocyclohexanol (0.43 g, 4.09 mmol) in THF (20 mL) was added di-tert-butyl dicarbonate (0.89 g, 4.09 mmol) and the mixture was stirred at rt for 2 h. . The mixture was concentrated under reduced pressure and the crude product obtained was used for the next reaction without further purification.
[630] 4-methylmorpholine N-oxide (0.695 g, 5.95 mmol) and tetrapropylammonium fur in a suspension of alcohol (~ 3.7 mmol) and 3 'molecular sieve (0.90 g) powder from the stomach in CH ₂ Cl ₂ (10 mL) Luthenate (0.089 g, 0.25 mmol) was added and the mixture was stirred overnight. The reaction was concentrated under reduced pressure and purified by column chromatography through a silica gel plug (ethyl acetate / hexane 1: 1) to afford the title compound (0.670 g, 84% over two steps) as a white solid. ¹ H NMR (CDCl ₃ ) δ 1.45 (br s, 9H), 1.64-1.73 (m, 2H), 2.21-2.27 (m, 2H), 2.37-2.44 (m, 4H), 3.89-3.95 (m, 1H ), 4.50 (br s, 1 H, NH).
[631] According to general process B: 8-amino-5,6,7,8-tetrahydroquinoline (195 mg, 1.32 mmol) and 4- [N- (tert-butyloxycarbonyl) in dry THF (5 mL)] To a stirred solution of amino-cyclohexanone (293 mg, 1.38 mmol) was added NaBH (OAc) ₃ (392 mg, 1.85 mmol) and the mixture was stirred at rt for 2 h. The reaction was diluted with CH ₂ Cl ₂ (20 mL) and saturated aqueous sodium bicarbonate (40 mL) and the aqueous phase was washed with CH ₂ Cl ₂ (2 × 10 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to afford the desired secondary amine as a mixture of diastereomers (520 mg).
[632] The diastereomers were separated and purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH, 96: 4) to reveal the less polar diastereomers (179 mg, 39%) and the lower ones as orange oils, respectively. Polar diastereomers (107 mg, 23%) were obtained.
[633] According to the general procedure for N-alkylation: N, N-diisopropylethylamine in a stirred solution of the upper, less polar diastereomer (179 mg, 0.52 mmol) from above in CH ₃ CN (5 mL) ( 0.18 mL, 1.04 mmol), KI (24 mg, 0.14 mmol) and 1- (tert-butoxycarbonyl) -2- (chloromethyl) benzimidazole (149 mg, 0.56 mmol) were added. The mixture was stirred at 60 ° C. for 4 h and then diluted with CH ₂ Cl ₂ (40 mL) and saturated aqueous sodium bicarbonate (30 mL). The aqueous phase was washed with CH ₂ Cl ₂ (2 × 10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The brown oil obtained was purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH, 96: 4) to give the desired alkylated cis-1,4-diamine, N1- (1-tert-butoxycarbonyl-benzimi Dazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-cis-1,4-diamine-4-carboxylic acid tert-butyl ester (142 mg , 47%) was obtained as a yellow oil.
[634] General Process D Use: Converting oil from the stomach (72 mg, 0.13 mmol) to a hydrobromide salt while simultaneously removing N-tert-butoxycarbonyl protecting groups, thereby reprecipitating intermediate solids from methanol / ether to give a compound 52 (67 mg, 82%) was obtained as an orange solid. ¹ H NMR (D ₂ O) δ 1.66-1.81 (m, 4H), 1.85-2.08 (m, 4H), 2.11-2.18 (m, 3H), 2.42-2.47 (m, 1H), 2.81-2.85 (m , 1H), 3.00-3.02 (m, 2H), 3.53-3.55 (m, 1H), 4.45 (d, 1H, J = 16.8 Hz), 4.57-4.63 (m, 1H), 4.60 (d, 1H, J = 16.8 Hz), 7.59 (dd, 2H, J = 6.3, 3.3 Hz), 7.76 (dd, 2H, J = 6.3, 3.3 Hz), 7.80 (dd, 1H, J = 7.8, 6.3 Hz), 8.28 (d , 1H, J = 7.8 Hz), 8.58 (d, 1H, J = 5.5 Hz); ¹³ C NMR (D ₂ O) δ 20.79, 23.38, 24.33, 25.64, 27.55, 27.70, 27.90, 43.83, 46.55, 58.06, 59.77, 114.25, 125.82, 127.02, 130.95, 139.12, 140.53, 147.99, 151.38, 152.14. ES-MS m / z 376 (M + H). Calcd for C ₂₃ H ₂₉ N ₅ .2.9HBr.2.5H ₂ O: C, 42.16; H, 5.68; N, 10.69; Br, 35.37. Found: C, 42.55; H, 5. 43; N, 10.31; Br, 35.28.
[635] Example 53
[636]
[637] Compound 53: N- {4-cis-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -cyclohexyl}- Preparation of 2-chloro-benzamide (hydrobromide salt)
[638] Diprotective amine from the stomach in CH ₂ Cl ₂ / TFA (1: 1, 2 mL), N1- (1-tert-butoxycarbonyl-benzimidazol-2-ylmethyl) -N1- (5,6, A solution of 7,8-tetrahydro-quinolin-8-yl) -cyclohexane-cis-1,4-diamine-4-carboxylic acid tert-butyl ester, (see compound 52) (70 mg, 0.12 mmol) was added at room temperature. Stir for 1.5 hours. The reaction was then concentrated and diluted with CH ₂ Cl ₂ (15 mL) and 1N NaOH (15 mL). The aqueous layer was washed with CH ₂ Cl ₂ (2 × 10 mL) and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. To a solution of the obtained crude amine (32 mg) in CH ₂ Cl ₂ (3 mL) was added Et 3 N (0.045 mL, 0.32 mmol) and 2-chlorobenzylchloride (0.030 mL, 0.24 mmol). The reaction was diluted with CH ₂ Cl ₂ (10 mL) and saturated aqueous sodium bicarbonate (10 mL). The aqueous phase was washed with CH ₂ Cl ₂ (2 × 5 mL) and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude foam was purified by silica gel radial chromatography gel (1 mm plate, 100: 1: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give the title amide (23 mg, 37% over two steps) as a yellow foam. Obtained.
[639] General Process D Use: The foam from the stomach (23 mg, 0.045 mmol) was converted to a hydrobromide salt and then reprecipitated the intermediate solid from methanol / ether to give compound 53 (27 mg, 83%) as a yellow solid. . ¹ H NMR (D ₂ O) δ 1.44-1.62 (m, 4H), 1.74-1.97 (m, 4H), 2.04-2.21 (m, 3H), 2.41-2.46 (m, 1H), 2.80-2.84 (m , 1H), 3.00-3.02 (m, 2H), 3.98-3.99 (m, 1H), 4.41 (d, 1H, J = 16.8 Hz), 4.55-4.60 (m, 1H), 4.58 (d, 1H, J = 16.8 Hz), 7.30-7.37 (m, 2H), 7.43-7.45 (m, 2H), 7.60 (dd, 2H, J = 6, 3 Hz), 7.75 (dd, 2H, J = 6, 3 Hz), 7.82 (dd, 1H, J = 7.8, 6 Hz), 8.31 (d, 1H, J = 8.1 Hz), 8.58 (d, 1H, J = 5.7 Hz); ¹³ C NMR (D ₂ O) δ 20.78, 23.87, 25.39, 27.11, 27.59, 28.54, 28.92, 44.11, 45.77, 59.89, 60.00, 114.24, 125.83, 127.07, 127.73, 128.61, 130.18, 130.88, 131.89, 135.36, 139.08 , 140.55, 148.01, 151.94, 152.11, 170.46. ES-MS m / z 514 (M + H). Calcd for C ₃₀ H ₃₂ N ₅ OCl .2 .2HBr. 1.9 H ₂ O: C, 49.61; H, 5. 27; N, 9.64; Br, 24.20. Found: C, 49.65; H, 5. 22; N, 9.50; Br, 24.17.
[640] Example 54
[641]
[642] Compound 54: N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,4-diamine ( Hydrobromide salts)
[643] According to the general procedure for N-alkylation: N, N-di in a stirred solution of the lower, more polar diastereomer (see Compound 52) (107 mg, 0.31 mmol) from above in CH ₃ CN (5 mL). Isopropylethylamine (0.11 mL, 0.63 mmol), KI (14 mg, 0.08 mmol) and 1- (tert-butoxycarbonyl) -2- (chloromethyl) benzimidazole (106 mg, 0.40 mmol) were added The mixture was stirred at 60 ° C. for 7 hours. The obtained brown oil was subjected to silica gel column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 96: 4: 0 to 95: 4: 1), followed by silica gel radial chromatography (1 mm plate, (CH ₂ Cl ₂₎ / MeOH / NH 4 OH, 50: 1: 1) to afford the desired alkylated trans-1,4-diamine (44 mg, 25%) as a clear oil.
[644] Use of General Process D: Compounds by converting the foam from the stomach (31 mg, 0.054 mmol) into hydrobromide salts, at the same time removing the N-tert-butoxycarnoyl protecting group and then reprecipitating the intermediate solids from methanol / ether 54 (32 mg, 90%) was obtained as a white solid. ¹ H NMR (D ₂ O) δ 1.40-1.61 (m, 4H), 1.86-2.30 (m, 7H), 2.42-2.46 (m, 1H), 2.76-2.84 (m, 1H), 3.00-3.02 (m , 2H), 3.11-3.18 (m, 1H), 4.44 (d, 1H, J = 16.8 Hz), 4.52-4.57 (m, 1H), 4.57 (d, 1H, J = 16.8 Hz), 7.60 (dd, 2H, J = 6, 3 Hz), 7.77 (dd, 2H, J = 6, 3 Hz), 7.81 (dd, 1H, J = 7.8, 6 Hz), 8.29 (d, 1H, J = 7.8 Hz), 8.58 (d , 1H, J = 5.7 Hz); ¹³ C NMR (D ₂ O) δ 20.73, 24.05, 27.54, 27.62, 29.60, 29.74, 29.85, 44.06, 49.58, 58.80, 59.30, 114.25, 125.80, 126.97, 131.03, 139.10, 140.46, 147.96, 151.62, 152.09. ES-MS mlz 376 (M + H). Calcd for C ₂₃ H ₂₉ N ₅ .3.0HBr.2.1H ₂ O: C, 42.11; H, 5.56; N, 10.67; Br, 36.54. Found: C, 42.24; H, 5. 60; N, 10.51; Br, 36.50.
[645] Example 55
[646]
[647] Compound 55: N1- (1H-benzimidazol-2-ylmethyl) -N1-((S) -5,6,7,8-tetrahydro-quinolin-8-yl) -trans-cyclohexane-1, Preparation of 4-diamine (hydrochloride salt)
[648] Di-tert-butyl dicarbonate (15.31 g) in a solution of trans-4-aminocyclohexanol hydrochloride (10.0 g, 65.9 mmol) and triethylamine (18.4 mL, 132.0 mmol) in tetrahydrofuran (132 mL) , 70.1 mmol) was added. The mixture was stirred at 25 ° C. under nitrogen for 17 h, at which time ethyl acetate (250 mL) was added. The solution was washed with water (2 × 100 mL), dried (Na ₂ SO ₄ ) and concentrated to give (4-hydroxycyclohexyl) -carbamic acid tert-butyl ester as a white solid (13.82 g, 97%) Obtained as. ¹ H NMR (CDCl 3) δ 1.09-1.25 (m, 2H), 1.31-1.39 (m, 2H), 1.44 (s, 9H), 1.94-2.03 (m, 4H), 3.42 (bs, 1H), 3.56- 3.64 (m, 1 H), 4.34 (bs, 1 H).
[649] Activated 3-molecular sieve (6.54 g), 4-methylmorpholine N- in a solution of (4-hydroxy-cyclohexyl) -carbamic acid tert-butyl ester (5.80 g, 26.9 mmol) in anhydrous methylene chloride (67 mL) Oxide (5.04 g, 43.0 mmol) and tetrapropylammonium perruthenate (380 mg, 1.08 mmol) were added sequentially. The mixture was stirred at 25 ° C. for 18 hours under nitrogen, then the mixture was concentrated. Column chromatography on silica gel (hexane / ethyl acetate (1: 1) to give (4-oxo-cyclohexyl) -carbamic acid tert- butyl ester as a white solid ^{(5.52g, 96%) 1 H} NMR (CDCl ₃ ) δ 1.46 (s, 9H), 1.64-1.74 (m, 2H), 2.21-2.27 (m, 2H), 2.39-2.45 (m, 4H), 3.97 (bs, 1H), 4.40 (bs, 1H).
[650] Acetic acid (2.9 mL, 50.7 mmol), (4-oxo-cyclohexyl) -carbamic acid tert-butyl ester (4.32 g, 20.2 mmol) and sodium triacetoxyborohydride (7.56 g, 35.7 mmol) were added to tetrahydrofuran. To a solution of (S) -5,6,7,8-tetrahydro-quinolin-8-ylamine (2.86 g, 19.3 mmol) in (78 mL) was added and the mixture was stirred at 25 ° C. for 3.5 h. The mixture was diluted with methylene chloride (500 mL) and washed with saturated sodium bicarbonate (600 mL). The aqueous layer was extracted with methylene chloride (2 x 150 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The crude isomeric mixture was purified by column chromatography on silica gel (methanol / methylene chloride (4:96)) to give the trans-isomer [4-((S) -5,6,7,8-tetrahydro-quinolin-8-yl. Amino) -trans-cyclohexyl] -carbamic acid tert-butyl ester was obtained as a white solid (2.01 g, 30%). ¹ H NMR (CDCl 3) δ 1.06-1.39 (m, 4H), 1.69 (s, 9H), 1.65-1.80 (m, 2H), 1.90-2.14 (m, 5H), 2.16-2.25 (m, 1H), 2.29 (bs, 1H), 2.56-2.71 (m, 1H), 2.72-2.88 (m, 2H), 3.43 (bs, 1H), 3.92 (t, 1H, J = 6.3 Hz), 4.39 (bs, 1H) , 7.04 (dd, 1H, J = 7.9, 4.5 Hz), 7.35 (d, 1H, J = 7.5 Hz), 8.38 (d, 1H, J = 4.5 Hz).
[651] Enantiomeric purity of [4-((S) -5,6,7,8-tetrahydroquinolin-8-ylamino) -trans-cyclohexyl] carbamic acid tert-butyl ester was determined using the following conditions: Measured to 95% by: Instrument: Hewlett Packard 1100 HPLC (VWD2); Column: Chiralpak AD, 2.1 cm × 100 cm; Mobile phase: A = 90: 10 hexanes / isopropyl (0.1% TFA), B = isopropanol; Isocratic: 90% A, 10% B; Total running time: 25 minutes; Flow rate: 1.0 ml / min; Temperature: 10 ° C .; Detector: UV @ 254 nm; Injection volume: 30 μl.
[652] Retention time for the S enantiomer = 5.3 min.
[653] Retention time of R enantiomers = 8.1 min.
[654] [4-((S) -5,6,7,8-Tetrahydro-quinolin-8-ylamino) -trans-cyclohexyl] -carbamic acid tert-butyl ester in anhydrous acetonitrile (60 mL) (1.95 g) , 5.64 mmol), 2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (1.65 g, 6.20 mmol), diisopropylethylamine (2.0 mL, 11.4 mmol) and potassium iodide (100 mg, 0.60 mmol) was added. The mixture was warmed to 60 ° C. and stirred under nitrogen for 2 days. The mixture was concentrated, extracted with methylene chloride (80 mL) and washed with brine (50 mL). The aqueous layer was extracted with methylene chloride (3 x 50 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (80 g) (methanol / methylene chloride (4:96)) to give 2-{[(4-tert-butoxycarbonylamino-trans-cyclohexyl)-(5, 6,7,8-Tetrahydro-quinolin-8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester was obtained as a white solid (1.82 g, 56%). ¹ H NMR (CDCl ₃ ) δ 1.09 (bs, 2H), 1.43 (s, 9H), 1.68 (s, 9H), 1.83-2.14 (m, 6H), 2.47-2.63 (m, 1H), 2.65-2.79 (m, 1H), 2.79-2.95 (m, 1H), 3.32 (bs, 1H), 4.30 (bs, 2H), 4.46 (s, 2H), 6.75-6.89 (m, 1H), 7.00-7.13 (m , 1H), 7.61-7.70 (m, 1H), 7.70-7.79 (m, 1H), 8.32 (bs, 1H).
[655] 2-{[(4-tert-butoxycarbonylamino-trans-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzimidazole- 1-carboxylic acid tert-butyl ester was dissolved in acetic acid (15 mL) and hydrogen chloride gas was bubbled through the solution for 10 minutes. The mixture was stirred for further 1.75 h and then diluted with acetic acid (15 mL). The acetic acid solution was added dropwise over 40 minutes quickly into a stirred flask of diethyl ether (300 mL) to form a white floppy precipitate. The ether mixture was precipitated and decanted. The slurry was washed with ether (4 x 300 mL), then the precipitate was recovered on a glass frit and rinsed thoroughly with ether. The frit was placed in a vacuum oven (40 ° C.) for 18 hours to afford compound 55 as a beige solid (1.36 g, 79%). ¹ H NMR (D ₂ O) δ 1.34-1.1.52 (m, 2H), 1.57 (dq, 2H, J = 12.3, 2.4 Hz), 1.77-1.92 (m, 1H), 1.97-2.21 (m, 6H ), 2.24-2.42 (m, 1H), 2.82 (tt, 1H, J = 11.6, 3.1 Hz), 3.09 (d, 2H, J = 3.9 Hz), 3.13 (tt, 1H, J = 11.7, 3.6 Hz) , 4.38 (d, 1H, J = 16.5 Hz), 4.51 (m, 2H), 7.52-7.58 (m, 2H), 7.71-7.77 (m, 3H), 8.23 (d, 1H, J = 7.5 Hz), 8.54 (d, 1 H, J = 4.8 Hz); ¹³ C NMR (D ₂ O) δ 20.70, 24.04, 27.51, 27.62, 29.62, 29.67, 29.85, 44.05, 49.60, 58.74, 59.42, 114.30 (2C), 125.64, 126.63 (2C), 131.62, 139.11, 140.28, 147.65 , 151.75, 152.19. ES-MS mlz 376 (M + H). Calcd for C ₂₃ H ₂₉ N ₅ .3.0HCl.2.5H ₂ O.0.2Et ₂ O: C 52.47, H 7.22, N 12.86, Cl 19.52. Found: C 52.46, H 6.97, N 12.85, Cl 19.56.
[656] Enantiomeric purity of Compound 55 was determined to be 97% by chiral HPLC using the following conditions: Instrument: Hewlett Packard 1100 HPLC (VWD2); Column: Chiralpak AD, 2.1 cm × 100 cm; Mobile phase: A = 90: 10 hexanes / isopropyl (0.1% TFA), B = isopropanol; Isocratic: 70% A, 30% B; Total running time: 20 minutes; Flow rate: 0.6 ml / min; Temperature: 5 ° C .; Detector: UV @ 270 nm; Injection volume: 20 μl.
[657] Retention time for the S enantiomer = 11.1 min.
[658] Retention time for R enantiomers = 8.8 min.
[659] Example 56
[660]
[661] Compound 56: N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -N2-benzyl-cyclohexane-trans-1, Preparation of 4-diamine (hydrobromide salt)
[662] Preparation of N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,4-diamine:
[663]
[664] Preparation of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine (Smith, J .; Liras, JL; Schneider, SE; Anslyn, E J. Org. Chem. 1996, 61, 8811-8818 ):
[665] A solution of di-tert-butyl dicarbonate (7.67 g, 35.1 mmol) in CHCl ₃ (50 mL) was added to a solution of trans-1,4-cyclohexanediamine (8.01 g, 70.1 mmol) in CHCl ₃ (230 mL). It was applied for 6 hours through a syringe pump. The resulting white suspension was stirred for an additional 10 h at rt under vacuum and then diluted with CH ₂ Cl ₂ (100 mL) and saturated aqueous Na ₂ CO ₃ (100 mL). The layers were separated and the organic layer was washed with saturated aqueous Na ₂ CO ₃ (2 × 30 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (5.30 g, 71% based on Boc ₂ O) as a white solid.
[666] According to general process B for reductive amination: 6,7-dihydro-5H-quinolin-8-one (3.04 g, 20.65 mmol) and N-tert-butoxycarbonyl- in dry THF (100 mL) To a stirred solution of trans-1,4-cyclohexanediamine (4.42 g, 20.65 mmol) was added AcOH (3 mL) and NaBH (OAc) ₃ (5.69 g, 26.85 mmol) and the mixture was stirred at rt overnight. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 96: 4: 0 and then 94: 5: 1) afforded the desired amine (3.79 g, 53%) as a white solid.
[667] According to the general procedure for N-alkylation: N, N-diisopropylethylamine (3.5) in a stirred solution of trans-1,4-diamine (3.79 g, 11.0 mmol) from above in CH ₃ CN (55 mL) ML, 19.7 mmol), KI (91 mg, 0.55 mmol) and 1- (tert-butoxycarbonyl) -2- (chloromethyl) benzimidazole (2.93 g, 11.0 mmol) were added and the mixture was stirred at 60 ° C. Stir overnight. The resulting orange foam was purified by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 96: 4: 0 and then 94: 5: 1) to give the desired alkylated amine (3.28 g, 52%) as yellow. Obtained as a foam.
[668] Yellow foam (3.28 g, 5.70 mmol) oil from above was dissolved in CH ₂ Cl ₂ / TFA (1: 1, 10 mL) and the mixture was stirred at rt for 2.5 h. The reaction was then concentrated and diluted with CH ₂ Cl ₂ (80 mL) and 1N NaOH (75 mL). The aqueous layer was washed with CH ₂ Cl ₂ (2 × 50 mL) and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (1.97 g, 92%) as a yellow foam. . ¹ H NMR (CDCl ₃ ) δ 0.92-1.10 (m, 2H), 1.21-1.28 (m, 2H), 1.45-1.58 (m, 4H), 1.66-1.77 (m, 2H), 1.82-1.90 (m, 2H), 1.95-2.09 (m, 1H), 2.17-2.35 (m, 1H), 2.39-2.59 (m, 2H), 2.67-2.80 (m, 1H), 2.83-2.96 (m, 1H), 4.10 ( dd, 1H, J = 9, 6 Hz), 4.19 (s, 2H), 7.14-7.21 (m, 4H), 7.43 (d, 1H, J = 6 Hz), 7.55-7.62 (br m, 2H), 8.60 ( d, 1H, J = 6 Hz); ¹³ C NMR (CDCl ₃ ) δ 21.85, 27.32, 29.31, 29.84, 30.97, 45.61, 50.03, 56.58, 62.37, 110.77, 118.96, 121.36, 122.23, 134.74, 137.52, 146.34, 158.32, 158.60.
[669] N ^1- (1H-benzimidazol-2-ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans- in anhydrous MeOH (3 mL) Benzaldehyde (0.038 mL, 0.37 mmol) was added to a stirred solution of 1,4-diamine (140 mg, 0.37 mmol), and the solution was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, analyzed by ¹ H NMR and redissolved in MeOH (3 mL) and CH ₂ Cl ₂ (0.8 mL). Sodium borohydride (28 mg, 0.74 mmol) was added to the solution, and the mixture was stirred at room temperature for 2 hours (see General Process B). The crude material was purified by silica gel radial chromatography gel (1 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, gradient elution from 100: 1: 1 to 20: 1: 1) to give the free amine (119 mg, 69% ) Was obtained as a clear oil.
[670] General Process D Use: The oil from the stomach (119 mg, 0.26 mmol) was converted to a hydrobromide salt, followed by reprecipitation of the intermediate solid from methanol / ether to give compound 56 (149 mg, 79%) as a white solid. . ¹ H NMR (D ₂ O) δ 1.44-1.60 (m, 4H), 1.79-1.93 (m, 1H), 2.00-2.11 (m, 1H), 2.14-2.32 (m, 5H), 2.40-2.44 (m , 1H), 2.77-2.85 (m, 1H), 2.98-3.01 (m, 2H), 3.12-3.20 (m, 1H), 4.21 (s, 2H), 4.42 (d, 1H, J = 16.8 Hz), 4.52-4.56 (m, 1H), 4.55 (d, 1H, J = 16.8 Hz), 7.41-7.47 (m, 5H), 7.59 (dd, 2H, J = 6, 3 Hz), 7.76 (dd, 2H, J = 6, 3 Hz), 7.79 (dd, 1H, J = 8.1, 6.3 Hz), 8.28 (d, 1H, J = 7.5 Hz), 8.57 (d, 1H, J = 5.5 Hz); ¹³ C NMR (D ₂ O) δ 20.72, 24.03, 27.54, 27.61, 28.08, 28.35, 29.71, 44.01, 48.93, 56.04, 58.79, 59.32, 114.24, 125.80, 126.95, 129.72, 130.04, 131.06, 131.31, 139.10, 140 , 147.95, 151.56, 152.03. ES-MS m / z 466 (M + H). Calcd for C ₃₀ H ₃₅ N ₅ .3.0HBr.2.0H ₂ O: C, 48.41; H, 5.69; N, 9.41; Br, 32.20. Found: C, 48.65; H, 5.92; N, 9. 32; Br, 31.97.
[671] Example 57
[672]
[673] Compound 57: N ^One-(1H-benzimidazol-2-ylmethyl) -N ⁴Preparation of -Butyl-N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,4-diamine (hydrobromide salt)
[674] Preparation of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine ^ref
[675] ^ref Smith, J .; Liras, JL; Schneider, SE; Anslyn, E. Solid and Solution Phase Organic Syntheses of Oligomeric Thioureas J. Org. Chem. 1996, 61, 8811-8818.
[676] A solution of di-tert-butyl dicarbonate (7.67 g, 35.1 mmol) in CHCl ₃ (50 mL) was added to a solution of trans-1,4-cyclohexanediamine (8.01 g, 70.1 mmol) in CHCl ₃ (230 mL). It was applied for 6 hours through a syringe pump. The resulting white suspension was stirred for an additional 10 hours at room temperature, then concentrated under reduced pressure and diluted with CH ₂ Cl ₂ (100 mL) and saturated aqueous Na ₂ CO ₃ (100 mL). The layers were separated and the organic layer was washed with saturated aqueous Na ₂ CO ₃ (2 × 30 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (5.30 g, 71% based on Boc ₂ O) as a white solid.
[677] N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,4-diamine
[678] According to general process B: 6,7-dihydro-5H-quinolin-8-one (3.04 g, 20.65 mmol) and N-tert-butoxycarbonyl-trans-1,4- in dry THF (100 mL) To a stirred solution of cyclohexanediamine (4.42 g, 20.65 mmol) was added AcOH (3 mL) and NaBH (OAc) ₃ (5.69 g, 26.85 mmol) and the mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and CH ₂ Cl ₂ (100㎖) and saturated aqueous sodium bicarbonate (100㎖) dilution, and the aqueous phase was CH ₂ Cl ₂ (100㎖) and saturated aqueous sodium bicarbonate with (100㎖) Dilute and extract the aqueous phase with CH ₂ Cl ₂ (3 × 75 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 96: 4: 0 and then 94: 5: 1) afforded the desired amine (3.79 g, 53%) as a white solid.
[679] According to the general procedure for N-alkylation: [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -trans-cyclohexyl]-from above in CH ₃ CN (55 mL) To a stirred solution of carbamic acid tert-butyl ester (3.79 g, 11.0 mmol) N, N-diisopropylethylamine (3.5 mL, 19.7 mmol), KI (91 mg, 0.55 mmol) and 1- (tert-butoxy Carbonyl) -2- (chloromethyl) benzimidazole (2.93 g, 11.0 mmol) was added. The mixture was stirred at 60 ° C. overnight, cooled, concentrated and diluted with CH ₂ Cl ₂ (100 mL) and saturated aqueous sodium bicarbonate (75 mL). The aqueous phase was washed with CH ₂ Cl ₂ (2 × 50 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The resulting orange foam was purified by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 96: 4: 0 and then 94: 5: 1) to give the desired alkylated amine (3.28 g, 52%) as yellow. Obtained as a foam.
[680] Yellow foam (3.28 g, 5.70 mmol) from above was dissolved in CH ₂ Cl ₂ / TFA (1: 1, 10 mL) and the mixture was stirred at rt for 2.5 h. The reaction was then concentrated and diluted with CH ₂ Cl ₂ (80 mL) and 1N NaOH (75 mL). The aqueous layer was washed with CH ₂ Cl ₂ (2 × 50 mL), the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to N ^1- (1H-benzimidazol-2-ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,4-diamine (1.97 g, 92%) was obtained as a yellow foam. ¹ H NMR (CDCl ₃ ) δ 0.92-1.10 (m, 2H), 1.21-1.28 (m, 2H), 1.45-1.58 (m, 4H), 1.66-1.77 (m, 2H), 1.82-1.90 (m, 2H), 1.95-2.09 (m, 1H), 2.17-2.35 (m, 1H), 2.39-2.59 (m, 2H), 2.67-2.80 (m, 1H), 2.83-2.96 (m, 1H), 4.10 ( dd, 1H, J = 9, 6 Hz), 4.19 (s, 2H), 7.14-7.21 (m, 4H), 7.43 (d, 1H, J = 6 Hz), 7.55-7.62 (br m, 2H), 8.60 ( d, 1H, J = 6 Hz); ¹³ C NMR (CDCl ₃ ) δ 21.85, 27.32, 29.31, 29.84, 30.97, 45.61, 50.03, 56.58,62.37, 110.77, 118.96, 121.36, 122.23, 134.74, 137.52, 146.34, 158.32, 158.60.
[681] N ^1- (1H-benzimidazol-2-ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans- in anhydrous MeOH (2 mL) To a stirred solution of 1,4-diamine (0.0753 g, 0.20 mmol) was added freshly upstream butyraldehyde (22 mL, 0.24 mmol). The resulting mixture was stirred at rt for 0.5 h and concentrated under reduced pressure. The residue was redissolved in anhydrous MeOH (2 mL) and NaBH ₄ (15 mg, 0.40 mmol) was added. The resulting mixture was stirred at rt for 22 h. The mixture was concentrated and the residue was partitioned between CH ₂ Cl ₂ (20 mL) and saturated aqueous sodium bicarbonate (30 mL). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 15 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude material was subjected to silica gel radial chromatography (TLC grade 1 mm plate, 100: 1: 1 CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH followed by 50: 1: 1 CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH). Purification with hexane gave 23 mg (30%) of the free base of the title compound as a pale yellow oil. General Process D Use: The foam from the stomach (23 mg, 0.05 mmol) was converted to a hydrobromide salt and then reprecipitated the intermediate solid from methanol / ether to give compound 57 (73 mg, quant.) As a white solid. ¹ H NMR (D ₂ O) δ 0.88 (t, 3H, J = 7.5 Hz), 1.26-1.47 (m, 4H), 1.48-1.65 (m, 4H), 1.79-1.92 (m, 1H), 1.93- 2.34 (br m, 7H), 2.35-2.47 (m, 1H), 2.75-2.88 (m, 1H), 2.95-3.14 (m, 5H), 4.42 (d, 1H, J = 16.8 Hz), 4.49-4.55 (m, 1H), 4.56 (d, 1H, J = 16.5 Hz), 7.54-7.63 (m, 2H), 7.72-7.84 (m, 3H), 8.28 (d, 1H, J = 7.5 Hz), 8.56 ( d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 13.17, 19.61, 20.71, 24.03, 27.53, 27.59, 28.09, 28.20, 28.34, 29.69, 44.00, 45.15, 56.08, 58.78, 59.39, 114.24, 125.79, 126.96, 131.06, 139.10, 140.46 , 147.942, 151.58, 152.05. ES-MS m / z 432 (M + H). Calcd for C ₂₇ H ₃₇ N ₅ .3.0HBr.2.1H ₂ O: C, 45.54; H, 6. 26; N, 9.83; Br, 33.66. Found: C, 45.62; H, 6.07; N, 9.66; Br, 33.51.
[682] Example 58
[683]
[684] Compound 58: N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -N2, N2-dimethyl-cyclohexane-trans-1,4 Preparation of Diamines (hydrobromide salts)
[685] N ^1- (1H-benzimidazol-2-ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans- in anhydrous MeOH (3 mL) Paraformaldehyde (powder) (17 mg, 0.57 mmol) was added to a stirred solution of 1,4-diamine (157 mg, 0.42 mmol), and the solution was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, analyzed by ¹ H NMR and redissolved in MeOH (2.5 mL) and CH ₂ Cl ₂ (1 mL). Sodium borohydride (32 mg, 0.83 mmol) was added to this solution, and the mixture was stirred at room temperature for 1.5 hours (see General Steps A and B). The crude material was purified by silica gel radial chromatography gel (1 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, gradient elution from 50: 1: 1 to 10: 1: 1) to dimethylated and monomethylated free amines ( 138 mg) was obtained as a non-separable yellow foam mixture. Both amines were reconstituted with basic alumina phase column chromatography (CH ₂ Cl ₂ / MeOH, 98: 2 then 95: 5) and separated so that both were clear oils, dimethylated product (44 mg, 26%) and monomethylated glass. Amine (21 mg, 13%) was obtained.
[686] Use General Process D: Dimethylated amine (44 mg, 0.11 mmol) from the stomach is converted to hydrobromide salts and then reprecipitated intermediate solids from methanol / ether to make compound 58 (72 mg, 97%) as a white solid. Obtained. ¹ H NMR (D ₂ O) δ 1.46-1.65 (m, 4H), 1.79-1.93 (m, 1H), 2.05-2.21 (m, 5H), 2.31-2.53 (m, 2H), 2.75-2.82 (m , 1H), 2.77 (s, 6H), 2.99-3.01 (m, 2H), 3.15-3.22 (m, 1H), 4.43 (d, 1H, J = 16.8 Hz), 4.50-4.55 (m, 1H), 4.56 (d, 1H, J = 16.8 Hz), 7.58 (dd, 2H, J = 6, 3 Hz), 7.76 (dd, 2H, J = 6, 3 Hz), 7.80 (dd, 1H, J = 7.8, 6 Hz) , 8.28 (d, 1H, J = 7.8 Hz), 8.57 (d, 1H, J = 5.1 Hz); ¹³ C NMR (D ₂ O) δ 20.71, 23.97, 25.62, 25.82, 27.55, 27.76, 29.81, 40.05, 44.03, 58.87, 59.26, 64.33, 114.24, 125.82, 127.01, 130.98, 139.12, 140.48, 148.00, 151.53, 151.97 . ES-MS m / z 404 (M + H). Calcd for C ₂₅ H ₃₃ N ₅ .3.0HBr.2.0H ₂ O: C, 44.01; H, 5.91; N, 10.26; Br, 35.13. Found: C, 44.14; H, 6.02; N, 10.01; Br, 34.98.
[687] Example 59
[688]
[689] Compound 59: N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -N2-methyl-cyclohexane-trans-1,4-diamine (hydrobromide salt)
[690] Use General Process D: Convert monomethylated amine (see Compound 58) (21 mg, 0.054 mmol) from above into hydrobromide salt and then reprecipitate the intermediate solid from methanol / ether to give compound 59 (25 mg, 71% ) Was obtained as a white solid. ¹ H NMR (D ₂ O) δ 1.31-1.43 (m, 2H), 1.51-1.63 (m, 2H), 1.78-1.93 (m, 1H), 1.99-2.31 (m, 6H), 2.40-2.44 (m , 1H), 2.63 (s, 3H), 2.75-2.87 (m, 1H), 2.98-3.01 (m, 3H), 4.42 (d, 1H, J = 16.8 Hz), 4.51-4.55 (m, 1H), 4.55 (d, 1H, J = 16.8 Hz), 7.59 (dd, 2H, J = 6, 3 Hz), 7.75 (dd, 2H, J = 6, 3 Hz), 7.79 (dd, 1H, J = 7.8, 6 Hz) , 8.28 (d, 1H, J = 8.1 Hz), 8.56 (d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 20.71, 24.01, 27.54, 27.85, 28.09, 29.63, 30.36, 44.00, 57.11, 58.81, 59.40, 114.24, 125.78, 126.94, 131.09, 139.10, 140.45, 147.93, 151.59, 152.05. ES-MS m / z 390 (M + H). Calcd for C ₂₄ H ₃₁ N ₅ .2.9HBr.3.0H ₂ O: C, 42.50; H, 5.93; N, 10.33; Br, 34.17. Found: C, 42.48; H, 5.65; N, 10.12; Br, 34.31.
[691] Example 60
[692]
[693] Compound 60: N- {4-trans-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-inolinolin-8-yl) -amino] -cyclohexyl} Preparation of Guanidine (hydrobromide salt)
[694] N ^1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -N ² -benzyl-cyclo in anhydrous THF (1.5 mL) N, N'-bis- (tert-butoxycarbonyl) -1H-pyrazole-1-carboxamidine (Tetrahedron) in a solution of hexane-trans-1,4-diamine (174 mg, 0.46 mmol) Lett. 1993, 34, 3389) was added and the resulting mixture was stirred at rt for 26 h. The reaction was concentrated and purified by silica gel radial chromatography (2 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, gradient elution of 50: 1: 1 to 5: 1: 1) to give the desired guanidine (51 mg, 18%) was obtained as a clear oil.
[695] General Process D Use: The oil from the stomach (51 mg, 0.083 mmol) was converted to the hydrobromide salt and then reprecipitated the intermediate solid from methanol / ether to give compound 60 (50 mg, 85%) as a white solid. . ¹ H NMR (D ₂ O) δ 1.22-1.34 (m, 2H), 1.49-1.60 (m, 2H), 1.79-2.21 (m, 8H), 2.40-2.44 (m, 1H), 2.70-2.78 (m , 1H), 2.98-3.01 (m, 2H), 3.24-3.32 (m, 1H), 4.42 (d, 1H, J = 16.8 Hz), 4.50-4.55 (m, 1H), 4.56 (d, 1H, J = 16.8 Hz), 7.59 (dd, 2H, J = 6, 3 Hz), 7.76 (dd, 2H, J = 6, 3 Hz), 7.80 (dd, 1H, J = 7.8, 6 Hz), 8.28 (d, 1H, J = 7.8 Hz), 8.57 (d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 20.75, 24.04, 27.55, 28.14, 30.36, 31.23, 31.51, 44.11, 50.20, 58.86, 59.67, 114.23, 125.78, 126.98, 130.97, 139.05, 140.45, 147.94, 151.73, 152.23, 152.23 . ES-MS m / z 418 (M + H). Calcd for C ₂₄ H ₃₁ N ₇ .3.0HBr. 2.0H ₂ O.0.2C ₄ H ₁₀ O: C, 41.78; H, 5.68; N, 13.75; Br, 33.62. Found: C, 41.74; H, 5.63; N, 13.62; Br, 33.65.
[696] Example 61
[697]
[698] Compound 61: N ^One-(1H-benzimidazol-2-ylmethyl) -N ⁴-(1H-indol-3-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,4-diamine (free base)
[699] General Process B (2-Step Reductive Amination): N ^1- (1H-benzimidazol-2-ylmethyl) -N ^1- (5,6,7,8-tetrahydro in CH ₃ OH (5 mL) Indole-3-carboxaldehyde (52 mg, 0.36 mmol) was added to a solution of -quinolin-8-yl) -cyclohexane-trans-1,4-diamine (104 mg, 0.28 mmol), and the resulting solution was room temperature. Stir overnight at. NaBH ₄ (26 mg, 0.68 mg) was added and the mixture was stirred for an additional 15 minutes. The mixture was concentrated under reduced pressure and the residue was partitioned between CH ₂ Cl ₂ (20 mL) and saturated aqueous NaHCO ₃ (5 mL). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 5 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel radial chromatography (1 mm plate, 50: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 105 mg of compound 61 as a white foam. ¹ HNMR (CDCl ₃ ) δ 0.93-1.30 (m, 3H), 1.47-2.02 (m, 9H), 2.20-2.25 (m, 1H), 2.50-2.51 (m, 2H), 2.65-2.76 (m, 1H ), 2.83-2.94 (m, 1H), 3.93 (s, 2H), 4.10 (dd, 1H, J = 5.7, 10.2 Hz), 4.20 (s, 2H), 7.07-7.12 (m, 2H), 7.15- 7.21 (m, 4H), 7.34 (d, 1H, J = 7.8 Hz), 7.42-7.49 (m, 2H), 7.59 (d, 1H, J = 7.8 Hz), 7.66-7.69 (m, 1H), 8.23 (br s, 1 H), 8.34 (br s, 1 H), 8.60 (d, 1 H, J = 3.6 Hz); ¹³ C NMR (CDCl ₃ ) δ 22.22, 27.63, 29.71, 30.34, 31.43, 33.00, 33.14, 42.46, 46.01, 56.15, 57.61, 62.78, 111.30, 111.65, 115.35, 119.00 (2 carbons), 119.78, 121.59, 121.88, 122.40, 122.60, 122.78, 127.31, 134.03, 135.12, 136.78, 137.87, 145.03, 146.74, 158.77, 159.11. ES-MS m / z 505 (M + H). Calcd for C ₃₂ H ₃₆ N ₆ .0.5 H ₂ O.0.5CH ₂ Cl ₂ : C, 70.19; H, 6.89; N, 15.11. Found: C, 69.94; H, 6.81; N, 15.15.
[700] Example 62
[701]
[702] Compound 62: N ^One-(1H-benzimidazol-2-ylmethyl) -N ⁴-(Pyridin-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,4-diamine (hydrobromide salt)
[703] General Process B (2-Step Reductive Amination) Use: N ^1- (1H-benzimidazol-2-ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) Cyclohexene-trans-1,4-diamine (98 mg, 0.26 mmol) with pyridine-2-carboxaldehyde (30 mL, 0.32 mmol) in CH ₃ OH (5 mL) for 2.5 h, NaBH ₄ ( 27 mg, 0.71 mmol) for 15 minutes, and then the crude material was purified by radial chromatography on silica gel (1 mm plate, 50: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give the title compound. The free base was obtained as a colorless oil.
[704] General Process D Use: The oil from the stomach (79 mg, 0.17 mmol) was converted to a hydrobromide salt and then reprecipitated intermediate solids from methanol / ether to give 62 (126 mg, 85%) as a white solid. . ¹ H NMR (D ₂ O) δ 1.45-1.63 (m, 4H), 1.79-1.93 (m, 1H), 2.02-2.45 (m, 7H), 2.79-2.86 (m, 1H), 2.99-3.01 (m , 2H), 3.25-3.33 (m, 1H), 4.41-4.60 (m, 5H), 7.56-7.61 (m, 2H), 7.75-7.82 (m, 5H), 8.22-8.30 (m, 2H), 8.57 (d, 1H, J = 5.1 Hz), 8.69 (d, 1H, J = 4.5 Hz); ¹³ C NMR (D ₂ O) δ 20.71, 24.03, 27.55 (2 carbons), 28.06, 28.31, 29.67, 43.99, 47.18, 57.04, 58.78, 59.21, 114.22, 125.83, 126.41, 126.60, 127.03, 130.91, 139.10, 140.51 , 143.47, 146.81, 148.02, 148.03, 151.48, 151.97. ES-MS m / z 467 (M + H). Calcd for C ₂₉ H ₃₄ N ₆ .4.2HBr.3.7H ₂ O: C, 39.89; H, 5. 26; N, 9.63; Br, 38.44. Found: C, 39.95; H, 5. 19; N, 9.61; Br, 38.45.
[705] Example 63
[706]
[707] Compound 63: 1-N '-[trans-4- (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -cyclohexanyl-N, Preparation of N-dimethylformamidine (hydrobromide salt)
[708] 2-pyridinesulfonyl chloride (71 mg, 0.40) in DMF (1 mL) using the process [L. Cai (Y. Han and L. Cai Tetrahedron Lett. 1997, 38 (31), 5423-5426)]. mmol) was stirred at rt for 10 min. Then N '-(1H-benzimidazol-2-ylmethyl) -N'-(5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,4-diamine (100 mg, 0.267 mmol) was added and the mixture was stirred at rt for 2 h. The DMF was then removed in vacuo, the residue dissolved in dichloromethane, washed with saturated aqueous sodium carbonate solution and then with distilled water. The organic fractions were then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography to give two products: 1-N '-[trans-4- (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro Quinolin-8-yl) -amino] -cyclohexanyl-N, N-dimethylformamidine (52 mg (45%)) and N '-(1H-benzimidazol-2-ylmethyl) -N'- (5,6,7,8-Tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,4-diamine-N- (2-pyridinyl) -sulfonamide (41 mg, 29%). The spectral data for formamidine are as follows: ¹ H NMR (CDCl ₃ ) δ 1.41 (m, 2H), 1.56 (m, 2H), 1.67 (m, 2H), 1.79-1.91 (m, 3H), 2.21 (m, 1H), 2.51 (m, 1H), 2.74-2.81 (m, 3H), 2.83 (s, 6H), 4.06 (dd, 1H, J = 8.1, 5.4 Hz), 4.17 (s, 2H) , 7.16 (m, 5H), 7,41 (d, 1H, J = 8.1 Hz), 7.44 (br s, 1H (NH)), 7.68 (br s, 1H), 8.58 (d, 1H, J = 4.8 Hz). Sulfonamide showed excessive resonance expansion of the ¹ H NMR spectrum (CDCl ₃ ), which was not fully characterized at this stage, instead leading directly to the chlorination reaction.
[709] 1-N '-[trans-4- (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -cyclohexanyl-N, N-dimethylformamidine (52 mg, 0.120 mmol) was dissolved in acetic acid (1 mL), and thereto was added a saturated solution of HBr in acetic acid (1 mL). The mixture was then stirred, precipitated and separated for step D to afford compound 63 as white crystals (36 mg). ¹ H NMR (D ₂ O). δ 1.45 (m, 4H), 1.82-2.20 (m, 7H), 2.42 (m, 1H), 3.74 (dd, 1H, J = 10.5, 11.1 Hz), 2.94 (s, 3H), 2.99 (m, 2H ), 3.16 (s, 3H), 3.33 (m, 1H), 4.41 (d, 1H, J = 15.3 Hz), 4.52 (d, 1H, J = 15.3 Hz), 4.54 (m, 1H), 7.58 (m , 2H), 7.75 (m, 2H), 7.77 (s, 1H), 7.80 (dd, 1H, J = 8.1,5.7 Hz), 8.28 (d, 1H, J = 8.1 Hz), 8.56 (d, 1H, J = 5.7 Hz). ¹³ C NMR (D 2 O) δ 20.73, 24.04, 27.54, 28.10, 30.34, 32.07, 32.32, 36.05, 43.21, 44.11, 56.62, 58.79, 59.36, 114.21, 125.78, 126.99, 130.92, 139.03, 140.45, 147.99, 152.68 , 155.22. ES-MS m / z 431 (M + H); Calcd for (C ₂₆ H ₃₄ N ₆ x 2.9 HBr x 2.7H ₂ O): C, 43.74; H, 5.97; N, 11.77; Br 32.46. Found: C, 43.81; H, 5. 70; N, 11.44; Br, 32.39.
[710] Example 64
[711]
[712] Compound 64: N '-(1H-benzimidazol-2-ylmethyl) -N'-(5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,4-diamine-N Preparation of-(2-pyridinyl) -sulfonamide
[713] N '-(1H-benzimidazol-2-ylmethyl) -N'-(5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,4-diamine-N -(2-pyridinyl) -sulfonamide (from the above reaction, 41 mg, 0.079 mmol) was dissolved in acetic acid (1 mL), and saturated HBr solution in acetic acid (1 mL) was added thereto. The mixture was then stirred, precipitated and separated for process D to afford compound 64 as a white crystalline solid (52 mg). ¹ H NMR (D ₂ O) δ 1.20-2.16 (series of m, 9H), 2.38 (m, 1H), 2.60 (m, 1H), 2.82 (m, 1H), 2.98 (m, 2H), 3.10 (m, 1H), 3.62 (m, 1H), 4.46 (d, 1H, J = 15.3 Hz), 4.49 (m, 1H), 4,51 (d, 1H, J = 15.3 Hz), 7.56 (m, 2H), 7.73 (m, 3H), 7.94 (m, 1H), 8.06 (m, 1H), 8.26 (m, 1H), 8.56 (m, 2H). ¹³ C NMR (D ₂ O) δ 20.70, 27.51, 28.25, 30.44, 32.47, 44.04, 49.31, 52.58, 58.81, 59.48, 114.18, 122.92, 125.74, 126.97, 128.47, 130.87, 138.98, 140.25, 140.38, 147.90, 150.28 , 151.72, 152.19. ES-MS m / z 517 (M + H); Calcd for _{(C 28 H 32 N 6 O} 2 S × 2.6HBr × 3.3H 2 O): C, 42.76; H, 5. 28; N, 10.69; Br 26.42. Found: C, 42.86; H, 5.07; N, 10.32; Br, 26.77.
[714] Example 65
[715]
[716] Compound 65: N1- (1H-benzimidazol-2-ylmethyl) -N4- (1H-indol-2-ylmethyl) -N1- (5,6,7,8-tetrahydroquinolin-8-yl) Preparation of -cyclohexane-1,4-diamine
[717] Preparation of 2-hydroxymethylindole:
[718] A suspension of LiAlH ₄ (248 mg, 6.2 mmol) in THF (6 mL) was added to a solution of indole-2-carboxylic acid (485 mg, 3.01 mmol) in HF (20 mL) cooled to 0 ° C. under nitrogen. The green suspension obtained was stirred at room temperature for 4 hours. The reaction was quenched by the slow addition of 80% MeOH aqueous solution (1.0 mL) and the solvent was evaporated under reduced pressure. The residue was suspended in MeOH, filtered through celite and rinsed with MeOH. The filtrate was concentrated under reduced pressure to give a yellow oil. Purification by flash column chromatography on silica (MeOH / CH ₂ Cl ₂ , 9: 1 after 19: 1) afforded the alcohol as a beige solid (357 mg, 2.43 mmol, 81%). ¹ H NMR (CDCl ₃ ) δ 1.85 (t, 1H, J = 6.0 Hz), 4.83 (d, 2H, J = 6.0 Hz), 6.42 (d, 1H, J = 1.5 Hz), 7.11 (td, 1H, J = 6.9, 1.5 Hz), 7.20 (td, 1H, J = 6.9, 1.5 Hz), 7.35 (dd, 1H, J = 6.9, 1.5 Hz), 7.59 (d, 1H, J = 6.9 Hz), 8.33 ( br s., 1H).
[719] Preparation of indole-2-carboxaldehyde:
[720] To a solution of alcohol (341 mg, 2.32 mmol) in CH ₂ Cl ₂ (12 mL) was added activated MnO ₂ (2.40 g, 22.1 mmol). The suspension was stirred at rt for 2.5 h, then diluted with CH ₂ Cl ₂ and suction filtered through celite. The filtrate was concentrated under reduced pressure to give crude aldehyde as orange oil (288 mg, 1.98 mmol, 86%). ¹ H NMR (CDCl ₃ ) δ 7.18 (td, 1H, J = 6.9, 1.5 Hz), 7.29 (d, 1H, J = 1.5 Hz), 7.37-7.50 (m, 2H), 7.76 (d, 1H, J = 6.9 Hz), 9.18 (br s., 1 H), 9.86 (s, 1 H).
[721] Preparation of Compound 65:
[722] Aldehyde (74 mg, 0.51 mmol) and N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydroquinolin-8-yl)-in MeOH (5 mL) A cyclohexane-1,4-diamine (189 mg, 0.50 mmol) solution was stirred at room temperature under nitrogen for 20 hours. NaBH ₄ (39 mg, 1.0 mmol) was added and the reaction stirred for an additional 20 minutes. The solvent was evaporated under reduced pressure and the residue was dissolved in CH ₂ Cl ₂ (50 mL) and washed with saturated aqueous NaHCO ₃ (5 mL) and brine (5 mL). The organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 19: 1: 0.1) gave Compound 65 as a light yellow solid (118 mg, 0.23 mmol, 47%). ¹ H NMR (CDCl ₃ ) δ 0.88-1.13 (m, 2H), 1.16-1.29 (m, 1H), 1.39-1.52 (m, 1H), 1.63-1.73 (m, 1H), 1.80-2.04 (m, 6H), 2.19-2.23 (m, 1H), 2.33-2.41 (m, 1H), 2.44-2.52 (m, 1H), 2.67-2.74 (m, 1H), 2.81-2.94 (m, 1H), 3.91 ( s, 2H), 4.09 (dd, 1H, J = 9.9, 5.9 Hz), 4.18 (s, 2H), 6.27 (s, 1H), 7.02-7.21 (m, 5H), 7.28 (d, 1H, J = 10.2 Hz), 7.43 (d, 1H, J = 7.8 Hz), 7.45-7.48 (m, 1H), 7.52 (d, 1H, J = 7.8 Hz), 7.66-7.69 (m, 1H), 8.60 (d, 1 H, J = 4.2 Hz), 8.69 (br s., 1 H). ¹³ C NMR (CDCl ₃ ) δ 21.8, 27.3, 29.3, 29.9, 31.0, 32.7, 32.9, 44.4, 45.7, 56.1, 57.2, 62.1, 99.6, 110.6, 110.9, 118.6, 119.5, 120.0, 121.2, 121.3, 121.5, 122.2, 128.5, 133.6, 134.7, 135.8, 137.4, 138.3, 144.6, 146.4, 158.4, 158.5. ES-MS m / z 505 (M + H). Calcd for C ₃₂ H ₃₆ N ₆ CH ₂ Cl ₂ 0.1H ₂ O: C, 67.07; H, 6.51; N, 14.22. Found: C, 67.34; H, 6.55; N, 14.23.
[723] Example 66
[724]
[725] Compound 66: cis- (1H-benzimidazol-2-ylmethyl)-(4-morpholin-4-yl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) Preparation of Amine
[726] Cis- (4-morpholin-4-yl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine was prepared as described in compound 67. ¹ H NMR (CDCl ₃ ) δ 1.61-1.75 (m, 12H), 1.85-1.92 (m, 1H), 2.01-2.18 (m, 1H), 2.54 (t, 4H, J = 4.5 Hz), 2.76-2.81 (m, 2H), 2.92 (br m, 1H), 3.74 (t, 4H, J = 4.5 Hz), 3.87-3.93 (m, 1H), 7.03-7.07 (m, 1H), 7.36 (d, 1H, J = 9.0 Hz), 8.39 (d, 1H, J = 6.0 Hz).
[727] Stomach amine (69.0 mg, 0.22 mmol), 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (70.0 mg, 0.26 mmol), N, N-diisopropyl in CH ₃ CN (1.5 mL) Ethylamine (50 mL, 0.28 mmol) and potassium iodide (3.7 mg, 0.02 mmol) were stirred at 60 ° C. overnight. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The crude material was purified by silica gel radial chromatography (1 mm plate, NH ₄ OH / MeOH / CH ₂ Cl ₂ , 1: 2: 97 after 1: 1: 98) to afford the desired compound (56.8 mg, 47%). Obtained as a pale yellow solid. ¹ H NMR (CDCl ₃ ) δ 1.30-1.34 (m, 2H), 1.45-1.66 (m, 11H), 1.88-2.01 (m, 4H), 2.05-2.16 (m, 4H), 2.40 (br m, 4H ), 2.54 (t, 1H, J = 4.4 Hz), 2.59 (t, 1H, J = 3.9 Hz), 2.68-2.73 (m, 1H), 3.04-3.11 (m, 1H), 3.61-3.71 (m, 4H), 4.29 (dd, 1H, J = 8.7, 5.7 Hz), 4.43 (s, 2H), 6.829 (dd, 1H, J = 7.5, 4.8 Hz), 7.07 (d, 1H, J = 6.9 Hz), 7.22-7.28 (m, 2H), 7.61-7.70 (m, 1H), 7.73-7.79 (m, 1H), 8.32 (dd, 1H, J = 4.8, 1.5 Hz).
[728] A solution of bromic acid in acetic acid (0.5 mL) was added to a solution of the above solid (56.8 mg, 0.10 mmol) in acetic acid (1 mL) and the reaction mixture was stirred for 1 h. Diethyl ether was added until a precipitate of compound 67 was obtained as a pale yellow solid (49.1 mg, 62%). ¹ H NMR (D ₂ O) δ 1.75-1.89 (m, 6H), 2.12-2.36 (m, 8H), 2.98-3.99 (m, 4H), 3.11 (br m, 2H), 3.31 (br t, 2H ), 3.64 (br m, 2H), 3.91 (m, 2H), 4.07 (br m, 2H), 7.565 (dd, 2H, J = 6.0, 3.2 Hz), 7.72-7.77 (m, 3H), 8.24 ( d, 1H, J = 7.8 Hz), 8.52 (d, 1H, J = 6.0 Hz). ¹³ C NMR (D ₂ O) δ 20.73, 23.37, 24.35, 24.46, 25.70, 27.50, 43.76, 50.48, 57.69, 59.40, 63.50, 63.78, 114.25, 125.73, 126.91, 131.23, 139.12, 140.44, 147.84, 151.29, 152. . ES-MS m / z 446 [M + H] &lt; + &gt;. Calcd for C ₂₇ H ₃₅ N ₅ O. 3.0HBr. 2.0H ₂ O: C, 44.83; H, 5.71; N, 9.68; Br, 33.14. Found: C, 44.88; H, 5.72; N, 9.49; Br, 33.13.
[729] Example 67
[730]
[731] Compound 67: trans- (1H-benzimidazol-2-ylmethyl)-(4-morpholin-4-yl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) Preparation of -amines (hydrobromide salts)
[732] Preparation of (4-morpholin-4-yl-cyclohexylamine) -carbamic acid tert-butyl ester:
[733] Sodium in a solution of (4-oxo-cyclohexyl) -carbamic acid tert-butyl ester (426 mg, 2.00 mmol) and morpholine (175 mL, 2.00 mmol) in CH ₂ Cl 2 (25 mL) and acetic acid (120 mL) Triacetoxyborohydride (636 mg, 3.00 mmol) was added and the mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure and diluted with saturated aqueous sodium carbonate (30 mL). The aqueous layer was washed with CH ₂ Cl ₂ (4 × 20 mL) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (MeOH / CH ₂ Cl ₂ , 1: 9) afforded the title compound as a white solid (76.2 mg, 13%). ¹ H NMR (CDCl ₃ ) δ 1.04-1.17 (m, 6H), 1.25-1.38 (m, 4H), 1.44 (s, 9H), 1.93 (d, 2H, J = 12.0 Hz), 2.07 (d, 2H , J = 12.0 Hz), 2.12-2.17 (m, 2H), 3.25-3.36 (br m, 1H), 4.35 (br m, 1H), 4.81 (br d, 1H).
[734] Preparation of 4-morpholin-4-yl-cyclohexylamine:
[735] To a solution of acetamine (60.7 mg, 0.21 mmol) from the stomach in CH ₂ Cl ₂ (2 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure, and the residue was dissolved in NaOH (10N) and the same amount of water. The aqueous layer was washed with CH ₂ Cl ₂ (5 × 10 mL), the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated under reduced pressure to afford the product as an off-white solid (33.5 mg, 85%). ¹ H NMR (CDCl ₃ ) δ 1.08-1.27 (m, 4H), 1.39 (s, 2H), 1.88 (dd, 1H, J = 10.5, 2.4 Hz), 2.16 (tt, 1H, J = 11.3, 3.2 Hz ), 2.53 (t, 4H, J = 4.7 Hz), 2.61 (tt, 4H, J = 10.8, 3.6 Hz), 3.69 (t, 4H, J = 4.5 Hz).
[736] Preparation of trans- (4-morpholin-4-yl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine:
[737] Amine (50.2 mg, 0.27 mmol) and 6,7-dihydro-5H-quinolin-8-one (40.1 mg, 0.27 mmol) from the stomach in MeOH (2 mL) were stirred overnight at room temperature to form imine. Sodium borohydride (20.6 mg, 0.544 mmol) was added to the above solution, and the mixture was further stirred for 2 hours. The solvent was removed under reduced pressure and CH ₂ Cl ₂ and NaOH (0.5N) were added to the residue until it became basic. The mixture was extracted with CH ₂ Cl ₂ (3 × 15 mL) and the combined organic extracts were dried (MgSO 4), filtered and concentrated under reduced pressure. Purification by silica gel radial chromatography (1 mm plate, CH ₂ Cl _{2 and} then NH ₄ OH / CH ₂ Cl ₂ , 1:99) afforded the desired amine (35.9 mg, 42%) as a yellow oil. ¹ H NMR (CDCl ₃ ) δ 1.24-1.29 (m, 2H), 1.71-1.74 (m, 2H), 1.95-2.16 (m, 8H), 2.56 (t, 3H, J = 4.5 Hz), 2.75-2.79 (m, 2H), 3.41 (s, 2H), 3.71 (t, 4H, J = 4.5 Hz), 3.92 (t, 1H, J = 6.0 Hz), 7.02-7.06 (m, 1H), 7.35 (d, 1H, J = 9.0 Hz), 8.37 (d, 1H, J = 3.0 Hz).
[738] Trans-2-{[(4-morpholin-4-yl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzimidazole-1 Preparation of carboxylic acid tert-butyl esters:
[739] Stomach amine (35.9 mg, 0.11 mol), 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (36.7 mg, 0.14 mmol), N, N-diisopropylethylamine (25 mL, 0.14 mmol ) And potassium iodide (1.8 mg, 0.01 mmol) were stirred overnight at 60 ° C. in CH ₃ CN (1 mL). The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The crude material was purified by silica gel radial chromatography (1 mm plate, CH ₂ Cl ₂ then NH ₄ OH / CH ₂ Cl ₂ , 1:99) to afford the desired compound (33.7 mg, 54%) as a yellow oil. . ¹ H NMR (CDCl ₃ ) δ 1.13-1.36 (m, 3H), 1.49-1.68 (m, 11H), 1.89-1.97 (m, 4H), 2.02-2.14 (m, 4H), 2.49-2.52 (m, 4H), 2.59 (br t, 1H), 2.67-2.84 (m, 2H), 3.68 (t, 4H, J = 4.5 Hz), 4.24 (t, 1H, J = 6.0 Hz), 4.44 (d, 2H, J = 6.0 Hz), 6.834 (dd, 1H, J = 7.5, 4.7 Hz), 7.08 (d, 1H, J = 6.3 Hz), 7.22-7.25 (m, 2H), 7.34-7.69 (m, 1H), 7.71-7.78 (m, 1 H), 8.32 (dd, 1 H, J = 4.5, 1.2 Hz).
[740] (S)-(1H-benzimidazol-2-ylmethyl)-(4-morpholin-4-yl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)- Preparation of amines (hydrobromide salts):
[741] A solution of bromic acid in acetic acid (1 mL) was added to a solution of the above oil (33.7 mg, 0.062 mmol) in acetic acid (1.5 mL) and the reaction mixture was stirred for 1 h. Diethyl ether was added until precipitation of compound 67 was obtained as a pale yellow solid (28.9 mg, 63%). ¹ H NMR (D ₂ O) δ 1.48-1.61 (m, 4H), 1.82-1.88 (m, 2H), 2.07-2.39 (m, 6H), 2.75-2.81 (br t, 2H), 2.99 (br d , 2H, J = 4.5 Hz), 3.19 (t, 2H, J = 10.7 Hz), 3.44 (br d, 2H, J = 12.3 Hz), 3.76 (br td, 2H, J = 12.3 Hz), 4.09 (br d, 2H, J = 11.7 Hz, 4.39-4.57 (m, 3H), 7.59 (dd, 2H, J = 6.3, 3.2 Hz), 7.74-7.77 (m, 3H), 8.27 (d, 1H, J = 7.8 Hz), 8.55 (d, 1H, J = 5.7 Hz). ¹³ C NMR (D ₂ O) δ 20.68, 23.95, 25.72, 25.93, 27.52, 27.80, 29.81, 43.97, 49.29, 58.82. 59.19, 64.38, 64.77, 114.23, 125.79, 126.96, 131.07, 139.11, 140.45, 147.95, 151.53, 151.95. ES-MS m / z 446 [M + H] ⁺ , 468 [M + Na] ⁺ . Calcd for C ₂₇ H ₃₅ N ₅ O. 3.0HBr. 3.0H ₂ O: C, 43.68; H, 5.97; N, 9.43; Br, 32.29. Found: C, 43.72; H, 5. 76; N, 9.25; Br, 32.06.
[742] Example 68
[743]
[744] Compound 68: N- (1H-benzoimidazol-2-ylmethyl) -N'-pyrimidin-2-ylmethyl-N- (5,6,7,8-tetrahydro-quinolin-8-yl)- Preparation of transcyclohexane-1,4-diamine (hydrobromide salt)
[745] Preparation of pyrimidine-2-carboxylic acid methyl esters:
[746]
[747] To a saturated HCl (g) / MeOH solution (40 mL) was added 2-cyanopyrimidine (1.97 g, 18.7 mmol) in MeOH (6 mL) at 0 ° C. The solution was stirred at room temperature for 30 minutes and then poured into diethyl ether (200 mL) to give a colorless precipitate which was recovered by filtration. The crude material was dissolved in H ₂ O (50 mL), adjusted to pH 4 with saturated NaHCO ₃ (aq) and 10% HCl (aq) and then extracted with CHCl ₃ (5 × 25 mL). The combined organic extracts were washed with saturated NaHCO ₃ (aq) (25 mL), then dried (MgSO ₄ ) and concentrated in vacuo to give a colorless solid (1.49 g, 58%). ¹ H NMR (CDCl ₃ ) δ 4.08 (s, 3H), 7.51 (t, 1H, J = 5.1 Hz), 8.96 (d, 2H, J = 5.1 Hz).
[748] To a solution of pyrimidine-2-carboxylic acid methyl ester (243 mg, 1.76 mmol) in THF (17 mL) was added LiAlH ₄ (1.0 M / THF, 0.47 mL, 0.47 mmol) at −78 ° C. over 30 minutes, and the solution Was stirred at −78 ° C. for 15 minutes. Acetic acid (0.25 mL, 4.4 mmol) was added dropwise and the solution was allowed to warm to room temperature and then concentrated in vacuo. The residue was dissolved in H ₂ O (15 mL), adjusted to pH 4 with 10% HCl (aq) and then extracted with CHCl ₃ (4 × 10 mL). The combined organic extracts were washed with NaHCO ₃ (aq) (20 mL), then dried (MgSO ₄ ) and concentrated in vacuo to give a yellow liquid (156 mg). The crude material was determined by ¹ H NMR as a mixture of pyrimidine-2-carbaldehyde, pyrimidine-2-carboxylic acid methyl ester, and THF (1.0: 1.7: 7.7 respectively) and used in the next step without further purification. It was.
[749] General process B use: crude aldehyde (156 mg) and N- (1H-benzoimidazol-2-ylmethyl) -N- (5,6,7,8-tetrahydro- from stomach in THF (2 mL) To a solution of quinolin-8-yl) -cyclohexane-trans-1,4-diamine (68 mg, 0.18 mmol) was added NaBH (OAc) ₃ (114 mg, 0.538 mmol), and the mixture was stirred at room temperature for 1.5 hours. It was. The crude material was dissolved in saturated HBr / AcOH (2 mL) and stirred at room temperature for 5 minutes. The solution was made basic with 10N NaOH (aq) and extracted with CH ₂ Cl ₂ (3 × 15 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (200: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give a colorless oil (50 mg).
[750] General Process D Use: The oil from the stomach (50 mg, 0.11 mmol) was converted to a hydrobromide salt and then reprecipitated the intermediate solid from methanol / ether to give compound 68 (78 mg, 85%) as a colorless solid. . ¹ H NMR (D ₂ O) δ 1.58 (m, 4H), 1.89 (m, 1H), 2.03-2.45 (m, 7H), 2.84 (m, 1H), 3.00 (m, 2H), 3.30 (m, 1H), 4.42-4.60 (m, 5H), 7.50 (t, 1H, J = 5.1 Hz), 7.58 (m, 2H), 7.78 (m, 3H), 8.29 (d, 1H, J = 8.1 Hz), 8.58 (d, 1H, J = 5.7 Hz), 8.79 (d, 2H, J = 5.1 Hz); ¹³ C NMR (D ₂ O) δ 20.73, 24.04, 27.56, 28.08, 28.33, 29.73, 44.05, 48.59, 56.44, 58.80, 59.26, 114.24, 121.65, 125.84, 127.02, 130.91, 139.12, 140.51, 148.03, 151.51, 152.00 , 158.38, 160.98. ES-MS m / z 468 (M + H). Calcd for C ₂₈ H ₃₃ N ₇ .3.9HBr. 3.2H ₂ 0.0.2C ₄ H ₁₀ O: C, 40.43; H, 5. 34; N, 11.46; Br, 36.42. Found: C, 40.37; H, 5.05; N, 11.35; Br, 36.58.
[751] Example 69
[752]
[753] Compound 69: N- (1H-benzoimidazol-2-ylmethyl) -1-methyl-N- (5,6,7,8-tetrahydro-quinolin-8-yl) -trans-cyclohexane-1, Preparation of 4-diamine (hydrobromide salt)
[754] Preparation of trans- (4-cyano-4-diallylamino-cyclohexyl) -carbamic acid tert-butyl ester:
[755] To a stirred solution of (4-oxo-cyclohexyl) -carbamic acid tert-butyl ester (3.07 g, 14.4 mmol) and diallylamine (1.78 mL, 14.4 mmol) in anhydrous ClCH ₂ CH ₂ Cl (25 mL) was added IV) Isopropoxide (4.28 mL, 14.4 mmol) was added at 0 ° C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then cooled to 0 ° C. and diethylaluminum cyanide (1M in toluene, 17 mL, 17 mmol) was added with vigorous stirring. The reaction was allowed to warm to rt and stirred for an additional 3.5 h, then CH ₂ Cl ₂ (30 mL), EtOAc (40 mL) and celite (3 g). The reaction mixture was cooled to 0 ° C. and water (8 mL) was added slowly with vigorous stirring, then stirred for an additional 5 minutes at room temperature and the excess water was quenched with Na ₂ SO ₄ . The final mixture was then filtered through celite, concentrated under reduced pressure, flash chromatography with silica gel (hexanes / EtOAc, 4: 1) to give the desired nitrile (3.11 g, 68% over two steps) as pale yellow oil. Obtained. ¹ H NMR (CDCl ₃ ) δ 1.44 (s, 9H), 1.53-1.59 (m, 3H), 1.78-1.99 (m, 2H), 2.07 (d, 2H, J = 9 Hz), 2.28 (d, 2H, J = 12 Hz), 3.33 (t, 4H, J = 4.5 Hz), 3.37-3.55 (br m, 1H), 4.33-4.53 (br m, 1H), 5.12-5.24 (m, 4H), 5.82-5.94 ( m, 2H).
[756] Preparation of trans- (4-diallylamino-4-methyl-cyclohexyl) -carbamic acid tert-butyl ester:
[757] To a solution of nitrile (3.11 g, 9.7 mmol) from the stomach in anhydrous THF (30 mL) was added dropwise methylmagnesium bromide (3.0 M in Et ₂ O, 10.0 mL, 29.2 mmol). After addition, the reaction was warmed to RT and stirred overnight. The reaction was then quenched with saturated aqueous NaHCO ₃ (50 mL), diluted with EtOAc (30 mL) and the layers separated. The aqueous layer was extracted with EtOAc (1 × 20 mL) and CH ₂ Cl ₂ (1 × 20 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford the desired product (19%) and N- (4-diallylamino-4-methyl-cyclohexyl) -acetamide (72% A mixture of is obtained. The crude yellow oil (1.21 g) obtained was used for the next step without further purification.
[758] Preparation of trans-N, N-diallyl-1-methyl-cyclohexane-1,4-diamine:
[759] To a stirred solution of the crude mixture from above in anhydrous CH ₂ Cl ₂ (4 mL) was added TFA (4 mL) and the reaction stirred at RT for 2.5 h. The reaction mixture was diluted with CH ₂ Cl ₂ (30 mL) and concentrated under reduced pressure. The residue was diluted with CH ₂ Cl ₂ (50 mL), washed with 1N NaOH (1 × 40 mL) and the aqueous phase extracted with CH ₂ Cl ₂ (2 × 25 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to yield a yellow oil (0.840 g, 12% desired amine).
[760] By-product N- (4-diallylamino-4-methyl-cyclohexyl) -acetamide (0.1979 g, 0.79 mmol) from the stomach was dissolved in 6N HCl (6 mL) and refluxed for 6 hours. The reaction was cooled to RT, basified with 10N NaOH and extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford the desired primary amine (0.1063 g, 65%) as a yellow / green oil, which was taken to the next step without further purification. Used.
[761] 2-{[trans- (4-amino-4-methyl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzoimidazole-1- Preparation of carboxylic acid tert-butyl esters:
[762] According to general process B: 6,7-dihydro-5H-quinolin-8-one (0.0895 g, 0.61 mmol) and crude N, N-diallyl-1-methyl-cyclohexane- in dry THF (5 mL) To a stirred solution of 1,4-diamine from above (0.1063 g, 0.51 mmol) was added AcOH (5 drops) and NaBH (OAc) ₃ (0.1805 g, 0.85 mmol) and the mixture was stirred at rt overnight. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 96: 4: 0 then 95: 4: 1) afforded the desired amine (75.2 mg, 36%) as a colorless oil.
[763] According to the general procedure for N-alkylation: N, N-diisopropylethylamine (0.17 mL, 0.98 mmol) in a stirred solution of combined amine (0.1842 g, 0.54 mmol) from above in CH ₃ CN (4 mL) , KI (4.5 mg, 0.027 mmol) and 1- (tert-butoxycarbonyl) -2- (chloromethyl) benzimidazole (0.1449 g, 0.54 mmol) were added. The resulting orange oil was purified by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 89: 10: 1 after 96: 4: 0) to afford the desired alkylated amine (0.1364 g, 44%) in orange. Obtained as a foam.
[764] To a stirred solution of amine (0.1364 g, 0.24 mmol) from above in anhydrous CH ₂ Cl ₂ (4 mL) N, N-dimethylbabituric acid (0.1869 g, 1.2 mmol) and tetrakis (triphenylphosphine)- Palladium (0) (0.028 g, 0.024 mmol) was added and the mixture was stirred at rt for 64 h. The reaction was diluted with CH ₂ Cl ₂ (20 mL) and saturated aqueous NaHCO ₃ (30 mL). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 20 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude material was purified by silica gel radial chromatography (2 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, 50: 1: 1 and then 25: 1: 1) to give the desired amine (28.9 mg, 25%) and Monoallyl-protected amine (51.0 mg, 40%) was obtained.
[765] 2-{[trans- (4-tert-butoxycarbonylamino-4-methyl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl}- Preparation of benzimidazole-1-carboxylic acid tert-butyl ester:
[766] To a stirred solution of the desired primary amine (28.9 mg, 0.059 mmol) from above in anhydrous THF (1.5 mL) was added di-tert-butyl dicarbonate (47 mg, 0.22 mmol) and the mixture was stirred at rt overnight. . The reaction was concentrated under reduced pressure, and the residue was purified by radial chromatography on silica gel (1 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 1: 1) to give the protective amine (25 mg, 71%) as a colorless oil. Obtained as.
[767] Using General Process D: Oil (25 mg, 0.042 mmol) from the stomach was converted to a hydrobromide salt and then reprecipitated intermediate solids from methanol / ether to give 69 (23 mg, 82%) as a white solid. . ¹ H NMR (D ₂ O) δ 1.29 (s, 3H), 1.56-1.78 (m, 4H), 1.79-2.04 (m, 4H), 2.07-2.27 (m, 3H), 2.38-2.48 (m, 1H ), 2.77-2.83 (m, 1H), 2.99 (d, 2H, J = 5.4 Hz), 4.42 (d, 1H, J = 16.5 Hz), 4.58 (d, 1H, J = 16.8 Hz), 4.54-4.61 (m, 1H), 7.56-7.61 (m, 2H), 7.72-7.81 (m, 3H), 8.27 (d, 1H, J = 7.8 Hz), 8.55 (d, 1H, J = 5.1 Hz); ¹³ C NMR (D ₂ O) δ 20.71, 24.24, 26.56, 26.86, 27.50, 34.87, 35.05, 43.78, 53.48, 58.03, 59.84, 114.21, 125.76, 126.97, 131.05, 139.08, 140.46, 147.91, 151.38, 152.11. ES-MS m / z 390 (M + H). Calcd for C ₂₄ H ₃₁ N ₅ 2.9 HBr 3.1 H ₂ O: C, 42.39; H, 5.94; N, 10.30; Br, 34.08. Found: C, 42.30; H, 5.69; N, 10.11; Br, 34.18.
[768] Example 70
[769]
[770] Compound 70: N ^One-Allyl-N- (1H-benzoimidazol-2-ylmethyl) -1-methyl-N- (5,6,7,8-tetrahydro-quinolin-8-yl) -trans-cyclohexane-1, Preparation of 4-diamine (hydrobromide salt):
[771] Monoallyl-protected amine (51 mg, 0.10 mmol) from above was subjected to radial chromatography on silica gel (1 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, after 100: 1: 1 and after 50: 1: 1 25: 1: 1) to afford monoallyl-protected amine (24.6 mg, 20%) as an orange oil.
[772] General Process D Use: The oil from the stomach (25 mg, 0.047 mmol) was converted to a hydrobromide salt and then reprecipitated the intermediate solid from methanol / ether to give compound 70 (32 mg, 94%) as an off-white solid. . ¹ H NMR (D ₂ O) δ 1.29 (s, 3H), 1.55-1.95 (br m, 7H), 2.01-2.22 (m, 6H), 2.38-2.45 (m, 1H), 2.77-2.86 (m, 1H), 2.97-3.02 (m, 2H), 3.65 (d, 2H, J = 6.9 Hz), 4.43 (d, 1H, J = 16.8 Hz), 4.57 (d, 1H, J = 16.8 Hz), 4.59- 4.65 (m, 1H), 5.44 (d, 1H, J = 16.2 Hz), 5.48 (d, 1H, J = 23.1 Hz), 5.86-6.00 (m, 1H), 7.56-7.62 (m, 2H), 7.72 -7.81 (m, 3H), 8.27 (d, 1H, J = 7.8 Hz), 8.55 (d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 14.52 (Et ₂ O), 20.70, 23.66, 24.11, 24.33, 26.08, 27.49, 33.48, 33.85, 43.72, 44.50, 66.47 (Et2O), 114.20, 123.96, 125.78, 127.03, 128.43, 130.95 , 139.08, 140.51, 147.95, 151.28, 152.12. ES-MS m / z 430 (M + H). Calcd for C ₂₇ H ₃₅ N ₅ .3.0HBr.2.9H ₂ O: C, 44.76; H, 6.09; N, 9.67; Br, 33.08. Found: C, 45.00; H, 5.96; N, 9.61; Br, 32.72.
[773] Example 71
[774]
[775] Compound 71: N- (1H-benzoimidazol-2-ylmethyl) -1-phenyl-N- (5,6,7,8-tetrahydro-quinolin-8-yl) -trans-cyclohexane-1, Preparation of 4-diamine (hydrobromide salt)
[776] Preparation of trans- (4-cyano-4-diallylamino-cyclohexyl) -carbamic acid tert-butyl ester:
[777] 0 ° C. in a stirred solution of (4-oxo-cyclohexyl) -carbamic acid tert-butyl ester (3.55 g, 16.6 mmol) and diallylamine (2.05 mL, 16.6 mmol) in anhydrous ClCH ₂ CH ₂ Cl (30 mL). Titanium (IV) isopropoxide (4.95 mL, 16.6 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then cooled to 0 ° C. and diethylaluminum cyanide (1M in toluene, 19.6 mL, 19.6 mmol) was added with vigorous stirring. The tallow was allowed to warm to room temperature, stirred for an additional 5 hours and then diethylaluminum cyanide (1M in toluene, 19.6 mL, 19.6 mmol) was added. The reaction mixture was cooled to 0 ° C. and water (10 mL) was added slowly with vigorous stirring, then stirred for an additional 5 minutes at room temperature and the excess water was quenched with Na ₂ SO ₄ . The final mixture was then filtered through celite, concentrated under reduced pressure, flash chromatography on silica gel (hexanes / EtOAc, 4: 1) to give the desired nitrile (2.62 g, 66% over two steps) as a pale yellow oil. Obtained. ¹ H NMR (CDCl ₃ ) δ 1.44 (s, 9H), 1.50-1.70 (m, 4H), 1.77-1.99 (m, 2H), 2.07 (d, 2H, J = 9 Hz), 2.28 (d, 2H, J = 12 Hz), 3.33 (t, 4H, J = 6.0 Hz), 4.33-4.53 (br m, 1H), 5.11-5.24 (m, 4H), 5.82-5.95 (m, 2H).
[778] Preparation of trans- (4-diallylamino-4-phenyl-cyclohexyl) -carbamic acid tert-butyl ester:
[779] To a solution of nitrile (1.00 g, 3.1 mmol) from above in THF (16 mL) was added dropwise phenylmagnesium bromide (3.0 M in Et ₂ O, 3.1 mL, 9.4 mmol) at 0 ° C. After the dropwise addition, the reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was then quenched with saturated aqueous NH ₄ Cl (40 mL), diluted with EtOAc (30 mL) and the layers separated. The aqueous layer was extracted with EtOAc (1 × 20 mL) and CH ₂ Cl ₂ (1 × 20 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (hexane / EtOAc, 4: 1) gave the desired product (0.2057 g, 32%) and N- (4-diallylamino-4-phenyl-cyclohexyl) -benzamide (0.11 g , 17%) was obtained as a white solid.
[780] Preparation of trans-N, N-diallyl-1-phenyl-cyclohexane-1,4-diamine:
[781] To a stirred solution of the desired product (0.2057 g, 0.56 mmol) from above in anhydrous CH ₂ Cl ₂ (2 mL) was added TFA (2 mL) and the reaction stirred at rt for 4 h. The reaction mixture was diluted with CH ₂ Cl ₂ (15 mL) and concentrated under reduced pressure. The residue was diluted with CH ₂ Cl ₂ (20 mL), washed with 1N NaOH (1 × 30 mL) and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 20 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a yellow oil (0.1055 g, 70%). The obtained amine was used for the next step without further purification.
[782] By-product from the stomach, trans-N- (4-diallylamino-4-phenyl-cyclohexyl) -benzamide (0.4558 g, 1.22 mmol) was added H ₂ O (2.5 mL), 6N HCl (3.5 mL) and THF (2 mL) solution and refluxed overnight. The reaction was cooled to rt, diluted with H ₂ O (15 mL), basified with 10N NaOH, and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH 4 OH, 89: 10: 1 after 96: 4: 0) gave the desired primary amine (80 mg, 24%) as a yellow oil.
[783] 2-{[trans- (4-amino-4-phenyl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzoimidazole-1- Preparation of carboxylic acid tert-butyl esters:
[784] General Process B (Stepwise Reductive Amination with NaBH ₄ ) Use: 6,7-Dihydro-5H-quinolin-8-one (0.099 g, 0.67 mmol) and N, N-di in anhydrous MeOH (3 mL) To a stirred solution of allyl-1-phenyl-cyclohexane-1,4-diamine (0.181 g, 0.48 mmol) was added NaBH ₄ (0.051 g, 1.3 mmol) after 2 hours, and after 2 hours, the mixture was further added for 2 hours. Stirred at room temperature. Purified by silica gel radial chromatography (2 mm plate, CH ₂ Cl ₂ / MeOH / NH 4 OH, 100: 1: 1 then 75: 1: 1) to the desired amine (150 mg, 56%). Was obtained as a pale yellow oil.
[785] According to the general procedure for N-alkylation: N, N-diisopropylethylamine (0.12 mL, 0.67 mmol), in a stirred solution of amine (0.150 g, 0.37 mmol) from above in CH ₃ CN (2 mL), KI (3 mg, 0.019 mmol) and 1- (tert-butoxycarbonyl) -2- (chloromethyl) benzimidazole (0.099 g, 0.37 mmol) were added. The mixture was stirred at 60 ° C. overnight. The beige foam obtained was purified by silica gel radial chromatography (2 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 1: 1 and then 50: 1: 1) to obtain the desired alkylated amine (0.149 g, 64%) was obtained as a yellow oil.
[786] To a stirred solution of alkylated amine (0.149 g, 0.24 mmol) in anhydrous CH ₂ Cl ₂ (2.5 mL) N, N-dimethylbabituric acid (0.1841 g, 1.2 mmol) and tetrakis (triphenylphosphine) -palladium ( 0) (0.068 g, 0.06 mmol) was added and the mixture was stirred at rt for 64 h. The reaction was diluted with CH ₂ Cl ₂ (20 mL) and saturated aqueous NaHCO ₃ (30 mL). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 20 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude material was purified by silica gel radial chromatography (2 mm plate, CH ₂ Cl ₂ / MeOH / NH 4 OH, 50: 1: 1 after 25: 1: 1 20: 1: 1) to obtain deprotected amine (28.9 mg, 25%) and monoallyl-protected amine (70.1.0 mg, 54%, purity 90%) were obtained.
[787] 2-{[trans- (4-tert-butoxycarbonylamino-4-phenyl-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl}- Preparation of benzimidazole-1-carboxylic acid tert-butyl ester:
[788] To a stirred solution of the desired primary amine (28.9 mg, 0.13 mmol) in dry THF (2 mL) was added di-tert-butyl dicarbonate (42 mg, 0.19 mmol) and the mixture was stirred at rt overnight. The reaction was concentrated under reduced pressure, and the residue was purified by radial chromatography on silica gel (1 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, 100: 1: 1 to 50: 1: 1) to boc-protected amines. (34 mg, 44%) was obtained as a colorless oil.
[789] Using General Process D: Oil (24 mg, 0.037 mmol) from the stomach was converted to a hydrobromide salt, followed by reprecipitation of the intermediate solid from methanol / ether to give compound 71 (24 mg, 85%) as a beige solid. It was. ¹ H NMR (D 2 O) δ 1.80-1.99 (m, 3H), 2.00-2.27 (m, 5H), 2.28-2.53 (m, 4H), 2.89-3.04 (m, 3H), 4.47 (d, 1H, J = 16.8 Hz), 4.61 (d, 1H, J = 16.5 Hz), 4.60-4.68 (m, 1H), 7.40-7.53 (m, 5H), 7.55-7.61 (m, 2H), 7.71-7.81 (m, 3H), 8.26 (d, 1H, J = 7.2 Hz), 8.55 (d, 1H, J = 5.1 Hz); 13C NMR (D 2 O) δ 20.74, 24.26, 24.54, 26.75, 27.53, 34.29, 34.46, 43.85, 57.40, 58.08, 59.61, 114.24, 125.12, 125.79, 126.97, 129.40, 129.64, 131.08, 139.14, 140.51, 140.51, 140. 151.34, 152.04. ES-MS m / z 452 (M + H). Calcd for C ₂₉ H ₃₃ N ₅ .2.7HBr.5.3H ₂ O: C, 45.50; H, 6. 10; N, 9.15; Br, 28.18 Found: C, 45.43; H, 5. 43; N, 8.93; Br, 28.23.
[790] Example 73
[791]
[792] Compound 73 (R) and (S): N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohex-2 Preparation of Two Diastereomers of N-Trans-1,4-Diamine
[793] Cis-1-acetoxy-4-chloro-2-cyclohexene from 1,3-cyclohexadiene is described in Backwall et al (J. Am. Chem. Soc. 1985, 107, 3676-3686.). It was prepared according to the process reported in. To a stirred solution of cis-1-acetoxy-4-chloro-2-cyclohexene (6.87 g, 39.4 mmol) in DMF (160 mL) was added sodium azide (5.29 g, 81.1 mmol) and the resulting mixture was allowed to room temperature. Stirred for 2 h. The reaction mixture was poured into brine (160 mL) and diluted with diethyl ether (300 mL) and water (80 mL). The phases were separated and the organic phase was washed with brine (5 x 50 mL). The organic phase was dried (MgSO ₄ ) and concentrated to afford 6.13 g (85%) of trans-1-acetoxy-4-azido-2-cyclohexene as pale red oil which was used without further purification. .
[794] Trans-1-acetoxy-4-azido-2-cyclohexene (6.13 g, 33.9 mmol), Lindler catalyst (1.18 g) and di-tert-butyl dicarbonate (11.35 g, 52.1 in methanol (170 mL)) mmol) was hydrogenated at atmospheric pressure for 19 h. The mixture was filtered through celite and the cake was washed with methanol. The filtrate was concentrated and the oil obtained was purified by column chromatography on silica gel (6: 1 hexane-ethyl acetate) and trans-1-acetoxy-4- (tert-butoxycarbonylamino) -2-cyclohexene 6.70 g (77%) was obtained as a white solid.
[795] Solid K ₂ CO ₃ (7.50 g, 54.4 mmol) in a solution of trans-1-acetoxy-4- (tert-butoxycarbonylamino) -2-cyclohexene (6.70 g, 26.3 mmol) in methanol (130 mL) ) Was added and the mixture was stirred at rt for 1 h. The reaction mixture was concentrated and the residue was dissolved in CH ₂ Cl ₂ (250 mL) and saturated aqueous NaHCO ₃ (100 mL). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 50 mL). The combined organic extracts were dried (N _a2 SO ₄ ) and concentrated. Crude was purified by column chromatography on silica gel (20: 1 CH ₂ Cl ₂ -CH ₃ OH) to give 3.38 g of trans-1-hydroxy-4- (tert-butoxycarbonylamino) -2-cyclohexene. (60%) was obtained as a white solid. ¹ H NMR (CDCl ₃ ) δ 1.44 (s, 9H), 1.52-1.57 (m, 1H), 2.05-2.14 (m, 3H), 4.20-4.26 (br s, 2H), 4.45 (br s, 1H) , 4.47-4.60 (m, 1H), 5.70 (d, 1H, J = 10.2 Hz), 5.81 (d, 1H, J = 10.2 Hz);
[796] Triphenylphosphine (7.51 g, 28.6) in a mixture of trans-1-hydroxy-4- (tert-butoxycarbonylamino) -2-cyclohexene (2.93 g, 13.8 mmol) in hexachloroacetone (70 mL) mmol) was added and the mixture was stirred at rt for 1 h. The mixture was concentrated and the oil thus obtained was purified by column chromatography on silica gel (10: 1 hexane-ethyl acetate) and cis-1- (tert-butoxycarbonylamino) -4-chloro-2-cyclohexene 1.98 g (62%) was obtained as a yellow solid.
[797] Sodium azide (1.17 g, 18.0 mmol) was added to a stirred solution of cis-1- (tert-butoxycarbonylamino) -4-chloro-2-cyclohexene (1.85 g, 8.00 mmol) in DMF (40 mL). Was added and the resulting mixture was stirred at rt for 16 h. The reaction mixture was poured into brine (40 mL) and diluted with ethyl acetate (120 mL) and water (20 mL). The phases were separated and the organic phase was washed with brine (4 × 25 mL). The organic phase was dried (MgSO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (10: 1 hexane-ethyl acetate) to give 1.14 g (60%) of trans-1-azido-4- (tert-butoxycarbonylamino) -2-cyclohexene. Obtained as a colorless oil.
[798] Triphenylphosphine (1.14 g, 4.79 mmol) in a solution of trans-1-azido-4- (tert-butoxycarbonylamino) -2-cyclohexene (1.14 g, 4.79 mmol) in THF (50 mL) and water (5 mL). 2.60 g, 10 mmol) was added and the mixture was stirred at rt for 20 h. The mixture was concentrated and the material thus obtained was purified by column chromatography on silica gel (10: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) followed by silica gel radial chromatography (2 mm plate, 100 Purified by 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to 0.32 g (31%) of trans-1-amino-4- (tert-butoxycarbonylamino) -2-cyclohexene. Obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.44 (s, 9H), 1.50-1.92 (m, 2H), 1.99-2.10 (m, 2H), 3.32 (br s, 1H), 4.10-4.19 (m, 1H), 4.47-4.60 (m, 1 H), 5.57-5.77 (m, 2 H);
[799] General process B use: trans-1-amino-4- (tert-butoxycarbonylamino) -2-cyclohexene (0.222 g, 1.05 mmol) and 6,7-dihydro-5H- in THF (10 mL) Quinoline-8-one (0.304 g, 2.06 mmol) was reacted with NaBH (OAc) ₃ (0.423 g, 2.00 mmol) for 4 hours, and then the crude material was subjected to column chromatography on silica gel (25: 1 CH ₂ Cl ₂ −). CH ₃ OH) purified by N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -N ^4- (tert-butoxycarbonyl) -cyclohex-2-ene-trans- 0.277 g (77%) of 1,4-diamine was obtained as a yellow foam.
[800] General process use for N-alkylation: N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -N ^4- (tert-butoxycarbonyl) in CH ₃ CN (8 mL) -Cyclohex-2-ene-trans-1,4-diamine (0.277 g, 0.81 mmol), 1-tert- (butoxycarbonyl) -2- (chloromethyl) benzimidazole (0.327 g, 1.22 mmol) A solution of catalytic potassium iodide (14 mg) and N, N-diisopropylethylamine (0.28 mL, 1.61 mmol) was heated at 60 ° C. for 20 h. The crude material was subjected to column chromatography on silica gel (20: 1: 1 CH ₂ Cl ₂ -MeOH-NH ₄ OH) followed by silica gel radial chromatography (1 mm plate, 100: 1: 1 CH ₂ Cl ₂ -MeOH-NH). ₄ OH) to N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -N ^1- (1-tert-butoxycarbonyl-1H-benzimidazol-2-yl Methyl) -N ^4- (tert-butoxycarbonyl) -cyclohex-2-ene-trans-1,4-diamine, two portions of white foam 129 mg (28%) and white solid 18 mg (4%) Stereoisomers were obtained.
[801] General Process D: Compound 73 (R) (103 mg, 88%) by converting the main diastereomer (100 mg) to a hydrobromide salt while removing the BOC protecting group and then reprecipitating the intermediate solid from methanol / ether. Was obtained as a white solid. ¹ H NMR (D ₂ O) δ 1.45-1.57 (m, 1H), 1.70-1.82 (m, 2H), 2.00-2.17 (m, 4H), 2.48-2.52 (m, 1H), 2.93 (br d, 2H, J = 5.1 Hz), 3.61-3.63 (m, 1H), 3.88-3.91 (m, 1H), 4.38-4.46 (m, 2H), 4.55 (d, 1H, J = 16.8 Hz), 5.88 (br d, 1H, J = 10.5 Hz, 6.25 (d, 1H, J = 10.5 Hz), 7.52-7.57 (m, 2H), 7.69-7.77 (m, 3H), 8.22 (d, 1H, J = 8.1 Hz ), 8.55 (d, 1H, J = 5.1 Hz; ¹³ C NMR (D ₂ O) δ 20.63, 23.56, 27.14, 27.30, 27.52, 42.75, 47.46, 56.83, 60.11, 114.17, 125.84, 127.00, 128.66, 130.94, 133.97, 139.22, 140.59, 147.98, 151.38, 151.46; ES-MS m / z 374 (M + H) .Calculated for C ₂₃ H ₂₇ N ₅ .3.0HBr.2.9H ₂ O: C, 41.33; H, 5.40 ; N, 10.48; Br, 35.86. Found: C, 41.14; H, 5.15; N, 10.28; Br, 36.10.
[802] General Process D: Converting the diastereomer (18 mg) to the hydrobromide salt, while removing the BOC protecting group, then reprecipitating the intermediate solid from methanol / ether to give compound 73 (S) (15 mg, 68%) Was obtained as a white solid. ¹ H NMR (D ₂ O) δ 1.45-1.56 (m, 1H), 1.73-1.90 (m, 2H), 2.03-2.37 (m. 5H), 2.96 (d, 2H, J = 4.8 Hz), 3.66- 3.70 (m, 1H), 3.89-3.91 (m, 1H), 4.34-4.46 (m, 2H), 4.52 (d, 1H, J = 16.2 Hz), 5.75 (d, 1H, J = 10.25 Hz), 6.05 (d, 1H, J = 10.2 Hz), 7.53-7.56 (m, 2H), 7.70 -7.76 (m, 3H), 8.22 (d, 1H, J = 7.8 Hz), 8.52 (d, 1H, J = 5.7 Hz); ¹³ C NMR (D ₂ O) δ 20.56, 24.42, 25.14, 27.03, 27.40, 43.22, 47.65, 57.18, 58.39, 114.24, 125.76, 126.90, 128.40, 131.22, 135.51, 139.13, 140.42, 147.75, 150.87, 152.02; ES-MS m / z 374 (M + H). Calcd for C ₂₃ H ₂₇ N ₅ .3.0HBr. 3.1H ₂ O: C, 41.10; H, 5. 43; N, 10.42; Br, 35.67. Found: C, 41.38; H, 5.09; N, 10.35; Br, 35.36.
[803] Example 74
[804]
[805] Compound 74: (Z) -N '-(1H-benzimidazol-2-ylmethyl) -N'-(5,6,7,8-tetrahydro-quinolin-8-yl) -but-2-ene Preparation of -1,4-diamine
[806] Preparation of ((Z) -4-chloro-but-2-enyl) -carbamic acid tert-butyl ester:
[807]
[808] N, N-diisopropylethylamine (2.7 mL) in a stirred solution of (Z) -4-chloro-2-butenylamine hydrochloride (1.0 g, 7.0 mmol) in THF (35 mL) and water (0.2 mL) , 15.4 mmol), followed by di-tert-butyl dicarbonate (1.8 g, 8.4 mmol). The resulting solution was stirred for 3 hours, at which time the aqueous layer was extracted with Et ₂ O (3 × 30 mL). The combined organic extracts were washed once with brine (20 mL), dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4: 1 hexanes-EtOAc) to give 1.3 g (90%) of the title compound as a white solid. ¹ H NMR (CDCl ₃ ) δ 1.44 (s, 9H), 3.82 (t, 2H, J = 6 Hz), 4.12 (d, 2H, J = 9 Hz), 4.62 (br s, 1H), 5.60-5.70 (m , 1H), 5.72-5.77 (m, 1H).
[809] According to the general procedure for N-alkylation: 1H-N-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro in CH ₃ CN (3 mL) In a solution of quinolin-8-yl) -amine (200 mg, 0.53 mmol) and ((Z) -4-chloro-but-2-enyl) -carbamic acid tert-butyl ester (130 mg, 0.64 mmol) N, N-diisopropylethylamine (138 μl, 0.80 mmol) and KI (4.4 mg, 0.027 mmol) were added and the reaction stirred at 60 ° C. for 18 h. The crude material was dissolved in pure TFA (1 mL) and stirred for 3 hours. Saturated aqueous sodium bicarbonate (5 mL) was added carefully and the resulting mixture was extracted with CH ₂ Cl ₂ (3 × 10 mL), then the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude material was purified by radial chromatography (1 mm plate, 50: 1: 1 CH ₂ Cl ₂ -MeOH-NH ₄ OH) to give the title compound (57 mg, 31%) as a white solid. ¹ H NMR (CDCl ₃ ) δ 1.68-1.72 (m, 1H), 1.84-2.05 (m, 2H), 2.15-2.22 (m, 1H), 2.71 (dt, 1H, J = 17, 5 Hz), 2.84 ( ddd, 1H, J = 16, 10, 5 Hz), 3.15-3.26 (m, 3H), 3.38 (dd, 1H, J = 14, 7 Hz), 3.97-4.12 (m, 3H), 5.46-5.54 (m, 2H), 7.13 (dd, 1H, J = 8, 5 Hz), 7.16-7.21 (m, 2H), 7.40 (dd, 1H, J = 7, 1 Hz), 7.57 (br s, 2H), 8.57 (dd, 1H, J = 5, 1 Hz); ¹³ C NMR (CDCl ₃ ) δ 21.0, 22.9, 28.9, 37.4, 46.4, 48.6, 60.5, 115.0, 121.8, 122.2, 130.7, 131.6, 134.6, 137.4, 146.6, 154.2, 156.8. ES-MS m / z 348 (M + H). Calcd for C ₂₁ H ₂₅ N ₅ 0.1CHCl ₃ 0.8CH ₄ O: C, 68.32; H, 7.41; N, 18.19. Found: C, 68.60; H, 7.05; N, 17.82.
[810] Example 75
[811]
[812] Compound 75: 2- {4-[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino]-(E) -but- Preparation of 2-enyl} -isoindole-1,3-dione
[813]
[814] 2-{[[(Z) -4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -but-2-enyl]-(5,6,7,8- Preparation of Tetrahydro-quinolin-8-yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester:
[815] According to the general procedure for N-alkylation: (1H-N-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)- Amine (293 mg, 0.77 mmol) and (E) -N- (4-bromo-2-butenyl) phthalimide [Norman, MH; Minick, DJ; Rigdon, GCJ Med. Chem. (260 mg, 0.93 mmol) was converted to the corresponding alkylation product using the following reagents and solvent amounts: diisopropylethylamine (202 μl, 1.16 mmol). ), CH ₃ CN (4 mL). In this case, the reaction time was 18 hours while the reaction temperature was 40 ° C. The obtained crude material was purified by flash chromatography (silica gel, 20: 2: 1 CH ₂ Cl ₂ -MeOH-NH ₄ OH) to give 2-{[[(Z) -4- (1,3-dioxo- 1,3-dihydro-isoindol-2-yl) -but-2-enyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzoimidazole 360 mg (81%) of 1-carboxylic acid tert-butyl ester were obtained. ¹ H NMR (CDCl ₃ ) δ 1.67 (s, 9H), 1.68-1.70 (m, 1H), 1.79-1.91 (m, 1H), 1.93-2.04 (m, 1H), 2.14-2.19 (m, 1H) , 2.59-2.79 (m, 2H), 3.33-3.48 (m, 2H), 4.00 (d, 2H, J = 6 Hz), 4.25 (dd, 1H, J = 10, 6 Hz), 4.42 (d, 1H, J = 16 Hz), 4.60 (d, 1H, J = 16 Hz), 5.29-5.57 (m, 1H), 5.65-5.74 (m, 1H), 6.95 (dd, 1H, J = 7, 5 Hz), 7.17-7.25 ( m, 3H), 7.63-7.72 (m, 3H), 7.74-7.80 (m, 3H), 8.37 (d, 1H, J = 4 Hz).
[816] 2-{[[(Z) -4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -but-2-enyl]-(5,6,7,8- Tetrahydro-quinolin-8-yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester (150 mg, 0.26 mmol) was dissolved in pure TFA (2 mL) and stirred for 3 hours. . Saturated aqueous sodium bicarbonate (10 mL) was added carefully and the resulting mixture was extracted with CH ₂ Cl ₂ (3 × 10 mL), then the combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude material thus obtained was purified by radial chromatography (silica gel, 1 mm plate, 50: 1: 1 CH ₂ Cl ₂ -MeOH-NH ₄ OH) to give 102 mg (81%) of compound 75 as a white solid. . ¹ H NMR (CDCl ₃ ) δ 1.66-1.71 (m, 1H), 1.84-1.97 (m, 2H), 2.13-2.15 (m, 1H), 2.66-2.79 (m, 2H), 3.22-3.26 (m, 2H), 3.99-4.07 (m, 3H), 4.13-4.16 (m, 2H), 5.67-5.71 (m, 2H), 7.10 (dd, 1H, J = 8, 5 Hz), 7.14-7.20 (m, 2H ), 7.36 (dd, 1H, J = 8, 1 Hz), 7.43-7.62 (m, 2H), 7.64-7.69 (m, 2H), 7.74-7.79 (m, 2H), 8.56 (dd, 1H, J = 5, 1 Hz); ¹³ C NMR (CDCl ₃ ) δ 21.3, 24.0, 29.1, 39.1, 49.2, 52.0, 61.0, 110.9, 118.7, 121.6, 122.1, 123.2, 126.1, 132.0, 132.8, 133.9, 134.5, 137.2, 146.7, 156.3, 157.5, 167.8. ES-MS m / z 478 (M + H). Calcd for C ₂₉ H ₂₇ N ₅ 0 ₂ 0.2CH ₂ Cl ₂ 0.3H ₂ O: C, 70.15; H, 5. 64; N, 14.01. Found: C, 70.40; H, 5.73; N, 13.90.
[817] Example 76
[818]
[819] Compound 76: (Z) -N1- (1H-benzimidazol-2-ylmethyl) -N1-5,6,7,8-tetrahydro-quinolin-8-yl-but-2-ene-1,4 Preparation of diamines (hydrochloride salts)
[820] (Z) -4-chloro-2-butenylamine hydrochloride (3.88 g, 27.3 mmol), water (1 mL) and diisopropylethylamine (9.6 mL, 55.1 mmol) were added to tetrahydrofuran (140 mL). Dissolved and stirred for 5 minutes. Di-tert-butyl dicarbonate (15.31 g, 70.1 mmol) was added and the mixture was stirred at 25 ° C. for a further 4 h. The mixture was concentrated and the residue was dissolved in methylene chloride (100 mL) and washed with saturated sodium bicarbonate (80 mL). The aqueous layer was extracted with methylene chloride (2 x 50 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated to give a brown oil which was left to solidify. Purification by column chromatography on silica gel gave 6.4 g of the mixture of the desired product and di-tert-butyl dicarbonate. Recrystallization from hot hexanes gave (4-chloro-but-2-enyl) -carbamic acid tert-butyl ester (3.27 g, 50%) as white crystals. ¹ H NMR (CDCl ₃ ) δ 1.45 (s, 9H), 3.83 (t, 2H, J = 6.2 Hz), 4.12 (d, 2H, J = 7.4 Hz), 4.58 (bs, 1H), 5.58-5.68 ( m, 1H), 5.71-5.81 (m, 1H).
[821] (4-Chloro-but-2-enyl) -carbamic acid tert-butyl ester (1.81 g, 7.47 mmol), potassium iodide (59 mg, 0.36 mmol) and diisopropylethylamine (1.80 mL, 10.3 mmol) were aceto Of 2-[(5,6,7,8-tetrahydroquinolin-8-ylamino) -methyl] -benzimidazole-1-carboxylic acid tert-butyl ester (2.57 g, 6.79 mmol) in nitrile (70 mL) It was added to the solution, warmed to 60 ° C. and stirred for 17 h under nitrogen. The solvent was removed in vacuo. The residue was dissolved in methylene chloride (100 mL) and washed with brine (100 mL). The aqueous layer was extracted with methylene chloride (2 x 150 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The crude mixture was purified by column chromatography on silica gel (150 g) to give 2-{[(S)-((Z) -4-tert-butoxycarbonylamino-but-2-enyl) -5,6,7, 8-Tetrahydro-quinolin-8-yl-amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester (5.99 g, 88%) was obtained as a white effervescent solid. ¹ H NMR (CDCl ₃ ) δ 1.43 (s, 9H), 1.72 (s, 9H), 1.95-2.08 (m, 4H), 2.09-2.20 (m, 1H), 2.61 (d, 1H, J = 16.2Hz ), 3.28 (dd, 1H, J = 14.1, 5.4 Hz), 3.62 (dd, 1H, J = 13.7, 7.2 Hz), 3.69-3.85 (m, 2H), 4.29 (dd, 1H, J = 9.2, 6.6 Hz), 4.42 (d, 1H, J = 14.9 Hz), 4.48 (d, 1H, J = 14.9 Hz), 5.43-5.63 (m, 2H), 6.19 (s, 1H), 6.87 (dd, 1H, J = 7.5, 4.8 Hz), 7.17 (d, 1H, J = 7.7 Hz), 7.23-7.28 (m, 1H), 7.65-7.71 (m, 1H), 7.75-7.80 (m, 1H), 8.34 (d, 1H, J = 4.4 Hz).
[822] 2-{[(S)-((Z) -4-tert-butoxycarbonylamino-but-2-enyl) -5,6,7,8-tetrahydro-quinolin-8-yl-amino]- Methyl} -benzimidazole-1-carboxylic acid tert-butyl ester was dissolved in acetic acid (15 mL) and hydrogen chloride gas was bubbled through the solution for 10 minutes. The mixture was stirred for an additional 60 minutes and then diluted with acetic acid (15 mL). The acetic acid solution was lowered into a flask containing diethyl ether (600 mL) and stirred rapidly to form a white floppy precipitate. The ether mixture was precipitated and decanted. The slurry was washed with ether (3 × 500 mL), then the precipitate was recovered on glass frit and rinsed thoroughly with ether. The frit was placed in a vacuum oven (40 ° C.) for 18 hours to yield compound 76 as a light pink solid (2.20 g, 72%). ¹ H NMR (D ₂ O) δ 1.75-1.88 (m, 1H), 1.98-2.11 (m, 1H), 2.17-2.22 (m, 1H), 2.37-2.42 (m, 1H), 3.00 (dd, 2H , J = 7.8, 3.9 Hz), 3.25 (dd, 1H, J = 14.7, 4.4 Hz), 3.58-3.65 (m, 3H), 4.4.32 (d, 1H, J = 16.5 Hz), 4.46-4.55 ( m, 2H), 5.43-5.53 (m, 1H), 5.77-5.86 (m, 1H), 7.55-7.62 (m, 2H), 7.74-7.81 (m, 2H), 7.84 (dd, 1H, J = 7.9 , 5.9 Hz), 8.33 (d, 1H, J = 7.8 Hz), 8.62 (d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) 20.35, 20.47, 27.61, 36.45, 48.00, 48.67, 60.52, 114.31 (2C), 124.75, 125.91, 126.81 (2C), 131.27, 132.58, 139.49, 140.64, 147.98, 150.92, 151.47. ES-MS m / z 348 (M + H). Calcd for C ₂₁ H ₂₅ N _{5 3} .1 HCl _2.5 H ₂ O 0.3 Et ₂ O: C 50.70, H 6.88, N 13.32, Cl 20.90. Found: C 50.81, H 6.89, N 13.45, Cl 20.80.
[823] Enantiomeric purity of Compound 76 was determined to be 98% by chiral HPLC using the following conditions: Instrument: Hewlett Packard 1100 HPLC (VWD2); Column: Chiralpak AD, 4.6 cm x 25 cm; Mobile phase: A = 90: 10 hexanes / isopropyl (0.1% DEA), B = alcohol reagent; Isocratic: 90% A, 10% B; Total running time: 40 minutes; Flow rate: 0.5 ml / min; Temperature: 40 ° C .; Detector: UV @ 270 nm; Injection volume: 10 μl.
[824] Retention time for the S enantiomer = 21.4 min.
[825] Retention time of R enantiomers = 14.3 min.
[826] Example 77
[827]
[828] Compound 77: N1- (1H-benzoimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl)-(E) -but-2-ene-1 Preparation of 4-diamine
[829] 2-{[[(Z) -4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -but-2-enyl]-(5,6,7,8- Tetrahydro-quinolin-8-yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester (prepared as described for compound 75) (200 mg, 0.35 mmol) was added EtOH (3 mL). ) And hydrazine monohydrate (0.5 mL, 10 mmol) was added. The resulting mixture was heated to reflux for 18 hours, at which time saturated aqueous sodium bicarbonate (15 mL) was added, the resulting mixture was extracted with CH ₂ Cl ₂ (3 × 20 mL) and the combined organic extracts were dried ( MgSO ₄ ), concentrated in vacuo. The crude material thus obtained was purified by radial chromatography (silica gel, 1 mm plate, 50: 1: 1 CH ₂ Cl ₂ -MeOH-NH ₄ OH) to give 53 mg (44%) of compound 77 as a white solid. . ¹ H NMR (CDCl ₃ ) δ 1.47-1.71 (m, 3H), 1.89-2.08 (m, 2H), 2.18-2.20 (m, 1H), 2.74-2.83 (m, 2H), 3.13 (d, 2H, J = 6 Hz), 3.25-3.27 (m, 2H), 4.06-4.10 (m, 3H), 5.46 (dt, 1H, J = 15, 6 Hz), 5.71 (dt, 1H, J = 15, 6 Hz), 7.12 -7.21 (m, 3H), 7.41 (d, 1H, J = 8 Hz), 7.50-7.58 (m, 2H), 8.60 (dd, 1H, J = 5, 1 Hz); ¹³ C NMR (CDCl ₃ ) δ 21.3, 23.6, 29.2, 43.1, 48.8, 52.5, 61.3, 114.3, 121.5, 122.1, 128.5, 133.4, 134.6, 137.3, 146.7, 156.4, 157.5. ES-MS m / z 348 (M + H). Calcd for C ₂₁ H ₂₅ N ₅ .0.2CH ₂ Cl ₂ .0.9CH ₄ O: C, 67.49; H, 7. 43; N, 17.81. Found: C, 67.59; H, 7.31; N, 17.46.
[830] Example 78
[831]
[832] Compound 78: N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -but-2-yn-1,4-diamine
[833] Preparation of (4-chlorobut-2-ynyl) carbamic acid tert-butyl ester:
[834] To a stirred solution of 1-amino-4-chloro-2-butyne hydrochloride (1.12 g, 8.01 mmol) and Boc ₂ O (2.12 g, 9.71 mmol) in THF (40 mL) and H ₂ O (15 drops) solution DIPEA (3.1 mL, 17.8 mmol) was added. The resulting solution was stirred at rt for 4.5 h. Saturated aqueous NaHCO ₃ (20 mL) was added, the layers were separated and the aqueous solution was extracted with Et ₂ O (25 mL × 2). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by column chromatography on flash silica gel (hexane / EtOAc, 7: 3) gave Boc protected amines as off-white solids (1.38 g, 6.79 mmol, 85%). ¹ H NMR (CDCl ₃ ) δ 1.44 (s, 9H), 3.97 (d, 2H, J = 4.5 Hz), 4.13 (t, 2H, J = 2.1 Hz), 4.74 (br. S, 1H).
[835] 2-{[(4-tert-butoxycarbonylamino-2-butynyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -methyl} -benzimidazole-1 Preparation of carboxylic acid tert-butyl esters:
[836] Chloride (182 mg, 0.89 mmol) from the stomach in CH ₃ CN, (1-tert-butoxycarbo-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinoline- 8-yl) -amine (285 mg, 0.75 mmol), DIPEA (0.20 mL, 1.2 mmol) and catalytic KI (8 mg, 0.05 mmol) were heated at 60 ° C. for 17 h. Saturated aqueous NaHCO ₃ (10 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (25 mL × 3). The organic solution was dried (MgSO ₄ ), filtered and evaporated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 9: 1: 0.1) afforded tertiary amine as a pale brown foam (374 mg, 0.69 mmol, 91%). ¹ H NMR (CDCl ₃ ) δ 1.43 (s, 9H), 1.67 (s, 9H), 1.97-2.14 (m, 4H), 2.61-2.73 (m, 1H), 2.75-2.88 (m, 1H), 3.61 -3.80 (m, 4H), 4.31 (dd, 1H, J = 7.8, 5.6 Hz), 4.45 (d, 1H, J = 15.9 Hz), 4.54 (d, 1H, J = 15.9 Hz), 4.63 (br. s, 1H), 7.01 (dd, 1H, J = 7.5, 4.8 Hz), 7.27-7.34 (m, 3H), 7.72 (dd, 1H, J = 6.0, 3.0 Hz), 7.83 (dd, 1H, J = 6.0, 3.3 Hz), 8.39 (d, 1H, J = 3.3 Hz).
[837] Preparation of Compound 78:
[838] Di-Boc protective amine (365 mg, 0.67 mmol) was stirred in TFA (6 mL) for 1.5 h at room temperature. Saturated aqueous NaHCO ₃ (about 100 mL) was added until the mixture became neutral, and the aqueous solution was extracted with CH ₂ Cl ₂ (50 mL × 3). The organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by column chromatography on flash silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 19: 1: 0.1) gave compound 78 as a beige foam (90.4 mg, 0.26 mmol, 39%). ¹ H NMR (CDCl ₃ ) δ 1.65-1.79 (m, 1H), 1.94-2.14 (m, 2H), 2.16-2.28 (m, 1H), 2.69-2.81 (m, 1H), 2.81-2.95 (m, 1H), 3.21 (s, 2H), 3.54 (d, 2H, J = 2.1 Hz), 4.04 (d, 1H, J = 16.2 Hz), 4.15 (d, 1H, J = 16.2 Hz), 7.14-7.23 ( m, 3H), 7.45 (d, 1H, J = 7.5 Hz), 7.54-7.64 (m, 2H), 8.58 (d, 1H, J = 4.3 Hz). ¹³ C NMR (CDCl ₃ ) δ 21.1, 24.6, 29.3, 31.9, 41.0, 49.9, 61.6, 79.2, 85.8, 122.1, 122.8, 135.0, 137.9, 147.0, 155.5, 157.4. ES-MS m / z 346 (M + H). Calcd for C ₂₁ H ₂₃ N ₅ .0.2CH ₂ Cl ₂ .0.1C ₄ H ₁₀ O: C, 70.15; H, 6.65; N, 18.94. Found: C, 69.97; H, 6. 85; N, 18.96.
[839] Example 79
[840]
[841] Compound 79: 3-Aminomethyl-N '-(1H-benzimidazol-2-ylmethyl) -N'-(5,6,7,8-tetrahydro-quinolin-8-yl) -but-2-ene-1 , 4-diamine (hydrobromide salt)
[842] Preparation of (3-tert-butoxycarbonylamino-2-oxo-propyl) -carbamic acid tert-butyl ester
[843] Di-tert-butyl dicarbonate (11.77 g, 0.054 mol) in a suspension of 1,3-diamino-2-hydroxypropane (2.43 g, 0.027 mol) in THF / H ₂ O (15: 1, 80 mL) Was added and the reaction stirred for 2.5 h and then concentrated in vacuo.
[844] To a solution of oxalyl chloride in CH ₂ Cl ₂ (2.0 M, 7.7 mL, 15.4 mmol) was added a solution of DMSO (1.7 mL, 24.0 mmol) in CH ₂ Cl ₂ (12 mL) at −78 ° C., and the mixture was −78 ° C. Stir for 30 min at and then add crude alcohol (2.86 g) from above in CH ₂ Cl ₂ (10 mL). Stirring was continued for 15 minutes and then Et ₃ N (5.0 mL, 35.9 mmol) was added dropwise. The cold bath was removed and stirring continued for 1.5 h and the mixture diluted with CH ₂ Cl ₂ (20 mL) and water (30 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (20 mL) and the combined organic extracts were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using 40% ethyl acetate in CH ₂ Cl ₂ to afford the title compound (350 mg, 16% over two steps) as a beige solid. ¹ H NMR (CDCl ₃ ) δ 1.42 (s, 18H), 4.03 (br d, 4H, J = 6 Hz), 5.26 (br s, 2H).
[845] Preparation of (4-tert-butoxycarbonylamino-3- (tert-butoxycarbonylamino-methyl) -but-2-enoic acid ethyl ester:
[846] (Caethoxymethylene) -triphenyl phosphoran to a solution of (3-tert-butoxycarbonylamino-2-oxo-propyl) -carbamic acid tert-butyl ester (310 mg, 1.08 mmol) in benzene (20 mL) (825 mg, 2.37 mmol) was added and the reaction mixture was stirred at 45 ° C. overnight. The mixture was cooled to rt and the solvent was concentrated. Purification by radial chromatography on silica gel (2 mm plate, using CH ₂ Cl ₂ ) afforded the desired compound as a yellow oil (290 mg, 75%). ¹ H NMR (CDCl ₃ ) δ 1.26 (t, 3H, J = 9.0 Hz), 1.42 (s, 18H), 3.87 (d, 2H, J = 6.0 Hz), 4.09 (d, 2H, J = 6.0 Hz) , 4.15 (q, 2H, J = 9.0 Hz), 5.34 (br s, 1H), 5.85 (s, 1H), 7.34 (s, 1H).
[847] Preparation of [2- (tert-butoxycarbonylaminomethyl) -4-hydroxy-but-2-enyl] -carbamic acid tert-butyl ester:
[848] To a solution of the above ester (290 mg, 0.81 mmol) in THF (10 mL) was added DIBAL (1.0 M in CH ₂ Cl ₂ ) (2.4 mL, 2.42 mmol) at -78 ° C. The temperature was increased to room temperature for 40 minutes. After 1 hour, the reaction was quenched with Rochelle's salt (10 mL) and stirred overnight. Then it was extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered, concentrated and dried under vacuum to give a yellow oil. Purification by column chromatography on flash silica gel using 50% hexanes / ethyl acetate gave the desired product as a pale yellow oil (210 mg, 83%). ¹ H NMR (CDCl ₃ ) δ 1.42 (s, 10H), 1.85 (br t, 1H), 3.89 (d, 4H, J = 9.0 Hz), 4.15 (t, 2H, J = 7.5 Hz), 4.75 (br t, 1H), 5.55 (br s, 1H), 5.78 (t, 1H, J = 7.5 Hz).
[849] 2-{[[4-tert-butoxycarbonylamino-3- (tert-butoxycarbonylamino-methyl) -but-2-enyl]-(5,6,7,8-tetrahydro-quinoline- Preparation of 8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester:
[850] To a solution of the above alcohol (107 mg, 0.34 mmol) and triethylamine (70 mL, 0.41 mmol) in CH ₂ Cl ₂ was added methanesulfonyl chloride (30 mL, 0.41 mmol) at 0 ° C. After 20 minutes at this temperature, the reaction mixture was quenched with saturated NH ₄ Cl (10 mL). The organic layer was washed with saturated NH ₄ Cl (2 × 10 mL), dried (Na ₂ SO ₄ ), filtered, concentrated and dried under vacuum to give a yellow oil (150 mg). It was used without further purification. ¹ H NMR (CDCl ₃ ) δ 1.43 (s, 18H), 3.02 (s, 3H), 3.76 (t, 4H, J = 6.0 Hz), 4.89 (d, 2H, J = 6.0 Hz), 4.90 (br s , 1H), 4.99 (br s, 1H), 5.64 (t, 1H, J = 6.0 Hz).
[851] Gastric mesylate (150 mg, 0.43 mmol), 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -benzimidazole- in CH ₃ CN (10 mL) 1-carboxylic acid tert-butyl ester (195 mg, 0.52 mmol), N, N-diisopropylethylamine (90 mL, 0.52 mmol) and potassium iodide (7 mg, 0.04 mmol) were stirred at 40 ° C. for 3 days. . Then the solvent was concentrated and the residue was dissolved in CH ₂ Cl ₂ (15 mL). The organic layer was extracted with saturated NaHCO ₃ (3 × 15 mL), dried (MgSO ₄ ), filtered, concentrated and dried under vacuum to give a yellow oil. Silica gel radial chromatography (2 mm plate, using CH ₃ OH / NH ₄ OH / CH ₂ Cl ₂ (0: 1: 99 → 4: 1: 95); 1 mm plate, CH ₃ OH / NH ₄ OH / CH ₂ Cl ₂ (0: 1: 99 → 2: 1: 97); 1 mm plate, with ethyl acetate; 1 mm plate, 4 times with CH ₃ OH / NH ₄ OH / CH ₂ Cl ₂ (1: 1: 100) Purification gave the desired compound as a white foam (39 mg, 13%). ¹ H NMR (CDCl 3) δ 1.38 (s, 9H), 1.43 (s, 9H), 1.70 (s, 9H), 2.04-2.11 (m, 3H), 2.56 (d, 1H, J = 16.2 Hz), 2.77 (br t, 1H), 3.22 (dd, 1H, J = 13.7, 6.2 Hz), 3.39 (dd, 1H, J = 15.6, 5.4 Hz), 3.49-3.58 (m, 2H), 3.76 (dd, 1H, J = 14.1, 8.1 Hz), 3.96 (dd, 1H, J = 14.1, 4.2 Hz), 4.22 (t, 1H, J = 8.1 Hz), 4.39 (ABq, 2H, J = 38.4, 14.4 Hz), 5.20 ( br m, 1H), 5.47 (br m, 1H), 6.72 (dd, 1H, J = 7.5, 4.8 Hz), 7.04 (d, 1H, J = 7.2 Hz), 7.20-7.25 (m, 3H), 7.54 -7.62 (m, 2H), 7.69-7.72 (m, 1H), 8.25 (d, 1H, J = 3.9 Hz).
[852] 3-Aminomethyl-N '-(1H-benzimidazol-2-ylmethyl) -N'-(5,6,7,8-tetrahydro-quinolin-8-yl) -but-2-ene-1 Preparation of, 4-diamine (hydrobromide salt):
[853] To a solution of the above diamine (39 mg, 0.06 mmol) in acetic acid (1 mL) was added bromic acid saturated acetic acid (0.5 mL) and the reaction mixture was stirred for 20 minutes. Diethyl ether was then added until a precipitate of compound 79 was obtained as a pink solid (20 mg, 30%). ¹ H NMR (D ₂ O) δ 1.76-1.84 (m, 1H), 2.16-2.21 (m, 1H), 2.37-2.41 (m, 1H), 2.98 (br d, 2H, J = 5.1 Hz), 3.41 (dm, 1H, J = 15.0 Hz), 3.68-3.70 (m, 3H), 3.76-3.85 (m, 2H), 4.26-4.46 (m, 3H), 6.23 (dd, 1H, J = 10.8, 4.2 Hz ), 7.56-7.60 (m, 2H), 7.73-7.84 (m, 3H), 8.30 (d, 1H, J = 7.5 Hz), 8.59 (d, 1H), J = 6.0 Hz). ¹³ C NMR (D ₂ O) δ 20.22, 20.30, 27.59, 37.12, 42.32, 46.68, 48.91, 59.19, 114.28, 126.03, 127.04, 128.73, 131.00, 136.26, 139.60, 140.88, 148.14, 150.51. ES-MS m / z 399 [M + H] &lt; + &gt;, 399 [M + Na] &lt; + &gt;. _{C 22 H 28 N 6 · 4.2HBr} · 2.2H Calcd _{2 O · 0.6C 4 H 10 O} : C, 36.61; H, 5. 36; N, 10.50; Br, 41.93. Found: C, 36.68; H, 5.08; N, 10.48; Br, 41.87.
[854] Example 80
[855]
[856] Compound 80: (E) -2-Aminomethyl-4-[(1H-benzimidazol-2-yl-methyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino]- Preparation of but-2-en-1-ol
[857] To a solution of 3-amino-1,2 propanediol (7.75 g, 0.085 mmol) in THF (430 mL) was added water (20 mL) followed by tert-butyl dicarbonate (19.60 g, 0.0898 mmol) in one portion. . The solution was stirred at rt for 23 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL) and saturated sodium carbonate (100 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 × 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give (1,2-dihydroxy-ethyl) -carbamic acid tert-butyl ester as a crude white solid (15 g, 92%).
[858] To a solution of crude (494 mg, 2.6 mmol) from the stomach in CH ₂ Cl ₂ (13 mL) was added imidazole (236 mg, 3.5 mmol) followed by TBDMS-Cl (410 mg, 2.7 mmol) and the reaction was added. Stir overnight at room temperature. The reaction mixture was diluted with CH ₂ Cl ₂ (40 mL) and saturated aqueous sodium bicarbonate (40 mL). The phases were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude was purified by column chromatography (15 g of silica, 8: 1 hexanes / EtOAc) to afford [2- (tert-butyl-dimethyl-silanyloxy) -1-hydroxy-ethyl] -carbamic acid tert-butyl ester Obtained as a colorless oil (555 mg, 70%). ¹ H NMR (CDCl ₃ ) d: 4.96 (broad s, 1H), 3.74-3.71 (m, 1H), 3.67-3.62 (m, 1H), 3.56-3.50 (m, 1H), 1.44 (s, 9H) , 0.90 (s, 9H), 0.07 (s, 6H).
[859] NMO (324 mg, 2.77 mmol) was added to a solution of the substance from the stomach (555 mg, 1.81 mmol) in CH ₂ Cl ₂ (9 mL), followed by lower molecular sieves (960 mg) and TPAP (62 mg, 0.18 mmol). Was added. The green-black solution was stirred at room temperature for 2 hours. The reaction was monitored by TLC (coloured with 2: 1 hexanes / EtOAc-ninhydrin). The reaction mixture was filtered through a silica gel cake and the cake washed with ethyl acetate. The filtrate was concentrated to give [2- (tert-butyl-dimethyl-silanyloxy) -acetyl] -carbamic acid tert-butyl ester as a yellow oil (458 mg, 83%).
[860] Preparation of 3-tert-butoxycarbonylamino-4- (tert-butyl-dimethyl-silanyloxy) -but-2-enoic acid ethyl ester
[861] To a ketone (458 mg, 1.51 mmol) from above in benzene (8 mL) was added (carbethoxymethylene) triphenyl phosphorolane (815 mg, 2.35 mmol). The bation mixture was heated to ˜40-45 ° C. and stirred at this temperature overnight. The reaction mixture was then concentrated and the residue was purified by column chromatography (25 g silica, 25: 1 hexanes / EtOAc) to give two yellow oils (cis / trans isomers) as main product (total 430 mg, 76%). It was. ¹ H NMR of trans-isomer (CDCl ₃ ) d: 6.06 (s, 1H), 5.41 (broad s, 1H), 4.31 (s, 2H), 4.18 (q, 2H, J = 7.5Hz), 3.94 (d , 2H, J = 7.0 Hz), 1.42 (s, 9H), 1.30 (t, 3H, J = 7.5 Hz), 0.92 (s, 9H), 0.07 (s, 6H). ¹ H NMR of cis-isomer (CDCl ₃ ) d: 5.78 (s, 1H), 4.87 (s, 2H), 4.14 (q, 2H, J = 7.5 Hz), 4.00 (d, 2H, J = 7.0 Hz) , 1.45 (s, 9H), 1.27 (t, 3H, J = 7.5 Hz), 0.91 (s, 9H), 0.09 (s, 6H).
[862] Solution of trans-3-tert-butoxycarbonylamino-4- (tert-butyl-dimethyl-silanyloxy) -but-2-enoic acid ethyl ester (0.66 g, 1.8 mmol) in dichloromethane (18 mL) To 0 ° C. was added a solution of DIBAL-H (8.8 mL, 1.0 M in CH ₂ Cl ₂ , 8.8 mmol). The solution was stirred for 1 hour while warming to room temperature. Saturated potassium sodium tartrate solution (20 ml) was then added and the solution was stirred for an additional hour. The phases were separated, the organic phase was dried (MgSO ₄ ), stirred and concentrated under reduced pressure followed by column chromatography (1: 3 ethyl acetate / hexanes) followed by trans- [2- (tert-butyl-dimethyl-silanyl Oxymethyl) -4-hydroxy-but-2-enyl] -carbamic acid tert-butyl ester (0.255 g, 39%) was obtained.
[863] Methanesulfonyl chloride (65 mL, 0.8 mmol) and triethylamine (0.15 mL, 1.0 mmol) were added to a solution of the above alcohol (0.23 g, 0.7 mmol) in dichloromethane (7.0 mL) at room temperature and stirred for 0.5 h. It was. After aqueous workup, crude allylic methanesulfonate (0.25 g, 80%) was obtained as a pale yellow crystalline solid.
[864] Methanesulfonate (0.25 g, 0.7 mmol), (N-tert-butoxycarbonylbenzimidazol-2-ylmethyl)-(5,6,7,8 -Tetrahydroquinolin-8-yl) -amine (0.26 g, 0.70 mmol) and potassium iodide (6 mg, 35 mmol) in 60 ° C. in acetonitrile (7.0 mL) and diisopropylethylamine (0.18 mL, 1.0 mmol) After stirring for 16 hours at post-treatment and column chromatography (2.5: 97.5 MeOH / CH ₂ Cl ₂ ), the desired alkylated E-regioisomer (0.200 g, 42%) was obtained.
[865] A solution of the above compound (0.20 g, 0.30 mmol) in THF (1.0 mL) was treated with TBAF (0.6 mL, 1.0 M in THF, 0.6 mmol) for 0.5 h. This was subjected to column chromatography (1:99 MeOH / CH ₂ Cl ₂ ), followed by di-boc-protected E-2-{[[3- (tert-butoxycarbonylaminomethyl) -4-hydroxy-buty 2-enyl]-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester (60 mg, 38%) was obtained. It was. ¹ H NMR (CDCl ₃ ) δ 1.41 (s, 9H), 1.65 (br, 1H), 1.69 (s, 9H), 2.11 (m, 3H), 2.60 (m, 1H), 2.77 (m, 1H), 3.27 (m, 1H), 3.60 (m, 1H), 3.88 (m, 3H), 4.07 (m, 1H), 4.23 (m, 1H), 4.29 (d, 1H, J = 15.0 Hz), 4.46 (d , 1H, J = 15.0 Hz, 5.50 (m, 1H), 6.74 (m, 1H), 7.05 (d, 1H, J = 6.0 Hz), 7.24 (m, 2H), 7.59 (m, 1H), 7.70 (m, 2H), 8.26 (d, 1H, J = 3.0 Hz).
[866] The above material (60 mg, 0.11 mmol) was then dissolved in pure TFA (1 mL) and stirred for 1 hour. CH ₂ Cl ₂ (10 mL) and 15% aqueous NaOH were added until pH was 13. The organic phase was separated and the aqueous phase extracted with CH ₂ Cl ₂ (2 × 5 mL). The combined organic phases were then dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give the free base of compound 80 as a pale yellow glass flow powder (14 mg, 10%). ¹ H NMR (CDCl ₃ ) δ 1.66 (br, 1H), 1.85 (m, 1H), 2.00 (br, 1H), 2.17 (br, 1H), 2.80 (m, 3H), 3.19 (m, 1H), 3.30 (m, 1H), 3.36 (s, 2H), 3.90 (d, 1H, J = 15.0 Hz), 4.01 (d, 1H, J = 18.0 Hz), 4.10 (br, 3H), 5.64 (m, 1H ), 7.09 (m, 1H), 7.15 (m, 2H), 7.40 (d, 1H, J = 9.0 Hz), 7.54 (br, 2H), 8.49 (d, 1H, J = 3.0 Hz); ¹³ C NMR (CDCl ₃ ) δ 21.46, 23.21, 29.47, 39.86, 47.47, 49.46, 61.34, 67.08, 115.11 (3C), 122.165 (2C), 122.62, 126.31 (2C), 135.25, 137.97, 142.19, 147.02, 155.11 , 157.26. ES-MS m / z 378 (M + H). Calcd for C ₂₂ H ₂₇ N ₅ 0.0.7CH ₂ Cl ₂ : C, 62.40; H, 6.55; N, 16.03. Found: C, 62.70; H, 6. 70; N, 15.97.
[867] Example 81
[868]
[869] Compound 81: (Z) -2-Aminomethyl-4-[(1H-benzimidazol-2-yl-methyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino]- Preparation of but-2-en-1-ol
[870] To a solution of cis-3-tert-butoxycarbonylamino-4- (tert-butyl-dimethyl-silanyloxy) -but-2-enoic acid ethyl ester (0.49 g, 1.3 mmol) in dichloromethane (13 mL) At 0 ° C. DIBAL-H (6.5 mL, 1.0 M in CH ₂ Cl ₂ , 6.5 mmol) was added. The solution was stirred for 1 hour while warming to room temperature. Then saturated potassium sodium tartrate solution (15 mL) was added and the solution was stirred for an additional hour. The phases were separated and the organic phase was dried (MgSO ₄ ), filtered and concentrated to crude cis- [2- (tert-butyl-dimethyl-silanyloxymethyl) -4-hydroxy-but-2-enyl] Carbamic acid tert-butyl ester (0.33 g, 77%) was obtained.
[871] Methanesulfonyl chloride (39 mL, 0.42 mmol) and triethylamine (0.090 mL, 0.63 mmol) were added to a solution of the above alcohol (0.14 g, 0.42 mmol) in dichloromethane (4.2 mL) and stirred for 0.5 h. After workup, a crude allylic methanesulfonate (0.14 g) was obtained, which was used immediately for the next reaction.
[872] Using the general process for N-alkylation, methanesulfonate (0.14 g, 0.42 mmol), (N-tert-butoxycarbonylbenzimidazol-2-ylmethyl)-(5,6,7,8- Tetrahydroquinolin-8-yl) -amine (0.16 g, 0.42 mmol) and potassium iodide (3 mg, 21 mmol) in acetonitrile (4.2 mL) and diisopropylethylamine (0.11 mL, 0.63 mmol) at 60 ° C. Stir for 16 hours and give the desired alkylated Z-regioisomer (0.100 g, 34%) after workup and column chromatography (1:99 MeOH / CH ₂ Cl ₂ ).
[873] A solution of the above compound (0.10 g, 0.16 mmol) in THF (2 mL) and 3N HCl (2 mL) was stirred for 1.5 h. The solution was then cooled to 0 ° C. and 15% aqueous sodium hydroxide was added until the pH reached 12. The aqueous phase was then extracted with CH ₂ Cl ₂ (3 × 15 mL) and the combined organic phases were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. This was subjected to radial chromatography (8: 2.5: 89.5 MeOH / NH ₄ OH / CH ₂ Cl ₂ ), followed by Z- {4-[(1H-benzimidazol-2-yl-methyl)-(5,6,7, 8-tetrahydroquinolin-8-yl) -amino] -2-hydroxymethyl-but-2-enyl} -carbamic acid tert-butyl ester (35 mg, 58%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H), 1.77 (br, 1H), 1.97 (m, 1H), 2.10 (m, 3H), 2.80 (m, 2H), 3.27 (m, 2H), 3.64 (br, 2H), 3.72 (d, 1H, J = 15.0 Hz), 3.92 (d, 1H, J = 15.0 Hz), 4.02 (s, 2H), 4.12 (m, 1H), 4.58 (m, NH ), 7.18 (m, 3H), 7.50 (m, 2H), 7.68 (br, 1H), 8.52 (d, 1H, J = 3.0 Hz).
[874] The above compound (35 mg, 0.07 mmol) was then dissolved in pure TFA (1 mL), stirred for 1 h, CH ₂ Cl ₂ (10 mL) and 15% aqueous NaOH until pH was 12 Was added. The organic phase was separated and the aqueous phase extracted with CH ₂ Cl ₂ (2 × 5 mL). The combined organic phases were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. This was subjected to radial chromatography (8: 2.5: 89.5 MeOH / NH ₄ OH / CH ₂ Cl ₂ ) to give the free base of compound 81 as a pale yellow glass flow powder (18 mg, 68%). ¹ H NMR (CDCl ₃ ) δ 1.75 (br, 1H), 1.94 (m, 1H), 2.08 (br, 2H), 2.85 (m, 3H), 3.30 (m, 4H), 3.78 (d, 1H, J = 14.4 Hz), 3.95 (d, 1H, J = 15.6 Hz), 4.11 (d 2H), 4.15 (m, 1H), 5.48 (m, 1H), 7.19 (m, 3H), 7.46 (d, 1H, J = 7.2 Hz), 7.58 (br, 2H), 8.53 (d, 1H, J = 3.3 Hz); ¹³ C NMR (CDCl ₃ ) δ 20.88, 23.54, 29.20, 47.22, 47.74, 49.28, 59.50, 61.77, 115.24 (3C), 122.42 (2C), 122.82, 125.40 (2C), 135.27, 138.23, 143.73, 146.88, 155.01 , 157.26. ES-MS m / z 378 (M + H). Calcd for C ₂₂ H ₂₇ N ₅ 0.0.7CH ₂ Cl ₂ .0.2C ₆ H ₁₂ : C, 63.26; H, 6. 84; N, 15.43. Found: C, 63.36; H, 6.79; N, 15.59.
[875] Example 82
[876]
[877] Compound 82: N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-trans-1,2-diamine (hydrobromide salt)
[878] Preparation of N- (2-nitrobenzenesulfonyl) -7-azabicyclo [4.1.0] heptane (N- (2-nitrobenzenesulfonyl) -1,2-cyclohexeneaziridine)
[879]
[880] A solution of trans-2-aminocyclohexanol hydrochloride (1.185 g, 7.81 mmol) and 2-nitrobenzenesulfonyl chloride (1.73 g, 7.81 mmol) in CH ₂ Cl ₂ (20 mL) was cooled in an ice bath under a nitrogen atmosphere. Et ₃ N (2.40 mL, 17.2 mmol) was added. The mixture was heated to reflux for 35 minutes and then concentrated in vacuo. Water (100 mL) was added to the residue and the mixture was extracted with EtOAc (100 mL). The organic extract was washed with brine (2 × 30 mL), then dried (MgSO ₄ ), filtered and concentrated in vacuo to give a green foam (2.32 g).
[881] Foams from above in CH ₂ Cl ₂ (15 mL) and Et ₃ N (1.3 mL, 9.3 mmol) were stirred under argon at −78 ° C., while methanesulfonyl chloride (0.66 mL, 8.5 mmol) was added. The mixture was stirred at −78 ° C. for 10 minutes, then the cold bath was removed and stirring continued at room temperature for 30 minutes, then the solution was concentrated in vacuo. Water (30 mL) and saturated NaHCO ₃ (aq) (30 mL) were added to the residue and the mixture was extracted with EtOAc (1 × 50 mL, 3 × 20 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to afford crude mesylate as a light yellow solid (2.65 g).
[882] Crude mesylate (2.65 g, 7.0 mmol) was stirred at room temperature as a suspension in toluene (30 mL), while a 85% KOH (2.01 g, 35.9 mmol) solution in H ₂ O (12 mL) was added. The mixture was stirred for 40 minutes and then diluted with EtOAc (50 mL) and brine (40 mL). The aqueous phase was separated and washed with EtOAc (1 × 40 mL), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (25% EtOAc / hexanes) to afford the desired aziridine as colorless crystals (1.54 g, 71% over 3 steps). ¹ H NMR (CDCl ₃ ) δ 1.23-1.30 (m, 2H), 1.35-1.42 (m, 2H), 1.84-1.93 (m, 4H), 3.22 (dd, 2H, J = 6, 1 Hz), 7.72- 7.76 (m, 3 H), 8.18-8.20 (m, 1 H).
[883] N- (2-nitrobenzenesulfonyl) -1,2-cyclohexeneaziridine (341 mg, 1.21 mmol), (1-tert-butoxycarbonyl-1H-benzimi from stomach in THF (5 mL) A solution of dazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (434 mg, 1.15 mmol) and Et ₃ N (0.16 mL, 1.15 mmol) was added 60 Heated at 2.5 ° C. under nitrogen atmosphere for 2.5 days. The solution was then cooled, concentrated and diluted with CH ₂ Cl ₂ (40 mL) and saturated aqueous NaHCO ₃ (40 mL). The aqueous phase was extracted with CH ₂ Cl 2 (2 × 20 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 98: 2 then 96: 4) to afford the desired alkylation product as a yellow foam (411 mg, 54%).
[884] Foam (271 mg, 0.41 mmol) oil from above was dissolved in CH ₂ Cl ₂ / TFA (1: 1, 2 mL) and the mixture was stirred overnight. The reaction was then concentrated and diluted with CH ₂ Cl ₂ (30 mL) and 1N NaOH (30 mL). The aqueous layer was washed with CH ₂ Cl ₂ (2 × 10 mL), the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give the Boc deprotection material as a yellow foam (159 mg, 69%). Obtained.
[885] Deprotection of 2-nitrobenzenesulfonamide (nosyl) group: Benzene thiol (0.175 mL, 1.71 mmol) and a stirred solution of the nosyl protected adduct (159 mg, 0.28 mmol) from above in anhydrous CH ₃ CN (5 mL) and Potassium carbonate powder (240 mg, 1.74 mmol) was added and the mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and partitioned between CH ₂ Cl ₂ (15 mL) and water (15 mL). The aqueous layer was separated, extracted with CH ₂ Cl ₂ (2 × 10 mL), the combined organic phases were dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to evaporate the crude product as a yellow oil. Purification by basic column chromatography on alumina (CH ₂ Cl ₂ / MeOH, 95: 5 after 100: 0) gave the desired amine (85 mg, 80%) as a yellow foam.
[886] General Process D Use: The foam (34 mg, 0.091 mmol) from the stomach was converted to a hydrobromide salt and then reprecipitated the intermediate solid from methanol / ether to give compound 82 (38 mg, 65%) as a white solid. . ¹ H NMR (D ₂ O) δ 1.36-1.46 (m, 2H), 1.59-1.91 (m, 5H), 2.22-2.32 (m, 3H), 2.35-2.45 (m, 2H), 2.81-2.84 (m , 2H), 3.21-3.28 (m, 1H), 3.44-3.56 (m, 1H), 4.33 (d, 1H, J = 15.9 Hz), 4.42 (d, 1H, J = 15.9 Hz), 4.65 (t, 1H, J = 8.4 Hz), 7.23 (dd, 1H, J = 7.5, 6 Hz), 7.51 (dd, 2H, J = 6.3, 3.3 Hz), 7.59 (dd, 2H, J = 6.3, 3.3 Hz), 7.86 (d, 1H, J = 8.1 Hz), 8.11 (d, 1H, J = 5.5 Hz); ¹³ C NMR (D ₂ O) δ 19.35, 22.02, 22.46, 23.56, 26.46, 27.94, 29.94, 37.81, 50.82, 61.34, 66.88, 112.92, 123.83, 126.14, 129.54, 138.38, 139.34, 146.03, 148.26, 148.34 ES-MS mlz 376 (M + H). Calcd for C ₂₃ H ₂₉ N ₅ 2.9 HBr 1.8 H ₂ 0: C, 42.99; H, 5.57; N, 10.90; Br, 36.06. Found: C, 43.29; H, 5.55; N, 10.60; Br, 35.67.
[887] Example 83
[888]
[889] Compound 83: N- (1H-benzimidazol-2-ylmethyl) -N- (5,6,7,8-tetrahydro-quinolin-8-yl) -cyclohexane-1,3-diamine (hydrobromide Salts)
[890] Preparation of N-tert-butoxycarbonyl-1,3-cyclohexanediamine (Smith, J .; Liras, J.L .; Schneider, S.E .; Anslyn, E J. Org. Chem. 1996, 61, 8811-8818):
[891]
[892] To a solution of 1,3-cyclohexanediamine (cis and trans) (1.00 g, 8.76 mmol) in CHCl ₃ (20 mL) di-tert-butyl dicarbonate (0.95 g, 4.35 mmol) in CHCl ₃ (15 mL) Was added for 3 hours through a syringe pump. The resulting white suspension was stirred at rt overnight, then concentrated in vacuo and purified by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 90: 8: 2) to give the title compound (0.66 g, starting). 35%) is obtained as a clear oil, based on diamine.
[893] According to general process B: 6,7-dihydro-5H-quinolin-8-one (444 mg, 3.00 mmol) and N-tert-butoxycarbonyl-1,3-cyclohexane in dry THF (5 mL) To a stirred solution of diamine (660 mg, 3.08 mmol) was added AcOH (0.4 mL) and NaBH (OAc) ₃ (822 mg, 3.88 mmol), and the mixture was stirred at rt overnight. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 96: 4) gave the desired amine (370 mg, 60%) as a mixture of non-separable diastereomers.
[894] According to general co-authoring for N-alkylation: N, N-diisopropylethylamine (0.35 mL, 2.01 mmol) in a stirred solution of yellow foam (370 mg, 1.07 mmol) from above in CH ₃ CN (5 mL). , KI (30 mg, 0.18 mmol) and 1- (tert-butoxycarbonyl) -2- (chloromethyl) benzimidazole (343 mg, 1.29 mmol) were added. The mixture was stirred at 60 ° C. overnight. The orange foam obtained was purified by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 96: 4 then 92: 8) to give the desired alkylated amine (430 mg, 70%) as a mixture of diastereomers.
[895] Use of General Process D: Compounds by converting the foam from the stomach (96 mg, 0.17 mmol) into hydrobromide salts, at the same time removing the N-tert-butoxycarbonyl protecting group and then reprecipitating the intermediate solid from methanol / ether 83 (96 mg, 88%) was obtained as an orange solid (mixture of diastereomers). ¹ H NMR (D ₂ O) δ 1.27-1.64 (m, 4H), 1.74-2.00 (m, 4H), 2.07-2.38 (m, 3H), 2.40-2.44 (m, 1H), 2.84-2.90 (m , 1H), 2.98-3.01 (m, 2H), 3.15-3.20 (m, 1H), 4.43-4.62 (m, 3H), 7.60 (dd, 2H, J = 6, 3 Hz), 7.76 (dd, 2H, J = 6, 3 Hz), 7.78-7.83 (m, 1H), 8.28 (br d, 1H, J = 7.8 Hz), 8.57-8.60 (m, 1H); ¹³ C NMR (D ₂ O) δ 19.58, 20.71, 22.37, 22.45, 24.23, 27.21, 27.51, 28.60, 29.16, 29.70, 30.54, 31.08, 31.75, 34.35, 36.21, 43.65, 48.61,49.79, 54.46, 58.57, 58.70 , 58.93, 114.23, 125.86, 127.05, 130.91, 139.16, 140.55, 148.03, 151.18, 151.26, 151.83. ES-MS mlz 376 (M + H). Calcd for C ₂₃ H ₂₉ N ₅ .3.0HBr. 1.96H ₂ O: C, 42.34; H, 5.53; N, 10.73; Br, 36.74. Found: C, 42.27; H, 5.59; N, 10.37; Br, 37.04.
[896] Example 85
[897]
[898] Compound 85: (1H-benzimidazol-2-ylmethyl)-[2- (4-benzylamino-piperidin-1-yl) -ethyl]-(5,6,7,8-tetrahydroquinoline- Preparation of 8-yl) -amine (hydrobromide salt)
[899] To a solution of N-Boc-piperidone (3.0 g, 15.1 mmol) in THF (76 mL) benzylamine (1.65 mL, 15.1 mmol), acetic acid (0.86 mL, 15.1 mmol) and sodium triacetoxyborohydride (4.8 g) , 22.6 mmol) was added. After 2.5 h, the reaction mixture was concentrated under reduced pressure and CH ₂ Cl ₂ (50 mL) and saturated aqueous NaHCO ₃ solution (50 mL) were added. The organic phase was separated and the aqueous phase extracted with CH ₂ Cl ₂ (2 × 50 mL). The combined organic phases were then dried (MgSO ₄ ), filtered and concentrated under reduced pressure to afford 4-benzylamino-piperidine-1-carboxylic acid tert-butyl ester (4.30 g, 98%).
[900] Crude from the stomach (4.30 g, 14.8 mmol) and 2-nitrobenzenesulfonyl chloride (3.60 g, 16.3 mmol) were dissolved in CH ₂ Cl ₂ (75 mL) and triethylamine (2.68 mL, 19.2 mmol) Was added. The solution was stirred for 16 h and saturated aqueous NaHCO ₃ solution (70 mL) was added. The organic phase was separated and the aqueous phase extracted with CH ₂ Cl ₂ (50 mL). The combined organic phases were then dried (MgSO ₄ ), filtered and concentrated under reduced pressure. This was followed by column chromatography (CH ₂ Cl ₂ ) to afford the desired nosyl protected substrate (3.92 g, 56%).
[901] A solution of the above material (3.92 g, 8.2 mmol) in 1: 1 TFA / CH ₂ Cl ₂ (26 mL) was stirred for 0.5 h and then concentrated under reduced pressure. CH ₂ Cl ₂ (50 mL), saturated aqueous NaHCO ₃ solution (50 mL) and 15% aqueous NaOH (10 mL) were added until the pH reached 14. The organic phase was separated and the aqueous phase extracted with CH ₂ Cl ₂ (30 mL). The combined organic phases were then dried (MgSO ₄ ), filtered and concentrated under reduced pressure. This gave the desired unprotected cyclic amine (2.74 g, 89%).
[902] To a solution of cyclic amine (2.74 g, 7.3 mmol) in anhydrous acetonitrile (73 mL) was added 2-bromoethanol (0.52 mL, 7.3 mmol) and triethylamine (1.25 mL, 8.7 mmol). The reaction was stirred at 50 ° C. for 16 h and saturated aqueous NaHCO ₃ solution (50 mL) and ethyl acetate (50 mL) were added. The organic phase was separated and washed with brine (35 mL), then the extract was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. This was followed by column chromatography (2:98 MeOH / CH ₂ Cl ₂ ) followed by N-benzyl-N- [1- (2-hydroxy-ethyl) -piperidin-4-yl] -2-nitro-benzenesulfon Amide was obtained as a colorless solid (1.62 g, 53%). ¹ H NMR (CDCl ₃ ) δ 1.62-1.71 (m, 4H), 2.14 (dt, 2H, J = 12.0, 3.0 Hz), 2.47 (t, 2H, J = 6.0 Hz), 2.88 (br d, 2H, J = 12.0 Hz), 3.53 (t, 2H, J = 4.5 Hz), 3.92 (m, 1H), 4.54 (s, 2H), 7.21 (m, 3H), 7.30 (m, 2H), 7.47 (m, 1H), 7.61 (d, 2H, J = 4.5 Hz), 7.77 (d, 1H, J = 9.0 Hz).
[903] To methanesulfonyl chloride (100 mL, 1.2 mmol) and triethylamine (0.20 mL, 1.4 mmol) was added a solution of the above alcohol (0.40 g, 0.95 mmol) in CH ₂ Cl ₂ (3 mL) at 0 ° C., Warm at room temperature over 20 minutes. After workup, the desired crude methanesulfonate (0.53 g, quant) was obtained as a white solid which was used immediately in the next step.
[904] Crude methanesulfonate (0.47 g, 0.94 mmol) and (N-tert-butoxycarbonylbenzimidazol-2-ylmethyl)-(5,6,7,8- Tetrahydroquinolin-8-yl) -amine (0.36 g, 0.94 mmol) was stirred in acetonitrile (10 mL) and diisopropylethylamine (0.25 mL, 1.4 mmol) at room temperature for 16 hours. This was followed by work up and column chromatography (5:95 MeOH / CH ₂ Cl ₂ ) followed by 2-{[{2- [4- (benzyl-2-nitrobenzenesulfonyl-amino) -piperidin-1-yl ] -Ethyl}-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester as a colorless flaky solid (0.25 g, 34 Obtained as%).
[905] Potassium carbonate (0.27 g, 1.9 mmol) was added to a solution of the above substance (0.25 g, 0.32 mmol) and thiophenol (0.17 mL, 1.6 mmol) in anhydrous acetonitrile (2.0 mL). The reaction was stirred for 5 hours. CH ₂ Cl ₂ (10 mL) was then added, and the mixture was filtered through a pad of celite and concentrated under reduced pressure. This gave the desired nosyl deprotection product (0.75 g, 60%) after column chromatography (5:95 MeOH / CH ₂ Cl ₂ ).
[906] To a solution of the above material (75 mg, 0.15 mmol) in dry THF (1.5 mL) was added di-tert-butyldicarbonate (100 mg, 0.45 mmol). The solution was stirred for 16 h and then concentrated under reduced pressure. This was subjected to radial chromatography (1.5: 1.5: 97 MeOH / NH ₄ OH / CH ₂ Cl ₂ ) to give the desired di-boc-deprotection product (42 mg, 40%). ¹ H NMR (CDCl ₃ ) δ 1.32 (br s, 9H), 1.47 (br s, 5H), 1.67 (s, 9H), 1.77 (br s, 4H), 1.97 (m, 1H), 2.15 (m, 2H), 2.29 (m, 1H), 2.73 (m, 6H), 4.22 (m, 1H), 4.26 (br s, 2H), 4.53 (d, 1H, J = 15.0 Hz), 4.73 (d, 1H, J = 15.0 Hz), 6.97 (m, 1H), 7.16 (m, 3H), 7.23 (m, 5H), 7.68 (m, 1H), 7.81 (m, 1H), 8.36 (d, 1H, J = 3.0 Hz).
[907] General Process D Use: The above material (24 mg, 0.0345 mmol) was converted to the hydrobromide salt to give compound 85 (26 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.82 (br m, 1H), 1.97 (m, 3H), 2.17 (br m, 1H), 2.45 (m, 3H), 3.00-3.23 (br m, 5H), 3.38 -3.75 (br m, 6H), 4.29 (s, 2H), 4.39 (d, 1H, J = 16.8 Hz), 4.50 (m, 1H), 4.56 (d, 1H, J = 16.8 Hz), 7.47 (br s, 5H), 7.60 (m, 2H), 7.79 (m, 2H), 7.83 (t, 1H, J = 6.0 Hz), 8.32 (d, 1H, J = 7.8 Hz), 8.61 (d, 1H, J = 5.7 Hz), ¹³ C NMR (D ₂ O) δ 20.29, 20.64, 26.15 (2C), 27.65, 46.41, 47.13, 49.13, 51.39 (2C), 51.91, 54.39, 60.07, 114.41 (2C), 126.16, 127.06 (2C), 129.82 (2C), 130.16 (2C), 130.26, 130.71, 131.30, 139.85 (2C), 140.96, 148.27, 149.95, 150.18. ES-MS m / z 495 (M + H). Calcd for _{C 31 H 38 N 6 · 4.2HBr} · 3.0H 2 O: C, 42.05; H, 5.49; N, 9.49; Br, 37.51. Found: C, 42.13; H, 5. 64; N, 9. 16; Br, 37.53.
[908] Example 86
[909]
[910] Compound 86: [2- (4-amino-piperidin-1-yl) -ethyl]-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinoline- Preparation of 8-yl) -amine (hydrobromide salt)
[911] N-benzyl-N- [1- (2-hydroxy-ethyl) -piperidin-4-yl] -2-nitro-benzenesulfonamide (0.62 g, 1.5 mmol) in anhydrous acetonitrile (9 mL) and Potassium carbonate (1.22 g, 8.8 mmol) was added to a thiophenol (0.76 mL, 7.4 mmol) solution. The reaction was stirred for 16 hours. The mixture was then filtered through celite to give the desired nosyl deprotection intermediate (0.30 g, 86%) after column chromatography (10:90 MeOH / CH ₂ Cl ₂ ).
[912] The above material (0.30 g, 1.3 mmol) was dissolved in anhydrous ethanol (15 mL) and the solution was purged with nitrogen gas. 10% palladium on carbon (130 mg) was added and the reaction mixture was stirred for 16 h under fresh hydrogen (one pressure) atmosphere. The mixture was then filtered through celite and a crude yellow residue of 2- (4-amino-piperidin-1-yl) -ethanol (0.20 g, quant.) Was obtained.
[913] To a solution of the above material (0.20 g, 1.5 mmol) in dry THF (7.5 mL) was added di-tert-butyldicarbonate (0.37 g, 1.7 mmol). The solution was stirred for 16 h and then concentrated under reduced pressure. This was followed by column chromatography (5:95 MeOH / CH ₂ Cl ₂ ) to afford the desired boc-deprotected amine (0.14 g, 37%). ¹ H NMR (CDCl ₃ ) δ 1.42 (m, 2H), 1.44 (s, 9H), 1.92 (br d, 2H), 2.14 (br t, 2H), 2.50 (t, 2H, J = 6.0 Hz), 2.82 (br d, 2H), 3.45 (br, 1H), 3.57 (t, 2H, J = 6.0 Hz), 4.48 (br, NH).
[914] Methanesulfonyl chloride (60 mL, 0.7 mmol) and triethylamine (0.12 mL, 0.9 mmol) were added to a solution of the above substance (0.14 g, 0.6 mmol) in CH ₂ Cl ₂ (3 mL) at 0 ° C. Warmed to room temperature over 20 minutes. After aqueous workup, the desired methanesulfonate (0.16 g) was obtained and used immediately in the next step without further purification.
[915] Crude methanesulfonate (0.16 g, 0.5 mmol) and (5,6,7,8-tetrahydroquinolin-8-yl)-[1- (2-trimethylsilanyl) using the general process for N-alkylation -Ethoxymethyl) -1H-benzimidazol-2-ylmethyl] -amine (0.18 g, 0.44 mmol) was dissolved in acetonitrile (5 mL) and diisopropylethylamine (0.13 mL, 0.75 mmol) at room temperature. After stirring and column chromatography (5:95 MeOH / CH ₂ Cl ₂ ), the desired alkylation product (27 mg, 12%) was obtained.
[916] The material from the stomach (27 mg, 0.042 mmol) was dissolved in 6N HCl (1 mL) and stirred at 50 ° C. for 3 hours. 15% aqueous NaOH (2 mL) was added until the pH reached 12 and the aqueous phase was concentrated under reduced pressure. It was filtered from methanol and subjected to radial chromatography (5: 1: 94 MeOH / NH ₄ OH / CH ₂ Cl ₂ ) to afford the desired SEM-deprotected free base (12 mg, 69%). ¹ H NMR (CDCl ₃ ) δ 1.48 (m, 2H), 1.70 (m, 1H), 1.82 (m, 3H), 1.98 (m, 2H), 2.23 (m, 2H), 2.66-2.95 (m, 8H ), 3.74 (s, 1H), 3.98 (d, 2H, J = 15.0 Hz), 4.13 (m, 1H), 7.13 (m, 1H), 7.19 (m, 2H), 7.40 (d, 1H, J = 9.0 Hz), 7.58 (m, 2 H), 8.49 (d, 1 H, J = 3.0 Hz).
[917] General Process D Use: The material from the stomach (12 mg, 0.030 mmol) was converted to a hydrobromide salt to give compound 86 (14 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.85-2.05 (br m, 3H), 2.20-2.30 (br m, 3H), 2.47 (m, 1H), 3.00 (br m, 2H), 3.15 (br m, 2H ), 3.34 (m, 1H), 3.44-3.63 (br m, 4H), 4.35 (d, 1H, J = 16.5 Hz), 4.47 (m, 1H), 4.53 (d, 1H, J = 16.5 Hz), 4.80-4.93 (br, 4H), 7.58 (m, 2H), 7.80 (m, 3H), 8.30 (d, 1H, J = 7.5 Hz), 8.58 (d, 1H, J = 5.7 Hz), ¹³ C NMR (D ₂ O) δ 20.30, 20.64, 27.29 (2C), 27.65, 45.53, 46.43, 47.14, 51.41 (2C), 54.36, 60.08,114.44 (2C), 126.08, 126.90 (2C), 131.59, 139.88, 140.86 ( 2C), 148.10, 150.06, 150.30. ES-MS m / z 405 (M + H). Calcd for C ₂₄ H ₃₂ N ₆ .4.1HBr.3.3H ₂ O: C, 36.41; H, 5. 42; N, 10.62; Br, 40.93. Found: C, 36.52; H, 5.49; N, 10.26; Br, 40.94.
[918] Example 87
[919]
[920] Compound 87: of 4-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyramidine (hydrobromide salt) Produce
[921] [N- (tert-butoxycarbonyl) -benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-(3-cyano-prop-1 -Yl) -amine (0.14 g, 0.30 mmol) was dissolved in anhydrous methanol (3 mL) and anhydrous diethyl ether (5 mL). The solution was cooled to 0 ° C. and hydrogen chloride gas was saturated by bubbling through the solution for 0.5 h. The reaction was then stirred at rt for 16 h before the solvent was removed in vacuo. The residue was then washed with diethyl ether (3 x 20 mL) and dried in vacuo. 4-purpose-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyramid acid methyl ester (hydrochloride) Salt) was obtained and used immediately in the next step.
[922] Salt from above (0.30 mmol) was dissolved in ammonia solution in methanol (2M, 3 mL, 1.5 mmol) and stirred for 16 h. The solution was then concentrated under reduced pressure and purified by column chromatography (10: 1: 89 MeOH / NH ₄ OH / CH ² Cl ₂ ) to afford the desired 4-[(1H-benzimidazol-2-ylmethyl)-. (5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyramidine free base was obtained as a crystalline solid (42 mg, 38%, 2 steps). ¹ H NMR (CDCl ₃ ) δ 1.50 (m, 1H), 1.73-1.95 (br m, 4H), 2.14 (m, 1H), 2.40-2.80 (br m, 6H), 3.91 (m, 1H), 3.95 (br d, 1H, J = 15.0 Hz), 4.10 (br d, 1H, J = 15.0 Hz), 7.10 (br, 3H), 7.37 (d, 1H, J = 6.0 Hz), 7.55 (br, 2H) , 8.44 (br, 1 H), 8.87 (br, NH), 9.51 (br, NH).
[923] General Process D Use: The material from the stomach (42 mg, 0.11 mmol) was converted to a hydrobromide salt to give compound 87 (28 mg). ¹ H NMR (D ₂ O) δ 1.85 (br m, 3H), 1.95 (m, 1H), 2.17 (br m, 1H), 2.37 (t, 3H, J = 7.8 Hz), 2.56 (m, 1H) , 2.86 (m, 1H), 3.00 (br, 2H), 4.37 (d, 1H, J = 16.8 Hz), 4.48 (m, 1H), 4.53 (d, 1H, J = 16.8 Hz), 7.60 (m, 2H), 7.79 (m, 2H), 7.86 (t, 1H, J = 6.9 Hz), 8.34 (d, 1H, J = 7.8 Hz), 8.62 (d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 20.37, 20.50, 25,60, 27.63, 30.11, 47.89, 50.91, 60.41, 114.27 (2C), 126.01, 127.02 (2C), 130.99, 139.43, 140.74 (2C), 148.20, 151.41, 152.06. ES-MS m / z 363 (M + H). Calcd for C ₂₁ H ₂₆ N ₆ .3.1HBr.1.3H ₂ O.0.3C ₄ H ₁₀ O: C, 40.17; H, 5. 27; N, 12.66; Br, 37.32. Found: C, 40.09; H, 5. 27; N, 12.62; Br, 37.31.
[924] Example 88
[925]
[926] Compound 88: N1- (1H-benzimidazol-2-ylmethyl) -N1- (R) -5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine (crystal Manufacturing
[927] Solution A: To a solution of anhydrous zinc (II) chloride (70.80 g, 0.52 mol) in tetrahydrofuran (320 mL) was added sodium borohydride (17.86 g, 0.47 mol) and the mixture was stirred for 1 hour. The solution was then cooled to -20 ° C.
[928] Solution B: (R)-(5,6,7,8-tetrahydro-quinolin-8-yl) amine (70.0 g, 0.47 mol) and 4- (1,3-di) in tetrahydrofuran (160 mL) To a solution of oxo-1,3-dihydro-isoindol-2-yl) -butyraldehyde (102.59 g, 0.47 mol) was added potassium carbonate (65.28 g, 0.47 mol) at room temperature and the mixture was stirred for 1 hour. It was. The suspension was then filtered and cooled to 0 ° C. The cold filtrate was slowly added into solution A through the cannula for 35 minutes. The resulting mixture was stirred at −20 ° C. for 1 hour until the reaction was completed by NMR aliquots. The reaction was then neutralized by careful addition of 5N HCl until the pH was 2-3 and the temperature maintained at -7 ° C. The solution was then warmed to 22 ° C. and basified with 13 w / v% Na ₂ CO ₃ (aq) until pH was 4. Tetrahydrofuran was removed under reduced pressure and the concentrate was diluted with water (700 mL) and CH ₂ Cl ₂ (530 mL). The phases were separated and the organic phase was washed with concentrated ammonium hydroxide (1 × 230 mL) and water (1 × 315 mL). The organic phase was then concentrated to 200-250 mL and filtered through conditioned silica gel pads (14 g). Silica gel was rinsed with CH ₂ Cl ₂ (2 × 20 mL). The combined filtrates were concentrated to 100-150 mL and diluted with diisopropyl ether (1000 mL). The solution was concentrated to 300-350 mL, cooled to -10 ° C, at which temperature the product began to precipitate. Mechanical stirring was continued at −10 ° C. for 45 minutes, after which the product was recovered by filtration. The product was washed with diisopropyl ether (100 mL) and dried under reduced pressure to afford pure 2- {4-[(R)-(5,6,7,8-tetrahydro-quinolin-8-yl) amino]- Butyl} -isoindole-1,3-dione (135.3 g, 82%) was obtained. ¹ H NMR (300 MHz, CDCl 3, δ ppm) 1.55-1.85 (m, 6H), 1.95-2.05 (m, 1H), 2.05-2.20 (m, 1H), 2.50 (b, 1H), 2.65-2.85 ( m, 4H), 3.65-3.80 (m, 3H), 7.04 (dd, 1H, J = 4.5 & 7.5 Hz), 7.35 (d, 1H, J = 7.5 Hz), 7.65-7.75 (m, 2H), 7.75 -7.85 (m, 2H), 8.36 (d, 1H, J = 4.5 Hz).
[929] 2- {4-[(R)-(5,6,7,8-tetrahydro-quinolin-8-yl) amino] -butyl} -isoindole-1,3-dione in acetonitrile (780 mL) 135.3 g, 0.39 mol) and diisopropylethylamine (101 mL, 0.58 mol) and potassium iodide (101 mL, 0.58 mol) at room temperature in a solution of 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (103 g, 0.39 mol) 6.4 g, 0.04 mol) was added and the mixture was heated to 50 ° C. for 3 hours. The mixture was then concentrated under reduced pressure and redissolved in methyl t-butyl ether (500 mL) and water (500 mL). The pH was adjusted to 2 with 6N HCl and then the phases were separated. The aqueous phase was washed with methyl t-butyl ether (500 mL). The aqueous phase was stirred for 22 hours and 6N HCl was added as needed to maintain pH at 2. The solution was basified to pH 10-11 with 10N NaOH and extracted with toluene (2 × 1.5 L). The organic phase was washed with 1N NaOH (1 × 200 mL) and brine (1 × 200 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford 2- {4-[(R)-(1H-benzimidazol-2-ylmethyl) -5,6,7,8- Tetrahydro-quinolin-8-yl-amino] -butyl} -isoindole-1,3-dione (209 g) was obtained. ¹ H NMR (300 MHz, CDCl 3, δ ppm) 0.75-1.75 (series of m, 5H), 1.80-2.10 (2m, 2H), 2.15-2.25 (m, 1H), 2.55-2.90 (m, 4H), 3.52 (t, 2H, J = 7.0 Hz), 3.95-4.10 (m, 1H), 4.01 (d, 1H, J = 17.0 Hz), 4.11 (d, 1H, J = 17.0 Hz), 7.10-7.30 (m , 4H), 7.39 (d, 1H, J = 7.5 Hz), 7.50-7.55 (m, 1H), 7.60-7.70 (m, 2H), 7.70-7.80 (m, 2H), 8.60 (d, 1H, J = 3.5 Hz).
[930] 2- {4-[(R)-(1H-benzimidazol-2-ylmethyl) -5,6,7,8-tetrahydro-quinolin-8-yl-amino] -butyl} in methanol (2 L)} To a solution of isoindole-1,3-dione (209 g, max 0.39 mol) was added hydrazine hydrate (179 mL, 3.12 mol) at room temperature and the mixture was stirred for 15 hours. The solution was filtered and the filtrate was concentrated. The residue was dissolved in 1N HCl until the pH was 2-3. The suspension obtained was filtered. The filtrate was basified to pH 6 with 10N NaOH and washed with CH ₂ Cl ₂ (2 × 400 mL). The aqueous phase was further basified to pH 12 with 10N NaOH and extracted with CH ₂ Cl ₂ (3 × 1000 mL). The combined organic phases were concentrated to about 1.4 L under reduced pressure. Charcoal (48 g) was added and the suspension was stirred for 1 hour. Charcoal was removed by filtration and the filtrate was filtered through a pad of silica gel (140 g). Silica was eluted with 20: 1 CH ₂ Cl ₂ : MeOH until no product was detected by UV (1.0 L). The filtrate was washed with 0.1N NaOH (1 × 800 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to anhydrous N ^1- (1H-benzimidazol-2-ylmethyl) -N ¹ -(R) -5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine (99 g, 73% over two steps) was obtained. ¹ H NMR (300 MHz, CDCl 3, δ ppm) 1.05-1.35 (m, 4H), 1.30-1.50 (m, 1H), 1.60-1.85 (2m, 2H), 1.90-2.05 (m, 1H), 2.25- 2.70 (m, 6H), 3.75-4.00 (m, 3H), 6.90 (dd, 1H, J = 4.5 & 7.5 Hz), 6.95-7.05 (m, 2H), 7.15 (d, 1H, J = 7.5 Hz) , 7.35-7.45 (m, 2H), 8.37 (d, 1H, J = 4.5 Hz).
[931] Anhydrous N ^1- (1H-benzimidazol-2-ylmethyl) -N ^1- (R) -5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine (90.98 g, 0.260 mol) was diluted with ethyl acetate (730 mL, 0.125 g / mL) and heated with stirring until all solids dissolved (T _max = 62 ° C.). The solution was slowly cooled to room temperature with stirring. Stirring was continued at room temperature for 20 hours. The crystals were then recovered in a Buddha funnel under N ₂ atmosphere. The crystals were dried under reduced pressure and then ground with mortar and pestle. The crystals were then dried in a vacuum oven (40 ° C., greater than 30 Hg) for two nights to dry N ^1- (1H-benzimidazol-2-ylmethyl) -N ^1- (R) -5,6,7 , 8-tetrahydro-quinolin-8-yl-butane-1,4-diamine crystals (69.52 g, 77%) were obtained. ¹ H NMR (CDCl ₃ ) δ 1.21-1.47 (m, 4H), 1.58-1.73 (m, 1H), 1.82-2.06 (m, 2H), 2.12-2.23 (m, 2H), 2.45-2.59 (m, 3H), 2.64-2.89 (m, 3H), 3.97-4.12 (m, 3H), 7.08-7.20 (m, 3H), 7.49 (d, 1H, J = 7.4 Hz), 7.53-7.60 (m, 2H) , 8.57 (d, 1H, J = 4.2 Hz). ¹³ C NMR (CDCl ₃ ) δ 21.15, 23.50, 25.78, 28.96, 30.96, 41.61, 49.23, 50.26, 61.62, 114.83, 121.22, 121.88, 134.28, 137.01, 146.42, 156.49, 157.39. Purity (HPLC) = 99.40%. Diastereomeric excess (HPLC) = 99.66%. Hydrazine (HPLC) = 4.7 ppm. ES-MS m / z 350 (M + H). Calcd for C ₂₁ H ₂₇ N ₅ : C, 72.17; H, 7.79; N, 20.04. Found: C, 71.82; H, 7. 74; N, 19.74.
[932] Example 89
[933]
[934] Compound 89: N1- (4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl)- Preparation of Butane-1,4-diamine
[935] To a solution of 4,5,6,7-tetrahydro-1H-benzoimidazole (1.9992 g, 16.4 mmol) and triethylamine (4.60 mL, 32.8 mmol) in CH ₂ Cl ₂ (20 mL) _A solution of dimethyl sulfamoyl chloride (1.76 mL, 16.4 mmol) in ₂ Cl ₂ (10 mL) was added dropwise. The reaction was allowed to warm to rt and stirred for 3.5 h. CH ₂ Cl ₂ (80 mL) was added and the organic phase was washed with distilled water (1 × 80 mL). The aqueous wash was extracted with CH ₂ Cl ₂ (2 × 40 mL) and the combined organic extracts were washed with brine (1 × 80 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (2: 1 hexane-EtOAc) to give 2.89 g (77%) of 4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide as a white solid. Obtained. ¹ H NMR (CDCl ₃ ) δ 1.77-1.86 (m, 4H), 2.58-2.61 (m, 2H), 2.72 (t, 2H, J = 6 Hz), 2.87 (s, 6H), 7.77 (s, 1H) .
[936] 2-formyl-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide is described in Journal of Medicinal Chemistry, 40; 14, 1997, 2205]. To a solution of 4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide (2.67 g, 11.6 mmol) in dry THF (100 mL), hexane (7.0 mL, 17.5 at -78 ° C under argon). 2.5 M n-butyllithium in mmol) was added dropwise. The reaction was stirred at -78 ° C for 1 hour, then DMF (1.1 mL, 13.9 mmol) was added dropwise, the reaction was allowed to warm to room temperature and stirred for 2 hours. Saturated NH ₄ Cl (25 mL) was added and the reaction mixture was concentrated, then diluted with CH ₂ Cl ₂ (500 mL) and distilled water (25 mL). The layers were separated and the aqueous phase extracted with CH ₂ Cl ₂ (2 × 100 mL). The combined organic extracts were washed with brine (1 × 100 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude was purified by column chromatography on silica gel (1: 1 hexanes-EtOAc) to yield 1.53 g (51%) of 2-formyl-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide. ) Was obtained as a yellow solid. ¹ H NMR (CDCl ₃ ) δ 1.82-1.86 (m, 4H), 2.66-2.68 (m, 2H), 2.86-2.88 (m, 2H), 2.96 (s, 6H), 9.99 (s, 1H).
[937] ₂ -formyl-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide (0.3991 g, 1.5 mmol) and 2- [4- (5 in CH ₂ Cl ₂ (13 mL) Sodium triacetoxyborohydride (0.5539 g, in a solution of 6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione (0.4424 g, 1.3 mmol) 2.6 mmol) was added and the reaction was stirred at room temperature for 22 hours. Saturated NaHCO ₃ (20 mL) is added, the aqueous phase is extracted with CH ₂ Cl ₂ (2 × 100 mL), the combined organic extracts are washed with brine (1 × 75 mL), dried (NaSO ₄ ) and concentrated It was. The crude material was purified by column chromatography on silica gel (33: 1: 1 CH ₂ Cl ₂ -MeOH-NH ₄ OH) to give 2-{[[4- (1,3-dioxo-1,3-dihydro- Isoindol-2-yl) -butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -4,5,6,7-tetrahydro-benzoimidazole 0.4564 g (52%) of -1-sulfonic acid dimethylamide was obtained as a yellow foam. ¹ H NMR (CDCl ₃ ) δ 1.28 (t, 2H, J = 9 Hz), 1.49-1.52 (m, 2H), 1.74-1.81 (m, 6H), 1.91-2.00 (m, 1H), 2.11-2.20 ( m, 1H), 2.50-2.73 (m, 7H), 2.92 (s, 2H), 2.95 (s, 4H), 3.52-3.57 (m, 2H), 4.17-4.22 (m, 2H), 4.32-4.37 (m, 1H), 4.81 (s, 1H), 6.95-6.98 (m, 1H), 7.27-7.28 (m, 1H), 7.68-7.70 (m, 2H), 7.79-7.82 (m, 2H), 8.32 (d, 1H, J = 3 Hz).
[938] 2-{[[4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl ) -Amino] -methyl} -4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid (0.4564 g, 0.77 mmol) and 2N HCl (7.5 mL) were stirred at reflux for 23 h. . The reaction mixture was cooled to room temperature and 15% (w / v) aqueous NaOH (5 mL) was added. The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 150 mL) and the combined organic extracts were washed with brine (1 × 100 mL), dried (Na ₂ SO ₄ ) and concentrated. 2- {4-[(4,5,6,7-Tetrahydro-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino 0.2466 g (64%) of] -butyl} -isoindole-1,3-dione was isolated as a pale yellow foam. ¹ H NMR (CDCl ₃ ) δ 1.37-1.39 (m, 2H), 1.79-1.88 (m, 10H), 1.98-2.11 (m, 2H), 2.51-2.63 (m, 8H), 3.50-3.52 (m, 1H), 3.66-3.86 (m, 2H), 3.97-3.99 (m, 1H), 7.02-7.11 (m, 2H), 7.37-7.40 (m, 2H), 7.68-7.71 (m, 1H), 7.80- 7.82 (m, 1 H), 8.44-8.46 (m, 1 H).
[939] 2- {4-[(4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinoline- in ethanol (5 mL) Hydrazine hydrate (0.3 mL, 2.5 mmol) was added to a solution of 8-yl) -amino] -butyl} -isoindole-1,3-dione (0.2466 g, 0.51 mmol) and stirred at room temperature for 18 hours. The reaction mixture was concentrated and the crude was purified by column chromatography on silica gel (20: 1: 1 CH ₂ Cl ₂ -MeOH-NH ₄ OH) to give 0.1031 g (58%) of 89 as a pale yellow solid. ¹ H NMR (CDCl ₃ ) δ 1.32-1.43 (m, 5H), 1.60-1.68 (m, 1H), 1.72-1.81 (m, 5H), 1.96-2.02 (m, 1H), 2.08-2.17 (m, 1H), 2.45-2.60 (m, 9H), 2.69-2.71 (m, 1H), 2.76-2.86 (m, 1H), 3.70-3.84 (m, 2H), 3.95-4.01 (m, 1H), 7.05- 7.10 (m, 1H), 7.36 (d, 1H, J = 7.5 Hz), 8.44 (d, 1H, J = 3 Hz). ¹³ C NMR (CDCl ₃ ) δ 20.80, 22.38, 22.71, 23.07, 25.37, 28.77, 30.54, 41.23, 48.53, 49.81, 60.54, 121.36, 133.94, 136.52, 146.20, 146.32, 157.37. ES-MS mlz 354.5 (M + H). Calcd for (C ₂₁ H ₃₁ N ₅ ) 0.7 (H ₂ 0) 0.1 (CH ₂ Cl ₂ ): C, 67.65; H, 8. 77; N, 18.69. Found: C, 67.46; H, 8. 80; N, 18.43.
[940] Example 90
[941]
[942] Compound 90: N1- (1H-benzimidazol-2-ylmethyl) -2-methylene-N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine Preparation of (hydrobromide salt)
[943] To a cold (0 ° C.), stirred solution of AlCl ₃ (9.43 g, 70.7 mmol) in Et ₂ O (250 mL) was added LiAlH ₄ (8.10 g, 213 mmol) powder. The resulting gray suspension was stirred for 40 minutes, then a solution of dimethyl itaconate (8.49 g, 53.7 mmol) in Et ₂ O (130 mL) was added dropwise over 30 minutes by cannula. The mixture was stirred for an additional 60 minutes and then treated with saturated aqueous NH ₄ Cl (110 mL). The mixture was diluted with Et ₂ O (500 mL) and filtered through filter paper. The filtrate was concentrated and 4.52 g of 2-methylene-butane-1,4-diol was obtained as pale yellow oil. To a stirred solution of 2-methylene-butane-1,4-diol (4.52 g, 44.3 mmol) in CH ₂ Cl ₂ (330 mL) at room temperature followed by triethylamine (10.0 mL, 71.7 mmol) followed by benzoic anhydride ( 7.53 g, 33.3 mmol) was added. After 16 hours, the mixture was washed sequentially with 1.0M HCl (2 × 35 mL), saturated aqueous NH ₄ Cl (2 × 50 mL) and brine (2 × 50 mL), dried (Na ₂ SO ₄ ) and concentrated It was. The crude material was purified by column chromatography on silica gel (2: 1 hexane-ethyl acetate) to give 5.5 to benzoic acid 4-hydroxy-2-methylene-butyl ester and benzoic acid 3-hydroxymethyl-but-3-enyl ester. 3.57 g (32% from dimethyl itaconate) of 1 mixture were obtained.
[944] Et to a 5.5: 1 mixture of benzoic acid 4-hydroxy-2-methylene-butyl ester and benzoic acid 3-hydroxymethyl-but-3-enyl ester (3.57 g, 17.3 mmol) in CH ₂ Cl ₂ (175 mL) ₃ N (6.00 mL, 43.0 mmol) was added followed by methanesulfonyl chloride (2.40 mL, 31.0 mmol). The resulting mixture was stirred at rt for 15 h. The mixture was washed with brine (3 × 50 mL), dried (Na ₂ SO ₄ ) and concentrated. The oil obtained was dissolved in DMF (90 mL), treated with potassium phthalimide (6.38 g, 34.4 mmol) and the resulting mixture was heated at 80 ° C. for 24 h and then cooled to rt. The mixture was diluted with ethyl acetate (200 mL), brine (90 mL) and water (45 mL) and the phases separated. The organic phase was washed with brine (5 × 25 mL), dried (MgSO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (4: 1 hexane-ethyl acetate), and the benzoic acid 4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2-methylene 4.11 g (71%) of a ˜3: 1 mixture of butyl ester and benzoic acid 3- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -but-3-enyl ester Obtained.
[945] Benzoic acid 4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2-methylene-butyl ester and benzoic acid 3- (1,3-dioxo- in methanol (123 mL) To a ~ 3: 1 mixture (4.11 g, 12.3 mmol) of 1,3-dihydro-isoindol-2-ylmethyl) -but-3-enyl ester was added NaOH (1.21 g, 30.3 mmol) and the mixture was allowed to stand at room temperature. Stir for 30 minutes. The mixture was diluted with ethyl acetate (250 mL) and saturated aqueous NaHCO ₃ (125 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (3 × 100 mL). The combined organic extracts were washed with brine (3 × 30 mL), dried (MgSO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (2: 1 hexane-ethyl acetate) to 0.83 g (29%) of 2- (3-hydroxymethyl-but-3-enyl) -isoindole-1,3-dione As a white solid, 0.19 g (7%) of 2- (4-hydroxy-2-methylene-butyl) -isoindole-1,3-dione was obtained as a white solid.
[946] 2- (3-hydroxymethyl-but-3-enyl) -isoindole-1,3-dione: ¹ H NMR (CDCl ₃ ) δ 2.07 (br s, 1H), 2.49 (t, 2H, J = 6.0 Hz), 3.91 (t, 2H, J = 6.0 Hz), 4.18 (m, 2H), 4.79 (s, 1H), 5.01 (s, 1H), 7.70-7.73 (m, 2H), 7.81-7.85 (m , 2H); ¹³ C NMR (CDCl ₃ ) δ 32.67, 37.04, 66.30, 113.60, 123.30, 132.00, 134.02, 145.30, 168.60; ES-MS m / z 231 (M + H).
[947] 2- (4-hydroxy-2-methylene-butyl) -isoindole-1,3-dione: ¹ H NMR (CDCl ₃ ) δ 1.88 (br s, 1H), 2.36 (t, 2H, J = 6.0 Hz ); 3,83 (m, 2H), 4.29 (s, 2H), 4.99 (s, 1H), 5.02 (s, 1H), 7.72-7.77 (m, 2H), 7.84-7.88 (m, 2H); ¹³ C NMR (CDCl ₃ ) δ 37.64, 42.24, 61.21, 114.23, 123.84, 132.37, 134.53, 140.73, 168.57; ES-MS m / z 231 (M + H).
[948] Et ₃ N (0.28 mL, 2.01) in a solution of 2- (3-hydroxymethyl-but-3-enyl) -isoindole-1,3-dione (0.229 g, 0.99 mmol) in CH ₂ Cl ₂ (10 mL). mmol) was added followed by methanesulfonyl chloride (0.12 mL, 1.55 mmol). The resulting mixture was stirred at rt for 1 h. The mixture was diluted with CH ₂ Cl ₂ (40 mL), washed with brine (3 × 10 mL), dried (Na ₂ SO ₄ ) and concentrated to give 0.31 g (100%) of a yellow oil.
[949] N-alkylation general process use: oil (0.31 g) from above in CH ₃ CN (13 mL), (1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6 Of, 7,8-tetrahydro-quinolin-8-yl) -amine (0.252 g, 0.67 mmol), KI (33 mg, 0.20 mmol) and N, N-diisopropylethylamine (0.35 mL, 2.00 mmol) The solution was heated at 60 ° C. for 21 hours. The crude material was purified by column chromatography on silica gel (50: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 2-{[[4- (1,3-dioxo-1,3-dihydro Isoindol-2-yl) -2-methylene-butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert- 239 mg (60%) of butyl ester were obtained as a beige foam.
[950] 2-{[[4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2-methylene-butyl]-(5,6,7, in ethanol (8 mL) To a solution of 8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester (0.239 g, 0.40 mmol) was added hydrazine monohydrate (0.40 mL, 8.26 mmol). The resulting mixture was stirred at rt overnight. The mixture was filtered through filter paper and concentrated. The crude material was purified by column chromatography on silica gel (20: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 86 mg (55%) of the free base of the title compound as a yellow oil.
[951] General Process D Use: The free base was converted to a hydrobromide salt and then reprecipitated the intermediate solid from methanol / ether to give 90 (97 mg, 69%) as a beige solid. ¹ H NMR (D ₂ O) δ 1.75-1.84 (m, 1H), 2.03-2.15 (m, 2H), 2.24-2.40 (m, 3H), 2.79-2.88 (m, 1H), 2.94-3.01 (m , 3H), 3.18 (d, 1H, J = 13.8 Hz), 3.41 (d, 1H, J = 13.8 Hz), 4.37 (d, 1H, J = 16.5 Hz), 4.48 (d, 1H, J = 16.5 Hz ), 4.59-4.62 (m, 1H), 4.89 (s, 1H), 5.25 (s, 1H), 7.60-7.62 (m, 2H), 7.78-7.81 (m, 2H), 7.87-7.91 (m, 1H) ), 8.37 (br d, 1H, J = 7.8 Hz), 8.69 (br d, 1H, J = 5.4 Hz); 13C NMR (D 2 O) δ 20.06, 20.30, 27.82, 31.03, 37.47, 48.28, 57.13, 60.45, 114.26, 118.52, 126.12, 127.05, 130.93, 139.65, 139.79, 141.16, 148.31, 150.83, 151.36; ES-MS mlz 362 (M + H). Calc. For C ₂₂ H ₂₇ N ₅ .3.0HBr.2.2H ₂ O: C, 41.04; H, 5.39; N, 10.88; Br, 37.23. Found: C, 40.99; H, 5. 25; N, 10.78; Br, 37.21.
[952] Example 91
[953]
[954] Compound 91: [1- (2-Amino-ethyl) -cyclopropylmethyl]-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) Preparation of -amines (hydrobromide salts)
[955] To a cold (0 ° C.) stirred solution of diethyl zinc (1.0 M in hexane, 4.0 mL, 4.0 mmol) in CH ₂ Cl ₂ (10 mL) was added dropwise pure ClCH ₂ I (0.59 mL, 8.10 mmol) by syringe. After 30 minutes, a solution of 2- (3-hydroxymethyl-but-3-enyl) -isoindole-1,3-dione (0.456 g, 1.97 mmol) in CH ₂ Cl ₂ (6 mL) was added by cannula. . After 60 minutes, the reaction mixture was treated with saturated aqueous NH ₄ Cl (20 mL), diluted with CH ₂ Cl ₂ (20 mL) and allowed to warm to room temperature. The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 20 mL) and the combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (1: 1 hexane-ethyl acetate) to give 1- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -ethyl] 0.31 g (64%) of cyclopropane-methanol was obtained as a white solid. ¹ H NMR (CDCl ₃ ) δ 0.31-0.34 (m, 2H), 0.38-0.43 (m, 2H), 1.75 (t, 2H, J = 6.9 Hz), 3.54 (s, 2H), 3.90 (t, 2H , J = 6.6 Hz), 7.70-7.73 (m, 2H), 7.81-7.85 (m, 2H);
[956] 1- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -ethyl] -cyclopropane-methanol (0.31 g, 1.26 mmol in CH ₂ Cl ₂ (6 mL) To the solution of was added 3 ′ molecular sieves (0.644 g), N-methylmorpholine N-oxide (0.223 g, 1.90 mmol) and tetrapropylammonium perruthenate (88 mg, 0.25 mmol) in that order. After 30 minutes, the mixture was filtered through silica gel and the cake washed with ether. The solvent was removed from the filtrate under reduced pressure and 0.25 g (82%) of 1- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -ethyl] -cyclopropanecarboxaldehyde ) Was obtained as a colorless oil.
[957] General process B use: (1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (0.269 g , 0.70 mmol) and 1- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -ethyl] -cyclopropanecarboxaldehyde (0.25, 1.03 mmol) were CH ₂ After stirring for 6 h with NaBH (OAc) ₃ (0.433 g, 2.04 mmol) in Cl ₂ (7 mL), the crude material was purified by column chromatography on silica gel (50: 1: 1 CH ₂ Cl ₂ —CH ₃ OH— NH ₄ OH) followed by silica gel radial chromatography (1 mm plate, 100: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 2-{[{1- [2- (1, 3-dioxo-1,3-dihydro-isoindol-2-yl) -ethyl] -cyclopropylmethyl}-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino]- 0.125 g (29%) of methyl} -benzimidazole-1-carboxylic acid tert-butyl ester were obtained as a white foam.
[958] 2-{[{1- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -ethyl] -cyclopropylmethyl}-(5, in ethanol (4 mL) Hydrazine monohydrate (0.20 mL, in a solution of 6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester (0.121 g, 0.20 mmol) 4.12 mmol) was added and the resulting mixture was stirred at rt overnight. The mixture was filtered through filter paper and concentrated. The crude material was purified by column chromatography on silica gel (20: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 39 mg (50%) of the free base of the title compound as a yellow oil.
[959] General Process D Use: The free base was converted to a hydrobromide salt and then reprecipitated intermediate solids from methanol / ether to give compound 91 (50 mg, 76%) as a white solid. ¹ H NMR (D ₂ O) δ 0.31-0.41 (m, 3H), 0.52-0.58 (m, 1H), 1.34-1.45 (m, 1H), 1.75-1.98 (m, 1H), 2.02-2.20 (m , 3H), 2.27-2.33 (m, 1H), 2.44 (d, 1H, J = 13.5 Hz), 2.81-2.91 (m, 3H), 2.98-3.01 (m, 2H), 4.39 (s, 2H) , 4.69 (dd, 1H, J = 6.3, 9.3 Hz), 7.60-7.63 (m, 2H), 7.79-7.90 (m, 3H), 8.36 (br d, 1H, J = 7.8 Hz), 8.71 (br d , 1H, J = 5.7 Hz); ¹³ C NMR (D ₂ O) δ 9.00, 12.17, 15.30, 19.79, 20.30, 27.87, 31.06, 37.62, 48.20, 57.47, 59.82, 114.31, 126.04, 127.00, 131.20, 139.66, 141.14, 148.20, 151.16, 151.31 ES-MS mlz 376 (M + H). Calcd for C ₂₃ H ₂₉ N ₅ .3.0HBr.2.2H ₂ O: C, 41.99; H, 5.58; N, 10.65; Br, 37.44. Found: C, 42.03; H, 5.41; N, 10.62; Br, 36.42.
[960] Example 92
[961]
[962] Compound 92: N1- (1H-benzimidazol-2-ylmethyl) -3-methoxy-N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4- Preparation of diamines (hydrobromide salts)
[963] Preparation of 4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3-methoxy-butyraldehyde:
[964]
[965] 2- [4- (tert-butyl-dimethyl-silanyloxy) -2-hydroxy-butyl] -isoindole-1,3-dione in pure MeI (2 mL) (N ^1- (1H- for preparation) Benzimidazol-2-ylmethyl) -3,3-difluoro-N ^1- (5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine See Example Ag ₂ O (224 mg, 0.97 mmol) was added to a solution of 455 mg, 1.30 mmol, and the reaction was stirred at 60 ° C. for 2 days. The mixture was cooled, concentrated, diluted with CH ₂ Cl ₂ (10 mL), filtered through celite and washed with washing with Et ₂ O (75 mL). The filtrate was concentrated and purified by column chromatography (3: 1 hexanes / EtOAc) to give methylated product (291 mg, 62%) as a clear oil.
[966] A solution of TBS protected alcohol (291 mg, 0.80 mmol) from the stomach in THF / 1N HCl (1: 1, 7 mL) was stirred for 3 hours. The mixture was diluted with EtOAc (35 mL), water (10 mL) and saturated aqueous ammonium chloride (10 mL). The phases were separated and the organic phase was washed with brine (1 × 25 mL), dried (Na ₂ SO ₄ ) and concentrated to afford crude product (242 mg) as a clear oil which was then purified without further purification. Used for step.
[967] To the alcohol from the stomach (242 mg) in CH ₂ Cl ₂ (10 mL) were added 3 ′ molecular sieves (265 mg), NMO (137 mg, 1.17 mmol) and TPAP (25 mg, 0.071 mmol) and the reaction was allowed to 1.5 hours. Was stirred. The mixture was concentrated and purified by flash chromatography (EtOAc / hexanes, 1: 2) to give the title compound (95 mg, 48% over two steps) as a clear solid. ¹ HNMR (CDCl ₃ ) δ 2.65-2.69 (m, 2H), 3.46 (s, 3H), 3.82 (t, 2H, J = 6 Hz), 4.02-4.08 (m, 1H), 7.74 (dd, 2H, J = 6, 3 Hz), 7.86 (dd, 2H, J = 6, 3 Hz), 9.78 (s, 1H).
[968] According to General Process B: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine in anhydrous CH ₂ Cl ₂ (10 mL) 108 mg, 0.39 mmol) and NaBH in 4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3-methoxy-butyraldehyde (95 mg, 0.385 mmol). OAc) ₃ (125 mg, 0.59 mmol) was added and the mixture was stirred at rt for 2.5 h. The crude yellow foam obtained (230 mg) was used for next step without further purification.
[969] Anhydrous hydrazine (0.06 mL, 1.89 mmol) was added to a phthalimide solution (0.38 mmol) from above in EtOH (3.5 mL) and the mixture was stirred overnight. The white solid obtained was filtered through filter paper, washed thoroughly with CH ₂ Cl ₂ and the filtrate was concentrated in vacuo. The crude product was purified by silica gel radial chromatography (1 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, 50: 1: 1 then 25: 1: 1) to afford the desired free amine (85 mg, 58% 2 Step) was obtained as a pale yellow oil.
[970] General Process D Use: The material from the stomach was converted to (78 mg, 0.21 mmol) hydrobromide salt to give compound 92 (124 mg, 89%) as a yellow solid. Mixture of ¹ H NMR (D ₂ O) diastereomers δ 1.81-1.86 (br m, 3H), 2.01-2.07 (m, 1H), 2.18-2.24 (m, 1H), 2.37-2.42 (m, 1H) , 2.54-2.63 (m, 1H), 2.88-3.10 (m, 5H), 3.24 (s, 3H), 3.51-3.56 (m, 1H), 4.40 (d, 1H, J = 16.8 Hz), 4.50-4.58 (m, 2H), 7.60 (dd, 2H, J = 6.3, 3.3 Hz), 7.81 (dd, 2H, J = 6.3, 3.3 Hz), 7.88 (br t, 1H, J = 6.8 Hz), 8.36 (d , 1H, J = 8.1 Hz), 8.63-8.66 (m, 1H); ¹³ C NMR (D ₂ O) mixture of diastereomers δ 20.43, 27.65, 29.90, 30.52, 42.10, 47.48, 48.01, 48.20, 57.04, 57.28, 60.47, 75.71, 75.92, 114.30, 126.02, 127.00, 131.01, 139.45, 140.69, 140.69, 140.78, 148.21, 151.06, 151.51. ES-MS m / z 380 (M + H). Calcd for C ₂₂ H ₂₉ N ₅ O.3.1HBr.1.5H ₂ O.0.3C ₄ H ₁₀ O: C, 41.00; H, 5.65; N, 10.31; Br, 36.45. Found: C, 41.01; H, 5. 62; N, 10.34; Br, 36.39.
[971] Example 93
[972]
[973] Compound 93: N1- (1H-benzimidazol-2-ylmethyl) -3,3-difluoro-N1- (5,6,7,8-tetrahydroquinolin-8-yl) -butane-1, Preparation of 4-diamine
[974] To a mixture of potassium phthalimide (310.39 g, 1.68 mol) in DMF (1.0 L) was added allyl bromide (290.4 mL, 3.36 mol) from the dropping funnel at 0 ° C. for 30 minutes. The reaction was then warmed to room temperature and stirred for 5 days. The mixture was filtered to remove salts, while the residue was washed with ethyl acetate (1 L) and the filtrate was concentrated under reduced pressure. The residue was then partitioned between saturated aqueous NaHCO ₃ (0.5 L) and CH ₂ Cl ₂ (0.8 L) and the organic phase was separated. The aqueous phase was extracted with CH ₂ Cl ₂ (2 × 0.8 L), the combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give N-allylphthalimide as a white powder (294 g, 94 Obtained as%). ¹ H NMR (CDCl ₃ ) δ 4.30 (d, 2H, J = 6.0 Hz), 5.22 (m, 2H), 5.88 (m, 1H), 7.73 (m, 2H), 7.85 (m, 2H).
[975] A solution of paraformaldehyde (245 g) was heated to 70 ° C. in a solution of H ₂ SO ₄ (360 mL) and H ₂ O (90 mL) using a hot water bath until the mixture was homogeneous. Solid N-allylphthalimide (133 g, 0.71 mol) is then added over 10 minutes and the exotherm is kept under control. The solution was then stirred for an additional 0.5 h at this temperature and poured into ice water (1.5 L). The mixture was extracted with ethyl acetate (3 × 1 L), dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude solid was then purified from CH ₂ Cl ₂ as a eluent through a silica gel plug (1 kg, SiO ₂ ). This resulted in the desired 1,3-dioxan-4-ylmethylphthalimide as a white solid (95 g, 54%).
[976] 1,3-dioxan-4-ylmethylphthalimide (95 g, 390 mmol) was dissolved in a saturated solution of hydrochloric acid in methanol (600 mL) and stirred at 80 ° C for 2 days. The reaction was then cooled to rt and the acid was neutralized to pH 7 with solid NaHCO ₃ . Ethyl acetate (1 L) was added and the mixture was filtered to remove salt. The filtrate was then concentrated under reduced pressure and dried under vacuum overnight. The crude material was purified via silica gel plug (1 kg silica) using a 2:98 CH ₃ OH: CH ₂ Cl ₂ eluent to afford the desired N- (2,4-dihydroxybutyl) phthalimide as a white solid ( 45 g, 50%). ¹ H NMR (MeOD) δ 1.62 (m, 1H), 1.75 (m, 1H), 3.31 (s, 1H), 3.64 (m, 2H), 3.69 (d, 2H, J = 5.1 Hz), 4.06 (sept , 1H), 7.79 (m, 2H), 7.85 (m, 2H).
[977] To a solution of N- (2,4-dihydroxybutyl) phthalimide (51 g, 217 mmol) in pyridine (725 mL) was added acetic anhydride (20.5 mL, 217 mmol) at 0 ° C. The solution was stirred at 0 ° C. for 4 hours and then concentrated on a rotary evaporator using a water bath at 35 ° C. The crude residue was then separated, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford clean N- (4-acetoxy-2-hydroxybutyl) phthalimide as a white solid (10.2 g, 17). Obtained as%).
[978] A solution of N- (4-acetoxy-2-hydroxybutyl) phthalimide (10.2 g, 36.8 mmol) in CH ₂ Cl ₂ (185 mL) was prepared at 0 ° C. with molecular sieve (18.4 g), N-methylmor Treated with Pauline oxide (6.46 g, 55.2 mmol) and tetrapropylammonium perruthenate (1.29 g, 3.7 mmol). The mixture was warmed for 20 minutes at room temperature and immediately filtered through silica (using 500 g of SiO ₂ in a crude glass frit funnel). The silica was washed with excess diethyl ether (2 L) and concentrated under reduced pressure to afford the desired N- (4-acetoxy-2-oxobutyl) phthalimide (9.22 g, 92%).
[979] The ketone (8.0 g, 29 mmol) was added to pure DAST (20 mL) as a dry solid at 0 ° C. and then heated to 50 ° C. for 40 h. The homogeneous solution was then cooled to 0 ° C., diluted with CH ₂ Cl ₂ (75 mL) and quenched with excess brine (50 mL). The organic phase was separated and the aqueous phase extracted with CH ₂ Cl ₂ (3 × 75 mL). The combined organic phases were then dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude red solid was then purified by column chromatography on silica gel (1: 4 ethyl acetate / hexane) to give the desired N- (4-acetoxy-2,2-difluorobutyl) phthalimide as a peach solid ( 3.84 g, 44%). ¹ H NMR (CDCl ₃ ) δ 2.07 (s, 3H), 2.32 (tt, 2H, J = 16.5, 6.0 Hz), 4.11 (t, 2H, J = 13.5 Hz), 4.35 (t, 2H, J = 7.5 Hz), 7.75 (m, 2 H), 7.90 (m, 2 H).
[980] The above N- (4-acetoxy-2,2-difluorobutyl) phthalimide (3.84 g, 12.9 mmol) was dissolved in THF (65 mL) and cooled to -78 ° C. A solution of DIBAL-H (32.3 mL, 1.0 M in hexanes, 32.3 mmol) was added slowly and the solution was stirred for 0.5 h. Then saturated aqueous NH ₄ Cl solution (15 mL) was added and the solution was allowed to warm to room temperature. MgSO ₄ (15 g) and diethyl ether (200 mL) were added and the mixture was filtered through celite and washed with excess 1: 1 Et ₂ O / THF (1 L). The filtrate is then concentrated under reduced pressure and the crude is purified by column chromatography on silica gel (1: 2 EtOAc / hexanes) to give the desired N- (2,2-difluoro-4-hydroxybutyl) phthalimide Was obtained as a pale yellow solid (1.47 g, 45%). ¹ H NMR (CDCl ₃ ) δ 1.97 (t, OH, J = 6.0 Hz), 2.22 (tt, 2H, J = 16.5, 6.0 Hz), 3.95 (q, 2H, J = 6.0 Hz), 4.19 (t, 2H, J = 15 Hz), 7.75 (m, 2H), 7.90 (m, 2H).
[981] Methanesulfonyl chloride (0.50 mL, 6.3 mmol) and triethylamine (1.20 mL, 8.6 mmol) were added to a solution of the above alcohol (1.47 g, 5.76 mmol) in CH ₂ Cl ₂ (29 mL) and 30 minutes at room temperature Warmed up. After workup, the desired crude methanesulfonate (1.84 g, 96%) was obtained as a fine pale yellow powder which was used immediately in the next step.
[982] The above crude methanesulfonate (1.84 g) solution in DMF (19 mL) was treated with sodium azide (1.87 g, 28.8 mmol) and treated at 80 ° C. for 2 hours. The reaction mixture was then concentrated and the residue partitioned between ethyl acetate (20 mL) and brine (15 mL). The organic phase was separated, washed with brine (3 × 15 mL) and dried over MgSO ₄ . The mixture was then filtered and concentrated under reduced pressure to afford the desired N- (4-azido-2,2-difluorobutyl) phthalimide (1.37 g, 85% two steps).
[983] The material from above (1.37 g) was dissolved in anhydrous methanol (50 mL) and the reaction vessel was purged with nitrogen. Palladium on carbon 10% (275 mg) was added and the mixture was stirred for 16 h under hydrogen atmosphere (30 psi). The reaction mixture was then filtered through celite and purified by column chromatography using silica gel (2:98 methanol: dichloromethane) to give N- (4-amino-2,2-difluorobutyl) phthalimide (0.71 g, 57%) was obtained. ¹ H NMR (CDCl ₃ ) δ 2.32 (tt, 2H, J = 16.5, 6.0 Hz), 3.02 (t, 2H, J = 15.0 Hz), 3.94 (t, 2H, J = 7.5 Hz), 7.73 (m, 2H), 7.85 (m, 2H).
[984] Using General Process B from above, N- (4-amino-2,2-difluorobutyl) phthalimide (0.28 g, 1.1 mmol), 6,7-dihydro-5H-quinoline-8- Warm (0.21 g, 1.4 mmol) and sodium triacetoxyborohydride (0.45 g, 2.2 mmol) were stirred in dichloromethane (5.5 mL) for 16 hours at room temperature, followed by work-up and column chromatography (2:98 MeOH). : CH ₂ Cl ₂ ) then 2- [2,2-difluoro-4- (5,6,7,8-tetrahydroquinolin-8-ylamino) -butyl] -isoindole-1,3-dione Was obtained as sticky oil (0.36 g, 85%).
[985] Secondary amine (0.36 g, 0.93 mmol), N- (tert-butoxycarbonyl) -2-chloromethylbenzimidazole (0.25 g, 0.93 mmol) and potassium iodide in anhydrous acetonitrile (9.3 mL) Diisopropylethylamine (0.24 mL, 1.4 mmol) was added to a solution of 8 mg, 0.05 mmol), and the mixture was stirred at 60 ° C. for 16 hours. The mixture was then concentrated under reduced pressure and the residue was partitioned between dichloromethane (20 mL) and brine (15 mL). The organic phase was separated and the aqueous phase extracted with dichloromethane (2 x 15 mL). The combined organic phases were then dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford a crude residue which was purified by silica gel column chromatography (2:98 MeOH / CH ₂ Cl ₂ ). 2-{[[4- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -3,3-difluorobutyl]-(5,6,7,8- Tetrahydroquinolin-8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester (0.24 g, 41%) was obtained.
[986] The above substrate (0.24 g, 0.39 mmol) in anhydrous ethanol (3.7 mL) was treated with hydrazine monohydrate (0.20 mL, 3.9 mmol) and stirred for 16 h. The white solid was then filtered, concentrated under reduced pressure, purified by silica gel column chromatography (5: 0.5: 94.5 methanol: ammonium hydroxide: dichloromethane) to N- (1H-benzimidazol-2-ylmethyl ) -3,3-difluoro-N- (5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine as a light beige solid (87 mg, 66%) Obtained. ¹ H NMR (CDCl ₃ ) δ 1.67 (m, 1H), 1.70-2.20 (m, 4H), 2.28 (m, 1H), 2.55-3.00 (m, 5H), 3.10 (m, 1H), 4.12 (m , 1H), 4.26 (s, 2H), 7.20 (m, 3H), 7.45 (d, 1H, J = 7.5 Hz), 7.59 (br, 2H), 8.61 (d, 1H, J = 3.9 Hz). ¹³ C NMR (CDCl ₃ ) δ 21.88, 24.85, 29.49, 35.88 (t, 1C, J = 20 Hz), 38.24 (t, 1C, J = 92 Hz), 51.74, 55.25 (t, 1C, J = 116 Hz), 62.99 , 115.41 (br, 3C), 122.14 (2C), 122.92, 125.40, 128.61, 135.29, 137.93, 147.10, 155.75, 156.98. ES-MS mlz 385 (M + H). Calcd for C ₂₁ H ₂₅ N ₅ F ₂ .0.2CH ₂ Cl ₂ : C, 63.27; H, 6. 36; N, 17.40. Found: C, 63.27; H, 6. 60; N, 17.26.
[987] Example 94
[988]
[989] Compound 94: N ^One-(1H-benzimidazol-2-ylmethyl) -2,2-difluoro-N ^OnePreparation of-(5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine
[990] Di-tert-butyldicarbonate (0.31 g, 1.4 mmol) in a solution of N- (4-amino-2,2-difluorobutyl) phthalimide (0.33 g, 1.3 mmol) in dry THF (7 mL). And 1 drop of water was added. The solution was stirred for 30 minutes, saturated aqueous ammonium chloride solution (25 mL) was added and the solution extracted with ethyl acetate (2 x 30 mL). The combined organic phases were then dried (MgSO ₄ ), filtered and concentrated under reduced pressure. This gave a crude boc-protected primary amine as a yellow solid (0.42 g, 91%).
[991] A solution of the above amine (0.42 g, 1.2 mmol) in anhydrous ethanol (12 mL) was treated with hydrazine monohydrate (0.57 mL, 12 mmol) and stirred for 16 h. The cloudy white mixture is then filtered, concentrated under reduced pressure, purified by silica gel column chromatography (1: 1: 10 methanol: ammonium hydroxide: dichloromethane) (4-amino-3,3-difluoro Robutyl) -carbamic acid tert-butyl ester (0.21 g, 77%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.30 (br, NH 2), 1.45 (s, 9H), 2.01 (tt, 2H, J = 16.5, 6.0 Hz), 2.95 (t, 2H, J = 6.0 Hz), 3.52 ( td, 2H, J = 15.0, 7.0 Hz), 5.00 (br, NH).
[992] Using General Process B from above, N- (4-amino-2,2-difluorobutyl) phthalimide (0.26 g, 1.2 mmol), 6,7-dihydro-5H-quinoline-8- Warm (0.22 g, 1.5 mmol) and sodium triacetoxyborohydride (0.49 g, 2.3 mmol) were stirred in dichloromethane (5.5 mL) for 16 hours at room temperature, followed by work-up and column chromatography (1:99 MeOH). : CH ₂ Cl ₂ ), [3,3-difluoro-4- (5,6,7,8-tetrahydroquinolin-8-ylamino) -butyl] -carbamic acid tert-butyl ester with sticky oil Obtained as (0.37 g, 90%).
[993] Secondary amine (0.37 g, 1.0 mmol), N- (tert-butoxycarbonyl) -2-chloromethylbenzimidazole (0.44 g, 1.7 mmol) and potassium iodide (9 mg) in anhydrous acetonitrile (10.0 mL) , 0.05 mmol) was added diisopropylethylamine (0.36 mL, 2.1 mmol) and stirred at 60 ° C. for 16 hours. The mixture was then concentrated under reduced pressure, the residue was partitioned between dichloromethane (20 mL) and brine (15 mL), the organic phase separated and the aqueous phase extracted with dichloromethane (2 x 15 mL). The combined organic phases were then dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford the crude product, which was purified by silica gel column chromatography (2:98 MeOH / CH ₂ Cl ₂ ). 2-{[(4-tert-butoxycarbonylamino-2,2-difluorobutyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -methyl} -Benzimidazole-1-carboxylic acid tert-butyl ester was obtained as a pale yellow solid (0.23 g, 41%).
[994] A solution of the above material (0.23 g, 0.4 mmol) in pure TFA (4 mL) was stirred for 0.5 h. The solution was diluted with CH ₂ Cl ₂ (20 mL) and 15% aqueous NaOH was added until pH> 10. The organic phase was separated and the aqueous layer extracted with CH ₂ Cl ₂ (2 × 20 mL). The combined organic phases were then dried (Na 2 SO 4), filtered and concentrated under reduced pressure. This was subjected to radial chromatography (2: 1: 97 MeOH: NH 4 OH: CH ₂ Cl ₂ ), followed by N- (1H-benzimidazol-2-ylmethyl) -2,2-difluoro-N- (5, 6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine was obtained as a pale yellow flaky solid (0.11 g, 72%). ¹ H NMR (CDCl ₃ ) δ 1.69 (m, 1H), 1.85-2.10 (m, 4H), 2.23 (m, 1H), 2.70-2.97 (m, 6H), 4.03 (d, 1H, J = 17.1 Hz ), 4.07 (m, 1H), 4.15 (d, 1H, J = 16.8 Hz), 7.15-7.24 (m, 3H), 7.45 (d, 1H, J = 7.8 Hz), 7.58 (br, 2H), 8.57 (d, 1H, J = 3.9 Hz). ¹³ C NMR (CDCl ₃ ) δ 21.62, 24.35, 29.47, 34.03 (t, 1C, J = 93 Hz), 44.55 (t, 1C, J = 20 Hz), 47.26 (t, 1C, J = 112 Hz), 50.12, 62.87 , 118 (br, 3C), 122.09 (2C), 122.80, 123.86, 127.06, 135.10, 137.99, 147.06, 156.27, 157.41. ES-MS mlz 385 (M + H). Calcd for C ₂₁ H ₂₅ N ₅ F ₂ .0.2CH ₂ Cl ₂ : C, 63.27; H, 6. 36; N, 17.40. Found: C, 63.34; H, 6.68; N, 17.29.
[995] Example 95
[996]
[997] Compound 95: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-2- (O-methyloxime) -butane Preparation of -4-yl) -amine
[998] To a solution of 3-butene-1-ol (10 g, 138 mmol) in dichloromethane (150 mL) was added acetic anhydride (13 mL, 138 mmol) and 4-dimethylaminopyridine (244 mg, 2 mmol). The mixture was then stirred at rt for 8 h. The reaction mixture was then introduced into saturated aqueous sodium bicarbonate solution (100 mL). After separating the aqueous layer and the organic layer, the aqueous layer was extracted twice with 100 ml portions of dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-buten-1-yl acetate as a colorless oil in 12.9 g (82%) yield. ¹ H NMR (CDCl ₃ ) δ 2.04 (s, 3H), 2.38 (m, 2H), 4.11 (t, 3H, J = 7.1 Hz), 5.04 (d, 1H, J = 9.1 Hz), 5.08 (d, 1H, J = 15.3 Hz), 5.77 (m, 1H).
[999] To a solution of 3-buten-1-yl acetate (5.7 g, 50 mmol) in dichloromethane (200 mL) was added m-chloroperoxybenzoic acid (12.9 g, 75 mmol). The reaction was then stirred at rt for 3 h. The reaction mixture was then filtered through celite and concentrated in vacuo. The residue was purified by silica gel flash chromatography (4: 1 hexanes: ethyl acetate) to give 3,4-epoxybutan-1-yl acetate as a colorless oil in a yield of 3.8 g (58%). ¹ H NMR (CDCl ₃ ) δ 1.78-1.88 (m, 2H), 2.03 (s, 3H), 2.47 (m, 1H), 2.75 (m, 1H), 2.99 (m, 1H), 4.18 (t, 1H , J = 6.6 Hz).
[1000] To a solution of 3,4-epoxybutan-1-yl acetate (3.9 g, 29 mmol) in DMF (50 mL) was added potassium phthalimide (6.47 g, 35 mmol). The stirred mixture was then heated to 90 ° C. for 16 hours. After cooling, the mixture was diluted with ethyl acetate (200 mL) and extracted repeatedly with water. The organic fractions were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1: 1 hexanes: ethyl acetate) to give 1.65 g (20) of N- (3-hydroxybutan-4-yl-1-acetate) -phthalimide as pale yellow oil. Yield). ¹ H NMR (CDCl ₃ ) δ 1.69-1.88 (m, 2H), 2.04 (s, 3H), 2.90 (m, 1H (OH)), 3.79 (d, 2H, J = 5.7 Hz), 4.03 (m, 1H), 4.21-4.31 (m, 2H), 7.70 (m, 2H), 7.83 (m, 2H). MS m / z 300 (M + Na).
[1001] Imidazole (150 mg, 2.2 mmol) and t- in a solution of N- (3-hydroxybutan-4-yl-1-acetate) -phthalimide (554 mg, 2.0 mmol) in acetonitrile (15 mL) Butyldimethylsilyl chloride (310 mg, 2.05 mmol) was added. The mixture was then stirred overnight at room temperature. Dichloromethane (50 mL) was then added to the reaction and the mixture was extracted with saturated ammonium chloride solution. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oily residue which was purified by silica gel flash chromatography (3: 1 hexanes: ethyl acetate) to give N- (3-t-butyldimethyl Siloxybutan-4-yl-1-acetate) -phthalimide was obtained in a yield of 570 mg (73%). ¹ H NMR (CDCl ₃ ) δ -0.04 (s, 3H), -0.01 (s, 3H), 0.84 (s, 9H), 1.78 (m, 2H), 3.68 (dd, 1H, J = 8.1, 6.5Hz ), 3.73 (dd, 1H, J = 8.1, 6.2 Hz), 4.15 (m, 3H), 7.71 (m, 2H), 7.85 (m, 2H).
[1002] DIBAL-H (N- (3-t-butyldimethylsiloxybutan-4-yl-1-acetate) -phthalimide (670 mg, 1.71 mmol) in THF (20 mL) was added to a stirred solution at -78 ° C. 5.1 ml of a 1.0 M solution in hexane, 5.1 mmol) was added. The reaction was stirred at −78 ° C. for 45 minutes, then a saturated solution of ammonium chloride (5 mL) was added. The mixture was allowed to warm to room temperature, then ethyl acetate (20 mL) and 1N HCl (2 mL) were added. The mixture was then shaken in a separatory funnel to accelerate the separation of the layers and then the organic and aqueous phases were separated. The aqueous layer was extracted twice with ethyl acetate, then the combined organic fractions were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic fractions were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1: 1 hexanes: ethyl acetate) to give 465 mg of N- (3-t-butyldimethylsiloxybutan-1-ol-4-yl) -phthalimide as a colorless oil. Obtained in the yield (78%). ¹ H NMR (CDCl ₃ ) δ -0.02 (s, 3H), 0.09 (s, 3H), 0.86 (s, 9H), 1.71-1.82 (m, 2H), 2.11 (m, 1H (OH)), 3.76 (m, 4H), 4.28 (m, 1H), 7.73 (m, 2H), 7.85 (m, 2H).
[1003] To a solution of N- (3-t-butyldimethylsiloxybutan-1-ol-4-yl) -phthalimide (160 mg, 0.4 mmol) in dichloromethane (10 mL) des-martin periodinan (212) Mg, 0.5 mmol) was added. The mixture was then stirred at rt for 30 min. A 5% solution of sodium thiosulfate (10 mL) and saturated sodium bicarbonate solution (10 mL) were added along with another 20 mL of dichloromethane. The mixture was then stirred rapidly for 20 minutes and the aqueous and organic layers were separated. The aqueous layer was extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give N- (3-t-butyldimethylsiloxybutan-1-al-4-yl)- Phthalimide was obtained as a yellow oil which was used immediately in the next reaction without further purification. ¹ H NMR (CDCl ₃ ) δ -0.02 (s, 3H), 0.05 (s, 3H), 0.81 (s, 9H), 2.61 (m, 2H), 3.74 (m, 2H), 4.51 (m, 1H) , 7.71 (m, 2H), 7.85 (m, 2H), 9.81 (m, 1H).
[1004] To a solution of N- (3-t-butyldimethylsiloxybutan-1-al-4-yl) -phthalimide (0.4 mmol) in dichloromethane (15 mL) (5,6,7,8-tetrahydro Quinolin-8-yl)-[(Nt-butoxycarbonyl) -benzimidazol-2-yl) methyl] -amine (151 mg, 0.4 mmol) was added. The mixture was stirred at rt for 30 min, then sodium triacetoxyborohydride (170 mg, 0.8 mmol) was added and the reaction stirred for 16 h. Saturated sodium bicarbonate solution (10 ml) was added and the aqueous and organic layers were separated. The aqueous layer was then extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by silica gel flash chromatography (3% methanol in dichloromethane) to [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetra 224 mg (79%) of hydro-quinolin-8-yl)-(1- (N-phthalimidyl) -butan-2- (t-butyldimethylsiloxy) -4-yl) -amine as a pale yellow foam Obtained in the yield. ¹ H NMR (CDCl ₃ ) δ -0.25 (s, 3H), -0.23 (s, 3H), 0.69 (s, 9H), 1.44-1.63 (m, 4H), 1.68 (s, 9H), 2.00 (m , 2H), 2.16 (m, 1H), 2.65-2.74 (m, 3H), 3.48-3.62 (m, 2H), 3.94 (m, 1H), 4.23 (m, 1H), 4.44 (d, 1H, J = 15.3 Hz), 4.72 (m, 1H, J = 15.3 Hz), 6.95 (m, 1H), 7.20 (m, 3H), 7.67 (m, 3H), 7.77 (m, 3H), 8.44 (m, 1H ).
[1005] [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1- (N in THF (8 mL)) To a solution of -phthalimidyl) -butan-2- (t-butyldimethylsiloxy) -4-yl) -amine (170 mg, 0.24 mmol) was added 1N HCl (2 mL). The mixture was then heated at 50 ° C. for 2 hours. After cooling, dichloromethane (50 mL) was added and the mixture was shaken with saturated sodium bicarbonate solution (20 mL). After separating the aqueous and organic layers, the aqueous layer was extracted twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate and concentrated in vacuo to yield an effervescent residue which was purified by silica gel flash chromatography (5% methanol in dichloromethane) (1-H-benzimidazole-2- Ilmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1- (N-phthalimidyl) -butan-2-ol-4-yl) -amine as a white foam Obtained in a yield of 73 mg (49%). ¹ H NMR (CDCl ₃ ) δ 1.50-1.59 (m, 2H), 1.70-2.07 (m, 5H), 2.21 (m, 1H), 2.75-3.00 (m, 4H), 3.78-3.94 (m, 2H) , 4.00-4.22 (m, 2H), 7.04 (m, 1H), 7.16 (m, 2H), 7.24 (d, 1H, J = 5.8 Hz), 7.68 (br s, 1H (NH)), 7.71 (m , 3H), 7.81 (m, 3H), 8.21 and 8.42 (d, 1H total, J = 4.9, 5.1 Hz respectively).
[1006] (1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1- (N-phthalimidyl) in dichloromethane (10 mL) To a solution of) -butan-2-ol-4-yl) -amine (132 mg, 0.246 mmol) was added Dess Martin Periodinan (145 mg, 0.344 mmol). The reaction mixture was then stirred for 60 minutes. Then 5% Na ₂ S ₂ O ₃ /5% NaHCO ₃ aqueous solution (10 mL) was added and the resulting mixture was stirred vigorously at room temperature for 20 minutes (aqueous and organic layers separated). The layers were then separated and the aqueous layer was extracted twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate, filtered and concentrated and the residue was purified by silica gel flash chromatography (5% methanol in dichloromethane) to give the desired product (1-H-benzimidazole-2). -Ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1- (N-phthalimyl) -butan-2-one-4-yl) -amine pale yellow Obtained as a foam in a yield of 109 mg (84%). ¹ H NMR (CDCl ₃ ) δ 1.73 (m, 1H), 1.85 (m, 1H), 2.03 (m, 1H), 2.26 (m, 1H), 2.57-2.81 (m, 4H), 3.10 (m, 1H ), 4.08 (s, 2H), 4.08 (m, 1H), 4.35 (d, 1H, J = 16.5 Hz), 4.63 (d, 1H, J = 16.5 Hz), 7.00 (m, 1H), 7.19 (m , 2H), 7.18 (m, 1H), 7.38 (br s, 1H (NH)), 7.75 (m, 4H), 7.88 (m, 2H), 8.56 (m, 1H).
[1007] (1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1- (N-phthalimidyl) in methanol (5 mL) To a solution of -butan-2-one-4-yl) -amine (58 mg, 0.117 mmol) was added hydroxylamine hydrochloride (83.5 mg, 1.0 mmol). The resulting solution was stirred overnight at room temperature. Then aqueous sodium bicarbonate (saturated solution 5 ml) was added, dichloromethane (10 ml) was also added, the aqueous layer and the organic layer were separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography using a 5% methanol mixture in dichloromethane as eluent to afford (1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinoline -8-yl)-(1- (N-phthalimidyl) -butan-2- (O-methyloxime) -4-yl) -amine was obtained as a pale yellow foam in a yield of 29 mg (49%). . ¹ H NMR (CDCl ₃ ) δ 1.73-2.05 (series of m, 5H), 2.45 (t, 2H, J = 6.9 Hz), 2.87-2.98 (m, 4H), 3.16 and 3.79 (s, total of 3H) , 4.01-4-12 (m, 3H), 4.26 and 4.30 (d, J = 16.7 and 16.9 Hz respectively, total of 1H), 4.47 and 4.85 (d, J = 16.7 and 16.9 Hz respectively, total of 1H), 7.13-7.17 (m, 2H), 7.25 (m, 2H), 7.22 (m, 1H), 7.60 (br s, 1H (NH)), 7.75 (m, 4H), 7.87 (m, 2H), 8.38 and 8.44 (m, total of 1 H).
[1008] (1-H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1- (N-phthalimidyl) in modified ethanol (5 mL) To a solution of) -butan-2- (O-methyloxime) -4-yl) -amine (29 mg, 0.055 mmol) was added hydrazine hydrate (0.07 mL, 1.5 mmol). The mixture was then heated to 60 ° C. for 60 minutes. After cooling, the reaction was concentrated in vacuo, dissolved in dichloromethane (20 mL) and washed with aqueous sodium carbonate solution (5 mL). The aqueous layer was then washed twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated to give an effervescent residue, which was subjected to silica gel flash chromatography (10% methanol, 0.5% in dichloromethane). Purification with Ammonium Hydroxide) (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-2- (O- Methyloxime) -butan-4-yl) -amine (Compound 95-diastereomer mixture) was obtained as a white foam in a yield of 10 mg. ¹ H NMR (CDCl ₃ ) δ 1.65 (m, 1H), 1.98 (m, 1H), 2.02 (m, 1H) 2.19 (m, 1H), 2.42 (m, 2H), 2.78-2.87 (m, 4H) , 3.31 (m, 2H), 3.55 and 3.73 (s, 3H), 4.03 (m, 3H), 7.13 (m, 3H), 7.40 (t, 1H, J = 8.1 Hz), 7.56 (m, 2H), 8.51 and 8.51 (d, J = 5.4 Hz, 5.3 Hz each, 1 H total); ¹³ C NMR (two isomers-CDCl ₃ ) δ 21.77, 23.51, 27.85, 29.58, 32.47, 43.34, 47.55, 49.09, 49.62, 49.94, 53.81, 61.60, 62.02, 122.07, 122.61, 132.33, 134.41, 137.79, 142.65, 147. , 154.98.
[1009] Example 96
[1010]
[1011] Compound 96: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-2- (cyclopropanyl) -butane- Preparation of 4-yl) -amine
[1012] Et to a ˜7: 1 mixture of benzoic acid 4-hydroxy-2-methylene-butyl ester and benzoic acid 3-hydroxymethyl-but-3-enyl ester (0.705 g, 3.42 mmol) in CH ₂ Cl ₂ (17 mL). ₃ N (1.00 mL, 7.17 mmol) was added followed by tert-butyldimethylsilyl chloride (0.792 g, 5.25 mmol) and 4- (dimethylamino) pyridine (84 mg, 0.69 mmol). The mixture was stirred at rt for 2 h, diluted with CH ₂ Cl ₂ (50 mL), washed with brine (3 × 20 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (25: 1 hexane-ethyl acetate) to give the benzoic acid 4- (tert-butyldimethylsilyloxy) -2-methylene-butyl ester and the benzoic acid 3- (tert-butyldimethylsilyloxymethyl 1.00 g (92%) of a ˜7: 1 mixture of) -but-3-enyl ester were obtained as a colorless oil.
[1013] ˜7: 1 mixture of benzoic acid 4- (tert-butyldimethylsilyloxy) -2-methylene-butyl ester and benzoic acid 3- (tert-butyldimethylsilyloxymethyl) -but-3-enyl ester in methanol (31 mL) NaOH (0.306 g, 7.64 mmol) was added to (1.00 g, 3.13 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (75 mL) and saturated aqueous NaHCO ₃ (20 mL). The phases were separated and the organic phase was washed with brine (2 × 10 mL), dried (MgSO ₄ ) and concentrated. The crude was purified by column chromatography on silica gel (9: 1 hexane-ethyl acetate) to give 0.58 g (58%) of 4- (tert-butyldimethylsilyloxy) -2-methylene-butan-1-ol as colorless oil. Obtained. ¹ H NMR (CDCl ₃ ) δ 0.06 (s, 6H), 0.90 (s, 9H), 2.34 (t, 2H, J = 6.0 Hz); 2.78 (br s, 1H), 3.75 (t, 2H, J = 6.0 Hz), 4.07-4.11 (m, 2H), 4.90 (s, 1H), 5.04 (s, 1H);
[1014] To a cold (0 ° C.) stirred solution of diethyl zinc (1.0 M in hexane, 4.0 mL, 4.0 mmol) in CH ₂ Cl ₂ (8 mL), pure ClCH ₂ I (0.58 mL, 7.96 mmol) was added dropwise by syringe. After 1 h, 4- (tert-butyldimethylsilyloxy) -2-methylene-butan-1-ol (0.395 g, 1.83 mmol) in CH ₂ Cl ₂ (4 mL) was added by cannula. After 30 minutes, the reaction mixture was treated with saturated aqueous NH ₄ Cl (10 mL), diluted with CH ₂ Cl ₂ (12 mL) and warmed to room temperature. The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (9: 1 hexane-ethyl acetate), 0.41 g (97%) {1- [2- (tert-butyldimethylsilyloxy) -ethyl] -cyclopropyl} -methanol Was obtained as a colorless oil.
[1015] Et ₃ N (0.50 mL, 3.59 mmol) in a solution of {1- [2- (tert-butyldimethylsilyloxy) -ethyl] -cyclopropyl} -methanol (0.41 g, 1.78 mmol) in CH ₂ Cl ₂ (18 mL) Methanesulfonyl chloride (0.21 mL, 2.71 mmol) was added. The resulting mixture was stirred at rt for 17 h. The mixture was diluted with CH ₂ Cl ₂ (50 mL), washed with brine (3 × 20 mL), dried (Na ₂ SO ₄ ) and concentrated. The oil obtained was dissolved in DMF (16 mL), treated with potassium phthalimide (0.606 g, 3.27 mmol) and the mixture was heated at 80 ° C. for 6 h and then cooled to rt. The mixture was diluted with ethyl acetate (40 mL), brine (20 mL) and water (10 mL) and the phases separated. The organic phase was washed with brine (3 × 10 mL), dried (MgSO ₄ ) and concentrated. The crude material was purified by column chromatography on silica gel (20: 1 hexane-ethyl acetate) to give 2- {1- [2- (tert-butyldimethylsilyloxy) -ethyl] -cyclopropylmethyl} -isoindole-1, 0.24 g (38%) of 3-dione was obtained as a colorless oil.
[1016] 1.0 in a solution of 2- {1- [2- (tert-butyldimethylsilyloxy) -ethyl] -cyclopropylmethyl} -isoindole-1,3-dione (0.24 g, 0.68 mmol) in THF (3 mL). M HCl (3 mL) was added. The resulting solution was stirred at rt for 3 h. The mixture was diluted with saturated aqueous NH ₄ Cl (10 mL) and extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude was purified by column chromatography on silica gel (2: 1 hexane-ethyl acetate) and 0.146 g of 2- [1- (2-hydroxy-ethyl) -cyclopropylmethyl] -isoindole-1,3-dione (88%) was obtained as a white solid. ¹ H NMR (CDCl 3) δ 0.29-0.35 (m, 2H), 0.59-0.62 (m, 2H), 1.41 (t, 2H, J = 6.6 Hz), 2.80 (br s, 1H), 3.53 (s, 2H ), 3.76 (t, 2H, J = 6.6 Hz), 7.59-7.63 (m, 2H), 7.69-7.74 (m, 2H);
[1017] To a solution of alcohol (146 mg, 0.595 mmol) from the stomach in dichloromethane (15 mL) was added des-martin periodinan (303 mg, 0.715 mmol). The mixture was stirred at rt for 45 min. A 5% solution of sodium thiosulfate (10 mL) and saturated sodium bicarbonate solution (10 mL) were added along with another 20 mL of dichloromethane. The mixture was then stirred rapidly for 20 minutes and the aqueous and organic layers were separated. The aqueous layer was extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give N- (3-cyclopropanyl-butan-1-al-4-yl) -phthalic acid. The mead was obtained as a yellow foam which was used immediately in the next step without further purification. ¹ H NMR (CDCl 3) δ 0.43 (m, 2H), 0.86 (m, 2H), 2.40 (s, 2H), 3.65 (s, 2H), 7.68 (m, 2H), 7.83 (m, 2H), 9.79 (s, 1 H).
[1018] (5,6,7,8-tetrahydroquinoline-8) in a solution of N- (3-cyclopropanyl-butan-1-al-4-yl) -phthalimide (0.595 mmol) in dichloromethane (15 mL) -Yl)-[(Nt-butoxycarbonyl) -benzimidazol-2-yl) methyl] -amine (227 mg, 0.6 mmol) was added. The mixture was stirred at rt for 30 min, then sodium triacetoxyborohydride (254 mg, 1.2 mmol) was added and the reaction stirred for 16 h. Saturated sodium bicarbonate solution (10 ml) was added and the aqueous and organic layers were separated. The aqueous layer was then washed twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by silica gel flash chromatography (3% methanol in dichloromethane) to [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetra Hydro-quinolin-8-yl)-[1- (N-phthalimidyl) -butan-2- (cyclopropanyl) -4-yl] -amine as pale yellow foam in a yield of 130 mg (36%). Obtained. ¹ H NMR (CDCl ₃ ) δ 0.23 (m, 2H), 0.55 (m, 2H), 1.15 (m, 1H), 1.35 (m, 1H), 1.66 (s, 9H), 1.70 (m, 2H), 2.00 (m, 2H), 2.16 (m, 1H), 2.69 (m, 1H), 2.97 (m, 2H), 3.31 (d, 1H, J = 15.3 Hz), 3.51 (d, 1H, J = 15.3 Hz ), 4.23 (m, 1H), 4.43 (d, 1H, J = 17.1 Hz), 4.62 (d, 1H, J = 17.1 Hz), 7.00 (m, 1H), 7.23 (m, 4H), 7.65 (m , 2H), 7.74 (m, 2H), 7.74 (m, 1H), 8.38 (m, 1H).
[1019] [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1- (N in ethanol (8 mL) Hydrazine hydrate (0.1 mL) was added to a solution of -phthalimidyl) -butan-2- (cyclopropanyl) -4-yl) -amine (187 mg, 0.31 mmol). The mixture was then heated to 60 ° C. for 60 minutes. After cooling, the reaction was concentrated in vacuo, dissolved in dichloromethane (20 mL) and washed with aqueous sodium carbonate solution (5 mL). The aqueous layer was then extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated to give an effervescent residue, which was subjected to silica gel flash chromatography (10% methanol, 0.5% in dichloromethane). Purified by Ammonium Hydroxide) to (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(1-amino-2- (cyclopropanyl ) -Butan-4-yl) -amine was obtained as a white foam in a yield of 100 mg (86%). ¹ H NMR (CDCl ₃ ) δ 0.17 (s, 2H), 0.25 (s, 2H), 1.32 (m, 1H), 1.61 (m, 2H), 1.85 (m, 1H), 1.93 (m, 1H), 2.19 (m, 1H), 2.39 (s, 1H), 2.86 (m, 4H), 3.99 (m, 4H), 5.40 (br s, 2H (NH2)), 7.03 (dd, 1H, J = 4.8, 8.1 Hz), 7.15 (m, 2H), 7.32 (d, 1H, J = 8.1 Hz), 7.54 (m, 2H), 8.48 (d, 1H, J = 4.8 Hz).
[1020] According to general process D: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(1-amino-2- in glacial acetic acid (2 mL) To a solution of (cyclopropanyl) -butan-4-yl) -amine (100 mg, 0.267 mmol) was added a saturated solution of HBr in acetic acid (0.5 mL), and after precipitation and drying, (1H-benzimidazole-2- Monomethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(1-amino-2- (cyclopropanyl) -butan-4-yl) -amine (HBr salt -compound 96) Was obtained as a cream powder (126 mg, 69%). ¹ H NMR (D ₂ O) δ 0.36 (m, 1H), 0.52 (m, 2H), 1.31 (m, 1H), 1.75 (m, 2H), 2.01 (m, 1H), 2.06 (m, 1H) , 2.63 (m, 1H), 2.64 (d, 1H, J = 13.5 Hz), 2.87 (d, 1H, J = 13.5 Hz), 2.99 (m, 3H), 4.36 (d, 1H, J = 16.8 Hz) , 4.55 (m, 1H), 4.49 (d, 1H, J = 16.8 Hz), 7.60 (m, 2H), 7.79 (m, 2H), 7.85 (dd, 1H, J = 7.8, 5.4 Hz), 8.32 ( d, 1H, J = 7.8 Hz), 8.60 (d, 1H, J = 5.4 Hz); ¹³ C NMR (D ₂ O) δ 11.39, 11.52, 17.02, 20.44, 27.64, 32.22, 45.79, 47.91, 49.32, 49.82, 60.58, 114.26, 125.98, 126.97, 130.98, 139.32, 140.69, 148.15, 151.17, 151.72. ES-MS mlz 376 (M + H). Calcd for C ₂₃ H ₂₉ N ₅ x 1.4 H ₂ O x 3.1 HBr x 0.4 Et ₂ O: C, 43.37; H, 5. 76; N, 10.28; Br, 36.36. Found: C, 43.41; H, 5.73; N, 10.27; Br, 36.37.
[1021] Example 97
[1022]
[1023] Compound 97: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-2-methyl-but-2-ene- Preparation of 4-yl) -amine
[1024] N- (3-methylenyl-butan-1-ol-4-yl) -phthalimide (180 mg, 0.83 mmol) in dichloromethane (15 mL) (details, N ^1- (1H-benzimidazole) Solution of -2-ylmethyl) -2-methylene-N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine, see hydrobromide salt) To this was added Dess-Martin Feriodinan (424 mg, 1.0 mmol). A 5% solution of sodium thiosulfate (10 mL) and saturated sodium bicarbonate solution (10 mL) were added along with another 20 mL of dichloromethane. The mixture was then stirred rapidly for 20 minutes and the aqueous and organic layers were separated. The aqueous layer was extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give N- (3-methylenyl-butan-1-al-4-yl) -phthalimide Was obtained as a yellow foam which was used immediately in the next step without further purification. ¹ H NMR (CDCl ₃ ) δ 3.19 (s, 2H), 4.32 (s, 2H), 5.07 (s, 1H), 5.24 (s, 1H), 7.70 (m, 2H), 7.84 (s, 2H), 9.66 (s, 1 H).
[1025] To a solution of N- (3-methylenyl-butan-1-al-4-yl) -phthalimide (0.83 mmol) in dichloromethane (15 mL) (5,6,7,8-tetrahydroquinoline-8 -Yl)-[(Nt-butoxycarbonyl) -benzimidazol-2-yl) methyl] -amine (227 mg, 0.6 mmol) was added. The mixture was stirred at rt for 30 min, then sodium triacetoxyborohydride (254 mg, 1.2 mmol) was added and the reaction stirred for 16 h. Saturated sodium bicarbonate solution (10 ml) was added and the aqueous and organic layers were separated. The aqueous layer was then extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by silica gel flash chromatography (3% methanol in dichloromethane) to [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetra Hydro-quinolin-8-yl)-[1- (N-phthalimidyl) -2-methyl-but-2-en-4-yl] -amine as pale yellow foam in a yield of 88 mg (26%). Obtained. ¹ H NMR (CDCl ₃ ) δ 1.26 (s, 3H) 1.48 (m, 3H), 1.68 (s, 9H), 2.04 (m, 1H), 2.74 (m, 2H), 3.47 (dd, 1H, J = 13.1, 5.9 Hz), 3.61 (dd, 1H, J = 13.1, 5.9 Hz), 4.19 (m, 1H), 4.33 (d, 1H, J = 16.1 Hz), 4.49 (d, 1H, J = 16.1 Hz) , 5.43 (t, 1H, J = 5.9 Hz), 6.95 (m, 1H), 7.13 (m, 2H), 7.64 (m, 2H), 7.73 (m, 2H), 7.81 (m, 2H), 8.22 ( m, 1H), 8.61 (m, 1H).
[1026] [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1- (N in ethanol (8 mL) To a solution of -phthalimidyl) -2-methyl-but-2-en-4-yl] -amine (88 mg, 0.15 mmol) was added hydrazine hydrate (0.1 mL). The mixture was heated to 60 ° C. for 60 minutes. After cooling, the reaction was concentrated in vacuo, dissolved in dichloromethane (20 mL) and washed with aqueous sodium carbonate solution (5 mL). The aqueous layer was then washed twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated to give an effervescent residue, which was subjected to silica gel flash chromatography (10% methanol, 0.5% in dichloromethane). Purified by Ammonium Hydroxide) to [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1- Amino-2-methyl-but-2-en-4-yl] -amine was obtained as a white foam in a yield of 33 mg (61%). ¹ H NMR (CDCl ₃ ) δ 1.57 (s, 9H), 1.71 (m, 1H), 1.89 (m, 1H), 2.01 (m, 2H), 2.27 (m, 1H), 2.74 (m, 3H), 3.01 (s, 3H), 3.16 (dd, 1H, J = 7.1, 4.3 Hz), 3.31 (dd, 1H, J = 7.1, 4.3 Hz), 4.02 (m, 3H), 5.30 (m, 1H), 7.13 (m, 4H), 7.40 (d, 1H, J = 7.8 Hz), 7.54 (m, 1H), 8.54 (d, 1H, J = 4.8 Hz).
[1027] [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-amino- in glacial acetic acid (2 mL) To a solution of 2-methyl-but-2-en-4-yl] -amine (33 mg, 0.091 mmol) was added a saturated solution of HBr in acetic acid (0.5 mL). The resulting mixture was stirred, treated according to standard process D, and after precipitation and drying, [(1H-benzimidazol-2-yl) methyl]-(5,6,7,8-tetrahydro-quinoline-8 -Yl)-[1-amino-2-methyl-but-2-en-4-yl] -amine (HBr salt -Compound 97) was obtained as a cream powder (28 mg, 46%). ¹ H NMR (D ₂ O) δ 1.63 (s, 3H), 1.83 (m, 1H), 2.06 (m, 1H), 2.17 (m, 1H), 2.40 (m, 1H), 3.01 (m, 5H) , 3.21 (m, 1H), 4.30 (d, 1H, J = 16.8 Hz), 4.48 (d, 1H, J = 16.8 Hz), 4.49 (m, 1H), 5.47 (t, 1H, J = 5.8 Hz) , 7.60 (m, 2H), 7.79 (m, 2H), 7.80 (m, 1H), 8.33 (d, 1H, J = 7.8 Hz), 8.63 (d, 1H, J = 5.1 Hz); ¹³ C NMR (D ₂ O) δ 14.12, 20.41, 20.69, 27.63, 46.26, 48.25, 49.15, 60.97, 114.24, 125.95, 127.10, 127.52, 130.87, 132.88, 139.45, 140.69, 148.08, 151.08, 151.73. ES-MS mlz 362 (M + H). Calcd for C ₂₂ H ₂₅ N ₅ x _1.5 H ₂ O x 3.1 HBr 0.5 Et ₂ O: C, 42.62; H, 5.68; N, 10.35; Br, 36.62. Found: C, 42.37; H, 5. 31; N, 10.18; Br, 36.31.
[1028] Example 98
[1029]
[1030] Compound 98: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(1-amino-2-methylenyl-butan-4-yl ) -Amine Preparation
[1031] N- (3-methylenyl-butan-1-ol-4-yl) -phthalimide (209 mg, 0.90 mmol) in dichloromethane (5 mL) (details N ^1- (1H-benzimidazole-) 2-ylmethyl) -2-methylene-N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine, see Preparation of Hydrobromide Salts) Methanesulfonyl chloride (0.092 mL, 1.2 mmol) was added. The mixture was then stirred at rt for 30 min and then treated with aqueous ammonium chloride (5 mL). The layers were separated and the aqueous layer was washed twice with 10 ml of dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in DMF (5 mL) and sodium azide (25 mg, 0.38 mmol) was added thereto. The mixture was then heated to 80 ° C. and stirred overnight. The reaction was then cooled and poured into ethyl acetate (100 mL). The solution was then extracted repeatedly with distilled water (5 ×). The organic layer was then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography using a 1: 1 mixture of ethyl acetate: hexane as eluent. Product 1-N-phthalimidyl- (2-methylenyl-butan-4-yl) -azide was obtained as a white solid. ¹ H NMR (CDCl ₃ ) δ 2.36 (t, 2H, J = 6.9 Hz), 3.49 (t, 2H, J = 6.9 Hz), 4.13 (s, 2H), 5.03 (s, 1H), 5.08 (s, 1H), 7.72 (m, 2H), 7.88 (m, 2H).
[1032] To a solution of [1-N-phthalimidyl- (2-methylenyl-butan-4-yl)]-azide (199 mg, 0.78 mmol) in methanol (20 mL) palladium on calcium carbonate (Lindlar's Catalyst, 40 mg) The mixture was then placed under 1 atm hydrogen gas and quickly stirred for 3 hours. The mixture was then filtered and concentrated to give the product [1- (N-phthalimidyl) -2-methylenyl-butan-4-yl] -amine as a yellow gum (160 mg, 84%). ¹ H NMR (CDCl ₃ ) δ 3.32 (t, 2H, J = 7.1 Hz), 3.76 (t, 2H, J = 7.1 Hz), 4.28 (s, 2H), 5.14 (s, 1H), 5.30 (s, 1H), 7.70 (m, 2H), 7.82 (m, 2H).
[1033] 5,6,7,8-tetra in a solution of [1- (N-phthalimidyl) -2-methylenyl-butan-4-yl] -amine (160 mg, 0.658 mmol) in dichloromethane (8 mL) Hydroquinolin-8-one (58 mg, 0.4 mmol) was added. The mixture was stirred at rt for 30 min, then sodium triacetoxyborohydride (348 mg, 1.65 mmol) was added and the reaction stirred for 16 h. Saturated sodium bicarbonate solution (10 ml) was added and the aqueous and organic layers were separated. The aqueous layer was then extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by silica gel flash chromatography (3% methanol in dichloromethane) to give (5,6,7,8-tetrahydro-quinolin-8-yl)-[1- (N-phthalimidyl)- 2-Methylenyl-butan-4-yl] -amine was obtained as a pale yellow foam in a yield of 75 mg (52%). ¹ H NMR (CDCl ₃ ) δ 1.74 (m, 1H), 2.02 (m, 1H), 2.52 (m, 2H), 2.77 (m, 4H), 3.41 (d, 1H, J = 7.7 Hz), 3.55 ( d, 1H, J = 7.7 Hz, 3.78 (m, 3H), 4.86 (m, 1H), 5.05 (1H), 7.04 (m, 1H), 7.37 (m, 1H), 7.68 (m, 2H), 7.80 (m, 2 H), 8.36 (m, 1 H).
[1034] (5,6,7,8-tetrahydro-quinolin-8-yl)-[1- (N-phthalimidyl) -2-methylenyl-butan-4-yl] -amine in acetonitrile (5 mL) To a solution of (75 mg, 0.21 mmol) was added Nt-butoxycarbonyl-2-chloromethylbenzimidazole (80 mg, 0.3 mmol). Di-isopropylethylamine (0.052 mL, 0.3 mmol) was then added and the resulting solution was warmed to 70 ° C. and stirred overnight. After cooling, saturated ammonium solution (10 mL) and dichloromethane (30 mL) were added and the aqueous and organic layers were separated. The aqueous layer was then extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by silica gel flash chromatography (3% methanol in dichloromethane) to [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetra Hydro-quinolin-8-yl)-[1- (N-phthalimidyl) -2-methylene-4-yl] -amine was obtained as pale yellow foam in a yield of 62 mg (50%). ¹ H NMR (CDCl ₃ ) δ 1.68 (s, 9H), 1.89 (m, 1H), 2.03 (m, 2H), 2.11 (m, 1H), 2.40 (t, 2H, J = 6.9 Hz), 2.75 ( m, 2H), 3.27 (d, 1H, J = 13.1 Hz), 3.46 (d, 1H, J = 13.1 Hz), 3.61 (m, 2H), 4.11 (m, 1H), 4.48 (d, 1H, J = 16.1 Hz), 4.63 (d, 1H, J = 16.1 Hz), 6.95 (m, 1H), 7.23 (m, 2H), 7.64 (m, 2H), 7.76 (m, 3H), 8.61 (m, 2H ).
[1035] [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1- (N in ethanol (8 mL) To a solution of -phthalimidyl) -2-methylene-4-yl] -amine (62 mg, 0.10 mmol) was added hydrazine hydrate (0.1 mL). The mixture was then heated at 80 ° C. for 60 minutes. After cooling, the reaction was concentrated in vacuo, dissolved in dichloromethane (20 mL) and washed with aqueous sodium carbonate solution (5 mL). The aqueous layer was then extracted twice with dichloromethane and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated to give an effervescent residue, which was subjected to silica gel flash chromatography (10% methanol, 0.5% in dichloromethane). Purified by Ammonium Hydroxide) to [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1- (Amino) -2-methylene-4-yl] -amine was obtained as a white foam in a yield of 29 mg (74%). ¹ H NMR (CDCl ₃ ) δ 1.64 (m, 1H), 1.89-2.02 (m, 3H), 2.08 (m, 1H), 2.35 (m, 2H), 2.77 (m, 1H), 2.81 (m, 1H ), 2.94 (m, 1H), 3.04 (d, 1H, J = 13.1 Hz), 3.16 (d, 1H, J = 13.1 Hz), 4.03 (m, 3H), 4.87 (s, 1H), 5.06 (s , 1H), 7.12 (m, 3H), 7.40 (d, 1H, J = 8.1 Hz), 7.57 (m, 2H), 8.58 (m, 1H).
[1036] [(Nt-butoxycarbonyl) -benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-[1- (amino in glacial acetic acid (2 mL) To a solution of) -2-methylene-4-yl] -amine (29 mg, 0.080 mmol) was added a saturated solution of HBr in acetic acid (0.5 mL). The resulting mixture was stirred and treated for standard step D, followed by precipitation and drying, followed by [(1H-benzimidazol-2-yl) methyl]-(5,6,7,8-tetrahydro-quinoline-8 -Yl)-[1- (amino) -2-methylene-4-yl] -amine (HBr salt -Compound 98) was obtained as a cream powder (28 mg, 55%). ¹ H NMR (D ₂ O) δ 1.81 (m, 1H), 2.05 (m, 2H), 2.23 (m, 3H), 2.79 (m, 1H), 2.94 (m, 3H), 3.18 (d, 1H, J = 14.1 Hz), 3.41 (d, 1H, J = 14.1 Hz), 4.34 (d, 1H, J = 16.1 Hz), 4.48 (d, 1H, J = 16.1 Hz), 4.60 (m, 1H), 5.26 (m, 2H), 7.53 (m, 2H), 7.79 (m, 2H), 7.89 (dd, 1H, J = 5.1, 7,8 Hz), 8.54 (d, 1H, J = 7.8 Hz), 8.68 (d , 1H, J = 5.1 Hz); 13C NMR (D-2O) δ 20.05, 20.29, 27.81, 31.02, 37.45, 48.26, 57.09, 60.44, 114.26, 118.49, 126.09, 127.01, 131.00, 139.67, 139.79, 141.13, 148.25, 150.85, 151.38. ES-MS mlz 362 (M + H). Calcd for C ₂₂ H ₂₅ N ₅ x 1.8 H ₂ O x 3.0 HBr: C, 41.50; H, 5. 32; N, 11.00; Br, 37.65. Found: C, 41.54; H, 5. 17; N, 10.85; Br, 37.55.
[1037] Example 99
[1038]
[1039] Compound 99: (1H-benzimidazol-4-methoxy-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(1-aminobutan-4-yl)- Preparation of Amine
[1040]
[1041] To a 0 ° C. solution of potassium t-butoxide (5.87 g, 52.3 mmol) in DMF (40 mL) was added copper (I) chloride (0.2 g, 2.0 mmol) under an inert argon atmosphere. The resulting suspension was stirred for 10 minutes, then 3-nitroanisole (1.55 g, 10.1 mmol) and methoxylamine hydrochloride (1.08 g, 12.9 mmol) in DMF (15 mL) were added dropwise over 15 minutes. Was added. The mixture was then slowly warmed to rt and stirred for 48 h. Water (20 mL) was then added to the reaction and the mixture was poured into a separatory funnel containing 100 mL ethyl acetate. The aqueous and organic layers were then separated and the organic layer was extracted five times with 20 mL portions of water. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography using a 3: 1 hexanes: ethyl acetate mixture as eluent. Three isomeric products were separated in sequence from the column, first as the desired 2-amino-3-nitroanisole and as an orange powder in 465 mg (29%) yield. ¹ H NMR (CDCl ₃ ) δ 3.Anal. Calcd. for 95 (s, 3H), 6.44 (br s, 2H (NH)), 6.61 (dd, 1H, J = 7.8, 7.1 Hz), 6.87 (d, 1H, J = 7.1 Hz), 7.73 (d, 1H , J = 7.8 Hz)
[1042] Palladium on carbon (10% Pd, 100 mg) was added to a solution of 2-amino-3-nitroanisole (465 mg, 2.94 mmol) in methanol (50 mL). The mixture was then placed under an atmosphere of hydrogen gas (1 atm) and stirred for 1 hour. The mixture was then filtered through celite and concentrated to give 2,3-diaminoanisole as a yellow foam in a yield of 400 mg (98%). ¹ H NMR (CDCl ₃ ) δ 3.45 (br s, 4H (NH)), 3.84 (s, 3H), 6.40 (m, 2H), 6.67 (t, 1H, J = 7.8 Hz)
[1043]
[1044] A solution of 2,3-diaminoanisole (400 mg, 2.89 mmol) and chloroacetic acid (557 mg, 6 mmol) in 4N HCl was heated to 1-5 ° C. for 16 h. The mixture was then cooled, neutralized with aqueous sodium bicarbonate (pH 8) and extracted twice with dichloromethane. The organic fractions were then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography using a 1: 1 mixture of hexanes: ethyl acetate as eluent to give 1H-2-chloromethyl-4-methoxybenzimidazole as a yellow foam of 386 mg (68%). Obtained in yield. ¹ H NMR (CDCl ₃ ) δ 3.96 (s, 3H), 4.85 (s, 2H), 6.71 (m, 1H), 7.19 (m, 2H).
[1045] 1H-2-Chloromethyl-4-methoxybenzimidazole (138 mg, 0.7 mmol) and (5,6,7,8-tetrahydroquinolin-8-yl)-(1- in acetonitrile (8 mL) To a solution of (N-phthalimidyl) -butan-4-yl) -amine (180 mg, 0.515 mmol) was added di-isopropylethylamine (0.13 mL, 0.75 mmol). The resulting solution was heated to 70 ° C. for 6 hours. The reaction was then cooled and partitioned between aqueous ammonium chloride and dichloromethane. After separating the layers, the aqueous layer was extracted twice with dichloromethane. The combined organic fractions were then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography using 5% methanol solution in dichloromethane as eluent. Product (1H-benzimidazol-4-methoxy-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[1- (N-phthalimidyl) -aminobutane 4-yl] -amine was obtained as a pale yellow foam in a yield of 212 mg. (8268 (m, 4H), 1.90-2.05 (m, 2H), 2.03 (m, 2H), 2.61-2.83 (m, 4H), 3.80-4.10 (m, 8H), 6,60 (m, 1H) , 7.06 (m, 3H), 7.63 (m 1H), 7.63-7.77 (m, 4H), 8.40 (m, 1H).
[1046] Product (1H-benzimidazol-4-methoxy-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[1- (N- in modified ethanol (10 mL) To a solution of phthalimidyl) -aminobutan-4-yl] -amine (212 mg, 0.417 mmol) was added hydrazine hydrate (0.25 mL). The resulting mixture was heated to 80 ° C. for 60 minutes, then cooled and concentrated. The residue was filtered through a silica gel plug (5 g of silica) using a 10: 1 dichloromethane: methanol mixture as eluent. The recovered eluent (200 mL) was then cooled, redissolved in THF (10 mL) and di-t-butyl carbonate (212 mg, 1.0 mmol) was added. The mixture was then stirred at rt overnight. The reaction was then concentrated and the residue was purified by silica gel flash chromatography using 5% methanol mixture in dichloromethane as eluent to afford the desired (1-t-butoxycarbonyl-benzimidazole-4-methoxy. 2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[1- (Nt-butoxycarbonyl) -aminobutan-4-yl] -amine as a pale foam Obtained in the yield of 68 mg (28%). ¹ H NMR (CDCl ₃ ) δ 1.18-1.23 (m, 4H), 1.39 (s, 9H), 1.70 (s, 9H), 1.97-2.07 (m, 4H), 2.58-2.95 (m, 6H), 4.01 (s, 3H), 4.18 (m, 1H), 4.58 (m, 2H), 4.92 (br s, 1H (NH)), 6.72 (d, 1H, J = 8.1 Hz), 6.91 (m, 1H), 7.16 (m, 2H), 7.35 (d, 1H, J = 8.1 Hz), 8.33 (m, 1H).
[1047] (1-t-butoxycarbonyl-benzimidazol-4-methoxy-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[1- (Nt-part Toxylcarbonyl) -aminobutan-4-yl] -amine (68 mg, 0.117 mmol) was dissolved in acetic acid (1 mL) and a saturated solution of HBr in acetic acid (0.1 mL) was added. The mixture was then filtered, precipitated and separated according to process D to afford compound 99 as a white crystalline solid in a yield of 49 mg (65%). ¹ H NMR (D ₂ O). δ 1.52 (m, 4H), 1.79 (m, 1H), 1.98 (m, 1H), 2.14 (m, 1H), 2.35 (m, 1H), 2.53 (m, 1H), 2.79 (m, 3H), 2.99 (m, 2H), 4.03 (s, 3H), 4.36 (d, 1H, J = 16.8 Hz), 4.49 (m, 1H), 4.50 (d, 1H, J = 16.8 Hz), 7.10 (d, 1H , J = 8.1 Hz), 7.34 (d, 1H, J = 8.4 Hz), 7.51 (t, 1H, J = 8.4 Hz), 7.85 (dd, 1H, J = 8.1, 5.4 Hz), 8.34 (d, 1H , J = 8.1 Hz), 8.60 (d, 1H, J = 5.4 Hz). ¹³ C NMR (D ₂ O) δ 20.44, 20.84, 25.05, 25.41, 27.66, 39.54, 48.10, 51.76, 56.70, 60.54, 106.20, 107.45, 121.85, 125.90, 128.14, 132.39, 139.30, 140.56, 147.45, 148.89, 150.89, 150.89 , 151.30. ES-MS m / z 380 (M + H); Calcd for (C ₂₂ H ₂₉ N ₅ O x 3.0 HBr x 1.0H ₂ O): C, 41.27; H, 5. 35; N, 10.94; Br 37.44. Found: C, 41.28; H, 5. 33; N, 10.67; Br, 37.24.
[1048] Example 100
[1049]
[1050] Compound 100: N1- (1H-benzimidazol-2-ylmethyl) -N1- (4-methoxy-5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4- Preparation of diamines (hydrobromide salts)
[1051] 8-amino-5,6,7,8-tetrahydroquinoline (prepared as described in US Patent Application Serial No. 09 / 535,314 (Bridger et al.)) Amino-4-methoxy-5,6,7,8-tetrahydroquinoline was prepared from 8-hydroxy-4-methoxy-5,6,7,8-tetrahydroquinoline in a yield of 68% (preparation) And characterization see: Uchida, M .; Morita, S .; Chihiro, M .; Kanbe, T .; Yamasaki, K .; Yabuuchi, Y .; Nakagawa, K. Chem. Pharm. Bull. 1989, 37 , 1517-1523). ¹ H NMR (CDCl ₃ ) δ 1.59-2.15 (m, 6H), 2.60-2.65 (m, 2H), 3.84 (s, 3H), 3.95 (dd, 1H, J = 6.0, 9.0 Hz), 6.61 (d , 1H, J = 6.0 Hz). 8.32 (d, 1 H, J = 6.0 Hz); ¹³ C NMR (CDCl ₃ ) δ 19.53, 22.89, 31.94, 51.57, 55.62, 104.04, 120.94, 148.52, 160.42, 163.71; ES-MS m / z 179 (M + H).
[1052] General process B use: 8-amino-4-methoxy-5,6,7,8-tetrahydroquinoline (0.297 g, 1.67 mmol) and 4- (1,3-dioxo-1,3-dihydro- Isoindol-2-yl) -butyraldehyde (0.371, 1.71 mmol) was reacted with NaBH (OAc) ₃ (0.493 g, 2.33 mmol) in CH ₂ Cl ₂ (8 mL) for 60 minutes, then the crude material was Purification by column chromatography on silica gel (20: 1 CH ₂ Cl ₂ -CH ₃ OH) 2- [4- (4-methoxy-5,6,7,8-tetrahydro-quinolin-8-ylamino) 0.345 g (54%) of -butyl] -isoindole-1,3-dione was obtained as off-white solid.
[1053] General process use for N-alkylation: 2- [4- (4-methoxy-5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl]-in CH ₃ CN (9 mL) Isoindole-1,3-dione (0.340 g, 0.90 mmol), 1-tert- (butoxycarbonyl) -2- (chloromethyl) -benzimidazole (0.492 g, 1.84 mmol) and N, N-di A solution of isopropylethylamine (0.48 mL, 2.76 mmol) was heated at 80 ° C. for 22 hours. The crude material was subjected to column chromatography on silica gel (20: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) followed by silica gel radial chromatography (2 mm plate, 100: 1: 1 CH ₂ Cl ₂ -CH). Purified with ₃ OH-NH ₄ OH) 2-{[[4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyl]-(4-methoxy-5 133 mg (24%) of 6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester were obtained as a yellow solid.
[1054] 2-{[[4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyl]-(4-methoxy-5,6,7 in ethanol (4 mL) Hydrazine monohydrate (0.20 mL, 4.12 mmol) in a solution of, 8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester (0.133 g, 0.22 mmol) Was added and the resulting mixture was stirred at rt overnight. The mixture was filtered through filter paper and concentrated. The crude material was purified by column chromatography on silica gel (10: 1: 1 CH ₂ Cl ₂ -CH ₃ OH-NH ₄ OH) to give 56 mg (68%) of the free base of the title compound as a yellow oil.
[1055] Using General Process D: The free base was converted to a hydrobromide salt and then reprecipitated intermediate solids from methanol / ether to give compound 100 (72 mg, 71%) as a tan solid. ¹ H NMR (D ₂ O) δ 1.53 (br s, 4H), 1.64-1.74 (m, 1H), 1.86-1.98 (m, 1H), 2.14-2.19 (m, 1H), 2.28-2.32 (m, 1H), 2.50-2.63 (m, 2H), 2.71-2.87 (m, 4H), 4.09 (s, 3H), 4.31-4.40 (m, 2H), 4.48 (d, 1H, J = 16.8 Hz), 7.34 (d, 1H, J = 7.2 Hz), 7.56-7.61 (m, 2H), 7.76-7.80 (m, 2H), 8.49 (d, 1H, J = 7.2 Hz); ¹³ C NMR (D ₂ O) δ 19.74, 20.00, 21.76, 25.03, 25.37, 39.51, 47.98, 51.69, 58.09, 60.11, 107.55, 114.22, 126.91, 128.05, 130.98, 141.05, 150.21, 151.88, 170.91; ES-MS m / z 380 (M + H). Calc. For C 22 H 29 N 5 O. 3.2 HBr. 2.2 H 2 O: C, 38.97; H, 5. 44; N, 10.335; Br, 37.71. Found: C, 39.08; H, 5.13; N, 10.46; Br, 37.57.
[1056] Example 101
[1057]
[1058] Compound 101: N1- (1H-benzimidazol-2-ylmethyl) -N1- (3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine Preparation of (hydrobromide salt)
[1059] A solution of 3-bromoquinoline (24.4 g, 117 mmol) in anhydrous DMF (250 mL) was treated with sodium methoxide (12.7 g, 235 mmol) and stirred at 140 ° C. for 40 h. The reaction mixture was then concentrated under reduced pressure and diluted with ethyl acetate (300 mL) and water (60 mL). The organic phase was separated, washed with brine (2 × 60 mL), dried (MgSO ₄ ), filtered and concentrated under reduced pressure. It was purified by column chromatography on silica gel (ethyl acetate / hexane; 1: 4) to give 3-methoxyquinoline as a pale yellow liquid (1.15 g, 6%). ¹ H NMR (CDCl ₃ ) δ 3.95 (s, 3H), 7.38 (d, 1H, J = 1.5 Hz), 7.54 (m, 2H), 7.72 (d, 1H, J = 7.5 Hz), 8.04 (d, 1H, J = 7.5 Hz), 8.67 (d, 1H, J = 1.5 Hz).
[1060] A solution of 3-methoxyquinoline (1.15 g, 7.2 mmol) in TFA (24 mL) was prepared and the reaction flask was purged with argon. Platinum oxide (82 mg, 0.36 mmol) was then added and hydrogen gas was bubbled through the solution at room temperature for 16 hours. The mixture was then cooled to 0 ° C., basified to pH 12 with 15% aqueous sodium hydroxide solution and extracted with ethyl acetate (3 × 100 mL). The organic phase was then dried (MgSO ₄ ), filtered and concentrated to give 3-methoxy-5,6,7,8-tetrahydroquinoline (0.88 g, 74%). ¹ H NMR (CDCl ₃ ) δ 1.77 (m, 2H), 1.85 (m, 2H), 2.75 (t, 2H, J = 6.0 Hz), 2.85 (t, 2H, J = 6.0 Hz), 3.81 (s, 3H), 6.88 (d, 1H, J = 1.5 Hz), 8.07 (d, 1H, J = 1.5 Hz).
[1061] 50% hydrogen peroxide (0.30 mL, 5.4 mmol, 1 equiv) was added to a solution of 3-methoxy-5,6,7,8-tetrahydroquinoline (0.87 g, 5.3 mmol) in acetic acid (12 mL) and 70 ° C Heated for 7 hours. Then a second equivalent of 50% hydrogen peroxide (0.30 mL, 5.4 mmol) was added and the solution was stirred at 70 ° C. for a further 16 h. The solution was then concentrated under reduced pressure, and chloroform (20 mL) and sodium carbonate (5 g) were added. The mixture was stirred for a short time, the supernatant decanted and the solid washed with chloroform (50 mL). The organics were then dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford N-oxide as a yellow crystalline solid (0.67 g, 70%). ¹ H NMR (CDCl ₃ ) δ 1.76 (m, 2H), 1.86 (m, 2H), 2.74 (t, 2H, J = 6.0 Hz), 2.88 (t, 2H, J = 6.0 Hz), 3.81 (s, 3H), 6.67 (d, 1H, J = 1.5 Hz), 7.98 (d, 1H, J = 1.5 Hz).
[1062] A solution of 3-methoxy-5,6,7,8-tetrahydroquinolinium oxide (0.67 g, 3.7 mmol) in acetic anhydride (9 mL, 95 mmol) was heated to 90 ° C. for 18 hours and then under reduced pressure. Concentrated. From this rearrangement 8-acetyl-3-methoxy-5,6,7,8-tetrahydroquinoline was obtained as crude brown oil (0.83 g, 100%), which was also immediately used for the next step. ¹ H NMR (CDCl ₃ ) δ 1.83 (m, 2H), 2.09 (s, 3H), 2.11 (m, 2H), 2.80 (m, 2H), 3.84 (s, 3H), 5.94 (t, 1H, J = 4.5 Hz), 6.94 (d, 1H, J = 1.5 Hz), 8.22 (d, 1H, J = 1.5 Hz).
[1063] A solution of 8-acetyl-3-methoxy-5,6,7,8-tetrahydroquinoline (0.83 g, 3.7 mmol) in anhydrous methanol (18 mL) was treated with potassium carbonate (1.03 g, 7.5 mmol), Stir at room temperature for 16 hours. The mixture was concentrated under reduced pressure and CH ₂ Cl ₂ (30 mL) and water (15 mL) were added. The aqueous phase is then extracted with CH ₂ Cl ₂ (2 × 30 mL), the combined organic phases are dried (MgSO ₄ ), filtered and concentrated to give column chromatography (1: 3 ethyl acetate / hexanes), followed by ( 3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl) -alcohol was obtained as a pale yellow solid (0.35 g, 51%). ¹ H NMR (CDCl ₃ ) δ 1.81 (m, 2H), 1.99 (m, 1H), 2.22 (m, 1H), 2.77 (m, 2H), 3.83 (s, 3H), 4.69 (t, 1H, J = 7.5 Hz), 6.92 (d, 1H, J = 3.0 Hz), 8.12 (d, 1H, J = 3.0 Hz).
[1064] The alcohol from the stomach (0.35 g, 1.9 mmol) was then dissolved in anhydrous CH ₂ Cl ₂ (19 mL) and treated with manganese dioxide (1.67 g, 19 mmol) at room temperature for 18 hours. The black mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. This gave the desired 3-methoxy-5,6,7,8-tetrahydroquinolin-8-one (0.23 g, 68%) which was used in the next step without purification. ¹ H NMR (CDCl ₃ ) δ 2.18 (m, 2H), 2.74 (t, 2H, J = 6.0 Hz), 2.99 (t, 2H, J = 6.0 Hz), 3.90 (s, 3H), 7.00 (d, 1H, J = 3.0 Hz), 8.35 (d, 1H, J = 4.0 Hz).
[1065] 3-methoxy-5,6,7,8-tetrahydroquinolin-8-one (0.23 g, 1.3 mmol), (4-aminobutyl) -carbamic acid tert-butyl using general process B from above Ester (0.27 g, 1.4 mmol) and sodium triacetoxyborohydride (0.55 g, 2.6 mmol) were stirred for 18 h in CH ₂ Cl ₂ (7 mL) at room temperature. This was followed by post-treatment and column chromatography (3:97 MeOH / CH ₂ Cl ₂ to 15: 1: 84 MeOH / NH ₄ OH / CH ₂ Cl ₂ ) followed by [4- (3-methoxy-5,6,7 , 8-tetrahydroquinolin-8-ylamino) -butyl] -carbamic acid tert-butyl ester (0.38 g, 84%) was obtained.
[1066] Secondary amine (0.15 g, 0.43 mmol), N- (t-butoxycarbonyl) -2-chloromethylbenzimidazole (0.18 g, 0.69 mmol) and potassium iodide in anhydrous acetonitrile (4.3 mL) 5 mg, 0.02 mmol) was added diisopropylethylamine (0.15 mL, 0.9 mmol) and stirred at 60 ° C. for 16 hours. The mixture was then concentrated under reduced pressure and the residue was partitioned between CH ₂ Cl ₂ (10 mL) and brine (5 mL). The organic phase was separated and the aqueous phase extracted with CH ₂ Cl ₂ (2 × 10 mL). The combined organic phases are then dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a crude residue which is purified by silica gel column chromatography (1:99 MeOH / CH ₂ Cl ₂ ), Purification with a second column with silica gel (saturated NH ₃ / Et ₂ O). 2-{[(4-tert-butoxycarbonylaminobutyl)-(3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl) -amino] -methyl} -benzimi Dazol-1-carboxylic acid tert-butyl ester (98 mg, 39%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H), 1.43 (br m, 4H), 1. 62 (m, 1H), 1.69 (s, 9H), 1.87-2.05 (m, 3H), 2.62- 2.80 (m, 4H), 3.01 (br, 2H), 3.75 (s, 3H), 4.16 (m, 1H), 4.44 (d, 1H, J = 15.0 Hz), 4.55 (d, 1H, J = 15.0 Hz ), 4.90 (br, 1H), 6.71 (d, 1H, J = 3.0 Hz), 7.27 (m, 2H), 7.70 (m, 1H), 7.79 (m, 1H), 8.08 (d, 1H, J = 3.0 Hz).
[1067] General Process D Use: The above material (97 mg, 0.17 mmol) was converted to a hydrobromide salt to give compound 101 (85 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.54 (br, 4H), 1.75 (m, 1H), 1.93 (m, 1H), 2.15 (m, 1H), 2.33 (m, 1H), 2.56 (br, 1H) , 2.80 (br m, 1H), 2.87 (br, 2H), 2.96 (br d, 2H), 3.96 (s, 3H), 4.37 (d, 1H, J = 17.1 Hz), 4.43 (m, 1H), 4.50 (d, 1H, J = 16.8 Hz), 7.60 (m, 2H), 7.79 (m, 2H), 7.93 (br, 1H), 8.28 (d, 1H, J = 2.1 Hz). ¹³ C NMR (D ₂ O) δ 20.54 (2C), 25.08, 25.43, 28.01, 39.54, 47.95, 51.73, 57.43, 60.13, 114.25 (2C), 126.95 (2C), 127.25, 131.00, 131.96, 141.38, 143.54, 151.85, 157.19. ES-MS m / z 380 (M + H). Calcd for _{C 22 H 29 N 5O · 3.2HBr} · 1.7H 2 O: C, 39.50; H, 5. 36; N, 10.47; Br, 38.22. Found: C, 39.77; H, 5. 27; N, 10.34; Br, 37.96.
[1068] Example 102
[1069]
[1070] Compound 102: N1- (1-methyl-1H-benzoimidazol-2-ylmethyl) -N1- (S)-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1 Preparation of 4,4-diamine hydrochloride salt
[1071] 2- {4-[(1-Methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -isoindole Preparation of -1,3-dione:
[1072] (S) -2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione (3.89 g) in acetonitrile (111 mL) , 11.1 mmol) 2-chloromethyl-1-methyl-1H-benzoimidazole (Phillips, MAJ Chem. Soc. 1928, 2393; Goker, H .; Kus, C. Arch. Pharm. Weinheim) 1995, 328, 425-430, prepared by reacting N-methyl-ortho-phenylenediamine with chloroacetic acid (2.42 g, 13.4 mmol), diisopropylethylamine (1.93 ml, 11.1 ML) and potassium iodide (0.18 g, 1.11 mL) were added. The mixture was stirred at 50 ° C. for 16 h. The mixture was concentrated, redissolved in methylene chloride (200 mL) and diluted with saturated NaCl (400 mL). The reaction was extracted with methylene chloride (3 x 300 mL) and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford a dark red oil. Purification by column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH 4 OH, 95: 4: 1, v / v / v) gave the product as a bright red foam (5.12 g, 77%). ¹ H NMR (CDCl 3) δ 1.63 (m, 8H), 2.65 (m, 4H), 3.54 (m, 2H), 4.10 (m, 6H), 6.98 (dd, 1H, J = 7.89, 4.38 Hz), 7.21 (m, 4H), 7.71 (m, 5H), 8.49 (d, 1H, J = 3.95 Hz).
[1073] Preparation of N- (1-Methyl-1H-benzoimidazol-2-ylmethyl) -N- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine:
[1074] To a solution of the substance from the stomach (5.12 g, 10.37 mmol) in ethanol (75 mL) was added hydrazine hydrate (1.94 mL, 62.2 mmol). The solution was stirred for 16 h at room temperature under N ₂ atmosphere. White precipitate formed. Diethyl ether (75 mL) was added to the mixture and the reaction stirred for 10 minutes. The mixture was filtered and concentrated. Purification by column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH ₄ OH, 94: 5: 1, v / v / v), followed by column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH ₄ OH , 94: 5: 1, v / v / v) to give the product as a light yellow oil (2.63 g, 55%). ¹ H NMR (CDCl 3) δ 1.39 (m, 5H), 1.99 (m, 3H), 2.63 (m, 6H), 3.48 (s, 2H), 3.97 (s, 3H), 4.11 (m, 3H), 7.00 (dd, 1H, J = 7.45, 4.38 Hz), 7.25 (m, 4H), 7.71 (d, 1H, J = 7.45 Hz), 8.46 (d, 1H, J = 4.38 Hz).
[1075] Preparation of Compound 102:
[1076] N- (1-Methyl-1H-benzoimidazol-2-ylmethyl) -N- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (2.63 g HCl-saturated methanol (11 mL) was added to the solution, and the mixture was stirred at room temperature under N ₂ atmosphere for 1 hour. The solution was added dropwise with diethyl ether (1 L) to give a thick white precipitate. The white solid was separated by suction filtration under a continuous stream of nitrogen, washed with diethyl ether and dried overnight under vacuum at 40 ° C. (2.75 g, 91%). ¹ H NMR (D ₂ O) δ 1.67 (m, 3H), 1.99 (m, 4H), 2.55 (m, 2H), 2.89 (m, 3H), 3.07 (m, 2H), 3.31 (s, 1H) , 4.07 (s, 3H), 4.43 (d, 1H, J = 17.9 Hz), 4.69 (m, 2H), 7.62 (m, 2H), 7.92 (m, 3H), 8.42 (d, 1H, J = 7.89 Hz), 8.85 (d, 1 H, J = 5.7 Hz). 13C NMR d (D 2 O) 21.92, 26.65, 29.17, 32.42, 40.78, 53.61, 61.82, 113.89, 115.76, 127.15, 127.89, 128.11, 131.79, 135.1, 141.38, 141.91, 149.14, 152.75, 153.72. ES-MS mlz 364 (M + H). C ₂₂ H ₂₉ N ₅ 3.05 HCl 0.06 C ₂ H ₄ O ₂ Calcd for 3.07H ₂ O: C, 49.80; H 7.26; N, 13.13; Cl, 20.24. Found. C, 49.80; , 7.25; N, 13.13; Cl, 20.24.
[1077] Example 103
[1078]
[1079] Compound 103: N1- (1H-benzimidazol-2-ylmethyl) -N1- (2-chloro-5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine Preparation of (hydrobromide salt)
[1080] Preparation of methanesulfonic acid 2-chloro-5,6,7,8-tetrahydro-quinolin-8-yl ester:
[1081] 2-chloro-8-hydroxy-5,6,7,8-tetrahydroquinoline in CH ₂ Cl ₂ (19 mL) cooled to 0 ° C. under nitrogen (prepared as described by Zimmerman, SC; Zeng, Z .; Wu, W .; Reichert, DEJ Am. Chem. Soc. 1991, 113, 183-196) (700 mg, 3.81 mmol) in NEt ₃ (0.80 mL, 5.7 mmol) followed by MsCl (0.35 mL, 4.5 mmol). Was added. The solution was stirred at 0 ° C. for 40 min and then diluted with saturated aqueous NaHCO ₃ (20 mL). The layers were separated and the aqueous solution extracted with CH ₂ Cl ₂ (20 mL × 2). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (hexane / EtOAc, 2: 1) afforded mesylate as a white solid (904 mg, 3.45 mmol, 91%). ¹ H NMR (CDCl 3) δ 1.82-2.17 (m, 3H), 2.35-2.47 (m, 1H), 2.63-2.77 (m, 1H), 2.79-2.91 (m, 1H), 3.29 (s, 3H), 5.62 (t, 1H, J = 3.9 Hz), 7.23 (d, 1H, J = 8.1 Hz), 7.45 (d, 1H, J = 8.1 Hz).
[1082] Preparation of 8-azido-2-chloro-5,6,7,8-tetrahydro-quinoline:
[1083] A solution of mesylate (886 mg, 3.39 mmol) and NaN ₃ (285 mg, 4.38 mmol) in DMF (10 mL) was stirred at 80 ° C. under nitrogen for 35 minutes. Once stirred, the mixture was diluted with brine (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (hexane / EtOAc, 2: 1) afforded azide as a pale yellow oil (679 mg, 3.25 mmol, 96%). ¹ H NMR (CDCl ₃ ) δ 1.75-2.11 (m, 4H), 2.63-2.86 (m, 2H), 4.66 (t, 1H, J = 4.2 Hz), 7.20 (d, 1H, J = 8.1 Hz), 7.42 (d, 1 H, J = 8.1 Hz).
[1084] Preparation of 8-amino-2-chloro-5,6,7,8-tetrahydro-quinoline:
[1085] To a solution of azide (351 mg, 1.68 mmol) in 10% H ₂ O in THF (10 mL) was added PPh ₃ (867 mg, 3.31 mmol) and the reaction was stirred at rt for 18 h. The solution was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH, 9: 1) to give the amine as a pale yellow oil (276 mg, 1.51 mmol, 90%). ¹ H NMR (CDCl 3) δ 1.62-1.83 (m, 2H), 1.86-2.03 (m, 3H), 2.13-2.22 (m, 1H), 2.66-2.84 (m, 2H), 3.97 (dd, 1H, J = 7.5, 5.4 Hz), 7.09 (d, 1H, J = 8.1 Hz), 7.33 (d, 1H, J = 8.1 Hz).
[1086] Preparation of 2- [4- (2-Chloro-5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione:
[1087] Amine (269 mg, 1.47 mmol) and 4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyraldehyde (266 mg, in CH ₂ Cl ₂ (8 mL), 1.22 mmol) was stirred at room temperature under nitrogen for 30 minutes. NaBH (OAc) ₃ (398 mg, 1.88 mmol) was then added in one portion as a solid and the reaction stirred for an additional 15 hours. The mixture was washed with 1M NaOH (10 mL × 2) and brine (10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 49: 1: 0.25) afforded secondary amine as a colorless oil (289 mg, 0.75 mmol, 62%). ¹ H NMR (CDCl 3) δ 1.55-1.81 (m, 6H), 1.93-2.03 (m, 1H), 2.06-2.14 (m, 1H), 2.26 (br. S, 1H), 2.73 (t, 4H, J = 7.1 Hz), 3.72 (t, 3H, J = 6.9 Hz), 7.07 (d, 1H, J = 8.1 Hz), 7.32 (d, 1H, J = 8.1 Hz), 7.69 (dd, 2H, J = 5.4 , 3.0 Hz), 7.83 (dd, 2H, J = 5.3, 3.0 Hz).
[1088] 2-({(2-chloro-5,6,7,8-tetrahydro-quinolin-8-yl)-[4- (1,3-dioxo-1,3-dihydro-isoindole-2- Preparation of 1) -Butyl] -amino} -methyl) -benzimidazole-1-carboxylic acid tert-butyl ester:
[1089] Amine (274 mg, 0.72 mmol) in CH ₃ CN (5 mL), 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (227 mg, 0.85 mmol), DIPEA (0.18 mL, 1.0 mmol) and A solution of KI (24 mg, 0.14 mmol) was stirred at 60 ° C. under nitrogen for 17 hours. Once cooled to room temperature, the solution was diluted with saturated aqueous NaHCO ₃ (10 mL) and extracted with CH ₂ Cl ₂ (20 mL × 3). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH, 19: 1) gave tertiary amine as an off-white foam (435 mg, 0.71 mmol, 99%). ¹ H NMR (CDCl ₃ ) δ 1.28-1.41 (m, 2H), 1.50-1.61 (m, 2H), 1.64-1.76 (m, 10H), 1.80-1.91 (m, 1H), 1.93-2.05 (m, 1H), 2.09-2.22 (m, 1H), 2.54-2.89 (m, 4H), 3.53 (t, 2H, J = 7.2 Hz), 4.18 (dd, 1H, J = 9.8, 6.2 Hz), 4.49 (d , 1H, J = 15.6 Hz, 4.74 (d, 1H, J = 15.6 Hz), 6.93 (d, 1H, J = 8.1 Hz), 7.19 (d, 1H, J = 8.1 Hz), 7.22-7.26 (m , 2H), 7.63-7.71 (m, 3H), 7.74-7.85 (m, 3H).
[1090] N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(2-Chloro-5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine:
[1091] A solution of amine (212 mg, 0.345 mmol) and hydrazine monohydrate (0.20 mL, 4.1 mmol) in EtOH was stirred at reflux for 75 minutes under nitrogen. Excess solvent was removed under reduced pressure, and the residue was dissolved in saturated aqueous NaHCO ₃ (10 mL) and extracted with CH ₂ Cl ₂ (20 mL × 3). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 9: 1: 0.05) gave the primary amine as a white foam (99.9 mg, 0.260 mmol, 75%). ¹ H NMR (CDCl ₃ ) δ 1.29-1.52 (m, 4H), 1.61-1.77 (m, 1H), 1.79-1.94 (m, 1H), 1.99-2.11 (m, 1H), 2.18-2.30 (m, 1H), 2.47-2.62 (m, 3H), 2.65-2.88 (m, 3H), 3.94-4.09 (m, 3H), 7.15 (d, 1H, J = 8.1 Hz), 7.19-7.23 (m, 2H) , 7.38 (d, 1H, J = 8.1 Hz), 7.60-7.64 (m, 2H).
[1092] Preparation of Compound 103:
[1093] To a solution of amine (99.9 mg, 0.260 mmol) in ice HOAc (1.5 mL) was added a saturated solution of HBr in HOAc (0.5 mL). The solution was stirred at rt for 30 min and then Et ₂ O (5 mL) was added. The solvent was removed by pipette and the precipitate was washed with Et ₂ O (2 mL × 2) and then dissolved in MeOH (2 mL). The mixture was stirred for about 5 minutes and the product was reprecipitated by addition of Et ₂ O (5 mL). The solvent was removed again by pipette and the precipitate was washed with Et ₂ O (2 mL × 3). The product was dried under reduced pressure to afford compound 103 as an off-white powder (156 mg, 0.240 mmol, 92%). ¹ H NMR (D ₂ O) δ 1.67-2.00 (m, 5H), 2.12-2.32 (m, 2H), 2.39-2.52 (m, 1H), 2.67-2.82 (m, 2H), 3.03 (t, 2H , J = 7.4 Hz), 3.40-3.56 (m, 2H), 4.80-4.89 (m, 3H), 6.96 (d, 1H, J = 8.1 Hz), 7.35 (d, 1H, J = 8.1 Hz), 7.51 -7.55 (m, 2 H), 7.68-7.71 (m, 2 H). ¹³ C NMR (D ₂ O) δ 20.3, 21.1, 23.2, 24.6, 27.0, 39.3, 46.6, 54.1, 63.2, 114.9, 124.2, 126.9, 132.6, 134.5, 141.7, 144.4, 147.9, 150.2. ES-MS mlz 384 (M + H), 386 (M + 2 + H). Calcd for C ₂₁ H ₂₆ ClN ₅ .3.1 HBr 0.2C ₄ H ₁₀ O: C, 40.31; H, 4.83; N, 10.78; Br 38.13. Found: C, 40.20; H, 4.91; N, 10.73; Br 38.44.
[1094] Example 105
[1095]
[1096] Compound 105: N ^One-(1H-benzoimidazol-2-ylmethyl) -N ^One-(5,6,7,8-tetrahydroquinoxalin-5-yl) -butane-1,4-diamine.
[1097] Preparation of 5-bromo-5,6,7,8-tetrahydroquinoxaline:
[1098] In a commercially available solution of 5,6,7,8-tetrahydroquinoxaline (3.08 g, 23.0 mmol) in CCl ₄ (200 mL), the amount of N-bromosuccinamide (4.09 g, 23.0 mmol) and catalyst amount (56 mg) Benzoyl peroxide was added. The reaction mixture was heated at reflux for 17 h. Saturated sodium bicarbonate solution was added (100 mL), the layers were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 200 mL). The organic extract was dried and concentrated. The crude material contained the starting material, mono- and dibromo products in a 1: 3: 1 ratio (GC), which was separated by column chromatography on silica gel using a mixture of 1: 1 EtOAc: hexanes to give 5-bro Parent-5,6,7,8-tetrahydroquinoxaline (3.03 g, 54%) was obtained as a brown liquid. ¹ H NMR (CDCl ₃ ): δ 1.99-2.03 (m, 1H), 2.20-2.49 (m, 3H), 2.97-3.10 (m, 1H), 3.11-3.20 (m, 1H), 5.48 (t, 1H , J = 1.5 Hz), 8.40 (s, 2H). It should be noted that the material is unstable upon exposure to air for 2-3 days, so it is used immediately for the next reaction.
[1099] Preparation of 5-azido-5,6,7,8-tetrahydroquinoxaline:
[1100] 5-bromo-5,6,7,8-tetrahydroquinoxaline (2.75 g, 12.9 mmol) and sodium azide (1.68 g, 25.8 mmol) were dissolved in DMF (50 mL) under a nitrogen atmosphere and the reaction mixture Warmed at 60 ° C. for 2 days. The mixture was cooled to rt, poured into water (500 mL) and extracted with CH ₂ Cl ₂ (3 × 300 mL). The organic extract was washed with brine (2 x 200 mL), dried and concentrated in vacuo. The crude material was purified by column chromatography on flash silica gel using 1: 1 EtOAc / hexanes to give 2.19 g (97%) of 5-azido-5,6,7,8-tetrahydroquinoxaline as a yellow liquid. ¹ H NMR (CDCl 3): δ 1.80-1.96 (m, 1H), 2.00-2.10 (m, 3H), 2.75-3.06 (m, 2H), 4.74 (t, 1H, J = 6.5 Hz), 8.44 ( d, 1H, J = 3 Hz), 8.45 (d, 1H, J = 3 Hz); 13 C NMR (CDCl 3): δ 18.6, 28.9, 31.7, 60.2, 142.6, 144.3, 150.3, 153.6.
[1101] Preparation of 5,6,7,8-tetrahydroquinoxalin-5-ylamine
[1102] Into a Parr shaker flask was placed 5-azido-5,6,7,8-tetrahydroquinoxaline (1.81 g, 10.33 mmol) and 10% palladium on carbon (10 wt% of Pd / C; 0.18 g). The reaction vessel was evacuated and filled with nitrogen. Methanol (30 mL) was added and the reaction was hydrogenated at 30 psi for 40 minutes. The reaction mixture was flushed with nitrogen and filtered through a plug of celite to give 5,6,7,8-tetrahydroquinoxalin-5-ylamine as an orange liquid (1.54 g, 99%), which was rapidly It turned dark brown. It was stored at -20 ° C under argon atmosphere. ¹ H NMR (CDCl 3): δ 1.62-1.79 (m, 1H), 1.80-2.18 (m, 4H), 2.18-2.30 (m, 1H), 2.91-3.01 (m, 2H), 4.07 (dd, 1H, J = 8.4, 5.4 Hz), 8.32-8.38 (m, 2H); 13 C NMR (CDCl 3): δ 19.7, 31.7, 32.2, 51.5, 142.0, 142.5, 152.6, 155.4; MS m / z: 150 (M + H &lt; + &gt;), 133.
[1103] Preparation of 2- [4- (5,6,7,8-tetrahydro-quinoxalin-5-ylamino) -butyl] -isoindole-1,3-dione:
[1104] To a solution of 5,6,7,8-tetrahydroquinoxalin-5-ylamine (313 mg, 2.09 mmol) in CH ₂ Cl ₂ (20 mL) at room temperature under 4- (1,3, -di Oxo-1,3-dihydro-isoindol-2-yl) -butyraldehyde (227.8 mg, 1.05 mmol) was added followed by sodium triacetoxyborohydride (444 mg, 2.10 mmol). The reaction mixture was stirred at rt for 2 h. Saturated sodium bicarbonate solution (10 mL) was added and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated. The obtained material was purified by column chromatography on silica gel (10: 1: 0.5 CH ₂ Cl ₂ : MeOH: NH ₄ OH) to give the product as a clear oil (298 mg, 81%): ¹ H NMR (CDCl ₃₎ ): δ 1.56-1.66 (m, 2H), 1.70-1.95 (m, 4H), 2.04-2.22 (m, 4H), 2.71-2.85 (m, 2H), 2.87-3.05 (m, 2H), 7.69- 7.73 (m, 2H), 7.80-7.85 (m, 2H), 8.34 (br s, 2H).
[1105] 2-{[[4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyl]-(5,6,7,8-tetrahydroquinoxalin-5-yl Preparation of) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester
[1106] 2- [4- (5,6,7,8-tetrahydro-quinoxalin-5-ylamino) -butyl] -isoindole-1,3-dione (298 mg, 0.850 in CH ₃ CN (12 mL) mmol) was added 2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (295 mg, 1.11 mmol), potassium iodide (14 mg) and diisopropylethylamine (0.296 mL, 1.70 mmol). It was. The reaction mixture was stirred at 60 ° C. for 17 h. Saturated sodium bicarbonate (15 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 × 30 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated. The crude material was purified by column chromatography on silica gel (1:10 EtOAc: hexanes then EtOAc then 1:10 MeOH: EtOAc) to give the product as a clear oil (422 mg, 85%): ¹ H NMR (CDCl ₃ ) δ 1.34-1.43 (m, 2H), 1.48-1.60 (m, 2H), 1.68 (s, 9H), 1.71-1.81 (m, 1H), 1.88-1.97 (m, 1H), 2.00-2.21 (m , 2H), 2.60-2.69 (m, 1H), 2.76-2.93 (m, 3H), 3.55 (t, 2H, J = 6.9 Hz), 4.29 (dd, 1H, J = 9.6, 5.4 Hz), 4.46 ( d, 1H, J = 15.3 Hz, 4.61 (d, 1H, J = 15.3 Hz), 7.19-7.24 (m, 2H), 7.63-7.69 (m, 3H), 7.74-7.81 (m, 3H), 8.18 (d, 1H, J = 2.1 Hz), 8.27 (d, 1H, J = 2.1 Hz).
[1107] N ^One-(1H-benzoimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydroquinoxalin-5-yl) -butane-1,4-diamine (Compound 105)
[1108] 2-{[[4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyl]-(5,6,7,8-tetrahydro in ethanol (20 mL) Hydrazine hydrate (0.20 mL) was added to a solution of quinoxalin-5-yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester (420 mg, 0.723 mmol) at room temperature. The mixture was stirred for 17 hours. The mixture was concentrated in vacuo and the material obtained was purified by column chromatography on silica gel (1: 1: 10 MeOH: NH ₄ OH: CH ₂ Cl ₂ ) to give compound 105 as a colorless foam (161 mg, 64%). ¹ H NMR (CDCl ₃ ) δ 1.37-1.48 (m, 5H), 1.70-1.79 (m, 1H), 1.81-1.97 (m, 1H), 2.07-2.16 (m, 1H), 2.18-2.31 ( m, 1H), 2.49-2.59 (m, 4H), 2.71-2.78 (m, 1H), 2.90-3.08 (m, 2H), 3.98 (d, 1H, J = 16.5 Hz), 4.07 (d, 1H, J = 16.5 Hz), 4.06-4.12 (m, 1 H), 7.18-7.21 (m, 2 H), 7.57-7.59 (m, 2 H), 8.41 (s, 1 H), 8.54 (s, 1 H); ¹³ C NMR (CDCl ₃ ) δ 21.2, 22.9, 26.3, 30.5, 32.6, 41.7, 49.8, 51.4, 62.0, 122.3, 142.1, 143.3, 153.8, 155.4, 155.5; ES-MS m / z 351 (M + H). _{C 20 H 26 N6 · 0.3CH 2} Cl 2 · calculated for _{0.2H 2 O: C 64.24, H} 7.17, N 22.14. Found: C 64.16, H 7.41, N 22.15.
[1109] Example 106
[1110]
[1111] Compound 106: N1- (1H-benzimidazol-2-ylmethyl) -N1- (3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-yl) -butane-1, Preparation of 4-diamine (hydrobromide)
[1112] To a solution of triphenylphosphine (10.9 g, 41.5 mmol), 3-butene-ol (2.49 g, 34.6 mmol) and 2-bromo-3-pyridinol (6.01 g, 34.6 mmol) in THF (200 mL) Diisopropyl azodicarboxylate (7.49 mL, 38.0 mmol) was added very slowly at 0 ° C. The ice bath was removed after addition of diisopropyl azodicarboxylate and the mixture was stirred at 50 ° C. under argon for 20 hours. The reaction mixture was diluted with EtOAc (300 mL), washed with saturated NaHCO ₃ (2 × 150 mL) and brine (2 × 150 mL) and dried over Na ₂ SO ₄ . The solvent was evaporated and the residue was purified by flash chromatography on silica gel (hexane / EtOAc, 90:10 after 85:10) to 2-bromo-3-but-3-enyloxy-pyridine (7.04 g, 89%). Was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 2.58 -2.66 (m, 2H), 4.08 (t, 2H, J = 6.9 Hz), 5.13 -5.24 (m, 2H), 5.87 -5.98 (m, 1H), 7.10 -7.14 (m, 1H), 7.18 -7.22 (m, 1H), 7.97 (dd, 1H, J = 6.0, 1.5 Hz).
[1113] Anhydrous DMF solution (120 mL) of 2-bromo-3-but-3-enyloxy-pyridine (6.43 g, 28.2 mmol) in a round bottom Schlenk flask was degassed with argon using freeze / pump / thaw method. Triphenylphosphine (2.66 g, 10.2 mmol), palladium acetate (696 mg, 3.10 mmol), potassium acetate (13.84 g, 141 mmol) and tetraethylammonium chloride hydrate (9.35 g, 56.4 mmol) were added to this freshly degassed solution. Was added. The resulting mixture was heated at 110 ° C. under argon for 18 hours. The reaction mixture was cooled to rt and diluted with EtOAc (300 mL), brine (120 mL) and H ₂ O (60 mL). The organic phase was separated, washed with brine (3 x 120 mL) and dried over Na ₂ S0 ₄ . The solvent was evaporated and the residue was purified by chromatography on silica gel (hexane / EtOAc, 95: 5) to give 4-methylene-3,4-dihydro-2H-pyrano [3,2-b] pyridine (2.8 g, 67%) was obtained as a white solid. ¹ H NMR (CDCl ₃ ) δ 2.79 -2.86 (m, 2H), 4.25 (t, 2H, J = 5.7 Hz), 5.08 (d, 1H, J = 1.6 Hz), 6.19 (d, 1H, J = 1.6 Hz), 7.08 -7.17 (m, 2H), 8.20 (dd, 1H, J = 4.7, 1.6 Hz).
[1114] 4-methylene-3,4-dihydro-2H-pyrano [3,2-b] pyridine (2.77 g, 18.8 mmol) and 4-methylmorpholine N-oxide (6.61) in CH ₂ Cl ₂ (45 mL) g, 56.5 mmol) was added osmium tetraoxide (2.5 wt% solution in 2-methyl-2-propanol, 6.8 mL, 0.68 mmol). The resulting mixture was stirred at rt under N ₂ for 80 h, diluted with EtOAc (300 mL) and then filtered through a pad of celite. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH 4 OH, 95: 4: 1) to 4-hydroxymethyl-3,4-dihydro-2H-pyrano [3 , 2-b] pyridinyl-4-ol (2.13 g, 62%) was obtained as a yellow solid.
[1115] Sodium peroxide in a solution of 4-hydroxymethyl-3,4-dihydro-2H-pyrano [3,2-b] pyridinyl-4-ol (2.13 g, 11.8 mmol) in H ₂ O (15 mL). Iodate (5.03 g, 23.5 mmol) was added and the mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc (100 mL) and H ₂ O (20 mL) and stirred vigorously for 10 minutes. The aqueous phase was separated and extracted with CH ₂ Cl ₂ (2 × 50 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel (hexane / EtOAc, 0: 100 after 60:40) to give 2,3-dihydro-pyrano [3,2-b] pyridin-4-one (1.28 g). , 73%) was obtained as a white solid. ¹ H NMR (CDCl 3) δ 2.98 (t, 2H, J = 6.6 Hz), 4.62 (t, 2H, J = 6.6 Hz), 7.36 -7.44 (m, 2H), 8.44 (dd, 1H, J = 12.6, 2.1 Hz).
[1116] 2,3-dihydro-pyrano [3,2-b] pyridin-4-one (277 mg, using a general procedure for reductive amination with NaBH (OAc) ₃ (605 mg, 2.86 mmol) 1.85 mmol) is reacted with (4-amino-butyl) -carbamic acid tert-butyl ester (269 mg, 1.43 mmol), followed by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH 4 OH, 97: 2: 1). followed by 95: 4: 1) purified by [4- (3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-ylamino) -butyl] -carbamic acid tert-butyl ester (330 mg, 72%) was obtained as a yellow oil.
[1117] [4- (3,4-Dihydro-2H-pyrano [3,2-b] pyridin-4-ylamino) -butyl] -carbamic acid tert-butyl ester in CH ₃ CN (5 mL) (329 mg) , 1.02 mmol) N, N-diisopropylethylamine (0.28 mL, 1.63 mmol), followed by 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (328 mg, 1.23 mmol) and potassium iodide (20 mg, 0.1 mmol) was added. The resulting mixture was heated to 60 ° C. for 16 h and then cooled to rt. The mixture was concentrated and the residue was partitioned between CH ₂ Cl ₂ (25 mL) and saturated aqueous NaHCO ₃ (20 mL). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 15 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by column chromatography on flash silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 95: 4: 1) to give 2-{[(4-tert-butoxycarbonylamino-butyl)-(3 , 4-Dihydro-2H-pyrano [3,2-b] pyridin-4-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester (380 mg, 67%) was white Obtained as a foam.
[1118] Use General Process D: Convert white foam (107 mg, 0.19 mmol) from above into hydrobromide salt and then reprecipitate intermediate solid from methanol / ether to give compound 106 (110 mg, 90%) as a cream solid It was. ¹ H NMR (D ₂ O) δ 1.43-1.66 (m, 4H), 2.38-2.50 (m, 2H), 2.53-2.63 (m, 1H), 2.78-2.92 (m, 3H), 4.33-4.43 (m , 1H), 4.43 (d, 1H, J = 17.4 Hz), 4.55 (d, 1H, J = 17.1 Hz), 4.64-4.78 (m, 2H), 7.57-7.63 (m, 2H), 7.76-7.87 ( m, 3H), 7.98 (dd, 1H, J = 8.7, 0.9 Hz), 8.40 (dd, 1H, J = 5.4, 0.9 Hz); ¹³ C NMR (CDCl ₃ ) δ 19.72, 24.98, 25.32, 39.52, 47.95, 51.48, 56.53, 67.48, 114.28, 126.93, 127.55, 131.03, 134.75, 134.84, 138.80, 151.75, 155.80; ES-MS m / z 352 (M + H). Calcd for C ₂₀ H ₂₅ N ₅ O.3.1HBr.1.0H ₂ O.0.2C ₄ H ₁₀ O: C, 39.34; H, 5.09; N, 11.03; Br, 39.00. Found: C, 39.29; H, 4.92; N, 10.96; Br, 39.02.
[1119] Example 107
[1120]
[1121] Compound 107: N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(S) -3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-yl-butane-1,4-diamine (hydrochloride salt)
[1122] Preparation of 4-methylene-3,4-dihydro-2H-pyrano [3,2-b] pyridine:
[1123] Stirred 0 of 2-bromo-3-pyridinol (14.7 g, 84 mmol), 3-butene-1-ol (7.25 mL, 84 mmol) and triphenylphosphine (26.5 g, 100 mmol) in THF (420 mL) DIAD (18.3 mL, 93 mmol) was added to the solution over 5 minutes. The mixture was heated to 50 ° C. under a nitrogen atmosphere for 21 h, cooled to rt and concentrated. The resulting brown oil was dissolved in ethyl acetate (1 L), washed with saturated sodium bicarbonate solution (2 × 500 mL), washed with brine (2 × 500 mL), dried over Na ₂ SO ₄ and concentrated. The crude material was purified by column chromatography on silica gel (5: 1 hexanes / EtOAc) to afford the desired bromide (20.2 g, 100%) as a yellow oil.
[1124] The bromide (19.2 g, 84 mmol) solution from the stomach in anhydrous DMF (170 mL) was frozen under argon atmosphere and thawed under high vacuum to degas the solution. This freeze-thaw cycle was repeated four times. The pressure-flask was purged with argon, triphenylphosphine (7.96 g, 30 mmol), potassium acetate (41.4 g, 420 mmol), tetraethylammonium chloride hydrate (27.9 g, 170 mmol), palladium (II) acetate (2.08 g, 9.3 mmol) and degassed solution from above. The flask was evacuated, postfilled four times with argon, sealed, heated to 110 ° C. and stirred for 39 hours. The mixture was cooled to warm, diluted with ethyl acetate (1 L) and stirred for 30 min with a mixture of brine (500 mL) and water (200 mL). The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution (500 mL) and brine (3 × 500 mL). The organic layer was dried over Na ₂ S0 ₄ , concentrated and dried under high vacuum for 1 hour. The crude material (25 g) was purified by column chromatography on silica gel (200: 1 CH ₂ Cl ₂ / MeOH) to give the title compound (5.9 g, 47%) as a yellow oil. ¹ H NMR (CDCl ₃ ) 2.80-2.85 (m, 2H), 4.25 (t, 2H, J = 5.7 Hz), 5.08 (s, 1H), 6.20 (s, 1H), 7.08-7.17 (m, 2H) , 8.20 (dd, 1H, J = 4.0, 1.8 Hz).
[1125] Preparation of (S)-(3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-yl) amine:
[1126] 4-methylene-3,4-dihydro-2H-pyrano [3,2-b] pyridine (5.9 g, 40 mmol) in dichloromethane (100 mL), 4-methylmorpholine-N-oxide (14.0 g, 120 mmol), and a solution of osmium tetraoxide (15.4 mL, 2.5 wt% in tert-butanol, 1.2 mmol) was stirred at room temperature under nitrogen atmosphere for 7 days. The mixture was diluted with diethyl ether (100 mL), filtered through diatomaceous earth and concentrated. The crude material was purified by column chromatography on silica gel (25: 1 CH ₂ Cl ₂ / MeOH) to give diol (4.5 g, 62%) as a brown oil.
[1127] To a stirred solution of diol (4.5 g, 25 mmol) from above in deionized water (100 mL) was added sodium periodate (10.7 g, 50 mmol) carefully (pyrogenic) and stirring was continued for 1.5 hours. The mixture was diluted with ethyl acetate (200 mL), stirred for 2 hours, and the layers separated. The aqueous layer was extracted with dichloromethane (2 x 50 mL). The organic layers were combined, dried over Na ₂ S0 ₄ and concentrated to afford the desired ketone (2.9 g, 78%) as off-white solid.
[1128] A solution of ketone (2.9 g, 19 mmol) and hydroxylamine hydrochloride (1.6 g, 23 mmol) from the stomach in methanol (100 mL) was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (80 mL) was added and the mixture was concentrated on a rotary evaporator to remove methanol. The resulting mixture was extracted with dichloromethane (1 × 200 mL, 3 × 75 mL) and 9: 1 CHCl ₃ / MeOH (5 × 200 mL). The organic layers were combined, dried over Na ₂ S0 ₄ and concentrated to give oxime (3.0 g, 94%) as a brown solid.
[1129] Zinc dust was slowly added to a stirred 0 ° C. suspension of oxime (3.0 g, 18 mmol), ammonium acetate (1.6 g, 20 mmol), ammonium hydroxide (85 mL) and ethanol (16 mL) from above. The cooling bath was removed and stirring continued for 2.5 hours. The slurry was filtered through celite and the filtrate was extracted with dichloromethane (3 x 150 mL). The organic extracts were combined, dried over MgSO ₄ , concentrated and dried under high vacuum to give racemic amine (2.6 g, 94%).
[1130] A stirred slurry of amine (2.6 g, 17 mmol) and CAL (0.80 g) in ethyl acetate (65 mL) was heated to 40 ° C for 3 h. The mixture was cooled to rt, filtered and concentrated. The crude material by column chromatography on silica to give the title compound _{(20: 1 CH 2 Cl 2} / MeOH after _{20:: 1 1 CH 2 Cl} 2 / MeOH / NH 4 OH) (1.14g, 88%) of red-brown oil Obtained as. ¹ H NMR (CDCl 3) 1.90-2.02 (m, 1H), 2.24-2.35 (m, 1H), 4.13 (t, 1H, J = 6.4 Hz), 4.18-4.36 (m, 2H), 7.06-7.13 (m , 2H), 8.17 (dd, 1H, J = 3.9, 2.2 Hz).
[1131] N ^One-(1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(S) -3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-yl-butane-1,4-diamine hydrochloride salt (Compound 107):
[1132] (S)-(3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-yl) amine (1.14 g, 7.6 mmol), 4- (from above in THF (15 mL) A slurry of 1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyraldehyde (1.57 g, 7.2 mmol) and potassium carbonate (1.00 g, 7.2 mmol) was stirred at room temperature for 1 hour. Stirred. The mixture was filtered through a glass frit funnel and the filter cake was washed with THF (15 mL). The combined filtrates were treated with sodium triacetoxyborohydride (4.7 g, 22 mmol) and the mixture was stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution (150 mL) and stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (3 × 75 mL). The combined organic layer was dried over Na ₂ S0 ₄ and concentrated. The crude brown oil was purified by column chromatography on silica gel (EtOAc) to afford the desired secondary amine (2.25 g, 89%) as a white solid.
[1133] Amine from the stomach (2.25 g, 6.4 mmol), N-boc-2-chloromethyl-benzimidazole (1.87 g, 7.0 mmol), diisopropylethylamine (1.8 mL, 10 mmol), potassium iodide (50 mg, 0.3 mmol) and acetonitrile (65 mL) were stirred at 50 ° C. under nitrogen atmosphere for 40 hours. The mixture was dissolved in dichloromethane (75 mL), washed with saturated sodium bicarbonate solution (3 x 50 mL), and brine (50 mL). The organic layer was dried over Na ₂ S0 ₄ and concentrated. The crude material was purified by repeated column chromatography on silica (first column: EtOAc, second column: 30: 1 CH ₂ Cl ₂ / MeOH) to afford the desired protective amine (2.97 g, 80%) as a pale yellow foamy solid. Obtained as.
[1134] To a stirred solution of protective amine (2.97 g, 5.1 mmol) from the stomach in ethanol (50 mL) was added hydrazine hydrate (2.5 mL, 50 mmol) and continued at room temperature for 66 hours. The mixture was diluted with diethyl ether (50 mL). The white slurry obtained was filtered and concentrated. The crude material was purified by column chromatography on silica gel (20: 1: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to afford the desired amine (1.80 g, 100%) as a white effervescent solid.
[1135] According to General Process D: The free base (1.80 g, 5.1 mmol) from above was converted to the hydrochloride salt to give compound 107 (2.14 g, 82%) as a white solid. ¹ H NMR (D ₂ O) 1.49-1.60 (m, 4H), 2.39-2.49 (m, 2H), 2.52-2.63 (m, 1H), 2.78-2.91 (m, 3H), 4.32-4.42 (m, 1H), 4.48 (q, 2H, J = 17.2 Hz), 4.65-4.72 (m, 2H), 7.56-7.7.63 (m, 2H), 7.76-7.85 (m, 3H), 7.97 (dd, 1H, J = 8.7, 1.2 Hz), 8.39 (dd, 1H, J = 5.7, 1.2 Hz) HHH; ¹³ C NMR (D ₂ O) 19.74, 24.95, 25.27, 39.48, 47.87, 51.46, 56.51, 67.41, 114.25 (2), 126.92 (2), 127.50, 131.04, 134.66, 134.82, 138.84,151.77, 155.74; ES-MS m / z 352 (M + H). _{C 20 H 25 N 5 O ·} 3.0HCl · 2.5H 2 O · 0.1 (C 2 H 5) Calcd ₂ O: C, 47.74; H, 6.68; N, 13.64; Cl, 20.72. Found: C, 47.74; H, 6.94; N, 13.33; Cl, 20.75.
[1136] Enantiomeric purity of Compound 107 was determined to be 98% by chiral HPLC using the following conditions: Instrument: Hewlett Packard 1100 HPLC (VWD2); Column: Chiralpak AD, 4.6 cm x 25 cm; Mobile phase: A = 90: 5: 5 hexanes / alcohol reagent / methanol (0.1% DEA), B: hexanes; Isocratic: 80% A, 20% B; Total running time: 25 minutes; Flow rate: 1.0 ml / min; Temperature: 40 ° C .; Detector: UV @ 270 nm; Injection volume: 10 μl.
[1137] Retention time of the S enantiomer = 12.0 minutes.
[1138] Retention time for R enantiomer = 15.2 min.
[1139] Example 108
[1140]
[1141] Compound 108: N ^One-(1H-benzoimidazol-2-ylmethyl) -N ^One-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine (hydrobromide salt)
[1142] Preparation of N- (2-methyl-5,6,7,8-tetrahydroquinolin-8-yl) acetamide:
[1143] To a three-necked 500 ml round bottom flask containing a high bar was added 2-methyl-8-acetamidoquinoline (5.69 g, 28.4 mmol) and platinum (IV) oxide (322 mg, 5 mol%). The flask is equipped with a Teflon cannula, one for purging the reaction flask with nitrogen gas, introducing hydrogen, and the other to the flask connected to the bubbler. Trifluoroacetic acid (100 mL) was added to the reaction flask under an atmosphere of nitrogen. The stirred reaction mixture was flushed with nitrogen gas and warmed to 60 ° C. Hydrogen gas was bubbled through the stirring reaction for 3 hours. Progress of the reaction was monitored by GC and / or TLC. The reaction mixture was cooled to room temperature, purged with nitrogen gas, the catalyst was filtered through a pad of celite and washed with CH ₂ Cl ₂ (100 mL). The solvent was removed in vacuo and the residue basified with saturated NaOH (pH> 14). The mixture was then extracted with CHCl ₃ (3 × 250 mL). The organic extract was dried (MgSO ₄ ), filtered and concentrated. The crude material was purified by flash chromatography using 10% MeOH in EtOAc to afford the product (3.83 g, 66%) as a white solid. ¹ H NMR δ 1.57-1.66 (m, 1H), 1.77-1.86 (m, 2H), 2.02 (s, 3H), 2.44 (s, 3H), 2.43-2.57 (m, 1H), 2.68-2.73 (m , 2H), 4.67-4.74 (m, 1H), 6.79 (br s, 1H), 6.92 (d, 1H, J = 8 Hz), 7.24 (d, 1H, J = 8 Hz); ¹³ C NMR δ 21.6, 25.4, 25.8, 29.6, 31.0, 53.0, 123.4, 131.4, 139.2, 155.9, 157.2, 172.2; ES-MS m / z: 227 (M + Na ⁺ ).
[1144] Preparation of 2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamine:
[1145] N- (2-methyl-5,6,7,8-tetrahydroquinolin-8-yl) acetamide (4.51 g, 22.1 mmol) was dissolved in 6N HCl (40 mL). The mixture was heated at reflux for 17 h. The reaction mixture was cooled to room temperature, basified with saturated NaOH (pH> 14) and extracted with chloroform (5 x 100 mL). The organic extract was dried (MgSO ₄ ) and concentrated. The crude was distilled off and purified (bp 102-104 ° C. at 0.20 mm Hg) to give the product as a clear solution (3.25 g, 99%). ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.62-1.82 (m, 2H), 1.84-2.00 (m, 3H), 2.11-2.20 (m, 1H), 2.49 (s, 3H), 2.61-2.82 (m , 2H), 3.93-4.00 (m, 1H), 6.91 (d, 1H, J = 7.8 Hz), 7.25 (d, 1H, J = 7.8 Hz); ¹³ C NMR (CDCl ₃ ) δ 20.4, 24.6, 29.1, 32.6, 51.8, 121.7, 128.6, 137.6, 155.9, 159.0; ES-MS m / z: 163 (M + H &lt; + &gt;), 146 (M-NH2).
[1146] Preparation of 2- [4- (2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamino) -butyl] -isoindole-1,3-dione
[1147] To a solution of 2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamine (237 mg, 1.46 mmol) in CH ₂ Cl ₂ (20 mL) at room temperature under an inert atmosphere at 4- (1,3 , -Dioxo-1,3-dihydro-isoindol-2-yl) -butyraldehyde (159 mg, 0.731 mmol) was added followed by sodium triacetoxyborohydride (309 mg, 2.92 mmol). The reaction mixture was stirred at rt for 2 h. Saturated sodium bicarbonate solution (10 mL) was added and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated. The obtained material was purified by column chromatography on silica gel (10: 1: 0.5 CH ₂ Cl ₂ : MeOH: NH ₄ OH) to give the product as a yellow oil (210 mg, 79%): ¹ H NMR (CDCl ₃₎ ): δ 1.56-1.83 (m, 6H), 1.90-2.04 (m, 2H), 2.04-2.18 (m, 2H), 2.47 (s, 3H), 2.64-2.80 (m, 4H), 3.70-3.76 ( m, 3H), 6.90 (d, 1H, J = 7.8 Hz), 7.24 (d, 1H, J = 7.8 Hz), 7.69-7.73 (m, 2H), 7.81-7.85 (m, 2H).
[1148] 2-{[[4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyl]-(2-methyl-5,6,7,8-tetrahydroquinoline- Preparation of 8-yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester
[1149] 2- [4- (2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamino) -butyl] -isoindole-1,3-dione (210 mg) in CH ₃ CN (12 mL) , 0.578 mmol) in 2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (200 mg, 0.751 mmol), potassium iodide (14 mg) and diisopropylethylamine (0.201 mL, 1.16 mmol) Was added. The reaction mixture was stirred at 60 ° C. for 17 h. Saturated sodium bicarbonate (15 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 × 30 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated. The crude was purified by column chromatography on silica gel (1:10 EtOAc: hexanes then EtOAc then 1:10 MeOH: EtOAc) to give the product as a clear oil (228 mg, 66%): ¹ H NMR (CDCl ₃ ) δ 1.23-1.31 (m, 2H), 1.46-1.58 (m, 2H), 1.63-1.73 (m, 1H), 1.68 (s, 9H), 1.73-1.85 (m, 1H), 1.89-1.98 (m , 1H), 2.10-2.18 (m, 1H), 2.40 (s, 3H), 2.60-2.83 (m, 5H), 3.50 (t, 2H, J = 7.2 Hz), 4.20 (dd, 1H, J = 9.6 , 6.0 Hz), 4.50 (d, 1H, J = 15.6 Hz), 4.72 (d, 1H, J = 15.6 Hz), 6.79 (d, 1H, J = 7.5 Hz), 7.14 (d, 1H, J = 7.5 Hz), 7.19-7.24 (m, 2H), 7.63-7.69 (m, 3H), 7.74-7.81 (m, 3H).
[1150] Preparation of N1- (1H-Benzoimidazol-2-ylmethyl) -N1- (2-methyl-5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine
[1151] 2-{[[4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyl]-(2-methyl-5,6,7, in ethanol (10 mL) Hydrazine hydrate (0.10 mL) was added to a solution of 8-tetrahydroquinolin-8-yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester (228 mg, 0.384 mmol) at room temperature. The mixture was stirred for 4 days. The mixture was concentrated in vacuo and the material obtained was purified by column chromatography on silica gel (1: 1: 10 MeOH: NH ₄ OH: CH ₂ Cl ₂ ) to give the product as a colorless oil: ¹ H NMR (CDCl ₃₎ ) δ 1.25-1.45 (m, 4H), 1.60-1.70 (m, 1H), 1.81-1.93 (m, 1H), 1.97-2.04 (m, 1H), 2.10-2.18 (m, 1H), 2.46-2.56 (m, 3H), 2.62-2.82 (m, 6H), 3.95-3.99 (m, 1H), 4.00 (d, 1H, J = 17.1 Hz), 4.09 (d, 1H, J = 17.1 Hz), 6.98 ( d, 1H, J = 7.8 Hz, 7.15-7.21 (m, 2H), 7.30 (d, 1H, J = 7.8 Hz), 7.57-7.60 (m, 2H).
[1152] N ^One-(1H-benzoimidazol-2-ylmethyl) -N ^OnePreparation of-(2-Methyl-5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine (hydrobromide salt) (Compound 108)
[1153] N ^1- (1H-benzoimidazol-2-ylmethyl) -N ^1- (2-methyl-5,6,7,8-tetrahydroquinolin-8-yl) -butane-1 in glacial acetic acid (0.5 mL) To a solution of, 4-diamine (82 mg, 0.23 mmol) was added HBr saturated acetic acid (1 mL). The reaction mixture was stirred for 10 minutes and then diethyl ether was added (50 mL). The white precipitate was allowed to settle and the solvent was removed by pipette. Et ₂ O (50 mL) was added again and then decanted. The obtained precipitate was dissolved in methanol (1.5 mL), ether was added (3 x 50 mL) and then pipette removed. The yellow powder obtained was dried under reduced pressure to give 113 mg (76%) of product: ¹ H NMR (D ₂ O) δ 1.48-1.63 (m, 4H), 1.65-1.78 (m, 1H), 1.82-2.01 (m, 1H), 2.02-2.15 (m, 1H), 2.25-2.31 (m, 1H), 2.50-2.63 (m, 1H), 2.67-2.78 (m, 4H), 2.78-3.00 (m, 4H) , 4.39 (d, 1H, J = 16.8 Hz), 4.49 (d, 1H, J = 16.8 Hz), 7.52-7.64 (m, 3H), 7.70-7.79 (m, 2H), 8.13 (d, 1H, J = 7.8 Hz); ¹³ C NMR (D ₂ O) δ 19.7, 20.3, 20.5, 25.1, 27.4, 39.6, 47.7, 51.8, 60.1, 114.3, 126.9, 130.9, 137.6, 147.8, 150.0, 151.7, 152.8; ES-MS m / z 365 (M + H). Calcd for C ₁₇ H ₂₂ N ₄ .3.0HBr 2.3H ₂ O: C 40.80, H 5.70, N 10.81, Br 37.01. Found: C 40.78, H 5.82, N 10.54, Br 37.09.
[1154] Example 110
[1155]
[1156] Compound 110: N1- (1H-benzoimidazol-2-ylmethyl) -N1- (4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl) -butane-1,4-diamine (Hydrobromide salt)
[1157] Preparation of 4,5,6,7-tetrahydrobenzoimidazol-4-one:
[1158] According to the modified process of Helv. Chim. Acta 1979, 62, 497, N ₂ O ₄ was reacted with 1,3-cyclohexanedione in anhydrous diethyl ether (500 mL) at 0 ° C. for about 10 minutes. It was bubbled with a homogeneous mixture of (6.98 g, 62.3 mmol) (recrystallized from benzene). The mixture was warmed to room temperature and N ₂ O ₄ was further bubbled until the reaction mixture became homogeneous and orange in color. The mixture was stirred for 0 h. Excess N ₂ O ₄ was removed by bubbling argon gas and the solvent was removed from the rotosnake to give a dark orange oil, which quickly turned black.
[1159] About half of this material was dissolved in glacial acetic acid (50 mL) in a Parr shaker flask. Freshly prepared formic acid acetic anhydride (50 ml) (50 ml formic acid was mixed with 25 ml acetic anhydride and prepared for stirring for 2 hours, -J. Med. Chem. 2001, 44, 36-46) and palladium on carbon (10%) -2 g were added and the mixture was hydrogenated at 50 psi for 2 hours. The volatiles were removed from the high vacuum roto snake and the ¹ H NMR of the crude material (5.2 g, black tar) contained a signal at δ 7.99 ppm (formylated amine product).
[1160] 15 ml of formic acid and 60 ml of formamide were added to the crude black oil and the mixture was heated at 150 ° C. for 30 minutes. The volatiles were rotobapped in a high vacuum rotocheb (bath heated to 80 ° C.). Freshly prepared formic acid acetic anhydride (40 mL) and glacial acetic acid (20 mL) were added, and the black mixture was heated at 100 ° C. for 1 hour. The volatiles were removed again under high vacuum. The material was purified repeatedly by silica gel flash column chromatography (4: 1: 0.2 CH ₂ Cl ₂ : MeOH: NH ₄ OH) to give 4,5,6,7-tetrahydrobenzoimidazol-4-one (893 mg). ) Was contaminated with formamide and other impurities. ¹ H NMR (CDCl ₃ ): δ 2.02 (p, 2H, J = 6.3 Hz), 2.39 (t, 2H, J = 6.3 Hz), 2.75 (t, 2H, J = 6.3 Hz), 7.82 (s, 1H ).
[1161] Preparation of 7-oxo-4,5,6,7-tetrahydrobenzoimidazole-1-carboxylic acid tert-butyl ester
[1162] The material (893 mg, 6.56 mmol) was treated with tert-butyl musum (2.15 g, 9.84 mmol) in DMF (15 mL). The residue was dissolved in MeOH and EtOAc and placed in the refrigerator for 3 days. Precipitated solid (2 recrystallization) was purified 7-oxo-4,5,6,7-tetrahydrobenzoimidazole-1-carboxylic acid tert-butyl ester (759 mg, 5.5% from 1,3-cyclohexanedione) It was. ¹ H NMR (CDCl ₃ ): δ 1.64 (s, 9H), 2.21 (m, 2H), 2.56 (dd, 2H, J = 6.6, 6.3 Hz), 3.14 (dd, 2H, J = 6.3, 6.0 Hz) , 8.05 (s, 1H).
[1163] Preparation of 7- (4-tert-butoxycarbonylamino-butylamino) -4,5,6,7-tetrahydrobenzoimidazole-1-carboxylic acid tert-butyl ester
[1164] In a solution of 7-oxo-4,5,6,7-tetrahydrobenzoimidazole-1-carboxylic acid tert-butyl ester (632 mg, 2.82 mmol) in CH ₂ Cl ₂ (50 mL) at room temperature under an inert atmosphere ( 4-amino-butyl) carbamic acid tert-butyl ester (745 mg, 4.23 mmol) followed by sodium triacetoxyborohydride (896 mg, 4.23 mmol) was added. The reaction mixture was stirred at rt for 17 h. Saturated sodium bicarbonate solution (20 mL) was added and the mixture was extracted with dichloromethane (3 x 30 mL). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated. The obtained material was purified by column chromatography on silica gel (20: 1: 1 CH ₂ Cl ₂ : MeOH: NH ₄ OH) to give the product (558 mg, 48%): ¹ H NMR (CDCl ₃ ): δ 1.42 (s, 9H), 1.59 (s, 9H), 1.50-1.62 (m, 4H), 1.71-1.77 (2H), 1.82-2.00 (m, 2H), 2.06 (s, 1H), 2.73-2.87 ( m, 4H), 3.09-3.13 (m, 2H), 3.33 (br s, 1H), 3.75-3.80 (m, 1H), 5.01 (br s, 1H), 7.96 (s, 1H).
[1165] 2-{[[4-tert-butoxycarbonylamino-butyl)-(3-tert-butoxycarbonyl-4,5,6,7-tetrahydro-3H-benzimidazol-4-yl)- Preparation of amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester
[1166] 7- (4-tert-butoxycarbonylamino-butylamino) -4,5,6,7-tetrahydrobenzoimidazole-1-carboxylic acid tert-butyl ester in CH ₃ CN (12 mL) (365 mg, 0.893 mmol) was added 2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (357 mg, 1.33 mmol), potassium iodide (14 mg) and diisopropylethylamine (0.311 mL, 1.78 mmol). It was. The reaction mixture was stirred at 40 ° C for 17 h. Saturated sodium bicarbonate (15 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 × 30 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated. The crude was purified by column chromatography on silica gel (diethyl ether with ammonia) to give the product as a white foam (269 mg, 47%): ¹ H NMR (CDCl ³ ): δ 1.41 (s, 9H), 1.34-1.50 (m, 6H), 1.59 (s, 9H), 1.68 (s, 9H), 1.60-1.75 (m, 2H), 1.88 (s, 2H), 1.93-2.03 (m, 2H), 2.63- 2.76 (m, 4H), 2.79-3.01 (m, 2H), 4.04-4.80 (m, 1H), 4.35 (d, 1H, J = 16.2 Hz), 4.45 (d, 1H, J = 16.2 Hz), 4.94 -4.99 (m, 1H), 7.26-7.31 (m, 2H), 7.71-7.76 (m, 2H), 7.80-7.86 (m, 1H), 7.94 (s, 1H).
[1167] N ^One-(1H-benzoimidazol-2-ylmethyl) -N ^OnePreparation of-(4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl) -butane-1,4-diamine (hydrobromide salt) (Compound 110)
[1168] 2-{[[4-tert-butoxycarbonylamino-butyl)-(3-tert-butoxycarbonyl-4,5,6,7-tetrahydro-3H-benzamidazole in glacial acetic acid (1.0 mL) To a solution of -4-yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester (204 mg, 0.319 mmol) was added HBr saturated acetic acid (1.5 mL). The white precipitate was allowed to settle and the solvent was removed by pipette. Et ₂ O (50 mL) was added again and then decanted. The obtained precipitate was dissolved in methanol (1 mL), ether (3 × 50 mL) was added and then pipette removed. The white powder obtained was dried under reduced pressure to give 170 mg (78%) of compound 110: ¹ H NMR (D ₂ O) δ 1.45-1.67 (m, 4H), 1.67-1.86 (m, 2H), 2.06- 2.21 (m, 2H), 2.50-2.66 (m, 3H), 2.74-2.78 (m, 1H), 2.79-2.89 (m, 2H), 4.26-4.40 (m, 3H), 7.55-7.60 (m, 2H ), 7.75-7.80 (m, 2 H), 8.54 (s, 1 H); ¹³ C NMR (D ₂ O) δ 20.3, 21.3, 22.0, 25.0, 25.6, 39.7, 47.3, 51.2, 55.4, 114.2, 126.9, 127.9, 130.9, 131.7, 132.8, 153.5; ES-MS mlz 339 (M + H). Calcd for C ₁₇ H ₂₂ N ₄ .3.5HBr 2.1H ₂ O.0.3C ₄ H ₁₀ O: C 35.59, H 5.43, N 12.33, Br 41.02. Found: C 35.44, H 5.35, N 12.25, Br 41.26.
[1169] Example 111
[1170]
[1171] Compound 111: N1- (5,6-dimethyl-1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4 Preparation of Diamines (HBr Salts)
[1172] 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione (154 mg, 0.441 mmol) in acetonitrile (2.5 mL) , 2-chloromethyl-5,6-dimethyl-1H-benzimidazole (US Patent Application USSN No. 09 in a stirred solution of diisopropylethylamine (0.15 mL, 0.861 mmol) and potassium iodide (15 mg, 0.090 mmol)) / 535,314 (prepared according to the process described in Bridger et al.) (77 mg, 0.426 mmol) was added and the mixture was heated at 60 ° C. for 18 h. Then the mixture was concentrated and the residue was diluted with CH ₂ Cl ₂ (30 mL). The solution was washed with saturated aqueous NaHCO ₃ (1 × 20 mL) and brine (2 × 15 mL). The combined aqueous phases were extracted with CH ₂ Cl ₂ (1 × 15 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give crude brown foam. The foam was purified by flash chromatography (1.75 cm ID, silica 12g, 50: 1: 1 CH ₂ Cl ₂ : MeOH: NH ₄ OH) to give pure 2- {4-[(5,6-dimethyl-1H-benzimi Obtained Dazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -isoindole-1,3-dione (60 mg, 28%). It was. ¹ H NMR (CDCl ₃ ) δ 1.34-1.51 (m, 2H), 1.53-1.73 (m, 3H), 1.81-2.06 (m, 2H), 2.12-2.22 (m, 1H), 2.34 (s, 6H) , 2.55-2.89 (m, 4H), 3.51 (t, 2H, J = 7.3 Hz), 3.93-4.08 (m, 3H), 7.1 (dd, 1H, J = 7.5, 4.8 Hz), 7.31-7.39 (m , 3H), 7.63-7.67 (m, 2H), 7.72-7.77 (m, 2H), 8.58 (d, 1H, J = 4.0 Hz).
[1173] 2- {4-[(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-in ethanol (2.5 mL)- To a stirred solution of amino] -butyl} -isoindole-1,3-dione (60 mg, 0.118 mmol) was added hydrazine hydrate (0.05 mL, 1.03 mmol) and the mixture was stirred at rt for 16 h. The mixture was then diluted with diethyl ether, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give a crude yellow oil. The oil was purified by flash chromatography (1.75 cm ID, silica 12 g, 10: 1: 1 CH ₂ Cl ₂ : MeOH: NH ₄ OH) to give pure N ^1- (5,6-dimethyl-1H-benzimidazole-2 -Ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (18 mg, 38%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.30-1.46 (m, 4H), 1.60-1.75 (m, 1H), 1.82-1.96 (m, 1H), 1.98-2.08 (m, 1H), 2.14-2.24 (m, 1H), 2.35 (s, 6H), 2.47-2.59 (m, 3H), 2.65-2.90 (m, 3H), 3.92-4.06 (m, 3H), 7.13 (dd, 1H, J = 7.9, 4.8 Hz) , 7.34 (s, 2H), 7.40 (d, 1H, J = 7.1 Hz), 8.58 (s, 1H, J = 3.5 Hz).
[1174] According to standard HBr chlorination process D: N ^1- (5,6-dimethyl-1H-benzimidazol-2-ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl ) -Butane-1,4-diamine (17 mg, 0.045 mmol) was converted to HBr salt (28 mg, 97%). ¹ H NMR (D ₂ O) δ 1.46-1.59 (m, 4H), 1.76-1.89 (m, 1H), 1.94-2.08 (m, 1H), 2.13-2.24 (m, 1H), 2.29-2.63 (m , 8H) containing 2.41 (s, 6H), 2.77-2.92 (m, 3H), 2.95-3.05 (m, 2H), 4.33 (d, 1H, J = 16.2 Hz), 4.43-4.52 (m, 2H), 7.56 (s, 2 H), 7.81-7.88 (m, 1 H), 8.30-8.35 (m, 1 H), 8.58-8.63 (m, 1 H). ¹³ C NMR (D ₂ O) δ 19.96, 20.38, 25.03, 25.38, 27.62, 39.50, 47.99, 51.72, 60.53, 113.72, 125.86, 129.54, 137.22, 139.31, 140.54, 147.98, 150.29, 151.36. ES-MS m / z 378 (M + H). Calcd for C ₂₃ H ₃₁ N ₅ .3.0HBr.1.5H ₂ O: C, 42.68; H, 5. 76; N, 10.82; Br, 37.03. Found: C, 42.53; H, 5. 64; N, 10.59; Br, 37.32.
[1175] Example 112
[1176]
[1177] Compound 112: N1- [1- (1H-benzimidazol-2-yl) -ethyl] -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4- Preparation of diamines (hydrobromide salts)
[1178] Preparation of 1- (1H-benzimidazol-2-yl) -ethanone:
[1179]
[1180] A solution of 1,2-phenylene diamine (3.25 g, 0.030 mol) and L-lactic acid (2.3 mL, 0.026 mol) in 3M HCl (15 mL) was refluxed overnight. The reaction was cooled to rt, diluted with EtOAc (50 mL) and brought to pH 10 by addition of saturated aqueous Na ₂ CO ₃ and solid Na ₂ CO ₃ . The aqueous phase was washed with EtOAc (1 × 50 mL) and the combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated to give a brown-orange solid which was used for the next reaction without further purification.
[1181] To a stirred solution of crude alcohol (0.026 mol) from above in anhydrous CH ₂ Cl ₂ / MeOH (6: 1, 35 mL) was added activated manganese dioxide (purity 85%, <5 μ, 23.28 g, 0.228 mol) and the suspension was Stir overnight, at which time the black slurry was filtered through a cake of celite and washed with MeOH (3 x 50 mL). The combined washes were concentrated to give a dark brown solid. The crude product was purified by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 98: 2 to 95: 5) to give the title compound a reddish brown solid (1.65 g, 39%). Obtained). ¹ H NMR (CD 3 OD) δ 2.72 (s, 3H), 7.37 (dd, 2H, J = 6, 3 Hz), 7.66-7.73 (br m, 2H).
[1182] General process B use: 1- (1H-benzimidazol-2-yl)-in a solution of 8-amino-5,6,7,8-tetrahydroquinolin (266 mg, 1.80 mmol) in MeOH (5 mL). Ethanone (285 mg, 1.78 mmol) was added and the resulting solution was stirred at room temperature for 4.5 hours. Solid NaBH ₄ (125 mg, 3.30 mmol) was added to the solution and the mixture was stirred at rt for 30 min. The crude brown oil obtained was purified by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 98: 2 then 96: 4) to give the desired amine (125 mg, 24%) as a mixture of brown foam and diastereomer ( 6: 1)
[1183] According to general process B: amine (mixture of diastereomers, 125 mg, 0.43 mmol) and 4- (1,3-dioxo-1,3-dihydro from the stomach in anhydrous CH ₂ Cl ₂ (5 mL) To a stirred solution of -isoindol-2-yl) -butyraldehyde (97 mg, 0.45 mmol) was added NaBH (OAc) ₃ (127 mg, 0.59 mmol) and the mixture was stirred at rt overnight. The crude brown oil (215 mg) obtained was purified by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 96: 4 after 98: 2) to afford the desired amine (175 mg, 83%) as a brown foam. .
[1184] Anhydrous hydrazine (0.06 mL, 1.89 mmol) was added to a solution of phthalimide from above in EtOH (3 mL) and the mixture was stirred overnight. The white solid obtained was filtered through filter paper, washed thoroughly with CH ₂ Cl ₂ and the filtrate was concentrated in vacuo. The crude product was purified by silica gel radial chromatography (1 mm plate, CH ₂ Cl ₂ / MeOH / NH ₄ OH, 50: 1: 1 and then 25: 1: 1) to afford the desired free amine (67 mg, 52% 2 steps) were obtained as pale yellow oil.
[1185] General Process D Use: The material from the stomach (67 mg, 0.18 mmol) was converted to a hydrobromide salt to give compound 112 (95 mg, 78%) as a pale green solid. Mixture of ¹ H NMR (D ₂ O) diastereomers δ 1.37-1.55 (m, 4H), 1.81-1.85 (m, 1H), 1.83 (d, 3H, J = 6.9 Hz), 2.05-2.16 (m, 3H), 2.69-2.74 (m, 1H), 2.85 (t, 2H, J = 7.8 Hz), 2.86-3.00 (m, 3H), 4.52-4.57 (m, 1H), 4.79-4.85 (m, 1H, overlap with HOD), 7.61 (dd, 2H, J = 6.3, 3.3 Hz), 7.79 (dd, 2H, J = 6.3, 3.3 Hz), 7.84 (dd, 1H, J = 7.5, 6 Hz), 8.31 (d, 1H, J = 8.1 Hz), 8.60 (d, 1H, J = 5.4 Hz); Mixture of ¹³ C NMR (D ₂ O) diastereomers δ 16.56, 20.64, 23.25, 25.19, 25.77, 27.47, 39.46, 48.19, 53.93, 58.37, 114.33, 125.82, 127.06, 130.91, 139.02, 140.22, 148.02, 152.36, 154.55. ES-MS m / z 364 (M + H). Calcd for C ₂₂ H ₂₉ N ₅ .3.1HBr.0.9H ₂ O.0.4C ₄ H ₁₀ O: C, 42.94; H, 5.79; N, 10.61; Br, 37.52. Found: C, 42.99; H, 5.58; N, 10.64; Br, 37.42.
[1186] Example 113
[1187]
[1188] Compound 113: N1- (4-Fluoro-1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4- Preparation of Diamines (HBr Salts)
[1189] 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione (146 mg, 0.418 mmol) in acetonitrile (2.5 mL) , 2-chloromethyl-7-fluoro-1H-benzimidazole (September 15, 2000) in a stirred solution of diisopropylethylamine (0.15 mL, 0.861 mmol) and potassium iodide (14 mg, 0.084 mmol) (80 mg, 0.433 mmol) prepared according to the process described in US Patent Application No. 60 / 232,891 filed (Bridger et al.) And filed September 22, 2000, filed 60 / 234,510) Heated at 60 ° C. for 18 h. Then the mixture was concentrated and the residue was diluted with CH ₂ Cl ₂ (30 mL). The solution was washed with brine (3 x 15 mL). The combined aqueous phases were extracted with CH ₂ Cl ₂ (1 × 15 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give crude brown foam. The foam was purified by flash chromatography (1.75 cm ID, silica 12 g, 50: 1: 1 CH ₂ Cl ₂ : MeOH: NH 4 OH) to give pure 2- {4-[(4-fluoro-1H-benzimidazole-2 -Ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -isoindole-1,3-dione (86 mg, 41%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.33-1.76 (m, 5H), 1.85-2.10 (m, 3H), 2.14-2.25 (m, 1H), 2.54-2919 (m, 4H), 3.45-3.55 (m, 2H), 3.98-4.24 (m, 3H), 7.29-7.45 (m, 2H), 7.63-7.69 (m, 2H), 7.72-7.77 (m, 2H), 8.56-8.63 (m, 1H).
[1190] 2- {4-[(4-Fluoro-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino in ethanol (2.0 mL) To a stirred solution of] -butyl} -isoindole-1,3-dione (86 mg, 0.173 mmol) was added hydrazine hydrate (0.05 mL, 1.03 mmol) and the mixture was stirred at rt for 20 h. The mixture was then diluted with diethyl ether, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to afford a crude yellow oil. The oil was purified by flash chromatography (1.75 cm ID, silica 12 g, 25: 1: 1 CH ₂ Cl ₂ : MeOH: NH ₄ OH) to give pure N ^1- (4-fluoro-1H-benzimidazole-2 -Ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (29 mg, 46%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.28-1.47 (m, 4H), 1.63-1.77 (m, 1H), 1.85-2.09 (m, 2H), 2.15-2.25 (m, 1H), 2.46-2.60 (m, 3H), 2.65-2.76 (m, 2H), 2.79-2.91 (m, 1H), 4.01-4.18 (m, 3H), 6.89 (dd, 1H, J = 10.3, 8.0 Hz), 7.05-7.11 (m, 1H), 7.12-7.18 (m, 1H), 7.35 (d, 1H, J = 7.8 Hz), 7.43 (d, 1H, J = 7.9 Hz), 8.59 (d, 1H, J = 4.4 Hz).
[1191] According to standard HBr chloride process D: N ^1- (4-Fluoro-1H-benzimidazol-2-ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) Butane-1,4-diamine (29 mg, 0.079 mmol) was converted to HBr salt (40 mg, 79%). ¹ H NMR (D ₂ O) δ 1.50-1.62 (m, 4H), 1.77-1.91 (m, 1H), 1.98-2.12 (m, 1H), 2.15-2.25 (m, 1H), 2.33-2.43 (m , 1H), 2.54-2.64 (m, 1H), 2.81-2.93 (m, 3H), 2.97-3.04 (m, 2H), 4.38 (d, 1H, J = 16.7 Hz), 4.46-4.55 (m, 2H ), 7.30-7.37 (m, 1H), 7.49-7.60 (m, 2H), 7.84 (dd, 1H, J = 7.9, 6.1 Hz), 8.32 (d, 1H, J = 8.0 Hz), 8.60 (d, 1H, J = 5.6 Hz). ¹³ C NMR (D ₂ O) δ 20.37, 20.44, 25.01, 25.33, 27.61, 39.49, 48.39, 51.76, 60.64, 110.31, 111.57, 111.78, 125.81, 127.28, 127.38, 139.35, 140.44, 147.80, 149.83 (d, 1C , JC-F = 227.9 Hz), 151.35, 152.82. ES-MS m / z 368 (M + H). Calcd for C ₂₁ H ₂₆ N ₅ F.3.0HBr.9H ₂ O: C, 39.14; H, 5.13; N, 10.87; F, 2.95; Br, 37.20. Found: C, 39.43; H, 4.99; N, 10.53; F, 2.86; Br, 37.02.
[1192] Example 114
[1193]
[1194] Compound 114: N ^One-(4-methoxy-1 H-benzoindiazol-2-ylmethyl) -N ^One-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine) hydrochloride salt)
[1195] (S) -2-{[(4-amino-butyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -4-methoxy-benzoimidazole- Preparation of 1-carboxylic acid tert-butyl ester:
[1196] (S) -2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione (3.65 g) in acetonitrile (52 mL) , 10.46 mmol), 2-chloromethyl-4-methoxy-benzoimidazole-1-carboxylic acid tert-butyl ester (3.10 g, 10.46 mmol), potassium iodide (87 mg, 0.52 mmol) and diisopropylethyl Amine (1.82 mL, 10.46 mmol) was added. The mixture was stirred at 50 ° C. for 16 h under N ₂ atmosphere. The mixture was concentrated, redissolved in methylene chloride (100 mL) and diluted with H ₂ O (300 mL). The aqueous layer was extracted with methylene chloride (2 × 75 mL) and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a dark orange oil. Purification by column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH ₄ OH, 94: 5: 1, v / v / v), followed by column chromatography on silica gel (ethyl acetate: NH ₄ OH, 98: 2 , v / v), to afford the product as a yellow oil (4.22 g, 66%). ¹ H NMR (CDCl ₃ ) δ 1.23 (m, 2H), 1.45 (m, 2H), 1.69 (s, 9H), 1.93 (m, 2H), 2.62 (m, 2H), 2.75 (m, 2H), 3.50 (t, 2H), 3.98 (s, 3H), 4.10 (m, 2H), 4.60 (m, 2H), 6.68 (dd, 1H, J = 7.89, 2.19 Hz), 6.92 (m, 1H), 7.13 (m, 2H), 7.36 (dd, 1H, J = 8.77, 2.63 Hz), 7.68 (m, 2H), 7.78 (m, 2H), 8.31 (m, 1H).
[1197] Preparation of N- (4-methoxy-1H-benzoindiazol-2-ylmethyl) -N (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine
[1198] 2-{[(4-amino-butyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -4methoxy-benzoimidazole in ethanol (69 mL) To a solution of -1-carboxylic acid tert-butyl ester (4.22 g, 6.93 mmol) was added hydrazine hydrate (1.09 mL, 34.65 mmol). The solution was stirred for 16 h at room temperature under N ₂ atmosphere. White precipitate formed. Diethyl ether (69 mL) was added to the mixture and the mixture was stirred for 10 minutes. The mixture was filtered and concentrated. Purification by column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH ₄ OH, 94: 5: 1, v / v / v) gave the product as a yellow oil (2.60 g, 98%). ¹ H NMR (CDCl ₃ ) δ 1.35 (m, 4H), 1.93 (m, 6H), 2.68 (m, 5H), 4.06 (m, 5H), 6.63 (d, 1H, J = 8.33 Hz), 7.15 ( m, 3H), 7.43 (d, 1H, J = 7.02 Hz), 8.60 (d, 1H, J = 4.38 Hz)
[1199] Preparation of Compound 114:
[1200] N- (4-methoxy-1 H-benzoindiazol-2-ylmethyl) -N (5,6,7,8-tetrahydro-quinolin-8-yl) -butane- dissolved in methanol (20 mL) HCl-saturated methanol (50 mL) was added to a solution of 1,4-diamine and the mixture was stirred for 1 hour at room temperature under N ₂ atmosphere. The solution was added dropwise to diethyl ether (1.5 L) to give a thick white precipitate. The white solid was separated by suction filtration under a continuous stream of nitrogen, washed with diethyl ether and dried overnight under vacuum at 40 ° C. (4.32 g, 76%). ¹ H NMR (D ₂ O) δ 1.52 (m, 4H), 1.78 (m, 1H), 2.00 (m, 1H), 2.13 (m, 1H), 2.36 (m, 1H), 2.53 (m, 1H) , 2.74 (m, 1H), 2.79 (m, 2H), 2.88 (m, 2H), 4.20 (s, 2H), 4.42 (t, 1H), 7.75 (d, 1H, J = 7.89 Hz), 7.83 ( dd, 1H, J = 7.89, 5.70 Hz), 7.80 (d, 1H, J = 8.33 Hz), 8.38 (m, 2H), 8.57 (d, 1H, J = 5.70 Hz); ¹³ C NMR d (D ₂ O) 19.53, 20.12, 20.44, 25.11, 25.23, 27.64, 39.57, 51.18, 53.04, 59.60, 124.72, 125.79, 127.50, 139.29, 140.53, 147.21, 147.87, 151.71, 152.96, 155.00. ES-MS mlz 326 (M + H). Calcd for _{C 20 H 28 N 4 · 3.91HCl} · 2.47H 2 O: C, 46.95; H, 7. 26; N, 10.95; Cl, 27.10. Found: C, 46.93; H, 7. 32; N, 11.05; Cl, 27.11.
[1201] Example 115
[1202] Compound 115: N1- (4-methyl-1H-benzoimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine
[1203] 2-{-(4-Methyl-1H-indol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -isoindole-1,3 Preparation of Dion:
[1204]
[1205] 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione (95 mg, 0.27 mmol) in acetonitrile (5 mL) , 2-chloromethyl-4-methyl-1H-benzoimidazole (59 mg, 0.33 mmol), N, N-diisopropylethylamine (62 mL, 0.35 mmol) and potassium iodide (4 mg, 0.03 mmol) Heat overnight at 60 ° C. The reaction mixture was cooled down and the solvent removed under reduced pressure to give a brown oil. Purification by column chromatography on flash silica gel using NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ (1: 2: 100) gave the desired product as an orange foam (109 mg, 81%). ¹ H NMR (CDCl ₃ ) δ 1.41-1.71 (m, 5H), 1.89-2.04 (m, 2H), 2.15-2.19 (m, 1H), 2.58-2.88 (m, 7H), 3.43-3.51 (m, 2H), 4.01-4.15 (m, 3H), 6.97 (d, 1H, J = 7.2 Hz), 7.06-7.14 (m, 2H), 7.39 (d, 1H, J = 7.5 Hz), 7.64 (br m, 2H), 7.71 (br m, 2H), 8.59 (d, 1H, J = 4.2 Hz).
[1206] N ^One-(4-methyl-1H-benzoimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine:
[1207] To a solution of the above amine (109 mg, 0.22 mmol) in ethanol (8 mL) was added hydrazine hydrate (54 mL, 1.10 mmol). The reaction mixture was stirred for 2 days at room temperature. The mixture was then concentrated to dryness. The product obtained by purification by silica gel radial chromatography (1 mm plate, using NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ , 1: 1: 100 → 1: 5: 100 gradient eluent) was yellow oil ( 45 mg, 56%). ¹ H NMR (CDCl ₃ ) δ 1.29-1.45 (m, 4H), 1.66-1.71 (m, 1H), 1.91-2.05 (m, 2H), 2.17-2.21 (m, 1H), 2.47-2.55 (m, 3H), 2.64 (s, 3H), 2.67-2.74 (m, 2H), 2.80-2.90 (m, 1H), 4.02-4.18 (m, 3H), 6.98 (d, 1H, J = 7.2 Hz), 7.07 -7.16 (m, 2H), 7.40-7.51 (m, 2H), 8.58 (d, 1H, J = 3.9 Hz).
[1208] N ^One-(4-methyl-1H-benzoimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt):
[1209] To a solution of the above amine (45 mg, 0.12 mmol) in acetic acid (3 mL) was added bromic acid saturated acetic acid (2 mL) and the reaction mixture was stirred for 30 minutes. This was then triturated three times with diethyl ether to give a white solid. The solid was dissolved in methanol (1 mL) and triturated with diethyl ether three times to give compound 115 as a white solid (62 mg, 76%). ¹ H NMR (D ₂ O) δ 1.54 (m, 4H), 1.76-1.90 (m, 1H), 1.97-2.09 (m, 1H), 2.17-2.22 (m, 1H), 2.36-2.40 (m, 1H ), 2.55-2.62 (m, 4H), 2.81-2.88 (m, 3H), 3.00-3.02 (m, 2H), 4.35-4.79 (m, 3H), 7.51 (ABq, 2H, J = 62.7, 7.8 Hz ), 7.79 (t, 1H, J = 7.5 Hz), 7.86 (dd, 1H, J = 7.5, 6.3 Hz), 8.34 (d, 1H, J = 7.8 Hz), 8.61 (d, 1H, J = 5.7 Hz ). ¹³ C NMR (D ₂ O) δ 16.44, 20.33, 20.45, 25.06, 25.39, 27.64, 39.52, 48.12, 51.75, 60.50, 111.46, 125.29, 125.89, 126.99, 127.30, 130.83, 139.26, 140.56, 148.02, 151.38, 151.38, 151.38 . ES-MS m / z 364 [M + H] ⁺ . Calcd for C ₂₂ H ₂₉ N ₅ .3.1HBr.2.3H2O: C, 40.30; H, 5. 64; N, 10.68; Br, 37.77. Found: C, 40.50; H, 5.56; N, 10.67; Br, 37.48.
[1210] Example 116
[1211]
[1212] Compound 116: N1- (4,5-dimethyl-1H-benzoimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4 Diamines (hydrobromide salts)
[1213] {4-[(4,5-Dimethyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -carbamic acid Preparation of tert-butyl esters:
[1214] 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione (490 mg, 1.40 mmol) in acetonitrile (5 mL) , 2-chloromethyl-4,5-dimethyl-1H-benzoimidazole (328 mg, 1.68 mmol), N, N-diisopropylethylamine (0.32 mL, 1.82 mmol) and potassium iodide (23 mg, 0.14 mmol ) Was stirred at 60 ° C overnight. The reaction mixture is then cooled and the solvent is removed under reduced pressure. Purification by column chromatography on flash silica gel using NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ (2: 1: 97) gave the impure product as a brown oil (440 mg).
[1215] To a solution of the above amine (440 mg, 0.87 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.21 mL, 4.33 mmol). The reaction mixture was stirred at rt overnight. The solvent was then removed under reduced pressure and the orange solid was dried under vacuum. Purified by silica gel radial chromatography (2 mm plate, using NH ₄ OH.CH ₃ OH / CH ₂ Cl ₂ ; 1: 1: 100 → 1: 5: 100, gradient eluent) to partially pure product (183 mg) ) Was obtained as a yellow oil.
[1216] Di-tert-butyl dicarbonate was added to a solution of the above amine (183 mg, 0.49 mmol) in THF (10 mL). The reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure to give a yellow oil. Purification by column chromatography on flash silica gel using NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ (1: 2: 97) gave the desired product as a yellow oil (67 mg, 29%). ¹ H NMR (CDCl ₃ ) δ 1.35-1.41 (m, 11H), 1.63-1.67 (m, 2H), 1.91-2.02 (m, 2H), 2.09-2.14 (m, 1H), 2.35 (s, 3H) , 2.53 (s, 3H), 2.59-2.68 (m, 2H), 2.71-2.81 (m, 2H), 2.97-2.99 (m, 2H), 4.24 (dd, 1H, J = 9.0, 6.0 Hz), 4.54 (q, 2H, J = 14.7 Hz), 4.97 (br s, 1H), 6.93 (dd, 1H, J = 7.7, 4.8 Hz), 7.05 (d, 1H, J = 8.4 Hz), 7.22 (d, 1H , J = 7.5 Hz, 7.18 (d, 1H, J = 8.1 Hz), 8.36 (d, 1H, J = 3.6 Hz).
[1217] N ^One-(4,5-dimethyl-1H-benzoimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt):
[1218] To a solution of the above amine (67 mg, 0.14 mmol) in acetic acid (3 mL) was added bromic acid saturated acetic acid (2 mL) and the reaction mixture was stirred for 30 minutes. Then triturated with diethyl ether three times to give a white solid. The solid was dissolved in methanol (1 mL) and triturated three times with diethyl ether to give compound 116 as a white solid (66 mg, 62%). ¹ H NMR (D ₂ O) δ 1.54 (br m, 4H), 1.79-1.86 (m, 1H), 2.03 (q, 1H, J = 12.9 Hz), 2.20 (br d, 1H, J = 13.2 Hz) , 2.36-2.43 (m, 4H), 2.47 (s, 3H), 2.52-2.60 (m, 1H), 2.81-2.88 (m, 3H), 3.00-3.03 (m, 2H), 4.33-4.79 (m, 3H), 7.46 (ABq, 2H, J = 24.9, 8.4 Hz), 7.85 (dd, 1H, J = 7.8, 6.0 Hz), 8.33 (d, 1H, J = 7.8 Hz), 8.60 (d, 1H, J = 5.1 Hz). ¹³ C NMR (D ₂ O) δ 13.37, 18.87, 20.28, 20.43, 25.04, 25.36, 27.62, 39.50, 47.98, 51.75, 60.42, 110.75, 122.89, 125.85, 129.03, 131.47, 135.59, 139.22, 140.53, 147.97, 150. , 151.38. ES-MS m / z 378 [M + H] ⁺ . Calcd for C ₂₃ H ₃₁ N ₅ .3.0HBr.2.1H ₂ O: C, 41.98; H, 5.85; N, 10.64; Br, 36.42. Found: C, 41.95; H, 5.47; N, 10.39; Br, 36.17.
[1219] Example 117
[1220]
[1221] Compound 117: N1- (6-Fluoro-1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine Manufacture
[1222] 2- [4- (5,6,7,8-tetrahydroquinolin-8-ylamino) -butyl] -isoindole-1,3-dione (0.17 g, 0.5 mmol) in anhydrous acetonitrile (5.0 mL) To a solution of 2-chloromethyl-5-fluoro-1H-benzimidazole (0.44 g, 1.7 mmol) and potassium iodide (5 mg, 0.02 mmol) was added diisopropylethylamine (0.13 mL, 0.73 mmol), Stir at 60 ° C. for 16 h. The mixture was then concentrated under reduced pressure and the residue was partitioned between dichloromethane (20 mL) and brine (15 mL). The organic phase was separated and the aqueous phase extracted with dichloromethane (2 x 15 mL). The combined organic phases were then dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to purify the crude residue by silica gel column chromatography (2:98 MeOH / CH ₂ Cl ₂ ). 2- {4-[(6-fluoro-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyl}- Isoindole-1,3-dione was obtained as an orange solid (0.17 g, 71%).
[1223] A solution of the above compound (0.15 g, 0.3 mmol) in anhydrous ethanol (3 mL) was treated with hydrazine monohydrate (0.15 mL, 3.0 mmol) and stirred for 16 h. The white mixture was then filtered, concentrated under reduced pressure and purified by silica gel column chromatography (4: 1: 95 methanol: ammonium hydroxide: dichloromethane) to give compound 117 as a pale yellow solid (0.070 g, 58%). Obtained as. ¹ H NMR (CDCl ₃ ) δ 1.41 (br, 4H), 1.68 (m, 1H), 1.89 (q, 1H, J = 7.2 Hz), 2.02 (m, 1H), 2.21 (m, 1H), 2.53 ( br, 3H), 2.71 (m, 2H), 2.82 (m, 1H), 4.03 (m, 3H), 6.93 (t, 1H, J = 8.4 Hz), 7.13 (t, 1H, J = 6.0 Hz), 7.25 (br, 1 H), 7.41 (d, 1 H, J = 7.8 Hz), 7.49 (m, 1 H), 8.57 (d, 4.5 Hz). ¹³ CNMR (CDCl ₃ ) δ 21.75, 23.00, 26.30, 29.51 (2C), 41.12, 49.69, 51.00, 62.10, 101.63 (br, 1C), 110.24 (d, 1C, J = 25.52Hz), 115.72 (br, 1C ), 122.62, 135.11 (2C), 137.91, 146.73, 147.02, 156.83, 157.93, 159.20 (d, 1C, J = 281.69 Hz). ES-MS m / z 368 (M + H). Calcd for C ₂₁ H ₂₆ N ₅ F.0.5CH ₂ Cl ₂ : C, 62.99; H, 6. 64; N, 17.08. Found: C, 63.39; H, 6.88; N, 16.77.
[1224] Example 118
[1225]
[1226] Compound 118: N ^One-(1H-imidazo [4,5-b] pyridin-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt).
[1227] Preparation of 1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazo [4,5-b] pyridine-2-carboxaldehyde (Whitten, JP; Matthews, DP; McCarthy, JRJ Org. Chem. 1986, 51, 1891-1894).
[1228] To a solution of 4-azabenzimidazole (605 mg, 5.08 mmol) in DMF (10 mL) was added DIPEA (1.3 mL, 7.5 mmol) under nitrogen followed by SEMCl (1.1 mL, 6.2 mmol). The reaction was stirred at 80 ° C. for 2 hours, once cooled to room temperature, poured into brine (20 mL) and diluted with EtOAc (30 mL). The layers were separated and the aqueous solution was extracted with EtAOc (15 mL × 2). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification via short silica plug (CH ₂ Cl ₂ / MeOH, 9: 1) gave SEM-protected benzimidazole as orange oil (984 mg, 77%).
[1229] A solution of this material (132 mg, 0.527 mmol) in THF (1.5 mL) was cooled to −78 ° C. under nitrogen and t-BuLi (1.7 M in pentane, 0.33 mL, 0.56 mmol) was added slowly. The resulting dark red solution was warmed to 0 ° C., stirred for 10 minutes and then DMF (0.10 mL, 1.3 mmol) was added. The reaction was stirred for an additional 17 hours at room temperature and then quenched by addition of saturated aqueous NH ₄ Cl (10 mL). The mixture was extracted with EtOAc (15 mL × 2) and the organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (hexane / EtOAc, 4: 1, then 1: 1) afforded aldehyde as a yellow oil (43.2 mg, 0.156 mmol, 30%). ¹ H NMR (CDCl ₃ ) δ -0.09 (s, 9H), 0.91 (t, 2H, J = 8.3 Hz), 3.63 (t, 2H, J = 8.3 Hz), 6.08 (s, 2H), 7.39 (dd) , 1H, J = 8.4, 4.8 Hz, 8.24 (dd, 1H, J = 8.4, 1.2 Hz), 8.62 (dd, 1H, J = 4.8, 1.2 Hz), 10.11 (s, 1H).
[1230] 2- (4-{(5,6,7,8-tetrahydro-quinolin-8-yl)-[1- (2-trimethylsilanyl-ethoxy-methyl) -1H-imidazo [4,5- b] Preparation of pyridin-2-ylmethyl] -amino} -butyl) -isoindole-1,3-dione:
[1231] Aldehyde (43.2 mg, 0.156 mmol) and 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1 in CH ₂ Cl ₂ (1 mL) A solution of, 3-dione (63 mg, 0.18 mmol) was stirred at room temperature under nitrogen for 3 minutes and then NaBH (OAc) ₃ (53 mg, 0.25 mmol) was added. The reaction was further stirred for 17.5 h, then diluted with CH ₂ Cl ₂ (5 mL) and washed with 1M NaOH (2 mL × 2) and brine (2 mL). The organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 33: 1: 0.2) afforded tertiary amine as a light yellow foam (74.2 mg, 0.121 mmol, 78%). ¹ H NMR (CDCl ₃ ) δ -0.13 (s, 9H), 0.81 (dd, 2H, J = 9.3, 7.2 Hz), 1.35-1.48 (m, 2H), 1.53-1.72 (m, 3H), 1.87- 2.03 (m, 2H), 2.05-2.16 (m, 1H), 2.55-2.64 (m, 2H), 2.72-2.82 (m, 2H), 3.46-3.56 (m, 4H), 4.03 (dd, 1H, J = 9.3, 6.6 Hz), 4.18 (d, 1H, J = 13.8 Hz), 4.41 (d, 1H, J = 13.5 Hz), 6.03 (d, 1H, J = 10.8 Hz), 6.11 (d, 1H, J = 10.8 Hz), 6.94 (dd, 1H, J = 7.7, 4.7 Hz), 7.15 (dd, 1H, J = 7.8, 4.8 Hz), 7.23 (d, 1H, J = 7.5 Hz), 7.66-7.71 (m , 2H), 7.76-7.80 (m, 2H), 7.92 (dd, 1H, J = 8.1, 1.2 Hz), 8.30 (dd, 1H, J = 4.7, 1.4 Hz), 8.40 (d, 1H, J = 3.3 Hz).
[1232] N ^One-(1H-imidazo [4,5-b] pyridin-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine:
[1233] A solution of phthalimide (74.2 mg, 0.121 mmol) and hydrazine monohydrate (0.06 mL, 1.2 mmol) in EtOH (1.5 mL) was heated at reflux for 1 hour under nitrogen. Excess solvent was then removed under reduced pressure. The residue was dissolved in saturated aqueous NaHCO ₃ (5 mL) and extracted with CH ₂ Cl ₂ (10 mL × 3). The combined organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give crude primary amine as a colorless oil (55 mg, 95%).
[1234] To a solution of this material in CH ₂ Cl ₂ (1.5 mL) was added TFA (0.5 mL) and the reaction was stirred at room temperature under nitrogen for 3 hours. Excess solvent was removed under reduced pressure, the residue was dissolved in saturated aqueous NaHCO ₃ (10 mL) and the mixture was extracted with CH ₂ Cl ₂ (10 mL × 3). The combined organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 9: 1: 0.1) afforded the free base as an off-white foam (23 mg, 0.066 mmol, 58%). ¹ H NMR (CDCl ₃ ) δ 1.27-1.50 (m, 4H), 1.61-1.78 (m, 1H), 1.84-1.96 (m, 1H), 1.98-2.10 (m, 1H), 2.14-2.26 (m, 1H), 2.44-2.61 (m, 3H), 2.65-2.91 (m, 3H), 4.03-4.15 (m, 3H), 5.09 (br.s, 2H), 7.11-7.15 (m, 2H), 7.41 ( d, 1H, J = 7.8 Hz, 7.88 (d, 1H, J = 8.1 Hz), 8.32 (d, 1H, J = 4.8 Hz), 8.65 (d, 1H, J = 4.2 Hz).
[1235] Preparation of Compound 118 :
[1236] A solution of amine (22.5 mg, 0.064 mmol) in ice HOAc (1.0 mL) and saturated HBr in HOAc (0.5 mL) was stirred at room temperature for 30 minutes. Et ₂ O (5 mL) was added and the suspension was stirred for 5 minutes, then excess solvent was removed by pipette. The precipitate was washed with Et ₂ O (˜2 mL × 5) and then dried under reduced pressure to yield compound 118 as an off-white powder (35.4 mg, 0.053 mmol, 83%). ¹ H NMR (D ₂ O) δ 1.45-1.65 (m, 4H), 1.72-1.89 (m, 1H), 1.94-2.08 (m, 1H), 2.12-2.23 (m, 1H), 2.27-2.42 (m , 1H), 2.52-2.64 (m, 1H), 2.77-2.92 (m, 3H), 2.94-3.04 (m, 2H), 4.32 (d, 1H, J = 16.8 Hz), 4.42 (d, 1H, J = 16.8 Hz), 4.46 (dd, 1H, J = 9.9, 6.0 Hz), 7.73-7.84 (m, 2H), 8.30 (d, 1H, J = 7.8 Hz), 8.55-8.63 (m, 3H). ¹³ C NMR (D ₂ O) δ 20.4, 20.5, 25.1, 25.3, 27.6, 39.6, 49.7, 51.5, 60.4, 119.9, 125.7, 129.4, 137.3, 139.2, 140.4, 146.9, 147.6, 151.9, 161.3. ES-MS m / z 351 (M + H). Calcd for _{C 20 H 26 N 6 · 3.2HBr} · 1.5H 2 O · 0.7C 2 H 4 O 2: C, 38.52; H, 5. 29; N, 12.60; Br 38.32. Found: C, 38.54; H, 5.00; N, 12.63; Br 38.25.
[1237] Example 119
[1238]
[1239] Compound 119: N ^One-(1H-imidazo [4,5-c] pyridin-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt)
[1240] To a solution of 5-azabenzimidazole (460 mg, 3.86 mmol) in DMF (8 mL) was added DIPEA (1.0 mL, 5.7 mmol) followed by SEMCl (0.82 mL, 4.6 mmol) under nitrogen. The reaction was stirred at 80 ° C. for 2 h, then cooled to rt, poured into brine (20 mL) and diluted with EtOAc (30 mL). The layers were separated and the aqueous solution was extracted with EtAOc (15 mL × 2). The organic solution was washed with brine (5 mL × 3), dried (MgSO 4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH, 9: 1) afforded SEM-protected benzimidazoles as about a 1: 1 mixture of the two regioisomers (811 mg, 84%).
[1241] A solution of this material (802 mg, 3.22 mmol) in THF (10 mL) was cooled to −78 ° C. under nitrogen and t-BuLi (1.7 M in pentane, 2.0 mL, 3.4 mmol) was added slowly. The solution was warmed to 0 ° C. and stirred for 20 minutes before DMF (0.60 mL, 7.7 mmol) was added. The reaction was stirred for an additional 15 hours while slowly warming to room temperature. Saturated aqueous NH ₄ Cl (25 mL) was added and the mixture was extracted with EtOAc (25 mL × 2). The combined organic solution (MgSO ₄ ) was filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH, 19: 1) afforded aldehyde as a mixture containing starting material, DMF and other unidentified species. This material was used for reductive amination.
[1242] This material and 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione (74 mg, 0.21 mmol) was CH ₂ Cl ₂ (1.5 mL) was stirred for 25 min, then NaBH (OAc) ₃ (61 mg, 0.29 mmol) was added. The reaction was stirred for 16 h, then diluted with CH ₂ Cl ₂ (5 mL) and washed with 1M NaOH (2 mL × 2) and brine (5 mL). The organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 49: 1: 0.25) gave SEM-protected azabenzimidazole (140 mg, 0.126 mmol, SEM-protected 5). Obtained as about 55% by weight mixture with 4%) from azabenzimidazole.
[1243] A solution of this material and hydrazine monohydrate (0.06 mL, 1.2 mmol) in EtOH (1.5 mL) was heated at reflux for 1 h under nitrogen. Excess solvent was evaporated under reduced pressure, and the residue was dissolved in saturated aqueous NaHCO ₃ (5 mL) and extracted with CH ₂ Cl ₂ (10 mL × 3). The combined organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH 4 OH, 9: 1: 0.05, then MeOH) gave the primary amine as a light yellow foam (2: 1 mixture of legioisomers, 40.1 mg, 0.083 mmol, 66%).
[1244] To a solution of this material in CH ₂ Cl ₂ (1 mL) was added TFA (0.1 mL, 1.3 mmol) and the reaction was stirred at room temperature under nitrogen for 3.5 h. The solution was diluted with saturated aqueous NaHCO ₃ (10 mL) and extracted with CH ₂ Cl ₂ (10 mL × 3). The combined organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 9: 1: 0.1) afforded the free base as a white foam (10.1 mg, 0.029 mmol, 35%).
[1245] To a solution of free base in HOAc (0.5 mL) was added a solution of saturated HBr in HOAc (0.25 mL) and the reaction was stirred at room temperature for 20 minutes. The solution was diluted with Et ₂ O (4 mL) and the solvent was removed by pipette. The precipitate was washed with Et ₂ O (˜2 mL × 5) and then dried under reduced pressure to give compound 119 as a white powder (14.9 mg, 0.022 mmol, 75%). ¹ H NMR (D 2 O) δ 1.48-1.67 (m, 4H), 1.72-1.88 (m, 1H), 1.96-2.08 (m, 1H), 2.12-2.22 (m, 1H), 2.28-2.40 (m, 1H ), 2.53-2.65 (m, 1H), 2.79-3.02 (m, 5H), 4.29 (d, 1H, J = 16.4 Hz), 4.39 (d, 1H, J = 16.4 Hz), 4.44 (dd, 1H, J = 11.1, 6.0 Hz), 7.81 (dd, 1H, J = 8.1, 6.0 Hz), 8.11 (d, 1H, J = 6.6 Hz), 8.29 (d, 1H, J = 7.8 Hz), 8.50 (d, 1H, J = 6.9 Hz, 8.59 (d, 1H, J = 5.4 Hz), 9.16 (s, 1H). ¹³ C NMR (D ₂ O) δ 20.4, 20.5, 25.0, 25.2, 27.6, 39.6, 49.6, 51.4, 60.2, 111.6, 125.6, 132.7, 133.9, 138.3, 139.2, 140.3, 147.5, 152.1, 162.5. ES-MS m / z 351 (M + H). Calcd for _{C 20 H 26 N 6 · 3.3HBr} · 1.2C 2 H 4 O 2: C, 39.02; H, 4.98; N, 12.19; Br 38.24. Found: C, 38.90; H, 5.03; N, 12.50; Br 38.10.
[1246] Example 120
[1247]
[1248] Compound 120: N ^One-(5-trifluoromethyl-1H-benzoimidazol-2-ylmethyl) -N ^One-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt)
[1249] 2- {4-[(5,6,7,8-tetrahydro-quinolin-8-yl)-(5-trifluoromethyl-1H-benzoimidazol-2-ylmethyl) -amino] -butyl} Preparation of Isoindole-1,3-Dione :
[1250] 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione (160 mg, 0.46 mmol), 2-chloro in acetonitrile Methyl-6-trifluoromethyl-1H-benzoimidazole (129 mg, 0.55 mmol), N, N-diisopropylethylamine (100 mL, 0.60 mmol) and potassium iodide (8 mg, 0.05 mmol) Stir at C for 3 days. The reaction mixture was then cooled and the solvent removed under reduced pressure to give a red oil. Purification by column chromatography on flash silica gel using NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ (1: 2: 97) gave the product as an orange foam (190 mg, 76%). ¹ H NMR (CDCl ₃ ) δ 1.37-1.45 (m, 5H), 1.56-1.70 (m, 2H), 2.18-2.20 (m, 1H), 2.57-2.61 (m, 1H), 2.72-2.80 (m, 3H), 3.49-3.54 (m, 2H), 3.98-4.16 (m, 3H), 7.13-7.15 (m, 1H), 7.40-7.45 (m, 2H), 7.62-7.74 (m, 5H), 7.86 ( br m, 1 H), 8.62 (br m, 1 H).
[1251] 2-{[(4-amino-butyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -5-trifluoromethyl-benzoimidazole-1- Preparation of carboxylic acid tert-butyl esters:
[1252] To a solution of the above amine (190 mg, 0.35 mmol) in ethanol (10 mL) was added hydrazine hydrate (80 mL, 1.74 mmol). The reaction mixture was stirred at rt overnight, then the solvent was removed under reduced pressure. The partially purified product was purified by silica gel radial chromatography (1 mm plate, using NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ ; 1: 1: 100 → 1: 4: 100, gradient eluent) to yellow Obtained as an oil (140 mg).
[1253] To a solution of the above amine (140 mg, 0.34 mmol) in THF (10 mL) was added di-tert-butyl dicarbonate (146 mg, 0.67 mmol). The reaction mixture was stirred for 1 hour and the solvent was removed under reduced pressure to give a yellow oil. Purification by silica gel radial chromatography (1 mm plate, NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ ; using 1: 1: 100) gave the desired product as a yellow oil (34 mg, 19% over two steps). Obtained as ¹ H NMR (CDCl ₃ ) δ 1.45-1.48 (m, 9H), 1.68-1.76 (m, 1H), 1.92 (q, 1H, J = 12.3 Hz), 2.02-2.07 (m, 1H), 2.18-2.22 (m, 1H), 2.31 (br s, 1H), 2.51-2.60 (m, 1H), 2.60-2.72 (m, 2H), 2.75-2.91 (m, 3H), 4.03 (t, 1H, J = 6.3 Hz), 4.10 (d, 1H, J = 11.4 Hz), 4.48 (br t, 1H), 7.17 (dd, 1H, J = 7.2, 4.8 Hz), 7.44 (d, 2H, J = 8.1 Hz), 7.56 And 7.73 (d, total 1 H, J = 7.2 Hz), 7.79 and 7.94 (s, total 1 H), 8.59 (s, 1 H).
[1254] N ^1- (5-Trifluoromethyl-1H-benzoimidazol-2-ylmethyl) -N ^1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4 Preparation of diamines (hydrobromide salts) :
[1255] To a solution of the above amine (34 mg, 0.07 mmol) in acetic acid (2 mL) was added bromic acid saturated acetic acid (2 mL) and the reaction mixture was stirred for 30 minutes. It was then triturated five times with diethyl ether and compound 120 was obtained as a white solid (29 mg, 60%). ¹ H NMR (D ₂ O) δ 1.55 (br s, 4H), 1.83-1.86 (m, 1H), 2.05 (q, 1H, J = 11.6 Hz), 2.17-2.21 (m, 1H), 2.37 (br s, 1H), 2.57-2.59 (m, 1H), 2.88 (br s, 3H), 3.00-3.01 (m, 2H), 4.37-4.59 (m, 3H), 7.82-7.93 (m, 3H), 8.17 (s, 1H), 8.32 (d, 1H, J = 7.5 Hz), 8.62 (d, 1H, J = 5.4 Hz). ¹³ C NMR (D ₂ O) δ ES-MS m / z 418 [M + H] ⁺ . Calcd for C ₂₂ H ₂₆ N ₅ F ₃ .3.0HBr.2.0H ₂ O: C, 37.95; H, 4.78; N, 10.06; Br, 34.43. Found: C, 37.86; H, 4.61; N, 9.89; Br, 34.71.
[1256] Example 121
[1257]
[1258] Compound 121: N ^One-(5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2-ylmethyl) -N ^One-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt)
[1259] 2- {4-[(5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2ylmethyl)-(5,6,7,8-tetrahydro-quinoline-8- Preparation of 1) -amino] -butyl} -isoindole-1,3-dione:
[1260] Selenium (IV) in a solution of 2-methyl-5,6-dihydro-4H-imidazole [4,5,1-ij] quinoline (497 mg, 2.67 mmol) in dioxane / water (10 mL: 1 mL) ) Oxide (326 mg, 2.94 mmol) was added. The reaction mixture was heated to 110 ° C overnight. The mixture was then cooled and the solvent removed in vacuo to yield a dark brown solid. Purification by column chromatography on flash silica gel using 2% CH ₃ OH / CH ₂ Cl ₂ gave the product as a yellow oil (180 mg), which was used without further purification.
[1261] Stomach crude aldehyde (180 mg, 0.97 mmol) and 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -iso in CH ₂ Cl ₂ (10 mL) To a solution of indole-1,3-dione (372 mg, 1.06 mmol) was added sodium triacetoxyborohydride (410 mg, 1.93 mmol). The reaction mixture was stirred at rt for 3 days. The solvent was then removed under reduced pressure to yield a yellow oil. Purification by column chromatography on flash silica gel using 2% CH ₃ OH / CH ₂ Cl ₂ gave the product as a yellow oil (135 mg, 27%). ¹ H NMR (CDCl ₃ ) δ 1.42-1.47 (m, 2H), 1.56-1.63 (m, 2H), 1.93-1.96 (m, 2H), 2.06-2.07 (m, 2H), 2.22 (t, 2H, J = 6.0 Hz), 2.60-2.67 (m, 3H), 2.70 (m, 1H), 2.95 (t, 2H, J = 6.0 Hz), 3.56 (t, 2H, J = 6.0 Hz), 4.01 (t, 1H, J = 6.0 Hz), 4.16 (ABq, 2H, J = 42.0, 15.0 Hz), 4.29-4.35 (m, 1H), 4.51 (br s, 1H), 4.58-4.66 (m, 1H), 6.94 ( d, 1H, J = 7.2 Hz, 7.01-7.06 (m, 1H), 7.09 (t, 1H, J = 8.1 Hz), 7.29 (d, 1H, J = 7.5 Hz), 7.47 (d, 1H, J = 8.1 Hz), 7.68-7.70 (m, 2H), 7.78-7.81 (m, 2H), 8.41 (d, 1H, J = 3.9 Hz).
[1262] 2- {4-[(5,6-Dihydro-4H-imidazo [4,5,1-ij] quinolin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinoline-8 Preparation of -yl) -amino] -butyl} -isoindole-1,3-dione:
[1263] To a solution of the above amine (135 mg, 0.26 mmol) in ethanol (10 mL) was added hydrazine hydrate (63 mL, 1.30 mmol). The reaction mixture was stirred overnight. The solvent was then removed under reduced pressure to yield a yellow oil. Purified by silica gel radial chromatography (1 mm plate, using NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ ; 1: 1: 100 → 1: 6: 100, gradient eluent) to afford the product as a yellow oil (47 mg). , 46%). ¹ H NMR (CDCl ₃ ) δ 1.30-1.47 (m, 4H), 1.67-1.69 (m, 2H), 1.86-2.00 (m, 4H), 2.08-2.10 (m, 1H), 2.21 (t, 2H, J = 6.0 Hz), 2.54-2.69 (m, 4H), 2.74-2.79 (m, 1H), 2.95 (t, 2H, J = 6.0 Hz), 4.08 (ABq, 2H, J = 38.1, 9.6 Hz), 4.04-4.10 (m, 1H), 4.27-4.31 (m, 1H), 4.54-4.60 (m, 1H), 6.95 (d, 1H, J = 7.2 Hz), 7.02 (dd, 1H, J = 7.7, 4.5 Hz), 7.10 (t, 1H, J = 7.2 Hz), 7.32 (d, 1H, J = 7.5 Hz), 7.48 (d, 1H, J = 8.1 Hz), 8.46 (d, 1H, J = 4.5 Hz) .
[1264] N ^One-(5,6-dihydro-4H-imidazo [4,5,1-ij] quinolin-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine:
[1265] Hydrobromide saturated acetic acid (2 mL) was added to a solution of the above amine (47 mg, 0.12 mmol) in acetic acid (3 mL). The reaction mixture was stirred for 30 minutes. Then it was triturated with diethyl ether three times. The pale yellow solid was dried under vacuum, redissolved in methanol (1 mL) and triturated with diethyl ether three times. The obtained solid was dried under vacuum overnight (54.7 mg, 68%). ¹ H NMR (D ₂ O) δ 1.55 (br s, 4H), 1.76-1.90 (m, 1H), 2.15 (q, 1H, J = 17.4 Hz), 2.30-2.32 (m, 1H), 2.33-2.42 (m, 3H), 2.52-2.59 (m, 1H), 2.80-2.88 (m, 3H), 3.01-3.09 (m, 4H), 4.34-4.58 (m, 5H), 7.38 (d, 1H, J = 7.2 Hz), 7.50-7.61 (m, 2H), 7.85 (dd, 1H, J = 7.5, 6.0 Hz), 8.34 (d, 1H, J = 7.8 Hz), 8.61 (d, 1H, J = 6.0 Hz) . ¹³ C NMR (D ₂ O) δ 20.43, 22.12, 23.04, 25.05, 25.45, 27.68, 39.50, 43.86, 46.85, 51.94, 60.59, 111.29, 123.82, 125.92, 126.19, 127.36, 129.06, 139.36, 140.64, 148.09 , 151.30. ES-MS m / z 390 [M + H] ⁺ . Calcd for C ₂₄ H ₃₁ N ₅ .3.0HBr.2.1H ₂ O: C, 43.02, H, 5.75; N, 10.45; Br, 35.77. Found: C, 42.86; H, 5.75; N, 10.49; Br, 35.88.
[1266] Example 122
[1267]
[1268] Compound 122: N1- (1-allyl-1H-benzoimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (Hydrobromide salt)
[1269] Preparation of (1-allyl-1H-benzoimidazol-2-yl) -methanol:
[1270] N, N-diisopropylethylamine (0.71) in a solution of (1H-benzoimidazol-2-yl) -methanol (501 mg, 3.38 mmol) and allyl bromide (0.29 mL, 3.38 mmol) in DMF (15 mL). ML, 4.06 mmol) was added. The reaction mixture was stirred at 60 ° C. overnight. The mixture is then cooled to room temperature and quenched with saturated NaHCO ₃ (25 mL). Then it was extracted with CH ₂ Cl ₂ (3 × 25 mL). The combined organic layers were washed with brine (2 × 25 mL), dried (MgSO ₄ ), filtered, concentrated and dried in vacuo to give a brown oil. Purification by column chromatography on flash silica gel using 2% CH ₃ OH / CH ₂ Cl ₂ gave the product as a yellow oil (180 mg, 28%). ¹ H NMR (CDCl ₃ ) δ 4.85 (br s, 5H), 4.98 (d, 1H, J = 17.1 Hz), 5.17 (d, 1H, J = 10.5 Hz), 5.88-6.01 (m, 1H), 7.20 -7.26 (m, 3 H), 7.66 (t, 1 H, J = 3.9 Hz).
[1271] Preparation of 1-allyl-1H-benzoimidazole-2-carbaldehyde:
[1272] To a solution of the above alcohol (180 mg, 0.96 mmol) in CH ₂ Cl ₂ (10 mL) was added manganese (IV) oxide (831 mg, 9.56 mmol). The reaction mixture was stirred for 4 hours. The mixture was then filtered through a celite bed and the filtrate was concentrated to dryness to yield a yellow oil (158 mg, 88%). ¹ H NMR (CDCl ₃ ) δ 5.02 (d, 2H, J = 15.0 Hz), 5.16-5.27 (m, 2H), 5.96 (br s, 1H), 7.39-7.44 (m, 3H), 7.92 (d, 1H, J = 6.0 Hz), 10.09 (s, 1H).
[1273] 2- {4-[(1-allyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -isoindole Preparation of -1,3-dione:
[1274] Gastric aldehydealdehyde (158 mg, 0.85 mmol) and 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -iso in CH ₂ Cl ₂ (10 mL) To a solution of indole-1,3-dione (326 mg, 0.93 mmol) was added sodium triacetoxyborohydride (360 mg, 1.70 mmol). The reaction mixture was stirred overnight. The solvent was then removed under reduced pressure to give a yellow foam. Purification by column chromatography on flash silica gel using NH ₄ OH / CH ₃ OH / CHCl ₂ (0: 2: 98 → 1: 2: 98) afforded the product as a yellow oil (165 mg, 37%), It was used without further purification.
[1275] Stomach amine (165 mg, 0.32 mmol) in concentrated H ₂ SO ₄ (2 mL) / water (20 mL) was refluxed overnight. The reaction was then cooled and basified to pH 11 with 10N NaOH. This was then extracted with CHCl ₃ (5 × 25 mL). The organic layer was dried (Na ₂ SO 4), filtered, concentrated and dried under vacuum to give a yellow oil. Purified by silica gel radial chromatography (1 mm plate, NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ ; using 1: 1: 100 → 1: 6: 100) to give the product as a yellow oil (23 mg, 19% Obtained). ¹ H NMR (CDCl ₃ ) δ 1.23-1.46 (m, 4H), 1.65-1.70 (m, 1H), 1.93-2.10 (m, 3H), 2.53 (t, 2H, J = 6.9 Hz), 2.62 (t , 2H, J = 7.8Hz), 2.68-2.70 (m, 1H), 2.75-2.80 (m, 1H), 4.03-4.13 (m, 3H), 4.81 (d, 1H, J = 18.0 Hz), 5.02- 5.09 (m, 2H), 5.47 (dm, 1H, J = 16.2 Hz), 5.84-5.96 (m, 1H), 7.02 (dd, 1H, J = 7.5, 4.8 Hz), 7.18-7.24 (m, 2H) , 7.29-7.33 (m, 3H), 7.67-7.72 (m, 1H), 8.46 (d, 1H, J = 4.2 Hz).
[1276] N ^One-(1-allyl-1H-benzoimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt):
[1277] Hydrobromide saturated acetic acid (2 mL) was added to a solution of amine (23 mg, 0.06 mmol) in acetic acid (3 mL). The reaction mixture was stirred for 30 minutes. This was then triturated five times with diethyl ether to give compound 122 as a cream solid which was dried under vacuum for 3 days. ¹ H NMR (D ₂ O) δ 1.54 (s, 4H), 1.74-1.88 (m, 1H), 2.05 (q, 1H, J = 10.5 Hz), 2.17-2.22 (m, 1H), 2.39-2.43 ( m, 1H), 2.54-2.59 (m, 1H), 2.78-2.88 (m, 3H), 3.01 (br d, 2H, J = 4.8 Hz), 4.49 (dd, 1H, J = 10.8, 5.7 Hz), 4.50 (ABq, 2H, J = 57.5, 17.7 Hz), 5.09-5.14 (m, 3H), 5.35 (d, 1H, J = 10.2 Hz), 6.01-6.14 (m, 1H) 7.61-7.67 (m, 2H ), 7.80-7.89 (m, 3H), 8.35 (d, 1H, J = 7.8 Hz), 8.63 (d, 1H, J = 5.7 Hz). ¹³ C NMR (D ₂ O) δ 20.42, 25.03, 25.47, 27.69, 39.50, 47.43, 47.62, 52.00, 60.90, 113.16, 114.52, 119.04, 125.95, 126.94, 127.31, 130.34, 130.57, 132.81, 139.37, 140.65, 148.65, 148.65 , 151.09, 151.68. ES-MS m / z 390 [M + H] ⁺ . Calcd for C ₂₄ H ₃₁ N ₅ .3.0HBr.2.0H ₂ O: C, 43.13; H, 5.73; N, 10.48; Br, 35.87. Found: C, 43.09; H, 5. 60; N, 10.28; Br, 36.08.
[1278] Example 123
[1279]
[1280] Compound 123: N ^One-(1-allyl-1H-benzimidazol-2-ylmethyl) -N ^OnePreparation of-(S) -5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine (hydrochloride salt)
[1281] Preparation of N- (5,6,7,8-tetrahydro-quinolin-8yl) -butane-1,4-diamine:
[1282] 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione (15.0 g, 42.98 mmol) dissolved in ethanol (215 mL) Hydrazine hydrate (13.4 mL) was added to the solution. The solution was stirred for 16 h at room temperature under N ₂ atmosphere. White precipitate formed. Diethyl ether (215 mL) was added and the mixture was stirred for 10 minutes, then filtered and concentrated. Purification by column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH 4 OH, 96: 3: 1, v / v / v) gave the product as a brown oil (6.77 g, 74%). ¹ H NMR (CDCl ₃ ) δ 1.57 (m, 9H), 2.05 (m, 2H), 2.75 (m, 6H), 3.78 (t, 1H), 7.06 (dd, 1H, J = 7.89, 4.82 Hz), 7.37 (d, 1H, J = 7.89 Hz), 8.39 (d, 1H, J = 4.82 Hz).
[1283] Preparation of [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -carbamic acid tert-butyl ester:
[1284] Triethylamine (4.30) in a solution of N- (5,6,7,8-tetrahydro-quinolin-8yl) -butane-1,4-diamine (6.77 g, 30.9 mmol) in tetrahydrofuran (155 mL). ML, 30.9 mmol) and Boc-ON (7.60 g, 30.9 mmol) were added slowly. The mixture was stirred at rt for 72 h under N ₂ atmosphere. The mixture was concentrated and purified by column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH ₄ OH, 96: 3: 1, v / v / v). Second purification by column chromatography on silica gel (ethyl acetate) gave the product as a brown oil (8.03 g, 80%). ¹ H NMR (CDCl ₃ ) δ 1.43 (s, 9H), 1.60 (s, 4H), 1.78 (m, 2H), 1.99 (m, 2H), 2.78 (m, 5H), 3.15 (m, 2H), 3.77 (t, 1H), 4.87 (s, 1H), 7.07 (dd, 1H, J = 7.45, 4.82 Hz), 7.83 (d, 1H, J = 7.89 Hz), 8.38 (d, 1H, J = 4.38 Hz ).
[1285] {4- [1-Allyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -carbamic acid tert-butyl Preparation of ester
[1286] To a solution of [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -carbamic acid tert-butyl ester (5.12 g, 16.04 mmol) in tetrahydrofuran (80 mL) 1-allyl-1H-benzoimidazole-2-carbaldehyde (3.0 g, 16.04 mmol) and potassium carbonate (2.22 g, 16.04 mmol) were added. The mixture was then stirred for 1 hour, filtered, concentrated and diluted with methylene chloride (80 mL). Sodium triacetoxyborohydride (6.80 g, 32.08 mmol) was added and the mixture was stirred for 16 h at room temperature under N ₂ atmosphere. The reaction mixture was quenched with a solution of saturated aqueous NaHCO ₃ (100 mL). Methylene chloride (2 x 100 mL) was extracted. The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a brown oil. Purification by column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH ₄ OH, 96: 3: 1, v / v / v) gave the product as a white foam (4.64 g, 74%). ¹ H NMR (CDCl ₃ ) δ 1.41 (s, 1H), 1.63 (s, 3H), 1.99 (m, 3H), 2.36 (m, 3H), 2.99 (m, 2H), 4.01 (s, 2H), 4.13 (m, 1H), 4.80 (m, 2H), 5.07 (m, 2H), 5.40 (d, 1H, J = 18 Hz), 5.91 (m, 1H), 7.02 (dd, 1H, J = 7.45, 4.82 Hz), 7.31 (m, 4H), 7.71 (m, 1H), 8.47 (d, 1H, J = 3.95 Hz).
[1287] Preparation of Compound 123
[1288] {4- [1-Allyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} in methanol (20 mL) To a solution of carbamic acid tert-butyl ester (5.84 g, 15.01 mmol) was added HCl-saturated methanol (40 mL) and the mixture was stirred for 1.5 h at room temperature under N ₂ atmosphere. The solution was added dropwise to diethyl ether (1.5 L) to give a thick white precipitate. The white solid was separated by suction filtration under a continuous stream of nitrogen, washed with diethyl ether and dried overnight under vacuum at 40 ° C. (4.92 g, 73%). ¹ H NMR (D ₂ O) δ 1.56 (s, 4H), 1.81 (m, 1H), 2.07 (m, 2H), 2.41 (m, 2H), 2.89 (m, 2H), 3.54 (m, 2H) , 4.49 (m, 3H), 5.10 (m, 3H), 5.37 (d, 1H, J = 10.52 Hz), 6.08 (m, 1H), 7.63 (m, 1H), 7.88 (m, 3H), 8.37 ( d, 1H, J = 8.33 Hz), 8.67 (d, 1H, J = 5.26 Hz); 13C NMR (D 2 O) δ 13.47, 19.30, 23.92, 24.36, 26.58, 38.41, 46.36, 46.52, 50.85, 59.76, 65.34, 112.09, 113.34, 118.0, 124.88, 125.87, 126.29, 129.19, 131.60, 138.27, 139.139. 149.90, 150.56. ES-MS m / z 390 (M + H). (C24H31N5) 2.87 (HCl) 1.51 (H 2 O) 0.47 (C 4 H ₁₀ O) Calcd for: C, 55.91; H, 7.54; N, 12.60; Cl, 18.27. Found: C, 55.91; H, 7.55; N, 12.60; Cl, 18.27.
[1289] Example 124
[1290]
[1291] Compound 124: N ^One-(1-cyclopropylmethyl-1H-benzoimidazol-2-ylmethyl) -N ^One-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt):
[1292] Preparation of (1-cyclopropylmethyl-1H-benzoimidazol-2-yl) -methanol:
[1293] N, N-diiso in a solution of (bromomethyl) cyclopropane (0.39 mL, 4.02 mmol) and (1H-benzoimidazol-2-yl) -methanol (596 mg, 4.02 mmol) in DMF (10 mL) Propylethylamine (0.84 mL, 4.82 mmol) was added. The reaction mixture was stirred at 80 ° C. for 3 days. It was then cooled to rt, quenched with saturated NaHCO ₃ (15 mL) and the phases separated. The aqueous phase was washed with CH ₂ Cl ₂ (3 × 20 mL). The combined organic layers were washed with brine (2 × 30 mL), dried (MgSO ₄ ), filtered, concentrated and dried under vacuum to give a dark brown oil. Purification by column chromatography on flash silica gel using 2% CH ₃ OH / CH ₂ Cl ₂ gave 210 mg (26%) as a yellow solid. ¹ H NMR (CDCl ₃ ) δ 0.40-0.45 (m, 2H), 0.52-0.61 (m, 2H), 1.22-1.33 (m, 1H), 4.13 (d, 2H, J = 6.6 Hz), 4.88 (s , 2H), 7.22-7.24 (m, 2H), 7.36-7.38 (m, 1H), 7.66-7.69 (m, 1H).
[1294] Preparation of 1-cyclopropylmethyl-1H-benzoimidazole-2-carbaldehyde:
[1295] Manganese (IV) oxide (910 mg, 10.50 mmol) was added to a solution of stomach alcohol (210 mg, 1.05 mmol) in CH ₂ Cl ₂ (15 mL). The reaction mixture was stirred overnight. It was then filtered through a layer of celite and the filtrate was concentrated to dryness to yield a brown oil (160 mg, 76%) which was used without further purification. ¹ H NMR (CDCl ₃ ) δ 0.43-0.48 (m, 2H), 0.50-0.58 (m, 2H), 1.33-1.38 (m, 1H), 4.54 (d, 2H, J = 9.0 Hz), 7.38-7.53 (m, 3H), 7.95 (d, 1H, J = 9.0 Hz), 10.12 (s, 1H).
[1296] 2- {4-[(1-cyclopropylmethyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] butyl} -iso Preparation of indole-1,3-dione:
[1297] Stomach aldehyde (160 mg, 0.80 mmol) and 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole in CH ₂ Cl ₂ (10 mL) To a solution of -1,3-dione (307 mg, 0.88 mmol) was added sodium triacetoxyborohydride (339 mg, 1.60 mmol). The reaction mixture was stirred overnight. The solvent was then removed under reduced pressure to yield a yellow oil. Purification by column chromatography on flash silica gel using 2% CH ₃ OH / CH ₂ Cl ₂ gave the product as a yellow oil (332 mg, 79%). ¹ H NMR (CDCl ₃ ) δ 0.17-0.22 (m, 1H), 0.28-0.33 (m, 1H), 1.04-1.06 (m, 1H), 1.38-1.45 (m, 2H), 1.51-1.65 (m, 3h), 1.96-2.06 (m, 3H), 2.58-2.64 (m, 3H), 2.77-2.81 (m, 1H), 3.52 (t, 2H, J = 7.5 Hz), 4.04-4.09 (m, 3H) , 4.18-4.25 (m, 1H), 4.48-4.55 (m, 1H), 6.96 (dd, 1H, J = 7.5, 4.8 Hz), 7.14-7.20 (m, 2H), 7.25-7.34 (m, 2H) , 7.63-7.69 (m, 3H), 7.70-7.80 (m, 2H), 8.44 (d, 1H, J = 3.3 Hz).
[1298] N ^One-(1-cyclopropylmethyl-1H-benzoimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8, -tetrahydro-quinolin-8-yl) -butane-1,4-diamine:
[1299] To a solution of the above amine (332 mg, 0.62 mmol) in ethanol (15 mL) was added hydrazine hydrate (0.15 mL, 3.11 mmol). The reaction mixture was stirred overnight. The solvent was then removed under reduced pressure to give a pale yellow oil. Purified by silica gel radial chromatography (2 mm plate; NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ ; 1: 3: 100 → 1: 7: 100; gradient eluent) to afford the desired product as a yellow oil ( 168 mg, 67%). ¹ H NMR (CDCl ₃ ) δ 0.21-0.23 (m, 1H), 0.28-0.31 (m, 1H), 0.42-0.47 (m, 2H), 1.09-1.12 (m, 1H), 1.32-1.41 (m, 3H), 1.65-1.73 (m, 1H), 1.95-2.05 (m, 3H), 2.52-2.61 (m, 3H), 2.70-2.73 (m, 1H), 2.75-2.81 (m, 3H), 3.66 ( s, 2H), 4.03-4.07 (m, 1H), 4.19-4.21 (m, 1H), 4.49-4.52 (m, 1H), 7.03 (dd, 1H, J = 7.7, 4.5 Hz), 7.15-7.23 ( m, 2H), 7.31-7.36 (m, 2H), 7.65-7.71 (m, 1H), 8.47 (d, 1H, J = 3.9 Hz).
[1300] N ^One-(1-cyclopropylmethyl-1H-benzoimidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8, -tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt):
[1301] Hydrobromide saturated acetic acid (2 mL) was added to a solution of the above amine (142 mg, 0.35 mmol) in acetic acid (3 mL). The reaction mixture was stirred for 30 minutes. Then it was triturated with diethyl ether three times and the solid was concentrated in vacuo. The solid was then redissolved in anhydrous methanol (1 mL) and triturated with diethyl ether three times. Pale yellow solid (198 mg, 80%) was dried under vacuum overnight. ¹ H NMR (D ₂ O) δ 0.51 (d, 2H, J = 4.8 Hz), 0.65 (d, 2H, J = 7.5 Hz), 1.31-1.32 (m, 1H), 1.53 (br s, 4H), 1.77-1.91 (m, 1H), 2.02-2.23 (m, 2H), 2.42-2.46 (m, 1H), 2.55-2.60 (m, 1H), 2.86 (s, 3H), 3.02 (d, 2H, J = 4.5 Hz), 4.39 (d, 2H, J = 7.2 Hz), 4.47 (s, 1H), 4.45-4.50 (m, 1H), 4.65 (d, 1H, J = 17.4 Hz), 7.62-7.65 (m , 2H), 7.83-7.89 (m, 3H), 8.35 (d, 1H, J = 7.8 Hz), 8.64 (d, 1H, J = 5.7 Hz). ¹³ C NMR (D ₂ O) δ 4.11, 4.15, 14.55, 20.45, 25.06, 25.55, 27.73, 39.50, 48.03, 49.95, 52.08, 60.97, 113.35, 114.33, 125.98, 126.80, 127.22, 130.45, 132.94, 139.40, 140.67 , 148.18, 151.08, 151.32. ES-MS m / z 404 [M + H] &lt; + &gt;. Calcd for C25H33N5.3.1HBr.1.5H2O.0.3C4H10O: C, 44.72; H, 6.03; N, 9.95; Br, 35.20. Found: C, 44.82; H, 6.07; N, 9.98; Br, 35.00.
[1302] Example 125
[1303]
[1304] Compound 125: N ^One-(1-pyridin-2-ylmethyl-1H-imidazol-2-ylmethyl) -N ^One-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt)
[1305] Preparation of 1-pyridin-2-ylmethyl-1H-imidazole-2-carbaldehyde:
[1306] N, N-diisopropylethylamine (3.0 in 2-imidazolcarboxaldehyde (545 mg, 5.67 mmol) and 2- (bromomethyl) pyridine hydrobromide (1.58 g, 6.24 mmol) in DMF (20 mL) Ml, 17.01 mmol) was added. The reaction mixture was heated at 80 ° C overnight. It was then cooled and quenched with saturated NaHCO ₃ (20 mL). It was extracted with CH ₂ Cl ₂ (c × 20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO ₄ ), filtered, concentrated and dried under vacuum to give a dark brown oil. Purification by column chromatography on flash silica gel using 1% → 2% CH ₃ OH / CH ₂ Cl ₂ gave a yellow solid (397 mg, 37%). ¹ H NMR (CDCl ₃ ) δ -5.71 (s, 2H), 7.18-7.24 (m, 2H), 7.32 (s, 1H), 7.36 (s, 1H), 7.65 (td, 1H, J = 10.4, 1.5 Hz), 8.56 (d, 1 H, J = 4.5 Hz), 9.82 (s, 1 H).
[1307] 2- {4-[(1-pyridin-2-ylmethyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl }-Preparation of Isoindole-1,3-dione:
[1308] Stomach aldehyde (543 mg, 2.90 mmol) and 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole in CH ₂ Cl ₂ (20 mL) To a solution of -1,3-dione (1.11 g, 3.19 mmol) was added sodium triacetoxyborohydride (1.23 g, 5.80 mmol). The reaction mixture was stirred overnight. Then it was extracted with saturated NaHCO ₃ (3 × 25 mL). The combined aqueous washes were washed once with CH ₂ Cl ₂ (30 mL). The organic layer was dried (MgSO ₄ ), filtered, concentrated and dried in vacuo to give a yellow foam. Purification by radial chromatography on silica gel using NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ (1: 1: 100) yielded a yellow oil (135 mg, 9%). ¹ H NMR (CDCl ₃ ) δ 1.18-1.28 (m, 2H), 1.49-1.67 (m, 3H), 1.75-1.95 (m, 2H), 2.01-2.06 (m, 1H), 2.51-2.777 (m, 4H), 3.51 (t, 2H, J = 7.2 Hz), 3.87 (s, 2H), 4.00 (dd, 1H, J = 6.3, 2.7 Hz), 5.70 (ABq, 2H, J = 94.8, 16.5 Hz), 6.79 (d, 1H, J = 7.6 Hz), 6.86 (d, 2H, J = 7.5, 4.5 Hz), 7.12 (dd, 1H, J = 7.2, 5.1 Hz), 7.24 (d, 1H, J = 7.8 Hz ), 7.55 (td, 1H, J = 6.9, 1.8 Hz), 7.66-7.69 (m, 2H), 7.78-7.81 (m, 2H), 8.24 (d, 1H, J = 3.6 Hz), 8.53 (d, 1H, J = 4.8 Hz).
[1309] N ^One-(1-pyridin-2-ylmethyl-1H-imidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine:
[1310] To a solution of the above amine (135 mg, 0.26 mmol) in ethanol (5 mL) was added hydrazine hydrate (60 mL, 1.30 mmol). The reaction mixture was stirred overnight. The solvent was then removed under reduced pressure to give a white solid. Purification by silica gel radial chromatography (1 mm plate; NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ ; 1: 3: 100 → 1: 8: 100) afforded the desired product as a yellow oil (42 mg, 41 Obtained as%). ¹ H NMR (CDCl ₃ ) δ 1.30-1.33 (m, 4H), 1.57-1.66 (m, 1H), 1.82-1.97 (m, 2H), 2.02-2.06 (m, 2H), 2.51-2.60 (m, 5H), 2.64-2.73 (m, 2H), 3.87 (d, 2H, J = 3.0 Hz), 4.02 (dd, 1H, J = 9.0, 6.0 Hz), 5.69 (ABq, 2H, J = 108.0, 18.0 Hz ), 6.77 (d, 1H, J = 7.8 Hz), 6.89 (s, 1H), 6.91-6.94 (m, 1H), 6.96 (d, 1H, J = 0.9 Hz), 7.16 (dd, 1H, J = 7.2, 5.1 Hz), 7.29 (s, 1H), 7.56 (td, 1H, J = 7.7, 1.5 Hz), 8.29 (d, 1H, J = 4.2 Hz), 8.55 (d, 1H, J = 4.5 Hz) .
[1311] N ^One-(1-pyridin-2-ylmethyl-1H-imidazol-2-ylmethyl) -N ^One-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt):
[1312] A bromic acid saturated acetic acid (2 ml) was added to a solution of the above amine (42 mg, 0.11 mmol) in acetic acid (3 ml). The reaction mixture was stirred for 30 minutes and then triturated with diethyl ether three times. The precipitate obtained was dried under vacuum. The precipitate was dissolved in methanol (1 mL, triturated with diethyl ether three times. The separated cream solid (66 mg, 83%) was dried under vacuum ¹ H NMR (D-2-O) δ 1.44 (br) s, 4H), 1.69-1.72 (m, 1H), 1.87 (q, 1H, J = 12.0 Hz), 2.09 (br d, 2H, J = 8.7 Hz), 2.40 (br s, 1H), 2.60 (br d, 1H, J = 8.1 Hz), 2.84 (br s, 2H), 2.95 (br d, 2H, J = 4.8 Hz), 4.23 (q, 2H, J = 18.9 Hz), 4.32 (m, 1H), 5.71 (d, 2H, J = 8.7 Hz), 7.55 (s, 2H), 7.64-7.71 (m, 2H), 7.83 (t, 1H, J = 6.6 Hz), 8.16 .21 (m, 1H), 8.31 (d, 1H, J = 7.8 Hz), 8.55 (d, 1H, J = 5.4 Hz), 8.61 (m, 1H) 13 C NMR (D-2-O) δ 20.02, 20.42, 25.00, 25.30, 27.63, 46.66, 50.83, 51.63, 60.15, 119.89, 124.23, 124.84, 125.92, 126.11, 139.36, 140.58, 142.86, 146.09, 147.42, 148.11, 151.05.ES-MS m / z 391 {M + H] ⁺ .C23H30N6 · 3.9 Eq. For 1.7H 2 O: C, 37.35; H, 4.95; N, 11.28; Br, 42.59 Found: C, 37.50; H, 5.10; N, 11.41; Br, 42.30.
[1313] Example 126
[1314]
[1315] Compound 126: N ^One-(4-methyl-1H-imidazol-2-ylmethyl) -N ^One-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt)
[1316] 2-{[[4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl Preparation of) -Amino] -methyl} -4-methyl-imidazole-1-sulfonic acid dimethylamide:
[1317] To a solution of 4-methylimidazole (1.0 g, 12.18 mmol) and triethylamine (1.3 mL, 12.18 mmol) in CH ₂ Cl ₂ (25 mL) at 25 ° C. dimethyl sulfamoyl chloride (3.4 mL, 24.36 mmol) Was added. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then extracted with water (25 mL) and saturated NaCl (2 × 25 mL). The organic layer was dried (MgSO ₄ ), filtered, concentrated and dried in vacuo to give a pale yellow solid. Purification by column chromatography on flash silica gel using 5% CH ₃ OH / CH ₂ Cl ₂ gave a mixture of product and starting material as a pale yellow solid, which was used without further purification.
[1318] To a solution of the above amine (505 mg, 2.67 mmol) in anhydrous THF (27 mL) was added n-butyl lithium (1.18 mL, 2.94 mmol, 2.5 M in hexane) at -78 ° C. under Ar ₂ (g). After 45 minutes, N, N-dimethylformamide (0.25 mL, 3.20 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature. After 1.5 h, the reaction was quenched with saturated NH ₄ Cl (6 mL). The solvent was removed under reduced pressure. It was then dissolved in CH ₂ Cl ₂ (25 mL) and water (10 mL) and the phases were separated. The aqueous phase was washed with CH ₂ Cl ₂ (2 × 25 mL). The combined organic washes were washed with brine (50 mL), dried (Na ₂ SO ₄ ), filtered, concentrated and dried under vacuum to give a yellow oil. Purification by column chromatography on flash silica gel using 2% CH ₃ OH / CH ₂ Cl ₂ afforded an impure yellow oil which was used without further purification.
[1319] Stomach aldehyde (190 mg, 0.88 mmol) and 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole in CH ₂ Cl ₂ (10 mL) To a solution of -1,3-dione (338 mg, 0.97 mmol) was added sodium triacetoxyborohydride (373 mg, 1.76 mmol). The reaction mixture was stirred for 3 days. Then it was extracted with saturated NaHCO ₃ (3 × 25 mL). The organic layer was dried (MgSO ₄ ), filtered, concentrated and dried in vacuo to give a yellow foam. Purification by column chromatography on flash silica gel using 2% CH ₃ OH / CH ₂ Cl ₂ gave a pale yellow solid (307 mg, 67%) as product. ¹ H NMR (CDCl ₃ ) δ 1.19-1.27 (m, 2H), 1.43-1.51 (m, 2H), 1.64-1.78 (m, 2H), 1.91-1.96 (m, 1H), 2.07 (s 1H), 2.10-2.14 (m, 1H), 2.53-2.75 (m, 4H), 2.92 (s, 6H), 3.53 (t, 2H, J = 7.2 Hz), 4.17 (t, 1H, J = 8.4 Hz), 4.25 (q, 2H, J = 14.4 Hz), 6.81 (s, 1H), 6.94 (dd, 1H, J = 7.5, 4.8 Hz), 7.26 (d, 1H, J = 6.9 Hz), 7.65-7.70 (m, 2H), 7.75-7.81 (m, 2H), 8.31 (d, 1H, J = 3.6 Hz).
[1320] N ^One-(4-methyl-1H-imidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine:
[1321] The above amine (300 mg, 0.58 mmol) in 2N HCl (6 mL) was stirred at reflux overnight. The reaction mixture was cooled down and basified with 15% aqueous NaOH. Then extracted with CH ₂ Cl ₂ (3 × 15 mL). The combined organic washes were washed with saturated NaCl (25 mL), dried (Na-2-SO-4-), filtered, concentrated and dried under vacuum to give a yellow oil. Purified by silica gel radial chromatography (1 mm plate; NH ₄ OH / CH ₃ OH / CH ₂ Cl ₂ ; 1: 3: 100 → 1: 10: 100; gradient eluent) to afford the product as a yellow oil (72.5 mg, 40%). ¹ H NMR (CDCl ₃ ) δ 1.24-1.38 (m, 4H), 1.63-1.68 (m, 1H), 1.82-1.86 (m, 1H), 1.96-2.00 (m, 1H), 2.10-2.15 (m, 1H), 2.21 (s, 3H), 2.42-2.81 (m, 6H), 3.77 (q, 2H, J = 15.9 Hz), 3.96 (dd, 1H, J = 9.2, 6.0 Hz), 6.63 (s, 1H ), 7.08 (dd, 1H, J = 7.5, 4.8 Hz), 7.37 (d, 1H, J = 7.5 Hz), 8.45 (d, 1H, J = 4.2 Hz).
[1322] N ^One-(4-methyl-1H-imidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt):
[1323] A bromic acid saturated acetic acid (2 mL) was added to a solution of the above amine (72.5 mg, 0.23 mmol) in acetic acid (3 mL). The reaction mixture was stirred for 30 minutes. Then it was triturated with diethyl ether three times and the precipitate was dried under vacuum. The solid was reprecipitated in methanol (1 mL) and further triturated three times with dieting ether. The yellow solid obtained (82 mg, 58%) was dried under vacuum. ¹ H NMR (D ₂ O) δ 1.45-1.61 (m, 4H), 1.78-2.01 (m, 2H), 2.15-2.19 (m, 1H), 2.25-2.31 (m, 4H), 2.48-2.53 (m , 1H), 2.71-2.78 (m, 1H), 2.89-2.91 (m, 2H), 2.98-3.00 (m, 2H), 4.16 (q, 2H, J = 18.0 Hz), 4.39 (dd, 1H, J = 10.7, 5.4 Hz), 7.11 (s, 1H), 7.85 (dd, 1H, J = 10.7, 6.3 Hz), 8.34 (d, 1H, J = 7.8 Hz), 8.59 (d, 1H, J = 5.7 Hz ). ¹³ C NMR (D ₂ O) δ 9.43, 20.24, 20.45, 25.07, 25.32, 27.61, 39.59, 47.07, 51.25, 60.06, 66.48, 115.91, 125.84, 125.84, 130.37, 139.25, 140.47, 144.17, 147.98, 151.58. ES-MS m / z 314 [M + H] &lt; + &gt;. Calc. For C-18-H-27-N-5-.3.0HBr.1.8H-2-O.0.2C-4-H-10-O: C, 37.42; H, 5.95; N, 11.61; Br, 39.72. Found: C, 37.17; H, 5.65; N, 11.37; Br, 40.10.
[1324] Example 127
[1325]
[1326] Compound 127: N ^One-(1-Isopropyl-1H-imidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt )
[1327] Preparation of 1-isopropyl-1H-imidazole (Gridnev, A.A .; Mihaltseva, I.M. Synth.Commun. 1994, 24, 1547-1555):
[1328] A solution of isopropylamine (4.25 mL, 50 mmol) in H 2 O (5 mL) was acidified to pH about 2 with concentrated H ₃ PO ₄ . Glyoxal (40% in water, 7.5 mL, 52 mmol) and formaldehyde (37% in water, 4.0 mL, 49 mmol) were added and the reaction flask was fritted with a reflux condenser and dropping funnel. The solution was warmed to 90-95 ° C. and saturated aqueous solution of NH ₄ Cl (10 mL) was added dropwise over 20 minutes. The reaction was stirred at 100 ° C. for 30 minutes, then cooled once and made basic (pH ˜10) with additional solid NaOH. The solution was extracted with EtOAc (25 mL × 3) and the combined organic solutions were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification under vacuum distillation (bp 57-70 ° C./0.25 mm Hg) afforded imidazole as anhydrous liquid (899 mg, 8.16 mmol, 17%). ¹ H NMR (CDCl ₃ ) δ 1.47 (d, 6H, J = 6.9 Hz), 4.33 (septet, 1H, J = 6.8 Hz), 6.95 (s, 1H), 7.04 (s, 1H), 7.52 (s, 1H).
[1329] Preparation of 1-isopropyl-1H-imidazole-2-carboxaldehyde:
[1330] A solution of imidazole (890 mg, 8.08 mmol) in THF (10 mL) was cooled to −78 ° C. under nitrogen and n-BuLi (2.5 M in hexane, 4.5 mL, 11.3 mmol) was added. The light yellow solution was stirred at 0 ° C. for 25 min and then DMF (1.5 mL, 19 mmol) was added. The reaction was stirred at rt for 1 h and then quenched by addition of saturated aqueous NH ₄ Cl (10 mL). The layers were separated and the aqueous solution was extracted with EtAOc (10 mL × 2). The combined organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (hexane / EtOAc, 1: 1) afforded the aldehyde as a pale yellow solid (731 mg, 5.29 mmol, 65%). ¹ H NMR (CDCl ₃ ) δ 1.46 (d, 6H, J = 6.6 Hz), 5.46 (septet, 1H, J = 6.8 Hz), 7.29 (s, 1H), 7.31 (s, 1H), 9.81 (s, 1H).
[1331] 2- {4-[(1-Isopropyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -isoindole Preparation of -1,3-dione:
[1332] Aldehyde (222 mg, 1.61 mmol), 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1 in CH ₂ Cl ₂ (7 mL) A solution of, 3-dione (354 mg, 1.01 mmol) and NaBH (OAc) 3 (319 mg, 1.51 mmol) was stirred at room temperature under nitrogen for 15 hours. The reaction was diluted with CH ₂ Cl ₂ (10 mL) and washed with 1M NaOH (10 mL) and brine (10 mL). The organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH, 19: 1) gave tertiary amine as a white foam (210 mg, 0.45 mmol, 44%). ¹ H NMR (CDCl 3) δ 1.27 (d, 3H, J = 6.9 Hz), 1.41 (d, 3H, J = 6.6 Hz), 1.49-1.72 (m, 3H), 1.78-2.10 (m, 5H), 2.46 -2.84 (m, 4H), 3.58 (t, 2H, J = 7.1 Hz), 3.85 (d, 1H, J = 13.5 Hz), 3.92-4.02 (m, 2H), 5.07 (septet, 1H, J = 6.6 Hz), 6.83 (s, 1H), 6.87 (s, 1H), 7.01 (dd, 1H, J = 7.5, 4.8 Hz), 7.31 (d, 1H, J = 7.5 Hz), 7.69-7.73 (m, 2H) ), 7.79-7.83 (m, 2H), 8.41 (d, 1H, J = 3.6 Hz).
[1333] N ^One-(1-isopropyl-1H-imidazol-2-ylmethyl) -N ^OnePreparation of-(5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine:
[1334] A solution of phthalimide (206 mg, 0.44 mmol) and hydrazine monohydrate (0.20 mL, 4.1 mmol) in EtOH (4.5 mL) was heated at reflux for 1.5 h. The solvent was removed under reduced pressure, and the residue was dissolved in saturated aqueous NaHCO 3 (10 mL) and extracted with CH 2 Cl 2 (10 mL × 3). The organic solution was dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH 2 Cl 2 / MeOH / NH 4 OH, 9: 1: 0.1) gave the primary amine as a yellow oil (128 mg, 0.37 mmol, 85%). 1 H NMR (CDCl 3) δ 1.26 (d, 3H, J = 6.6 Hz), 1.31-1.37 (m, 4H), 1.41 (d, 3H, J = 6.6 Hz), 1.54-1.77 (m, 3H), 1.86- 2.10 (m, 3H), 2.51-2.60 (m, 4H), 2.62-2.86 (m, 2H), 3.84 (s, 2H), 4.04 (dd, 1H, J = 8.1, 5.7 Hz), 5.07 (septet, 1H, J = 6.6 Hz, 6.91 (s, 1H), 6.92 (s, 1H), 7.05 (dd, 1H, J = 7.7, 4.7 Hz), 7.35 (d, 1H, J = 7.5 Hz), 8.46 ( d, 1H, J = 3.3 Hz).
[1335] Preparation of Compound 127:
[1336] To a solution of free base (121 mg, 0.35 mmol) in ice HOAc (1.0 mL) was added saturated HBr in HOAc (0.5 mL). The reaction was stirred at rt for 20 min and then diluted with Et 2 O (5 mL). The salt formed an oil and the solvent was removed by pipette. The residue was dissolved in anhydrous MeOH (0.5 mL), stirred for about 5 minutes and then diluted with Et 2 O (5 mL). The solvent was again pipetted off and the insoluble material was washed with Et 2 O (2 mL × 2) and dried under reduced pressure to give the hydrobromide salt as a fine white powder (136 mg, 0.25 mmol, 71%). 1 H NMR (D 2 O) δ 1.45 (d, 6H, J = 6.6 Hz), 1.46-1.62 (m, 4H), 1.67-1.84 (m, 1H), 1.92-2.16 (m, 2H), 2.20-2.32 (m , 1H), 2.49-2.62 (m, 1H), 2.75-2.94 (m, 5H), 4.08 (d, 1H, J = 16.5 Hz), 4.23-4.33 (m, 2H), 4.65 (septet, 1H, J = 6.6 Hz), 7.37 (d, 1H, J = 1.8 Hz), 7.49 (d, 1H, J = 1.5 Hz), 7.54 (dd, 1H, J = 7.7, 5.6 Hz), 7.95 (d, 1H, J = 8.1 Hz), 8.48 (d, 1H, J = 4.8 Hz). 13 C NMR (D 2 O) δ 23.0, 24.0, 24.7, 27.4, 30.6, 42.0, 49.0, 52.8, 53.9, 63.4, 121.7, 122.6, 127.1, 140.8, 145.4, 145.9, 147.0, 155.7. ES-MS m / z 342 (M + H). Calcd for C20H31N5.2.0HBr.1.2CH4O: C, 47.00; H, 7.03; N, 12.93; Br 29.50. Found: C, 47.20; H, 6.92; N, 12.91; Br 29.13.
[1337] Example 128
[1338]
[1339] Compound 128: N1- [1- (2-methoxy-ethyl) -1H-imidazol-2-ylmethyl] -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane Preparation of -1,4-diamine (hydrobromide salt).
[1340] Preparation of imidazol-1-yl-acetic acid ethyl ester:
[1341] To a 0 ° C. suspension of NaH (60% in mineral oil, 658 mg, 16.5 mmol) in THF (20 mL) was added a solution of imidazole (1.03 g, 15.1 mmol) in THF (20 mL) under nitrogen. The resulting suspension was stirred at 0 ° C. for 15 minutes, then ethyl bromoacetate (2.2 mL, 20 mmol) was added. The reaction was stirred at rt for 4.5 h and then diluted with H 2 O (25 mL). THF was evaporated under reduced pressure, and the remaining aqueous solution was extracted with CH 2 Cl 2 (25 mL × 3). The combined organic solution was dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH 2 Cl 2 / MeOH, 19: 1) afforded the ester as a yellow solid (1.52 g, 9.87 mmol, 65%). 1 H NMR (CDCl 3) δ 1.28 (t, 3H, J = 7.1 Hz), 4.24 (q, 2H, J = 7.1 Hz), 4.68 (s, 2H), 6.95 (s, 1H), 7.09 (s, 1H) , 7.50 (s, 1 H).
[1342] Preparation of 1- (2-methoxy-ethyl) -1 H-imidazole:
[1343] A solution of ester (1.51 g, 9.81 mmol) in THF (25 mL) was cooled to 0 ° C. under nitrogen and LiAlH 4 (1.0 M in THF, 5.0 mL, 5.0 mmol) was added slowly. The reaction was stirred at room temperature for 20 minutes and then quenched by addition of H 2 O (0.2 mL), 15% aqueous NaOH (0.2 mL) and H 2 O (0.6 mL). The mixture was suction filtered through celite and washed with EtOAc. The filtrate was dried (Na 2 SO 4), filtered and concentrated under reduced pressure to give crude alcohol as a yellow oil (896 mg, 81%).
[1344] To a 0 ° C. suspension of NaH (60% in mineral oil, 410 mg, 10.3 mmol) in THF (10 mL) was slowly added a solution of alcohol (890 mg, 7.94 mmol) in THF (10 mL) under nitrogen. The mixture was stirred at 0 ° C. for 10 minutes and dimethyl sulfate (0.95 mL, 10.0 mmol) was added. The reaction was stirred for an additional 30 minutes at room temperature, then THF was removed under reduced pressure. The residue was dissolved in H 2 O (25 mL) and extracted with CH 2 Cl 2 (25 mL × 3). The combined organic solution was dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH 2 Cl 2 / MeOH, 19: 1) afforded methyl ether as a colorless oil (347 mg, 2.75 mmol, 35%). 1 H NMR (CDCl 3) δ 3.34 (s, 3H), 3.63 (t, 2H, J = 5.1 Hz), 4.09 (t, 2H, J = 5.1 Hz), 6.97 (s, 1H), 7.05 (s, 1H) , 7.52 (s, 1 H).
[1345] Preparation of 1- (2-methoxy-ethyl) -1 H-imidazole-2-carboxaldehyde:
[1346] A solution of imidazole (342 mg, 2.71 mmol) in THF (3.5 mL) was cooled to −78 ° C. under nitrogen and n-BuLi (2.5 M in hexane, 1.4 mL, 3.5 mmol) was added. The resulting light yellow solution was stirred at 0 ° C. for 10 minutes and then DMF (0.5 mL, 6.5 mmol) was added. The reaction was stirred at room temperature for 45 minutes and then quenched by addition of saturated aqueous NH 4 Cl (5 mL). The layers were separated and the aqueous solution was extracted with CH 2 Cl 2 (10 mL × 2). The organic solution was dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH 2 Cl 2 / MeOH, 32: 1) gave the aldehyde as a yellow liquid (1: 1 with DMF, 254 mg, 1.12 mmol, 41%). 1 H NMR (CDCl 3) δ 3.30 (s, 3H), 3.66 (t, 2H, J = 5.1 Hz), 4.58 (t, 2H, J = 5.0 Hz), 7.26 (s, 1H), 7.27 (s, 1H) , 9.80 (s, 1 H).
[1347] 2- {4-[[1- (2-methoxy-ethyl) -1 H-imidazol-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] Preparation of -Butyl} -isoindole-1,3-dione:
[1348] Aldehyde (170 mg, 1.10 mmol), 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3- in CH2Cl2 (8 mL) A solution of dione (422 mg, 1.21 mmol) and NaBH (OAc) 3 (324 mg, 1.53 mmol) was stirred at room temperature under nitrogen for 16 hours. The reaction was diluted with CH 2 Cl 2 (10 mL) and washed with 1M NaOH (10 mL) and brine (10 mL). The organic solution was dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH 2 Cl 2 / MeOH / NH 4 OH, 49: 1: 0.25) afforded tertiary amine as a white foam (244 mg, 0.50 mmol, 45%). 1 H NMR (CDCl 3) δ 1.20-1.35 (m, 2H), 1.47-1.70 (m, 3H), 1.80-2.16 (m, 3H), 2.55 (t, 2H, J = 7.2 Hz), 2.60-2.85 (m , 2H), 3.27 (s, 3H), 3.48-3.67 (m, 4H), 3.87 (s, 2H), 3.98 (dd, 1H, J = 9.3, 6.0 Hz), 4.24-4.35 (m, 1H), 4.54-4.66 (m, 1H), 6.80 (d, 1H, J = 1.2 Hz), 6.89 (d, 1H, J = 1.2 Hz), 7.00 (dd, 1H, J = 7.7, 4.7 Hz), 7.31 (d , 1H, J = 7.5 Hz), 7.67-7.73 (m, 2H), 7.79-7.84 (m, 2H), 8.40 (d, 1H, J = 3.9 Hz).
[1349] N1- [1- (2-methoxy-ethyl) -1H-imidazol-2-ylmethyl] -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1, Preparation of 4-diamine:
[1350] A solution of phthalimide (238 mg, 0.49 mmol) and hydrazine monohydrate (0.25 mL) in EtOH (5 mL) was stirred at reflux for 1.5 h. The solvent was removed under reduced pressure, and the residue was dissolved in saturated aqueous NaHCO 3 (10 mL) and extracted with CH 2 Cl 2 (15 mL × 3). The combined organic solution was dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH 2 Cl 2 / MeOH / NH 4 OH, 9: 1: 0.1) gave the primary amine as a colorless oil (130 mg, 0.36 mmol, 74%). 1 H NMR (CDCl 3) δ 1.23-1.42 (m, 4H), 1.60-1.75 (m, 1H), 1.84-2.14 (m, 3H), 2.48-2.60 (m, 4H), 2.63-2.86 (m, 2H) , 3.28 (s, 3H), 3.49-3.56 (m, 1H), 3.58-3.66 (m, 1H), 3.83 (s, 2H), 4.03 (dd, 1H, J = 8.4, 6.0 Hz), 4.22-4.31 (m, 1H), 4.56-4.64 (m, 1H), 6.88 (d, 1H, J = 1.5 Hz), 6.93 (d, 1H, J = 1.5 Hz), 7.04 (dd, 1H, J = 7.5, 4.5 Hz), 7.34 (dd, 1H, J = 7.5, 1.5 Hz), 8.45 (dd, 1H, J = 4.5, 1.5 Hz).
[1351] Preparation of Compound 128:
[1352] To a solution of free base (48 mg, 0.13 mmol) in ice AcOH (1.0 mL) was added saturated HBr in AcOH (0.5 mL). The reaction was stirred at rt for 20 min and then diluted with Et 2 O (5 mL). The salt formed a yellow oil and the solvent was removed by pipette. The residue was dissolved in anhydrous MeOH (0.5 mL), stirred for about 5 minutes and then diluted with Et 2 O (5 mL). The solvent was removed again by pipette and the insoluble material was washed with Et 2 O (2 mL × 2) and dried under reduced pressure to give the hydrobromide salt as a fine off-white powder (76 mg, 0.12 mmol, 87%). 1 H NMR (D 2 O) δ 1.41-1.60 (m, 4H), 1.74-1.88 (m, 1H), 1.92-2.08 (m, 1H), 2.12-2.24 (m, 1H), 2.31-2.42 (m, 1H) , 2.43-2.55 (m, 1H), 2.68-2.81 (m, 1H), 2.84-2.94 (m, 2H), 2.96-3.06 (m, 2H), 3.33 (s, 3H), 3.83 (t, 2H, J = 4.8 Hz), 4.16 (d, 1H, J = 16.5 Hz), 4.35 (d, 1H, J = 16.5 Hz), 4.40-4.44 (m, 3H), 7.49 (d, 1H, J = 1.8 Hz) , 7.51 (d, 1H, J = 1.8 Hz), 7.86 (dd, 1H, J = 7.8, 6.0 Hz), 8.34 (d, 1H, J = 7.8 Hz), 8.60 (d, 1H, J = 5.7 Hz) . 13C NMR (D 2 O) δ 20.2, 20.5, 25.1, 25.4, 27.7, 39.6, 46.8, 47.9, 51.7, 59.0, 60.3, 70.5, 119.3, 123.3, 125.9, 139.4, 140.6, 145.6, 148.1, 151.3. ES-MS m / z 358 (M + H). Calculated for _{C20H31N5O · 3.1HBr · 1.4H2O · 0.2C4H 10} O: C, 38.34; H, 6.02; N, 10.75; Br38.02. Found: C, 38.59; H, 5.93; N, 10.77; Br 37.63.
[1353] Example 129
[1354]
[1355] Compound 129: N1- (4-methyl-1-propyl-1H-imidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1, 4-diamine (hydrobromide salt)
[1356] Preparation of 1-allyl-4-methyl-1H-imidazole:
[1357] 4-methylimidazole (2.0 g, 24.36 mmol), allyl bromide (2.2 mL, 24.36 mmol), N, N-diisopropylethylamine (5.0 mL, 29.24 mmol) in DMF (50 mL) at 80 ° C. Stir overnight. The reaction mixture was cooled down, quenched with saturated NaHCO 3 (30 mL) and extracted with CH 2 Cl 2 (4 × 40 mL). The combined organic layers were dried (MgSO 4), filtered, concentrated and dried under vacuum to give a brown oil. Purification by flash column chromatography on silica using 2% CH3OH / CH2Cl2 gave the product as a yellow oil (1.13 g, 40%). 1 H NMR (CDCl-3-) (as a mixture of regio-isomers) δ 2.17 and 2.22 (s, total 3H), 4.44-4.48 (m, total 2H), 5.19-5.24 (m, total 2H), 5.89- 6.00 (m, 1H total), 6.61 and 6.79 (s, total 1H), 7.35 and 7.39 (s, total 1H).
[1358] Preparation of 1-allyl-4-methyl-1H-imidazole-2-carbaldehyde:
[1359] To a solution of the above imidazole (1.23 g, 10.07 mmol) in THF (40 mL) was added n-butyllithium (2.5 M in hexane) under Ar (g) at -78 ° C. After 45 minutes, DMF was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. Then it was quenched with saturated NH 4 Cl (20 mL) and the solvent was removed under reduced pressure. The residue was dissolved in CH 2 Cl 2 (20 mL) and water (10 mL) and the phases were separated. The aqueous phase was washed twice with CH 2 Cl 2 (25 mL). The organic phase was dried (Na 2 SO 4), filtered, concentrated and dried under vacuum to give a yellow oil. Purification by column chromatography on flash silica gel using 2% CH3OH / CH2Cl2 gave the product as a yellow oil (575 mg, 38%). 1 H NMR (CDCl-3-) (as a mixture of regio-isomers) δ 2.26 and 2.30 (s, total 3H), 4.96-5.25 (m, total 4H), 5.91-5.97 (m, total 1H), 6.74 and 6.92 (m, 1H total), 9.70 and 9.73 (s, 1H total).
[1360] 2- {4-[(1-allyl-4-methyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} Preparation of Isoindole-1,3-Dione:
[1361] Stomach aldehyde (268 mg, 1.773 mmol) and 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1 in CH 2 Cl 2 (17 mL), To a 3-dione (743 mg, 2.13 mmol) solution was added sodium triacetoxyborohydride (752 mg, 3.55 mmol). The reaction mixture was stirred at rt overnight. Then it was extracted with saturated NaHCO 3 (3 × 20 mL). The organic layer was dried (MgSO 4), filtered, concentrated and dried in vacuo to give a yellow foam. Purification by column chromatography on flash silica gel using 10% CH 3 OH / ethyl acetate gave the product as a pale yellow foam (263 mg, 31%). 1 H NMR (CDCl 3) (as a mixture of regio-isomers) δ 1.52-1.60 (m, total 4H), 1.89-2.11 (m, total 8H), 2.56-2.66 (m, total 4H), 2.55 (t, 2H , J = 7.5 Hz), 3.76 (d, 2H, J = 6.0 Hz), 3.99 (t, 1H, J = 6.0 Hz), 4.84-4.90 (m, total 1H) 4.93 and 4.96 (s, total 1H), 5.03-5.06 (m, total 2H), 5.83-5.87 (m, 1H), 6.43 (s, 1H), 6.99 (dd, 1H, J = 3.0 Hz), 7.27 (d, 1H, J = 6.0 Hz), 7.68-7.70 (m, 2H), 7.80-7.82 (m, 2H), 8.39 (d, 1H, J = 3.0 Hz).
[1362] N1- (4-Methyl-1-propyl-1H-imidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine Manufacture of:
[1363] To a solution of the above amine (263 mg, 0.54 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.13 mL, 2.72 mmol). The reaction mixture was stirred at rt for 3 days. Then the solvent was removed under reduced pressure. Purification by silica gel radial chromatography (2 mm plate; NH 4 OH / CH 3 OH / CH 2 Cl 2; 1: 4: 100 → 1: 6: 100) yields a yellow oil, which is obtained from the allyl product and the n-propyl product in 1 H NMR. It appeared to be a mixture.
[1364] Stomach amine (150 mg, 0.31 mmol) in methanol (15 mL) was hydrogenated overnight at 40 psi in the presence of palladium / carbon (15 mg). The reaction mixture was then filtered through a celite bed and the filtrate was concentrated to dryness to yield a yellow oil. Purification by radial chromatography (1 mm plate; NH 4 OH / CH 3 OH / CH 2 Cl 2; 1: 4: 100 → 1: 7: 100) afforded the product as a yellow oil (67 mg, 61%). 1 H NMR (CDCl-3-) δ 0.83 (t, 3H, J = 7.5 Hz), 1.59-1.69 (m, 3H), 1.97-2.02 (m, 4H), 2.13 (s, 3H), 2.53-2.70 ( m, 8H), 3.72 (d, 2H), 3.87-3.92 (m, 1H), 4.03-4.07 (m, 2H), 6.50 (s, 1H), 7.04 (d, 1H, J = 3.0 Hz), 7.34 (d, 1H, J = 9.0 Hz), 8.50 (d, 1H, J = 6.0 Hz).
[1365] N1- (4-Methyl-1-propyl-1H-imidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine Preparation of Hydrobromide Salts:
[1366] Stomach amine (67 mg, 0.19 mmol) in acetic acid (2 mL) was added to hydrobromide saturated acetic acid (2 mL). The reaction mixture was stirred for 30 minutes. It was then triturated three times with diethyl ether and the precipitate was dried under vacuum. The solid was redissolved in anhydrous methanol (0.5 mL) and triturated with diethyl ether three times to give a yellow solid (40 mg, 32%). 1 H NMR (D 2 O) δ 0.89 (t, 3H, J = 7.5 Hz), 1.51 (br s, 4H), 1.80 (q, 3H, J = 7.5 Hz 0, 1.97-2.01 (m, 1H), 2.16-2.20 ( m, 1H), 2.31-2.35 (m, 4H), 2.49 (br m, 1H), 2.71-2.76 (m, 1H), 2.88-2.90 (m, 2H), 2.99-3.01 (m, 2H), 4.06 (t, 3H, J = 6.9 Hz), 4.27 (d, 1H, J = 16.8 Hz), 4.38-4.43 (m, 1H), 7.14 (s, 1H), 7.87 (t, 1H, J = 6.3 Hz) , 8.35 (d, 1H, J = 7.8 Hz), 8.59 (d, 1H, J = 5.4 Hz) 13 C NMR (D2O) δ 9.40, 10.39, 20.24, 20.42, 23.27, 25.08, 25.42, 27.66, 39.55, 46.43 , 49.39, 51.59, 60.27, 119.71, 125.90, 129.96, 139.27, 140.56, 143.47, 148.08, 151.38.ES-MS m / z 356 [M + H] +. C21H33N53.0HBr2.0H2O0.3C4H10O Found: C, 40.61; H, 6.60; N, 10.67; Br, 36.51. Found: C, 4.35; H, 6.35; N, 10.43; Br, 36.39.
[1367] Example 130
[1368]
[1369] Compound 130: N1- (1-propyl-1H-imidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine (hydro Bromide salts)
[1370] To a solution of 2-imidazol carboxaldehyde (0.81 g, 8.4 mmol) and diisopropylethylamine (2.2 mL, 12.6 mmol) in anhydrous DMF (28 mL) was added allyl bromide (0.88 mL, 10.1 mmol) and the solution Was stirred at 60 ° C. for 16 h. The mixture was then concentrated under reduced pressure and the residue partitioned between dichloromethane (20 mL) and sodium bicarbonate (15 mL). The organic phase was separated and the aqueous phase extracted with dichloromethane (2 x 15 mL). The combined organic phases were then dried (Na 2 SO 4), filtered and concentrated under reduced pressure to afford a crude residue which was purified by Rica gel column chromatography (1:99 MeOH / CH 2 Cl 2). This gave 2- (N-allylimidazole) -carboxaldehyde (0.62 g, 54%). 1 H NMR (CDCl 3) δ 5.02 (d, 2H, J = 6.0 Hz), 5.10 (d, 1H, J = 18.0 Hz), 5.25 (d, 1H, J = 9.0 Hz), 5.96 (m, 1H), 7.16 (s, 1 H), 7.30 (s, 1 H), 9.81 (s, 1 H).
[1371] Using general process B, 2- [4- (5,6,7,8-tetrahydroquinolin-8-ylamino) -butyl] -isoindole-1,3-dione (0.80 g, 2.3 mmol), 2- (N-allylimidazole) -carboxaldehyde (0.62 g, 4.5 mmol) and sodium triacetoxyborohydride (1.16 g, 5.5 mmol) were stirred in dichloromethane (22 mL) at room temperature for 16 hours. Post-treatment and column chromatography (1: 4 ethyl acetate: hexane) followed by 2- {4-[(1-allyl-1H-imidazol-2-ylmethyl)-(5,6,7,8- Tetrahydroquinolin-8-yl) -amino] -butyl} -isoindole-1,3-dione was obtained as a yellow oil (0.45 g, 40%). 1 H NMR (CDCl 3) δ 1.26 (m, 2H), 1.50-1.70 (m, 3H), 1.75-2.00 (m, 1H), 2.03 (m, 2H), 2.54 (m, 2H), 2.57-2.80 (m , 2H), 3.55 (t, 2H, J = 6.0 Hz), 3.83 (s, 2H), 3.97 (m, 1H), 4.84 (d, 1H, J = 15.0 Hz), 4.92 (d, 1H, J = 15.0 Hz), 5.07 (br d, 2H, J = 7.5 Hz), 5.93 (m, 1H), 6.77 (s, 1H), 6.82 (s, 1H), 7.01 (m, 1H), 7.30 (d, 1H) , J = 7.0 Hz), 7.70 (m, 2H), 7.82 (m, 2H), 8.40 (d, 1H, J = 3.0 Hz).
[1372] A solution of the above compound (0.45 g, 0.96 mmol) in anhydrous ethanol (10 mL) was treated with hydrazine monohydrate (0.50 mL, 9.6 mmol) and stirred for 16 h. The white mixture was then filtered, concentrated under reduced pressure and purified by silica gel column chromatography (10: 1: 84 methanol: ammonium hydroxide: dichloromethane) to give the N-propyl and N-allylimidazole products (0.19 g, 58%) was obtained.
[1373] The material from above (0.19 g) was dissolved in anhydrous methanol (5.6 mL) and the reaction vessel was purged with nitrogen. Palladium on carbon (40 mg) was added and the mixture was stirred for 16 h under hydrogen atmosphere (30 psi). The reaction mixture was then filtered through celite and the solvent was removed under reduced pressure. The crude was then diluted with ethyl acetate (20 mL) and washed with brine (4 x 15 mL) to remove DMF. The organic phase was then dried (Na 2 SO 4), filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (5: 1: 94 methanol: ammonium hydroxide: dichloromethane). From this N- (1-propyl-1H-imidazol-2-ylmethyl) -N- (5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine (67 mg , 35%) was obtained. 1 H NMR (CDCl 3) δ 0.84 (t, 3H, J = 7.5 Hz), 1.40 (br, 4H), 1.67 (m, 3H), 1.80-2.05 (m, 3H), 2.50-2.85 (m, 6H), 3.31 (br, 2H, NH), 3.78 (s, 2H), 3.96 (m, 1H), 4.07 (m, 1H), 4.14 (m, 1H), 6.81 (s, 1H), 6.89 (s, 1H) , 7.06 (m, 1H), 7.35 (d, 1H, J = 6.0 Hz), 8.51 (d, 1H, J = 6.0 Hz).
[1374] General Process D Use: The above material (67 mg, 0.19 mmol) was converted to a hydrobromide salt to give compound 130 (108 mg) as a white solid. 1 H NMR (D 2 O) δ 0.90 (t, 3H, J = 7.4 Hz), 1.50 (br, 4H), 1.81 (m, 3H), 2.04 (m, 1H), 2.17 (br m, 1H), 2.36 (br m, 1H), 2.48 (br m, 1H), 2.75 (br m, 1H), 2.89 (br, 2H), 3.00 (br, 2H), 4.10-4.18 (m, 3H), 4.34 (d, 1H, J = 16.8 Hz), 4.40 (m, 1H), 7.47 (s, 2H), 7.86 (t, 2H, J = 7.0 Hz), 8.34 (d, 1H, J = 8.1 Hz), 8.59 (d, 1H, J = 5.7 Hz). 13C NMR (D 2 O) δ 10.43, 20.30, 20.42, 23.28, 25.08, 25.42, 27.68, 39.56, 46.60, 49.72, 51.63, 60.36, 119.11, 123.29, 125.93, 139.35, 140.59, 144.68, 148.12, 151.28 ES-MS m / z 342 (M + H). Calcd for _{C20H31N5 · 3.5HBr · 1.9H2O · 0.3C4H 10} O: C, 37.38; H, 6. 11; N, 10.28; Br, 41.06. Found: C, 37.43; H, 5.86; N, 10.28; Br, 40.90.
[1375] Example 131
[1376]
[1377] Compound 131: N1- (1-methyl-1H-imidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) butane-1,4-diamine (hydro Bromide salts).
[1378] 2- {4-[(1-Methyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl} -isoindole- Preparation of 1,3-dione:
[1379] 2- [4- (5,6,7,8-tetrahydro-quinoline-8-ylaminol) -butyl] -isoindole-1,3-dione (190 mg, 0.544 mmol) in CH 2 Cl 2 (2.5 mL) And sodium triacetoxyborohydride (209 mg, 0.99 mmol) were added to a solution of 1-methyl-2-imidazolcarboxaldehyde (54 mg, 0.49 mmol). It was then diluted with CH 2 Cl 2 (15 mL) and extracted with saturated NaHCO 3 (2 × 15 mL). The organic layer was dried (MgSO 4), filtered, concentrated and dried under vacuum to give a yellow oil. Purification by silica gel radial chromatography (2 mm plate, using NH 4 OH / CH 3 OH / CH 2 Cl 2; 1: 1: 100 → 1: 3: 100, gradient eluent) afforded the desired product as a yellow oil (160 mg, 73%). Obtained as. 1 H NMR (CDCl-3-) δ 1.24-1.31 (m, 2H), 1.51-1.66 (m, 2H), 1.84-2.07 (m, 3H), 2.53-2.76 (m, 5H), 3.54 (t, 2H , J = 7.2 Hz), 3.77 (2, 3H), 3.74 (d, 2H, J = 15.9 Hz), 3.97 (t, 1H, J = 9.0 Hz), 6.73 (s, 1H), 6.77 (s, 1H ), 6.99 (dd, 1H, J = 7.5, 4.8 Hz), 7.30 (d, 1H, J = 7.5 Hz), 7.68-7.72 (m, 2H), 7.78-7.84 (m, 2H), 8.40 (d, 1H, J = 3.9 Hz).
[1380] Preparation of N1- (1-Methyl-1H-imidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine:
[1381] To a solution of the above amine (152 mg, 0.34 mmol) in ethanol (8 mL) was added hydrazine hydrate (83 mL, 1.71 mmol). The reaction mixture was stirred overnight. The solvent was then removed under reduced pressure to give a yellow solid. Purification by silica gel radial chromatography (1 mm plate, using NH4-H / CH3OH / CH2Cl2; 1: 3: 100 → 1: 6: 100, gradient eluent) afforded the desired product as a yellow oil (48 mg, 47%). Obtained). 1 H NMR (CDCl 3) δ 1.33-1.35 (br s, 2H), 1.64-1.67 (m, 1H), 1.87-2.05 (m, 3H), 2.52-2.77 (m, 6H), 3.43 (s, 2H), 3.71 (s, 3H), 3.81 (s, 2H), 4.00 (t, 1H, J = 7.4 Hz), 6.76 (s, 1H), 6.84 (s, 1H), 7.03 (dd, 1H, J = 7.7, 4.8 Hz), 7.33 (d, 1H, J = 7.5 Hz), 8.44 (d, 1H, J = 4.5 Hz),
[1382] N1- (1-methyl-1H-imidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (hydrobromide salt Manufacture of
[1383] To a solution of the above amine (48 mg, 0.015 mmol) in acetic acid (3 mL) was added hydrobromic acid saturated acetic acid (2 mL) and the reaction mixture was stirred for 30 minutes. This was then triturated three times with diethyl ether to give a white solid. The solid was dissolved in methanol (1 mL) and triturated with diethyl ether three times to give compound 131 as a white solid (72 mg, 79%). 1 H NMR (D 2 O) δ 1.52-1.55 (m, 4H), 1.75-1.89 (m, 1H), 2.01 (q, 1H, J = 13.2 Hz), 2.15-2.21 (m, 1H), 2.36-2.39 (m , 1H), 2.49-2.55 (m, 1H), 2.74-2.82 (m, 1H), 2.89-2.91 (m, 2H), 3.00-3.03 (m, 2H), 3.83 (s, 3H), 4.22 (ABq , 2H, J = 53.9, 16.8 Hz, 4.42 (dd, 1H, J = 9.0, 5.4 Hz), 7.42 (ABq, 2H, J = 12.9, 2.1 Hz), 7.86 (dd, 1H, J = 8.1, 6.0 Hz), 8.35 (d, 1H, J = 8.1 Hz), 8.59 (d, 1H, J = 5.1 Hz). 13C NMR (D 2 O) δ 20.29, 20.43, 25.08, 25.36, 27.67, 34.73, 39.56, 46.37, 51.71, 60.28, 118.73, 124.50, 125.90, 139.35, 140.60, 144.98, 148.10, 151.33. ES-MS m / z 314 [M + H] &lt; + &gt;. Latch for C18H27N5.3.0HBr.2.1H2O: C, 36.40; H, 5.80; N, 11.79; Br, 40.35. Found: C, 36.28; H, 5.78; N, 11.48; Br, 40.66.
[1384] Example 132
[1385]
[1386] Compound 132: N1- (1-allyl-1H-imidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine (hydro Bromide salts)
[1387] Allyl bromide (0.88 mL, 10.1 mmol) was added to a solution of 2-imidazolecarboxaldehyde (0.81 g, 8.4 mmol) and diisopropylethylamine (2.2 mL, 12.6 mmol) in anhydrous DMF (28 mL), and the solution was Stir at 60 ° C. for 16 h. The mixture was then concentrated under reduced pressure and the residue partitioned between dichloromethane (20 mL) and sodium bicarbonate (15 mL). The organic phase was separated and the aqueous phase extracted with dichloromethane (2 x 15 mL). The combined organic phases were then dried (Na 2 SO 4), filtered and concentrated under reduced pressure to afford a crude residue which was purified by silica gel column chromatography (1:99 MeOH / CH 2 Cl 2). From this, 2- (N-allylimidazole) -carboxaldehyde (0.62 g, 54%) was prepared. 1 H NMR (CDCl 3) δ 5.02 (d, 2H, J = 6.0 Hz), 5.10 (d, 1H, J = 18.0 Hz), 5.25 (d, 1H, J = 9.0 Hz), 5.96 (m, 1H), 7.16 (s, 1 H), 7.30 (s, 1 H), 9.81 (s, 1 H).
[1388] Using general process B, 2- [4- (5,6,7,8-tetrahydroquinolin-8-ylamino) -butyl] -isoindole-1,3-dione (0.80 g, 2.3 mmol), 2- (N-allylimidazole) -carboxaldehyde (0.62 g, 4.5 mmol) and sodium triacetoxyborohydride (1.16 g, 5.5 mmol) were stirred for 16 h in dichloromethane (22 mL) at room temperature. Post-treatment and column chromatography (1: 4 ethyl acetate: hexane), followed by 2- {4-[(1-allyl-1H-imidazol-2-ylmethyl)-(5,6,7,8-tetra Hydroquinolin-8-yl) -amino] -butyl} -isoindole-1,3-dione was obtained as a yellow oil (0.45 g, 40%). 1 H NMR (CDCl 3) δ 1.26 (m, 2H), 1.50-1.70 (m, 3H), 1.75-2.00 (m, 1H), 2.03 (m, 2H), 2.54 (m, 2H), 2.57-2.80 (m , 2H), 3.55 (t, 2H, J = 6.0 Hz), 3.83 (s, 2H), 3.97 (m, 1H), 4.84 (d, 1H, J = 15.0 Hz), 4.92 (d, 1H, J = 15.0 Hz), 5.07 (br d, 2H, J = 7.5 Hz), 5.93 (m, 1H), 6.77 (s, 1H), 6.82 (s, 1H), 7.01 (m, 1H), 7.30 (d, 1H) , J = 7.0 Hz), 7.70 (m, 2H), 7.82 (m, 2H), 8.40 (d, 1H, J = 3.0 Hz).
[1389] A solution of the above compound (0.40 g, 0.85 mmol) in anhydrous ethanol (8.4 mL) was treated with n-butylamine (0.85 mL, 8.5 mmol) and stirred at 80 ° C. for 16 h. The solution was then concentrated under reduced pressure and purified by silica gel column chromatography (2: 1: 97 methanol: ammonium hydroxide: dichloromethane) to give N- (1-allyl-1H-imidazol-2-ylmethyl)- N- (5,6,7,8-tetrahydroquinolin-8-yl) -butane-1,4-diamine (0.19 g, 66%) was obtained. 1 H NMR (CDCl 3) δ 1.35 (br, 4H), 1.67 (m, 1H), 1.80-2.10 (m, 3H), 2.55 (br, 4H), 2.62-2.80 (m, 2H), 3.80 (s, 2H ), 4.02 (m, 1H), 4.75 (dd, 1H, J = 4.5, 18.0 Hz), 4.89 (d, 1H, J = 18.0 Hz), 5.05 (dd, 1H, J = 4.5, 18.0 Hz), 5.09 (d, 1H, J = 18.0 Hz), 5.88 (m, 1H), 6.81 (s, 1H), 6.90 (s, 1H), 7.04 (m, 1H), 7.33 (d, 1H, J = 6.0 Hz) , 8.45 (d, 1H, J = 6.0 Hz).
[1390] General Process D Use: The above material (180 mg, 0.53 mmol) was converted to a hydrobromide salt to give compound 132 (312 mg) as a white solid. 1 H NMR (D 2 O) δ 1.53 (br, 5H), 1.81 (br m, 1H), 1.96 (m, 1H), 2.18 (br m, 1H), 2.34 (br m, 1H), 2.48 (br m, 1H ), 2.74 (br m, 1H), 2.89 (br, 2H), 3.00 (br, 2H), 4.14 (d, 1H, J = 16.8 Hz), 4.32 (d, 1H, J = 16.5 Hz), 4.38 ( m, 1H), 4.85 (br d, 2H, J = 5.1 Hz), 5.18 (d, 1H, J = 17.1 Hz), 5.40 (d, 1H, J = 10.5 Hz), 6.02 (m, 1H), 7.48 (d, 1H, J = 1.8 Hz), 7.51 (d, 1H, J = 1.8 Hz), 7.87 (t, 2H, J = 6.8 Hz), 8.35 (d, 1H, J = 7.8 Hz), 8.60 (d , 1H, J = 5.7 Hz). 13C NMR (D 2 O) δ 20.23, 20.39, 25.08, 25.39, 27.66, 39.57, 46.51, 50.32, 51.57, 60.32, 119.20, 119.92, 123.65, 125.95, 131.00, 139.35, 140.60, 145.01, 148.14, 151.27. ES-MS m / z 340 (M + H). Calcd for C20H29N5.3.0HBr.1.6H2O: C, 39.31; H, 5.81; N, 11.46; Br, 39.23. Found: C, 39.54; H, 5.80; N, 11.07; Br, 39.13.
[1391] Example 133
[1392]
[1393] Compound 133: N1- (5,6,7,8-tetrahydro-imidazo [1,5-a] pyridin-3-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinoline- Preparation of 8-yl) -butane-1,4-diamine (hydrobromide salt)
[1394] Preparation of 5,6,7,8-tetrahydro-imidazo [1,5-a] pyridine-3-carbaldehyde:
[1395]
[1396] Prepared according to 5,6,7,8-tetrahydro-imidazo [1,5-a] pyridine (Lattrell, R. et al. The J. of Antibiotics 1988, 41, 1395-1408 in THF (7 mL). To the solution was added n-BuLi (2.5 M in hexane, 0.70 mL, 1.75 mmol) solution at -78 ° C, and the reaction was stirred at -78 ° C for 10 minutes. DMF (1.0 mL) was added to the mixture at −78 ° C. and the reaction was allowed to warm to rt and stirred for 2 h before quenching with saturated aqueous NH 4 Cl (5 mL). The mixture was diluted with EtOAc (30 mL) and brine, and the organic phase was washed with brine (1 × 30 mL), dried (Na 2 SO 4) and concentrated in vacuo. The resulting brown oil (191 mg) was purified by column chromatography on silica gel (CH 2 Cl 2 / MeOH, 96: 4) to afford the desired aldehyde (105 mg, 40%) as an orange oil. 1 H NMR (CDCl 3) δ 1.83-1.89 (m, 2H), 1.94-2.02 (m, 2H), 2.85 (t, 2H, J = 6 Hz), 4.39 (t, 2H, J = 6 Hz), 7.05 (s, 1H), 9.71 (s, 1H).
[1397] According to general process B: 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione in anhydrous CH2Cl2 (7 mL) 174 mg, 0.50 mmol) and NaBH (OAc) 3 (in a stirred solution of 5,6,7,8-tetrahydro-imidazo [1,5-a] pyridine-3-carbaldehyde (82 mg, 0.48 mmol). 152 mg, 0.72 mmol) was added and the mixture was stirred at rt for 5.5 h. The resulting yellow foam (271 mg) was purified by column chromatography on silica gel (CH 2 Cl 2 / MeOH / NH 4 OH, 96: 4: 0 then 92: 8: 0 then 94: 4: 2) to give the desired amine (153 mg, 66 %) Was obtained as a white foam.
[1398] Anhydrous hydrazine (0.055 mL, 1.73 mmol) was added to a solution of phthalimide (153 mg, 0.32 mmol) from the stomach in EtOH (4 mL), and the mixture was stirred overnight. The white solid obtained was filtered through filter paper, washed thoroughly with CH 2 Cl 2 and the filtrate was concentrated in vacuo. The crude product was purified by silica gel radial chromatography (1 mm plate, CH 2 Cl 2 / MeOH / NH 4 OH, 50: 1: 1 then 20: 1: 1 then 10: 1: 1) to give the desired free amine (72 mg, 64% ) Was obtained as a pale yellow oil.
[1399] General Process D Use: The material from the stomach (72 mg, 0.20 mmol) was converted to a hydrobromide salt to give compound 133 (106 mg, 78%) as a yellow solid. 1 H NMR (D 2 O) δ 1.48-1.60 (m, 4H), 1.75-1.87 (m, 3H), 1.96-2.07 (m, 3H), 2.16-2.20 (m, 1H), 2.34-2.38 (m, 1H) , 2.49-2.55 (m, 1H), 2.74-2.83 (m, 3H), 2.89-2.95 (m, 2H), 2.99-3.02 (m, 2H), 4.06-4.13 (m, 3H), 4.24 (d, 1H, J = 16.8 Hz, 4.42 (dd, 1H, J = 10.5, 5.4 Hz), 7.14 (s, 1H), 7.85 (dd, 1H, J = 7.8, 6 Hz), 8.33 (d, 1H, J = 7.8 Hz), 8.58 (d, 1 H, J = 5.7 Hz); 13C NMR (D 2 O) δ 18.77, 20.19, 20.42, 21.77, 25.10, 25.39, 27.68, 39.59, 44.44, 46.04, 51.84, 60.13, 114.38, 125.85, 132.38, 139.32, 140.57, 142.58, 148.04, 151.44. ES-MS m / z 354 (M + H). Calcd for _{C21H31N5 · 3.3HBr · 0.9H2O · 0.4C4H 10} O: C, 40.73; H, 6.07; N, 10.51; Br, 39.57. Found: C, 40.48; H, 5.71; N, 10.34; Br, 39.83.
[1400] Example 134
[1401]
[1402] Compound 134: N1- (4-methoxymethyl-1H-imidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4- Preparation of diamines (hydrobromide salts)
[1403] Preparation of 4 (and 3) -methoxymethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbaldehyde:
[1404]
[1405] To a solution of 4- (hydroxymethyl) imidazole hydrochloride (578 mg, 4.30 mmol) in DMF (3.5 mL), DIPEA (1.9 mL, 10.9 mmol) and 2- (trimethylsilyl) ethoxymethyl chloride (0.83 mL, 4.69) mmol) was added and the mixture was stirred overnight. The reaction was diluted with EtOAc (60 mL) and brine (40 mL) and the organic phase was washed with brine (2 × 40 mL), dried (Na 2 SO 4) and concentrated. The resulting yellow oil (1.04 g) was purified by column chromatography on silica gel (CH 2 Cl 2 / MeOH / NH 4 OH, 96: 4: 0 then 94: 4: 2 then 88: 10: 2) to give the desired SEM-protected imidazole. (416 mg, 42%) was obtained as a mixture of legioisomers.
[1406] To a solution of alcohol (416 mg, 1.82 mmol) from the stomach in THF (10 mL) was added NaH at 0 ° C. and the mixture was stirred for 30 minutes. MeI was added to the obtained suspension, and the reaction was stirred at 0 ° C. to room temperature over 2.5 hours, then diluted with H 2 O (20 mL) and EtOAc (25 mL). The organic phase was washed with brine (1 × 25 mL), dried (Na 2 SO 4) and concentrated to afford the desired methyl ether (430 mg) as a yellow oil.
[1407] To a solution of imidazole (430 mg, 1.78 mmol) from the stomach in THF (10 mL) was added a solution of n-BuLi (2.5 M in hexane, 0.71 mL, 1.78 mmol) at -78 ° C and the reaction was carried out at -78 ° C 10. Stir for minutes. DMF (1.0 mL) was added at −78 ° C. and the reaction was allowed to warm to rt, stirred for 2 h and then quenched with saturated aqueous NH 4 Cl (10 mL). The mixture was diluted with EtOAc (30 mL) and brine (20 mL), and the organic phase was washed with brine (1 x 30 mL), dried (Na2SO4) and concentrated in vacuo. The yellow oil obtained was purified by column chromatography on silica gel (hexane / EtOAc, 2: 1) to give a mixture of the two desired regioisomeric aldehydes (194 mg, 40%) as a yellow oil. 1 H NMR (CDCl 3) δ 1.83-1.89 (m, 2H), 1.94-2.02 (m, 2H), 2.85 (t, 2H, J = 6 Hz), 4.39 (t, 2H, J = 6 Hz), 7.05 (s, 1H), 9.71 (s, 1H).
[1408] According to general process B: 2- [4- (5,6,7,8-tetrahydro-quinolin-8-ylamino) -butyl] -isoindole-1,3-dione in anhydrous CH2Cl2 (8 mL) 269 mg, 0.77 mmol) and a stirred solution of 4 (and 3) -methoxymethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbaldehyde (194 mg, 0.72 mmol) To NaBH (OAc) 3 (236 mg, 1.11 mmol) was added and the mixture was stirred at rt for 4 h. The crude brown oil (459 mg) obtained was purified by column chromatography on silica gel (CH 2 Cl 2 / MeOH, 96: 4) to afford the desired amine (329 mg, 76%) as pale yellow oil.
[1409] A solution of SEM-protected imidazole (329 mg, 0.55 mmol) in 4N HCl (8 mL) was stirred at 60 ° C. for 4.5 h, then cooled to rt and neutralized with solid K 2 CO 3 (8.1 g). The slurry was diluted with H 2 O (15 mL) and CH 2 Cl 2 (30 mL) and the aqueous phase was extracted with CH 2 Cl 2 (3 × 30 mL). The combined organic layers were dried (Na 2 SO 4), concentrated and purified by column chromatography on silica gel (CH 2 Cl 2 / MeOH, 96: 4 then 92: 8) to afford the desired product (248 mg, 96%) as a clear oil.
[1410] Anhydrous hydrazine (0.10 mL, 3.15 mmol) was added to a phthalimide solution from above in EtOH (4 mL) and the mixture was stirred overnight. The white solid obtained was filtered through filter paper, washed thoroughly with CH 2 Cl 2 and the filtrate was concentrated in vacuo. The crude product was purified by silica gel radial chromatography (1 mm plate, CH 2 Cl 2 / MeOH / NH 4 OH, 50: 1: 1 then 25: 1: 1 then 10: 1: 1) to give the desired free amine (83 mg, 46% ) Was obtained as a clear oil.
[1411] General Process D Use: The material from the stomach (83 mg, 0.18 mmol) was converted to a hydrobromide salt to give compound 134 (137 mg, 88%) as a white solid. 1 H NMR (D 2 O) δ 1.44-1.55 (m, 4H), 1.79-2.01 (m, 2H), 2.14-2.18 (m, 1H), 2.26-2.31 (m, 1H), 2.43-2.53 (m, 1H) , 2.72-2.79 (m, 1H), 2.88-2.92 (m, 2H), 2.98-3.01 (m, 2H), 3.40 (s, 3H), 4.16 (d, 1H, J = 16.2 Hz), 4.29 (d , 1H, J = 16.2 Hz), 4.42 (dd, 1H, J = 10.5, 5.4 Hz), 4.58 (s, 2H), 7.47 (s, 1H), 7.86 (dd, 1H, J = 7.8, 6 Hz), 8.34 (d, 1H, J = 7.8 Hz), 8.59 (d, 1H, J = 5.7 Hz); 13C NMR (D 2 O) δ 20.33, 20.46, 25.08, 25.37, 27.63, 39.59, 47.43, 51.36, 58.23, 60.30, 63.39, 118.68, 125.90, 129.93, 139.28, 140.51, 146.34, 148.04, 151.45. ES-MS m / z 344 (M + H). Calculated for _{C19H29N5O · 3.2HBr · 0.7H2O · 0.4C4H 10} O: C, 38.38; H, 5.88; N, 10.86; Br, 39.66. Found: C, 38.42; H, 5.75; N, 10.92; Br, 39.56.
[1412] Example 135
[1413]
[1414] Compound 135: N1- (1-allyl-1H-imidazol-2-ylmethyl) -N1- (S) -5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4- Preparation of Diamines (hydrochloride Salts)
[1415] Preparation of 1-allyl-1H-imidazole-2-carbaldehyde:
[1416] A solution of 2-imidazole carboxaldehyde (15.0 g, 156 mmol), allyl bromide (22.6 g, 187 mmol) and diisopropylethylamine (40.7 mL, 234 mmol) was added in N, N-dimethylformamide (500 mL). Stir for hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (370 mL). The solution was made of sodium carbonate (185 mL). Wash once with saturated solution. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 280 mL). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. The crude material was then purified by flash chromatography (99: 1 CH 2 Cl 2 / methanol) to afford the desired compound (12.8 g, 60%) as a yellow oil. 1 H NMR (300 MHz, CDCl 3, δ ppm) 5.04 (d, 2H, J = 5.5 Hz), 5.11 (d, 1H, J = 17.5 Hz), 5.25 (d, 1H, J = 10.0 Hz), 5.90-6.05 (m, 1 H), 7.16 (s, 1 H), 7.30 (s, 1 H), 9.81 (s, 1 H); 13 C NMR (75 MHz, CDCl 3, δ ppm) 49.77, 118.61, 126.00, 131.74, 132.39, 143.17, 182.05.
[1417] N1- (1-allyl-1H-imidazol-2-ylmethyl) -N1- (S) -5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine (compound 135)
[1418] General process B use: N '-(S) -5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine (29.86 g, 85 mmol) and 1-allyl-1H-imide Dozol-2-carbaldehyde (12.8 g, 94 mmol) was reacted with NaBH (OAc) 3 (18.0 g, 85 mmol) for 39 hours in CH2Cl2 (470 mL), and then the crude material was flash chromatographed (4: 1 AcOEt / Hexane) gave 21 g of yellow oil. 1 H NMR (300 MHz, CDCl 3, δ ppm) 3.55 (t, 2H, J = 7.0 Hz), 1.20-2.80 (series of m, 12H), 3.84 (s, 2H), 3.98 (m, 1H), 4.87 ( dd, 1H, J = 1.0 & 17.0 Hz, 4.70-5.15 (m, 2H), 5.08 (dd, 1H, J = 1.0 & 10.0 Hz), 5.80-6.00 (m, 1H), 6.76 (d, 1H, J = 1.0 Hz), 6.82 (d, 1H, J = 1.0 Hz), 7.00 (dd, 1H, J = 4.5 & 7.5 Hz), 7.31 (d, 1H, J = 7.5 Hz), 7.65-7.75 (m, 2H), 7.75-7.85 (m, 2H), 8.41 (d, 1H, J = 4.5 Hz).
[1419] 2- {4-[(S)-(1-allyl-1H-imidazol-2-ylmethyl) -5,6,7,8-tetrahydro-quinolin-8-yl-amino] -butyl} -iso Indole-1,3-dione (21 g, 45 mmol) was dissolved in ethanol (450 mL) and treated with n-butylamine (44.6 mL, 450 mmol). The solution was stirred at 60 ° C. for 21 hours. The mixture was concentrated under reduced pressure and purified by flash chromatography (slowly increasing the amount of 97: 2: 1 CH 2 Cl 2 / methanol / NH 4 OH and methanol from 2% to 10%). The cleanest fraction (7.37 g, 77%) was carried out by chlorination process.
[1420] According to general process D, the material was converted to a hydrochloride salt and reprecipitated from methanol / diethyl ether to give compound 135 (7.97 g, 82%) as a beige solid. 1 H NMR (300 MHz, D2O, δ ppm) 1.45-1.60 (m, 4H), 1.65-1.85 (m, 1H), 1.85-2.05 (m, 1H), 2.05-2.20 (m, 1H), 2.25-2.40 (m, 1H), 2.40-2.55 (m, 1H), 2.65-2.80 (m, 1H), 2.85-2.95 (m, 2H), 2.95-3.05 (m, 2H), 4.10 (d, 1H, J = 17.0 Hz), 4.28 (d, 1H, 17.0 Hz), 4.30-4.40 (m, 1H), 4.80-4.85 (m, 2H), 5.14 (d, 1H, J = 17.0 Hz), 5.36 (d, 1H, J = 10.5 Hz), 5.90-6.10 (m, 1H), 7.46 (d, 1H, J = 2.0 Hz), 7.81 (dd, 1H, J = 5.5 & 8.0 Hz), 8.28 (d, 1H, J = 8.0 Hz), 8.57 (d, 1 H, J = 5.5 Hz); 13C NMR ((75 MHz, D2O, δ ppm) 20.20, 20.40, 25.06, 25.37, 27.66, 39.58, 46.50, 50.30, 51.56, 60.29, 119.17, 119.91, 123.62, 125.93, 131.02,139.34, 140.55, 145.01, 148.11 . 151.23 ES-MS m / z 340 (M + H) C20H29N5 · 3.2HCl · 3H2O · 0.3C4H calculated for _{10 O: C, 47.82; H} , 7.80; N, 13.15; Cl, 21.31 found:.. C, 47.98; H, 7.60; N, 13.11; Cl, 21.17.
[1421] Example 136
[1422]
[1423] Compound 136: N1- {2-[(1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -ethyl} -guanidine (hydrobromide Salts)
[1424] General process B use: N- (tert-butoxycarbonyl) -2-amino-acetaldehyde (0.204 g, 1.28 mmol) and (1H-benzimidazol-2-ylmethyl)-(5,6,7, 8-tetrahydro-quinolin-8-yl) -amine (0.284 g, 1.02 mmol) was reacted in NaBH (OAc) 3 (0.430 g, 2.03 mmol) with CH 2 Cl 2 (10 mL) to give 0.71 g of a yellow foam. The foam was dissolved in THF (10 mL) and treated with 6N hydrochloric acid (10 mL). The resulting solution was stirred overnight at room temperature. The solution was neutralized with solid K 2 CO 3 (5 g), diluted with water (5 mL) and extracted with CH 2 Cl 2 (3 × 20 mL). The combined organic extracts were dried (Na 2 SO 4) and concentrated. Purified by column chromatography on silica gel (20: 1: 1 CH 2 Cl 2 -CH 3 OH-NH 4 OH) to give N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinoline 0.205 g (64%) of -8-yl) -ethane-1,2-diamine was obtained as a yellow solid. N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -ethane-1,2-diamine in dry THF (6 mL) (0.205 g, 0.64 mmol) N, N'-bis- (tert-butoxycarbonyl) -1H-pyrazole-1-carboxamidine (Tetrahedron Lett. 1993, 34, 3389.) g, 0.64 mmol) was added and the resulting mixture was stirred at rt for 18 h. The mixture was concentrated and the oil obtained was purified by column chromatography on silica gel (40: 1: 1 CH 2 Cl 2 -CH 3 OH-NH 4 OH) and N, N'-bis (tert-butoxycarbonyl) -N- {2- 0.267 g (74%) of [(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -ethyl} -guanidine as a white foam Obtained
[1425] Using General Process D: Converting white foam (257 mg) to a hydrobromide salt while removing the BOC-protecting group and then reprecipitating the intermediate solid from methanol / ether to give compound 136 (253 mg, 86%) as a white solid Obtained as. 1 H NMR (D 2 O) δ 1.77-1.87 (m, 1H), 1.97-2.18 (m, 2H), 2.32-2.37 (m, 1H), 2.75-2.84 (m, 1H), 2.96-3.10 (m, 3H) , 3.19-3.33 (m, 2H), 4.39 (d, 1H, J = 16.5 Hz), 4.51-4.57 (m, 2H), 7.58-7.61 (m, 2H), 7.77-7.88 (m, 3H), 8.34 (d, 1H, J = 8.1 Hz), 8.65 (d, 1H, J = 5.7 Hz); 13 C NMR (D 2 O) δ 20.33, 20.57, 27.71, 39.96, 48.11, 50.17, 60.70, 114.33, 126.03, 126.99, 131.28, 139.68, 140.87, 148.18, 150.46, 150.84 ,; ES-MS m / z 364 (M + H). Calcd for _{C20H25N7 · 3.0HBr · 1.5H2O · 0.2C4H 10} O: C, 38.55; H, 5.13; N, 15.13; Br, 36.99. Found: C, 38.54; H, 5.07; N, 15.05; Br, 36.95.
[1426] Example 137
[1427]
[1428] Compound 137: {4-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butylamino} -acetic acid methyl ester ( Hydrobromide salts)
[1429] Preparation of [(2-nitro-benzenesulfonyl)-(4-oxo-butyl) -amino] -acetic acid methyl ester:
[1430] (293-2)
[1431] To a solution of 4-amino-1-butanol (555 mg, 6.23 mmol) in THF / saturated aqueous NaHCO ₃ (2: 1, 15 mL) was added 2-nitrobenzenesulfonyl chloride (1.4492 g, 6.54 mmol) at 0 ° C. The reaction was stirred overnight. The mixture was diluted with CH 2 Cl 2 (40 mL) and saturated aqueous NaHCO 3 (30 mL) and the aqueous layer was extracted with CH 2 Cl 2 (1 × 30 mL). The combined organic extracts were dried (Na 2 SO 4) and concentrated in vacuo. The yellow solid obtained (1.74 g) was washed with Et 2 O (3 × 15 mL) and dried under vacuum to give nonyl-protected alcohol (1.34 g, 78%) as a white solid.
[1432] Methyl bromoacetate (0.55 mL, 5.81 mmol) was added to a suspension of alcohol from the stomach (1.34 g, 4.89 mmol) and K 2 CO 3 (1.346 g, 9.94 mmol) in CH 3 CN (20 mL) and the reaction was stirred at 50 ° C. for 4 hours. Was stirred. The mixture was cooled to rt, concentrated, diluted with CH 2 Cl 2 (50 mL) and washed with H 2 O (40 mL). The aqueous layer was extracted with CH 2 Cl 2 (1 × 15 mL) and the combined organic layers were dried (Na 2 SO 4) and concentrated to give alkylated amine (1.59 g) as pale yellow oil.
[1433] A solution of gastric alcohol (881 mg, 2.55 mmol) in CH 2 Cl 2 (10 mL) was treated with molecular seed (837 mg), N-methylmorpholine oxide (673 mg, 5.75 mmol) and TPAP (64 mg, 0.18 mmol) It was. The mixture was stirred for 1.5 h, then filtered through silica and washed with 1: 1 EtOAc / hexanes. The filtrate was then concentrated under reduced pressure to afford the title compound (414 mg, 47%) as a pale yellow oil. 1 H NMR (CDCl 3) δ 1.86 (q, 2H, J = 6 Hz), 2.57 (t, 2H, J = 6 Hz), 3.43 (t, 2H, J = 6 Hz), 3.65 (s, 3H), 4.17 (s, 2H), 7.59-7.62 (m, 1H), 7.68-7.71 (m, 2H), 8.02-8.05 (m, 1H), 9.75 (s, 1H).
[1434] According to general process B: (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (155 mg, in anhydrous CH2Cl2 (10 mL) 0.56 mmol) and NaBH (OAc) 3 (159 mg, 0.75) in a stirred solution of [(2-nitro-benzenesulfonyl)-(4-oxo-butyl) -amino] -acetic acid methyl ester (189 mg, 0.55 mmol) mmol) was added and the mixture was stirred at rt overnight. The resulting crude brown oil (0.81 g) was purified by column chromatography on silica gel (CH 2 Cl 2 / MeOH / NH 4 OH, 95: 4: 1) to afford the desired amine (166 mg, 48%) as a yellow foam.
[1435] To a stirred solution of nonyl-protected amine (125 mg, 0.21 mmol) from above in anhydrous CH 3 CN (5 mL) was added thiophenol (0.12 mL, 1.17 mmol) followed by K 2 CO 3 (177 mg, 1.28 mmol) powder. The resulting light yellow solution was stirred overnight at room temperature. The solvent was removed under reduced pressure and CH 2 Cl 2 (30 mL) and water (30 mL) were added to the residue. The phases were separated and the aqueous phase was extracted with CH 2 Cl 2 (2 × 10 mL). The combined organic phases were dried (Na 2 SO 4) and concentrated. The crude material was purified by column chromatography on silica gel (CH 2 Cl 2 / MeOH / NH 4 OH, 94: 4: 2) followed by radial chromatography on silica gel (1 mm plate, CH 2 Cl 2 / MeOH / NH 4 OH, 100: 1: 1 the 50: 1: 1 then 25: 1: 1) to give the free base (33 mg, 37%) as a clear oil.
[1436] General Process D Use: The material from the stomach (33 mg, 0.078 mmol) was converted to the hydrobromide salt to give compound 137 (43 mg, 78%) as a white solid. 1 H NMR (D 2 O) δ 1.54-1.59 (m, 4H), 1.76-1.90 (m, 1H), 1.97-2.09 (m, 1H), 2.16-2.21 (m, 1H), 2.36-2.39 (m, 1H) , 2.55-2.61 (m, 1H), 2.81-2.88 (m, 1H), 2.99-3.02 (br m, 4H), 3.78 (s, 3H), 3.93 (s, 2H), 4.40 (d, 1H, J = 16.8 Hz), 4.49-4.57 (m, 1H), 4.54 (d, 1H, J = 16.8 Hz), 7.60 (dd, 2H, J = 6, 3 Hz), 7.80 (dd, 2H, J = 6, 3 Hz ), 7.87 (dd, 1H, J = 7.8, 6 Hz), 8.34 (d, 1H, J = 7.8 Hz), 8.64 (d, 1H, J = 5.7 Hz); 13C NMR (D 2 O) δ 20.44, 23.66, 25.38, 27.65, 47.57, 47.62, 48.26, 51.64, 53.85, 60.67, 114.27, 125.94, 126.93, 131.00, 139.35, 140.61, 148.11, 151.24, 151.77, 168.15. ES-MS m / z 422 (M + H). Calcd for C24H31N5O2.3.0HBr.2.2H2O: C, 40.95; H, 5.50; N, 9.95; Br, 34.05. Found: C, 40.91; H, 5.57; N, 9.67; Br, 34.32.
[1437] Example 138
[1438]
[1439] Compound 138: pyrazine-2-carboxylic acid {4-[(1H-benzimidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydro-quinolin-8-yl-amino] -butyl } -Preparation of Amide
[1440] N '-(1H-benzimidazol-2-ylmethyl) -N'-(S) -5,6,7,8-tetrahydro-quinolin-8-yl-butane-1 in CH 2 Cl 2 (5 mL), 2-pyrazinecarboxylic acid (74.8 mg, 0.60 mmol), N, N-diisopropylethylamine (0.21 mL, 1.2 mmol), HOBT (97.7 mg, 0.72 mmol) in 4-diamine (211 mg, 0.60 mmol) and EDC (139 mg, 0.72 mmol) was added. The resulting solution was stirred at rt for 16 h. The reaction mixture was diluted with CH 2 Cl 2 (15 mL) and brine (25 mL) and the phases mixed and separated. The aqueous layer was extracted with CH 2 Cl 2 (2 × 15 mL) and the combined organic extracts were dried (Na 2 SO 4), filtered and concentrated in vacuo. The crude white foam was purified by flash chromatography on silica gel (CH 2 Cl 2 / MeOH / NH 4 OH, 100: 3: 1) to afford the title compound (166 mg, 60%) as a white solid. 1 H NMR (CDCl 3) δ 1.42-1.80 (m, 7H), 1.86-2.09 (m, 2H), 2.16-2.26 (m, 1H), 2.58-2.90 (m, 4H), 3.23-3.37 (m, 2H) , 4.13 (d, 1H, J = 16.8 Hz), 4.04 (d, 1H, J = 16.8 Hz), 4.02-4.11 (m, 1H), 7.11-7.22 (m, 3H), 7.42 (d, 1H, J = 7.5 Hz), 7.46-7.52 (m, 1H), 7.60-7.76 (m, 2H), 8.43 (t, 1H, J = 1.5 Hz), 8.58 (d, 1H, J = 3.9 Hz), 8.71 (d , 1H, J = 2.4 Hz), 9.34 (d, 1H, J = 1.2 Hz); 13C NMR (CDCl3) δ 21.76, 24.03, 26.20, 27.35, 29.56, 39.38, 49.92, 50.39, 62.15, 111.37, 119.11, 121.91, 122.59, 134.98, 137.73, 142.83, 144.64, 144.83, 147.01, 84.47, 147. 163.25; ES-MS m / z 456 (M + H). Calc. For C 24 H 25 N 7 O 2 .0.6 H 2 O: C, 66.96; H, 6.53; N, 21.02. Found: C, 66.94; H, 6. 54; N, 21.05.
[1441] Example 139
[1442]
[1443] Compound 139: pyridine-2-carboxylic acid {3-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl}- Preparation of Amides (hydrobromide)
[1444] To a stirred solution of picolinic acid (36.7 mg, 0.30 mmol) in DMF (3 mL), N, N-diisopropylethylamine (0.10 mL, 0.6 mmol), HOBT (48.3 mg, 0.36 mmol), EDC (68.6) Mg, 0.36 mmol) and N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -propane-1,3-diamine ( 100 mg, 0.30 mmol) was added. The resulting solution was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (40 mL), brine (15 mL) and H 2 O (5 mL) and the two layers were mixed vigorously for 15 minutes. The layers were separated and the organic layer was washed with brine (5 × 15 mL), dried (Na 2 SO 4), filtered and concentrated in vacuo. The beige foam was purified by radial chromatography on 1 mm TLC grade silica gel plate (CH 2 Cl 2 / MeOH / NH 4 OH, 50: 1: 1) to give the free base (63.0 mg, 48%) of the title compound as a white foam.
[1445] General Process D Use: The foam from the stomach (63.0 mg, 0.14 mmol) was converted to a hydrobromide salt and then reprecipitated the intermediate solid from methanol / ether to give compound 139 (81.3 mg, 79%) as a cream solid. . ¹ H NMR (D 2 O) δ 1.72-1.92 (m, 3H), 1.93-2.10 (m, 1H), 2.11-2.23 (m, 1H), 2.33-2.44 (m, 1H), 2.52-2.64 (m, 1H ), 2.83-3.05 (m, 3H), 3.24-3.50 (m, 2H), 4.29 (d, 1H, J = 16.2 Hz), 4.44 (d, 1H, J = 16.5 Hz), 4.55 (dd, 1H, J = 10.4, 5.7 Hz), 7.42-7.49 (m, 2H), 7.59-7.66 (m, 2H), 7.80 (t, 1H, J = 6.8 Hz), 7.89 (t, 1H, J = 6.5 Hz), 7.95 (d, 1H, J = 8.1 Hz), 8.24-8.34 (m, 2H), 8.62 (d, 2H J = 5.1 Hz); 13C NMR (D 2 O) δ 20.43, 27.63, 37.76, 48.05, 48.93, 59.91, 114.12, 123.82, 125.87, 126.99, 129.16, 130.71, 139.39, 140.66, 144.19, 144.86, 145.77, 148.03, 151.25, 163. ES-MS m / z 441 (M + H). Calcd for C26H28N6O.2.9HBr.2.7H2O: C, 43.14; H, 5.05; N, 11.61; Br, 32.01. Found: C, 43.26; H, 5.07; N, 11.24; Br, 32.37.
[1446] Example 140
[1447]
[1448] Compound 140: isoquinoline-3-carboxylic acid {3-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} Preparation of -amide (hydrobromide)
[1449] To a stirred solution of 1-isoquinolinecarboxylic acid (51.6 mg, 0.30 mmol) in anhydrous DMF (3 mL), N, N-diisopropylethylamine (0.10 mL, 0.6 mmol), HOBT (48.3 mg, 0.36 mmol), EDC (68.6 mg, 0.36 mmol) and N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -propane-1,3- Diamine (100 mg, 0.30 mmol) was added. The resulting solution was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (40 mL), brine (15 mL) and H 2 O (5 mL) and the two layers were mixed vigorously for 15 minutes. The layers were separated and the organic layer was washed with brine (5 × 15 mL), dried (Na 2 SO 4), filtered and concentrated in vacuo. The crude material was purified by radial chromatography on 1 mm TLC grade silica gel plate (CH 2 Cl 2 / MeOH / NH 4 OH, 50: 1: 1) to give the free base (79.2 mg, 54%) of the title compound as a white foam.
[1450] Use General Process D: Convert white foam (79.2 mg, 0.16 mmol) from above into hydrobromide salt and then reprecipitate the intermediate solid from methanol / ether to give compound 140 (106 mg, 86%) as a yellow solid. It was. 1 H NMR (D 2 O) δ 1.76-1.97 (m, 3H), 1.95-2.12 (m, 1H), 2.12-2.23 (m, 1H), 2.33-2.45 (m, 1H), 2.57-2.70 (m, 1H) , 2.88-3.04 (m, 3H), 3.39-3.54 (m, 2H), 4.33 (d, 1H, J = 16.5 Hz), 4.48 (d, 1H, J = 16.5 Hz), 4.57 (dd, 1H, J = 10.8, 5.7 Hz), 7.32-7.40 (m, 2H), 7.51-7.60 (m, 2H), 7.73-7.83 (m, 2H), 8.02 (t, 1H, J = 7.2 Hz), 8.12 (d, 1H, J = 6.3 Hz, 8.14 (d, 1H, J = 7.8 Hz), 8.22 (d, 1H, J = 6.3 Hz), 8.27 (d, 1H, J = 7.8 Hz), 8.36 (d, 1H, J = 6.0 Hz), 8.61 (d, 1 H J = 5.4 Hz); 13C NMR (D 2 O) δ 20.40, 27.66, 38.12, 48.23, 49.24, 60.06, 114.00, 124.73, 125.86, 126.61, 126.74, 126.83, 128.43, 130.67, 131.35, 134.81, 135.30, 139.26, 139.41, 140.07, 140. 151.26, 164.46; ES-MS m / z 491 (M + H). Calc. For C30H30N6O.2.9 HBr.2.3 H2O: C, 47.00; H, 4.93; N, 10.96; Br, 30.22. Found: C, 47.21; H, 5.01; N, 10.65; Br, 30.06.
[1451] Example 141
[1452]
[1453] Compound 141: N- {3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -6-hydro Roxy-nicotinamide (hydrobromide salt)
[1454] Preparation of (4-oxo-propyl) -carbamic acid tert-butyl ester:
[1455] To a solution of oxalyl chloride in CH 2 Cl 2 (2.0M, 12.3 mL, 24.63 mmol) was added dropwise DMSO at -78 ° C. The reaction mixture was stirred at -78 ° C for 20 minutes. Then a solution of (4-hydroxy-propyl) -carbamic acid tert-butyl ester (3.32 g, 18.95 mmol) in CH 2 Cl 2 was added, followed by addition of triethylamine (13.2 mL, 94.75 mmol) and the reaction mixture at room temperature. Warmed up. After 1.5 h, the mixture was diluted with brine (50 mL) and the phases separated. The organic layer was washed with brine (2 × 50 mL) and saturated NaHCO 3 (2 × 50 mL). The combined organic layers were dried (MgSO 4), filtered, concentrated and dried under vacuum to give an orange oil (2.76 g, 84%). 1 H NMR (CDCl 3) δ 1.42 (s, 9H), 2.710 (t, 2H, J = 6.0 Hz), 3.42 (q, 2H, J = 7.5 Hz), 4.90 (br s, 1H), 9.80 (s, 1H ).
[1456] 2-{[(3-tert-butoxycarbonylamino-propyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester:
[1457] Stomach aldehyde (1.70 g, 9.82 mmol) and 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -benzimidazole-1-carboxylic acid in CH 2 Cl 2 (20 mL) To a solution of tert-butyl ester (3.38 g, 8.92 mmol) was added sodium triacetoxyborohydride (3.78 g, 17.84 mmol). The reaction mixture was stirred at rt for 4 days. Then it was extracted with saturated NaHCO 3 (3 × 50 mL). The organic layer was dried (MgSO 4), filtered, concentrated and dried in vacuo to give a yellow foam. Purification by column chromatography on flash silica gel using 2% CH 3 OH / CH 2 Cl 2 gave the product as a yellow foam (4.23 g, 91%). 1 H NMR (CDCl 3) δ 1.41 (s, 9H), 1.60 (s, 9H), 1.64-1.75 (m, 2H), 1.89-2.04 (m, 3H), 2.21-2.25 (m, 1H), 2.66-2.89 (m, 3H), 3.20-3.24 (m, 2H), 3.40-3.44 (m, 1H), 4.17-4.43 (m, 3H), 6.90 (d, 1H, J = 3.0 Hz), 7.19-7.25 (m , 2H), 7.40 (m, 1H), 7.74-7.76 (m, 1h), 7.82-7.84 (m, 1H), 8.35 (d, 1H, J = 6.0 Hz).
[1458] Preparation of N1- (1H-Benzoimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -propane-1,3-diamine:
[1459] The above amine (4.23 g, 8.11 mmol) in 3N HCl / THF (2: 1) (30 mL) was stirred overnight at room temperature. It was then basified to pH 9 with potassium carbonate and extracted with CHCl 3 (3 × 50 mL). The combined organics were dried (Na 2 SO 4), filtered, concentrated and dried under vacuum to give a yellow foam (2.88 g, 100%). 1 H NMR (CDCl 3) δ 1.62-1.79 (m, 3H), 2.09 (m, 1H), 2.42-2.68 (m, 3H), 2.76-2.84 (m, 4H), 3.35 (d, 1H, J = 12.0 Hz ), 4.00 (d, 1H, J = 12.0 Hz), 4.10-4.15 (m, 1H), 4.34 (d, 1H, J = 15.0 Hz), 7.05-7.09 (m, 1H), 7.13-7.16 (m, 2H), 7.39 (d, 1H, J = 9.0 Hz), 7.60-7.61 (br m, 2H), 8.59 (d, 1H, J = 3.0 Hz).
[1460] N- [3-[(1-H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -6-hydroxy Preparation of Nicotinamide:
[1461] To a solution of the above amine (173 mg, 0.52 mmol) in DMF (3 mL), 1-hydroxybenzotriazole hydrate (104 mg, 0.77 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide Hydrochloride (148 mg, 0.77 mmol) and 6-hydroxynicotinic acid (86 mg, 0.62 mmol) were obtained. The reaction was stirred at rt overnight. It was then diluted with ethyl acetate (40 mL) and water (25 mL). The organic layer was washed with saturated NaHCO 3 (30 mL) and brine (30 mL), dried (Na 2 SO 4), filtered, concentrated and dried under vacuum to give a yellow oil. Purification by radial chromatography on silica gel (1 mm plate; NH 4 OH / CH 3 OH / CH 2 Cl 2; 1: 2: 100 → 1: 10: 100) gave the product as a yellow foam (63 mg, 27%). 1 H NMR (CDCl 3) δ 1.61-1.88 (m, 4H), 2.01-2.06 (m, 1H), 2.20-2.24 (m, 1H), 2.61-2.70 (m, 1H), 2.76-2.85 (m, 3H) , 3.26-3.30 (m, 1H), 3.45-3.51 (m, 1H), 4.00 (s, 2H), 4.13 (dd, 1H, J = 9.0, 6.0 Hz). 6.37 (d, 1H, J = 9.6 Hz), 7.13-7.18 (m, 3H), 7.43-7.46 (m, 3H), 7.52 (br s, 1H), 7.66 (dd, 1H, J = 9.6, 2.4 Hz ), 7.91 (d, 1H, J = 2.1 Hz), 8.48 (d, 1H, J = 3.6 Hz).
[1462] N- {3-[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -6-hydroxy-nicotine Preparation of the amide (hydrobromide salt):
[1463] Hydrobromide saturated acetic acid (2 mL) was added to a solution of the above amine (63 mg, 0.14 mmol) in acetic acid (2 mL). The reaction mixture was stirred for 30 minutes. Then it was triturated four times with diethyl ether to give the title compound as a white solid (80 mg), which was dried under vacuum. ¹ H NMR (D-2-O) δ 1.81-2.01 (m, 4H), 2.16-2.20 (m, 1H), 2.37-2.41 (m, 1H), 2.50-2.59 (m, 1H), 2.87-2.92 (m, 1H), 3.00 (br s, 2H), 3.11-3.16 (m, 1H), 3.37-3.42 (m, 1H), 3.53 (q, 1H, J = 6.0 Hz), 4.25 (ABq, 2H, J = 43.8, 15.3 Hz), 4.57-4.79 (m, 1H), 6.36 (d, 1H, J = 9.6 Hz), 7.46-7.48 (m, 2H), 7.53 (s, 1H), 7.57-7.63 (m , 3H), 7.85 (t, 1H, J = 6.3 Hz), 8.34 (d, 1H, J = 7.8 Hz), 8.65 (d, 1H, J = 5.4 Hz). 13C NMR (D-2-O) δ 20.33, 20.45, 36.87, 47.77, 48.22, 59.04, 114.10, 119.38, 125.90, 126.99, 130.69, 137.16, 139.46, 139.85, 140.66, 148.01, 150.87, 151.39. ES-MS m / z 457 [M + H] &lt; + &gt;. Calcd for C26H28N6O2.3.0HBr.3.4H2O.0.2C4H10O: C, 41.52; H, 5. 17; N, 10.84; Br, 30.92. Found: C, 41.70; H, 4. 90; N, 10.71; Br, 30.63.
[1464] Example 142
[1465]
[1466] Compound 142: N-3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -benzamide (hydro Bromide salts)
[1467] Preparation of N- {3-[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -benzamide:
[1468] N1- (1H-benzoimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -propane-1,3-diamine in DMF (3 mL) 166 mg, 0.50 mmol) 1-hydroxybenzotriazole hydrate (100 mg, 0.74 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (142 mg, 0.74 mmol) and Benzoic acid (73 mg, 0.59 mmol) was added. The reaction mixture was stirred at rt overnight. It was then diluted with ethyl acetate (40 mL) and water (25 mL). The organic layer was washed with saturated NaHCO 3 (30 mL) and brine (30 mL), dried (Na 2 SO 4), filtered, concentrated and vacuum Drying under gave yellow oil. Purification by radial chromatography on silica gel (1 mm plate; using NH 4 OH / CH 3 OH / CH 2 Cl 2; 1: 1: 100 → 1: 3: 100) gave the product as a yellow foam (80 mg, 37%). 1 H NMR (CDCl-3-) δ 1.68-1.74 (m, 4H), 2.02-2.04 (m, 1H), 2.22 (m, 1H), 2.62-2.69 (m, 2H), 2.81 (t, 1H, J = 4.8 Hz), 2.84-2.90 (m, 2H), 3.34-3.38 (m, 1H), 3.55-3.59 (m, 1H), 4.01-4.05 (m, 2H), 7.10-7.18 (m, 4H), 7.32 (t, 2H, J = 7.8 Hz), 7.42-7.48 (m, 2H), 7.59 (dd, 2H, J = 8.0, 1.5 Hz), 7.65 (br s, 1H), 8.43 (dd, 1H, J = 3.9, 1.2 Hz).
[1469] N- {3-[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -benzamide (hydrobromide salt Manufacture of
[1470] Hydrobromide saturated acetic acid (2 mL) was added to a solution of amine (80 mg, 0.18 mmol) in acetic acid (2 mL). The reaction mixture was stirred for 30 minutes. It was then triturated four times with diethyl ether to give the title compound as a yellow solid (99 mg), which was dried under vacuum. 1 H NMR (D 2 O) δ 1.73-1.86 (m, 2H), 1.93-2.01 (m, 1H), 2.13-2.17 (m, 1H), 2.34-2.38 (m, 1H), 2.43-2.53 (m, 1H) , 2.80-2.87 (m, 1H), 2.95-2.97 (br m, 2H), 3.17-3.23 (m, 1H), 3.28-3.35 (m, 1H), 3.53 (q, 1H, J = 6.9 Hz), 4.28-4.54 (m, 3H), 7.31-7.38 (m, 4H), 7.49-7.51 (m, 3H), 7.63-7.72 (m, 3H), 8.24 (d, 1H, J = 7.8 Hz), 8.55 ( d, 1H, J = 5.7 Hz). 13C NMR (D 2 O) δ 20.36, 20.49, 27.63, 28.08, 37.37, 48.27, 49.01, 60.18, 114.12, 125.86, 126.98, 129.20, 130.75, 132.67, 132.99, 139.30, 140.59, 147.99, 151.17, 172.84. ES-MS m / z 440 [M + H] &lt; + &gt;. Calcd for C-27H29N5O.2.1HBr.2.2H2O: C, 49.96; H, 5.51; N, 10.79; Br, 25.85. Found: C, 49.96; H, 5. 45; N, 10.65; Br, 25.95.
[1471] Example 143
[1472]
[1473] Compound 143: N- {3-[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -5-bro Mo-nicotinamide
[1474] N- [3-[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -5-bromo-nicotine Preparation of Amides:
[1475] To a solution of 5-bromonicotinic acid (120 mg, 0.60 mmol) in DMF (3 mL), 1-hydroxybenzotriazole hydrate (96 mg, 0.72 mmol), 1- (3-dimethylaminopropyl) -3-ethylka Bodyimide hydrochloride (137 mg ,, 0.72 mmol), N, N-diisopropylethylamine (0.21 mL, 1.19 mmol) and N1- (1H-benzoimidazol-2-ylmethyl) -N1- (5, 6,7,8-tetrahydro-quinolin-8-yl) -propane-1,3-diamine (200 mg, 0.60 mmol) was added. The reaction mixture was stirred at rt overnight. Then it was diluted with ethyl acetate (40 mL) and water (25 mL). The aqueous phase was concentrated and dried under vacuum to give a brown oil. It was purified by radial chromatography (1 mm plate, using NH 4 OH / CH 3 OH / CH 2 Cl 2; 1: 1: 100 → 1: 4: 100) to give the product as pale yellow foam (220 mg, 71%). 1 H NMR (CDCl-3-) δ 1.59-1.85 (m, 4H), 1.99-2.03 (m, 1H), 2.16-2.20 (m, 1H), 2.58-2.62 (m, 1H), 2.73-2.85 (m , 3H), 3.27-3.34 (m, 1H), 3.50-3.54 (m, 1H), 3.95 (d, 2H, J = 2.4 Hz), 4.03-4.08 (m, 1H), 7.09-7.16 (m, 3H ), 7.31 (br s, 1H), 7.42 (d, 1H, J = 7.5 Hz), 7.58 (br s, 1H), 7.91 (t, 1H, J = 5.7 Hz), 8.07 (t, 1H, J = 2.1 Hz), 8.40 (d, 1H, J = 3.6 Hz), 8.64 (d, 1H, J = 2.4 Hz), 8.74 (d, 1H, J = 1.8 Hz).
[1476] N- {3-[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -5-bromo-nicotine Preparation of Amides:
[1477] Hydrobromide saturated acetic acid (2 mL) was added to a solution of the above amine (220 mg, 0.42 mmol) in acetic acid (2 mL). The reaction mixture was stirred for 30 minutes. This was then triturated four times with diethyl ether to precipitate the product. The solid was redissolved in anhydrous methanol (0.5 mL) and triturated twice with diethyl ether. Pale yellow solid (225 mg) was dried under vacuum. 1 H NMR (D-2-O) δ 1.82-1.99 (m, 4H), 2.17-2.21 (m, 1H), 2.38-2.42 (m, 1H), 2.50-2.59 (m, 1H), 2.86-2.95 ( m, 1H), 3.00-3.02 (m, 2H), 3.19-3.25 (m, 1H), 3.36-3.43 (m, 1H), 4.32 (ABq, 2H, J = 45.2, 16.2 Hz), 4.57 (dd, 1H, J = 10.7, 5.4 Hz), 7.43-7.46 (m, 2H), 7.59-7.62 (m, 2H), 7.83 (dd, 1H, J = 7.5, 6.0 Hz), 8.08 (t, 1H, J = 1.8 Hz), 8.34 (d, 1H, J = 7.8 Hz), 8.51 (d, 1H, J = 1.5 Hz), 8.65 (d, 1H, J = 5.1 Hz), 8.74 (d, 1H, J = 1.8 Hz ). 13C NMR (D-2-O) δ 20.47, 27.48, 27.68, 37.82, 48.12, 48.88, 59.78, 114.04, 121.93, 125.94, 126.96, 130.59, 132.11, 139.48, 140.66, 142.49, 142.93, 148.09, 149.65, 149.65 151.20. ES-MS m / z 521 [M + H] &lt; + &gt;. Calcd for C26H27N6OBr.2.9HBr.2.1H2O: C, 39.52; H, 4. 32; N, 10.64; Br, 39.44. Found: C, 39.47; H, 4.33; N, 10.26; Br, 39.55.
[1478] Example 144
[1479]
[1480] Compound 144: Cinnoline-4-carboxylic acid- {3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl } -Amides (hydrobromide salts):
[1481] Of cinnoline-4-carboxylic acid- {3-[(1H-benzoimidazol-2-ylmethyl- (5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -amide Produce:
[1482] To a solution of cinnoline-4-carboxylic acid (80 mg, 0.46 mmol) in DMF (3 mL) 1-hydroxybenzotriazole hydrate (74 mg, 0.55 mmol), 1- (3-dimethylaminopropyl) -3-ethyl Carbodiimide hydrochloride (106 mg, 0.55 mmol), N, N-diisopropylethylamine (0.16 mL, 0.92 mmol) and N1- (1H-benzoimidazol-2-ylmethyl) -N1- (5, 6,7,8-tetrahydro-quinolin-8-yl) -propane-1,3-diamine (154 mg, 0.46 mmol) was added. The reaction mixture was stirred for 3 days. It was then diluted with ethyl acetate (40 mL) and water (25 mL) and the phases separated. The organic phase was washed with saturated NaHCO 3 (30 mL) and saturated NaCl (30 mL). The combined aqueous layers were washed with ethyl acetate (2 x 30 mL). The combined organic layers were dried (MgSO 4), filtered, concentrated and dried under vacuum to give a yellow oil. Purification by radial chromatography on silica gel (1 mm plate; NH 4 OH / CH 3 OH / CH 2 Cl 2; 1: 1: 100 → 1: 2: 100) gave the product as a yellow foam (85 mg, 38%). 1 H NMR (CDCl-3-) δ 1.61-1.67 (m, 1H), 1.80-1.90 (m, 3H), 2.00-2.06 (m, 1H), 2.20-2.24 (m, 2H), 2.64-2.75 (m , 3H), 3.00-3.06 (m, 1H), 3.27-3.29 (m, 1H), 3.80-3.83 (m, 1H), 3.86 (d, 2H, J = 3.6 Hz), 4.02 (dd, 1H, J = 10.1, 6.0 Hz), 6.78 (dd, 1H, J = 7.5 Hz), 7.12-7.17 (m, 2H), 7.21 (d, 1H, J = 6.9 Hz), 7.59 (br s, 1H), 7.67- 7.73 (m, 2H), 7.78-7.83 (m, 1H), 8.06 (d, 1H, J = 8.4 Hz), 8.14 (br s, 1H), 8.48 (d, 1H, J = 8.4 Hz), 9.11 ( s, 1 H).
[1483] Cinnoline-4-carboxylic acid- {3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -amide Preparation of Hydrobromide Salts:
[1484] To a solution of the above amine (85 mg, 0.17 mmol) in acetic acid (2 mL) was added hydrobromide saturated acetic acid (2 mL) and the reaction mixture was stirred for 30 minutes. It was then triturated three times with diethyl ether and the precipitate was dried under vacuum. The solid was then redissolved in methanol (0.5 mL) and triturated further three times with diethyl ether. Yellow solid (61 mg) was dried under vacuum. 1 H NMR (D 2 O) δ 1.65-1.89 (m, 3H), 2.04 (q, 1H, J = 12.9 Hz), 2.18-2.23 (m, 1H), 2.41-2.44 (m, 1H), 2.59-2.68 (m , 1H), 2.89-3.01 (m, 3H), 3.32-3.57 (m, 2H), 4.38 (ABq, 2H, J = 48.3, 15.9 Hz), 4.58-4.61 (m, 1H), 7.32-7.37 (m , 2H), 7.49-7.57 (m, 2H), 7.82 (t, 1H, J = 6.6 Hz), 7.89-8.08 (m, 3H), 8.33 (d, 1H, J = 7.8 Hz), 8.46 (d, 1H, J = 8.4 Hz), 8.65 (d, 1H, J = 5.7 Hz), 8.92 (s, 1H). ES-MS m / z 492 [M + H] &lt; + &gt;. Calcd for C29H29N7O.2.8HBr.2.0H2O: C, 46.19; H, 4.78; N, 13.00; Br, 29.67. Found: C, 46.35; H, 4.92; N, 12.68; Br, 29.50.
[1485] Example 145
[1486]
[1487] Compound 145: N- {4- [1H-benzolimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyl} -6-hydroxy Preparation of Nicotinamide Hydrobromide
[1488] EDC (0.083 g, 0.43 mmoles), HOBT (0.056 g, 0.41 mmoles) and N1- (1H-benzimidazol-2-yl) in a solution of 6-hydroxynicotinic acid (0.049 g, 0.35 mmoles) in DMF (2.7 mL) Methyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (0.1 g, 0.29 mmoles) was added and the reaction was stirred at rt overnight. Ethyl acetate (40 mL) and water (25 mL) were added and the organic layer was washed with brine (30 mL) and saturated aqueous NaHCO 3 (30 mL). The aqueous layer was extracted with ethyl acetate (3 × 30 mL) and the combined organic extracts were dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel radial chromatography (1 mm plate, 2% MeOH / 1% NH4OH / CH2Cl2, then 10% MeOH / 1% NH4OH / CH2Cl2) to give N- {4- [1H-benzolimidazole-2 -Ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyl} -6-hydroxynicotinamide was obtained as off-white foam (30 mg, 16%).
[1489] According to general process D, the free base was converted to an HBr salt to form compound 145 (42 mg. 81%). 1 H NMR (D 2 O): δ 1.1-1.24 (m, 2H), 1.27-1.4 (m, 2H), 1.75-1.85 (m, 1H), 1.85-2.01 (m, 1H), 2.04- 2.15 (m, 1H ), 2.15-2.31 (m, 1H), 2.50- 2.53 (m, 1H), 2.71-2.8 (m, 1H), 2.80-3.05 (m, 2H), 3.09-3.2 (m, 1H), 3.22- 3.30 (m, 1H), 4.31-4.60 (m, 3H), 6.48-6.51 (d, 1H, J = 9.3 Hz), 7.45-7.47 (m, 2H), 7.61-7.62 (m, 4H), 7.82- 7.86 (t, 1H, J = 7.2 Hz,), 8.3-8.33 (d, 1H, J = 7.8 Hz), 8.60-8.62 (d, 1H, J = 5.4 Hz). 13 C NMR (D 2 O): δ 20.44, 20.65, 25.93, 26.48, 27.68, 39.05, 49.88, 52.68, 62.22, 114.01, 115.18, 119.26, 125.89, 126.76, 130.65, 137.11, 139.27, 140.41, 140.53, 148.05 , 165.27, 166.17. ES-MS mlz 471.4 (M + H). C 27 H 30 N 6 O 2. 3.1 HBr. 1.8 H 2 O. 0.8 Calcd for C 4 H ₁₀ O: C, 44.61; H, 5.54; N, 10.34; Br, 30.46. Found: C, 44.42; H, 5. 30; N, 10.26; Br, 30.77.
[1490] Example 146
[1491]
[1492] Compound 146: N- {4-[(1H-Benzolimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyl} -benzamide hydro Preparation of Bromide
[1493] To a solution of benzoic acid in DMF (3 mL), EDC (0.097 g, 0.51 mmol), HOBT (0.064 g, 0.47 mmol), N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7 , 8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (0.12 g, 0.34 mmol) and DIPEA were added. The orange solution was stirred overnight at room temperature and then diluted with dichloromethane (20 mL) and water (20 mL). The organic layer was washed with brine (20 mL) and saturated NaHCO 3 solution (20 mL), dried over Na 2 SO 4 and concentrated to give an orange oil. The crude product was purified by silica gel radial chromatography (1 mm plate, 2% MeOH / 1% NH4OH / CH2Cl2, then 4% MeOH / 1% NH4OH / CH2Cl2) to give N- {4-[(1H-benzolimidazole- 2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyl} -benzamide was obtained as off-white foam (80 mg, 51%).
[1494] Using general process D, the foam was converted to an HBr salt, which was reprecipitated from methanol / ether to form compound 146 (93 mg. 77%). H NMR (D 2 O): δ 1.25-1.37 (m, 2H), 1.37-1.54 (m, 2H), 1.75-1.85 (m, 1H), 1.90-2.02 (m, 1H), 2.02-2.23 (m, 1H), 2.25-2.35 (m, 1H), 2.50-2.60 (m, 1H), 2.70-2.82 (m, 1H), 2.82-3.0 (m, 2H), 3.13-3.26 (m, 2H), 4.33- 4.57 (m, 3H), 7.44 (s, 4H), 7.49-7.50 (m, 2H), 7.50-7.60 (m, 1H), 7.60-7.75 (m, 2H), 7.75-7.80 (m, 1H), 8.21 (d, 1H, J = 7.8 Hz), 8.54 (d, 1H, J = 5.1 Hz). 13 C NMR (D 2 O): δ 20.44 (2 carbons), 25.83, 26.48, 27.61, 39.29, 49.50, 52.22, 61.57, 114.08 (2 carbons), 125.85, 126.87 (2 carbons), 127.15 (2 carbons), 129.21 (2 carbons), 130.73, 132.57, 132.59, 139.13, 140.26 (2 carbons), 147.97, 151.32, 152.10. ES-MS mlz 454.4 (M + H). Calcd for C 28 H 31 N ₅ O. 2.2 HBr. 1.9H ₂ O. 0.3C ₄ H ₁₀ O: C, 50.97; H, 5.86; N, 10.18; Br 25.55. Found: C, 51.23; H, 5. 70; N, 10.17; Br, 25.28.
[1495] Example 147
[1496]
[1497] Compound 147: Pyridine-2-carboxylic acid {4- [1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyl} -amide hydro Preparation of Bromide
[1498] To a solution of picolinic acid (0.042 g, 0.34 mmol) in DMF (2.5 mL), EDC (0.077 g, 0.40 mmol), HOBT (0.051 g, 0.38 mmol), N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -butane-1,4-diamine (0.096 g, 0.28 mmol) and DIPEA (0.10 ml, 0.56 mmol) were added and the orange solution Was stirred at rt overnight. The mixture was diluted with dichloromethane (20 mL) and water (20 mL) and the orange layer was washed with brine (3 x 20 mL) and saturated aqueous NaHCO 3 solution (20 mL). The crude product was purified by silica gel radial chromatography (1 mm plate, 2% MeOH / 1% NH4OH / CH2Cl2 and then 4% MeOH / 1% NH4OH / CH2Cl2) to give the pyridine-2-carboxylic acid {4- [1H-benzoimidazole 2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyl} -amide was obtained as off-white foam (55 mg, 44%).
[1499] Using general process D, the free base was converted to hydrobromide with HBr / acetic acid to give compound 147 (67.4 mg. 73%) as an off-white solid. 1 H NMR (D 2 O): δ 1.25-1.40 (m, 2H), 1.40-1.68 (m, 2H), 1.75-1.95 (m, 1H), 2.00-2.12 (q, 1H, J = 13.2 Hz), 2.12- 2.25 (m, 1H), 2.26-2.48 (m, 1H), 2.51-2.57 (m, 1H), 2.75-2.88 (m, 1H), 2.90-3.05 (m, 2H), 3.25-3.48 (m, 2H ), 4.44-4.58 (q, 2H, J = 17.1 Hz), 4.48-4,55 (m, 1H), 7.44-7.47 (m, 2H), 7.61-7.64 (m, 2H), 7.77-7.98 (m , 3H), 8.23-8.30 (m, 2H), 8.58-8.73 (m, 2H). 13 C NMR (D 2 O): δ 20.43, 20.54, 25.92, 26.43, 27.65, 39.61, 49.47, 52.34, 61.77, 114.05 (2 carbons), 123.99, 125.87, 126.79 (2 carbons), 129,10, 130.69, 139.24, 140.49 (2 carbons), 144.32, 145.18, 145.69, 148.02, 151.33, 152.38, 162.96. ES-MS mlz 455.4 (M + H). Elemental Analysis for C27H30N6O · 3.2 HBr · 2.1H2O · 0.2 C4H 10 O: Calculated: C, 43.58; H, 5. 18; N, 10.97; Br, 33.37. Found: C, 43.44; H, 5.05; N, 10.91; Br, 33.64.
[1500] Example 148
[1501]
[1502] Compound 148: N- {4-[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyl} -5-bromo Preparation of Nicotinamide Hydrobromide
[1503] EDC (0.086 g, 0.45 mmol), HOBT (0.57 g, 0.42 mmol), Compound 18 free base (0.105 g, 0.30 mmol) in a 5-bromonicontinic acid (0.061 g, 0.30 mmol) solution in DMF (2.2 mL) And DIPEA (0.10 ml, 0.57 mmol) were added and the orange solution was stirred at rt overnight. The mixture was diluted with dichloromethane (20 mL) and water (20 mL) and the organic layer was washed with brine (20 mL) and aqueous saturated NaHCO 3 solution (20 mL). The organic layer was dried over Na 2 SO 4 and concentrated to give an orange oil. The crude product was purified by silica gel radial chromatography (1 mm plate, 2% MeOH / 1% NH 4 OH / CH 2 Cl 2) to give the final product as off-white foam (110 mg, 69%).
[1504] Using general process D, the foam was dissolved in acetic acid / HBr to convert to a hydrobromide salt to give compound 148 (133 mg. 78%) as an off-white solid. 1 H NMR (D 2 O): δ 1.23-1.37 (m, 4H), 1.37-1.5 (m, 4H), 1.75-1.90 (m, 2H), 1.90 (q, 2H, J = 11.7 Hz), 2.12-2.25 ( m, 2H), 2.26-2.45 (m, 2H), 2.48-2.55 (m, 2H), 2.75-2.88 (m, 2H), 2.90-3.01 (m, 4H), 3.12- 3.25 (m, 2H), 3.25-3.37 (m, 2H), 4.33 (d, 1H, J = 17.1 Hz) 4.51-4.60 (m, 1H), 4.60 (d, 1H, J = 17.1 Hz), 7.4-7.42 (m, 2H), 7.58-7.61 (m, 2H), 7.76-7.93 (m, 1H), 8.09 (s, 1H) 8.30 (d, 1H, J = 7.5 Hz), 8.50 (s, 1H), 8.60 (d, 1H, J = 5.4 Hz), 8.82 (d, 1H, J = 3 Hz). 13 C NMR (D 2 O): δ 20.45, 20.63, 26.01, 26.56, 27.69, 39.55, 49.66, 52.53, 62.02, 113.96 (2 carbons), 121.79, 125.90, 126.74 (2 carbons), 130.62 (2 carbons), 132.32, 138.30 , 140.54, 141.84, 143.51, 148.06, 150.30, 151.28, 152.49, 165.0. ES-MS m / z 534.8 (M + H). Calcd for C27H29N6BrO · 3.1 HBr · 2.1H2O · 0.1 C4H 10 O: C, 39.67; H, 4.52; N, 10.13; Br, 39.49. Found: C, 39.63; H, 4.40; N, 10.09; Br, 39.45.
[1505] Example 149
[1506]
[1507] Compound 149: Quinoline-2-carboxylic acid {2-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyl} -amide Preparation of Hydrobromide
[1508] Isoquinolinecarboxylic acid (0.061 g, 0.55 mmol) and N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinoline-8- in DMF (2.5 mL) EDC (0.10 g, 0.52 mmol), HOBT (0.066 g, 0.49 mmol) and DIPEA (0.12 mL, 0.69 mmol) were added to the solution of I) -butane-1,4-diamine (0.12, 0.35 mmoles), and an orange solution was added. Stir at room temperature for 2 days. The mixture was diluted with dichloromethane (20 mL) and water (20 mL) and the orange layer was washed with brine (3 x 20 mL) and saturated NaHCO 3 solution (20 mL). The organic layer was dried over Na 2 SO 4 and concentrated to orange oil. The crude product was purified by silica gel radial chromatography (1 mm plate, 2% MeOH / 1% NH 4 OH / CH 2 Cl 2) to give the final product as off-white foam (95 mg, 53%).
[1509] Use of General Process D: The foam was dissolved in acetic acid and acetic acid, contained with bromic acid, was added to convert the free base to a hydrobromide salt. HBr salt was precipitated with methanol / ether to give compound 149 (115 mg. 72%) as off-white solid. 1 H NMR (D 2 O): δ 1.37-1.65 (m, 4H), 1.75-1.95 (m, 1H), 2.12-2.25 (m, 1H), 2.27-2.48 (m, 1H), 2.57-2.75 (m, 1H ), 2.75-3.02 (m, 2H), 3.28-3.51 (m 2H), 4.35 (d, 2H, J = 17.1 Hz), 4.56 (d, 2H, J = 16.8 Hz), 4.5-4.65 (m, 1H ), 7.18-7.21 (dd, 2H, J = 6.3, 3.0 Hz), 7.40-7.43 (dd, 2H, J = 6.3, 3.3 Hz), 7.78-7.84 (m, 2H), 8.05-8.07 (t, 1H) , J = 9 Hz), 8.15-8.18 (m, 2H), 8.25-8.29 (m, 2H), 8.41 (d, 1H, J = 7.8 Hz), 8.68 (d, 1H, J = 5.4 Hz). 13 C NMR (D 2 O): δ 20.45, 20.69. 26.35, 26.78, 27.67, 39.93, 49.42, 52.52, 61.85, 113.78 (2 carbons), 124.56, 125.89, 126.41 (2 carbons), 126.94, 127.08, 128.56, 130.51 (2 carbons), 131.70, 133.75, 135.99, 139.29, 139.67, 140.56 (2 carbons), 148.07, 148.96, 151.24, 152.29. ES-MS mlz 505.4 (M + H). Calcd for C31H32N6O.3.1 HBr.9.H2O.0.8C4H10O: C, 48.38; H, 5.57; N, 9.90; Br, 29.18. Found: C, 48.47; H, 5.52; N, 9.93; Br, 29.04.
[1510] Example 150
[1511]
[1512] Compound 150: Cinnoline-4-carboxylic acid {4-[(1H-benzoimidazol-2-ylmethyl) -5,6,7,8-tetrahydroquinolin-8-yl) -amino] -butyl} -amide Manufacture
[1513] Cinnoline-4-carboxylic acid (0.061 g, 0.34 mmol) and N1- (1H-benzimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinoline in DMF (2.5 mL) EDC (0.10 g, 0.52 mmol), HOBT (0.065 g, 0.48 mmol) and DIPEA (0.12 mL, 0.69 mmol) were added to a -8-yl) -butane-1,4-diamine (0.12, 0.34 mmoles) solution, The orange solution was stirred overnight at room temperature. The mixture was diluted with dichloromethane (20 mL) and water (20 mL) and the orange layer was washed with brine (3 x 20 mL) and saturated NaHCO 3 solution (20 mL). The organic layer was dried over Na 2 SO 4 and concentrated to orange oil. The crude product was purified by radial chromatography on silica gel (1 mm plate, 2% MeOH / 1% NH 4 OH / CH 2 Cl 2) to give the final product as off-white foam (656 mg, 37%).
[1514] General Process D Use: The foam was converted to its HBr salt in HBr / AcOH to precipitate compound 150 (79.3 mg. 76%) as an off-white solid. 1 H NMR (D 2 O): δ 1.25-1.62 (m, 8H), 1.74-1.97 (m, 2H), 1.97-2.25 (m, 4H), 2.25-2.50 (m, 2H), 2.50-2.75 (m, 2H ), 2.75-3.13 (m, 6H) 3.23-3.55 (m, 4H), 7.0-7.13 (m, 2H), 7.27-7.37 (m, 2H), 7.76-7.87 (m, 1H), 7.95 (s, 2H), 7.99-8.07 (m, 1H), 8.31 (d, 1H, J = 7.5 Hz), 8.48 (d, 1H, J = 9.0 Hz), 8.61 (d, 1H, J = 5.1 Hz), 9.00 ( s, 1 H). 13 C NMR (D 2 O): δ 20.47, 20.69, 26.25, 26.85, 27.68, 39.42, 49.64, 52.69, 62.04, 113.62 (2 carbons), 123.94, 124.21, 125.89, 126.28 (2 carbons), 128.95, 130.45 (2 carbons) , 130.79, 133.55, 134.73, 139.28, 140.60 (2 carbons), 141.07, 148.08, 150.42, 151.29, 152.44, 166.11. ES-MS mlz 506.4 (M + H) Calcd for C30H31N7.3.1HBr.2.3 H2O.0.2 C4H10O: C, 45.52; H, 5.05; N, 12.06; Br, 30.48. Found: C, 45.59; H, 4.91; N, 12.03; Br, 30.31.
[1515] Example 152
[1516]
[1517] Compound 152: of N- {2-[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -ethyl} -3,5-dichloro Preparation of Isonicinamide
[1518] Sodium perododate (2.35 g, 11.0 mmol) was added to a stirred solution of (2,3-dihydroxy-propyl) -carbamic acid tert-butyl ester (0.955 g, 5.00 mmol) in water (12 mL). The mixture was stirred at rt for 1 h and then extracted with dichloromethane (3 × 10 mL). The extract was dried over Na 2 SO 4 and concentrated to give (2-oxo-ethyl) -carbamic acid tert-butyl ester as a colorless liquid (778 mg, 98%). 1 H NMR (CDCl 3) δ 1.45 (s, 9 H), 4.07 (d, J = 4.5 Hz, 2 H), 5.20 (brs, 1 H), 9.65 (s, 1 H).
[1519] 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -benzoimidazole-1-carboxylic acid tert-butyl ester (0.378 g, 1.00 mmol) in dichloromethane (5 mL) ) And (2-oxo-ethyl) -carbamic acid tert-butyl ester (0.159 g, 1.00 mmol) were added sodium triacetoxyborohydride (0.223 g, 1.05 mmol). The mixture was stirred at rt for 15 h and then poured into saturated aqueous NaHCO 3 (30 mL). The mixture was extracted with chloroform (3 X 20 mL). The extract was dried over Na 2 SO 4 and concentrated. The crude material was purified by column chromatography on silica gel (98: 1: 1 CH 2 Cl 2 -CH 3 OH-NH 4 OH) to give 2-{[(2-tert-butoxycarbonylamino-ethyl)-(5,6,7,8- 499 mg (96%) of tetrahydroquinolin-8-yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester were obtained as a yellow foam. 1 H NMR (CDCl 3) δ 1.48 (s, 9 H), 1.64 (s, 9 H), 1.69-1.85 (m, 2 H), 1.94-1.99 (m, 1 H), 2.24 (m, 1 H), 2.61-2.87 (m, 3H), 3.09-3.19 (m, 3H), 4.07 (dd, J = 9.9 Hz, 5.7 Hz, 1 H), 4.26 (d, J = 16.2 Hz, 1 H), 4.52 (d, J = 16.2 Hz, 1 H), 6.98 (dd, 1H, J = 7.7 Hz, 4.7 Hz, 1 H), 7.26-7.32 (m, 3 H), 7.57 (brs, 1 H), 7.74 ( m, 1 H), 7.86 (m, 1 H), 8.41 (d, J = 3.9 Hz, 1 H).
[1520] 2-{[(2-tert-butoxycarbonylamino-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl}-in dichloromethane (4 mL) Trifluoroacetic acid (4 mL) was added to a solution of benzimidazole-1-carboxylic acid tert-butyl ester (0.490 g, 0.94 mmol). The mixture was stirred at rt for 1 h. Sodium hydroxide (2M, 30 mL) was added and the mixture was extracted with chloroform (3 X 20 mL). The extract was dried over Na 2 SO 4 and concentrated. The crude was purified by column chromatography on silica gel (90: 5: 5 CH 2 Cl 2 -CH 3 OH-NH 4 OH) to give N1- (1H-benzoimidazol-2-ylmethyl) -N1- (5,6,7,8-tetra 294 mg (97%) of hydro-quinolin-8-yl) -ethane-1,2-diamine were obtained as a colorless oil. 1 H NMR (CDCl 3) δ 1.60-1.75 (m, 1 H), 1.87-1.98 (m, 1 H), 2.01 (m, 1 H), 2.22 (m, 1 H), 2.56-2.85 (m, 6 H ), 4.03 (m, 1 H), 4.04 (d, J = 16.8 Hz, 1 H), 4.17 (d, J = 16.8 Hz, 1 H), 7.11-7.21 (m, 3 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.56 (brs, 2 H), 8.55 (d, J = 4.2 Hz, 1 H).
[1521] To a suspension of 3,5-dichloro-isonicotinoylyl chloride (0.34 mmol) in THF (3 mL) at 0 ° C. N1- (1H-) in dichloromethane (3 mL), THF (1 mL) and Et 3 N (0.087 mL) A solution of benzoimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinolin-8-yl) -ethane-1,2-diamine (0.100 g, 0.312 mmol) was added. After 5 minutes of stirring at 0 ° C., the mixture was allowed to warm to room temperature and stirred for 2.5 hours. The solvent was evaporated and the residue was dissolved in saturated aqueous NaHCO 3 (30 mL). The mixture was extracted with chloroform (3 X 20 mL). The extract was dried over Na 2 SO 4 and concentrated. The crude material was purified by column chromatography on silica gel (200: 1: 1 CH 2 Cl 2 -CH 3 OH-NH 4 OH) to give 55 mg (44%) of compound 152 as a pale yellow solid. 1 H NMR (CDCl 3) δ 1.55-1.70 (m, 1 H), 1.78-1.85 (m, 1 H), 2.03 (m, 1 H), 2.29 (m, 1 H), 2.66-2.82 (m, 3 H ), 3.20 (d, J = 13.5 Hz, 1 H), 3.39 (m, 1 H), 3.55 (m, 1 H), 3.90 (dd, J = 10.8 Hz, 5.7 Hz, 1 H), 4.12 (d , J = 16.7 Hz, 1 H), 4.30 (d, J = 16.7 Hz, 1 H), 6.99 (dd, 1H, J = 7.8 Hz, 4.8 Hz, 1 H), 7.15-7.21 (m, 2 H) , 7.27 (m, 1H), 7.41 (d, J = 7.8Hz, 1H), 7.54 (d, J = 4.2Hz, 1H), 7.63 (d, J = 4.2Hz, 1H), 8.40 ( m, 1H), 8.56 (s, 2H); 13C NMR (CDCl 3) δ 21.79, 23.08, 29.32, 38.68, 48.54, 49.25, 61.63, 119.35, 122.24, 122.69, 123.19, 129.64, 133.76, 135.76, 138.70, 143.50, 144.39, 146.46, 148.03, 157. ES-MS m / z 496 (M + H). Calcd for C25H24N6Cl2O.0.9CH2Cl2: C, 54.40; H, 4.55; N, 14.70; Cl, 23.56. Found: C, 54.64; H, 4.53; N, 14.62 Cl, 23.41.
[1522] Example 153
[1523]
[1524] Compound 153: N- {3-[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -3,5 Preparation of -dichloro-isonicotinamide
[1525] To a solution of (3-hydroxy-propyl) -carbamic acid tert-butyl ester (200 mg, 1.15 mmol) in CH 2 Cl 2 (11.5 mL) was added dess-martin furiodinan (489 mg, 1.15 mmol) at 0 ° C. and obtained. One mixture was stirred at rt for 1 h. The mixture was diluted with CH 2 Cl 2 (40 mL) and washed with 1N NaOH (2 × 10 mL). The organic phase was dried (MgSO 4), filtered and concentrated under reduced pressure. Colorless syrup (180 mg) was used for the next step without further purification.
[1526] 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -benzoimidazole-1-carboxylic acid tert-butyl ester (390 mg, 0.98 mmol) from the stomach, (3 To a solution of oxo-propyl) -carbamic acid tert-butyl ester (170 mg, 0.98 mmol) and THF (9.8 mL) was added NaBH (OAc) 3 (623 mg, 2.94 mmol) and the resulting mixture was allowed to stand at room temperature for 1 hour. Was stirred. AcOH (56 mL, 0.98 mmol) was added and the mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure, diluted with CH 2 Cl 2 (40 mL) and washed with 1N NaOH (10 mL). The aqueous phase was washed with (2 × 20 mL) and the combined organic extracts were dried (MgSO 4), filtered and concentrated under reduced pressure. A solution of the resulting orange foam in CH 2 Cl 2 (4 mL) and TFA (4 mL) was stirred at rt for 2.5 h. The mixture was concentrated under reduced pressure, partially dissolved in H 2 O (2 mL), basified with 1N NaOH and extracted with CH 2 Cl 2 (3 × 25 mL). The combined organic extracts were dried (MgSO 4), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH 2 Cl 2 / MeOH / NH 4 OH, 100: 7: 1) yields N 1-(1H-benzoimidazol-2-ylmethyl) -N 1-(5,6,7,8-tetrahydro- Quinolin-8-yl) -propane-1,3-diamine (290 mg, 75% over 3 steps) was obtained as a white foam.
[1527] To a mixture of 3,5-dichloro-isonicotinic acid (52 mg, 0.27 mmol) in CH 2 Cl 2 (1.1 mL) was added oxalyl chloride (70 mL, 0,81 mmol) and DMF (1 drop) at 0 ° C., The resulting mixture was stirred at 0 ° C. for 5 minutes and at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure and dried under vacuum for 5 minutes. The beige solid obtained was dissolved in THF (3 mL) and N1- (1H-benzoimidazol-2-ylmethyl) -N1- (5,6,7,8-tetrahydro-quinoline-8- from above. Il) -propane-1,3-diamine (100 mg, 0.30 mmol) and Et 3 N (76 mL, 0.54 mmol) were added and the resulting mixture was stirred at rt for 3 h. The mixture was concentrated under reduced pressure, diluted with EtOAc (40 mL) and subsequently diluted with saturated aqueous NaHCO 3 (5 mL) and saturated aqueous NaCl (5 mL). The organic phase was dried (MgSO 4), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH 2 Cl 2 / MeOH / NH 4 OH, 100: 1: 1) gave compound 153 (55 mg, 40%) as a white foam. 1 H NMR (CDCl 3) δ 1.70-1.94 (m, 4 H), 2.04-2.15 (m, 1H), 2.26-2.33 (m, 1H), 2.64-2.96 (m, 4H), 3.10-3.15 (m, 1H ), 3.68 (d, 1H, J = 15.6 Hz), 3.80 (d, 1H, J = 15.6 Hz), 3.98-4.07 (m, 1H), 4.19-4.25 (m, 1H), 6.83 (dd, 1H, J = 7.8, 4.8 Hz), 7.20-7.23 (m, 2H), 7.35-7.40 (m, 2H), 7.66-7.68 (m, 2H), 8.34 (s, 2H), 8.78 (br s, 1H); 13 C NMR (CDCl 3) δ 21.69, 21.92, 26.70, 29.38, 39.04, 49.41, 49.87, 59.45, 111.10, 119.37, 122.63, 122.95, 129.27, 135.68, 138.29, 143.68, 146.10, 147.70, 154.94, 157.51. 162.27. ES-MS m / z 510 (M + H). Calc. For C 26 H 26 N 6 Cl 2 O. 0.3 CH 2 Cl 2 .0.1H 2 O: C, 58.86; H, 5.03; N, 15.66; Cl, 17.17. Found: C, 59.22; H, 5. 21; N, 15.74; Cl, 16.80.
[1528] Example 154
[1529]
[1530] Compound 154: N- {4-[(1-allyl-1H-benzimidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydro-quinolin-8-ylamino] -butyl } -3,5-Dichloro-isonicotinamide:
[1531] 4-[(1-allyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -butyl hydrochloride salt (120 mg, 0.215 mmol) was neutralized with 1M NaOH (25 mL) and the free base was extracted with CHCl 3 (25 mL × 3). The combined organic solution was dried (Na 2 SO 4), filtered and concentrated under reduced pressure to give the free base as a cloudy yellow oil.
[1532] Oxalyl chloride (0.11 mL, 1.3 mmol) was added to a suspension of 3,5-dichloropyridine-4-carboxylic acid (82 mg, 0.43 mmol) and DMF (1 drop) in CH 2 Cl 2 (4 mL). The resulting white suspension was stirred at room temperature under jigsaw for 35 minutes and then the solvent was evaporated under reduced pressure. The crude acid chloride was dried under reduced pressure and then a free base solution in THF (4 mL) and NEt 3 (0.05 mL, 0.4 mmol) was added. The resulting suspension was stirred at room temperature under nitrogen for 1 hour and for 10 minutes. The mixture was diluted with CH 2 Cl 2 (25 mL) and washed with H 2 O (10 mL). The aqueous solution was extracted with CH 2 Cl 2 (10 mL) and the organic solution was washed with saturated aqueous NaHCO 3 (20 mL). The aqueous solution was extracted again with CH 2 Cl 2 (10 mL) and the combined organic solutions were dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH 2 Cl 2 / MeOH / NH 4 OH, 19: 1: 0.2) gave the amide as a white foam (92.3 mg, 0.164 mmol, 76%). 1 H NMR (CDCl 3) δ 1.40-1.60 (m, 2H), 1.63-1.89 (m, 3H), 1.95-2.19 (m, 3H), 2.60-3.03 (m, 5H), 3.55-3.67 (m, 1H) , 3.70 (d, 1H, J = 13.2 Hz), 3.86 (d, 1H, J = 13.2 Hz), 4.26 (dd, 1H, J = 8.1, 6.3 Hz), 4.61 (d, 1H, J = 17.1 Hz) , 4.67 (dd, 1H, J = 16.4, 5.1 Hz), 4.96 (d, 1H, J = 10.5 Hz), 5.57-5.71 (m, 1H), 6.85 (dd, 1H, J = 7.5, 4.8 Hz), 7.17-7.25 (m, 4H), 7.61-7.65 (m, 1H), 7.89 (d, 1H, J = 3.6 Hz), 8.32 (s, 2H), 8.97 (br. T, 1H). 13 C NMR (CDCl 3) δ 23.1, 23.8, 24.0, 28.2, 30.9, 40.3, 47.2, 49.8, 51.3, 61.0, 111.6, 118.1, 120.5, 123.5, 123.7, 124.4, 130.6, 134.1, 136.6, 137.1, 138.7, 143.7, 145.1, 147.6, 149.0, 153.7, 158.7, 164.2. ES-MS m / z 564 (M + H). Calcd for C30H32Cl2N6O.0.2C4H10O.0.1CH2Cl2: C, 63.24; H, 5.87; N, 14. 32; Cl, 13.29. Found: C, 63.02; H, 5. 74; N, 14.31; Cl, 13.04.
[1533] Example 155
[1534]
[1535] Compound 155: N- {4-[(1H-benzimidazol-2-ylmethyl)-(R) -5,6,7,8-tetrahydro-quinolin-8-yl-amino] -butyl} -3 Preparation of, 5-dichloro-isonicotinamide.
[1536] Oxalyl chloride (0.18 mL, 2.1 mmol) was added to a suspension of 3,5-dichloropyridine-4-carboxylic acid (135 mg, 0.70 mmol) and DMF (2 drops) in CH 2 Cl 2 (7 mL). The resulting suspension was stirred at room temperature under nitrogen for 35 minutes and then the solvent was evaporated under reduced pressure. The crude acid chloride was dried under reduced pressure and then N1- (1H-benzimidazol-2-ylmethyl) -N1- (R) -5,6, in THF (4 mL) and NEt3 (0.06 mL, 0.4 mmol). A solution of 7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine (120 mg, 0.344 mmol) was added. The resulting suspension was stirred at room temperature under nitrogen for 1 hour. The reaction was extracted with saturated aqueous NaHCO 3 (25 mL) and extracted with CH 2 Cl 2 (25 mL × 3). The combined organic solution was dried (MgSO 4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH 2 Cl 2 / MeOH / NH 4 OH, 32: 1: 0.2) gave the amide as a white foam (134 mg, 0.256 mmol, 74%). 1 H NMR (CDCl 3) δ 1.47-1.61 (m, 4H), 1.63-1.78 (m, 1H), 1.81-195 (m, 1H), 2.02-2.13 (m, 1H), 2.15-2.25 (m, 1H) , 2.60-2.85 (m, 4H), 3.10-3.23 (m, 1H), 3.31-3.43 (m, 1H), 3.87 (d, 1H, J = 16.2 Hz), 3.98 (d, 1H, J = 16.2 Hz ), 4.05 (dd, 1H, J = 9.6, 5.7 Hz), 6.94 (br.t, 1H), 7.12 (dd, 1H, J = 7.8, 4.8 Hz), 7.15-7.20 (m, 2H), 7.42 ( d, 1H, J = 7.8 Hz), 7.44-7.62 (m, 2H), 8.39 (s, 2H), 8.47 (d, 1H, J = 4.8 Hz). 13 C NMR (CDCl 3) δ 21.6, 23.9, 25.8, 26.9, 29.4, 39.6, 49.6, 50.5, 62.1, 122.1, 122.7, 129.2, 135.1, 138.0, 143.2, 146.8, 147.7, 156.4, 157.7, 162.6. ES-MS m / z 523 (M + H), 525 (M + 2 + H). Calc. For C 27 H 28 Cl 2 N 6 O. 0.3H 2 O. 0.2CH 2 Cl 2: C, 59.85; H, 5. 35; N, 15.40; Cl, 15.59. Found: C, 59.62; H, 5. 38; N, 15.22; Cl, 15.98.
[1537] Example 156
[1538]
[1539] Compound 156: N- {4-[(1-allyl-1H-imidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydro-quinolin-8-ylamino] -butyl} Preparation of -3,5-dichloro-isonicotinamide:
[1540] N1- (1-allyl-1H-imidazol-2-ylmethyl) -N1- (S) -5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine, hydro The chloride salt (115.1 mg, 0.216 mmol) was neutralized with 1 M NaOH (25 mL) and the free base was extracted with CHCl 3 (25 mL × 3). The combined organic solution was dried (Na 2 SO 4), filtered and concentrated under reduced pressure to give the free base as a cloudy yellow oil.
[1541] Oxalyl chloride (0.11 mL, 1.3 mmol) was added to a suspension of 3,5-dichloropyridine-4-carboxylic acid (83 mg, 0.43 mmol) and DMF (1 drop) in CH 2 Cl 2 (4 mL). The resulting white suspension was stirred at room temperature under nitrogen for 30 minutes and then the solvent was evaporated under reduced pressure. The crude acid chloride was dried under reduced pressure and a solution of free base in THF (4 mL) and NEt 3 (0.04 mL, 0.3 mmol) was added. The resulting suspension was stirred at room temperature under jigsaw for 1 hour. The reaction was dissolved in saturated aqueous NaHCO 3 (25 mL) and extracted with CH 2 Cl 2 (25 mL × 3). The combined organic solution was dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH 2 Cl 2 / MeOH / NH 4 OH, 19: 1: 0.1) gave the amide as an off-white foam (77.4 mg, 0.151 mmol, 70%). 1 H NMR (CDCl 3) δ 1.38-1.57 (m, 2H), 1.60-2.16 (m, 7H), 2.61-2.86 (m, 5H), 3.37 (d, 1H, J = 13.5 Hz), 3.57 (d, 1H , J = 13.5 Hz), 3.63-3.72 (m, 1H), 4.20 (dd, 1H, J = 8.4, 6.3 Hz), 4.35 (dd, 1H, J = 13.7, 5.1 Hz), 4.52 (dd, 1H, J = 13.7, 5.7 Hz), 4.71 (dd, 1H, J = 17.1, 0.9 Hz), 5.02 (dd, 1H, J = 10.2, 0.9 Hz), 5.56-5.69 (m, 1H), 6.74 (d, 1H , J = 1.2 Hz), 6.81 (d, 1H, J = 1.2 Hz), 6.86 (dd, 1H, J = 7.5, 4.8 Hz), 7.30 (d, 1H, J = 6.9 Hz), 7.74 (d, 1H , J = 3.9 Hz), 8.34 (s, 2H), 9.44 (br. S, 1H). 13C NMR (CDCl 3) δ 21.8, 22.1, 22.3, 27.3, 29.7, 38.5, 47.1, 48.1, 49.3, 59.5, 117.4, 120.5, 122.2, 127.5, 129.4, 133.5, 135.3, 137.5, 145.7, 146.1, 147.6, 157.6, 162.9. ES-MS m / z 513 (M + H). Calcd for C26H30Cl2N6O.0.2H2O.0.05CH2Cl2: C, 60.02; H, 5. 90; N, 16.12; Cl, 14.28. Found: C, 60.20; H, 5. 90; N, 15.80; Cl, 14.28.
[1542] Example 157
[1543] Example 157
[1544]
[1545] Compound 157: (cis-2-aminomethyl-cyclopropylmethyl)-(1H-benzimidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydro-quinolin-8-yl- Preparation of amines (hydrochloride salts).
[1546] Preparation of tert-butyl- (cis-2-chloromethyl-cyclopropylmethyoxy) -dimethyl-silane:
[1547] To a stirred solution of dimethyl cis-1,2-cyclopropanedicarboxylate (22.0 g, 140 mmol) in dry THF (185 mL) at 0 ° C. was added a solution of 1M lithium aluminum hydride in THF (180 mL, 180 mmol) in 20 minutes. Under nitrogen atmosphere. The cooling bath was removed and stirring continued for 1.5 hours. The mixture was quenched carefully with deionized water (7 mL), then 15% NaOH solution (7 mL), followed by deionized water (20 mL). The precipitate obtained was filtered off, the filter cake was washed with ethyl acetate (50 mL) and the filtrate was concentrated. The orange oil obtained was purified by column chromatography on silica gel (50: 1 CH 2 Cl 2 / MeOH) to give diol (10.2 g, 72%) as a pale yellow oil.
[1548] To a 0 ° C. stirred solution of sodium hydride in anhydrous THF (130 mL) was added a solution of diol (9.22 g, 90 mmol) from above in anhydrous THF (50 mL) and stirred for 10 minutes. To the above stirred solution was added tert-butyldimethylsilyl chloride (14.3 g, 95 mmol) in three portions over 1 minute. The cooling bath was removed and stirring continued for 30 minutes. The mixture was poured into saturated sodium bicarbonate solution (200 mL) and extracted with dichloromethane (3 x 150 mL). The organic extracts were combined, dried over Na 2 SO 4 and concentrated. The resulting yellow oil (22 g) was purified by column chromatography on silica gel (5: 1 hexanes / EtOAc) to afford the desired mono-protected diol (18.9 g, 97%) as pale yellow oil.
[1549] To a stirred solution of alcohol from the stomach (18.9 g, 87 mmol) and triethylamine (36 mL, 260 mmol) in dichloromethane (300 mL) was added pure methanesulfonyl chloride (15 mL, 190 mmol) for 5 minutes. The stirred mixture was heated to reflux for 16 hours, then cooled to room temperature, washed with water (2 × 200 mL), washed with brine (200 mL), dried over MgSO 4 and concentrated. The resulting brown oil (21 g) was purified by column chromatography on silica gel (20: 1 hexanes / EtOAc) to give the title compound (13.5 g, 66%) as a yellow oil. 1 H NMR (CDCl 3) δ 0.06 (s, 3H), 0.07 (s, 3H), 0.38 (q, 1H, J = 6.0 Hz), 0.85-0.89 (m, 1H), 0.90 (s, 9H), 1.23 -1.36 (m, 2H), 3.57-3.68 (m, 3H), 3.78-3.84 (m, 1H).
[1550] Preparation of methanesulfonic acid cis-2- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -cyclopropylmethyl ester:
[1551] Stirred slurry of tert-butyl- (cis-2-chloromethyl-cyclopropylmethicoxy) -dimethyl-silane (13.5 g, 57 mmol) and potassium phthalimide (16.0 g, 86 mmol) from above in DMF (380 mL) Heated to 100 ° C. under nitrogen for 3 hours. The mixture was cooled to rt and concentrated. The obtained residue was dissolved in ethyl acetate (500 mL), washed with brine (3 × 200 mL), dried over MgSO 4 and concentrated. The crude material was purified by column chromatography on silica gel (9: 1 hexanes / EtOAc) to afford the desired phthalimide (8.55 g, 43%) as a white crystalline solid.
[1552] Phthalimide (8.5 g, 25 mmol) from above was stirred vigorously for 20 minutes in a mixture of THF (100 mL) and 1N HCl (100 mL). The mixture was concentrated to remove THF and then extracted with dichloromethane (3 × 100 mL). The combined organic extracts were dried over MgSO 4 and concentrated. The obtained material was filtered through a silica gel plug. First, the plug was eluted with 9: 1 hexanes / EtOAc to wash off nonpolar impurities and then eluted with EtOAc to afford the desired alcohol (5.6 g, 97%) as a white solid.
[1553] Methanesulfonyl chloride (2.3 mL, 29 mmol) was added to a 0 ° C. stirred solution of alcohol (5.6 g, 24 mmol) and triethylamine (5.0 mL, 36 mmol) from above in dichloromethane (80 mL) and room temperature for 40 minutes. Stirring was continued at. The reaction was quenched by addition of saturated sodium bicarbonate solution (100 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined, dried over MgSO 4 and concentrated to give a sieve compound (7.9 g, 100%) as a white solid. 1 H NMR (CDCl 3) δ 0.53 (q, 1H, J = 6.0 Hz), 0.91-0.99 (m, 1H), 1.28-1.41 (m, 1H), 1.55-1.62 (m, 1H), 3.01 (s, 3H), 3.67-3.83 (m, 2H), 4.24 (dd, 1H, J = 12.0, 9.0 Hz), 4.58 (dd, 1H, J = 10.5, 7.5 Hz), 7.72-7.76 (m, 2H), 7.83 -7.87 (m, 2 H).
[1554] (Cis-2-aminomethyl-cyclopropylmethyl)-(1H-benzimidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydro-quinolin-8-yl-amine (hydro Chloride salt) (Compound 157):
[1555] Methanesulfonic acid (1R, 2S) -2- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -cyclopropylmethyl ester from stomach in anhydrous acetonitrile (200 mL) (7.4 g, 24 mmol),, (1H-benzimidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydro-quinolin-8-yl-amine (7.6 g, 20 mmol, prepared according to the procedures in Bridger et al. US Pattent Application USSN 09 / 535,314), a stirred slurry of diisopropylamine (5.2 mL, 30 mmol), and potassium iodide (170 mg, 1.0 mmol) was heated at 60 ° C. for 16 h. It was. The mixture was cooled to rt and concentrated. The obtained residue was partitioned between ethyl acetate (200 mL) and saturated sodium bicarbonate solution (100 mL). The layers were separated and the organic layer was washed with water (2 × 100 mL) and brine (2 × 100 mL), dried over MgSO 4 and concentrated. The crude brown oil obtained was purified by column chromatography on silica gel (first column: 2% MeOH / CH2Cl2, second column: 5% NH4OH / EtOAc) to afford the desired protective amine (2.3 g, 19%) as a white effervescent solid. It was.
[1556] Hydrazine hydrate (3.1 mL, 64 mmol) was added to a stirred solution of protective amine (6.3 g, 11 mmol) from above in ethanol (50 mL). The mixture was heated with stirring at 50 ° C. for 1 hour. The resulting white slurry was cooled to room temperature, diluted with diethyl ether (50 mL) and filtered through a glass frit funnel to remove the precipitate and concentrated. The crude material was purified by repeated column chromatography on silica gel (first column: 20: 1: 1 CH2Cl2 / MeOH / NH4OH, second column: 50: 1: 1 CH2Cl2 / MeOH / NH4OH) to give the desired primary amine (2.80 g, 74%) was obtained as a white effervescent solid.
[1557] According to General Process D: The free base (2.80 g, 7.7 mmol) from the stomach was converted to the hydrochloride salt to give compound 157 (3.30 g, 87%) as a white solid. 1 H NMR (D 2 O) δ 0.08 (q, 1H, J = 5.0 Hz), 0.22 (q, 1H, J = 5.0 Hz), 0.46-0.52 (m, 1H), 0.62 (q, 1H, J = 6.0 Hz ), 1.01-1.09 (m, 2H), 1.80-1.92 (m, 1H), 2.02-2.10 (m, 1H), 2.16-2.21 (m, 1H), 2.32-2.38 (m, 1H), 2.51-2.63 (m, 1H), 2.64-2.71 (m, 1H), 2.99-3.16 (m, 4H), 4.43-4.69 (m, 3H), 7.55-7.59 (m, 2H), 7.75-7.85 (m, 3H) , 8.32 (t, 1H, J = 7.5 Hz), 8.62 (dd, 1H, J = 7.5, 6.2 Hz); 13C NMR (D 2 O) δ9.99, 10.85, 12.41, 13.59, 15.40, 20.46, 20.69, 27.65, 39.84, 48.54, 49.49, 51.76, 61.21, 61.81, 114.31, 114.35, 125.80, 126.56, 126.61, 131.41, 131.69, 139.69 , 139.53, 140.33, 140.46, 147.74, 147.86, 151.31, 151.97, 152.61; ES-MS mlz 362 (M + H). Calcd for C22H27N5.3.0HCl.1.3H2O: C, 53.46; H, 6.65; N, 14.17; Cl, 21.52. Found: C, 53.67; H, 6.87; N, 13.85; Cl, 21.53.
[1558] Enantiomeric purity of Compound 157 at the 5,6,7,8-tetrahydroquinolin-8-yl center was determined to be 100% ee by chiral HPLC using the following conditions: Instrument: Hewlett Packard 1100 HPLC (VWD2 ); Column: Chiralpak AD-H, 0.46 cm × 25 cm; Mobile phase: A = 90:10 hexane / alcohol reagent (0.1% DEA), B: alcohol reagent; Isocratic: 90% A, 10% B; Total running time: 40 minutes; Flow rate: 0.5 ml / min; Temperature: 40 ° C .; Detector: UV @ 270 nm; Injection volume: 10 ml.
[1559] Retention time for the S enantiomer = 17.0 min.
[1560] Retention time for R enantiomer = 20.4 min.
[1561] Example 158
[1562]
[1563] Compound 158: N- (2-{[(1H-benzimidazol-2-ylmethyl)-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl } -Cis-cyclopropylmethyl) -3,5-dichloro-isonicotinamide:
[1564] ((1R, 2S) -2-Aminomethyl-cyclopropylmethyl)-(1H-benzimidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydro-quinolin-8-yl -Amine, hydrochloride salt (107.2 mg, 0.217 mmol) was neutralized with 1M NaOH (25 mL) and the free base was extracted with CHCl 3 (25 mL × 3). The combined organic solution was dried (Na 2 SO 4), filtered, concentrated under reduced pressure, and the free base obtained as a white foam.
[1565] Oxalyl chloride (0.11 mL, 1.3 mmol) was added to a suspension of 3,5-dichloropyridine-4-carboxylic acid (85 mg, 0.44 mmol) and DMF (1 drop) in CH 2 Cl 2 (4 mL). The resulting white suspension was stirred at room temperature under nitrogen for 30 minutes and then the solvent was evaporated under reduced pressure. The crude acid chloride was evaporated under reduced pressure and then a free base solution in NEt 3 (0.06 mL, 0.4 mmol) and THF (4 mL) was added. The solution was stirred at room temperature under nitrogen for 1 hour and 15 minutes. The reaction was dissolved in CH 2 Cl 2 (25 mL) and washed with H 2 O (10 mL). The aqueous solution was extracted with CH 2 Cl 2 (10 mL × 2) and the combined organic solutions were washed with saturated aqueous NaHCO 3 (15 mL). The aqueous solution was extracted with CH 2 Cl 2 (10 mL) and the combined organic solutions were dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH2Cl2 / MeOH, 99: 1, increased to 49: 1) yielded diastereomer A, a white foam (44.9 mg, 0.084 mmol, 39%), as a white foam (48.0 mg, 0.090 mmol). , 41%) with diastereomer B.
[1566] Characteristic data for diastereomer A: 1 H NMR (CDCl 3) δ 0.07 (q, 1H, J = 5.2 Hz), 0.72-0.84 (m, 1H), 1.09-1.35 (m, 2H), 1.61-1.96 (m , 2H), 2.03-2.18 (m, 2H), 2.24-2.40 (m, 2H), 2.77-2.88 (m, 2H), 3.32 (dd, 1H, J = 13.2, 5.1 Hz), 4.41 (ddd, 1H , J = 13.8, 9.6, 3.0 Hz), 4.68 (dd, 1H, J = 10.5, 5.4 Hz), 6.81 (dd, 1H, J = 7.8, 4.8 Hz), 7.16-7.28 (m, 2H), 7.33- 7.45 (m, 2H), 7.64 (d, 1H, J = 6.6 Hz), 8.36 (s, 2H), 9.48 (d, 1H, J = 8.1 Hz), 10.37 (br. S, 1H). 13 C NMR (CDCl 3) δ 9.5, 12.4, 16.2, 20.9, 21.4, 28.9, 38.5, 49.1, 51.9, 58.9, 110.5, 119.1, 121.7, 122.3, 122.7, 129.0, 133.4, 135.2, 137.8, 142.9, 143.4, 145.4, 147.2, 154.1, 157.3, 162.3. ES-MS mlz 535 (M + H), 537 (M + 2 + H). Calcd for C28H28Cl2N6O.0.5CH3OH.0.4CH2Cl2: C, 59.29; H, 5. 30; N, 14.35; Cl, 16.96. Found: C, 59.46; H, 5. 24; N, 14.31; Cl, 16.60.
[1567] Characteristic data for diastereomer B: 1 H NMR (CDCl 3) δ −0.01 (dd, 1H, J = 9.0, 6.0 Hz), 0.54-0.92 (m, 3H), 1.65-1.92 (m, 2H), 2.03- 2.15 (m, 1H), 2.18-2.30 (m, 1H), 2.47 (dd, 1H, J = 13.5, 10.8 Hz), 2.67 (ddd, 1H, J = 14.6, 10.7, 2.1 Hz), 2.74-2.86 ( m, 2H), 3.29 (dd, 1H, J = 13.5, 3.3 Hz), 3.77 (d, 1H, J = 15.9 Hz), 3.92 (d, 1H, J = 15.9 Hz), 4.08 (dd, 1H, J = 9.6, 5.4 Hz), 4.41 (ddd, 1H, J = 14.6, 8.4, 4.8 Hz), 6.97 (dd, 1H, J = 7.8, 4.8 Hz), 7.20 (d, 2H, J = 5.7 Hz), 7.39 (d, 1H, J = 7.2 Hz), 7.59 (br. s, 1H), 7.70 (d, 1H, J = 3.9 Hz), 8.38 (s, 2H), 8.60 (d, 1H, J = 7.5 Hz) .
[1568] Example 159
[1569]
[1570] Compound 159: N-{(E) -2-aminomethyl-4-[(1H-benzimidazol-2-ylmethyl)-(S)-(5,6,7,8-tetrahydro-quinoline-8 -Yl) -amino] -but-2-enyl} -3,5-dichloro-isonicotinamide and N-{(Z) -2-aminomethyl-4-[(1H-benzimidazol-2-ylmethyl Preparation of)-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -but-2-enyl} -3,5-dichloro-isonicotinamide:
[1571] 3-Aminomethyl-N- (1H-benzoimidazol-2-ylmethyl) -N- (5,6,7,8-tetrahydro-quinolin-8-yl) -but-2-ene-1,4 Diamine, hydrochloride salt (213.8 mg, 0.365 mmol) was neutralized with 1 M NaOH (25 mL) and the free base was extracted with CHCl 3 (25 mL × 3). The combined organic solution was dried (Na 2 SO 4), filtered and concentrated under reduced pressure to give the free base as a yellow foam.
[1572] Oxalyl chloride (0.12 mL, 1.4 mmol) was added to a suspension of 3,5-dichloropyridine-4-carboxylic acid (86 mg, 0.45 mmol) and DMF (1 drop) in CH 2 Cl 2 (4 mL). The resulting white suspension was stirred at room temperature under nitrogen for 30 minutes and then the solvent was evaporated under reduced pressure. The crude acid chloride was dried under reduced pressure and then a free base solution in THF (7 mL) and NEt 3 (0.08 mL, 0.6 mmol) was added. The resulting suspension was stirred at room temperature under nitrogen for 1.5 hours. The reaction was dissolved in H 2 O (25 mL) and extracted with CH 2 Cl 2 (25 mL × 3). The combined organic solution was dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH 2 Cl 2 / MeOH / NH 4 OH, 19: 1: 0.1) afforded both regioisomer amides as a about 1: 1 mixture (26.1 mg, 0.047 mmol, 13%) (the ratio of regioisomers was Evaluation is based on the difference between the two components of the 1 H NMR spectrum Separation of the two isomers is not observed during chromatography with bis-amide as yellow foam (39.9 mg, 0.055 mmol, 15%) or during analysis by HPLC. )
[1573] Data for mono-amide mixtures: 1 H NMR (CDCl 3) δ 1.67-1.96 (m, 6H), 2.02-2.30 (m, 4H), 2.71-2.95 (m, 4H), 3.24 (s, 2H), 3.27- 3.39 (m, 5H), 3.44-3.51 (m, 1H), 3.61 (d, 1H, J = 15.3 Hz), 3.76 (d, 1H, J = 15.3 Hz), 3.83-3.98 (m, 5H), 4.08 -4.22 (m, 3H), 5.47 (t, 1H, J = 6.9 Hz), 5.55 (t, 1H, J = 6.9 Hz), 6.52 (br. S, 1H), 6.97-7.08 (m, 3H), 7.12-7.23 (m, 3H), 7.36-7.49 (m, 6H), 8.06 (d, 1H, J = 4.2 Hz), 8.47 (s, 2H), 8.51 (s, 2H), 8.56 (d, 1H, J = 3.9 Hz), 9.79 (br. T, 1H). ES-MS m / z 551 (M + H). Calcd for C28H29Cl2N7O.0H2O.0.2CH2Cl2.0.4C4H8O2: C, 56.04; H, 5.78; N, 15.35; Cl, 13.32. Found: C, 56.19; H, 5. 38; N, 15.36; Cl, 13.02.
[1574] Example 160
[1575]
[1576] Compound 160: 3-Aminomethyl-N1- (1H-benzoimidazol-2-ylmethyl) -N1- (S)-(5,6,7,8-tetrahydro-quinolin-8-yl) -but- 2-ene-1,4-diamine hydrochloride salt
[1577] Preparation of (3-tert-butoxycarbonylamino-2-hydroxy-propyl) -carbamic acid tert-butyl ester:
[1578] To a solution of 1,3 diamino-2-hydroxypropane (10 g, 0.11 mol) in methanol (500 mL) was added di-tert-butyl dicarbonate (48 g, 0,22 mol) and the reaction was carried out at room temperature for 2 hours with N2. Stirred under atmosphere. The mixture was concentrated to give the product as light yellow oil (31.9 g, 100%). 1 H NMR (CD 3 OD) δ 1.44 (s, 18H), 3.10 (m, 4H), 3.63 (m, 1H).
[1579] Preparation of (3-tert-butoxycarbonylamino-2-oxo-propyl) -carbamic acid tert-butyl ester:
[1580] A solution of dimethyl sulfoxide (25.2 mL, 0.36 mol) in methylene chloride (357 mL) was stirred at −78 ° C. for 30 min under N 2 atmosphere, then methylene chloride (300 mL) and triethylamine (75 mL, 0.54 mol) A solution of (3-tert-butoxycarbonylamino-2-hydroxy-propyl) -carbamic acid tert-butyl ester (31.9 g, 0.11 mol) in water was added. The reaction was stirred for 16 hours and the reaction was allowed to warm to room temperature. The combined organic extracts were dried (Na 2 SO 4), filtered and concentrated in vacuo to yield a yellow oil. Purification by column chromatography on silica gel (ethyl acetate: hexane, 3: 7, v / v) gave the product as a white solid (28 g, 88%). 1 H NMR (CDCl 3) δ 1.44 (s, 18H), 4.04 (m, 4H), 5.19 (s, 1H).
[1581] Preparation of 4-tert-butoxycarbonylamino-3- (tert-butoxycarbonylamino-methyl) -but-2-enoic acid ethyl ester:
[1582] (Caethoxymethylene) -triphenyl phosphate in a solution of (3-tert-butoxycarbonylamino-2-oxo-propyl) -carbamic acid tert-butyl ester (28 g, 97.0 mmol) dissolved in benzene (350 mL) Porcine (89 g, 0.26 mol) was added and the reaction mixture was stirred for 16 h at 45 ° C. under N 2 atmosphere. The mixture was concentrated and purified by column chromatography on silica gel (ethyl acetate: hexane, 1: 3, v / v) to give the product as a yellow solid (26 g, 75%). 1 H NMR (CDCl 3) δ 1.43 (s, 18H), 1.59 (s, 3H), 3.90 (d, 2H, J = 4.75 Hz), 4.11 (m, 4H,), 5.35 (m, 2H), 5.87 (s , 1H).
[1583] Preparation of [2- (tert-butoxycarbonylamino-methyl) -4-hydroxy-but-2-enyl] -carbamic acid tert-butyl ester
[1584] To a solution of 4-tert-butoxycarbonylamino-3- (tert-butoxycarbonylamino-methyl) -but-2-enoic acid ethyl ester (7.0 g, 19.5 mmol) in tetrahydrofuran (195 mL) Diisobutylaluminum hydride (1 M in CH 2 Cl 2, 59 mL, 59 mmol) was added at −78 ° C. (dry ice / acetone) and the reaction mixture was stirred at −78 ° C. under N 2 atmosphere for 2 h. The reaction was quenched with a saturated solution of sodium tartrate tetrahydrate (300 mL) and stirred vigorously until the layers separated and extracted with methylene chloride (2 x 100 mL). The combined organic extracts were dried (Na 2 SO 4), filtered and concentrated in vacuo to yield a yellow oil. Purification by column chromatography on silica gel (ethyl acetate: hexane, 1: 1, v / v) gave the product as a yellow oil (5.90 g, 96%). 1 HNMR (CDCl 3) δ 1.43 (s, 18H), 3.72 (s, 4H), 4.18 (t, 2H), 4.76 (s, 1H), 5.54 (s, 1H), 5.96 (t, 1H).
[1585] Preparation of methane sulfonic acid 4-tert-butoxycarbonyl amino-3- (tert-butoxycarbonyl amino-methyl) -but-2-enyl ester
[1586] 0 ° C. in a solution of [2- (tert-butoxycarbonylamino-methyl) -4-hydroxy-but-2-enyl] -carbamic acid tert-butyl ester (9.13 g, 29 mmol) in dichloromethane (290 mL) Triethylamine (8.1 mL, 58 mmol) and methanesulfonyl chloride (2.24 mL, 29 mmol) were added at the reaction temperature of. The reaction mixture was stirred at 0 ° C. for 30 min under N 2 atmosphere and then diluted with a saturated solution of ammonium chloride (250 mL). The aqueous layer was extracted with methylene chloride (3 x 150 mL). The combined organic extracts were dried (Na 2 SO 4), filtered and concentrated in vacuo to yield a yellow oil (11.0 g, 93%). 1 HNMR (CDCl 3) δ 1.43 (s, 18H), 3.03 (s, 3H), 3.78 (m, 4H), 4.92 (d, 1H, J = 4.75 Hz), 5.01 (s, 1H), 5.17 (s, 1H ), 5.66 (t, 1 H).
[1587] 2-{[[4-tert-butoxycarbonylamino-3- (tert-butoxycarbonylamino-methyl) -but-2-enyl] -N- (S)-(5,6,7,8 Preparation for Tetrahydro-quinoline-8yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester:
[1588] Iodide in a solution of 4-tert-butoxycarbonyl amino-3- (tert-butoxycarbonyl amino-methyl) -but-2-enyl ester (5.2 g, 13.2 mmol) in methane sulfonic acid in acetonitrile (60 mL) 2-[(5,6,7,8-tetrahydro-quinolin-8-yl amino in potassium (1.1 g, 6.6 mmol), diisopropylethylamine (2.3 mL, 13.2 mmol) and acetonitrile (60 mL) ) -Methyl] -benzoimidazole-1-carboxylic acid tert-butyl ester (5.0 g, 13.2 mmol) solution was added and the reaction was stirred at room temperature under N 2 atmosphere. A solution of methane sulfonic acid 4-tert-butoxycarbonyl amino-3- (tert-butoxycarbonyl amino-methyl) -but-2-enyl ester (5.2 g, 13.2 mmol) in acetonitrile (60 mL) was added The reaction mixture was stirred at rt for 16 h under N 2 atmosphere. The reaction mixture was concentrated, redissolved in methylene chloride (200 mL) and diluted with saturated NaCl (200 mL). The aqueous layer was extracted with methylene chloride (3 × 150 mL) and the combined organic extracts were dried (Na 2 SO 4), filtered and concentrated in vacuo to give a yellow oil (6.3 g, 70%). 1 HNMR (CDCl 3) δ 1.43 (s, 18H), 2.10 (m, 3H), 2.53 (m, 1H), 2.77 (m, 1H), 3.19 (m, 1H), 3.52 (m, 3H), 3.77 (m , 1H), 3.94 (m, 1H), 4.29 (m, 3H), 5.21 (s, 1H), 5.47 (s, 1H), 6.73 (s, 1H), 7.05 (s, 1H), 7.25 (s, 1H), 7.69 (m, 3H), 8.25 (s, 1H).
[1589] 3-Aminomethyl-N- (1H-benzoimidazol-2-ylmethyl) -N- (S)-(5,6,7,8-tetrahydro-quinolin-8-yl) -but-2-ene Preparation of -1,4-diamine
[1590] 2-{[[4-tert-butoxycarbonylamino-3- (tert-butoxycarbonylamino-methyl) -but-2-enyl] -N- (S dissolved in HCl saturated acetic acid (35 mL) )-(5,6,7,8-tetrahydro-quinoline-8yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester solution was stirred at room temperature under N2 atmosphere for 5 hours. The solution was added dropwise to diethyl ether (550 mL) to give a white precipitate. The white solid was separated by suction filtration under a continuous stream of nitrogen, washed with diethyl ether and dried overnight under vacuum at 40 ° C. (3.8 g, 71%). 1 H NMR (D 2 O) δ 1.79 (m, 1H), 1.83 (m, 1H), 2.01 (m, 1H), 2.43 (m, 1H), 3.00 (s, 2H), 3.31 (m, 2H), 3.76 ( m, 5H), 4.49 (m, 3H), 6.66 (dd, 1H, J = 8.77, 3.95 Hz), 7.62 (m, 2H), 7.88 (m, 3H), 8.41 (d, 1H, J = 7.45 Hz ), 8.83 (d, 1H, J = 5.7 Hz); 13 CNMR d (D 2 O) 20.32, 27.61, 37.09, 42.34, 46.68, 48.93, 59.29, 114.32, 126.01, 126.98, 128.73, 131.22, 136.30, 139.63, 140.36, 148.08, 150.73. ES-MS mlz 377 (M + H). Calcd for C22H28N6.3.93HCl2.16H2O.0.46 (C2H4O2): C, 46.96; H, 6.55; N, 14.44; Cl, 23.74. Found: C, 46.97; H, 6.67; N, 14.31; Cl, 23.75.
[1591] Example 161
[1592]
[1593] Compound 161: (1H-Benzoimidazol-2-ylmethyl)-(2-piperidin-3-ylidene-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)- Preparation of amines (hydrobromide salts).
[1594] Dess-Martin periodinane (4.8470 g, 11.4 mmol) in a solution of 3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.9169 g, 9.5 mmol) in CH ₂ -Cl ₂ (50 mL) Was added and the mixture was stirred at rt for 5 h. CH ₂ -Cl ₂ (75 mL), saturated NaHCO ₃ (100 mL), and 20% aqueous sodium thiosulfate (100 mL) were added and the mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (1 × 75 mL). The organic extract was washed with brine (1 × 100 mL), dried (Na 2 SO 4) and concentrated. Purification of the crude by column chromatography on silica gel (4: 1 hexane-EtOAc) provided 1.80 g (95%) of 3-oxo-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil. 1 H NMR (CDCl 3) δ 1.49 (s, 9H), 1.93-2.02 (m, 2H), 2.46 (t, 2H, J = 6 Hz), 3.58 (t, 2H, J = 6 Hz), 4.00 (s, 2H) .
[1595] (Carbethoxymethylene) -triphenylphosphorane (4.72 g, 13.6 mmol) in a solution of 3-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.80 g, 9.0 mmol) in benzene (20 mL) Was added and stirred at 65 ° C. for 3.5 h. The reaction was refluxed (80 ° C.), stirred and concentrated for 23 hours before cooling to room temperature. Purification of the crude by column chromatography on silica gel (6: 1 hexane-EtOAc) yielded 0.4874 g (20%) of cis-3-ethoxycarbonylmethylene-piperidine-1-carboxylic acid tert-butyl ester Served as a crystal. NOESY experiments were performed to determine if the product was the desired cis isomer. 1 H NMR (CDCl 3) δ 1.23-1.30 (m, 3H), 1.45 (s, 9H), 1.70-1.76 (m, 2H), 2.34 (t, 2H, J = 6 Hz), 3.48 (t, 2H, J = 6 Hz), 4.13-4.21 (m, 2H), 4.61 (s, 2H), 5.66 (s, 1H).
[1596] A solution of cis-3-ethoxycarbonylmethylene-piperidine-1-carboxylic acid tert-butyl ester (0.4701 g, 1.7 mmol) in CH ₂ Cl ₂ (17 mL) was cooled to −78 ° C. and replaced with argon. Flushed. 1.0 M diisobutylaluminum hydride in hexane (5.1 mL, 5.1 mmol) was added dropwise to the solution and the reaction was stirred at -78 ° C for 50 min. The reaction was carried out at room temperature and stirred for 3.5 hours before cooling to 0 ° C. Saturated aqueous KNa tartrate (salt of Rochelle, 6 mL) was added dropwise, followed by water (10 mL) and CH ₂ Cl ₂ (75 mL). The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 50 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. Purification of the crude by column chromatography on silica gel (3: 1 hexanes-EtOAc) yielded 0.1652 g (43) of cis-3- (2-hydroxy-ethylidene) -piperidine-1-carboxylic acid tert-butyl ester %). 1 H NMR (CDCl 3) δ 1.45 (s, 9H), 1.60-1.68 (m, 2H), 2.27 (t, 2H, J = 6.1 Hz), 2.87 (s, 1H), 3.47 (t, 2H, J = 6 Hz ), 3.96 (s, 2H), 4.06-4.13 (m, 2H), 5.59 (s, 1H).
[1597] To a solution of cis-3- (2-hydroxy-ethylidene) -piperidine-1-carboxylic acid tert-butyl ester (0.1652 g, 0.7 mmol) in CH ₂ Cl ₂ (10 mL) at −78 ° C. Ethylamine (0.2 mL, 1.4 mmol) and methane sulfonyl chloride (0.1 mL, 0.9 mmol) were added slowly. The reaction was stirred at −78 ° C. for 40 minutes and then at room temperature for 40 minutes. Water (10 mL) and CH ₂ Cl ₂ (40 mL) were added and the layers were separated. The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 50 mL), the combined organic extracts were dried (Na 2 SO 4) and concentrated to cis-3- (2-methanesulfonyloxy-ethylidene) -piperidine-1- 0.1985 g (93%) of carboxylic acid tert-butyl ester were obtained as a pale pink oil. 1 H NMR (CDCl 3) δ 1.46 (s, 9H), 1.78 (s, 2H), 2.31 (t, 2H, J = 6 Hz), 3.01 (s, 3H), 3.48 (t, 2H, J = 6 Hz), 4.01 (s, 2H), 4.82 (d, 2H, J = 7.4 Hz), 5.46 (t, 1H, J = 7.4 Hz).
[1598] In a solution of cis-3- (2-methanesulfonyloxy-ethylidene) -piperidine-1-carboxylic acid tert-butyl ester (0.1985 g, 0.6 mmol) in CH ₃ CN (6 mL), 2-[( 5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -benzoimidazole-1-carboxylic acid tert-butyl ester (0.2531 g, 0.6 mmol), potassium iodide (0.0110 g, 0.06 mmol ), And DIPEA (0.2 mL, 0.9 mmol) were added and stirred at 60 ° C. for 17 h. Saturated NaHCO ₃ (15 mL) and CH ₂ Cl ₂ (50 mL) were added and separated. The aqueous phase was extracted with CH ₂ Cl ₂ (2 × 30 mL) and the combined organic extracts were dried (Na 2 SO 4) and concentrated. Purification of the crude material by column chromatography on silica gel (70: 1: 1 CH 2 Cl 2 -CH ₃ OH-NH ₄ OH) followed by another column on silica gel (ether saturated with NH ₄ OH) was carried out in cis-2-{[[2 -(1-tert-butoxycarbonyl-piperidin-3-ylidene) -ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl}- 0.1282 g (36%) of benzimidazole-1-carboxylic acid tert-butyl ester was provided as a white solid. 1 H NMR (CDCl 3) δ 1.41-1.47 (m, 1H), 1.68 (s, 9H), 1.73 (s, 9H), 1.85-1.96 (m, 5H), 2.17 (s, 2H), 2.59-2.79 (m , 2H), 3.21-3.31 (m, 1H), 3.37-3.60 (m, 3H), 3.72 (s, 1H), 3.94-4.01 (m, 1H), 4.21-4.29 (m, 1H), 4.38-4.62 (m, 2H), 5.21-5.30 (m, 1H), 6.94-6.98 (m, 1H), 7.27-7.28 (m, 3H), 7.68-7.71 (m, 1H), 7.79-7.82 (m, 1H) , 8.39-8.40 (m, 1 H).
[1599] Cis-2-{[[2- (l-tert-butoxycarbonyl-piperidine-3-ylidene) -ethyl]-(S)-(5,6,7, 8-tetrahydro-quinolin-8-yl) -amino] -methyl} -benzoimidazole-1-carboxylic acid tert-butyl ester (0.1282 g, 0.2 mmol) was converted to hydrobromide salt and from methanol / ether Intermediate solid gave compound 161 (0.1168 g, 87%) as a white solid. 1 H NMR (D 2 O) 1.12-1.21 (m, 2H), 1.58-1.67 (m, 3H), 1.79-1.94 (m, 2H), 1.98-2.24 (m, 2H), 2.33-2.43 (m, 1H), 2.97-3.04 (m, 2H), 3.07-3.24 (m, 2H), 3.46-3.65 (m, 2H), 3.78-3.84 (m, 1H), 4.29-4.38 (m, 1H), 4.49-4.61 (m , 3H), 5.44 (s, 1H), 7.61-7.62 (m, 2H), 7.77-7.80 (m, 2H), 7.86 (t, 1H, J = 6.9 Hz), 8.34 (d, 1H, J = 7.5 Hz), 8.64 (d, 1 H, J = 4.8 Hz). 13C NMR (D 2 O) δ 20.36, 20.63, 23.60, 27.63, 30.03, 31.84, 43.82, 44.67, 48.82, 61.29, 114.22, 125.97, 126.29, 127.06, 130.93, 132.83, 139.48, 140.66, 148.09, 150.93, 151.83, 151.83 ES-MS m / z 388 (M + H). Calcd C24H29N5.3.0HBr.2.3H2O: C, 42.92; H, 5.49; N, 10.43; Br, 35.69. Found: C, 43.20; H, 5. 38; N, 10.03; Br, 35.92.
[1600] Example 162
[1601]
[1602] Compound 162: N- {4-[(1H-benzimidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydro-quinolin-8-yl-amino] -butyl} -acet Preparation of Amides (Free Bases).
[1603] Preparation of Compound 162:
[1604] N '-(1H-benzimidazol-2-ylmethyl) -N'-(S) -5,6,7,8-tetrahydro-quinolin-8-yl-butane-1,4-diamine (500 mg , 1.43 mmol) was dissolved in ethyl acetate (10 mL) to give a yellow solution. The reaction mixture was stirred at reflux for 48 hours. The resulting yellow / orange solution was concentrated under reduced pressure to give an orange oil. Purification via column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH ₄ OH, 90: 5: 5, v / v / v) gave the product as a pale yellow foam (56 mg, 10%). 1 H NMR (CDCl-3-) δ 1.37-1.45 (m, 4H), 1.65-1.73 (m, 1H), 1.85 (s, 3H), 1.87-1.90 (m, 1H), 2.04-2.10 (m, 1H ), 2.14-2.22 (m, 1H), 2.60-2.65 (m, 1H), 2.69-2.77 (m, 2H), 2.77-2.83 (m, 1H), 3.02-3.06 (m, 2H), 3.97 (d , 1H, J = 15.0 Hz), 4.02 (m, 1H), 4.08 (d, 1H, J = 15.0 Hz), 5.48 (br t, 1H), 7.16-7.22 (m, 3H), 7.44 (d, 1H , J = 6.0), 7.53 (br s, 2H), 8.58 (d, 1H, J = 3.0 Hz). 13 C NMR (CDCl 3) δ 21.61, 23.60, 24.24, 26.10,27.26, 29.51, 39.47, 49.82, 50.69, 62.46, 115.26, 122.08, 122.69, 135.10, 137.92, 146.92, 156.89, 157.84, 170.47. ES-MS m / z 392 [M + H] &lt; + &gt;. Calc. For C23-H-29-N5O-.7H-2-O: C, 68.36, H, 7.58; N, 17.33. Found: C, 68.45; H, 7.47; N, 17.25.
[1605] Example 163
[1606]
[1607] Compound 163: {4-[(1H-benzimidazol-2-ylmethyl)-(S) -5,6,7,8-tetrahydro-quinolin-8-yl-amino] -butyl} -urea (free Base).
[1608] Preparation of Compound 163:
[1609] In a flask purged with nitrogen, N '-(1H-benzimidazol-2-ylmethyl) -N'-(S) -5,6,7,8-tetrahydro-quinolin-8-yl-butane-1 , 4-Diamine (208 mg, 0.60 mmol) was dissolved in iso-propanol (4 mL) to give a yellow solution. Trimethylsilyl isocyanate (113 mL, 0.83 mmol) was added by syringe and the reaction mixture was stirred at rt for 18 h. The resulting yellow solution was concentrated under reduced pressure to yield a yellow oil. Purification via column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH 4 OH, 90: 5: 5, v / v / v) gave the product as a white solid (167 mg, 71%). 1 H NMR (CDCl-3-) δ 1.37-1.45 (m, 4H), 1.65-1.75 (m, 1H), 1.88-1.92 (m, 1H), 2.00-2.07 (m, 1H), 2.17-2.24 (m , 2H), 2.51-2.59 (m, 1H), 2.66-2.77 (m, 2H), 2.80-2.83 (m, 1H), 2.96-3.00 (m, 2H), 3.95 (d, 1H, J = 15.0 Hz ), 4.03 (m, 1H), 4.04 (d, 1H, J = 15.0 Hz), 4.47 (s, 2H), 5.20 (br t, 1H), 7.16-7.22 (m, 3H), 7.43 (d, 1H) , J = 7.5), 7.53 (br s, 2H), 8.55 (d, 1H, J = 3.0 Hz). 13 C NMR (CDCl 3) δ 21.51, 24.18, 25.88, 27.64, 29.50, 40.34, 49.67, 50.99, 62.64, 111.64, 119.13, 122.19, 122.74, 135.23, 137.99, 146.95, 156.64, 157.78, 159.33. ES-MS m / z 393 [M + H] &lt; + &gt;. Calc. For C 22 H 28 N 6 O. 15 CH 2 Cl 2: C, 65.65, H, 7.04; N, 20.74. Found: C, 65.56; H, 7. 26; N, 20.90.
[1610] Example 164
[1611]
[1612] Compound 164: pyrazine-2-carboxylic acid {3-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl}- Preparation of Amides.
[1613] Preparation of pyrazine-2-carboxylic acid (3-hydroxy-propyl) -amide:
[1614] In a solution of 3-amino-1-propanol (1.20 mL, 15.7 mmol) in CH ₂ Cl ₂ (80 mL), 2-pyrazinecarboxylic acid (1.99 g, 16.0 mmol), DIPEA (5.6 mL, 32.1 mmol), HOBT (2.61) g, 19.3 mmol) and EDC-HCl (3.70 g, 19.3 mmol) were added. The solution was stirred at room temperature under nitrogen for 14.5 hours and then diluted with brine (25 mL). The layers were separated and the aqueous solution was extracted with EtOAc (50 mL × 3) and CHCl ₃ (50 mL × 3). The combined organic solution was dried (Na ₂ SO), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 19: 1: 0.1) provided the amide as a white solid (1.94 g, 10.7 mmol, 68%). 1 H NMR (CDCl 3) δ 1.83 (quint, 2H, J = 5.9 Hz), 3.03 (br. S, 1H), 3.61-3.74 (m, 4H), 8.12 (br. S, 1H), 8.53 (dd, 1H , J = 2.4, 1.5 Hz), 8.75 (d, 1H, J = 2.4 Hz), 9.40 (d, 1H, J = 1.5 Hz).
[1615] Preparation of pyrazine-2-carboxylic acid (3-oxo-propyl) -amide:
[1616] To a solution of amide (184 mg, 1.02 mmol) in CH ₂ Cl ₂ (5 mL) was added des-martin periodinan (468 mg, 1.10 mmol) and the reaction was stirred at room temperature for 20 minutes. The mixture was diluted with 10% aqueous Na ₂ S ₂ O ₃ (20 mL) and saturated aqueous NaHCO ₃ (20 mL), stirred vigorously for 15 minutes and extracted with CH ₂ Cl ₂ (25 mL × 3). The combined organic solution was dried (MgSO 4), filtered and concentrated under reduced pressure to give crude aldehyde as an orange solid (143 mg, 0.80 mmol, 78%). 1 H NMR (CDCl 3) δ 2.85 (quint, 2H, J = 6.0 Hz), 3.77 (q, 2H, J = 6.0 Hz), 8.16 (br. S, 1H), 8.50 (dd, 1H, J = 2.4, 1.5 Hz), 8.72 (d, 1H, J = 2.4 Hz), 9.35 (d, 1H, J = 1.5 Hz), 9.83 (s, 1H).
[1617] Preparation of Compound 164:
[1618] Aldehyde (140 mg, 0.78 mmol) and (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) in CH ₂ Cl ₂ (4.5 mL)- A solution of amine (201 mg, 0.72 mmol) was stirred at room temperature for 10 minutes, then NaBH (OAc) ₃ (180 mg, 0.85 mmol) was added. The reaction mixture was stirred for a further 6.5 h and then washed with 1M NaOH (10 mL × 2) and brine (10 mL). The organic solution was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 19: 1: 0.1) provided tertiary amine as a yellow foam (271 mg, 0.63 mmol, 85%). 1 H NMR (CDCl 3) δ 1.60-2.10 (m, 5H), 2.18-2.29 (m, 1H), 2.65-2.74 (m, 2H), 2.79-2.90 (m, 2H), 3.41-3.59 (m, 2H) , 4.03-4.15 (m, 3H), 7.11-7.20 (m, 3H), 7.41 (d, 1H, J = 7.5 Hz), 7.45-7.63 (m, 2H), 8.06 (m, 1H), 8.31 (dd , 1H, J = 2.1, 1.8 Hz), 8.51 (d, 1H, J = 3.6 Hz), 8.67 (d, 1H, J = 2.4 Hz), 9.32 (d, 1H, J = 1.2 Hz). 13 C NMR (CDCl 3) δ 21.8, 23.5, 28.2, 29.6, 37.9, 48.5, 49.7, 62.0, 122.1, 122.6, 135.1, 137.8, 142.6, 144.8, 147.2, 147.4, 156.3, 157.7, 163.4. ES-MS m / z 442 (M + H). Calc. For C 25 H 27 N 7 O. 0.3CH 2 Cl 2: C, 65.07; H, 5.96; N, 20.99. Found: C, 64.74; H, 6. 10; N, 20.90.
[1619] Example 165
[1620]
[1621] Compound 165: N- {3-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -propyl} -guanidine (hydro Bromide salts)
[1622] A solution of (3-hydroxypropyl) -carbamic acid tert-butyl ester (0.60 g, 3.4 mmol) in anhydrous CH ₂ Cl ₂ (17 mL) with Dess-Martin reagent (1.74 g, 4.1 mmol) for 3 hours. Treated at room temperature. The reaction mixture was diluted with Et ₂ O (30 mL) and washed with a 20% aqueous solution of sodium thiosulfate (15 mL) followed by a saturated aqueous solution of sodium bicarbonate (15 mL). The combined aqueous phases were then washed with Et ₂ O (2 × 35 mL), washed with 20% sodium thiosulfate solution (30 mL), saturated NaHCO ₃ solution (25 mL), and brine (25 mL). The organic component was then dried (MgSO ₄ ), filtered and concentrated under reduced pressure to afford (3-oxopropyl) -carbamic acid tert-butyl ester as a colorless oil (0.54 g, 91%).
[1623] Using General Process B, (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (0.69 g, 2.5 mmol), (3 -Oxopropyl) -carbamic acid tert-butyl ester (0.54 g, 3.1 mmol) and sodium triacetoxyborohydride (0.95 g, 4.5 mmol) were stirred in CH ₂ Cl ₂ (13 mL) at room temperature for 18 hours. It was. This was obtained after work-up and column chromatography (5: 0.5: 94.5 MeOH: NH ₄ OH: CH ₂ Cl ₂ ), whereby a mixture of the desired alkylated product with the product containing boron acetyl ester group was obtained from benzimidazole (1.31). g, excess). This was done prior to the next reaction.
[1624] The solution of compound (1.31 g) was dissolved in CH ₂ Cl ₂ (2 mL) and treated with trifluoroacetic acid (20 mL) for 2 hours. The solution was cooled to 0 ° C. and diluted with CH ₂ Cl ₂ (50 mL). Thereafter, 10N aqueous NaOH solution (5 mL) was added slowly until the acid content was neutralized and the solution became basic (pH> 9). After this time the phases were separated and the aqueous solution was extracted with CH ₂ Cl ₂ (2 × 50 mL). The combined organics were then dried (Na ₂ SO ₄ ) and concentrated under reduced pressure, followed by column chromatography (10: 1: 89 MeOH: NH ₄ OH: CH ₂ Cl ₂ ) followed by N- (1H-benzimidazole). Obtain 2-ylmethyl) -N- (5,6,7,8-tetrahydroquinolin-8-yl) -propane-1,3-diamine as pale yellow crystalline solid (0.57 g, 68%, 2 steps) It was. 1 H NMR (CDCl 3): δ 1.55-1.85 (m, 3H), 2.10 (br, 1H), 2.25 (q, 1H, J = 13.5 Hz), 2.54 (t, 1H, J = 12.0 Hz), 2.65 (br , 1H), 2.79 (br, 4H), 3.31 (d, 1H, J = 12.0 Hz), 3.98 (d, 1H, J = 15.0 Hz), 4.00 -4.25 (m, 2H), 7.08 (m, 1H) , 7.16 (m, 2H), 7.40 (d, 1H), J = 7.5 Hz, 7.57 (br, 2H), 8.42 (d, 1H, J = 4.5 Hz), 9.35 (br, 2H).
[1625] The amine (0.14 g, 0.43 mmol) and (tert-butoxycarbonylimino-pyrazol-1-yl-methyl) -carbamic acid tert-butyl ester (0.13 g, 0.39 mmol) were THF (0.4 mL). ) And stirred for 5 hours. The solvent was removed under reduced pressure and CH ₂ Cl ₂ (10 mL) was added. The organic phase was washed with 15% aqueous solution of NaOH (5 × 5 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. This gives the di-BOC-protected guanidine adduct as a pale yellow oil (0.18 g, 73%) after column chromatography (2: 0.5: 97.5 MeOH: NH ₄ OH: CH ₂ Cl ₂ ). 1 H NMR (CDCl 3): δ 1.45 (s, 9H), 1.49 (s, 9H), 1.66 (m, 3H), 1.85-2.10 (m, 2H), 2.18 (br, 1H), 2.50 -2.85 (m, 4H), 3.38 (m, 2H), 4.05 (m, 2H), 4.17 (d, 1H, J = 15.0 Hz), 7.13 (m, 1H), 7.17 (m, 2H), 7.40 (d, 1H, J) = 7.0 Hz), 7.47 (m, 1 H), 7.67 (m, 1 H), 8.06 (br, 1 H), 8.58 (d, 1 H, J = 4.5 Hz).
[1626] General Process D Use: The above material (176 mg, 0.29 mmol) was converted to hydrobromide salt to give compound 165 (152 mg) as a white solid. 1 H NMR (D 2 O) δ 1.69 (m, 2H), 1.80 (m, 1H), 1.98 (q, 1H, J = 12.0 Hz), 2.15 (br, 1H), 2.34 (br, 1H), 2.52 (m, 1H), 2.80 (m, 1H), 2.97 (br d, 2H, J = 4.5 Hz), 3.01 (m, 2H), 4.32 (d, 1H, J = 16.5 Hz), 4.48 (m, 1H), 4.48 (d, 1H, J = 16.8 Hz), 7.56 (m, 2H), 7.76 (m, 2H), 7.83 (m, 1H), 8.31 (d, 1H, J = 7.8 Hz), 8.59 (d, 1H, J = 4.8 Hz). 13C NMR (D 2 O) δ 20.40, 20.49, 27.49, 27.67, 39.10, 48.31, 49.21, 60.60, 114.30 (2C), 126.00, 126.96 (2C), 131.05, 139.41, 140.69 (2C), 148.14, 151.13, 151.51, 151.51 . ES-MS m / z 378 (M + H). Calc. For C 21 H 27 N 7 3.1 HBr 1.5 H 2 O 0.2 C 4 H 10 O: C, 39.07; H, 5. 28; N, 14.63; Br, 36.96. Found: C, 39.20; H, 5.41; N, 14.69; Br, 36.85.
[1627] Example 166
[1628]
[1629] Compound 166: {3-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -propyl} -urea (hydrobromide salt) Manufacture
[1630] N- (1H-benzimidazol-2-ylmethyl) -N- (5,6,7,8-tetrahydroquinolin-8-yl) -propan-1,3-diamine (0.14) in isopropanol (2.8 mL) g, 0.42 mmol-N- {3-[(1H-benzimidazol-2-ylmethyl)-(S)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -propyl } -See preparation of guanidine) with trimethylsilyl isocyanate (80 mL, 0.58 mmol) at room temperature. The reaction was stirred for 20 hours and concentrated under reduced pressure. This gave silica gel column chromatography (5: 1: 94 MeOH: NH ₄ OH: CH ₂ Cl ₂ ) the desired urea (37 mg, 23%). 1 H NMR (CDCl 3) δ 1.57 (m, 1H), 1.70 -1.85 (m, 3H), 2.06 (br, 1H), 2.26 (br, 1H), 2.62 (m, 1H), 2.70 -3.00 (m, 4H ), 3.38 (br, 1H), 3.87 (m, 2H), 4.18 (m, 1H), 4.50 (br, 2H, NH2), 6.95 (br, 1H, NH), 7.18 (m, 3H), 7.46 ( d, 1H, J = 7.0 Hz), 7.45 -7.70 (br, 2H), 8.55 (d, 1H, J = 4.0 Hz).
[1631] General Process D Use: The above material (37 mg, 0.10 mmol) was converted to hydrobromide salt to give compound 166 (45 mg) as a white solid. 1 H NMR (D 2 O) δ 1.61 (m, 2H), 1.83 (m, 1H), 2.04 (q, 1H, J = 10.8 Hz), 2.18 (m, 1H), 2.36 (br, 1H), 2.50 (m, 1H), 2.79 (m, 1H), 2.98 (m, 4H), 4.34 (d, 1H, J = 16.5 Hz), 4.50 (m, 1H), 4.50 (d, 1H, J = 16.5 Hz), 7.60 ( m, 2H), 7.79 (m, 2H), 7.86 (m, 1H), 8.34 (d, 1H, J = 7.2 Hz), 8.62 (d, 1H, J = 5.1 Hz). 13 C NMR (D 2 O) δ 20.28, 20.37, 27.62, 28.54, 37.60, 48.22, 49.16, 60.38, 114.22 (2C), 125.88, 126.90 (2C), 130.95, 139.32, 140.58 (2C), 148.02, 151.28, 151.56, 161.67 . ES-MS m / z 379 (M + H). Calcd C21H26N6O.2.8HBr.1.6H2O: C, 39.79; H, 5.09; N, 13.26; Br, 35.30. Found: C, 40.13; H, 5. 12; N, 12.91; Br, 35.09.
[1632] Example 167
[1633]
[1634] Compound 167: {2-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -ethyl} -urea (hydrobromide salt) Manufacture
[1635] Di-tert-butyldicarbonate (25.0 g, 114 mmol) was added to a solution of 3-aminopropane-1,2-diol (9.92 g, 109 mmol) in THF (350 mL) and H ₂ O (15 mL). . The solution was stirred for 16 h and then concentrated under reduced pressure. EtOAc (200 mL) was added and the solution was washed with saturated aqueous NaHCO ₃ (100 mL). After this time the aqueous phase was washed with EtOAc (2 × 100 mL) and the organic phase was dried (MgSO 4), filtered and concentrated. This was purified through a plug of silica gel (1:99 MeOH / CH ₂ Cl ₂ ramping 4:96 MeOH / CH ₂ Cl ₂ ) followed by (2,3-dihydroxy-propyl) -carbamic acid tert-butyl ester (20.2 g, 97%). 1 H NMR (CDCl 3) δ 1.44 (s, 9H), 3.11 (br, 1H, OH), 3.25 (m, 2H), 3.58 (m, 2H), 3.74 (m, 1H), 5.03 (br, 1H, NH ).
[1636] A solution of the compound (0.28 g, 1.5 mmol) in water (5 mL) is treated with sodium periodate (0.29 g, 1.4 mmol) with stirring for 16 h at room temperature. The solution was extracted with CH ₂ Cl ₂ (2 × 20 mL), the combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to afford (2-oxo-ethyl) -carbamic acid tert-butyl ester (0.17 g, 73%).
[1637] Using General Process B, (1H-benzimidazol-2-ylmethyl)-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amine (0.11 g, 0.41 mmol ), (2-oxo-ethyl) -carbamic acid tert-butyl ester (0.17 g, 1.1 mmol) and sodium triacetoxyborohydride (0.17 g, 0.82 mmol) at room temperature CH ₂ Cl ₂ (3 mL) Stir for 18 hours. This was followed by work up and column chromatography (2: 0.5: 97.5 MeOH: NH ₄ OH: CH ₂ Cl ₂ ) followed by {2-[(1H-benzimidazol-2-ylmethyl)-(5 , 6,7,8-tetrahydroquinolin-8-yl) -amino] -ethyl} -carbamic acid tert-butyl ester (0.17 g, 100%) was provided.
[1638] A solution of the compound (0.17 g) was dissolved in CH ₂ Cl ₂ (0.5 mL) and treated with trifluoroacetic acid (0.5 mL) for 2 hours. CH ₂ Cl ₂ (10 mL) was added and the solution was basified to pH> 9 with 15% aqueous NaOH solution (3 mL). The phases were then separated and the aqueous solution extracted with CH ₂ Cl ₂ (2 × 5 mL). The combined organics are then dried (Na 2 SO 4) and concentrated under reduced pressure to give N- (1H-benzimidazol-2-ylmethyl) -N- (5,6,7,8-tetrahydroquinolin-8-yl) Ethane-1,2-diamine (0.10 g, 76%, 2 steps) was obtained. 1 H NMR (CDCl 3): δ 1.65-1.95 (m, 3H), 2.02 (br, 1H), 2.25 (br, 1H), 2.60 -2.90 (m, 5H), 4.05 (m, 2H), 4.17 (d, 1H, J = 15.0 Hz), 7.14 (m, 3H), 7.42 (d, 1H, J = 7.5 Hz), 7.58 (br, 2H), 8.57 (d, 1H, J = 4.5 Hz).
[1639] N- (1H-benzimidazol-2-ylmethyl) -N- (5,6,7,8-tetrahydroquinolin-8-yl) -ethane-1,2-diamine (0.10) in isopropanol (2 mL) g, 0.31 mmol) was treated with trimethylsilyl isocyanate (60 mL, 0.44 mmol) at room temperature. The reaction mixture was stirred for 2 hours and concentrated under reduced pressure. This was followed by silica gel column chromatography (2: 0.5: 97.5 MeOH: NH ₄ OH: CH ₂ Cl ₂ ), followed by {2-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8 -Tetrahydroquinolin-8-yl) -amino] -ethyl} -urea (67 mg, 59%). 1 H NMR (CDCl 3) δ 1.68 (m, 1H), 1.86 (m, 1H), 2.02 (br, 1H), 2.23 (br, 1H), 2.65 (m, 1H), 2.82 (m, 3H), 3.17 ( m, 2H), 4.00 (m, 1H), 4.07 (d, 1H, J = 15.0 Hz), 4.18 (d, 1H, J = 15.0 Hz), 4.43 (br, 2H, NH2), 6.00 (br, 1H , NH), 7.18 (m, 3H), 7.46 (d, 1H, J = 7.0 Hz), 7.45 -7.70 (br, 2H), 8.55 (d, 1H, J = 4.0 Hz).
[1640] General Process D Use: The above material (67 mg, 0.18 mmol) was converted to hydrobromide salt to give compound 167 (88 mg) as a white solid. 1 H NMR (D 2 O) δ 1.83 (m, 1H), 2.02 (q, 1H, J = 12.8 Hz), 2.15 (m, 1H), 2.36 (br, 1H), 2.59 (m, 1H), 2.90 -3.10 ( m, 4H), 3.26 (m, 1H), 4.29 (d, 1H, J = 16.2 Hz), 4.46 (d, 1H, J = 16.5 Hz), 4.47 (m, 1H), 7.60 (m, 2H), 7.79 (m, 2H), 7.86 (m, 1H), 8.33 (d, 1H, J = 7.8 Hz), 8.64 (d, 1H, J = 5.1 Hz). 13 C NMR (D 2 O) δ 20.41, 20.47, 27.72, 38.81, 47.77, 52.14, 60.29, 114.33 (2C), 125.89, 126.99 (3C), 131.03, 139.61, 140.71, 147.92, 150.93 (2C), 161.79. ES-MS m / z 365 (M + H). Calc. For C20H24N6O.2.8HBr.1.8H2O.0.3C4H10O: C, 39.44; H, 5. 21; N, 13.02; Br, 34.65. Found: C, 39.33; H, 5.09; N, 12.93; Br, 34.72.
[1641] Example 168
[1642]
[1643] Compound 168: (3-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -piperidine- Preparation of 1-yl)-(3,5-dichloro-pyridin-4-yl) -methanone
[1644] Preparation of (3,5-Dichloro-pyridin-4-yl)-(3-hydroxymethyl-piperidin-1-yl) -methanone:
[1645] (p. 338-2)
[1646] 3,5-Dichloroisonicotinic acid (250 mg, 1.30 mmol) in CH ₂ Cl ₂ (6.5 ml) is added to DMF (catalyst) and oxalyl chloride (0.45 mL, 5.2 mmol) and the mixture is kept at room temperature for 2 hours. After stirring, it was concentrated in vacuo. To the residue was added a solution of 3-piperidinmethanol (150 mg, 1.30 mmol) in THF (2 mL), Et ₃ N (0.27 mL, 1.9 mmol), and THF (4.5 mL), and the mixture was kept at room temperature for 21 hours. Stirred. The mixture was diluted with CH ₂ Cl ₂ (50 mL) and brine (30 mL) and the phases separated. The organic phase was washed with brine (2 × 50 mL) and saturated NaHCO ₃ (2 × 50 mL). The organic layer was dried (MgSO ₄ ), filtered, concentrated and dried in vacuo to afford crude oil. The crude material was purified by column chromatography on silica gel (100: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give a yellow oil (isomer mixture) (147 mg, 39%). ¹ H NMR (CDCl ₃ ) δ 1.28-1.96 (m, 4H), 2.89-3.26 (m, 3H), 3.35-3.45 (m, 1H), 3.50-3.72 (m, 2H), 4.29-4.56 (m, 1H), 8.54 (m, 2H).
[1647] (3,5-Dichloro-pyridin-4-yl)-{3-[(5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -piperidin-1-yl}- Preparation of Methanone:
[1648]
[1649] Death in a solution of (3,5-dichloro-pyridin-4-yl)-(3-hydroxymethyl-piperidin-1-yl) -methanone (147 mg, 0.508 mmol) in CH ₂ Cl ₂ (5 mL) Martin Periodinan (226 mg, 0.533 mmol) was added at room temperature. After stirring at room temperature for 45 minutes, the mixture was washed with 1N NaOH (aq) (2 × 10 mL), then dried (MgSO ₄ ) and concentrated in vacuo to give a colorless oil (121 mg, 83%). .
[1650] Use of General Process A: aldehyde (121 mg, 0.421 mmol) and 5,6,7,8-tetrahydro-quinolin-8-ylamine from above in 4: 1 MeOH / trimethyl orthoformate (4.2 mL) ( 75 mg, 0.51 mmol) of NaBH ₃ CN (106 mg, 1.69 mmol) was added and the mixture was heated to 60 ° C. for 21 h. The crude material was purified by column chromatography on silica gel (150: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give a colorless oil (isomer mixture) (66 mg, 37%). ¹ H NMR (CDCl ₃ ) δ 1.24-3.79 (m, 17H), 4.48-4.67 (m, 1H), 7.05 (m, 1H), 7.36 (m, 1H), 8.24-8.52 (m, 3H).
[1651] (3,5-Dichloro-pyridin-4-yl)-{3-[(5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -piperi in acetonitrile (3.0 mL) Din-1-yl} -methanone (63 mg, 0.15 mmol), 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (60 mg, 0.22 mmol), potassium iodide (1 mg, 0.006 mmol ) And N, N-diisopropylethylamine (0.052 mL, 0.30 mmol) were heated at 60 ° C. for 16 h. Saturated NaHCO ₃ (aq) (10 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 × 12 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (300: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give a yellow foam (79 mg).
[1652] The amine from above (79 mg) in 1: 1 TFA / CH ₂ Cl ₂ (4 mL) was stirred at rt for 1 h and then concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (15 mL) and washed with 1N NaOH (aq) (10 mL). The aqueous phase is extracted with CH ₂ Cl ₂ (2 × 10 mL) and the combined organic extracts are dried (MgSO ₄ ) and concentrated in vacuo to give compound 168 as a yellow foam (isomer mixture) (72 mg, 87%). It was. ¹ H NMR (CDCl ₃ ) δ 1.25-4.76 (m, 20H), 7.12-8.64 (m, 9H); ¹³ C NMR (CDCl ₃ ) δ 21.37, 21.47, 21.75, 22.83, 23.51, 23.87, 24.06, 24.20, 24.87, 25.26, 26.90, 27.18, 27.61, 27.94, 29.03, 29.24, 29.45, 29.68, 34.12, 34.54, 34.85, 34.85, 35.53, 38.16, 38.69, 39.37, 42.30, 42.38, 44.48, 45.57, 46.22, 47.05, 47.23, 48.61, 49.61, 49.83, 49.97, 51.06, 51.39, 52.89, 53.11, 55.30, 59.44, 61.61, 61.85, 62.03, 62.03 64.26, 111.28, 118.80, 121.66, 121.74, 122.29, 128.10, 128.18, 128.35, 128.52, 128.60, 128.68, 134.61, 137.35, 137.48, 142.26, 142.43, 146.49, 146.74, 146.147, 147.39, 48.59, 147.39, 48. 156.11, 156.74, 156.90, 157.23, 161.08, 161.20. ES-MS m / z 550 (M + H). Calc. For C ₂₉ H ₃ 0N ₆ Cl ₂ O.0.5CH ₂ Cl ₂ .0.6H ₂ O.0.2C ₆ H ₁₄ : C, 59.47; H, 5.69; N, 13.55; Cl, 17.15. Found: C, 59.62; H, 5.39; N, 13.51; Cl, 16.92.
[1653] Example 169
[1654]
[1655] Compound 169: (3-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl) -amino] -methyl} -pyrrolidine- Preparation of 1-yl)-(3,5-dichloro-pyridin-4-yl) -methanone
[1656] Preparation of Carbonic Acid 1-benzyl-pyrrolidin-3-ylmethyl ester vinyl ester:
[1657]
[1658] (1-benzyl-pyrrolidin-3-yl) -methanol in 1,2-dichloroethane (10 mL) (see Y.-H. Wu and RF Feldkamp, Pyrrolidines I, 1961, 26, 1519-1524) (455 mg, 2.38 mmol) and vinyl chloroformate (0.40 mL, 4.7 mmol) were heated to reflux for 2 hours and then concentrated in vacuo. The crude material was purified by column chromatography on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give a yellow oil (440 mg, 71%). ¹ H NMR (CDCl ₃ ) δ 1.84 (m, 1H), 2.26 (m, 1H), 3.03 (m, 5H), 4.01 (br s, 2H), 4.23 (m, 2H), 4.61 (dd, 1H, J = 6.2, 2.3 Hz), 4.93 (dd, 1H, J = 14, 2.1 Hz), 7.06 (dd, 1H, J = 14, 6.3 Hz), 7.41 (m, 3H), 7.53 (m, 2H).
[1659] Preparation of 3-vinyloxycarbonyloxymethyl-pyrrolidine-1-carboxylic acid vinyl esters:
[1660]
[1661] A solution of carboxylic acid 1-benzyl-pyrrolidin-3-ylmethyl ester vinyl ester (440 mg, 1.68 mmol) and vinyl chloroformate (0.30 mL, 3.5 mmol) in 1,2-dichloroethane (10 mL) was added. Heated to reflux for hours and then concentrated in vacuo. The crude material was purified by column chromatography on silica gel (20% EtOAc / hexanes) to give a yellow oil (335 mg, 83%). ¹ H NMR (CDCl ₃ ) δ 1.68-1.85 (m, 1H), 2.03-2.16 (m, 1H), 2.59-2.71 (m, 1H), 3.26 (m, 1H), 3.41-3.52 (m, 1H) , 3.55-3.72 (m, 2H), 4.11-4.28 (m, 2H), 4.45 (dd, 1H, J = 6.3, 1.5 Hz), 4.61 (m, 1H), 4.78 (dd, 1H, J = 14, 1.5 Hz), 4.94 (m, 1 H), 7.08 (m, 1 H), 7.22 (dd, 1 H, J = 14, 6.3 Hz).
[1662] Preparation of Carbonic Acid Pyrrolidin-3-ylmethyl Ester Vinyl Ester Hydrochloride:
[1663]
[1664] 3-vinyloxycarbonyloxymethyl-pyrrolidine-1-carboxylic acid vinyl ester (335 mg, 1.39 mmol) was dissolved in CH ₂ Cl ₂ (10 mL) and HCl (g) was passed through the solution for 2 minutes. The solution was then concentrated in vacuo. The residue was dissolved in MeOH (10 mL), heated to reflux for 15 minutes and then concentrated in vacuo to give a colorless oil (284 mg, 99%). ¹ H NMR (CD ₃ OD) δ 1.78-1.91 (m, 1H), 2.17-2.28 (m, 1H), 2.79 (m, 1H), 3.09 (dd, 1H, J = 12, 7.8 Hz), 3.25- 3.51 (m, 3H), 4.19-4.33 (m, 2H), 4.62 (dd, 1H, J = 6.2, 2.0 Hz), 4.89 (m, 1H), 7.11 (dd, 1H, J = 14, 6.0 Hz) .
[1665] Preparation of (3,5-Dichloro-pyridin-4-yl)-(3-hydroxymethyl-pyrrolidin-1-yl) -methanone:
[1666]
[1667] To a suspension of 3,5-dichloroisonicotinic acid (267 mg, 1.39 mmol) in CH ₂ Cl ₂ (7.0 mL) was added DMF (catalyst) and oxalyl chloride (0.49 mL, 5.6 mmol), and the mixture was stirred at room temperature 2.5. Stir for hours and then concentrate in vacuo. To the residue was added a solution of carboxylic acid pyrrolidin-3-ylmethyl ester vinyl ester hydrochloride (284 mg, 1.37 mmol) in THF (4 mL), Et3N (0.58 mL, 4.2 mmol), and THF (3 mL), The mixture was stirred at rt for 21 h. The mixture was diluted with CH ₂ Cl ₂ (50 mL) and brine (30 mL) and the phases separated. The organic phase was washed with brine (2 × 50 mL) and saturated NaHCO ₃ (2 × 50 mL). The organic layer was dried (MgSO ₄ ), filtered, concentrated and dried in vacuo to yield a yellow oil (315 mg).
[1668] To a crude amide (315 mg) solution from above in MeOH (315 g) was added 10N NaOH (aq) (1.0 mL, 10 mmol) and the solution was stirred at room temperature for 30 minutes. Water (15 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (4 × 15 mL), then the combined organic extracts were dried (MgSO 4) and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (100: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give a yellow oil (isomer mixture) (172 mg, 46%). ¹ H NMR (CDCl ₃ ) δ 1.44-4.24 (m, 10H), 8.54 (s, 2H).
[1669] (3,5-Dichloro-pyridin-4-yl)-{3-[(S)-(5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -pyrrolidine-1 Preparation of Methylone:
[1670]
[1671] To a solution of (3,5-dichloro-pyridin-4-yl)-(3-hydroxymethyl-pyrrolidin-1-yl) -methanone (172 mg, 0.625 mmol) in CH ₂ Cl ₂ (6.3 mL) Dess-Martin periodinan (278 mg, 0.655 mmol) was added at room temperature. After stirring for 40 min at rt, the mixture was washed with 1N NaOH (aq) (2 × 10 mL), dried (MgSO ₄ ) and concentrated in vacuo to give a yellow oil (163 mg, 95%).
[1672] Use of General Process A: Aldehyde (163 mg, 0.597 mmol) and 5,6,7,8-tetrahydro-quinolin-8-ylamine from above in 4: 1 MeOH / trimethyl orthoformate (6.0 mL) ( 106 mg, 0.715 mmol) of NaBH ₃ CN (150 mg, 2.39 mmol) was added and the mixture was heated at 60 ° C. for 15 h. The crude was purified by column chromatography on silica gel (150: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give a yellow oil (isomer mixture) (86 mg, 36%). ¹ H NMR (CDCl ₃ ) δ 1.57-3.96 (m, 16H), 7.06 (m, 1H), 7.37 (m, 1H), 8.36 (m, 1H), 8.51 (m, 2H).
[1673] (3,5-Dichloro-pyridin-4-yl)-{3-[(5,6,7,8-tetrahydro-quinolin-8-ylamino) -methyl] -pyrroli in acetonitrile (4.2 mL) Din-1-yl} -methanone (85 mg, 0.21 mmol), 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (84 mg, 0.31 mmol), potassium iodide (2 mg, 0.01 mmol ) And N, N-diisopropylethylamine (0.073 mL, 0.42 mmol) were heated at 60 ° C. for 24 h. Saturated NaHCO ₃ (aq) (10 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 × 12 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (300: 5: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give a yellow oil (124 mg).
[1674] A solution of amine (124 mg) from above in 1: 1 TFA / CH ₂ Cl ₂ (4 mL) was stirred at RT for 1 h and then concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (15 mL) and washed with 1N NaOH (aq) (10 mL). The organic phase is extracted with CH ₂ Cl ₂ (2 × 10 mL) and the combined organic extracts are dried (MgSO ₄ ) and concentrated in vacuo to give compound 169 as a yellow foam (isomer mixture) (94 mg, 84%). It was. ¹ H NMR (CDCl ₃ ) δ 1.09-4.27 (m, 18H), 7.12-7.25 (m, 3H), 7.43-7.61 (m, 3H), 8.11-8.73 (m, 3H); 13 C NMR (CDCl 3) δ 21.37, 23.37, 23.73, 27.80, 28.27, 28.71, 29.16, 36.35, 37.82, 38.65, 44.13, 45.13, 45.41, 45.77, 49.18, 49.44, 49.62, 50.06, 50.50, 52.37, 52.89, 53.89, 53.89 53.45, 61.92, 62.01, 62.38, 62.55, 121.80, 122.37, 122.55, 122.65, 128.04, 128.41, 134.35, 134.67, 134.90, 137.41, 137.59, 137.70, 142.99, 146.05, 146.147, 147.44, 73. 156.56, 157.01, 161.03, 161.31. ES-MS m / z 536 (M + H). Calcd _{C 28 H 28 N 6 Cl 2} O · 0.1CH 2 Cl 2 · 1.1H 2 O · 0.1C 6 H 14: C, 60.22; H, 5. 60; N, 14.68; Cl, 13.63. Found: C, 60.11; H, 5.39; N, 14.42; Cl, 13.85.
[1675] Example 170
[1676]
[1677] Compound 170: 4-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -piperidine-1-carboxamidine Preparation of (hydrobromide salt)
[1678] Use of general process B: [tert-butoxycarbonylimino- (4-oxo-piperidin-1-yl) -methyl] -carbamic acid tert-butyl ester (490 mg, 1.43 mmol), ( 5,6,7,8-tetrahydroquinolin-8-yl) -amine (210 mg, 1.43 mmol) and sodium triacetoxyborohydride (450 mg, 2.14 mmol) were placed in dichloromethane (4 mL) at room temperature. After stirring for 16 h, post-treatment and column chromatography (2: 0.5: 97.5 MeOH: NH ₄ OH: CH ₂ Cl ₂ ) followed by {tert-butoxycarbonylimino- [4- (5, 6,7,8-tetrahydroquinolin-8-ylamino) -piperidin-1-yl] -methyl} -carbamic acid tert-butyl ester was obtained as a white solid (560 mg, 82%).
[1679] Secondary amine (560 mg, 1.18 mmol), 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (470 mg, 1.77 mmol) and potassium iodide from above in anhydrous CH ₃ CN (12 mL) Diisopropylethylamine (0.41 mL, 2.35 mmol) was added to a solution of (10 mg, 0.06 mmol) and the reaction was stirred at 40 ° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between CH ₂ Cl ₂ (30 mL) and brine (15 mL). The organic phase was separated and the aqueous phase extracted with CH ₂ Cl ₂ (2 × 15 mL). The combined organic phases are then dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a crude residue which is purified by radial chromatography with silica gel (saturated NH ₃ / Et ₂ O) to give 2 -{[[1- (tert-butoxycarbonylimino-tert-butoxycarbonyliminomethyl) -piperidin-4-yl]-(5,6,7,8-tetrahydroquinoline- 8-yl) -amino] -methyl} -benzimidazole-1-carboxylic acid tert-butyl ester was obtained as light yellow oil (336 mg, 40%). ¹ H NMR (CDCl ₃ ) δ 1.45 (s, 9H), 1.48 (s, 9H), 1.62 (br, 3H), 1.66 (s, 9H), 1.77 (m, 3H), 2.03 (m, 4H), 2.56 (m, 1H), 2.72 (m, 1H), 2.90 (br t, 2H, J = 12.0 Hz), 3.15 (br t, 1H), 4.22 (m, 1H), 4.34 (d, 1H, J = 15.0 Hz), 4.48 (d, 1H, J = 15.0 Hz), 6.85 (m, 1H), 7.10 (d, 1H, J = 7.8 Hz), 7.24 (m, 2H), 7.64 (m, 1H), 7.75 (m, 1H), 8.31 (d, 1H, J = 5.4 Hz), 10.09 (s, 1H, NH).
[1680] Use of General Process D: A portion of the material (75 mg, 0.11 mmol) was converted to a hydrobromide salt to give compound 170 (58 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.60 -2.00 (m, 4H), 2.05 -2.25 (m, 3H), 2.42 (m, 1H), 2.90 -3.15 (m, 5H), 3.86 (m, 2H), 4.42 (d, 1H, J = 16.8 Hz), 4.53 (m, 1H), 4.56 (d, 1H, J = 16.8 Hz), 7.58 (m, 2H), 7.70 -7.85 (m, 3H), 8.26 (d , 1H, J = 7.5 Hz), 8.54 (d, 1H, J = 5.4 Hz). ¹³ C NMR (D ₂ O) δ 20.69, 23.95, 27.54, 29.01, 30.59, 43.81, 45.51, 45.58, 58.32, 58.71, 114.24 (2C), 125.85, 127.01 (2C), 131.02, 139.19, 140.53 (2C), 148.02, 151.32, 151.75, 156.21. ES-MS m / z 404 (M + H). Calc. For C ₂₃ H ₂₉ N ₇ .3.0 HBr. 2.0H ₂ O: C, 40.49; H, 5. 32; N, 14.37; Br, 35.13. Found: C, 40.57; H, 5. 33; N, 14.15; Br, 35.25.
[1681] Example 171
[1682]
[1683] Compound 171: 4-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -piperidine-1-carboxylic acid amide (hydro Bromide salts)
[1684] 4-hydroxypiperidine (2.58 g, 25.5 mmol) was dissolved in THF (100 mL), treated with di-tert-butyl dicarbonate (5.57 g, 25.5 mmol) and then stirred at room temperature for 40 minutes. It was. The solvent was removed under reduced pressure to give 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester as light yellow oil, which was used for the next step.
[1685] A solution of the alcohol (0.79 g, 3.9 mmol) in CH ₂ Cl ₂ (20 mL) was charged with molecular sieve (1.95 g), N-methylmorpholine oxide (0.69 g, 5.9 mmol) and TPAP (0.14 g, 0.40 mmol). Treated with. The mixture was stirred at room temperature for 2 hours and then filtered through a silica gel plug eluting with Et20. The filtrate was concentrated under reduced pressure to afford the desired 4-oxopiperidine-1-carboxylic acid tert-butyl ester (0.69 g, 89%). ¹ H NMR (CDCl ₃ ) δ 1.49 (s, 9H), 2.44 (t, 4H, J = 7.0 Hz), 3.72 (t, 4H, J = 7.0 Hz).
[1686] Use of general process B: 4-oxopiperidine-1-carboxylic acid tert-butyl ester (0.69 g, 3.4 mmol), (5,6,7,8-tetrahydroquinolin-8-yl) -amine (0.51 g, 3.4 mmol) and sodium triacetoxyborohydride (1.10 g, 5.2 mmol) were stirred for 16 h in dichloromethane (20 mL) at room temperature, followed by work-up and silica gel column chromatography (5: 0.5: 94.5 MeOH: NH ₄ OH: CH ₂ Cl ₂ ), then 4- (5,6,7,8-tetrahydroquinolin-8-ylamino) -piperidine-1-carboxylic acid tert-butyl ester is white Obtained as a solid (1.00 g, 87%).
[1687] 4- (5,6,7,8-tetrahydroquinolin-8-ylamino) -piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.0 mmol), 2 in anhydrous acetonitrile (30 mL) Diisopropylethylamine (1.05 mL, 6.0 mmol) was added to a solution of chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (1.20 g, 4.5 mmol) and potassium iodide (25 mg, 0.15 mmol). And stirred at 40 ° C. for 16 h. The mixture was then concentrated under reduced pressure and the residue was partitioned between dichloromethane (30 mL) and brine (25 mL). The organic phase was separated and the aqueous phase extracted with dichloromethane (2 x 25 mL). The combined organic phases are then dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford crude residue, which is silica gel column chromatography (2: 0.5: 97.5 MeOH: NH ₄ OH: CH ₂ Cl ₂ Purified by) 2-{[(1-tert-butoxycarbonyl-piperidin-4-yl)-(5,6,7,8-tetrahydroquinolin-8-yl) -amino] -methyl} -Benzimidazole-1-carboxylic acid tert-butyl ester was obtained as a pale orange solid (0.50 g, 30%).
[1688] A solution of the compound (0.50 g, 0.9 mmol) was dissolved in CH ₂ Cl ₂ (2 mL) and treated with trifluoroacetic acid (2.5 mL) for 1 hour. CH ₂ Cl ₂ (20 mL) was added and the solution basified to pH> 9 with 15% aqueous NaOH solution (10 mL). Brine (20 mL) was added to ease emulsification. The phases were then separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 40 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give (1H-benzimidazol-2-ylmethyl) -piperidin-4-yl- (5,6,7,8-tetrahydroquinoline- 8-yl) -amine (0.32 g, 100%) was obtained. ¹ H NMR (CDCl ₃ ): δ 1.35 (m, 1H), 1.50 -1.75 (m, 3H), 1.84 (m, 2H), 2.05 (br, 1H), 2.23 (br, 1H), 2.40 -2.65 ( m, 3H), 2.74 (m, 1H), 2.80 -2.95 (m, 2H), 3.07 (m, 1H), 4.13 (m, 1H), 4.21 (s, 2H), 7.16 (m, 3H), 7.43 (d, 1H, J = 7.5 Hz), 7.44 (br, 1H), 7.67 (br, 1H), 8.59 (d, 1H, J = 4.5 Hz).
[1689] (1H-benzimidazol-2-ylmethyl) -piperidin-4-yl- (5,6,7,8-tetrahydroquinolin-8-yl) -amine (0.16 g, in isopropanol (3 mL) 0.43 mmol) solution was treated with trimethylsilyl isocyanate (81 mL, 0.60 mmol) at room temperature. The reaction was stirred for 20 hours and concentrated under reduced pressure. After purification by silica gel column chromatography (5: 0.5: 94.5 MeOH: NH ₄ OH: CH ₂ Cl ₂ ), 4-[(1H-benzimidazol-2-ylmethyl)-(5,6,7, 8-tetrahydroquinolin-8-yl) -amino] -piperidine-1-carboxylic acid amide (112 mg, 66%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.42 (m, 1H), 1.60 -1.95 (m, 5H), 2.02 (br, 1H), 2.24 (br, 1H), 2.60 -2.80 (m, 4H), 2.89 (m , 1H), 3.70 (br, 1H), 4.03 (br, 1H), 4.15 (m, 3H), 4.39 (br, 2H, NH2), 7.18 (m, 3H), 7.45 (d, 1H, J = 7.5 Hz), 7.66 (br, 2H), 8.59 (d, 1H, J = 4.0 Hz).
[1690] Use of General Process D: The material (105 mg, 0.26 mmol) was converted to a hydrobromide salt to give compound 171 (107 mg) as a white solid. ¹ H NMR (D ₂ O) δ 1.56 (dqt, 2H, J = 2.1, 12.0 Hz), 1.82 (br, 2H), 2.14 (br, 3H), 2.42 (br, 1H), 2.77 (br t, 2H , J = 12.3 Hz), 2.97 (br, 3H), 3.92 (br t, 2H, J = 17.1 Hz), 4.42 (d, 1H, J = 16.8 Hz), 4.54 (m, 1H), 4.57 (d, 1H, J = 16.8 Hz, 7.59 (m, 2H), 7.75 (m, 2H), 7.79 (m, 1H), 8.28 (d, 1H, J = 8.1 Hz), 8.55 (d, 1H, J = 5.7 Hz). 13 C NMR (D ₂ O) δ 20.71, 23.89, 27.55, 29.45, 31.09, 43.98 (3C), 58.88, 58.97, 114.21 (2C), 125.83, 127.03 (2C), 130.90, 139.11, 140.49 (2C), 148.02, 151.55, 151.96, 160.13. ES-MS m / z 405 (M + H). Calc. For C ₂₃ H ₂₈ N ₆ O. 3.0HBr. 1.3H ₂ O. 0.3C ₄ H ₁₀ O: C, 41.95; H, 5. 32; N, 12.13; Br, 34.60. Found: C, 42.08; H, 5. 30; N, 12.19; Br, 34.52.
[1691] Efficacy Examples:
[1692] Inhibition assay of HIV-1 (NL4.3) replication in PBMC
[1693] Assays for inhibiting HIV-1 NL4.3 replication in PBMCs (peripheral vascular mononuclear cells) are described previously in De Clercq et al. Proc. Natl. Acad. Sci, 1992, 89, 5286-5290; De Clercq et al. Antimicrob. Agents Chemother. 1994, 38, 668-674; Schols, D. et al. J. Exp. Med. 1997, 186, 1383-1388. Briefly, PBMCs from healthy donors were separated by density gradient centrifugation and stimulated with PHA 1 mg / ml (Sigma Chemical Co., Bornem, Belgium) at 37 ° C. for 3 days. The activating cells (PHA stimulated blasts) were washed three times with PBS and viral infection was performed as described in Cocchi et al. (Science 1995, 270, 1811-1815). HIV infected or mock infected PHA stimulated blasts were incubated in the presence of 25 U / ml IL-2 and the concentration of test compound was varied. Supernatants were recovered on days 6 and 10 and HIV-1 core antigens in culture supernatants were analyzed by p24 ELISA kit (DuPont-Merck Pharmaceutical Co, Wilmington, DE). 50% inhibitory concentration (IC ₅₀ ) was defined as the concentration of test compound required to 50% inhibit p24 antigen production.
[1694] Many of the compounds of the present invention exhibited IC ₅₀ in the range of 5 to 5.5 nM when tested in the assay described above.
[1695] Assay for Inhibition of SDF-1α Induced Ca Flow in CEM Cells
[1696] Inhibition of SDF-1 induced calcium flux was assayed using CCRF-CEM cells, a T-lymphoblastoid cell line expressing CXCR4. CCRF-CEM cells (5 × 10 ⁶ cells / ml in RPMI 1640 medium containing fetal bovine serum) were preweighted with 1 mm fluor-4 fluorescent calcium indicator dye and incubated at 37 ° C. for 40 minutes. The weighted cells are washed and resuspended in buffer containing 20 mm HEPES pH 7.4, 1 × Hanks Balanced Salt Solution (HBSS), 0.2% bovine serum albumin, 2.5 mM Probenic Acid, and 3.5 × per well. 10 ⁵ cells were plated out in 96-well tissue culture plates. Cells were incubated at 37 ° C. for 15 minutes with test compounds or buffered controls. Calcium flow was stimulated by the addition of 25 nM SDF-1 and fluorescence was measured using a Flex Station Fluorescent Plate Reader (Molecular Devices). 80 seconds after adding SDF-1, ionomycin was added to measure total calcium load. Compounds were tested at a concentration range of 2000-0.126 nM. Fluorescence measurements were normalized to untreated controls. The 50% inhibitory concentration (IC ₅₀ value) is defined as the concentration of test compound required to inhibit SDF-1 induced calcium flow by 50% relative to untreated control.
[1697] When the compounds of the present invention were tested in the assay described above, IC ₅₀ was shown in the range of 5 nM to 5 μM.

权利要求:
Claims (39)
[1" claim-type="Currently amended] A compound of formula (I), or a salt or prodrug form thereof, and any stereoisomeric form thereof.
Formula I

In Formula I above,
X and Y are independently N or CR ¹ ,
Z is S, O, NR ¹ or CR ¹ ₂ ,
R ¹ to R ⁶ are independently H or non-interfering substituents,
n1 is 0 to 4,
n2 is 0-1 (where * indicates that C≡C may be substituted by CR ⁵ = CR ⁵ ),
n3 is 0 to 4,
n1 + n2 + n3 is 2 or more,
b is 0 to 2,
R ² + R ² , one R ² + R ³ , R ³ + one R ⁴ , R ⁴ + R ⁴ , one R ⁵ + another R ⁵ , one R ⁵ + one R ⁶ and R ⁶ The combination of the R groups of + R ⁶ may be cuffed to give rise to a ring which may be saturated or unsaturated,
The ring may not be aromatic when the participants of the ring formation are two R ⁵ ,
When n2 is 1, n1 and n3 cannot be zero.
[2" claim-type="Currently amended] The compound of claim 1, wherein each R ¹ to R ⁶ is independently H, or alkyl (C _1-10 ), alkenyl (C _2-10 ), alkynyl (C _2-10 ), aryl (“C” _5-12 ), arylalkyl, arylalkenyl or arylalkynyl [where each of these may optionally contain one or more heteroatoms selected from O, S and N, each of which may be further substituted or acyl , Arylacyl, alkyl-, alkenyl-, alkynyl- or arylsulfonyl and optionally substituted forms thereof containing heteroatoms in alkyl, alkenyl, alkynyl or aryl moieties], or OR , SR, NR ₂ , COOR, CONR ₂ wherein R is H or an alkyl, alkenyl, alkynyl or aryl as defined above, wherein the compound is a non-interfering substituent, wherein the substituted atom is C Non-interfering substituents can be halo, OOCR, NROCR, where R is H or the substituents described above, or = O.
[3" claim-type="Currently amended] The compound of claim 1, which is a compound of Formula II, or a salt or prodrug thereof, and any stereoisomeric form thereof.
Formula II

In Formula II above,
R ¹ to R ⁶ and n1 to n3 are as defined in claim 1.
[4" claim-type="Currently amended] The compound of claim 3, wherein each R ¹ to R ⁶ is independently H, alkyl (C _1-10 ), alkenyl (C _2-10 ), alkynyl (C _2-10 ), aryl (“C” _5-12 ), arylalkyl, arylalkenyl or arylalkynyl [where each of these may optionally contain one or more heteroatoms selected from O, S and N, each of which may be further substituted or acyl , Arylacyl, alkyl-, alkenyl-, alkynyl- or arylsulfonyl and optionally substituted forms thereof containing heteroatoms in alkyl, alkenyl, alkynyl or aryl moieties], or OR , SR, NR ₂ , COOR, CONR ₂ wherein R is H or an alkyl, alkenyl, alkynyl or aryl as defined above, wherein the compound is a non-interfering substituent, wherein the substituted atom is C Non-interfering substituents can be halo, OOCR, NROCR, where R is H or the substituents described above, or = O.
[5" claim-type="Currently amended] The compound of claim 1, which is a compound of Formula IIIa or Formula IIIb, or a salt or prodrug form thereof, and any diastereomeric form thereof.
Formula IIIa

Formula IIIb

In Formula IIIa and Formula IIIb above,
d is 0 to 3,
The dotted line represents any π bond,
R ¹ to R ⁶ are as defined in claim 1.
[6" claim-type="Currently amended] The compound of claim 5, wherein each R ¹ to R ⁶ is independently H, or alkyl (C _1-10 ), alkenyl (C _2-10 ), alkynyl (C _2-10 ), aryl (“C” _5-12 ), arylalkyl, arylalkenyl or arylalkynyl [where each of these may optionally contain one or more heteroatoms selected from O, S and N, each of which may be further substituted or acyl , Arylacyl, alkyl-, alkenyl-, alkynyl- or arylsulfonyl and optionally substituted forms thereof containing heteroatoms in alkyl, alkenyl, alkynyl or aryl moieties], or OR , SR, NR ₂ , COOR, CONR ₂ , wherein R is a non-interfering substituent including H or alkyl, alkenyl, alkynyl or aryl, as defined above, wherein the substituted atom is C Non-interfering substituents can be halo, OOCR, NROCR, where R is H or the substituents described above, or = O.
[7" claim-type="Currently amended] The compound of claim 1, which is a compound of Formula IIIc or Formula IIId, or a salt or prodrug form thereof, and any diastereomeric form thereof.
Formula IIIc

Formula IIId

In Formula IIIc and Formula IIId above,
d is 0 to 3,
The dotted line represents any π bond,
R ¹ to R ⁶ are as defined in claim 1.
[8" claim-type="Currently amended] 8. The compound of claim 7, wherein each R ¹ to R ⁶ is independently H or alkyl (C _1-10 ), alkenyl (C _2-10 ), alkynyl (C _2-10 ), aryl (“C” _5-12 ), arylalkyl, arylalkenyl or arylalkynyl [where each of these may optionally contain one or more heteroatoms selected from O, S and N, each of which may be further substituted or acyl , Arylacyl, alkyl-, alkenyl-, alkynyl- or arylsulfonyl and optionally substituted forms thereof containing heteroatoms in alkyl, alkenyl, alkynyl or aryl moieties], or OR , SR, NR ₂ , COOR, CONR ₂ , wherein R is a non-interfering substituent including H or alkyl, alkenyl, alkynyl or aryl, as defined above, wherein the substituted atom is C Non-interfering substituents can be halo, OOCR, NROCR, where R is H or the substituents described above, or = O.
[9" claim-type="Currently amended] The compound of claim 1, which is a compound of Formula IIIe, or a salt or prodrug form thereof, and any diastereomeric form thereof.
Formula IIIe

In Formula IIIe above,
R ¹ to R ₆ are as defined in claim 1,
n4 is 2-6.
[10" claim-type="Currently amended] The compound of claim 9, wherein each R ¹ to R ⁶ is independently H, or alkyl (C _1-10 ), alkenyl (C _2-10 ), alkynyl (C _2-10 ), aryl (“C” _5-12 ), arylalkyl, arylalkenyl or arylalkynyl [where each of these may optionally contain one or more heteroatoms selected from O, S and N, each of which may be further substituted or acyl , Arylacyl, alkyl-, alkenyl-, alkynyl- or arylsulfonyl and optionally substituted forms thereof containing heteroatoms in alkyl, alkenyl, alkynyl or aryl moieties], or OR , SR, NR ₂ , COOR, CONR ₂ wherein R is H or an alkyl, alkenyl, alkynyl or aryl as defined above, wherein the compound is a non-interfering substituent, wherein the substituted atom is C Non-interfering substituents can be halo, OOCR, NROCR, where R is H or the substituents described above, or = O.
[11" claim-type="Currently amended] The compound of claim 1, wherein each R ¹ is independently H, halo, alkyl, alkoxy or CF ₃ .
[12" claim-type="Currently amended] The compound of claim 1, wherein each R ² is independently H or alkyl.
[13" claim-type="Currently amended] The compound of claim 1, wherein R ³ is H, alkyl, alkenyl, arylalkyl or aryl.
[14" claim-type="Currently amended] The compound of claim 1, wherein R ⁴ is each H or alkyl, or two R ⁴ together form an aromatic ring.
[15" claim-type="Currently amended] The compound of claim 1, wherein each R ⁵ is independently H, alkyl or alkenyl, wherein alkyl or alkenyl may be optionally substituted.
[16" claim-type="Currently amended] 16. The compound of claim 15, wherein the alkyl or alkenyl substituent on a single carbon or non-adjacent or adjacent carbon forms a saturated or unsaturated ring, wherein the ring cannot be aromatic.
[17" claim-type="Currently amended] The compound of claim 1, wherein R ⁵ is oxime, alkylated oxime, alkylated hydroxylamine, hydroxylamine or halo.
[18" claim-type="Currently amended] The compound of claim 1, wherein each R ⁶ is independently H or optionally arylalkyl, arylsulfonyl containing heteroatoms, or comprises guanidyl, carbonyl or carbamido groups.
[19" claim-type="Currently amended] The compound of claim 1, wherein two R ^{6 form} a saturated, unsaturated or aromatic ring, wherein the ring may optionally contain one or more heteroatoms (N, S or O).
[20" claim-type="Currently amended] The compound of claim 1, wherein one R ⁵ and one R ^{6 form} a saturated or unsaturated or aromatic ring, wherein the ring may optionally contain additional heteroatoms.
[21" claim-type="Currently amended] A pharmaceutical composition comprising at least one compound of claim 1 together with a pharmaceutically acceptable excipient.
[22" claim-type="Currently amended] The composition of claim 21 comprising one or more additional biologically active agents.
[23" claim-type="Currently amended] A method of modulating a CXCR4 and / or CCR5 receptor comprising contacting a cell representing the receptor (s) with an amount of the compound of claim 1 that is effective to modulate the receptor (s).
[24" claim-type="Currently amended] A method of treating such a condition comprising administering an effective amount of the compound of claim 1 or a pharmaceutical composition thereof to a patient in need thereof for treatment of a condition characterized by inappropriate activity of the CXCR4 and / or CCR5 receptor.
[25" claim-type="Currently amended] Unnecessary conditions of a human or animal patient, comprising administering an effective amount of a compound of claim 1 or a pharmaceutical composition thereof to a patient in need thereof by a clinically acceptable route of administration according to a clinically effective method Method of treatment.
[26" claim-type="Currently amended] The method of claim 25, wherein the condition is regulated by chemokine receptors.
[27" claim-type="Currently amended] The method of claim 26, wherein the chemokine receptor is a CXCR4 or CCR5 receptor.
[28" claim-type="Currently amended] The method of claim 25, wherein the condition is characterized by angiogenesis.
[29" claim-type="Currently amended] The method of claim 26, wherein the condition comprises a tumor.
[30" claim-type="Currently amended] The method of claim 29, wherein the tumor is brain, breast, prostate, lung, or haematopoetic tissue.
[31" claim-type="Currently amended] The method of claim 26, wherein the condition is HIV infection.
[32" claim-type="Currently amended] The method of claim 26, wherein the condition is rheumatoid arthritis.
[33" claim-type="Currently amended] The method of claim 26, wherein the condition is an inflammatory or allergic disease.
[34" claim-type="Currently amended] The method of claim 33, wherein the condition is asthma.
[35" claim-type="Currently amended] 27. The method of claim 26, wherein the condition is allergic rhinitis, irritable lung disease, irritable pneumonia, eosinophilic pneumonia, delayed-type hypersensitivity, interstitial lung disease; Systematic or hypersensitivity reactions, drug allergies, pest bite allergy; Autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myasthenia gravis, childhood onset diabetes; Transplant rejection or graft-versus-host disease, including glomerulonephritis, autoimmune throiditis, allograft rejection; Inflammatory bowel disease such as Crohn's disease and ulcerative colitis; Spondyloarthropathy; Scleroderma; psoriasis; Dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; Vasculitis; Method that is eosinophilic myotis, eosinophilic fasciitis and cancer.
[36" claim-type="Currently amended] The method of claim 26, wherein the condition is associated with immunosuppression.
[37" claim-type="Currently amended] The method of claim 36, wherein the patient experiences chemotherapy, radiation therapy, wound treatment, burn treatment, or treatment for autoimmune disease.
[38" claim-type="Currently amended] Use of the compound of claim 1 for the manufacture of an agent for the treatment of HIV.
[39" claim-type="Currently amended] Use of the compound of claim 1 for the manufacture of a medicament for the treatment of conditions controlled by chemokine receptors.

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同族专利:

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公开号 | 公开日

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NZ533542A|2007-04-27|

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US20060100240A1|2006-05-11|

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PL369856A1|2005-05-02|

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US20030220341A1|2003-11-27|

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WO2003055876A1|2003-07-10|

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JP4556020B2|2010-10-06|

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ES2623982T3|2017-07-12|

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MXPA04006136A|2004-11-01|

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BR0215050A|2004-10-13|

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CN102153540A|2011-08-17|

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JP2005518397A|2005-06-23|

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HU0402458A2|2005-07-28|

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IL161784A|2011-07-31|

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RU2004122406A|2006-01-20|

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RU2325387C2|2008-05-27|

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CN1596255A|2005-03-16|

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EP1465889B1|2017-03-22|

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EP1465889A4|2008-05-14|

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US7354934B2|2008-04-08|

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BR0215050B1|2017-11-14|

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IL161784D0|2005-11-20|

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EP1465889A1|2004-10-13|

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CA2467718A1|2003-07-10|

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NO20042578L|2004-09-07|

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AU2002357379A1|2003-07-15|

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CA2467718C|2011-04-26|

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:
2001-12-21|Priority to US34271601P

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2001-12-21|Priority to US60/342,716

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2002-01-17|Priority to US35082202P

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2002-01-17|Priority to US60/350,822

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2002-12-23|Application filed by 아노르메드 인코포레이티드

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2002-12-23|Priority to PCT/US2002/041407

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2004-07-30|Publication of KR20040068339A

优先权:

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申请号 | 申请日 | 专利标题

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US34271601P| true| 2001-12-21|2001-12-21|

---

US60/342,716|2001-12-21|

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US35082202P| true| 2002-01-17|2002-01-17|

---

US60/350,822|2002-01-17|

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PCT/US2002/041407|WO2003055876A1|2001-12-21|2002-12-23|Chemokine receptor binding heterocyclic compounds with enhanced efficacy|