JP2006523704A - Modulators of chemokine receptor active heterocyclic cyclopentyltetrahydroisoquinoline and tetrahydropyridopyridine - Google Patents

Abstract

式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｘ、ｎおよび破線は明細書中に記載されたものであり、ケモカイン受容体活性のモジュレーターとして有用である。特に、これらの化合物はケモカイン受容体ＣＣＲ−２のモジュレーターとして有用である。The present invention is directed to compounds of formula (I).

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, n and the dashed line are those described in the specification and are chemokine receptors It is useful as a modulator of activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2.

Description

  Chemokines are a small (70-120 amino acids) family of inflammatory cytokines with potent chemotactic activity. Chemokines are chemotactic cytokines released by a wide range of cells to migrate various cells such as mononuclear leukocytes, macrophages, T cells, eosinophils, basophils and neutrophils to the inflammatory site. (Review by Schall, Cytokine, 3, 165-183 (1991) and Murphy, Rev. Immun., 12, 593-633 (1994)). These molecules were originally defined by four conserved cysteines and are divided into two subfamilies by the sequence of the first cysteine pair. The CXC-chemokine family includes IL-8, GROα, NAP-2 and IP-10, where the two cysteines are separated by a single amino acid, while the CC-chemokine family includes RANTES, MCP -1, MCP-2, MCP-3, MIP-1α, MIP-1β and eotaxin, and these two residues are adjacent.

  Α-chemokines such as interleukin-8 (IL-8), neutrophil activating protein-2 (NAP-2), melanoma growth stimulating activity protein (MGSA) are mainly chemotactic for neutrophils. On the other hand, β-chemokines such as RANTES, MIP-1α, MIP-1β, mononuclear leukocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3, eotaxin are macrophages, mononuclear leukocytes It is chemotactic for T-cells, eosinophils and basophils (Deng et al., Nature, 381, 661-666 (1996)).

  Chemokines are secreted by a wide variety of cells and bind to specific G-protein coupled receptors (GPCRs) present in leukocytes and other cells (reviewed by Horuk, Trends Pharm. Sci., 15, 159-165 ( 1994)). These chemokine receptors form the GPCR subfamily and are now composed of 15 identified members and a number of isolated members. Unlike promiscuous chemotactic substance receptors such as C5a, fMLP, PAF, LTB4, chemokine receptors are more selectively expressed on a subset of leukocytes. Thus, a mechanism is provided that when a specific chemokine is generated, a specific subset of leukocytes is recruited.

  When bound to a cognate ligand, the chemokine receptor transduces intracellular signals through the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least seven human chemokine receptors that bind to or respond to β-chemokines and have the following characteristic pattern: CCR-1 (or “CKR-1” or “CC-CKR-1”) [MIP-1α, MIP-1β, MCP-3, RANTES] (Ben-Barruch et al., J. Biol. Chem., 270, 22123-22128 (1995); Beote et al., Cell, 72, 415-425 (1993)); CCR-2A And CCR-2B (or "CKR-2A" / "CKR-2A" or "CC-CKR-2A" / "CC-CKR-2A") [MCP-1, MCP-2, MCP-3, MCP-4 CCR-3 (or “CKR-3” or “CC-CKR-3”) [eotaxin, eotaxin 2, RANTES, M P-2, MCP-3] (Rollins et al., Blood, 90, 908-928 (1997)); CCR-4 (or “CKR-4” or “CC-CKR-4”) [MIP-1α, RANTES, MCP-1] (Rollins et al., Blood, 90, 908-928 (1997)); CCR-5 (or “CKR-5” or “CC-CKR-5”) [MIP-1α, RANTES, MIP-1β] (Sanson et al., Biochemistry, 35, 3362-3367 (1996)); and Duffy blood group antigen [RANTES, MCP-1] (Chaudhun et al., J. Biol. Chem., 269, 7835-7838 (1994)). β-chemokines include, among other chemokines, eotaxin, MIP (“macrophage inflammatory protein”), MCP (“monocyte chemotactic factor protein”) and RANTES (“regulation on activation, normal T cells” Expression and secretion ").

  Chemokine receptors such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4 are effective in treating asthma, rhinitis and allergic diseases. It has been pointed out to be an important mediator of inflammatory and immunoregulatory disorders and diseases including autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. It has been shown that homozygous humans in a 32-base pair deletion in the CCR-5 gene are less sensitive to rheumatoid arthritis (Gomez et al., Arthritis & Rheumatism, 42, 989-992 (1999). ). A review of the role of eosinophils in allergic inflammation is provided by Kita, H. et al. Et al. Exp. Med. 183, 2421 to 2426 (1996). A general review of the role of chemokines in allergic inflammation is found in Lastger, A. et al. D. By New England J .; Med. 338 (7), 426-445 (1998).

  A subset of chemokines is a potent chemotactic agent for mononuclear leukocytes and macrophages. Of these, MCP-1 (mononuclear leukocyte chemotactic protein-1) is the most well-defined and its main receptor is CCR2. MCP-1 is produced in response to inflammatory stimuli in various cell types in various species, including rodent animals and humans, and stimulates chemotaxis in mononuclear leukocytes and lymphocyte subsets . In particular, MCP-1 production is associated with infiltration of mononuclear leukocytes and macrophages at inflammatory sites. If either MCP-1 or CCR2 is lost by homologous recombination in mice, the supply of mononuclear leukocytes is significantly attenuated in response to thioglycolate injection and Listeria monocytogenes infection ( Lu et al., J. Exp. Med. 187, 601-608 (1998); Kurihara et al., J. Exp. Med., 186, 1757-1762 (1997); Boring et al., J. Clin. Invest., 100, 2552. -2561 (1997); Kuziel et al., Proc. Natl. Acad. Sci., 94, 12053-12058 (1997)). In addition, these animals have been found to have reduced mononuclear leukocyte infiltration into granulomatous lesions caused by schistosome or mycobacterial antigen injection (Boring et al. J. Clin. Invest., 100, 2552-2561 (1997); Warmington et al. Am J. Path., 154, 1407-1416 (1999)). These data indicate that activation of CCR2 induced by MCP-1 plays a major role in the supply of mononuclear leukocytes to the site of inflammation, and antagonism of this activity sufficiently suppresses the immune response, which is immune inflammation Suggests that it can help treat sexual and autoimmune diseases.

  Thus, agents that modulate chemokine receptors such as the CCR-2 receptor should be useful for such disorders and diseases.

  In addition, the supply of mononuclear leukocytes to inflammatory lesions of the vessel wall is a major component of the pathogenesis of atherogenic speckle formation. When the vascular wall is damaged in a hypercholesterolemic situation, MCP-1 is produced and secreted by endothelial cells and intimal smooth muscle cells. Mononuclear leukocytes supplied to the injury site infiltrate the vascular wall and react with the released MCP-1 to differentiate into foam cells. Currently several groups are backcrossed to APO-E − / −, LDL-R − / − or ApoB transgenic mice and in MCP-1 − / − or CCR2 − / − mice continued on a high fat diet It has been shown that aortic lesion size, macrophage content and necrosis are attenuated (Boring et al., Nature, 394, 894-897 (1998); Gosling et al., J. Clin. Invest., 103, 773-778 (1999). ). Thus, CCR2 antagonists may be able to inhibit atherosclerotic lesion formation and pathological progression by reducing mononuclear leukocyte supply and differentiation in the arterial wall.

  The present invention further becomes a modulator of chemokine receptor activity, atopic conditions including certain inflammatory disorders and diseases, immune regulation disorders and diseases, allergic diseases and allergic rhinitis, dermatitis, conjunctivitis, asthma, and It is directed to compounds that are useful for preventing or treating autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The present invention is also directed to pharmaceutical compositions comprising these compounds and their use in the protection or treatment of diseases involving chemokine receptors.

  The present invention is directed to compounds of formula I and their pharmaceutically acceptable salts and their respective diastereomers.

式中、
ＸはＣ、Ｎ、Ｏ、ＳおよびＳＯ_２から選択され、
ＹはＮまたはＣから選択され、
Ｒ^１は水素、−Ｃ_１〜６アルキル、−Ｃ_０〜６アルキル−Ｏ−Ｃ_１〜６アルキル、−Ｃ_０〜６アルキル−Ｓ−Ｃ_１〜６アルキル、−（Ｃ_０〜６アルキル）−（Ｃ_３〜７シクロアルキル）−（Ｃ_０〜６アルキル）、ヒドロキシ、複素環、−ＣＮ、−ＮＲ^１２Ｒ^１２、−ＮＲ^１２ＣＯＲ^１３、−ＮＲ^１２ＳＯ_２Ｒ^１４、−ＣＯＲ^１１、−ＣＯＮＲ^１２Ｒ^１２およびフェニルから選択されるものであり、
Ｒ^１１は独立にヒドロキシ、水素、Ｃ_１〜６アルキル、−Ｏ−Ｃ_１〜６アルキル、ベンジル、フェニル、Ｃ_３〜６シクロアルキルから選択され、ここでアルキル、フェニル、ベンジル、およびシクロアルキル基は非置換でも１〜３個の置換基で置換されたものでもよく、その置換基は独立にハロ、ヒドロキシ、Ｃ_１〜３アルキル、Ｃ_１〜３アルコキシ、−ＣＯ_２Ｈ、−ＣＯ_２−Ｃ_１〜６アルキルおよびトリフルオロメチルから選択され、
Ｒ^１２は水素、Ｃ_１〜６アルキル、ベンジル、フェニル、Ｃ_３〜６シクロアルキルから選択され、ここで、アルキル、フェニル、ベンジル、およびシクロアルキル基は非置換でも１〜３個の置換基で置換されたものでもよく、その置換基は独立にハロ、ヒドロキシ、Ｃ_１〜３アルキル、Ｃ_１〜３アルコキシ、−ＣＯ_２Ｈ、−ＣＯ_２−Ｃ_１〜６アルキル、およびトリフルオロメチルから選択され、
Ｒ^１３は水素、Ｃ_１〜６アルキル、−Ｏ−Ｃ_１〜６アルキル、ベンジル、フェニル、Ｃ_３〜６シクロアルキルから選択され、ここでアルキル、フェニル、ベンジル、およびシクロアルキル基は非置換でも１〜３個の置換基で置換されたものでもよく、その置換基は独立にハロ、ヒドロキシ、Ｃ_１〜３アルキル、Ｃ_１〜３アルコキシ、−ＣＯ_２Ｈ、−ＣＯ_２−Ｃ_１〜６アルキル、およびトリフルオロメチルから選択され、
Ｒ^１４はヒドロキシ、Ｃ_１〜６アルキル、−Ｏ−Ｃ_１〜６アルキル、ベンジル、フェニル、Ｃ_３〜６シクロアルキルから選択され、ここでアルキル、フェニル、ベンジル、シクロアルキル基は非置換でもよいし、１〜３個の置換基で置換されたものでもよく、その置換基は独立にハロ、ヒドロキシ、Ｃ_１〜３アルキル、Ｃ_１〜３アルコキシ、−ＣＯ_２Ｈ、−ＣＯ_２−Ｃ_１〜６アルキル、トリフルオロメチルから選択され、
アルキルおよびシクロアルキルは非置換であるかまたは１〜７個の置換基で置換されており、その置換基は独立に、
（ａ）ハロ、
（ｂ）ヒドロキシ、
（ｃ）−Ｏ−Ｃ_１〜３アルキル、
（ｄ）トリフルオロメチル、
（ｆ）Ｃ_１〜３アルキル、
（ｇ）−Ｏ−Ｃ_１〜３アルキル、
（ｈ）−ＣＯＲ^１１、
（ｉ）−ＳＯ_２Ｒ^１４、
（ｊ）−ＮＨＣＯＣＨ_３、
（ｋ）−ＮＨＳＯ_２ＣＨ_３、
（ｌ）−複素環、
（ｍ）＝Ｏ、
（ｎ）−ＣＮ
から選択され、
フェニルおよび複素環は非置換であるかまたは１〜３個の置換基で置換されており、その置換基は独立にハロ、ヒドロキシ、Ｃ_１〜３アルキル、Ｃ_１〜３アルコキシおよびトリフルオロメチルから選択され、
Ｒ^２は
（ａ）水素、
（ｂ）ヒドロキシ、
（ｃ）ハロ、
（ｄ）Ｃ_１〜３アルキル（アルキルは非置換でも独立にフルオロ、およびヒドロキシから選択される１〜６個の置換基で置換されたものでもよい）、
（ｅ）−ＮＲ^１２Ｒ^１２、
（ｆ）−ＣＯＲ^１１、
（ｇ）−ＣＯＮＲ^１２Ｒ^１２、
（ｈ）−ＮＲ^１２ＣＯＲ^１３、
（ｉ）−ＯＣＯＮＲ^１２Ｒ^１２、
（ｊ）−ＮＲ^１２ＣＯＮＲ^１２Ｒ^１２、
（ｋ）−複素環、
（ｌ）−ＣＮ、
（ｍ）−ＮＲ^１２−ＳＯ_２−ＮＲ^１２Ｒ^１２、
（ｎ）−ＮＲ^１２−ＳＯ_２−Ｒ^１４、
（ｏ）−ＳＯ_２−ＮＲ^１２Ｒ^１２および
（ｐ）＝Ｏ（Ｒ^２は二重結合経由で環に結合している）
から選択され、
Ｒ^３は酸素であるかＹがＮの場合は不在であり、
Ｒ^３はＹがＣの場合、以下のリストから選択され、
（ａ）水素、
（ｂ）ヒドロキシ、
（ｃ）ハロ、
（ｄ）Ｃ_１〜３アルキル（アルキルは非置換でも独立にフルオロ、ヒドロキシ、−ＣＯＲ^１１から選択される１〜６個の置換基で置換されたものでもよい）、
（ｅ）−ＮＲ^１２Ｒ^１２、
（ｆ）−ＣＯＲ^１１、
（ｇ）−ＣＯＮＲ^１２Ｒ^１２、
（ｈ）−ＮＲ^１２ＣＯＲ^１３、
（ｉ）−ＯＣＯＮＲ^１２Ｒ^１２、
（ｊ）−ＮＲ^１２ＣＯＮＲ^１２Ｒ^１２、
（ｋ）−複素環、
（ｌ）−ＣＮ、
（ｍ）−ＮＲ^１２−ＳＯ_２−ＮＲ^１２Ｒ^１２、
（ｎ）−ＮＲ^１２−ＳＯ_２−Ｒ^１４、
（ｏ）−ＳＯ_２−ＮＲ^１２Ｒ^１２および
（ｐ）ニトロ；
Ｒ^４は
（ａ）水素、
（ｂ）Ｃ_１〜６アルキル、
（ｃ）トリフルオロメチル、
（ｄ）トリフルオロメトキシ、
（ｅ）クロロ、
（ｆ）フルオロ、
（ｇ）ブロモおよび
（ｈ）フェニル
から選択され、
Ｒ^５は
（ａ）Ｃ_１〜６アルキル、（アルキルは非置換でも１〜６個のフルオロで置換されたものでもよく、場合によってはヒドロキシルで置換されたものでもよい）、
（ｂ）−Ｏ−Ｃ_１〜６アルキル、（アルキルは非置換でも１〜６個のフルオロで置換されたものでもよい）、
（ｃ）−ＣＯ−Ｃ_１〜６アルキル、（アルキルは非置換でも１〜６個のフルオロで置換されたものでもよい）、
（ｄ）−Ｓ−Ｃ_１〜６アルキル、（アルキルは非置換でも１〜６個のフルオロで置換されたものでもよい）、
（ｅ）−ピリジル、（非置換であるかまたは、ハロ、トリフルオロメチル、Ｃ_１〜４アルキル、ＣＯＲ^１１からなる群から選択される１個または複数の置換基で置換されている）、
（ｆ）フルオロ、
（ｇ）クロロ、
（ｈ）ブロモ、
（ｉ）−Ｃ_４〜６シクロアルキル、
（ｊ）−Ｏ−Ｃ_４〜６シクロアルキル、
（ｋ）フェニル（非置換であるかまたはハロ、トリフルオロメチル、Ｃ_１〜４アルキル、ＣＯＲ^１１からなる群から選択される１個または複数の置換基で置換されている）、
（ｌ）−Ｏ−フェニル（非置換でもハロ、トリフルオロメチル、Ｃ_１〜４アルキル、ＣＯＲ^１１からなる群から選択される１個または複数の置換基で置換されたものでもよい）、
（ｍ）−Ｃ_３〜６シクロアルキル（アルキルは非置換でも１〜６個のフルオロで置換されたものでもよい）、
（ｎ）−Ｏ−Ｃ_３〜６シクロアルキル、（アルキルは非置換でも１〜６個のフルオロで置換されたものでもよい）、
（ｏ）−複素環、
（ｐ）−ＣＮおよび
（ｑ）−ＣＯＲ^１１
から選択され、
Ｒ^６は
（ａ）水素、
（ｂ）Ｃ_１〜６アルキル、
（ｃ）トリフルオロメチル、
（ｄ）フルオロ、
（ｅ）クロロおよび
（ｆ）ブロモ
から選択され、
Ｒ^７は
不在（Ｘ＝Ｏの場合）、水素、（Ｃ_０〜６アルキル）−フェニル、（Ｃ_０〜６アルキル）−複素環、（Ｃ_０〜６アルキル）−Ｃ_３〜７シクロアルキル、（Ｃ_０〜６アルキル）−ＣＯＲ^１１、（Ｃ_０〜６アルキル）−（アルケン）−ＣＯＲ^１１、（Ｃ_０〜６アルキル）−ＳＯ_３Ｈ、（Ｃ_０〜６アルキル）−Ｗ−Ｃ_０〜４アルキル、（Ｃ_０〜６アルキル）−ＣＯＮＲ^１２−フェニル、（Ｃ_０〜６アルキル）−ＣＯＮＲ^１５−Ｖ−ＣＯＲ^１１、不在（ＸがＯ、Ｓ、またはＳＯ_２の場合）から選択され、
ここでＶはＣ_１〜６アルキルまたはフェニルから選択され、
Ｗは単結合、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ_２−、−ＣＯ−、−ＣＯ_２−、−ＣＯＮＲ^１２−および−ＮＲ^１２−から選択され、
Ｒ^１５は水素、Ｃ_１〜４アルキルであるか、Ｒ^１５は１〜５個の炭素結合を経由してＶの炭素の１つに結合して環を形成し、Ｃ_０〜６アルキルは非置換であるかまたは１〜５個の置換基で置換されており、その置換基は独立に、
（ａ）ハロ、
（ｂ）ヒドロキシ、
（ｃ）−Ｃ_０〜６アルキル、
（ｄ）−Ｏ−Ｃ_１〜３アルキル、
（ｅ）トリフルオロメチルおよび
（ｆ）−Ｃ_０〜２アルキル−フェニル、
から選択され、
ここで前記フェニル、複素環、シクロアルキル、およびＣ_０〜４アルキルは非置換または〜１〜５個の置換基で置換されており、その置換基は独立に
（ａ）ハロ、
（ｂ）トリフルオロメチル、
（ｃ）ヒドロキシ、
（ｄ）Ｃ_１〜３アルキル、
（ｅ）−Ｏ−Ｃ_１〜３アルキル、
（ｆ）−Ｃ_０〜３−ＣＯＲ ^１１、
（ｇ）−ＣＮ、
（ｈ）−ＮＲ^１２Ｒ^１２、
（ｉ）−ＣＯＮＲ^１２Ｒ^１２および
（ｊ）−Ｃ_０〜３−複素環
から選択され、
あるいは前記フェニルおよび複素環は別の複素環に縮合していてもよく、その環自体は非置換でも独立にヒドロキシ、ハロ、−ＣＯＲ^１１、および−Ｃ_１〜３アルキルから選択される１〜２個の置換基で置換されたものでもよく、
アルケンは非置換でも１〜３個の置換基で置換されたものでもよく、その置換基は独立に
（ａ）ハロ、
（ｂ）トリフルオロメチル、
（ｃ）Ｃ_１〜３アルキル、
（ｄ）フェニルおよび
（ｅ）複素環
から選択され、
Ｒ^８は
（ａ）水素、
（ｂ）ＸがＯ、Ｓ、ＳＯ_２またはＮのいずれかの場合あるいは二重結合がＲ^７およびＲ^１０が付いている炭素に結合している場合不在、
（ｃ）ヒドロキシ、
（ｄ）Ｃ_１〜６アルキル、
（ｅ）Ｃ_１〜６アルキル−ヒドロキシ、
（ｆ）−Ｏ−Ｃ_１〜３アルキル、
（ｇ）−ＣＯＲ^１１、
（ｈ）−ＣＯＮＲ^１２Ｒ^１２および
（ｉ）−ＣＮ
から選択され、
あるいはＲ^７とＲ^８が一緒に結合して
（ａ）１Ｈ−インデン、
（ｂ）２，３−ジヒドロ−１Ｈ−インデン、
（ｃ）２，３−ジヒドロ−ベンゾフラン、
（ｄ）１，３−ジヒドロ−イソベンゾフラン、
（ｅ）２，３−ジヒドロ−ベンゾチオフラン、
（ｆ）１，３−ジヒドロ−イソベンゾチオフラン、
（ｇ）６Ｈ−シクロペンタ［ｄ］イソオキサゾール−３−オール、
（ｈ）シクロペンタンおよび
（ｉ）シクロヘキサン
から選択される環を形成し、
ここで形成された環は非置換であるかまたは独立に
（ａ）ハロ、
（ｂ）トリフルオロメチル、
（ｃ）ヒドロキシ、
（ｄ）Ｃ_１〜３アルキル、
（ｅ）−Ｏ−Ｃ_１〜３アルキル、
（ｆ）−Ｃ_０〜３−ＣＯＲ^１１、
（ｇ）−ＣＮ、
（ｈ）−ＮＲ^１２Ｒ^１２、
（ｉ）−ＣＯＮＲ^１２Ｒ^１２および
（ｊ）−Ｃ_０〜３−複素環
から選択される１〜５個の置換基で置換されており、
あるいはここでＲ^７とＲ^９またはＲ^８とＲ^１０は一緒になってフェニルまたは複素環である環を形成していてもよく、その環は非置換でも〜１〜７個の置換基で置換されたものでもよく、その置換基は独立に
（ａ）ハロ、
（ｂ）トリフルオロメチル、
（ｃ）ヒドロキシ、
（ｄ）Ｃ_１〜３アルキル、
（ｅ）−Ｏ−Ｃ_１〜３アルキル、
（ｆ）−ＣＯＲ^１１、
（ｇ）−ＣＮ、
（ｈ）−ＮＲ^１２Ｒ^１２および
（ｉ）−ＣＯＮＲ^１２Ｒ^１２
から選択され、
Ｒ^９およびＲ^１０は独立に
（ａ）水素、
（ｂ）ヒドロキシ、
（ｃ）Ｃ_１〜６アルキル、
（ｄ）Ｃ_１〜６アルキル−ＣＯＲ^１１、
（ｅ）Ｃ_１〜６アルキル−ヒドロキシ、
（ｆ）−Ｏ−Ｃ_１〜３アルキル、
（ｇ）＝Ｏ、（Ｒ^９またはＲ^１０は二重結合経由で環に結合している）
（ｈ）ハロ
から選択され、
ｎは０、１および２から選択され、
破線は単結合または二重結合を表す。

Where
X is selected from C, N, O, S and SO ₂ ;
Y is selected from N or C;
R ¹ is hydrogen, —C _1-6 alkyl, —C _0-6 alkyl-O—C _1-6 alkyl, —C _0-6 alkyl-S—C _1-6 alkyl, — (C _0-6 alkyl). - _{(C 3 to 7} cycloalkyl) - _{(C Less than six} alkyl), hydroxy, ^{heterocycle, -CN, -NR 12 R 12,} -NR 12 COR 13, -NR 12 SO 2 R 14, -COR 11, -CONR ¹² R ¹² and phenyl,
R ¹¹ is independently selected from hydroxy, hydrogen, C _1-6 alkyl, —O—C _1-6 alkyl, benzyl, phenyl, C _3-6 cycloalkyl, wherein alkyl, phenyl, benzyl, and cycloalkyl groups May be unsubstituted or substituted with 1 to 3 substituents, and the substituents are independently halo, hydroxy, C _1-3 alkyl, C _1-3 alkoxy, —CO ₂ H, —CO ₂ —. Selected from C _1-6 alkyl and trifluoromethyl;
R ¹² is selected from hydrogen, C _1-6 alkyl, benzyl, phenyl, C _3-6 cycloalkyl, wherein the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents. The substituents may be independently selected from halo, hydroxy, C _1-3 alkyl, C _1-3 alkoxy, —CO ₂ H, —CO ₂ —C _1-6 alkyl, and trifluoromethyl. And
R ¹³ is selected from hydrogen, C _1-6 alkyl, —O—C _1-6 alkyl, benzyl, phenyl, C _3-6 cycloalkyl, wherein the alkyl, phenyl, benzyl, and cycloalkyl groups may be unsubstituted It may be those substituted with 1-3 substituents independently halo substituents thereof, _{hydroxy, C 1-3 alkyl, C 1-3 alkoxy, -CO 2 H, -CO 2 -C} 1~6 Selected from alkyl, and trifluoromethyl,
R ¹⁴ is selected from hydroxy, C _1-6 alkyl, —O—C _1-6 alkyl, benzyl, phenyl, C _3-6 cycloalkyl, wherein the alkyl, phenyl, benzyl, cycloalkyl groups may be unsubstituted and it may be those substituted with 1-3 substituents independently halo of the substituent, _{hydroxy, C 1-3 alkyl, C 1-3 alkoxy, -CO 2 H, -CO 2 -C} 1 ₆ is selected from alkyl, trifluoromethyl,
Alkyl and cycloalkyl are unsubstituted or substituted with 1 to 7 substituents, which are independently
(A) Halo,
(B) hydroxy,
(C) -O-C _1-3 alkyl,
(D) trifluoromethyl,
(F) C _1-3 alkyl,
(G) -O-C _1-3 alkyl,
(H) -COR ¹¹ ,
_(I) -SO ^{2 R 14,}
(J) -NHCOCH _3,
(K) -NHSO ₂ CH _3,
(L) -heterocycle,
(M) = O,
(N) -CN
Selected from
The phenyl and heterocycle are unsubstituted or substituted with 1 to 3 substituents, which substituents are independently from halo, hydroxy, C _1-3 alkyl, C _1-3 alkoxy and trifluoromethyl. Selected
R ² is (a) hydrogen,
(B) hydroxy,
(C) Halo,
(D) C _1-3 alkyl (the alkyl may be unsubstituted or substituted with 1 to 6 substituents independently selected from fluoro and hydroxy),
^{(E) -NR 12 R} 12,
(F) -COR ¹¹ ,
(G) -CONR ¹² R ¹² ,
(H) -NR ¹² COR ¹³ ,
(I) -OCONR ¹² R ¹² ,
^{(J) -NR 12 CONR 12 R} 12,
(K) -heterocycle,
(L) -CN,
^{_{(M) -NR 12 -SO 2 -NR}} 12 R 12,
^{_{(N) -NR 12 -SO 2 -R}} 14,
(O) —SO ₂ —NR ¹² R ¹² and (p) ═O (R ² is bonded to the ring via a double bond)
Selected from
R ³ is oxygen or absent when Y is N;
R ³ is selected from the following list when Y is C:
(A) hydrogen,
(B) hydroxy,
(C) Halo,
(D) C _1-3 alkyl (the alkyl may be unsubstituted or substituted with 1-6 substituents independently selected from fluoro, hydroxy, -COR ¹¹ ),
^{(E) -NR 12 R} 12,
(F) -COR ¹¹ ,
(G) -CONR ¹² R ¹² ,
(H) -NR ¹² COR ¹³ ,
(I) -OCONR ¹² R ¹² ,
^{(J) -NR 12 CONR 12 R} 12,
(K) -heterocycle,
(L) -CN,
^{_{(M) -NR 12 -SO 2 -NR}} 12 R 12,
^{_{(N) -NR 12 -SO 2 -R}} 14,
(O) —SO ₂ —NR ¹² R ¹² and (p) nitro;
R ⁴ is (a) hydrogen,
(B) C _1-6 alkyl,
(C) trifluoromethyl,
(D) trifluoromethoxy,
(E) Chloro,
(F) fluoro,
(G) selected from bromo and (h) phenyl;
R ⁵ is (a) C _1-6 alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro, optionally substituted with hydroxyl,
(B) -O-C _1-6 alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro;
(C) -CO-C _1-6 alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro;
(D) -S-C _1-6 alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro;
(E) -pyridyl, (unsubstituted or substituted with one or more substituents selected from the group consisting of halo, trifluoromethyl, C _1-4 alkyl, COR ¹¹ ),
(F) fluoro,
(G) Chloro,
(H) Bromo,
(I) _{-C4-6cycloalkyl} ,
(J) -O-C _4-6 cycloalkyl,
(K) phenyl (unsubstituted or substituted with one or more substituents selected from the group consisting of halo, trifluoromethyl, C _1-4 alkyl, COR ¹¹ ),
(L) —O-phenyl (which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, trifluoromethyl, C _1-4 alkyl, COR ¹¹ ),
(M) -C _3-6 cycloalkyl (alkyl may be unsubstituted or substituted with 1-6 fluoro),
(N) -O-C _3-6 cycloalkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro;
(O) -heterocycle,
(P) -CN and (q) -COR ¹¹
Selected from
R ⁶ is (a) hydrogen,
(B) C _1-6 alkyl,
(C) trifluoromethyl,
(D) fluoro,
(E) chloro and (f) bromo
R ⁷ is absent (when _X═O ), hydrogen, (C _0-6 alkyl) -phenyl, (C _0-6 alkyl) _-heterocycle , (C _0-6 alkyl) -C _3-7 cycloalkyl, (C _0-6 alkyl) -COR ¹¹ , (C _0-6 alkyl)-(alkene) -COR ¹¹ , (C _0-6 alkyl) -SO ₃ H, (C _0-6 alkyl) -W—C _{0 to 4 alkyl, (C Less than six} alkyl) -CONR ¹² - _phenyl, are selected from _{(C Less than six} ^alkyl) -CONR 15 ^{-V-COR 11,} absent (when X is O, S or SO _2,) ,
Wherein V is selected from C _1-6 alkyl or phenyl;
W is selected from a single bond, —O—, —S—, —SO—, —SO ₂ —, —CO—, —CO ₂ —, —CONR ¹² — and —NR ¹² —;
R ¹⁵ is hydrogen, C _1-4 alkyl, or R ¹⁵ is bonded to one of the V carbons via 1-5 carbon bonds to form a ring, and C _0-6 alkyl is non- Is substituted or substituted with 1 to 5 substituents, and the substituents are independently
(A) Halo,
(B) hydroxy,
(C) -C _0-6 alkyl,
(D) -O-C _1-3 alkyl,
(E) trifluoromethyl and (f) -C _0-2 alkyl-phenyl,
Selected from
Wherein the phenyl, heterocycle, cycloalkyl, and C _0-4 alkyl are unsubstituted or substituted with ˜1-5 substituents, the substituents being independently (a) halo,
(B) trifluoromethyl,
(C) hydroxy,
(D) C _1-3 alkyl,
(E) -O-C _1-3 alkyl,
_(F) -C 0~3 -COR ^11,
(G) -CN,
^{(H) -NR 12 R} 12,
(I) selected from —CONR ¹² R ¹² and (j) —C _0-3 -heterocycle,
Alternatively, the phenyl and heterocycle may be fused to another heterocycle, and the ring itself may be unsubstituted or independently selected from hydroxy, halo, —COR ¹¹ , and —C _1-3 alkyl. May be substituted with one substituent,
Alkenes may be unsubstituted or substituted with 1 to 3 substituents, the substituents being independently (a) halo,
(B) trifluoromethyl,
(C) C _1-3 alkyl,
(D) selected from phenyl and (e) heterocycle
R ⁸ is (a) hydrogen,
(B) absent when X is any of O, S, SO ₂ or N, or when the double bond is bound to carbon with R ⁷ and R ¹⁰ ;
(C) hydroxy,
(D) C _1-6 alkyl,
(E) C _1-6 alkyl-hydroxy,
(F) -O-C _1-3 alkyl,
(G) -COR ¹¹ ,
(H) -CONR ¹² R ¹² and (i) -CN
Selected from
Or R ⁷ and R ⁸ are bonded together and (a) 1H-indene,
(B) 2,3-dihydro-1H-indene,
(C) 2,3-dihydro-benzofuran,
(D) 1,3-dihydro-isobenzofuran,
(E) 2,3-dihydro-benzothiofuran,
(F) 1,3-dihydro-isobenzothiofuran,
(G) 6H-cyclopenta [d] isoxazol-3-ol,
Forming a ring selected from (h) cyclopentane and (i) cyclohexane;
The ring formed here is unsubstituted or independently (a) halo,
(B) trifluoromethyl,
(C) hydroxy,
(D) C _1-3 alkyl,
(E) -O-C _1-3 alkyl,
_(F) -C 0~3 -COR ^11,
(G) -CN,
^{(H) -NR 12 R} 12,
(I) ^{-CONR 12 R} 12 and _{(j) -C} 0~3 - is substituted with 1-5 substituents selected from heterocycle,
Alternatively, R ⁷ and R ⁹ or R ⁸ and R ¹⁰ may be combined to form a ring that is phenyl or heterocyclic, which ring is unsubstituted or substituted with ˜1-7 substituents And the substituents are independently (a) halo,
(B) trifluoromethyl,
(C) hydroxy,
(D) C _1-3 alkyl,
(E) -O-C _1-3 alkyl,
(F) -COR ¹¹ ,
(G) -CN,
(H) -NR ¹² R ¹² and (i) -CONR ¹² R ¹²
Selected from
R ⁹ and R ¹⁰ are independently (a) hydrogen,
(B) hydroxy,
(C) C _1-6 alkyl,
(D) C _1-6 alkyl-COR ¹¹ ,
(E) C _1-6 alkyl-hydroxy,
(F) -O-C _1-3 alkyl,
(G) = O, (R ⁹ or R ¹⁰ is bonded to the ring via a double bond)
(H) selected from halo,
n is selected from 0, 1 and 2;
A broken line represents a single bond or a double bond.

  Another embodiment of the present invention includes a compound of formula Ia and pharmaceutically acceptable salts and respective diastereomers thereof.

式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、Ｒ^９、Ｙ、およびｎは本明細書で定義の通りであり、
Ｒ^１６およびＲ^１７は独立に
（ａ）水素、
（ｂ）ハロ、
（ｃ）トリフルオロメチル、
（ｄ）ヒドロキシ、
（ｅ）Ｃ_１〜３アルキル、
（ｆ）−Ｏ−Ｃ_１〜３アルキル、
（ｇ）−Ｃ_０〜３−ＣＯ_２Ｈ、
（ｈ）−Ｃ_０〜３−ＣＯ_２Ｃ_１〜３アルキル、
（ｉ）−ＣＮおよび
（ｊ）−Ｃ_０〜３−複素環
から選択されるか、
あるいはＲ^１６およびＲ^１７が一緒に結合してフェニル環に縮合した複素環を形成し、その環は非置換でもまたは独立にヒドロキシ、ハロ、−ＣＯＲ^１１、−Ｃ_１〜３アルキルから選択される１〜２個の置換基で置換されたものでもよい。

Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁹ , Y, and n are as defined herein,
R ¹⁶ and R ¹⁷ are independently (a) hydrogen,
(B) Halo,
(C) trifluoromethyl,
(D) hydroxy,
(E) C _1-3 alkyl,
(F) -O-C _1-3 alkyl,
_{(G) -C 0~3 -CO 2 H} ,
_{(H) -C 0~3 -CO 2 C} 1~3 alkyl,
Selected from (i) -CN and (j) _-C0-3 -heterocycle,
Alternatively, R ¹⁶ and R ¹⁷ are joined together to form a heterocyclic ring fused to a phenyl ring, which ring is unsubstituted or independently selected from hydroxy, halo, —COR ¹¹ , —C _1-3 alkyl It may be substituted with 1 to 2 substituents.

  Another embodiment of the present invention also includes compounds of formula lb and their pharmaceutically acceptable salts and their respective diastereomers.

式中、破線は単結合または二重結合を表し、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、Ｒ^９、Ｒ^１６、Ｒ^１７、Ｙ、ｎは本明細書で定義の通りである。

In the formula, a broken line represents a single bond or a double bond, and R ¹ , R ² , R ³ , R ⁵ , R ⁹ , R ¹⁶ , R ¹⁷ , Y, and n are as defined in this specification.

  Further embodiments of the present invention include compounds of formula Ic and pharmaceutically acceptable salts and respective diastereomers thereof.

式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、Ｒ^９、Ｒ^１６、Ｒ^１７、Ｙ、ｎは本明細書で定義の通りであり、Ｈは複素環である。

Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁹ , R ¹⁶ , R ¹⁷ , Y, n are as defined herein, and H is a heterocyclic ring.

  Another embodiment of the present invention includes compounds of Formula Id and pharmaceutically acceptable salts and respective diastereomers thereof.

式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、Ｒ^９、Ｒ^１１、Ｙ、Ｗ、ｎは本明細書で定義の通りであり、
またＣ_１〜４炭素鎖は非置換でも独立に
（ａ）ハロ、
（ｂ）ヒドロキシ、
（ｃ）−Ｃ_０〜６アルキル、
（ｄ）−Ｏ−Ｃ_１〜３アルキル、
（ｅ）トリフルオロメチルおよび
（ｆ）−Ｃ_０〜２アルキル−フェニル
から選択される１〜４個の置換基で置換されたものでもよく、
あるいはＣ_１〜４炭素鎖はＣ_３〜７シクロアルキル環に含まれていてもよい。

Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁹ , R ¹¹ , Y, W, n are as defined herein,
Also, the C _1-4 carbon chain is independently unsubstituted but (a) halo,
(B) hydroxy,
(C) -C _0-6 alkyl,
(D) -O-C _1-3 alkyl,
It may be substituted with 1 to 4 substituents selected from (e) trifluoromethyl and (f) -C _0-2 alkyl-phenyl,
Alternatively _{C 1 to 4} carbon chain may also be included in the _{C 3 to 7} cycloalkyl ring.

  Further embodiments of the present invention include compounds of formula Ie and pharmaceutically acceptable salts and respective diastereomers thereof.

式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、Ｒ^９、Ｒ^１６、Ｒ^１７、Ｘ、Ｙ、ｎは本明細書で定義の通りであり、破線は単結合または二重結合のいずれかを表すことができ、
ｏは１または２であり得、
Ａ、Ｂ、Ｄは独立にＣ、Ｎ、ＯまたはＳから選択されて、フェニル環（Ｘ、Ａ、Ｂ、Ｄ、のすべてがＣであり、ｏ＝２の場合）を作るか、あるいは複素環を作る（Ｘ、Ａ、Ｂ、Ｄのうちの少なくとも１つがＮ、Ｏ、またはＳであってＣでない場合）。

In the formula, R ¹ , R ² , R ³ , R ⁵ , R ⁹ , R ¹⁶ , R ¹⁷ , X, Y, n are as defined in this specification, and the broken line is either a single bond or a double bond Can represent
o can be 1 or 2,
A, B, D are independently selected from C, N, O or S to form a phenyl ring (when X, A, B, D are all C and o = 2) or complex Create a ring (if at least one of X, A, B, D is N, O, or S and not C).

  Further embodiments of the present invention include compounds of formula If and pharmaceutically acceptable salts and respective diastereomers thereof.

式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、Ｒ^７、Ｒ^９、Ｒ^１０、Ｙ、ｎは本明細書で定義の通りであり、ＸはＮか、Ｏ（この場合Ｒ^７は不在である）のいずれかである。

Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁷ , R ⁹ , R ¹⁰ , Y, n are as defined herein, and X is N or O (in this case R ⁷ is Is absent).

  Another embodiment of the present invention includes a compound of formula Ig and pharmaceutically acceptable salts and respective diastereomers thereof.

式中、Ｒ^１、Ｒ^５、Ｒ^９、Ｒ^１６、Ｒ^１７およびＹは本明細書で定義の通りであるか、
あるいはＲ^１６およびＲ^１７は一緒になってフェニル環に縮合した複素環を形成し、その環は非置換でも独立にヒドロキシ、ハロ、−ＣＯＲ^１１、および−Ｃ_１〜３アルキルから選択される１〜２個の置換基で置換されたものであってもよい。

In which R ¹ , R ⁵ , R ⁹ , R ¹⁶ , R ¹⁷ and Y are as defined herein,
Alternatively, R ¹⁶ and R ¹⁷ together form a heterocyclic ring fused to a phenyl ring, which ring is independently selected from hydroxy, halo, —COR ¹¹ , and —C _1-3 alkyl 1 It may be substituted with ~ 2 substituents.

  Further embodiments of the present invention include compounds of Formula Ih and pharmaceutically acceptable salts and respective diastereomers thereof.

式中、破線は単結合または二重結合を表し、Ｒ^１、Ｒ^５、Ｒ^９、Ｒ^１６、Ｒ^１７、Ｙは本明細書で定義の通りである。

In the formula, a broken line represents a single bond or a double bond, and R ¹ , R ⁵ , R ⁹ , R ¹⁶ , R ¹⁷ , and Y are as defined in this specification.

  Additional embodiments of the present invention include compounds of Formula Ii and pharmaceutically acceptable salts and respective diastereomers thereof.

式中、Ｒ^１、Ｒ^５、Ｒ^９、Ｒ^１６、Ｒ^１７、Ｙは本明細書で定義の通りであり、Ｈは複素環である。

In the formula, R ¹ , R ⁵ , R ⁹ , R ¹⁶ , R ¹⁷ and Y are as defined in this specification, and H is a heterocyclic ring.

  Further embodiments of the present invention include compounds of formula Ij and pharmaceutically acceptable salts thereof and their respective diastereomers.

式中、Ｒ^１、Ｒ^５、Ｒ^９、Ｒ^１１、Ｙ、Ｗは本明細書で定義の通りであり、
またＣ_１〜４炭素鎖は非置換でも独立に
（ａ）ハロ、
（ｂ）ヒドロキシ、
（ｃ）−Ｃ_０〜６アルキル、
（ｄ）−Ｏ−Ｃ_１〜３アルキル、
（ｅ）トリフルオロメチルおよび
（ｆ）−Ｃ_０〜２アルキル−フェニル
から選択される１〜４個の置換基で置換されたものでもよい。

Wherein R ¹ , R ⁵ , R ⁹ , R ¹¹ , Y, W are as defined herein,
Also, the C _1-4 carbon chain is independently unsubstituted but (a) halo,
(B) hydroxy,
(C) -C _0-6 alkyl,
(D) -O-C _1-3 alkyl,
It may be substituted with 1 to 4 substituents selected from (e) trifluoromethyl and (f) -C _0-2 alkyl-phenyl.

  Another embodiment of the present invention includes compounds of Formula Ik and pharmaceutically acceptable salts and respective diastereomers thereof.

式中、Ｒ^１、Ｒ^５、Ｒ^９、Ｒ^１０、Ｙは本明細書で定義の通りである。

In the formula, R ¹ , R ⁵ , R ⁹ , R ¹⁰ , and Y are as defined in this specification.

  In a further embodiment of the invention X is C, O or N.

  In another embodiment of the invention, X is C or O.

In another embodiment of this invention R ¹ is —C _1-6 alkyl, —C _0-6 alkyl-O—C _1-6 alkyl, and — (C _0-6 alkyl)-(C _3-7 cyclo). Alkyl)-(C _0-6 alkyl);
Where alkyl and cycloalkyl are unsubstituted or substituted with 1 to 7 substituents, the substituents being independently (a) halo,
(B) hydroxy,
(C) -O-C _1-3 alkyl,
(D) trifluoromethyl,
(F) C _1-3 alkyl,
(G) -O-C _1-3 alkyl,
(H) -COR ¹¹ ,
(I) -CN,
(J) -NR ¹² R ¹² and (k) -CONR ¹² R ¹²
Selected from.

In another aspect of the invention, R ¹ is (1) —C _1-6 alkyl, unsubstituted or substituted with 1-6 substituents, the substituents independently being (a) halo,
(B) hydroxy,
(C) -O-C _1-3 alkyl,
(D) trifluoromethyl and (e) -COR ¹¹
And (2) —C _0-6 alkyl-O—C _1-6 alkyl-, which is unsubstituted or substituted with _1-6 substituents, the substituents are independently (a) halo,
(B) trifluoromethyl and (c) -COR ¹¹
And (3) — (C _3-5 cycloalkyl)-(C _0-6 alkyl), unsubstituted or substituted with 1-7 substituents, provided that the substituents are independently (a )Halo,
(B) hydroxy,
(C) -O-C _1-3 alkyl,
(D) trifluoromethyl and (e) -COR ¹¹
Selected from
Is selected from.

In yet another embodiment of the present invention, R ¹ is (a) C _1-6 alkyl,
(B) C _1-6 alkyl substituted with hydroxy,
(C) selected from C _1-6 alkyl substituted with 1-6 fluoro.

In yet another aspect of the invention, R ¹ is (a) —CH (CH ₃ ) ₂ ,
(B) —CH (OH) CH ₃ and (c) —CH ₂ CF ₃
Selected from.

In another aspect of the invention, R ² is (a) hydroxy,
(B) hydrogen,
(C) = O (R ² is bonded to the ring via a double bond)
Selected from.

In another aspect of the invention, R ² is hydrogen.

In yet another aspect of the invention, when Y is N, R ³ is absent or O (becomes an N-oxide).

In a further aspect of the invention, when Y is N, R ³ is absent.

In yet another embodiment of the present invention, when Y is C, R ³ is (a) hydrogen,
(B) Halo,
(C) hydroxy,
(D) C _1-3 alkyl (wherein alkyl is unsubstituted or substituted with 1-6 substituents independently selected from fluoro and hydroxy),
(E) -COR ¹¹ ,
(F) -CONR ¹² R ¹² ,
(G) -heterocycle,
_{^{(H) -NR 12 -SO 2 -NR}} 12 R 12,
_{^{(I) -NR 12 -SO 2 -R}} 14,
_{^{(J) -SO 2 -NR 12 R}} 12,
(K) -nitro and (l) -NR ¹² R ¹²
Selected from.

In another embodiment of the present invention, when Y is C, R ³ is hydrogen.

In another aspect of the invention, R ⁴ is hydrogen.

In another aspect of the invention, R ⁵ is (a) C _1-6 alkyl substituted with _1-6 fluoro,
(B) -O-C _1-6 alkyl substituted with _1-6 fluoro,
(C) chloro,
(D) selected from bromo and (e) phenyl.

In another aspect of the invention, R ⁵ is (a) trifluoromethyl,
(B) trifluoromethoxy,
(C) chloro,
(D) selected from bromo and (e) phenyl.

In another aspect of the invention, R ⁵ is trifluoromethyl.

In another aspect of the invention, R ⁶ is hydrogen.

In another aspect of the invention, R ⁷ is phenyl, heterocycle, C _3-7 cycloalkyl, C _1-6 alkyl, COR ¹¹ and —CONH—V—COR ^{11 where} V is C _1-6 alkyl or Selected from phenyl),
The phenyl, heterocycle, C _3-7 cycloalkyl, C _1-6 alkyl is unsubstituted or substituted with 1-5 substituents, and the substituents are independently (a) halo,
(B) trifluoromethyl,
(C) hydroxy,
(D) C _1-3 alkyl,
(E) -O-C _1-3 alkyl,
(F) -COR ¹¹ ,
(G) -CN,
(H) -heterocycle and (i) -CONR ² R ¹²
Selected from.

In yet another embodiment of the invention (when X is not O), R ⁷ is phenyl, heterocycle, C _1-4 alkyl, —COR ¹¹ , —CONH—V—COR ^{11 where} V is C _1-6 alkyl. Or selected from phenyl)
The phenyl, heterocycle, and C _1-4 alkyl are unsubstituted or substituted with 1 to 3 substituents, and the substituents are independently (a) halo,
(B) hydroxy,
(C) C _1-3 alkyl,
(D) -O-C _1-3 alkyl,
(E) -COR ¹¹ and (f) -heterocycle.

In yet another embodiment of the present invention (when X is C), R ⁷ is selected from (a) to (r) of Table 1.

In another aspect of the invention, when X is C, R ⁸ is (a) hydrogen,
(B) hydroxy,
(C) -CN and (d) -F
Selected from.

In another aspect of the invention, R ⁷ and R ⁸ are taken together (a) 1H-indene,
(B) forming a ring selected from 2,3-dihydro-1H-indene;
In this case, the ring formed is independently unsubstituted (a) halo,
(B) hydroxy,
(C) C _1-3 alkyl,
(D) -O-C _1-3 alkyl,
It may be substituted with 1 to 3 substituents selected from (e) -COR ¹¹ and (f) -heterocycle.

In another aspect of the invention, R ⁹ and R ¹⁰ are independently (a) hydrogen,
(B) hydroxy,
(C) _-CH 3,
(D) —O—CH ₃ and (e) ═O (when R ⁹ and / or R ¹⁰ combine to form a ring via a double bond)
Selected from.

  In yet another embodiment of the invention, n = 1 or n = 2.

  Exemplary compounds of the present invention include those shown in the Examples and their pharmaceutically acceptable salts and their respective diastereomers.

  The compounds of the present invention have at least two asymmetric centers at the 1- and 3-positions of the cyclopentyl ring. Additional asymmetric centers may exist depending on the nature of the various substituents on the molecule. Each such asymmetric center independently produces two optical isomers, but all possible optical isomers and diastereomers are within the scope of the present invention, whether they are mixtures or pure or partially purified compounds. . The absolute configuration of one embodiment of the compounds of the present invention in which the substituents on the cyclopentyl ring (amide and amine units) are cis is shown below.

  The absolute configuration of further embodiments of the compounds of the present invention is that of the illustrated configuration.

式中、アミン置換基の付いた炭素は（Ｒ）絶対配置となっており、アミドサブユニットの付いた炭素はＲ^１の優先順位次第で（Ｓ）絶対配置にも（Ｒ）絶対配置にもなる可能性がある。例えば、Ｒがイソプロピルであれば、シクロペンチル環上のアミドユニットとアミンユニットはシス配列となるのが好ましいのでアミドサブユニットの付いた炭素の絶対立体化学は（Ｓ）となる。

Where the carbon with the amine substituent is in the (R) absolute configuration and the carbon with the amide subunit is either in the (S) absolute configuration or the (R) absolute configuration, depending on the priority of R ^1. There is a possibility. For example, if R is isopropyl, the amide unit and the amine unit on the cyclopentyl ring are preferably in a cis arrangement, so the absolute stereochemistry of the carbon with the amide subunit is (S).

  As known to those skilled in the art, independent synthesis of diastereomers and enantiomers or chromatographic separation thereof can be achieved by appropriate modification of the methodology disclosed herein. Its absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates derived using reagents containing asymmetric centers with known absolute configurations.

  As will be appreciated by those skilled in the art, halo or halogen as used herein is intended to include chloro, fluoro, bromo and iodo.

As used herein, “alkyl” shall mean linear, branched and cyclic structures having no double or triple bonds. C _1-6 alkyl is thus defined as the group having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, thus C _1-6 alkyl is specifically methyl, Including ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl. “Cycloalkyl” is an alkyl, part or all of which forms a ring of three or more atoms. C ₀ or C ₀ alkyl is defined as a direct covalent bond present.

  As used herein, the term “heterocycle” is intended to include: Benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indrazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, Isothiazolyl, isoxazolyl, naphthopyridinyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolylyl, tetrazolyl, pyrazolyl Thienyl, triazolyl, aze Dinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, Dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, Dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzo , Tetrahydrofuranyl, tetrahydrothienyl, and its N- oxides.

  The phrase “pharmaceutically acceptable” is used herein within the scope of sound medical judgment, and without excessive toxicity, hypersensitivity, allergic reactions, or other problems or complications in human and animal tissues. Refers to compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with, and that meet a reasonable benefit / risk ratio.

  As used herein, “pharmaceutically acceptable salts” refers to derivatives in which the parent compound is modified by making salts of those acids or bases. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. It is not something. The pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid. , Malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfone Salts prepared from organic acids such as acids, ethanedisulfonic acid, oxalic acid, isethionic acid and the like are included.

  The pharmaceutically acceptable salts of the present invention can be prepared from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In general, such salts may be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or in a mixture of the two. . In general, non-aqueous solvents such as ether, ethyl acetate, ethanol, isopropanol, acetonitrile are used. For example, Remington's Pharmaceutical Sciences, 17th ed. Mack Publishing Company, Easton, PA, 1985, p. A suitable salt can be found at 1418.

  Exemplifying the invention is the use of the compounds disclosed in the Examples and herein.

  Specific compounds of the invention include the compounds selected from the group consisting of the title compounds of the Examples and their pharmaceutically acceptable salts and their respective diastereomers.

  The subject compounds are useful in methods of modulating chemokine receptor activity in patients in need of such modulation comprising administering an effective amount of the compound.

  The present invention is directed to the use of the above compounds as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of chemokine receptors, particularly CCR-2.

  The utility of the compounds of the present invention as modulators of chemokine receptor activity has been shown to those skilled in the art, such as the evaluation of chemokine binding disclosed by Van Riper et al. (J. Exp. Med., 177, 851-856 (1993)). It can be shown by known methodologies. This method can be easily adapted to measure CCR-2 binding.

Receptor affinity assessment for CCR-2 binding includes endogenous CCR on various types of cells, including mononuclear leukocytes, THP-1 cells, etc., or after heterologous expression of cloned receptors in eukaryotic cells. This was done by measuring the inhibition of ¹²⁵ I-MCP-1 on the -2 receptor. These cells are suspended in binding buffer (50 mM HEPES, pH 7.2, 5 mM MgCl ₂ , 1 mM CaCl ₂ , and 0.50% BSA) at room temperature and mixed with test compound or DMSO and ¹²⁵ I-MCP-1. In addition, it was allowed to bind for 1 hour. These cells were then collected on a GFB filter and washed with 25 mM HEPES buffer containing 500 mM NaCl to quantify ¹²⁵ I-MCP-1 bound to the cells.

In chemotaxis assessment, chemotaxis was isolated from whole venous blood or leukocyte-free blood, purified by Ficoll-Hypaque centrifugation, then rosetted with neuraminidase-treated sheep erythrocytes to deplete PBMCs with depleted T cells. Done using. Once isolated, the cells were washed with HBSS containing 0.1 mg / ml BSA and suspended at a concentration of 1 × 10 ⁷ cells / ml. Cells were fluorescently labeled with 2 μM Calcien-AM (Molecular Probes) at 37 ° C. for 30 minutes in the dark. The labeled cells were washed twice and suspended at 5 × 10 ⁶ cells / ml in RPMI 1640 with L-glutamine (no phenol red) containing 0.1 mg / ml BSA. MCP-1 (Peprotech) or medium alone diluted at 10 ng / ml in the same medium was added to the bottom well (27 μl). Mononuclear leukocytes (150,000 cells) were preincubated with DMSO or various concentrations of test compound for 15 minutes before being placed on the top of the filter (30 μl). The same concentration of test compound or DMSO was added to the bottom well to prevent dilution by diffusion. After culturing at 37 ° C. and 5% CO ₂ for 60 minutes, the filter was removed, and the upper end was washed with HBSS containing 0.1 mg / ml BSA to remove cells that had not migrated into the filter. Spontaneous migration (chemical motility) was determined in the absence of chemotactic substances.

In particular, the compounds of the following examples had activity to bind to the CCR-2 receptor with an IC ₅₀ of generally less than about 1 μM in the foregoing evaluation. Such results indicate that these compounds have intrinsic activities that can be used as modulators of chemokine receptor activity.

  Mammalian chemokine receptors are targets for preventing or promoting eosinophil and / or lymphocyte function in mammals such as humans. Compounds that inhibit or promote chemokine receptor function are particularly useful for modulating eosinophil and / or lymphocyte function for therapeutic purposes. Therefore, a wide variety of compounds, including allergic rhinitis, dermatitis, conjunctivitis, and asthma, and autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, with compounds that inhibit or promote chemokine receptor function It is useful for treating, preventing, ameliorating, modulating or reducing the risk of inflammatory and immunoregulatory disorders and diseases, allergic diseases, and atopic conditions.

  For example, if the compound inhibits one or more functions of a mammalian chemokine receptor (eg, human chemokine receptor), it can be administered to suppress (ie, reduce or prevent) inflammation. As a result, one or more inflammatory processes such as leukocyte migration, chemotaxis, exocytosis (eg of enzymes, histamine) or release of inflammatory mediators are inhibited.

  In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For example, cattle, sheep, goats, horses, dogs, cats, guinea pigs, rats or other cattle, sheep, horses, dogs, cats, rodents or mice, etc. Animals can be treated. However, this method can also be implemented in other species such as birds (eg, chickens).

  Diseases and conditions associated with inflammation and infection can be treated using the compounds of the present invention. In one embodiment, the disease or condition is one that needs to inhibit or promote lymphocyte activity in order to modulate an inflammatory response.

  Human or other species of disease situations that can be treated with inhibitors of chemokine receptor function include asthma, particularly bronchial asthma, allergic rhinitis, irritable lung disease, irritable pneumonia, eosinophilic pneumonia (eg, Lefler syndrome, chronic eosinophilic pneumonia), late-acting hypersensitivity, interstitial lung disease (ILD) (eg idiopathic pulmonary fibrosis or rheumatoid arthritis, systemic lupus lupus erythematosus, ankylosing spondylitis, Inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis related ILD), systemic anaphylaxis or hypersensitivity response, drug allergy ( Eg penicillin, cephalosporin), insect needle allergy; rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, all Autoimmune diseases such as lupus lupus erythematosus, myasthenia gravis, juvenile-onset diabetes; glomerulonephritis, autoimmune thyroid, Behcet's disease; grafts including allograft rejection or graft-versus-host disease Inflammatory bowel diseases such as Crohn's disease and colitis; spondyloarthropathy; psoriasis (including T-cell mediated psoriasis) and dermatitis, eczema, atopic dermatitis, allergic contact skin Inflammatory skin diseases such as inflammation, urticaria; vasculitis (eg, necrotizing vasculitis, dermatovasculitis, and hypersensitivity vasculitis); eosinophilic myositis, eosinophilic fasciitis; Cancers with leukocyte infiltration are included, but are not limited to these. Other diseases or conditions that can treat undesired inflammatory responses to be inhibited include reperfusion injury, atherosclerosis, certain hematological malignancies, cytokine-induced toxicity (eg, septic shock, internal Toxic shock), polymyositis, dermatomyositis, but is not limited to these.

  Human or other species of diseases or conditions that can be treated with modulators of chemokine receptor function include immunodeficiency syndromes such as people with AIDS or other viral infections, causing immunosuppression, radiation therapy, chemotherapy Immunosuppression, such as those undergoing treatment of autoimmune diseases or drug treatment (eg, corticosteroid treatment); immunosuppression due to congenital receptor deficiency or other causes; and nematodes (roundworms) , (Trichuriasis, helminthiasis, roundworm, helminth, faecal nematosis, faecal nematode, filariasis), fluke (flux) (schistosomiasis, liver fluke), multi-noded worms ) (Eg, helminthiasis, anthracnose disease, cystocystiasis), visceral worms, visceral larva migraine (eg, Toxocara), etc., and eosinophilic gastroenteritis (eg, Anisakis species, Phocanemas) .), And migration of larvae (Brazil hookworm skin, but including such as dogs hookworms) include infectious diseases such as parasitic diseases, but not limited to, but are not limited to. In addition, deliver enough compound to cause internalization of the chemokine receptor or to deliver the compound to cause a shift in the direction of cell migration and cause loss of receptor expression on the cell. It is also possible to envisage a chemokine receptor function promoter for the treatment of the aforementioned inflammatory diseases, allergic diseases and autoimmune diseases.

  Accordingly, the compounds of the present invention are useful in the treatment, prevention, amelioration, regulation or reduction of risk of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic conditions, atopic conditions, and autoimmune pathologies . In a specific embodiment, the present invention is directed to the use of the subject compounds for the treatment, prevention, amelioration, regulation or risk reduction of autoimmune diseases such as rheumatoid arthritis or psoriatic arthritis. .

  In another aspect, the present invention can be used to evaluate agonists or antagonists of chemokine receptors including CCR-2 with putative specificity. Accordingly, the present invention is directed to the use of these compounds to prepare and perform screening evaluations of compounds that modulate chemokine receptor activity. For example, the compounds of the present invention are useful for isolating receptor mutants, which are excellent screening tools for more powerful compounds. Furthermore, the compounds of the invention are useful for establishing or determining the binding site of other compounds for chemokine receptors, for example, by competitive inhibition. The compounds of the present invention are also useful for evaluating chemokine receptor modulators, including CCR-2, with putative specificity. As will be appreciated by those skilled in the art, a thorough evaluation of the specific agonists and antagonists of the chemokine receptors described above is non-peptidic (metabolic resistance) with high binding affinity for these receptors. ) Has been hampered by the unavailability of compounds. Accordingly, the compounds of the present invention are commercial products sold for these purposes.

  The present invention is further directed to a method of producing a drug that modulates human and animal chemokine receptor activity comprising combining a compound of the present invention with a drug carrier or diluent.

  The invention further treats the compound with a retrovirus, in particular herpes virus or human immunodeficiency virus (HIV), to treat, prevent, ameliorate, modulate or reduce the risk of infection and pathology such as AIDS resulting therefrom. It is intended for use in treating the situation and delaying the onset. Treating AIDS or preventing or treating infections caused by HIV is potential for AIDS, ARC (AIDS-related complex), non-symptomatic, and actually exposed to HIV Exposed to the public is defined as including, but not limited to, treating a wide range of conditions of HIV infection. For example, the compounds of the present invention are useful in the treatment of HIV infections suspected of previous exposure to HIV, for example, by blood transfusion, organ transplantation, fluid exchange, biting, needle stick accidents, or exposure to patient blood during surgery. It is.

  In one aspect of the invention, the compound of interest can be used in a method that prevents a chemokine from binding to a chemokine receptor of a target cell, such as CCR-2, where the target cell has a chemokine. Contacting with an amount of the compound effective to prevent binding to the chemokine receptor.

  The subject to be treated in the above manner is a mammal, such as a human, male or female, that is expected to modulate chemokine receptor activity. As used herein, “modulation” is intended to encompass antagonism, agonist, partial antagonism, reverse agonist and / or partial agonist. In one aspect of the invention, modulation refers to antagonism of chemokine receptor activity. The term “therapeutically effective amount” refers to the amount of a compound of interest that causes a biological or medical response in a tissue, system, animal or human that a researcher, veterinarian, medical doctor or other clinician seeks. Means.

  As used herein, the term “composition” includes products that contain a specific component in a specific amount, as well as products that can be combined directly or indirectly with a specific component in a specific amount. To do. “Pharmaceutically acceptable” means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not injurious to the recipient.

  The terms “administration” and / or “administering” the compound should be understood to mean subjecting the compound of the invention to an individual in need of treatment.

  As used herein, the term “treatment” refers to the treatment and prevention or prevention treatment of the above-mentioned situations.

  The term “substituted” in reference to substitution of alkyl, cycloalkyl, phenyl, heterocycle, or some other chemical group means that the mono- or poly-substitution by the listed substituent is chemically related to the described chemical group. Including one or more substitutions within the allowable range.

It is understood that the definition of a substituent at a particular position of a molecule is independent of the definition of other positions on that molecule. Thus, for example, in the case of alkyl substituted with R ³ = 1-5 R ¹² (defined separately), each R ¹² is independently selected from its possible meanings, ie, each R ¹² is another R ^{12 12} may be the same or different from any other R ¹² .

  The term “optionally substituted” is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl may represent pentafluorophenyl or a phenyl ring.

  Treatment, prevention, amelioration, regulation of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies (such as rheumatoid arthritis and atherosclerosis) and the pathologies mentioned above Alternatively, combination therapies that modulate chemokine receptor activity to reduce risk are indicated by the combination of a compound of the invention and other compounds known for such use.

  For example, to reduce the risk of treatment, prevention, amelioration, regulation or inflammation, the compounds are anti-inflammatory agents, analgesics such as sedatives, lipoxygenase inhibitors such as 5-lipoxygenase inhibitors, cyclooxygenase-2 inhibition Together with cyclooxygenase inhibitors such as agents, interleukin inhibitors such as interleukin-1 inhibitors, NMDAh antagonists, nitric oxide inhibitors or nitric oxide synthesis inhibitors, nonsteroidal anti-inflammatory agents, or cytokine-suppressing anti-inflammatory agents, For example, acetaminophen, aspirin, codeine, embrel, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, steroidal analgesics, sufentanil, sulindac It may be used with compounds such as tenidap. Similarly, these compounds are analgesics; potentiators such as caffeine, H2-antagonists, simethicone, aluminum hydroxide, magnesium hydroxide; phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine (ephinephrine). ), Naphazoline, xylometazoline, propylhexedrine, levo-desoxyephedrine and other decongestants; codeine, hydrocodone, calamiphen, carbetapentane, dextromethorphan and other antiseptics; diuretics; May be administered together with antihistamines having low sedation.

  Similarly, the compounds of the present invention may be used in conjunction with other agents used in the treatment / prevention / suppression or amelioration of the diseases or conditions for which the compounds of the present invention are effective. Such other agents may be administered by the routes and amounts generally used and may therefore be administered simultaneously or sequentially with the compound of the present invention. When used concurrently with one or more other drugs of the compound of the present invention, pharmaceutical compositions containing such other drugs are commonly used in addition to the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention.

Examples of other active ingredients that can be administered separately or combined with the compounds of the invention in the same pharmaceutical composition include, but are not limited to: (A) US Pat. No. 5,510,332, International Patent Publication Nos. WO95 / 15973, WO96 / 01644, WO96 / 06108, WO96 / 20216, WO96 / 22966, WO96 / 31206, WO96 / 40781, WO97 / 03094, WO97 / 02289, WO 98/42656, WO 98/53814, WO 98/53817, WO 98/53818, WO 98/54207, WO 98/58902, (b) beclomethasone, methylprednisolone, betamethasone, prednisone, Steroids such as dexamethasone, hydrocortisone, (c) immunosuppressants such as cyclosporine, tacrolimus, rapamycin and other immunosuppressants of the FK-506 type, (d) bromfu Bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyralin, tripelenamine, hydroxyzine, methodirazine, promethazine, trimeprazine, azatazine, cyproheptadine, antazoline, phenazolamine, phenazolazine , Desloratadine, cetirizine, fexofenadine, descarboethoxyloratadine and other antihistamines (H1-histamine antagonists), (e) β2-agonists s (terbutaline, metaproterenol, fenoterol, isoetarine, albuterol, vitorterol, and pyrbuterol ), Theophylline, cromolyn sodium, atropine, Non-steroidal anti-asthma drugs such as ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, povirukast, SKB-106, 203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005), (f) Propionic acid derivatives (aluminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, myloprofen, naproxen, oxaprozin, pyrprofen, Pranoprofen, suprofen, thiaprofenic acid, and thiooxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, chestnut Nac, diclofenac, fenclofenac, fenclozic acid, fenthiazac, flofenac, ibufenac, isoxepac, oxypinac, sulindac, thiopinac, tolmethine, didamethacin, zomepirac), phenamic acid derivatives (flufenamic acid, meclofenamic acid, meclofenamic acid, meclofenamic acid Acid and tolfenamic acid), biphenyl carboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxicam), salicylates (acetylsalicylic acid, sulfasalazine) and pyrazolones (apazone, benzpiperilone, feprazone) , Mofebutazone, oxyphenbutazone, phenylbutazone) Any non-steroidal anti-inflammatory drugs (NSAIDs), (g) cyclooxygenase-2 (COX-2) inhibitors, (h) phosphodiesterase IV (PDE-IV) inhibitors, (i) chemokine receptors, especially CCR-1 Other antagonists of CCR-2, CCR-3, CXCR-3 and CCR-5, (j) HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, rosuvastatin, and other statins ), Inhibitors (cholestyramine and colestipol), cholesterol absorption inhibitors (ezetimibe), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), and probucol Choleste Anti-diabetic drugs such as roll-lowering agents, (k) insulin, sulfonylureas, biguanides (methformin), α-glucosidase inhibitors (acarbose), glitazones (troglitazone and pioglitazone), (l) interferon β (interferon beta − other compounds such as lα, interferon beta-1β) preparations, (m) 5-aminosalicylic acid and its prodrugs, antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents The weight ratio of the compound for the second active ingredient can be varied depending on the effective dose of each ingredient. In general, each effective dose is used. Thus, for example, when a compound of the present invention is combined with an NSAID, the weight ratio of the compound of the present invention to the NSAID is generally in the range of about 1000: 1 to about 1: 1000, alternatively about 200: 1 to about 1: 200. . Combinations of the compounds of the present invention and other active ingredients are generally within the ranges described above, but in each case, an effective dosage of each active ingredient should be used.

  In such combinations, the compounds of the present invention and other active agents may be administered separately or together. Furthermore, the administration of one component may occur prior to the administration of the other agent, or may be simultaneous or subsequent.

  The compounds of the invention can be oral or parenteral (eg, intramuscular, intraperitoneal, intravenous, ICV, intracapsular injection or infusion, subcutaneous injection, implantation), inhalation spray, nasal, vaginal, rectal, sublingual, Alternatively, it may be administered by a local route of administration, alone or formulated in a suitable dosage unit formulation containing the usual non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles suitable for each route of administration. May be. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cows, sheep, dogs, cats, monkeys, etc., the compounds of the present invention are effective for use in humans.

  Pharmaceutical compositions for administration of the compounds of the present invention are conveniently in dosage unit form and can be prepared by any method well known in the pharmaceutical industry. Any method includes the step of bringing into association the active ingredient with the carrier which comprises one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately integrating the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active substance compound is included in an amount sufficient to produce the desired effect in the method or disease state. As used herein, the term “composition” includes products that contain a specific component in a specific amount, and any product that can be combined directly or indirectly with a specific component in a specific amount. Yes.

  The pharmaceutical composition containing the active ingredient is in a form suitable for oral use, for example tablets, troches, medicinal drops, aqueous suspensions, oily suspensions, dispersible powders or granules, emulsions, hard capsules, soft capsules, syrups or elixirs It can be. Compositions for oral use can be prepared by any method known to those skilled in the art for producing pharmaceutical compositions, which provide an elegant and palatable formulation as a drug. In order to do so, one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives can be included. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binders such as starch, gelatin or It may be acacia, and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Also coated by the techniques described in U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release. May be.

  Formulations for oral use also include hard gelatin capsules where the active ingredient is miscible with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient is an aqueous or oily medium such as peanut oil, It may be present as a soft gelatin capsule if it is miscible with liquid paraffin or olive oil.

  Aqueous suspensions contain the active materials in admixture with excipients suitable for making aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum, and dispersants or wetting agents are naturally occurring phospholipids, For example, it may be lecithin, or a condensation product of an alkylene oxide and a fatty acid, such as a polyoxyethylene stearate, or a condensation product of an ethylene oxide and a long-chain aliphatic alcohol, such as heptadecaethyleneoxycetanol, or Condensation products of fatty acid and hexitol partial esters and ethylene oxide, for example, polyoxyethylene sorbitol monooleate or fatty acid and hexitol anhydride partial ester The condensation products of ethylene oxide, for example, be a polyethylene sorbitan monooleate. Aqueous suspensions also contain one or more preservatives, such as ethyl p-hydroxybenzoate, or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavorings, and One or more sweeteners such as sucrose or saccharin may be included.

  Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. This oily suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

  Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water are those in which the active ingredient is admixed with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and dispersing agents are exemplified by those already mentioned above. Additional additives; for example sweetening, flavoring and coloring agents may be present.

  The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil. For example, it can be olive oil or peanut oil or mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifiers include naturally occurring gums such as gum acacia or tragacanth, naturally occurring phospholipids such as soy, lecithin, and esters or partial esters of fatty acids and hexitol anhydrides such as sorbitan monoolein. It may be an acid ester and a condensation product of the partial ester and ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

  Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

  The pharmaceutical composition may be in a sterile injectable form of an aqueous or oily suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils can be conveniently employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

  The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ambient temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. . Such materials are cocoa butter and polyethylene glycol.

  For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the invention are used (for such applications, topical applications include mouthwashes and mouthwashes. included).

  The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically effective compounds as mentioned herein which are usually applied in the treatment of the above pathological situations.

  In treating, preventing, ameliorating, modulating or reducing the risk of situations requiring modulation of chemokine receptors, suitable dosage levels are generally about 0.01 to 500 mg per kg patient body weight per day, with a single dose However, it may be administered multiple times. The dosage level is about 0.1 to about 250 mg / kg · day; or about 0.5 to about 100 mg / kg · day. Suitable dosage levels may be about 0.01 to 250 mg / kg · day, about 0.05 to 100 mg / kg · day, or about 0.1 to 50 mg / kg · day. Within this range, administration may be 0.05-0.5, 0.5-5, or 5-50 mg / kg · day. For oral administration, this composition is in the form of a tablet containing 1.0-1000 mg of active ingredient in order to tailor the dosage to the patient to be treated in the form of 2.0-500, 3.0-200, Alternatively 1, 5, 10, 15, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200, 250, 300, 400, 500, 600, 750, 800, 900 and / or 1000 mg effective It can be provided in component amounts. These compounds can be administered on a regimen of 1 to 4 times / day, preferably once / day or twice / day.

  However, the specific dose concentration and frequency of administration for a particular patient can vary and the activity, metabolic stability and duration of action of the specific compound used, age, weight, general health, sex, diet It will be understood that it depends on various factors, including the mode and frequency of administration, the rate of excretion, the combination of drugs, the severity of the particular condition, and the subject being treated.

  Several methods for preparing the compounds of this invention are illustrated in the following schemes and examples. Starting materials are commercially available, made by known procedures, or prepared as described herein.

One of the major routes used to prepare compounds with 1,1,3-trisubstituted cyclopentane backbone 1-5 within the scope of the present invention is depicted in Scheme 1. According to this route, keto acid 1-1 (preparation described in Schemes 2A, 2B, 2C, and 2D) is coupled with amine 1-2 (preparation described in Schemes 3A-G). This can be accomplished in various ways. First, the acid is converted to acid chloride with a reagent such as oxalic acid chloride, and then coupled with amine 1-2 in the presence of a base such as triethylamine. For example, using NaB (OAc) ₃ H or NaBH ₃ CN as a reducing agent, 1-3 is reductively aminated with amine 1-4 to obtain chemokine receptor modulator 1-5. Compound 1-9 can be synthesized according to the chemistry described in Scheme 1, which is a mixture of stereoisomers (Eliel, EE, Wilen, SH, Stereochemistry of Organic Compounds, John Wiley & Sons, Inc.). , New York). In particular, compounds 1-5 are often obtained as a mixture of cis and trans isomers. When 1-1 is a single stereoisomer (1-la), there are only two possible isomers of 1-5 (cis and trans). These can be separated in a variety of ways, including preparative TLC, flash chromatography, MPLC, or HPLC using a column with a chiral stationary phase. When 1-1 is a racemate, all four possible isomers of 1-5 may be obtained. These may be separated again by HPLC using a column with a chiral stationary phase or by a combination of the methods described above. The synthesis of racemic 1-1 is detailed in Scheme 2A, while the synthesis of chiral 1-la is described in Schemes 2B and 2C.

  Furthermore, compound 1-5 itself can be modified to be a new chemokine receptor modulator 1-5.1. For example, the ester functional group of compound 1-5 can be hydrolyzed to the corresponding carboxylic acid, which can also be a chemokine receptor modulator.

As illustrated in Scheme 1A, reductive amination of ketoester 1-6 with amine 1-4 under various conditions such as sodium triacetoxyborohydride or sodium cyanoborohydride provides aminoester 1-7 Can be formed. Intermediate ester 1-8 by alkylating ester 1-7 with an alkylating reagent such as alkyl chloride, alkyl bromide or alkyl iodide in the presence of a suitable base such as lithium bis (trimethylsilyl) amide. Is obtained. These esters formed in the above transformation will generally be a mixture of 1,3-cis- and 1,3-trans-diastereoisomers, which can be obtained using column chromatography for each diastereoisomer. Can be divided into pairs. Ester 1-8 can be cleaved by hydrolysis to give each acid 1-9, followed by a similar resolution of diastereoisomers. This hydrolysis was easily performed under normal conditions such as lithium hydroxide, sodium hydroxide or potassium hydroxide at room temperature to high temperature, depending on the nature of the ester group and substituent R ¹ . Taking advantage of the fact that the acids of the cis-diastereoisomers are less soluble than their transepimers, these diastereoisomers can be separated by crystallization from various solvents.

  The compound of formula 1-5 is then converted to the acid 1-9 and tetrahydroisoquinoline derivative 1-2 under standard amide bond forming reaction conditions including a carbodiimide reagent such as DCC, EDC and a catalyst such as DMAP, HOAT or HOBT. Formed from.

Intermediate 1-3 can also be resolved by chiral HPLC to give 1-3a and 1-3b (Scheme 1B). From this, cis / trans isomers 1-5a and 1-5b can then be obtained.

One of the major routes used in the preparation of Intermediate 1-1 and Intermediate 1-6 is outlined in Scheme 2A. According to this route, 3-oxocyclopentanecarboxylic acid (2-1), which can be synthesized by known procedures (Stetter, H., Kuhlman, H., Liebigs Ann. Chim., 1979, 944) under standard conditions Esterify below. When R ¹⁸ represents a tert-butyl group, each ester 1-6 can be prepared by reacting a suitable alcohol, in this case tert-butanol, with acid 2-1 in the presence of sulfuric acid. The protection of the 2-1 oxo group can be accomplished in a number of ways (Greene, T., Wuts, PGM, Protective Groups in Organic Chemistry, John Wiley & Sons, Inc., New York, NY 1991). ). A particularly suitable dimethyl acetal protecting group can be introduced using trimethyl orthoformate as a reagent in the presence of an acidic catalyst in a suitable solvent such as dichloromethane and methyl alcohol. Alternatively, when R ¹⁸ is a methyl group, the acid 2-1 can be directly converted to 2-3 using trimethyl orthoformate and an acidic catalyst such as paratoluenesulfonic acid. Intermediate 2-4 is prepared by alkylating ester 2-3 with an alkylating reagent such as alkyl chloride, alkyl bromide or alkyl iodide in the presence of a suitable base such as lithium diisopropylamide. . The ester protecting group contained in 2-4 can be removed in a number of ways depending on the nature of the ester. Methyl esters (R ¹⁸ = methyl) can be hydrolyzed at ambient or elevated temperatures in the presence of acids or bases, ^whereas tert-butyl esters (R ¹⁸ = tert-butyl) are easily cleaved under acidic conditions it can. Under these conditions, dimethyl acetal is simultaneously deprotected to give 1-1.

  Intermediate 1-1 can be prepared as a single stereoisomer (1-la) in a variety of ways, including those illustrated in Schemes 2B and 2C. According to Scheme 2B, racemic 1-1 can be converted to a benzyl ester. This esterification can be carried out in a number of ways, one of which is, for example, a procedure such as conversion to the corresponding acid chloride using oxalyl chloride and then treatment with benzyl alcohol in the presence of a base such as triethylamine. There is a thing by. The racemic benzyl ester 2-5 can then be separated by chiral preparative HPLC to give 2-5a as a single stereoisomer. In several ways, the benzyl group can be removed to give the chiral keto acid 1-1a. One convenient method is by hydrocracking in the presence of a catalyst such as Pd / C.

According to Scheme 2C, chiral keto acid intermediate 1-1a can be prepared starting from commercially available optically pure amino acids 2-6. Protection of the carboxylic acid group can be achieved in various ways. When ^Rl8 is methyl, it can be esterified by treatment with methanol in the presence of an acid catalyst such as HCl. Treatment with Boc ₂ O protects the 2-7 amine group. By stereoselectively alkylating ester 2-8 with an alkylating reagent such as alkyl chloride, alkyl bromide or alkyl iodide in the presence of a suitable base such as lithium bis (trimethylsilyl) amide. The body 2-9 is obtained. Hydrogenation in the presence of a catalyst such as Pd / C gives 2-10. ^Depending on the ^Rl8 group, 2-11 can be obtained by hydrolyzing the ester under standard conditions. For example, when ^Rl8 is methyl (methyl ester), hydrolysis can be performed by treatment with a base such as sodium hydroxide, lithium hydroxide, or potassium hydroxide with or without heating. The Boc protecting group can be removed under standard acidic conditions, such as with TFA or with HCl in a solvent such as dioxane. The method of oxidizing 2-12 to give 1-la (as a single stereoisomer if component R ¹ is achiral or as a mixture of stereoisomers if component R ¹ has a chiral center) Can also be performed in several ways, including, for example, treatment with NBS followed by treatment with sodium methoxide.

Reacting an enolate from ester 2-3 with an aldehyde (R ^1a CHO) or ketone (R ^1a R ^2a CO) in the presence of a strong base such as lithium diisopropylamide (R ¹⁸ is a benzyl or tert-butyl group) To produce intermediate 2-4.1 substituted with an appropriate hydroxyalkyl as shown in Scheme 2D. The obtained hydroxy group can be protected by various methods, for example, a method of treating with acetic anhydride in the presence of a base such as triethylamine to obtain intermediate 2-4.2 is also included. Again, the ester protecting group is removed under conditions suitable for the particular protecting group. In the case of a tert-butyl ester (R ¹⁸ is t-butyl), deprotection is achieved under acidic conditions. The latter usually induces the cleavage of the acetal protecting group as well, and keto acids 1-1.1 can thus be prepared in a one-pot procedure. Conversion to the final modulator 1-9 with chemokine activity can be accomplished as described above with minor modifications to accommodate the protected hydroxyl group of 1-1.1.

Amine 1-2 can be prepared in several ways as shown in Schemes 3A-3G. The 5-aza-tetrahydroisoquinoline fragment is described in MarCoux, JF. (J. Chem. Lett., 2000, 2 (15), 2339 to 2341). Alternatively, it can be prepared as outlined in Scheme 3A. Compound 3-1 is typically obtained from commercial sources, 3-2 can be obtained by bromination _(Br 2, AcOH). Metal halogen exchange (NaH, t-butyllithium) followed by treatment with DMF gives aldehyde 3-3. Conversion of aldehyde groups to nitriles can be accomplished using sodium formate, hydroxylamine hydrochloride and formic acid. 2-Chloropyridine 3-5 can be obtained by treating the obtained nitrile 3-4 with phosphorus oxychloride. Replacement of the chlorine group can be performed using a sodium salt of dialkyl malonate. Reduction of the nitrile group of 3-6 using hydrogen and Raney Ni catalyst is performed by cyclization to give compound 3-7. Decarboxylation can be carried out in various ways depending on the ester. In the case shown in Scheme 3A, the t-butyl ester was decarboxylated with TFA to give 3-8. Reduction (BH ₃ ) and then protection of the resulting amine with Boc ₂ O provides 3-9. This may be purified for convenience. The Boc protecting group can be removed by various methods to give 1-2a, including, for example, treatment with anhydrous HCl in dioxane or other solvents.

1-2a type compounds could also be prepared according to Scheme 3B. 3-11 can be obtained by methylating commercially available 3-10 with methyl iodide in the presence of a base such as K ₂ CO ₃ . Cycloaddition with a protected piperidinone in the presence of NH ₃ in methanol gives 5-azatetrahydroisoquinoline 3-12 (R ^10c may be various protecting groups such as benzyl or benzoyl). It was. Hydrogenation of the nitro group of compound 3-12 using hydrogen and a catalyst such as Pd / C provides 3-13. A diazonium salt was formed and then warmed with sulfuric acid to give 5-aza-7-hydroxytetrahydroisoquinoline 3-14. Removal of the protecting group R ^10c is done in different ways depending on the nature of R ^10c . If R ^10c is benzyl, hydrogenation can be carried out in the presence of a catalyst such as HCl and Pd / C. If R ^10c is benzoyl, it can be hydrolyzed by heating in concentrated HCl solution. Introduction of the Boc protecting group to 3-15 can be easily performed using Boc ₂ O to give 3-16. Various R ^10d can then be introduced to give an ester (see Scheme 3C). The Boc protecting group of the resulting compound 3-17 can be finally removed with HCl or TFA to give 1-2b. Alternatively, compound 3-14 itself may be converted to ether (according to Scheme 3C). The resulting ether 3-18 may be converted to compound 3-19 by removing R ^10c as described above.

5-aza-7-hydroxytetrahydroisoquinolines 3-14 and 3-16 of Scheme 3B may be converted to various ethers (see Scheme 3C). Alkyl ethers can be prepared from alkyl halides and bases (such as K ₂ CO ₃ , NaOH, or NaH) to give compounds 3-19 and 3-22. Trifluoromethyl ether first forms methyl xanthate (NaH, CS ₂ ; MeI), then treated sequentially with 1,3-dibromo-5,5-dimethylhydantoin (or NBS) and HF / pyridine solution. 3-20 is obtained. Aryl ethers can be prepared in a number of ways, such as reaction of aryl boronic acids in the presence of copper (II) acetate and triethylamine, to give compound 3-21.

Compound 1-2c where R ⁵ is halide (IVc) can be prepared according to Scheme 3D. Compound 3-13 can be converted to halide 3-22 via a diazonium salt according to classical techniques. Alternatively, known cycloaddition reactions to appropriately protected piperidinones may be utilized. Removal of the protecting group R ^10c can be accomplished as described above.

After introduction into the advanced intermediate, fragment 1-2c may be further modified to prepare 7-aryl-5-azotetrahydroisoquinoline-containing analogs. This can be done by coupling a 5-aza-7-halotetrahydroisoquinoline intermediate to an arylboronic acid (or arylstannane) mediated by a transition metal catalyst such as Pd (OAc) ₂ .

  The preparation of the tetrahydroisoquinolinamine component is outlined in Schemes 3E-3G. Tetrahydroisoquinolines introduced at the 1-5 amide sites often contain one or two substituents at various positions. Most of these are not commercially available, but can be obtained synthetically, representative examples of which are shown in Schemes 3F and 3G.

  A synthesis example of simple tetrahydroisoquinoline (1-2d) is illustrated in Scheme 3E. According to this, commercially available 4-trifluoromethylphenylacetonitrile (3-23) is converted to the corresponding amine (3-24) using hydrogenation in the presence of Ra-Ni, and then trifluoroacetic acid Anhydride is used to protect the amine. The obtained amide (3-25) is treated with formaldehyde in the presence of sulfuric acid to obtain a cyclized compound (3-26), which is further converted to tetrahydroisoquinoline (1-2d).

  Many 5-position substituted tetrahydroisoquinolines can also be prepared based on 3-26 (Scheme 3F). Intermediate 3-28 is obtained by iodination at the 5-position. After conversion to the cyano compound (3-29) under palladium (0) catalytic conditions, the amide is cleaved to the amine 3-30. This can be converted in high yield to the amino ester 1-2e in two successive steps. The iodo compound 3-28 can also be converted to other compounds as shown in the Examples section. Modification of these substitutions can also be made after formation of the final structure (1-5), forming a new chemokine modulator of type 1-5.1 (see Scheme 1). An example of this is the hydrolysis of the methyl ester (from 1-2e), which appears to form the corresponding carboxylic acid (see Examples).

  The tetrahydroisoquinoline substituted at the 7-position of the heterocyclic ring could be obtained by using a commercially available tetrahydroisoquinoline. Tetrahydroisoquinoline (3-32) is nitrated by treatment with potassium nitrate in the presence of concentrated sulfuric acid as described in Scheme 3G. 7-Nitro-tetrahydroisoquinoline 3-33 is treated with trifluoroacetic anhydride to protect the amine and then the resulting amide is hydrogenated with 10% palladium on carbon under hydrogen at a pressure of 50 psi. Thus, the aniline derivative 3-34 is obtained. By base hydrolysis, tetrahydroisoquinoline (3-35) in which the amino group at the 7-position is substituted is obtained. This could further be used for the synthesis of CCR2 antagonists or other tetrahydroisoquinoline derivatives. Protection of 3-35 with benzyl chloroformate in the presence of an organic base such as triethylamine or diisopropylethylamine provides carbamate ester 3-37. Utilizing this intermediate, tetrazole and substituted tetrazole such as 1-2 g were obtained. Intermediate 3-37 is treated with trifluoroacetic anhydride to prepare an amide protected with a trifluoroacetyl group, which is then reacted with triphenylphosphine, heated at reflux for 15 hours, and then azimuthally at room temperature. Conversion to tetrazole substituted with trifluoromethyl by continuous reaction with a solution of sodium fluoride in DMF. Hydrogenation with 10% palladium on carbon in a hydrogen atmosphere gives 1-2 g of tetrahydroisoquinoline substituted with a heterocycle.

  Alternatively, as shown in the figure, 3-34 is directly derivatized to triazole 3-36 by heating to reflux for 24 to 48 hours using N, N-dimethylformamide azine in the presence of a catalytic amount of acid such as toluenesulfonic acid. May be. By amine hydrolysis of this intermediate, amine component 1-2f is obtained.

  Further examples of tetrahydroisoquinolines introduced into the amide sites of compounds within the scope of the present invention are further described in the Examples section along with their synthetic methods.

Amine 1-4 was obtained from various sources. Most are commercially available, some were known from the literature, some were prepared according to published procedures, and some were prepared as described herein. Since these structures and preparation methods vary, only two schemes are outlined in this section. The individual synthesis of amines 1-4 can be found in the example section. Scheme 4A shows one method for the synthesis of piperidine substituted at the 4-position with aryl. Enol triflate 4-1 (prepared according to Wustrow, DJ, Wise, L.D., Synthesis, (1991), 993-995) is coupled to boronic acid 4-2 as described in Wustrow and Wise. We were able to. Hydrogenation of 4-3 olefins could be performed using hydrogen in the presence of a catalyst such as Pd (OH) ₂ / C. Removal of the Boc protecting group could be done using standard acidic conditions such as HCl in dioxane or TFA / DCM to give piperidine 1-4.

  Another example of the synthesis method of amine 1-4 is shown in Scheme 4B. Commercially available alcohol (4-5) is first sulfonylated with methanesulfonyl chloride to give intermediate 4-6. This can be directly substituted with tetrazole to give heteroarylpiperidine 4-7. Removal of the Boc protecting group under standard conditions provides amine hydrochloride 4-8.

  Another major pathway for the synthesis of chemokine receptor modulators is illustrated in Scheme 5. According to this route, 2-1 is obtained by condensing intermediate 2-11 (described in Scheme 2C) with amine 1-2 (described in Scheme 1) using a peptide binding reagent such as EDC. . The Boc protecting group is removed under standard conditions such as using HCl in a solvent such as dioxane, and the resulting amine 5-2 is then removed from the dialdehyde in the presence of a reducing agent such as sodium triacetoxyborohydride. Treatment with 5-3 results in two consecutive reductive alkylations with concomitant cyclization to give 1-5.2. Similar to Scheme 1, further modifications such as hydrolysis of ester groups within 1-5.2 can be made, resulting in new chemokine receptor modulators 1-5.3.

  One method for preparing dialdehyde 5-3 is outlined in Scheme 6. According to this route, dialdehyde is obtained by oxidative cleavage of cycloalkane 6-1 using, for example, ozone and then dimethyl sulfide. Alternatively, instead of dialdehyde 5-3, intermediate ozonide 6-2 itself may be used directly in the reductive amination reaction to give 1-5.2.

  In some cases, the order in which the above reaction schemes are performed may be varied, which facilitates the reaction or avoids unwanted reaction products. The following examples are provided for the purpose of further illustration and are not intended to be limited to the disclosed invention.

Concentration of the solution was usually performed by a rotary evaporator under reduced pressure. Flash chromatography was performed on silica gel (230-400 mesh). MPLC refers to medium pressure liquid chromatography and was carried out on a silica gel stationary phase unless otherwise noted. NMR spectra were obtained with CDCl ₃ solution unless otherwise noted. The coupling constant (J) is hertz (Hz). Abbreviations: diethyl ether (ether), triethylamine (TEA), N, N-diisopropylethylamine (DIEA), saturated aqueous solution (sat'd), room temperature (rt), time (h), minutes (min).

  The following are representative methods for preparing compounds that may be used in the examples described below or compounds that may be used in place of the compounds used in the examples described below and that may not be commercially available.

  In some cases, the order in which the above reaction schemes are performed may be varied, which facilitates the reaction or avoids unwanted reaction products. The following examples are provided for the purpose of further illustration and are not intended to be limited to the disclosed invention.

Concentration of the solution was usually performed by a rotary evaporator under reduced pressure. Flash chromatography was performed on silica gel (230-400 mesh). NMR spectra were obtained with CDCl ₃ solution unless otherwise noted. The coupling constant (J) is hertz (Hz). Abbreviations: diethyl ether (ether), triethylamine (TEA), N, N-diisopropylethylamine (DIEA), saturated aqueous solution (sat'd), room temperature (rt), time (h), minutes (min).

  The following are representative methods for preparing compounds that may be used in the examples described below or compounds that may be used in place of the compounds used in the examples described below and that may not be commercially available.

  Intermediate 1

ステップＡ：

Step A:

  A solution of 4-trifluoromethylphenylacetonitrile (10 g, 49 mmol) in a mixture of ethanol (100 mL) and ammonium hydroxide (20 mL of 29.3% aqueous solution) was hydrogenated with Raney nickel (1 g) for 16 hours. The catalyst was removed by filtration through celite and the filtrate was evaporated to dryness. The neat residue was added dropwise to trifluoroacetic anhydride (25 mL, 180 mmol) cooled to 0 ° C., and the resulting mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was poured onto ice (250 mL) and the resulting mixture was stirred for 30 minutes, after which the precipitate was removed by filtration and air dried to give the product as a white solid (13.4 g, 90%). .

  Step B:

To a mixture of the product obtained from Step A (13.4 g, 44.0 mmol) and paraformaldehyde (2 g, 50 mmol) was added a mixture of concentrated sulfuric acid (90 mL) and glacial acetic acid (60 mL) in one portion, resulting in The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a mixture of ice and water (1 L) and extracted with ethyl acetate (3 × 150 mL), and the combined ethyl acetate layers were washed with water (3 × 500 mL), saturated NaHCO ₃ (200 mL), saturated NaCl (100 mL). ), Dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was purified by column chromatography on silica eluting with 10% Et ₂ O in hexane to give the product (8.29 g, 60%).

  Step C:

To a solution of trifluoroacetamide (8.29 g, 26.0 mmol) prepared in Step B in ethanol (200 mL) was added potassium carbonate (20 g, 150 mmol) in water (50 mL) and the resulting mixture was refluxed with 1 Stir for hours. Ethanol was removed on a rotary evaporator and water (150 mL) was added to the residue. Extract with CH ₂ Cl ₂ (3 × 100 mL) and wash the combined CH ₂ Cl ₂ layers with saturated NaCl (100 mL), dry over Na ₂ SO ₄ , filter and evaporate in vacuo to give the product (5 .2 g, 91%). ¹ H NMR 500 MHz (CDCl ₃ ) δ = 1.81 (1H, br s), 2.84 (2H, d, J = 6.0 Hz), 3.15 (2H, t, J = 6.0 Hz), 4.05 (2H, s), 7.19 (1H, d, J = 8.0 Hz), 7.27 (1H, s), 7.37 (1H, d, J = 8.0 Hz).

  Intermediate 2

  Step A:

To a solution of 5-trifluoromethyl-2-pyridinol (51.0 g, 307 mmol) and sodium acetate (26.2 g, 319 mmol) in glacial acetic acid (200 mL) was added bromine (16.7 mL, 325 mmol) and the resulting mixture Was heated at 80 ° C. for 2.5 hours. The reaction was allowed to cool to room temperature and then evaporated under reduced pressure. The residue was neutralized with saturated NaHCO ₃ solution and extracted with ethyl acetate (3 × 200 mL). The organic layers were combined, dried over MgSO ₄ , filtered and evaporated in vacuo to give 74.45 g (98.7%) of the crude product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (d, J = 2.6 Hz, 1H), 7.89 (m, 1H).

  Step B:

Under nitrogen, the substituted pyridine described in Step A (48.8 g, 202 mmol) was added in portions to a suspension of NaH (8.9 g, 220 mmol) in anhydrous THF (500 mL). After complete addition of the intermediate, the reaction mixture was cooled to −78 ° C. and treated with tert-butyllithium (260 mL, 444 mmol) added dropwise by syringe. After 5 minutes of stirring, DMF (50 mL, 707 mmol) was added slowly so as to maintain a temperature below −50 ° C. The resulting mixture was then stirred for 10 hours and warmed to room temperature. The mixture was quenched with 2N HCl and then diluted with ethyl acetate (1000 mL). The organic layer was separated, washed with brine, dried over MgSO ₄ and evaporated in vacuo. The desired product was precipitated from ethyl acetate and hexane and filtered to give a light brown solid (28.55 g, 73.8%). ¹ H NMR (500 MHz, CD ₃ OD) δ 10.13 (s, 1 H), 8.21 (s, 2 H).

  Step C:

A mixture of the intermediate from Step B (18 g, 95 mmol), sodium formate (7.1 g, 105 mmol), hydroxylamine hydrochloride (7.3 g, 110 mmol), and formic acid (150 mL) was stirred at room temperature for 2 hours, It was then refluxed overnight. The reaction mixture was cooled and left at room temperature for 7 days. The reaction was poured into water and extracted with ethyl acetate (3x). The combined organic layers were washed with water (2 ×), saturated NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the desired product as a brown powder (17.84 g). 89.8%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 (d, J = 2.7 Hz, 1H), 8.19 (q, J = 0.7 Hz, 0.3? / Hz, 1H).

  Step D:

To the mixture of phosphorus oxychloride (13.4 mL, 144 mmol) and quinone (8.7 mL, 73.4 mmol) was added the product from Step C (24.6 g, 131 mmol) and the resulting mixture was added for 3 hours. Refluxed. The reaction was cooled to 100 ° C. and then water (70 mL) was added slowly. The mixture was further cooled to room temperature and carefully neutralized with saturated NaHCO ₃ solution. The aqueous layer was extracted with ethyl acetate (3 ×) and the organic layers were combined, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude product was purified by flash chromatography to give the desired compound (23.5 g, 87.0%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.88 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H).

  Step E:

To a THF (100 mL) suspension of NaH (7.8 g, 200 mmol), a solution of tert-butyl methyl malonate (20 mL, 120 mmol) in anhydrous THF (100 mL) was added dropwise with a syringe under nitrogen. The reaction mixture was stirred for 0.5 h, after which a solution of the intermediate prepared in Step D (20.1 g, 97.6 mmol) in THF (200 mL) was slowly added via syringe. The reaction was stirred at room temperature overnight and then quenched with a saturated solution of NH ₄ Cl. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with water (3 ×), dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. Flash chromatography gave 31.76 g (94.6%) pure desired product. 1H NMR (500 MHz, CDCl ₃ ) δ 9.03 (d, J = 1.5 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 5.25 (s, 1H), 3.86 (S, 3H), 1.52 (s, 9H).

  Step F:

A suspension of Raney Ni (1 g) and the product from Step E (18.2 g, 52.9 mmol) in ethanol (130 mL) was placed in a Parr Apparatus and hydrogenated overnight at 40 psi. The suspension was filtered through celite and the filtrate was evaporated in vacuo to give 16.35 g (97.8%) of crude product. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.83 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 4.83 (d, J = 16 Hz, 1H), 4 .72 (s, 1H), 4.49 (d, J = 16 Hz, 1H), 1.45 (s, 9H).

  Step G:

To a mixture containing the product from Step F (16 g, 51 mmol) in DCM (60 mL) was added TFA (30 mL) and the resulting mixture was stirred at room temperature for 0.5 h. The solution was evaporated under reduced pressure and the residue was dissolved in DCM. The mixture was neutralized by slowly adding saturated sodium bicarbonate solution and the organic layer was removed. The aqueous layer was extracted with DCM (4x), then all organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give 10.42 g (95.2%) of the desired product. It was. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 7.78 (s, 1H), 7.30 (s, 1H), 4.63 (s, 2H), 3.90 (s , 2H).

  Step H:

  To a solution of the product from Step G (18.0 g, 83.3 mmol) in THF (50 mL) was added 1.0 M borane in THF (417 mL, 420 mmol) and the resulting solution was stirred at room temperature overnight. did. The solution was evaporated under reduced pressure, then the residue was treated with 1% HCl / MeOH solution and the resulting mixture was heated at 50 ° C. overnight to destroy the borane complex. The borane complex was reliably broken by repeating the treatment with acidic methanol twice. Thereafter, the crude product obtained from this reaction was directly used in the next reaction.

Treatment of the crude product just described (83.3 mmol, assuming 100% conversion) and DIEA (43 mL, 250 mmol) in DCM with di-tert-butyl dicarbonate (36.4 g, 167 mmol) gave The mixture was stirred overnight at room temperature. This solution was washed with saturated sodium bicarbonate solution, water, and brine. The aqueous layers were combined and backwashed with DCM (2x). The combined organic layers were then dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The crude product was purified by flash chromatography and MPLC to give a yellow solid (11.89 g, 47.2% in the last two steps). ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.69 (s, 1H), 7.66 (s, 1H), 4.67 (s, 2H), 3.79 (t, J = 6.0 Hz, 2H) 3.08 (t, J = 5.5 Hz, 2H), 1.51 (s, 9H).

  Step I:

The product described in Step H (11.89 g) was treated with 4M HCl in dioxane. The solution was stirred at room temperature for 2 hours and then evaporated in vacuo to give Intermediate 2 (10.85 g, 99%) as a yellow powder. _{C 9 H 10 F 3 N 2} [M + H +] of the LC-MS calc. 202.07, measurements 203.0.

  Intermediate 3

  Step A:

Obtained by treating a methanolic solution of methyl 3-oxocyclopentanecarboxylate (20 g, 160 mmol) and trimethyl orthoformate (85 mL, 780 mmol) with a catalytic amount of p-toluenesulfonic acid (3.00 g, 15.6 mmol). The solution was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure and then the residue was dissolved in ether (600 mL). The solution was washed with saturated sodium bicarbonate (2 × 200 mL), water (150 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered and the solvent evaporated as before. Purification by flash column chromatography (eluent: 25% ether / pentane) gave 21.52 g (73%) of the desired product as a clear oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ 3.68 (s, 3H), 3.21 (d, J = 9.9 Hz, 6H), 2.89 (p, J = 8.5 Hz, 1H), 2. 14 to 2.05 (m, 2H), 2.02 to 1.80 (m, 4H).

  Step B:

To a flame-dried 500 mL round bottom flask was added 150 mL dry THF, then placed under nitrogen and cooled to −78 ° C. using an acetone / dry ice bath. Diisopropylamine (19.2 mL, 137 mmol) was added to the chilled solvent with a syringe, and then 2.5 M n-butyllithium in hexane (55 mL, 140 mmol) was added slowly. After stirring for 5 minutes, 50 mL of THF containing methyl ketal (21.52 g, 114.4 mmol) described in Step A of Intermediate 3 was added dropwise with a syringe, and the resulting mixture was stirred at −78 ° C. for 2 hours. . Then 2-iodopropane (34.3 mL, 343 mmol) was added dropwise with a syringe and the resulting mixture was stirred overnight and allowed to warm slowly to room temperature. The reaction was quenched with 10% citric acid solution and the organic layer was separated. The aqueous layer was extracted with ether (3 × 150 mL) and all organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified on a flash column using 20% ether / pentane as eluent to give 16.74 g (64%) of the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.69 (s, 3H), 3.18 (d, J = 20.5 Hz, 6H), 2.57 (d, J = 13.9 Hz, 1H), 2. 29 to 2.20 (m, 1H), 1.90 (p, J = 6.8 Hz, 1H), 1.88 to 1.80 (m, 2H), 1.69 to 1.61 (m, 2H) ), 0.89 (dd, J = 11.9 Hz, 6.8 Hz, 6H).

  Step C:

A solution of the ester (described in Intermediate 3 Step B, 16.7 g, 72.7 mmol) in ethanol (30 mL) was treated with 5M NaOH (55 mL) and the resulting mixture was heated to reflux for 3 days. The mixture was then cooled to room temperature and acidified with concentrated hydrochloric acid. The organic solvent was evaporated under reduced pressure and then the aqueous layer was extracted with DCM (5 × 100 mL). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give crude 3-oxocyclopentanecarboxylic acid (11.07 g, 90%) as a yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ 2.70 (d, J = 18.1 Hz, 1H), 2.44 to 2.39 (m, 1H), 2.30 to 2.15 (m, 2H), 2.14 (dd, J = 18.1, 1.0 Hz, 1H), 2.06 (p, J = 6.9 Hz, 1H), 1.98 (m, 1H), 0.98 (dd, J = 11.4, 6.9 Hz, 6H).

  Step D:

Procedure A:
To a solution of acid (described in Intermediate 3 Step C, 2.00 g, 11.8 mmol) in DCM (50 mL) was added oxalyl chloride (1.54 mL, 17.6 mmol) followed by 2 drops of DMF. The solution was stirred at room temperature for 80 minutes and then evaporated under reduced pressure. The residue was dissolved in DCM (2 mL) and added via syringe to a solution of intermediate 1 (2.36 g, 11.8 mmol) and triethylamine (2.13 mL, 15.3 mmol) in DCM (40 mL). The resulting mixture was stirred at room temperature for 18 hours and then quenched with water (25 mL). The organic layer was separated, washed with 1N HCl, saturated sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product was purified by MPLC using 60% ethyl acetate / hexane as eluent to give Intermediate 3 (3.18 g, 77%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.46 (d, J = 7.3 Hz, 1H), 7.39 (s, 1H), 7.29 (d, J = 7.7 Hz, 1H), 4. 81 (m, 2H), 3.93 (m, 1H), 3.82 (m, 1H), 2.94 (m, 3H), 2.54 (m, 1H), 2.43 (d, J = 8.5 Hz, 1H), 2.32 (m, 2H), 2.26 (p, J = 6.6 Hz, 1H), 2.16 (m, 1H), 0.93 (dd, J = 19) .7Hz, 6.8Hz, 6H). LC ₁₉ calculated for C ₁₉ H ₂₃ F ₃ NO ₂ 353.16, found [M + H ⁺ ] 354.25.

Procedure B:
The acid prepared in Step 3 of Intermediate 3 (1.0 g, 5.9 mmol), Intermediate 1 (1.18 g, 5.88 mmol), DMAP (71 mg, 0.59 mmol), and N in dichloromethane (20 mL) , N-diisopropylethylamine (1.02 mL, 5.88 mmol) was treated with 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDC, 2.25 g, 11.7 mmol). And stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (30 mL), washed with water (2 × 20 mL), brine (1 × 30 mL), dried over anhydrous sodium sulfate and the solvent was evaporated. Pure compound was obtained by MPLC purification (eluent 60% ethyl acetate / hexane) to yield 1.08 g (52%). LC ₁₉ calculated for C ₁₉ H ₂₃ F ₃ NO ₂ 353.16, found [M + H ⁺ ] 354.25.

  Intermediate 4

  To a solution of the acid (described in Intermediate 3 Step C, 540 mg, 3.20 mmol) in DCM (50 mL) was added oxalyl chloride (0.834 mL, 9.60 mmol) followed by 2 drops of DMF. The solution was stirred at room temperature for 80 minutes and then evaporated under reduced pressure. The residue was dissolved in DCM (2 mL) and added to a solution of Intermediate 2 (880 mg, 3.20 mmol) and triethylamine (0.820 mL, 6.50 mmol) in DCM (20 mL) prepared by syringe. The resulting mixture was stirred at room temperature for 18 hours and then quenched with water (25 mL). The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was obtained by MPLC using 0-70% ethyl acetate / hexane as a step gradient eluent to give Intermediate 2 (720 mg, 64%). ESI-MS C18H21F3N2O2 calculated 354.16, measured 355 (M + H).

  Intermediate 5

  Resolution of Intermediate 4 into individual enantiomers was performed by chiral separation using HPLC equipped with a preparative ChiralPak AD column. Separation was achieved by injecting 100 mg / dose and using an eluent consisting of 25% isopropanol and 75% heptane at a flow rate of 9 mL / min.

  Intermediate 6

  Step A:

Procedure A:
A solution of 3-oxocyclopentanecarboxylic acid (Stetter, H., Kuhlmann, H. Liebigs Ann. Chem., 1979, 7, 944-9) (5.72 g, 44.6 mmol) in dichloromethane (30 mL) was added to N, N Treated with '-diisopropyl-O-tert-butylisourea (21.2 mL, 89.3 mmol) and the reaction mixture was stirred overnight at ambient temperature. The precipitated N, N′-diisopropylurea is filtered off, the filtrate is concentrated in vacuo, and the residue is purified by distillation (18 mm Hg bp: 125-129 ° C.) to give pure product 4.74 g (58%) Got. ¹ H NMR (500 MHz, CDCl ₃ ): δ 3.02 (p, J = 7.8 Hz, 1H), 2.05 to 2.50 (m, 6H), 1.45 (s, 9H). ¹³ C NMR (125 MHz, CDCl ₃ ): δ 217.00, 173.47, 80.99, 41.88, 41.14, 27.94, 26.57.

Procedure B:
To a 2 L round bottom flask was added anhydrous magnesium sulfate (113 g, 940 mmol) and dichloromethane (940 mL) was added. With stirring, the suspension was treated with concentrated sulfuric acid (12.5 mL, 235 mmol) and then 15 minutes later with 3-oxo-cyclopentanecarboxylic acid (30.1 g, 235 mmol). After stirring for 15 minutes, tert-butanol (87 g, 1.2 mol) was added. The reaction vessel was closed with a stopper to aid in the storage of isobutylene and stirred at ambient temperature for 72 hours. The solid was filtered off through a pad of celite, the filtrate volume was reduced to approximately 500 mL and washed with a saturated solution of sodium bicarbonate (2 × 150 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent removed by distillation under reduced pressure (180 mmHg). The crude product was purified by distillation to give 39.12 g (90%) of pure product.

  Step B:

A solution of tert-butyl 3-oxocyclopentanecarboxylate (11.54 g, 62.64 mmol) in dichloromethane (200 mL) was added with trimethyl orthoformate (41.4 mL, 251 mmol) in the presence of p-toluenesulfonic acid (400 mg). Treated and stirred at room temperature for 48 hours. The dark reaction mixture was poured into a saturated solution of sodium bicarbonate and the crude product was extracted with dichloromethane. The combined organic extracts are dried over anhydrous magnesium sulfate, the solvent is removed in vacuo, and the crude product is purified by distillation (4 mm Hg bp .: 104 ° C.) to yield 12.32 g (85%) of the desired product. Obtained. ¹ H NMR (500 MHz, CDCl ₃ ): δ 3.21 (s, 3H), 3.20 (s, 3H), 2.80 (m, 1H), 2.10 to 1.80 (bm, 6H), 1.46 (s, 9H). ¹³ C NMR (125 MHz, CDCl ₃ ): δ 174.9, 111.2, 80.3, 67.8, 49.2, 42.5, 37.4, 33.8, 28.3, 22.0.

  Step C:

  To a flame-dried 500 mL round bottom flask was added 100 mL dry THF, then placed under nitrogen and cooled to −78 ° C. using an acetone / dry ice bath. Diisopropylamine (7.9 mL, 56 mmol) was added to the chilled solvent with a syringe, and then 2.5 M n-butyllithium in hexane (22.6 mL, 56.45 mmol) was added slowly. After stirring for 5 minutes, 50 mL of THF containing acetal (described in Intermediate B, Step B, 10.0 g, 43.4 mmol) was added dropwise with a syringe, and the resulting mixture was stirred at −78 ° C. for 2 hours. Acetylaldehyde (7.3 mL, 130 mmol) was then added dropwise with a syringe, and the resulting mixture was stirred at −78 ° C. for 2 hours. The reaction was quenched by pouring the mixture into 10% citric acid solution (300 mL) and then extracted with dichloromethane (2 × 150 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. Since some acetal was hydrolyzed to the ketone during the reaction or workup, the crude mixture was used in the next step without purification.

  Step D:

  The crude intermediate (described in Intermediate C, Step C, assuming 56.45 mmol assuming 100% conversion in Step C) was treated with 10% trifluoroacetic acid in dichloromethane and the resulting mixture was stirred at room temperature overnight. did. The reaction was concentrated in vacuo then diluted with water and extracted with dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give 8.04 g (83%) of crude product. This was used without further purification.

  Step E:

  Acid (described in Step 6 of Intermediate 6, 300 mg, 1.74 mmol), Intermediate 2 (486, 1.74 mmol), HOAt (237 mg, 1.74 mmol), and N, N-diisopropyl in dichloromethane (15 mL) A mixture containing ethylamine (0.606 mL, 3.48 mmol) was treated with 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDC, 667 mg, 3.48 mmol) and at room temperature for 5 days. Stir. The reaction mixture was diluted with dichloromethane (30 mL), washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered and the solvent evaporated in vacuo. The product, Intermediate 6, was obtained by preparative plate purification (eluent 100% ethyl acetate) to give 260 mg (42%).

  Intermediate 7

  Step A

A solution of 2-fluoro-4-trifluoromethylphenylacetonitrile (10 g, 49 mmol) in a mixture of ethanol (100 mL) and ammonium hydroxide (20 mL of 29.3% aqueous solution) was charged with Raney nickel (1 g) for 16 hours. Turned into. The catalyst was removed by filtration through celite and the filtrate was evaporated to dryness. The neat residue was added dropwise to trifluoroacetic anhydride (25 mL, 180 mmol) cooled to 0 ° C. and the resulting mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was poured onto ice (250 g) and the resulting mixture was stirred for 30 minutes, after which time the precipitate was removed by filtration and air dried to give the product as a white solid (13.4 g, 90% ). ¹ H NMR 500 MHz (CDCl ₃ ) δ = 3.02 (2H, t, J = 7.0 Hz), 3.66 (2H, q, J = 6.6 Hz), 6.44 (1H, br s), 7.34 (2H, m), 7.41 (1H, d, J = 7.8 Hz).

  Step B

To a mixture of the product from Step A (13 g, 44 mmol) and paraformaldehyde (2.0 g, 48 mmol), a mixture of concentrated sulfuric acid (90 mL) and glacial acetic acid (60 mL) was added in one portion, and the resulting mixture was Stir at room temperature for 16 hours. The reaction mixture was poured into a mixture of ice and water (1 L) and extracted with ethyl acetate (3 × 150 mL), and the combined ethyl acetate layers were water (3 × 500 mL), saturated NaHCO ₃ (200 mL), and saturated NaCl (100 mL). ), Dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was purified by column chromatography on silica eluting with 10% Et ₂ O in hexane to give the product (8.29 g, 60%). ¹ H NMR 500 MHz (CDCl ₃ ) δ = 3.01 (2H, m), 3.91 and 3.97 (2H, t, J = 6.2 Hz), 4.83 and 4.88 (2H, s) , 7.21-7.28 (3H, m).

  Step C

To a solution of trifluoroacetamide (8.3 g, 26 mmol) prepared in Step B in ethanol (200 mL) is added potassium carbonate (20 g, 150 mmol) in water (50 mL) and the resulting mixture is refluxed for 1 hour. Stir. Ethanol was removed under reduced pressure and water (150 mL) was added to the residue and extracted with CH ₂ Cl ₂ (3 × 100 mL). The combined CH ₂ Cl ₂ layers were washed with saturated NaCl (100 mL), dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give the product (5.2 g, 91%). ¹ H NMR 500 MHz (CDCl ₃ ) δ = 1.74 (1H, br s), 2.78 (2H, d, J = 6.0 Hz), 3.17 (2H, t, J = 6.0 Hz), 4.05 (2H, s), 7.04-7.14 (3H, m).

  Intermediate 8

  Step A

A three-necked round bottom flask equipped with an addition funnel and condenser and containing zinc powder (2.45 g, 37.4 mmol) was dried in a flame. After cooling, the system was purged with nitrogen gas and 6 mL of THF was added followed by 1,2-dibromoethane (0.298 mL, 3.46 mmol). The mixture was heated to reflux vigorously using a heat gun, stirred at reflux for ~ 30 seconds (gas evolution was observed) and then cooled to room temperature. Heating and cooling were repeated two more times. Chlorotrimethylsilane (0.402 mL, 3.17 mmol) was then added and the mixture was stirred at room temperature for 20 minutes. 15 mL of THF containing Nt-butoxycarbonyl-4-iodopiperidine (known: Billotte, S. Synlett (1998), 379., 8.97 g, 28.8 mmol) was added over about 1 minute. The reaction mixture was stirred at 50 ° C. for 1.5 hours and then cooled to room temperature. At the same time, a mixture of tri-2-furylphosphine (267 mg, 1.15 mmol) and tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (298 mg, 0.288 mmol) was dissolved in 6 mL of THF under a nitrogen atmosphere at room temperature. At 15 minutes and added to the organozinc solution. Then, a solution containing 2-bromopyrimidine (5.50 g, 34.6 mmol) in a mixture of 58 mL of THF and 20 mL of N, N-dimethylacetamide was added. The reaction mixture was warmed to 80 ° C. and stirred for 3.5 hours, then cooled to room temperature and stirred for 36 hours. The reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The filtrate was further diluted with ethyl acetate and washed with saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate and the organic layers were combined and washed twice with water and once with brine. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. Purification by flash chromatography (silica, step gradient: 25% ethyl acetate / hexane, 40% ethyl acetate / hexane, 60% ethyl acetate / hexane, 80% ethyl acetate / hexane, 100% ethyl acetate) 4.92 g Of pure 4- (2-pyrimidyl) piperidine product was obtained (65%). ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.70 (d, J = 5.0 Hz, 2H), 7.16 (appt, J = 4.5 Hz, 1H), 4.24 (brs, 2H) 3.05 (m, 1H), 2.89 (br m, 2H), 2.01 (br d, J = 13 Hz, 2H), 1.84 (dq, J = 4.5, 12.5 Hz, 2H), 1.49 (s, 9H).

  Step B

Nt-butoxycarbonylpiperidine (4.64 g, 17.6 mmol) prepared in Step A was dissolved in 4N HCl in dioxane (50 mL) and stirred at room temperature for 2.25 hours. The reaction mixture was concentrated to give 4.16 g of piperidine hydrochloride (100%). This did not require further purification. ¹ H NMR (500 MHz, CD ₃ OD): δ 8.95 (d, J = 5.5 Hz, 2H), 7.60 (t, J = 5.0 Hz, 1H), 3.53 (dt, J = 13) , 3.5 Hz, 2H), 3.35 (tt, J = 4.0, 11.0 Hz, 1H), 3.20 (br t, J = 13.8 Hz, 2H), 2.30 (br d, J = 14.0Hz, 2H), 2.11~2.20 (m, 2H); calculated for _{ESI-MS C 9 H 13 N} 3: 163, measurements: 164 (M + H).

  Intermediate 9

This intermediate was prepared using the procedure described in Intermediate 8 except that 4-bromopyrimidine was used instead of 2-bromopyrimidine. C ₉ H ₁₃ N ₃ of LC-MS calc. 163.28, measured value ^{[M +} H] ⁺ 164.

Intermediate 10
4- (1H-1,2,4-triazol-1-yl) piperidine hydrochloride

Step A
tert-Butyl 4-hydroxypiperidine-1-carboxylate

To a stirred solution of 4-hydroxypiperidine (60.8 g) in dichloromethane (500 mL) was added very slowly a solution of di-ter-butyl dicarbonate (19 g, 0.55 mol) in dichloromethane (500 mL). After addition over 1 hour, the resulting mixture was stirred at ambient temperature for 5 hours. The mixture was then washed with saturated NaHCO ₃ , 3N HCl, brine, dried and evaporated to give tert-butyl 4-hydroxypiperidine-1-carboxylate as a thick oil (90 g).

  Step B: tert-Butyl 4-[(methylsulfonyl) oxy] piperidine-1-carboxylate

To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (21.1 g, 100 mmol) and triethylamine (22 mL) in dichloromethane (250 mL) at 0 ° C. was added methanesulfonyl chloride (9.0 mL, 1.1 mL). Eq) was added slowly. The resulting mixture was stirred for an additional hour, during which time a white solid formed. The mixture was then washed with 3N HCl, dried over Na ₂ SO ₄ and evaporated to give tert-butyl 4-[(methylsulfonyl) oxy] piperidine-1-carboxylate as a white solid (29.2 g). . ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.92 to 4.87 (m, 1H), 3.75 to 3.69 (m, 2H), 3.34 to 3.28 (m, 2H), 3 .05 (s, 3H), 2.01-1.94 (m, 2H), 1.87-1.78 (m, 2H).

Step C: 4- (1H-1,2,4-triazol-1-yl) piperidine hydrochloride tert-butyl 4-[(methylsulfonyl) oxy] piperidine-1-carboxylate (5) stirred at ambient temperature 0.9 g, 21 mmol) and 1,2,4-triazole (1.8 g, 25 mmol equiv) in DMF were added sodium hydride (60% in mineral oil, 1.0 g, 25 mmol). The mixture was stirred at 60 ° C. for 5 days and TLC showed no starting mesylate remained. The mixture was poured into ice water and extracted with ethyl acetate (3x). The organic layer was dried, evaporated and purified on a silica flash column eluting with 0-10% methanol in ethyl acetate to give tert-butyl 4- (1H-1,2,4-triazole-1- Yl) Piperidine-1-carboxylate was obtained as a white solid. The solid was then treated with a solution of hydrogen chloride in dioxane (4N, 10 mL) for 2 hours. The mixture was then evaporated to remove most of the dioxane to give a white solid. This was washed with ethyl acetate to obtain the desired 4- (1H-1,2,4-triazol-1-yl) piperidine hydrochloride (5.55 g). ¹ H NMR (300 MHz, CD ₃ OD): δ 10.00 (s, 1 H), 8.97 (s, 1 H), 5.10 to 5.00 (m, 1 H), 3.63 to 3.58 ( br.d, 2H), 3.33 to 3.26 (br.d, 2H), 2.50 to 2.30 (m, 4H).

  The following intermediates 10-16 were prepared in a similar manner as intermediate 10 using tert-butyl 4-[(methylsulfonyl) oxy] piperidine-1-carboxylate and the appropriate heterocyclic compound.

Intermediate 11
4- (1H-pyrazol-1-yl) piperidine hydrochloride

  Prepared using pyrazole according to the procedure for Intermediate 10.

Intermediate 12
4- (1H-imidazol-1-yl) piperidine hydrochloride

Prepared from imidazole according to the procedure of Intermediate 10. ¹ H NMR (400 MHz, CD ₃ OD): δ 9.18 (s, 1H), 7.86 (s, 1H), 7.65 (s, 1H), 4.9 to 4.8 (CD ₃ OD Hidden in the peak, 1H), 3.61-3.61 (br.d., 2H), 3.33-3.26 (m, 2H), 2.49-2.45 (br.d, 2H), 2.39-2.28 (m, 2H).

Intermediate 13
4- (1H-1,2,3-triazol-1-yl) piperidine hydrochloride

  Prepared from 1,2,3-triazole according to the procedure of Intermediate 10.

4- (1H-1,2,3-triazol-1-yl) piperidine hydrochloride. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.77 (s, 1H), 8.54 (s, 1H), 5.26-5.19 (m, 1H), 3.65-3.59 ( m, 2H), 3.37 to 3.29 (m, 2H), 2.60 to 2.54 (m, 2H), 2.50 to 2.39 (m, 2H).

Intermediate 14
4- (2H-1,2,3-triazol-2-yl) piperidine hydrochloride:

  Prepared from 1,2,3-triazole according to the procedure of Intermediate 10.

4- (2H-1,2,3-triazol-2-yl) piperidine hydrochloride. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.72 (s, 2H), 4.94 to 4.87 (m, 1H), 3.54 to 3.48 (m, 2H), 3.28 to 3.22 (m, 2H), 2.46-2.32 (m, 4H).

Intermediate 15
4- (1H-tetrazol-1-yl) piperidine hydrochloride

  Prepared from tetrazole according to the procedure for Intermediate 10.

4- (1H-tetrazol-1-yl) piperidine hydrochloride. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.77 (s, 1H), 5.30-5.23 (m, 1H), 3.58-3.53 (m, 2H), 3.35 3.29 (m, 2H), 2.58 to 2.2.52 (m, 2H), 2.48 to 2.38 (m, 2H).

Intermediate 16
4- (2H-tetrazol-2-yl) piperidine hydrochloride

  Prepared from tetrazole according to the procedure for Intermediate 10.

4- (2H-tetrazol-2-yl) piperidine hydrochloride. ¹ H NMR (400 MHz, CD ₃ OD): δ 9.32 (s, 1H), 5.08 to 5.00 (m, 1H), 3.61 to 3.57 (m, 2H), 3.33 to 3.28 (m, 2H), 2.52 to 2.47 (m, 2H), 2.42 to 2.32 (m, 2H).

  Intermediate 17

  Prepared from 5-methyltetrazole according to the procedure for Intermediate 10.

¹ H NMR (400 MHz, CD ₃ OD): δ 5.08 to 5.00 (m, 1H), 3.61 to 3.57 (m, 2H), 3.33 to 3.28 (m, 2H), 2.52 to 2.47 (m, 2H), 2.42 to 2.32 (m, 2H), 1.68 (s, 3H).

  Intermediate 18

  Step A

Hydroxylamine hydrochloride (8.26 g, 119 mmol) and triethylamine (16.6 mL, 119 mmol) were mixed in DMSO 50 mL. The suspension was filtered to remove triethylamine hydrochloride and the filter cake was washed with THF. The filtrate was concentrated to some extent to remove THF. Commercially available 1-tert-butoxycarbonyl-4-cyanopiperidine (5.0 g, 24 mmol) was then added to the DMSO solution and the resulting reaction mixture was stirred at 75 ° C. for 3 hours and then at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was further back extracted with ethyl acetate and the combined organic layers were washed 4 times with water and once with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated to give 3.51 g of product.

  Step B

When a solution containing the intermediate obtained from Step A (1.02 g, 4.19 mmol) in 20 mL of THF was treated with thiocarbonyldiimidazole (897 mg, 5.03 mmol), gas evolution and exotherm were observed. . The reaction mixture was stirred at room temperature for 1 hour and then transferred to a suspension containing silica gel # 60 (20 g) in 180 mL of 5: 1 CHCl ₃ / methanol. The reaction mixture was stirred at room temperature for 5 days, then filtered and concentrated. Purification by MPLC (silica, 50% ethyl acetate / hexane) gave 143 mg of thiodiazolone.

Boc intermediate, ¹ H NMR (500 MHz, CD ₃ OD): δ 4.16 (m, 2H), 2.86 (t, J = 11.5 Hz, 2H), 2.77 (tt, J = 4.0) , 11.0 Hz, 1H), 1.98 (dd, J = 2.0, 13.0 Hz, 2H), 1.73 (dq, J = 4.5, 12.0 Hz, 2H), 1.47 ( s, 9H).

  The Boc intermediate (139 mg, 0.487 mmol) was dissolved in 4N HCl in dioxane (5 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to give 94.3 mg of piperidine hydrochloride product.

Intermediate 19
4- (1H-pyrazol-3-yl) piperidine

Step A: 4- (1H-pyrazol-3-yl) pyridine To a mixture of 4-acetylpyridine (75 mL, 0.68 mol) and ethyl formate (109 mL) in anhydrous benzene (1 L), sodium methoxide (73 g) And the resulting mixture was refluxed for 18 hours. The mixture was cooled and benzene was decanted from the viscous solid formed during the reaction. The crude product was dissolved in water (700 mL), hydrazine dihydrochloride was added, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was redissolved by adding 5N NaOH. A precipitate formed which was removed by filtration and dried to give 4- (1H-pyrazol-3-yl) pyridine (35 g).

Step B: 1-Benzyl-4- (1H-pyrazol-3-yl) -1,2,3,6-tetrahydropyridine Hot (80 ° C.) 4- (1H-pyrazol-3-yl) pyridine (9.6 g) ) In 2-propanol (60 mL) was added benzyl bromide (20 mL, 2.5 eq) and the resulting mixture was heated at reflux for 10 min. After cooling in an ice bath, the precipitate was filtered, further washed with 2-propanol, and air dried. This solid was suspended in ethanol at 0 ° C., sodium borohydride (13 g) was added in several portions over 30 minutes, and the mixture was stirred for an additional 30 minutes. The reaction was carefully quenched by adding water, the ethanol was removed by evaporation, and the residue was partitioned between dichloromethane and water. The organic layer was dried over MgSO ₄ , filtered and evaporated to give 1-benzyl-4- (1H-pyrazol-3-yl) -1,2,3,6-tetrahydropyridine (16 g).

Step C: 4- (1H-pyrazol-3-yl) piperidine A solution of 1-benzyl-4- (1H-pyrazol-3-yl) -1,2,3,6-tetrahydropyridine (16 g) on palladium on carbon Hydrogenated at 40 psi overnight (10%, 1 g). The catalyst was removed by filtration through celite and the filtrate was evaporated. NMR indicates that the product is 1-benzyl-4- (1H-pyrazol-3-yl) piperidine (16 g).

To a solution of 1-benzyl-4- (1H-pyrazol-3-yl) piperidine (16 g) and formic acid (30 mL) in ethanol (400 mL) was added palladium on carbon (10%, 2 g) and the resulting mixture was stirred at room temperature. Stir overnight. The catalyst was removed by filtration and the filtrate was evaporated. The product was purified by the addition of di-tert-butyl dicarbonate (2 eq) and triethylamine (1.5 eq) in dichloromethane to give the Boc protected intermediate. Pure tert-butyl 4- (1H-pyrazol-3-yl) piperidine-1-carboxylate was purified by evaporation and purification by silica column chromatography eluting with 20-40% ethyl acetate in hexane. Obtained. This Boc intermediate was then treated with methanolic HCl to give 4- (1H-pyrazol-3-yl) piperidine hydrochloride (3.5 g). Di-Boc product was formed and material was lost and not recovered. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.00 (s, 2H), 3.48 (br.d, J = 13 Hz, 2H), 3.28-3.20 (m, 1H), 3.13 (Br.t, J = 13 Hz, 2H), 2.23 (br.d, J = 14 Hz, 2H), 1.97 to 1.85 (m, 2H).

  Intermediate 20

  Step A:

To a mixture of 4-bromophenethylamine hydrobromide (25 g, 89 mmol) and pyridine (36 mL, 445 mmol) in CH ₂ Cl ₂ (100 mL) cooled to 0 ° C. is added trifluoroacetic anhydride (18.8 mL, 133 mmol). Added dropwise. After the addition was complete, the mixture was stirred at room temperature for 48 hours and then poured onto ice (500 g). The mixture was extracted with CH ₂ Cl ₂ (4 × 100 mL) and the combined CH ₂ Cl ₂ layers were washed with 1N HCl (4 × 100 mL), saturated NaCl (100 mL), dried over MgSO ₄ , filtered, Evaporation in vacuo gave the product (26.13 g, 100%). ¹ H NMR 500 MHz (CDCl ₃ ) □ = 2.86 (2H, t, J = 7.1 Hz), 3.59 (2H, q, J = 6.6 Hz), 6.57 (1H, br s), 7.09 (2H, d, J = 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz).

  Step B:

To a mixture of the product from Step A (26 g, 88 mmol) and paraformaldehyde (5.6 g, 130 mmol), a mixture of concentrated sulfuric acid (130 mL) and glacial acetic acid (195 mL) was added in one portion and the resulting mixture was added. Stir at room temperature for 17 hours. The reaction mixture was poured into ice / water (1.5 L) and extracted with ethyl acetate (3 × 300 mL) and the combined ethyl acetate layers were washed with water (2 × 600 mL), saturated NaHCO ₃ (300 mL), and saturated NaCl ( 150 mL), dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was dissolved in ethanol (450 mL) and a solution of potassium carbonate (60 g, 434 mmol) in water (150 ml) was added. The mixture was heated to reflux for 1 hour, then cooled and evaporated in vacuo. Water (500 mL) is added to the residue and extracted with CH ₂ Cl ₂ (3 × 300 mL) and the combined CH ₂ Cl ₂ layers are washed with water (500 mL), saturated NaCl (150 mL) and dried over Na ₂ SO ₄ . Filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 5% CH ₃ OH in CH ₂ Cl ₂ containing 0.5% NH ₄ OH to give the product (10 g, 54%). ¹ H NMR 500 MHz (CDCl ₃ ) δ = 1.77 (1H, br s), 2.77 (2H, d, J = 6.0 Hz), 3.11 (2H, t, J = 6.0 Hz), 3.97 (2H, s), 6.95 (1H, d, J = 8.0 Hz), 7.15 (1H, s) 7.23 (1H, dd, J = 1.2 and 8.2 Hz) .

  Intermediate 21

  Step A

To a solution of 3-cyclopentane-1-carboxylic acid (Org. Synth. 75, pp. 95-200, 1998) (31.5 g, 281 mmol) in anhydrous N, N-dimethylformamide (300 mL) was added potassium carbonate under a nitrogen atmosphere. (97 g, 710 mmol) and iodomethane (35 mL, 560 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours, then poured into water (1 L) and extracted with diethyl ether (3 × 400 mL). The combined diethyl ether layers were washed with water (3 × 500 mL), saturated NaCl (200 mL), dried over MgSO ₄ , filtered and concentrated in vacuo to give 34 g (96%).

¹ H NMR (CDCl ₃ , 500 MHz): δ 5.64 (s, 2H), 3.68 (s, 3H), 3.11 (quintage, J = 8.5 Hz, 1H), 2.63 (d , J = 8.3 Hz, 4H).

  Step B

To a cooled (−78 ° C.) diisopropylamine (34.4 mL, 250 mmol) in anhydrous tetrahydrofuran (250 mL) was slowly added n-butyllithium (2.5 M hexane solution 100 mL, 250 mmol) under a nitrogen atmosphere. The mixture was stirred at −78 ° C. for 10 minutes. To this mixture was added methyl-3-cyclopentenecarboxylate (25.8 g, 200 mmol) and after stirring for another 15 minutes, 2-iodopropane (41 mL, 410 mmol) was added and the mixture was stirred at −78 ° C. for 30 minutes. Then it was raised to + 4 ° C. and maintained at this temperature for 72 hours and left to stand. The reaction mixture was poured into 5% citric acid (700 mL) and extracted with diethyl ether (3 × 300 mL). The combined diethyl ether layers were washed with water (2 × 500 mL), saturated NaCl (1 × 100 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by vacuum distillation (50 ° C. at 5 mm Hg) to give 28.9 g (86%) of product.

¹ H NMR (CDCl ₃ , 500 MHz): δ 5.54 (s, 2H), 3.67 (s, 3H), 2.85 (d, J = 15.1 Hz, 2H), 2.30 (dd, J = 14.9 Hz, 2H), 2.07 (t, J = 6.6 Hz, 1H), 0.82 (d, J = 6.6 Hz, 6H).

  Step C

To the cooled (0 ° C.) borane-methyl sulfide (20 mL, 200 mmol) in anhydrous tetrahydrofuran (100 mL) was added the cyclopentene ester (28.9 g, 172 mmol) solution prepared in Step B using a double-ended needle under a nitrogen atmosphere. It was. After the addition was complete, the reaction mixture was stirred at room temperature for 20 hours. The mixture was cooled in an ice bath and sodium hydroxide (3N solution 60 mL, 181 mmol) was added dropwise followed by 30% hydrogen peroxide (65 mL) and the resulting mixture was stirred at 40 ° C. for 1 hour. The mixture is poured into water (600 mL) and extracted with diethyl ether (3 × 200 mL) and the combined diethyl ether layers are washed with water (3 × 500 mL), saturated NaCl (100 mL), dried over MgSO ₄ and filtered. And concentrated in vacuo. The residue was purified by silica column chromatography eluting with 20% EtOAc / hexanes to give 18.5 g (58%) of product.

  Step D

Dimethyl sulfoxide (15.5 mL, 219 mmol) was added dropwise to a solution of oxalyl chloride (55 mL, 110 mmol) in anhydrous dichloromethane (300 mL) (−78 ° C.) under a nitrogen atmosphere, and the resulting mixture was added at −78 ° C. Stir for 10 minutes. To this mixture was added a solution of the product from Step C (18.5 g, 100 mmol) in anhydrous dichloromethane (100 mL) using a double-ended needle. The reaction mixture was stirred at −78 ° C. for an additional 15 minutes, then triethylamine (69 mL, 500 mmol) was added and the resulting mixture was allowed to rise to room temperature over 2 hours. The reaction mixture was washed with water (500 mL), saturated NaCl (150 mL), dried over MgSO ₄ , filtered and concentrated in vacuo to give 18 g of product. This was used in the next step without further purification.

  Step E

To a solution of cyclopentanone (18 g, 98 mmol) prepared in step D in anhydrous 1,2-dichloroethane (500 mL) under a nitrogen atmosphere, 4- (4-fluorophenyl) piperidine hydrochloride (25 g, 120 mmol), diisopropylethylamine (20.4 mL, 116 mmol), sodium triacetoxyborohydride (112 g, 531 mmol), and 4Å molecular sieve (10 g powder) were added. The mixture was stirred at room temperature for 48 hours, then diluted with dichloromethane (500 mL) and filtered through celite. The filtrate was washed with saturated NaHCO ₃ solution (500 mL), water (500 mL), saturated NaCl (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 28 g (82%) of product. It was. This material was used in the next step without further purification.

Step F
1-isopropyl-3- (4- (4-fluorophenyl) piperidin-1-yl) cyclopentanecarboxylic acid

To a solution of cyclopentane methyl ester (28 g, 81 mmol) prepared in Step E in ethanol (500 mL) is added potassium hydroxide (30 g, 540 mmol) in water (100 mL) and the resulting mixture is heated at reflux for 18 hours. did. The cooled mixture was concentrated in vacuo to remove the ethanol and water (200 mL) was added to the residue. This mixture was extracted with diethyl ether (3 × 200 mL), and the aqueous layer was neutralized by adding concentrated hydrochloric acid. The mixture was extracted with a 9/1 chloroform / 2-propanol (3 × 150 mL) mixture and the combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Acetone (70 mL) was added to the residue and the mixture was heated to reflux briefly and then left at + 5 ° C. for 16 hours. Acetone was decanted from the white solid and the remaining solid was dried to give 11.5 g (43%) of product. This was a 10: 1 mixture of cis and trans isomers.

  ESI-MS C20H28FNO2 calculated: 333, measured: 334 (M + H).

  Intermediate 22

2,5-Dimethyl-3-pyrroline (3.128 g, 32.19 mmol) was dissolved in triethylamine (8.97 mL, 64.4 mmol) and cooled to 0 ° C. A small amount of dichloromethane containing carbobenzyloxychloride (10.11 mL, 70.83 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 48 hours. The reaction was quenched with saturated sodium bicarbonate solution (150 mL), then the organic layer was washed with saturated sodium bicarbonate solution (2 × 100 mL), and brine (1 × 100 mL), dried over MgSO ₄ , filtered And concentrated. The residue was purified by silica gel flash column chromatography using a gradient solvent system from 5% EtOAc in hexane to 10% EtOAc in hexane to give Intermediate 1 (3.844 g) in 52% yield. . _{ESI-MS C l4 H l7 NO} 2 Calculated: 231.29, measured value: 232 (M + H).

  Intermediate 23

Procedure A:
Step A

(1S)-(+)-2-Azabicyclo [2.2.1] hept-5-en-3-one (10.3 g, 94.4 mmol) in ethyl acetate (200 mL) and 10% Pd / C (0.5 g) of the mixture was hydrogenated at room temperature. After 24 hours, the reaction mixture was filtered and evaporated, leaving 10.4 g (100%) of product. This was taken up in 250 mL methanol and HCl (12 M, 6 mL). The resulting mixture was stirred at room temperature until the reaction was complete (72 hours). The methanol was evaporated and then dried under high vacuum to give the title compound as an off-white solid (16.0 g, 96%). ¹ H NMR (500 MHz, D ₂ O): δ 3.70 (s, 3H), 3.01 (m, 1H), 2.38 (m, 1H), 2.16 to 1.73 (m, 6H) .

  Step B

  To a suspension of the intermediate obtained from Step A (10.2 g, 56.8 mmol) in dry dichloromethane (200 mL) was added benzophenone imine (10.2 g, 56.8 mmol) at room temperature and the resulting mixture was Stir for hours. The reaction mixture was filtered and the filtrate evaporated to leave a yellow oil. This was triturated with ether (100 mL), filtered and evaporated. This operation was repeated twice to ensure that the product was free of ammonium chloride impurities. The resulting oil was completely dried in vacuo to give the title compound (18.03 g,> 100%) and did not require further purification. 1H NMR (500 MHz, CDCl3): δ 7.5-7.18 (m, 10H), 3.75 (m, 1H), 3.7 (s, 3H), 2.78 (m, 1H), 2. 26-1.71 (m, 6H).

  Step C

  To a solution of lithium diisopropylamide (prepared from diisopropylamine (7.7 g, 76 mmol) and n-butyllithium (30.4 mL, 2.5 M) in hexane, 76 mmol) in tetrahydrofuran (120 mL) at −78 ° C. The ester obtained from (18.0 g, 58.6 mmol) was added. The resulting red-purple colored solution was stirred for 20 minutes, after which it was quenched with 2-iodopropane (14.9 g, 88.0 mmol). The reaction mixture was gradually warmed to 0 ° C. over 3 hours and maintained at this temperature for an additional 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (anhydrous magnesium sulfate) and concentrated to give an oil. To a solution of the crude Schiff base (20.0 g) in tetrahydrofuran (100 mL) was added HCl (5.0 mL, 12M). The resulting reaction mixture was allowed to stir at room temperature for 3 hours. After removing all volatiles, the hydrochloride salt was taken up in dichloromethane (250 mL) and a saturated solution of sodium bicarbonate (250 mL) and di-tert-butyl dicarbonate (26.0 g, 1.4 eq) were added. . The resulting mixture was stirred vigorously at room temperature overnight. The organic layer was separated, washed with water, brine, dried (anhydrous magnesium sulfate) and concentrated to an oil. Purification by flash column chromatography (eluent: hexane / ethyl acetate 19: 1) gave the desired product (4.91 g, 30%). 1H NMR (500 MHz, CDCl3): 4.79 (br, 1H), 4.01 (m, 1H), 3.71 (s, 3H), 2.18 to 1.60 (m, 6H), 1. 44 (s, 9H), 0.87 (d, J = 6.9 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H).

  Step D

  To a solution of the ester obtained from Step C (4.91 g, 17.2 mmol) in methanol (100 mL) was added a solution of LiOH (3.6 g, 85 mmol) in water (20 mL) and tetrahydrofuran (10 mL). The resulting mixture was heated at 80 ° C. until the reaction was complete (18 hours). The methanol was removed in vacuo and the crude product was treated with water / ethyl acetate (200 mL, 1: 4) and cooled to 0 ° C. The acidity of this mixture was adjusted to pH 6. The ethyl acetate layer was separated and washed with water, brine, dried (anhydrous magnesium sulfate) and concentrated to an oil. Purification by flash column chromatography (eluent: hexane / ethyl acetate 1: 1 + 2% AcOH) gave intermediate 11 (3.9 g, 84%). 1H NMR (500 MHz, CDCl3): 11.36 (br, 1H), 6.49 (br, 1H), 4.83 (m, 1H), 3.71 (s, 3H), 2.30-1. 55 (m, 6H), 1.46 (s, 9H), 0.94 (d, J = 6.9 Hz, 3H), 0.933 (d, J = 6.9 Hz, 3H).

Procedure B:
Step A:

  Commercially available (lR, 4S) -4-aminocyclopent-2-ene-1-carboxylic acid was converted to its methyl ester hydrochloride salt by classical procedures.

  Step B:

To a suspension of acetone (40 mL) and water (20 mL) containing the amine from Step A (6.31 g, 35.5 mmol), solid NaHCO ₃ (6.6 g, 78 mmol) was added in one portion. After 5 minutes, a solution of di-tert-butyl dicarbonate (8.5 g, 39 mmol) in acetone (60 mL) was added and the reaction mixture was stirred at room temperature. After 3 hours, the acetone was removed in vacuo and the residue was partitioned between ether (500 mL) and saturated aqueous NaHCO ₃ (120 mL). The ether layer was further washed with aqueous NaHCO ₃ (1 × 100 mL), brine (1 × 100 mL), dried over anhydrous Na ₂ SO ₄ , concentrated and purified by flash chromatography (15% ethyl acetate / hexane). The product (7.25 g, 85%) was obtained.

  Step C:

To a solution of lithium bis (trimethylsilyl) amide (10.4 g, 62.1 mmol) in tetrahydrofuran (100 mL) was added a solution of the intermediate (6.71 g, 27.8 mmol) obtained in Step B in tetrahydrofuran (10 mL) at −78 ° C. Over 10 minutes. The resulting solution was stirred at −78 ° C. for 30 minutes, after which isopropyl iodide (3.3 mL, 33 mmol) was added in one portion. The reaction was warmed to −25 ° C. and this temperature was maintained overnight. The reaction was then quenched with saturated aqueous NH ₄ Cl (250 mL). The organic layer was separated and the aqueous layer was further extracted with diethyl ether (3 × 100 mL). The combined organic layers were then washed with brine (1 × 100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography (5-10% ethyl acetate / hexane), The product (5.66 g, 72%) was obtained as a clear oil (cis / trans = 4.3 / 1). ¹ H NMR (500 MHz, CDCl ₃ ) cis isomer: δ 5.79 (s, 2H), 4.75 (m, 1H), 3.72 (s, 3H), 2.28-2.20 (m, 2H), 2.0 (dd, J = 15, 4 Hz, 1H), 1.45 (s, 9H), 0.85 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 7Hz, 3H).

  Step D:

To a solution of the product from Step C (1.6 g, 5.7 mmol) in tetrahydrofuran (50 mL), methanol (50 mL) and water (10 mL) was added LiOH monohydrate (400 mg) and TLC was added. The reaction was heated to reflux overnight until indicates that the reaction was complete. The organic solvent was removed in vacuo and the aqueous layer was washed with ether (1 ×) and then slowly acidified with concentrated HCl until the pH was 4. The resulting suspension was extracted with CH ₂ Cl ₂ (3 ×). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated to give the product as a yellow foamy solid as a mixture of two cis / trans isomers (1.5 g). This solid was dissolved in ethyl acetate (2 mL) with heating and diluted with hexane (50 mL) to give a clear solution. The solution was slowly cooled to room temperature over 1 hour and then stored in a −25 ° C. freezer overnight. The trans isomer crystallized with some desired cis isomer (total 500 mg). The mother liquor was collected and concentrated to give the title compound (1 g, 66%, cis isomer only). ¹ H NMR (500 MHz, CDCl ₃ ) cis isomer: δ 5.80 (m, 2H), 4.80 (m, 1H), 2.40-2.20 (m, 2H), 2.15-2. 0 (m, 1H), 1.5 (m, 9H), 1.0 to 0.8 (m, 3H).

  Step E:

Step The product from D in ethanol (30 mL) solution of (1 g), a 10% Pd / C (100mg) was added and the resulting mixture was stirred vigorously overnight Parr Aparatus with _{H 2} pressure 50 lb. The mixture was filtered through celite and concentrated in vacuo to give the title compound (1 g, 99%). 1H NMR (500 MHz, CDCl3): 11.36 (br, 1H), 6.49 (br, 1H), 4.83 (m, 1H), 3.71 (s, 3H), 2.30-1. 55 (m, 6H), 1.46 (s, 9H), 0.94 (d, J = 6.9 Hz, 3H), 0.933 (d, J = 6.9 Hz, 3H).

  Intermediate 24

  Step A

Intermediate 2 (4.6 g, 16 mmol) and intermediate 23 (4.0 g, 14 mmol) were dried by azeotropic distillation with toluene (3 × 50 mL) and placed under high vacuum for 30 minutes. Under nitrogen, 4-dimethylaminopyridine (1.08 g, 8.60 mmol), anhydrous dichloromethane (40 mL), and diisopropylethylamine (7.0 mL, 40 mmol) were added in succession. After dissolving the intermediate, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (6.80 g, 14.3 mmol) was added, followed immediately by additional diisopropylethylamine (7.0 mL, 40 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with saturated NaHCO ₃ . The aqueous layer was backwashed with dichloromethane (3 × 50 mL) and the organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The crude product was purified by flash chromatography (step gradient 0-60%, ethyl acetate / hexane) to give the product (4.80 g, 74%) as a yellow foam. ¹ H NMR (500 MHz, CDCL3) δ 8.72 (s, 1H), 7.70 (s, 1H), 4.88 (br d, J = 17.0 Hz, 1H), 4.78 (d, J = 17.6 Hz, 1 H), 4.04 to 3.84 (m, 2 H), 3.52 (br s, 1 H), 3.12 (br t, J = 5.6 Hz, 1 H), 2.32 to 2.06 (m, 3H), 1.98 to 1.70 (m, 4H), 1.64 to 1.54 (m, 1H), 1.44 (s, 9H), 0.92 to 0. 82 (m, 6H). _{C 23 H 32 F 3 N 3} 0 3 of LC-MS calc. 455.24, measured value ^[M + H] + 456.2.

  Step B

The product from Step A (1.2 g, 2.6 mmol) was dissolved in 4M HCl in dioxane (50 mL) and the resulting solution was stirred at room temperature for 1 hour. The reaction mixture was evaporated under vacuum to give the product (904 mg, 97%) as a white powder. Calculated _{LC-MS C 18 H 24 F} 3 N 3 O is 355.20, the measurement value is ^[M + H] + 356.2.

  Intermediate 25

  Step A

Intermediate 23 (1.1 g, 4.0 mmol), Intermediate 1 (0.944 g, 4.00 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.85 g, 4.00 mmol), DMAP (0 .29 g, 2.4 mmol), DIEA (2.77 mL, 16 mmol) and DCM (20 mL) were added to the flask. The resulting mixture was stirred for 36 hours under nitrogen. The entire mixture was applied to a silica gel column and eluted with 20% EtOAc / hexane. The desired Boc-amide was obtained as a sticky solid (1.5 g, 82%). Calculated _{ESI-MS C 24 H 33 F} 3 N 2 O 3: 454, measurements: 455 (M + H).

  Step B

The Boc aminoamide obtained from Step A was treated with 10 mL of 4N HCl / dioxane for 1 hour. The reaction mixture was evaporated and the product was dried under vacuum. Intermediate 25 was obtained as a yellow solid (1.2 g). _{ESI-MS C 19 H 25 F} 3 N 2 O Calculated: 354, measured value 355 (M + H).

  Intermediate 26

  Step A

To a flask containing Intermediate 1 (10 g, 50 mmol) was added 30 mL of 70% nitric acid. The mixture was cooled to 0 ° C. and 30 mL of concentrated sulfuric acid was added over 30 minutes. The resulting solution was stirred at room temperature overnight, poured into an ice-water mixture and adjusted to pH> 10 at 0 ° C. with solid LiOH—H ₂ O. A solution of di-tert-butyl carbonate (21.8 g, 100 mmol) in 500 mL DCM was added with vigorous stirring. The mixture was stirred for 30 minutes, the organic layer was separated and the aqueous layer was extracted with DCM (2 × 200 mL). The combined extracts were washed with water (500 mL), dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography (silica gel, 20% ethyl acetate / hexanes) to give the title compound as a white solid (17.0 g, 98%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.62 (s, 1H), 4.72 (s, 2H), 3.67 (t, J = 6.0 Hz, 2H), 3 .13 (t, J = 6.0 Hz, 2H), 1.49 (s, 9H).

  Step B

  The above intermediate obtained from Step A (17.0 g) was dissolved in 100 mL of 4M HCl / dioxane, stirred for 1 hour, evaporated and dried under vacuum. Intermediate 26 was obtained as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.75 (s, 1H), 8.00 (s, 1H), 2.58 (s, 2H), 3.57 (t, J = 6.0 Hz, 2H), 3 .42 (t, J = 6.0 Hz, 2H).

  Intermediate 27

  Step A

Intermediate 27 (1.10 g, 4.00 mmol), Intermediate 23 (1.15 g, 4.00 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.85 g, 4.00 mmol), DMAP (0 .29 g, 2.4 mmol), DIEA (2.7 mL, 16 mmol) and DCM (20 mL) were added to the flask. The resulting mixture was stirred for 36 hours under nitrogen. The entire mixture was applied to a silica gel column and eluted with 20% EtOAc / hexanes to give the title compound as a sticky solid (1.5 g, 75%). Calculated _{ESI-MS C 24 H 32 F} 3 N 3 O 5: 499, measurements: 500 (M + H).

  Step B

The coupling product (1.5 g) obtained from the previous step was treated with 10 mL of 4N HCl / dioxane for 1 hour, evaporated and dried under vacuum to give the title compound as a yellow solid (1.2 g). 1H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 7.95 (wide, 1H), 4.98 (s, 2H), 4.00 (dd, 2H), 3.90 (t, 2H) ), 3.68 (m, 1H), 3.45 (m, 3H), 3.20 (s, 2H), 2.15 to 2.50 (m, 3H), 1.80 to 2.10 ( m, 2H), 1.80 (m, 2H), 0.90 (m, 6H). Calculated _{ESI-MS C 19 H 24 F} 3 N 3 O 3: 399, measurements: 400 (M + H).

  Intermediate 28

  Step A

N-trifluoroacetyl-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline (6.0 g, 20 mmol), NIS (6.9 g, 30 mmol) and TFA obtained from Intermediate 1 of Step B Concentrated sulfuric acid (1.5 mL) was added dropwise to the stirring mixture (15 mL). A large amount of solid was formed. The mixture was stirred at room temperature overnight, poured into an ice-water mixture and extracted with ethyl acetate (3x). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and evaporated. The residue was purified on silica gel (eluting with 10% EtOAc / hexanes). The combined fractions were washed with saturated NaHSO ₃ , dried over Na ₂ SO ₄ , evaporated and dried under vacuum to give the title compound as a white solid (5.0 g). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 2.5 Hz, 1H), 7.42 (d, j = 3.0 Hz, 1H), 4.85, 4.79 (ss, 2H), 3.95, 3.90 (tt, J = 1.5, 1.5 Hz, 2H), 2.97 (m, 2H). _{ESI-MS C 12 H 8 F} 6 INO Calculated: 423, measurements: 424 (M + H).

  Step B

A mixture containing an iodo compound (Step A, 4.2 g, 10 mmol), zinc cyanide (2.3 g, 20 mmol) and tetrakis-triphenylphosphene palladium (0) complex (0.4 g) in 50 mL of DMF was mixed with nitrogen. Purge several times and then heated at 85 ° C. under nitrogen. LC-MS showed complete conversion. Insoluble material was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (3x). The ethyl acetate layers were combined and filtered through celite, then washed with water, dried over Na ₂ SO ₄ and evaporated. The residue was purified on silica gel (eluting with 10% EtOAc / Hex) to give the title compound as a white solid (2.5 g). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 2.6 Hz, 1H), 4.91, 4.86 (ss, 2H), 4.00 (m, 2H), 3.25 (m, 2H). _{ESI-MS C 13 H 8 F} 6 N 2 O Calculated: 323, measurements: 323 (M + H).

  Step C

Mixture of the amide intermediate obtained from Step B (500 mg, 1.55 mmol), potassium carbonate (1.5 g), ethanol (20 mL) and water (0.5 mL) until TLC indicates complete cleavage. Heated at 80 ° C. The solvent was evaporated, diluted with water, and extracted with DCM (3 ×), dried over _Na 2 SO _4, evaporated, and dried under vacuum. The title product was obtained as a white solid (0.41 g). _{ESI-MS C 11 H 9 F} 3 N 2 Calculated: 226, measurements: 227 (M + H).

  Step D

The above cyano intermediate obtained from Step C (1.9 g, 8.5 mmol) was refluxed with 50 mL of concentrated aqueous HCl for 48 hours. LC-MS showed complete hydrolysis. The mixture was cooled to room temperature and the resulting precipitate was collected by filtration and washed with concentrated aqueous HCl. After drying under high vacuum, the desired product was obtained as its HCl salt (1.75 g, 73%). ¹ H NMR (CD ₃ OD, 400 MHz): δ 8.20 (s, 1H), 7.80 (s, 1H), 4.51 (s, 2H), 3.55 (m, 4H). Calculated _{LC-MS C 11 H 10 F} 3 NO 2: 245, ^{measurements: [M + H] + 246} .

  Step E

A neat solution of acetyl chloride (5 mL) was slowly added to a suspension of the above amino acid HCl salt obtained from Step D (1.75 g, 6.25 mmol) in 50 mL of methanol. The resulting mixture was refluxed until LC-MS showed complete esterification (˜3 hours), then
The solvent was evaporated and dried under high vacuum to give the title compound as a white solid (1.85 g, 100%). ¹ H NMR (CD ₃ OD, 400 MHz): 8.19 (s, 1H), 7.82 (s, 1H), 4.50 (s, 2H), 3.94 (s, 3H), 3.53 (S, 4H). Calculated _{LC-MS C 12 H 12 F} 3 NO 2: 259, ^{measurements: [M + H] + 260} .

  Intermediate 29

Procedure A:
Step A:

H ₂ SO ₄ (concentrated, 15.3 g, 8.30 mL, 156 mmol) was added dropwise to a vigorously stirred suspension of MgSO ₄ (75 g, 620 mmol) in DCM (650 mL). The mixture was stirred for 0.5 h, then known cyclopentanone-3-carboxylate (20.0 g, 156 mmol) was added followed by t-butanol (58 g, 780 mmol). The reaction vessel was tightly sealed and the mixture was stirred overnight at room temperature. The next morning, another 30 mL of t-butanol was added. Again the reaction vessel was tightly sealed and the reaction mixture was stirred over the weekend. The reaction mixture was then filtered through celite. The filtrate was washed with 2N NaOH. The aqueous layer was back washed with DCM. The organic layers were combined, washed with water then brine, dried over anhydrous MgSO ₄ , filtered and concentrated to give 19.9 g (69%) of tert-butyl 3-oxocyclopentanecarboxylate. The progress of the reaction was monitored by anisaldehyde-stained TLC using 50% ethyl acetate / hexane (starting material and product dyed purple). ¹ H NMR (500 MHz, CDCl ₃ ): 3.02 (p, J = 7.8 Hz, 1H), 2.05 to 2.50 (m, 6H), 1.45 (s, 9H). ¹³ C NMR (125 MHz, CDCl ₃ ): 217.00, 173.47, 80.99, 41.88, 41.14, 27.94, 26.57.

  Step B:

To a 1: 1 DCM / methanol (150 mL) solution of tert-butyl 3-oxocyclopentanecarboxylate (19.8 g, 107 mmol), trimethyl orthoformate (46.8 mL, 428 mmol), then TsOH.H ₂ O (˜0. 5 g) was added. The reaction mixture was stirred at room temperature for 2 hours. Then more TsOH.H ₂ O (˜0.25 g) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated at room temperature and the resulting residue was dissolved in ether and washed with saturated NaHCO ₃ solution then brine. The ether layer was dried over anhydrous MgSO ₄ , filtered and concentrated. Purification by flash chromatography (silica, 15% ethyl acetate / hexane) gave 22.2 g (90%) of tert-butyl 3,3-dimethoxycyclopentanecarboxylate. ¹ H NMR (500 MHz, CDCl ₃ ): 3.21 (s, 3H), 3.20 (s, 3H), 2.80 (m, 1H), 2.10 to 1.80 (bm, 6H), 1.46 (s, 9H). ¹³ C NMR (125 MHz, CDCl ₃ ): 174.9, 111.2, 80.3, 67.8, 49.2, 42.5, 37.4, 33.8, 28.3, 22.0.

  Step C:

To a cooled (−78 ° C.) LDA (1.5 M cyclohexane solution, 41 mL, 61 mmol) in THF (150 mL) was added tert-butyl 3,3-dimethoxycyclopentanecarboxylate (9.37 g, 40 mL) over 10 min. .5 mmol) of THF was added dropwise. The resulting mixture was stirred at −78 ° C. for 30 minutes and then treated dropwise with 2-iodopropane (16.3 mL, 163 mmol). After an additional 10 minutes of stirring, the reaction mixture was warmed to room temperature. After stirring overnight, the reaction mixture was diluted with ether and washed with brine. The ether layer was dried over anhydrous MgSO ₄ , filtered and concentrated. After the crude product was stored under vacuum overnight, it was purified by MPLC (silica, 20% ethyl acetate / hexane) to yield 8.32 g of tert-butyl 1-isopropyl-3,3-dimethoxycyclopentanecarboxylate ( 75%).
¹ H NMR (500 MHz, CDCl ₃ ) δ 3.21 (s, 3H), 3.18 (s, 3H), 2.56 (app d, J = 14 Hz, 1H), 2.26 (m, 1H), 1.78 to 1.89 (m, 3

  Step D:

Tert-butyl 1-isopropyl-3,3-dimethoxycyclopentanecarboxylate (8.32 g, 30.5 mmol) was dissolved in a dioxane (50 mL) solution containing 4N anhydrous HCl, and water (10 mL) was added. The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was dissolved in DCM, dried over anhydrous MgSO ₄ , filtered and concentrated to give 5.44 g of 1-isopropyl-3-oxocyclopentanecarboxylic acid (used without purification).

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.70 (d, J = 18.1 Hz, 1H), 2.44 to 2.39 (m, 1H), 2.30 to 2.15 (m, 2H), 2.14 (dd, J = 18.1, 1.0 Hz, 1H), 2.06 (p, J = 6.9 Hz, 1H), 1.98 (m, 1H), 0.98 (dd, J = 11.4, 6.9 Hz, 6H).

  Step E:

A cooled (0 ° C.) solution of 1-isopropyl-3-oxocyclopentanecarboxylic acid (5.44 g, 32.0 mmol) in DCM (75 mL) was added with oxalyl chloride (8.36 mL, 95.9 mmol), followed by 3 drops of DMF. Processed. The reaction mixture was warmed to room temperature and stirred for 1.75 hours. The reaction mixture was then concentrated and stored under vacuum for 30 minutes. The resulting acid chloride was dissolved in DCM (75 mL), cooled to 0 ° C. and treated with benzyl alcohol (8.28 mL, 80.0 mmol) followed by triethylamine (8.92 mL, 64.0 mmol, dropwise). . Then about 100 mg of DMAP was added and the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with DCM and washed with 1N HCl solution, saturated NaHCO ₃ solution, and brine. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. Purification by MPLC (silica, 50% ethyl acetate / hexane) gave 6.11 g (73%) of benzyl 1-isopropyl-3-oxocyclopentanecarboxylate. ¹ HNMR (CDCl ₃ , 500 MHz): δ 7.36 (m, 5H), 5.17 (d, J = 2.5 Hz, 2H), 2.85 (d, J = 18.5 Hz, 1H), 2. 48 (m, 1H), 2.29 (dd, J = 10.0, 3.0 Hz, 1H), 1.98 to 2.23 (m, 3H), 1.93 (m, 1H),. 95 (m, 6H). The racemic product was resolved by chiral HPLC using a chiralcel OD column eluting with 15% 2-propanol / hexane (100 mg / injection; performed using a programmed Gilson HPLC system). 2.11 g of the desired early eluting isomer, benzyl (1S) -1-isopropyl-3-oxocyclopentanecarboxylate, was obtained.

  Step F:

Benzyl (1S) -1-isopropyl-3-oxocyclopentanecarboxylate (1.27 g, 4.88 mmol) is mixed with 20 mL of methanol containing Pd / C (10% Degussa, 500 mg) under a hydrogen atmosphere (balloon ) For 2 hours. The reaction proceeded only partially (˜30% conversion), so the reaction mixture was filtered, more Pd / C (500 mg) was added and the mixture was stirred under a hydrogen atmosphere for 5 hours. Since this reaction was completed immediately, the reaction mixture was filtered through celite and concentrated to obtain 704 mg of (1S) -1-isopropyl-3-oxocyclopentanecarboxylic acid. This did not require further purification. It should be pointed out that a large amount of catalyst was used because the ester obtained after chiral separation must have been contaminated with impurities. This was unique to this particular sample. Usually a smaller amount of catalyst is used. ¹ H NMR was consistent with that of the racemic acid (step D).

  Procedure B:

(1S, 3R) -3-[(tert-Butoxycarbonyl) amino] -1-isopropylcyclopentanecarboxylic acid (7.46 g, 27.5 mmol) in dioxane (10 mL) to 4N HCl in dioxane (30 mL) Was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give the corresponding amino acid salt as a white solid. This solid was then dissolved in CH ₂ Cl ₂ (100 mL) and solid NaHCO ₃ (7.0 g, 82.5 mmol) was added. After cooling to 0 ° C., a solution of NBS (20.0 g, 110 mmol) in CH ₂ Cl ₂ (200 mL) was slowly added to the reaction over 4 hours. After the addition, the reaction was concentrated, dried in vacuo and then dissolved in ethanol (100 mL). To this ethanol solution was added NaOMe (4.45 g, 82.5 mmol) and the reaction was heated to reflux. After refluxing for 1 hour, the reaction was cooled to 0 ° C. and 2N H ₂ SO ₄ aqueous solution (50 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to a volume of about 60 mL. The remaining mixture was partitioned between water (150 mL) and ethyl acetate (100 mL). The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous MgSO ₄ , concentrated, purified by flash chromatography (silica, ethyl acetate / hexane) and purified by flash chromatography (1S) -1-isopropyl-3-oxocyclopentane. Carboxylic acid (3.00 g, 64%) was obtained.

  Intermediate 30

  Step A:

To a stirred solution of tert-butyl 4- [3- (ethoxycarbonyl) phenyl] piperidine-1-carboxylate (48 g, 220 mmol) in chloroform (900 mL) was added ruthenium (IV) oxide hydride (6.0 g, 45 mmol). ) And then a solution of sodium periodate (150 g, 700 mmol) in water (900 mL). The resulting heterogeneous reaction mixture was stirred at room temperature for 11 days and then filtered through a short column of celite. The organic layer was removed and the aqueous layer was extracted twice with DCM. The combined organic layers were washed twice with 10% aqueous sodium thiosulfate and once with brine. The solution was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The product was purified by flash chromatography (silica gel, 20% EA / hexane) and tert-butyl 4- [3- (ethoxycarbonyl) phenyl] -2-oxopiperidine-1-carboxylate 22.5 g (64.8 mmol) ) Was obtained (29%).

Calculated _{ESI-MS C 19 H 25 NO} 5: 347.17, measured value: 370.1 (M + Na).

  Step B:

Potassium bis (trimethylsilyl) amide (14 g, 71 mmol) was mixed with 300 mL of THF in a 1000 mL flame dried round bottom flask and the resulting mixture was cooled to −78 ° C. Tert-Butyl 4- [3- (ethoxycarbonyl) phenyl] -2-oxopiperidine-1-carboxylate (22.5 g, 64.8 mmol) dissolved in 150 mL of THF was slowly added to the mixture with an addition funnel, resulting The reaction mixture was stirred at −78 ° C. for 30 minutes. Then methyl iodide (12.1 mL, 195 mmol) was added dropwise and the reaction mixture was stirred at −78 ° C. for 4 hours and then warmed at room temperature overnight. The reaction was quenched with saturated ammonium chloride and extracted three times with ether. The combined ether layers were washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The product was purified by flash chromatography (10-20% EA / hexane) to give a trans racemic tert-butyl 4- [3- (ethoxycarbonyl) phenyl] -3-methyl-2-oxopiperidine-1-carboxylate. 6.1 g (26%) of compound were obtained.

Calculated _{ESI-MS C 20 H 27 NO} 5: 361.19, measured value: 384.25 (M + Na).

  Step C:

  The product from Step B (6.1 g, 17 mmol) was dissolved in 4.0 M HCl in dioxane and stirred at room temperature for 2 hours, then concentrated under reduced pressure to give the desired product as an orange-yellow solid. Obtained. This was taken directly to the next step without further purification.

Calculated _{ESI-MS C 15 H 19 NO} 3: 261.14, measured value: 262.1 (M + H).

  Step D:

The product obtained from the previous step (total amount ˜17 mmol) was dissolved in THF (100 mL) and treated dropwise with 2.0 M borane-methyl sulfide in THF (31 mL, 62 mmol). The resulting solution was stirred at room temperature for 4 hours and then stored at 4 ° C. for 72 hours. The solvent was removed under reduced pressure and the resulting residue was dissolved in an ethanol solution of 0.5M HCl (aq. To 38%). The solution was heated to 50 ° C. and stirred for 4 hours. The solvent was removed and this procedure was repeated again to ensure decomposition of the borane complex. The solvent was removed and the product was purified by _{MPLC (0~15% (10% NH} 4 OH / MeOH) / DCM), to give the desired product. The purity was 80%. This crude material was dissolved in DCM (100 mL) and treated with di-tert-butyl dicarbonate (2.95 g, 13.5 mmol), diisopropylethylamine (2.30 mL, 13.5 mmol) and DMAP (10 mg). The resulting reaction mixture was stirred at room temperature overnight then diluted with DCM and washed with 1N aqueous sodium bicarbonate and brine. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The intermediate was purified by MPLC (0-40% EA / hexane). The resulting colorless oil was dissolved in 4.0 M HCl in dioxane and the resulting reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness to give 2.13 g (7.52 mmol) of the desired HCl salt.

Calculated _{ESI-MS C 15 H 21 NO} 2: 247.16, measured value: 248.15 (M + H).

Example 1

To a solution containing Intermediate 3 (150 mg, 0.425 mmol), 4-carboethoxypiperidine (125 mg, 0.425 mmol) and DCM (25 mL), molecular sieve (4Å) and NaBH (OAc) ₃ (450 mg, 2.12 mmol). ) Was added. The reaction mixture was stirred at room temperature for 18 hours, then filtered through celite, diluted with saturated NaHCO ₃ and extracted with DCM (× 3). The combined organic layers were dried over Na ₂ SO ₄ and purified by preparative TLC (3 / 96.7 / 0.3, MeOH / DCM / NH ₄ OH) to give Example 1 (220 mg, 97.8%). Got. _{LC-MS C 27 H 38 F} 3 N 2 O 3 [M + H +] Calculated: 495.28, measured value 495.25.

  A number of compounds were prepared as detailed in Example 1 using various amines. These compounds are summarized in the table below.

(Example 7)

A mixture of the product from Example 1 (185 mg, 0.349 mmol), 5N NaOH (200 μL, 1.04 mmol), and MeOH (5 mL) was heated at 60 ° C. for 3 hours before 4N HCl in dioxane. To neutralize the base. The reaction solution was concentrated and purified by reverse phase HPLC to give Example 7 (115 mg, 65.7%). _{LC-MS C 25 H 34 F} 3 N 2 O 3 [M + H +] Calculated: 467.24, Found: 467.35.

  Examples 8-12 were prepared as described in Example 7 using Examples 2-6 as starting materials. These compounds are summarized in the table below.

(Example 13)

  To a solution of intermediate 4 (50 mg, 0.14 mmol) in methylene chloride (20 mL) was added 1-ethoxycarbonylpiperazine (23 mg, 0.14 mmol). Powdered 4 粉末 molecular sieve (25 mg) was added followed by sodium triacetoxyborohydride (180 mg, 0.84 mmol) and the reaction mixture was stirred overnight. The mixture was diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative TLC (7 / 92.3 / 0.7, methanol / methylene chloride / ammonium hydroxide) to give Example 13 as a mixture of four diastereomers (55 mg, 79%). It was. LC-MS: MW calculated 496.27, measured 497.3.

  A number of compounds were prepared as detailed in Example 13, substituting various piperazines for 1-ethoxycarbonylpiperazine. These compounds, each prepared as a mixture of four diastereomers, are summarized in the table below.

(Example 17)

  To a solution of intermediate 4 (50 mg, 0.14 mmol) in methylene chloride (20 mL) was added 4-benzoylpiperidine hydrochloride (32 mg, 0.14 mmol) and N, N-diisopropylethylamine (73 μL, 0.42 mmol). After addition of 4 kg of powdered molecular sieve (25 mg), sodium triacetoxyborohydride (180 mg, 0.84 mmol) was added and the reaction mixture was stirred overnight. The mixture was extracted with methylene chloride, washed with sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative TLC (7 / 92.3 / 0.7, methanol / methylene chloride / ammonium hydroxide) to give Example 17 (30 mg, 43%) as a mixture of four diastereomers. It was.

  ESI-MS: MW calculated value 527.28, measured value: 528.25.

(Example 18)

Intermediate 4 (176 mg, 0.5 mmol), spiropiperidine (115 mg, 0.6 mmol as HCl salt), DIEA (100 mg, 0.8 mmol), molecular sieves (4Å, 200 mg) and triacetoxy in dichloromethane (10 mL) A mixture containing sodium borohydride (212 mg, 1.0 mmol) was stirred overnight. The reaction was quenched with saturated aqueous sodium carbonate. The solid was removed by filtration through celite. The crude product was extracted into dichloromethane and purified by preparative TLC (1000 micron, 10% [aq. NH ₄ OH / MeOH 1/9] / DCM). The title compound was obtained as a mixture of cis and trans racemic isomers (155 mg, 63%). LC-MS calcd for C26H35F3N4O2: 492, found: 493 (M + H).

  C. ZHOU

(Example 19)

To a stirred solution of intermediate 5 (50 mg, 0.14 mmol) and piperidine (28 L, 0.28 mmol) in DCM (10 mL) was added 4 × powdered molecular sieves (50 mg) and sodium triacetoxyborohydride (150 mg, 0.71 mmol) was added. The resulting solution was stirred at room temperature for 3 days, then filtered through celite and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude oil. This was purified by preparative TLC (0.5% NH ₄ OH / 4.5% MeOH / 95% DCM) to give 16 mg of a colorless solid as a mixture of two diastereomers. A small amount of the free base was converted to the hydrochloride salt by adding 2N HCl in ethyl ether.

_{ESI-MS C 23 H 32 F} 3 N 3 O Calculated: 423.25, measured value: 424 (M + H).

  Several other examples were prepared according to the procedure described in Example 19 except that various substituted piperidines were used as the amine component instead of piperidine. These examples are shown in Table 4.

(Example 29 and Example 30)

  The product free base prepared in Example 22 (55 mg) was resolved into the individual diastereomers using an HPLC equipped with a ChiralCel OD column eluting with 25% ethanol / hexane. Each compound was converted to the hydrochloride salt by adding 2N HCl in ethyl ether. 27 mg of the earlier eluting diastereomer (Example 29) and 20 mg of the later eluting diastereomer (Example 30) were recovered.

  Example 29: ESI-MS Calcd for C26H36F3N3O3: 495.27, found: 496 (M + H).

  Example 30: ESI-MS Calcd for C26H36F3N3O3: 495.27, found: 496 (M + H).

(Example 31)

Example 29 (10 mg, 0.018 mmol) was dissolved in a mixture of methanol (1 mL) and THF (1 mL) and treated with a solution of lithium hydroxide monohydrate (5 mg, 0.12 mmol) in water (1 mL). . . The resulting solution was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The product was purified by reverse phase HPLC (C18, 20-100% MeCN / H ₂ O) and converted to the hydrochloride salt by adding 2N HCl in ethyl ether to give 6.8 mg (70%) of product. It was.

  ESI-MS C24H32F3N3O3 calculated: 467.24, measured: 468 (M + H).

(Example 32)

Example 30 (10 mg, 0.018 mmol) was dissolved in a mixture of methanol (1 mL) and THF (1 mL) and treated with a solution of lithium hydroxide monohydrate (5 mg, 0.12 mmol) in water (1 mL). The resulting solution was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The product was purified by reverse phase HPLC (C18, 20-100% MeCN / H ₂ O) and converted to the hydrochloride salt by adding 2N HCl in ethyl ether to give 3.8 mg (39%) of product. It was.

  ESI-MS C24H32F3N3O3 calculated: 467.24, measured: 468 (M + H).

(Example 33)

To a solution of Example 30 (15 mg, 0.026 mmol) in THF (2 mL) was added lithium triethylborohydride (1.0 M THF solution, 150 μL, 0.15 mmol). After 18 hours at room temperature, further lithium triethylborohydride (100 μL) was added, and the resulting mixture was stirred for 24 hours and then concentrated under reduced pressure. The resulting residue was dissolved in DCM and washed with saturated aqueous sodium bicarbonate, 1N aqueous HCl, then brine. The organic layer was dried over Na ₂ SO ₄ , filtered, treated with 2N HCl in ether then hexanes and concentrated under reduced pressure to give 1.5 mg of the desired product as the hydrochloride salt (11%).

ESI-MS calcd for C24H34F3N3O2: 453.26, found: 454 (M + H).
(Example 34 and Example 35)

  The free base of the product prepared in Example 20 (60 mg) was separated into the individual diastereomers using HPLC equipped with a ChiralCel OD column eluting with 25% ethanol / hexane. Each compound was converted to the hydrochloride salt by adding 2N HCl in ethyl ether. 26 mg of the first eluting diastereomer (Example 34) and 17 mg of the later eluting diastereomer (Example 35) were recovered.

  Example 34: ESI-MS calcd for C25H35F3N4O2: 480.27, found: 481 (M + H).

  Example 35: ESI-MS calcd for C25H35F3N4O2: 480.27, measured value: 481 (M + H).

(Example 36 and Example 37)

  The product free base (54 mg) prepared in Example 22 was separated into two mixtures of two diastereomers, eluting with 13% ethanol / hexane, using an HPLC equipped with a ChiralCel OD column. Each compound was converted to the hydrochloride salt by adding 2N HCl in ethyl ether. 33 mg of the first eluting diastereomer (Example 36) and 10 mg of the later eluting diastereomer (Example 37) were recovered.

  Example 36: ESI-MS Calcd for C26H36F3N3O3: 495.27, found: 496 (M + H).

  Example 37: ESI-MS Calcd for C26H36F3N3O3: 495.27, found: 496 (M + H).

(Examples 38 to 41)

  The product free base prepared in Example 24 (40 mg) was separated into the individual diastereomers using HPLC equipped with a ChiralCel OD column eluting with 20% ethanol / hexane. Each compound was converted to the hydrochloride salt by adding 2N HCl in ethyl ether. First eluting diastereomer (Example 38) 15 mg, Diastereomer 2 (Example 39) 1.5 mg, Diastereomer 3 (Example 40) 7 mg, Last eluting diastereomer (Example 41) 6 mg was recovered.

  Example 38: Calculated value of ESI-MS C24H34F3N3O: 437.27, measured value: 438 (M + H).

  Example 39: ESI-MS calcd for C24H34F3N3O: 437.27, found: 438 (M + H).

  Example 40: ESI-MS calcd for C24H34F3N3O: 437.27, found: 438 (M + H).

Example 41: Calculated for ESI-MS C24H34F3N3O: 437.27, found: 438 (M + H).
(Examples 42 to 46)

  The product free base prepared in Example 25 (40 mg) was separated into individual diastereomers using HPLC equipped with ChiralCel OD column eluting with 20% ethanol / hexane. Each compound was converted to the hydrochloride salt by adding 2N HCl in ethyl ether. Although all six diastereomers were resolved, peaks 2 and 6 were combined in an overlapping procedure, resulting in four pure diastereomers and one mixture of two diastereomers.

  Example 42: Peak 1: ESI-MS calcd for C25H36F3N3O: 451.28, found: 452 (M + H).

  Example 43: Peak 2/6: Calculated: ESI-MS C25H36F3N3O: 451.28, found: 452 (M + H).

  Example 44: Peak 3: ESI-MS calcd for C25H36F3N3O: 451.28, found: 452 (M + H).

  Example 45: Peak 4: ESI-MS calcd for C25H36F3N3O: 451.28, found: 452 (M + H).

  Example 46: Peak 5: ESI-MS calcd for C25H36F3N3O: 451.28, found: 452 (M + H).

(Example 47 and Example 48)

  The product free base prepared in Example 27 (20 mg) was separated into individual diastereomers using HPLC equipped with ChiralCel OD column eluting with 25% ethanol / hexane. Each compound was converted to the hydrochloride salt by adding 2N HCl in ethyl ether. 7 mg of the earlier eluting diastereomer (Example 47) and 6 mg of the later eluting diastereomer (Example 48) were recovered.

  Example 47: ESI-MS calcd for C23H32F3N3O2: 439.24, found: 440 (M + H).

  Example 48: ESI-MS calcd for C23H32F3N3O2: 439.24, found: 440 (M + H).

(Example 49)

To a stirred solution of intermediate 5 (50 mg, 0.14 mmol) and morpholine (25 μL, 0.28 mmol) in DCM (10 mL) was added 4Å powdered molecular sieves (50 mg) and sodium triacetoxyborohydride (150 mg, 0.71 mmol) was added. The resulting solution was stirred at room temperature for 3 days, then filtered through celite and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude oil. This was purified by preparative TLC (0.5% NH ₄ OH / 4.5% MeOH / 95% DCM) to give 57 mg of a colorless solid as a mixture of two diastereomers. A small amount of the free base was converted to the hydrochloride salt by adding 2N HCl in ethyl ether.
ESI-MS calcd for C22H30F3N3O2: 425.23, found: 426 (M + H).

  Prepared according to the procedure described in Example 49 except that various substituted morpholines were used as the amine component instead of morpholine. These examples are shown in Table 5.

(Example 53 and Example 54)

  The product free base (60 mg) prepared in Example 50 was separated into the individual diastereomers using an HPLC equipped with a ChiralCel OD column eluting with 20% ethanol / hexane. Each compound was converted to the hydrochloride salt by adding 2N HCl in ethyl ether. 26 mg of the first eluting diastereomer (Example 53) and 27 mg of the later eluting diastereomer (Example 54) were recovered.

  Example 53: Calculated value for ESI-MS C24H34F3N3O2: 453.26, measured value: 454 (M + H).

  Example 54: ESI-MS calcd for C24H34F3N3O2: 453.26, found: 454 (M + H).

(Example 55 and Example 56)

  The product free base (48 mg) prepared in Example 52 was separated into the individual diastereomers using an HPLC equipped with a ChiralCel OD column eluting with 25% ethanol / hexane. Each compound was converted to the hydrochloride salt by adding 2N HCl in ethyl ether. 18 mg of the earlier eluting diastereomer (Example 53) and 23 mg of the later eluting diastereomer (Example 54) were recovered.

  Example 55: ESI-MS calcd for C23H30F3N3O2: 437.23, found: 438 (M + H).

  Example 56: ESI-MS calcd for C23H30F3N3O2: 437.23, found: 438 (M + H).

(Example 57)

To a stirred solution of intermediate 5 (50 mg, 0.14 mmol) and pyrrolidine (23 μL, 0.28 mmol) in DCM (10 mL) was added 4 × powdered molecular sieves (50 mg) and sodium triacetoxyborohydride (150 mg, 0.71 mmol) was added. The resulting solution was stirred at room temperature for 3 days, then filtered through celite and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude oil. This was purified by preparative TLC (0.5% NH ₄ OH / 4.5% MeOH / 95% DCM) to give 15 mg high diastereomer and 35.5 mg low isomer, both of which were colorless Collected as a solid. A small amount of the free base was converted to the hydrochloride salt by adding 2N HCl in ethyl ether.

  Upper: ESI-MS C22H30F3N3O calculated: 409.23, measured: 410 (M + H).

  Bottom: Calculated value of ESI-MS C22H30F3N3O: 409.23, measured value: 410 (M + H).

  Several other examples were prepared according to the procedure described in Example 57 except that various substituted pyrrolidines were used as the amine component instead of pyrrolidine. These examples are shown in Table 6.

(Example 63)

Intermediate 3 (55 mg, 0.15 mmol), (1S, 4S)-(−) 2- (4-fluorophenyl) -2,5-diazabicyclo [2.2.1] heptane (HBr) in dichloromethane (5 mL) A mixture containing 85 mg, 0.3 mmol), DIEA (65 mg, 0.5 mmol), molecular sieves (4Å, 250 mg) and sodium triacetoxyborohydride (212 mg, 1.0 mmol) as a salt was stirred overnight. The reaction was quenched with saturated aqueous sodium carbonate. The solid was removed by filtration through celite. The crude product was extracted into dichloromethane and purified by preparative TLC (1000 microns, 5% [NH ₄ OH / MeOH 1/9 aqueous solution] / DCM). The title compound was obtained as a mixture of cis and trans racemic isomers (75 mg, 95%). LC-MS calcd for C30H35F4N3O: 529, found: 530 (M + H).

(Example 64)

Intermediate 3 (55 mg, 0.15 mmol), (1S, 4S)-(−) 2- (2-methyl) -2,5-diazabicyclo [2.2.1] heptane (maleic acid) in dichloromethane (5 mL) A mixture containing 100 mg, 0.3 mmol), DIEA (65 mg, 0.5 mmol), molecular sieves (4Å, 250 mg) and sodium triacetoxyborohydride (212 mg, 1.0 mmol) as a salt was stirred overnight. The reaction was quenched with saturated aqueous sodium carbonate. The solid was removed by filtration through celite. The crude product was extracted into dichloromethane and purified by preparative TLC (1000 microns, 5% [NH ₄ OH / MeOH 1/9 aqueous solution] / DCM). The title compound was obtained as a mixture of cis and trans racemic isomers (52 mg, 66%). _{LC-MS C 31 H 38 F} 3 N 3 O Calculated: 525, measurements: 526 (M + H).

(Example 65)

  Step A:

A neat mixture of 54 g (0.29 mol) of ethyl (2-aminothiazol-4-yl) acetate and 50 g (0.276 mol) of benzophenone imine was stirred at 190 ° C. for 5 hours, then cooled to room temperature and 100 mL of CH ₂ Cl ₂ Diluted with The entire mixture was transferred to a silica gel column and eluted with 20% EtOAc / hexane. The title compound was obtained as a pale yellow solid (70 g, 69% yield). ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.26 (t, 3H), 3.74 (s, 2H), 4.15 (q, 2H), 6.87 (s, 1H), 77.25 7.86 (m, 10H); mass spectroscopy _{(NH 3 -CI): m /} z 351 (M + 1).

  Step B:

A mixture containing 35 g (0.10 mol) of the Schiff base ester obtained from Step A in 500 mL of DME and cis-1,3-dichloro-2-butane (13 mL, 0.11 mol) was divided into solids in several portions at room temperature. NaH (60% oil, 10.0 g, 0.25 mol) was added. The resulting mixture was stirred for 2 days, poured into 2000 mL ice-water and extracted with 1500 mL ether. The ether layer was washed with water (3 × 500 mL), dried over Na ₂ SO ₄ and evaporated. FC (silica gel, 5% EtOAc / hexane) gave the title compound as an oil (24 g, 59%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.20 (t, 3H), 2.87 (d, 2H), 3.19 (d, 2H), 4.14 (q, 2H), 5.29 ( s, 2H), 6.71 (s, 1H), 7.26-7.81 (m, 10H). Mass spectrometry _{(NH 3 -CI): m /} z 403 (M + 1).

  Step C:

24.0 g (0.059 mol) of cyclopentene Schiff base obtained from Step B was dissolved in 100 mL of 4N HCl / dioxane. After 1 hour, 1.8 mL of water was added. The mixture was stirred for 3 hours and evaporated to dryness. The residue was dissolved in 100 mL CH ₂ Cl ₂ and 15 mL DIEA was added. The entire mixture was discharged onto a silica gel column to elute with 20% EtOAc / hexane to remove benzophenone and then with 40% EtOAc / hexane to give the title compound as a pale yellow solid (12.0 g, 85%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.19 (t, 3H), 2.79 (d, 12H), 3.15 (d, 2H), 4.13 (q, 2H), 5.66 ( s, 2H), 5.82 (wide, 2H), 6.19 (s, 1H).

  Step D:

A mixture containing 12 g (50 mmol) of aminothiazole obtained from Step C, 28 g (130 mmol) of di-tert-butyl dicarbonate and 0.6 g of DMAP in 250 mL of DCM was stirred overnight and evaporated. After purification by flash chromatography on silica gel (10% EtOAc / hexane), the title compound (21.0 g, 96%) was obtained as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.18 (t, 3H), 1.49 (d, 18H), 2.88 (d, 2H), 3.18 (d, 2H), 4.13 ( q, 2H), 5.65 (s, 2H), 6.83 (s, 1H). Mass spectrometry _{(NH 3 -CI): m /} z 439 (M + 1).

  Step E:

To a solution containing 13.1 g (30.0 mmol) of the ester obtained from Step D in 50 mL of anhydrous ether was added dropwise a solution of BH ₃ -DMS in THF (14 mL, 24 mmol) at −78 ° C. The cold bath was removed and the mixture was stirred at room temperature for 3 hours, diluted with 250 mL DCM, and 25 g sodium acetate and 55 g PCC were added. The mixture was stirred overnight. The entire mixture was applied to a silica gel column and eluted with 10% EtOAc / hexane then 30% EtOAc / hexane. Two components were obtained. The previously eluted isomer (yellow oil, 6.0 g) was identified as the title compound. ¹ H NMR (300 MHz, CDCl ₃ ): 1.21 (t, 3H), 1.50 (s, 18H), 2.33 (t, 2H), 2.42 to 2.70 (m, 2H), 2.78-3.10 (dd, 2H), 4.18 (q, 3H), 6.88 (s, 1H). Mass spectrometry _{(NH 3 -CI): m /} z 455 (M + 1).

  Step F:

The late eluting component obtained from above was found to be the title compound (tacky material, 1.80 g). ¹ H NMR (300 MHz, CDCl ₃ ): δ (t, 3H), 1.46 (s, 9H), 2.27 (3, 2H), 2.38 to 2.62 (m, 2H), 2. 64-3.00 (dd, 2H), 4.11 (q, 2H), 6.66 (s, 1H). Mass spectrometry _{(NH 3 -CI): m /} z 355 (M + 1).

  Step G:

A mixture containing 1.40 g (4.00 mmol) of the keto ester obtained from Step F and 0.82 g (13 mmol) of lithium hydroxide monohydrate in a solution of 20 mL of MeOH and 2 mL of water was stirred overnight at room temperature. The entire mixture was applied to a silica gel column and eluted with 10% MeOH / CH ₂ Cl ₂ . Evaporation in vacuo gave a pale yellow solid. 1.30 g of the title product was obtained as a fluffy solid. ¹ H NMR (300 MHz, CDCl ₃ ): δ (t, 9H), 2.10 to 3.20 (m, 8H), 6.60 (s, 1H).

  Step H:

Keto acid prepared in Step G (1.0 g, 3.0 mmol), Intermediate 1 (0.66 g, 3.0 mmol as HCl salt) and EDC (0.95 g, 5.0 mmol) in dichloromethane (10 mL). The mixture containing was stirred for 2 days. The mixture was diluted with dichloromethane, washed with 1N aqueous HCl, dried over sodium sulfate and evaporated. The residue was purified by preparative TLC (1500 microns, 10% [NH ₄ OH / MeOH 1/9 aqueous solution] / DCM) to give the title product as a yellow solid (0.52 g, 34%). LC-MS calcd for C25H27F3N2O4S: 508, found: 509 (M + H).

  Step I:

The product from Step H (510 mg, 1.0 mmol) was mixed with TFA (10 mL) for 30 minutes. TFA was removed and the residue was purified by preparative TLC (10% [NH ₄ OH / MeOH 1/9 aqueous solution] / DCM) to give the desired product as a white solid (223 mg, 55%). LC-MS calcd for C20H19F3N2O2S: 408, found: 409 (M + H).

  Step J:

The product from Step I (210 mg, 0.50 mmol), morpholine (440 mg, 5.0 mmol), molecular sieves (4Å, 500 mg) and sodium triacetoxyborohydride (420 mg, 2.50 mg) in dichloromethane (15 mL). The mixture containing 0 mmol) was stirred overnight. The reaction was quenched with saturated aqueous sodium carbonate. The solid was removed by filtration through celite. The crude product was extracted into dichloromethane and purified by preparative TLC (1000 microns, 10% [NH ₄ OH / MeOH 1/9 aqueous solution] / DCM). The title compound was obtained as a mixture of cis and trans racemic isomers (200 mg, 84%). LC-MS calcd for C24H28F3N3O2S: 479, found: 480 (M + H).

Example 66

Intermediate 3 (70 mg, 0.20 mmol), cis-2,6-dimethylmorpholine (23 μL, 0.20 mmol), molecular sieve (4 μL, 200 mg) and sodium triacetoxyborohydride (210 mg, 0.99 mmol) in DCM ) Was stirred for 5 days. The reaction was diluted with DCM, filtered and washed with saturated aqueous NaHCO ₃ , water and brine. The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (1000 microns) (developed with 3% [aq. NH ₄ OH / MeOH 1/9] / DCM) to give the final title compound as the free base. The HCl salt (62.2 mg) was formed by treatment with 4N HCl / dioxane. ESI-MS calcd for C25H35F3N2O2: 45.27, measured value: 453 (M + H).

  The diastereoisomers were separated into one mixture of two cis diastereoisomers and two single diastereomers using HPLC (AD column, 5% EtOH / hexane).

(Example 67)

Example 68 was started from Intermediate 3 and (1S, 4S)-(+)-2-aza-5-oxabicyclo [2.2.1] heptane hydrochloride as detailed in Example 66. Prepared. The cis and trans isomers were resolved by preparative TLC (4 / 95.6 / 0.4, MeOH / DCM / NH ₄ OH). Upper spot: Calculated value of ESI-MS C24H31F3N2O2: 436.23, measured value: 437 (M + H). Lower spot: Calculated value of ESI-MS C24H31F3N2O2: 436.23, measured value: 437 (M + H).

Example 68

Example 68 was prepared starting from piperidine and Intermediate 3 as detailed in Example 49. _{ESI-MS C 24 H 33 F} 3 N 2 O Calculated: 422.25, measured value: 423 (M + H).

(Example 69)

Intermediate 22 (563 mg, 2.43 mmol) was dissolved in dichloromethane and cooled to -78 ° C. Ozone was bubbled through the solution until the blue color remained intact. Nitrogen gas was then bubbled through the solution until the blue color disappeared. Na ₂ SO ₄ was added to the stirring solution. The reaction mixture was filtered into a flask containing intermediate 23. Dichloromethane (20 mL), triethylamine (136 μL, 0.974 mmol), and NaB (OAc) ₃ H (929 mg, 4.38 mmol) were added to the reaction flask. The reaction mixture was stirred at room temperature under N ₂ gas for 2 hours, then diluted with dichloromethane and washed with saturated sodium bicarbonate solution (2 × 100 mL) and brine (1 × 100 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was divided into 3 batches and applied to 3 ion exchange columns. Impurities were flushed with 40% MeOH / hexane (100 mL). The desired product was then eluted from the column with 30% 2N NH ₃ in MeOH and further diluted with dichloromethane. Example 69 (131 mg, 0.223 mmol, 46% yield) was purified by preparative TLC using 32% EtOAc / hexane. The diastereomers were then isolated by preparative TLC using 45% EtOAc / hexanes (upper isomer: 20 mg, 0.034 mmol, 7% yield; middle isomer: 45 mg, 0.076 mmol, 16% yield; bottom isomer: 54 mg, 0.092 mmol, 19% yield). Calculated _{ESI-MS C 32 H 41 F} 3 N 4 O 3: 586.69, measured value: 587 (M + H).

  Several other piperazines and homopiperazines were prepared according to procedures similar to those described in Example 69. These compounds are summarized in Table 7.

(Example 73)

  The above compound was prepared from Intermediate 5 and 4,5,6,7-tetrahydro-1H-pyrazolo [4,3-] pyridine according to the procedure described in Example 49. ESI-MS C24H30F3N5O calculated: 461.24, measured: 462 (M + H).

(Example 74)

  The above compound was prepared from Intermediate 5 and 1,4-diazepan-5-one according to the procedure described in Example 49. ESI-MS calcd for C23H31F3N4O2: 452.24, found: 453 (M + H).

(Example 75)

上記化合物を、実施例５７に記載の手順に従って、中間体５および２，３，４，５−テトラヒドロ−１，４−ベンズオキサゼピンから調製した。上のスポット：ＥＳＩ−ＭＳ Ｃ２７Ｈ３２Ｆ３Ｎ３Ｏ２の計算値：４８７．２４、測定値：４８８（Ｍ＋Ｈ）。下のスポット：ＥＳＩ−ＭＳ Ｃ２７Ｈ３２Ｆ３Ｎ３Ｏ２の計算値：４８７．２４、測定値：４８８（Ｍ＋Ｈ）。

The above compound was prepared from Intermediate 5 and 2,3,4,5-tetrahydro-1,4-benzoxazepine according to the procedure described in Example 57. Upper spot: Calculated value of ESI-MS C27H32F3N3O2: 487.24, measured value: 488 (M + H). Lower spot: Calculated value of ESI-MS C27H32F3N3O2: 487.24, measured value: 488 (M + H).

(Example 76)

Carbon supported palladium catalyst (top: 6 mg, middle: 18 mg, bottom: 20 mg) was added to one of the three diastereomers of Example 70 (top: 29.6 mg, middle: 89.9 mg, bottom: 102.3 mg). Were added to three flasks each containing one. This mixture was dissolved in MeOH (3-6 mL) and the reaction vessel was washed repeatedly with hydrogen gas. The mixture was stirred at room temperature for 4.5 hours under a hydrogen atmosphere and then passed through an Acrodisc® syringe filter with a 0.45 μm PTFE membrane. Compound 76 (top isomer: 16.0 mg, 0.0354 mmol, 71% yield; middle isomer: 42.7 mg, 0.0943 mmol, 62% yield; bottom isomer: 34.5 mg, 0.0762 mmol, 44% yield) was isolated by preparative TLC using a dichloromethane solvent system containing 10% NH ₄ OH / MeOH (1: 9). _{ESI-MS C 24 H 35 F} 3 N 4 O Calculated: 452.56, measured value: 453 (M + H).

(Example 77)

Example 76 (TLC middle stereoisomer, 11 mg, 0.024 mmol) was dissolved in dichloromethane (3 mL) and cooled to 0 ° C. Ethyl chloroformate (5 μL, 0.05 mmol), triethylamine (10 μL, 0.07 mmol), and a catalytic amount of DMAP (1-2 mg) were added to the reaction flask. The reaction was warmed to room temperature and stirred for 2 hours under a nitrogen atmosphere. The reaction was then diluted with DCM and washed with saturated sodium bicarbonate solution (1 × 25 mL) and brine (1 × 25 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated. Example 77 (4.2 mg, 0.0080 mmol, 33% yield) was purified by preparative TLC using a dichloromethane solvent system containing 2% NH ₄ OH / MeOH (1: 9). Calculated _{ESI-MS C 27 H 39 F} 3 N 4 O 3: 524.62, measured value: 525 (M + H).

(Example 78)

Example 76 (TLC middle stereoisomer, 11 mg, 0.024 mmol) was dissolved in dichloromethane (3 mL) and cooled to 0 ° C. Acetic anhydride (11 μL, 0.12 mmol), triethylamine (23 μL, 0.17 mmol), and a catalytic amount of DMAP (1-2 mg) were added to the reaction flask. The reaction was warmed to room temperature and stirred for 2.5 hours under a nitrogen atmosphere. The reaction was then diluted with DCM and washed with saturated sodium bicarbonate solution (1 × 25 mL) and brine (1 × 25 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated. Example 78 (5.3 mg, 0.011 mmol, 45% yield) was purified by preparative TLC using a dichloromethane solvent system containing 2% NH ₄ OH / MeOH (1: 9). _{ESI-MS C 26 H 37 F} 3 N 4 O 2 Calculated: 494.59, measured value: 495 (M + H).

(Example 79)

Three separations containing three diastereomers of dichloromethane (approx. 2-3 mL per flask) in Example 77 (top: 16 mg, 0.035 mmol, middle: 11 mg, 0.023 mmol, bottom: 14 mg, 0.031 mmol) Added to the flask. Methyl isocyanate (top: 21 μL, 0.35 mmol, middle: 14 μL, 0.23 mmol, bottom: 19 μL, 0.31 mmol) was added to each reaction vessel. The reaction was stirred for 3 hours, then Example 79 (upper isomer: 12.8 mg, 0.0251 mmol, 72% yield, middle isomer: 10.4 mg, 0.0204 mmol, 89% yield). , Lower isomer: 11.1 mg, 0.0218 mmol, 70% yield) was purified by preparative TLC using a dichloromethane solvent system containing 2% NH ₄ OH / MeOH (1: 9). _{ESI-MS C 26 H 38 F} 3 N 5 O 2 Calculated: 509.61, measured value: 510 (M + H).

(Example 80)

  Step A

A solution of cis-hydroxy-D-proline (2.98 g, 22.7 mmol) in methanol (20 mL) was treated with thionyl chloride (1.78 mL, 24.4 mmol) and stirred at room temperature for 1 hour. The reaction mixture was then heated to 65 ° C. overnight. Volatiles were evaporated to give the crude methyl ester (4.0816 g), dissolved in dichloromethane (50 mL) and diisopropylethylamine (9.59 mL, 55.1 mmol) was added. The reaction mixture was cooled to 0 ° C. and benzyl neat chloroformate (3.71 mL, 26.0 mmol) was added via syringe. After stirring at 0 ° C. for 30 minutes, the cold bath was removed. The reaction was quenched by pouring into aqueous citric acid (10%, 50 mL) and the product was extracted into dichloromethane. The combined organic layers were backwashed with brine, dried over anhydrous sodium sulfate and the solvent removed in vacuo. The crude product was purified by flash chromatography (silica gel, ethyl acetate: hexane / 4: 6) to give 4.0717 g (69%) of pure product. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.35 m (5H), 5.21 (d, J = 12.6 Hz, 2H), 5.10 (d, J = 13 Hz, 1H), 5.06 ( d, J = 12.35 Hz, 1H), 4.45 (m, 2H), 3.80 (s, 3H), 2.35 (m, 1H), 2.15 (m, 1H).

  Step B

A solution containing the alcohol obtained from the previous step (2.63 g, 9.42 mmol) and diisopropylethylamine (3.28 mL, 18.8 mmol) in 40 mL of dichloromethane was cooled to −78 ° C. and tert-butyl trifluoromethanesulfonate was added. Dimethylsilyl (2.596 mL, 11.30 mmol) was added via syringe. The reaction mixture was stirred at −78 ° C. for 2 hours and quenched by pouring into 50 mL of a saturated solution of sodium bicarbonate. The organic layer was separated and dried over magnesium sulfate and volatiles were removed in vacuo. The residue (6.0 g) was further purified by column chromatography (silica gel, ethyl acetate: hexane / 1: 4) to give 2.8355 g (76%) of pure product. ¹ H NMR (500 MHz, CDCl ₃ ): 7.35 m (5H), 5.20 (m = 2H), 4.45 (m, 2H), 3.70 (m, 4H), 3.45 (m , 1H), 2.23 (m, 2H) 0.87 (bs, 9H), 0.05 (m, 6H).

  Step C

A solution of the ester obtained from the previous step (2.83 g, 7.19 mmol) in THF (10 mL) is treated with lithium borohydride (250 mg, 11.5 mmol) at 0 ° C. and the reaction mixture is stirred at room temperature for 72 hours. did. It was then diluted with diethyl ether and washed with water and 1M phosphoric acid solution. The combined organic layers were dried (sodium sulfate) and the solvent removed in vacuo. The crude product was further purified by column chromatography (silica gel, ethyl acetate: hexane / 3: 7) to give 1.5636 g (60%) of pure product. Calculated _{LC-MS C 19 H 31 NO} 4 Si: 365.20, measured ^{value: 366.25 [M + H] +} .

  Step D

A solution containing the alcohol from the previous step (1.56 g, 4.27 mmol) and diisopropylethylamine (1.49 mL, 8.53 mmol) in dichloromethane (20 mL) was added at 0 ° C. to methanesulfonyl chloride (496 μL, 6. 41 mmol). The reaction mixture was stirred for 15 minutes while cooling and then stirred for an additional 30 minutes at room temperature. It was diluted with dichloromethane, washed with water and dried over magnesium sulfate. The solvent was removed in vacuo and the crude product was used as such in the next step without delay. Calculated _{LC-MS C 20 H 33 NSO} 6 Si: 443.18, measured ^{value: 444.25 [M + H] +} .

  Step E

A solution of TBS-ether obtained from the previous step (1.82 g, 4.10 mmol) in THF (50 mL) was treated with tetrabutylammonium fluoride (4.51 mL, 1 M THF solution). The reaction mixture was stirred at room temperature for about 15 minutes until LC MS analysis indicated complete removal of the TBS group. The reaction mixture was then cooled to 0 ° C. and sodium hydride (180 mg, 60% suspension, 45.1 mmol) was added. Stirring was continued at room temperature for 24 hours. The reaction was quenched by pouring into water and the crude product was extracted into ethyl acetate. The solvent was removed in vacuo and the crude product was purified by flash chromatography (dichloromethane: ether / 7: 3) to give 595 mg (59%) of the desired product. ¹ H NMR (500 MHz, CDCl ₃ ): 7.38 (m, 5H), 5.30 (m, 2H), 4.52 (m, 2H), 3.80 (m, 2H), 3.40 ( m, 2H), 1.70 (m, 2H).

  Step F

  A solution of CBZ-amine (590 mg, 2.53 mmol) in ethyl alcohol (30 mL) obtained from the previous step was hydrogenated with balloon pressure in the presence of Pd / C (142 mg, 10%). The reaction was monitored by LC until the starting material disappeared and toluene appeared. The catalyst was filtered off and the filtrate was evaporated to dryness to give 321 mg (94%) of the desired product.

  Step G

Intermediate 3 (120 mg, 0.340 mmol), amine hydrochloride obtained from the previous step (46 mg, 0.34 mmol), diisopropylethylamine (60 μL, 0.34 mmol) and 4 モ molecular sieves (crushed, 360 mg) of dichloroethane ( 10 mL) solution was treated with sodium triacetoxyborohydride and stirred at room temperature for 24 hours. The reaction was quenched by pouring into a saturated solution of sodium bicarbonate and the crude product was extracted with dichloromethane. Volatiles were removed in vacuo and pure product (118 mg, 80%) was obtained by preparative TLC (ethyl acetate: ethyl alcohol: ammonium hydroxide / 90: 8: 2). _{LC-MS C 24 H 31 N} 2 F 3 O 2 Calculated: 436.23, measured ^{value: 437.20 [M + H] +} .

(Example 81)

To a solution of intermediate 21 (150 mg, 0.43 mmol) in dichloromethane (10 mL) was added EDC (414 mg, 2.16 mmol), HOAt (59 mg, 0.43 mmol) and intermediate 1 (87 mg, 0.43 mmol) to give The resulting mixture was stirred at room temperature for 4 days. The reaction was quenched with water and diluted with 20 mL dichloromethane. The organic layer was separated and the aqueous layer was extracted with DCM (2 × 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative TLC (eluent; 10% methanol: 89.5% dichloromethane: 0.5% NH ₄ OH) to give 40 mg (17%) of the pure desired final product as two cis isomers. As a mixture of Calculated _{LC-MS C 30 H 36 N} 2 OF 4: 516.28, measured ^{value: [M + H] + 517} .

(Example 82)

Pyrimidylpiperidine hydrochloride (intermediate 8) (67 mg, 0.34 mmol) was added to intermediate 4 (100 mg, 0.28 mmol), triethylamine (46 μL, 0.35 mmol) and 4Å powdered molecular sieves (100 mg). Mixed with DCM solution. After 15 minutes at room temperature, sodium triacetoxyborohydride (240 mg, 1.13 mmol) was added and the resulting mixture was stirred for 3 days, then filtered through celite, diluted with DCM, saturated sodium bicarbonate and brine. Washed with. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a crude oil. This was purified by preparative TLC (silica gel, 0.3% NH ₄ OH / 2.7% MeOH / 97% DCM) to give 110 mg of a colorless oil. The resolution of the individual diastereomers was performed by HPLC using a ChiralPak AD column, eluting with 30% isopropanol / hexane to separate two single diastereomers and one mixture of two other diastereomers. Obtained.

  First peak 10 mg: Calculated for ESI-MS C28H35F3N4O: 500.28, found: 504 (M + H).

  Second peak 11 mg: Calculated for ESI-MS C28H35F3N4O: 500.28, found: 504 (M + H).

  Third peak 7.0 mg: ESI-MS calcd for C28H35F3N4O: 500.28, found: 504 (M + H).

(Examples 83-91)

  Several other examples were prepared similarly to Example 82 using different piperidine intermediates. These Examples (83-91) are shown below.

(Example 92)

This product was prepared in a manner similar to that of Example 81 except that Intermediate 21 was replaced with commercially available 4-cyano-4-phenylpiperidine. The crude product was purified by preparative TLC (eluent: 5% methanol: 94.5% DCM: 0.5% NH ₄ OH) to give Example 92 as a mixture of 4 isomers. _{LC-MS C 31 H 36 F} 3 N 3 O Calculated: 523.28, measured ^{value: [M + H] + 524} .

(Example 93)

This product was prepared in a manner similar to that of Example 81 except that Intermediate 21 was replaced with commercially available 4-phenylpiperidine. The crude product was purified by preparative TLC (eluent: 10% methanol: 89.5% DCM: 0.5% NH ₄ OH) to give Example 93 as a mixture of four isomers. _{LC-MS C 30 H 37 F} 3 N 2 O Calculated: 498.29, measured ^{value: [M + H] + 499} .

(Example 94)

  Step A

  To a solution of cyclopentanone carboxylic acid (from Step C, Intermediate 3) (2.3 g, 14 mmol) in dichloromethane (70 mL) was added oxalyl chloride (1.8 mL, 21 mmol), followed by 2 drops of DMF. The solution was stirred at room temperature for 80 minutes and then evaporated under reduced pressure. The residue was dissolved in DCM (20 mL) and added via syringe to a solution of intermediate 3 (3.0 g, 14 mmol) and triethylamine (2.1 mL, 15 mmol) prepared in DCM (50 mL). The resulting mixture was stirred at room temperature for 18 hours and then quenched with water (25 mL). The organic layer was separated and washed with 1N HCl, saturated sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on Biotage Flash 40 (eluent: 40% ethyl acetate / 60% hexane) to give 2.2 g (43%) of the title compound.

  Step B

The product described in Step A (200 mg, 0.54 mmol), commercially available 4-fluorophenylpiperidine hydrochloride (120 mg, 0.54 mmol), diisopropylethylamine (94 μL, 0.54 mmol) and crushed molecular sieves (4 kg, 100 mg). ) In dichloromethane (10 mL) was treated with sodium triacetoxyborohydride (343 mg, 1.60 mmol) and stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate (10 mL) and further diluted with 10 mL DCM. The organic layer was separated and the aqueous layer was washed with dichloromethane (2 × 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC (eluent: 8% ethanol: 90% ethyl acetate: 2% NH ₄ OH), two isomers of unknown absolute stereochemistry, high eluent (25 mg, 5%) and low An eluent (37.2 mg, 7.6%) was obtained. Calculated _{LC-MS C 30 H 35 N} 2 OF 5: 534.28, measured ^{value: [M + H] + 535} .

(Example 95)

This product was prepared in a manner similar to that of Example 94 except that 4-fluorophenylpiperidine hydrochloride was replaced with intermediate 9. The crude product was purified by preparative TLC (eluent: 90% ethyl acetate: 8% ethanol: 2% NH ₄ OH) to give 450 mg (66%) of the title product as a mixture of 4 isomers. Calculated _{LC-MS C 28 H 34 N} 4 OF 4: 518.27, measured ^{value: [M + H] + 519} .

  Several other examples were prepared as in Example 94 using different piperidine intermediates. These examples (96-104) are shown below.

(Example 105)

To a solution of intermediate 21 (150 mg, 0.43 mmol) in dichloromethane (10 mL) was added EDC (170 mg, 0.86 mmol), HOAt (59 mg, 0.43 mmol) and intermediate 21 (91 mg, 0.43 mmol) to give The resulting mixture was stirred at room temperature for 3 days. The reaction was quenched with water and diluted with 20 mL dichloromethane. The organic layer was separated and the aqueous layer was extracted with DCM (2 × 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative TLC (eluent: 7% ethanol: 92% dichloromethane: 1.0% NH ₄ OH) to give 121 mg (50%) of the desired final product as a mixture of two cis isomers. It was. _{LC-MS C 29 H 36 BrFN} 2 O Calculated: 526.28, measured value: [M ^{+ H] +} 527 and ^{[(M + 2) + H} ] + 529.

(Example 106)

To a solution of Example 105 (100 mg, 0.210 mmol), phenylboronic acid (30 mg, 0.23 mmol), toluene (1.4 mL), and MeOH (0.6 mL) was added Na ₂ CO ₃ (80 mg, 0.74 mmol). ) And Pd (PPh ₃ ) ₂ Cl ₂ (8 mg, 0.01 mmol) in H ₂ O (0.4 mL) was added. The reaction mixture was heated in a high-pressure tube for 12 hours at 80 ° C., then filtered through celite, concentrated and dried. The concentrate was diluted with DCM, washed with 1N NaOH solution (3 ×), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by preparative TLC (eluent: 5 / 94.5 / 0.5, MeOH / DCM / NH ₄ OH) to give Example 106 (63.3 mg, 63.3%) Obtained as a mixture of isomers. _{LC-MS C 35 H 41 FN} 2 O Calculated: 524.29, measured ^{value: [M + H] + 525.4} .

(Example 107)

This product was prepared in a manner similar to that of Example 106 except that phenylboronic acid was replaced with 4-pyridylboronic acid. The crude product was purified by preparative TLC (eluent: 10/89 / 1.0, MeOH / DCM / NH ₄ OH) to give Example 107 as a mixture of two cis isomers. _{LC-MS C 34 H 40 FN} 3 O Calculated: 525.26, measured ^{value: [M + H] + 526.3} .

(Example 108)

This product was prepared in a manner similar to that of Example 106 except that phenylboronic acid was replaced with 3-pyridylboronic acid. The crude product was purified by preparative TLC (eluent: 10/89 / 1.0, MeOH / DCM / NH ₄ OH) to give Example 108 as a mixture of two cis isomers. _{LC-MS C 34 H 40 FN} 3 O Calculated: 525.26, measured ^{value: [M + H] + 526.3} .

(Example 109)

This product was prepared in a manner similar to that of Example 106 except that phenylboronic acid was replaced with 2-pyridylboronic acid. The crude product was purified by preparative TLC (eluent: 10/89 / 1.0, MeOH / DCM / NH ₄ OH) to give Example 109 as a mixture of two cis isomers. _{LC-MS C 34 H 40 FN} 3 O Calculated: 525.26, measured ^{value: [M + H] + 526.3} .

(Example 110)

  Step A

To ice-cold concentrated sulfuric acid, 1,2,3,4-tetrahydroisoquinoline (23 mL, 170 mmol) and then potassium nitrate (18.8 g, 186 mmol) were added dropwise at such a rate that the temperature did not rise above 5 ° C. After the addition was complete, the mixture was stirred at room temperature for 18 hours and then poured into a stirring mixture of ice (700 g) and NH ₄ OH (150 mL). The mixture was extracted with CHCl ₃ (3 × 300 mL). The combined CHCl ₃ layers were washed with saturated NaCl (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in ethanol (130 mL) and cooled in an ice bath while adding concentrated hydrochloric acid (22 mL). The formed precipitate was removed by filtration and recrystallized from methanol to give the product (12.45 g, 34%). ¹ H NMR 500 MHz (DMSO-d ₆ ) δ = 3.13 (2H, t, J = 6.2 Hz), 3.35 (2H, t, J = 6.2 Hz), 4.35 (2H, s) 7.50 (1H, d, J = 8.5 Hz), 8.07 (1H, dd, J = 2.3 and 8.5 Hz), 8.19 (1H, d, J = 2.3 Hz) 10 .02 (2H, br s).

  Step B

To a suspension of the product from Step A cooled to 0 ° C. (12 g, 58 mmol) and pyridine (23.7 mL, 293 mmol) in anhydrous CH ₂ Cl ₂ (50 mL) was added trifluoroacetic anhydride (12 mL, 87 mmol). ) Was added dropwise and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured onto ice (500 g) and extracted with CH ₂ Cl ₂ (4 × 150 mL). The combined CH ₂ Cl ₂ layers were washed with 1N HCl (4 × 100 mL), saturated NaCl (100 mL), dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give the product (15.92 g, 89% ) ¹ H NMR 500 MHz (CDCl ₃ ) δ = 3.07 (2H, m), 3.91 and 3.94 (2H, t, J = 6.2 Hz), 4.85 and 4.88 (2H, s) 7.36 (1H, dd, J = 8.7 and 11.9 Hz), 8.07 (1H, dd, J = 2.3 and 8.5 Hz), 8.01 to 8.08 (2H m) .

  Step C

A solution of the product from Step B (16 g, 58 mmol) in ethanol (200 mL) was hydrogenated with Parr Apparatus under 50 psi, PtO ₂ until the absorption of hydrogen ceased. The catalyst was removed and the filtrate was concentrated in vacuo by filtration through celite to give the product (14.2 g, 100%). ¹ H NMR 500 MHz (CDCl ₃ ) δ = 2.84 (2H, t, J = 5.7 Hz), 3.35 (2H, br s), 3.80 and 3.84 (2H, t, J = 6) .0Hz), 4.64 and 4.69 (2H, s), 6.45 (1H, d, J = 10.0Hz), 6.57 (1H, td, J = 2.4 and 8.5Hz) ), 6.95 (1H, d, J = 8.5 Hz).

  Step D

To a solution of the product obtained in Step C (2.0 g, 8.7 mmol) in toluene (50 mL) was added N, N-dimethylformamide azine (2.3 g, 16 mmol) and a spatula tip of toluenesulfonic acid. The resulting mixture was heated at reflux for 24 hours. The mixture was concentrated in vacuo and the residue was partitioned between CH ₂ Cl ₂ (50 mL) and water (50 mL). The organic layer was separated and washed with saturated NaHCO ₃ (25 mL) and saturated NaCl (25 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was triturated with CH ₂ Cl ₂ (4 mL), filtered and dried to give the product (1.0 g, 39%). ¹ H NMR 500 MHz (CDCl ₃ ) δ = 3.05 (2H, t, J = 5.7 Hz), 3.90 and 3.95 (2H, t, J = 6.0 Hz), 4.83 and 4. 89 (2H, s), 7.20 (1H, d), 7.26 (1H, t), 7.38 (1H, t) 8.45 (2H, s).

  Step E

To a solution of the product obtained from Step D (1.0 g, 3.4 mmol) in ethanol (50 mL) was added potassium carbonate (2.3 g, 17 mmol) in water (10 mL) and the resulting mixture was refluxed. For 90 minutes. The cooled reaction mixture was concentrated in vacuo and the solid residue was extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined CH ₂ Cl ₂ layers were evaporated in vacuo and the residue was purified by silica column chromatography eluting with 10% CH ₃ OH in CH ₂ Cl ₂ containing 0.5% NH ₄ OH to give the product (550 mg, 82%) was obtained. ¹ H NMR 500 MHz (CDCl ₃ ) δ = 2.69 (1H, br s), 2.85 (2H, t, J = 5.9 Hz), 3.17 (2H, t, J = 6.0 Hz), 4.07 (2H, s), 7.20 (1H, d, J = 1.8 Hz), 7.14 (1H, dd, J = 1.8 and 8.0 Hz), 7.23 (1H, d , J = 8.0 Hz), 8.43 (2H, s).

  Step F

This product was prepared in a manner similar to that of Example 81, except that Intermediate 1 was replaced with the product described in Step E. The crude product was purified by preparative TLC (eluent: 10% methanol: 89.5% DCM: 0.5% NH ₄ OH) to give Example 30 as a mixture of two cis isomers. _{LC-MS C 31 H 38 FN} 5 O Calculated: 515.31, measured ^{value: [M + H] + 516} .

(Example 111)

  Step A

To a solution of trifluoroacetamide (7.5 g, 31 mmol) prepared in Step 110 of Example 110 in ethanol (200 mL) was added potassium carbonate (17 g, 120 mmol) in water (50 mL) and the resulting mixture was refluxed. For 90 minutes. The cooled reaction mixture was concentrated in vacuo and the residue was diluted with water (200 mL). This mixture was extracted with CH ₂ Cl ₂ (3 × 100 mL). The combined CH ₂ Cl ₂ layers were dried over Na ₂ SO ₄ , filtered and concentrated to give the product (3.76 g, 83%). ¹ H NMR 500 MHz (CDCl ₃ ) δ = 2.69 (2H, t, J = 6.0 Hz), 3.11 (2H, t, J = 6.0 Hz), 3.45 (2H, br s), 3.92 (2H, s), 6.36 (1H, d, J = 2.3 Hz), 6.52 (1H, dd, J = 2.3 and 8.0 Hz), 6.89 (1H, d , J = 8.0 Hz).

  Step B

To a solution of the product from Step A (3.76 g, 25.4 mmol) in tetrahydrofuran (100 mL) was added triethylamine (4.24 mL, 30.5 mmol) and benzyl chloroformate (4.0 mL, 28 mmol) to obtain The resulting mixture was stirred at room temperature for 4 hours. Ethyl acetate (100 mL) was added to the reaction mixture and the whole was washed with water (250 mL), 5% citric acid solution (150 mL), saturated NaHCO ₃ (150 mL), and saturated NaCl (100 mL), dried over MgSO ₄ , Filtration and concentration in vacuo gave the product (7.2 g, 100%).

  Step C:

To a solution of the product from Step B cooled in an ice bath (7.2 g, 25 mmol) and pyridine (5.1 mL, 64 mmol) in CH ₂ Cl ₂ (150 mL) was added trifluoroacetic anhydride (5.38 mL, 38.1 mmol) was added and the resulting mixture was stirred at room temperature for 5 hours. The mixture was poured onto ice (150 g) and extracted with CH ₂ Cl ₂ (4 × 100 mL). The combined CH ₂ Cl ₂ layers were washed with 1N HCl (4 × 75 mL), saturated NaCl (100 mL), dried over MgSO ₄ , filtered and evaporated. The residue was dissolved in CCl ₄ (200 mL), triphenylphosphine (10 g, 38 mmol) was added and the resulting mixture was heated at reflux for 15 hours, cooled and concentrated in vacuo. The residue was dissolved in anhydrous N, N-dimethylformamide (150 mL) and this solution was added to a solution of sodium azide (1.65 g, 25.4 mmol) in anhydrous N, N-dimethylformamide (75 mL) and the resulting mixture Was stirred at room temperature for 3 hours. The reaction mixture was poured into water (500 mL) and extracted with Et ₂ O (3 × 100 mL). The combined Et ₂ O layers were washed with water (2 × 250 mL), saturated NaCl (100 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 10% EtOAc in hexane to 20% EtOAc in hexane to give the product (3.4 g, 33%). ¹ H NMR 500 MHz (CDCl ₃ ) δ = 2.99 (2H, br m), 3.80 (2H, t, J = 6.0 Hz), 4.75 (2H, s), 5.21 (2H, s), 7.20-7.45 (8H, m).

  Step D:

10% palladium on carbon (500 mg) was added to a solution of the product from Step C (3.4 g, 8.4 mmol) in methanol (100 mL), flushed with nitrogen, and the resulting mixture was added under a balloon of hydrogen. Stir for 5 hours. The catalyst was removed by filtration through celite and the filtrate was evaporated in vacuo to give the product (2.2 g, 97%). ¹ H NMR 500 MHz (CDCl ₃ ) δ = 2.33 (1H, br s), 2.91 (2H, t, J = 6.0 Hz), 3.19 (2H, t, J = 6.0 Hz), 4.08 (2H, s), 7.14 (1H, d, 1.8 Hz), 7.22 (1H, dd, J = 1.8 and 8.2 Hz), 7.31 (1H, d, J = 8.2 Hz).

  Step E:

This product was prepared in a manner similar to that of Example 81, except that Intermediate 1 was replaced with the product described in Step D. The crude product was purified by preparative TLC (eluent: 10% methanol: 89.5% DCM: 0.5% NH ₄ OH) to give Example 31 as a mixture of two cis isomers. _{LC-MS C 31 H 36 F} 3 N 6 O Calculated: 584.29, measured ^{value: [M + H] + 585} .

(Example 112)

This product was prepared in a manner similar to that of Example 81, except that Intermediate 1 was replaced with commercially available 6,7-diethoxy-tetrahydroisoquinoline. The crude product was purified by preparative TLC (eluent: 5% ethanol: 94% DCM: 1.0% NH ₄ OH) to give Example 32 as a mixture of two cis isomers. Calculated _{LC-MS C 33 H 45 FN} 2 O 3: 536.34, measured ^{value: [M + H] + 537} .

(Example 113)

  Step A

This product was prepared in a similar manner to Intermediate 1 except that 2-fluoro-4-trifluoromethylphenylacetonitrile was replaced with 3,4-di-fluoromethylphenylacetonitrile. Calculated _{LC-MS C 9 H 9 F} 2 N: 169.07, measured ^{value: [M + H] + 170.1} .

  Step B

This product was prepared in a manner similar to that of Example 81 except that Intermediate 1 was replaced with the product described in Step A. The crude product was purified by preparative TLC (eluent: 6% ethanol: 93% DCM: 1.0% NH ₄ OH) to give Example 33 as a mixture of two cis isomers. _{LC-MS C 29 H 35 F} 3 N 2 O Calculated: 484.27, measured ^{value: [M + H] + 485} .

(Example 114)

This product was prepared in a manner similar to that of Example 82, except that Intermediate 8 was replaced with commercially available 4-hydroxy-4-phenylpiperidine. The crude product was purified by preparative TLC (eluent: 10% methanol: 89% DCM: 1.0% NH ₄ OH) to give Example 114 as a mixture of 4 isomers. _{LC-MS C 30 H 37 F} 3 N 2 O 2 Calculated: 514.28, measured ^{value: [M + H] + 515} .

(Examples 115 and 116)

Intermediate 5 (100 mg, 0.22 mmol), 4-fluorophenylpiperidine hydrochloride (57 mg, 0.26 mmol), diisopropylethylamine (45 μL, 0.26 mmol) and crushed molecular sieves (4Å, 50 mg) in dichloroethane (5 mL) The solution was treated with sodium triacetoxyborohydride (233 mg, 1.10 mmol) and stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate (10 mL) and further diluted with 10 mL DCE. The organic layer was separated and the aqueous layer was washed with dichloromethane (2 × 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC (eluent; 0.5% NH ₄ OH: 5% MeOH: 94.5% CH ₂ Cl ₂ ), and 72.3 mg (63%) of the final product Obtained as a mixture of stereomers. Separations were performed using an HPLC equipped with a preparative ChiralCel OD column eluting with 15% ethanol and 85% hexane eluent at a flow rate of 9 mL / min. This gave the undesired trans isomer (35 mg, 50%) and the desired cis isomer (25 mg, 36%). Total yield was 86%. Calculated _{LC-MS C 29 H 35 N} 3 OF 4: 517.28, measured ^{value: [M + H] + 518.3} .

Example 115: ¹ H NMR (first isomer, undesired) (500 MHz, CDCl ₃ ) δ 8.73 (s, 1H), 7.69 (s, 1H), 7.20 (app dd, J = 5.5, 8.6 Hz, 2H) 6.98 (app t, J = 8.6 Hz, 2H), [4.88 (d, J = 17.5 Hz, 1H), 4.80 (d, J = 17.5 Hz, 1H) (ABx q)] 4.05 to 3.96 (m, 1H), 3.88 (app dt, J = 5.9, 13.1 Hz, 1H), 3.27 (br d , J = 11.4 Hz, 1H), 3.12 (br t, J = 5.6 Hz, 3H), 2.83 (dd, J = 5.7, 11.9 Hz, 1H), 2.52-2 .44 (m, 1H), 2.43 to 2.34 (m, 1H), 2.16 to 1.95 (m, 6H), 1.86 to 1.74 ( m, 4H), 1.45 (br t, J = 10.0, 3H), 1.03 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H) .

Example 116: ¹ H NMR (second isomer, desired) (500 MHz, CDCl ₃ ) δ 8.72 (s, 1H), 7.69 (s, 1H), 7.19 (app dd, J = 5.5, 8.6 Hz, 2H) 6.98 (app t, J = 8.6 Hz, 2H), [4.94 (br s, 1H), 4.69 (br d, J = 17.6 Hz). , 1H) (ABx q)] 4.05 to 3.80 (m, 1H), 3.20 to 3.08 (m, 4H), 2.68 (dd, J = 6.6, 12.8 Hz, 1H), 2.52 to 2.43 (m, 2H), 2.28 (dd, J = 7.3, 12.8 Hz, 1H), 2.14 to 2.00 (m, 3H), 97-1.87 (m, 2H), 1.83 (brd, J = 12.8 Hz, 2H) 1.75 (brd, 12.4 Hz, 2H), 1.56 1.48 (m, 1H), 1.42~1.34 (m, 1H), 1.01 (d, J = 6.5Hz, 3H), 0.80. (D, J = 6.6 Hz, 3H).

(Example 117)

Pyrimidylpiperidine hydrochloride (Intermediate 8, 133 mg, 0.564 mmol) was added Intermediate 5 (100 mg, 0.282 mmol), DIEA (240 μL, 1.40 mmol), and 4Å powdered molecular sieve (200 mg) in DCM. ). After 15 minutes at room temperature, sodium triacetoxyborohydride (300 mg, 1.41 mmol) was added and the resulting mixture was stirred for 3 days, then filtered through celite, diluted with DCM, saturated sodium bicarbonate and brine. Washed. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and the crude oil was purified by preparative TLC (silica gel, 0.5% NH ₄ OH / 4.5% MeOH / 95% DCM). 126 mg of a colorless oil was obtained. Resolution of the cis / trans isomer was performed by HPLC using a ChiralPak OD column eluting with 20% ethyl alcohol / hexane to give 57 mg of the trans isomer and 45 mg of the cis isomer.

  First peak 57 mg: Calculated for ESI-MS C27H34F3N5O: 501.27, found: 502 (M + H).

  Second peak 45 mg: Calculated for ESI-MS C27H34F3N5O: 501.27, found: 502 (M + H).

(Examples 118 to 129)

  Several other examples were prepared similar to Example 117 using different piperidine intermediates. Examples of these (118 to 129) are shown below.

(Example 130)

  Step A

The ketone was obtained from racemic intermediate 6 on a ChiralCel OD preparative column, eluting with 15% ethyl alcohol in hexane and resolving at 9.0 mL / min. The retention time of the first eluting enantiomer was 11.25 minutes under similar analytical conditions (1.0 mL / min). Calculated _{LC-MS C 17 H 19 F} 3 N 2 O 3: 356.13, measured ^{value: 357.05 [M + H] +} .

  Step B

The final compound was synthesized according to the procedure described in Example 19, starting from the previously eluting ketone and intermediate 10 described in Step A of this example. Each mixture of cis and trans diastereoisomers was separated by preparative TLC. _{LC-MS C 24 H 31 F} 3 N 6 O 2 Calculated: 492.25, measured ^{value: 493.30 [M + H] +} .

(Example 131)

This compound was synthesized according to the procedure described in Example 19, starting from the ketone preparation described in Step A of Example 130 and Intermediate 9. _{LC-MS C 26 H 32 F} 3 N 5 O 2 Calculated: 503.25, measured ^{value: 504.25 [M + H] +} .
(Example 132)

  Step A

This ketone was prepared according to the procedure described for Intermediate 6 except that methoxymethyl chloride was used in place of the acetaldehyde of Step 6 of Intermediate 6. Each enantiomer was obtained by HPLC separation using a ChiralCel OD preparative column (eluent hexane: ethyl alcohol / 85: 15, 9.0 mL / min). _{LC-MS C 26 H 32 F} 3 N 5 O 2 Calculated: 503.25, measured ^{value: 504.25 [M + H] +} .

  Step B

The final compound was prepared according to the procedure described in Example 19 starting from the ketone obtained from Step A and 4- (4-fluorophenyl) piperidine. Each isomer was obtained by preparative TLC (eluent ethyl acetate: ethyl alcohol: ammonium hydroxide / 90: 9: 1). _{LC-MS C 26 H 32 F} 3 N 5 O 2 Calculated: 503.25, measured ^{value: 504.70 [M + H] +} .

(Example 133)

  Step A

To a mixture containing 2- (trifluoromethyl) acrylic acid (20.0 g, 143 mmol) and benzyl alcohol (14.8 mL, 142 mmol) in DCM (150 mL) was added EDC (40.93 g, 214.2 mmol) at once. added. The reaction mixture was stirred for 2 h, diluted with DCM, washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 5% EtOAc / hexanes) to give the product as a viscous oil (13.7 g, 42%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.36-7.43 (m, 5H), 6.78 (d, 1H), 6.48 (d, 1H), 5.32 (s, 2H).

  Step B

In a flame-dried flask, 2-[(trimethylsilyl) methyl] -2-propen-1-yl acetate (12.18 mL, 57.35 mmol) and the intermediate described in Example 52, Step A (13.2 g, A solution of 57.4 mmol) and tetrakis (triphenylphosphine) palladium (0) (13.3 g, 11.5 mmol) in THF (200 mL) was added under nitrogen. The reaction mixture was refluxed overnight, diluted with DCM (150 mL), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 100% hexane to 2.5% EtOAc / hexane to 5% EtOAc / hexane) to give the product (11.68 g, 71.7%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.33 to 7.42 (m, 5H), 5.23 (s, 2H), 4.93 (m, 2H), 3.03 (m, 1H), 2.78 (m, 1H), 2.36 to 2.52 (m, 3H), 2.12 to 2.24 (m, 1H).

  Step C

A solution of the product described in Step B (11.6 g, 40.8 mmol) in DCM (150 mL) was cooled to −78 ° C. and saturated with nitrogen. Ozone was bubbled through the reaction mixture until the solution turned blue, then triphenylphosphine (12.8 g, 49.0 mmol) was added to the mixture. The reaction mixture was stirred overnight and then evaporated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 30% EtOAc / hexane) to give the title compound (8.49 g, 72.7%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.33-7.42 (m, 5H), 5.26 (s, 2H), 2.92 (m, 1H), 2.65 (m, 1H), 2.35 to 2.54 (m, 4H).

  Step D

To a solution of the intermediate described in Step C (1.00 g, 3.49 mmol) in ethanol (60 mL) was added Pd / C (10%, 100 mg). The reaction mixture was placed in Parr-shaker, shaken for 1.5 hours under a _{H 2} pressure of 50 lb. The solution was diluted with methanol, filtered through celite and evaporated under vacuum to give the acid (692 mg, 100%) as a yellow oil. LC-MS Calculated for C7H7F3O3: 196.03, found: 197 (M + H).

  Step E

To a mixture of the product described in Step D (684 mg, 3.49 mmol), EDC (2.01 g, 10.5 mmol), and Intermediate 2 (916 mg, 3.84 mmol) in DCM (30 mL) was added DIEA (670 μL, 3 mL). .84 mmol) was added and the resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel, 50% EtOAc / hexane) to give the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.75 (s, 1H), 7.71 (s, 1H), 4.86 (d, J = 5.5 Hz, 2H), 3.91 to 4.08 (M, 2H), 3.18 (t, J = 5.0 Hz, 2H), 2.98 (s, 2H), 2.64 to 2.85 (m, 2H), 2.43 to 2.56 (M, 2H). LC-MS Calcd for C16H14F6N2O2: 380.10, found: 381 (M + H).

  Step F

Compound described in Step E (100 mg, 0.263 mmol), 4-phenylpiperidine HCl salt (52 mg, 0.26 mmol), molecular sieve (4Å, 180 mg), DIEA (46 μL, 0.26 mmol) in DCM (5 mL). To the mixture containing was added sodium triacetoxyborohydride (167 mg, 0.789 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction was diluted with DCM, filtered through celite and evaporated under reduced pressure. The residue was purified by preparative TLC (1000 microns, eluent; 0.4% aqueous NH ₄ OH: 4% MeOH: 95.6% DCM) to give a mixture of cis and trans isomers as the free base. The cis and trans isomers were separated by preparative chiral HPLC (chiral OD column, eluent: 5% EtOH / hexane) to give the final product, the title compound, as the desired cis isomer. The HCl salt (20.4 mg) was formed by treatment with 4N HCl / dioxane. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.74 (s, 1H), 7.70 (s, 1H), 7.20-7.35 (m, 5H), 4.85 (m, 2H), 3.99 (m, 2H), 3.14 to 3.24 (m, 5H), 2.46 to 2.56 (m, 3H), 2.02 to 2.22 (m, 5H), 1. 70-1.91 (m, 5H). LC-MS Calculated for C27H29F6N3O: 525.22, found: 526 (M + H).

(Example 134)

  Step A

  A stirred solution of cyclohexene (15 mL) in 100 mL of dichloromethane at −78 ° C. was bubbled with ozone until a light blue color appeared. Excess ozone was removed with a stream of nitrogen and then 60 mL of dimethyl sulfide was added. The mixture was left overnight and dried over sodium sulfate. Solvent and DMS were removed under low vacuum. The crude product was used in the next step without further purification.

  Step B

Intermediate 27 (135 mg, 0.3 mmol) in DCM (10 mL, crude material), 1,6-hexane-dialdehyde obtained from Step A (˜100 mg), molecular sieves (4１３０, 50 mg), DIEA (130 mg) , 1.0 mmol) was stirred for 5 minutes. Then sodium triacetoxyborohydride (424 mg, 2.0 mmol) was added. The resulting mixture was stirred for 2 hours, quenched with saturated aqueous Na ₂ CO ₃ solution, filtered and washed with DCM. The filtrate was separated and the aqueous solution was extracted with DCM. The combined DCM layers were dried over Na ₂ SO ₄ and evaporated. The residue was purified by preparative TLC (1000 microns) (developed with 10% [aq. NH ₄ OH / MeOH 1/9] / DCM) to give the title compound as the final product as the free base. The HCl salt (42 mg) was formed by treatment with 4M HCl / dioxane. Calculated _{ESI-MS C 25 H 34 F} 3 N 3 O 3: 481, measurements: 482 (M + H).

(Example 135)

  A mixture of Example 134 (35 mg), Pd / C (5%, 5 mg) and methanol (20 mL) was hydrogenated with Parr Apparatus for 1 hour. The catalyst was removed by filtration. The filtrate was evaporated to give the title product as a white solid (32 mg). ESI-MS calculated for C25H36F3N3O: 451, measured: 452 (M + H).

(Example 136)

  Step A

  A stirred solution of cycloheptene (5 mL) in dichloromethane (50 mL) at −78 ° C. was bubbled with ozone until a light blue color appeared. Excess ozone was removed with a stream of nitrogen and then 20 mL of dimethyl sulfide was added. The mixture was left overnight and dried over sodium sulfate. Solvent and DMS were removed under low vacuum. The crude product was used in the next step without further purification.

  Step B

Intermediate 27 (135 mg, 0.3 mmol) in DCM (10 mL, crude material), 1,7-heptane-dialdehyde obtained from Step A (˜100 mg), molecular sieves (4Å, 50 mg), DIEA (130 mg) , 1.0 mmol) was stirred for 5 minutes. Then sodium triacetoxyborohydride (424 mg, 2.0 mmol) was added. The resulting mixture was stirred for 2 hours, quenched with saturated Na ₂ CO ₃ , filtered and washed with DCM. The filtrate was separated and the aqueous solution was extracted with DCM. The combined DCM layers were dried over Na ₂ SO ₄ and evaporated. The residue was purified by preparative TLC (1000 microns) (developed with 10% [aq. NH4OH / MeOH 1/9] / DCM) to give the title compound as the final product as the free base. The HCl salt (50 mg) was formed by treatment with 4M HCl / dioxane. ESI-MS calcd for C26H36F3N3O3: 485, found: 486 (M + H).

(Example 137)

  Step A

  5-norbornene-2-carboxylic acid (5.4 g, 40 mmol), benzyl alcohol (4.3 g, 40 mmol), EDAC. HCl (9.5 g, 50 mmol), DIEA (5.2 g, 40 mmol) were placed in a flask and weighed. Dichloromethane 50 mL was added. The mixture was stirred overnight, washed with 2M aqueous HCl, water and saturated aqueous sodium carbonate, dried over sodium sulfate and evaporated. The residue was purified by MPLC (10% EtOAc / hexane). The title compound was obtained as a mixture of exo and endo isomers (5.2 g).

  Step B

  A stirred solution of benzyl 5-norbornene-2-carboxylate (1.2 g, 5 mmol) in dichloromethane (50 mL) at −78 ° C. was bubbled with ozone until a pale blue color appeared. Excess ozone was removed with a stream of nitrogen and then 20 mL of dimethyl sulfide was added. The mixture was left overnight and dried over sodium sulfate. Solvent and DMS were removed under low vacuum. The crude product was used in the next step without further purification.

  Step C

Intermediate 27 (86 mg, 0.2 mmol), dialdehyde ester obtained from Step B (˜200 mg), molecular sieves (4Å, 500 mg), DIEA (130 mg, 1.0 mmol) in DCM (10 mL crude). The containing mixture was stirred for 5 minutes. Then sodium triacetoxyborohydride (420 mg, 2.0 mmol) was added. The resulting mixture was stirred for 2 hours, quenched with saturated aqueous Na ₂ CO ₃ solution, filtered and washed with DCM. The filtrate was separated and the aqueous solution was extracted with DCM. The combined DCM layers were dried over Na ₂ SO ₄ and evaporated. The residue was purified by preparative TLC (1000 microns) (developed with 10% [aq. NH ₄ OH / MeOH 1/9] / DCM) to give the title compound as the final product as the free base. The HCl salt (62 mg) was formed by treatment with 4N HCl / dioxane. ESI-MS calculated for C34H40F3N3O5: 627, found: 428 (M + H).

  Step D

A mixture of the amino ester obtained from Step C (60 mg), Pd / C (5%, 100 mg) and methanol (20 mL) was hydrogenated with Parr Apparatus under 50 lb of hydrogen for 1 hour. The catalyst was removed by filtration. The filtrate was evaporated and the residue was removed by filtration. The filtrate was evaporated and the residue was purified by preparative TLC (developed with methanol) to give the title product as a white solid (18 mg). _{ESI-MS C 27 H 36 F} 3 N 3 O Calculated: 507, measurements: 508 (M + H).

(Example 138)

  Step A

Intermediate 26 (1.2 g, 4.0 mmol as HCl salt), Intermediate 23 (1.1 g, 4.0 mmol), PyBrOP (1.9 g, 4.0 mmol), DMAP (0.29 g) in 10 mL dichloromethane. (2.4 mmol) and DIEA (2.8 mL, 16 mmol) were stirred overnight at room temperature. The entire mixture was applied to a silica gel column and eluted with 20% ethyl acetate / hexane. The title compound was obtained as a white solid (1.7 g, 83%). LC-MS Calcd for C26H35F3N2O5: 512, found: [M + H-100] ⁺ 413.

  Step B

The above amide obtained from Step A (1.7 g, 3.3 mmol) was mixed with 20 mL of 4M HCl / dioxane. The resulting solution was stirred for 1 hour, evaporated and dried under high vacuum to give the title product as a white solid (1.45 g, 100%). Calculated _{LC-MS C 21 H 27 F} 3 N 2 O 3: 412, ^{measurements: [M + H] + 413} .

  Step C

The above intermediate from Step B (140 mg, 0.30 mmol), glutaraldehyde (50% H ₂ O, 120 mg, 0.60 mmol), molecular sieves (4Å, 1500 mg), DIEA (52 mg) in DCM (10 mL). , 0.40 mmol) was stirred for 5 minutes. Then sodium triacetoxyborohydride (212 mg, 1.00 mmol) was added. The resulting mixture was stirred for 1 h, quenched with saturated aqueous Na ₂ CO ₃ solution, filtered and washed with DCM. The filtrate was separated and the aqueous solution was extracted with DCM. The combined DCM layers were dried over Na ₂ SO ₄ and evaporated. The residue was purified by preparative TLC (1000 microns) (developed with 10% [aq. NH ₄ OH / MeOH 1/9] / DCM) to give the title compound as the final product as the free base. The HCl salt (80 mg) was formed by treatment with 4N HCl / dioxane. ESI-MS Calcd for C26H35F3N2O3: 480, found: 481 (M + H).

(Example 139)

A mixture of Example 138 (45 mg, 0.090 mmol), lithium hydroxide monohydrate (50 mg), water (0.1 mL) and methanol (1.0 mL) was stirred overnight at room temperature, and the entire mixture was separated. TLC applied and developed with methanol. The title compound was obtained as a white solid (34 mg). Calculated _{LC-MS C 25 H 33 F} 3 N 2 O 3: 466, ^{measurements: [M + H] + 467} .

(Example 140)

Intermediate (140 mg, 0.30 mmol) obtained from Step B of Example 138 in DCM (20 mL), 1,6-hexanedialdehyde (˜100 mg) obtained from Step A of Example 136, molecular sieve (4Å, 500 mg), a mixture containing DIEA (130 mg, 1.00 mmol) was stirred for 5 minutes. Then sodium triacetoxyborohydride (424 mg, 2.00 mmol) was added. The resulting mixture was stirred for 1 hour, washed with saturated aqueous Na ₂ CO ₃ solution, filtered and washed with DCM. The filtrate was separated and the aqueous solution was extracted with DCM. The combined DCM layers were dried over Na ₂ SO ₄ and evaporated. The residue was purified by preparative TLC (1000 microns) (developed with 10% [aq. NH ₄ OH / MeOH 1/9] / DCM) to give the title compound as the final product as the free base. The HCl salt (75 mg) was formed by treatment with 4M HCl / dioxane. Calculated _{ESI-MS C 27 H 37 F} 3 N 2 O 3: 494, measurements: 495 (M + H).

(Example 141)

  A mixture of Example 140 (20 mg, 0.04 mmol), lithium hydroxide monohydrate (50 mg), water (0.1 mL) and methanol (1.0 mL) was stirred overnight at room temperature, and the entire mixture was separated. TLC applied and developed with methanol. The title compound was obtained as a white solid (15 mg). LC-MS Calcd for C26H35F3N2O3: 480, found: 481 (M + H).

(Example 142)

  Step A

To a solution of intermediate 29 (190 mg, 1.1 mmol) in 1 mL of dichloromethane was added a solution of oxalyl chloride (2M, 0.70 mL, 1.4 mmol) in dichloromethane followed by a small amount of DMF. The mixture was stirred at room temperature for 30 minutes and then evaporated under vacuum to remove the solvent and excess reagent. The residue was dissolved in 1 mL of dichloromethane and added to a solution of intermediate 2 (295 mg, 1.00 mmol) and DIEA (260 mg, 2.0 mmol) in dichloromethane (2 mL). The reaction was stirred for 2 hours. The entire mixture was applied to a preparative TLC plate (1000 microns) and developed with 10% MeOH / DCM. The title compound was obtained as a yellow solid (300 mg). LC-MS Calculated for C21H24F3NO4: 411, found: [M + H] ⁺ 412.

  Step B

The above ketone from step A (300 mg, 0.73 mmol), 4-fluorophenylpiperidine hydrochloride (214 mg, 1.00 mmol), DIEA (129 mg, 1.00 mmol), molecular sieve (4Å, 500 mg) in 10 mL of dichloromethane. ) And sodium triacetoxyborohydride (212 mg, 1.00 mmol) was stirred over the weekend at room temperature, quenched with saturated aqueous sodium carbonate, extracted with dichloromethane, and preparative TLC (1000 microns). Purified eluting with 10% MeOH / DCM. The title compound was obtained as a mixture of cis and trans isomers (270 mg). Calculated _{LC-MS C 32 H 38 F} 4 N 2 O 3: 574, ^{measurements: [M + H] + 575} .

(Example 143)

A mixture of Example 142 (22 mg, 0.04 mmol) and lithium hydroxide monohydrate (30 mg) in MeOH / H ₂ O (9/1, 0.5 mL) was stirred at 60 ° C. for 2 hours until all The mixture was applied to a preparative TLC plate and developed with methanol. The title compound was obtained as a white solid (12 mg). Calculated _{LC-MS C 31 H 34 F} 4 N 2 O 3: 560, ^{measurements: [M + H] + 561} .

(Example 144)

  Step A:

Intermediate 29 (100 mg, 0.588 mmol) was dissolved in DCM (20 mL) followed by treatment with oxalyl chloride (153 μL, 1.76 mmol) and DMF (1 drop). The resulting solution was stirred at room temperature for 2 hours, then concentrated to dryness and further dried under high vacuum for 30 minutes. The resulting residue was dissolved in DCM (5 mL) and a solution of intermediate 1 (177 mg, 0.882 mmol) in DCM (5 mL) and triethylamine (5 mL) were added dropwise. The resulting reaction mixture was stirred at room temperature overnight then diluted with DCM and washed with bicarbonate, 1N aqueous HCl, and brine. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 230 mg of the desired crude product. This was used in the next step without further purification.

  Step B:

Product from previous step (115 mg, 0.326 mmol) in 10 mL of dichloromethane, ethyl 3-piperidin-4-ylbenzoate (131 mg, 0.489 mmol), DIEA (83 μL, 0.49 mmol), A mixture containing molecular sieves (4Å, 100 mg) and sodium triacetoxyborohydride (346 mg, 1.63 mmol) was stirred over the weekend at room temperature, quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and preparative. Purified by TLC (silica gel, eluted with 40% THF / hexane). The title compound was obtained as a mixture of cis and trans isomers (200 mg). Calculated _{LC-MS C 33 H 41 F} 3 N 2 O 3: 570.3, ^{measurements: [M + H] + 571.6} .

  Individual stereoisomers were obtained by resolution on a ChiralCel OD column eluting with 10% ethanol / hexane.

Peak 1: Calculated for LC-MS C33H41F3N2O3: 570.3, found: [M + H] ⁺ 571.6.

Peak 2: Calculated for LC-MS C33H41F3N2O3: 570.3, found: [M + H] ⁺ 571.6.

(Example 145)

A mixture of Example 144 Peak 2 (80 mg), lithium hydroxide monohydrate (30 mg) in EtOH / H ₂ O (4/1, 4 mL) was stirred at room temperature overnight. The product was purified by reverse phase HPLC and converted to the HCl salt in the usual manner. The title compound was obtained as a white solid (45 mg). LC-MS calcd for C31H37F3N2O3: 542.28, found: [M + H] ⁺ 543.

(Example 146)

A mixture of Example 144 peak 1 (78 mg), lithium hydroxide monohydrate (30 mg) in EtOH / H ₂ O (4/1, 4 mL) was stirred at room temperature overnight. The product was purified by reverse phase HPLC and converted to the HCl salt by conventional methods. The title compound was obtained as a white solid (49 mg). Calculated _{LC-MS C 31 H 37 F} 3 N 2 O 3: 542.28, measured ^{value: [M + H] + 543} .

(Example 147)

  Example 147 is prepared according to the procedure described in Example 144 except that intermediate 30 is used in place of the hydrochloride salt of ethyl 3-piperidin-4-ylbenzoate. The resulting four stereoisomers are separated by chiral chromatography.

(Example 148)

  Example 148 is prepared according to the procedure described in Example 145 except that one of the stereoisomers obtained from Example 147 is used in place of one of the products obtained from Example 144.

(Example 149)

  Example 149 is prepared according to the procedure described in Example 145 except that one of the stereoisomers obtained from Example 147 is used in place of one of the products obtained from Example 144.

(Example 150)

  Example 150 is prepared according to the procedure described in Example 145 except that one of the stereoisomers obtained from Example 147 is used in place of one of the products obtained from Example 144.

(Example 151)

  Example 151 is prepared according to the procedure described in Example 145 except that one of the stereoisomers obtained from Example 147 is used in place of one of the products obtained from Example 144.

Claims (19)

Compounds of formula I and their pharmaceutically acceptable salts and their respective diastereomers

[Where:
X is selected from the group consisting of C, N, O, S and SO ₂ ;
Y is N or C;
R ¹ is hydrogen, —C _1-6 alkyl, —C _0-6 alkyl-O—C _1-6 alkyl, —C _0-6 alkyl-S—C _1-6 alkyl, — (C _0-6 alkyl). - _{(C 3 to 7} cycloalkyl) - _{(C Less than six} alkyl), hydroxy, ^{heterocycle, -CN, -NR 12 R 12,} -NR 12 COR 13, -NR 12 SO 2 R 14, -COR 11, Selected from the group consisting of -CONR ¹² R ¹² and phenyl;
R ¹¹ is independently selected from the group consisting of hydroxy, hydrogen, C _1-6 alkyl, —O—C _1-6 alkyl, benzyl, phenyl and C _3-6 cycloalkyl, wherein said alkyl, phenyl, benzyl and The cycloalkyl group may be unsubstituted or substituted with 1 to 3 substituents, and the substituents are independently halo, hydroxy, C _1-3 alkyl, C _1-3 alkoxy, —CO ₂ H, — is selected from CO ₂ -C _{1 to 6} alkyl and the group consisting of trifluoromethyl,
R ¹² is selected from the group consisting of hydrogen, C _1-6 alkyl, benzyl, phenyl, and C _3-6 cycloalkyl, wherein the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1 to 3 substituents The substituent is independently composed of halo, hydroxy, C _1-3 alkyl, C _1-3 alkoxy, —CO ₂ H, —CO ₂ —C _1-6 alkyl and trifluoromethyl. Selected from the group,
R ¹³ is selected from the group consisting of hydrogen, C _1-6 alkyl, —O—C _1-6 alkyl, benzyl, phenyl and C _3-6 cycloalkyl, wherein the alkyl, phenyl, benzyl and cycloalkyl groups are non- It may be those substituted in one to three substituents substituted independently halo substituents thereof, _{hydroxy, C 1-3 alkyl, C 1-3 alkoxy, -CO 2 H, -CO 2 -C} 1 is selected from the group consisting of ₆ alkyl and trifluoromethyl,
R ¹⁴ is selected from the group consisting of hydroxy, C _1-6 alkyl, —O—C _1-6 alkyl, benzyl, phenyl and C _3-6 cycloalkyl, wherein the alkyl, phenyl, benzyl and cycloalkyl groups are non- It may be those substituted in one to three substituents substituted independently halo substituents thereof, _{hydroxy, C 1-3 alkyl, C 1-3 alkoxy, -CO 2 H, -CO 2 -C} 1 is selected from the group consisting of ₆ alkyl and trifluoromethyl,
The alkyl and the cycloalkyl are unsubstituted or substituted with 1 to 7 substituents, the substituents being independently (a) halo,
(B) hydroxy,
(C) -O-C _1-3 alkyl,
(D) trifluoromethyl,
(F) C _1-3 alkyl,
(G) -O-C _1-3 alkyl,
(H) -COR ¹¹ ,
_(I) -SO ^{2 R 14,}
(J) -NHCOCH _3,
(K) -NHSO ₂ CH _3,
(L) -heterocycle,
(M) = O and (n) -CN
Selected from the group consisting of
The phenyl and heterocyclic rings are unsubstituted or substituted with 1 to 3 substituents, and the substituents are independently halo, hydroxy, C _1-3 alkyl, C _1-3 alkoxy and trifluoromethyl. Selected from the group consisting of
R ² is (a) hydrogen,
(B) hydroxy,
(C) Halo,
(D) C _1-3 alkyl, where alkyl is unsubstituted or substituted with 1-6 substituents independently selected from fluoro and hydroxy
^{(E) -NR 12 R} 12,
(F) -COR ¹¹ ,
(G) -CONR ¹² R ¹² ,
(H) -NR ¹² COR ¹³ ,
(I) -OCONR ¹² R ¹² ,
^{(J) -NR 12 CONR 12 R} 12,
(K) -heterocycle,
(L) -CN,
^{_{(M) -NR 12 -SO 2 -NR}} 12 R 12,
^{_{(N) -NR 12 -SO 2 -R}} 14,
(O) —SO ₂ —NR ¹² R ¹² and (p) ═O, (R ² is attached to the ring via a double bond)
Selected from the group consisting of
R ³ is oxygen or absent when Y is N;
R ³ is when Y is C,
(A) hydrogen,
(B) hydroxy,
(C) Halo,
(D) C _1-3 alkyl, where alkyl is unsubstituted or independently substituted with 1-6 substituents selected from fluoro, hydroxy and —COR ^{11
(E) -NR 12 R} 12,
(F) -COR ¹¹ ,
(G) -CONR ¹² R ¹² ,
(H) -NR ¹² COR ¹³ ,
(I) -OCONR ¹² R ¹² ,
^{(J) -NR 12 CONR 12 R} 12,
(K) -heterocycle,
(L) -CN
^{_{(M) -NR 12 -SO 2 -NR}} 12 R 12,
^{_{(N) -NR 12 -SO 2 -R}} 14,
(O) —SO ₂ —NR ¹² R ¹² and (p) nitro
R ⁴ is (a) hydrogen,
(B) C _1-6 alkyl,
(C) trifluoromethyl,
(D) trifluoromethoxy,
(E) Chloro,
(F) fluoro,
(G) selected from the group consisting of bromo and (h) phenyl;
R ⁵ is (a) C _1-6 alkyl (the alkyl may be unsubstituted or substituted with 1 to 6 fluoro, and optionally substituted with hydroxyl)
(B) —O—C _1-6 alkyl (alkyl may be unsubstituted or substituted with 1-6 fluoro)
(C) —CO—C _1-6 alkyl (the alkyl may be unsubstituted or substituted with 1-6 fluoro)
(D) —S—C _1-6 alkyl (alkyl may be unsubstituted or substituted with 1-6 fluoro)
(E) -pyridyl (which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, trifluoromethyl, C _1-4 alkyl and COR ¹¹ )
(F) fluoro,
(G) Chloro,
(H) Bromo,
(I) _{-C4-6cycloalkyl} ,
(J) -O-C _4-6 cycloalkyl,
(K) phenyl (which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, trifluoromethyl, C _1-4 alkyl and COR ¹¹ ),
(L) —O-phenyl (which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, trifluoromethyl, C _1-4 alkyl and COR ¹¹ ),
(M) -C _3-6 cycloalkyl (alkyl may be unsubstituted or substituted with ˜1-6 fluoro),
(N) -O-C _3-6 cycloalkyl (alkyl may be unsubstituted or substituted with 1-6 fluoro),
(O) -heterocycle,
(P) -CN and (q) -COR ¹¹
Selected from the group consisting of
R ⁶ is (a) hydrogen,
(B) C _1-6 alkyl,
(C) trifluoromethyl,
(D) fluoro,
(E) chloro and (f) bromo
R ⁷ is hydrogen, (C _0-6 alkyl) -phenyl, (C _0-6 alkyl) _-heterocycle , (C _0-6 alkyl) -C _3-7 cycloalkyl, (C _0-6 alkyl) -COR ¹¹ , (C _0-6 alkyl)-(alkene) -COR ¹¹ , (C _0-6 alkyl) -SO ₃ H, (C _0-6 alkyl) -W—C _0-4 alkyl, (C _0-6 Alkyl) -CONR ¹² -phenyl, (C _0-6 alkyl) -CONR ¹⁵ -V-COR ¹¹ , and absence (when X is O, S, or SO ₂ ), where V is C _{1- 6} alkyl or phenyl, and W is a group consisting of a single bond, —O—, —S—, —SO—, —SO ₂ —, —CO—, —CO ₂ —, —CONR ¹² — and —NR ¹² —. Selected from
Wherein R ¹⁵ may be hydrogen, C _1-4 alkyl, or R ¹⁵ is bonded to one of the V carbons via 1-5 carbon chains to form a ring;
C _0-6 alkyl may be unsubstituted or substituted with 1 to 5 substituents, the substituents being independently (a) halo,
(B) hydroxy,
(C) -C _0-6 alkyl,
(D) -O-C _1-3 alkyl,
Selected from (e) trifluoromethyl and (f) -C _0-2 alkyl-phenyl;
The phenyl, heterocycle, cycloalkyl, C _0-4 alkyl may be unsubstituted or substituted with 1 to 5 substituents, and the substituents are independently (a) halo,
(B) trifluoromethyl,
(C) hydroxy,
(D) C _1-3 alkyl,
(E) -O-C _1-3 alkyl,
_(F) -C 0~3 -COR ^11,
(G) -CN,
^{(H) -NR 12 R} 12,
(I) selected from the group consisting of —CONR ¹² R ¹² and (j) —C _0-3 -heterocycle,
Alternatively, the phenyl and heterocycle may be fused with another heterocycle, which is itself unsubstituted or substituted with 1 to 2 substituents independently selected from hydroxy, halo, —COR ¹¹ , —C _1-3 alkyl It may be substituted with a group,
Alkenes can be unsubstituted but independently (a) halo,
(B) trifluoromethyl,
(C) C _1-3 alkyl,
It may be substituted with 1 to 3 substituents selected from the group consisting of (d) phenyl and (e) heterocycle,
R ⁸ is (a) hydrogen,
(B) absent when X is O, S, SO ₂ or N, or when a double bond is attached to the carbon with R ⁷ and R ¹⁰ ;
(C) hydroxy,
(D) C _1-6 alkyl,
(E) C _1-6 alkyl-hydroxy,
(F) -O-C _1-3 alkyl,
(G) -COR ¹¹ ,
(H) -CONR ¹² R ¹² and (i) -CN
Selected from the group consisting of
Or R ⁷ and R ⁸ together
(A) 1H-indene,
(B) 2,3-dihydro-1H-indene,
(C) 2,3-dihydro-benzofuran,
(D) 1,3-dihydro-isobenzofuran,
(E) 2,3-dihydrobenzothiofuran,
(F) 1,3-dihydro-isobenzothiofuran,
(G) 6H-cyclopenta [d] isoxazol-3-ol,
Forming a ring selected from the group consisting of (h) cyclopentane and (i) cyclohexane,
The ring formed here is independently unsubstituted but (a) halo,
(B) trifluoromethyl,
(C) hydroxy,
(D) C _1-3 alkyl,
(E) -O-C _1-3 alkyl,
_(F) -C 0~3 -COR ^11,
(G) -CN,
^{(H) -NR 12 R} 12,
(I) ^{-CONR 12 R} 12 and _{(j) -C} 0~3 - may be those substituted with 1 to 5 substituents selected from the group consisting of heterocyclic,
Alternatively, R ⁷ and R ⁹ or R ⁸ and R ¹⁰ may be combined to form a ring that becomes phenyl or a heterocyclic ring, and the ring may be unsubstituted or independently (a) halo,
(B) trifluoromethyl,
(C) hydroxy,
(D) C _1-3 alkyl,
(E) -O-C _1-3 alkyl,
(F) -COR ¹¹ ,
(G) -CN,
(H) -NR ¹² R ¹² and (i) -CONR ¹² R ¹²
It may be substituted with 1 to 7 substituents selected from the group consisting of:
R ⁹ and R ¹⁰ are independently (a) hydrogen,
(B) hydroxy,
(C) C _1-6 alkyl,
(D) C _1-6 alkyl-COR ¹¹ ,
(E) C _1-6 alkyl-hydroxy,
(F) -O-C _1-3 alkyl,
(G) ═O (R ⁹ or R ¹⁰ is attached to the ring via a double bond) and (h) halo
n is selected from 0, 1 and 2;
Dashed lines represent single or double bonds. 2. The compound of claim 1 having the formula Ia and pharmaceutically acceptable salts and respective diastereomers

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁹ , Y and n are as defined in claim 1;
R ¹⁶ and R ¹⁷ are independently (a) hydrogen,
(B) Halo,
(C) trifluoromethyl,
(D) hydroxy,
(E) C _1-3 alkyl,
(F) -O-C _1-3 alkyl,
_{(G) -C 0~3 -CO 2 H} ,
_{(H) -C 0~3 -CO 2 C} 1~3 alkyl,
(I) selected from the group consisting of -CN and (j) _-C0-3 -heterocycle,
Or R ¹⁶ and R ¹⁷ together form a heterocyclic ring fused to a phenyl ring, which itself is unsubstituted or independently selected from hydroxy, halo, —COR ¹¹ and —C _1-3 alkyl May be substituted with ~ 2 substituents]. The compound of claim 1 having the formula Ib and pharmaceutically acceptable salts thereof and their respective diastereomers.

[In the formula, a broken line represents a single bond or a double bond, and R ¹ , R ² , R ³ , R ⁵ , R ⁹ , R ¹⁶ , R ¹⁷ , Y and n are as defined in claim 1] . The compound of claim 1 having the formula Ic and pharmaceutically acceptable salts thereof and their respective diastereomers.

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁹ , R ¹⁶ , R ¹⁷ , Y and n are as defined in claim 1 and H is a heterocycle]. 2. The compound of claim 1 having the formula Id and pharmaceutically acceptable salts and respective diastereomers thereof.

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁹ , R ¹¹ , Y, W and n are as defined in claim 1;
The C _1-4 carbon chain may be unsubstituted or independently (a) halo,
(B) hydroxy,
(C) -C _0-6 alkyl,
(D) -O-C _1-3 alkyl,
It may be substituted with 1 to 4 substituents selected from the group consisting of (e) trifluoromethyl and (f) -C _0-2 alkyl-phenyl,
Or the _{C 1 to 4} carbon chain may also be included in the _{C 3 to 7} cycloalkyl ring. 2. The compound of claim 1 having formula Ie and pharmaceutically acceptable salts and respective diastereomers thereof.

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁹ , R ¹⁶ , R ¹⁷ , X, Y and n are as defined in claim 1, and the broken line is a single bond or a double bond] Any one, o may be 1 or 2,
A, B and D are independently selected from C, N, O or S to form a phenyl ring (when X, A, B, D are all C and o = 2) or complex Create a ring (if at least one of X, A, B, D is N, O or S and not C)]. 2. The compound of claim 1 having the formula If and pharmaceutically acceptable salts and respective diastereomers thereof.

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁷ , R ⁹ , R ¹⁰ , Y and n are as defined in claim 1, X is N or O (in this case R ⁷ Is absent)]. 2. The compound of claim 1 having the formula Ig and pharmaceutically acceptable salts and respective diastereomers thereof.

[Wherein R ¹ , R ⁵ , R ⁹ , R ¹⁶ , R ¹⁷ and Y are as defined in claim 1;
Alternatively, R ¹⁶ and R ¹⁷ together form a heterocyclic ring fused with a phenyl ring, which ring itself is independently selected from the group consisting of hydroxy, halo, —COR ¹¹ and —C _1-3 alkyl. May be substituted with 1 to 2 substituents]. 2. The compound of claim 1 having the formula Ih and pharmaceutically acceptable salts thereof and their respective diastereomers.

[Wherein the broken line represents a single bond or a double bond, and R ¹ , R ⁵ , R ⁹ , R ¹⁶ , R ¹⁷ and Y are as defined herein]. 2. The compound of claim 1 having the formula Ii and pharmaceutically acceptable salts and respective diastereomers thereof.

[Wherein R ¹ , R ⁵ , R ⁹ , R ¹⁶ , R ¹⁷ and Y are as defined herein;
H is a heterocycle].
The compound of claim 1 having the formula Ij and pharmaceutically acceptable salts thereof and their respective stereoisomers.

[Wherein R ¹ , R ⁵ , R ⁹ , R ¹¹ , Y, W are as defined herein;
The C _1-4 carbon chain is independently unsubstituted but (a) halo,
(B) hydroxy,
(C) -C _0-6 alkyl,
(D) -O-C _1-3 alkyl,
It may be substituted with 1 to 4 substituents selected from the group consisting of (e) trifluoromethyl and (f) -C _0-2 alkyl-phenyl]. 2. The compound of claim 1 having the formula Ik and pharmaceutically acceptable salts thereof and their respective diastereomers.

[Wherein R ¹ , R ⁵ , R ⁹ , R ¹⁰ and Y are as defined herein]. R ¹ is —C _1-6 alkyl, —C _0-6 alkyl-O—C _1-6 alkyl and — (C _0-6 (alkyl)-(C _3-7 cycloalkyl)-(C _0-6 alkyl). ) Is selected from the group consisting of:
Alkyl and cycloalkyl are unsubstituted or substituted with 1 to 7 substituents, the substituents being independently (a) halo,
(B) hydroxy,
(C) -O-C _1-3 alkyl,
(D) trifluoromethyl,
(F) C _1-3 alkyl,
(G) -O-C _1-3 alkyl,
(H) -COR ¹¹ ,
(I) -CN,
(J) -NR ¹² R ¹² and (k) -CONR ¹² R ¹²
The compound according to claim 1, which is selected from: R ¹ is the following (1) to (3)
(1) —C _1-6 alkyl, unsubstituted or substituted with 1-6 substituents, the substituents being independently (a) halo,
(B) hydroxy,
(C) -O-C _1-3 alkyl,
(D) trifluoromethyl and (e) -COR ¹¹
Selected from the group consisting of
(2) —C _0-6 alkyl-O—C _1-6 alkyl-, unsubstituted or substituted with _1-6 substituents, the substituents being independently (a) halo,
(B) trifluoromethyl and (c) -COR ¹¹
And (3) — (C _3-5 cycloalkyl)-(C _0-6 alkyl), unsubstituted or substituted with 1-7 substituents, the substituents independently (A) Halo,
(B) hydroxy,
(C) -O-C _1-3 alkyl,
(D) trifluoromethyl and (e) -COR ¹¹
Selected from the group consisting of
The compound of claim 1 selected from the group consisting of: R ¹ is
(A) C _1-6 alkyl,
_14. The compound of claim 13, selected from the group consisting of (b) _C1-6 alkyl substituted with hydroxy and (c) _C1-6 alkyl substituted with 1-6 fluoro. R ¹ is
_{(A) -CH (CH 3)} 2,
(B) —CH (OH) CH ₃ and (c) —CH ₂ CF ₃
15. A compound according to claim 14 selected from the group consisting of:   A pharmaceutical composition comprising an inert carrier and the compound of claim 1.   A method of modulating chemokine receptor activity in a mammal comprising administering an effective amount of the compound of claim 1.   A method for the treatment, amelioration, modulation or reduction of risk of inflammatory and immunoregulatory disorders or diseases comprising administering to a patient an effective amount of the compound of claim 1.   A method for the treatment, amelioration, modulation or reduction of risk of rheumatoid arthritis comprising administering to a patient an effective amount of a compound according to claim 1.