This application is a continuation of U.S. application Ser. No. 16/065,397, filed Jun. 22, 2018, now U.S. Pat. No. 10,800,780, which is a U.S. national phase application under 35 USC 371 of International Patent Application No. PCT/CN2016/111730, filed Dec. 23, 2016, which claims the benefit of International Application No. PCT/CN2015/098685, filed Dec. 24, 2015; International Application No. PCT/CN2016/103358, filed Oct. 26, 2016; and International Application No. PCT/CN2016/106624, filed Nov. 21, 2016.

BACKGROUND OF THE INVENTION

›Field of the Invention

The present disclosure relates to compounds and methods for inhibition of tryptophan 2,3-dioxygenase (TDO2); further the disclosure relates to method of treatment of diseases and disorders mediated by tryptophan deficiency.

Summary of the Related Art

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 step in the degradation of L-tryptophan to N-formyl-kynurenine. Although these enzymes catalyze the same reaction, differential expression and compartmentalization of IDO1 and TDO2 in different tissues is thought to mediate their different biological roles. IDO1 is normally expressed in cells of the gastrointestinal and pulmonary epithelia, epididymus, placenta, pDCs in draining lymph nodes and tumor cells. IDO2 is expressed mainly in brain and placenta, but certain splice variants are also detected in liver, small intesting, spleen, placenta, thymus lung, brain, kidney and colon. TDO2 is expressed mainly in liver, and controls the flux of dietary Trp to the serotonin and kynurenine pathways, and is also expressed in tumors and tumor cell lines.

Several lines of evidence suggest that IDO1 and TDO2 are involved in induction of immune tolerance. Studies of mammalian pregnancy, tumor resistance, chronic infections and autoimmune diseases have shown that cells expressing IDO1 can suppress 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 diseases and AIDS, as well as during pregnancy. It was proposed that IDO1 is induced chronically by HIV infection, and is further increased by opportunistic infections, and that the chronic loss of Trp initiates mechanisms responsible for cachexia, dementia and diarrhea and possibly immunosuppression of AIDS patients (Brown, et al., 1991, Adv. Exp. Med. Biol., 294: 425-35). To this end, it has recently been shown that IDO1 inhibition can enhance the levels of virus-specific T cells and, concomitantly, reduce the number of virally infected macrophages in a mouse model of HIV (Portula et al., 2005, Blood, 106:2382-90).

IDO1 is believed to play a role in the immunosuppressive processes that prevent fetal rejection in utero. More than 40 years ago, it was observed that, during pregnancy, the genetically disparate mammalian conceptus survives in spite of what would be predicted by tissue transplantation immunology (Medawar, 1953, Symp. Soc. Exp. Biol. 7: 320-38). Anatomic separation of mother and fetus and antigenic immaturity of the fetus cannot fully explain fetal allograft survival. Recent attention has focused on immunologic tolerance of the mother. Because IDO1 is expressed by human syncytiotrophoblast cells and systemic tryptophan concentration falls during normal pregnancy, it was hypothesized that IDO1 expression at the maternal-fetal interface is necessary to prevent immunologic rejection of the fetal allografts. To test this hypothesis, pregnant mice (carrying syngeneic or allogeneic fetuses) were exposed to 1MT, and a rapid, T cell-induced rejection of all allogeneic concepti was observed. Thus, by catabolizing tryptophan, the mammalian conceptus appears to suppress T-cell activity and defends itself against rejection, and blocking tryptophan catabolism during murine pregnancy allows maternal T cells to provoke fetal allograft rejection (Munn, et al., 1998, Science 281: 1191-3).

Further evidence for a tumoral immune resistance mechanism based on tryptophan degradation by IDO1 comes from the observation that most human tumors constitutively express IDO, and that expression of IDO1 by immunogenic mouse tumor cells prevents their rejection by preimmunized mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partly reverted by systemic treatment of mice with an inhibitor of IDO, in the absence of noticeable toxicity. Thus, it was suggested that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO1 inhibitor (Uyttenhove et al., 2003, Nature Med., 9: 1269-74). It has also been shown that the IDO1 inhibitor, 1-MT, can synergize with chemotherapeutic agents to reduce tumor growth in mice, suggesting that IDO1 inhibition may also enhance the anti-tumor activity of conventional cytotoxic therapies (Muller et al., 2005, Nature Med., 11:312-9).

A similar situation has been observed with TDO2. It has been shown that a significant proportion of primary human tumors express elevated levels of TDO2 or TDO2 plus IDO1 (Pilotte et al. 2012, P.N.A.S). Moreover, pharmacological inhibition of TDO2 activity with TDO2 inhibitors, leads to immune-mediated rejection of tumors overexpressing TDO2, which means that TDO2, just as seen in IDO1, can mediate tumor-promoting immunosuppressive effects.

Small molecule inhibitors of IDO1 are being developed to treat or prevent IDO1-related diseases such as those described above. For example, PCT Publication WO 99/29310 reports methods for altering T cell-mediated immunity comprising altering local extracellular concentrations of tryptophan and tryptophan metabolites, using an inhibitor of IDO1 such as 1-methyl-DL-tryptophan, p-(3-benzofuranyl)-DL-alanine, p-[3-benzo(b)thienyl]-DL-alanine, and 6-nitro-L-tryptophan) (Munn, 1999). Reported in WO 03/087347, also published as European Patent 1501918, are methods of making antigen-presenting cells for enhancing or reducing T cell tolerance (Munn, 2003). Compounds having indoleamine-2,3-dioxygenase (IDO) inhibitory activity are further reported in WO 2004/094409; WO 2009/073620; WO 2009/132238; WO 2011/056652 and WO 2012/142237. In particular, the compounds of WO 2012/142237 encompass a series of tricyclic imidazoisoindoles with potent IDO1 inhibitory activity.

›SUMMARY OF THE INVENTION · 1 of 2

We recognized that in light of the experimental data indicating a role for IDO1 and/or TDO2 in immunosuppression, tumor resistance and/or rejection, chronic infections, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhea), autoimmune diseases or disorders (such as rheumatoid arthritis), and immunologic tolerance and prevention of fetal rejection in utero, therapeutic agents aimed at suppression of 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 and therefore enhance T cell activation when the T cells are suppressed by pregnancy, malignancy or a virus such as HIV. Inhibition of IDO1 and/or TDO2 may also be an important treatment strategy for patients with neurological or neuropsychiatric diseases or disorders such as depression. The compounds, compositions and methods herein help meet the current need for IDO1 and TDO2 modulators.

In this disclosure, we describe novel structures related to imidazoisoindoles, with different electronic and heme binding properties, that can specifically inhibit IDO1 or TDO2, or that can exert combined inhibition of tryptophan degradation mediated by any of these enzymes.

In one aspect, the invention comprises compounds according to the formula (I),

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein

R 1 is C 1-6 alkyl, C 3-10 cycloalkyl, 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), —C 1 alkyl-C 3-10 cycloalkyl, —C 1 alkyl-3-7 membered heterocyclyl (e.g., a —C 1 alkyl-4-6 membered heterocyclyl or a —C 1 alkyl-5-6 membered heterocyclyl) or —C 1 alkyl-heteroaryl, wherein the C 3-10 cycloalkyl or 3-7 membered heterocyclyl is optionally fused to aryl, heteroaryl, C 3-8 cycloalkyl or 3-7 membered heterocyclyl; or wherein the C 3-10 cycloalkyl or 3-7 membered heterocyclyl is optionally substituted by =(spiro-C 3-7 cycloalkyl) or =(spiro-(3-7 membered heterocyclyl)); wherein R 1 is optionally substituted by one, two, three, or four R a groups independently selected from oxo, halogen, cyano, nitro, C 1-6 alkyl, —C 1-6 haloalkyl, C 1-6 alkyl-cyano, —OR, —NR 2 , —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) 2 R, —S(O) 2 OR, —S(O) 2 N(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 ;

n is 0, 1, 2, 3 or 4;

each R 2 is independently halogen, cyano, C 1-6 alkyl, C 3 cycloalkyl, —C 1-6 haloalkyl, —OR, —NR 2 or —SR; and

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

provided that

(a) when R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), no member of the 3-7 membered heterocyclyl is an —NH—; (b) when R 1 is C 1-6 alkyl, R 1 is substituted with —NR 2 or —OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl; and (c) when R 1 is C 3-10 cycloalkyl, 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), —C 1 alkyl-C 3-10 cycloalkyl, —C 1 alkyl-3-7 membered heterocyclyl (e.g., a —C 1 alkyl-4-6 membered heterocyclyl or a —C 1 alkyl-5-6 membered heterocyclyl) or —C 1 alkyl-heteroaryl, R 1 is substituted with —NR 2 or —OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl, or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl.

In an embodiment, the invention provides compounds of formula (I), wherein

R 1 is C 3-10 cycloalkyl, 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), —C 1 alkyl-C 3-10 cycloalkyl, —C 1 alkyl-3-7 membered heterocyclyl (e.g., a —C 1 alkyl-4-6 membered heterocyclyl or a —C 1 alkyl-5-6 membered heterocyclyl) or —C 1 alkyl-heteroaryl,

wherein the C 3-10 cycloalkyl or 3-7 membered heterocyclyl is optionally fused to aryl, heteroaryl, C 3-8 cycloalkyl or 3-7 membered heterocyclyl; or wherein the C 3-10 cycloalkyl or 3-7 membered heterocyclyl is optionally substituted by =(spiro-C 3-7 cycloalkyl) or =(spiro-(3-7 membered heterocyclyl)); wherein R 1 is optionally substituted by one, two, three, or four R a groups independently selected from oxo, halogen, cyano, nitro, C 1-6 alkyl, —C 1-6 haloalkyl, C 1-6 alkyl-cyano, —OR, —NR 2 , —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) 2 R, —S(O) 2 OR, —S(O) 2 N(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 ;

n is 0, 1, 2, 3 or 4; each R 2 is independently halogen, cyano, C 1-6 alkyl, C 3 cycloalkyl, —C 1-6 haloalkyl, —OR, —NR 2 or —SR; and each R is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl; provided that

(a) when R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), no member of the 3-7 membered heterocyclyl is an —NH—; and (b) when R 1 is C 3-10 cycloalkyl, 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), —C 1 alkyl-C 3-10 cycloalkyl, —C 1 alkyl-3-7 membered heterocyclyl (e.g., a —C 1 alkyl-4-6 membered heterocyclyl or a —C 1 alkyl-5-6 membered heterocyclyl) or —C 1 alkyl-heteroaryl, R 1 is substituted with —NR 2 or —OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl, or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl.

In an embodiment, the invention provides compounds of formula (I), wherein

R 1 is C 3-10 cycloalkyl, 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl),

›SUMMARY OF THE INVENTION · 2 of 2

(a) when R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), no member of the 3-7 membered heterocyclyl is an —NH—; and

(b) when R 1 is C 3-10 cycloalkyl, 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), R 1 is substituted with —NR 2 or —OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl, or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl.

In one embodiment of the compounds for Formula (I), R 1 is substituted with —OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl, or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl. In other embodiments, the invention comprises compounds of Formula (I) R 1 is substituted with —OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl, or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl and n is 0. In other embodiments, the invention comprises compounds of Formula (I) R 1 is substituted with —OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl, or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl and n is 1.

In an embodiment, the invention comprises compounds of Formula (II),

which are compounds of Formula (I) wherein

R 1 is

ring A is C 3-10 cycloalkyl or 3-7 membered heterocyclyl;

m is 0, 1, 2, 3 or 4; and

R 4 is —NR 2 or —OR.

In one embodiment, the invention comprises compounds 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.

In another embodiment, the invention comprises compounds of Formula (III),

which are compounds of Formula (I) wherein

R 1 is

is a fused bicyclic ring system consisting of a ring A and a ring B;

ring A is C 3-8 cycloalkyl or 3-7 membered heterocyclyl;

ring B is aryl, heteroaryl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;

m is 0, 1, 2, 3 or 4; and

the hydroxy moiety is bonded to the A ring and each R a is independently a substituent of

the A ring or the B ring.

In one embodiment, the invention comprises compounds of Formula (III) wherein n is 0. In other embodiments, n is 1.

In another embodiment, the invention comprises compounds of Formula (IV),

which are compounds of Formula (I) wherein

R 1 is

ring A and ring B form a spirocyclic system,

ring A is C 3-8 cycloalkyl or 3-7 membered heterocyclyl;

ring Bis C 3-7 cycloalkyl,3-7 membered heterocyclyl, aryl or heteroaryl;

m is 0, 1, 2, 3 or 4; and

the hydroxy moiety is bonded to the A ring and each R a is independently a substituent of the A ring or the B ring.

In one embodiment, the invention comprises compounds of Formula (IV) wherein n is 0. In other embodiments, n is 1.

In an embodiment, the invention comprises compounds of Formula (V),

which are compounds of Formula (I) wherein

R 1 is

ring A is C 3-10 cycloalkyl, 3-7 membered heterocyclyl or heteroaryl and R 4 is a substituent on the A ring or the methylene bonded to the A ring;

m is 0, 1, 2, 3 or 4; and

R 4 is —NR 2 or —OR.

In one embodiment, the invention comprises compounds 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.

In another aspect, pharmaceutical compositions are provided comprising a pharmaceutically acceptable excipient, diluent, or carrier, and a compound according to formula (I), (II), (III), (IV) or (V).

In another aspect, pharmaceutical compositions are provided comprising a pharmaceutically acceptable excipient, diluent, or carrier, a compound according to formula (I), (II), (III), (IV) or (V), and a second therapeutic agent.

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

In another aspect methods are provided for

a) modulating an activity of IDO1 or TDO2 in a cell-free system or in a cell (ex vivo or in vivo) comprising contacting an IDO1 or TDO2 with a modulation effective amount of a compound according to formula (I), or a pharmaceutical composition comprising a compound according to formula (I); b) treating IDO1 or TDO2 mediated immunosuppression in a subject in need thereof, comprising administering an effective inhibiting amount of a compound according to formula (I), or a pharmaceutical composition comprising a compound according to formula (I); c) treating a medical condition that benefits from the inhibition of tryptophan degradation mediated by IDO1 and/or TDO2 comprising administering an effective amount of a compound of formula (I), or a pharmaceutical composition comprising a compound according to formula (I); 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 e) treating immunosuppression associated with cancer comprising administering an effective amount of a compound according to formula (I), or a pharmaceutical composition comprising a compound according to formula (I).

In another aspect, the invention comprises use of any genus of compounds or species defined herein for the manufacture of a medicament for the treatment of medical conditions that benefit from the inhibition of enzymatic activity of IDO1 or TDO2.

In another aspect, the invention comprises any genus of compounds or species defined herein for use in the inhibition of enzymatic activity of IDO1 or TDO2 and the treatment of medical conditions that benefit from the inhibition of enzymatic activity of IDO1 or TDO2.

In another aspect, the invention comprises use of any genus of compounds or species defined herein for the treatment of immunosuppression associated with cancer, infectious diseases, or viral infections.

›DETAILED DESCRIPTION OF THE INVENTION · 1 of 10

The purpose of the present invention to develop small molecules that inhibit the enzymatic activity of TDO2. Alignment between IDO1 and IDO2 amino acid sequences reveals highly conserved features that mediate heme and substrate binding. Even though the amino acid sequence identity between IDO1 and IDO2 or IDO1 and TDO2 are not particularly high, significant residues determined to be important for catalytic activity by IDO1 and TDO2 mutagenesis and by crystallographic analysis are highly conserved between IDO1, IDO2 and TDO2, suggesting a structural and functional analogy in the mechanism of tryophan dioxygenation. Despite these structural similarities at the active site, IDO1 and TDO2 have different substrate specificity with TDO2 being almost exclusively specific for L-Trp and L-Trp derivatives substituted at the 5- and 6-positions of the indole group, while IDO1 can accept and oxygenate a wider variety of substrates such as D-Trp, tryptamine, serotonin and 1-methyl-L-Trp. These minor structural differences in the active site of IDO1 and TDO2 determine that these two proteins show differential response to the same enzymatic inhibitor molecules, with some inhibitors showing TDO2-specific response, others showing IDO1-specific response and some showing dual IDO1 and TDO2 inhibition. Moreover, the specificity of IDO1 and TDO2 inhibition by a particular class of small molecule inhibitors depends on whether IDO1 and TDO2 activity is measured using bioassays that employ recombinant purified IDO1 or TDO2 protein, or IDO1 or TDO2 protein expressed within a cell. For example, compounds described in patent applications WO2012142237 and WO2014159248 show potent IDO1 inhibition when tested against the purified recombinant protein and against cellularly expressed IDO1, or against recombinant purified TDO2 protein. However, compounds of that class show a remarkable 10-100 fold decreased potency when tested against TDO2 expressed within a cell. Therefore, those compounds are not likely to contribute to significant inhibition of TDO2 in vivo. For this reason, the present invention describes a novel class of molecules that show potent TDO2 inhibition in cellular bioassays and in vivo.

In one aspect, the invention provides compounds of formula (I),

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein

In one embodiment, the invention provides compounds of formula (I), wherein

(a) when R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), no member of the 3-7 membered heterocyclyl is an —NH—; (b) when R 1 is C 3-10 cycloalkyl, 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), —C 1 alkyl-C 3-10 cycloalkyl, —C 1 alkyl-3-7 membered heterocyclyl (e.g., a —C 1 alkyl-4-6 membered heterocyclyl or a —C 1 alkyl-5-6 membered heterocyclyl) or a -C 1 alkyl-heteroaryl, R 1 is substituted with —NR 2 or —OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl, or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl.

›DETAILED DESCRIPTION OF THE INVENTION · 2 of 10

In another embodiment, the invention provides compounds of formula (I), wherein

R 1 is C 3-10 cycloalkyl or 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl),

(a) when R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), no member of the 3-7 membered heterocyclyl is an —NH—; and (b) when R 1 is C 3-10 cycloalkyl, 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), R 1 is substituted with —NR 2 or —OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl, or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl.

In another embodiment, the invention provides compounds of formula (I),

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein

R 1 is —C 1 alkyl-C 3-10 cycloalkyl, —C 1 alkyl-3-7 membered heterocyclyl (e.g., a —C 1 alkyl-4-6 membered heterocyclyl or a —C 1 alkyl-5-6 membered heterocyclyl) or —C 1 alkyl-heteroaryl,

wherein the C 3-10 cycloalkyl, 3-7 membered heterocyclyl or heteroaryl is optionally fused to aryl, heteroaryl, C 3-8 cycloalkyl or 3-7 membered heterocyclyl; or wherein the C 3-10 cycloalkyl or 3-7 membered heterocyclyl is optionally substituted by =(spiro-C 3-7 cycloalkyl) or =(spiro-(3-7 membered heterocyclyl)); wherein R 1 is optionally substituted by one, two, three, or four R a groups independently selected from oxo, halogen, cyano, nitro, C 1-6 alkyl, —C 1-6 haloalkyl, C 1-6 alkyl-cyano, —OR, —NR 2 , —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) 2 R, —S(O) 2 OR, —S(O) 2 N(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 ;

(a) when R 1 is —C 1 alkyl-C 3-10 cycloalkyl, —C 1 alkyl-3-7 membered heterocyclyl (e.g., a —C 1 alkyl-4-6 membered heterocyclyl or a —C 1 alkyl-5-6 membered heterocyclyl) or —C 1 alkyl-heteroaryl, R 1 is substituted with —NR 2 or —OH on the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl, or on a carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl.

The invention further comprises subgenera and species of formula (I) that are any combination of species and genera of structural formula (I), n, R 1 , and R 2 , as defined herein below. So, for example, the invention also comprises the subgenus of compounds of structural formula (I) where n is defined as in (1c) below, R 1 is defined in (2h) below, and R 2 is defined in (3k) below.

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

(1a) n is 1, 2, 3, or 4. (1b) n is 0, 1, 2, or 3. (1c) n is 0, 1, or 2. (1d) n is 0 or 1. (1e) n is 1 or 2. (1f) n is 2 or 3. (1g) n is 1. (1h) n is 2. (1i) nis 3. (1j) n is 4. (1k) n is 0.

R 2 is selected from one of the following groups (2a)-(2t):

(2a) R 2 is independently halogen, cyano, C 1-6 alkyl, C 3 cycloalkyl, —C 1-6 haloalkyl, —OR, or —NR 2 . (2b) R 2 is independently halogen, cyano, C 1-6 alkyl, C 3 cycloalkyl, —OR, or —NR 2 . (2c) R 2 is independently halogen, cyano, C 1-6 alkyl, C 3 cycloalkyl, or —OR. (2d) R 2 is independently halogen, C 1-6 alkyl, C 3 cycloalkyl, or —OR. (2e) R 2 is independently halogen, cyano, C 1-6 alkyl, or —OR. (2f) R 2 is independently halogen, C 1-6 alkyl or —OR. (2g) R 2 is independently halogen or —OR. (2h) R 2 is independently C 1-6 alkyl or —OR. (2i) R 2 is independently-OR. (2j) R 2 is independently halogen, methyl or —OR. (2k) R 2 is independently halogen, methyl, —OH or —OMe. (2i) R 2 is independently chloro, fluoro, methyl or —OR. (2m) R 2 is independently chloro, fluoro, methyl, —OH or —OMe. (2n) R 2 is independently chloro, fluoro, methyl or —OH. (2o) R 2 is independently fluoro, methyl or —OH. (2p) R 2 is independently fluoro or —OH. (2q) R 2 is independently fluoro or methyl. (2r) R 2 is fluoro. (2s) R 2 is methyl. (2t) R 2 is —OH.

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

(3a) R 1 is C 3-10 cycloalkyl or 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl),

wherein the C 3-10 cycloalkyl or 3-7 membered heterocyclyl is optionally fused to aryl, heteroaryl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; or wherein the C 3-10 cycloalkyl or 3-7 membered heterocyclyl is optionally substituted by =(spiro-C 3-7 cycloalkyl) or =(spiro-(3-7 membered heterocyclyl)); wherein R 1 is optionally substituted by one, two, three, or four R a groups independently selected from oxo, halogen, cyano, nitro, C 1-6 alkyl, —C 1-6 haloalkyl, C 1-6 alkyl-cyano, —OR, —NR 2 , —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) 2 R, —S(O) 2 OR, —S(O) 2 N(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 .

›DETAILED DESCRIPTION OF THE INVENTION · 3 of 10

(3b) Group (3a), wherein R 1 is C 4-6 cycloalkyl or 5-6 membered heterocyclyl,

wherein the C 4-6 cycloalkyl or 5-6-membered heterocyclyl is optionally fused to aryl or heteroaryl; or wherein the C 4-6 cycloalkyl is optionally substituted by =(spiro-C 4 cycloalkyl) or =(spiro-(4-membered heterocyclyl)).

(3c) Group (3a), wherein R 1 is C 4-6 cycloalkyl or 5-6 membered heterocyclyl,

wherein the C 4-6 cycloalkyl or 5-6 membered heterocyclyl is optionally fused to aryl or heteroaryl; or wherein the C 4-6 cycloalkyl or 5-6 membered heterocyclyl is optionally substituted by =(spiro-C 4 cycloalkyl) or =(spiro-(4-membered heterocyclyl)).

(3d) Group (3a), wherein R 1 is cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl,

wherein the cyclopentyl is optionally fused to phenyl, the cyclohexyl is optionally fused to pyridinyl or phenyl, and the piperidinyl is optionally fused to pyrrolidinyl or phenyl; or wherein the cyclobutyl is optionally substituted by =(spiro-cyclobutyl) or =(spiro-azetidinyl).

(3e) Group (3a), wherein R 1 is C 3-10 cycloalkyl or 3-7 membered heterocyclyl. (3f) Group (3a), wherein R 1 is C 3-10 cycloalkyl. (3g) Group (3a), wherein R 1 is C 5-8 bridged bicyclic. (3h) Group (3a), wherein R 1 is cyclobutyl or cyclopentyl. (3i) Group (3a), wherein R 1 is cyclobutyl. (3j) Group (3a), wherein R 1 is cyclopentyl. (3k) Group (3a), wherein R 1 is 3-7 membered heterocyclyl. (3l) Group (3a), wherein R 1 is pyrrolidinyl or piperdinyl. (3m) Group (3a), wherein R 1 is pyrrolidinyl. (3n) Group (3a), wherein R 1 is piperdinyl. (3o) Group (3a), wherein R 1 is C 3-8 cycloalkyl or 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), wherein the C 3-8 cycloalkyl or 3-7 membered heterocyclyl is fused to aryl, heteroaryl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl. (3p) Group (3a), wherein R 1 is C 3-8 cycloalkyl,

wherein the C 3-8 cycloalkyl is fused to aryl, heteroaryl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl.

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

wherein the C 3-8 cycloalkyl is fused to heteroaryl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl.

(3r) Group (3a), wherein R 1 is C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is fused to aryl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl. (3s) Group (3a), wherein R 1 is C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is fused to aryl, heteroaryl, or 3-7 membered heterocyclyl. (3t) Group (3a), wherein R 1 is C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is fused to aryl, heteroaryl or C 3-7 cycloalkyl. (3u) Group (3a), wherein R 1 is C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is fused to aryl. (3v) Group (3a), wherein R 1 is C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is fused to heteroaryl. (3w) Group (3a), wherein R 1 is C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is fused to C 3-7 cycloalkyl. (3x) Group (3a), wherein R 1 is C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is fused to 3-7 membered heterocyclyl. (3y) Group (3a), wherein R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl),

wherein the 3-7 membered heterocyclyl is fused to aryl, heteroaryl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl.

(3z) Group (3a), wherein R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl),

wherein the 3-7 membered heterocyclyl is fused to heteroaryl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl.

(3aa) Group (3a), wherein R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl),

wherein the 3-7 membered heterocyclyl is fused to aryl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl.

(3bb) Group (3a), wherein R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl),

wherein the 3-7 membered heterocyclyl is fused to aryl, heteroaryl, or 3-7 membered heterocyclyl.

(3cc) Group (3a), wherein R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl),

wherein the 3-7 membered heterocyclyl is fused to aryl, heteroaryl or C 3-7 cycloalkyl.

(3dd) Group (3a), wherein R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), wherein the 3-7 membered heterocyclyl is fused to aryl. (3ee) Group (3a), wherein R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), wherein the 3-7 membered heterocyclyl is fused to heteroaryl. (3ff) Group (3a), wherein R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), wherein the 3-7 membered heterocyclyl is fused to C 3-7 cycloalkyl. (3gg) Group (3a), wherein R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), wherein the 3-7 membered heterocyclyl is fused to 3-7 membered heterocyclyl. (3hh) Group (3a), wherein R 1 is C 3-10 cycloalkyl or 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), wherein the C 3-7 cycloalkyl or 3-7 membered heterocyclyl is substituted by =(spiro-C 3-8 cycloalkyl) or =(spiro-(3-7 membered heterocyclyl)). (3ii) Group (3a), wherein R 1 is C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is substituted by =(spiro-C 3-7 cycloalkyl). (3jj) Group (3a), wherein R 1 is C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is substituted by =(spiro-(3-7 membered heterocyclyl)). (3kk) Group (3a), wherein R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), wherein the 3-7 membered heterocyclyl is substituted by =(spiro-C 3-7 cycloalkyl). (3ll) Group (3a), wherein R 1 is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), wherein the 3-7 membered heterocyclyl is substituted by =(spiro-(3-7 membered heterocyclyl)). (3mm) Any of groups (3b)-(3ll), wherein R 1 is substituted by at least one R a group selected from —OR and —NR 2 . (3nn) Any of groups (3b)-(3ll), wherein R 1 is substituted by at least one R a group selected from —OR. (3oo) Any of groups (3b)-(3ll), wherein R 1 is substituted by at least one R a group selected from —NR 2 . (3pp) Any of groups (3b)-(3oo), wherein R 1 is substituted by one, two or three R a groups independently selected from oxo, halogen, cyano, nitro, C 1-6 alkyl, —C 1-6 haloalkyl, C 1-6 alkyl-cyano, —OR, —NR 2 , —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) 2 R, —S(O) 2 OR, —S(O) 2 N(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 . (3qq) Any of groups (3b)-(3oo), wherein R 1 is substituted by one, two or three R a groups independently selected from oxo, halogen, C 1-6 alkyl, —C 1-6 haloalkyl, C 1-6 alkyl-cyano, —OR, —NR 2 , —S(O) 2 R, —S(O) 2 OR, —S(O) 2 N(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 . (3rr) Any of groups (3b)-(3oo), wherein R 1 is substituted by one, two or three R a groups independently selected from 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) 2 R, —S(O) 2 OR, —S(O) 2 N(R) 2 , —OC(O)R, —OC(O)OR and —OC(O)N(R) 2 . (3ss) Any of groups (3b)-(3oo), wherein R 1 is substituted by one, two or three R a groups independently selected from 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) 2 R, —S(O) 2 OR, —S(O) 2 N(R) 2 , —N(R)C(O)R, —N(R)C(O)OR, and —N(R)C(O)N(R) 2 . (3tt) Any of groups (3b)-(3oo), wherein R 1 is substituted by one, two or three R a groups independently selected from oxo, halogen, C 1-6 alkyl, —C 1-6 haloalkyl, C 1-6 alkyl-cyano, —OR, —S(O) 2 R, —S(O) 2 OR and —S(O) 2 N(R) 2 . (3uu) Any of groups (3b)-(3oo), wherein R 1 is substituted by one, two or three R a groups independently selected from oxo, halogen, C 1-6 alkyl, —C 1-6 haloalkyl, C 1-6 alkyl-cyano, —OR, —S(O) 2 R, —S(O) 2 OR and —S(O) 2 N(R) 2 . (3vv) Any of groups (3b)-(3oo), wherein R 1 is substituted by one, two or three R a groups independently selected from C 1-6 alkyl, —OR, —S(O) 2 R, —S(O) 2 OR and —S(O) 2 N(R) 2 . (3ww) Any of groups (3b)-(3oo), wherein R 1 is substituted by one, two or three R a groups independently selected from oxo, halogen, C 1-6 alkyl, —OR, —S(O) 2 R, —S(O) 2 OR and —S(O) 2 N(R) 2 . (3xx) Any of groups (3b)-(3oo), wherein R 1 is substituted by one, two or three R a groups independently selected from oxo, halogen, C 1-6 alkyl, —OR, —S(O) 2 R and —S(O) 2 N(R) 2 . (3yy) Any of groups (3b)-(3oo), wherein R 1 is substituted by one, two or three R a groups independently selected from C 1-6 alkyl, —OR, —S(O) 2 R and —S(O) 2 N(R) 2 . (3zz) Any of groups (3b)-(3oo), wherein R 1 is substituted by one or two R a groups independently selected from C 1-6 alkyl, —OR, —S(O) 2 R and —S(O) 2 N(R) 2 . (3aaa) Any of groups (3b)-(3oo), wherein R 1 is substituted by one or two R a groups independently selected from C 1-6 alkyl, —OR and —S(O) 2 N(R) 2 . (3bbb) Any of groups (3b)-(3oo), wherein R 1 is substituted by one or two R a groups independently selected from C 1-6 alkyl, —OR and —S(O) 2 R. (3ccc) Any of groups (3b)-(3oo), wherein R 1 is substituted by one or two R a groups independently selected from C 1-6 alkyl and —OR. (3ddd) Any of groups (3b)-(3oo), wherein R 1 is substituted by one or two R a groups independently selected from methyl, ethyl, propyl, -iso-propyl, —OMe and —OH. (3eee) Any of groups (3b)-(3oo), wherein R 1 is substituted by one or two R a groups independently selected from methyl and ethyl. (3fff) Any of groups (3b)-(3oo), wherein R 1 is substituted by one R a group independently selected from C 1-6 alkyl, —OR, —S(O) 2 R and —S(O) 2 N(R) 2 . (3ggg) Any of groups (3b)-(3oo), wherein R 1 is substituted by one R a group independently selected from C 1-6 alkyl, —OR and —S(O) 2 N(R) 2 . (3hhh) Any of groups (3b)-(3oo), wherein R 1 is substituted by one R a group independently selected from C 1-6 alkyl, —OR and —S(O) 2 R. (3iii) Any of groups (3b)-(3oo), wherein R 1 is substituted by one R a group independently selected from C 1-6 alkyl and —OR. (3jjj) Any of groups (3b)-(3oo), wherein R 1 is substituted by one R a group independently selected from methyl, ethyl, propyl, -iso-propyl, —OMe and —OH. (3kkk) Any of groups (3b)-(3oo), wherein R 1 is substituted by one R a group independently selected from methyl and ethyl. (3lll) Any of groups (3b)-(3oo), wherein R 1 is substituted by one methyl group. (3mmm) Any of groups (3b)-(3oo), wherein R 1 is substituted by one ethyl group. (3nnn) R 1 is C 1-6 alkyl, C 3-10 cycloalkyl, 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), —C 1 alkyl-C 3-10 cycloalkyl, —C 1 alkyl-3-7 membered heterocyclyl (e.g., a —C 1 alkyl-4-6 membered heterocyclyl or a —C 1 alkyl-5-6 membered heterocyclyl) or —C 1 alkyl-heteroaryl

›DETAILED DESCRIPTION OF THE INVENTION · 4 of 10

(3ooo) Group (3nnn), wherein R 1 is C 1-6 alkyl, C 4-6 cycloalkyl or 5-6 membered heterocyclyl,

wherein the C 4-6 cycloalkyl or 5-6-membered heterocyclyl is optionally fused to aryl or heteroaryl; or wherein the C 4 cycloalkyl is optionally substituted by =(spiro-C 4 cycloalkyl) or =(spiro-(4-membered heterocyclyl)).

(3ppp) Group (3nnn), wherein R 1 is C 1-6 alkyl, C 4-6 cycloalkyl or 5-6 membered heterocyclyl,

(3qqq) Group (3nnn), wherein R 1 is C 1-6 alkyl. (3rrr) Group (3nnn), wherein R 1 is methyl, ethyl, propyl, butyl, pentyl or hexyl. (3sss) Group (3nnn), wherein R 1 is methyl, ethyl, propyl or butyl. (3ttt) Group (3nnn), wherein R 1 is methyl, ethyl or butyl. (3uuu) Group (3nnn), wherein R 1 is methyl or ethyl. (3vvv) Group (3nnn), wherein R 1 is methyl. (3www) Group (3nnn), wherein R 1 is ethyl. (3xxx) Group (3nnn), wherein R 1 is butyl. (3yyy) Any of groups (3nnn)-(3xxx), wherein R 1 is substituted by one or two R a groups independently selected from halogen, C 1-6 alkyl, —C 1-6 haloalkyl, C 3 cycloalkyl or —OR. (3zzz) Any of groups (3nnn)-(3xxx), wherein R 1 is substituted by C 3 cycloalkyl and —OH. (3aaaa) Any of groups (3nnn)-(3xxx), wherein R 1 is substituted by one or two —OH. (3bbbb) Any of groups (3nnn)-(3xxx), wherein R 1 is substituted by one —OH. (3cccc) Any of groups (3nnn)-(3xxx), wherein R 1 is substituted by two —OH.

The invention further comprises subgenera and species of formula (I) that are any combination of species and genera of structural formula (I) can be any of formula (Ia)-(Ii) wherein n, R 2 and R 1 are defined above. So, for example, the invention also comprises the subgenus of compounds of structural formula (Ie) where n is defined as in (1g) above, and R 2 is defined in (2r) above.

Structural Formula I is One of Formulae (Ia)-(Ii):

Particular embodiments of this aspect of the invention include compounds of any one of the formulae (I) and (Ia)-(Ii), each as defined in each of the following rows, wherein each entry is a group number as defined above (e.g., (2r) refers to R 2 is fluoro), an “X” indicates that the variable is defined by another group in the embodiment (e.g., in embodiment (1)-X below, R 1 is defined in Formula (X)) and a dash “-” indicates that the variable is as defined for Formula (I) or (Ia)-(Ii) or defined according to any one of the applicable variable definitions (1a)-(3cccc) [e.g., when the entry for R 2 is a dash, it can be either as defined for Formula (I)—(IVi) or any one of definitions (2a)-(2t)]:

In an embodiment, the invention comprises compounds of Formula (II),

which is a compound of Formula (I) wherein

R 1 is

ring A is C 3-10 cycloalkyl or 3-7 membered heterocyclyl;

m is 0, 1, 2, 3 or 4; and

R 4 is —NR 2 or —OR.

In one embodiment, the invention comprises compounds 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.

The invention further comprises subgenera of formula (II) in which the substituents are selected as any and all combinations of one or more of structural formula (II), R 2 , R a , m and ring A, as defined herein, including without limitation, the following:

Structural Formula I is One of Formulae (Ia)-(II):

Ring A is selected from one of the following groups (4a)-(4ccc);

(4a) Ring A is C 3-10 cycloalkyl or 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl),

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

(4b) R 1 is:

In another embodiment, the invention comprises compounds of Formula (III),

which are compounds for Formula (I) wherein

R 1 is

is a fused bicyclic ring system consisting of a ring A and a ring B;

ring A is C 3-8 cycloalkyl or 3-7 membered heterocyclyl;

ring B is aryl, heteroaryl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;

m is 0, 1, 2, 3 or 4; and

the hydroxy moiety is bonded to the A ring and each R a is independently a substituent of

the A ring or the B ring.

In one embodiment, the invention comprises compounds of Formula (III) wherein n is 0. In other embodiments, n is 1.

The invention further comprises subgenera of formula (III) in which the substituents are selected as any and all combinations of one or more of structural formula (III), R 2 , R a , m, ring A and ring B, as defined herein, including without limitation, the following:

Structural Formula I is One of Formulae (IIIa)-(IIIi):

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

(5a) Ring A is C 3-8 cycloalkyl or 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), and ring B is aryl, heteroaryl, C 3-8 cycloalkyl or 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl),

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) 2 R and —S(O) 2 N(R) 2 .

(5b) Group (5a), wherein ring A is C 5-6 cycloalkyl, and ring B is aryl or heteroaryl. (5c) Group (5a), wherein ring A is cyclopentyl or cyclohexyl, and ring B is aryl or heteroaryl. (5d) Group (5a), wherein ring A is C 5-6 cycloalkyl, and ring B is phenyl or pyridinyl. (5e) Group (5a), wherein ring A is cyclopentyl or cyclohexyl, and ring B is phenyl or pyridinyl. (5f) Group (5a), wherein ring A is C 3-8 cycloalkyl, and ring B is aryl, heteroaryl, C 3-8 cycloalkyl or 3-7 membered heterocyclyl. (5g) Group (5a), wherein ring A is cyclopropyl, and ring B is aryl, heteroaryl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl. (5h) Group (5a), wherein ring A is cyclobutyl, and ring B is aryl, heteroaryl, C 3-8 cycloalkyl or 3-7 membered heterocyclyl. (5i) Group (5a), wherein ring A is cyclopentyl or cyclohexyl, and ring B is aryl, heteroaryl, C 3-8 cycloalkyl or 3-7 membered heterocyclyl. (5j) Group (5a), wherein ring A is C 3-8 cycloalkyl, and ring B is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, oxazolyl or oxadiazolyl. (5k) Group (5a), wherein ring A is cyclopentyl or cyclohexyl, and ring B is aryl. (5l) Group (5a), wherein ring A is cyclopentyl or cyclohexyl, and ring B is phenyl. (5m) Group (5a), wherein ring A is cyclopentyl, and ring B is heteroaryl. (5n) Group (5a), wherein ring A is cyclopentyl or cyclohexyl, and ring B is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, oxazolyl or oxadiazolyl. (5o) Group (5a), wherein ring A is cyclopentyl, and ring B is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, oxazolyl or oxadiazolyl. (5p) Group (5a), wherein ring A is cyclohexyl, and ring B is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, oxazolyl or oxadiazolyl. (5q) Group (5a), wherein ring A is cyclohexyl, and ring B is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. (5r) Group (5a), wherein ring A is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), and ring B is aryl, heteroaryl, C 3-8 cycloalkyl or 3-7 membered heterocyclyl. (5s) Group (5a), wherein ring A is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), and ring B is aryl, or heteroaryl. (5t) Group (5a), wherein ring A is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), and ring B is aryl. (5u) Group (5a), wherein ring A is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), and ring B is heteroaryl. (5v) Group (5a), wherein ring A is piperdinyl, and ring B is aryl. (5w) Group (5a), wherein ring A is piperdinyl, and ring B is heteroaryl. (5x) Any of groups (5b)-(5w), wherein 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) 2 R and —S(O) 2 N(R) 2 . (5y) Any of groups (5b)-(5w), wherein m is 1, 2 or 3, and each R a is independently selected from methyl, —OH, —S(O) 2 ethyl, —C(O)NH 2 , —C(O)N(Me)(H), —S(O) 2 NMe 2 and —S(O) 2 NH 2 . (5z) Any of groups (5b)-(5w), wherein m is 1 or 2, and each R a is independently selected from C 1-6 alkyl, —OR, —S(O) 2 R and —S(O) 2 N(R) 2 . (5aa) Any of groups (5b)-(5w), wherein m is 3, and each R a is independently selected from C 1-6 alkyl and —OR. (5bb) Any of groups (5b)-(5w), wherein m is 3, and each R a is independently selected from methyl and —OH. (5cc) Any of groups (5b)-(5w), wherein m is 2, and each R a is independently selected from C 1-6 alkyl and —OR. (5dd) Any of groups (5b)-(5w), wherein m is 2, and each R a is independently selected from methyl and —OH. (5ee) Any of groups (5b)-(5w), wherein m is 1, and R a is selected from C 1-6 alkyl, —OR, —C(O)N(R) 2 , —S(O) 2 R and —S(O) 2 N(R) 2 . (5ff) Any of groups (5b)-(5w), wherein m is 1, and R a is selected from C 1-6 alkyl, —OR and —S(O) 2 N(R) 2 . (5gg) Any of groups (5b)-(5w), wherein m is 1, and R a is selected from C 1-6 alkyl, —OR and —S(O) 2 R. (5hh) Any of groups (5b)-(5w), wherein m is 1, and R a is selected from C 1-6 alkyl and —OR. (5ii) Any of groups (5b)-(5w), wherein m is 1, and R a is selected from methyl, —C(O)NH 2 , —C(O)N(Me)(H), and —OH. (5jj) Any of groups (5b)-(5w), wherein m is 1, and R a is selected from C 1-6 alkyl, —S(O) 2 R and —S(O) 2 N(R) 2 . (5kk) Any of groups (5b)-(5w), wherein m is 1, and R a is C 1-6 alkyl. (5ll) Any of groups (5b)-(5w), wherein m is 1, and R a is methyl or ethyl. (5mm) Any of groups (5b)-(5w), wherein m is 1, and R a is methyl. (5nn) Any of groups (5b)-(5w), wherein m is 1, and R a is —OMe or —OH. (5oo) Any of groups (5b)-(5w), wherein m is 0. (5pp) R 1 is

›DETAILED DESCRIPTION OF THE INVENTION · 5 of 10

(5qq) R 1 is

(5rr) R 1 is

(5ss) R 1 is

(5tt) R 1 is

(5uu) R 1 is

(5vv) R 1 is

(5ww) R 1 is

(5xx) R 1 is

(5yy) R 1 is

In another embodiment, the invention comprises compounds of Formula (IV),

which are compounds of Formula (I) wherein

R 1 is

ring A and ring B form a spirocyclic system,

ring A is C 3-8 cycloalkyl or 3-7 membered heterocyclyl;

ring B is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, aryl or heteroaryl;

m is 0, 1, 2, 3 or 4; and

the hydroxy moiety is bonded to the A ring and each R a is independently a substituent of the A ring or the Bring.

In one embodiment, the invention comprises compounds of Formula (IV) wherein n is 0. In other embodiments, n is 1.

The invention further comprises subgenera of formula (IV) in which the substituents are selected as any and all combinations of one or more of structural formula (IV), R 2 , R a , m, ring A and ring B, as defined herein, including without limitation, the following:

Structural Formula I is One of Formulae (IVa)-(IVi):

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

(6a) Ring A is C 3-8 cycloalkyl or 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), and ring B is C 3-8 cycloalkyl or 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), aryl or heteroaryl,

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

(6b) Group (6a), wherein ring A is C 4-5 cycloalkyl or 4-6 membered heterocyclyl, and ring B is C 4-6 cycloalkyl or 4-6 membered heterocyclyl. (6c) Group (6a), wherein ring A is C 3-8 cycloalkyl, and ring B is C 3-8 cycloalkyl or 3-7 membered heterocyclyl. (6d) Group (6a), wherein ring A is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), and ring B is C 3-7 cycloalkyl. (6e) Group (6a), wherein ring A is C 3-8 cycloalkyl or 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), and ring B is C 3-7 cycloalkyl. (6f) Group (6a), wherein ring A is C 3-8 cycloalkyl or 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), and ring B is 3-7 membered heterocyclyl. (6g) Group (6a), wherein ring A is C 3-8 cycloalkyl, and ring B is aryl or heteroaryl. (6h) Group (6a), wherein ring A is C 3-8 cycloalkyl, and ring B is 3-7 membered heterocyclyl. (6i) Group (6a), wherein ring A is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), and ring B is aryl. (6j) Group (6a), wherein ring A is 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl), and ring B is heteroaryl. (6k) Group (6a), wherein ring A is cyclobutyl, and ring B is C 3-8 cycloalkyl or 3-7 membered heterocyclyl. (6l) Group (6a), wherein ring A is cyclobutyl, and ring B is C 3-8 cycloalkyl. (6m) Group (6a), wherein ring A is cyclobutyl, and ring B is cyclobutyl. (6n) Group (6a), wherein ring A is cyclobutyl, and ring B is 3-7 membered heterocyclyl. (60) Group (6a), wherein ring A is cyclobutyl, and ring B is 4-6 membered heterocyclyl. (6p) Group (6a), wherein ring A is cyclobutyl, and ring B is 4-membered heterocyclyl. (6q) Group (6a), wherein ring A is cyclobutyl, and ring B is 5-membered heterocyclyl. (6r) Group (6a), wherein ring A is cyclobutyl, and ring B is 6-membered heterocyclyl. (6s) Group (6a), wherein ring A is cyclobutyl, and ring B is azetidinyl, oxatanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl or tetrahydropyranyl. (6t) Group (6a), wherein ring A is cyclobutyl, and ring B is azetidinyl, oxatanyl, piperidinyl or tetrahydropyranyl. (6u) Group (6a), wherein ring A is cyclobutyl, and ring B is azetidinyl or oxatanyl. (6v) Group (6a), wherein ring A is cyclobutyl, and ring B is piperidinyl or tetrahydropyranyl. (6w) Group (6a), wherein ring A is cyclobutyl, and ring B is azetidinyl or piperidinyl. (6x) Group (6a), wherein ring A is cyclobutyl, and ring B is oxatanyl or tetrahydropyranyl. (6y) Any 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) 2 R and —S(O) 2 N(R) 2 . (6z) Any of groups (6b)-(6x), wherein m is 1, 2 or 3, and each R a is independently selected from chloro, fluoro, methyl, —OH, —S(O) 2 ethyl, —S(O) 2 NMe 2 . and —S(O) 2 NH 2 . (6aa) Any 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) 2 R and —S(O) 2 N(R) 2 . (6bb) Any of groups (6b)-(6x), wherein m is 3, and each R a is independently selected from halogen, C 1-6 alkyl and —OR. (6cc) Any of groups (6b)-(6x), wherein m is 3, and each R a is independently selected from fluoro, methyl and —OH. (6dd) Any of groups (6b)-(6x), wherein m is 2, and each R a is independently selected from C 1-6 alkyl and —OR. (6ee) Any of groups (6b)-(6x), wherein m is 2, and each R a is independently selected from methyl and —OH. (6ff) Any of groups (6b)-(6x), wherein m is 2, and both R a are methyl. (6gg) Any of groups (6b)-(6x), wherein m is 2, and both R a are fluoro. (6hh) Any of groups (6b)-(6x), wherein m is 1, and R a is selected from C 1-6 alkyl, —OR, —S(O) 2 R and —S(O) 2 N(R) 2 . (6ii) Any of groups (6b)-(6x), wherein m is 1, and R a is selected from C 1-6 alkyl, —OR and —S(O) 2 N(R) 2 . (6jj) Any of groups (6b)-(6x), wherein m is 1, and R a is selected from C 1-6 alkyl, —OR and —S(O) 2 R. (6kk) Any of groups (6b)-(6x), wherein m is 1, and R a is selected from C 1-6 alkyl and —OR. (6ll) Any of groups (6b)-(6x), wherein m is 1, and R a is selected from methyl and —OH. (6mm) Any of groups (6b)-(6x), wherein m is 1, and R a is selected from C 1-6 alkyl, —S(O) 2 R and —S(O) 2 N(R) 2 . (6nn) Any of groups (6b)-(6x), wherein m is 1, and R a is C 1-6 alkyl. (6oo) Any of groups (6b)-(6x), wherein m is 1, and R a is methyl or ethyl. (6pp) Any of groups (6b)-(6x), wherein m is 1, and R a is methyl. (6qq) Any of groups (6b)-(6x), wherein m is 1, and R a is —OMe or —OH. (6rr) Any of groups (6b)-(6x), wherein m is 0. (6ss) R 1 is

›DETAILED DESCRIPTION OF THE INVENTION · 6 of 10

wherein

R 3 is methyl, ethyl, propyl, butyl, —O-methyl, —O-ethyl, —O-propyl, or —O-butyl.

(6tt) R 1 is

(6uu) R 1 is

(6vv) R 1 is

(6ww) R 1 is

(6xx) R 1 is

(6yy) R 1 is

(6zz) R 1 is

In another embodiment, the invention comprises compounds of Formula (V),

wherein

ring A is C 3-10 cycloalkyl, 3-7 membered heterocyclyl or heteroaryl; m is 0, 1, 2, 3 or 4; and R 4 is —NR 2 or —OR substituted on the A ring or the methylene bonded to the A ring.

In one embodiment, the invention comprises compounds 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.

The invention further comprises subgenera of formula (V) in which the substituents are selected as any and all combinations of one or more of structural formula (V), R 4 , R a , m, and ring A, as defined herein, including without limitation, the following:

Structural Formula I is One of Formulae (Va)-(Vf):

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

(7a) Ring A is C 3-8 cycloalkyl, 3-7 membered heterocyclyl or heteroaryl,

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

(7b) Group (7a), wherein ring A is C 3-6 cycloalkyl, 4-6 membered heterocyclyl or heteroaryl. (7c) Group (7a), wherein ring A is (7d)

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

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

(7g) Group (7a), wherein ring A is cyclopropyl.

(7h) Group (7a), wherein ring A is cyclohexyl.

(7i) Group (7a), wherein ring A is 3-7 membered heterocyclyl.

(7j) Group (7a), wherein ring A is 4-6 membered heterocyclyl.

(7k) Group (7a), wherein ring A is 4-membered heterocyclyl.

(7l) Group (7a), wherein ring A is 5-membered heterocyclyl.

(7m) Group (7a), wherein ring A is 6-membered heterocyclyl.

(7n) Any of groups (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) 2 R, —C(O)N(R) 2 and C 1-6 alkyl-cyano.

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

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

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

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

(7s) Group (7m), wherein each R a is halogen.

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

(7u) Group (7m), wherein each R a is —S(O) 2 R.

(7v) Group (7m), wherein each R a is —C(O)N(R) 2 .

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

(7x) Any of groups (7b)-(7v), wherein m is 0, 1, 2 or 3.

(7y) Any of groups (7b)-(7v), wherein m is 0, 1 or 2.

(7z) Any of groups (7b)-(7v), wherein m is 0 or 1.

(7aa) Any of groups (7b)-(7v), wherein m is 3.

(7bb) Any of groups (7b)-(7v), wherein m is 2.

(7cc) Any of groups (7b)-(7v), wherein m is 1.

(7dd) Any of groups (7b)-(7v), wherein m is 0.

Particular embodiments of this aspect of the invention include compounds of any one of the formulae (II), (IIa)-(IIi), (III), (IIIa)-(IIIi), (IV) and (IVa)-(IVi), (V) and (Va)-(Vf) each as defined in each of the following rows, wherein each entry is a group number as defined above (e.g., (2r) refers to R 2 is fluoro), an “X” indicates that the variable is defined by another group in the embodiment (e.g., in embodiment (2)-X below, ring A is defined in Formula (X)) and a dash “-” indicates that the variable is as defined for Formula (I)—(Vf) or defined according to any one of the applicable variable definitions (1a)-(7xx) [e.g., when the entry for R 2 is a dash, it can be either as defined for Formula (II)—(Vf) or any one of definitions (2a)-(2t)]:

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

In another embodiment, the compounds of the invention are of Formulae (IIk) or (IIl),

which are compounds of Formula (I) wherein,

R 1 is

ring A is C 3-10 cycloalkyl or 3-7 membered heterocyclyl (e.g., a 4-6 membered heterocyclyl or a 5-6 membered heterocyclyl),

m is 0, 1, 2, 3 or 4; and 1

R 4 is —NR 2 or —OR.

In another aspect, the present disclosure provides compounds that are:

No.

Structure

Name

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

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

2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol

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

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

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

7-(5H-imidazo[4,3-a]isoindol-5-yl)-5H,6H,7H,8H- imidazo[1,5-a]pyridin-8-ol

6-(5H-imidazo[4,3-a]isoindol-5-yl)-5,6,7,8- tetrahydroisoquinolin-5-ol

1-(3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5- yl)piperidin-1-yl)ethan-1-one

tert-butyl 3-hydroxy-4-(5H-imidazo[5,1-a]isoindol- 5-yl)piperidine-1-carboxylate

tert-butyl 4-hydroxy-3-(5H-imidazo[5,1-a]isoindol- 5-yl)piperidine-1-carboxylate

1-(4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5- yl)piperidin-1-yl)ethan-1-one

2-(8-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)cyclobutan-1-ol

2-(4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5- yl)piperidin-1-yl)acetonitrile

1-(ethylsulfonyl)-3-(5H-imidazo[5,1-a]isoindol-5- yl)piperidin-4-ol

1-(ethylsulfonyl)-4-(5H-imidazo[5,1-a]isoindol-5- yl)piperidin-3-ol

2-(5H-imidazo[5,1-a]isoindol-5- yl)spiro[3.3]heptan-1-ol

4,4-difluoro-2-((S)-5H-imidazo[5,1-a]isoindol-5- yl)cyclohexan-1-ol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro- 1H-inden-1-ol

2-(8-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)cyclopentan-1-ol

4-(5H-imidazo[5,1-a]isoindol-5-yl)-2,2- dimethylcyclobutan-1-ol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-3,3- dimethylcyclobutan-1-ol

5-(5H-imidazo[5,1-a]isoindol-5-yl)-2,2- dimethylcyclopentan-1-ol

6-(5H-imidazo[5,1-a]isoindol-5-yl)-2,2- dimethylcyclohexan-1-ol

2-(8-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)cyclohexan-1-ol

4-(5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran- 3-ol

›DETAILED DESCRIPTION OF THE INVENTION · 7 of 10

2-(3-hydroxy-4-(-5H-imidazo[5,1-a]isoindol-5- yl)piperidin-1-yl)acetonitrile

3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5- yl)pyrrolidine-1-sulfonamide

9-hydroxy-8-(5H-imidazo[5,1-a]isoindol-5-yl)- 6,7,8,9-tetrahydro-4H-quinolizin-4-one

4-(8-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)tetrahydrofuran-3-ol

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

4-(5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran- 3-amine

4-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)- tetrahydro-2H-pyran-3-ol

3-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)- tetrahydro-2H-pyran-4-ol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- methylcyclobutan-1-ol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-6- (methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

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

3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5- yl)tetrahydrothiophene 1,1-dioxide

3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5- yl)piperidine-1-sulfonamide

1-(ethylsulfonyl)-4-(5H-imidazo[5,1-a]isoindol-5- yl)pyrrolidin-3-ol

tert-butyl 7-hydroxy-6-(5H-imidazo[1,5-b]isoindol- 5-yl)-2-azaspiro[3.3]heptane-2-carboxylate

1-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol

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

2-(5H-imidazo[5,1-a]isoindol-5-yl)propan-2-ol

3-(5H-imidazo[5,1-a]isoindol-5-yl)thietan-3-ol

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

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

3-(5H-imidazo[5,1-a]isoindol-5-yl)oxetan-3-ol

1-(5H-imidazo[5,1-a]isoindol-5-yl)ethane-1,2-diol

3,3-difluoro-1-(5H-imidazo[5,1-a]isoindol-5- yl)cyclobutan-1-ol

1-(5H-imidazo[5,1-a]isoindol-5-yl)-2- methylpropan-1-ol

cyclopropyl(5H-imidazo[5,1-a]isoindol-5- yl)methanol

4,4-difluoro-1-(5H-imidazo[5,1-a]isoindol-5- yl)cyclohexan-1-ol

3,3-bis(fluoromethyl)-1-(5H-imidazo[5,1- a]isoindol-5-yl)cyclobutan-1-ol

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

5-(5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-4-ol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-7- oxaspiro[3.5]nonan-1-ol

2-(4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5- yl)piperidin-1-yl)acetonitrile

6-(5H-imidazo[5,1-a]isoindol-5-yl)-3-methyl-6,7- dihydro-5H-cyclopenta[c]pyridin-7-ol

5-hydroxy-6-(5H-imidazo[5,1-a]isoindol-5-yl)- 5,6,7,8-tetrahydronaphthalene-2-carboxamide

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

5-hydroxy-6-(5H-imidazo[5,1-a]isoindol-5-yl)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile

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

4-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (methylsulfonyl)piperidin-3-ol

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

1-(5H-imidazo[5,1-a]isoindol-5- yl)spiro[3.3]heptan-2-ol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-8- oxaspiro[4.5]decan-1-ol

4-(6-chloro-5H-imidazo[5,1-a]isoindol-5- yl)tetrahydro-2H-pyran-3-ol

69-1

3-(6-chloro-5H-imidazo[5,1-a]isoindol-5- yl)tetrahydro-2H-pyran-4-ol

1-(cyclopropylsulfonyl)-3-(5H-imidazo[5,1- a]isoindol-5-yl)piperidin-4-ol

6-(5H-imidazo[5,1-a]isoindol-5-yl)-6,7-dihydro- 5H-cyclopenta[c]pyridin-7-ol

4-(5H-imidazo[5,1-a]isoindol-5-yl)spiro[2.3]hexan- 5-ol

3-(6-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)tetrahydro-2H-pyran-4-ol

3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)-N- methylpiperidine-1-sulfonamide

3-(7-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)tetrahydro-2H-pyran-4-ol

75-1

4-(7-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)tetrahydro-2H-pyran-3-ol

8-(ethylsulfonyl)-2-(5H-imidazo[5,1-a]isoindol-5- yl)-8-azaspiro[4.5]decan-1-ol

1-(cyclopropylsulfonyl)-4-(5H-imidazo[5,1- a]isoindol-5-yl)piperidin-3-ol

3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)- N,N-dimethylpiperidine-1-sulfonamide

4-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (methylsulfonyl)piperidin-3-ol

4-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (isopropylsulfonyl)piperidin-3-ol

1-(cyclopropylsulfonyl)-4-(5H-imidazo[5,1- a]isoindol-5-yl)piperidin-3-ol

4-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(2,2,2- trifluoroethyl)piperidin-3-ol

4-(5H-imidazo[5,1-a]isoindol-5-yl)-1- methylpiperidin-3-ol

4-(5H-imidazo[5,1-a]isoindol-5-yl)-2,2,5,5- tetramethyltetrahydrofuran-3-ol

4-(5H-Imidazo[5,1-a]isoindol-5-yl)-2,2- dimethyltetrahydrofuran-3-ol

3-(5H-imidazo[5,1-a]isoindol-5-yl)oxepan-4-ol

5-(5H-imidazo[5,1-a]isoindol-5-yl)-2- oxaspiro[3.3]heptan-6-ol

7-(5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyridin-8-ol

4-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (isopropylsulfonyl)piperidin-3-ol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-2,6,6- trimethyleyclohexan-1-ol

3-(5H-imidazo[5,1-a]isoindol-5-yl)-7- (methylsulfonyl)chroman-4-ol

5-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (methylsulfonyl)azepan-4-ol

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

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

2-(fluoromethyl)-5-(5H-imidazo[5,1-a]isoindol-5- yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol

4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5- yl)thiochromane 1,1-dioxide

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

5-hydroxy-6-(5H-imidazo[5,1-a]isoindol-5-yl)-N,N- dimethyl-5,6,7,8-tetrahydronaphthalene-2- carboxamide

4-(9-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)tetrahydro-2H-pyran-3-ol

100

5-hydroxy-6-(5H-imidazo[5,1-a]isoindol-5-yl)- 5,6,7,8-tetrahydronaphthalene-2-sulfonamide

101

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

102

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1,2,3,4- tetrahydronaphthalen-1-ol

103

4-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(oxetan-3- yl)piperidin-3-ol

104

5-hydroxy-6-(5H-imidazo[5,1-a]isoindol-5-yl)- 5,6,7,8-tetrahydroquinoline-2-carboxamide

105

8-hydroxy-7-(5H-imidazo[5,1-a]isoindol-5-yl)- 5,6,7,8-tetrahydronaphthalene-2-sulfonamide

106

2,2-difluoro-6-(5H-imidazo[5,1-a]isoindol-5- yl)cyclohexan-1-ol

107

8-hydroxy-7-(5H-imidazo[5,1-a]isoindol-5-yl)- 5,6,7,8-tetrahydroquinoline-3-carbonitrile

108

3-((5H-imidazo[5,1-a]isoindol-5-yl)methyl)-1- (ethylsulfonyl)azetidin-3-ol

109

2-(8-fluoro5H-imidazo[5,1-a]isoindol-5-yl)-7- oxaspiro[3.5]nonan-1-ol

›DETAILED DESCRIPTION OF THE INVENTION · 8 of 10

110

4-(7-methyl-5H-imidazo[5,1-a]isoindol-5- yl)tetrahydrofuran-3-ol

111

2-amino-6-(5H-imidazo[5,1-a]isoindol-5-yl)- 5,6,7,8-tetrahydroquinazolin-5-ol

112

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

113

8-hydroxy-7-(5H-imidazo[5,1-a]isoindol-5-yl)- 5,6,7,8-tetrahydronaphthalene-2-carbonitrile

114

7-(ethylsulfonyl)-2-(5H-imidazo[5,1-a]isoindol-5- yl)-7-azaspiro[3.5]nonan-1-ol

115

2-(5H-imidazo[5,1-a]isoindol-5-yl)cycloheptan-1-ol

116

3-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (methylsulfonyl)pyrrolidin-3-ol

117

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

118

3-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1- (methylsulfonyl)piperidin-4-ol

119

4-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1- (methylsulfonyl)piperidin-3-ol

120

4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)tetrahydro-2H-pyran-3-ol

121

2-amino-6-(5H-imidazo[5,1-a]isoindol-5-yl)- 5,6,7,8-tetrahydroquinolin-5-ol

122

8-hydroxy-7-(5H-imidazo[5,1-a]isoindol-5-yl)- 5,6,7,8-tetrahydronaphthalene-2-carboxamide

123

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

124

6-(5H-imidazo[5,1-a]isoindol-5-yl)-2-methyl- 5,6,7,8-tetrahydroquinazolin-5-ol

125

5-(5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7- tetrahydrobenzo[d]thiazol-4-ol

126

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

127

tert-Butyl 3-hydroxy-3-(5H-imidazo[5,1-a]isoindol- 5-yl)piperidine-1-carboxylate

128

1-(5H-imidazo[5,1-a]isoindol-5-yl)cycloheptan-1-ol

129

3-(5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran- 3-ol

130

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

131

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

132

1-(5H-imidazo[5,1-a]isoindol-5-yl)-4,4- dimethylcyclohexan-1-ol

133

5-(5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a]azepin-4-ol

134

3-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (methylsulfonyl)piperidin-3-ol

135

1-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-2- methylpropan-1-ol

136

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

137

1-(5H-imidazo[5,1-a]isoindol-5-yl)propan-1-ol

138

(5H-imidazo[5,1-a]isoindol-5-yl)(tetrahydro-2H- pyran-4-yl)methanol

139

5-(5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7- tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-4-ol

139-1

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

140

4-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5- yl)cyclohexane-1-carboxamide

141

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

142

2-(5H-imidazo[5,1-a]isoindol-5-yl)-7- (methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol

143

1-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H- imidazol-2-yl)ethan-1-ol

144

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

145

4-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5- yl)cyclohexane-1-carbonitrile

146

5-(5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7- tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-4-ol

146-1

7-(5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-ol

147

1-(5H-imidazo[5,1-a]isoindol-5-yl)-3,3- dimethylcyclobutan-1-ol

148

cyclohexyl(5H-imidazo[5,1-a]isoindol-5- yl)methanol

149

4-hydroxy-5-(5H-imidazo[5,1-a]isoindol-5-yl)- 4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxamide

150

3,3-bis(fluoromethyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)cyclobutan-1-ol

151

3-fluoro-5-(5H-imidazo[5,1-a]isoindol-5-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol

152

(5H-imidazo[5,1-a]isoindol-5-yl)(pyridin-4- yl)methanol

153

1-(hydroxy(5H-imidazo[5,1-a]isoindol-5- yl)methyl)cyclopropane-1-carbonitrile

154

(1-fluorocyclopropyl)(5H-imidazo[5,1-a]isoindol-5- yl)methanol

155

3-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5-yl)-2,2- dimethylpropanamide

156

4-hydroxy-5-(5H-imidazo[5,1-a]isoindol-5-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3- carbonitrile

157

6-(5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7- tetrahydro-1H-indazol-7-ol

158

3-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutane- 1,2-diol

159

5-(5H-imidazo[5,1-a]isoindol-5-yl)-3-methyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol

160

3-chloro-5-(5H-imidazo[5,1-a]isoindol-5-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol

161

2-amino-5-(5H-imidazo[5,1-a]isoindol-5-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol

162

4-hydroxy-5-(5H-imidazo[5,1-a]isoindol-5-yl)-N- methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxamide

163

5-(5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7- tetrahydrobenzo[c][1,2,5]oxadiazol-4-ol

164

1-(5H-imidazo[5,1-a]isoindol-5-yl)-2,2- dimethylcyclohexan-1-ol

165

1-(hydroxy(5H-imidazo[5,1-a]isoindol-5- yl)methyl)cyclopropane-1-carboxamide

166

5-(5H-imidazo[5,1-a]isoindol-5-yl)-2-methyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol

167

6-(5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7- tetrahydrobenzo[d]thiazol-7-ol

168

5H-imidazo[5,1-a]isoindol-5-yl)-2-methyl-4,5,6,7- tetrahydrobenzo[d]oxazol-4-ol

169

8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8- tetrahydroquinolin-5-ol

170

3-(9-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)tetrahydro-2H-pyran-4-ol

171

4-(8-methyl-5H-imidazo[5,1-a]isoindol-5- yl)tetrahydrofuran-3-ol

172

4-hydroxy-5-(5H-imidazo[5,1-a]isoindol-5-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a] pyridine-2-carboxamide

173

2-(difluoromethyl)-5-(5H-imidazo[5,1-a]isoindol-5- yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol

174

4-hydroxy-5-(5H-imidazo[5,1-a]isoindol-5-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2- carbonitrile

175

7-(5H-imidazo[5,1-a]isoindol-5-yl)-3-methyl- 5,6,7,8-tetrahydroisoquinolin-8-ol

176

6-(5H-imidazo[5,1-a]isoindol-5-yl)-2-methyl- 4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol

177

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

178

5-(5H-imidazo[5,1-a]isoindol-5-yl)-2-methyl- 4,5,6,7-tetrahydrobenzo[d]oxazol-4-ol

179

8-(methylsulfonyl)-2-(5H-imidazo[5,1-a]isoindol-5- yl)-8-azaspiro[4.5]decan-1-ol

180

8-(methylsulfonyl)-2-(5H-imidazo[5,1-a]isoindol-5- yl)-8-azaspiro[4.5]decan-1-ol

181

1-hydroxy-2-(5H-imidazo[4,3-a]isoindol-5-yl)-7- azaspiro[3.5]nonane-7-sulfonamide

182

8-(methylsulfonyl)-2-(5H-imidazo[5,1-a]isoindol-5- yl)-8-azaspiro[4.5]decan-1-ol

183

6-(5H-imidazo[5,1-a]isoindol-5-yl)-2- (methylsulfonyl)-2-azaspiro[3.3]heptan-5-ol

or a pharmaceutically acceptable salt thereof, or an enantio 182mer or diastereoisomer thereof, or a racemic mixture thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 9 of 10

In one embodiment, the compounds of the invention are

(1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol; 5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol; (3S,4S)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol; (5R,6R)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinazolin-5-ol; (7R,8R)-8-hydroxy-7-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide; and (6S,7R)-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol.

In another embodiment, the compounds of the invention are

(7S,8S)-7-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol; 8-fluoro-5H-imidazo[4,3-a]isoindol-5-yl]cyclobutan-1-ol; 3-(-5H-imidazo[5,1-a]isoindol-5-yl) bicyclo[2.2.2]octan-2-ol; (5S,6S)-5-hydroxy-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-N-methyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide; (1R,2S)-2-((R)-8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-7-oxaspiro[3.5]nonan-1-ol; and (4S,5R)-5-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-4-ol;

In another embodiment, the compounds of the invention are

4-(5H-imidazo[1,5-b]isoindol-5-yl)-2,2-dimethyl-cyclobutanol; (S)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol; (R)-1-(5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol; (4S,5S)-5-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol; ((5R,6S)-5-hydroxy-6-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydronaphthalene-2-sulfonamide; and (4S,5S)-4-hydroxy-5-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxamide.

In another embodiment, the compounds of the invention are

2-(5H-imidazo[1,5-b]isoindol-5-yl)spiro[3.3]heptan-3-ol; (1R,2S)-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol; (5S,6S)-5-hydroxy-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide; 4-hydroxy-5-(5H-imidazo[5,1-a]isoindol-5-yl)azepane-1-sulfonamide; (5R,6R)-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydrophthalazin-5-ol; and (6S,7S)-6-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7-tetrahydro-1H-indazol-7-ol.

In another embodiment, the compounds of the invention are

(3S,4S)-1-(ethylsulfonyl)-4-((S)-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-3-ol; 3-(5H-imidazo[5,1-a]isoindol-5-yl)thietan-3-ol; (4S,5S)-5-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol; (7S,8S)-7-((S)-8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol; (4S,5S)-4-hydroxy-5-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-N-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxamide; and 6-(5H-imidazo[5,1-a]isoindol-5-yl)-3-(methylsulfonyl)-3-azabicyclo[3.1.1]heptan-6-ol.

The invention further comprises subgenera of formula (I), in which the structure of any of formulae (I), (Ia)-(Ii), (II), (IIa)-(IIi), (III), (IIIa)-(IIIi), (IV), (IVa)-(IVi), (V) or (Va)-(Vf) comprising the structural element

having the stereoisomeric configuration of any of configurations 1-27 below, wherein the stereochemistry of each stereoisomeric carbon atom (labeled “a,” “b,” and “c” above) is designated as racemic (“-”), “S,” or “R”:

Structural Formula I is One of Stereoisomeric Configurations (1)-(27):

In one embodiment, the compounds of the disclosure are in the S stereoconfiguration at the position labeled “a” above. For example, the compounds have a stereoconfiguration of configuration 1, 7, 8, 15, 16 or 19-22.

In another embodiment, the compounds of the disclosure are in the R stereoconfiguration at the position labeled “a” above. For example, the compounds have a stereoconfiguration of configuration 2, 9, 10, 17, 18 or 23-26.

In one embodiment, the compounds of the disclosure are in the stereoconfiguration of configuration 20.

In another embodiment, the compounds of the disclosure are in the stereoconfiguration of configuration 19.

In another aspect, the present disclosure 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 stereoisomeric configurations 1-27. For example:

The invention further comprises subgenera of formula (I), in which the structure of any of formulae (I), (I) or (IIj)-(IIo) comprising the structural element,

having the stereoisomeric configuration of any of configurations 28-36 below, wherein the stereochemistry of each stereoisomeric carbon atom (labeled “d” and “c” above) is designated as racemic (“-”), “S,” or “R”:

Structural Formula I is One of Stereoisomeric Configurations (28)-(36):

In another aspect, the present disclosure 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 as each of stereoisomeric configurations 28-36. For example:

In another aspect, the present disclosure provides a compound according to any one of the preceding aspects includes one or more stable isotopes. The stable isotope may replace any atom, for example, hydrogen, and may include any stable isotope, for example, deuterium.

In another aspect, the present disclosure provides compounds and pharmaceutical compositions comprising the compounds according to any one of the preceding aspects of the invention or any embodiment thereof, together with a pharmaceutically acceptable excipient, diluent, or carrier.

In another aspect, the invention provides methods for treating tryptophan 2,3-dioxygenase (TDO2) mediated immunosuppression in a subject in need thereof, comprising administering an effective tryptophan 2,3-dioxygenase inhibiting amount of a compound or a pharmaceutical composition according to any of the preceding aspects of the invention or any embodiment thereof.

In one embodiment, the immunosuppression is associated with cancer.

In an embodiment, the immunosuppression is tumor-specific immunosuppression associated with cancer.

In another embodiment, the immunosuppression is associated with a cancer, wherein the cancer is colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head, or neck cancer, or lymphoma, leukemia, or melanoma.

›DETAILED DESCRIPTION OF THE INVENTION · 10 of 10

In another aspect, the invention provides the use of compounds described by any one of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament for the treatment of medical conditions that benefit from the inhibition of enzymatic activity of IDO1 or TDO2. Medical conditions contemplated in this aspect include all the conditions described herein.

In another aspect, the invention provides a use of compounds described by any one of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament to stimulate T cell proliferation or to reverse an immunologic state of anergy or immunosuppression.

In one embodiment, the invention provides the use of compounds described in to any one of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament for the treatment of tumor-specific immunosuppression associated with cancer. Preferably, the cancer is cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, or head and neck, lymphoma, leukemia, melanoma, and the like.

›Definitions · 1 of 7

Terms used herein may be preceded and/or followed by a single dash, “-”, or a double dash, “=”, to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond or a pair of single bonds in the case of a spiro-substituent. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read “left to right” unless a dash indicates otherwise. For example, C 1 -C 6 alkoxycarbonyloxy and —OC(O)C 1 -C 6 alkyl indicate the same functionality; similarly arylalkyl, arylalkyl-, and -alkylaryl indicate the same functionality.

Further, certain terms herein may be used as both monovalent and divalent linking radicals as would be familiar to those skilled in the art, and by their presentation linking between two other moieties. For example, an alkyl group can be both a monovalent radical or divalent radical; in the latter case, it would be apparent to one skilled in the art that an additional hydrogen atom is removed from a monovalent alkyl radical to provide a suitable divalent moiety.

The term “alkenyl” as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 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.

The term “alkoxy” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term “alkyl” as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 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, then it may also be a straight or branched chain; examples include, but are not limited to —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CHC(CH 3 )—, —CH 2 CH(CH 2 CH 3 )CH 2 —.

The term “aryl,” as used herein, means a phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the phenyl portion of the bicyclic system, or any carbon atom with the napthyl or azulenyl ring. The fused monocyclic cycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl are optionally substituted with one or two oxo and/or thia groups. Representative examples of the bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-1-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl, inden-3-yl, inden-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-on-5-yl, 2H-chromen-2-on-6-yl, 2H-chromen-2-on-7-yl, 2H-chromen-2-on-8-yl, isoindoline-1,3-dion-4-yl, isoindoline-1,3-dion-5-yl, inden-1-on-4-yl, inden-1-on-5-yl, inden-1-on-6-yl, inden-1-on-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]oxazin3(4H)-on-5-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-6-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-7-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-8-yl, benzo[d]oxazin-2 (3H)-on-5-yl, benzo[d]oxazin-2 (3H)-on-6-yl, benzo[d]oxazin-2 (3H)-on-7-yl, benzo[d]oxazin-2 (3H)-on-8-yl, quinazolin-4 (3H)-on-5-yl, quinazolin-4 (3H)-on-6-yl, quinazolin-4 (3H)-on-7-yl, quinazolin-4 (3H)-on-8-yl, quinoxalin-2 (1H)-on-5-yl, quinoxalin-2 (1H)-on-6-yl, quinoxalin-2 (1H)-on-7-yl, quinoxalin-2 (1H)-on-8-yl, benzo[d]thiazol-2 (3H)-on-4-yl, benzo[d]thiazol-2 (3H)-on-5-yl, benzo[d]thiazol-2 (3H)-on-6-yl, and, benzo[d]thiazol-2 (3H)-on-7-yl. In certain embodiments, the bicyclic aryl is (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.

The term “arylalkyl,” “-alkylaryl,” and “arylalkyl-” as used herein, means an aryl group, as defined herein, appended 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-naphth-2-ylethyl.

The terms “cyano” and “nitrile” as used herein, mean a —CN group.

The term “cycloalkyl” as used herein, means a monocyclic or a bicyclic cycloalkyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 10 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In certain embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form —(CH 2 ) w —, 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. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia.

›Definitions · 2 of 7

“Cycloalkenyl” as used herein refers to a monocyclic or a bicyclic cycloalkenyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 10 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon-carbon double bond), but not aromatic. Examples of monocyclic ring systems include cyclopentenyl and cyclohexenyl. Bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form —(CH 2 ) w —, where w is 1, 2, 3 or 4). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct-2-enyl. Fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. Cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkyl” as used herein, means at least one halogen, as defined herein, appended 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.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl 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 consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted with one or two groups which are independently oxo or thia. When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon or nitrogen atom contained within the monocyclic heteroaryl portion of the bicyclic ring system. When the bicyclic heteroaryl is a monocyclic heteroaryl fused to a phenyl ring or a monocyclic heteroaryl, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon atom or nitrogen atom within the bicyclic ring system. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, 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, thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, and 6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments, the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroaryl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.

The term “heteroarylalkyl” and “-alkylheteroaryl” as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, fur-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, thien-2-ylmethyl, and thien-3-ylmethyl.

The term “heterocyclyl” as used herein, 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 the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of 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 the group consisting of O, N and S. The monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycle 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, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. Bicyclic heterocycles that are fused through a heteroatom can be categorized according to the ring A/B convention of the present disclosure as if the heteroatom was in either of ring A or ring B. For example, 6,7,8,9-tetrahydro-4H-quinolizin-4-on-yl:

›Definitions · 3 of 7

can be categorized as a ring A=C 6 cycloalkyl and ring B=6-membered heterocyclyl substituted with an oxo group, or A=6-membered heterocyclyl and ring B=C 6 cycloalkenyl substituted with an oxo group. The bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. Heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia.

The term “hydroxy” as used herein, means an —OH group.

The term “nitro” as used herein, means a —NO 2 group.

The term “oxo” as used herein means a ═O group.

The term “saturated” as used herein means the referenced chemical structure does not contain any multiple carbon-carbon bonds. For example, a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like.

The term “spiro” as used herein refers to a cyclic moiety formed by the substituted atom and two available substitutable positions on that same atom. For example, moiety such as

where R is a spiro-cycloalkyl=group includes compounds such as

where the spiro-cyclopentyl group is the R group attached to the parent cyclohexyl ring by two single bonds. Similarly, where R is a spiro-heterocyclyl group, such compounds include

where the spiro-1,3-dioxolanyl ring is the R group attached to the parent cyclohexyl ring by two single bonds.

The term “thia” as used herein means a ═S group.

The term “unsaturated” as used herein means the referenced chemical structure contains at least one multiple carbon-carbon bond, but is not aromatic. For example, a unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.

As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” the TDO2 enzyme with a compound includes the administration of a compound described herein to an individual or patient, such as a human, having TDO2, as well as, for example, introducing a compound into a sample containing a cellular or purified preparation containing the TDO2 enzyme.

As used herein, the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.

In certain embodiments, a therapeutically effective amount can be an amount suitable for

(1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; or (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.

As used here, the terms “treatment” and “treating” means (i) ameliorating the referenced disease state, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or improving the pathology and/or symptomatology) such as decreasing the severity of disease; or (ii) eliciting the referenced biological effect (e.g., TDO2 modulation or tryptophan degradation inhibition).

Manifestation of amelioration of a disease condition with underlying TDO2-mediated immunosuppression may require the concomitant or sequential administration of additional therapeutic agents, such as antineoplastic agents in the case of cancer, or antiretroviral agents in the case of viral diseases. For example, administration of TDO2 inhibitors for the treatment of cancer does not always produce a direct antitumor effect when used as a single agent. However, when combined with chemotherapeutic drugs (antineoplastic) the antitumor effect observed is higher than the sum of effects of each agent alone.

As used herein, the terms “catalytic pocket”, “catalytic site”, “active site” collectively and indistinctly refer to a region of the enzyme that contains amino acid residues responsible for the substrate binding (charge, hydrophobicity, steric hindrance) and catalytic amino acid residues which act as proton donors or acceptors or are responsible for binding a cofactor and participate in the catalysis of a chemical reaction.

›Definitions · 4 of 7

As used herein, the phrase “pharmaceutically acceptable salt” refers to both pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH 2 ) n —COOH where n is 0-4, and the like. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

Methods of Use

The compounds and pharmaceutical compositions described herein can modulate activity of the enzyme tryptophan 2,3-dioxygenase (TDO2). The term “modulate” is meant to refer to an ability to decrease activity of an enzyme or receptor. Accordingly, compounds described herein can be used in methods 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 act as inhibitors of TDO2. In further embodiments, the compounds described herein can be used to modulate activity of TDO2 in cell or in an individual in need of modulation of the enzyme by administering a modulating (e.g., inhibiting) amount of a compound described herein.

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

Further provided are methods of inhibiting immunosuppression such as TDO2-mediated immunosuppression in a patient by administering to the patient an effective amount of a compound or composition recited herein. TDO2-mediated immunosuppression has been associated with, for example, cancers, tumor growth, metastasis, infectious diseases (e.g., viral infection), viral replication, etc.

Further provided are methods for treating tumor-specific immunosuppression associated with cancer in a patient by administering to the patient an effective amount of a compound or composition recited herein. Example tumor-specific immunosuppression associated with cancers treatable by the methods herein include immunosuppression associated with cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head and neck, lymphoma, leukemia, melanoma, and the like.

For example, a patient undergoing or having completed a course of chemotherapy and/or radiation therapy for the treatment of a disease state, such as a cancer, can benefit from administering to the patient a therapeutically effective amount of a compound or composition recited herein for inhibiting immunosuppression resulting from the disease state and/or treatment thereof.

Further provided are methods of treating diseases associated with activity or expression, including abnormal activity and/or overexpression, of TDO2 in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound described herein or a pharmaceutical composition thereof. Example diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the TDO2 enzyme, such as over expression or abnormal activity. An TDO2-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating enzyme activity.

Examples of TDO2-associated diseases include cancer, viral infection such as HIV infection, depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (e.g., organ transplant rejection), and autoimmune diseases including asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis and systemic lupus erythematosusor. Example cancers treatable by the methods herein include cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head and neck, lymphoma, leukemia, melanoma, and the like.

Combination Therapy

One or more additional pharmaceutical agents for treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral 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 treatment of TDO2-associated diseases, disorders or conditions (as noted above) or for enhancing the effectiveness of the treatment of a disease state or condition, such as cancer. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

Therapeutic agents that constitute the standard of care for a particular cancer type or infectious disease are expected to benefit when combined with TDO2 inhibitors of the present invention. For example, for the case of tumors, is it preferable that the tumor is sensitive to the cytotoxic effects of the chemotherapeutic agent in order to stimulate the release of antigens that will eventually mediate an immune response that will be enhanced by addition of TDO2 inhibitors to the combination treatment. A person of skill in the art will know how to select such chemotherapeutic agent based on the clinical characteristics and known sensitivity of each tumor to different antineoplastic agents.

›Definitions · 5 of 7

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

Example 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; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD, ((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimid-inedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (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.

Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cis-platin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.

Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4,4-1BB, or antibodies to cytokines (IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2, CCR4 and CCR6.

Other anti-cancer agents also include those that augment the immune system such adoptive T cell transfer.

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

The compounds of the present application can also be used in combination therapy with therapeutic treatments suppressing or inhibiting biologic pathways modulated by PD-1 (programmed cell death protein 1) or its ligand PD-L1. Such therapeutic treatments include those that suppress or inhibit the expression of PD-1 or PD-L1 as well as those that suppress or inhibit the activity of the PD-1 or PD-L1 proteins themselves. 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.

Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the 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.

Pharmaceutical Formulations and Dosage Forms

The pharmaceutical compositions described herein generally comprise a combination of a compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient. Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application. In some embodiments of this aspect, if the compound is dissolved or suspended in water, the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient. In other embodiments, the pharmaceutical compositions described herein are solid pharmaceutical compositions (e.g., tablet, capsules, etc.).

These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

›Definitions · 6 of 7

Also, pharmaceutical compositions can contain, as the active ingredient, one or more of the compounds described herein above in combination with one or more pharmaceutically acceptable carriers. In making the compositions described herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of 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% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining 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.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of a compound described herein.

The tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

›Definitions · 7 of 7

The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds described herein can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

The compounds described herein can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like.

The following examples are offered for illustrative purposes, and are not intended to limit the disclosure in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results. The example compounds below were found to be inhibitors of TDO2 according to one or more of the assays described herein.

Kits

Also included are pharmaceutical kits useful, for example, in the treatment or prevention of TDO2-associated diseases or disorders, obesity, diabetes and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.

›EXAMPLES

All reagents and solvents were purchased from commercial sources. All commercial reagents and solvents were used as received without further purification. The reactions were monitored using analytical thin layer chromatography (TLC) with 0.25 mm EM Science silica gel plates (60F-254). The developed TLC plates were visualized by short wave UV light (254 nm) or immersion in potassium permanganate solution followed by heating on a hot plate. Flash chromatography was performed with Selecto Scientific silica gel, 32-63 μm particle sizes. All reactions were performed in flame or oven-dried glassware under a nitrogen atmosphere. All reactions were stirred magnetically at ambient temperature unless otherwise indicated. 1 H NMR spectra were obtained with a Bruker DRX400, Varian VXR400 or VXR300. 1 H NMR spectra were reported in parts per million (δ) relative to TMS (0.0), DMSO-d6 (2.50) or CD 3 OD (4.80) as an internal reference. All 1 H NMR spectra were taken in CDCl3 unless otherwise indicated. The phosphonates were prepared according to the literature procedure: (U.S. Pat. No. 5,807,892 A1, 1998; Patent: US2012/033245; Patent: US2008/306084 A1, 2008). 1-(azidomethyl)-2,4-dimethoxybenzene was synthesized according to Chem Med Chem, 2011, vol. 6, #5, 840-847.

Synthetic Route LA

(General Procedure for the Synthesis of Int-2:

Base (1 equiv) was added to a stirred mixture of 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 hours until TLC showed disappearance of SM. After cooling to rt, the reaction mixture was diluted with DCM (50 mL) and washed with water, dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by combi-flash using EtOAc/hexanes as eluent.

General Procedure for the Synthesis of Int-3 and Int-4:

Int-2 (1 equiv) was stirred in MeOH and AcOH (5:1) at 80° C. for 2 h. After cooling to rt, the solvent was removed under reduced pressure and sat'd NaHCO 3 was added to the residue until it was neutral. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The crude was purified by combi-flash using EtOAc/DCM as eluent to separate mixture of four diastereomers into two mixture of enantiomers represented by Int-3 and Int-4.

General Procedure for the Synthesis of 5 and 6:

Int-3 or Int-4 (1 equiv) was dissolved in MeOH (6 mL) and NaBH 4 (3 equiv) was added the reaction mixture was stirred for 2 h. NH 4 Cl (5 mL) was added to the reaction mixture and stirred for 5 min. The solution was poured into a separatory funnel containing water (10 mL). The aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were dried over Na 2 SO 4 and the solvent evaporated under reduced pressure to afford the crude product which was purified Combi-Flash using methanol/dem gradient.

Synthetic Route for C10-OH Analogues

General Procedure for Aldehyde or Ketone Addition

To a solution of 5H-imidazo[5,1-a]isoindole (650 mg, 4.16 mmol) in anhydrous THF (10 mL) at −40° C. was added n-BuLi (1.66 mL, 4.16 mmol) and the solution was stirred at −40° C. for 1 h. Aldehyde or ketone (6.24 mmol) was added and the reaction was allowed to warm to rt and stirred overnight. The reaction was quenched by adding saturated ammonium chloride (10 mL) solution and water (15 mL), the product was extracted with CH 2 Cl 2 (3×30 mL). The solvent was distilled under reduced pressure to afford the crude product. The crude product was purified by Combi-Flash to afford the desired product.

General Procedure of Chiral Separation of Stereoisomers and Analysis

Stereoisomers of final products were separated by chromatography. Unless otherwise specified, the following general conditions are used:

A. Method development/sequential Screening of 14 chiral columns

Fourteen chiral columns are routinely screened on a Waters UPC2 HPLC system under the following conditions: Mobile Phase A: carbon dioxide, mobile phase B: methanol w/0.1% NH 4 OH, or Ethanol, IPA, or mixtures, 5-60% B in 1.8 minutes, flow rate of 4 ml/min, run time: 2.5 min, pressure: 120 bar, temperature: 40° C. The 14 columns screened (4.6×50 mm, 3 um) on a regular basis are: Chiralpak AD, Chiralpak AS, Chiralpak IA, Chiralpak IB, Chiralpak IC, Chiralpak ID, Chiralpak IE, Chiralpak OJ, ChiralpakOX from Chiral Technologies, Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-3, Lux Cellulose-4 from Phenomenex and Whelk O-1 (s,s) from Regis.

B. Purification on Preparative SFC

The column that provided resolution value Rs>0.5 is picked to perform the preparative separation. The preparative runs are performed on PIC 100 SFC instrument, the corresponding column displaying best resolution of enantiomers from step A is used (150×20 mm, 5 um) 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.

C. Typical conditions to separate compounds with 2 chiral centers are:

Column: Chiralpak AD (250×20 mm, 5 um) Method: Isocratic at 25% B MP A: Carbon Dioxide MP B: Ethanol w/0.1% NH 4 OH Flow: 70 ml/min Pressure: 100 bar Temperature: 40 40° C.

D. Typical conditions to separate compounds with 3 chiral centers:

Stage: 1

Column: Chiralpak OX (250×20 mm, 5 um) Method: Isocratic at 20% B MP A: Carbon Dioxide MP B: Ethanol w/0.1% NH 4 OH Flow: 70 ml/min Pressure: 100 bar Temperature: 40 40° C.

Stage 2:

Column: Cellulose-1(250×20 mm, 5 um) Method: Isocratic at 15% B MP A: Carbon Dioxide MP B: Methanol w/0.1% NH 4 OH Flow: 70 ml/min Pressure: 100 bar Temperature: 40 degC.

Stage 3:

Column: Chiralcel OX (250×20 mm, 5 um) Method: Isocratic at 15% B MP A: Carbon Dioxide MP B: Methanol w/0.1% NH 4 OH Flow: 70 ml/min Pressure: 100 bar Temperature: 40° C.

E. QC of final products to obtain % ee

The purity of each isomer separated in Step B above is analyzed with chiral analytical SFC as the following:

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

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

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

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

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

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

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

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

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

›Step 1

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

To a solution of 2-[1-(triphenylmethyl)-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 anhydrous 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 hr. The reaction was quenched by 30 mL water and the mixture was extracted by dichloromethane (3×50 mL). The organic layer was combined, washed with brine and water, and dried by anhydrous Na 2 SO 4 . The product was purified by CombiFlash to afford (E)-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclobutan-1-one as yellow oil: LCMS (ESI, m/z): 466 [M+H] +

›Step 2

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

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 hr. The reaction was quenched by 30 mL saturated NaHCO 3 solution and the mixture was extracted by dichloromethane (3×20 mL). The organic layer was combined, washed with brine and water, and dried by anhydrous Na 2 SO 4 . The mixture of diastereomers was separated on CombiFlash to afford 2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-(cis) as a light yellow oil: LCMS (ESI, m/z): 225 [M+H] + .

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

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 hr. The reaction was quenched by 30 mL saturated NaHCO 3 solution and the mixture was extracted by dichloromethane (3×20 mL). The organic layer was combined, washed with brine and water, and dried by anhydrous Na 2 SO 4 . The mixture of diastereomers was separated on CombiFlash to afford 2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-(trans) as a light yellow solid: LCMS (ESI, m/z): 225 [M+H] + .

›Step 3

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

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

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

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

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) was added NaBH 4 (93 mg, 2.45 mmol) in portions at 0° C. and the solution was stirred at 0° C. for 30 min. The solvent was distilled off and saturated ammonium chloride (10 mL) was added. The aqueous layer was extracted with 5% CF 3 CH 2 OH in DCM (3×10 mL). The combined organic extract was dried over (Na 2 SO 4 ) and concentrated under reduced pressure to afford the crude product. The crude product was purified by Combi-Flash and further isolated by chiral separation to afford 4 isomers as white solid. The absolute configuration of isomers 1a, 1b, 1c, 1d, 1e was determined by X-ray crystallography. The configuration of the rest isomers was assigned arbitrarily.

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 HNMR (400 MHz, DMSO-d 6 ) 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).

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 HNMR (400 MHz, DMSO-d 6 ) 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).

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-d 6 ) 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).

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-d 6 ) 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).

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) was added NaBH 4 (60 mg, 1.59 mmol) in portions at 0° C. and the solution was stirred at 0° C. for 30 min. The solvent was distilled off and saturated ammonium chloride (10 mL) was added. The aqueous layer was extracted with 5% CF 3 CH 2 OH in DCM (3×10 mL). The combined organic extract was dried over (Na 2 SO 4 ) and concentrated under reduced pressure to afford the crude product. The crude product was purified by Combi-Flash and further isolated by chiral separation to afford 4 isomers as white solid.

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-d 6 ) 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).

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-d 6 ) 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).

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-d 6 ) 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).

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-d 6 ) 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).

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

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

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

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

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

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

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

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

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

›Step 1

(E)-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclopentan-1-one

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 hours until TLC showed-disappearance of SM. After cooling to rt, 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] + .

›Step 2

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

The title compound was synthesized by General Procedure for the Synthesis of Int-3.

The two diastereomeric pairs were separated by combin-flash using EtOAc/DCM as eluent: LCMS (ESI, m/z): +239.2

›Step 3a

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

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

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

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

The title compound was synthesized by 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

The absolute configuration of isomers 2a, 2b, 2c, 2d was determined by X-ray crystallography. The configuration of the rest isomers was assigned arbitrarily.

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-d 6 ) 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).

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-d 6 ) 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).

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 small sample quantity. Example 2h: -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 small sample quantity.

›Step 3b

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

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

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

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

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-d 6 ) 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).

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] + ; 1 HNMR (400 MHz, DMSO-d 6 ) 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).

Example 2e: 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 small sample quantity.

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 small sample quantity.

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

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

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

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

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

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

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

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

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

›Step 1

(E)-2-(2-(1-trityl-1H-imidazol-4-yl)benzylidene)cyclohexan-1-one

The title compound was synthesized by General Procedure for the Synthesis of Int-2: LCMS (ESI, m/z): 495.4 [M+H] +

›Step 2

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

The title compound was synthesized by General Procedure for the Synthesis of Int-3. The two diastereomeric pairs were separated by combin-flash using EtOAc/DCM as eluent: LCMS (ESI, m/z): 253.2

›Step 3a

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

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

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

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

The title compound was synthesized by 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 configuration of isomers 3a, 3b, 3g and 3h was determined by X-ray crystallography. The configuration of the rest isomers was assigned arbitrarily.

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-d 6 ) 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).

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-d 6 ) 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).

Example 3c: 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-d 6 ) 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).

Example 3d: 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-d 6 ) 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).

›Step 3b

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

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

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

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

The title compound was synthesized by 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

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-d 6 ) 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).

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-d 6 ) 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).

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] + ; 1 H NMR (400 MHz, DMSO-d 6 ) 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).

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 H NMR (400 MHz, DMSO-d 6 ) 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).

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

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

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

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

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

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

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

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

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

Synthetic Route IC [Scheme Changed]

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

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 for 6 h at room temperature and the resulting mixture was diluted with water (50 mL). The resulting solution was extracted with dichloromethane (3×200 mL) and the organic phase was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was diluted with dichloromethane (30 mL) and the solids were collected by filtration to afford 7-([2-[1-(triphenylmethyl)-1H-imidazol-4-yl]phenyl]methylidene)-5,6,7,8-tetrahydroisoquinolin-8-one (2.55 g, 39%) as a light yellow solid: LCMS (ESI, m/z): 544 [M+H] + . 1 HNMR (300 MHz, CDCl 3 ) 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).

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

To a solution of (2E)-2-([2-[1-(triphenylmethyl)-1H-imidazol-4-yl]phenyl]methylidene)-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 for 16 h at 80° C. and then concentrated under vacuum to afford 7-[5H-imidazo[4,3-a]isoindol-5-yl]-5,6,7,8-tetrahydroisoquinolin-8-one (2.0 g, crude) as light yellow oil: LCMS (ESI, m/z): 302 [M+H] +

›Step 3 · 1 of 2

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

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

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

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

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

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

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

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

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) was added sodium borohydride (2.5 g, 67.89 mmol). The reaction was stirred for 6 h at room temperature. The resulting mixture was concentrated under vacuum and then diluted with dichloromethane (200 mL). The solids were filtered out and the filtrate was concentrate under vacuum. The crude product was purified by Prep-HPLC and further isolated by chiral separation to afford 8 isomers as white solid. The stereochemistry of each isomer was arbitrarily assigned.

1. Column: Chiralpak IB, 2×25 cm, 5 um; Mobile Phase A:Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 40 B to 40 B in 12 min; 254/220 nm; 2. Column: Chiralpak IC, 2×25 cm, 5 um; Mobile Phase A:Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 40 B to 40 B in 32 min; 254/220 nm; 3. Column: lux-4, 2.12×20 cm, 5 um; Mobile Phase A:Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 50 B to 50 B in 20 min; 254/220 nm;

The absolute configuration of all isomers was assigned arbitrarily.

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, CD 3 OD) 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, 0.46×5 cm, 3 um, ethanol:hexane (0.1% DEA)=40:60, 1.0 mL/min). 4b and 4a are enantiomers.

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, CD 3 OD) 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, 0.46×5 cm, 3 um, ethanol:hexane (0.1% DEA)=40:60, 1.0 mL/min).

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] + ; 1 HNMR (300 MHz, CD 3 OD) 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, 0.46×5 cm, 3 um, ethanol:hexane (0.1% DEA)=40:60, 1.0 mL/min). 4d and 4c are enantiomers.

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, CD 3 OD) 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, 0.46×5 cm, 3 um, ethanol:hexane (0.1% DEA)=40:60, 1.0 mL/min).

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] + ; 1 HNMR (300 MHz, CD 3 OD) 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, 0.46×5 cm, 3 um, ethanol:hexane (0.1% DEA)=40:60, 1.0 mL/min). 4e and 4f are enantiomers.

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 HNMR (400 MHz, CD 3 OD) 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, 0.46×5 cm, 3 um, ethanol:hexane (0.1% DEA)=40:60, 1.0 mL/min).

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] + ; 1 HNMR (400 MHz, CD 3 OD) 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, 0.46×5 cm, 3 um, ethanol:hexane (0.1% DEA)=40:60, 1.0 mL/min). 4 h and 4g are enantiomers.

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 HNMR (300 MHz, CD 3 OD) 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, 0.46×5 cm, 3 um, ethanol:hexane (0.1% DEA)=40:60, 1.0 mL/min).

Example 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

›Step 3 · 2 of 2

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

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

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

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

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

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

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

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

Synthetic Route IIA

›Step 1: 1-(2-bromobenzyl)-1H-imidazole

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

›Step 2: 5H-imidazo[5,1-a]isoindole

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