TDO2 inhibitor

Abstract

The present invention provides inhibitors of cell-expressed TDO2 and pharmaceutical compositions thereof, which can be used to modulate the activity of tryptophan 2,3-dioxygenase; treat immunosuppression; treat medical conditions that benefit from inhibition of tryptophan degradation; enhance the effectiveness of anti-cancer treatment including administration of anti-cancer agents; and treat tumor-specific immunosuppression associated with cancer.

Description

[0001] This application is a divisional application of the patent application with the application date of December 23, 2016, application number 201680081161.5 (PCT / CN2016 / 111730), and the invention title of "TDO2 inhibitor". Background Art Technical Field

[0002] The present invention relates to compounds and methods for inhibiting tryptophan 2,3-dioxygenase (TDO2); the present invention also relates to methods for treating diseases and disorders mediated by tryptophan deficiency.

[0003] Contents of Related Fields

[0004] Tryptophan (Trp) is an essential amino acid required for the biosynthesis of proteins, niacin, and the neurotransmitter 5-hydroxytryptamine (serotonin). The enzymes indoleamine 2,3-dioxygenase 1 (also known as INDO1 or IDO1), indoleamine-2,3-dioxygenase 2 (INDOL1 or IDO2), and tryptophan-2,3-dioxygenase (TDO2) catalyze the first and rate-limiting steps in the degradation of L-tryptophan to N-formylkynurenine. Although these enzymes catalyze the same reaction, it is believed that the different expression and compartamentalization of IDO1 and TDO2 in different tissues result in their different biological roles. IDO1 is typically expressed in gastrointestinal and lung epithelial cells, epididymus, placenta, pDCs in draining lymph nodes, and tumor cells. IDO2 is mainly expressed in the brain and placenta, but certain splicing variants have also been detected in the liver, small intestesting, spleen, placenta, thymus lung, brain, kidney, and colon. TDO2 is mainly expressed in the liver and controls the flux of dietary Trp into the serotonin and kynurenine pathways, and is also expressed in tumors and tumor cell lines.

[0005] Multiple lines of evidence suggest that IDO1 and TDO2 are associated with the induction of immune tolerance. Studies of mammalian pregnancy, tumor drug resistance, chronic infection, and autoimmune disease have shown that cells expressing IDO1 can inhibit T-cell responses and promote tolerance. Accelerated Trp catabolism has been observed in diseases and disorders associated with cellular immune activation, such as infection, malignancy, autoimmune disease, and AIDS, as well as during pregnancy. It has been proposed that IDO1 is slowly induced by HIV infection and further elevated by opportunistic infections, and that chronic depletion of Trp initiates mechanisms leading to cachexia, dementia, and diarrhea in AIDS patients, as well as possible immunosuppression (Brown, et al., 1991, Adv. Exp. Med. Biol., 294:425-35). Accordingly, in recent years, it has been shown that IDO1 inhibition can increase the levels of virus-specific T cells in an HIV mouse model and concomitantly reduce the number of virus-infected macrophages (Portula et al., 2005, Blood, 106:2382-90).

[0006] IDO1 is believed to play an important role in the immunosuppressive process that prevents the rejection of the fetus in utero. More than 40 years ago, during pregnancy, it was observed that the survival of genetically different mammalian conceptuses was independent of what would be predicted by tissue transplantation immunology (Medawar, 1953, Symp. Soc. Exp. Biol. 7:320-38). Anatomic separation of the mother and fetus and the antigenic immaturity of the fetus do not fully explain the survival of the fetal allograft. Recent attention has focused on maternal immune tolerance. Since IDO1 is expressed by human syncytiotrophoblasts and systemic tryptophan concentrations decline during normal pregnancy, it has been speculated that IDO1 expression at the maternal-fetal interface is necessary to prevent immune rejection of the fetal allograft. To test this speculation, pregnant mice (carrying syngeneic or allogeneic fetuses) were exposed to 1MT, and rapid, T cell-induced rejection of all allogeneic concepti was observed. Thus, by catabolizing tryptophan, the mammalian conceptus appears to inhibit T-cell activity and protect itself from rejection, and blocking tryptophan catabolism during mouse pregnancy allows maternal T cells to cause rejection of the fetal allograft (Munn, et al., 1998, Science 281:1191-3).

[0007] Further evidence for a tumor immune response mechanism based on the degradation of tryptophan by IDO1 comes from the following observations: Most human tumors constitutively express IDO, and the IDO1 expression of immunogenic murine tumor cells prevents their rejection by pre-immunizing the mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partially reversed by systemic treatment of the mice with an IDO inhibitor without significant toxicity. Thus, this suggests that the efficacy of therapeutic vaccination in cancer patients can be improved by concomitant administration of an IDO1 inhibitor (Uyttenhove et al., 2003, Nature Med., 9:1269-74). This also shows that the IDO1 inhibitor 1-MT can act synergistically with chemotherapeutic agents to reduce tumor growth in mice, indicating that IDO1 inhibition can also enhance the anti-tumor activity of conventional cytotoxic therapies (Muller et al., 2005, Nature Med., 11:312-9).

[0008] Similar observations have been made for TDO2. It has been shown that most primary human tumors express elevated levels of TDO2 or TDO2+IDO1 (Pilotte et al., 2012, P.N.A.S). Additionally, pharmacological inhibition of TDO2 activity with a TDO2 inhibitor results in the immune-mediated rejection of tumors overexpressing TDO2, indicating that, as seen in IDO1, TDO2 can mediate pro-tumor immunosuppressive effects.

[0009] Small molecule inhibitors of IDO1 can be developed to treat or prevent IDO1-related diseases, such as those described above. For example, PCT Publication WO99 / 29310 reports methods for altering T cell-mediated immunity, including using IDO1 inhibitors to alter the local extracellular concentrations of tryptophan and tryptophan metabolites, such as 1-methyl-DL-tryptophan, p-(3-benzofuranyl)-DL-alanine, p-[3-benz(b)thienyl]-DL-alanine, and 6-nitro-L-tryptophan (Munn, 1999). Methods for preparing antigen-presenting cells for enhancing or reducing T cell tolerance are also reported in WO03 / 087347 (also published as European Patent 1501918) (Munn, 2003). Compounds having indoleamine-2,3-dioxygenase (IDO) inhibitory activity are also reported in WO 2004 / 094409, WO2009 / 073620, WO2009 / 132238, WO2011 / 056652, and WO2012 / 142237. In particular, the compounds of WO2012 / 142237 include a series of tricyclic imidazoisoindoles having potent IDO1 inhibitory activity. SUMMARY OF THE INVENTION

[0010] We recognize that, based on experimental data demonstrating the role of IDO1 and / or TDO2 in immunosuppression, tumor drug resistance and / or rejection, chronic infection, HIV-infection, AIDS (including its clinical manifestations such as cachexia, dementia and diarrhea), autoimmune diseases or disorders (such as rheumatoid arthritis) and immune tolerance, as well as prevention of fetal rejection in utero, therapeutic agents that inhibit tryptophan degradation by inhibiting IDO1 and / or TDO2 activity are desirable. Specific or dual inhibitors of IDO1 and TDO2 can be used to activate T cells when T cells are suppressed by pregnancy, malignancy or a virus such as HIV, thereby enhancing T cell activation. Inhibition of IDO1 and / or TDO2 can also be an important therapeutic strategy for patients suffering from neurological or neuropsychiatric diseases or disorders such as depression. The compounds, compositions and methods herein help to meet the current need for IDO1 and TDO2 regulators.

[0011] In the present invention, we describe novel structures related to imidazoisoindoles with different electronic and heme-binding properties that specifically inhibit IDO1 or TDO2, or that combinatorially inhibit tryptophan degradation mediated by either of these enzymes.

[0012] In one aspect, the present invention includes compounds according to formula (I),

[0013]

[0014] or stereoisomers thereof, or pharmaceutically acceptable salts thereof,

[0015] wherein

[0016] R 1 is C 1-6 alkyl, C 3-10 cycloalkyl, 3-7 membered heterocyclic group (e.g., 4-6 membered heterocyclic group or 5-6 membered heterocyclic group), -C1alkyl-C 3-10 cycloalkyl, -C1alkyl-3-7 membered heterocyclic group (e.g., -C1alkyl-4-6 membered heterocyclic group or -C1alkyl-5-6 membered heterocyclic group) or -C1alkyl-heteroaryl,

[0017] wherein said C 3-10 cycloalkyl or 3-7 membered heterocyclic group is optionally fused to aryl, heteroaryl, C 3-8 cycloalkyl or 3-7 membered heterocyclic group; or

[0018] wherein said C 3-10 cycloalkyl or 3-7 membered heterocyclic group is optionally substituted with =(spiro-C 3-7 cycloalkyl) or =(spiro-(3-7 membered heterocyclic group));

[0019] wherein R1 Optionally substituted with 1, 2, 3, or 4 Rs independently selected from the following a groups: oxo, halogen, cyano, nitro, C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkyl-cyano, -OR, -NR2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, and -N(R)C(O)N(R)2;

[0020] n is 0, 1, 2, 3, or 4;

[0021] Each R 2 is independently halogen, cyano, C 1-6 alkyl, C3 cycloalkyl, -C 1-6 haloalkyl, -OR, -NR2, or -SR; and

[0022] Each R is independently hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl;

[0023] provided that

[0024] (a) when R 1 is a 3- to 7-membered heterocyclic group (e.g., 4- to 6-membered heterocyclic group or 5- to 6-membered heterocyclic group), no member of the 3- to 7-membered heterocyclic group is -NH-;

[0025] (b) when R 1 is C 1-6 alkyl, R 1 is substituted with -NR2 or -OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group; and

[0026] (c) when R 1 is C 3-10 cycloalkyl, 3- to 7-membered heterocyclic group (e.g., 4- to 6-membered heterocyclic group or 5- to 6-membered heterocyclic group), -C1 alkyl-C 3-10 cycloalkyl, -C1 alkyl-3- to 7-membered heterocyclic group (e.g., -C1 alkyl-4- to 6-membered heterocyclic group or -C1 alkyl-5- to 6-membered heterocyclic group), or -C1 alkyl-heteroaryl, R 1 is substituted with -NR2 or -OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group.

[0027] In one embodiment, the present invention provides a compound of formula (I), wherein

[0028] R 1 is C 3-10 cycloalkyl, 3-7 membered heterocyclic group (e.g., 4-6 membered heterocyclic group or 5-6 membered heterocyclic group), -C1 alkyl-C 3-10 cycloalkyl, -C1 alkyl-3-7 membered heterocyclic group (e.g., -C1 alkyl-4-6 membered heterocyclic group or -C1 alkyl-5-6 membered heterocyclic group) or -C1 alkyl-heteroaryl,

[0029] wherein said C 3-10 cycloalkyl or 3-7 membered heterocyclic group is optionally fused to aryl, heteroaryl, C 3-8 cycloalkyl or 3-7 membered heterocyclic group; or

[0030] wherein said C 3-10 cycloalkyl or 3-7 membered heterocyclic group is optionally substituted with =(spiro-C 3-7 cycloalkyl) or =(spiro-(3-7 membered heterocyclic group));

[0031] wherein R 1 is optionally substituted with 1, 2, 3 or 4 R groups independently selected from the following a groups: oxo, halogen, cyano, nitro, C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkyl-cyano, -OR, -NR2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR and -N(R)C(O)N(R)2;

[0032] n is 0, 1, 2, 3 or 4;

[0033] each R 2 is independently halogen, cyano, C 1-6 alkyl, C3 cycloalkyl, -C 1-6 haloalkyl, -OR, -NR2 or -SR; and

[0034] each R is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0035] provided that

[0036] (a) when R 1When it is a 3- to 7-membered heterocyclic group (e.g., 4- to 6-membered heterocyclic group or 5- to 6-membered heterocyclic group), no member of the 3- to 7-membered heterocyclic group is -NH-; and

[0037] (b) When R 1 is C 3-10 cycloalkyl, 3- to 7-membered heterocyclic group (e.g., 4- to 6-membered heterocyclic group or 5- to 6-membered heterocyclic group), -C1 alkyl-C 3-10 cycloalkyl, -C1 alkyl-3- to 7-membered heterocyclic group (e.g., -C1 alkyl-4- to 6-membered heterocyclic group or -C1 alkyl-5- to 6-membered heterocyclic group) or -C1 alkyl-heteroaryl, R 1 is substituted with -NR2 or -OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group or on the carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group.

[0038] In one embodiment, the present invention provides a compound of formula (I), wherein

[0039] R 1 is C 3-10 cycloalkyl, 3- to 7-membered heterocyclic group (e.g., 4- to 6-membered heterocyclic group or 5- to 6-membered heterocyclic group),

[0040] wherein the C 3-10 cycloalkyl or 3- to 7-membered heterocyclic group is optionally fused to an aryl, heteroaryl, C 3-8 cycloalkyl or 3- to 7-membered heterocyclic group; or

[0041] wherein the C 3-10 cycloalkyl or 3- to 7-membered heterocyclic group is optionally substituted with =(spiro-C 3-7 cycloalkyl) or =(spiro-(3- to 7-membered heterocyclic group));

[0042] wherein R 1 is optionally substituted with 1, 2, 3 or 4 R a groups independently selected from: oxo, halogen, cyano, nitro, C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkyl-cyano, -OR, -NR2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR and -N(R)C(O)N(R)2;

[0043] n is 0, 1, 2, 3 or 4;

[0044] Each R 2 is independently halogen, cyano, C 1-6 alkyl, C3 cycloalkyl, -C 1-6 haloalkyl, -OR, -NR2 or -SR; and

[0045] each R is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0046] provided that

[0047] (a) when R 1 is a 3- to 7-membered heterocyclic group (e.g., 4- to 6-membered heterocyclic group or 5- to 6-membered heterocyclic group), no member of the 3- to 7-membered heterocyclic group is -NH-; and

[0048] (b) when R 1 is C 3-10 cycloalkyl, a 3- to 7-membered heterocyclic group (e.g., 4- to 6-membered heterocyclic group or 5- to 6-membered heterocyclic group), R 1 is substituted with -NR2 or -OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group.

[0049] In one embodiment of the compound of formula (I), R 1 is substituted with -OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group. In other embodiments, the present invention includes compounds of formula (I) wherein R 1 is substituted with -OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group and n is 0. In other embodiments, the present invention includes compounds of formula (I) wherein R 1 is substituted with -OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group and n is 1.

[0050] In one embodiment, the present invention includes compounds of formula (II),

[0051]

[0052] which are compounds of formula (I) wherein

[0053] R 1 is

[0054] Ring A is C 3-10 cycloalkyl or a 3- to 7-membered heterocyclic group;

[0055] m is 0, 1, 2, 3 or 4; and

[0056] R 4 is -NR2 or -OR.

[0057] In one embodiment, the present invention includes a compound of formula (II), wherein R 4 is -OH. In other embodiments, R 4 is –OH and n is 0. In other embodiments, R 4 is –OH and n is 1.

[0058] In another embodiment, the present invention includes a compound of formula (III),

[0059]

[0060] which is a compound of formula (I), wherein

[0061] R 1 is

[0062] a fused bicyclic ring system composed of Ring A and Ring B;

[0063] Ring A is C 3-8 cycloalkyl or a 3- to 7-membered heterocyclic group;

[0064] Ring B is aryl, heteroaryl, C 3-7 cycloalkyl or a 3- to 7-membered heterocyclic group;

[0065] m is 0, 1, 2, 3 or 4; and

[0066] the hydroxyl moiety is bonded to Ring A and each R a is independently a substituent of Ring A or Ring B.

[0067] In one embodiment, the present invention includes a compound of formula (III), wherein n is 0. In other embodiments, n is 1.

[0068] In another embodiment, the present invention includes a compound of formula (IV),

[0069]

[0070] which is a compound of formula (I), wherein

[0071] R 1 is

[0072] Ring A and Ring B form a spiro ring system,

[0073] Ring A is a C 3-8 cycloalkyl or a 3- to 7-membered heterocyclic group;

[0074] Ring B is a C 3-7 cycloalkyl, a 3- to 7-membered heterocyclic group, an aryl or a heteroaryl;

[0075] m is 0, 1, 2, 3 or 4; and

[0076] the hydroxyl moiety is bonded to Ring A and each R a is independently a substituent of Ring A or Ring B.

[0077] In one embodiment, the present invention includes a compound of formula (IV), wherein n is 0. In other embodiments, n is 1.

[0078] In one embodiment, the present invention includes a compound of formula (V),

[0079]

[0080] which is a compound of formula (I), wherein

[0081] R 1 is

[0082] Ring A is a C 3-10 cycloalkyl, a 3- to 7-membered heterocyclic group or a heteroaryl and R 4 is a substituent on Ring A or a methylene group bonded to Ring A;

[0083] m is 0, 1, 2, 3 or 4; and

[0084] R 4 is -NR2 or -OR.

[0085] In one embodiment, the present invention includes a compound of formula (V), wherein R 4 is -OH. In other embodiments, R 4 is –OH and n is 0. In other embodiments, R 4 is –OH and n is 1.

[0086] In another aspect, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier, and a compound according to formula (I), (II), (III), (IV) or (V).

[0087] In another aspect, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier, a compound according to formula (I), (II), (III), (IV) or (V), and a second therapeutic agent.

[0088] In another aspect, there is provided a kit comprising a pharmaceutically acceptable excipient, diluent or carrier, a compound according to formula (I), (II), (III), (IV) or (V), and a second therapeutic agent.

[0089] In another aspect, there is provided a method for

[0090] a) modulating the activity of IDO1 or TDO2 in a cell-free system or in a cell (ex vivo or in vivo), which comprises contacting IDO1 or TDO2 with a modulatory effective amount of a compound according to formula (I), or a pharmaceutical composition comprising a compound according to formula (I);

[0091] b) treating IDO1- or TDO2-mediated immunosuppression in a subject in need thereof, comprising administering an effective inhibitory amount of a compound according to formula (I), or a pharmaceutical composition comprising a compound according to formula (I);

[0092] c) treating a medical condition that benefits from inhibition of IDO1- and / or TDO2-mediated tryptophan degradation, comprising administering an effective amount of a compound of formula (I), or a pharmaceutical composition comprising a compound according to formula (I);

[0093] d) enhancing the effectiveness of an anti-cancer treatment, comprising administering an anti-cancer agent and a compound according to formula (I), or a pharmaceutical composition comprising a compound according to formula (I); and

[0094] e) treating cancer-related immunosuppression, comprising administering an effective amount of a compound according to formula (I), or a pharmaceutical composition comprising a compound according to formula (I).

[0095] In another aspect, the present invention includes the use of any kind of compound or substance defined herein in the preparation of a medicament for treating a medical condition that benefits from inhibition of the enzyme activity of IDO1 or TDO2.

[0096] In another aspect, the present invention includes any kind of compound or substance defined herein for inhibiting the enzyme activity of IDO1 or TDO2 and treating a medical condition that benefits from inhibition of the enzyme activity of IDO1 or TDO2.

[0097] In another aspect, the present invention includes the use of any kind of compound or substance defined herein for treating cancer-related immunosuppression, infectious diseases or viral infections. DETAILED DESCRIPTION OF THE INVENTION

[0098] The object of the present invention is to develop small molecules that inhibit the enzymatic activity of TDO2. Alignment between the IDO1 and IDO2 amino acid sequences reveals highly conserved features that mediate heme and substrate binding. Although the amino acid sequence identity between IDO1 and IDO2 or between IDO1 and TDO2 is not particularly high, significant residues important for catalytic activity determined by IDO1 and TDO2 mutagenesis and by crystallographic analysis are highly conserved among IDO1, IDO2, and TDO2, indicating structural and functional similarities in the tryophan dioxygenation mechanism. Despite these structural similarities at the active site, IDO1 and TDO2 have different substrate specificities. TDO2 is almost exclusively specific for L-Trp and L-Trp derivatives substituted at the 5- and 6-positions of the indole moiety, while IDO1 can accept and oxidize a variety of substrates such as D-Trp, tryptamine, serotonin, and 1-methyl-L-Trp. These minor structural differences at the active sites of IDO1 and TDO2 determine that these two proteins show different responses to the same enzyme inhibitor molecules, some of which show TDO2-specific responses, some show IDO1-specific responses, and some show dual IDO1 and TDO2 inhibition. In addition, the specificity of a particular class of small molecule inhibitors for IDO1 and TDO2 depends on whether IDO1 and TDO2 activities are measured using bioassays employing recombinant purified IDO1 or TDO2 proteins or intracellularly expressed IDO1 or TDO2 proteins. For example, the compounds described in patent applications WO2012142237 and WO2014159248 showed effective IDO1 inhibition when tested against purified recombinant proteins and against intracellularly expressed IDO1 or against recombinant purified TDO2 proteins. However, the compounds of this class showed a significantly 10- to 100-fold reduced potency when tested against intracellularly expressed TDO2. Therefore, these compounds are unlikely to contribute to significant inhibition of TDO2 in vivo. For this reason, the present invention describes a novel class of molecules that show effective TDO2 inhibition in cell-based bioassays and in vivo.

[0099] In one aspect, the present invention provides a compound of formula (I),

[0100]

[0101] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0102] wherein

[0103] R 1 is C 1-6 alkyl, C 3-10 cycloalkyl, a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), -C1 alkyl-C 3-10cycloalkyl, -C1-alkyl-3-7-membered heterocyclic group (e.g., -C1-alkyl-4-6-membered heterocyclic group or -C1-alkyl-5-6-membered heterocyclic group), or -C1-alkyl-heteroaryl,

[0104] wherein said C 3-10 cycloalkyl or 3-7-membered heterocyclic group is optionally fused to aryl, heteroaryl, C 3-8 cycloalkyl or 3-7-membered heterocyclic group; or

[0105] wherein said C 3-10 cycloalkyl or 3-7-membered heterocyclic group is optionally substituted with =(spiro-C 3-7 cycloalkyl) or =(spiro-(3-7-membered heterocyclic group));

[0106] wherein R 1 is optionally substituted with 1, 2, 3 or 4 R groups independently selected from the following a groups: oxo, halogen, cyano, nitro, C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkyl-cyano, -OR, -NR2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR and -N(R)C(O)N(R)2;

[0107] n is 0, 1, 2, 3 or 4;

[0108] each R 2 is independently halogen, cyano, C 1-6 alkyl, C3 cycloalkyl, -C 1-6 haloalkyl, -OR, -NR2 or -SR; and

[0109] each R is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0110] provided that

[0111] (a) when R 1 is a 3-7-membered heterocyclic group (e.g., 4-6-membered heterocyclic group or 5-6-membered heterocyclic group), no member of the 3-7-membered heterocyclic group is -NH-;

[0112] (b) when R 1 is C 1-6 alkyl, R 1Substituted with -NR2 or -OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group; and

[0113] (c) When R 1 is C 3-10 cycloalkyl, 3- to 7-membered heterocyclic group (e.g., 4- to 6-membered heterocyclic group or 5- to 6-membered heterocyclic group), -C1-alkyl-C 3-10 cycloalkyl, -C1-alkyl-3- to 7-membered heterocyclic group (e.g., -C1-alkyl-4- to 6-membered heterocyclic group or -C1-alkyl-5- to 6-membered heterocyclic group) or -C1-alkyl-heteroaryl, R 1 is substituted with -NR2 or -OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group.

[0114] In one embodiment, the present invention provides a compound of formula (I), wherein

[0115] R 1 is C 3-10 cycloalkyl, 3- to 7-membered heterocyclic group (e.g., 4- to 6-membered heterocyclic group or 5- to 6-membered heterocyclic group),

[0116] -C1-alkyl-C 3-10 cycloalkyl, -C1-alkyl-3- to 7-membered heterocyclic group (e.g., -C1-alkyl-4- to 6-membered heterocyclic group or -C1-alkyl-5- to 6-membered heterocyclic group) or -C1-alkyl-heteroaryl,

[0117] wherein the C 3-10 cycloalkyl or 3- to 7-membered heterocyclic group is optionally fused to an aryl, heteroaryl, C 3-8 cycloalkyl or 3- to 7-membered heterocyclic group; or

[0118] wherein the C 3-10 cycloalkyl or 3- to 7-membered heterocyclic group is optionally substituted with =(spiro-C 3-7 cycloalkyl) or =(spiro-(3- to 7-membered heterocyclic group));

[0119] wherein R 1 is optionally substituted with 1, 2, 3 or 4 R a groups independently selected from: oxo, halogen, cyano, nitro, C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6alkyl-cyano, -OR, -NR2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR and -N(R)C(O)N(R)2;

[0120] n is 0, 1, 2, 3 or 4;

[0121] each R 2 is independently halogen, cyano, C 1-6 alkyl, C3 cycloalkyl, -C 1-6 haloalkyl, -OR, -NR2 or -SR; and

[0122] each R is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0123] provided that

[0124] (a) when R 1 is a 3-7 membered heterocyclic group (e.g., 4-6 membered heterocyclic group or 5-6 membered heterocyclic group), no member of the 3-7 membered heterocyclic group is -NH-;

[0125] (b) when R 1 is C 3-10 cycloalkyl, 3-7 membered heterocyclic group (e.g., 4-6 membered heterocyclic group or 5-6 membered heterocyclic group), -C1 alkyl-C 3-10 cycloalkyl, -C1 alkyl-3-7 membered heterocyclic group (e.g., -C1 alkyl-4-6 membered heterocyclic group or -C1 alkyl-5-6 membered heterocyclic group) or -C1 alkyl-heteroaryl, R 1 is substituted with -NR2 or -OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl or on the carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl.

[0126] In another embodiment, the present invention provides a compound of formula (I), wherein

[0127] R 1 is C 3-10 cycloalkyl or 3-7 membered heterocyclic group (e.g., 4-6 membered heterocyclic group or 5-6 membered heterocyclic group),

[0128] wherein the C 3-10 cycloalkyl or 3-7 membered heterocyclic group is optionally fused to aryl, heteroaryl, C 3-8 cycloalkyl or 3-7 membered heterocyclic group; or

[0129] wherein said C 3-10 cycloalkyl or 3-7 membered heterocyclic group is optionally substituted with =(spiro-C 3-7 cycloalkyl) or =(spiro-(3-7 membered heterocyclic group));

[0130] wherein R 1 is optionally substituted with 1, 2, 3 or 4 R groups independently selected from the following: a oxo, halogen, cyano, nitro, C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkyl-cyano, -OR, -NR2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR and -N(R)C(O)N(R)2;

[0131] n is 0, 1, 2, 3 or 4;

[0132] each R 2 is independently halogen, cyano, C 1-6 alkyl, C3 cycloalkyl, -C 1-6 haloalkyl, -OR, -NR2 or -SR; and

[0133] each R is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0134] provided that

[0135] (a) when R 1 is a 3-7 membered heterocyclic group (e.g., 4-6 membered heterocyclic group or 5-6 membered heterocyclic group), no member of the 3-7 membered heterocyclic group is -NH-; and

[0136] (b) when R 1 is C 3-10 cycloalkyl, 3-7 membered heterocyclic group (e.g., 4-6 membered heterocyclic group or 5-6 membered heterocyclic group), R 1 is substituted with -NR2 or -OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group or on the carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl group.

[0137] In another embodiment, the present invention provides a compound of formula (I),

[0138]

[0139] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0140] wherein

[0141] R 1 is -C1 alkyl-C 3-10 cycloalkyl, -C1 alkyl-3-7 membered heterocyclic group (e.g., -C1 alkyl-4-6 membered heterocyclic group or -C1 alkyl-5-6 membered heterocyclic group) or -C1 alkyl-heteroaryl,

[0142] wherein said C 3-10 cycloalkyl, 3-7 membered heterocyclic group or heteroaryl is optionally fused to aryl, heteroaryl, C 3-8 cycloalkyl or 3-7 membered heterocyclic group; or

[0143] wherein said C 3-10 cycloalkyl or 3-7 membered heterocyclic group is optionally substituted with =(spiro-C 3-7 cycloalkyl) or =(spiro-(3-7 membered heterocyclic group));

[0144] wherein R 1 is optionally substituted with 1, 2, 3 or 4 R groups independently selected from the following a groups: oxo, halogen, cyano, nitro, C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkyl-cyano, -OR, -NR2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR and -N(R)C(O)N(R)2;

[0145] n is 0, 1, 2, 3 or 4;

[0146] each R 2 is independently halogen, cyano, C 1-6 alkyl, C3 cycloalkyl, -C 1-6 haloalkyl, -OR, -NR2 or -SR; and

[0147] each R is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0148] provided that

[0149] (a) when R 1is -C1 alkyl - C 3-10 cycloalkyl, -C1 alkyl - 3 - 7 - membered heterocyclic group (for example, -C1 alkyl - 4 - 6 - membered heterocyclic group or -C1 alkyl - 5 - 6 - membered heterocyclic group) or -C1 alkyl - heteroaryl, R 1 is substituted with -NR2 or -OH on the carbon atom bonded to the 5H - imidazo[5,1 - a]isoindolyl group or on the carbon atom adjacent to the carbon atom bonded to the 5H - imidazo[5,1 - a]isoindolyl group.

[0150] In one embodiment of the compound of formula (I), R 1 is substituted with -OH on the carbon atom bonded to the 5H - imidazo[5,1 - a]isoindolyl group or on the carbon atom adjacent to the carbon atom bonded to the 5H - imidazo[5,1 - a]isoindolyl group. In other embodiments, the present invention includes compounds of formula (I) wherein R 1 is substituted with -OH on the carbon atom bonded to the 5H - imidazo[5,1 - a]isoindolyl group or on the carbon atom adjacent to the carbon atom bonded to the 5H - imidazo[5,1 - a]isoindolyl group and n is 0. In other embodiments, the present invention includes compounds of formula (I) wherein R 1 is substituted with -OH on the carbon atom bonded to the 5H - imidazo[5,1 - a]isoindolyl group or on the carbon atom adjacent to the carbon atom bonded to the 5H - imidazo[5,1 - a]isoindolyl group and n is 1.

[0151] The present invention further includes subclasses and species of formula (I), which are any combination of the species and genera of structural formula (I), n, R 1 and R 2 as defined below. Thus, for example, the present invention also includes a sub - genus of compounds of structural formula (I) wherein n is defined as in the following (1c), R 1 is defined as in the following (2h), and R 2 is defined as in the following (3k).

[0152] n is selected from one of the following groups (1a)-(1k):

[0153] (1a) n is 1, 2, 3 or 4.

[0154] (1b) n is 0, 1, 2 or 3.

[0155] (1c) n is 0, 1 or 2.

[0156] (1d) n is 0 or 1.

[0157] (1e) n is 1 or 2.

[0158] (1f) n is 2 or 3.

[0159] (1g) n is 1.

[0160] (1h) n is 2.

[0161] (1i) n is 3.

[0162] (1j) n is 4.

[0163] (1k) n is 0.

[0164] R 2 selected from one of the following groups (2a)-(2t):

[0165] (2a) R 2 is independently halogen, cyano, C 1-6 alkyl, C3 cycloalkyl, -C 1-6 haloalkyl, -OR, or -NR2.

[0166] (2b) R 2 is independently halogen, cyano, C 1-6 alkyl, C3 cycloalkyl, -OR or -NR2.

[0167] (2c) R 2 is independently halogen, cyano, C 1-6 alkyl, C3 cycloalkyl or -OR.

[0168] (2d) R 2 is independently halogen, C 1-6 alkyl, C3 cycloalkyl or -OR.

[0169] (2e) R 2 is independently halogen, cyano, C 1-6 alkyl or -OR.

[0170] (2f) R 2 is independently halogen, C 1-6 alkyl or -OR.

[0171] (2g) R 2 is independently halogen or -OR.

[0172] (2h) R 2 is independently C 1-6 alkyl or -OR.

[0173] (2i) R 2 is independently -OR.

[0174] (2j) R 2 is independently halogen, methyl or -OR.

[0175] (2k) R 2 is independently halogen, methyl, -OH or -OMe.

[0176] (2l)R 2 Independently chlorine, fluorine, methyl or -OR.

[0177] (2m)R 2 Independently chlorine, fluorine, methyl, -OH or -OMe.

[0178] (2n)R 2 Independently chlorine, fluorine, methyl or -OH.

[0179] (2o)R 2 Independently fluorine, methyl or -OH.

[0180] (2p)R 2 Independently fluorine or -OH.

[0181] (2q)R 2 Independently fluorine or methyl.

[0182] (2r)R 2 Is fluorine.

[0183] (2s)R 2 Is methyl.

[0184] (2t)R 2 Is -OH.

[0185] R 1 selected from one of the following groups (3a) - (3cccc):

[0186] (3a)R 1 Is C 3-10 Cycloalkyl or 3- to 7-membered heterocyclic group (e.g., 4- to 6-membered heterocyclic group or 5- to 6-membered heterocyclic group),

[0187] Wherein said C 3-10 Cycloalkyl or 3- to 7-membered heterocyclic group is optionally fused to aryl, heteroaryl, C 3-7 Cycloalkyl or 3- to 7-membered heterocyclic group; or

[0188] Wherein said C 3-10 Cycloalkyl or 3- to 7-membered heterocyclic group is optionally substituted with =(spiro-C 3-7 Cycloalkyl) or =(spiro-(3- to 7-membered heterocyclic group));

[0189] Wherein R 1 Is optionally substituted with 1, 2, 3 or 4 R groups independently selected from the following a Groups: oxo, halogen, cyano, nitro, C 1-6 Alkyl, -C 1-6 Halogenoalkyl, C 1-6-alkyl-cyano, -OR, -NR2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR and -N(R)C(O)N(R)2.

[0190] (3b) subgroup (3a), wherein R 1 is C 4-6 cycloalkyl or a 5- or 6-membered heterocyclic group,

[0191] wherein said C 4-6 cycloalkyl or 5- or 6-membered heterocyclic group is optionally fused to an aryl or heteroaryl group;

[0192] or

[0193] wherein said C 4-6 cycloalkyl is optionally substituted with =(spiro-C4 cycloalkyl) or =(spiro-(4-membered heterocyclic group)).

[0194] (3c) subgroup (3a), wherein R 1 is C 4-6 cycloalkyl or a 5- or 6-membered heterocyclic group,

[0195] wherein said C 4-6 cycloalkyl or 5- or 6-membered heterocyclic group is optionally fused to an aryl or heteroaryl group;

[0196] or

[0197] wherein said C 4-6 cycloalkyl or 5- or 6-membered heterocyclic group is optionally substituted with =(spiro-C4 cycloalkyl) or =(spiro-(4-membered heterocyclic group)).

[0198] (3d) subgroup (3a), wherein R 1 is cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl,

[0199] wherein said cyclopentyl is optionally fused to a phenyl group, said cyclohexyl is optionally fused to a pyridyl or phenyl group, and said piperidinyl is optionally fused to a pyrrolidinyl or phenyl group; or

[0200] wherein said cyclobutyl is optionally substituted with =(spiro-cyclobutyl) or =(spiro-azetidinyl).

[0201] (3e) subgroup (3a), wherein R 1 is C 3-10 cycloalkyl or a 3- to 7-membered heterocyclic group.

[0202] (3f) subgroup (3a), wherein R1 is C 3-10 cycloalkyl.

[0203] (3g) Group (3a), wherein R 1 is C 5-8 bridged bicyclic.

[0204] (3h) Group (3a), wherein R 1 is cyclobutyl or cyclopentyl.

[0205] (3i) Group (3a), wherein R 1 is cyclobutyl.

[0206] (3j) Group (3a), wherein R 1 is cyclopentyl.

[0207] (3k) Group (3a), wherein R 1 is a 3- to 7-membered heterocyclic group.

[0208] (3l) Group (3a), wherein R 1 is pyrrolidinyl or piperidinyl.

[0209] (3m) Group (3a), wherein R 1 is pyrrolidinyl.

[0210] (3n) Group (3a), wherein R 1 is piperidinyl.

[0211] (3o) Group (3a), wherein R 1 is C 3-8 cycloalkyl or a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group),

[0212] wherein said C 3-8 cycloalkyl or 3- to 7-membered heterocyclic group is fused to an aryl, heteroaryl, C 3-7 cycloalkyl or 3- to 7-membered heterocyclic group.

[0213] (3p) Group (3a), wherein R 1 is C 3-8 cycloalkyl,

[0214] wherein said C 3-8 cycloalkyl is fused to an aryl, heteroaryl, C 3-7 cycloalkyl or 3- to 7-membered heterocyclic group.

[0215] (3q) Group (3a), wherein R 1 is C 3-8 cycloalkyl,

[0216] wherein said C 3-8 cycloalkyl is fused to a heteroaryl, C 3-7Cycloalkyl or 3- to 7-membered heterocyclic group.

[0217] (3r) subgroup (3a), wherein R 1 is C 3-8 cycloalkyl,

[0218] wherein said C 3-8 cycloalkyl is fused to aryl, C 3-7 cycloalkyl or 3- to 7-membered heterocyclic group.

[0219] (3s) subgroup (3a), wherein R 1 is C 3-8 cycloalkyl,

[0220] wherein said C 3-8 cycloalkyl is fused to aryl, heteroaryl, or 3- to 7-membered heterocyclic group.

[0221] (3t) subgroup (3a), wherein R 1 is C 3-8 cycloalkyl,

[0222] wherein said C 3-8 cycloalkyl is fused to aryl, heteroaryl or C 3-7 cycloalkyl.

[0223] (3u) subgroup (3a), wherein R 1 is C 3-8 cycloalkyl,

[0224] wherein said C 3-8 cycloalkyl is fused to aryl.

[0225] (3v) subgroup (3a), wherein R 1 is C 3-8 cycloalkyl,

[0226] wherein said C 3-8 cycloalkyl is fused to heteroaryl.

[0227] (3w) subgroup (3a), wherein R 1 is C 3-8 cycloalkyl,

[0228] wherein said C 3-8 cycloalkyl is fused to C 3-7 cycloalkyl.

[0229] (3x) subgroup (3a), wherein R 1 is C 3-8 cycloalkyl,

[0230] wherein said C 3-8 cycloalkyl is fused to 3- to 7-membered heterocyclic group.

[0231] (3y) subgroup (3a), wherein R1 is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), wherein the 3- to 7-membered heterocyclic group is fused to an aryl, heteroaryl, C 3-7 cycloalkyl or 3- to 7-membered heterocyclic group.

[0232] (3z) group (3a), wherein R 1 is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), wherein the 3- to 7-membered heterocyclic group is fused to a heteroaryl, C 3-7 cycloalkyl or 3- to 7-membered heterocyclic group.

[0233] (3aa) group (3a), wherein R 1 is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), wherein the 3- to 7-membered heterocyclic group is fused to an aryl, C 3-7 cycloalkyl or 3- to 7-membered heterocyclic group.

[0234] (3bb) group (3a), wherein R 1 is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), wherein the 3- to 7-membered heterocyclic group is fused to an aryl, heteroaryl, or 3- to 7-membered heterocyclic group.

[0235] (3cc) group (3a), wherein R 1 is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), wherein the 3- to 7-membered heterocyclic group is fused to an aryl, heteroaryl or C 3-7 cycloalkyl.

[0236] (3dd) group (3a), wherein R 1 is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), wherein the 3- to 7-membered heterocyclic group is fused to an aryl.

[0237] (3ee) group (3a), wherein R 1 is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), wherein the 3- to 7-membered heterocyclic group is fused to a heteroaryl.

[0238] (3ff) group (3a), wherein R 1 is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), wherein the 3- to 7-membered heterocyclic group is fused to C 3-7 cycloalkyl.

[0239] (3gg) group (3a), wherein R 1 is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), wherein the 3- to 7-membered heterocyclic group is fused to a 3- to 7-membered heterocyclic group.

[0240] (3hh) group (3a), where R 1 is a C 3-10 cycloalkyl or a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group),

[0241] wherein said C 3-7 cycloalkyl or 3- to 7-membered heterocyclic group is substituted with =(spiro-C 3-8 cycloalkyl) or =(spiro-(3- to 7-membered heterocyclic group)).

[0242] (3ii) group (3a), where R 1 is a C 3-8 cycloalkyl,

[0243] wherein said C 3-8 cycloalkyl is substituted with =(spiro-C 3-7 cycloalkyl).

[0244] (3jj) group (3a), where R 1 is a C 3-8 cycloalkyl,

[0245] wherein said C 3-8 cycloalkyl is substituted with =(spiro-(3- to 7-membered heterocyclic group)).

[0246] (3kk) group (3a), where R 1 is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group),

[0247] wherein said 3- to 7-membered heterocyclic group is substituted with =(spiro-C 3-7 cycloalkyl).

[0248] (3ll) group (3a), where R 1 is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group),

[0249] wherein said 3- to 7-membered heterocyclic group is substituted with =(spiro-(3- to 7-membered heterocyclic group)).

[0250] (3mm) group, any one of (3b)-(3ll), where R 1 is substituted with at least one R a group selected from -OR and -NR2.

[0251] (3nn) group, any one of (3b)-(3ll), where R 1 is substituted with at least one R a group selected from -OR.

[0252] (3oo) group, any one of (3b)-(3ll), where R 1substituted with at least one R selected from -NR2 a group.

[0253] (3pp) any one of groups (3b)-(3oo), wherein R 1 is substituted with 1, 2 or 3 R independently selected from the following a groups: oxo, halogen, cyano, nitro, C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkyl-cyano, -OR, -NR2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR and -N(R)C(O)N(R)2.

[0254] (3qq) any one of groups (3b)-(3oo), wherein R 1 is substituted with 1, 2 or 3 R independently selected from the following a groups: oxo, halogen, C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkyl-cyano, -OR, -NR2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR and -N(R)C(O)N(R)2.

[0255] (3rr) any one of groups (3b)-(3oo), wherein R 1 is substituted with 1, 2 or 3 R independently selected from the following a groups: oxo, halogen, C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkyl-cyano, -OR, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR and -OC(O)N(R)2.

[0256] (3ss) any one of groups (3b)-(3oo), wherein R 1 is substituted with 1, 2 or 3 R independently selected from the following a groups: oxo, halogen, C 1-6 alkyl, -C 1-6Halogenoalkyl, C 1-6 alkyl-cyano, -OR, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -N(R)C(O)R, -N(R)C(O)OR and -N(R)C(O)N(R)2.

[0257] (3tt) Any one of groups (3b)-(3oo), wherein R 1 is substituted with 1, 2 or 3 R groups independently selected from the following a groups: oxo, halogen, C 1-6 alkyl, -C 1-6 halogenoalkyl, C 1-6 alkyl-cyano, -OR, -S(O)2R, -S(O)2OR and -S(O)2N(R)2.

[0258] (3uu) Any one of groups (3b)-(3oo), wherein R 1 is substituted with 1, 2 or 3 R groups independently selected from the following a groups: oxo, halogen, C 1-6 alkyl, -C 1-6 halogenoalkyl, C 1-6 alkyl-cyano, -OR, -S(O)2R, -S(O)2OR and -S(O)2N(R)2.

[0259] (3vv) Any one of groups (3b)-(3oo), wherein R 1 is substituted with 1, 2 or 3 R groups independently selected from the following a groups: C 1-6 alkyl, -OR, -S(O)2R, -S(O)2OR and -S(O)2N(R)2.

[0260] (3ww) Any one of groups (3b)-(3oo), wherein R 1 is substituted with 1, 2 or 3 R groups independently selected from the following a groups: oxo, halogen, C 1-6 alkyl, -OR, -S(O)2R, -S(O)2OR and -S(O)2N(R)2.

[0261] (3xx) Any one of groups (3b)-(3oo), wherein R 1 is substituted with 1, 2 or 3 R groups independently selected from the following a groups: oxo, halogen, C 1-6 alkyl, -OR, -S(O)2R and -S(O)2N(R)2.

[0262] (3yy) Any one of groups (3b)-(3oo), wherein R1 substituted with 1, 2 or 3 Rs independently selected from the following a groups: C 1-6 alkyl, -OR, -S(O)2R and -S(O)2N(R)2.

[0263] (3zz) any one of groups (3b)-(3oo), wherein R 1 substituted with 1 or 2 Rs independently selected from the following a groups: C 1-6 alkyl, -OR, -S(O)2R and -S(O)2N(R)2.

[0264] (3aaa) any one of groups (3b)-(3oo), wherein R 1 substituted with 1 or 2 Rs independently selected from the following a groups: C 1-6 alkyl, -OR and -S(O)2N(R)2.

[0265] (3bbb) any one of groups (3b)-(3oo), wherein R 1 substituted with 1 or 2 Rs independently selected from the following a groups: C 1-6 alkyl, -OR and -S(O)2R.

[0266] (3ccc) any one of groups (3b)-(3oo), wherein R 1 substituted with 1 or 2 Rs independently selected from the following a groups: C 1-6 alkyl and -OR.

[0267] (3ddd) any one of groups (3b)-(3oo), wherein R 1 substituted with 1 or 2 Rs independently selected from the following a groups: methyl, ethyl, propyl, -isopropyl, -OMe and -OH.

[0268] (3eee) any one of groups (3b)-(3oo), wherein R 1 substituted with 1 or 2 Rs independently selected from the following a groups: methyl and ethyl.

[0269] (3fff) any one of groups (3b)-(3oo), wherein R 1 substituted with 1 R independently selected from the following a groups: C 1-6 alkyl, -OR, -S(O)2R and -S(O)2N(R)2.

[0270] (3ggg) any one of groups (3b)-(3oo), wherein R1 R is independently selected from one of the following: a groups: C 1-6 alkyl, -OR, and -S(O)2N(R)2.

[0271] (3hhh) Any one of groups (3b)-(3oo), wherein R 1 is independently selected from one of the following: a groups: C 1-6 alkyl, -OR, and -S(O)2R.

[0272] (3iii) Any one of groups (3b)-(3oo), wherein R 1 is independently selected from one of the following: a groups: C 1-6 alkyl and -OR.

[0273] (3jjj) Any one of groups (3b)-(3oo), wherein R 1 is independently selected from one of the following: a groups: methyl, ethyl, propyl, -isopropyl, -OMe, and -OH.

[0274] (3kkk) Any one of groups (3b)-(3oo), wherein R 1 is independently selected from one of the following: a groups: methyl and ethyl.

[0275] (3lll) Any one of groups (3b)-(3oo), wherein R 1 is substituted with one methyl group.

[0276] (3mmm) Any one of groups (3b)-(3oo), wherein R 1 is substituted with one ethyl group.

[0277] (3nnn) R 1 is C 1-6 alkyl, C 3-10 cycloalkyl, 3-7 membered heterocyclic group (e.g., 4-6 membered heterocyclic group or 5-6 membered heterocyclic group), -C1 alkyl - C 3-10 cycloalkyl, -C1 alkyl - 3-7 membered heterocyclic group (e.g., -C1 alkyl - 4-6 membered heterocyclic group or -C1 alkyl - 5-6 membered heterocyclic group), or -C1 alkyl - heteroaryl

[0278] wherein the C 3-10 cycloalkyl or 3-7 membered heterocyclic group is optionally fused to aryl, heteroaryl, C 3-7 cycloalkyl, or 3-7 membered heterocyclic group; or

[0279] wherein the C 3-10A cycloalkyl or 3- to 7-membered heterocyclic group is optionally substituted with =(spiro-C 3-7 cycloalkyl) or =(spiro-(3- to 7-membered heterocyclic group));

[0280] wherein R 1 is optionally substituted with 1, 2, 3, or 4 independently selected R a groups: oxo, halogen, cyano, nitro, C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkyl-cyano, -OR, -NR2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, and -N(R)C(O)N(R)2.

[0281] (3ooo) group (3nnn), wherein R 1 is C 1-6 alkyl, C 4-6 cycloalkyl or 5- to 6-membered heterocyclic group,

[0282] wherein the C 4-6 cycloalkyl or 5- to 6-membered heterocyclic group is optionally fused to an aryl or heteroaryl;

[0283] or

[0284] wherein the C4 cycloalkyl is optionally substituted with =(spiro-C4 cycloalkyl) or =(spiro-(4-membered heterocyclic group)).

[0285] (3ppp) group (3nnn), wherein R 1 is C 1-6 alkyl, C 4-6 cycloalkyl or 5- to 6-membered heterocyclic group,

[0286] wherein the C 4-6 cycloalkyl or 5- to 6-membered heterocyclic group is optionally fused to an aryl or heteroaryl;

[0287] or

[0288] wherein the C 4-6 cycloalkyl or 5- to 6-membered heterocyclic group is optionally substituted with =(spiro-C4 cycloalkyl) or =(spiro-(4-membered heterocyclic group)).

[0289] (3qqq) group (3nnn), wherein R 1 is C 1-6 alkyl.

[0290] (3rrr) group (3nnn), where R 1 is methyl, ethyl, propyl, butyl, pentyl or hexyl.

[0291] (3sss) group (3nnn), where R 1 is methyl, ethyl, propyl or butyl.

[0292] (3ttt) group (3nnn), where R 1 is methyl, ethyl or butyl.

[0293] (3uuu) group (3nnn), where R 1 is methyl or ethyl.

[0294] (3vvv) group (3nnn), where R 1 is methyl.

[0295] (3www) group (3nnn), where R 1 is ethyl.

[0296] (3xxx) group (3nnn), where R 1 is butyl.

[0297] (3yyy) group, any one of (3nnn)-(3xxx), where R 1 is substituted with 1 or 2 R's independently selected from the following a groups: halogen, C 1-6 alkyl, -C 1-6 haloalkyl, C3 cycloalkyl or -OR.

[0298] (3zzz) group, any one of (3nnn)-(3xxx), where R 1 is substituted with C3 cycloalkyl and -OH.

[0299] (3aaaa) group, any one of (3nnn)-(3xxx), where R 1 is substituted with 1 or 2 -OH.

[0300] (3bbbb) group, any one of (3nnn)-(3xxx), where R 1 is substituted with 1 -OH.

[0301] (3cccc) group, any one of (3nnn)-(3xxx), where R 1 is substituted with 2 -OH.

[0302] The present invention further includes subclasses and species of formula (I), which are any combinations of the species and genera of structural formula (I), and may be formula (Ia)-(Ii), where n, R 2 and R 1As defined above. Thus, for example, the present invention also includes a sub-genus of compounds of structural formula (Ie), wherein n is as defined above in (1g), and R 2 is as defined above in (2r).

[0303] Structural formula I is one of formulae (Ia)-(Ii):

[0304]

[0305]

[0306] Specific embodiments of this aspect of the present invention include compounds of formula (I) and any one of (Ia)–(Ii), each defined in the following rows, wherein each entry is the group number as defined above (for example, (2r) refers to R 2 being fluorine), "X" indicates that the variable is defined by another group in the embodiment (for example, in the following embodiment (1)-X, R 1 is defined in formula (X)) and the dash "-" indicates that the variable is defined as in formula (I) or (Ia)–(Ii) or defined according to any one of the applicable variable definitions (1a)-(3cccc) [for example, when the entry of R 2 is a dash, it can be defined as in formula (I)–(IVi) or as defined by any one of (2a)-(2t)]:

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314] In one embodiment, the present invention includes a compound of formula (II),

[0315]

[0316] which is a compound of formula (I), wherein

[0317] R 1 is

[0318] ring A is C 3-10 cycloalkyl or a 3- to 7-membered heterocyclic group;

[0319] m is 0, 1, 2, 3 or 4; and

[0320] R 4 is -NR2 or -OR.

[0321] In one embodiment, the present invention includes a compound of formula (II), wherein R 4 is -OH. In other embodiments, R 4 is –OH and n is 0. In other embodiments, R 4 is –OH and n is 1.

[0322] The present invention further includes a subclass of formula (II), wherein the substituents are selected according to one or more of the structural formula (II), R 2 , R a , m and ring A, including but not limited to, the following: Any and all combinations, including but not limited to, the following:

[0323] Structural formula I is one of formulae (IIa)-(IIi):

[0324]

[0325]

[0326] Ring A is selected from one of the following groups (4a)-(4ccc):

[0327] (4a) Ring A is C 3-10 cycloalkyl or a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group),

[0328] wherein m is 0, 1, 2 or 3, each R a is independently selected from halogen, C 1-6 alkyl, -OR, -S(O)2R and -S(O)2N(R)2, and each R is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl.

[0329] (4b) R 1 is:

[0330]

[0331]

[0332] wherein

[0333] each R is independently hydrogen or C 1-6 alkyl;

[0334] R 3 is methyl, ethyl or -O-butyl.

[0335] (4c) Group (4a), where ring A is C 4-6 cycloalkyl or a 4- to 6-membered heterocyclic group.

[0336] (4d) Group (4a), where ring A is C 3-8 cycloalkyl.

[0337] (4e) Group (4b), where ring A is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0338] (4f) Group (4b), where ring A is cyclobutyl, cyclopentyl or cyclohexyl.

[0339] (4g) Group (4b), where ring A is cyclobutyl or cyclohexyl.

[0340] (4h) Group (4b), where ring A is cyclobutyl or cyclopentyl.

[0341] (4i) Group (4b), where ring A is cyclopentyl or cyclohexyl.

[0342] (4j) Group (4b), where ring A is cyclopropyl.

[0343] (4k) Group (4b), where ring A is cyclobutyl.

[0344] (4l) Group (4b), where ring A is cyclopentyl.

[0345] (4m) Group (4b), where ring A is cyclohexyl.

[0346] (4n) R 1 is:

[0347]

[0348] (4o) R 1 is:

[0349]

[0350] (4p) R 1 is:

[0351]

[0352] (4q) R 1 is:

[0353]

[0354] (4r) Group (4a), where ring A is a 3- to 7-membered heterocyclic group.

[0355] (4s) group (4p), wherein ring A is aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl.

[0356] (4t) group (4p), wherein ring A is azetidinyl, pyrrolidinyl or piperidinyl.

[0357] (4u) group (4p), wherein ring A is azetidinyl or pyrrolidinyl.

[0358] (4v) group (4p), wherein ring A is azetidinyl or piperidinyl.

[0359] (4w) group (4p), wherein ring A is pyrrolidinyl or piperidinyl.

[0360] (4x) group (4p), wherein ring A is pyrrolidinyl.

[0361] (4y) group (4p), wherein ring A is piperidinyl.

[0362] (4z)R 1 is:

[0363]

[0364]

[0365] wherein

[0366] R 3 is methyl, ethyl, propyl, butyl, -O-methyl, -O-ethyl, -O-propyl or -O-butyl.

[0367] (4aa)R 1 is:

[0368]

[0369] wherein

[0370] R 3 is methyl, ethyl, propyl or butyl.

[0371] (4bb)R 1 is:

[0372]

[0373] (4cc)R 1 is:

[0374]

[0375] wherein

[0376] R 3 is methyl, ethyl, propyl or butyl.

[0377] (4dd)R 1 is:

[0378]

[0379] wherein

[0380] R 3 is methyl, ethyl, propyl, butyl, -O-methyl, -O-ethyl, -O-propyl or -O-butyl.

[0381] (4ee)R 1 is:

[0382]

[0383] wherein

[0384] R 3 is methyl, ethyl, propyl, butyl, -O-methyl, -O-ethyl, -O-propyl or -O-butyl.

[0385] (4ff)R 1 is:

[0386]

[0387] wherein

[0388] R 3 is methyl, ethyl, propyl, butyl, -O-methyl, -O-ethyl, -O-propyl or -O-butyl.

[0389] (4gg)R 1 is:

[0390]

[0391] wherein

[0392] R 3 is methyl, ethyl, propyl, butyl, -O-methyl, -O-ethyl, -O-propyl or -O-butyl.

[0393] (4hh)R 1 is:

[0394]

[0395] wherein

[0396] R 3 is methyl, ethyl, propyl, butyl, -O-methyl, -O-ethyl, -O-propyl or -O-butyl.

[0397] (4ii) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1, 2 or 3, and each R a is independently selected from halogen, C 1-6 alkyl, -OR, -S(O)2R and -S(O)2N(R)2.

[0398] (4jj) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1, 2 or 3, and each R a is independently selected from chlorine, fluorine, methyl, -OH, -S(O)2ethyl, -S(O)2NMe2 and -S(O)2NH2.

[0399] (4kk) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1 or 2, and each R a is independently selected from C 1-6 alkyl, -OR, -S(O)2R and -S(O)2N(R)2.

[0400] (4ll) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 3, and each R a is independently selected from halogen, C 1-6 alkyl and -OR.

[0401] (4mm) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 3, and each R a is independently selected from fluorine, methyl and -OH.

[0402] (4nn) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 2, and each R a is independently selected from C 1-6 alkyl and -OR.

[0403] (4oo) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 2, and both R a are methyl.

[0404] (4pp) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 2, and both R a are fluorine.

[0405] (4qq) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 2, and each R a is independently selected from methyl and -OH.

[0406] (4rr) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1, and Ra Selected from C 1-6 alkyl, -OR, -S(O)2R, and -S(O)2N(R)2.

[0407] (4ss) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1, and R a Selected from C 1-6 alkyl, -OR, and -S(O)2N(R)2.

[0408] (4tt) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1, and R a Selected from C 1-6 alkyl, -OR, and -S(O)2R.

[0409] (4uu) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1, and R a Selected from C 1-6 alkyl and -OR.

[0410] (4vv) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1, and R a Selected from methyl and -OH.

[0411] (4ww) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1, and R a Selected from C 1-6 alkyl, -S(O)2R, and -S(O)2N(R)2.

[0412] (4xx) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1, and R a is C 1-6 alkyl.

[0413] (4yy) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1, and R a is methyl or ethyl.

[0414] (4zz) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1, and R a is methyl.

[0415] (4aaa) Any one of groups (4c)-(4m) or (4r)-(4y), where m is 1, and R a is -OMe or -OH.

[0416] (4bbb) R 1 is:

[0417]

[0418]

[0419] wherein

[0420] each R is independently hydrogen or C 1-6 alkyl;

[0421] R 3 is methyl, ethyl or -O-butyl.

[0422] (4ccc)R 1 is:

[0423]

[0424] In another embodiment, the present invention includes a compound of formula (III),

[0425]

[0426] which is a compound of formula (I), wherein

[0427] R 1 is

[0428] a fused bicyclic ring system composed of ring A and ring B;

[0429] Ring A is C 3-8 cycloalkyl or a 3-7 membered heterocyclic group;

[0430] Ring B is aryl, heteroaryl, C 3-7 cycloalkyl or a 3-7 membered heterocyclic group;

[0431] m is 0, 1, 2, 3 or 4; and

[0432] the hydroxyl moiety is bonded to ring A and each R a is independently a substituent of ring A or ring B.

[0433] In one embodiment, the present invention includes a compound of formula (III) wherein n is 0. In other embodiments, n is 1.

[0434] The present invention further includes subclasses of formula (III) wherein the substituents are selected according to one or more of the structural formulas (III), R 2 , R a , m, ring A and ring B Any and all in combinations, including but not limited to, the following:

[0435] Structural formula I is one of formulae (IIIa)-(IIIi):

[0436]

[0437] Ring A / B is selected from one of the following groups (5a)-(5yy):

[0438] (5a) Ring A is C 3-8 cycloalkyl or a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), and ring B is aryl, heteroaryl, C 3-8 cycloalkyl or a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group),

[0439] wherein m is 0, 1, 2, or 3, and each R a is independently selected from halogen, C 1-6 alkyl, -OR, -C(O)N(R)2, -S(O)2R, and -S(O)2N(R)2.

[0440] (5b) Group (5a), wherein ring A is C 5-6 cycloalkyl, and ring B is aryl or heteroaryl.

[0441] (5c) Group (5a), wherein ring A is cyclopentyl or cyclohexyl, and ring B is aryl or heteroaryl.

[0442] (5d) Group (5a), wherein ring A is C 5-6 cycloalkyl, and ring B is phenyl or pyridyl.

[0443] (5e) Group (5a), wherein ring A is cyclopentyl or cyclohexyl, and ring B is phenyl or pyridyl.

[0444] (5f) Group (5a), wherein ring A is C 3-8 cycloalkyl, and ring B is aryl, heteroaryl, C 3-8 cycloalkyl or a 3- to 7-membered heterocyclic group.

[0445] (5g) Group (5a), wherein ring A is cyclopropyl, and ring B is aryl, heteroaryl, C 3-7 cycloalkyl or a 3- to 7-membered heterocyclic group.

[0446] (5h) Group (5a), wherein ring A is cyclobutyl, and ring B is aryl, heteroaryl, C 3-8 cycloalkyl or a 3- to 7-membered heterocyclic group.

[0447] (5i) Group (5a), wherein ring A is cyclopentyl or cyclohexyl, and ring B is aryl, heteroaryl, C 3-8 cycloalkyl or a 3- to 7-membered heterocyclic group.

[0448] (5j) Group (5a), wherein ring A is C 3-8cycloalkyl, and ring B is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, oxazolyl or oxadiazolyl.

[0449] (Group (5k) of (5a), wherein ring A is cyclopentyl or cyclohexyl, and ring B is aryl.

[0450] (Group (5l) of (5a), wherein ring A is cyclopentyl or cyclohexyl, and ring B is phenyl.

[0451] (Group (5m) of (5a), wherein ring A is cyclopentyl, and ring B is heteroaryl.

[0452] (Group (5n) of (5a), wherein ring A is cyclopentyl or cyclohexyl, and ring B is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, oxazolyl or oxadiazolyl.

[0453] (Group (5o) of (5a), wherein ring A is cyclopentyl, and ring B is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, oxazolyl or oxadiazolyl.

[0454] (Group (5p) of (5a), wherein ring A is cyclohexyl, and ring B is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, oxazolyl or oxadiazolyl.

[0455] (Group (5q) of (5a), wherein ring A is cyclohexyl, and ring B is pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl.

[0456] (Group (5r) of (5a), wherein ring A is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), and ring B is aryl, heteroaryl, C 3-8 cycloalkyl or a 3- to 7-membered heterocyclic group.

[0457] (Group (5s) of (5a), wherein ring A is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), and ring B is aryl or heteroaryl.

[0458] (Group (5t) of (5a), wherein ring A is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), and ring B is aryl.

[0459] (Group (5u) of (5a), wherein ring A is a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered heterocyclic group or a 5- to 6-membered heterocyclic group), and ring B is heteroaryl.

[0460] (Group (5v) of (5a), wherein ring A is piperidinyl, and ring B is aryl.

[0461] (Group (5w) of (5a), wherein ring A is piperidinyl, and ring B is heteroaryl.

[0462] Any one of groups (5b)-(5w) where m is 1, 2 or 3, and each R a is independently selected from C 1-6 alkyl, -OR, -C(O)N(R)2, -S(O)2R and -S(O)2N(R)2.

[0463] Any one of groups (5y)-(5w) where m is 1, 2 or 3, and each R a is independently selected from methyl, -OH, -S(O)2ethyl, -C(O)NH2, -C(O)N(Me)(H), -S(O)2NMe2 and -S(O)2NH2.

[0464] Any one of groups (5z)-(5w) where m is 1 or 2, and each R a is independently selected from C 1-6 alkyl, -OR, -S(O)2R and -S(O)2N(R)2.

[0465] Any one of groups (5aa)-(5w) where m is 3, and each R a is independently selected from C 1-6 alkyl and -OR.

[0466] Any one of groups (5bb)-(5w) where m is 3, and each R a is independently selected from methyl and -OH.

[0467] Any one of groups (5cc)-(5w) where m is 2, and each R a is independently selected from C 1-6 alkyl and -OR.

[0468] Any one of groups (5dd)-(5w) where m is 2, and each R a is independently selected from methyl and -OH.

[0469] Any one of groups (5ee)-(5w) where m is 1, and R a is selected from C 1-6 alkyl, -OR, -C(O)N(R)2, -S(O)2R and -S(O)2N(R)2.

[0470] Any one of groups (5ff)-(5w) where m is 1, and R a is selected from C 1-6 alkyl, -OR and -S(O)2N(R)2.

[0471] Any one of groups (5b)-(5w), where m is 1, and R a is selected from C 1-6 alkyl, -OR, and -S(O)2R.

[0472] (5hh) Any one of groups (5b)-(5w), where m is 1, and R a is selected from C 1-6 alkyl and -OR.

[0473] (5ii) Any one of groups (5b)-(5w), where m is 1, and R a is selected from methyl, -C(O)NH2, -C(O)N(Me)(H), and -OH.

[0474] (5jj) Any one of groups (5b)-(5w), where m is 1, and R a is selected from C 1-6 alkyl, -S(O)2R, and -S(O)2N(R)2.

[0475] (5kk) Any one of groups (5b)-(5w), where m is 1, and R a is C 1-6 alkyl.

[0476] (5ll) Any one of groups (5b)-(5w), where m is 1, and R a is methyl or ethyl.

[0477] (5mm) Any one of groups (5b)-(5w), where m is 1, and R a is methyl.

[0478] (5nn) Any one of groups (5b)-(5w), where m is 1, and R a is -OMe or -OH.

[0479] (5oo) Any one of groups (5b)-(5w), where m is 0.

[0480] (5pp) R 1 is

[0481]

[0482] (5qq) R 1 is

[0483]

[0484] (5rr) R 1 is

[0485]

[0486] (5ss)R 1 is

[0487]

[0488] (5tt)R 1 is

[0489]

[0490] (5uu)R 1 is

[0491]

[0492] (5vv)R 1 is

[0493]

[0494] (5ww)R 1 is

[0495]

[0496] (5xx)R 1 is

[0497]

[0498] (5yy)R 1 is

[0499]

[0500] In another embodiment, the invention includes a compound of formula (IV),

[0501]

[0502] which is a compound of formula (I), wherein

[0503] R 1 is

[0504] ring A and ring B form a spiro ring system,

[0505] ring A is C 3-8 cycloalkyl or a 3-7 membered heterocyclic group;

[0506] ring B is C 3-7 cycloalkyl, a 3-7 membered heterocyclic group, aryl or heteroaryl;

[0507] m is 0, 1, 2, 3 or 4; and

[0508] the hydroxyl moiety is bonded to ring A and each Ra Substituents independently for Ring A or Ring B.

[0509] In one embodiment, the invention includes compounds of formula (IV) wherein n is 0. In other embodiments, n is 1.

[0510] The invention further includes subclasses of formula (IV) wherein the substituents are selected in combination from Ring A and Ring B as defined by formula (IV), R 2 , R a , m, one or more of Any and all including, but not limited to, the following:

[0511] Structural formula I is one of formulae (IVa)-(IVi):

[0512]

[0513]

[0514] Ring A / B is selected from one of the following groups (6a)-(6zz):

[0515] (6a) Ring A is C 3-8 cycloalkyl or a 3-7 membered heterocyclic group (e.g., a 4-6 membered heterocyclic group or a 5-6 membered heterocyclic group), and Ring B is C 3-8 cycloalkyl or a 3-7 membered heterocyclic group (e.g., a 4-6 membered heterocyclic group or a 5-6 membered heterocyclic group), aryl or heteroaryl,

[0516] wherein m is 0, 1, 2 or 3, and each R a is independently selected from halogen, C 1-6 alkyl, -OR, -S(O)2R and -S(O)2N(R)2.

[0517] (6b) Group (6a) wherein Ring A is C 4-5 cycloalkyl or a 4-6 membered heterocyclic group, and Ring B is C 4-6 cycloalkyl or a 4-6 membered heterocyclic group.

[0518] (6c) Group (6a) wherein Ring A is C 3-8 cycloalkyl, and Ring B is C 3-8 cycloalkyl or a 3-7 membered heterocyclic group.

[0519] (6d) Group (6a) wherein Ring A is a 3-7 membered heterocyclic group (e.g., a 4-6 membered heterocyclic group or a 5-6 membered heterocyclic group), and Ring B is C 3-7 cycloalkyl.

[0520] (6e) Group (6a) wherein Ring A is C 3-8 cycloalkyl or a 3-7 membered heterocyclic group (e.g., a 4-6 membered heterocyclic group or a 5-6 membered heterocyclic group), and Ring B is C3-7 Cycloalkyl

[0521] (6f) Group (6a), wherein ring A is C 3-8 Cycloalkyl or 3-7 membered heterocyclic group (e.g., 4-6 membered heterocyclic group or 5-6 membered heterocyclic group), and ring B is 3-7 membered heterocyclic group.

[0522] (6g) Group (6a), wherein ring A is C 3-8 Cycloalkyl, and ring B is aryl or heteroaryl.

[0523] (6h) Group (6a), wherein ring A is C 3-8 Cycloalkyl, and ring B is 3-7 membered heterocyclic group.

[0524] (6i) Group (6a), wherein ring A is 3-7 membered heterocyclic group (e.g., 4-6 membered heterocyclic group or 5-6 membered heterocyclic group), and ring B is aryl.

[0525] (6j) Group (6a), wherein ring A is 3-7 membered heterocyclic group (e.g., 4-6 membered heterocyclic group or 5-6 membered heterocyclic group), and ring B is heteroaryl.

[0526] (6k) Group (6a), wherein ring A is cyclobutyl, and ring B is C 3-8 Cycloalkyl or 3-7 membered heterocyclic group.

[0527] (6l) Group (6a), wherein ring A is cyclobutyl, and ring B is C 3-8 Cycloalkyl.

[0528] (6m) Group (6a), wherein ring A is cyclobutyl, and ring B is cyclobutyl.

[0529] (6n) Group (6a), wherein ring A is cyclobutyl, and ring B is 3-7 membered heterocyclic group.

[0530] (6o) Group (6a), wherein ring A is cyclobutyl, and ring B is 4-6 membered heterocyclic group.

[0531] (6p) Group (6a), wherein ring A is cyclobutyl, and ring B is 4-membered heterocyclic group.

[0532] (6q) Group (6a), wherein ring A is cyclobutyl, and ring B is 5-membered heterocyclic group.

[0533] (6r) Group (6a), wherein ring A is cyclobutyl, and ring B is 6-membered heterocyclic group.

[0534] (6s) Group (6a), wherein ring A is cyclobutyl, and ring B is azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl or tetrahydropyranyl.

[0535] (6t) group (6a), wherein ring A is cyclobutyl and ring B is azetidinyl, oxetanyl, piperidinyl or tetrahydropyranyl.

[0536] (6u) group (6a), wherein ring A is cyclobutyl and ring B is azetidinyl or oxetanyl.

[0537] (6v) group (6a), wherein ring A is cyclobutyl and ring B is piperidinyl or tetrahydropyranyl.

[0538] (6w) group (6a), wherein ring A is cyclobutyl and ring B is azetidinyl or piperidinyl.

[0539] (6x) group (6a), wherein ring A is cyclobutyl and ring B is oxetanyl or tetrahydropyranyl.

[0540] (6y) any one of groups (6b)-(6x), wherein m is 1, 2 or 3, and each R a is independently selected from halogen, C 1-6 alkyl, -OR, -S(O)2R and -S(O)2N(R)2.

[0541] (6z) any one of groups (6b)-(6x), wherein m is 1, 2 or 3, and each R a is independently selected from chlorine, fluorine, methyl, -OH, -S(O)2ethyl, -S(O)2NMe2 and -S(O)2NH2.

[0542] (6aa) any one of groups (6b)-(6x), wherein m is 1 or 2, and each R a is independently selected from halogen, C 1-6 alkyl, -OR, -S(O)2R and -S(O)2N(R)2.

[0543] (6bb) any one of groups (6b)-(6x), wherein m is 3, and each R a is independently selected from halogen, C 1-6 alkyl and -OR.

[0544] (6cc) any one of groups (6b)-(6x), wherein m is 3, and each R a is independently selected from fluorine, methyl and -OH.

[0545] (6dd) any one of groups (6b)-(6x), wherein m is 2, and each R a is independently selected from C 1-6 alkyl and -OR.

[0546] (6ee) any one of groups (6b)-(6x), wherein m is 2, and each R aIndependently selected from methyl and -OH.

[0547] (6ff) Any one of groups (6b)-(6x), where m is 2, and both R a are methyl.

[0548] (6gg) Any one of groups (6b)-(6x), where m is 2, and both R a are fluorine.

[0549] (6hh) Any one of groups (6b)-(6x), where m is 1, and R a is selected from C 1-6 alkyl, -OR, -S(O)2R, and -S(O)2N(R)2.

[0550] (6ii) Any one of groups (6b)-(6x), where m is 1, and R a is selected from C 1-6 alkyl, -OR, and -S(O)2N(R)2.

[0551] (6jj) Any one of groups (6b)-(6x), where m is 1, and R a is selected from C 1-6 alkyl, -OR, and -S(O)2R.

[0552] (6kk) Any one of groups (6b)-(6x), where m is 1, and R a is selected from C 1-6 alkyl and -OR.

[0553] (6ll) Any one of groups (6b)-(6x), where m is 1, and R a is selected from methyl and -OH.

[0554] (6mm) Any one of groups (6b)-(6x), where m is 1, and R a is selected from C 1-6 alkyl, -S(O)2R, and -S(O)2N(R)2.

[0555] (6nn) Any one of groups (6b)-(6x), where m is 1, and R a is C 1-6 alkyl.

[0556] (6oo) Any one of groups (6b)-(6x), where m is 1, and R a is methyl or ethyl.

[0557] (6pp) Any one of groups (6b)-(6x), where m is 1, and R a is methyl.

[0558] (6qq) Any one of groups (6b)-(6x), where m is 1, and R a is -OMe or -OH.

[0559] (6rr) Any one of groups (6b)-(6x), where m is 0.

[0560] (6ss) R 1 is

[0561]

[0562] where

[0563] R 3 is methyl, ethyl, propyl, butyl, -O-methyl, -O-ethyl, -O-propyl or -O-butyl.

[0564] (6tt) R 1 is

[0565]

[0566] (6uu) R 1 is

[0567]

[0568] (6vv) R 1 is

[0569]

[0570] (6ww) R 1 is

[0571]

[0572] (6xx) R 1 is

[0573]

[0574] (6yy) R 1 is

[0575]

[0576] (6zz) R 1 is

[0577]

[0578] In another embodiment, the present invention includes a compound of formula (V),

[0579]

[0580] Wherein

[0581] ring A is C 3-10 cycloalkyl, 3- to 7-membered heterocyclic group or heteroaryl;

[0582] m is 0, 1, 2, 3 or 4; and

[0583] R 4 is -NR2 or -OR substituted on ring A or a methylene group bonded to ring A.

[0584] In one embodiment, the present invention includes a compound of formula (V), wherein R 4 is -OH. In other embodiments, R 4 is –OH and n is 0. In other embodiments, R 4 is –OH and n is 1.

[0585] The present invention further includes subclasses of formula (V), wherein the substituents are selected according to any and all combinations of one or more of the structural formula (V), R 4 , R a , m and ring A, including but not limited to, the following:

[0586] Structural formula I is one of formulae (Va)-(Vf):

[0587]

[0588] Ring A is selected from one of the following groups (7a)-(7cc):

[0589] (7a) Ring A is C 3-8 cycloalkyl, 3- to 7-membered heterocyclic group or heteroaryl,

[0590] wherein m is 0, 1, 2 or 3, and each R a is independently selected from halogen, C 1-6 alkyl, -S(O)2R, -C(O)N(R)2 and C 1-6 alkyl-cyano.

[0591] (7b) Group (7a), wherein ring A is C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group or heteroaryl.

[0592] (7c) Group (7a), wherein ring A is

[0593] (7d)

[0594] (7e) Group (7a), wherein ring A is C 3-8 cycloalkyl.

[0595] Group (7f) of (7a), wherein ring A is C 3-6 cycloalkyl.

[0596] Group (7g) of (7a), wherein ring A is cyclopropyl.

[0597] Group (7h) of (7a), wherein ring A is cyclohexyl.

[0598] Group (7i) of (7a), wherein ring A is a 3- to 7-membered heterocyclic group.

[0599] Group (7j) of (7a), wherein ring A is a 4- to 6-membered heterocyclic group.

[0600] Group (7k) of (7a), wherein ring A is a 4-membered heterocyclic group.

[0601] Group (7l) of (7a), wherein ring A is a 5-membered heterocyclic group.

[0602] Group (7m) of (7a), wherein ring A is a 6-membered heterocyclic group.

[0603] Group (7n) of any one of (7b)-(7l), wherein m is 0, 1, 2, or 3, and each R a is independently selected from halogen, C 1-6 alkyl, -S(O)2R, -C(O)N(R)2, and C 1-6 alkyl-cyano.

[0604] Group (7o) of (7m), wherein each R a is independently selected from halogen, C 1-6 alkyl, -S(O)2R, -C(O)N(R)2, and C 1-6 alkyl-cyano.

[0605] Group (7p) of (7m), wherein each R a is independently selected from halogen, C 1-6 alkyl, -S(O)2R, and -C(O)N(R)2.

[0606] Group (7q) of (7m), wherein each R a is independently selected from halogen, C 1-6 alkyl, and -S(O)2R.

[0607] Group (7r) of (7m), wherein each R a is independently selected from halogen, C 1-6 alkyl, and C 1-6 alkyl-cyano.

[0608] Group (7s) of (7m), wherein each R a is halogen.

[0609] Group (7t) (7m), wherein each R a is C 1-6 alkyl

[0610] Group (7u) (7m), wherein each R a is -S(O)2R

[0611] Group (7v) (7m), wherein each R a is -C(O)N(R)2

[0612] Group (7w) (7m), wherein each R a is C 1-6 alkyl-cyano

[0613] Group (7x), any one of (7b)-(7v), wherein m is 0, 1, 2 or 3

[0614] Group (7y), any one of (7b)-(7v), wherein m is 0, 1 or 2

[0615] Group (7z), any one of (7b)-(7v), wherein m is 0 or 1

[0616] Group (7aa), any one of (7b)-(7v), wherein m is 3

[0617] Group (7bb), any one of (7b)-(7v), wherein m is 2

[0618] Group (7cc), any one of (7b)-(7v), wherein m is 1

[0619] Group (7dd), any one of (7b)-(7v), wherein m is 0

[0620] Specific embodiments of this aspect of the invention include compounds of any one of formula (II), (IIa)–(IIi), (III), (IIIa)–(IIIi), (IV) and (IVa)–(IVi), (V) and (Va)–(Vf), each of which is defined in the following lines, where each entry is a group number as defined above (for example, (2r) means R 2 is fluorine), "X" indicates that the variable is defined by another group in the embodiment (for example, in the following embodiment (2)-X, ring A is defined in formula (X)) and the dash "-" indicates that the variable is defined as in formula (I)–(Vf) or according to any one of the applicable variable definitions (1a)-(7xx) [for example, when the entry for R 2 is a dash, it can be defined as in formula (II)–(Vf) or as any one of the definitions (2a)-(2t)]:

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629] In another embodiment, each R is independently hydrogen or C 1-6 alkyl. In other embodiments, R is independently hydrogen, methyl, ethyl, or trifluoromethyl.

[0630] In another embodiment, the compounds of the invention are of formula (IIk) or (IIl),

[0631]

[0632] which are compounds of formula (I), wherein,

[0633] R 1 is

[0634] Ring A is C 3-10 cycloalkyl or a 3- to 7-membered heterocyclic group (e.g., a 4- to 6-membered or 5- to 6-membered heterocyclic group),

[0635] m is 0, 1, 2, 3, or 4; and

[0636] R 4 is -NR2 or -OR.

[0637] In another aspect, the invention provides compounds which are:

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660] or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, or a racemic mixture thereof.

[0661] In one embodiment, the compound of the present invention is

[0662] (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol;

[0663] 5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol;

[0664] (3S,4S)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol;

[0665] (5R,6R)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinazolin-5-ol;

[0666] (7R,8R)-8-Hydroxy-7-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide; and

[0667] (6S,7R)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7-tetrahydrobenzothiazol-7-ol.

[0668] In another embodiment, the compounds of the invention are

[0669] (7S,8S)-7-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol;

[0670] 8-Fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclobutan-1-ol;

[0671] 3-(-5H-imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol;

[0672] (5S,6S)-5-Hydroxy-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-N-methyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide;

[0673] (1R,2S)-2-((R)-8-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-7-oxaspiro[3.5]nonan-1-ol; and

[0674] (4S,5R)-5-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-4-ol.

[0675] In another embodiment, the compounds of the invention are

[0676] 4-(5H-imidazo[1,5-b]isoindol-5-yl)-2,2-dimethyl-cyclobutanol;

[0677] (S)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol;

[0678] (R)-1-(5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol;

[0679] (4S,5S)-5-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol;

[0680] ((5R,6S)-5-Hydroxy-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydronaphthalene-2-sulfonamide; and

[0681] (4S,5S)-4-Hydroxy-5-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7-tetrahydrobenzothiazole-2-carboxamide.

[0682] In another embodiment, the compounds of the present invention are

[0683] 2-(5H-Imidazo[1,5-b]isoindol-5-yl)spiro[3.3]heptan-3-ol;

[0684] (1R,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol;

[0685] (5S,6S)-5-Hydroxy-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;

[0686] 4-Hydroxy-5-(5H-imidazo[5,1-a]isoindol-5-yl)azepane-1-sulfonamide;

[0687] (5R,6R)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydrophthalazin-5-ol; and

[0688] (6S,7S)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-4,5,6,7-tetrahydro-1H-indazol-7-ol.

[0689] In another embodiment, the compounds of the present invention are

[0690] (3S,4S)-1-(Ethylsulfonyl)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-3-ol;

[0691] 3-(5H-Imidazo[5,1-a]isoindol-5-yl)thietan-3-ol;

[0692] (4S,5S)-5-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol;

[0693] (7S,8S)-7-((S)-8-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol;

[0694] (4S,5S)-4-Hydroxy-5-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-N-methyl-4,5,6,7-tetrahydrobenzothiazole-2-carboxamide; and

[0695] 6-(5H-Imidazo[5,1-a]isoindol-5-yl)-3-(methylsulfonyl)-3-azabicyclo[3.1.1]heptan-6-ol.

[0696] The present invention further includes subclasses of formula (I), wherein the structure of any one of formula (I), (Ia)-(Ii), (II), (IIa)-(IIi), (III), (IIIa)-(IIIi), (IV), (IVa)-(IVi), (V) or (Va)-(Vf) includes the structural element

[0697]

[0698] which has a stereoisomeric configuration of any one of 1–27, wherein the stereochemistry of each stereoisomeric carbon atom (the “a,” “b,” and “c” marked above) is designated as racemic (“-”), “S,” or “R”:

[0699] Structural formula I is one of the stereoisomeric configurations (1)-(27):

[0700]

[0701]

[0702] In one embodiment, the compounds of the present invention have the S stereoconfiguration at the position marked “a” above. For example, the compound has a stereoconfiguration of configuration 1, 7, 8, 15, 16, or 19-22.

[0703] In another embodiment, the compounds of the present invention have the R stereoconfiguration at the position marked “a” above. For example, the compound has a stereoconfiguration of configuration 2, 9, 10, 17, 18, or 23-26.

[0704] In one embodiment, the compounds of the present invention have the stereoconfiguration of configuration 20.

[0705] In another embodiment, the compounds of the invention are in the stereoconfiguration of Configuration 19.

[0706] In another aspect, the present invention provides each of Compounds 1-41 and 56-115, 117-126, 130, 133, 136, 139, 139-1, 142, 146, 146-1, 149-151, 156-163, 166-176 and 178-183 in each of the stereoisomeric configurations 1-27. For example:

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743] The present invention further includes subclasses of formula (I), wherein the structure of any one of formula (I), (I) or (IIj)-(IIo) contains a structural element,

[0744]

[0745] which has a stereoisomeric configuration of any one of 28-36, wherein the stereochemistry of each stereoisomeric carbon atom (labeled "d" and "e" above) is specified as racemic ("-"), "S" or "R":

[0746] Structural formula I is one of the stereoisomeric configurations (28)-(36):

[0747]

[0748]

[0749] In another aspect, the present invention provides compounds 42-55, 116, 127-129, 131-132, 134-135, 137-138, 140-141, 143-145, 147-148, 152-155, 164-165 and 177, each in a stereoisomeric configuration 28-36. For example:

[0750]

[0751]

[0752]

[0753]

[0754] In another aspect, the present invention provides a compound according to any of the foregoing aspects, which comprises one or more stable isotopes. The stable isotope can replace any atom, for example, hydrogen, and can include any stable isotope, for example, deuterium.

[0755] In another aspect, the present invention provides a pharmaceutical composition comprising a compound and a pharmaceutically acceptable excipient, diluent or carrier, wherein the compound is any one or any embodiment of the foregoing aspects of the present invention.

[0756] In another aspect, the present invention provides a method for treating tryptophan 2,3-dioxygenase (TDO2)-mediated immunosuppression in a subject in need thereof, comprising administering a compound or a pharmaceutical composition according to any one or any embodiment of the foregoing aspects of the present invention in an effective tryptophan 2,3-dioxygenase inhibitory amount.

[0757] In one embodiment, the immunosuppression is associated with cancer.

[0758] In one embodiment, the immunosuppression is tumor-specific immunosuppression associated with cancer.

[0759] In another embodiment, the immunosuppression is associated with cancer, wherein the cancer is colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head cancer, or neck cancer, or lymphoma, leukemia, or melanoma.

[0760] In another aspect, the present invention provides the use of a compound according to any one of the foregoing aspects (and any embodiment thereof) as defined above in the preparation of a medicament for treating a medical condition that benefits from inhibition of the enzymatic activity of IDO1 or TDO2. The medical conditions contemplated in this aspect include all the conditions described herein.

[0761] On the other hand, the present invention provides the use of a compound as defined in any of the foregoing aspects (and any of its embodiments) for the preparation of a medicament for stimulating T-cell proliferation or reversing an unresponsive or immunosuppressed immune state.

[0762] On the other hand, the present invention provides the use of a compound as defined in any of the foregoing aspects (and any of its embodiments) for the preparation of a medicament for treating immunosuppression associated with cancer or viral infection.

[0763] In one embodiment, the present invention provides the use of a compound as defined in any of the foregoing aspects (and any of its embodiments) for the preparation of a medicament for treating tumor-specific immunosuppression associated with cancer. Preferably, the cancer is colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer or head and neck cancer, lymphoma, leukemia, melanoma, etc.

[0764] Definition

[0765] As used herein, a term may be prefixed or suffixed with a single line "-" or a double line "=", to indicate the bond order of the bond between the named substituent and its parent moiety; a single line indicates a single bond, a double line indicates a double bond or, in the case of a spiro-substituent, two single bonds. In the absence of a single or double line, it is understood that a single bond is formed between the substituent and its parent moiety; in addition, unless the short line is otherwise shown, the substituent is intended to be read "from left to right". For example, C1-C6 alkoxycarbonyloxy and -OC(O)C1-C6 alkyl represent the same functional group; similarly, arylalkyl, arylalkyl- and -alkylaryl represent the same functional group.

[0766] In addition, as is familiar to those skilled in the art, and by its expression of connection between two other moieties, certain terms herein may be applied as both monovalent and divalent linking groups. For example, an alkyl group may be both a monovalent group and a divalent group; in the latter case, those skilled in the art should clearly understand the removal of an additional hydrogen atom from the monovalent alkyl group to provide a suitable divalent moiety.

[0767] Unless otherwise specified, the term "alkenyl" as used herein means a straight-chain or branched-chain hydrocarbon containing 2 to 10 carbons and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl.

[0768] As used herein, the term "alkoxy" means an alkyl group as defined herein attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0769] Unless otherwise specified, the term "alkyl" as used herein refers to a straight-chain or branched-chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an "alkyl" group is a linking group between two other moieties, it may also be straight-chain or branched-chain; examples include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CHC(CH3)-, -CH2CH(CH2CH3)CH2-.

[0770] As used herein, the term "aryl" refers to phenyl (i.e., monocyclic aryl), or a bicyclic system containing at least one benzene ring, or an aromatic bicyclic containing only carbon atoms in the aromatic bicyclic system. The bicyclic aryl can be azulyl, naphthyl, or phenyl fused to a monocyclic cycloalkyl, monocyclic cycloalkenyl, or monocyclic heterocyclic group. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained in the phenyl portion of the bicyclic system or any carbon atom of the naphthalene or azulene ring. The fused monocyclic cycloalkyl or monocyclic heterocyclic group portion of the bicyclic aryl is optionally substituted with one or two oxo and / or thio groups.Representative examples of the bicyclic aryl include, but are not limited to, azulyl, naphthyl, indan-1-yl, indan-2-yl, indan-3-yl, indan-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, indene-1-yl, indene-2-yl, indene-3-yl, indene-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl, 2H-chromen-2-one-5-yl, 2H-chromen-2-one-6-yl, 2H-chromen-2-one-7-yl, 2H-chromen-2-one-8-yl, isoindoline-1,3-dione-4-yl, isoindoline-1,3-dione-5-yl, indene-1-one-4-yl, indene-1-one-5-yl, indene-1-one-6-yl, indene-1-one-7-yl, 2,3-dihydrobenzo[b][1,4]dioxan-5-yl, 2,3-dihydrobenzo[b][1,4]dioxan-6-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-5-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-6-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-7-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-8-yl, benzo[d]oxazin-2(3H)-one-5-yl, benzo[d]oxazin-2(3H)-one-6-yl, benzo[d]oxazin-2(3H)-one-7-yl, benzo[d]oxazin-2(3H)-one-8-yl, quinazolin-4(3H)-one-5-yl, quinazolin-4(3H)-one-6-yl, quinazolin-4(3H)-one-7-yl, quinazolin-4(3H)-one-8-yl, quinoxalin-2(1H)-one-5-yl, quinoxalin-2(1H)-one-6-yl, quinoxalin-2(1H)-one-7-yl, quinoxalin-2(1H)-one-8-yl, benzo[d]thiazol-2(3H)-one-4-yl, benzo[d]thiazol-2(3H)-one-5-yl, benzo[d]thiazol-2(3H)-one-6-yl, and benzo[d]thiazol-2(3H)-one-7-yl. In certain embodiments, the bicyclic aryl is (i) naphthyl or (ii) a benzene ring fused to a 5- or 6-membered monocyclic cycloalkyl, 5- or 6-membered monocyclic cycloalkenyl, or 5- or 6-membered monocyclic heterocyclic group, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclic groups are optionally substituted with one or two groups independently selected from oxo or thio.

[0771] As used herein, the terms "arylalkyl", "alkylaryl", and "arylalkyl-" mean an aryl group as defined herein attached to the parent molecular moiety through an alkyl group as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphthalen-2-ylethyl.

[0772] As used herein, the terms "cyano" and "nitrile" mean a -CN group.

[0773] As used herein, the term "cycloalkyl" means a monocyclic or bicyclic cycloalkyl ring system. A monocyclic ring system is a cyclic hydrocarbon group containing 3 to 10 carbon atoms, wherein such a group may be saturated or unsaturated, but not aromatic. In certain embodiments, the cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic or fused bicyclic. A bridged monocyclic contains a monocyclic cycloalkyl ring as follows: wherein two non-adjacent carbon atoms of the monocyclic are connected by an alkylene bridge having 1 to 3 other carbon atoms (i.e., -(CH2) w - in the form of a bridging group, where w is 1, 2, 3, or 4). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, and adamantane. A fused bicyclic cycloalkyl ring system contains a monocyclic cycloalkyl ring fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclic, or monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is connected to the parent molecular moiety through any carbon atom contained in the monocyclic cycloalkyl ring. The cycloalkyl group is optionally substituted by one or two groups independently selected from oxo or thio. In certain embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to a benzene ring, 5- or 6-membered monocyclic cycloalkyl, 5- or 6-membered monocyclic cycloalkenyl, 5- or 6-membered monocyclic heterocyclic, or 5- or 6-membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups independently selected from oxo or thio.

[0774] As used herein, "cycloalkenyl" means a monocyclic or bicyclic cycloalkenyl ring system. The monocyclic ring system means a cyclic hydrocarbon group containing 3 to 10 carbon atoms, wherein such a group is unsaturated (i.e., contains at least one ring carbon-carbon double bond), but not aromatic. Examples of monocyclic ring systems include cyclopentenyl and cyclohexenyl. A bicyclic cycloalkenyl ring is a bridged monocyclic or fused bicyclic. A bridged monocyclic contains a monocyclic cycloalkenyl ring as follows: wherein two non-adjacent carbon atoms of the monocyclic are connected by an alkylene bridge having 1 to 3 other carbon atoms (i.e., -(CH2) w-form bridging group, where w is 1, 2, 3 or 4) are linked. Representative examples of bicyclic cycloalkenyl include, but are not limited to, norbornyl and bicyclo[2.2.2]oct-2-enyl. The fused bicyclic cycloalkenyl ring system contains a monocyclic cycloalkenyl ring fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclic or monocyclic heteroaryl group. The bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained in the monocyclic cycloalkenyl ring. The cycloalkenyl group is optionally substituted by one or two groups independently selected from oxo or thio.

[0775] As used herein, the term "halo" or "halogen" refers to -Cl, -Br, -I or -F.

[0776] As used herein, the term "haloalkyl" refers to at least one halogen as described herein attached to the parent molecular moiety through an alkyl group as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.

[0777] As used herein, the term "heteroaryl" refers to a monocyclic heteroaryl ring system or a bicyclic ring system containing at least one heteroaromatic ring. The monocyclic heteroaryl can be a 5- or 6-membered ring. The 5-membered ring is composed of two double bonds and one, two, three, or four nitrogen atoms and optionally one oxygen or sulfur atom. The six-membered ring is composed of three double bonds and one, two, three, or four nitrogen atoms. The 5- or 6-membered heteroaryl is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl is composed of a monocyclic heteroaryl fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclic, or monocyclic heteroaryl. The fused cycloalkyl or heterocyclic moiety of the bicyclic heteroaryl group is optionally substituted with one or two groups independently selected from oxo or thio. When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclic ring, then the bicyclic heteroaryl group is attached to the parent molecular moiety through any carbon or nitrogen atom contained in the monocyclic heteroaryl moiety of the bicyclic ring system. When the bicyclic heteroaryl is a monocyclic heteroaryl fused to a benzene ring or a monocyclic heteroaryl, then the bicyclic heteroaryl group is linked to the parent molecular moiety through any carbon atom or nitrogen atom in the bicyclic ring system. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuryl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furanopyridyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thiophenopyridyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, and 6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-one. In certain embodiments, the fused bicyclic heteroaryl is a 5- or 6-membered monocyclic heteroaryl ring fused to a benzene ring, 5- or 6-membered monocyclic cycloalkyl, 5- or 6-membered monocyclic cycloalkenyl, 5- or 6-membered monocyclic heterocyclic, or 5- or 6-membered monocyclic heteroaryl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclic groups are optionally substituted with one or two groups independently selected from oxo or thio.

[0778] As used herein, the terms "heteroarylalkyl" and "-alkylheteroaryl" mean that a heteroaryl as defined herein is attached to a parent molecular moiety through an alkyl group as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, furan-3-ylmethyl, 1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, 1-(pyridin-4-yl)ethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidin-5-ylmethyl, 2-(pyrimidin-2-yl)propyl, thiophen-2-ylmethyl, and thiophen-3-ylmethyl.

[0779] As used herein, the term "heterocyclic group" means a monocyclic heterocycle or a bicyclic heterocycle. The monocyclic heterocycle is a 3-, 4-, 5-, 6- or 7-membered ring containing at least one heteroatom independently selected from O, N, and S, wherein the ring is saturated or unsaturated but not aromatic. The 3- or 4-membered ring contains 1 heteroatom selected from O, N, and S. The 5-membered ring may contain zero or one double bond and one, two, or three heteroatoms selected from O, N, and S. The 6- or 7-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from O, N, and S. The monocyclic heterocycle is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the monocyclic heterocycle. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Bicyclic heterocycles fused through a heteroatom can be classified according to the ring A / B provisions of the present invention as if the heteroatom were in ring A or ring B. For example, 6,7,8,9-tetrahydro-4H-quinolizin-4-one-yl:

[0780]

[0781] It can be classified as a 6-membered heterocyclic group where ring A = C6 cycloalkyl and ring B = a 6-membered heterocyclic group substituted with an oxo group, or A = 6-membered heterocyclic group and ring B = C6 cycloalkenyl substituted with an oxo group. The bicyclic heterocycle is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the monocyclic heterocyclic moiety of the bicyclic ring system. Representative examples of the bicyclic heterocyclic group include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, dihydroindol-1-yl, dihydroindol-2-yl, dihydroindol-3-yl, 2,3-dihydrobenzothiophen-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. The heterocyclic group is optionally substituted with one or two groups independently selected from oxo or thio. In certain embodiments, the bicyclic heterocyclic group is a 5- or 6-membered monocyclic heterocyclic ring fused to a benzene ring, 5- or 6-membered monocyclic cycloalkyl, 5- or 6-membered monocyclic cycloalkenyl, 5- or 6-membered monocyclic heterocyclic group, or 5- or 6-membered monocyclic heteroaryl, wherein the bicyclic heterocyclic group is optionally substituted with one or two groups independently selected from oxo or thio.

[0782] As used herein, the term "hydroxy" refers to the -OH group.

[0783] As used herein, the term "nitro" refers to the -NO2 group.

[0784] As used herein, the term "oxo" refers to the =O group.

[0785] As used herein, the term "saturated" means that the chemical structure mentioned does not contain any multiple carbon-carbon bonds. For example, the saturated cycloalkyl groups defined herein include cyclohexyl, cyclopropyl, etc.

[0786] As used herein, the term "spiro" refers to a cyclic moiety formed by a substituted atom and two available substitutable sites on the same atom. For example, a moiety such as , when R is a spiro-cycloalkyl = group, includes compounds such as , where the spiro-cyclopentyl group is an R group attached to the parent cyclohexyl ring through two single bonds. Similarly, when R is a spiro-heterocyclic group, such compounds include where the spiro-1,3-dioxolanyl ring is an R group attached to the parent cyclohexyl ring through two single bonds.

[0787] As used herein, the term "thio" refers to the =S group.

[0788] As used herein, the term "unsaturated" means that the chemical structure mentioned contains at least one multiple carbon-carbon bond, but is not aromatic. For example, the unsaturated cycloalkyl groups defined herein include cyclohexenyl, cyclopentenyl, cyclohexadienyl, etc.

[0789] As used herein, the term "cell" is intended to refer to cells in vitro, ex vivo, or in vivo. In some embodiments, ex vivo cells can be a part of a tissue sample excised from an organism such as a mammal. In some embodiments, in vitro cells can be cells in cell culture. In some embodiments, in vivo cells are cells that survive in an organism such as a mammal.

[0790] As used herein, the term "contact" means bringing the indicated moieties together in an in vitro system or in vivo system. For example, "contacting" a TDO2 enzyme with a compound includes administering the compounds described herein to an individual or patient (such as a human) having TDO2, and, for example, introducing the compound into a sample containing cells or a purification reagent containing the TDO2 enzyme.

[0791] The terms "individual" or "patient" used interchangeably refer to any animal, including mammals. Preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably humans.

[0792] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response that a researcher, veterinarian, physician or other clinician seeks in a tissue, system, animal, individual or human.

[0793] In certain embodiments, a therapeutically effective amount can be an amount suitable for:

[0794] (1) Preventing a disease; for example, preventing a disease, disorder or condition in an individual who may be susceptible to the disease, disorder or condition but has not yet experienced or shown the pathology or symptomatology of the disease;

[0795] (2) Inhibiting a disease; for example, inhibiting a disease, disorder or condition in an individual who is experiencing or showing the pathology or symptomatology of the disease, disorder or condition; or

[0796] (3) Alleviating a disease; for example, alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptomatology) in an individual who is experiencing or showing the pathology or symptomatology of the disease, disorder or condition, such as reducing the severity of the disease.

[0797] As used herein, the terms "treatment" (treatment and treating) refer to (i) alleviating the disease state mentioned, for example, alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptomatology) in an individual who is experiencing or showing the pathology or symptomatology of the disease, disorder or condition, such as reducing the severity of the disease; or (ii) eliciting the physiological effect mentioned (such as TDO2 regulation or inhibition of tryptophan degradation).

[0798] The manifestation of alleviation of a disease condition associated with potential TDO2-mediated immunosuppression may require concomitant or sequential administration of other therapeutic agents, such as anti-tumor agents in the case of cancer or antiretroviral agents in the case of viral diseases. For example, when used as a single agent, administration of a TDO2 inhibitor to treat cancer does not always produce a direct anti-tumor effect. However, when combined with chemotherapeutic drugs (anti-tumor drugs), the observed anti-tumor effect is higher than the sum of the effects of each agent alone.

[0799] As used herein, the terms “catalytic pocket,” “catalytic site,” “active site” are used interchangeably and without distinction to refer to the following enzyme regions: which contain amino acid residues responsible for substrate binding (charge, hydrophobicity, steric hindrance) and catalytic amino acid residues that act as proton donors or acceptors or are responsible for binding cofactors and participating in the catalysis of chemical reactions.

[0800] As used herein, the phrase “pharmaceutically acceptable salts” refers to addition salts and solvates of pharmaceutically acceptable acids and bases. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acids (such as acetic acid, HOOC-(CH2) n -COOH (where n is 0 to 4), etc.). Non-toxic drug base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, etc. Those skilled in the art are aware of a variety of non-toxic pharmaceutically acceptable addition salts.

[0801] Method of use

[0802] The compounds and pharmaceutical compositions described herein are capable of modulating the activity of the enzyme tryptophan-2,3-dioxygenase (TDO2). As used herein, the term “modulate” is intended to refer to the ability to reduce enzyme or receptor activity. Thus, the compounds described herein can be used in a method of modulating TDO2 by contacting the enzyme with any one or more of the compounds or compositions described herein. In some embodiments, the compounds described herein can be used as inhibitors of TDO2. In other embodiments, the compounds described herein can be used to modulate the activity of TDO2 in a cell or in an individual in need of modulation of the enzyme by administering a modulating (e.g., inhibitory) amount of the compounds described herein.

[0803] Also provided are methods for inhibiting tryptophan degradation and preventing the production of N-formylkynurenine in a system (such as a tissue, a living organism, or a cell culture) containing cells expressing TDO2. In some embodiments, methods for altering (e.g., increasing) extracellular tryptophan levels in a mammal include administering an effective amount of a compound or pharmaceutical composition provided herein. Methods for measuring tryptophan levels and tryptophan degradation are conventionally known in the art.

[0804] Also provided are methods for inhibiting immunosuppression (such as TDO2-mediated immunosuppression) in a patient by administering to the patient an effective amount of a compound or composition described herein. TDO2-mediated immunosuppression has been associated with, for example, cancer, tumor growth, metastasis, infectious diseases (e.g., viral infections), viral replication, and the like.

[0805] Also provided are methods for treating cancer-related tumor-specific immunosuppression in a patient by administering to the patient an effective amount of a compound or composition described herein. Examples of cancer-related tumor-specific immunosuppression treatable by the methods described herein include immunosuppression associated with the following cancers: colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, lymphoma, leukemia, melanoma, and the like.

[0806] For example, a patient who is undergoing or has completed a course of chemotherapy and / or radiotherapy for treating a disease state such as cancer may benefit from administering to the patient a therapeutically effective amount of a compound or composition described herein for inhibiting immunosuppression resulting from the disease state and / or its treatment.

[0807] Also provided are methods for treating a disease associated with TDO2 activity or expression (such as abnormal activity and / or overexpression) in an individual (e.g., a patient) by administering a therapeutically effective amount or dose of a compound or its pharmaceutical composition described herein. Examples of the disease may include any disease, disorder, or condition directly or indirectly associated with the expression or activity of the TDO2 enzyme (such as overexpression or abnormal activity). TDO2-related diseases may also include any disease, disorder, or condition that can be prevented, alleviated, or cured by modulating the enzyme activity.

[0808] Examples of TDO2-related diseases include cancer, viral infections such as HIV infection, depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataract, organ transplantation (e.g., organ transplant rejection), and autoimmune diseases (including asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus). Examples of cancers that can be treated by the methods described herein include colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, lymphoma, leukemia, melanoma, and the like.

[0809] Combination therapy

[0810] One or more other pharmaceutical agents for therapeutic methods (such as, for example, antiviral agents, chemotherapeutic agents or other anti-cancer agents, immunostimulants, immunosuppressants, radiotherapy, anti-tumor and antiviral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.) and / or indoleamine 2,3-dioxygenase (IDO) inhibitors) can be used in combination with the compounds and pharmaceutical compositions described herein for treating TDO2-related diseases, disorders or conditions (as described above) or for enhancing the therapeutic efficacy of a disease state or condition such as cancer. The agents can be combined with the compounds of the invention in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0811] When combined with the TDO2 inhibitors of the present invention, therapeutic agents that constitute the standard of care for a particular cancer type or infectious disease are expected to be beneficial. For example, in the case of tumors, it is preferred that the tumors are sensitive to the cytotoxic effects of chemotherapeutic agents in order to stimulate the release of antigens that will ultimately mediate an immune response, which will be enhanced by adding a TDO2 inhibitor to the combination therapy. Those skilled in the art know how to select such chemotherapeutic agents based on the clinical characteristics and known sensitivities of each tumor to different anti-tumor agents.

[0812] Suitable antiviral agents contemplated for use in combination with the compounds described herein can include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs.

[0813] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emtricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C and named β-L-2',3'-dideoxy(dicleoxy)-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and lodenosine (FddA). Typically suitable NNRTIs include nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidine-dione); and (+)-calanolide A (NSC-675451) and B. Typically suitable protease inhibitors include saquinavir (Ro31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.

[0814] Suitable chemotherapeutic agents or other anti-cancer agents include, for example, alkylating agents (including but not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazines), such as uramustine, chlormethine, cyclophosphamide (Cytoxan TM ), ifosfamide, melphalan, chlorambucil, guanoxan, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine and temozolomide.

[0815] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including but not limited to folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0816] Suitable chemotherapeutic or other anti-cancer agents also include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, anti-tumor antibodies, enzymes, lymphokines, and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, actinomycin D, daunomycin, doxorubicin, epirubicin, idarubicin, cytarabine, paclitaxel (Taxol TM )), docetaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferon (especially IFN-α), etoposide, and teniposide.

[0817] Other cytotoxic agents include navelbene, CPT-11, anastrozole, tetrazoles, capecitabine, raloxifene, cyclophosphamide, ifosfamide, and droloxafine.

[0818] Also suitable are cytotoxic agents: such as epidophyllotoxin; anti-tumor enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum complexes, such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; anti-hormone therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0819] Other anti-cancer agents include antibody therapeutic agents, such as trastuzumab (Herceptin), antibodies against co-regulatory molecules (such as CTLA-4, 4-1BB), or antibodies against cytokines (IL-10, TGF-β, etc.).

[0820] Other anti-cancer agents also include those that block the migration of immune cells, such as chemokine receptor antagonists, including CCR2, CCR4, and CCR6.

[0821] Other anti-cancer agents also include those that enhance the immune system, such as adoptive T cell transfer.

[0822] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.

[0823] The compounds of the present application can also be used in combination therapies for therapeutic treatment that curbs or inhibits biological pathways regulated by PD-1 (programmed cell death protein 1) or its ligand PD-L1. Such therapeutic treatments include those that curb or inhibit the expression of PD-1 or PD-L1, as well as those that inhibit or curb the activity of the PD-1 or PD-L1 protein itself. Examples of anti-PD-1 compounds include, for example, pembrolizumab, nivolumab, pidilizumab, and BMS 936559. Examples of anti-PD-L1 include, for example, atezolizumab and avelumab.

[0824] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. Additionally, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, N.J.), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0825] Pharmaceutical formulations and dosage forms

[0826] The pharmaceutical compositions described herein generally comprise a combination of the compounds described herein with a pharmaceutically acceptable carrier, diluent, or excipient. Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., the amount of non-pharmaceutically acceptable components contained is less than the amount permitted by U.S. regulatory requirements at the time of filing of the present application. In some embodiments in this regard, if the compound is dissolved or suspended in water, the composition may also optionally include other pharmaceutically acceptable carriers, diluents, or excipients. In other embodiments, the pharmaceutical compositions described herein are solid pharmaceutical compositions (e.g., tablets, capsules, etc.).

[0827] These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be local (including ocular and mucosal, including nasal, vaginal, and rectal delivery), via the lungs (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal, and transdermal), ocular, oral, or parenteral. Methods of ocular delivery can include topical administration (eye drops), subconjunctival, periocular, or intravitreal injection, or introduction via an ocular insert placed in the conjunctival sac by means of a balloon catheter or by surgery. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intracapsular or intraventricular administration. Parenteral administration can be in a single single-dose form or, for example, can be by means of a continuous infusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous solutions, powder or oily bases, thickening agents, etc. can be necessary or desirable.

[0828] In addition, the pharmaceutical compositions can comprise a combination of one or more of the compounds of the present invention as described above as the active ingredient with one or more pharmaceutically acceptable carriers. In preparing the compositions described herein, the active ingredient is usually admixed with an excipient, diluted with an excipient, or enclosed within a carrier in the form of, for example, capsules, sachets, or other containers. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 wt% of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0829] In the preparation of the formulations, the active compound can be milled to provide a suitable particle size before being combined with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

[0830] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations may also contain: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl- and propyl-hydroxybenzoates; sweetening agents; and flavoring agents. The compositions described herein may be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by procedures known in the art.

[0831] The compositions may be formulated in unit dosage form, each dosage containing from about 5 to about 100 mg, more usually from about 10 to about 30 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, together with the appropriate pharmaceutical excipients.

[0832] The active compounds are effective over a wide range of doses and are generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of the compound actually administered will usually be determined by a physician in the light of the relevant circumstances including the condition to be treated, the route of administration chosen, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0833] For the preparation of solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preparation composition which comprises a homogeneous mixture containing the compounds described herein. When referring to these preparation compositions as homogeneous, the active ingredient is generally uniformly distributed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. Such solid preparations are then subdivided into unit dosage forms of the type described above, which contain, for example, from 0.1 to about 500 mg of the active ingredient of the compounds described herein.

[0834] Tablets or pills may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, tablets or pills may comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an inert layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be released therein slowly. A variety of materials may be used for such inert layers or coatings. Such materials include polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0835] Liquid forms for oral or parenteral administration containing the compound and composition may include aqueous solutions, properly flavored syrups, aqueous or oil suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0836] Compositions for inhalation or insufflation include solutions and suspensions and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by the oral or nasal inhalation route to produce a local or systemic effect. The composition may be atomized using an inert gas. The atomized solution may be breathed directly from the atomizing device, or the atomizing device may be connected to a face mask stent or an intermittent positive pressure breathing machine. The solution, suspension or powder composition may be administered orally or nasally from a device for delivering the formulation in a suitable manner.

[0837] The amount of the compound or composition administered to a patient will vary depending on the substance being administered, the purpose of administration such as prophylaxis or treatment, the patient's condition, and the mode of administration. In therapeutic use, the composition may be administered to an affected patient in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease state to be treated and the judgment of the attending clinician based on various factors such as the severity of the disease, the patient's age, weight and general condition, etc.

[0838] The composition administered to a patient may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The aqueous solution may be packaged for administration as is, or may be lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier before administration. The pH of the compound preparation is generally 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It should be understood that the administration of the foregoing excipients, carriers or stabilizers will result in the formation of salts of the drug.

[0839] The therapeutic dosage of the compounds will vary depending on, for example, the specific use for which the treatment is being carried out, the mode of administration of the compounds, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds described herein in the pharmaceutical composition can vary depending on a variety of factors, including the dosage form, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds described herein can be provided in an aqueous physiological buffer solution containing from about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight per day. This dosage will most likely depend on variables such as the type or degree of progression of the disease or disorder, the overall health status of the specific patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be extrapolated from the dose-response curve from in vitro or animal model test systems.

[0840] The compounds described herein can also be formulated in combination with one or more other active ingredients, which other active ingredients can include any pharmaceutical agent, such as antiviral agents, vaccines, antibodies, immunostimulants, immunosuppressants, anti-inflammatory agents, and the like.

[0841] The following examples are provided for illustrative purposes and are not intended to limit the disclosure in any way. Those skilled in the art will readily recognize that numerous non-critical parameters can be varied or modified to obtain substantially the same results. The compounds of the following examples were found to be inhibitors of TDO2 according to one or more of the assays described herein.

[0842] Kit

[0843] Also included are pharmaceutical kits that can be used, for example, to treat or prevent diseases or disorders associated with TDO2, obesity, diabetes, and other diseases described herein, which kits contain one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of the compounds described herein. If desired, such kits can also include one or more of the various conventional pharmaceutical kit components, for example, containers having one or more pharmaceutically acceptable carriers, additional containers, etc., which will be apparent to those skilled in the art. The kit can also contain instructions, which can be in the form of an insert or label, indicating the amount of the components to be administered, administration instructions, and / or guidelines for mixing the components.

[0844] The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to produce substantially the same results. The compounds of the following examples were found to be inhibitors of TDO2 according to one or more of the assays described herein. Examples

[0845] All reagents and solvents were purchased from commercial sources. All commercial reagents and solvents were used as received without further purification. Analytical thin layer chromatography (TLC) was used to monitor the reactions using 0.25 mm EM Science silica gel plates (60F-254). Developed TLC plates were visually observed by short-wave UV light (254 nm) or by immersion in potassium permanganate solution followed by heating on a hot plate. Flash chromatography was performed using Selecto Scientific silica gel with a particle size of 32 - 63 μm. All reactions were carried out under nitrogen in oven-dried or flame-dried glassware. Unless otherwise specified, all reactions were mechanically stirred at ambient temperature. 1 1H NMR spectra were obtained using: Bruker DRX400, Varian VXR400 or VXR300. 1 1H NMR spectra were reported in parts per million relative to TMS (0.0), DMSO-d6 (2.50) or CD3OD (4.80) as internal references. Unless otherwise indicated, all 1 1H NMR spectra were acquired in CDCl3. Phosphates were prepared according to the following literature methods: (Patent: US5807892 A1, 1998; Patent: US2012 / 033245; Patent: US2008 / 306084A1, 2008). 1-(Azidomethyl)-2,4-dimethoxybenzene was synthesized according to ChemMedChem, 2011, vol.6, #5, 840 - 847.

[0846] Synthetic Route IA

[0847]

[0848]

[0849] General procedure for the synthesis of Int-2:

[0850] A base (1 equiv) was added to a stirred mixture of a ketone (1 equiv) and 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (1 equiv) in MeOH (15 mL). The reaction mixture was heated at 50 °C for 2 h until TLC showed disappearance of the SM. After cooling to room temperature, the reaction mixture was diluted with DCM (50 mL) and washed with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by combi-flash using EtOAc / hexanes as the eluent.

[0851] Table 1

[0852]

[0853] General procedure for the synthesis of Int-3 and Int-4:

[0854] Int-2 (1 equiv) was stirred in MeOH and AcOH (5:1) at 80 °C for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure and saturated NaHCO3 was added to the residue until it was neutral. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by combi-flash, using EtOAc / DCM as the eluent to separate the mixture of four diastereoisomers into two mixtures of enantiomers represented by Int-3 and Int-4.

[0855] General procedure for the synthesis of 5 and 6:

[0856] Int-3 or Int-4 (1 equiv) was dissolved in MeOH (6 mL) and NaBH4 (3 equiv) was added. The reaction mixture was stirred for 2 h. NH4Cl (5 mL) was added to the reaction mixture and stirred for 5 minutes. The solution was poured into a separatory funnel containing water (10 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated under reduced pressure to give the crude product, which was purified by Combi-Flash using a methanol / dcm gradient.

[0857] Synthetic route of C10-OH analogues

[0858]

[0859] General procedure for aldehyde or ketone addition

[0860] n-BuLi (1.66 mL, 4.16 mmol) was added to a solution of 5H-imidazo[5,1-a]isoindole (650 mg, 4.16 mmol) in anhydrous THF (10 mL) at -40 °C and the solution was stirred at -40 °C for 1 h. An aldehyde or ketone (6.24 mmol) was added and the reaction was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated ammonium chloride (10 mL) solution and water (15 mL), and the product was extracted with CH2Cl2 (3 x 30 mL). The solvent was distilled off under reduced pressure to give the crude product. The crude product was purified by combi-flash to give the desired product.

[0861] General procedure for chiral separation of stereoisomers and analysis

[0862] The stereoisomers of the final product were separated by chromatography. Unless otherwise stated, the following general conditions were used:

[0863] A. Method for developing / sequentially screening 14 chiral columns

[0864] Fourteen chiral columns were routinely screened on a Waters UPC2 HPLC system under the following conditions: Mobile phase A: carbon dioxide, Mobile phase B: methanol w / 0.1% NH4OH, or ethanol, IPA, or a mixture, 5 - 60% B in 1.8 minutes, flow rate: 4 ml / min, run time: 2.5 minutes, pressure: 120 bar, temperature: 40 °C. The fourteen columns (4.6 x 50 mm, 3 um) routinely screened were: Chiralpak AD, Chiralpak AS, Chiralpak IA, Chiralpak IB, Chiralpak IC, Chiralpak ID, Chiralpak IE, Chiralpak OJ, Chiralpak OX from Chiral Technologies, Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-3, Lux Cellulose-4 from Phenomenex, and WhelkO-1 (s,s) from Regis.

[0865] B. Purification on preparative SFC

[0866] Columns providing a resolution value Rs > 0.5 were selected for preparative separation. The preparative runs were carried out on a PIC 100 SFC instrument using the corresponding columns (150 × 20 mm, 5 μm) that showed the best separation of the enantiomers from step A, with isocratic mobile phase B identified in step A, Mobile phase A: carbon dioxide, Mobile phase B: methanol w / 0.1% NH4OH, flow rate: 70 ml / min, pressure: 100 bar, temperature: 40 °C

[0867] C. Typical conditions for separating compounds with 2 chiral centers are:

[0868] Column: Chiralpak AD (250x20mm, 5um)

[0869] Method: Isocratic elution at 25% B

[0870] MP A: carbon dioxide

[0871] MP B: ethanol w / 0.1% NH4OH

[0872] Flow: 70 ml / min

[0873] Pressure: 100 bar

[0874] Temperature: 4040 °C

[0875] D. Typical conditions for separating compounds with 3 chiral centers are:

[0876] Stage 1:

[0877] Column: Chiralpak OX (250x20mm, 5um)

[0878] Method: Isocratic elution at 20% B

[0879] MP A: Carbon dioxide

[0880] MP B: Ethanol w / 0.1% NH4OH

[0881] Flow: 70ml / min

[0882] Pressure: 100 bar

[0883] Temperature: 4040 °C

[0884] Stage 2:

[0885] Column: Cellulose-1 (250x20mm, 5um)

[0886] Method: Isocratic elution at 15% B

[0887] MP A: Carbon dioxide

[0888] MP B: Methanol w / 0.1% NH4OH

[0889] Flow: 70ml / min

[0890] Pressure: 100 bar

[0891] Temperature: 40 degC

[0892] Stage 3:

[0893] Column: Chiralcel OX (250x20mm, 5um)

[0894] Method: Isocratic elution at 15% B

[0895] MP A: Carbon dioxide

[0896] MP B: Methanol w / 0.1% NH4OH

[0897] Flow: 70ml / min

[0898] Pressure: 100 bar

[0899] Temperature: 40 °C

[0900] E. QC of the final product to obtain % ee

[0901] The purity of each isomer isolated in step B above was analyzed by the following chiral analysis SFC:

[0902] Instrument: Waters UPC2; Column: Column for purification (50x4.6mm, 3um); Method: Mobile phase A: carbon dioxide, isocratic elution Mobile phase B has the same percentage as that used in step B, Flow rate: 4 ml / min, Run time: 2.5 minutes, Pressure: 120 bar, Temperature: 40 °C.

[0903] Table 2

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065]

[1066]

[1067]

[1068] Example 1: 2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1069]

[1070] (1R,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1071] (1S,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1072] (1S,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1073] (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1074] (1S,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1075] (1R,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1076] (1S,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1077] (1R,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1078] Step 1:

[1079] (E)-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclobutan-1-one

[1080]

[1081] To a solution of 2-[1-(trityl)-1H-imidazol-4-yl]benzaldehyde (2.0 g, 4.82 mmol, 1.00 equiv) and cyclobutanone (0.72 mL, 9.65 mmol, 2.00 equiv) in absolute ethanol (100 mL) was added NaOH (0.192 g, 4.82 mmol, 1.00 equiv) and the resulting mixture was stirred at 50 °C for 1 h. The reaction was quenched with 30 mL of water and the mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine and water and dried over anhydrous Na2SO4. The product was purified by CombiFlash to afford (E)-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclobutan-1-one as a yellow oil: LCMS (ESI, m / z): 466 [M+H] +

[1082] Step 2:

[1083] 2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-one (cis)

[1084]

[1085] To (E)-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclobutan-1-one was added MeOH (16 mL) and AcOH (4 mL). The resulting mixture was stirred at 90 °C for 2 h. The reaction was quenched with 30 mL of saturated NaHCO3 solution and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine and water, and dried over anhydrous Na2SO4. The mixture of diastereomers was separated on CombiFlash to afford 2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-(cis), which was a pale yellow oil: LCMS (ESI, m / z): 225 [M+H] + .

[1086] 2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-one (trans)

[1087]

[1088] To (E)-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclobutan-1-one was added MeOH (16 mL) and AcOH (4 mL). The resulting mixture was stirred at 90 °C for 2 h. The reaction was quenched with 30 mL of saturated NaHCO3 solution and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine and water, and dried over anhydrous Na2SO4. The mixture of diastereomers was separated on CombiFlash to afford 2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-(trans), which was a pale yellow solid: LCMS (ESI, m / z): 225 [M+H] + .

[1089] Step 3:

[1090] (1R,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1091] (1S,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1092] (1S,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1093] (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1094]

[1095] At 0 °C, NaBH4 (93 mg, 2.45 mmol) was added portionwise to a solution of 2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-one (cis) (275 mg, 1.23 mmol) in MeOH (10 mL), and the solution was stirred at 0 °C for 30 minutes. The solvent was distilled off and saturated ammonium chloride (10 mL) was added. The aqueous layer was extracted with a solution of 5% CF3CH2OH in DCM (3 x 10 mL). The combined organic extracts were dried over (Na2SO4) and concentrated under reduced pressure to give the crude product. The crude product was purified by combi-flash and further separated by chiral separation to give 4 isomers, which were white solids. The absolute configurations of isomers 1a, 1b, 1c, 1d, 1e were determined by X-ray crystallography. The configurations of the remaining isomers were arbitrarily assigned.

[1096] Example 1a: (1R,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol: LCMS (ESI, m / z): 227.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.57 (dd, J = 13.5, 7.7 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.25 (td, J = 7.4, 1.1 Hz, 1H), 7.14 (s, 1H), 5.74 (d, J = 4.5 Hz, 1H), 5.49 (d, J = 6.2 Hz, 1H), 4.59–4.48 (m, 1H), 2.88–2.75 (m, 1H), 2.24–2.10 (m, 1H), 1.85–1.52 (m, 3H).

[1097] Example 1b: (1S,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol: LCMS (ESI, m / z): 227.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.57 (dd, J = 13.3, 7.6 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.29–7.20 (m, 1H), 7.14 (s, 1H), 5.74 (d, J = 4.0 Hz, 1H), 5.49 (d, J = 6.3 Hz, 1H), 4.52 (d, J = 11.3 Hz, 1H), 2.82 (p, J = 6.3 Hz, 1H), 2.24–2.09 (m, 1H), 1.85–1.52 (m, 3H).

[1098] Example 1c: (1S,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol: LCMS (ESI, m / z): 227.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.61–7.54 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.30–7.21 (m, 1H), 7.13 (s, 1H), 5.34 (dd, J = 15.3, 7.4 Hz, 2H), 4.25 (p, J = 7.8 Hz, 1H), 3.44–3.21 (m, 2H), 2.41 (dq, J = 9.7, 7.8 Hz, 1H), 2.15–2.03 (m, 1H), 1.73–1.50 (m, 2H), 1.12 (qd, J = 10.2, 8.1 Hz, 1H).

[1099] Example 1d: (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol: LCMS (ESI, m / z): 227.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.61–7.54 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.31–7.21 (m, 1H), 7.13 (s, 1H), 5.34 (dd, J = 15.4, 6.8 Hz, 2H), 4.25 (p, J = 7.5 Hz, 1H), 2.41 (dq, J = 9.6, 7.7 Hz, 1H), 2.15–2.03 (m, 1H), 1.73–1.50 (m, 2H), 1.12 (qd, J = 10.2, 8.1 Hz, 1H).

[1100]

[1101] To a solution of 2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-one (trans) (178 mg, 0.79 mmol) in MeOH (10 mL) at 0 °C was added NaBH4 (60 mg, 1.59 mmol) portionwise and the solution was stirred at 0 °C for 30 minutes. The solvent was distilled off and saturated ammonium chloride (10 mL) was added. The aqueous layer was extracted with a 5% solution of CF3CH2OH in DCM (3 x 10 mL). The combined organic extracts were dried over (Na2SO4) and concentrated under reduced pressure to give the crude product. The crude product was purified by combi-flash and further separated by chiral resolution to give 4 isomers, which were white solids.

[1102] Example 1e: (1S,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol: LCMS (ESI, m / z): 227.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.28–7.19 (m, 1H), 7.10 (s, 1H), 5.72 (d, J = 3.7 Hz, 1H), 5.45 (d, J = 9.6 Hz, 1H), 4.42 (s, 1H), 2.39 (tt, J = 10.2, 7.7 Hz, 2H), 2.24 (ddt, J = 14.9, 12.1, 7.4 Hz, 1H), 2.01–1.81 (m, 2H).

[1103] Example 1f: (1R,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol: LCMS (ESI, m / z): 227.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.42–7.31 (m, 2H), 7.29–7.20 (m, 1H), 7.10 (s, 1H), 5.30 (dd, J = 25.5, 8.2 Hz, 2H), 4.14 (p, J = 7.6 Hz, 1H), 2.33–2.05 (m, 2H), 1.84–1.50 (m, 3H).

[1104] Example 1g: (1S,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol: LCMS (ESI, m / z): 227.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.63–7.45 (m, 2H), 7.37 (q, J = 7.4 Hz, 1H), 7.24 (q, J = 7.1 Hz, 1H), 7.12 (d, J = 13.9 Hz, 1H), 5.73 (dd, J = 9.0, 5.1 Hz, 1H), 5.47 (dd, J = 14.1, 7.9 Hz, 1H), 4.42 (tp, J = 5.6, 2.5 Hz, 1H), 2.48–2.12 (m, 3H), 2.01–1.81 (m, 2H).

[1105] Example 1h: (1R,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol: LCMS (ESI, m / z): 227.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.28–7.19 (m, 1H), 7.10 (s, 1H), 5.72 (d, J = 3.7 Hz, 1H), 5.45 (d, J = 9.6 Hz, 1H), 4.42 (s, 1H), 2.39 (tt, J = 10.2, 7.7 Hz, 2H), 2.24 (ddt, J = 14.9, 12.1, 7.4 Hz, 1H), 2.01–1.81 (m, 2H).

[1106] Example 2: 2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1107]

[1108] (1R,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1109] (1S,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1110] (1R,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1111] (1S,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1112] (1S,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1113] (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1114] (1R,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1115] (1S,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1116] Step 1:

[1117] (E)-2-(2-(1-Trityl-1H-imidazol-4-yl)benzylidene)cyclopentan-1-one

[1118]

[1119] Pyrrolidine (0.22 mL, 2.65 mmol) was added to a stirred mixture of cyclopentanone (0.24 mL, 2.65 mmol) and 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (1.1 g, 2.65 mmol) in MeOH (15 mL). The reaction mixture was heated at 50 °C for 2 h until TLC showed disappearance of the SM. After cooling to room temperature, the reaction mixture was diluted with DCM (50 mL) and washed with water and dried over Na2SO4. The crude product was used directly in the next step: LCMS (ESI, m / z): 481.4 [M+H] + .

[1120] Step 2:

[1121] 2-(5H-Imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-one

[1122]

[1123] The title compound was synthesized by the general procedure for the synthesis of Int-3.

[1124] Two pairs of diastereoisomers were separated by combin-flash using EtOAc / DCM as eluent: LCMS (ESI, m / z): +239.2

[1125] Step 3a:

[1126] (1R,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1127] (1S,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1128] (1R,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1129] (1S,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1130]

[1131] The title compound was synthesized by the general procedure for the synthesis of Int-5. The product was isolated as a mixture of four diastereomers, which were separated by chiral SFC: LCMS (ESI, m / z): 241.3

[1132] The absolute configurations of isomers 2a, 2b, 2c, and 2d were determined by X-ray crystallography. The configurations of the remaining isomers were arbitrarily assigned.

[1133] Example 2a: (1R,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol: LCMS (ESI, m / z): 241.3 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.61 (dd, J = 22.5, 7.6 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.31–7.23 (m, 1H), 5.39 (d, J = 6.8 Hz, 1H), 5.16 (d, J = 3.8 Hz, 1H), 4.37 (q, J = 4.7 Hz, 1H), 2.14–2.01 (m, 1H), 1.84–1.39 (m, 7H).

[1134] Example 2b: (1S,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol. LCMS (ESI, m / z): 241.3 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.67–7.54 (m, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.31–7.22 (m, 1H), 5.39 (d, J = 6.9 Hz, 1H), 5.16 (d, J = 3.9 Hz, 1H), 4.38 (qd, J = 4.6, 2.6 Hz, 1H), 2.08 (p, J = 8.4 Hz, 1H), 1.84–1.37 (m, 7H).

[1135] Example 2f: 5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol: LCMS (ESI, m / z):..241.3 [M+H] + ; 1 HNMR was not obtained due to the small sample amount. Example 2h: -5H.imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol: LCMS (ESI, m / z): 241.3 [M+H] + ; 1HNMR was not obtained due to the small amount of the sample.

[1136] Step 3b:

[1137] (1R,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1138] (1S,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1139] (1S,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1140] (1R,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1141]

[1142] The title compound was synthesized by the general procedure for the synthesis of Int-5. The product was isolated as a mixture of four diastereomers, which were separated by chiral SFC: LCMS (ESI, m / z): 241.3

[1143] Example 2c: (1R,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol: LCMS (ESI, m / z): 241.3 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.24 (td, J = 7.7, 1.3 Hz, 1H), 7.12 (s, 1H), 5.26 (d, J = 10.2 Hz, 1H), 5.07 (d, J = 4.1 Hz, 1H), 4.30 (p, J = 3.7 Hz, 1H), 2.03–1.82 (m, 3H), 1.76–1.55 (m, 4H).

[1144] Example 2d: (1S,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol: LCMS (ESI, m / z): 241.3 [M+H] + ; 1HNMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.24 (td, J = 7.4, 1.2 Hz, 1H), 7.12 (s, 1H), 5.26 (d, J = 10.2 Hz, 1H), 5.06 (d, J = 4.2 Hz, 1H), 4.30 (q, J = 3.5 Hz, 1H), 2.02–1.82 (m, 3H), 1.76–1.58 (m, 4H).

[1145] Example 2e: 5H-Imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol: LCMS (ESI, m / z): 241.3 [M+H] + ; 1HNMR was not obtained due to the small amount of sample.

[1146] Example 2g: 5H-Imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol: LCMS (ESI, m / z): 241.3 [M+H] + ; 1 HNMR was not obtained due to the small amount of sample.

[1147] Example 3: 2-(5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1148]

[1149] (1S,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1150] (1R,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1151] (1S,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1152] (1R,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1153] (1S,2S)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1154] (1R,2S)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1155] (1S,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1156] (1R,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1157] Step 1:

[1158] (E)-2-(2-(1-Trityl-1H-imidazol-4-yl)benzylidene)cyclohexan-1-one

[1159]

[1160] The title compound was synthesized by the general procedure for the synthesis of Int-2: LCMS (ESI, m / z): 495.4 [M+H] +

[1161] Step 2:

[1162] 2-(5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-one

[1163]

[1164] The title compound was synthesized by the general procedure for the synthesis of Int-3.

[1165] Two pairs of diastereoisomers were separated by combin-flash using EtOAc / DCM as eluent: LCMS (ESI, m / z): 253.2

[1166] Step 3a:

[1167] (1S,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1168] (1R,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1169] (1S,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1170] (1R,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1171]

[1172] The title compound was synthesized by the general procedure for the synthesis of Int-5. The product was isolated as a mixture of four enantiomers, which were separated by chiral SFC: LCMS (ESI, m / z): 255.3. The absolute configurations of isomers 3a, 3b, 3g, and 3h were determined by X-ray crystallography. The configurations of the remaining isomers were arbitrarily assigned.

[1173] Example 3a: (1S,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol LCMS (ESI, m / z): 255.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.57–7.51 (m, 2H), 7.40–7.31 (m, 1H), 7.30–7.21 (m, 1H), 7.08 (s, 1H), 5.23 (d, J = 2.7 Hz, 1H), 4.94–4.89 (m, 1H), 4.27–4.22 (m, 1H), 2.03–1.93 (m, 1H), 1.83–1.75 (m, 1H), 1.65–1.43 (m, 3H), 1.39–1.30 (m, 1H), 1.22–0.98 (m, 2H), 0.79–0.71 (m, 1H).

[1174] Example 3b: (1R,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol LCMS (ESI, m / z): 255.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.40–7.32 (m, 1H), 7.27–7.18 (m, 1H), 7.10 (s, 1H), 5.16 (d, J = 5.4 Hz, 1H), 4.69 (d, J = 4.0 Hz, 1H), 4.09–4.04 (m, 1H), 1.82–1.30 (m, 7H), 1.18–1.10 (m, 1H).

[1175] Example 3c: 5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol LCMS (ESI, m / z): 255.3 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.51 (d, 1H), 7.41–7.34 (m, 1H), 7.30–7.23 (m, 1H), 7.11 (s, 1H), 5.73 (d, J = 3.9 Hz, 1H), 5.20 (d, J = 5.2 Hz, 1H), 3.69–3.57 (m, 1H), 2.20–1.92 (m, 2H), 1.65–1.54 (m, 1H), 1.42–1.20 (m, 2H), 1.12–0.89 (m, 1H), 0.62–0.51 (m, 1H), 0.26–0.12 (m, 1H).

[1176] Example 3d: 5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol LCMS (ESI, m / z): 255.3 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.61–7.55 (m, 1H), 7.50–7.41 (m, 1H), 7.41–7.33 (m, 1H), 7.33–7.25 (m, 1H), 7.14 (s, 1H), 5.73 (d, J = 2.2 Hz, 1H), 5.24 (d, J = 5.7 Hz, 1H), 3.70–3.58 (m, 1H), 2.05–1.90 (m, 2H), 1.66–1.56 (m, 1H), 1.41–1.21 (m, 2H), 1.20–0.89 (m, 2H), 0.75–0.64 (m, 1H), 0.26–0.10 (m, 1H).

[1177] Step 3b:

[1178] (1S,2S)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1179] (1R,2S)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1180] (1S,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1181] (1R,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1182]

[1183] The title compound was synthesized by the general procedure for the synthesis of Int-5.

[1184] The product was isolated as a mixture of 4 enantiomers, which was separated by chiral SFC: LCMS (ESI, m / z): 255.3

[1185] Example 3e: 5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol LCMS (ESI, m / z): 255.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.61–7.56 (m, 1H), 7.47–7.41 (m, 1H), 7.41–7.33 (m, 1H), 7.33–7.25 (m, 1H), 7.14 (s, 1H), 5.73 (d, J = 2.3 Hz, 1H), 5.25 (d, J = 5.7 Hz, 1H), 3.69–3.59 (m, 1H), 2.05–1.90 (m, 2H), 1.66–1.55 (m, 1H), 1.41–1.26 (m, 2H), 1.20–0.89 (m, 2H), 0.74–0.66 (m, 1H), 0.26–0.10 (m, 1H).

[1186] Example 3f: 5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol LCMS (ESI, m / z): 255.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 7.7, 1.1 Hz, 1H), 7.42–7.33 (m, 1H), 7.31–7.22 (m, 1H), 7.11 (s, 1H), 5.73 (d, J = 3.7 Hz, 1H), 5.20 (d, J = 5.2 Hz, 1H), 3.68–3.56 (m, 1H), 2.18–2.08 (m, 1H), 2.00–1.91 (m, 1H), 1.63–1.55 (m, 1H), 1.42–1.21 (m, 2H), 1.12–0.89 (m, 1H), 0.60–0.52 (m, 1H), 0.27–0.12 (m, 1H).

[1187] Example 3g: (1S,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol LCMS (ESI, m / z): 255.3 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.66 (d, J = 7.7, 0.9 Hz, 1H), 7.57 (d, 1H), 7.40–7.31 (m, 1H), 7.27–7.18 (m, 1H), 7.10 (s, 1H), 5.16 (d, J = 5.4 Hz, 1H), 4.69 (d, J = 3.9 Hz, 1H), 4.09–4.04 (m, 1H), 1.79–1.31 (m, 7H), 1.21–1.08 (m, 1H)

[1188] Example 3h: (1R,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol LCMS (ESI, m / z): 255.3 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.58–7.51 (m, 2H), 7.40–7.31 (m, 1H), 7.30–7.21 (m, 1H), 7.08 (s, 1H), 5.23 (d, J = 2.7 Hz, 1H), 4.94–4.89 (m, 1H), 4.27–4.22 (m, 1H), 2.03–1.93 (m, 1H), 1.83–1.74 (m, 1H), 1.61–1.46 (m, 2H), 1.39–1.30 (m, 1H), 1.21–1.02 (m, 2H), 0.79–0.71 (m, 1H).

[1189] Example 4: 7-(5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1190]

[1191] (7S,8S)-7-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1192] (7S,8R)-7-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1193] (7R,8S)-7-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1194] (7R,8R)-7-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1195] (7R,8R)-7-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1196] (7R,8S)-7-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1197] (7S,8R)-7-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1198] (7S,8S)-7-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1199] Synthetic route IC [Scheme change]

[1200]

[1201] Step 1: 7-([2-[1-(Triphenylmethyl)-1H-imidazol-4-yl]phenyl]methylene)-5,6,7,8-tetrahydroisoquinolin-8-one

[1202]

[1203] To a solution of 5,6,7,8-tetrahydroisoquinolin-8-one hydrochloride (2.01 g, 10.946 mmol, 1.000 equiv) in tetrahydrofuran (100 mL) was added 2-[1-(triphenylmethyl)-1H-imidazol-4-yl]benzaldehyde (9.07 g, 21.88 mmol) and sodium hydroxide (1.74 g, 43.50 mmol). The reaction was stirred at room temperature for 6 h and the resulting mixture was diluted with water (50 mL). The resulting solution was extracted with dichloromethane (3 x 200 mL) and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was diluted with dichloromethane (30 mL) and the solid was collected by filtration to give 7-([2-[1-(triphenylmethyl)-1H-imidazol-4-yl]phenyl]methylene)-5,6,7,8-tetrahydroisoquinolin-8-one (2.55 g, 39%), which was a pale yellow solid: LCMS (ESI, m / z): 544 [M+H] + . 1HNMR (300 MHz, CDCl3) δ 9.27 (s, 1H), 8.68 (s, 1H), 8.05 (d, J = 9.0 Hz, 1H), 7.88 (s, 1H), 7.57 (s, 1H), 7.56 - 7.09 (m, 18H), 7.10 (d, J = 9.0 Hz, 1H), 6.85 (s, 1H), 2.89 (t, J = 3.0 Hz, 2H), 2.73 (t, J = 3.0 Hz, 2H).

[1204] Step 2: 7-[5H-Imidazo[4,3-a]isoindol-5-yl]-5,6,7,8-tetrahydroisoquinolin-8-one

[1205]

[1206] To a solution of (2E)-2-([2-[1-(Triphenylmethyl)-1H-imidazol-4-yl]phenyl]methylene)-1,2,3,4-tetrahydronaphthalen-1-one (2.4 g, 4.42 mmol) in methanol (60 mL) was added acetic acid (2.6 mL, 45.37 mmol). The reaction was stirred at 80 °C for 16 h and then concentrated in vacuo to give 7-[5H-imidazo[4,3-a]isoindol-5-yl]-5,6,7,8-tetrahydroisoquinolin-8-one (2.0 g, crude), which was a pale yellow oil: LCMS (ESI, m / z): 302 [M+H] +

[1207] Step 3:

[1208] (7S,8S)-7-[(5R)-5H-Imidazo[4,3-a]isoindol-5-yl]-5,6,7,8-tetrahydroisoquinolin-8-ol

[1209] (7R,8R)-7-[(5S)-5H-Imidazo[4,3-a]isoindol-5-yl]-5,6,7,8-tetrahydroisoquinolin-8-ol

[1210] (7S,8R)-7-[(5R)-5H-Imidazo[4,3-a]isoindol-5-yl]-5,6,7,8-tetrahydroisoquinolin-8-ol

[1211] (7R,8S)-7-[(5S)-5H-Imidazo[4,3-a]isoindol-5-yl]-5,6,7,8-tetrahydroisoquinolin-8-ol

[1212] (7R,8S)-7-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1213] (7S,8R)-7-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1214] (7R,8R)-7-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1215] (7S,8S)-7-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[1216] Sodium borohydride (2.5 g, 67.89 mmol) was added to a solution of 7-[5H-imidazo[4,3-a]isoindol-5-yl]-5,6,7,8-tetrahydroisoquinolin-8-one (2.0 g, 6.64 mmol) in methanol (100 mL). The reaction was stirred at room temperature for 6 h. The resulting mixture was concentrated in vacuo and then diluted with dichloromethane (200 mL). The solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by prep-HPLC and further separated by chiral separation to obtain 8 isomers, which were white solids. The stereochemistry of each isomer was arbitrarily assigned.

[1217] 1. Column: Chiralpak IB, 2x25 cm, 5um; Mobile phase A: Hex--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 40B to 40B in 12 min; 254 / 220 nm;

[1218] 2. Column: Chiralpak IC, 2x25 cm, 5um; Mobile phase A: Hex--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 40B to 40B in 32 min; 254 / 220 nm;

[1219] 3. Column: lux-4, 2.12x20 cm, 5um; Mobile phase A: Hex--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 50B to 50B in 20 min; 254 / 220 nm;

[1220] The absolute configuration of all isomers was arbitrarily assigned.

[1221] Example 4a: 5H-imidazo[4,3-a]isoindol-5-yl]-5,6,7,8-tetrahydroisoquinolin-8-ol (47.3 mg, 2%): LCMS (ESI, m / z): 304 [M+H] + ;1 HNMR (300 MHz, CD3OD) δ 8.74 (s, 1H), 8.25 (d, J = 5.4 Hz, 1H), 7.91 (s, 1H), 7.68 - 7.62 (m, 2H), 7.46 - 7.41 (m, 1H), 7.34 - 7.29 (m, 1H), 7.11 (s, 1H), 7.10 (d, J = 5.4 Hz, 1H), 5.89 (d, J = 3.0 Hz, 1H), 5.09 (d, J = 10.5 Hz, 1H), 2.71 - 2.62 (m, 3H), 1.09 - 1.04 (m, 2H); tR = 1.309 min (Chiralpak IB - 3, 0.46 x 5 cm, 3 um, ethanol:hexane (0.1% DEA) = 40:60, 1.0 mL / min). 4b and 4a are enantiomers.

[1222] Example 4b: 5H - Imidazo[4,3 - a]isoindol - 5 - yl] - 5,6,7,8 - tetrahydroisoquinolin - 8 - ol (28.5 mg, 1%): LCMS (ESI, m / z): 304 [M + H] + ; 1 HNMR (300 MHz, CD3OD) δ 8.74 (s, 1H), 8.25 (d, J = 5.4 Hz, 1H), 7.91 (s, 1H), 7.68 - 7.62 (m, 2H), 7.46 - 7.41 (m, 1H), 7.34 - 7.29 (m, 1H), 7.11 (s, 1H), 7.10 (d, J = 5.4 Hz, 1H), 5.89 (d, J = 3.0 Hz, 1H), 5.09 (d, J = 10.5 Hz, 1H), 2.71 - 2.62 (m, 3H), 1.09 - 1.04 (m, 2H); tR = 2.147 min (Chiralpak IB - 3, 0.46 x 5 cm, 3 um, ethanol:hexane (0.1% DEA) = 40:60, 1.0 mL / min).

[1223] Example 4c: 5H - Imidazo[4,3 - a]isoindol - 5 - yl] - 5,6,7,8 - tetrahydroisoquinolin - 8 - ol (47.2 mg, 2%): LCMS (ESI, m / z): 304 [M + H] + ; 1HNMR (300 MHz, CD3OD) δ 8.42 (s, 1H), 8.27 (d, J = 5.1 Hz, 1H), 8.04 (s, 1H), 7.73 - 7.70 (m, 1H), 7.64 - 7.61 (m, 1H), 7.43 - 7.38 (m, 1H), 7.31 - 7.26 (m, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.15 (s, 1H), 5.50 (d, J = 3.0 Hz, 1H), 4.88 (d, J = 10.5 Hz, 1H), 3.06 - 2.93 (m, 1H), 2.82 - 2.70 (m, 1H), 2.26 - 1.97 (m, 3H); tR = 1.505 min, (Chiralpak IB - 3, 0.46 x 5 cm, 3 um, ethanol:hexane (0.1% DEA) = 40:60, 1.0 mL / min). 4d and 4c are enantiomers.

[1224] Example 4d: 5H - Imidazo[4,3 - a]isoindol - 5 - yl] - 5,6,7,8 - tetrahydroisoquinolin - 8 - ol (32.1 mg, 2%): LCMS (ESI, m / z): 304 [M + H] + ; 1 HNMR (300 MHz, CD3OD) δ 8.42 (s, 1H), 8.27 (d, J = 5.1 Hz, 1H), 8.04 (s, 1H), 7.73 - 7.70 (m, 1H), 7.64 - 7.61 (m, 1H), 7.43 - 7.38 (m, 1H), 7.31 - 7.26 (m, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.15 (s, 1H), 5.50 (d, J = 3.0 Hz, 1H), 4.88 (d, J = 10.5 Hz, 1H), 3.06 - 2.93 (m, 1H), 2.82 - 2.70 (m, 1H), 2.26 - 1.97 (m, 3H); tR = 2.147 min, (Chiralpak IB - 3, 0.46 x 5 cm, 3 um, ethanol:hexane (0.1% DEA) = 40:60, 1.0 mL / min).

[1225] Example 4e: 5H - Imidazo[5,1 - a]isoindol - 5 - yl) - 5,6,7,8 - tetrahydroisoquinolin - 8 - ol (30.3 mg, 2%): LCMS (ESI, m / z): 304 [M + H] + ; 11H NMR (300 MHz, CD3OD) δ 8.79 (s, 1H), 8.27 (d, J = 5.1 Hz, 1H), 7.99 (s, 1H), 7.66 - 7.64 (m, 1H), 7.50 - 7.32 (m, 3H), 7.20 (s, 1H), 7.18 (d, J = 5.1 Hz, 1H), 5.89 (d, J = 3.0 Hz, 1H), 5.10 (d, J = 10.5 Hz, 1H), 2.70 - 2.68 (m, 2H), 2.50 - 2.42 (m, 1H), 1.14 - 0.98 (m, 2H); tR = 2.893 min, (Chiralpak IC - 3, 0.46 x 5 cm, 3 um, ethanol:hexane (0.1% DEA) = 40:60, 1.0 mL / min). 4e and 4f are enantiomers.

[1226] Example 4f: 5H - Imidazo[5,1 - a]isoindol - 5 - yl) - 5,6,7,8 - tetrahydroisoquinolin - 8 - ol (79.2 mg, 5%): LCMS (ESI, m / z): 304 [M + H] + ; 1 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.27 (d, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.66 - 7.64 (m, 1H), 7.50 - 7.32 (m, 3H), 7.20 (s, 1H), 7.18 (d, J = 5.6 Hz, 1H), 5.89 (d, J = 3.0 Hz, 1H), 5.10 (d, J = 10.4 Hz, 1H), 2.70 - 2.68 (m, 2H), 2.50 - 2.42 (m, 1H), 1.14 - 0.98 (m, 2H); tR = 5.240 min, (Chiralpak IC - 3, 0.46 x 5 cm, 3 um, ethanol:hexane (0.1% DEA) = 40:60, 1.0 mL / min).

[1227] Example 4g: 5H - Imidazo[5,1 - a]isoindol - 5 - yl) - 5,6,7,8 - tetrahydroisoquinolin - 8 - ol (35.9 mg, 2%): LCMS (ESI, m / z): 304 [M + H] + ; 11H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 8.30 (d, J = 5.6 Hz, 1H), 8.11 (s, 1H), 7.62 - 7.56 (m, 2H), 7.43 - 7.39 (m, 1H), 7.34 - 7.30 (m, 1H), 7.16 (d, J = 5.6 Hz, 1H), 7.14 (s, 1H), 5.92 (d, J = 4.0 Hz, 1H), 5.12 (d, J = 10.4 Hz, 1H), 2.84 - 2.78 (m, 1H), 2.66 - 2.54 (m, 2H), 1.61 - 1.57 (m, 1H), 1.10 - 1.05 (m, 1H); tR = 4.569 min, (Chiralpak IC-3, 0.46 x 5 cm, 3 um, ethanol:hexane (0.1% DEA) = 40:60, 1.0 mL / min). 4h and 4g are enantiomers.

[1228] Example 4h: 5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol (74.7 mg, 5%): LCMS (ESI, m / z): 304 [M+H] + ; 1 1H NMR (300 MHz, CD3OD) δ 8.56 (s, 1H), 8.30 (d, J = 5.2 Hz, 1H), 8.11 (s, 1H), 7.62 - 7.56 (m, 2H), 7.43 - 7.39 (m, 1H), 7.34 - 7.30 (m, 1H), 7.16 (d, J = 5.4 Hz, 1H), 7.14 (s, 1H), 5.92 (d, J = 3.0 Hz, 1H), 5.12 (d, J = 10.5 Hz, 1H), 2.84 - 2.78 (m, 1H), 2.66 - 2.54 (m, 2H), 1.61 - 1.57 (m, 1H), 1.10 - 1.05 (m, 1H); tR = 6.44 min, (Chiralpak IC-3, 0.46 x 5 cm, 3 um, ethanol:hexane (0.1% DEA) = 40:60, 1.0 mL / min).

[1229] Examples 5 and 6: 3-(5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol and 4-(5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol

[1230]

[1231] (3R,4R)-3-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol

[1232] (3S,4S)-3-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol

[1233] (3R,4R)-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol

[1234] (3S,4S)-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol

[1235] (3S,4S)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol

[1236] (3R,4R)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol

[1237] (3S,4S)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol

[1238] (3R,4R)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol

[1239] Synthetic route IIA

[1240]

[1241] Step 1: 1-(2-bromobenzyl)-1H-imidazole

[1242]

[1243] At 0 °C, sodium hydride (20 g, 0.833 mol) was added to a solution of 1H-imidazole (40 g, 0.587 mol) in tetrahydrofuran (1 L), and the mixture was stirred at room temperature for 1 hour. Then 1-bromo-2-(bromomethyl)benzene (90 g, 0.36 mol) was added and the mixture was stirred at room temperature for another 1 hour. The reaction was then quenched with saturated ammonium chloride (200 mL) and the resulting solution was extracted with ethyl acetate (3 x 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with dichloromethane / ethyl acetate (1:1) to give 1-[(2-bromophenyl)methyl]-1H-imidazole (90 g, 65%), which was a yellow oil: LCMS (ESI, m / z): 237, 239 [M+H] + ;

[1244] Step 2: 5H-Imidazo[5,1-a]isoindole

[1245]

[1246] A solution of 1-[(2-bromophenyl)methyl]-1H-imidazole (90 g, 0.379 mol), palladium(II) acetate (3.5 g, 0.015 mol) / triphenylphosphine (8.1 g, 0.030 mol) and potassium carbonate (81 g, 0.586 mol) in DMSO (1 L) was stirred at 130 °C for 1 h and then diluted with water (100 mL). The resulting solution was extracted with ethyl acetate (3 x 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with dichloromethane / ethyl acetate (1:1) to give 5H-imidazo[4,3-a]isoindole, which was a yellow solid (20 g, 34%): LCMS (ESI, m / z): 157 [M+H] + .

[1247] Step 3:

[1248] (3R,4R)-3-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol

[1249] (3S,4S)-3-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol

[1250] (3R,4R)-3-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol

[1251] (3S,4S)-3-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol

[1252] (3S,4S)-4-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol

[1253] (3R,4R)-4-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol

[1254] (3S,4S)-4-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol

[1255] (3R,4R)-4-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol

[1256]

[1257] At -40 °C, n-BuLi (6.5 mL, 2.5 M in hexane) was added dropwise to a solution of 5H-imidazo[4,3-a]isoindole (1.6 g, 10.25 mmol) in tetrahydrofuran (25 mL). After stirring the reaction at -30 °C for 1 h, a solution of 3,7-dioxabicyclo[4.1.0]heptane (1.4 g, 13 mmol) in tetrahydrofuran (3 mL) was added dropwise at -40 °C, and then the temperature was slowly raised to room temperature and stirred at room temperature for another 1 h. The reaction was then quenched with saturated ammonium chloride (20 mL) and the resulting solution was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by prep-HPLC and further separated by chiral separation to obtain 8 isomers, which were white solids. The absolute configurations of isomers 5a - 5d were assigned by X-ray crystallography. The absolute configurations of isomers 6a - 6d were assigned by X-ray crystallography.

[1258] Example 5a: (3S,4S)-3-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol (65.3 mg, 2%): LCMS (ESI, m / z): 257 [M+H] + ; 1HNMR (300 MHz, CDCl3) δ 7.80 (s, 1H), 7.53 - 7.50 (m, 1H), 7.39 - 7.24 (m, 3H), 7.17 (s, 1H), 5.82 (d, J = 2.1 Hz, 1H), 4.14 - 4.06 (m, 1H), 3.94 - 3.89 (m, 1H), 3.31 - 3.21 (m, 2H), 2.57 - 2.49 (m, 1H), 2.42 - 2.33 (m, 1H), 2.11 - 2.05 (m, 1H), 1.90 - 1.77 (m, 1H); tR = 3.537 min (CHIRALCEL OJ - 3, 0.46 x 15 cm; 3 um, Hex(0.1% DEA):EtOH = 85:15, 1.0 ml / min).

[1259] Example 5b: (3R,4R)-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol (70.5 mg, 2%). LCMS (ESI, m / z): 257 [M+H] + ; 1 HNMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.55 - 7.53 (m, 1H), 7.41 - 7.29 (m, 3H), 7.20 (s, 1H), 5.82 (d, J = 2.1 Hz, 1H), 4.16 - 4.09 (m, 1H), 3.95 - 3.89 (m, 1H), 3.32 - 3.21 (m, 2H), 2.57 - 2.50 (m, 1H), 2.41 - 2.33 (m, 1H), 2.11 - 2.05 (m, 1H), 1.88 - 1.79 (m, 1H); tR = 4.966 min (CHIRALCEL OJ - 3, 0.46 x 15 cm; 3 um, Hex(0.1% DEA):EtOH = 85:15, 1.0 ml / min).

[1260] Example 5c: (3R,4R)-3-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol (62.7 mg, 2%): LCMS (ESI, m / z): 257 [M+H] + ; 1HNMR (300 MHz, CDCl3) δ 7.82 (s, 1H), 7.57 - 7.48 (m, 2H), 7.42 - 7.37 (m, 1H), 7.29 - 7.24 (m, 1H), 7.20 (s, 1H), 5.70 (d, J = 3.3 Hz, 1H), 4.07 - 3.90 (m, 2H), 3.32 - 3.23 (m, 2H), 2.81 - 2.73 (m, 1H), 2.50 - 2.43 (m, 1H), 2.00 - 1.96 (m, 1H), 1.77 - 1.72 (m, 1H); tR = 4.866 min (CHIRALCEL OJ-3, 0.46 x 15 cm; 3 um, Hex(0.1% DEA):EtOH = 85:15, 1.0 ml / min).

[1261] Example 5d: (3S,4S)-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol (63.3 mg, 2%): LCMS (ESI, m / z): 257 [M+H] + ; 1 HNMR (300 MHz, CDCl3) δ 7.98 (m, 1H), 7.58 - 7.48 (m, 2H), 7.43 - 7.38 (m, 1H), 7.31 - 7.24 (m, 1H), 7.20 (s, 1H), 5.73 (d, J = 2.7 Hz, 1H), 4.07 - 3.90 (m, 2H), 3.32 - 3.23 (m, 2H), 2.78 (t, J = 11.1 Hz, 1H), 2.54 - 2.47 (m, 1H), 2.02 - 1.96 (m, 1H), 1.82 - 1.73 (m, 1H); tR = 7.967 min (CHIRALCEL OJ-3, 0.46 x 15 cm; 3 um, Hex(0.1% DEA):EtOH = 85:15, 1.0 ml / min).

[1262] Example 6a: (3R,4R)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol (53.6 mg, 2%): LCMS (ESI, m / z): 257 [M+H] + ; 1HNMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 7.55 - 7.53 (m, 1H), 7.40 - 7.28 (m, 3H), 7.20 (s, 1H), 5.85 (d, J = 2.1 Hz, 1H), 4.16 - 4.11 (m, 1H), 4.07 - 3.97 (m, 1H), 3.75 - 3.69 (m, 1H), 3.27 - 3.12 (m, 2H), 2.40 - 2.30 (m, 1H), 0.92 - 0.72 (m, 2H); tR = 2.442 min (CHIRALCEL OJ-3, 0.46 x 15 cm; 3 um, Hex(0.1% DEA):EtOH = 85:15, 1.5 ml / min).

[1263] Example 6b: (3S,4S)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol (52.0 mg, 1%): LCMS (ESI, m / z): 257 [M+H] + ; 1 HNMR (300 MHz, CDCl3) δ 7.92 (s, 1H), 7.55 - 7.52 (m, 1H), 7.39 - 7.25 (m, 3H), 7.19 (s, 1H), 5.83 (d, J = 1.8 Hz, 1H), 4.16 - 4.11 (m, 1H), 4.06 - 3.95 (m, 1H), 3.76 - 3.70 (m, 1H), 3.27 - 3.18 (m, 2H), 2.29 - 2.19 (m, 1H), 0.91 - 0.72 (m, 2H); tR = 3.200 min (CHIRALCEL OJ-3, 0.46 x 15 cm; 3 um, Hex(0.1% DEA):EtOH = 85:15, 1.5 ml / min).

[1264] Example 6c: (3S,4S)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol (120.7 mg, 2%): LCMS (ESI, m / z): 257 [M+H] + ; 11H NMR (300 MHz, CDCl3) δ 7.72 (s, 1H), 7.58 - 7.55 (m, 1H), 7.49 - 7.46 (m, 1H), 7.42 - 7.37 (m, 1H), 7.27 - 7.19 (m, 2H), 5.79 (d, J = 3.3 Hz, 1H), 4.13 - 3.96 (m, 2H), 3.78 - 3.73 (m, 1H), 3.28 - 3.15 (m, 2H), 2.39 - 2.29 (m, 1H), 0.94 - 0.85 (m, 2H); tR = 4.117 min (CHIRALCEL OJ-3, 0.46 x 15 cm; 3 um, Hex(0.1% DEA):EtOH = 85:15, 1.5 ml / min).

[1265] Example 6d: (3R,4R)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol (23.9 mg, 2%): LCMS (ESI, m / z): 257 [M+H] + ; 1H NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.62 - 7.57 (m, 1H), 7.55 - 7.49 (m, 1H), 7.41 - 7.36 (m, 1H), 7.27 - 7.18 (m, 2H), 5.80 (d, J = 3.0 Hz, 1H), 4.11 - 3.97 (m, 2H), 3.76 - 3.72 (m, 1H), 3.28 - 3.15 (m, 2H), 2.40 - 2.30 (m, 1H), 0.97 - 0.84 (m, 2H); tR = 9.372 min (CHIRALCEL OJ-3, 0.46 x 15 cm; 3 um, Hex(0.1% DEA):EtOH = 85:15, 1.5 ml / min).

[1266] Example 6: 4-(5H-imidazo[5,1-a]isoindol-5-yl)tetrahydro-2H-pyran-3-ol

[1267]

[1268] Step 1: (3S,4R)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)tetrahydro-2H-pyran-3-yl 4-nitrobenzoate

[1269]

[1270] Under nitrogen, at 0 °C, PPh3 (801 mg, 3.05 mmol) and DIAD (606 mg, 3.00 mmol) were added to a solution of (3R,4R)-4-[(5R)-5H-imidazo[4,3-a]isoindol-5-yl]oxacyclohexan-3-ol (256 mg, 1.00 mmol) and 4-nitrobenzoic acid (200 mg, 1.20 mmol) in THF (50 mL). The resulting solution was stirred at room temperature for 4 h. The reaction was then quenched by the addition of water. The resulting solution was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by combi-flash, eluting with DCM / MeOH (20:1) to afford 300 mg (74%) of (3S,4R)-4-[(5R)-5H-imidazo[4,3-a]isoindol-5-yl]oxacyclohexan-3-yl 4-nitrobenzoate as a yellow solid: LCMS (ESI, m / z): 406 [M+H] + .

[1271] Step 2: (3S,4R)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)tetrahydro-2H-pyran-3-ol

[1272]

[1273] (3S,4R)-4-[(5R)-5H-imidazo[4,3-a]isoindol-5-yl]oxacyclohexan-3-yl 4-nitrobenzoate (300 mg, 0.74 mmol), LiOH (88 mg, 3.68 mmol) in a mixture of THF (10 mL) and water (10 mL) was stirred at room temperature for 4 h. The reaction was then quenched by the addition of water. The resulting solution was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by combi-flash, eluting with DCM / MeOH (10:1).

[1274] Example 006e: (3S,4R)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)tetrahydro-2H-pyran-3-ol (73.1 mg, 39%), which is a white solid: LCMS (ESI, m / z): 257.3 [M+H] + . 1HNMR (300 MHz, CDCl3) δ 8.09 (s, 1H), 7.58 - 7.15 (m, 5H), 5.27 (d, J = 4.3 Hz, 1H), 4.16 (s, 1H), 4.10 - 3.90 (m, 2H), 3.58 (dd, J = 12.2, 1.2 Hz, 1H), 3.42 - 3.26 (m, 2H), 2.16 - 1.98 (m, 1H), 1.79 - 1.60 (m, 1H), 1.19 (d, J = 12.6 Hz, 1H).

[1275] (3R,4S)-4-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)tetrahydro-2H-pyran-3-ol

[1276]

[1277] The title compound was synthesized by the same method as in Example 006e.

[1278] Example 006f: (3R,4S)-4-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)tetrahydro-2H-pyran-3-ol (77.5 mg, 41%), which was a white solid: LCMS (ESI, m / z): 257.2 [M+H] + . 1 HNMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.53 - 7.23 (m, 4H), 5.42 (d, J = 3.6 Hz, 1H), 4.23 (s, 1H), 4.07 (d, J = 12.1 Hz, 1H), 3.94 (dd, J = 11.5, 4.8 Hz, 1H), 3.64 - 3.53 (m, 1H), 3.32 (td, J = 12.1, 2.3 Hz, 1H), 2.19 (dd, J = 12.2, 3.1 Hz, 1H), 1.66 (td, J = 12.9, 4.9 Hz, 1H), 1.26 (s, 1H), 1.09 (d, J = 13.1 Hz, 1H).

[1279] 4-(5H-Imidazo[5,1-a]isoindol-5-yl)tetrahydro-2H-pyran-3-ol

[1280]

[1281] The title compound was synthesized by the same method as in Example 006e. The absolute configurations of 006g and 006h were arbitrarily assigned.

[1282] Example 006g: (3S,4R)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol (25.3 mg, 21%), which is a white solid: LCMS (ESI, m / z): 257.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.31 - 7.29 (m, 2H), 5.30 (d, J = 9.0 Hz, 1H), 4.14 - 4.03 (m, 3H), 3.49 - 3.31 (m, 2H), 2.19 (qd, J = 12.6, 4.7 Hz, 1H), 1.90 (d, J = 13.3 Hz, 1H), 1.80 - 1.71 (m, 1H).

[1283] Example 006h: (3R,4S)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol (24.0 mg, 21%), which is a white solid: LCMS (ESI, m / z): 257.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.56 - 7.37 (m, 2H), 7.26 - 7.24 (m, 2H), 5.20 (d, J = 8.9 Hz, 1H), 4.12 - 4.01 (m, 3H), 3.47 - 3.31 (m, 2H), 2.15 (qd, J = 12.7, 4.9 Hz, 1H), 1.89 (d, d, J = 13.3 Hz, 1H), 1.78 - 1.69 (m, 1H).

[1284] Example 7: 7-(5H-imidazo[4,3-a]isoindol-5-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-8-ol

[1285]

[1286] The title compound was synthesized by the same method as in Example 4.

[1287]

[1288] The crude product was purified by prep-HPLC and further separated by chiral separation using the following conditions:

[1289] 1. Column: CHIRALPAK AD-H-TC001 SFC, 20x250mm, 5um; Mobile phase A: Hex(0.1% DEA)--HPLC, Mobile phase B: IPA--HPLC; Flow rate: 20 mL / min; Gradient: 25B to 25B in 34 min; 254 / 220 nm;

[1290] 2. Column: CHIRALPAK ID, 2.0 cm I.D x 25 cm L; Mobile phase A: Hex(0.1% DEA)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 40B to 40B in 23 min; 254 / 220 nm;

[1291] 3. Column: CHIRALPAK ID, 2.0 cm I.D x 25 cm L; Mobile phase A: CO2:60, Mobile phase B: IPA(0.2% DEA):40; Flow rate: 40 mL / min; 220 nm;

[1292] The absolute configurations of isomers 7c, 7d, 7g, and 7h were assigned by X-ray crystallography. The absolute configurations of the remaining isomers were arbitrarily assigned.

[1293] Example 7a: 5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, was obtained as a white solid (38.3 mg, 4%); LCMS (ESI, m / z): 293.1 [M+H] + ; 1 1H NMR (300 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.62 (m, 2H), 7.45 - 7.35 (m, 2H), 7.28 - 7.23 (m, 1H), 7.17 (s, 1H), 6.90 (s, 1H), 6.06 (d, J = 6.6 Hz, 1H), 5.76 (d, J = 3.0 Hz, 1H), 4.98 - 4.93 (m, 1H), 3.96 - 3.90 (m, 1H), 3.70 - 3.61 (m, 1H), 2.67 - 2.57 (m, 1H), 1.16 - 0.92 (m, 2H); tR = 2.538 min, (Chiralpak AD-3, 0.46 x 5 cm, 3um; Hex(0.1% DEA):IPA = 75:25; 1.0 mL / min). 7a and 7b are enantiomers.

[1294] Example 7b: (5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, a white solid (41.0 mg, 4%); LCMS (ESI, m / z): 293.1 [M+H] + ; tR = 3.257 min, (Chiralpak AD-3, 0.46x5 cm, 3um; Hex(0.1% DEA):IPA = 75:25; 1.0 mL / min). 7a and 7b are enantiomers.

[1295] Example 7c: (7S,8R)-7-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, a white solid (35.8 mg, 4%); LCMS (ESI, m / z): 293.1 [M+H] + ; 1 1H NMR (300 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.65 - 7.62 (m, 1H), 7.51 - 7.39 (m, 3H), 7.35 - 7.29 (m, 1H), 7.18 (s, 1H), 6.93 (s, 1H), 7.78 - 7.75 (m, 1H), 5.05 - 4.99 (m, 1H), 3.95 - 3.89 (m, 1H), 3.58 - 3.68 (m, 1H), 2.49 - 2.40 (m, 1H), 1.04 - 0.95 (m, 2H); tR = 4.012 min, (Chiralpak AD-3, 0.46x5 cm, 3um; Hex(0.1% DEA):IPA = 75:25; 1.0 mL / min). 7c and 7d are enantiomers.

[1296] Example 7d: (7R,8S)-7-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, a white solid (35.6 mg, 4%): LCMS (ESI, m / z): 293.1 [M+H] + ; tR = 5.054 min, (Chiralpak AD-3, 0.46x5 cm, 3um; Hex(0.1% DEA):IPA = 75:25; 1.0 mL / min). 7c and 7d are enantiomers.

[1297] Example 7e: 5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, a white solid (37.7 mg, 4%): LCMS (ESI, m / z): 293.1 [M+H] + ; 1 1H NMR (300 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.74 - 7.72 (m, 1H), 7.63 - 7.60 (m, 1H), 7.50 (s, 1H), 7.42 - 7.37 (t, 1H), 7.27 - 7.21 (m, 1H), 7.14 (s, 1H), 6.87 (s, 1H), 5.62 - 5.60 (m, 1H), 5.45 - 5.44 (m, 1H), 5.02 - 4.96 (m, 1H), 4.21 - 4.16 (m, 1H), 3.77 - 3.68 (m, 1H), 2.23 - 2.17 (m, 2H), 1.82 - 1.78 (m, 1H); tR = 4.468 min, (Chiralpak ID-3, 0.46x10 cm, 3 um; Hex(0.1% DEA):IPA = 60:40; 1.0 mL / min). 7e and 7f are enantiomers.

[1298] Example 7f: 5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, a white solid (29.3 mg, 3%): LCMS (ESI, m / z): 293.1 [M+H] + ; tR = 6.020 min, (Chiralpak ID-3, 0.46x10 cm, 3 um; Hex(0.1% DEA):IPA = 60:40; 1.0 mL / min). 7e and 7f are enantiomers.

[1299] Example 7g: (7R,8R)-7-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, a white solid (30.5 mg, 4%): LCMS (ESI, m / z): 293.1 [M+H] + ; 1HNMR (300 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.65 - 7.57 (m, 2H), 7.49 (s, 1H), 7.42 - 7.36 (m, 1H), 7.31 - 7.26 (m, 1H), 7.12 (s, 1H), 6.92 (s, 1H), 5.90 - 5.86 (m, 1H), 5.53 - 5.50 (m, 1H), 5.21 - 5.18 (m, 1H), 4.09 - 4.03 (m, 1H), 3.67 - 3.57 (m, 1H), 2.56 - 2.51 (m, 1H), 1.86 - 1.71 (m, 1H), 1.15 - 1.07 (m, 1H). tR = 2.18 min, (Chiralpak ID, 4.6 x 100 mm, 3 um; IPA(0.1% DEA) = 40%; 4 mL / min). 7g and 7h are enantiomers.

[1300] Example 7h: (7S,8S)-7-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, as a white solid (30.6 mg, 4%): LCMS (ESI, m / z): 293.1 [M+H] + ; tR = 2.92 min, (Chiralpak ID, 4.6 x 100 mm, 3 um; IPA(0.1% DEA) = 40%; 4 mL / min). 7g and 7h are enantiomers.

[1301] Example 8: 6-(5H-imidazo[4,3-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol

[1302]

[1303] The title compound was synthesized by the same method as in Example 4:

[1304]

[1305] The crude product was purified by prep-HPLC and further separated by chiral separation using the following conditions:

[1306] 1. Column: Chiralpak IC, 2 x 25 cm, 5 um; Mobile phase A: CO2:50, Mobile phase B: MeOH:50; Flow rate: 40 mL / min; 220 nm;

[1307] 2. Column: CHIRALCEL OD-H, 20 x 250 mm; Mobile phase A: CO2:70, Mobile phase B: MeOH:30; Flow rate: 40 mL / min; 260 nm;

[1308] 3. Column: CHIRALPAK AD-H, 20 x 250 mm; Mobile phase A: CO2:60, Mobile phase B: MeOH:40; Flow rate: 40 mL / min; 220 nm;

[1309] The absolute configurations of all isomers were assigned by X-ray crystallography.

[1310] Example 8a: (5S,6S)-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol, as an off-white solid (23.9 mg, 1%); LCMS (ESI, m / z): 304 [M+H] + . 1 1H NMR (300 MHz, CD3OD) δ 8.39 - 8.37 (m, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.72 - 7.66 (m, 2H), 7.51 - 7.35 (m, 3H), 7.24 (s, 1H), 5.91 (s, 1H), 5.04 (d, J = 5.4 Hz, 1H), 2.71 - 2.68 (m, 2H), 2.53 - 2.46 (m, 1H), 1.20 - 1.17 (m, 1H), 1.08 - 0.94 (m, 1H). tR = 1.393 min, (CHIRALPAK AS-3 100 x 3 mm, 3 um; CO2:MeOH (20 mM NH3), gradient (B%): 10% to 50% in 4.0 min, hold at 50% for 2.0 min; 220 nm; 2 mL / min). 8a and 8b are enantiomers.

[1311] Example 8b: (5R,6R)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol, as an off-white solid (22.1 mg, 1%); LCMS (ESI, m / z): 304 [M+H] + . 1HNMR (300 MHz, CD3OD) δ 8.39 - 8.37 (m, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.72 - 7.66 (m, 2H), 7.51 - 7.35 (m, 3H), 7.24 (s, 1H), 5.91 (s, 1H), 5.04 (d, J = 5.4 Hz, 1H), 2.71 - 2.68 (m, 2H), 2.53 - 2.46 (m, 1H), 1.20 - 1.17 (m, 1H), 1.08 - 0.94 (m, 1H); tR = 1.524 min, (CHIRALPAK AS - 3 100x3 mm, 3 um; CO2:MeOH(20 mM NH3), gradient (B%) : 10% to 50% in 4.0 min, hold at 50% for 2.0 min; 220 nm; 2 mL / min). 8a and 8b are enantiomers.

[1312] Example 8c: (5R,6S)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol, as an off-white solid (101.8 mg, 3%); LCMS (ESI, m / z): 304 [M+H] + . 1 HNMR (300 MHz, CD3OD) δ 8.31 (s, 2H), 8.06 (s, 1H), 8.04 (s, 1H), 7.70 - 7.62 (m, 2H), 7.43 - 7.24 (m, 3H), 7.17 (s, 1H), 5.54 - 5.52 (m, 1H), 4.79 - 4.78 (m, 1H), 3.00 - 2.92 (m, 1H), 2.78 - 2.68 (m, 1H), 2.32 - 2.25 (m, 1H), 2.10 - 1.99 (m, 2H); tR = 1.632 min, (CHIRALPAK AS - 3 100x3 mm, 3 um; CO2:MeOH(20 mM NH3), gradient (B%) : 10% to 50% in 4.0 min, hold at 50% for 2.0 min; 220 nm; 2 mL / min). 8c and 8d are enantiomers.

[1313] Example 8d: (5S,6R)-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol, as an off-white solid (75.7 mg, 3%); LCMS (ESI, m / z): 304 [M+H] + . 1HNMR (300 MHz, CD3OD) δ 8.31 (s, 2H), 8.06 (s, 1H), 8.04 (s, 1H), 7.70 - 7.62 (m, 2H), 7.43 - 7.24 (m, 3H), 7.17 (s, 1H), 5.54 - 5.52 (m, 1H), 4.79 - 4.78 (m, 1H), 3.00 - 2.92 (m, 1H), 2.78 - 2.68 (m, 1H), 2.32 - 2.25 (m, 1H), 2.10 - 1.99 (m, 2H); tR = 1.914 min, (CHIRALPAK AS - 3 100x3mm, 3um; CO2:MeOH(20mMNH3), gradient (B%) : 10% to 50% in 4.0 min, hold at 50% for 2.0 min; 220 nm; 2 mL / min). 8c and 8d are enantiomers.

[1314] Example 8e: (5R,6R)-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol, as an off-white solid (18.8 mg, 1%); LCMS (ESI, m / z): 304 [M + H] + ； 1 HNMR (300 MHz, CD3OD) δ 8.38 - 8.36 (m, 1H), 8.23 (s, 1H), 7.92 (s, 1H), 7.69 - 7.61 (m, 3H), 7.46 - 7.42 (m, 1H), 7.35 - 7.29 (m, 1H), 7.20 (s, 1H), 5.90 - 5.89 (m, 1H), 4.98 (d, J = 5.1 Hz, 1H), 2.71 - 2.68 (m, 2H), 2.72 - 2.58 (m, 3H), 1.14 - 0.97 (m, 2H); tR = 1.403 min, (CHIRALPAK AS - 3 100x3mm, 3um mobile phase: CO2:MeOH(20mMNH3), gradient (B%) : 10% to 50% in 4.0 min, hold at 50% for 2.0 min; 2 ml / min; 220 nm). 8e and 8f are enantiomers.

[1315] Example 8f: (5S,6S)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol, as an off-white solid (19.9 mg, 1%); LCMS (ESI, m / z): 304 [M + H] + ; 1HNMR (300 MHz, CD3OD) δ 8.38 - 8.36 (m, 1H), 8.23 (s, 1H), 7.92 (s, 1H), 7.69 - 7.61 (m, 3H), 7.46 - 7.42 (m, 1H), 7.35 - 7.29 (m, 1H), 7.20 (s, 1H), 5.90 - 5.89 (m, 1H), 4.98 (d, J = 5.1 Hz, 1H), 2.71 - 2.68 (m, 2H), 2.72 - 2.58 (m, 3H), 1.14 - 0.97 (m, 2H); tR = 1.701 min, (CHIRALPAK AS - 3 100x3mm, 3um mobile phase: CO2:MeOH(20 mM NH3), gradient (B%) : 10% to 50% in 4.0 min, hold at 50% for 2.0 min; 2 ml / min; 220 nm). 8e and 8f are enantiomers.

[1316] Example 8g: (5S,6R)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol, as an off-white solid (239.8 mg, 6%); LCMS (ESI, m / z): 304 [M+H] + ; 1 HNMR (300 MHz, CD3OD) δ 8.39 - 8.38 (m, 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.63 - 7.57 (m, 2H), 7.54 - 7.49 (m, 1H), 7.45 - 7.41 (m, 1H), 7.36 - 7.32 (m, 1H), 7.14 (s, 1H), 5.63 - 5.61 (m, 1H), 5.12 - 5.11 (m, 1H), 2.82 - 2.77 (m, 1H), 2.64 - 2.53 (m, 2H), 1.58 - 1.48 (m, 1H), 1.15 - 1.13 (m, 1H); tR = 2.563 min, (CHIRALPAK AD - 3 100x3mm, 3um; mobile phase: CO2:MeOH(20 mM NH3), MeOH(20 mM NH3); gradient (B%) : 10% to 50% in 4.0 min, hold at 50% for 2.0 min; 220 nm). 8g and 8h are enantiomers.

[1317] Example 8h: (5R,6S)-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol, as an off-white solid (70.3 mg, 2%); LCMS (ESI, m / z): 304 [M+H] + ; 11H NMR (300 MHz, CD3OD) δ 8.39 - 8.38 (m, 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.63 - 7.57 (m, 2H), 7.54 - 7.49 (m, 1H), 7.45 - 7.41 (m, 1H), 7.36 - 7.32 (m, 1H), 7.14 (s, 1H), 5.63 - 5.61 (m, 1H), 5.12 - 5.11 (m, 1H), 2.82 - 2.77 (m, 1H), 2.64 - 2.53 (m, 2H), 1.58 - 1.48 (m, 1H), 1.15 - 1.13 (m, 1H); tR = 2.776 min, (CHIRALPAK AD - 3 100x3mm, 3um; mobile phase: CO2:MeOH(20 mM NH3), MeOH(20 mM NH3); gradient (B%): 10% to 50% in 4.0 min, hold at 50% for 2.0 min; 220 nm). 8g and 8h are enantiomers.

[1318] The absolute configurations of all isomers are arbitrarily assigned.

[1319] Example 9: 1-(3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)ethan-1-one

[1320]

[1321] The title compound was synthesized by the same method as in Example 27.

[1322]

[1323] The crude product was purified by prep - HPLC and further separated by chiral separation using the following conditions:

[1324] 1. CHIRALCEL OD - H, 20x250mm; mobile phase A: Hex - HPLC, mobile phase B: EtOH - HPLC; flow rate: 20 mL / min; gradient: 10B to 10B in 24 min; 254 / 220 nm;

[1325] 2. CHIRALPAK - AD - H - SL002, 20x250mm; mobile phase A: Hex(0.1% DEA) - HPLC, mobile phase B: IPA - HPLC; flow rate: 20 mL / min; gradient: 30B to 30B in 15 min; 254 / 220 nm;

[1326] Example 9a: 1-(3-Hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)ethan-1-one (10.0 mg, 11%), which is a white solid: LCMS (ESI, m / z): 298.2 [M+H] + ; 1 1H NMR (300 MHz, CD3OD) δ 7.95 - 7.90 (m, 1H), 7.64 - 7.62 (m, 1H), 7.52 - 7.36 (m, 3H), 7.20 (s, 1H), 5.84 - 5.83 (m, 1H), 4.88 - 3.67 (m, 3H), 3.06 - 2.85 (m, 1H), 2.55 - 2.28 (m, 2H), 2.14 - 1.98 (m, 3H), 1.00 - 0.85 (m, 1H), 0.59 - 0.58 (m, 1H); tR = 9.351 min, (ChiralCELOD-3, 0.46 x 5 cm, 3um; ethanol:hexane (0.1% DEA) = 7:93; 1.0 mL / min). 9a and 9b are enantiomers.

[1327] Example 9b: 1-(3-Hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)ethan-1-one (31.5 mg, 33%), which is a white solid: LCMS (ESI, m / z): 298.2 [M+H] + ; tR = 10.852 min, (ChiralCELOD-3, 0.46 x 5 cm, 3um; ethanol:hexane (0.1% DEA) = 7:93; 1.0 mL / min). 9a and 9b are enantiomers.

[1328] Example 9c: 1-(3-Hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)ethan-1-one (3.2 mg, 3%), which is a white solid: LCMS (ESI, m / z): 298.2 [M+H] + ; 1HNMR (400 MHz, CD3OD) δ 7.91 (s, 1H), 7.63 - 7.62 (m, 1H), 7.53 - 7.50 (m, 1H), 7.43 - 7.39 (m, 1H), 7.32 - 7.28 (m, 1H), 7.15 (s, 1H), 5.82 - 5.80 (m, 1H), 4.86 - 3.65 (m, 3H), 3.00 - 2.93 (m, 1H), 2.49 - 2.35 (m, 2H), 2.09 - 1.94 (m, 3H), 0.84 - 0.71 (m, 1H), 0.63 - 0.42 (m, 1H); tR = 13.717 min, (ChiralCELOD - 3, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 7:93; 1.0 mL / min). 9c and 9d are enantiomers.

[1329] Example 9d: 1-(3 - hydroxy - 4-(5H - imidazo[5,1 - a]isoindol - 5 - yl)piperidin - 1 - yl)ethan - 1 - one (7.0 mg, 7%), a white solid: LCMS (ESI, m / z): 298.2 [M + H] + ; tR = 16.140 min, (ChiralCELOD - 3, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 7:93; 1.0 mL / min). 9c and 9d are enantiomers.

[1330] Examples 10 and 11: tert-butyl 3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate and tert-butyl 4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate

[1331]

[1332] The following isomers were separated by Chiral - HPLC using inter - 6.

[1333]

[1334] The mixture of inter - 6 was purified by prep - HPLC and further separated by chiral separation using the following conditions:

[1335] 1. Chiralpak IA, 2 x 25 cm, 5 um; mobile phase A: Hex - HPLC, mobile phase B: EtOH - HPLC; flow rate: 20 mL / min; gradient: 30B to 30B in 10 min; 254 / 220 nm;

[1336] 2. Phenomenex Lux 5u Cellulose-4, AXIA Packed, 250x21.2mm, 5um; Mobile phase A: Hex--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 30B to 30B in 26 min; 254 / 220 nm;

[1337] 3. CHIRALPAK ID, 2.0 cm I.D x 25 cm L; Mobile phase A: Hex--HPLC, Mobile phase B: IPA--HPLC; Flow rate: 20 mL / min; Gradient: 15B to 15B in 18 min; 254 / 220 nm;

[1338] 4. CHIRALPAK ID, 2.0 cm I.D x 25 cm L; Mobile phase A: Hex--HPLC, Mobile phase B: IPA--HPLC; Flow rate: 20 mL / min; Gradient: 30B to 30B in 13 min; 254 / 220 nm;

[1339] 5. The absolute configurations of all isomers are arbitrarily assigned.

[1340] Example 10a: tert-Butyl 3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate (38.7 mg, 1%), a white solid: LCMS (ESI, m / z): 356.2 [M+H] + ;. 1 HNMR (400 MHz, CD3OD) δ 7.89 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.45 - 7.34 (m, 2H), 7.20 (s, 1H), 5.82 (d, J = 4.0 Hz, 1H), 4.37 - 4.33 (m, 1H), 3.86 - 3.71 (m, 2H), 2.62 - 2.50 (m, 2H), 2.27 - 2.20 (m, 1H), 1.43 (s, 9H), 0.87 - 0.83 (m, 1H), 0.47 - 0.42 (m, 1H); tR = 1.323 minutes, (Chiralpak IA, 0.46 x 5 cm, 3um; Ethanol:Hexane (0.1% DEA) = 30:70; 1.0 mL / min). 10a and 10b are enantiomers.

[1341] Example 10b: tert-Butyl 3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate (39.9 mg, 1%), a white solid: LCMS (ESI, m / z): 356.2 [M+H] +; tR = 1.866 min. (Chiralpak IA, 0.46 x 5 cm, 3 um; ethanol: hexane (0.1% DEA) = 30:70; 1.0 mL / min). 10a and 10b are enantiomers.

[1342] Example 10c: tert-Butyl 3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate (16.1 mg, 1%), which is a white solid: LCMS (ESI, m / z): 356.2 [M+H] + ; 1 1H NMR (400 MHz, CD3OD) δ 7.93 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.35 - 7.31 (m, 1H), 7.17 (s, 1H), 5.82 (d, J = 4.0 Hz, 1H), 4.31 - 4.28 (m, 1H), 3.87 - 3.74 (m, 2H), 2.61 - 2.50 (m, 2H), 2.40 - 2.34 (m, 1H), 1.41 (s, 9H), 0.73 - 0.70 (m, 1H), 0.56 - 0.46 (m, 1H). tR = 2.348 min (Lux Cellulose-4, 0.46 x 5 cm, 3 um; ethanol: hexane (0.1% DEA) = 30:70; 1.0 mL / min). 10c and 10d are enantiomers.

[1343] Example 10d tert-Butyl 3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate (16.0 mg, 1%), which is a white solid: LCMS (ESI, m / z): 356.2 [M+H] + ; tR = 2.841 min, (Lux Cellulose-4, 0.46 x 5 cm, 3 um; ethanol: hexane (0.1% DEA) = 30:70; 1.0 mL / min). 10c and 10d are enantiomers.

[1344] The absolute configurations of isomers 11a & 11b were assigned by X-ray crystallography. The absolute configurations of the remaining isomers were arbitrarily assigned.

[1345] Example 11a: (3S,4R)-tert-Butyl 4-hydroxy-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate (36.1 mg, 1%), which is a white solid: LCMS (ESI, m / z): 356.2 [M+H] + ; 1HNMR (400 MHz, CD3OD) δ 7.96 (s, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.21 (s, 1H), 5.83 (d, J = 4.0 Hz, 1H), 4.07 - 4.00 (m, 2H), 3.34 - 3.32 (m, 1H), 2.79 - 2.65 (m, 1H), 2.21 - 2.07 (m, 2H), 1.84 - 1.77 (m, 1H), 1.60 - 1.49 (m, 1H), 1.27 (s, 9H); tR = 2.511 min, (Chiralpak ID - 3, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 15:85; 1.0 mL / min). 11a and 11b are enantiomers.

[1346] Example 11b: (3R,4S)-tert-Butyl 4-hydroxy-3-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate (30.1 mg, 1%), which is a white solid: LCMS (ESI, m / z): 356.2 [M+H] + . tR = 3.240 min. (Chiralpak ID - 3, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 15:85; 1.0 mL / min). 11a and 11b are enantiomers.

[1347] Example 11c: tert-Butyl 4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate (10.6 mg, 1%), which is a white solid: LCMS (ESI, m / z): 356.2 [M+H] + . 1 HNMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.47 - 7.33 (m, 2H), 7.21 (s, 1H), 5.84 (d, J = 4.0 Hz, 1H), 4.06 - 4.00 (m, 2H), 3.18 - 3.11 (m, 1H), 2.71 - 2.55 (m, 1H), 2.35 - 2.21 (m, 1H), 2.11 - 2.04 (m, 1H), 1.95 - 1.85 (s, 1H), 1.61 - 1.49 (m, 1H), 1.37 (s, 9H); tR = 2.130 min (Chiralpak ID - 3, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 30:70; 1.0 mL / min). 11c and 11d are enantiomers.

[1348] Example 11d: tert-Butyl 4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate (11.4 mg, 1%), a white solid: LCMS (ESI, m / z): 356.3 [M+H] + ; tR = 2.788 min, (Chiralpak ID-3, 0.46 x 5 cm, 3 um; ethanol: hexane (0.1% DEA) = 30:70; 1.0 mL / min). 11c and 11d are enantiomers.

[1349] Example 12: 1-(4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)ethan-1-one

[1350]

[1351] The absolute configurations of all isomers are arbitrarily assigned.

[1352] Example 12a: 1-((3S,4R)-4-Hydroxy-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)ethanone (16.4 mg, 4%), a white solid: LCMS (ESI): M+H + = 298.2; 1 1H NMR (400 MHz, CD3OD) δ 7.95 - 7.90 (m, 1H), 7.69 - 7.60 (m, 1H), 7.50 - 7.37 (m, 3H), 7.21 (s, 1H), 5.84 - 5.82 (m, 1H), 4.55 - 4.45 (m, 0.5H), 4.08 - 4.07 (m, 1H), 3.88 - 3.84 (m, 1H), 3.05 - 2.98 (m, 1H), 2.55 - 2.53 (m, 0.5H), 2.27 - 2.03 (m, 4H), 1.72 - 1.48 (m, 3H); tR = 3.477 min, (column, Lux Cellulose-3, 0.46 x 5 cm, 3 um; ethanol: hexane (0.1% DEA) = 25:75; 1.0 mL / min). 12a and 12b are enantiomers.

[1353] Example 12b: 1-((3R,4S)-4-Hydroxy-3-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)ethanone (13.8 mg, 4%), a white solid: LCMS (ESI, m / z): 298.2 [M+H] +; tR = 4.190 minutes (column, Lux Cellulose-3, 0.46 x 5 cm, 3 um; ethanol: hexane (0.1% DEA) = 25:75; 1.0 mL / min). 12a and 12b are enantiomers.

[1354] Example 12c: 1-((3R,4S)-4-Hydroxy-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)ethanone (8.6 mg, 2%), a white solid: LCMS (ESI, m / z): 298.2 [M+H] + . 1 1H NMR (400 MHz, CD3OD) δ 8.05 - 7.92 (m, 1H), 7.70 - 7.62 (m, 2H), 7.49 - 7.35 (m, 2H), 7.24 - 7.20 (m, 1H), 5.87 - 5.82 (m, 1H), 4.55 - 4.45 (m, 0.5H), 4.12 - 4.05 (m, 1H), 3.94 - 3.71 (m, 1H), 3.55 - 3.53 (m, 0.5H), 3.01 - 2.75 (m, 1H), 2.51 - 2.04 (m, 4H), 1.82 - 1.75 (m, 3H); tR = 5121 minutes, (column, Lux Cellulose-3, 0.46 x 5 cm, 3 um; ethanol: hexane (0.1% DEA) = 25:75; 1.0 mL / min). 12c and 12d are enantiomers.

[1355] Example 12d: 1-((3S,4R)-4-Hydroxy-3-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)ethanone (10.2 mg, 2%), a white solid. LCMS (ESI, m / z): 298.2 [M+H] + ; tR = 10.013 min (column, Lux Cellulose-3, 0.46 x 5 cm, 3 um; ethanol: hexane (0.1% DEA) = 25:75; 1.0 mL / min). 12c and 12d are enantiomers.

[1356] Example 13: 2-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol

[1357]

[1358] The title compound was synthesized by the same method as in Example 3.

[1359]

[1360] The crude product was purified by prep-HPLC and further separated by chiral resolution using the following conditions:

[1361] 1. Column, Chiralpak OJ-H, 2x25 cm; Mobile phase: Hex(0.1% DEA):IPA = 12:12; Detector, uv 254 nm; Flow rate, 20 mL / min.

[1362] 2. Column, Chiralpak Chiralpak IA, 2x25 cm, 5um;; Mobile phase: Hex(0.1% DEA):IPA = 30:30; Detector, uv 254 nm; Flow rate, 20 mL / min

[1363] 3. Column, Chiralpak OJ-H, 2x25 cm; Mobile phase: Hex(0.1% DEA):IPA = 15:15; Detector, uv 254 nm; Flow rate, 20 mL / min

[1364] 4. Column, Chiralpak IA, 2x25 cm, 5um, 3um; Mobile phase: Hex(0.1% DEA):IPA = 10:10; Detector, uv 254 nm; Flow rate, 20 mL / min.

[1365] The absolute configurations of isomers 13c and 13d were assigned by X-ray crystallography. The absolute configurations of the remaining isomers were arbitrarily assigned.

[1366] Example 13a: 8-Fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclobutan-1-ol: LCMS(ESI, m / z): 245.2. 1 HNMR(300 MHz, CD3OD) δ 7.93(s, 1H), 7.63 - 7.59(m, 1H), 7.40 - 7.37(m, 1H), 7.23(s, 1H), 7.08 - 7.02(m, 1H), 5.37(d, J = 9 Hz, 1H), 4.34 - 4.30(m, 1H), 2.62 - 2.46(m, 1H), 2.32 - 2.14(m, 1H), 1.88 - 1.67(m, 2H), 1.38 - 1.20(m, 2H). tR = 6.997 minutes (Chiralpak OJ-3, 0.46x15 cm, 3um; Hex(0.1% DEA):IPA = 88:12; 1.0 mL / min). 13a and 13b are enantiomers.

[1367] Example 13b: 8-Fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclobutan-1-ol: LCMS (ESI, m / z): 245.2; tR = 8.947 min (Chiralpak OJ-3, 0.46x15 cm, 3 um; Hex(0.1% DEA):IPA = 88:12; 1.0 mL / min). 13a and 13b are enantiomers.

[1368] Example 13c: (1R,2S)-2-[(5R)-8-Fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclobutan-1-ol: LCMS (ESI, m / z): 245.2. 1 HNMR (300 MHz, CD3OD) δ 8.01 (s, 1H), 7.46 - 7.37 (m, 2H), 7.19 (s, 1H), 7.10 - 6.95 (m, 1H), 5.33 (d, J = 6 Hz, 1H), 4.22 - 4.18 (m, 1H), 2.52 - 2.34 (m, 1H), 2.36 - 2.23 (m, 1H), 2.01 - 1.79 (m, 2H), 1.78 - 1.59 (m, 1H). tR = 1.347 min (Chiralpak IA-3, 0.46x5 cm, 3 um; Mobile phase: Hex(0.1% DEA):IPA = 70:30; Detector, uv 254 nm; Flow rate, 1.0 mL / min). 13c and 13d are enantiomers.

[1369] Example 13d: (1S,2R)-2-[(5S)-8-Fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclobutan-1-ol: LCMS (ESI, m / z): 245.2 [M+H] + ; tR = 2.379 min (Chiralpak IA-3, 0.46x5 cm, 3 um; Mobile phase: Hex(0.1% DEA):IPA = 70:30; Detector, uv 254 nm; Flow rate, 1.0 mL / min). 13c and 13d are enantiomers.

[1370] Example 13e: 8-Fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclobutan-1-ol: LCMS (ESI, m / z): 245.2 [M+H] + ; 1HNMR (300 MHz, CD3OD) δ 8.19 (s, 1H), 7.58 - 7.53 (m, 1H), 7.39 - 7.36 (m, 1H), 7.23 (s, 1H), 7.09 - 6.96 (m, 1H), 5.55 (d, J = 5.9 Hz, 1H), 4.68 - 4.64 (m, 1H), 3.05 - 2.87 (m, 1H), 2.41 - 2.20 (m, 1H), 1.97 - 1.76 (m, 2H), 1.59 - 1.50 (m, 1H). tR = 4.185 min (Chiralpak OJ - 3, 0.46 x 15 cm, 3 um; Hex(0.1% DEA):IPA = 85:15; 1.0 mL / min).

[1371] Example 13f: 8 - fluoro - 5H - imidazo[4,3 - a]isoindol - 5 - yl]cyclobutan - 1 - ol: LCMS (ESI, m / z): 245.2 [M + H] + ; tR = 5.659 min (Chiralpak OJ - 3, 0.46 x 15 cm, 3 um; Hex(0.1% DEA):IPA = 85:15; 1.0 mL / min). 13e and 13f are enantiomers.

[1372] Example 13g: 8 - fluoro - 5H - imidazo[4,3 - a]isoindol - 5 - yl]cyclobutan - 1 - ol: LCMS (ESI, m / z): 245.2 [M + H] + ; 1 HNMR (300 MHz, CD3OD) δ 7.98 (s, 1H), 7.53 - 7.48 (m, 1H), 7.40 - 7.36 (m, 1H), 7.19 (s, 1H), 7.01 - 6.93 (m, 1H), 5.51 (d, J = 9.0 Hz, 1H), 4.56 - 4.51 (m, 1H), 2.60 - 2.31 (m, 3H), 2.21 - 1.90 (m, 2H). tR = 2.293 min (Chiralpak IA - 3, 0.46 x 5 cm, 3 um; Hex(0.1% DEA):IPA = 90:10; 1.0 mL / min). 13g and 13h are enantiomers.

[1373] Example 13h: 8 - fluoro - 5H - imidazo[4,3 - a]isoindol - 5 - yl]cyclobutan - 1 - ol: LCMS (ESI, m / z): 245.2 [M + H] + ; tR = 3.120 min (Chiralpak IA - 3, 0.46 x 5 cm, 3 um; Hex(0.1% DEA):IPA = 90:10; 1.0 mL / min). 13g and 13h are enantiomers.

[1374] Examples 15 and 16: 1-(ethylsulfonyl)-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-4-ol and 1-(ethylsulfonyl)-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-3-ol

[1375]

[1376] The title compound was synthesized by the same method as in Example 27.

[1377]

[1378] The crude product was purified by prep-HPLC and further separated by chiral resolution using the following conditions:

[1379] 1. Chiralpak IC, 2x25cm, 5um; Mobile phase A: Hex--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 15 mL / min; Gradient: 50B to 50B in 18 min; 254 / 220 nm;

[1380] 2. Phenomenex Lux 5u Cellulose-4, AXIA Packed, 250X21.2mm, 5um; Mobile phase A: Hex--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 40B to 40B in 38 min; 254 / 220 nm;

[1381] 3. CHIRALPAK IC, 2x25cm, 5um; Mobile phase A: Hex--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 30B to 30B in 20 min; 254 / 220 nm;

[1382] The absolute configuration of isomers 16a - 16d was assigned by X-ray crystallography.

[1383] Example 16a: (3S,4S)-1-(ethylsulfonyl)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-3-ol: LCMS (ESI, m / z): 348.2 [M+H] + ; 1HNMR (400 MHz, CD3OD) δ 7.95 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.46 - 7.32 (m, 2H), 7.17 (s, 1H), 5.83 (d, J = 3.6 Hz, 1H), 4.01 - 3.90 (m, 2H), 3.53 - 4.90 (m, 1H), 3.00 (q, J = 7.2 Hz, 2H), 2.74 - 2.65 (m, 2H), 2.42 - 2.30 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 0.85 - 0.79 (m, 1H), 0.75 - 0.60 (m, 1H); tR = 2.844 min, (LuxCellulose-4, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 30:70; 1.5 mL / min). 16a and 16b are enantiomers.

[1384] Example 16b: (3R,4R)-1-(ethylsulfonyl)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-3-ol: LCMS (ESI, m / z): 348.2 [M+H] + ; tR = 6.072 min, (Lu Cellulose-4, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 30:70; 1.5 mL / min). 16a and 16b are enantiomers.

[1385] Example 16c: (3R,4R)-1-(ethylsulfonyl)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-3-ol: LCMS (ESI, m / z): 348.2 [M+H] + ; 1HNMR (400 MHz, CD3OD) δ 7.93 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.21 (s, 1H), 5.84 (d, J = 3.6 Hz, 1H), 4.03 - 3.83 (m, 2H), 3.54 - 3.51 (m, 1H), 3.03 (q, J = 7.2 Hz, 2H), 2.78 - 2.67 (m, 2H), 2.25 - 2.19 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 0.98 - 0.94 (m, 1H), 0.69 - 0.55 (m, 1H); tR = 1.519 min (Chiralpak IC-3, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 30:70; 1.0 mL / min). 16c and 16d are enantiomers.

[1386] Example 16d: (3R,4R)-1-(ethylsulfonyl)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-3-ol: LCMS (ESI, m / z): 348.2 [M+H] + ; tR = 2.357 min (Chiralpak IC-3, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 30:70; 1.0 mL / min). 16c and 16d are enantiomers.

[1387] The absolute configurations of all isomers 15a-d are arbitrarily assigned.

[1388] Example 15a: (3S,4R)-1-(ethylsulfonyl)-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-4-ol: LCMS (ESI, m / z): 348.2 [M+H] + ; 1HNMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.48 - 7.34 (m, 2H), 7.21 (s, 1H), 5.85 (d, J = 4.0 Hz, 1H), 4.01 - 3.98 (m, 1H), 3.74 - 3.70 (m, 1H), 2.90 - 2.76 (m, 4H), 2.55 - 2.45 (m, 1H), 2.13 - 2.05 (m, 2H), 1.80 - 1.68 (m, 1H), 1.16 (t, J = 7.2 Hz, 3H); tR = 2.495 (Chiralpak IC-3, 0.46x5 cm, 3 um; hexane (0.1% DEA) = 30:70; 1.0 mL / min). 15a and 15b are enantiomers.

[1389] Example 15b: (3R,4S)-1-(ethylsulfonyl)-3-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-4-ol: LCMS (ESI, m / z): 348.2 [M+H] + ; tR = 3.738, (Chiralpak IC-3, 0.46x5 cm, 3 um; hexane (0.1% DEA) = 30:70; 1.0 mL / min). 15a and 15b are enantiomers.

[1390] Example 15c: (3R,4S)-1-(ethylsulfonyl)-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-4-ol: LCMS (ESI, m / z): 348.2 [M+H] + ; 1 HNMR (400 MHz, CD3OD) δ 7.93 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.19 (s, 1H), 5.83 (d, J = 3.6 Hz, 1H), 4.03 - 3.92 (m, 1H), 3.75 - 3.65 (m, 1H), 3.02 - 2.98 (m, 1H), 2.85 - 2.70 (m, 3H), 2.40 - 2.30 (m, 1H), 2.20 - 2.15 (m, 1H), 2.00 - 1.90 (m, 1H), 1.79 - 1.65 (m, 1H), 1.12 (t, J = 7.2 Hz, 3H); tR = 2.240 min (Lux Cellulose-4, 0.46x5 cm, 3 um; ethanol:hexane (0.1% DEA) = 30:70; 1.5 mL / min). 15c and 15d are enantiomers.

[1391] Example 15d: (3S,4R)-1-(ethylsulfonyl)-3-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-4-ol: LCMS (ESI, m / z): 348.2 [M+H] + ; tR = 3.661 min (Lux Cellulose-4, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 30:70; 1.5 mL / min). 15c and 15d are enantiomers.

[1392] Example 17: 2-(5H-imidazo[5,1-a]isoindol-5-yl)spiro[3.3]heptan-1-ol

[1393]

[1394] (1R,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)spiro[3.3]heptan-1-ol

[1395] (1R,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)spiro[3.3]heptan-1-ol

[1396] (1R,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)spiro[3.3]heptan-1-ol

[1397] (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)spiro[3.3]heptan-1-ol

[1398] (1S,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)spiro[3.3]heptan-1-ol

[1399] (1S,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)spiro[3.3]heptan-1-ol

[1400] (1S,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)spiro[3.3]heptan-1-ol

[1401] (1S,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)spiro[3.3]heptan-1-ol

[1402] Examples 17a-e were all synthesized using the reaction conditions of Preparation Examples 1a-h, where the reagent cyclobutanone was replaced with spiro[3.3]heptan-1-one. Each example is a single diastereomer with an undetermined absolute configuration.

[1403] The absolute configurations of all isomers 17a - e are arbitrarily assigned.

[1404] Example 17a: 2-(5H-imidazo[1,5-b]isoindol-5-yl)spiro[3.3]heptan-3-ol: LCMS (ESI, m / z): 267 [M+H] + ; 1 1H NMR: no NMR; tR = 0.45 min (Chiralpak AD (250x30 mm, 5um), ethanol w / 0.1% NH4OH, 1.5 ml / min).

[1405] Example 17b: 2-(5H-imidazo[1,5-b]isoindol-5-yl)spiro[3.3]heptan-3-ol: LCMS (ESI, m / z): 267 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.65–7.46 (m, 1H), 7.44–7.29 (m, 2H), 7.23 (td, J = 7.5, 1.1 Hz, 1H), 7.09 (s, 1H), 5.30 (d, J = 7.6 Hz, 2H), 3.86 (t, J = 7.5 Hz, 1H), 2.42–2.23 (m, 1H), 2.09–1.69 (m, 5H), 1.69–1.45 (m, 2H).; tR = 0.89 min (Chiralpak AD (250x30 mm, 5um), ethanol w / 0.1% NH4OH, 1.5 ml / min).

[1406] Example 17c: 2-(5H-imidazo[1,5-b]isoindol-5-yl)spiro[3.3]heptan-3-ol: LCMS (ESI, m / z): 267 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), δ 7.59 (t, J = 8.0 Hz, 2H), 7.36 (dd, J = 7.9, 6.8 Hz, 1H), 7.25 (td, J = 7.5, 1.0 Hz, 1H), 7.09 (s, 1H), 5.75 (d, J = 4.9 Hz, 1H), 5.35 (d, J = 8.3 Hz, 1H), 4.18 (s, 1H), 2.42 (d, J = 8.3 Hz, 1H), 2.35–2.18 (m, 1H), 2.04 (t, J = 9.9 Hz, 1H), 1.90 (q, J = 6.6 Hz, 3H), 1.76 (q, J = 7.3 Hz, 2H), 1.56 (d, J = 10.0 Hz, 1H).; tR = 0.79 min (Chiralpak AD (250x30 mm, 5um), ethanol w / 0.1% NH4OH, 1.5 ml / min).

[1407] Example 17d: 2-(5H-imidazo[1,5-b]isoindol-5-yl)spiro[3.3]heptan-3-ol: LCMS (ESI, m / z): 267 [M+H] + ; 1H NMR: no NMR; tR = 1.15 min (Chiralpak AD (250x30 mm, 5um), ethanol w / 0.1% NH4OH, 1.5 ml / min).

[1408] Example 17e (enantiomer of Example 17b): 2-(5H-imidazo[1,5-b]isoindol-5-yl)spiro[3.3]heptan-3-ol: LCMS (ESI, m / z): 267 [M+H] + ; No analytical SFC, Chiralpak AD (250x30 mm, 5um), ethanol w / 0.1% NH4OH, 1.5 ml / min).

[1409] Example 18: 4,4-difluoro-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1410]

[1411] (1S,2S)-4,4-difluoro-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol (18a)

[1412] (1S,2S)-4,4-difluoro-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol (18f)

[1413] (1S,2R)-4,4-difluoro-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1414] (1S,2R)-4,4-difluoro-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1415] (1R,2S)-4,4-difluoro-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1416] (1R,2S)-4,4-difluoro-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1417] (1R,2R)-4,4-difluoro-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol (18b)

[1418] (1R,2R)-4,4-difluoro-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol (18e)

[1419] Step 1:

[1420] (E)-4,4-difluoro-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclohexan-1-one

[1421]

[1422] The title compound was synthesized by the general procedure for the synthesis of Int-2. LCMS (ESI, m / z): 531.3 [M+H] +

[1423] Step 2:

[1424] 4,4-difluoro-2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-one

[1425]

[1426] The title compound was synthesized by the general procedure for the synthesis of Int-3. LCMS (ESI, m / z): 289.27 [M+H] +

[1427] Step 3:

[1428]

[1429] The title compound was synthesized by the general procedure for the synthesis of Int-5: LCMS (ESI, m / z): 291.26

[1430] The absolute configurations of isomers 18a and 18e were assigned by X-ray crystallography. The absolute configurations of the remaining isomers were assigned arbitrarily.

[1431] Example 18a: (1S,2S)-4,4-difluoro-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol: LCMS (ESI, m / z): 291.26 [M+H] + ;( 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.61 - 7.55 (m, 2H), 7.39 (d, J = 1.1 Hz, 1H), 7.32 - 7.32 (m, 1H), 5.45 (s, 1H), 7.11 (s, 1H), 5.32 (d, J = 3.1 Hz, 1H), 4.29 (s, 1H), 2.38 - 2.31 (m, 1H), 2.15 - 1.95 (m, 1H), 1.94 - 1.78 (m, 2H), 1.77 - 1.67 (m, 1H), 1.65 - 1.46 (m, 1H), 1.15 - 1.03 (m, 1H)

[1432] Example 18b: (1R,2R)-4,4-difluoro-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol: LCMS (ESI, m / z): 291.26 [M+H] + ;( 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.27 (dd, J = 7.5, 1.4 Hz, 1H), 7.12 (s, 1H), 5.33 (d, J = 6.2 Hz, 1H), 5.09–5.05 (s, 1H), 4.07 (s, 1H), 2.22–1.96 (m, 3H), 1.91 - 1.79 (m, 3H), 1.65 - 1.54 (m, 1H)

[1433] Example 18c: 4,4-difluoro-2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol: LCMS (ESI, m / z): 291.26 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 1.0 Hz, 1H), 7.31 (dd, J = 7.6, 1.4 Hz, 1H), 7.15 (s, 1H), 5.72 (t, J = 3.2 Hz, 1H) 5.52 (s, 1H), 3.87 - 3.76 (m, 1H), 2.04 - 1.70 (m, 3H), 1.58 - 1.45 (m, 1H), 0.90 - 0.73 (m, 2H)

[1434] Example 18d: 4,4-Difluoro-2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol: LCMS (ESI, m / z): 291.26 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 1.0 Hz, 1H), 7.31 (dd, J = 7.6, 1.4 Hz, 1H), 7.15 (s, 1H), 5.72 (t, J = 3.2 Hz, 1H) 5.52 (s, 1H), 3.87 - 3.76 (m, 1H), 2.04 - 1.70 (m, 3H), 1.58 - 1.45 (m, 1H), 0.9 - 0.73 (m, 2H).

[1435] Example 18e: (1R,2R)-4,4-Difluoro-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol: LCMS (ESI, m / z): 291.26 [M+H] + ;( 1 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.61 - 7.55 (m, 2H), 7.39 (d, J = 1.1 Hz, 1H), 7.32 - 7.25 (m, 1H), 5.45 (s, 1H), 7.11 (s, 1H), 5.32 (d, J = 3.1 Hz, 1H), 4.29 (s, 1H), 2.38 - 2.31 (m, 1H), 2.15 - 1.95 (m, 1H), 1.94 - 1.78 (m, 2H), 1.77 - 1.67 (m, 1H), 1.65 - 1.46 (m, 1H), 1.15 - 1.03 (m, 1H)

[1436] Example 18f: (1S,2S)-4,4-difluoro-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol: LCMS (ESI, m / z): 291.26 [M+H] + ;( 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.27 (dd, J = 7.5, 1.4 Hz, 1H), 7.12 (s, 1H), 5.33 (d, J = 6.2 Hz, 1H), 5.09–5.05 (s, 1H), 4.07 (s, 1H), 2.22-1.96 (m, 3H), 1.91-1.79 (m, 3H), 1.65-1.54 (m, 1H)

[1437] Example 18g: 4,4-difluoro-2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol: LCMS (ESI, m / z): 291.26 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.35–7.29 (m, 1H), 7.18 (s, 1H), 5.74 (s, 1H), 5.55 (d, J = 5.8 Hz, 1H), 3.86 (dt, J = 10.8, 5.8 Hz, 1H), 2.34–2.22 (m, 1H), 2.08–1.77 (m, 2H), 1.48–1.61 (m, 1H), 0.99 (d, J = 5.4 Hz, 1H), 0.90–0.70 (m, 1H).

[1438] Example 18h: 4,4-difluoro-2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol: LCMS (ESI, m / z): 291.26 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.35–7.29 (m, 1H), 7.18 (s, 1H), 5.74 (s, 1H), 5.55 (d, J = 5.8 Hz, 1H), 3.86 (dt, J = 10.8, 5.8 Hz, 1H), 2.34–2.22 (m, 1H), 2.08–1.77 (m, 2H), 1.48–1.61 (m, 1H), 0.99 (d, J = 5.4 Hz, 1H), 0.90–0.70 (m, 1H).

[1439] Example 19: 2-(5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1440]

[1441] (1S,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1442] (1R,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1443] (1S,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1444] (1R,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1445] (1S,2S)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1446] (1R,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1447] Step 1:

[1448] (E)-2-(2-(1-Trityl-1H-imidazol-4-yl)methylene)-2,3-dihydro-1H-inden-1-one

[1449]

[1450] To a solution of 2-[1-(triphenylmethyl)-1H-imidazol-4-yl]benzaldehyde (2.0 g, 4.82 mmol) and 1-2,3-dihydro-1-indenone (1.28 g, 9.65 mmol) in anhydrous methanol (40 mL) was added piperidine (0.48 mL, 4.82 mmol) and the resulting mixture was stirred at 90 °C for 6 h. The product precipitated from the solution. The mixture was cooled in an ice bath and the precipitate was filtered and washed with cold methanol (15 mL) to afford crude (E)-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)-2,3-dihydro-1H-inden-1-one, which was a pale yellow solid. The product was used directly without further purification: LCMS (ESI, m / z): 529.3 [M+H] + .

[1451] Step 2:

[1452] 2-(5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-one

[1453]

[1454] To (E)-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)-2,3-dihydro-1H-inden-1-one (2.20 g, 4.16 mmol) was added MeOH (56 mL) and AcOH (14 mL). The resulting mixture was stirred at 90 °C for 2 h. The solvent was removed under reduced pressure. The reaction was quenched with 30 mL of saturated NaHCO3 solution (30 mL) and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine and water, and dried over anhydrous Na2SO4. The product was separated by CombiFlash to afford 2-(5H-imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-one, which was a pale yellow solid: LCMS (ESI, m / z): 287.3 [M+H] + .

[1455] Step 3:

[1456] (1S,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1457] (1R,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1458] (1S,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1459] (1R,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1460] (1S,2S)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1461] (1R,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol

[1462]

[1463] At 0 °C, NaBH4 (280 mg, 7.40 mmol) was added portionwise to a solution of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-one (1.06 g, 3.70 mmol) in MeOH (25 mL), and the solution was stirred at 0 °C for 2 h. The solvent was distilled off, and saturated ammonium chloride (20 mL) was added. The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic extracts were dried over (Na2SO4) and concentrated under reduced pressure to give the crude product. The crude product was purified by combi-flash and further separated by chiral resolution to give 6 isomers as white solids. The absolute configurations of all isomers were arbitrarily assigned.

[1464] Example 19a: (1S,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol: LCMS (ESI, m / z): 289.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 5.5 Hz, 1H), 7.25–7.21 (m, 1H), 7.20–7.14 (m, 2H), 7.12 (s, 2H), 5.70 (d, J = 4.9 Hz, 1H), 5.57 (d, J = 6.5 Hz, 1H), 5.09 (s, 1H), 2.95 (dd, J = 7.3, 4.9 Hz, 1H), 2.78 (dd, J = 15.9, 8.6 Hz, 1H).

[1465] Example 19b: (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol: LCMS (ESI, m / z): 289.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.29–7.25 (m, 1H), 7.25–7.20 (m, 1H), 7.19–7.15 (m, 2H), 7.11 (d, J = 6.1 Hz, 2H), 5.70 (d, J = 4.9 Hz, 1H), 5.57 (d, J = 6.5 Hz, 1H), 5.09 (t, J = 6.7 Hz, 1H), 2.95 (tdd, J = 8.6, 7.0, 5.0 Hz, 1H), 2.78 (dd, J = 15.9, 8.6 Hz, 1H), 2.48–2.39 (m, 1H).

[1466] Example 19c: (1S,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol: LCMS (ESI, m / z): 289.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.49–7.42 (m, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.26–7.18 (m, 4H), 7.16 (s, 1H), 5.77 (d, J = 6.2 Hz, 1H), 5.53 (d, J = 9.8 Hz, 1H), 5.17 (t, J = 6.0 Hz, 1H), 3.28–3.20 (m, 1H), 2.97 (dd, J = 15.5, 7.8 Hz, 1H), 2.40 (tdd, J = 9.5, 7.7, 5.9 Hz, 1H).

[1467] Example 19d: (1R,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol: LCMS (ESI, m / z): 289.3 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.51 (s, 1H), 7.46–7.37 (m, 2H), 7.32 (dd, J = 7.5, 1.4 Hz, 1H), 7.26–7.19 (m, 1H), 7.17 (dd, J = 7.4, 1.4 Hz, 1H), 7.07–7.01 (m, 2H), 6.04 (d, J = 5.1 Hz, 1H), 5.63 (d, J = 5.4 Hz, 1H), 5.39 (dd, J = 7.1, 5.2 Hz, 1H), 2.99 (dtd, J = 8.3, 6.6, 5.1 Hz, 1H), 2.73 (dd, J = 16.1, 8.4 Hz, 1H), 2.45 (dd, J = 16.0, 6.4 Hz, 1H).

[1468] Example 19e: (1S,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol: LCMS (ESI, m / z): 289.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 7.4 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.51 (s, 1H), 7.41 (q, J = 7.2 Hz, 2H), 7.35–7.28 (m, 1H), 7.25–7.19 (m, 1H), 7.16 (td, J = 7.3, 1.4 Hz, 1H), 7.06–7.00 (m, 2H), 6.04 (d, J = 5.1 Hz, 1H), 5.63 (d, J = 5.4 Hz, 1H), 5.39 (dd, J = 7.0, 5.2 Hz, 1H), 3.04–2.92 (m, 1H), 2.73 (dd, J = 16.1, 8.3 Hz, 1H), 2.45 (dd, J = 16.1, 6.5 Hz, 1H).

[1469] Example 19f: (1R,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol: LCMS (ESI, m / z): 289.3 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.47–7.41 (m, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.27–7.19 (m, 4H), 7.16 (s, 1H), 5.77 (d, J = 6.1 Hz, 1H), 5.53 (d, J = 10.0 Hz, 1H), 5.17 (t, J = 6.1 Hz, 1H), 3.29–3.22 (m, 1H), 2.97 (dd, J = 15.5, 7.7 Hz, 1H), 2.40 (tdd, J = 9.5, 7.9, 6.0 Hz, 1H).

[1470] Example 20: 2-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol

[1471]

[1472] The title compound was synthesized according to Examples 5 and 6

[1473]

[1474] The crude product was purified by prep-HPLC and further separated by SFC using the following conditions:

[1475] Condition 1: Column: CHIRALPAK AD-H-TC001 SFC, 20x250 mm, 5 μm; Mobile phase A: CO2:50, Mobile phase B: IPA (0.2% DEA):50; Flow rate: 40 mL / min; 220 nm;

[1476] Condition 2: Column: Chiralpak AD-H, 2x25 cm; Mobile phase A: CO2:60, Mobile phase B: IPA (0.2% DEA):40; Flow rate: 40 mL / min; 220 nm;

[1477] The absolute configurations of all isomers were arbitrarily assigned.

[1478] Example 20a: (1S,2R)-2-[(5R)-8-Fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclopentan-1-ol: LCMS (ESI, m / z): 259.2 [M+H] + ; 11H NMR (300 MHz, CD3OD) δ 8.11 (s, 1H), 7.45 (dd, J = 8.5, 4.8 Hz, 1H), 7.34 (dd, J = 8.6, 2.5 Hz, 1H), 7.21 (s, 1H), 7.01 - 6.95 (m, 1H), 5.46 (d, J = 4.4 Hz, 1H), 3.97 - 3.94 (m, 1H), 2.48 - 2.38 (m, 1H), 1.67 - 1.56 (m, 3H), 1.54 - 1.42 (m, 2H), 1.16 - 1.10 (m, 1H). tR = 1.11 min (Chiralpak AD-H, 4.6 x 100 mm, 5 um; IPA (0.1% DEA) = 35%; 4 mL / min). 20a and 20b are enantiomers.

[1479] Example 20b: (1S,2R)-2-[(5S)-8-fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclopentan-1-ol: LCMS (ESI, m / z): 259.2 [M+H] + ; tR = 2.17 min (Chiralpak AD-H, 4.6 x 100 mm, 5 um; IPA (0.1% DEA) = 35%; 4 mL / min). 20a and 20b are enantiomers.

[1480] Example 20c: (1R,2S)-2-[(5R)-8-fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclopentan-1-ol: LCMS (ESI, m / z): 259.2 [M+H] + ; 1 1H NMR (300 MHz, CD3OD) δ 7.83 (s, 1H), 7.37 (dd, J = 8.4, 4.8 Hz, 1H), 7.26 (dd, J = 8.7, 2.5 Hz, 1H), 7.12 (s, 1H), 6.98 - 6.91 (m, 1H), 5.45 - 5.44 (m, 1H), 4.16 (q, J = 7.0 Hz, 1H), 2.43 - 2.39 (m, 1H), 1.80 - 1.75 (m, 1H), 1.55 - 1.48 (m, 2H), 1.34 - 1.18 (m, 2H), 0.62 - 0.55 (m, 1H). tR = 1.002 min (Chiralpak AD-3, 3 x 100 mm, 3 um; MEOH (0.1% DEA) = 15%; 2 mL / min). 20c and 20d are enantiomers.

[1481] Example 20d: (1R,2S)-2-[(5S)-8-fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclopentan-1-ol. LCMS (ESI, m / z): 259.2 [M+H] + ; tR = 1.186 min (Chiralpak AD-3, 3x100 mm, 3 um; MeOH (0.1% DEA) = 15%; 2 mL / min). 20c and 20d are enantiomers.

[1482] Example 21: 4-(5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclobutan-1-ol

[1483]

[1484] (1R,4R)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclobutan-1-ol

[1485] (1R,4R)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclobutan-1-ol

[1486] (1R,4S)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclobutan-1-ol

[1487] (1R,4S)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclobutan-1-ol

[1488] (1S,4R)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclobutan-1-ol

[1489] (1S,4R)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclobutan-1-ol

[1490] (1S,4S)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclobutan-1-ol

[1491] (1S,4S)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclobutan-1-ol

[1492] Examples 21a-f were all synthesized using the reaction conditions of Preparation Examples 1a-h, where the reagent cyclobutanone was replaced with 2,2-dimethylcyclobutan-1-one. Each example is a single diastereomer with undetermined stereochemistry

[1493] Example 21a: 4-(5H-Imidazo[1,5-b]isoindol-5-yl)-2,2-dimethyl-cyclobutanol: LCMS (ESI, m / z): 255 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.68–7.52 (m, 2H), 7.36 (tdd, J = 7.5, 1.2, 0.6 Hz, 1H), 7.25 (td, J = 7.5, 1.2 Hz, 1H), 7.12 (s, 1H), 5.62 (d, J = 5.0 Hz, 1H), 5.42 (d, J = 9.2 Hz, 1H), 3.94 (ddd, J = 8.9, 4.8, 2.1 Hz, 1H), 2.06–1.92 (m, 1H), 1.70 (ddd, J = 10.7, 8.3, 3.4 Hz, 1H), 1.04 (d, J = 7.6 Hz, 6H).; tR = 1.61 min (Whelk0-1 s,s (250x30mm, 5um), methanol w / 0.1% NH4OH, 1.5 ml / min).

[1494] Example 21b: 4-(5H-Imidazo[1,5-b]isoindol-5-yl)-2,2-dimethyl-cyclobutanol: LCMS (ESI, m / z): 255 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.58 (ddt, J = 9.6, 7.5, 0.9 Hz, 2H), 7.36 (tdd, J = 7.5, 1.2, 0.6 Hz, 1H), 7.25 (td, J = 7.5, 1.2 Hz, 1H), 7.13 (s, 1H), 5.36 (d, J = 7.6 Hz, 1H), 5.14 (d, J = 6.9 Hz, 1H), 4.03–3.81 (m, 1H), 2.45–2.21 (m, 1H), 1.46 (dd, J = 10.7, 9.0 Hz, 1H), 1.19–1.05 (m, 1H), 1.01 (s, 3H), 0.95 (s, 3H).; tR = 0.54 min (Chiralpak AD (250x30mm, 5um), methanol w / 0.1% NH4OH, 1.5 ml / min).

[1495] Example 21c: 4-(5H-Imidazo[1,5-b]isoindol-5-yl)-2,2-dimethyl-cyclobutanol: LCMS (ESI, m / z): 255 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.58 (dd, J = 7.6, 1.2 Hz, 1H), 7.36 (t, J = 7.9 Hz, 2H), 7.23 (td, J = 7.5, 1.1 Hz, 1H), 7.09 (s, 1H), 5.34 (d, J = 8.9 Hz, 1H), 5.09 (d, J = 7.1 Hz, 1H), 3.85 (t, J = 7.6 Hz, 1H), 2.31–2.07 (m, 1H), 1.65 (td, J = 9.7, 9.3, 1.0 Hz, 1H), 1.52 (t, J = 10.3 Hz, 1H), 1.05 (s, 3H), 0.95 (s, 3H).; tR = 0.67 min (Chiralpak AD (250x30 mm, 5um), methanol w / 0.1% NH4OH, 1.5 ml / min).

[1496] Example 21d (enantiomer of Example 21b): 4-(5H-imidazo[1,5-b]isoindol-5-yl)-2,2-dimethyl-cyclobutanol: LCMS (ESI, m / z): 255 [M+H] + ; tR = 0.74 min (Cellulose-1 (250x30 mm, 5um), methanol w / 0.1% NH4OH, 1.5 ml / min).

[1497] Example 21e (enantiomer of Example 21a): 4-(5H-imidazo[1,5-b]isoindol-5-yl)-2,2-dimethyl-cyclobutanol: LCMS (ESI, m / z): 255 [M+H] + ; tR = 0.99 min (Whelk0-1 s,s (250x30 mm, 5um), methanol w / 0.1% NH4OH, 1.5 ml / min).

[1498] Example 21f (enantiomer of Example 21c): 4-(5H-imidazo[1,5-b]isoindol-5-yl)-2,2-dimethyl-cyclobutanol: LCMS (ESI, m / z): 255 [M+H] + ; tR = 2.19 min (Chiralpak AD (250x30 mm, 5um), methanol w / 0.1% NH4OH, 1.5 ml / min).

[1499] Example 22: 2-(5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1500]

[1501] (1S,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1502] (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1503] (1S,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1504] (1R,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1505] (1R,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1506] (1R,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1507] (1S,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1508] (1S,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1509] Step 1:

[1510] (E)-3,3-dimethyl-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclobutan-1-one

[1511]

[1512] To a solution of 2-[1-(triphenylmethyl)-1H-imidazol-4-yl]benzaldehyde (2.5 g, 6.03 mmol) and 3,3-dimethylcyclobutan-1-one (888 mg, 9.05 mmol) in MeOH (40 mL) was added dropwise piperidine (0.595 mL, 6.03 mmol). The solution was refluxed overnight. The mixture was cooled to room temperature and saturated NH4Cl solution (30 mL) was added to quench the reaction. The aqueous phase was extracted with DCM (3 x 20 mL) and the organic phases were combined, dried over anhydrous Na2SO4, and concentrated. The product was separated by CombiFlash to give (E)-3,3-dimethyl-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclobutan-1-one, which was a pale yellow solid: LCMS (ESI, m / z): 495.3 [M+H] + .

[1513] Step 2:

[1514] 2-(5H-Imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-one

[1515]

[1516] (E)-3,3-Dimethyl-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclobutan-1-one was stirred in a solution of 20% AcOH in MeOH (20 mL) at 90 °C for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure and saturated NaHCO3 (20 mL) was added to the residue, followed by DCM (20 mL). The organic layer was collected and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by CombiFlash to give 2-(5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-one, which was a pale yellow solid: LCMS (ESI, m / z): 253.3 [M+H] + .

[1517] Step 3:

[1518] (1S,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1519] (1R,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1520] (1S,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1521] (1R,2S)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1522] (1R,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1523] (1R,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1524] (1S,2S)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1525] (1S,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol

[1526]

[1527] At 0 °C, NaBH4 (467 mg, 12.37 mmol) was added portionwise to a solution of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-one (1.04 g, 4.12 mmol) in MeOH (10 mL), and the solution was stirred at 0 °C for 2 h. The solvent was distilled off, and saturated ammonium chloride solution (10 mL) was added. The aqueous layer was extracted with a solution of 5% trifluoroethanol in DCM (3 x 10 mL). The combined organic extracts were dried over (Na2SO4) and concentrated under reduced pressure to give the crude product. The crude product was purified by combi-flash and further separated by chiral resolution to give 6 isomers as white solids.

[1528] The absolute configurations of isomers 22a, 22b, 22c, and 22e were assigned by X-ray crystallography. The absolute configurations of the remaining isomers were arbitrarily assigned.

[1529] Example 22a: (1S,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol: LCMS (ESI, m / z): 255.3 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 0.7 Hz, 1H), 7.70 (dt, J = 7.6, 0.9 Hz, 1H), 7.59 (dt, J = 7.6, 0.9 Hz, 1H), 7.40–7.33 (m, 1H), 7.29–7.22 (m, 1H), 7.14 (s, 1H), 5.58 (d, J = 3.2 Hz, 1H), 5.48 (d, J = 8.7 Hz, 1H), 4.45 (dq, J = 6.5, 3.1 Hz, 1H), 2.28–2.17 (m, 1H), 1.99–1.89 (m, 1H), 1.71–1.64 (m, 1H), 1.18 (s, 3H), 1.04 (s, 3H).

[1530] Example 22b: (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol: LCMS (ESI, m / z): 255.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 0.8 Hz, 1H), 7.62–7.55 (m, 2H), 7.40–7.33 (m, 1H), 7.25 (dd, J = 7.6, 1.1 Hz, 1H), 7.14 (s, 1H), 5.47–5.39 (m, 1H), 5.11 (d, J = 7.5 Hz, 1H), 4.45–4.32 (m, 1H), 2.11 (t, J = 8.1 Hz, 1H), 1.99 (dd, J = 10.4, 7.8 Hz, 1H), 1.53 (dd, J = 10.5, 8.1 Hz, 1H), 0.95 (s, 3H), 0.84 (s, 3H).

[1531] Example 22c: (1S,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol: LCMS (ESI, m / z): 255.3 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 7.87 (t, J = 0.6 Hz, 1H), 7.61–7.54 (m, 2H), 7.40–7.32 (m, 1H), 7.23 (td, J = 7.6, 1.1 Hz, 1H), 7.14 (s, 1H), 5.42 (d, J = 8.0 Hz, 1H), 5.11 (d, J = 7.4 Hz, 1H), 4.39 (p, J = 7.9 Hz, 1H), 2.11 (t, J = 8.1 Hz, 1H), 2.03–1.94 (m, 1H), 1.53 (dd, J = 10.4, 8.1 Hz, 1H), 0.94 (s, 3H), 0.84 (s, 3H).

[1532] Example 22d: (1R,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol: LCMS (ESI, m / z): 255.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.26 (td, J = 7.6, 1.2 Hz, 1H), 7.09 (s, 1H), 5.43 (d, J = 9.9 Hz, 1H), 5.08 (d, J = 7.9 Hz, 1H), 4.44 (p, J = 7.9 Hz, 1H), 2.07 (dd, J = 10.5, 7.7 Hz, 1H), 1.91 (dd, J = 9.9, 7.9 Hz, 1H), 1.53 (dd, J = 10.5, 8.2 Hz, 1H), 1.19 (s, 3H), 1.10 (s, 3H).

[1533] Example 22e: (1R,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol: LCMS (ESI, m / z): 255.3 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 7.96 (t, J = 0.6 Hz, 1H), 7.73–7.66 (m, 1H), 7.59 (dt, J = 7.5, 0.9 Hz, 1H), 7.40–7.31 (m, 1H), 7.25 (td, J = 7.6, 1.2 Hz, 1H), 7.14 (s, 1H), 5.59 (d, J = 3.2 Hz, 1H), 5.48 (d, J = 8.7 Hz, 1H), 4.44 (tt, J = 6.3, 2.9 Hz, 1H), 2.26–2.15 (m, 1H), 1.94 (ddd, J = 11.6, 5.9, 1.0 Hz, 1H), 1.67 (ddd, J = 11.9, 2.7, 0.8 Hz, 1H), 1.18 (s, 3H), 1.04 (s, 3H).

[1534] Example 22f: (1R,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol: LCMS (ESI, m / z): 255.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 0.7 Hz, 1H), 7.61 (dt, J = 7.6, 1.0 Hz, 1H), 7.53–7.47 (m, 1H), 7.42–7.36 (m, 1H), 7.27 (td, J = 7.6, 1.2 Hz, 1H), 7.12 (s, 1H), 5.62 (d, J = 3.2 Hz, 1H), 5.47 (d, J = 11.2 Hz, 1H), 4.33 (td, J = 5.8, 2.8 Hz, 1H), 1.99–1.89 (m, 2H), 1.68 (dt, J = 12.0, 0.9 Hz, 1H), 1.61 (s, 3H), 1.08 (s, 3H).

[1535] Example 22g: (1S,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol: LCMS (ESI, m / z): 255.3 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 7.89 (t, J = 0.7 Hz, 1H), 7.61 (dt, J = 7.6, 0.9 Hz, 1H), 7.52–7.46 (m, 1H), 7.42–7.35 (m, 1H), 7.28 (td, J = 7.6, 1.2 Hz, 1H), 7.12 (s, 1H), 5.62 (d, J = 3.0 Hz, 1H), 5.47 (d, J = 11.2 Hz, 1H), 4.36–4.30 (m, 1H), 2.00–1.87 (m, 2H), 1.74–1.64 (m, 1H), 1.61 (s, 3H), 1.08 (s, 3H).

[1536] Example 22h: (1S,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol: LCMS (ESI, m / z): 255.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.63–7.56 (m, 1H), 7.45 (dd, J = 7.6, 0.9 Hz, 1H), 7.37 (dd, J = 7.9, 7.1 Hz, 1H), 7.27 (dd, J = 7.6, 1.2 Hz, 1H), 7.09 (s, 1H), 5.43 (d, J = 10.0 Hz, 1H), 5.08 (d, J = 7.9 Hz, 1H), 4.44 (p, J = 7.9 Hz, 1H), 2.11–2.02 (m, 1H), 1.91 (dd, J = 9.9, 8.0 Hz, 1H), 1.53 (dd, J = 10.5, 8.2 Hz, 1H), 1.19 (s, 3H), 1.09 (s, 3H).

[1537] Example 23: 5-(5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1538]

[1539] (1R,5S)-5-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1540] (1R,5S)-5-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1541] (1R,5R)-5-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1542] (1S,5R)-5-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1543] (1S,5S)-5-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1544] (1S,5R)-5-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1545] Step 1:

[1546] (E)-2,2-Dimethyl-5-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclopentan-1-one

[1547]

[1548] 10% aqueous sodium hydroxide (1.93 mL, 4.82 mmol) was added to a stirred mixture of 2,2-dimethylcyclopentan-1-one (281 mg, 2.51 mmol) and 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (800 mg, 1.93 mmol) in MeOH (15 mL). The reaction mixture was heated at 65 °C for 6 h until TLC showed disappearance of the SM. The reaction mixture was diluted with DCM (30 mL) and the organics were washed with water, dried over Na2SO4, filtered and concentrated. The crude material was carried directly to the next step: LCMS (ESI, m / z): 509.4 [M+H] +

[1549] Step 2:

[1550] 5-(5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-one

[1551]

[1552] The title compound was synthesized by the general procedure for the synthesis of Int-3: LCMS (ESI, m / z): 267.4

[1553] Step 3:

[1554] (1R,5S)-5-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1555] (1R,5S)-5-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1556] (1R,5R)-5-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1557] (1S,5R)-5-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1558] (1S,5S)-5-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1559] (1S,5R)-5-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol

[1560]

[1561] The title compound was synthesized by the general procedure for the synthesis of Int-5. The product was isolated as a mixture of 8 diastereoisomers, which was purified by chiral SFC.

[1562] The absolute configuration of all isomers was arbitrarily assigned.

[1563] Example 23a: (1R,5S)-5-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol: LCMS (ESI, m / z): 269.2 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.26 (td, J = 7.6, 1.2 Hz, 1H), 7.10 (s, 1H), 5.43 (d, J = 4.4 Hz, 1H), 4.89–4.83 (m, 1H), 3.56 (d, J = 9.6 Hz, 1H), 2.64 (m, 1H), 1.39–1.20 (m, 3H), 1.14–1.00 (m, 1H), 0.90 (s, 3H), 0.84 (s, 3H).

[1564] Example 23b: (1R,5S)-5-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol: LCMS (ESI, m / z): 269.2 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.40–7.32 (m, 1H), 7.27–7.19 (m, 1H), 7.11 (s, 1H), 5.25 (dd, J = 15.3, 7.6 Hz, 2H), 3.61 (dd, J = 8.5, 1.1 Hz, 1H), 2.07 (dd, J = 13.3, 4.4 Hz, 2H), 2.00–1.87 (m, 1H), 1.83–1.70 (m, 1H), 1.45–1.34 (m, 1H), 1.06 (s, 3H), 0.79 (s, 3H).

[1565] Example 23c: (1R,5R)-5-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol: LCMS (ESI, m / z): 269.2 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.67 (dd, J = 7.6, 0.8 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.26 (td, J = 7.6, 1.2 Hz, 1H), 7.11 (s, 1H), 5.37 (d, J = 7.6 Hz, 1H), 5.28 (d, J = 5.2 Hz, 1H), 3.72 (t, J = 5.1 Hz, 1H), 2.41–2.28 (m, 1H), 1.80–1.55 (m, 3H), 1.35–1.26 (m, 1H), 1.02 (s, 3H), 0.82 (s, 3H).

[1566] Example 23d: (1S,5R)-5-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol: LCMS (ESI, m / z): 269.2 [M+H] + ; 1 The enantiomer of Example 23a.

[1567] Example 23e: (1S,5S)-5-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol: LCMS (ESI, m / z): 269.2 [M+H] + ; 1 HNMR is the enantiomer of Example 23c.

[1568] Example 23f: (1S,5R)-5-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol: LCMS (ESI, m / z): 269.2 [M+H] + ; 1 HNMR is the enantiomer of Example 23b.

[1569] Example 24: 6-(5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1570]

[1571] (1R,6S)-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1572] (1S,6S)-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1573] (1R,6R)-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1574] (1S,6R)-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1575] (1R,6S)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1576] (1S,6S)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1577] (1R,6R)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1578] (1S,6R)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1579] Step 1:

[1580] (E)-2,2-Dimethyl-6-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclohexan-1-one

[1581]

[1582] The title compound was synthesized by the general procedure for the synthesis of Int-2: LCMS (ESI, m / z): 533.2 [M+H] +

[1583] Step 2:

[1584] 6-(5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-one

[1585]

[1586] The title compound was synthesized by the general procedure for the synthesis of Int-3.

[1587] The two diastereoisomers were not separated and used as a mixture in Step 3: LCMS (ESI, m / z): 281.2

[1588] Step 3:

[1589] (1R,6S)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1590] (1S,6S)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1591] (1R,6R)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1592] (1S,6R)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1593] (1R,6S)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1594] (1S,6S)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1595] (1R,6R)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1596] (1S,6R)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol

[1597]

[1598] The title compound was synthesized by the general procedure for the synthesis of Int-5. The product was isolated as a mixture of 8 enantiomers, which were separated by chiral SFC: LCMS (ESI, m / z): 283.2, for all isomers.

[1599] The absolute configuration of all isomers was arbitrarily assigned.

[1600] Example 24a: (1R,6S)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol: LCMS (ESI, m / z): 281.2 [M+H] + ; 1 1H NMR was the same as that of Example 24h.

[1601] Example 24b: (1S,6S)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol: LCMS (ESI, m / z): 281.2 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 7.93 (t, J = 0.6 Hz, 1H), 7.64–7.55 (m, 2H), 7.41–7.32 (m, 1H), 7.23 (td, J = 7.6, 1.2 Hz, 1H), 7.10 (d, J = 0.5 Hz, 1H), 5.15 (d, J = 7.3 Hz, 1H), 4.83 (d, J = 5.8 Hz, 1H), 3.42–3.38 (m, 1H), 1.84–1.72 (m, 1H), 1.66–1.46 (m, 4H), 1.37 (dtd, J = 13.7, 10.0, 8.8, 3.5 Hz, 1H), 1.08–1.00 (m, 1H), 0.91 (s, 3H), 0.76 (s, 3H).

[1602] Example 24c: (1R,6R)-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol: LCMS (ESI, m / z): 281.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.58 (dt, J = 7.5, 1.0 Hz, 1H), 7.47 (dq, J = 7.5, 0.9 Hz, 1H), 7.36 (tdd, J = 7.5, 1.2, 0.6 Hz, 1H), 7.28 (td, J = 7.5, 1.2 Hz, 1H), 7.13 (s, 1H), 5.68 (d, J = 2.4 Hz, 1H), 5.18 (d, J = 6.5 Hz, 1H), 2.23–2.11 (m, 1H), 1.33 (dd, J = 13.0, 2.6 Hz, 1H), 1.26–1.12 (m, 2H), 1.09–1.03 (m, 1H), 1.02 (s, 3H), 0.92 (s, 3H), 0.68 (d, J = 13.2 Hz, 1H), 0.21–0.05 (m, 1H).

[1603] Example 24d: (1S,6R)-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol: LCMS (ESI, m / z): 281.2 [M+H] + ; 1 H NMR is the same as that of Example 24e.

[1604] Example 24e: (1R,6S)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol: LCMS (ESI, m / z): 281.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.58 (ddt, J = 12.8, 8.3, 0.8 Hz, 2H), 7.42–7.32 (m, 1H), 7.27 (td, J = 7.5, 1.2 Hz, 1H), 7.10 (s, 1H), 5.69 (d, J = 3.9 Hz, 1H), 5.12 (d, J = 6.3 Hz, 1H), 2.40–2.27 (m, 1H), 1.31 (dd, J = 13.0, 2.5 Hz, 1H), 1.20–1.13 (m, 2H), 0.98 (s, 3H), 0.92 (s, 3H), 0.52 (d, J = 13.1 Hz, 1H), 0.23–0.04 (m, 1H).

[1605] Example 24f: (1S,6S)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol: LCMS (ESI, m / z): 281.2 [M+H] + ; 1 1H NMR is the same as that of Example 24c.

[1606] Example 24g: (1R,6R)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol: LCMS (ESI, m / z): 281.2 [M+H] + ; 1 1H NMR is the same as that of Example 24b.

[1607] Example 24h: (1S,6R)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol: LCMS (ESI, m / z): 281.2 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 7.97 (t, J = 0.7 Hz, 1H), 7.56 (dt, J = 3.0, 0.8 Hz, 1H), 7.55–7.52 (m, 1H), 7.41–7.31 (m, 1H), 7.26 (td, J = 7.6, 1.2 Hz, 1H), 7.08 (s, 1H), 5.19 (d, J = 3.1 Hz, 1H), 5.06 (dd, J = 6.0, 0.7 Hz, 1H), 3.63–3.55 (m, 1H), 2.23–2.14 (m, 1H), 1.48 (td, J = 13.2, 4.3 Hz, 1H), 1.40–1.19 (m, 2H), 1.18–0.99 (m, 2H), 0.94 (s, 3H), 0.91 (s, 3H), 0.77 (dd, J = 12.3, 3.4 Hz, 1H).

[1608] Example 25: 2-(8-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

[1609]

[1610] The title compound was synthesized by the same method as in Examples 5 and 6

[1611]

[1612] The crude product was purified by prep-HPLC and further separated by chiral separation using the following conditions:

[1613] 1. Column, Chiralpak ID, 2.0 cm I.D x 25 cm; Mobile phase: Hex:IPA = 10:10; Detector, uv254 nm; Flow rate, 20 mL / min.

[1614] 2. Column, Chiralpak IC, 2 x 25 cm, 5 um; Mobile phase: Hex(0.1% DEA):IPA = 30:30; Detector, uv254 nm; Flow rate, 20 mL / min.

[1615] The absolute configurations of all isomers are arbitrarily assigned.

[1616] Example 25a: (1R,2S)-2-[(5S)-8-fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclohexan-1-ol: LCMS(ESI, m / z): 273.2 [M+H] + ; 1 1H NMR(300 MHz, CD3OD) 1 1H NMR(300 MHz, CD3OD) δ 7.90(s, 1H), 7.58 - 7.52(m, 1H), 7.43 - 7.38(m, 1H), 7.20(s, 1H), 7.09 - 7.02(m, 1H), 5.80(d, J = 3.0 Hz, 1H), 3.78 - 3.72(m, 1H), 2.26–2.03(m, 2H), 1.81–1.67(m, 1H), 1.39 - 1.31(m, 2H), 1.14 - 1.00(m, 2H), 0.75 - 0.60(m, 1H), 0.39 - 0.24(m, 1H); tR = 1.044 min (Chiralpak IC-3, 0.46 x 5 cm, 3 um; Hex(0.1% DEA):IPA = 70:30; 1.5 ml / min). 25a and 25b are enantiomers.

[1617] Example 25b: (1S,2R)-2-[(5S)-8-fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclohexan-1-ol: LCMS(ESI, m / z): 273.2 [M+H] + ; tR = 1.438 min (Chiralpak IC-3, 0.46 x 5 cm, 3 um; Hex(0.1% DEA):IPA = 70:30; 1.5 ml / min). 25a and 25b are enantiomers.

[1618] Example 25c: (1S,2R)-2-[(5R)-8-fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclohexan-1-ol: LCMS (ESI, m / z): 273.2 [M+H] + ; 1 HNMR (300 MHz, CD3OD) δ 7.90 (s, 1H), 7.50 - 7.34 (m, 2H), 7.22 (s, 1H), 7.07 - 7.04 (m, 1H), 5.80 (d, J = 3.0 Hz, 1H), 3.75 - 3.72 (m, 1H), 2.22 - 1.96 (m, 2H), 1.84 - 1.67 (m, 1H), 1.45 - 1.39 (m 2H), 1.34 - 1.02 (m, 2H), 0.96 - 0.83 (m, 1H), 0.45 - 0.23 (m, 1H). tR = 3.432 min (Chiralpak ID-3, 0.46x10 cm, 3um; Hex(0.1% DEA):IPA = 90:10; 1 mL / min). 25c and 25d are enantiomers.

[1619] Example 25d: (1R,2S)-2-[(5R)-8-fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclohexan-1-ol: LCMS (ESI, m / z): 273.2 [M+H] + ; tR = 4.010 min (Chiralpak ID-3, 0.46x10 cm, 3um; Hex(0.1% DEA):IPA = 90:10; 1 mL / min). 25c and 25d are enantiomers.

[1620] Example 26: 4-(5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol

[1621]

[1622] (3R,4S)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol

[1623] (3S,4R)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol

[1624] (3R,4S)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol

[1625] (3S,4R)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol

[1626] (3R,4S)-4-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol

[1627] (3S,4R)-4-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol

[1628] (3R,4S)-4-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol

[1629] (3S,4R)-4-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol

[1630]

[1631] (2.5 M in hexanes; 1.13 mL, 2.83 mmol) of n-butyllithium was added dropwise to a solution of 5H-imidazo[5,1-a]isoindole (442 mg, 2.83 mmol) in 6 mL of THF which had been cooled to -78 °C, and the mixture was stirred for 45 minutes. A solution of 3,4-epoxytetrahydrofuran (292 mg, 3.40 mmol) in THF (3 mL) was added slowly, followed by boron trifluoride etherate (0.42 mL, 3.40 mmol). The reaction solution was warmed to 0 °C and stirred for an additional 5 hours. It was then hydrolyzed with saturated ammonium chloride solution and the aqueous phase was extracted twice with DCM (30 mL). After drying, the solvent was removed under reduced pressure and the crude product was purified by Combi-rapid chromatography. The product was obtained as a mixture of four diastereomers (501 mg, 73%). The pure stereoisomers were obtained after purification by chiral SFC. The absolute configuration of all isomers was arbitrarily assigned.

[1632] Example 26a: (3R,4S)-4-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol: LCMS (ESI, m / z): 243.2 [M+H] + ; 1HNMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.54 (dd, J = 7.6, 0.9 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.27 (td, J = 7.6, 1.2 Hz, 1H), 7.14 (s, 1H), 5.58 (d, J = 4.1 Hz, 1H), 5.26 (d, J = 4.6 Hz, 1H), 4.31 (dt, J = 8.5, 4.2 Hz, 1H), 3.73–3.67 (m, 1H), 3.58 (dd, J = 9.2, 5.7 Hz, 1H), 3.43 (dd, J = 9.6, 3.6 Hz, 1H), 3.14 (dd, J = 9.1, 6.5 Hz, 1H), 2.86–2.79 (m, 1H).

[1633] Example 26b: (3S,4R)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol: LCMS (ESI, m / z): 243.2 [M+H] + ; 1 HNMR of the enantiomer of Example 26a.

[1634] Example 26c: (3R,4S)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol: LCMS (ESI, m / z): 243.2 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.52 (dd, J = 7.6, 0.8 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.28 (td, J = 7.6, 1.2 Hz, 1H), 7.12 (s, 1H), 5.50 (d, J = 4.6 Hz, 1H), 5.00 (d, J = 4.7 Hz, 1H), 4.02 (dd, J = 9.2, 7.8 Hz, 1H), 3.85–3.78 (m, 2H), 3.38 (d, J = 4.4 Hz, 2H), 2.81–2.72 (m, 1H).

[1635] Example 26d: (3S,4R)-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol: LCMS (ESI, m / z): 243.2 [M+H] + ; 1 HNMR of the enantiomer of Example 26c.

[1636] Examples 14 and 27: 2-(3-Hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1637]

[1638] 2-((3S,4R)-4-Hydroxy-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1639] 2-((3R,4S)-4-Hydroxy-3-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1640] 2-((3R,4S)-4-Hydroxy-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1641] 2-((3S,4R)-4-Hydroxy-3-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1642] 2-((3S,4S)-3-Hydroxy-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1643] 2-((3R,4R)-3-Hydroxy-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1644] 2-((3R,4R)-3-Hydroxy-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1645] 2-((3S,4S)-3-Hydroxy-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1646] Example 14: 2-(4-Hydroxy-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1647] Synthetic Route IIB

[1648]

[1649] Step 1: tert-Butyl 3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate and tert-butyl 4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate

[1650]

[1651] To a solution of 5H-imidazo[4,3-a]isoindole (3.0 g, 19.21 mmol) and tetrahydrofuran (40 mL) at -60 °C was added dropwise n-butyllithium (10 mL in hexane, 2.5 mol / L, 25 mmol). The resulting solution was stirred at -40 °C for 1 hour. A solution of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (4.8 g, 24.09 mmol) in tetrahydrofuran (10 mL) was added dropwise at -40 °C. The reaction was slowly warmed to room temperature and then stirred for an additional 1.5 h. The reaction was then quenched with saturated ammonium chloride (50 mL), extracted with ethyl acetate (3 x 100 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with dichloromethane / methanol (10 / 1) to give a mixture (2.5 g, 37%).

[1652] Step 2: 3-[5H-Imidazo[4,3-a]isoindol-5-yl]piperidin-4-ol and 4-[5H-imidazo[4,3-a]isoindol-5-yl]piperidin-3-ol

[1653]

[1654] To a solution of a mixture of tert-butyl 3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate and tert-butyl 4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate (2.5 g, 9.80 mmol) in dichloromethane (30 mL) was added TFA (10 mL). The solution was stirred at room temperature for 2 h. The solution was concentrated in vacuo to give a mixture of 3-[5H-imidazo[4,3-a]isoindol-5-yl]piperidin-4-ol and 4-[5H-imidazo[4,3-a]isoindol-5-yl]piperidin-3-ol as a brown oil (2.8 g, crude): LCMS (ESI, m / z): 256.0 [M+H] + ;

[1655] Step 3 :

[1656] 2-((3S,4S)-3-Hydroxy-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1657] 2-((3R,4R)-3-Hydroxy-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1658] 2-((3R,4R)-3-Hydroxy-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1659] 2-((3S,4S)-3-Hydroxy-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1660] 2-((3S,4R)-4-Hydroxy-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1661] 2-((3R,4S)-4-Hydroxy-3-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1662] 2-((3R,4S)-4-Hydroxy-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1663] 2-((3S,4R)-4-Hydroxy-3-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile

[1664]

[1665] To a solution of a mixture of 3-[5H-imidazo[4,3-a]isoindol-5-yl]piperidin-4-ol and 4-[5H-imidazo[4,3-a]isoindol-5-yl]piperidin-3-ol (2.8 g, crude) in dichloromethane (50 mL) was added triethylamine (50 mL) and 2-chloroacetonitrile (1.4 mL, 22.06 mmol). The resulting solution was stirred at room temperature for 6 h. The resulting solution was diluted with water (50 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude product (3.0 g, crude), which was a light brown solid. The crude product was purified by prep-HPLC and further separated by chiral separation using the following conditions:

[1666] 1. CHIRALCEL OD-H, 20 x 250 mm; Mobile phase A: Hex--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 10B to 10B in 24 min;

[1667] 2. CHIRALPAK-AD-H-SL002, 20 x 250 mm; Mobile phase A: Hex(0.1% DEA)--HPLC, Mobile phase B: IPA--HPLC; Flow rate: 20 mL / min; Gradient: 30B to 30B in 15 min; 254 / 220 nm;

[1668] The absolute configurations of all isomers are arbitrarily assigned.

[1669] Example 27a: 2-((3S,4S)-3-Hydroxy-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile (20.8 mg, 1%), which is an off-white solid: LCMS (ESI, m / z): 295.1 [M+H] + ; 1 1H NMR (300 MHz, CD3OD) δ 7.92 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.36 - 7.31 (m, 1H), 7.18 (s, 1H), 5.81 (d, J = 3.0 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.64 (s, 2H), 3.13 - 3.08 (m, 1H), 2.65 - 2.61 (m, 1H), 2.31 - 2.12 (m, 3H), 0.82 - 0.70 (m, 2H). tR = 3.169 min, (Chiralpak IC-3, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 30:70; 1.0 mL / min). 27a and 27b are enantiomers.

[1670] Example 27b: 2-((3R,4R)-3-Hydroxy-4-((R)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile (29.8 mg, 1%), which is an off-white solid: LCMS (ESI, m / z): 295.1 [M+H] + ; tR = 5.009 min, (Chiralpak IC-3, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 30:70; 1.0 mL / min). 27a and 27b are enantiomers.

[1671] Example 27c: 2-((3R,4R)-3-Hydroxy-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile (75.3 mg, 1%), which is a white solid: LCMS (ESI): 348.2 [M+H] + ; 1HNMR (300 MHz, CD3OD) δ 7.90 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.48 - 7.34 (m, 2H), 7.20 (s, 1H), 5.81 (d, J = 3.6 Hz, 1H), 4.00 - 3.91 (m, 1H), 3.65 (s, 2H), 3.19 - 3.14 (m, 1H), 2.63 - 2.60 (m, 1H), 2.31 - 2.03 (m, 3H), 0.94 - 0.89 (m, 1H), 0.72 - 0.58 (m, 1H); tR = 1.519 min, (Chiralpak AD - 3, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 30:70; 1.0 mL / min). 27c and 27d are enantiomers.

[1672] Example 27d: 2 - ((3S,4S) - 3 - hydroxy - 4 - ((R) - 5H - imidazo[5,1 - a]isoindol - 5 - yl)piperidin - 1 - yl)acetonitrile (94.8 mg, 1%), is a white solid: LCMS (ESI): 348.2 [M + H] + ; tR = 2.357 min, (Chiralpak AD - 3, 0.46 x 5 cm, 3 um; ethanol:hexane (0.1% DEA) = 30:70; 1.0 mL / min). 27c and 27d are enantiomers.

[1673] The absolute configurations of all isomers 14a - d are arbitrarily assigned.

[1674] Example 14a: 2 - ((3S,4R) - 4 - hydroxy - 3 - ((S) - 5H - imidazo[5,1 - a]isoindol - 5 - yl)piperidin - 1 - yl)acetonitrile (249.8 mg, 1%): LCMS (ESI, m / z): 295.2 [M + H] + ; 1HNMR (300 MHz, CD3OD) δ 7.93 (s, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.48 - 7.34 (m, 2H), 7.22 (s, 1H), 5.82 (d, J = 3.0 Hz, 1H), 3.95 - 3.83 (m, 1H), 3.52 - 3.33 (m, 2H), 2.92 - 2.83 (m, 1H), 2.47 - 2.05 (m, 4H), 1.85 - 1.73 (m, 1H), 1.48 - 1.41 (m, 1H); tR = 1.156 min, (Chiralpak AD - 3, 0.46x5 cm, 3 um; isopropanol:hexane (0.1% DEA) = 30:70; 1.0 mL / min). Example 14a and Example 14b are enantiomers.

[1675] Example 14b: 2 - ((3R,4S)-4 - hydroxy - 3 - ((R)-5H - imidazo[5,1 - a]isoindol - 5 - yl)piperidin - 1 - yl)acetonitrile (241.0 mg, 1%), which is an off - white solid. LCMS (ESI, m / z): 295.2 [M + H] + ; tR = 2.086 min, (Chiralpak AD - 3, 0.46x5 cm, 3 um; isopropanol:hexane (0.1% DEA) = 30:70; 1.0 mL / min). Example 14a and Example 14b are enantiomers.

[1676] Example 14c: 2 - ((3R,4S)-4 - hydroxy - 3 - ((S)-5H - imidazo[5,1 - a]isoindol - 5 - yl)piperidin - 1 - yl)acetonitrile (61.9 mg, 1%), which is an off - white solid: LCMS (ESI, m / z): 295.1 [M + H] + . 1HNMR (400 MHz, CD3OD) δ 7.89 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.45 - 7.34 (m, 2H), 7.20 (s, 1H), 5.82 (d, J = 4.0 Hz, 1H), 4.37 - 4.33 (m, 1H), 3.86 - 3.71 (m, 2H), 2.62 - 2.50 (m, 2H), 2.27 - 2.20 (m, 1H), 1.43 (s, 9H), 0.87 - 0.83 (m, 1H), 0.47 - 0.42 (m, 1H); tR = 4.384 min (Chiralpak AD - 3, 0.46 x 5 cm, 3 um; isopropanol:hexane (0.1% DEA) = 30:70; 1.0 mL / min). Example 14c and Example 14d are enantiomers.

[1677] Example 14d: 2 - ((3S,4R) - 4 - hydroxy - 3 - ((R) - 5H - imidazo[5,1 - a]isoindol - 5 - yl)piperidin - 1 - yl)acetonitrile (52.4 mg, 1%), which is an off - white solid: LCMS (ESI, m / z): 295.1 [M + H] + ; tR = 6.297 min. (Chiralpak AD - 3, 0.46 x 5 cm, 3 um; isopropanol:hexane (0.1% DEA) = 30:70; 1.0 mL / min). Example 14c and Example 14d are enantiomers.

[1678] Example 28: 3-Hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)pyrrolidine-1-sulfonamide

[1679]

[1680] Step 1: 4 - (5H - imidazo[5,1 - a]isoindol - 5 - yl)pyrrolidin - 3 - ol

[1681]

[1682] To a solution of tert - butyl 3 - hydroxy - 4 - [5H - imidazo[4,3 - a]isoindol - 5 - yl]pyrrolidine - 1 - carboxylate (2 g, 5.86 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (5 mL, 67.32 mmol). The resulting solution was stirred at 25 °C for 1 h and then concentrated in vacuo to give 4 - (5H - imidazo[5,1 - a]isoindol - 5 - yl)pyrrolidin - 3 - ol (3.4 g, crude), which is a yellow oil: LCMS (ESI, m / z): 242.2 [M + H] +

[1683] Step 2:tert-Butyl N-(3-hydroxy-4-[5H-imidazo[4,3-a]isoindol-5-yl]pyrrolidine-1-sulfonyl)carbamate

[1684]

[1685] To a solution of 4-[5H-imidazo[4,3-a]isoindol-5-yl]pyrrolidin-3-ol (1.8 g, 7.46 mmol) in dichloromethane (120 mL) was added TEA (2.2 g, 21.74 mmol), 2-methylpropan-2-ol (2.8 g, 37.776 mmol) and [(chlorosulfonyl)imino]methanone (1.6 g, 11.31 mmol). The resulting solution was stirred at 25 °C for 40 minutes. The resulting mixture was concentrated in vacuo. The residue was purified on a silica gel column using dichloromethane / methanol (15 / 1) to afford tert-butyl N-(3-hydroxy-4-[5H-imidazo[4,3-a]isoindol-5-yl]pyrrolidine-1-sulfonyl)carbamate (1.45 g, 46%) as a yellow oil: LCMS (ESI, m / z): 421.1 [M+H] +

[1686] Step 3:

[1687] (3R,4R)-3-Hydroxy-4-[(5R)-5H-imidazo[4,3-a]isoindol-5-yl]pyrrolidine-1-sulfonamide

[1688] (3R,4R)-3-Hydroxy-4-[(5S)-5H-imidazo[4,3-a]isoindol-5-yl]pyrrolidine-1-sulfonamide

[1689] (3S,4S)-3-Hydroxy-4-[(5R)-5H-imidazo[4,3-a]isoindol-5-yl]pyrrolidine-1-sulfonamide

[1690] (3S,4S)-3-Hydroxy-4-[(5S)-5H-imidazo[4,3-a]isoindol-5-yl]pyrrolidine-1-sulfonamide

[1691]

[1692] To a solution of tert-butyl N-(3-hydroxy-4-[5H-imidazo[4,3-a]isoindol-5-yl]pyrrolidine-1-sulfonyl)carbamate (400 mg, 0.951 mmol) in 1,4-dioxane (6 mL) was added hydrogen chloride (2 mL, 65.82 mmol). The resulting solution was stirred at 25 °C for 1.5 h and then concentrated in vacuo. The crude product was purified by prep-HPLC to give two products. These two products were separated by chiral resolution using the following conditions:

[1693] 1. Column, Chiralpak IC, 2 x 25 cm, 5 µm; mobile phase: ethanol:hexane = 40:40; detector, uv 254 / 220 nm; flow rate, 20 mL / min

[1694] 2. Column, Chiralpak IC, 2 x 25 cm, 5 µm; mobile phase: hexane:ethanol:methanol = 50:25:25; detector, uv 254 / 220 nm; flow rate, 20 mL / min

[1695] The absolute configuration of all isomers was arbitrarily assigned.

[1696] Example 28a: (3R,4R)-3-hydroxy-4-[(5R)-5H-imidazo[4,3-a]isoindol-5-yl]pyrrolidine-1-sulfonamide (32.1 mg, 11%): LCMS (ESI, m / z): 321 [M+H] + ; 1 HNMR (300 MHz, DMSO) δ 7.98 (s, 1H), 7.62 (d, J = 3.7 Hz, 1H), 7.57 (d, J = 3.7 Hz, 1H), 7.41 (t, J = 3.6 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.19 (s, 1H), 6.72 (s, 2H), 5.68 (d, J = 2.5 Hz, 1H), 5.60 (d, J = 0.6 Hz, 1H), 4.48 - 4.35 (m, 1H), 3.32 - 3.27 (m, 1H), 2.95 - 2.80 (m, 3H), 2.18 - 2.08 (m, 1H); tR = 3.129 min, (Chiralpak IB-3, 0.46 x 5 cm, 3 µm, Hex(0.1% DEA):EtOH = 70:30, 1.0 mL / min). 28a and 28b are enantiomers

[1697] Example 28b: (3R,4R)-3-hydroxy-4-[(5S)-5H-imidazo[4,3-a]isoindol-5-yl]pyrrolidine-1-sulfonamide (31.7 mg, 10%): LCMS (ESI, m / z): 321 [M+H]+ ; tR = 4.425 min, (Chiralpak IB-3, 0.46 x 5 cm, 3 um, Hex(0.1% DEA):EtOH = 70:30, 1.0 mL / min). 28a and 28b are enantiomers.

[1698] Example 28c: (3S,4S)-3-Hydroxy-4-[(5R)-5H-imidazo[4,3-a]isoindol-5-yl]pyrrolidine-1-sulfonamide (15.4 mg, 5%): LCMS (ESI, m / z): 321 [M+H] + ; 1 HNMR (300 MHz, CD3OD) δ 8.01 (s, 1H), 7.64 (d, J = 3.7 Hz, 1H), 7.57 (d, J = 3.9 Hz, 1H), 7.45 (t, J = 3.6 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.17 (s, 1H), 5.57 (d, J = 2.1 Hz, 1H), 4.05 (d, J = 2.7 Hz, 1H), 3.52 (dd, J = 4.3 Hz, 1H), 3.25 - 3.16 (m, 2H), 3.06 - 2.95 (m, 2H); tR = 2.173 minutes, (Chiralpak IB-3, 0.46 x 5 cm, 3 um, Hex(0.1% DEA):EtOH:MeOH(0.2% IPA) = 50:30:20, 1.0 mL / min). 28c and 28d are enantiomers.

[1699] Example 28d: (3S,4S)-3-Hydroxy-4-[(5S)-5H-imidazo[4,3-a]isoindol-5-yl]pyrrolidine-1-sulfonamide (22.9 mg, 8%): LCMS (ESI, m / z): 321 [M+H] + ; tR = 4.073 min (Chiralpak IB-3, 0.46 x 5 cm, 3 um, Hex(0.1% DEA):EtOH:MeOH(0.2% IPA) = 50:30:20, 1.0 mL / min). 28c and 28d are enantiomers.

[1700] Example 29: 9-Hydroxy-8-(5H-imidazo[5,1-a]isoindol-5-yl)-6,7,8,9-tetrahydro-4H-quinolizin- 4-one

[1701]

[1702] (8R,9R)-9-Hydroxy-8-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one

[1703] (8R,9R)-9-Hydroxy-8-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-6,7,8,9-tetrahydro-4H-quinazolin-4-one

[1704] (8R,9S)-9-Hydroxy-8-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-6,7,8,9-tetrahydro-4H-quinazolin-4-one

[1705] (8R,9S)-9-Hydroxy-8-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-6,7,8,9-tetrahydro-4H-quinazolin-4-one

[1706] (8S,9R)-9-Hydroxy-8-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-6,7,8,9-tetrahydro-4H-quinazolin-4-one

[1707] (8S,9R)-9-Hydroxy-8-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-6,7,8,9-tetrahydro-4H-quinazolin-4-one

[1708] (8S,9S)-9-Hydroxy-8-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-6,7,8,9-tetrahydro-4H-quinazolin-4-one

[1709] (8S,9S)-9-Hydroxy-8-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-6,7,8,9-tetrahydro-4H-quinazolin-4-one

[1710] Examples 29a-f were synthesized using the reaction conditions described in Example 1 starting from 3,4-dihydro-1H-quinazoline-1,6(2H)-dione. Each example is a single diastereoisomer. The absolute configuration of all isomers is arbitrarily assigned.

[1711] Example 29a: 1-Hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-3,4-dihydro-1H-quinazolin-6(2H)-one: LCMS (ESI) m / z: 320.1 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.50–7.46 (m, 1H), 7.45 (dd, J = 8.3, 6.2 Hz, 1H), 7.40 (t, J = 7.4 Hz, 1H), 7.28 (td, J = 7.6, 1.2 Hz, 1H), 7.20 (s, 1H), 6.57–6.50 (m, 2H), 6.27 (dt, J = 9.0, 1.0 Hz, 1H), 5.74 (d, J = 2.2 Hz, 1H), 4.90 (d, J = 10.9 Hz, 1H), 4.04 (dt, J = 14.1, 6.2 Hz, 1H), 3.43–3.29 (m, 1H), 2.62–2.48 (m, 1H), 1.29–1.18 (m, 1H), 0.88–0.76 (m, 1H); Preparative SFC: Chiralpak AD (250x20 mm, 5 μm), isocratic elution 70:30 – CO2: methanol w / 0.1% NH4OH, 40 °C, 70 ml / min; Analytical SFC: Chiralpak AD (50x4.6 mm, 3 μm), isocratic elution 25:75 – CO2: ethanol w / 0.1% NH4OH, 40 °C, 4.0 ml / min, retention time 0.999 min.

[1712] Example 29b (enantiomer of Example 29a): 1-Hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-3,4-dihydro-1H-quinazolin-6(2H)-one: LCMS (ESI) m / z: 320.1 [M+H] + ; Preparative SFC: Chiralpak AD (250x20 mm, 5 μm), isocratic elution 70:30 – CO2: methanol w / 0.1% NH4OH, 40 °C, 70 ml / min; Analytical SFC: Chiralpak AD (50x4.6 mm, 3 μm), isocratic elution 25:75 – CO2: ethanol w / 0.1% NH4OH, 40 °C, 4.0 ml / min, retention time 1.177 min.

[1713] Example 29c: 1-Hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-3,4-dihydro-1H-quinazolin-6(2H)-one: LCMS (ESI) m / z: 320.2 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.66–7.58 (m, 2H), 7.43–7.35 (m, 2H), 7.22 (td, J = 7.6, 1.1 Hz, 1H), 7.15 (s, 1H), 6.35–6.27 (m, 2H), 6.21 (d, J = 4.9 Hz, 1H), 5.49 (d, J = 6.4 Hz, 1H), 4.79 (t, J = 4.4 Hz, 1H), 4.09 (dt, J = 14.5, 5.2 Hz, 1H), 3.61 (ddd, J = 15.2, 9.0, 6.8 Hz, 1H), 2.39 (dtd, J = 10.3, 6.7, 3.8 Hz, 1H), 2.03–1.89 (m, 2H); Preparative SFC: Chiralpak AD (250x20 mm, 5 μm), isocratic elution 65:35–CO2:methanol w / 0.1% NH4OH, 40 °C, 70 ml / min; Analytical SFC: Chiralpak AD (50x4.6 mm, 3 μm), isocratic elution 25:75–CO2:ethanol w / 0.1% NH4OH, 40 °C, 4.0 ml / min, retention time 1.235 minutes.

[1714] Example 29d (enantiomer of Example 29c): 1-Hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-3,4-dihydro-1H-quinazolin-6(2H)-one: LCMS (ESI) m / z: 320.1 [M+H] + ; Preparative SFC: Chiralcel OX (150x20 mm, 5 μm), isocratic elution 60:40–CO2:methanol w / 0.1% NH4OH, 40 °C, 70 ml / min; Analytical SFC: Chiralpak AD (50x4.6 mm, 3 μm), isocratic elution 25:75–CO2:ethanol w / 0.1% NH4OH, 40 °C, 4.0 ml / min, retention time 1.458 minutes.

[1715] Example 29e: 1-Hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-3,4-dihydro-1H-quinazolin-6(2H)-one: LCMS (ESI) m / z: 320.1 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.45 (dd, J = 9.1, 6.8 Hz, 1H), 7.39 (dd, J = 8.1, 7.0 Hz, 1H), 7.30 (td, J = 7.5, 1.2 Hz, 1H), 7.10 (s, 1H), 6.51 (s, 1H), 6.42 (dd, J = 7.5, 1.3 Hz, 1H), 6.31 (dd, J = 9.1, 1.3 Hz, 1H), 5.62 (d, J = 2.8 Hz, 1H), 5.01 (d, J = 5.2 Hz, 1H), 4.11 (ddd, J = 14.3, 5.7, 3.6 Hz, 1H), 3.48–3.38 (m, 1H), 2.85–2.74 (m, 1H), 1.46–1.34 (m, 1H), 1.23 (dtd, J = 13.6, 10.7, 5.7 Hz, 1H); Preparative SFC: Chiralcel OX (150x20 mm, 5 μm), isocratic elution 60:40–CO2:ethanol w / 0.1% NH4OH, 40 °C, 70 ml / min; Analytical SFC: Chiralpak AD (50x4.6 mm, 3 μm), isocratic elution 25:75–CO2:ethanol w / 0.1% NH4OH, 40 °C, 4.0 ml / min, retention time 1.595 min.

[1716] Example 29f (enantiomer of Example 29e): 1-Hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-3,4-dihydro-1H-quinazolin-6(2H)-one: LCMS (ESI) m / z: 320.1 [M+H] + ; Preparative SFC: Chiralcel OX (150x20 mm, 5 μm), isocratic elution 60:40–CO2:ethanol w / 0.1% NH4OH, 40 °C, 70 ml / min; Analytical SFC: Chiralpak AD (50x4.6 mm, 3 μm), isocratic elution 25:75–CO2:ethanol w / 0.1% NH4OH, 40 °C, 4.0 ml / min, retention time 1.771 min.

[1717] Example 30: 4-(8-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol

[1718]

[1719] The title compound was synthesized by the same method as in Examples 5 and 6

[1720]

[1721] The mixture was separated by chiral separation using the following conditions: column, Chiralpak AD-H-SL002, 20x250 mm; mobile phase: Hex:IPA = 20:20; detector, uv 254 nm; flow rate, 20 mL / min.

[1722] Example 30a: (3R,4S)-4-[(5S)-8-fluoro-5H-imidazo[4,3-a]isoindol-5-yl]oxolan-3-ol: LCMS (ESI, m / z): 261.2 [M+H] + ; 1 HNMR (300 MHz, CD3OD) δ 8.01 (s, 1H), 7.60 - 7.56 (m, 1H), 7.43 - 7.39 (m, 1H), 7.25 (s, 1H), 7.07 - 7.05 (m, 1H), 5.59 (d, J = 6 Hz, 1H), 4.29 - 4.24 (m, 1H), 3.94 - 3.90 (m, 1H), 3.68 - 3.62 (m, 1H), 3.57 - 3.50 (m, 1H), 3.47 - 3.43 (m, 1H), 3.00 - 2.89 (m, 1H). tR = 5.312 min (Chiralpak AD-3, 0.46x25 cm, 3um; Hex(0.1% DEA):IPA = 80:20; 1 mL / min). 30a and 30b are enantiomers.

[1723] Example 30b: (3S,4R)-4-[(5S)-8-fluoro-5H-imidazo[4,3-a]isoindol-5-yl]oxolan-3-ol: LCMS (ESI, m / z): 261.2 [M+H] + ; tR = 6.457 min (Chiralpak AD-3, 0.46x25 cm, 3um; Hex(0.1% DEA):IPA = 80:20; 1 mL / min). 30a and 30b are enantiomers.

[1724] Example 30c: (3S,4R)-4-[(5R)-8-fluoro-5H-imidazo[4,3-a]isoindol-5-yl]oxolan-3-ol: LCMS (ESI, m / z): 261.2 [M+H] + ; 1HNMR (300 MHz, CD3OD) δ 7.97 (s, 1H), 7.58 - 7.54 (m, 1H), 7.47 - 7.41 (m, 1H), 7.22 (s, 1H), 7.10 - 7.03 (m, 1H), 5.52 (d, J = 3.0 Hz, 1H), 4.26 - 4.20 (m, 1H), 4.09 - 4.05 (m, 1H), 3.84 - 3.81 (m, 1H), 3.53 - 3.51 (m, 2H), 2.90 - 2.84 (m, 1H). tR = 10.558 min (Chiralpak AD - 3, 0.46 x 25 cm, 3 um; Hex(0.1% DEA):IPA = 80:20; 1 mL / min). 30c and 30d are enantiomers.

[1725] Example 30d: (3R,4S)-4-[(5R)-8-Fluoro-5H-imidazo[4,3-a]isoindol-5-yl]oxolan-3-ol: LCMS (ESI, m / z): 261.2 [M+H] + ; tR = 15.264 min (Chiralpak AD - 3, 0.46 x 25 cm, 3 um; Hex(0.1% DEA):IPA = 80:20; 1 mL / min). 30c and 30d are enantiomers.

[1726] Example 31: 6-(5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1727]

[1728] (5R,6S)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1729] (5S,6S)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1730] (5R,6R)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1731] (5S,6R)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1732] (5R,6S)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1733] (5S,6S)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1734] (5R,6R)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1735] (5S,6R)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1736] Step 1:

[1737] (E)-6-(2-(1-Trityl-1H-imidazol-4-yl)benzylidene)-7,8-dihydroquinolin-5(6H)-one

[1738]

[1739] The title compound was synthesized by the general procedure for the synthesis of Int-2: LCMS (ESI, m / z): 544.2 [M+H] +

[1740] Step 2:

[1741] (S)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-7,8-dihydroquinolin-5(6H)-one

[1742]

[1743] The title compound was synthesized by the general procedure for the synthesis of Int-3. The two diastereoisomers were not separated and used as a mixture in Step 3: LCMS (ESI, m / z): 302.1

[1744] Step 3:

[1745] (5R,6S)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1746] (5S,6S)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1747] (5R,6R)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1748] (5S,6R)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1749] (5R,6S)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1750] (5S,6S)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1751] (5R,6R)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1752] (5S,6R)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol

[1753]

[1754] The title compound was synthesized by the general procedure for the synthesis of Int-5. The product was isolated as a mixture of 8 enantiomers, which were separated by chiral SFC: LCMS (ESI, m / z): 303.1.

[1755] The absolute configurations of isomers 31a, 31b, 31g and 31h were assigned by X-ray crystallography. The absolute configurations of the remaining isomers were assigned arbitrarily.

[1756] Example 31a: (5S,6R)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol: LCMS (ESI, m / z): 303.1 [M+H] + ; 11H NMR (500 MHz, chloroform-d) δ 8.56 (dd, J = 4.8, 1.7 Hz, 1H), 8.16 (s, 1H), 7.84 (dd, J = 7.8, 1.8 Hz, 1H), 7.49 (dt, J = 7.6, 1.0 Hz, 1H), 7.41–7.32 (m, 2H), 7.25 (ddd, J = 7.6, 6.2, 1.2 Hz, 2H), 6.51 (s, 1H), 5.50 (s, 1H), 5.15–5.10 (m, 1H), 4.94 (s, 1H), 2.86 (dd, J = 17.7, 5.1 Hz, 1H), 2.68 (ddd, J = 18.2, 12.6, 6.2 Hz, 1H), 2.41 (dd, J = 12.8, 2.6 Hz, 1H), 1.34 (qd, J = 12.9, 5.6 Hz, 1H), 1.11–1.03 (m, 1H).

[1757] Example 31b: (5R,6R)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol: LCMS (ESI, m / z): 303.1 [M+H] + ; 1 1H NMR (500 MHz, chloroform-d) δ 8.42 (ddd, J = 4.8, 1.8, 0.7 Hz, 1H), 7.91 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.67 (s, 1H), 7.63–7.52 (m, 1H), 7.50 (dd, J = 7.7, 1.0 Hz, 1H), 7.46–7.36 (m, 1H), 7.31–7.21 (m, 1H), 7.23 (s, 1H), 7.18 (dd, J = 7.9, 4.8 Hz, 1H), 5.77 (d, J = 2.9 Hz, 1H), 4.96 (d, J = 10.4 Hz, 1H), 2.89 (dd, J = 8.9, 4.0 Hz, 2H), 2.59–2.49 (m, 1H), 1.48–1.28 (m, 2H).

[1758] Example 31c: 5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol: LCMS (ESI, m / z): 303.1 [M+H] +; 1H NMR (500 MHz, chloroform-d) δ 8.48–8.43 (m, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.75 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.45–7.38 (m, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.30 (td, J = 7.5, 1.1 Hz, 1H), 7.21 (dd, J = 7.9, 4.7 Hz, 2H), 5.84 (s, 1H), 5.03 (d, J = 10.5 Hz, 1H), 2.84 (dd, J = 10.1, 6.2 Hz, 1H), 2.40 (dd, J = 13.8, 9.3 Hz, 1H), 1.36–1.09 (m, 3H).

[1759] Example 31d: 5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol: LCMS (ESI, m / z): 303.1 [M+H] + ; 1 1H NMR (500 MHz, chloroform-d) δ 8.49 (dd, J = 4.8, 1.7 Hz, 1H), 7.98 (s, 1H), 7.64–7.54 (m, 3H), 7.41 (tt, J = 7.6, 0.8 Hz, 1H), 7.27 (td, J = 7.6, 1.2 Hz, 1H), 7.18 (s, 1H), 7.16 (dd, J = 7.7, 4.7 Hz, 1H), 5.37 (d, J = 7.6 Hz, 1H), 4.89 (s, 1H), 3.18 (ddd, J = 18.0, 5.3, 2.1 Hz, 1H), 2.91 (ddd, J = 18.4, 12.0, 6.9 Hz, 1H), 2.41–2.27 (m, 1H), 2.13–2.04 (m, 1H).

[1760] Example 31e: 5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol. LCMS (ESI, m / z): 303.1 [M+H] + ; 11H NMR (500 MHz, chloroform-d) δ 8.48 (dd, J = 4.8, 1.7 Hz, 1H), 7.98 (s, 1H), 7.65–7.52 (m, 3H), 7.45–7.34 (m, 1H), 7.27 (td, J = 7.6, 1.2 Hz, 1H), 7.19–7.12 (m, 2H), 5.37 (d, J = 7.6 Hz, 1H), 4.89 (d, J = 3.0 Hz, 1H), 3.18 (ddd, J = 17.9, 5.4, 2.1 Hz, 1H), 2.91 (ddd, J = 18.3, 12.0, 6.8 Hz, 2H), 2.42–2.28 (m, 1H), 2.31 (s, 1H), 2.08 (ddt, J = 9.1, 7.7, 3.7 Hz, 1H).

[1761] Example 31f: 5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol: LCMS (ESI, m / z): 303.1 [M+H] + ; 1 1H NMR (500 MHz, chloroform-d) δ 8.43 (dd, J = 4.9, 1.6 Hz, 1H), 8.03–7.97 (m, 1H), 7.74 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.41 (td, J = 7.4, 1.1 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.30 (dd, J = 7.4, 1.1 Hz, 1H), 7.20 (dd, J = 7.9, 4.7 Hz, 2H), 5.85 (s, 1H), 5.02 (d, J = 10.6 Hz, 1H), 2.84 (dt, J = 9.7, 4.4 Hz, 1H), 2.41 (t, J = 11.5 Hz, 1H), 1.34–1.24 (m, 2H), 1.23–1.07 (m, 1H).

[1762] Example 31g: (5S,6S)-6-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol. LCMS (ESI, m / z): 303.1 [M+H] +; 1H NMR (500 MHz, chloroform-d) δ 8.56 (dd, J = 4.8, 1.7 Hz, 1H), 8.16 (s, 1H), 7.84 (dd, J = 7.8, 1.8 Hz, 1H), 7.49 (dt, J = 7.6, 1.0 Hz, 1H), 7.41–7.32 (m, 2H), 7.25 (ddd, J = 7.6, 6.2, 1.2 Hz, 2H), 6.51 (s, 1H), 5.50 (s, 1H), 5.15–5.10 (m, 1H), 4.94 (s, 1H), 2.86 (dd, J = 17.7, 5.1 Hz, 1H), 2.68 (ddd, J = 18.2, 12.6, 6.2 Hz, 1H), 2.41 (dd, J = 12.8, 2.6 Hz, 1H), 1.34 (qd, J = 12.9, 5.6 Hz, 1H), 1.11–1.03 (m, 1H).

[1763] Example 31h: (5R,6S)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol: LCMS (ESI, m / z): 303.1 [M+H] + ; 1 1H NMR (500 MHz, chloroform-d) δ 8.55 (dd, J = 4.8, 1.8 Hz, 1H), 8.17 (s, 1H), 7.84 (dd, J = 7.8, 1.8 Hz, 1H), 7.49 (dt, J = 7.6, 1.0 Hz, 1H), 7.40–7.32 (m, 2H), 7.30–7.18 (m, 2H), 6.52 (s, 1H), 5.50 (d, J = 1.7 Hz, 1H), 5.12 (dt, J = 4.0, 2.0 Hz, 1H), 2.86 (dd, J = 17.7, 5.3 Hz, 1H), 2.68 (ddd, J = 18.2, 12.6, 6.2 Hz, 1H), 2.42 (dd, J = 12.7, 2.6 Hz, 1H), 1.41–1.24 (m, 1H), 1.06 (dd, J = 13.4, 6.0 Hz, 1H).

[1764] Example 32: 4-(5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-amine

[1765]

[1766] (3S,4S)-4-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydrofuran-3-amine

[1767] (3R,4R)-4-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydrofuran-3-amine

[1768] (3R,4R)-4-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydrofuran-3-amine

[1769] (3S,4S)-4-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydrofuran-3-amine

[1770] Inter-4 was synthesized by the same method as in Example 30.

[1771]

[1772] Step 1: 4-[5H-Imidazo[4,3-a]isoindol-5-yl]oxolan-3-ol

[1773]

[1774] Under nitrogen, diisopropyl azodicarboxylate (1.94 mL, 9.786 mmol), triphenylphosphine (2.5 g, 9.532 mmol) and phthalimide (1.45 g, 9.855 mmol) were added to a solution of 4-[5H-imidazo[4,3-a]isoindol-5-yl]oxolan-3-ol (2 g, 8.255 mmol) in tetrahydrofuran / dichloromethane (100 / 10 mL), and then the mixture was stirred at room temperature for 5 h. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column using dichloromethane / ethyl acetate (1:1) to give 2-(4-[5H-imidazo[4,3-a]isoindol-5-yl]oxolan-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (1.2 g, 39%), which was a yellow solid. LCMS (ES, m / z): 372 [M+H] + .

[1775] Step 2: (3S,4S)-4-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydrofuran-3-amine

[1776] (3R,4R)-4-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydrofuran-3-amine

[1777] (3R,4R)-4-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydrofuran-3-amine

[1778] (3S,4S)-4-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-tetrahydrofuran-3-amine

[1779]

[1780] A solution of 2-(4-[5H-imidazo[4,3-a]isoindol-5-yl]oxolan-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (1.2 g, 3.231 mmol) and hydrazine hydrate (5 mL, 102.876 mmol, 31.839 eq) in ethanol (50 mL) was stirred at 80 °C for 5 h. The resulting mixture was concentrated in vacuo. The residue was purified on a silica gel column using dichloromethane / methanol (20:1). The crude product was purified by prep-HPLC and further separated by chiral separation using the following conditions:

[1781] 1. Column: Lux 5u Celluloes-3, AXIA Packed, 250X21.2 mm; Mobile phase A: Hex (0.1% DEA)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 30B to 30B in 22 min; 254 / 220 nm;

[1782] 2. Column: Lux 5u Celluloes-3, AXIA Packed, 250X21.2 mm; Mobile phase A: Hex (0.1% DEA)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 30B to 30B in 17 min; 254 / 220 nm.

[1783] The absolute configurations of all isomers were arbitrarily assigned.

[1784] Example 32a: (3S,4S)-4-[(5R)-5H-imidazo[4,3-a]isoindol-5-yl]oxolan-3-amine (86.7 mg, 11%): LCMS (ESI, m / z): 242 [M+H] + ; 11H NMR (300 MHz, chloroform-d) δ 7.70 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.19 (s, 1H), 5.50 (d, J = 9.0 Hz, 1H), 4.14 (t, J = 8.3 Hz, 1H), 4.02 (dd, J = 9.6, 8.2 Hz, 1H), 3.93 (dd, J = 8.9, 4.0 Hz, 1H), 3.84 - 3.72 (m, 2H), 2.49 (qd, J = 9.1, 5.7 Hz, 1H); tR = 3.249 min (LuxCellulose-3, 0.46 x 5 cm, 3 um, Hex(0.1% DEA):EtOH = 70:30, 1.0 mL / min). 32a and 32b are enantiomers.

[1785] Example 32b: (3R,4R)-4-[(5S)-5H-imidazo[4,3-a]isoindol-5-yl]oxolane-3-amine (78.8 mg, 10%): LCMS (ESI, m / z): 242 [M+H] + ; tR = 5.074 min (Lux Cellulose-3, 0.46 x 5 cm, 3 um, Hex(0.1% DEA):EtOH = 70:30, 1.0 mL / min). 32a and 32b are enantiomers.

[1786] Example 32c: (3R,4R)-4-[(5R)-5H-imidazo[4,3-a]isoindol-5-yl]oxolane-3-amine (61.4 mg, 8%): LCMS (ESI, m / z): 242 [M+H] + ; 1 1H NMR (300 MHz, chloroform-d) δ 8.10 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.28 - 7.14 (m, 3H), 5.43 (d, J = 10.8 Hz, 1H), 4.20 (dd, J = 9.5, 4.7 Hz, 2H), 3.93 - 3.76 (m, 2H), 3.71 (dd, J = 5.4, 3.2 Hz, 1H), 2.47 - 2.28 (m, 1H); tR = 3.584 min (Lux Cellulose-3, 0.46 x 5 cm, 3 um, Hex(0.1% DEA):EtOH = 70:30, 1.0 mL / min). 32c and 32d are enantiomers.

[1787] Example 32d: (3S,4S)-4-[(5S)-5H-imidazo[4,3-a]isoindol-5-yl]oxolan-3-amine (70.8 mg, 9%): LCMS (ESI, m / z): 242 [M+H] + ; tR = 4.409 min (Lux Cellulose-3, 0.46 x 5 cm, 3 um, Hex(0.1% DEA):EtOH = 70:30, 1.0 mL / min). 32c and 32d are enantiomers.

[1788] Examples 33 and 34: 8-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol and 8- fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol

[1789]

[1790] The title compound was synthesized by the same method as in Examples 5 and 6

[1791]

[1792] The crude product was purified by prep-HPLC and further separated by chiral separation using the following conditions:

[1793] 1. Column: CHIRALPAK-AD-H-SL002, 20 x 250 mm; Mobile phase A: Hex(0.1% DEA)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 30B to 30B in 13.5 min; 254 / 220 nm;

[1794] 2. Column: Lux 5u Celluloes-3, AXIA Packed, 250X21.2 mm; Mobile phase A: EtOH(0.1% DEA)----HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 30B to 30B in 16 min; 254 / 220 nm;

[1795] 3. Column: Chiralpak IC, 2 x 25 cm, 5 um; Mobile phase A: Hex(0.1% DEA)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 20B to 20B in 16 min; 254 / 220 nm.

[1796] The absolute configuration of all isomers was arbitrarily assigned.

[1797] Example 33a: (3R,4R)-4-((S)-8-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol: LCMS (ESI, m / z): 274.0 [M+H] + ; 1 HNMR (300 MHz, CD3OD) δ 7.95 (s, 1H), 7.49 (dd, J = 8.4 Hz, 4.8 Hz, 1H), 7.41 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.25 (s, 1H), 7.12 - 7.07 (m, 1H), 5.80 (s, 1H), 4.05 (dd, J = 10.8 Hz, 4.8 Hz, 1H), 3.88 - 3.82 (m, 1H), 3.70 (dd, J = 11.2 Hz, 4.8 Hz, 1H), 3.28 - 3.16 (m, 2H), 2.27 (t, J = 2.0 Hz, 1H), 0.86 (d, J = 7.6 Hz, 1H), 0.71 - 0.60 (m, 1H). tR = 5.772 min (CHIRALCEL AD-3, 0.46 x 15 cm, 3 um; Hex(0.1% DEA):EtOH = 70:30, 1.0 ml / min). 33a and 33b are enantiomers.

[1798] Example 33b: (3S,4S)-3-((S)-8-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol: LCMS (ESI, m / z): 274.0 [M+H] + ; tR = 6.618 min (CHIRALCEL AD-3, 0.46 x 15 cm, 3 um; Hex(0.1% DEA):EtOH = 70:30, 1.0 ml / min). 33a and 33b are enantiomers.

[1799] Example 33c: (3S,4S)-4-((S)-8-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol: LCMS (ESI, m / z): 274.0 [M+H] + ; 1HNMR (300 MHz, CD3OD) δ 7.95 (s, 1H), 7.56 (dd, J = 8.4 Hz, 4.8 Hz, 1H), 7.42 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.22 (s, 1H), 7.11 - 7.06 (m, 1H), 5.79 (s, 1H), 3.99 (dd, J = 10.4 Hz, 4.8 Hz, 1H), 3.87 - 3.80 (m, 1H), 3.72 (d, J = 6.8 Hz, 1H), 3.29 - 3.22 (m, 1H), 3.15 (t, J = 10.4 Hz, 1H), 2.43 - 2.40 (m, 1H), 0.77 - 0.73 (m, 2H). tR = 2.288 min (CHIRALCEL Lux Cellulose - 3, 0.46 x 10 cm; 3 um, Hex(0.1% DEA):EtOH = 70:30, 1.0 ml / min). 33c and 33d are enantiomers.

[1800] Example 33d: (3S,4S)-4-((R)-8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol: LCMS (ESI, m / z): 274.0 [M+H] + ; 1 HNMR (300 MHz, CD3OD). tR = 4.721 min (CHIRALCEL Lux Cellulose - 3, 0.46 x 10 cm; 3 um, Hex(0.1% DEA):EtOH = 70:30, 1.0 ml / min). 33c and 33d are enantiomers.

[1801] Example 34a: (3R,4R)-3-((S)-8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol: LCMS (ESI, m / z): 274.0 [M+H] + ; 1HNMR (300 MHz, CD3OD) δ 8.0 (s, 1H), 7.59 (dd, J = 8.4 Hz, 4.8 Hz, 1H), 7.42 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.23 (s, 1H), 7.11 - 7.06 (m, 1H), 5.76 (s, 1H), 3.98 - 3.91 (m, 1H), 3.88 (dd, J = 11.6 Hz, 4.8 Hz, 1H), 3.34 - 3.26 (m 1H), 3.08 (dd, J = 11.6 Hz, 4.0 Hz, 1H), 2.71 (t, J = 11.2 Hz, 1H), 2.47 - 2.43 (m, 1H), 1.97 (dd, J = 12.8 Hz, 2.4 Hz, 1H), 1.71 - 1.67 (m, 1H). tR = 2.133 min (CHIRALCEL AD - 3, 0.46 x 5 cm; 3 um, Hex(0.1% DEA):EtOH = 70:30, 1.0 ml / min). 34a and 34b are enantiomers.

[1802] Example 34b: (3S,4S)-3-((R)-8-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol: LCMS (ESI, m / z): 274.0 [M+H] + ; tR = 3.330 min (CHIRALCEL AD - 3, 0.46 x 5 cm; 3 um, Hex(0.1% DEA):EtOH = 70:30, 1.0 ml / min). 34a and 34b are enantiomers.

[1803] Example 34c: (3R,4R)-4-((R)-8-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol: LCMS (ESI, m / z): 274.0 [M+H] + ; 1HNMR (300 MHz, CD3OD) δ 7.9 (s, 1H), 7.53 (dd, J = 8.4 Hz, 4.8 Hz, 1H), 7.41 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.25 (s, 1H), 7.14 - 7.09 (m, 1H), 5.80 (s, 1H), 4.07 - 4.03 (m, 1H), 3.90 (dd, J = 12.0 Hz, 4.8 Hz, 1H), 3.33 - 3.29 (m 1H), 3.16 (dd, J = 12.0 Hz, 4.4 Hz, 1H), 2.51 (t, J = 11.2 Hz, 1H), 2.34 - 2.31 (m, 1H), 2.06 (dd, J = 10.4 Hz, 2.4 Hz, 1H), 1.75 - 1.71 (m, 1H). tR = 4.004 min (CHIRALCEL AD - 3, 0.46 x 15 cm; 3 um, Hex(0.1% DEA):EtOH = 70:30, 1.0 ml / min). 34c and 34d are enantiomers.

[1804] Example 34d: (3R,4R)-3-((R)-8-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol: LCMS (ESI, m / z): 274.0 [M+H] + ; 1 HNMR (300 MHz, CD3OD). tR = 3.340 minutes tR = 4.489 minutes (CHIRALCEL AD - 3, 0.46 x 15 cm; 3 um, Hex(0.1% DEA):EtOH = 70:30, 1.0 ml / min). 34c and 34d are enantiomers.

[1805] Example 35: 2-(5H-Imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol

[1806] (1R,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol

[1807] (1S,2S)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol

[1808] (1R,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol

[1809] (1S,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol

[1810] Step 1: (E)-2-(2-(1-Trityl-1H-imidazol-4-yl)benzylidene)cyclobutan-1-one

[1811]

[1812] To a solution of 2-[1-(trityl)-1H-imidazol-4-yl]benzaldehyde (3.0 g, 7.24 mmol) and cyclobutanone (1.01 g, 14.47 mmol) in anhydrous ethanol (30 mL) was added piperidine (0.72 mL, 7.24 mmol) and the resulting mixture was stirred at 90 °C for 6 h. The mixture was cooled in an ice bath and the reaction was quenched with saturated NH4Cl (30 mL). The aqueous phase was extracted with DCM (3 x 20 mL) and the combined organic phases were dried over Na2SO4 and concentrated. The product was separated by CombiFlash to give (E)-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclobutan-1-one as a yellow oil: LCMS (ESI, m / z): 466 [M+H] + .

[1813] Step 2: 2-(5H-Imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-one

[1814]

[1815] To (E)-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclobutan-1-one was added MeOH (20 mL) and AcOH (5 mL). The resulting mixture was stirred at 90 °C for 2 h. The solvent was removed under reduced pressure. The reaction was quenched with 30 mL of saturated NaHCO3 solution (30 mL) and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine and water and dried over anhydrous Na2SO4. The crude product was separated by CombiFlash to give 2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-one as a pale yellow oil: LCMS (ESI, m / z): 225.3 [M+H] + .

[1816] Step 3:

[1817] (1R,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol

[1818] (1S,2S)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol

[1819] (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol

[1820] (1S,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol

[1821]

[1822] At 0 °C, methylmagnesium bromide (0.73 mL, 2.19 mmol) was added dropwise to a solution of 2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-one (0.41 g, 1.83 mmol) in anhydrous THF (10 mL), and the solution was stirred at 0 °C for an additional 1 h. The reaction was quenched with 30 mL of saturated NH4Cl solution (10 mL), and the mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine and water and dried over anhydrous Na2SO4. The crude product was purified by combi-flash and further separated by chiral separation to afford 4 isomers as white solids. The crude product was purified by combi-flash and further separated by chiral separation to afford 6 isomers as white solids. The absolute configurations of all isomers were arbitrarily assigned.

[1823] Example 35a: (1R,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol: LCMS (ESI, m / z): 241.3 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 8.02 (t, J = 0.7 Hz, 1H), 7.52 (dt, J = 7.6, 1.1 Hz, 1H), 7.48 (dq, J = 7.6, 0.9 Hz, 1H), 7.34 (tdd, J = 7.6, 1.1, 0.6 Hz, 1H), 7.22 (td, J = 7.6, 1.2 Hz, 1H), 7.19 (s, 1H), 5.46 (d, J = 5.9 Hz, 1H), 2.65–2.56 (m, 1H), 2.10–1.96 (m, 2H), 1.82 (dtd, J = 11.9, 8.8, 6.2 Hz, 1H), 1.70–1.63 (m, 1H), 1.51 (d, J = 0.5 Hz, 3H).

[1824] Example 35b: (1S,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol: LCMS (ESI, m / z): 241.3 [M+H]+ . 1 H NMR (500 MHz, chloroform-d) δ 8.02 (t, J = 0.7 Hz, 1H), 7.52 (dt, J = 7.6, 1.1 Hz, 1H), 7.48 (dq, J = 7.6, 0.9 Hz, 1H), 7.34 (tdd, J = 7.6, 1.1, 0.6 Hz, 1H), 7.22 (td, J = 7.6, 1.2 Hz, 1H), 7.19 (s, 1H), 5.46 (d, J = 5.9 Hz, 1H), 2.65–2.56 (m, 1H), 2.11–1.97 (m, 2H), 1.82 (dtd, J = 11.9, 8.8, 6.2 Hz, 1H), 1.66 (ddt, J = 11.9, 10.4, 6.7 Hz, 1H), 1.51 (d, J = 0.5 Hz, 3H).

[1825] Example 35c: (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol: LCMS (ESI, m / z): 241.3 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 8.00 (s, 1H), 7.52 (dt, J = 7.4, 1.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.18 (td, J = 7.6, 1.2 Hz, 1H), 7.15 (s, 1H), 5.43 (d, J = 10.2 Hz, 1H), 2.46–2.26 (m, 2H), 2.19–2.03 (m, 3H), 1.40 (s, 3H).

[1826] Example 35d: (1S,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol: LCMS (ESI, m / z): 241.3 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 8.00 (s, 1H), 7.52 (dt, J = 7.5, 1.1 Hz, 1H), 7.39–7.31 (m, 2H), 7.18 (td, J = 7.6, 1.2 Hz, 1H), 7.15 (s, 1H), 5.43 (d, J = 10.2 Hz, 1H), 2.46–2.26 (m, 2H), 2.21–2.02 (m, 3H), 1.40 (s, 3H).

[1827] Example 36: 2-(5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1828]

[1829] (1S,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1830] (1S,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1831] (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1832] (1R,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1833] (1R,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1834] (1R,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1835] (1R,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1836] (1S,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1837] Step 1: (E)-6-(methylthio)-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)-3,4-dihydronaphthalen-1(2H)-one

[1838]

[1839] The title compound was synthesized by the general procedure for the synthesis of Int-2. LCMS (ESI, m / z): 589.3 [M+H]

[1840] Step 2:2-(5H-Imidazo[5,1-a]isoindol-5-yl)-6-(methylthio)-3,4-dihydronaphthalen-1(2H)-one

[1841]

[1842] The title compound was synthesized by the general procedure for the synthesis of Int-3. LCMS (ESI, m / z): 347.19 [M+H] +

[1843] Step 3: 2-(5H-Imidazo[5,1-a]isoindol-5-yl)-6-(methylthio)-1,2,3,4-tetrahydronaphthalen-1-ol

[1844]

[1845] The title compound was synthesized by the general procedure for the synthesis of Int-5: LCMS (ESI, m / z): 349.1

[1846] Step 4:

[1847] (1S,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1848] (1S,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1849] (1R,2S)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1850] (1R,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1851] (1R,2R)-2-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1852] (1R,2S)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1853] (1R,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1854] (1S,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1855]

[1856] To a solution of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylthio)-1,2,3,4-tetrahydronaphthalen-1-ol (1.5 g, 4.3 mmol) in acetic acid (10 mL) was added hydrogen peroxide (30% aqueous solution, 4.88 g, 4.28 mL, 43.05 mmol), and the reaction was stirred at room temperature for 48 h. The acetic acid was then removed using a rotary evaporator, and the remaining acetic acid was quenched with saturated sodium carbonate solution. The solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by prep-HPLC and further separated by chiral resolution to give 8 isomers as white solids. The absolute configurations of all isomers were arbitrarily assigned.

[1857] Example 36a: (1S,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol. LCMS (ESI, m / z): 381.2 [M+H] + ; 1 H NMR (500 MHz, chloroform-d) δ 7.82 (d, J = 8.3 Hz, 1H), 7.77 (dd, J = 8.2, 1.9 Hz, 1H), 7.66 - 7.58 (m, 3H), 7.50 (dd, J = 7.7, 1.0 Hz, 1H), 7.45 – 7.37 (m, 1H), 7.29 - 7.21 (m, 2H), 5.78 (d, J = 2.9 Hz, 1H), 4.96 (d, J = 10.5 Hz, 1H), 3.02 (s, 3H), 2.80 (dd, J = 11.5, 5.5 Hz, 2H), 2.55 (s, 1H), 1.27 – 1.40 (m, 1H), 1.26 (s, 1H)

[1858] Example 36b: (1S,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol. LCMS (ESI, m / z): 381.2 [M+H] + ; 11H NMR (500 MHz, chloroform-d) δ 7.92 (d, J = 8.2 Hz, 1H), 7.68 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.62 - 7.54 (m, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.31 (dd, J = 20.3, 7.6 Hz, 2H), 7.19 (s, 1H), 5.86 (s, 1H), 4.98 (d, J = 10.7 Hz, 1H), 3.04 (s, 3H), 2.80 - 2.69 (m, 2H), 2.42 (t, J = 11.6 Hz, 1H), 1.25 (d, J = 14.1 Hz, 1H), 1.04 (dd, J = 12.4, 6.9 Hz, 1H)

[1859] Example 36c: (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol. LCMS (ESI, m / z): 381.2 [M+H] + ; 1 1H NMR (500 MHz, chloroform-d) δ 7.98 (s, 1H), 7.78 - 7.72 (m, 2H), 7.62 - 7.53 (m, 2H), 7.57 - 7.47 (m, 1H), 7.42 (tt, J = 7.6, 7.6, 0.8 Hz, 1H), 7.30 - 7.21 (m, 1H), 7.19 (s, 1H), 5.39 (d, J = 7.4 Hz, 1H), 4.91 (d, J = 3.0 Hz, 1H), 3.15 - 3.02 (m, 1H), 3.03 (s, 3H), 2.85 (ddd, J = 17.8, 11.6, 6.8 Hz, 1H), 2.69 (s, 1H), 2.34 - 2.21 (m,1H), 2.25 (s, 1H), 2.08 (ddt, J = 11.5, 7.3, 3.4 Hz, 1H)

[1860] Example 36d: (1R,2R)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol. LCMS (ESI, m / z): 381.2 [M+H] + ; 11H NMR (500 MHz, chloroform-d) δ 7.92 (d, J = 8.2 Hz, 1H), 7.68 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.62 - 7.54 (m, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.31 (dd, J = 20.3, 7.6 Hz, 2H), 7.19 (s, 1H), 5.86 (s, 1H), 4.98 (d, J = 10.7 Hz, 1H), 3.04 (s, 3H), 2.80 - 2.69 (m, 2H), 2.42 (t, J = 11.6 Hz, 1H), 1.25 (d, J = 14.1 Hz, 1H), 1.04 (dd, J = 12.4, 6.9 Hz, 1H)

[1861] Example 36e: (1R,2R)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol. LCMS (ESI, m / z): 381.2 [M+H] + ; 1 1H NMR (500 MHz, chloroform-d) δ 7.91 (s, 1H), 7.81 (dd, J = 7.8, 1.8 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.55 - 7.49 (m, 1H), 7.42 - 7.35 (m, 2H), 7.36 - 7.21 (m, 1H), 6.91 (s, 1H), 5.47 (d, J = 1.9 Hz, 1H), 5.15 (d, J = 3.4 Hz, 1H), 3.06 (s, 3H), 2.81 (dd, J = 17.1, 5.2 Hz, 1H), 2.64 (ddd, J = 17.8, 12.4, 6.0 Hz, 1H), 2.45 - 2.38 (m, 1H), 1.66 - 1.47 (m, 1H), 1.16 (dd, J = 11.3, 3.6 Hz, 1H)

[1862] Example 36f: (1R,2S)-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol. LCMS (ESI, m / z): 381.2 [M+H] + ; 11H NMR (500 MHz, chloroform-d) δ 7.91 (s, 1H), 7.81 (dd, J = 7.8, 1.8 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.55 - 7.49 (m, 1H), 7.42 - 7.35 (m, 2H), 7.36 - 7.21 (m, 1H), 6.91 (s, 1H), 5.47 (d, J = 1.9 Hz, 1H), 5.15 (d, J = 3.4 Hz, 1H), 3.06 (s, 3H), 2.81 (dd, J = 17.1, 5.2 Hz, 1H), 2.64 (ddd, J = 17.8, 12.4, 6.0 Hz, 1H), 2.45 - 2.38 (m, 1H), 1.66 - 1.47 (m, 1H), 1.16 (dd, J = 11.3, 3.6 Hz, 1H)

[1863] Example 36g: (1R,2S)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol. LCMS (ESI, m / z): 381.2 [M+H] + ; 1 1H NMR (500 MHz, chloroform-d) δ 7.82 (d, J = 8.3 Hz, 1H), 7.77 (dd, J = 8.2, 1.9 Hz, 1H), 7.66 - 7.58 (m, 3H), 7.50 (dd, J = 7.7, 1.0 Hz, 1H), 7.45–7.37 (m, 1H), 7.29 - 7.21 (m, 2H), 5.78 (d, J = 2.9 Hz, 1H), 4.96 (d, J = 10.5 Hz, 1H), 3.02 (s, 3H), 2.80 (dd, J = 11.5, 5.5 Hz, 2H), 2.55 (s, 1H), 1.27–1.40 (m, 1H), 1.26 (s, 1H)

[1864] Example 36h: (1S,2R)-2-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol. LCMS (ESI, m / z): 381.2 [M+H] + ; 11H NMR (500 MHz, chloroform-d) δ 7.98 (s, 1H), 7.78 - 7.72 (m, 2H), 7.62 - 7.53 (m, 2H), 7.57 - 7.47 (m, 1H), 7.42 (tt, J = 7.6, 7.6, 0.8 Hz, 1H), 7.30 - 7.21 (m, 1H), 7.19 (s, 1H), 5.39 (d, J = 7.4 Hz, 1H), 4.91 (d, J = 3.0 Hz, 1H), 3.15 - 3.02 (m, 1H), 3.03 (s, 3H), 2.85 (ddd, J = 17.8, 11.6, 6.8 Hz, 1H), 2.69 (s, 1H), 2.34 - 2.21 (m, 1H), 2.25 (s, 1H), 2.08 (ddt, J = 11.5, 7.3, 3.4 Hz, 1H)

[1865] Example 37: 3-(5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1866]

[1867] (2S,3S)-3-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1868] (2S,3R)-3-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1869] (2R,3R)-3-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1870] (2S,3S)-3-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1871] (2R,3S)-3-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1872] (2R,3R)-3-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1873] 3-(5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1874] Step 1:(E)-3-(2-(1-Trityl-1H-imidazol-4-yl)benzylidene)bicyclo[2.2.2]octan-2-one

[1875]

[1876] The title compound was synthesized by the general procedure for the synthesis of Int-2: LCMS (ESI, m / z): 521.2 [M+H] +

[1877] Step 2: (S)-6-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-7,8-dihydroquinolin-5(6H)-one

[1878]

[1879] The title compound was synthesized by the general procedure for the synthesis of Int-3. The two diastereomers were not separated and used as a mixture in Step 3: LCMS (ESI, m / z): 279.1. The absolute configuration of all isomers was arbitrarily assigned.

[1880] Step 3:

[1881] (2S,3S)-3-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1882] (2S,3R)-3-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1883] (2R,3R)-3-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1884] (2S,3S)-3-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1885] (2R,3S)-3-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1886] (2R,3R)-3-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1887] 3-(5H-Imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol

[1888]

[1889] The title compound was synthesized by the general procedure for the synthesis of Int-5. The product was isolated as a mixture of 6 enantiomers and 1 diastereomer, which was separated by chiral SFC: LCMS (ESI, m / z): 281.4. The absolute configurations of all isomers were arbitrarily assigned.

[1890] Example 37a: (2S,3S)-3-((S)-5H-imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol: LCMS (ESI, m / z): 28...

Claims

1. A compound of formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-6 alkyl, -C1 alkyl - C 3-10 cycloalkyl, -C1 alkyl - 3 - 7 - membered heterocyclic group or -C1 alkyl - 5 - or 6 - membered monocyclic heteroaryl, wherein R 1 substituted with -OH on the carbon atom bonded to 5H-imidazo[5,1-a]isoindolyl, and R 1 is also substituted with 1, 2, 3 or 4 R's independently selected from the following a groups: halogen, cyano, C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkyl-cyano, -C(O)N(R)2, -S(O)N(R)2, -S(O)2N(R)2 or -OC(O)N(R)2; n is 0, 1, 2, 3 or 4; Each R 2 is independently halogen, cyano, C 1-6 alkyl, C3 cycloalkyl, -C 1-6 haloalkyl, -OR, -NR2 or -SR; and Each R is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein said compound is not 2. The compound of claim 1, which is of formula (Ia), or a mixture of stereoisomers thereof.

3. The compound of claim 1, which is of formula (Ic), or a mixture of stereoisomers thereof.

4. The compound of claim 1, which is of formula (Id):

5. The compound of claim 1, which is of formula (If):

6. The compound of claim 1, which is of formula (Ih):

7. The compound of claim 1, wherein each R is hydrogen or C 1-6 alkyl.

8. The compound according to claim 1, wherein each R is hydrogen, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, wherein R 1 is wherein R 4 is —OR, wherein said R is H.

10. A compound which is 1-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol 2-(5H-imidazo[5,1-a]isoindol-5-yl)propan-2-ol 1-(5H-imidazo[5,1-a]isoindol-5-yl)ethane-1,2-diol 1-(5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol cyclopropyl(5H-imidazo[5,1-a]isoindol-5-yl)methanol 1-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol 1-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol 1-(5H-imidazo[5,1-a]isoindol-5-yl)propan-1-ol (5H-imidazo[5,1-a]isoindol-5-yl)(tetrahydro-2H-pyran-4-yl)methanol 1-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H-imidazol-2-yl)ethan-1-ol cyclohexyl(5H-imidazo[5,1-a]isoindol-5-yl)methanol (5H-imidazo[5,1-a]isoindol-5-yl)(pyridin-4-yl)methanol 1-(hydroxy(5H-imidazo[5,1-a]isoindol-5-yl)methyl)cyclopropane-1-carbonitrile (1-fluorocyclopropyl)(5H-imidazo[5,1-a]isoindol-5-yl)methanol; 1-(hydroxy(5H-imidazo[5,1-a]isoindol-5-yl)methyl)cyclopropane-1-carboxamide or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, or a racemic mixture thereof.

11. A compound which is (R)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol, (R)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol, (S)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol, (S)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol, (R)-2-(5H-imidazo[5,1-a]isoindol-5-yl)propan-2-ol, (S)-2-(5H-imidazo[5,1-a]isoindol-5-yl)propan-2-ol, (R)-1-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)ethane-1,2-diol, (R)-1-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)ethane-1,2-diol, (S)-1-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)ethane-1,2-diol, (S)-1-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)ethane-1,2-diol, (S)-1-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol, (R)-1-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol, (S)-1-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol, (R)-1-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol, (S)-Cyclopropyl((S)-5H-Imidazo[5,1-a]isoindol-5-yl)methanol, (S)-Cyclopropyl((R)-5H-Imidazo[5,1-a]isoindol-5-yl)methanol, (R)-Cyclopropyl((S)-5H-Imidazo[5,1-a]isoindol-5-yl)methanol, (R)-Cyclopropyl((R)-5H-Imidazo[5,1-a]isoindol-5-yl)methanol, (S)-1-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol, (R)-1-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol, (S)-1-((R)-8-Fluoro-5H-Imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol, (R)-1-((R)-8-Fluoro-5H-Imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol, (R)-1-((S)-8-Fluoro-5H-Imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol, (S)-1-((S)-8-Fluoro-5H-Imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol, (R)-1-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)propan-1-ol, (S)-1-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)propan-1-ol, (R)-1-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)propan-1-ol, (S)-1-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)propan-1-ol, (R)-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)(tetrahydro-2H-pyran-4-yl)methanol, (S)-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)(tetrahydro-2H-pyran-4-yl)methanol, (R)-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)(tetrahydro-2H-pyran-4-yl)methanol, (S)-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)(tetrahydro-2H-pyran-4-yl)methanol, (R)-1-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-(1H-imidazol-2-yl)ethan-1-ol, (R)-1-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-(1H-imidazol-2-yl)ethan-1-ol, (S)-1-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-(1H-imidazol-2-yl)ethan-1-ol, (S)-1-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)-1-(1H-imidazol-2-yl)ethan-1-ol, (R)-Cyclohexyl((S)-5H-Imidazo[5,1-a]isoindol-5-yl)methanol, (S)-Cyclohexyl((R)-5H-Imidazo[5,1-a]isoindol-5-yl)methanol, (R)-Cyclohexyl((R)-5H-Imidazo[5,1-a]isoindol-5-yl)methanol, (S)-Cyclohexyl((S)-5H-Imidazo[5,1-a]isoindol-5-yl)methanol, (S)-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)(pyridin-4-yl)methanol, (R)-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)(pyridin-4-yl)methanol, (S)-((S)-5H-Imidazo[5,1-a]isoindol-5-yl)(pyridin-4-yl)methanol, (R)-((R)-5H-Imidazo[5,1-a]isoindol-5-yl)(pyridin-4-yl)methanol, 1-((R)-Hydroxy((R)-5H-Imidazo[5,1-a]isoindol-5-yl)methyl)cyclopropane-1-carbonitrile, 1-((S)-Hydroxy((R)-5H-Imidazo[5,1-a]isoindol-5-yl)methyl)cyclopropane-1-carbonitrile, (R)-(1-Fluorocyclopropyl)((R)-5H-Imidazo[5,1-a]isoindol-5-yl)methanol, (S)-(1-Fluorocyclopropyl)((S)-5H-Imidazo[5,1-a]isoindol-5-yl)methanol, (S)-(1-Fluorocyclopropyl)((R)-5H-Imidazo[5,1-a]isoindol-5-yl)methanol, (R)-(1-Fluorocyclopropyl)((S)-5H-Imidazo[5,1-a]isoindol-5-yl)methanol, 1-((R)-Hydroxy((R)-5H-Imidazo[5,1-a]isoindol-5-yl)methyl)cyclopropane-1-carboxamide, 1-((R)-Hydroxy((S)-5H-imidazo[5,1-a]isoindol-5-yl)methyl)cyclopropane-1-carboxamide, 1-((S)-Hydroxy((R)-5H-imidazo[5,1-a]isoindol-5-yl)methyl)cyclopropane-1-carboxamide, or 1-((S)-Hydroxy((S)-5H-imidazo[5,1-a]isoindol-5-yl)methyl)cyclopropane-1-carboxamide.

12. A pharmaceutical composition comprising a compound according to any one of claims 1-11 and a pharmaceutically acceptable diluent, excipient or carrier.

13. The pharmaceutical composition according to claim 12, which further comprises a second therapeutic agent.

14. Use of the compound according to claim 1 in the preparation of a medicament for treating tryptophan 2,3-dioxygenase (TDO2)-mediated immunosuppression associated with a disease.

15. The use according to claim 14, wherein the disease is cancer.

16. The use according to claim 15, wherein the cancer is colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head cancer, or neck cancer, or lymphoma, leukemia, or melanoma.

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