NZ616457B2

NZ616457B2 - Fused imidazole derivatives useful as ido inhibitors

Info

Publication number: NZ616457B2
Application number: NZ616457A
Authority: NZ
Inventors: Firoz Jaipuri; Tanay Kesharwani; Sanjeev Kumar; Mario Mautino; Jesse Waldo; Xiaoxia Zhang
Original assignee: Newlink Genetics Corporation
Priority date: 2011-04-15
Filing date: 2012-04-12
Publication date: 2015-09-01

Abstract

Presently provided are IDO inhibitors and pharmaceutical compositions thereof, useful for modulating an activity of indoleamine 2,3-dioxygenase; treating indoleamine 2,3-dioxygenase (IDO) mediated inimunosuppression; treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase; enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent; treating tumor-specific immunosuppression associated with cancer; and treating immunosupression associated with an infectious disease. In one embodiment the compound is 1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-I-yl)-2-(3-hydroxyphenyl)ethanone. y of indoleamine-2,3-dioxygenase; enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent; treating tumor-specific immunosuppression associated with cancer; and treating immunosupression associated with an infectious disease. In one embodiment the compound is 1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-I-yl)-2-(3-hydroxyphenyl)ethanone.

Description

FUSED IMIDAZOLE DERIVATIVES USEFUL AS IDO INHIBITORS Cross-Reference to Related Applications This ation claims the beneﬁt of the ﬁling date of US. Provisional Application Serial No. 61/475,788, filed April 15, 2011, which is hereby incorporated by nce in its BACKGROUND OF THE INVENTION Field of the ion The present disclosure relates to compounds and methods for inhibition of indoleamine 2,3-dioxygenase; r the disclosure relates to method of treatment of diseases and disorders mediated by indoleamine 2,3—dioxygenase.

Summary of the d Art Tryptophan (Trp) is an essential amino acid required for the biosynthesis of proteins, niacin and the neurotransmitter oxytryptamine (serotonin). The enzyme indoleamine 2,3—dioxygenase (also known as INDO or IDO) catalyzes the first and rate limiting step in the degradation of L-tryptophan to N—formyl-kynurenine. In human cells, IFN—y stimulation induces activation of IDO, which leads to a depletion of Trp, thereby arresting the growth of pendent intracellular pathogens such as Toxoplasma gondii and Chlamydia trachomatis. IDO activity also has an antiproliferative effect on many tumor cells, and IDO induction has been observed in viva during rejection of allogeneic tumors, indicating a possible role for this enzyme in the tumor ion process.

It has been observed that HeLa cells co—cultured with peripheral blood cytes (PBLs) acquire an immunoinhibitory phenotype through up-regulation of IDO activity. A reduction in PBL proliferation upon treatment with interleukin-2 (IL-2) was believed to result from IDO released by the tumor cells in response to IFN—y secretion by the PBLs. This effect was reversed by treatment with l-methyl-tryptophan (lMT), a specific IDO inhibitor. It was proposed that IDO activity in tumor cells may serve to impair antitumor responses (Logan, et al., 2002, Immunology, 105: 478—87).

Several lines of evidence suggest that IDO is involved in induction of immune tolerance. Studies of mammalian pregnancy, tumor resistance, chronic infections and autoimmune diseases have shown that cells expressing IDO 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 IDO 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 ea 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 IDO inhibition can enhance the levels of virus—specific T cells and, concomitantly, reduce the number of virally infected hages in a mouse model of HIV (Portula et al., 2005, Blood, 106:23 82—90).

IDO is ed 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 ion has focused on immunologic tolerance of the mother. e IDO is expressed by human syncytiotrophoblast cells and systemic tryptophan concentration falls during normal pregnancy, it was hypothesized that IDO 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 d to 1MT, and a rapid, T cell—induced rejection of all allogeneic concepti was observed. Thus, by catabolizing phan, the mammalian conceptus appears to suppress T—cell activity and defends itself against rejection, and ng tryptophan catabolism during murine ncy allows maternal T cells to provoke fetal allograft rejection (Munn, et al., 1998, Science 281: 1191—3). r evidence for a tumoral immune resistance mechanism based on phan ation by IDO comes from the observation that most human tumors constitutively express IDO, and that expression of IDO 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 ent 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 stration of an IDO inhibitor (Uyttenhove et al., 2003, Nature Med., 9: 1269—74). It has also been shown that the IDO tor, l-MT, can synergize with chemotherapeutic agents to reduce tumor growth in mice, suggesting that IDO inhibition may also enhance the anti-tumor activity of conventional cytotoxic therapies r et al., 2005, Nature Med., 11:312—9).

One mechanism contributing to immunologic unresponsiveness toward tumors may be presentation of tumor antigens by tolerogenic host APCs. A subset of human IDO-expressing antigen-presenting cells (APCs) that coexpressed CD123 (IL3RA) and CCR6 and inhibited T-cell proliferation have also been described. Both mature and immature positive dendritic cells suppressed T—cell activity, and this IDO suppressive activity was blocked by 1MT (Munn, et al., 2002, Science 297: 1867—70). It has also been demonstrated that mouse draining lymph nodes (TDLNs) n a subset of plasmacytoid dendritic cells (pDCs) that constitutively express immunosuppressive levels of IDO. Despite comprising only 0.5% of lymph node cells, in vitro, these pDCs potently suppressed T cell responses to antigens presented by the pDCs themselves and also, in a dominant fashion, suppressed T cell responses to third—party antigens ted by nonsuppressive APCs. Within the population of pDCs, the ty of the functional IDO—mediated suppressor activity segregated with a novel subset of pDCs essing the B-lineage marker CD19. Thus, it was hypothesized that diated suppression by pDCs in TDLNs creates a local microenvironment that is potently suppressive of host antitumor T cell responses (Munn, et al., 2004, J. Clin. Invest., 114(2): 280—90).

IDO degrades the indole moiety of tryptophan, serotonin and melatonin, and initiates the production of neuroactive and immunoregulatory metabolites, collectively known as kynurenines. By locally depleting tryptophan and increasing proapoptotic kynurenines, IDO sed by dendritic cells (DCs) can greatly affect T—cell proliferation and survival. IDO induction in DCs could be a common ism of deletional nce driven by regulatory T cells. Because such tolerogenic responses can be expected to operate in a variety of physiopathological conditions, phan metabolism and kynurenine production might represent a crucial interface between the immune and nervous systems (Grohmann, et al., 2003, Trends Immunol., 24: 242-8).

Small molecule inhibitors of IDO are being developed to treat or prevent IDO-related es such as those described above. For example, PCT Publication WO 99/29310 reports s for altering T cell-mediated immunity comprising ng local ellular concentrations of tryptophan and tryptophan metabolites, using an inhibitor of IDO 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 ed in WO 2004/094409; and US. Patent Application Publication No. 2004/0234623 is directed to methods of ng a subject with a cancer or an infection by the administration of an inhibitor of indoleamine-2,3-dioxygenase in ation with other therapeutic modalities.

In light of the experimental data indicating a role for IDO in suppression, tumor ance and/or rejection, chronic infections, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhea), autoimmune es 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 IDO activity are desirable. Inhibitors of IDO can be used to activate T cells and therefore enhance T cell activation when the T cells are ssed by pregnancy, malignancy or a virus such as HIV. Inhibition of IDO 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 IDO modulators.

SUMMARY OF THE ION [0011a] According to a first aspect of the present invention, there is provided a compound of the formula, (R1)n or a pharmaceutically acceptable salt thereof, wherein bond α is a single or double bond; n is 0, 1, 2, 3, or 4; each R1 is independently n, cyano, nitro, C1-6alkyl, C1-6haloalkyl, -OR, -N(R)2, -SR, -C(O)OR, (R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)C(O)N(R)2; R2 is –C1-4alkyl-RA or –C2-4alkenyl-R3 when bond α is a single bond; and R2 is =C(H)RA when bond α is a double bond; wherein RA is –CN, –C(O)R3, –C(O)OR3, -C(O)N(R3)(RC), )(R3)(RC), -C(NHRB)(R3)(RC), or –C(=N-ORC)R3, wherein RB is hydrogen, C1-6alkyl, C1-6haloalkyl, -C1-6alkyl-RB1, -C(O)R3, (H)R3, or -S(O)2R3, -C(O)(CH2)1-4COOR, -C(O)(CH2)1-4(NR)COOR, – C(O)CH(NH2)(RD), -S(O)2OR3, -S(O)2N(R3)2, -CH2-OP(O)2(OR)2, or – P(O)(OR3)2, wherein RB1 is cyano, nitro, kyl, C1-6haloalkyl, -OR, -N(R)2, -SR, -C(O)OR, (R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)C(O)N(R)2; RD is hydrogen, methyl, -CH(CH3)2, -CH2CH(CH3)2, 3)(CH2CH3), benzyl, oxybenzyl, -CH2(3-indolyl), -CH2SH, -CH2CH2SCH3, -CH2OH, -CH(CH3)OH, -(CH2)4-NH2, -(CH2)3-N(H)C(=NH)NH2, -CH2(4-imidazolyl), -CH2COOH, -CH2CH2COOH, -CH2CONH2, -CH2CH2CONH2; each R3 is independently hydrogen, C1-6alkyl, loalkyl, aryl, heteroaryl, C3-8cycloalkyl, C3-8cycloalkenyl, 3-10 membered heterocyclyl, arylC1-6alkyl-, heteroarylC1-6 alkyl-, C3-8cycloalkylC1-6alkyl-, C3-8cycloalkenylC1-6alkyl-, (3-10 membered heterocyclyl)C1-6alkyl-, or (heteroaryl)-(3-10 ed heterocyclyl)-, wherein the alkyl, cloalkyl, C3-8cycloalkenyl, 3-10 membered heterocyclyl, C3-8cycloalkylC1-6alkyl-, C3-8cycloalkenylC1-6alkyl-, (3-10 membered heterocyclyl)C1-6alkyl-, and (heteroaryl)-(3-10 membered heterocyclyl)-, are each optionally and independently substituted by one =R32 group and each optionally substituted and independently by one, two, three, or four R31 groups; the aryl, heteroaryl, arylC1-6alkyl-, and heteroarylC1-6alkyl- groups, are each optionally substituted by one, two, three, or four R31 groups; wherein each R31 is independently halogen, cyano, nitro, C1-6alkyl, -C1-6alkyl-R33, C1-6haloalkyl, -OR, , -SR, -C(O)OR, -C(O)N(R)2, -C(O)N(OH)R, -C(O)R, -C(NR11)R, -C(NR11)N(R11)R, -S(O)R, R, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)N(R)2, wherein R33 is cyano, -OR, -N(R)2, -SR, R, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or (O)N(R)2; R32 is =O, =S, =N(R), =N(OR), )2, =(spiro-C3-8cycloalkyl), or =(spiro-(3-10 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, cyano, C1-6alkyl, - C1-6alkyl-OR, loalkyl, C3-8cycloalkyl, or 3-10 membered heterocyclyl; or both R34 taken together with the atom to which they are both attached form a monocyclic C3-8cycloalkyl or monocyclic 3-8 membered heterocyclyl; RC is hydrogen or C1-6alkyl; each R is independently en or R10, wherein R10 is C1-6alkyl, C1-6haloalkyl, aryl, heteroaryl, C3-8cycloalkyl, C3-8cycloalkenyl, 3-10 membered heterocyclyl, arylC1-6alkyl, heteroarylC1-6alkyl-, C3-8 cycloalkylC1-6alkyl-, C3-8cycloalkenylC1-6alkyl-, or (3-10 membered cyclyl)C1-6alkyl-, each R10 optionally substituted by one, two, three, or four groups that are each ndently halogen, cyano, nitro, C1-6alkyl, C1-6haloalkyl, -OR11, -N(R11)2, -SR11, -C(O)OR11, -C(O)N(R11)2, -C(O)R11, -S(O)R11, -S(O)OR11, -S(O)N(R11)2, -S(O)2R11, -S(O)2OR11, -S(O)2N(R11)2, -OC(O)R11, -OC(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)R11, )C(O)OR11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2R11, or – C(O)-(3-10 ed heterocyclyl), wherein each R11 is independently hydrogen or C1-6alkyl.

] According to a second aspect of the present invention, there is ed a pharmaceutical composition comprising a compound according to the first aspect above and a pharmaceutically acceptable diluent, excipient, or carrier. [0011c] According to a third aspect of the present invention, there is provided a kit comprising a compound according to the first aspect above.

In another aspect, the invention comprises compounds according to the formula (I), (R1)n AH26(9969527_1):JJC wherein R1, R2, n and α are each defined herein.

In another aspect, the invention comprises compounds according to the formula (II), (R1)n (II) n R1, R3, RC, and n are each defined herein.

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

AH26(9969527_1):JJC WO 42237 In another aspect methods are provided for (a) modulating an activity of indoleamine oxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation ive amount of a compound ing to formula (I) or (II), or a pharmaceutical composition comprising a compound according to formula (I) or (II); (b) treating indoleamine 2,3—dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an ive indoleamine 2,3-dioxygenase inhibiting amount of a compound according to a (I) or (II), or a pharmaceutical composition comprising a compound ing to formula (I) or (II); (c) treating a medical condition that benefits from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound according to formula (I) or (II), or a pharmaceutical composition comprising a compound according to formula (I) or (II); (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound according to formula (I) or (II), or a pharmaceutical composition comprising a nd according to a (I) or (II); (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound according to formula (I) or (II), or a pharmaceutical composition comprising a compound ing to formula (I) or (II); and (f) ng immunosupression associated With an infectious disease, e.g., HIV-1 infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound ing to formula (I) or (II), or a pharmaceutical composition comprising a compound according to formula (I) or (II).

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the absolute configuration of a diasteromer of the HBr salt of compound 1417 as confirmed by X-ray crystallography.

ED DESCRIPTION OF THE INVENTION In one aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein bond Cl is a single or double bond; n is 0,1, 2, 3, or4; each R1 is independently halogen, cyano, nitro, kyl, C1_6haloalkyl, -OR, -N(R)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)2R, -S(O)ZOR, —S(O)2N(R)2, R, -OC(O)OR, N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)C(O)N(R)2; R2 is —C1_4alkyl—RA or —C2_4alkenyl—R3 when bond or is a single bond; and R2 is =C(H)RA when bond or is a double bond; wherein RA is —CN, —C(O)R3, R3, —C(O)N(R3)(RC), —C(ORB)(R3)(RC), —C(NHRB)(R3)(RC), or —C(=N—ORC)R3, wherein RB is hydrogen, C1_6alkyl, C1_6haloalkyl, -C1_6alkyl-RB1, —C(O)R3, or —S(O)2R3, -C(O)(CH2)1_4COOR, —C(O)CH(NH2)(RD), —-S(O)ZOR3, —S(O)2N(R3)2, —CH2— OP(O)2(OR)2, or OR3)2, wherein RBl is cyano, nitro, C1_6alkyl, C1_6haloalkyl, —OR, —N(R)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)2R, -S(O)ZOR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)C(O)N(R)2; RD is hydrogen, methyl, -CH(CH3)2, -CH2CH(CH3)2, —CH(CH3)(CH2CH3), benzyl, oxybenzyl, -CH2(3-indolyl), -CHZSH, -CH2CHZSCH3, -CHZOH, -CH(CH3)OH, —(CH2)4—NH2, —(CH2)3—N(H)C(=NH)NH2, —CH2(4—imidazolyl), —CH2COOH, -CH2CH2COOH, -CH2CONH2, 2CONH2; each R3 is independently hydrogen, C1_6alkyl, loalkyl, aryl, aryl, C3_gcycloalkyl, C3_gcycloalkenyl, 3-10 membered heterocyclyl, arle1_6alkyl-, heteroarle1_6 alkyl-, C3_gcycloalkle1_6alkyl-, C3_gcycloalkenle1-6alkyl-, or (3 - 10 membered heterocyclyl)C1_6alkyl—, wherein the alkyl, C3_gcycloalkyl, C3_gcycloalkenyl, 3—10 membered heterocyclyl, C3_gcycloalkle1_6alkyl-, C3_gcycloalkenle1.6alkyl-, and (3—10 ed heterocyclyl)C1_6alkyl— are each optionally and independently substituted by one =R32 group and each WO 42237 optionally substituted and independently by one, two, three, or four R31 groups; the aryl, heteroaryl, arle1_6alkyl-, and heteroarle1_6alkyl- groups, are each optionally substituted by one, two, three, or four R31 ; wherein each R31 is independently halogen, cyano, nitro, C1_6alkyl, —C1_6alkyl—R33, C1_6haloalkyl, —OR, —N(R)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)2R, —S(O)ZOR, —S(O)2N(R)2, —OC(O)R, —OC(O)OR, —OC(O)N(R)2, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, wherein R33 is cyano, —OR, —N(R)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)2R, —S(O)20R, —S(O)2N(R)2, —OC(O)R, OR, —OC(O)N(R)2, —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)N(R)2; R32 is =0, =s, =N(R), =N(OR), =C(R34)2, =(spiro-C3_gcycloalkyl), or =(spiro—(3—10 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, C1_6alkyl, loalkyl, C3_gcycloalkyl, or 3—10 membered heterocyclyl, or both R34 taken together with the atom to which they are both attached form a monocyclic C3_gcycloalkyl or monocyclic 3—8 ed heterocyclyl, RC is hydrogen or C1_6alkyl; each R is independently hydrogen or R10, wherein R10 is C1_6alkyl, C1_6haloalkyl, aryl, heteroaryl, C3_gcycloalkyl, C3_gcycloalkenyl, 3—10 membered heterocyclyl, arle1_6alkyl, heteroarle1_6alkyl—, C3_g lkle1_6alkyl-, C3_gcycloalkenle1-6alkyl-, or (3-10 membered heterocyclyl)C1_6alkyl-, each R10 ally substituted by one, two, three, or four groups that are each independently halogen, cyano, nitro, C1_6alkyl, C1_6haloalkyl, —0R“, —N(R11)2, —SR“, R“, —C(O)N(R”)2, -C(O)R”, —S(O)R”, —S(O)OR”, (R“)2, —S(O)2R“, -S(O)ZOR“, —S(O)2N(R11)2, —OC(O)R“, —OC(O)OR“, —OC(O)N(R“)2, —N(R“)C(0)R“, —N(R”)C(O)OR”, —N(R11)C(O)N(R“)2, wherein each R“ is ndently hydrogen or C1_6alkyl.

In one embodiment, the compounds of formula (I) further include those compounds where, RB is additionally —C(O)N(H)R3 or —C(O)(CH2)1_4(NR)COOR; R3 is additionally (heteroaryl)-(3-10 membered heterocyclyl)—, R31 is additionally —C(O)N(OH)R, —C(N=R11)R, or —C(N=R“)N(R“)R; R34 is additionally cyano or - C1_6alkyl-OR; and/or R10 is additionally optionally substituted by —N(R11)S(O)2R“ or —C(O)—(3-10 membered heterocyclyl); such compounds are referred to as compounds of formula (1’).

The invention further comprises era of formula (I) and formula (1’) in which the substituents are selected as any and all combinations of one or more of structural formula (I), n, R1, R2, R3, RA, RB, and RC, as defined , ing without limitation, the following: Structural Formula I is one of formulae Ia — Ih : (R1)n (R1)n iv iv / R2 / R2 /N/)N /N/)N (13) (1b) (R|1\)n\ R1 / R2 R2 / N / N) N)/ (M) (16) R1 R1 MR2 R2 /N/)N /N/)N (1g) (1h) n and R1 are selected from one of the in rou s 1a — lu : (la) n is l, 2, 3, or 4, and each R1 is as d for formula (I). (110) n is 0, 1, 2, or 3, and each R1 is as deﬁned for formula (I). (1C) n is 0, 1, or 2 and each R1 is as deﬁned for formula (I). (1d) n is 0, 1, or 2 and each R1 is independently halogen, -OR, -N(R)2, or —SR. (16) n is 0, 1, or 2 and each R1 is independently halogen, -OR0, -N(R0)2, or -SR0, wherein each R0 is independently hydrogen or C1_6alkyl. (11) n is 0, 1, or 2 and each R1 is independently ﬂuoro, , hydroxy, or methoxy. (1g) n is 0, 1, or 2 and each R1 is independently halogen. (1h) n is 0, 1, or 2 and each R1 is independently ﬂuoro or chloro. (1i) n is 0 or 1 and R1 is as defined for formula (I). (lj) n is 0 or 1 and R1 is halogen, -OR, -N(R)2, or —SR. (1k) n is 0 or 1 and R1 is n, -OR0, -N(R0)2, or -SR0;wherein each R0 is independently hydrogen or C1_6alkyl. (11) n is 0 or 1 and R1 is fluoro, chloro, hydroxy, or methoxy. (1111) n is 0 or 1 and R1 is halogen. (111) n is 0 or 1 and R1 is ﬂuoro or chloro. (10) n is 1 and R1 is as defined for formula (I).

UP) n is 1 and R1 is halogen, -OR, , or —SR; (lq) n is 1 and R1 is halogen, -OR0, -N(R0)2, or -SR0;wherein each R0 is independently hydrogen or C1_6alkyl. (1r) n is 1 and R1 is fluoro, chloro, hydroxy, or y.

(IS) n is 1 and R1 is n.

(It) n is 1 and R1 is ﬂuoro or chloro. (111) nis 0.

R2 is selected from one of the following groups 12a) — 1211: (23) R2 is —C1_4alky1—RA. (210) R2 is —C1_2alky1—RA. (2C) R2 is -C(H)=C(H)R3. (2d) R2 is -C(H)=C(H)R30, wherein R30 is phenyl optionally substituted by one, two, three, or four R31 groups. (26) R2 is -C(H)=C(H)R30, wherein R30 is phenyl optionally substituted by one or two R31 groups. (21) R2 is —CH2—RA, —CH2CH2—RA, -C(H)(CH3)CH2-RA, or —C(H)=C(H)R3. (2g) R2 is —CH2—RA, —CH2CH2—RA, or CH3)CH2—RA. (2h) R2 is —CH2—RA, —CH2CH2—RA, or —C(H)=C(H)R3. (2i) R2 is —CH2—RA.

(Zj) R2 is 2—RA. (2k) R2 is —C(H)(CH3)CH2—RA. (21) R2 is A, —CH2CH2—RA, or —C(H)=C(H)R3.

RA is selected from one of the following groups (321) — g3n): (321) RA is —CN, —C(O)OR3, or —C(O)N(R3)(RC). (3b) RA is 3 or —C(0RB)(R3)(RC). (3c) RA is —C(NHRB)(R3)(RC), or ORC)R3. (3d) RA is B)(R3)(RC), wherein RB is hydrogen, C1_6alkyl, or 1_6alkyl. (3e) RA is —C(NH2)(R3)(RC). (31) RA is —C(0)0R3. (3g) RA is —C(0)N(R3)(RC). (3h) RA is —C(0)R3. (3i) RA is —C(0RB)(R3)(RC). (3j) RA is —C(0H)(R3)(RC). (3k) RA is —CH(0H)(R3). (31) RA is —CN, —C(0)R3, —C(0)0R3, —C(O)N(R3)(RC), —C(0RB)(R3)(RC), —C(NHRB)(R3)(RC), or —C(=N—0RC)R3. (3m) RA is —C(O)R3 or —C(ORB)(R3)(RC), wherein RB is hydrogen and RC is hydrogen or C1_6alkyl. (3n) RA is -C(ORB)(R3)(RC), wherein RB is hydrogen and RC is hydrogen or C1_6alkyl.

RB is selected from one of the following groups (421) — 14k): (421) RB is hydrogen, C1_6alkyl, C1_6haloalkyl, —C1_6alkyl—RBl, —C(O)(CH2)1_4COORBZ, -C(O)C(NH2)RD, —P(O3)(RBZ)2, —CH2—OP(O)2(OR)2, wherein RD is the side chain of l alpha amino acids , -C(O)R3, or -S(O)2R3, wherein RBl is cyano, nitro, C1_6alkyl, C1_6haloalkyl, —ORBZ, —N(RBZ)2, —SRBZ, —C(O)ORBZ, —C(O)N(RBZ)2, —C(O)RBZ, —S(O)RBZ, —S(O)ORBZ, -S(O)N(RBZ)2, -S(O)2RBZ, —S(O)ZORBZ, —S(O)2N(RBZ)2, —OC(O)RBZ, —OC(O)ORBZ, -OC(O)N(RBZ)2, —N(RBZ)C(O)RBZ, —N(RBZ)C(O)ORBZ, or —N(RBZ)C(O)N(RBZ)2, n each R132 is independently hydrogen or C1_6alkyl. (4b) RB is hydrogen, C1_6alkyl, C1_6haloalkyl, -C1_6alkyl-RBl, —C(O)R3, or —S(O)2R3, wherein RBl is cyano, nitro, C1_6alkyl, C1_6haloalkyl, -ORBZ, -N(RBZ)2, -SRBZ, —C(O)ORBZ, —C(O)N(RBZ)2, -C(O)RBZ, -S(O)RBZ, -S(O)ORBZ, —S(O)N(RBZ)2, —S(O)2RBZ, —S(O)ZORBZ, —S(O)2N(RBZ)2, —OC(O)RBZ, —OC(O)ORBZ, —OC(O)N(RBZ)2, —N(RBZ)C(O)RBZ, —N(RBZ)C(O)ORBZ, or )C(0)N(RBZ)2, wherein each R132 is independently hydrogen or C1_6alkyl. (4C) RB is en, C1_6alkyl, C1_6haloalkyl, or -C1_6alkyl-RBl, wherein RBl is cyano, nitro, C1_6alkyl, C1_6haloalkyl, —ORBZ, —N(RBZ)2, —SRBZ, —C(O)ORBZ, (RBZ)2, -C(O)RBZ, -S(O)RBZ, —S(O)ORBZ, —S(O)N(RBZ)2, —S(O)2RBZ, —S(O)ZORBZ, —S(O)2N(RBZ)2, -OC(O)RBZ, -OC(O)ORBZ, —OC(O)N(RBZ)2, —N(RBZ)C(O)RBZ, —N(RBZ)C(O)ORBZ, or —N(RBZ)C(O)N(RBZ)2, wherein each R132 is independently hydrogen or C1_6alkyl. (4d) RB is en, C1_6alkyl, C1_6haloalkyl, or -C1_6alkyl-RBl, wherein RBl is cyano, —C(O)ORBZ, —C(O)N(RBZ)2, -C(O)RBZ, -S(O)2RBZ, —S(O)ZORBZ, or —S(O)2N(RBZ)2, n each R132 is independently hydrogen or C1_6alkyl. (46) RB is -C1_6alkyl-RBl, wherein R31 is cyano, RBZ, —C(O)N(RBZ)2, BZ, —S(O)2RBZ, —S(O)ZORBZ, or —S(O)2N(RBZ)2, n each R132 is ndently hydrogen or kyl. (41) RB is hydrogen, C1_6alkyl, C1_6haloalkyl, -C1_6alkyl-RBl, —C(O)RBZ, or -S(O)2RBZ, wherein RBl is —C(O)ORB3, —C(O)N(RB3)2, —S(O)ZORB3, or —S(O)2N(R 3», R132 is c1.6 alkyl; and RB3 is hydrogen or C1_6 alkyl. (4g) RB is hydrogen, C1_6alkyl, or loalkyl. (4h) RB is hydrogen or C1_6alkyl; (4i) RB is hydrogen. (41) RB is C1_6alkyl. (4k) RB is hydrogen, -C(O)RBZ, —C(O)(CH2)1_4COORBZ, —C(O)C(NH2)RD, —P(O)(ORBZ)2, —CH2—OP(O)2(OR)2, —S(O)2RBZ, —C(O)N(RBZ)2, —S(O)ZORBZ, —S(O)2N(R 3», wherein and R132 is hydrogen or C1_6 alkyl.

RC is selected from one of the following groups 153) — 15g): (53) RC is hydrogen or C1_4alkyl. (5b) RC is hydrogen or C1_2alkyl. (5e) RC is en or methyl. (5d) RC is hydrogen. (5e) RCisChﬁﬂkyl (5f) 4dkyl (5g) RC is .

R3 is selected from one of the following groups 163) — 1622: (6a) R3 is hydrogen, C1_6alkyl, aryl, heteroaryl, C3_gcycloalkyl, C3_gcycloalkenyl, 3-10 membered heterocyclyl, or C3_gcycloalkle1_6alkyl—, wherein the C1_6alkyl, cloalkyl, C3_gcycloalkenyl, 3—10 membered heterocyclyl, and C3_gcycloalkle1_6alkyl—, are each optionally substituted by one =R32 group and one or two R31 groups; and the aryl and heteroaryl groups, are each optionally substituted by one or two R31 groups. (6b) R3 is aryl, heteroaryl, C3_gcycloalkyl, C3_gcycloalkenyl, 3—10 membered heterocyclyl, or C3_gcycloalkle1_6alkyl-, wherein the C3_gcycloalkyl, C3_gcycloalkenyl, 3-10 membered heterocyclyl, and C3_gcycloalkle1_6 alkyl—, are each ally and ndently tuted by one =R32 group and each optionally and independently substituted by one or two R31 groups; and the aryl and heteroaryl groups, are each optionally substituted by one or two R31 groups. (6C) R3 is phenyl, a ﬁve or six membered aryl, monocyclic C5_gcycloalkyl, monocyclic C5_gcycloalkenyl, a ﬁve or six membered monocyclic heterocyclyl, or (monocyclic C5_gcycloalkyl)C1_6 alkyl-, wherein the C5_gcycloalkyl, C5_gcycloalkenyl, — 6 membered heterocyclyl, and C5_8cycloalkle1_6 alkyl—, are each optionally and independently substituted by one =R32 group and each optionally and independently substituted by one or two R31 groups; and the phenyl and heteroaryl groups, are each optionally substituted by one or two R31 groups. (6d) R3 is phenyl or a ﬁve or six membered heteroaryl, each optionally substituted by one or two R31 groups. (66) R3 is monocyclic C5_gcycloalkyl, monocyclic C5_gcycloalkenyl, a ﬁve or six membered monocyclic heterocyclyl, or (monocyclic C5_8cycloalkyl)C1_6alkyl—, each ally substituted by one =R32 group and one or two R31 groups. \5\J?a! (R31)m (61) R3 is p wherein bond a is a single bond or a double bond; m is 0, , l, or 2; p is 0 or 1; and wherein when bond a is a single bond, then Z is —C(R36)2-, —C(=R32)-, —N(R35)—, or —O—, wherein each R36 is independently hydrogen or R31; and R35 is en, C1_6alkyl, —C(O)R, —S(O)2R, —C(O)OR, —C(O)N(R)2, —S(O)20R, or -S(O)2N(R)2; and when bond a is a double bond, then Z is —C(R36)= or —N=.

( R31 ) /M’Zm (6g) R3 is P wherein bond a is a single bond or a double bond; m is 0, , l, or 2; p is 0 or 1; and wherein when bond a is a single bond, then Z is —C(R36)2-, —C(=R32)—, —N(R35)—, or —O—, wherein each R36 is independently hydrogen or R31; and R35 is hydrogen, C1_6alkyl, —C(O)R, —S(O)2R, R, —C(O)N(R)2, —S(O)20R, or -S(O)2N(R)2; and when bond a is a double bond, then Z is —C(R36)= or —N=. (6h) As group (6g), wherein when bond a is a single bond, then Z is —C(R36)2— or 2)— ; and when bond a is a double bond, then Z is —C(R36)= or —N=. (6i) As group (6g), wherein m is 0; when bond a is a single bond, then Z is —C(R36)2- or —C(=R32)—; and when bond a is a double bond, then Z is —C(R36)= or —N=. (61) As group (6g), wherein bond a is a single bond; and Z is —C(R36)2- or —C(=R32)-. (6k) As group (6g), n bond a is a single bond; and Z is —C(R36)2—. (61) As group (6g), wherein bond a is a single bond; and Z is —C(=R32)-. (6111) As group (6g), wherein m is 0; bond a is a single bond; and Z is —C(R36)2- or — C(=R32)-. (611) As group (6g), wherein m is 0; bond a is a single bond; and Z is —C(R36)2-. (60) As group (6g), wherein m is 0; bond a is a single bond; and Z is —C(=R32)—. (6p) As group (6g), wherein bond a is a single bond; and Z is —C(R36)2- or 2)-, wherein each R36 is independently en, halogen, kyl, -C1_6alkyl-OH, C1_6haloalkyl, or -OH, wherein WO 42237 R32 is =0, =C(R34)2, =(spiro—C3_gcycloalkyl), or =(spiro—(3—8 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, kyl, C1_6haloalkyl, C3_gcycloalkyl, or 3—8 membered heterocyclyl. (6(1) As group (6g), wherein m is 0; bond a is a single bond; and Z is —C(R36)2- or — C(=R32)—, wherein each R36 is independently hydrogen, n, kyl, —C1_6alkyl-OH, C1_6haloalkyl, or -OH, wherein R32 is =0, =C(R34)2, =(spiro—C3_gcycloalkyl), or o—(3—8 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, C1_6alkyl, C1_6haloalkyl, C3_gcycloalkyl, or 3—8 membered heterocyclyl. (6F) As group (6g), wherein bond a is a single bond; and Z is —N(R35)— or —O—. (68) R3 is hydrogen, C1_6alkyl, aryl, heteroaryl, C3_gcycloalkyl, C3_gcycloalkenyl, 3-10 membered cyclyl, or C3_gcycloalkle1_6alkyl, wherein the C1_6alkyl, C3_gcycloalkyl, C3_gcycloalkenyl, 3—10 membered heterocyclyl, and C3_gcycloalkle1_6alkyl, are each optionally substituted by one =R32 group and one or two R31 groups; the aryl and heteroaryl groups, are each ally substituted by one or two R31 groups; wherein each R31 is independently halogen, cyano, nitro, C1_6alkyl, -C1_6alkyl-R33, loalkyl, —OR, —N(R)2, —SR, —C(O)OR, (R)2, —C(O)R, —S(O)R, —S(O)OR, —S(O)N(R)2, —S(O)2R, —S(O)ZOR, —S(O)2N(R)2, —OC(O)R, —OC(O)OR, —OC(O)N(R)2, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, wherein R33 is —OR, , or —SR; R32 is oxo, =C(R34)2, =(spiro—C3_gcycloalkyl), or =(spiro—(3—10 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, C1_6alkyl, or C3_gcycloalkyl. (6t) R3 is hydrogen, C1_6alkyl, aryl, heteroaryl, C3_gcycloalkyl, C3_gcycloalkenyl, 3-10 membered heterocyclyl, or C3_gcycloalkle1_6alkyl—, wherein the C1_6alkyl, C3_gcycloalkyl, C3_gcycloalkenyl, 3—10 ed heterocyclyl, and C3_gcycloalkle1_6alkyl-, are each optionally and independently substituted by one =R32 group and each optionally and independently substituted by one or two R31 groups; the aryl and heteroaryl , are each optionally substituted by one or two R31 groups; wherein each R31 is independently halogen, cyano, nitro, C1_6alkyl, -C1_6alkyl-R33, C1_6haloalkyl, —OR, —N(R)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)2R, —S(O)ZOR, N(R)2, —OC(O)R, —OC(O)OR, —OC(O)N(R)2, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, wherein R33 is —OR, , or —SR; R32 is oxo, =C(R34)2, =(spiro—C3_gcycloalkyl), or =(spiro—(3—10 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, C1_6alkyl, or C3_gcycloalkyl. (611) R3 is aryl, heteroaryl, C3_gcycloalkyl, C3_gcycloalkenyl, or 3—10 membered heterocyclyl, wherein the C3_gcycloalkyl, C3_gcycloalkenyl, and 3—10 membered heterocyclyl are each optionally tuted by one =R32 group and one, two, three, or four R31 groups; and the aryl and heteroaryl are each ally substituted by one, two, three, or four R31 groups. (6V) R3 is phenyl, entyl, cyclohexyl, cyclohexenyl, l, tetrahydropyranyl, piperidinyl, imidazolyl, thiazolyl, each ally substituted by one, two, three, or four R31 , and wherein the cyclopentyl, cyclohexyl, cyclohexenyl, andy piperidinyl groups are each optionally substituted by one =R32 group. (6W) R3 is phenyl, cyclopentyl, cyclohexyl, cyclohex-l-en-l-yl, exen-l-yl, furan- 2—yl, furanyl, tetrahydropyranyl, tetrahydropyranyl, piperidin-3 -yl, piperidin- 4—yl, imidazol—2—yl, imidazol—4—yl, thiazol—2—yl, thiazol—4—yl, thiazol—5—yl, each optionally substituted by one or two R31 groups, and wherein the cyclopentyl, cyclohexyl, cyclohexenyl, andy piperidinyl groups are each optionally substituted by one =R32 group. (6X) Any one of groups (6a) — (6w), wherein each R is independently hydrogen, C1_6alkyl, C1_6haloalkyl, aryl, heteroaryl, C3_gcycloalkyl, cloalkenyl, 3—10 membered heterocyclyl, arle1_6alkyl, heteroarle1_6alkyl-, C3_g cycloalkle1_6alkyl-, C3_gcycloalkenle1-6alkyl-, or (3-10 membered heterocyclyl)C1_6alkyl—. (6y) Any one of groups (6a) — (6w), wherein each R is independently hydrogen, C1_6alkyl, loalkyl, phenyl, 5- or 6-membered heteroaryl, cloalkyl, C3_gcycloalkenyl, 3—8 membered heterocyclyl, benzyl, (5— or 6—membered heteroaryl)C1_6alkyl—, C3_g cycloalkle1_6alkyl-, cloalkenle1-6alkyl—, or (3—8 membered heterocyclyl)C1_6alkyl—. (62) Any one of groups (6a) — (6w), wherein each R is independently hydrogen or C1_6alkyl.

Particular embodiments of this aspect of the invention e compounds of any one of the formulae (1), (1’), and (la) — (Id), each as d in each of the ing rows, wherein each entry is a group number as defined above (e.g., (ls) refers to n is l and each R1 is halogen), and a dash "— H indicates that the variable is as defined for formula (I) or (1’) or defined according to any one of the applicable variable definitions (la)-(6z) [e.g., when RC is a dash, it can be either as defined for Formula (I) or (1’) or any one of definitions (5a)-(5g)]: WO 42237 O\ ,_.1 00 WW (1)-98 6f (1)-99 6y (1)-100 6y (1)—101 6y (1)402 6y 3 6y (1)-108 60 (1)-109 6c (1)—110 O\O (1)—111 O\O (1)—112 O\O (1)—113 00 WW (1)419 O\ (1)420 O\ (1)—121 O\ (1)—122 O\ (1)—123 O\ (1)425 (1)426 (1)427 (1)428 (1)429 (1)-160 6f (1)430 (1)461 6f (1)431 (1)462 6y (1)432 3 6y (1)-133 (1)-164 6y (1)434 (1)-165 6y (1)435 (1)436 (1)437 (1)438 (1)439 (1)-170 6c (1)440 (1)471 6c (1)441 (1)472 O\O (1)442 (1)-173 O\O (1)443 (1)-174 O\O (1)444 (1)-175 O\o (1)445 9.5 (1)446 O\ (1)447 O\ (1)448 O\ (1)449 O\ (1)450 (1)481 O\ (1)451 (1)482 O\ (1)452 (1)-183 O\ (1)-153 (1)484 O\ (1)454 (1)-185 O\ (1)487 (1)488 (1)489 (1)490 (1)491 (1)422 (1)492 (1)—223 (1)-193 (1)—224 (1)494 (1)—225 (1)-195 (1)-226 (1)-196 7 (1)497 (1)498 (1)499 (1)—200 (1)—201 2 (1)—202 (1)-233 (1)-203 (1)—234 (1)-204 (1)-235 (1)-205 (1)-236 (1)-206 (1)-237 (1)-208 (1)—209 (1)—210 (1)—211 (1)—212 (1)—243 (1)—213 (1)—244 (1)—214 (1)—245 (1)—215 (1)-246 (1)-216 (1)-247 (1)—217 (1)—249 (1)—250 (1)—251 — (1)—252 (1)—253 (1)—254 (1)-255 (1)-256 (1)-257 (1)-258 (1)-263 2j DJ {3‘ (1)-264 2j b.) H. (1)-265 2j U.)W (1)-266 2b DJ {3‘ 7 2b b.) H. (1)-268 2b U.) H U.) (1)—274 — In another aspect, the invention provides the compound according to formula (II), (R1)n / N N) RC or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; each R1 is ndently n, -OR, -N(R)2, or -SR; each R3 is independently hydrogen, C1_6alkyl, aryl, heteroaryl, C3_gcycloalkyl, cloalkenyl, 3—10 membered heterocyclyl, or C3_gcycloalkle1_6alkyl—, wherein the C1_6alkyl, cloalkyl, C3_gcycloalkenyl, 3—10 membered heterocyclyl, and C3_gcycloalkle1_6alkyl-, are each optionally and independently substituted by one =R32 group and each optionally and independently tuted by one or two R31 groups; the aryl and heteroaryl groups, are each optionally substituted by one or two R31 groups; wherein each R31 is independently halogen, cyano, nitro, kyl, lkyl—R33, C1_6haloalkyl, —OR, —N(R)2, —SR, R, —C(O)N(R)2, —C(O)R, —S(O)R, —S(O)OR, —S(O)N(R)2, —S(O)2R, —S(O)ZOR, —S(O)2N(R)2, —OC(O)R, —OC(O)OR, —OC(O)N(R)2, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, wherein R33 is —OR, —N(R)2, or -SR; R32 is oxo, =C(R34)2, =(spiro—C3_gcycloalkyl), or =(spiro—(3—10 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, C1_6alkyl, or C3_gcycloalkyl; and RC is hydrogen or C1_6alkyl; and each R is independently hydrogen or R10, wherein R10 is C1_6alkyl, C1_6haloalkyl, aryl, heteroaryl, C3_gcycloalkyl, C3_gcycloalkenyl, 3-10 membered heterocyclyl, arle1_6alkyl, heteroarle1_6alkyl—, C3_g cycloalkle1_6alkyl-, C3_gcycloalkenle1-6alkyl-, or (3-10 membered heterocyclyl)C1_6alkyl-, each R10 optionally substituted by one, two, three, or four groups that are each independently halogen, cyano, nitro, C1_6alkyl, C1_6haloalkyl, —0R“, —N(R11)2, —SR“, -C(O)OR“, —C(O)N(R“)2, -C(O)R”, —S(O)R“, —S(O)OR“, —S(O)N(R“)2, R“, —S(O)ZOR“, —S(O)2N(R11)2, —OC(O)R“, —OC(O)OR“, N(R“)2, —N(R“)C(O)R“, —N(R”)C(O)OR”, —N(R11)C(O)N(R“)2, wherein each R“ is independently hydrogen or C1_6alkyl.

In one embodiment, the compounds of formula (11) further include those nds where, R3 is additionally (heteroaryl)—(3—10 membered heterocyclyl)—; R31 is additionally —C(O)N(OH)R, —C(N=R11)R, or —C(N=R11)N(R11)R; R34 is additionally cyano or - C1_6alkyl-OR; and/or R10 is onally optionally tuted by —N(R“)S(O)2R“ or —C(O)-(3-10 membered heterocyclyl); such compounds are referred to as compounds of a (11’).

The invention further comprises subgenera of formula (11) or (11’) in which the substituents are selected as any and all combinations of one or more of ural formula (11), n, R1, R3, and RC as deﬁned herein, including without limitation, the following: Structural Formula II is one of ae [Ila] — [11d]: (Ha): wherein the stereoisomeric conﬁguration of carbon-l (C-1) and carbon-3 (C—3) of formula (11) are respectively (R, R).

(IIb): n the stereoisomeric conﬁguration of carbon-l and carbon-3 are of formula (11) respectively (R, S). (11c): wherein the stereoisomeric conﬁguration of carbon—l and carbon—3 are of formula (11) respectively (S, R).

(IId): wherein the stereoisomeric conﬁguration of carbon-l and carbon-3 are of formula (11) respectively (S, S).

Structural Formula II is one of formulae [He] — [11h]: (He): wherein the isomeric conﬁguration of carbon—1 (C—1) and carbon—3 (C—3) of a (II) are respectively (R, R). (111): wherein the stereoisomeric conﬁguration of carbon—1 and carbon—3 are of formula (II) tively (R, S). (ﬁg): wherein the stereoisomeric conﬁguration of carbon-1 and carbon—3 are of formula (II) respectively (S, R).

(IIh): wherein the stereoisomeric conﬁguration of -l and carbon-3 are of formula (II) respectively (S, S). n and R1 are selected from one of the following groups 17a) — g7i]: (7a) n is 0 or 1 and R1 is halogen, -OR0, -N(R0)2, or -SR0; wherein each R0 is independently hydrogen or C1_6alkyl. (7b) n is 0 or 1 and R1 is ﬁuoro, chloro, y, or y. (7c) n is 0 or 1 and R1 is halogen. (7d) n is 0 or 1 and R1 is ﬁuoro or chloro. (7e) n is l and R1 is halogen, -OR0, -N(R0)2, or -SR0; wherein each R0 is independently hydrogen or C1_6alkyl. (71) n is l and R1 is ﬁuoro, chloro, hydroxy, or methoxy. (7g) n is 1 and R1 is halogen. (7h) n is 1 and R1 is ﬁuoro or chloro. (7i) n is 0.

RC is selected from one of the followin rou s 8a — 8 (8a) RC is hydrogen or C1_4alkyl. (8b) RC is hydrogen or C1_2alkyl. (8c) RC is hydrogen or methyl. (8d) RC is hydrogen. (8e) RC is C1_6alkyl. (81) RC is C1_4alkyl. (8g) RC is methyl.

R3 is ed from one of the following groups 1921)- 19X): (93) R3 is aryl, heteroaryl, C3_gcycloalkyl, C3_gcycloalkenyl, 3—10 membered heterocyclyl, or C3_gcycloalkle1_6alkyl-, wherein the C3_gcycloalkyl, C3_gcycloalkenyl, 3-10 membered heterocyclyl, and C3_gcycloalkle1_6 alkyl—, are each optionally and independently substituted by one =R32 group and each optionally and independently substituted by one or two R31 groups; and the aryl and heteroaryl groups, are each optionally substituted by one or two R31 groups. (9b) R3 is phenyl, a ﬁve or six membered heteroaryl, monocyclic cloalkyl, monocyclic C5_gcycloalkenyl, a ﬁve or six membered clic heterocyclyl, or (monocyclic C5_gcycloalkyl)C1_6 alkyl-, wherein the cloalkyl, C5_gcycloalkenyl, — 6 membered heterocyclyl, and cloalkle1_6 alkyl—, are each optionally and independently substituted by one =R32 group and each optionally and independently substituted by one or two R31 groups; and the phenyl and heteroaryl groups, are each optionally substituted by one or two R31 groups. (9C) R3 is phenyl or a ﬁve or six membered heteroaryl, each optionally tuted by one or two R31 groups. (9d) R3 is monocyclic C5_gcycloalkyl, monocyclic cloalkenyl, a ﬁve or six membered monocyclic heterocyclyl, or (monocyclic C5_gcycloalkyl)C1_6alkyl—, each optionally substituted by one =R32 group and one or two R31 groups.

\ \K» k a! (R )m/(\’)—Z (96) R . p where1n bond a 1s a s1ngle bond or a double bond; m 1s 0,. . . . , l, or 2; p is 0 or 1; and wherein when bond a is a single bond, then Z is —C(R36)2-, —C(=R32)-, —N(R35)—, or —O—, wherein each R36 is independently hydrogen or R31; and R35 is hydrogen, C1_6alkyl, , -S(O)2R, —C(O)OR, -C(O)N(R)2, —S(O)ZOR, or -S(O)2N(R)2; and when bond a is a double bond, then Z is )= or —N=.

R31 Z ( )m (91) R3 is P wherein bond a is a single bond or a double bond; m is 0, , l, or 2; p is 0 or 1; and wherein when bond a is a single bond, then Z is —C(R36)2-, —C(=R32)-, —N(R35)—, or —O—, wherein each R36 is ndently en or R31; and R35 is hydrogen, C1_6alkyl, -C(O)R, -S(O)2R, —C(O)OR, -C(O)N(R)2, —S(O)ZOR, or -S(O)2N(R)2; and when bond a is a double bond, then Z is —C(R36)= or —N=. (9g) As group (9f), wherein when bond a is a single bond, then Z is —C(R36)2- or 2)— ; and when bond a is a double bond, then Z is —C(R36)= or —N=. (9h) As group (9f), wherein m is 0; when bond a is a single bond, then Z is —C(R36)2- or —C(=R32)—; and when bond a is a double bond, then Z is —C(R36)= or —N=. (9i) As group (9f), wherein bond a is a single bond; and Z is —C(R36)2- or —C(=R32)—. (91) As group (9f), wherein bond a is a single bond; and Z is —C(R36)2-. (9k) As group (9f), wherein bond a is a single bond; and Z is —C(=R32)—. (91) As group (9f), wherein m is 0; bond a is a single bond; and Z is —C(R36)2- or — C(=R32)-. (9111) As group (9f), wherein m is 0; bond a is a single bond; and Z is )2—. (911) As group (9f), wherein m is 0; bond a is a single bond; and Z is —C(=R32)—. (90) As group (9f), n bond a is a single bond; and Z is —C(R36)2- or —C(=R32)—, wherein each R36 is independently hydrogen, halogen, C1_6alkyl, -C1_6alkyl-OH, loalkyl, or -OH, wherein R32 is =0, =C(R34)2, =(spiro—C3_gcycloalkyl), or =(spiro—(3—8 membered cyclyl)), wherein each R34 is independently hydrogen, halogen, C1_6alkyl, C1_6haloalkyl, C3_gcycloalkyl, or 3—8 membered heterocyclyl. (9p) As group (9f), wherein m is 0; bond a is a single bond; and Z is —C(R36)2- or — C(=R32)—, wherein each R36 is independently hydrogen, halogen, C1_6alkyl, -C1_6alkyl-OH, C1_6haloalkyl, or -OH, wherein R32 is =0, =C(R34)2, =(spiro—C3_gcycloalkyl), or =(spiro—(3—8 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, C1_6alkyl, C1_6haloalkyl, C3_gcycloalkyl, or 3—8 membered heterocyclyl. (9(1) As group (9f), wherein bond a is a single bond; and Z is —N(R35)— or —O—. (9r) R3 is en, C1_6alkyl, aryl, aryl, C3_gcycloalkyl, cloalkenyl, 3-10 membered heterocyclyl, or C3_gcycloalkle1_6alkyl, wherein the C1_6alkyl, cloalkyl, C3_gcycloalkenyl, 3—10 membered heterocyclyl, and C3_gcycloalkle1_6alkyl, are each optionally substituted by one =R32 group and one or two R31 groups; the aryl and heteroaryl groups, are each optionally substituted by one or two R31 groups; wherein each R31 is independently halogen, cyano, nitro, kyl, -C1_6alkyl-R33, C1_6haloalkyl, —OR, —N(R)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)2R, —S(O)ZOR, —S(O)2N(R)2, —OC(O)R, -OC(O)OR, -OC(O)N(R)2, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, wherein R33 is —OR, —N(R)2, or -SR; R32 is oxo, =C(R34)2, o—C3_gcycloalkyl), or =(spiro—(3—10 membered cyclyl)), wherein each R34 is independently hydrogen, halogen, kyl, or C3_gcycloalkyl. (95) R3 is aryl, aryl, C3_gcycloalkyl, C3_gcycloalkenyl, or 3—10 membered heterocyclyl, wherein the C3_gcycloalkyl, C3_gcycloalkenyl, and 3—10 membered heterocyclyl are each ally substituted by one =R32 group and one, two, three, or four R31 groups; and the aryl and heteroaryl are each optionally substituted by one, two, three, or four R31 groups. (9t) R3 is phenyl, cyclopentyl, cyclohexyl, cyclohexenyl, furanyl, tetrahydropyranyl, piperidinyl, imidazolyl, thiazolyl, each optionally substituted by one, two, three, or four R31 groups, and wherein the cyclopentyl, cyclohexyl, cyclohexenyl, andy piperidinyl groups are each optionally substituted by one =R32 group. (911) R3 is phenyl, entyl, cyclohexyl, cyclohex-l-en-l-yl, cyclohexen-l-yl, furan- 2—yl, furanyl, tetrahydropyranyl, tetrahydropyranyl, piperidin-3 -yl, piperidin- 4—yl, imidazol—2—yl, imidazol—4—yl, thiazol—2—yl, thiazol—4—yl, thiazol—S—yl, each optionally substituted by one or two R31 groups, and wherein the cyclopentyl, cyclohexyl, exenyl, andy piperidinyl groups are each optionally substituted by one =R32 group. (9V) Any one of groups (9a) — (9u), wherein each R is independently hydrogen, C1_6alkyl, C1_6haloalkyl, aryl, aryl, cloalkyl, C3_gcycloalkenyl, 3—10 membered heterocyclyl, arle1_6alkyl, heteroarle1_6alkyl-, C3_g cycloalkle1_6alkyl-, cloalkenle1-6alkyl-, or (3-10 membered heterocyclyl)C1_6alkyl-. (9w) Any one of groups (9a) — (9u), wherein each R is independently hydrogen, C1_6alkyl, C1_6haloalkyl, phenyl, 5- or 6-membered heteroaryl, C3_gcycloalkyl, C3_gcycloalkenyl, 3—8 membered heterocyclyl, benzyl, (5— or 6—membered heteroaryl)C1_6alkyl—, C3_g cycloalkle1_6alkyl-, C3_gcycloalkenle1-6alkyl—, or (3—8 membered heterocyclyl)C1_6alkyl—. (9X) Any one of groups (9a) — (9u), n each R is independently hydrogen or C1_6alkyl.

Particular embodiments of this aspect of the invention include compounds of any one of the formulae (11), (11’), and (Ila) — (11d), each as deﬁned in each of the following rows, wherein each entry is a group number as d above and a dash "-" indicates that the variable is as defined for a (11), or (11’), or defined according to any one of the able variable def1nitions (7a)—(9t) [e.g., when RC is a dash, it can be either as defined for Formula (11) or (11’) or any one of definitions (821)—(8g)]: WO 42237 (2)-37 11b 7g (2)-38 Hc (2)-39 11d (2)-99 Ed 7i (2)430 (2)400 Hf 7i (2)431 (2)401 Hg 7i (2)432 (2)402 11h 7i (2)433 (2)—103 11b (2)434 (2)404 11c (2)—135 (2)—105 Hd (2)—136 (2)—106 Hf (2)—137 (2)—107 Hg (2)—138 (2)—108 (2)439 (2)440 (2)441 (2)442 (2)443 (2)413 (2)444 (2)414 (2)445 (2)415 (2)-146 (2)-116 (2)447 (2)417 8 (2)-118 (2)449 (2)450 (2)451 (2)452 (2)453 (2)454 (2)424 (2)455 (2)425 6 (2)-126 (2)—157 (2)427 (2)—158 (2)-128 (2)—159 (2)—160 (2)-161 (2)—170 (2)-162 (2)—171 (2)—163 — (2)—172 (2)-164 (2)—173 (2)-165 (2)—174 - 7h 9b 7a 9b - (2)—175 - 7i 9e - (2)—167 - 7a 9e - (2)—176 - 7i 9V - (2)—168 - 7a 9b 7i 9b - (2)—169 — 7g 9e — In r aspect, the present disclosure provides compounds that are Structure Name N 2-(5H-imidazo[5,1-a]isoindoly1)ethanol l /> \l ethyl 2-(5H-imidazo[5,1-a]isoindoly1)acetate N O / /> N 0 2—(5H—imidazo[5, 1—a]isoindol—5—y1)acetic acid I /> \ 2-(5H-imidazo[5,1-a]isoindol—5—y1)—N— methylacetamide (E)—5-(2—bromostyry1)-5H-imidazo[5, 1- 1273 a]isoindole 2-(6-chloro-5H-imidazo[5,1-a]isoindolyl) 1286 N OH cyclohexylethanol 2-(6-chloro-5H-imidazo[5,1-a]isoindolyl) 1287 N O cyclohexylethanone imidazo[5,1-a]isoindolyl)ethyl 2- 1288 O O (((1R,2R,5S)isopropyl N O N methylcyclohexyl)oxy)acetate N O O tert-butyl (4-(2-(5H-imidazo[5,1-a]isoindol 1300 N O yl)acetyl)phenyl)carbamate 1-(4-aminophenyl)(5H-imidazo[5,1- 1301 N O a]isoindolyl)ethanone N O tert-butyl (4-(1-hydroxy(5H-imidazo[5,1- 1302 O N OH a]isoindolyl)ethyl)phenyl)carbamate AH26(9298372_1):RTK Structure Name N H2 0 O 1-(4-amin0pheny1)(5H-imidazo[5,1- 1303 N 0H a]isoind01—5 —y1)ethan01 I /> 1-cyclohexyl-Z-(SH-imidazo[5,1-a]isoind01 1304 N CH y1)ethan01 I /) O 0 +0" 2—(5H-imidazo[5,1-a]isoind01y1)—1—(3 — 1306 W N O O nitropheny1)ethan0ne / /> O 0 +0" 2—(5H-imidazo[5,1-a]isoind01y1)—1—(3 — 1307 Ff N OH O nitropheny1)ethan01 imidazo[5,1-a]isoind01y1)(2— nitropheny1)ethan0ne 2-(5H-imidazo[5,1-a]isoind01y1)(2— nitropheny1)ethan01 tert-butyl (2-(2-(5H-imidazo[5,1-a]isoind01—5— y1)acety1)phenyl)carbamate Structure Name tert-butyl (2-(1-hydr0xy-2—(5H-imidazo[5 ,1- a]isoindol-S-y1)ethy1)pheny1)carbamate 1-(2-amin0pheny1)-2—(5H-imidazo [5 ,1- a]isoind01y1)ethan0ne 1-(2-amin0pheny1)-2—(5H-imidazo [5 ,1- a]isoind01—5 -y1)ethan01 1-(2-ch10r0pheny1)(5H-imidazo [5 ,1- nd01y1)ethan0ne 1-(5H-imidazo[5,1-a]isoind01—5-y1) methylpropan01 1-(2-ch10r0phenyl)(5H-imidazo[5, 1- a]isoind01—5 han01 1-(3 -ch10r0pheny1)(5H-imidazo[5 ,1- a]isoind01—5 -y1)ethan01 2—(5H-imidazo[5,1-a]isoind01y1) phenylethanone Structure Name 2—(5H-imidazo[5, 1-a]isoind01—5-y1)-1 - 1349 phenylethanol — -dimethylfuran-3 -y1)(6-ﬂu0r0—5H— 1352 \ o . . .

N 1m1dazo[5, 1 -a]1501nd01-5 -y1)ethan01;.

/ /) HO O O (a. 1-(3 -ch10r0pheny1)(5H-imidazo[5 ,1- 13 5 3 N G a]isoind01—5—y1)ethan0ne I x) ohexy1(6-ﬂu0r0-5H-imidazo[5, 1 - 13 5 6 a]isoind01y1)ethan0ne 1-cyclohexy1—2-(6-ﬂu0r0-5H-imidazo[5 ,1- 13 5 7 a]isoind01—5 -y1)ethan01 2—(5H-imidazo[5,1-a]isoind01y1) 13 5 8 / N) OH (tetrahydro-ZH-pyrany1)ethanol 2-(7-ch10r0-5H-imidazo[5, 1-a]isoind01y1)— 1- 1359 N (3H cyclohexylethanol / /> (Z)—1-cyclohexy1(5H-imidazo[5, 1-a]isoind01- 1360 | N N \ 5— 1 ethanone oxime I /> W Y) N0. Structure Name 1-cyclopenty1-2—(5H-imidazo[5,1-a]isoind01—5- 1362 N OH / x} y1)ethan01 «Lax tert-butyl 4-(1-hydr0xy(5H-imidazo[5 ,1- a] ol-S -y1)ethy1)piperidinecarb0xy1ate 1363 1-cyclohexyl-Z-(SH-imidazo[5,1-a]isoind01-5— 1364 N N H2 y1)ethanamine / /> O 0 EL 1367 g OX tert-butyl (3 dr0xy-2—(5H-1m1dazo[5, 1- ’ N> a]isoindol-S-y1)ethy1)pheny1)carbamate O O N H2 1-(3 -amin0pheny1)-2—(5H-imidazo [5 ,1— 13 69 N 0H a]isoind01—5 -y1)ethan01 I /> 2-(5H-imidazo[5,1-a]isoind01y1)(piperidin- 1370 N OH 4-y1)ethan01 / /> 4-(2—(6-ﬂu0r0-5H-imidazo[5,1-a]isoind01y1)— 1371 W 1-hydr0xyethy1)cyclohexanol; N CH 1-cyclohexy1(9-meth0xy-5H-imidazo[5,1- 13 72 \O N CH a]isoind01—5 —y1)ethan01 / x> N0 Structure Name 1373 H0); 5—(2—CyClohexy1hydr0xyethy1)-5H- N7 I HO imidazo[5,1—a]isoind01—9—01 / /> OH 2-(8-ch10r0-5H-imidazo[5, oind01y1)— 1- 1374 / . /) cyclohexylethanol, 1-(cyclohexeny1)-2—(5H-imidazo[5, 1- 1375 a]isoind01-5 -y1)ethan01; ohexy1—2-(8-ﬂu0r0-5H-imidazo[5 ,1- 13 76 F W a]isoind01-5 -y1)ethan01; 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01y1) 1378 / E‘) HO (1,4—di0xaspir0[4.5]decany1)ethan01; 4-(2—(6-ﬂu0r0-5H-imidazo[5,1-a]isoind01y1)- 1379 1 -hydr0xyethy1)cyclohexan0ne; \ N» F oH 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01y1) 13 81 \ W (4-methylenecyc10hexy1)ethan01; O 1— C( yclohexeny)1 5H-imidazo 5,1-( [ 1382 a]isoind01-5 -y1)ethan01; Structure Name 1—(4-(hydr0xymethy1)cyclohexyl)'2'(5H' 1383 OH imidazo[5 soind01—5 -y1)ethan01; \ T|N (4-(1-hydr0xy(5H-imidazo[5,1-a]isoind01—5— 1384 N N yl)ethy1)piperidiny1)(thi0phen 2, EHO / y1)methan0ne; db? 1-(4-(1-hydr0xy(5H-imidazo[5 ,1-a]isoind01— hy1)piperidiny1)ethan0ne; \7N N 2-(5H-imidazo[5,1-a]isoind01—5-y1)(4- 1386 @{hN\j methylenecyc10hexy1)ethan01; F OH 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01—5-y1) 13 87 N (4-methylcyclohexy1)ethanol; \ W N 2—(5H-imidazo[5,1-a]isoind01—5-y1)(1-methy1— 1389 l y . .

N N 1H-1m1dazoly1)ethan01; \ \ 2-(5H-imidazo[5, 1-a]isoind01—5-y1)(thiazol 1390 N / j] 1)et anoh 1 ; \ W y 2-(5H-imidazo[5,1-a]isoind01—5-y1)(thiazol 1391 _ N 8VN y1)ethan01; N0 Structure Name 1—(4—(1—hydr0xy—2—(5H—imidazo[5,1—a]isoind01— 1392 N o 5-y1)ethy1)piperidiny1)-2,2—dimethy1pr0pan \ \N {i one; 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01—5-y1) 1393 O N / (f 2 1) th 1 uran— e —y ano; \ P ’ F OH 2—(6—ﬂu0r0—5H-imidazo[5, 1-a]isoind01—5-y1) 1394 N/ / 7 N\) (1-methy1— 1 H-imidazol-Z-y1)ethan01; \ / (1 S)cyc10hexy1—2—(5H-imidazo[5, 1 -a]isoind01— 1396 \ P 5—y1)ethan01; -cyclohexy1—2—(5H-imidazo[5, 1- 1397 W a]isoind01-5 -y1)ethan01; u0r0-5H-imidazo[5, 1-a]isoind01—5-y1) 1398 \II \ (4—(i0domethylene)cyc10hexy1)ethan01; 1-cyc10hexy1—2—(5H-imidazo[5, 1 -a]isoind01—5- 1400 \ x) y1)pr0pan01; 1402 WN 2—(5H-imidazo[5,1-a]isoindol-S-y1)acet0nitrile; \ /> WO 42237 N0 Structure Name 1—cyc10hexy1—3 —(6—ﬂu0r0-5H—imidazo[5 ,1— 1403 N a]isoindol-S-y1)pr0pan-2—01; \ /> 1-cyc10hexy1—3-(5H-imidazo[5,1-a]isoind01—5- 1404 I /> y1)pr0pan-2—01; 1-(4-(1-hydr0xy(5H-imidazo[5 ,1-a]isoind01— 1405 -y1)ethy1)piperidiny1)phenylethan0ne; 1-(4,4-diﬂuorocyclohexy1)—2—(6—ﬂu0r0—5H— 1406 N imidazo[5, 1 -a]isoind01—5 -y1)ethan01; \ N F 1-(4,4-diﬂuorocyclohexy1)(5H-imidazo[5, 1 - 1407 \ W a]isoind01-5 -y1)ethan01; N F F \N /\\ 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01—5-y1) 1409 N OH hy1— 1 H-imidazol-S -y1)ethan01; | /> F 1-(4-(cyclopropylmethylene)cyc10hexy1)-2—(6- 1410 SW \ ﬂuoro-SH-imidazo[5, 1-a]isoindol-S-y1)ethan01; 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01—5-y1) 141 1 N (4-(pr0pany1idene)cyc10hexy1)ethan01; \ j'N Structure Name \ (E)(2—cyclohexy1viny1)-5H-imidazo[5, 1- 1412 N a]isoindole; / x) 2-(9-ﬂu0r0-5H-imidazo[5, oind01—5-y1) 1413 (4-methylcyclohexy1)ethanol; 1-(cyclohex-3 -en-1—y1)—2—(6—ﬂu0r0—5H— 1414 imidazo[5 ,1-a]isoindol-S-y1)ethan01; (R)—1-cyclohexy1—2-((R)-5H-imidazo[5, 1- 1415 a]isoind01—5 -y1)ethan01 (S)—1—cyclohexy1—2-((R)—5H-imidazo[5, 1- a]isoind01—5 -y1)ethan01 (S)— 1 —CyCthexy1—2-((S)-5H-imidazo[5, 1 - a]isoind01—5 -y1)ethan01 (R)cyclohexy1—2—((S)-5H-imidazo[5, 1- a]isoind01—5 -y1)ethan01 0hexy1—2—(5H-imidazo[5, 1 -a]isoind01—5— ylidene)ethan01 N0 ure Name 1-cyc10hexy1—2-(5H-imidazo[5,1-a]isoind01—5— 1420 y1)ethy1 acetate 1 -(4-(2-(benzyloxy)ethylidene)cyc10hexy1)—2- 1421 (5H-imidazo[5,1-a]isoind01—5-y1)ethan01 1 -(1-(benzylsulfony1)piperidiny1)(5H- 1422 imidazo[5,1-a]isoind01—5-y1)ethan01 1-(4-(1-hydr0xy(5H-imidazo[5 ,1-a]isoind01— 1423 5 -y1)ethy1)piperidiny1)(pyrimidin-5 - y1)ethan0ne 2-(3 ,4-diﬂu0r0pheny1)(4-(1-hydr0xy(5H- 1424 imidazo[5,1-a]isoind01—5 -y1)ethy1)piperidin an0ne cyclohexy1(4-(1-hydr0xy(5H-imidazo[5,1- 1425 a] isoindol-S -y1)ethy1)piperidiny1)methan0ne methyl 4-(1-hydr0xy(5H-imidazo[5,1- 1426 a]isoindol-S-y1)ethy1)cyclohexanecarboxylate 1-cyc10hexy1—2-(5H-imidazo[5,1-a]isoind01-5— 1427 y1)ethy1 phenylcarbamate 4-(1-cyclohexyl(5H-imidazo[5,1- 1428 a]isoindolyl)ethoxy) anoic acid 4-(1-hydroxy(5H-imidazo[5,1- 1429 a]isoindolyl)ethyl)cyclohexanol ohexyl(5H-imidazo[5,1- 1431 a]isoindolyl)ethyl benzoate 4-(1-hydroxy(5H-imidazo[5,1- a]isoindolyl)ethyl)-N-(2- 1432 (methylsulfonamido)ethyl) cyclohexanecarboxamide (2S)(1-cyclohexyl(5H- imidazo[5,1-a]isoindolyl)ethoxy)- 1433 3-methyloxobutanaminium chloride sodium 1-cyclohexyl(5H- 1434 imidazo[5,1-a]isoindolyl)ethyl phosphate AH26(9298372_1):RTK Structure Name OH 4-(1-hydr0xy(5H-imidazo[5,1-a]isoind01—5— 143 6 HO y1)ethy1)cyclohexanecarboxylic acid / N) / 1-(4-(1-hydr0xy(5H-imidazo[5 ,1-a]isoind01— 1437 \ / 5—y1)ethy1)piperidiny1)-2—(pyridin /N/) HO y1)ethan0ne 2—(5H-imidazo[5,1-a]isoind01—5-y1) 1438 / N (Spiro[2.5]octan—6—y1)ethan01 J HO O 2—(4-ﬂu0r0pheny1)(4-(1-hydr0xy(5H- 143 9 NWF imidazo[5,1-a]isoindol-S-y1)ethy1)piperidin /N/) HO y1)ethan0ne (ZS)cyclohexyl-Z-(SH-imidazo[5,1-a]isoind01- 1440 N / A O O 5-y1)ethy1 2-aminopr0pan0ate H2N“W: / OH 1-(4-(2-hydr0xyethylidene)cyc10hexy1)-2—(5H— 1441 / 3 1m1dazo[5, 1-a]1somd01y1)ethan01 1442 O (ZS)cyclohexyl-Z-(SH-imidazo[5,1-a]isoind01- / j W thy1 idine-Z-carboxylate (2 S)—5—( 1 —cyclohexy1(5H-imidazo[5, 1- a]isoind01—5-y1)ethyl) 1-methy12- aminopentanedioate 2012/033245 Structure Name 0 1—(4—((S)—1—hydr0xy—2—((S)—5H—imidazo[5,1— 1447 a]isoind01—5—y1)ethy1)piperidin—1—y1)—2— N ”YORK/Q /N/ HO phenylethanone O (3 —ﬂu0r0hydr0xypheny1)(4-(1-hydr0xy 1448 (5H-imidazo[5,1-a]isoind01y1)ethy1)piperidin- / A HO 1-y1)methan0ne N,4 4-(1-hydr0xy(5H-imidazo[5,1-a]isoind01—5- 1449 N H y1)ethy1)-N—pheny1piperidinecarb0xamide 0 (4-ﬂu0ropheny1)(4-(1-hydr0xy(5H- 1450 imidazo[5,1-a]isoind01—5 -y1)ethy1)piperidin \ \\,Z I0 han0ne z “Fl (ZS)amin0(4-(1-hydr0xy-2—(5H- 1451 H21:ll imidazo[5,1-a]isoind01—5 -y1)ethy1)piperidin \ \\/z I0 y1)—3 -pheny1pr0pan0ne (4-(1-hydr0xy(5H-imidazo[5,1-a]isoind01—5— 1454 y1)ethy1)piperidiny1)((S)-pyrr01idin-2— ; N HO y1)methan0ne (1R,4s)—4-(2-((S)ﬂu0r0-5H-imidazo[5, 1- 1455 / N HOBQOW, )0H a]isoind01—5-y1)hydr0xyethy1)cyclohexy1 benzoate H (1R,4s)—4-(2-((S)ﬂu0r0-5H-imidazo[5, 1— 1456 ""' / N a]isoind01—5-y1)hydr0xyethy1)cyclohexanol NA HO Structure Name 1-(3 -(1-hydr0xy(5H-imidazo[5,1-a]isoind01— N 5-y1)ethy1)azetidiny1)-2—phenylethan0ne 9 HO N4NH 3 -(1-hydr0xy(5H-imidazo[5,1-a]isoind01—5- / 5 HO y1)-N-pheny1azetidinecarb0xamide N4 tert—butyl 3—(1—hydr0xy—2—(5H—imidazo[5,1— X a]1s01nd01—5-y1)ethy1)azet1d1necarb0xy1ate. . . .

/ S HO NH 1-(azetidin-3 -y1)-2—(5H-imidazo[5, 1 -a]isoind01— —y1)ethan01 tert—butyl 4—((S)—1—hydr0xy—2—((R)—5H— 1469 imidazo[5,1-a]isoind01—5 -y1)ethy1)piperidine carboxylate tert—butyl 4—((R)—1—hydr0xy—2—((R)—5H— 1470 o[5,1-a]isoind01y1)ethy1)piperidine carboxylate utyl 4—((R)—1—hydr0xy—2—((S)—5H— 1471 imidazo[5,1-a]isoind01—5 -y1)ethy1)piperidine carboxylate tert—butyl 4—((S)—1—hydr0xy—2—((S)—5H— 1472 imidazo[5,1-a]isoind01—5 -y1)ethy1)piperidine carboxylate Structure Name 1-((1s,4s)—4-(benzyloxy)cyclohexy1)—2—(6—ﬂu0r0— 1473 5H-imidazo[5,1-a]isoind01—5-y1)ethan01 / 2-(5H-imidazo[5,1-a]isoind01—5-y1)(pyridin 1474 N [<1 1 h 1 / A y )et ano (1r,4r)(2—(6-ﬂu0r0-5H-imidazo[5, 1 — 1475 H / JN OH d01—5-y1)hydr0xyethy1)cyclohexanol.

/ HO O 4-((S)hydr0xy((R)-5H-imidazo[5,1- 1476 N N4” a]isoind01—5 -y1)ethy1)-N-pheny1piperidine A HO carboxamide 4-((R)hydr0xy((R)-5H-imidazo[5 ,1- 1477 a]isoind01—5 -y1)ethy1)-N-pheny1piperidine carboxamide 4-((R)hydr0xy((S)-5H-imidazo[5,1- 1478 a]isoind01—5 hy1)-N-pheny1piperidine carboxamide 4-((S)hydr0xy((S)-5H-imidazo[5,1- 1479 a]isoind01—5 -y1)ethy1)-N-pheny1piperidine carboxamide 1-(4-((R)hydr0xy-2—((S)-5H-imidazo[5 ,1- 1480 a] isoindol-S -y1)ethy1)piperidiny1) phenylethanone (1R,4s)((S)((R)fluoro-5H-imidazo[5,1- 1482 a]isoindolyl)hydroxyethyl)cyclohexanol (1S,4s)((R)((R)fluoro-5H-imidazo[5,1- 1483 ndolyl)hydroxyethyl)cyclohexanol (1S,4s)((R)((S)fluoro-5H-imidazo[5,1- 1484 a]isoindolyl)hydroxyethyl)cyclohexanol (1R,4s)((S)((S)fluoro-5H-imidazo[5,1- 1485 a]isoindolyl)hydroxyethyl)cyclohexanol (1S,4r)((S)((S)fluoro-5H-imidazo[5,1- 1486 a]isoindolyl)hydroxyethyl)cyclohexanol (1S,4r)((S)((R)fluoro-5H-imidazo[5,1- 1487 a]isoindolyl)hydroxyethyl)cyclohexanol (1R,4r)((R)((S)fluoro-5H-imidazo[5,1- 1488 a]isoindolyl)hydroxyethyl)cyclohexanol AH26(9298372_1):RTK N0 Structure Name (1R,4r)((R)-2—((R)ﬂu0r0-5H-imidazo[5, 1 — 1489 a]isoind01—5-y1)hydr0xyethy1)cyclohexanol 1-(4-((S)hydr0xy((S)-5H-imidazo[5,1- 1490 a]isoind01—5-y1)ethy1)piperidiny1) (tetrahydro-2H-pyrany1)ethanone 1-(4-((R)hydr0xy((R)-5H-imidazo[5,1- 1491 nd01—5-y1)ethy1)piperidiny1) phenylethanone N—((1s,4s)(1-hydr0xy(5H-imidazo[5,1- 1492 a] isoindol-S -y1)ethy1)cyc10hexy1)benzamide 1-(4-((S)hydr0xy((R)-5H-imidazo[5,1- 1493 a] isoindol-S -y1)ethy1)piperidiny1) phenylethanone 2-(5H-imidazo[5,1-a]isoind01—5-y1)(1- 1494 (phenylcarbam0y1)piperidiny1)ethy1 phenylcarbamate 4-((R)hydr0xy((S)-5H-imidazo[5,1- 1495 a]isoind01—5 -y1)ethy1)-N—((1r,4R) hydroxycyc10hexy1)piperidinecarb0xamide hydr0xy((S)-5H-imidazo[5,1- 1496 a] isoindol-S -y1)ethy1)-N-(tetrahydr0-2H-pyran y1)piperidinecarb0xamide Structure Name 4-((S)hydr0xy((S)-5H-1m1dazo[5,1- 1497 N "MB/C Q’ C : a]isoind01—5—y1)ethy1)—N—((1r,4S)—4— /N/ HO hydroxycyc10hexy1)piperidinecarb0xamide 1498 O/\© 1-((1r,4r)—4-(benzyl0xy)cyc10hexy1)-2—(5H- / N) H0 imidazo[5,1-a]isoind01—5-y1)ethan01 F Q O 1-((1r,4r)(benzy10xy)cyc10hexy1)—2—(6—ﬂu0r0— 1499 N 5H-imidazo[5, 1-a] isoind01y1)ethan01 / H /) HO O 1-(4-((R)hydr0xy-2—((S)-5H-imidazo[5 ,1- 1500 N \=/C/NWC a] isoind01-5 -y1)ethy1)piperidiny1) /N/) HO (tetrahydro-2H-pyrany1)ethanone N 2-(5H-imidazo[5,1-a]isoind01—5-y1)(pyridin 1501 N y1)et anoh 1 / 9 HO / imidazo[5,1-a]isoind01—5-y1)(pyridin-2— 1502 \ / N N y1)et anoh 1 / A HO O 4-((R)hydr0xy((S)-5H-imidazo[5,1- 1503 4NC0 a]isoind01—5 hy1)—N—(tetrahydro-ZH—pyran—4— N VON§ /N/ H HO y1)piperidine—1—carb0xamide O N-cyclohexy1((R)hydr0xy-2—((S)-5H- "m\_/C/N4N 1504 imidazo[5,1-a]isoind01y1)ethy1)piperidine N : /N/) H HO carboxamide N-((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol 1505 yl)ethyl)cyclohexyl)benzamide N-cyclopentyl((R)hydroxy((S)-5H-imidazo[5,1- 1507 a]isoindolyl)ethyl)piperidinecarboxamide 2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)(4- 1508 (trifluoromethyl)cyclohexyl)ethanol 2-(5H-imidazo[5,1-a]isoindolyl)(4- 1509 (trifluoromethyl)cyclohexyl)ethanol 2-(4-fluorophenyl)(4-((R)hydroxy((S)-5H- 1511 imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)ethanone hydroxy((S)-5H-imidazo[5,1-a]isoindol 1512 yl)ethyl)-N-(4-(trifluoromethyl)phenyl)piperidine carboxamide (4-((R)hydroxy((S)-5H-imidazo[5,1-a]isoindol 1513 yl)ethyl)piperidinyl)(1H-imidazolyl)methanone AH26(9298372_1):RTK 1-(5H-imidazo[5,1-a]isoindolyl)methylbutanol N OH 2-(5H-imidazo[5,1-a]isoindolyl)(tetrahydro-2H- N pyranyl)ethanol N HO O 2-(5H-imidazo[5,1-a]isoindolyl)(piperidin N yl)ethanol N HO NH 1-cyclohexyl((R)-5H-imidazo[5,1-a]isoindol N anol N HO 1-cyclohexyl((S)-5H-imidazo[5,1-a]isoindol N yl)ethanol N HO 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)propan N ol N OH AH26(9298372_1):RTK Structure Name F 1-cyclohexy1(9-ﬂu0r0-5H-imidazo[5, 1 - / N a]isoind01—5 han01 Na Ho O “m N—(4—(1—hydr0xy—2—(5H—imidazo[5,1—a]isoind01— O O O -y1)ethy1)pheny1)(tetrahydr0-2H-pyran N OH I N/> y1)acetamide 2—(5H—imidazo[5, 1 —a]isoind01—5—y1)—1—(1H— / N OH imidazol-Z-yl)ethan01 \ NH 2—(5H-imidazo[5, oind01—5-y1)(1H- / S OH 1m1dazolyl)ethan01 l \ 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01y1) N OH (thiazoly1)ethan01 (5 S)—5—(2—cyclohexy1—2—hydr0xyethy1)—5H— / N OH imidazo[5,1—a]isoind01—6—01 1-(2-aminocyclohexy1)(5H-imidazo[5,1- / N a]isoind01—5 -y1)ethan01 N-(1-cyclohexy1(5H-imidazo[5,1-a]isoind01— -y1)ethy1)acetamide / aN N0 Structure Name N-(2-(1-hydr0xy(5H-imidazo[5,1-a]isoind01— -y1)ethy1)cyclohexy1)acetamide 1-cyclohexyl-Z-(SH-imidazo[5,1-a]isoind01-5— yl)—N-methylethanamine cyclohexy1((S)-5H-imidazo[5,1- \ \\,z E ,_/ a]isoindol-S-y1)ethyl)amin0)ethanesulf0namide \0Z IN 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01y1)- 1- \ \\,z OI (1-methy1piperidiny1)ethan01 I0 ZIN 1-(4-aminocyclohexy1)(5H-imidazo[5,1- \ Z a]isoind01—5 -y1)ethan01 HO N 37/ N—(4—(1—hydr0xy—2—(5H—imidazo[5, 1 —a]isoind01— / N 5-y1)ethy1)cyclohexy1)acetamide N H2 1-(4-(aminomethy1)cyc10hexy1)-2—(5H- imidazo[5, 1-a]isoind01y1)ethan01 / aN O 4-(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexanecarboxamide 1-(3-aminocyclohexyl)(5H-imidazo[5,1-a]isoindol N anol 2-(5H-imidazo[5,1-a]isoindolyl)((1r,4r)(pyridin ylmethoxy)cyclohexyl)ethanol 2-(5H-imidazo[5,1-a]isoindolyl)((1r,4r)(pyridin ylmethoxy)cyclohexyl)ethanol 2-(5H-imidazo[5,1-a]isoindolyl)((1r,4r)(pyridin ylmethoxy)cyclohexyl)ethanol 1-((1r,4r)((2-aminopyridinyl)methoxy)cyclohexyl)- 2-(5H-imidazo[5,1-a]isoindolyl)ethanol AH26(9298372_1):RTK Structure Name 2—(5H-imidazo[5,1-a]isoind01—5-y1)((1r,4r) OH (pyraziny1meth0xy)cyc10hexy1)ethan01 2—(5H-imidazo[5,1-a]isoind01—5-y1)((1r,4r) OH (pyrimidin-S -ylmethoxy)cyclohexy1)ethan01 O /N\ NH2 ,4r)((6-aminopyridin om y1)meth0xy)cyc10hexy1)—2—(5H-imidazo[5, 1- b) nd01—5 -y1)ethan01 /‘N 1-((1r,4r)((6-aminopyridin-3 - yl)meth0xy)cyc10hexy1)—2—(5H-imidazo[5,1- N OHH NH2 0) a]isoind01—5 -y1)ethan01 1-((1r,4r)((3 -amin0pyridin N \ NHZ N H y1)meth0xy)cyc10hexy1)—2—(5H-imidazo[5, 1- /) 1/ / nd01—5 -y1)ethan01 1-((1r,4r)—4-((2—amin0pyrimidin y1)meth0xy)cyc10hexy1)—2—(5H-imidazo[5, 1- a]isoind01—5 -y1)ethan01 1-((1r,4r)—4-((4-amin0pyrimidin y1)meth0xy)cyc10hexy1)—2—(5H-imidazo[5, 1- /) NvN a]isoind01—5 -y1)ethan01 1-((1r,4r)((5 -amin0pyridin N HOH y1)meth0xy)cyc10hexy1)—2—(5H-imidazo[5, 1- I) \I N a]isoind01—5 -y1)ethan01 N0 Structure Name W0N 4-((((1r,4r)—4-(1-hydr0xy(5H-imidazo[5, 1- /N/) a]isoindol-S-y1)ethy1)cyc10hexy1)0xy)methy1)- N,N—dimethy1benzamide O N/ W0/ 3-((((1r,4r)(1-hydr0xy(5H-imidazo[5, 1 - a]isoindol-S-y1)ethy1)cyc10hexy1)0xy)methy1)- N)/ () N,N—dimethy1benzamide 2N) o o 2—((((1r,4r)—4-(1-hydr0xy(5H-imidazo[5, 1 - N HoH N/ a]isoindol-S-y1)ethy1)cyc10hexy1)0xy)methy1)- N,N—dimethylbenzamide 1r,4r)—4-(1-hydr0xy(5H-imidazo[5, 1 - N HOH nd01—5— //) yl)ethy1)cyc1ohexy1)0xy)methy1)benzenesulfona o‘,§\NH2 mide O 3-((((1r,4r)(1-hydr0xy(5H-imidazo[5, 1 - a]isoind01—5— / NT) 8,,0 yl)ethy1)cyc1ohexy1)0xy)methy1)benzenesulfona 6/ \NHZ mide 2—((((1r,4r)—4-(1-hydr0xy(5H-imidazo[5, 1 - 6/ “OO\\S,NH2 a]isoind01—5— :1) H / yl)ethy1)cyc1ohexy1)0xy)methy1)benzenesulfona mide 4-((((1r,4r)—4-(1-hydr0xy(5H-imidazo[5, 1 - / I; a]isoind01—5— N yl)ethy1)cyc10hexy1)0xy)methy1)benzamide 0 NH2 Structure Name 3-((((lr,4r)—4-( l -hydr0xy(5H-imidazo[5, l - a]isoind01—5— yl)ethyl)cycl0hexyl)0xy)methyl)benzamide 2-((((lr,4r)—4-( l -hydr0xy(5H-imidazo[5, l - a]isoind01—5— yl)ethyl)cycl0hexyl)0xy)methyl)benzamide methyl 4-((((lr,4r)( l -hydr0xy-2—(5H- imidazo[5, l -a]isoind01—5— yl)ethyl)cyclohexyl)0xy)methyl)benzoate methyl 3-((((lr,4r)( l xy-2—(5H- imidazo[5, l -a]isoind01—5— yl)ethyl)cyclohexyl)0xy)methyl)benzoate methyl 2-((((lr,4r)( l -hydr0xy-2—(5H- imidazo[5, l -a]isoind01—5— yl)ethyl)cyclohexyl)0xy)methyl)benzoate imidazo[5, l -a]isoindolyl)- l -((lr,4r) methoxycyclohexyl)ethanol l-((lr,4r)—4-eth0xycyclohexyl)-2—(5H— imidazo [5, l -a] isoindol-S -yl)ethanol 2—(5H-imidazo[5, l indolyl)- l -((lr,4r) isopropoxycyclohexyl)ethanol N0 Structure Name 1-((1r,4r)(cyclopr0py1meth0xy)cyc10hexy1) Z\\/Z 9: idazo[5,1-a]isoind01y1)ethan01 1-((1r,4r)—4-(cyclopentylmethoxy)cycl0hexy1)-2— II (5H-imidazo[5,1-a]isoind01y1)ethan01 \ \\/Z o 2—(5H-imidazo[5,1-a]isoind01—5-y1)((1r,4r) (thiophen-Z-y1meth0xy)cyc10hexy1)ethan01 \ \\/Z oI: 1-((1r,4r)((1H-ind01—3 -y1)0xy)cyclohexy1)—2— II (5H-imidazo[5,1-a]isoind01y1)ethan01 \ \\/2 O 1-((1r,4r)((1H-ind01—5 -y1)0xy)cyclohexy1)—2— \ L2 o (5H-imidazo[5,1-a]isoind01y1)ethan01 2-(5H-imidazo[5,1-a]isoind01y1)(4- ahydro-ZH-pyran yl)meth0xy)cyclohexy1)ethanol 4-(((4-(1-hydr0xy(5H-imidazo[5,1-a]isoind01— 0 II ‘\0 5- yl)ethy1)cyc1ohexy1)0xy)methy1)benzenesulfona mide Structure Name H0 /—<\] . . . .

O N 2—(5H-1m1dazo[5,1-a]1somd01—5-y1)(4-(0xazol- / N 2-y1meth0xy)cyc10hexy1)ethan01 H0 /—<\ ] 2-(5H-1m1dazo[5,1-a]1somd01—5-y1)(4-. . . .

O N / N (thiazoly1meth0xy)cyc10hexy1)ethan01 NW 2—(5H—imidazo[5, 1 —a]isoind01—5—y1)— 1—(1—(1 — / HO imino-Z-phenylethy1)piperidiny1)ethan01 N—<ME 4-(1-hydroxy(5H-imidazo[5,1-a]isoind01—5— / N yl)ethy1)—N-phenylpiperidinecarb0ximidamide HO HN \‘ N 4-(1-hydroxy(5H-imidazo[5,1-a]isoind01—5— N-< ’ . . . . .

NH y1)ethy1)-N-(pyrldlny1)p1perld1ne {HN carboximidamide HO 4-(1-hydroxy(5H-imidazo[5, oind01—5- N‘ﬁ y1)ethy1)-N-(tetrahydro-2H-pyran gg/N NH y1)piperidinecarb0ximidamide HO HNQCN N—(4—cyan0pheny1)—4—(1-hydroxy—2-(5H— imidazo[5,1-a]isoind01—5 -y1)ethy1)piperidine N/J carboxamlde.

HO HNl< N—ﬁ t—buty1)(1-hydroxy-2—(5H-imidazo[5, 1— / N a]isoindol-S-y1)ethy1)piperidinecarb0xam1de N-(tert-butyl)(1-hydroxy(5H-imidazo[5,1-a]isoindol- -yl)ethyl)piperidinesulfonamide 1-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)piperidinyl)(3-hydroxyphenyl)ethanone 2-(1-(azetidinecarbonyl)piperidinyl)hydroxy(4- (1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)piperidinyl)ethanone 2-cyclopentyl(4-(1-hydroxy(5H-imidazo[5,1- a]isoindolyl)ethyl)piperidinyl)ethanone 1-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)piperidinyl)(2-methylthiazolyl)ethanone N-cyclohexyl-N-hydroxy(1-hydroxy(5H- imidazo[5,1-a]isoindolyl)ethyl)piperidine amide N-(4-(2-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)piperidinyl) oxoethyl)phenyl)methanesulfonamide AH26(9298372_1):RTK WO 42237 N0 Structure Name HO ‘N—<] N—cyc10pr0py1—N—hydr0xy(1-hydr0xy—2-(5H— imidazo[5,1-a]isoind01y1)ethy1)piperidine carboxamide HO 3 ,3 r0—1—(4—(1—hydr0xy—2—(5H- N F imidazo[5,1-a]isoind01—5 -y1)ethy1)piperidin y1)butan-1 -0ne Z 1-(4-( 1 -hydr0xy(5H-imidazo [5 ,1-a]isoind01— \L2 5-y1)ethy1)piperidiny1)-2—(p—t01y1)ethan0ne .5: 1-(1-(4-aminopyrimidin-Z-y1)piperidiny1) \L2 zA (5H-imidazo[5,1-a]isoind01y1)ethan01 I0 Z/v2 .5: 1-(1-(2-aminopyrimidinyl)piperidiny1) \L2 z([12\ZAZ (5H-imidazo[5,1-a]isoind01y1)ethan01 N—cyclopropy1—4—(1—hydr0xy—2-(5H—imidazo[5, 1— a]is0ind01—5-y1)ethy1)piperidinecarb0xamide HO 2-cyclopr0pyl(4-(1-hydr0xy(5H- imidazo[5,1-a]isoind01—5 -y1)ethy1)piperidin y1)ethan0ne 2-(4-(1-hydr0xy(5H-imidazo[5,1-a]isoind01— —y1)ethy1)cyclohexylidene)acetonitrile 2c Structure Name N CF3 Ho HH 1 4-(1-hydr0xy(5H-imidazo[5,1-a]isoind01—5— O yl)ethyl)-N-(4-(triﬂuoromethy1)thiazol y1)piperidinecarb0xamide I0 i 4-(2—(4-(1-hydr0xy-2—(5H-imidazo[5, 1 - O nd01—5-y1)ethy1)piperidiny1) 2\ Z oxoethy1)benzamide 3IS’K 1-(4-(1-hydr0xy(5H-imidazo[5 ,1-a]isoind01— Z O: O 04 5-y1)ethy1)piperidiny1)—2—(4- 2\ Z (methylsulfony1)pheny1)ethanone I0 4-(1-hydr0xy(5H-imidazo[5,1-a]isoind01—5— Z023 y1)ethy1)-N—((1r,4r)—4- z\ \\—2 methylcyclohexy1)piperidinecarb0xamide HO 1-(4-(1-hydr0xy(5H-imidazo[5 ,1-a]isoind01— O 5 -y1)ethy1)piperidiny1)-3 ,3 -dimethy1butan \ L2 01’16 O:m\o” 4-(2—(4-(1-hydr0xy-2—(5H-imidazo[5, 1 - 0 a]isoind01—5-y1)ethy1)piperidiny1) 2\ Z 0X0ethy1)benzenesu1f0namide § N—(tert—buty1)—4—(2—(4—(1—hydr0xy—2—(5H— I0 \ :0) Z 0’ imidazo[5,1-a]isoind01—5 -y1)ethy1)piperidin 2\L2 yl)0x0ethy1)benzenesu1f0namide 4-(2—(4-(1-hydr0xy-2—(5H-imidazo[5, 1 - 3; a] ol-S -y1)ethy1)piperidiny1) 2\L2 oxoethy1)benzoic acid diﬂuoromethylene)cyc10hexy1)(5H- imidazo[5,1-a]isoind01—5-y1)ethan01 N0 Structure Name 2-(5H-imidazo[5, oindolyl)- l -(4-(2,2,2- triﬂuoroethylidene)cyclohexyl)ethanol N—benzyl—4—(2—(6-ﬂuoro-5H-imidazo[5, l- a]isoindol-5 -yl)- l - hydroxyethyl)cyclohexanecarboxamide 0 4-(2—(6-ﬂuoro-5H-imidazo[5, l indolyl)— I2 l-hydroxyethyl)—N— \ \\/z IO phenylcyclohexanecarboxamide N—(4-(2-(6-fluoro-5H-imidazo[5, oindol-5— / 3 Ho J’Q yl)- l -hydroxyethyl)cyclohexyl)benzamide l-(4-(2—(6—ﬂuoro—5H-imidazo[5, l -a]isoindol—5— yl)- l -hydroxyethyl)cyclohexyl)-3 -phenylurea N—(4-(2-(6-fluoro-5H-imidazo[5, l-a]isoindol yl)- l -hydroxyethyl)cyclohexyl) phenylacetamide and pharmaceutically acceptable salts thereof.

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

In another aspect, the invention provides s for treating indoleamine 2,3—dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound or a pharmaceutical composition according to any of the preceding aspects of the invention or any ment f.

In one embodiment, the immunosuppression is associated with an infectious e, or cancer.

In another embodiment, the suppression is associated with an infectious disease and the infectious disease is a viral infection selected from the group consisting of: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein—Barr virus (EBV), poliovirus, varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV).

In another embodiment, the immunosuppression is immunosupression associated with HIV-1 infection.

In another embodiment, the immunosuppression is associated With a .

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.

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 ment for the treatment of medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase. 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 s (and any embodiment thereof), as defined above, for the preparation of a medicament to ate T cell eration or to reverse an immunologic state of anergy or immunosuppression.

In one embodiment, the anergy or immunosuppression is caused by sion of the enzyme indoleamine—2,3 —dioxygenase.

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 ment for the treatment of immunosuppression ated with cancer, infectious diseases, or viral infections.

In one embodiment, the ion provides the use of compounds described in to any one of the ing 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, te, lung, brain, ovary, cervix, testes, renal, or head and neck, lymphoma, leukemia, melanoma, and the like.

In another ment, the invention provides the use of compounds described in any of the preceding aspects (and any embodiment thereof), as defined above, and embodiments thereof as deﬁned above, for the preparation of a medicament for the treatment of infectious diseases where the ious disease is a viral infection. Preferably, the viral infection is selected from the group consisting of: inﬂuenza, hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein—Barr virus (EBV), varicella zoster virus, poliovirus, coxsackie virus, and human immunodeficiency virus (HIV). More preferably, the viral infection is human immunodeficiency virus (HIV).

Deﬁnitions 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 ; 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 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, tuents are intended to be read “left to right” unless a dash indicates otherwise. For example, C1-C6alkoxycarbonyloxy and -OC(O)C1-C6alkyl 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 ar 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 d in the art that an additional hydrogen atom is removed from a monovalent alkyl radical to provide a suitable divalent .

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 double bond. entative examples of alkenyl include, but are not d to, ethenyl, 2—propenyl, 2—methylpropenyl, nyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6—dienyl.

The term “alkoxy” as used , 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, y, 2-propoxy, butoxy, utoxy, pentyloxy, and hexyloxy.

The term “alkyl” as used herein, means a straight or ed chain arbon 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, utyl, 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 -CH2-, -CH2CH2-, —CH2CH2CHC(CH3)—, —CH2CH(CH2CH3)CH2—.

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 . The bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl. The ic 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 clic 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 e, but are not limited to, azulenyl, naphthyl, dihydroinden-l-yl, dihydroinden-2—yl, dihydroindenyl, dihydroindenyl, 2,3-dihydroindolyl, 2,3-dihydroindolyl, 2,3-dihydroindolyl, 2,3-dihydroindolyl, l-yl, inden-2—yl, indenyl, indenyl, dihydronaphthalenyl, dihydronaphthalen-3 -yl, dihydronaphthalenyl, dihydronaphthalen- l -yl, ,6,7,8-tetrahydronaphthalen- l -yl, 5 ,6,7, 8-tetrahydronaphthalen-2 -yl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzofuran-5 -yl, hydrobenzofuranyl, 2,3—dihydrobenzofuran—7—yl, benzo[d] [ l ,3]dioxol—4—yl, benzo[d][1,3]dioxol—5—yl, omenonyl, 2H-chromenonyl, 2H-chromen-2—onyl, 2H-chromen-2—onyl, isoindoline- l ,3 -dionyl, isoindoline- 1,3 -dion-5 -yl, inden- l -onyl, inden- l -onyl, inden- l -onyl, inden- l -onyl, 2,3 -dihydrobenzo[b] [ l ,4] dioxan-5 -yl, 2,3—dihydrobenzo[b] [ l ,4]dioxanyl, 2H-benzo[b] [ l zin3 nyl, 2H-benzo [b] [ l ,4] oxazin3 (4H)-onyl, 2H-benzo[b] [ l ,4] oxazin3 (4H)-onyl, 2H-benzo [b] [ l ,4] oxazin3 (4H)-onyl, benzo[d]oxazin-2(3H)-on-5 -yl, WO 42237 benzo[d]oxazin-2(3H)-onyl, d]oxazin-2(3H)—onyl, benzo[d]oxazin-2(3H)-onyl, quinazolin-4(3 H)—onyl, quinazolin-4(3 H)-onyl, quinazolin-4(3 H)—onyl, quinazolin-4(3 H)—onyl, quinoxalin-2(lH)-on-5 -yl, quinoxalin-2(lH)-onyl, quinoxalin-2(lH)-onyl, quinoxalin-2(lH)-onyl, benzo[d]thiazol-2(3 H)-onyl, benzo[d]thiazol-2(3H)—on-5 -yl, benzo[d]thiazol-2(3H)-onyl, and, benzo[d]thiazol-2(3H)-onyl. 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 cyclyl, 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 lkyl-” as used herein, means an aryl group, as defined herein, appended to the parent lar moiety through an alkyl group, as defined herein. Representative examples of kyl include, but are not limited to, benzyl, ylethyl, 3-phenylpropyl, and 2-naphthylethyl.

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. clic ring s are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In certain embodiments, cycloalkyl groups are fully saturated. es 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 clic rings contain a monocyclic lkyl 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 —(CH2)w—, where w is l, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.l.l]heptane, bicyclo[2.2.l]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, o[3.3.l]nonane, and bicyclo[4.2.l]nonane. 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 ed to the parent molecular moiety h any carbon atom ned 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.

“Cycloalkenyl” as used herein refers to a monocyclic or a bicyclic cycloalkenyl ring . Monocyclic ring s are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon—carbon double bond), but not aromatic. es 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 —(CH2)W-, where w is l, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and o[2.2.2]oct-2—enyl. Fused bicyclic lkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a clic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkenyl is ed to the parent molecular moiety h 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 en” 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. entative examples of haloalkyl include, but are not limited to, methyl, 2-ﬂuoroethyl, triﬂuoromethyl, pentafluoroethyl, and 2—chloroﬂuoropentyl.

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 lar moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. entative examples of monocyclic heteroaryl e, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, WO 42237 tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a clic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a clic heteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted with one or two groups which are ndently oxo or thia. When the ic 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 en atom within the bicyclic ring system. Representative examples of bicyclic heteroaryl e, but are not d to, benzimidazolyl, benzofuranyl, hienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolinyl, ,6—dihydroisoquinolin-l-yl, furopyridinyl, lyl, indolyl, isoquinolinyl, yridinyl, quinolinyl, purinyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolinyl, ,6,7, 8—tetrahydroquinolinyl, 5,6,7, 8-tetrahydroisoquinolin- l -yl, thienopyridinyl, 7-tetrahydrobenzo[c] [ l ,2,5 ] oxadiazolyl, and 6,7-dihydrobenzo[c][l,2,5]oxadiazol—4(5H)—onyl. In n 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 lar moiety through an alkyl group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, furylmethyl, lH-imidazol-2—ylmethyl, lH-imidazolylmethyl, l-(pyridinyl)ethyl, pyridin-3 -ylmethyl, pyridinylmethyl, pyrimidinylmethyl, 2—(pyrimidinyl)propyl, thienylmethyl, and 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 ed 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 d to, azetidinyl, azepanyl, aziridinyl, diazepanyl, l,3—dioxanyl, l,3—dioxolanyl, l,3—dithiolanyl, l,3—dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, idinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, l,l-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The ic cycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic lkenyl, a monocyclic cycle, or a clic heteroaryl.

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 ic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl, indolin-l-yl, indolinyl, indolinyl, 2,3-dihydrobenzothien-2—yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-lH-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 ed monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered clic heteroaryl, wherein the bicyclic cyclyl 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 —NOz 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 d herein includes cyclohexyl, cyclopropyl, and the like.

WO 42237 The term “spiro” as used herein refers to a cyclic moiety formed by the subsituted atom and two available substitutable postions on that same atom. For example, moiety such (TR where R is a spiro—cycloalkyl= group includes compounds such as 7 7 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 Go03 where the spiro-l,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 , 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 IDO enzyme with a compound includes the administration of a compound described herein to an individual or patient, such as a human, having IDO, as well as, for example, introducing a compound into a sample containing a cellular or purified ation containing the IDO enzyme.

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

As used herein, the phrase “therapeutically ive ” refers to the amount of active compound or ceutical agent that elicits the biological or medicinal response that 2012/033245 is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.

In n embodiments, a therapeutically effective amount can be an amount suitable for (l) 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 ogy 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 matology of the e, 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 ment” and “treating” means (i) rating 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 nced biological effect (e.g., IDO modulation or tryptophan degradation tion).

Manifestation of amelioration of a e condition with underlying IDO-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 IDO 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”, ytic site”, “active site” collectively and indistinctly refer to a region of the enzyme that contains amino acid residues responsible for the substrate binding (charge, hobicity, steric hindrance) and tic amino acid residues which act as proton donors or ors or are responsible for binding a cofactor and participate in the catalysis of a chemical reaction.

As used herein, the phrase “pharmaceutically acceptable salt” refers to both pharmaceutically acceptable acid and base addition salts and es. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, WO 42237 sulfuric, sulf1nic, formic, esulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH2)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 indoleamine-2,3-dioxygenase (IDO). The term “modulate” is meant to refer to an ability to decrease activity of an enzyme or receptor. ingly, compounds bed herein can be used in methods of ting IDO 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 IDO. In further embodiments, the compounds described herein can be used to modulate activity of IDO in cell or in an individual in need of modulation of the enzyme by administering a ting (e.g., inhibiting) amount of a compound described herein.

Further provided are s of inhibiting the degradation of tryptophan and preventing the production of N—formylkynurenine in a system containing cells expressing IDO such as a tissue, living organism, or cell culture. In some embodiments methods of altering (e.g., increasing) ellular 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 IDO—mediated immunosuppression in a patient by administering to the patient an effective amount of a compound or composition recited herein. IDO—mediated immunosuppression has been associated with, for e, cancers, tumor growth, metastasis, infectious es (e.g., viral infection), viral ation, 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 nd or composition recited herein. Example tumor—specific immunosuppression associated with s treatable by the methods herein e immunosuppression associated with cancer of the colon, pancreas, breast, te, 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 ive amount of a compound or composition recited herein for inhibiting immunosuppression resulting from the disease state and/or ent thereof.

Further provided are methods for treating immunosupression associated with an infectious disease, e.g., HIV-1 infection, in a patient by administering to the patient an effective amount of a compound or composition recited herein.

For e, IDO—mediated suppression associated with viral infection, is associated with a viral infection selected from the group consisting of: inﬂuenza, hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), poliovirus, lla zoster virus, coxsackie virus, human immunodeficiency virus (HIV).

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

Examples of IDO—associated diseases include cancer, viral infection such as HIV infection, depression, neurodegenerative disorders such as Alzheimer's e 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 ble by the methods herein include cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, , 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., 1L2, GM—CSF, eta), and/or ne kinase inhibitors can be used in ation with the nds and pharmaceutical compositions described herein for treatment of IDO—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 aneously 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 ed with IDO inhibitors of the present invention. For example, for the case of tumors, is it preferable that the tumor is sensitive to the xic effects of the chemotherapeutic agent in order to stimulate the release of ns that will eventually mediate an immune response that will be enhanced by addition of IDO 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 sensititivity of each tumor to different antineoplastic agents.

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 (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); ir dipivoxil [bis(POM)-PMEA]; lobucavir (EMS-180194); BCH-10652; emitricitabine [(-)-FTC]; beta—L—FD4 (also called beta—L—D4C and named —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— 14272 1; AG— 1549; MKC—442 (1 xy-methyl)—5-(1-methylethyl)(phenylmethyl)-(2,4(1H,3 H)—pyrimid- i nedione); and (+)—calanolide A (NSC—675451) and B. Typical suitable protease tors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); vir (AG-1343); amprenavir (141W94); lasinavir (EMS-234475); DMP-450; EMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607. le chemotherapeutic or other anti-cancer agents include, for e, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine tives, alkyl sulfonates, oureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, mbucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, tine, lomustine, streptozocin, dacarbazine, and temozolomide.

Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, t limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-ﬂuorouracil, ﬂoxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, bine phosphate, pentostatine, and gemcitabine.

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

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

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

Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory les such as CTLA-4,4-1BB and PD-l, or antibodies to cytokines (IL—10, TGF—B, eta).

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

Other ancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.

Anti—cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and inant viruses.

Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In on, 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 ty.

Pharmaceutical Formulations and Dosage Forms The pharmaceutical compositions described herein generally comprise a combination of a compound described herein and a ceutically acceptable carrier, t, 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 nd is dissolved or suspended in water, the composition further optionally ses an additional pharmaceutically acceptable carrier, diluent, or excipient. In other embodiments, the pharmaceutical compositions described herein are solid pharmaceutical compositions (e.g., tablet, capsules, eta).

These itions 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), ary (e. g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, asal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or itreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the ctival sac. eral 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 stration may include transdermal s, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.

Conventional ceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

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 ient 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, olid, 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 ), ointments containing, for example, up to % by weight of the active compound, soft and hard gelatin es, suppositories, sterile inj ectable solutions, and sterile packaged powders.

In preparing a formulation, the active nd 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 ents include lactose, dextrose, sucrose, sorbitol, mannitol, es, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium te, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The ations can additionally e: lubricating agents such as talc, magnesium te, 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 ient after administration to the patient by ing 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 y 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 se of the individual patient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the pal 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 y 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 . 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 um or to be delayed in release. A y of als can be used for such enteric layers or coatings, such materials ing a number of polymeric acids and mixtures of polymeric acids with such als as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms in which the nds 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 zed by use of inert gases. zed solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent ve pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate .

The amount of compound or composition administered to a patient will vary depending upon what is being administered, the e of the administration, such as laxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic ations, 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 WO 42237 treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the e, the age, weight and general condition of the patient, and the like.

The compositions stered to a patient can be in the form of ceutical compositions described above. These compositions can be ized 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 ably 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 t, and the judgment of the prescribing physician. The proportion or tration 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 ug/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 ve biological cy 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 , es, antibodies, immune enhancers, immune ssants, nﬂammatory agents and the like.

Labeled Compounds and Assay Methods Another aspect relates to ﬂuorescent dye, spin label, heavy metal or radio-labeled derivatives of the compounds described herein that would be useful not only in imaging but also in assays, both in vitro and in viva, for localizing and quantitating the IDO enzyme in tissue samples, including human, and for identifying IDO enzyme ligands by inhibition binding of a labeled compound. Accordingly, further ed are IDO enzyme assays that n such labeled compounds.

Further provided are ically—labeled compounds of the nds described herein. An “isotopically” or “radio—labeled” nd is a compound described herein where one or more atoms are ed or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 1251 and 131I. The radionuclide that is incorporated in the t radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro IDO enzyme labeling and competition , compounds that incorporate 3H, 14C, 82Br, 1251, 131I, 35S or will generally be most useful. For radio-imaging applications 11C, 18F, 1251, 123I, 1241, 1311, 75Br, 76Br or 77Br will lly be most useful.

It is understood that a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of 3H, 14C, 1251, 35S and 82Br.

Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds described herein and are well known in the art.

A radio—labeled compound described herein can be used in a screening assay to fy/evaluate compounds. In general terms, a newly synthesized or identifled compound (i.e., test compound) can be evaluated for its ability to reduce binding of the radio—labeled compound described herein to the IDO enzyme. ingly, the ability of a test compound to compete with the radio-labeled compound for binding to the IDO enzyme directly correlates to its binding affinity.

Also included are pharmaceutical kits useful, for e, in the treatment or prevention of IDO—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 e, if desired, one or more of various conventional pharmaceutical kit ents, 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. ctions, either as s or as labels, indicating quantities of the ents to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.

The following examples are d for illustrative es, and are not ed 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 ed to yield essentially the same results.

The example compounds below were found to be inhibitors of IDO according to one or more of the assays described herein.

EXAMPLES All reagents and solvents were purchased from commercial s. 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 811011 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 um particle sizes. All reactions were performed in flame or oven—dried glassware under a nitrogen atmosphere. All reactions were d magnetically at ambient temperature unless otherwise indicated. 1H NMR spectra were obtained with a Bruker DRX400, Varian VXR400 or VXR300. 1H NMR spectra were ed in parts per million (5) relative to TMS (0.0), DMSO—d6 (2.50) or CD3OD (4.80) as an internal nce. All 1H NMR spectra were taken in CDCl3 unless otherwise indicated. The following starting materials were prepared according to their literature procedures: (E)-ethyl 3-(2-iodophenyl)acrylate . Comm. 2007, 37, 2989—2994), 2—chloro—6—iodobenzaldehyde (J. Agric. Food Chem. 2008, 56, 5247— 5253), 2—iodo—3—methoxybenzaldehyde (Chem. — Eur. J., 2004, 10, 5233—5242), dimethyl (2— (cyclohex-l-en-l-yl)oxoethyl)phosphonate (Phosphorus, Sulfur Silicon Relat. Elem., 1999, 155, 67—80), dimethyl (2—cyclohexyl—2—oxo)ethylphosphonate (Patent: U85807892 A1, 1998), ethyl l,4—dioxaspiro[4.5]decane—8—carboxylate (Patent: U82008/306084 A1, 2008), (trans)-ethyl 4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (Patent: US2006/25383 A1, 2006), ethyl spiro[2.5]octane—6—carboxylate (Bioorg. Med.

Chem. Lett. 2008, 18, 5280—5284), ethyl 4-(cyclopropylmethylene)cyclohexanecarboxylate (Patent: US4584013 A1, 1986), The aforementioned compounds are assigned compound identiﬁcation numbers 86— 91 and 113-115 respectively for future nce in this patent. (4.80) as an internal reference.

All spectra are recorded in CDCl3 unless otherwise indicated.

A variety of methods used in this patent to synthesize intermediate A are outlined below in Scheme 1. Palladium—catalyzed Suzuki cross—coupling of 4—iodo—l—trityl— 1H- imidazole with boronic acids gives rise to 2-(l-trityl- dazolyl)benzaldehydes.

The resulting 2—(l-trityl-lH-imidazolyl)benzaldehydes are affected by aldol condensations or Homer—Wadsworth reactions to afford intermediate A. Alternatively, the synthesis of intermediate A can be ed by allowing 2-iodobenzaldehydes to react with substituted methyl ketones in the presence of a base to afford 3-(2—iodophenyl)propen-l- ones. Negishi cross—coupling of the resulting 3-(2-iodophenyl)propen-l-ones with 4— iodo-l-trityl-lH-imidazole, also leads to ediate A. Subjecting intermediate A to trityl ection conditions gives rise to 2—(5H-imidazo[5,l-a]isoindol—5—yl)ethanone B, which may be reduced to 2—(5H-imidazo[5, l—a]isoindol—5—yl)ethanol C (Scheme 2).

Scheme 1. sis of (E)—3-(2—(l-trityl- lH—imidazolyl)phenyl)propen-l-ones (Intermediate A) | B(OH)2 \\ o Z~N CHO | \ cat Pd / 3 + | . CHO R1i;}3\,OEt _, OEt [ll R2// / Trt N o NJ J\ Trt’ R1 [Trt R2 R2 N I R11 |\\ | IN» / —> / / R1 I ('3 O base Negishi ooupling Scheme 2. Synthesis of 2-(5H-imidazo[5,l-a]isoindolyl)ethanones and Their Corresponding 2-(5H-imidazo[5, l -a]isoindol-5 -yl)ethanols R\\2 I R1 R|\\2 \ / / N N HO \ \> / x) N N A B c Example 1 General ure for the Synthesis of 3—(2—Iodophenyl)prop—2—en—l—ones by Aldol Condensation R2 R2 O \ NaOMe \ R1JJ\ + |\/ —> WW I (I) I o To a solution of the appropriate commercially available benzaldehyde or 87 (4.31 mmol) in ous MeOH (15 mL) at rt was added NaOMe (4.31 mmol, 0.5 M in MeOH) and the yellow solution was allowed to stir for 5 min. The appropriate ketone (4.31 mmol) was added dropwise as a solution in MeOH (3 mL). After stirring overnight, the solvent was removed under reduced pressure and the crude was d with satd. NH4Cl (20 mL). The aqueous layer was extracted with CHzClz (3 x 20 mL) and the combined c extracts were dried (MgSO4) and the solvent distilled off under reduced pressure to afford a crude residue. The crude product was purified by silica ﬂash chromatography to afford the following compounds. # nd Name Yield (%) \ (ID—3—(2—chloro—6-iodophenyl)—l— cyclohexylprop—2—en— 1 —one 1H NMR 1.22—1.45 (m, 5 H), 1.70—174 (m, 1H), 1.79—1.85 (m, 2H), 1.93-1.99 (m, 2H), 2.61-2.65 (m, 1H), 6.67 (d, 1H, J= 16 Hz), 6.93 (t, 1H, J: 8 Hz), 7.42 (d, 1H, J: 8 Hz), 7.48 (d, 1H, J= 16 Hz), 7.82 (d, 1H, J: 8 Hz) (ID—3 —(2—iodophenyl)- l -(3 -nitrophenyl)prop- 2—en—l—one 1H NMR 7.10—7.16 (m, 1H), 7.34 (d, 1H, J: 15.6 Hz), .46 (m, 1H), 7.71—7.76 (m, 2H), 7.94—7.97 (m, 1H), 8.05 (d, 1H, J: 15.6 Hz), 8.34—8.48 (m, 2H), 8.81 (s, 1H) Example 2 General Procedure for the Synthesis of 2-(5H-imidazo[5,l-a]isoindol—5— yl)ethanones by Palladium-Catalyzed i Cross—Coupling of Aryl s l and 2 with 4-Iodo-l-Trityl- lH-imidazole.

R2 R2\\ PC\ AdDH \ // R1 / / 1 N o I o I x) CPh3 To a d solution of 4-iodo-l-trityl-lH-imidazole (218 mg, 0.5 mmol) in anhydrous THF (4 mL) at rt was added EtMgBr (1.0 M in THF, 0.5 mmol, 0.5 mL) dropwise, under an atmosphere of N2. The resulting solution was allowed to stir for 90 min and anhydrous ZnClz (0.5 mmol, 68.2 mg) was added. The resulting white sion was d to stir for 90 min and a solution of the appropriate aryl iodide 1, 2 or 86 (0.5 mmol) in THF (1 mL) was added followed by the immediate on of Pd(PPh3)4 (56 mg, 0.05 mmol). The reaction mixture was allowed to stir at 70 0C for 12 h under an atmosphere of N2. After cooling to room temperature, the solution was diluted with CHzClz (20 mL) and the c layer was washed with an EDTA (aq) buffer (pH = 9) (2 x 5 mL) and brine. The organic layer was dried (NaZSO4) and concentrated under reduced pressure. The crude residue was used in next step without further puriﬁcation. To a solution of the crude imidazole from the preVious step was added acetic acid (1.0 mL) and MeOH (4.0 mL). The solution was stirred at 90 0C for 3 h. The reaction mixture was allowed to cool to room temperature and the pH was adjusted to ~10 with satd. K2CO3 (aq). The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water, brine and dried. The solvent was removed in vacuo to afford the crude residue, which was purified by ﬂash column chromatography on silica gel to afford the following compounds. 2—(6-chloro-5H—imidazo[5, l -a]isoindol-5— yl)- l -cyclohexylethanone 1H NMR 1.18—1.36 (m, 5H), 1.68—1.88 (m, 5H), 2.37—2.40 (m, 1H), 2.64 (dd, 1H, J: .0 Hz, 10.0 Hz), 3.79 (dd, 1H, J: 16.0 Hz, 4.0 Hz), 5.70 (d, 1H, J: 8.0 Hz), .20 (m, 2H), 7.32 (t, 1H, J: 8.0 Hz), 7.43 (d, 1H, J: 8.0 Hz), 7.61 (s, 1H) ethyl 2-(5H—imidazo[5, l -a]isoindol—5— yl)acetate 1H NMR 1.31 (t, 3H, J: 7.5 Hz), 2.67 (dd, 1H, J: 20.0 Hz, 12.0 Hz), 3.07 (dd, 1H, J: .0 Hz, 4.0 Hz), 4.25 (q, 2H, J: 6.0 Hz), 5.53 (dd, 1H, J: 12.0 Hz, 4.0 Hz), 7.16 (s, 1H), 7.21—7.37 (m, 3H), 7.51 (d, 1H, J: 6.0 Hz), 7.75 (s, 1H 2-(5H-imidazo[5, l-a]isoindol-5—yl)— l —(3 — nitrophenyl)ethanone 1H NMR 3.49 (dd, 1H, J: 18.6 Hz, 9.6 Hz), 3.80 (dd, 2H, J = 18.3 Hz, 3.3 Hz), 5.84 (dd, 1H, J = 3 Hz, 9.3 Hz), 7.26—7.32 (m, 1H), 7.38—7.49 (m, 2H), 7.55—7.59 (m, 1H), 7.70—7.76 (m, 2H), 8.32 (d, 1H, J = 6 Hz), 8.46—8.50 (m, 1H), 8.78 (s, 1H) Example 3 Suzuki Cross-Coupling of 4-Iodo-l-trityl-lH-imidazole with Phenylboronic Acids Trt\N/\\ | B(OH)2 kg \ N + l —> CH0 I}! // \ R I Trt / / A suspension of —l—trytyl— lH—imidazole (6.88 mmol ), the appropriate 2—formyl boronic acid tive (10.31 mmol) and K3PO4 (20.63 mmol) in MN—dimethylformamide (30 mL) and water (6 mL) was purged with en for 5 minutes, followed by the addition of Pd(PPh3)4 and the mixture was purged with nitrogen for another 5 minutes. The reaction mixture was stirred at 90 0C for 16 h under an atmosphere of N2.The on was allowed to cool and was filtered through a plug of celite. The mixture was diluted with water (50 mL) and EtOAc (25 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined c extracts were washed with water (2 x 25 mL), brine and dried (NaZSO4). The solution was ed and the solvent was d under reduced pressure to afford the crude product which was purified by ﬂash column chromatography on silica gel to provide the following compounds. # mm ,Trt / N 2-( l l- lH—imidazolyl)benzaldehyde 52 1H NMR7.03 (s, 1H), 7.18—7.20 (m, 6 H), 7.36—7.39 (m, 10H), 7.53—7.58 (m, 3H), 7.64 (d, 1H, J= 7.78 Hz), 7.93 (d, 1H, J= 7.87 Hz) NF/N/ 2—fluoro—6—( l —trityl— lH-imidazol—4— \ F yl)benzaldehyde 1H NMR7.02—7.07 (m, 1H), 7.10 (d, 1H, J= 1.6 Hz), 7.16—7.18 (m, 6H), 7.36—7.39 (m, 9H), 7.46—7.52 (m, 2H), 7.57 (s, 1H), 10.27 (s, 1H) -chloro( l -trityl- lH—imidazol yl)benzaldehyde 1H NMR7.04 (d, 1H, J: 1.2 Hz), 7.10—7.19 (m, 5H), 7.32—7.38 (m, 12H), 7.58 (dd, 1H, J: 2.4, 8.4 Hz), 7.57—7.59 (m, 2H), 7.89 (d, 1H, J: 2.0 Hz), 10.34 (s, 1H) rt N \ 4-chloro( l -trityl- lH—imidazol N zaldehyde 1H NMR7.08—7.38 (m, 18 H), 7.60 (s, 1H), 7.88 (d, 1H, J= 8.4 Hz), 10.41 (s, 1H) Trt\ N \ 4—fluoro—2—( l —trityl— lH-imidazol—4— 7 RN 89 yl)benzaldehyde H NMR(MeOH-d4) 7.16—7.27 (m, 6H), 7.29—7.47 (m, 3H), 7.60—7.70 (m, 9H), 7.85— 7.90 (m, 2H), 10.26 (s, 1H) Example 4 3 -Methoxy(1-trityl-1H-imidazolyl)benzaldehyde \[\>N 2 ) /JN Trt/N N 8 A suspension of 88 (667 mg, 2.55 mmol), bis(pinacolato)diboron (711 mg, 2.88 mmol), KOAc (749 mg, 7.64 mmol), Pd(OAc)2 (17 mg, 76 pmol) in DMF (10 mL) was stirred at 80 CC for 16 h. The mixture was ﬁltered through a plug of Celite and the ﬁltrate poured into water. The aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (2 x 10 mL), brine, dried and trated. The crude product was used without further puriﬁcation. A suspension of 4-iodo—1-trityl—1H- ole (400 mg, 0.917 mmol), 3-methoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)benzaldehyde (288 mg, 1.10 mmol), K2C03 (444 mg, 3.21 mmol), f)Clz°CH2Clz complex (150 mg, 0.18 mmol) in DMSO (10 mL) was heated at 80 CC for 20 h. The solution was ﬁltered through Celite and the ﬁltrate poured into water. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), brine, dried, and concentrated. The crude was puriﬁed by ﬂash column chromatography to afford 8 as a white solid (78 mg, 19%). 1H NMR: 3.75 (s, 3H), 7.08 (d, 1H, J= 8.0 Hz), 7.20—7.25 (m, 7H), 7.30—7.36 (m, 10H), 7.52 (s, 1H), 7.55 (d, 1H, J= 4.0 Hz), 10.31 (s, 1H).

Example 5 General Procedure for the sis of 2-(5H-imidazo[5,1-a]isoindol yl)ethanones by Aldol Condensation of 2-(1-trityl-1H—imidazol zaldehydes with Methyl Ketones Followed by Cyclization R2 R2 o 1 ) NaOEt JJ\ R1 R1 I 0 2) AcOH / o N\ ,) LN‘ N To a solution of the riate aldehyde 3-8 (0.97 mmol) and ketone (0.97 mmol) in anhydrous THF (5 mL) at rt was added NaOEt (1.25 mmol, 21 wt % solution in EtOH) and the yellow solution was d to stir 3 h at rt. The solvent was distilled off and the crude was diluted with saturated NH4Cl (10 mL) and the s layer was extracted with romethane (3 x 20 mL). The ed organic extracts were washed with brine, dried over NaZSO4 and the solvent evaporated under reduced pressure to afford the crude product.

To the crude imidazole from the previous step was added acetic acid (1.0 mL) and MeOH (4.0 mL). The solution was stirred at 90 0C for 3-10 h. The reaction mixture was allowed to cool to room temperature and the pH was adjusted to ~10 with satd. K2CO3 (aq). The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water, brine, and dried. The solvent was removed in vacuo to afford the crude residue, which was purified by ﬂash column chromatography on silica gel to afford the following compounds.

Yield (%) 2-(5H—imidazo[5,1—a]isoindol—5— yl)— l -(2-nitrophenyl)ethanone 1H NMR 3.19 (dd, 1H, J: 20.0 Hz, 8.0 Hz), 3.65 (dd, 1H, J: 20.0 Hz, 4.0 Hz), 5.81 (dd, 1H, J: 8.0 Hz, 4.0 Hz), 7.19 (s, 1H), 7.22—7.28 (m, 1H), 7.36 (m, 3H), 7.54 (d, 1H, J: 8.0 Hz), 7.61—7.65 (m, 1H), 7.70—7.74 (m, 1H), 7.85 (s, 1H), 8.16 (d, 1H, J: 8.0 Hz). tert-butyl (2-(2-(5H-imidazo[5, l - a]isoindol—5— yl)acetyl)phenyl)carbamate 1H NMR 1.50 (s, 9H), 3.47 (dd, 1H, J: 18.0 Hz, 9.6 Hz), 3.77 (dd, 1H, 18.0 Hz, 3.3 Hz), 5.77—5.81 (m, 1H), 6.98 (t, 1H, J: 8.0 Hz), 7.19 (s, 1H), 7.28 (d, 1H, J: 7.6 Hz), 7.37 (d, 1H, J= 8.0 Hz), 7.41 (d, 1H, J= 8.0 Hz), 7.52—7.56 (m, 2H), 7.72 (d, 1H, J= 8.0 Hz), 7.77 (s, 1H), 8.54 (d, 1H, .1: 8.4 Hz) tert-butyl (4-(2-(5H—imidazo[5, 1- a]isoind01—5— 39 yl)acetyl)phenyl)carbamate H NMR 1.52 (s, 9H), 3.39 (dd, 1H, J = 18.6 Hz, 9.6 Hz), 3.68 (dd, 1H, J = 18.3 Hz, 3.3 Hz), 5.83 (dd, 1H, J= 3 Hz, 9.3 Hz), 6.88 (s, 1H), 7.14—7.58 (m, 7H), 7.75 (s, 1H), 7.92 (d, 2H, .1: 9 Hz) 0 O 2-(5H—imidazo[5,1-a]isoind01—5— 2V2 O y1)phenylethan0ne 1348 1H NMR 3.44 (dd, 1H, J= 20.0 Hz, 8.0 Hz), 3.72 (dd, 1H, J= 20.0 Hz, 4.0 Hz), 5.83 (d, 1H, J= 8.0 Hz), 7.18 (s, 1H), 7.25—7.29 (m, 1H), 7.40 (t, 2H, .1: 10 Hz), 7.47 (t, 2H, J= 8.0 Hz), 7.57 (d, 1H, J= 8.0 Hz), 7.61 (t, 1H, J= 6.0 Hz), 7.74 (s, 1H), 7.97 (d, 2H, .1: 8 Hz) tert-butyl 4-(2-(5H-imidazo[5,1- a]isoind01—5 -y1)acety1)piperidine- 19 l-carboxylate H NMR 1.44 (s, 9H), 1.50—1.82 (m, 4H), 2.72-2.76 (m, 2H), 2.90 (dd, 1H, J= 18.5 Hz, 9.4 Hz), 3.21 (dd, 1H, J= 18.57 Hz, 3.6 Hz), 5.63 (dd, 1H, J= 9.6 Hz, 3.6 Hz), 7.16 (s, 1H), 7.23 (m, 2H), 7.35-7.39 (m, 1H), 7.53 (d, 1H, J= 7.5 Hz), 7.59 (s, 1H) %) 2—(6—ﬂuoro-5H-imidazo[5, 1- F ind01—5—y1)(1,4- 18 / N O d10xasp110[4.5]decan—8— Na 0 y1)ethan0ne 1H NMR (MeOH—d4) 1.50—1.90 (m, 6H), .60 (m, 2H), 2.98 (dd, 1H, J= 18.9 Hz, 10.2 Hz), 3.61 (dd, 1H, J= 18.9 Hz, 2.7 Hz), 5.78—5.82 (m, 1H), 7.01—7.07 (m, 1H), 7.16 (s, 1H), 7.42—7.45 (m, 2H), 7.66 (s, 1H) _—9» 2-(8-chloro-5H-imidazo[5,1- a]isoind01—5-y1)—1— 21 I) cyclohexylethanone HNMR (MeOHd4) 110190 (m 10H), 242248 (m 1H), 299 (dd 1H, J: 189 Hz,9Hz),34,0(dd1H, J=189,Hz 3.6Hz), 5.585,62(m 1H), 695708(m 1H), 716788 (m 4H) 2-(7-chloro-5H-imidazo[5,1- a]isoind01—5-y1)—1— 43 / 5) O cyclohexylethanone HNMR1. 19—1.46(m, 5H), 1.68— 1.70(m, 1H), 1.7—8 1.91 (m, 5H), 2.35—2.43 (m, 1H), 2. 91 (dd, 1H, J= 10.0, 20.0 Hz), 3.18 (dd, 1H, J=4.0, 20.0 Hz), 5.611 (dd, 1H, J =40, 8.0,Hz)7.15(s,1H),7.2,8(s1H),7.35(d,1H, J= 8.0,Hz)7.4,5(d1H, J= 8.0 Hz), 7.60 (s, 1H) 1—cyc10hexy1—2—(6—ﬂuoro—5H- imidazo[5,1-a]isoind01—5— 50 I [>0 y1)ethan0ne HNMR12014,8(m 5H),1.6616,9(m1H)17819,2(m 5H),2.362.,44(m1H), 27,9(de—120200Hz)35,0(dd1H,J—40200Hz)57,7(d1H,J—80Hz), 69,4(t1H, J= 80,Hz) 71,8(s 1H), ,37(m 2H), 76,2(s 1H) 1-cyc10hexy1—2-(9-meth0xy-5H- o[5,1-a]isoind01—5- 41 / N /) O y1)ethan0ne 1HNMR13214,2(m 2H),1.6—.,6169(m1H),17819,0(m 4H), 235238(m ,8(dd1H, J=184,H210Hz),31,7(dd1H, J=138,Hz 32,Hz) 39,6(s 3H), 564(m 1H), 68,8(d 2H, J=8Hz),71,5(s 1H),72,1(t1H, J= 8Hz), 75,9(s 1H), 2-(5H-imidazo[5,1—a]isoind01—5— O y1)- 1-(tetrahydro-2H-pyran 6 1 / N /) O y1)ethan0ne H NMR 1.75—1.84 (m, 4H), 2.58—2.62 (m, 1H), 2.90 (dd, 1H, .1: 18.4 Hz, 9.6 Hz), 3.21 (dd, 1H, J: 18.4 Hz, 3.6 Hz), 3.38—3.45 (m, 2H), 3.99—4.01 (m, 2H), 5.65 (dd, 1H, J: 9.6 Hz, 3.6 Hz), 7.17 (s, 1H), 7.22—7.30 (m, 2H), 7.38 (dt, 1H, J: 7.2 Hz, 0.8 Hz), 7.54 (d, 1H, J: 7.6 Hz), 7.61 (s, 1H) F 1—cyc10hexy1—2—(8—ﬂuoro—5H- o[5,1—a]isoind01—5— 5 8 16 N O / /> y1)ethan0ne tert—butyl (3—(2-(5H-imidazo[5, 1- a]isoind01—5— 80 yl)acetyl)phenyl)carbamate 1-cyclopenty1—2-(5H-imidazo[5, 1- 18 N / O nd01—5 —y1)ethan0ne 1H NMR a 0 CI 1-(2—chlorophenyl)(5H- O imidazo[5,1—a]isoind01—5— 15 1334 O \—\\N yl)ethan0ne H NMR 3.30—3.50 (m, 1H), 3.65—3.85 (m, 1H), 5.50—5.70 (m, 1H), 7.17 (s, 1H), 7.20— 7.60 (m, 8H), 7.75 (s, 1H) CI 1-(3 -chlorophenyl)(5H- 1353 O imidazo[5,1—a]isoind01—5— 20 O N\—\\N y1)ethan0ne I HNMR 3.30—3.50 (m, 1H), 3.60-3.75 (m, 1H), 5.75-5.85 (m, 1H), 7.15 (s, H), 7.20—7.60 (m, 6H), 7.69 (s, 1H), 7.82 (d, 1H, J= 10.4 Hz), 7930, 1H, .1: 2.4 Hz) aThe compound was not characterized and was used as such for the next synthetic step Example 6 Ethyl 4-methylenecyclohexanecarboxylate O O\/ O O\/ n-BuLi To a suspension of methyltriphenylphosphonium e (1.57 g, 4.41 mmol) in THF (9 mL) at -10 CC was added n-BuLi (2.5 M in hexanes, 1.65 mL, 4.11 mmol) dropwise and the solution was allowed to stir for 1h. Ethyl 4-oxocyclohexanecarboxylate (0.47 mL, 2.94 mmol) was added and the reaction was allowed to warm to room temperature over 3 h.

Acetone (3 mL) was added and the solvent was removed under reduced pressure. The residue was suspended in dichloromethane and ethyl ether (1:1), d and concentrated. The crude was puriﬁed by ﬂash column chromatography to afford 19 as clear oil (419 mg, 85%). 1H NMR: 1.25 (t, 3H), 1.50—1.70 (m, 2H), 1.90—2.16 (m, 4H), 2.30—2.50 (m, 3H), 4.12 (q, 2H), 4.65 (s, 2H).

Example 7 Ethyl 4-(iodomethylene)cyclohexanecarboxylate I' E": o 2040 7”“ 0 ' Ph A34 | o < 20 K KHMDS To a suspension of iodomethyltriphenylphosphonium iodide (1.95 g, 3.67 mmol) in THF (10 mL) at -23°C was slowly added a solution of potassium hexamethyldisilazane (20% in toluene, 7.34 mL, 3.67 mmol) and the resulting solution was allowed to stir for 15 min.

Ethyl 4—oxocyclohexanecarboxylate (500 mg, 2.94 mmol) was added. The cold bath was removed and the solution was allowed to stir at room temperature for 2 days. The reaction mixture was diluted with water (20 mL) and extracted with ether (3 x 20 mL). The ed organic layers were dried over anhydrous MgSO4 and concentrated to obtain the crude product. The crude residue was d by column chromatography to obtain 20 as light pink oil (207 mg, 24%). 1H NMR: 1.21—1.52 (m, 2H), 1.93—2.13 (m, 4H), 2.30—2.50 (m, 4H), 2.49— 2.70 (m, 4H), 4.12 (q, 2H), 4.60 (s, 1H) Example 8 Ethyl panylidene)cyclohexanecarboxylate To a suspension of isopropyltriphenylphosphonium iodide (3.81g, 8.81 mmol) in anhydrous THF (20 mL) at 0 0C was added a solution of t—BuOK (1.19g, 10.58 mmol) in THF (15 mL). The reaction mixture was allowed to warm to rt and stirred for 1 h. The resulting mixture was cooled to 0 0C, 4—Oxo—cyclohexanecarboxylic acid ethyl ester (1.0 g, .88 mmol) was added over a period of 5 min. The solution was allowed to slowly warm to rt and d for 2h. The solution was stirred at 50 °C overnight. The solvent was distilled off under reduced pressure and the crude was partitioned between CHzClz (50 mL) and satd.

NH4Cl (30 mL). The organic layer was collected and the aqueous layer was extracted with CHzClz (2 x 30 mL). The organic layer was washed with brine, dried 4) and concentrated under reduced pressured to obtain the crude product. The crude was puriﬁed by column chromatography on silica gel to afford 21 as a clear oil (280 mg, 24%). 1H NMR: 1.24 (t, 3H, J: 6.0 Hz), 1.43—1.50 (m, 2H), 1.63 (s, 6H), 1.74—1.83 (m, 2H), 1.92—1.98 (m, 2H), 2.39—2.47 (m, 1H), 2.58-2.69 (m, 2H).

Example 9 Ethyl lopropylmethylene)cyclohexanecarboxylate o e O o:<:>—/< V/gppm KOtBu — 0 + Br o To a suspension of cyclopropylmethyltriphenylphosphonium iodide (3.5 g, 8.81 mmol) in anhydrous THF (20 mL) at 0 0C was added a solution of t—BuOK (1.19g, 10.58 mmol) in THF (15 mL). The reaction e was allowed to warm to rt and stirred for 1 h.

The resulting e was cooled to 0 0C, 4-Oxo—cyclohexanecarboxylic acid ethyl ester (1.0 g, 5.88 mmol) was added over a period of 5 min. The solution was allowed to slowly warm to rt and stirred for 2h. The solution was stirred at 50 °C overnight. The solvent was distilled off under reduced pressure and the crude was partitioned between CHzClz (50 mL) and satd.

NH4Cl (30 mL). The organic layer was collected and the aqueous layer was extracted with CHzClz (2 x 30 mL). The organic layer was washed with brine, dried (NaZSO4) and concentrated under reduced pressured to obtain the crude product. The crude was ed by column chromatography on silica gel to afford 22 as colorless oil (800 mg, 65%). 1H NMR: CDCl3 0.22—0.26 (m, 2H), 0.62—0.68 (m, 2H), 1.22 (t, 3H, J: 7.2 Hz), .47 (m, 3H), 1.75—2.04 (m, 4H), 2.14—2.20 (m, 1H), .46 (m, 1H), .75 (m, 1H), 4.10 (q, 2H, J: 7.2 Hz), 4.49 (d, 1H, J= 9.3 Hz).

Example 10 Ethyl 4-(trityloxy)cyclohexanecarboxylate ( 23 < To a solution of triphenylmethyl de (0.97 g, 3.48 mmol) in dichloromethane (10 mL) was added DBU (0.61 mL, 4.06 mmol) and ethyl 4-hydroxycyclohexanecarboxylate (500 mg, 2.90 mmol) and the mixture was reﬂuxed for 24 h. The reaction mixture cooled and cold water (40 mL) was added. The organic layer was collected and the aqueous layer was extracted with dichloromethane (2 x 30 ml). The combined organic layers were dried (NaZSO4) and concentrated under reduced pressure. The crude was puriﬁed by ﬂash column chromatography to afford 23 as colorless oil (714 mg, 59%). 1HNMR: (mixture of cis and trans isomers (1:14)) 1.06 (t, 2H, J = 12.4 Hz), 1.16—1.26 (m, 14H), 1.32—1.35 (m, 2H), 1.54— 1.58 (m, 2H), 1.76—1.79 (m, 3H),1.95-2.04 (m, 2H), .22 (m, 2H), 3.35—3.41 (m, 1.4H), 3.72—3.76 (m, 1H), 4.04 (q, 2.8H, J = 7.2 Hz), 4.14 (q, 2H, J = 6.8 Hz), 7.22-7.27 (m, 24H, merged with CHCl3), 7.49—7.51 (m, 13H).

Example 11 Methyl cisaminocyclohexanecarboxylate hydrochloride NH2 NHZHCI A solution of cisaminocyclohexanecarboxylic acid (1.04 g, 7.26 mmol) in 10 mL of methanol was cooled to 0 0C and l chloride (1.58 mL, 21.79 mmol) was added. The reaction mixture was warmed to RT and stirred for 18 h. The reaction solution was concentrated, and the residue was washed with ethyl ether to obtain 115 as ess crystals (1.3 g, 92%). 1H NMR (CD3OD): 1.73—1.77 (m, 4H), .96 (m, 2H), 2.16—2.73 (m, 2H), 2.70—2.73 (m, 1H), 3.19—3.24 (m, 1H), 3.74 (s, 3H).

Example 12 Methyl cisbenzamidocyclohexanecarboxylate O O O O NHZIHCI HN To a suspension of methyl cis—4—aminocyclohexanecarboxylate hydrochloride (0.63 g, 3.26 mmol) in CHzClz (10 mL) at 0 0C was added diisopropylethylamine (1.71 mL, 9.79 mmol) and the suspension was stirred for 10 minutes. Benzoyl chloride (0.45 mL, 3.92 mmol) was added dropwise and the clear solution was d to warm to rt and stirred overnight. The reaction was d with water (15 mL) and CHzClz (15 mL), the organic layer was collected and the aqueous layer was extracted with CHzClz (2 x 25 mL). The combined organic extracts were dried over NaZSO4 and concentrated under reduce pressure to afford 116 as a clear gel (850 mg, 100%). 1H NMR: 1.70—1.73 (m, 2H), 1.76—1.90 (m, 4H), 1.95-2.06 (m, 2H), 2.55-2.61 (m, 1H), 3.72 (s, 3H), .20 (m, 1H), 6.14 (d, 1H, J: 6.0 Hz), 7.43-7.47 (m, 2H), 7.49—7.51 (m, 1H), 7.76-7.78 (m, 2H).

Example 13 Methyl transaminocyclohexanecarboxylate hydrochloride SeSNH2HC| A solution of transaminocyclohexanecarboxylic acid (1.24 g, 8.66 mmol) in 12 mL of methanol was cooled to 0 0C and thionyl chloride (1.89 mL, 25.98 mmol) was added. The reaction mixture was warmed to RT and d for 18 h. The reaction solution was concentrated, and the residue was washed with ethyl ether to obtain 117 as ess crystals (1.61 g, 95%). 1H NMR (CD3OD): 1.43—1.61 (m, 4H), 2.11—2.15 (m, 4H), 2.39 (dt, 1H, J: 2.8, 11.8 Hz), 3.12 (dt, 1H, J: 3.2, 8.0 Hz), 3.70 (s, 3H).

Example 14 Methyl transbenzamidocyclohexanecarboxylate NH2HC| HNY To a suspension of methyl trans—4—aminocyclohexanecarboxylate hydrochloride, 9.79 mmol) and the suspension was stirred for 10 minutes. Benzoyl chloride (0.45 mL, 3.92 mmol) was added se and the clear solution was allowed to warm to rt and stirred overnight. The reaction was d with water (15 mL) and CHzClz (15 mL), the organic layer was separated and the aqueous layer was extracted with CHzClz (2 x 25 mL). The combined organic t was dried over NaZSO4 and concentrated under reduce pressure to afford 118 as a white solid (200 mg, 24%). 1H NMR (CD3OD): 1.46 (q, 2H, J: 11.5 Hz), 1.60 (q, 2H, J: 12.0 Hz), 2.09 (d, 4H, J: 11.2 Hz), 2.37 (t, 1H, J: 12.0 Hz), 3.71 (s, 3H), 3.90 (t, 1H, J= 11.4 Hz), 7.46—7.57 (m, 3H), 7.83 (d, 2H, J= 7.1 Hz).

Example 15 1-tert—butyl 3 -methyl azetidine- 1,3 -dicarboxylate O OH O 0 v8“ —’ yOMHO 1—(t-butoxycarbonyl)azetidinecarboxylic acid (2.03 g, 10.09 mmol) was dissolved in MeOH (10 ml) and DCM (10 mL) and then cooled to 0 0C. A 2M solution of trimethylsilyldiazomethane in ether (7.57 ml, 15.1 mmol) was then added drop—wise over 5 minutes. The on was stirred for 10 minutes at 0 0C and then warmed to room temperature over 30 minutes. The solution was concentrated under reduced pressure to remove volatiles to afford crude 119, which was used directly in the next step without further cation. 1H NMR: 1.44 (s, 9H), 3.35 (m, 1H), 3.75 (s, 3H), 4.10 (d, 4H, J = 7.6 Hz).

Example 16 Methyl cishydroxycyclohexanecarboxylate O OH O / OH OH To a solution of hydroxycyclohexanecarboxylic acid (5.0 g, 34.7 mmol) in dry MeOH (40 mL) at RT, was added concentrated H2804 (0.2 mL, 3.47 mmol) and the solution was stirred at 65 0C for 16 h. The solvent was led off and the crude was dissolved in EtOAc (40 mL) and the solution was washed with sat’d NaHCO3 solution (25 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 20 mL).

The combined organic extracts were dried over NaZSO4 and concentrated under d pressure to afford 120 (4.90 g, 89%).1H NMR: 1.62—2.01 (m, 8H), 2.34—2.38 (m, 1H), 3.64 (s, 3H), 3.82—3.88 (m, 1H).

Example 17 Methyl cis(benzyloxy)cyclohexanecarboxylate O O o 0 + Clka —> OH 0 To a solution of methyl ciS-4—hydr'ox37cyclohexanecarboxylate (4.80 g, 30.3 mmol) in hexane/CHC13 2:1 (60 mL) was added benzyl oroacetimidate (9.19 g, 36.4 mmol) and trifluoromethanesulfonic acid (683 mg, 4.55 mmol) at 23 C. The reaction mixture was d for 18 h and diluted with EtOAc (300 mL). The mixture was washed with saturated aqueous NaHCO3, water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude reside was puriﬁed by column chromatography on silica gel to afford 121 (4.60 g, 18.5 mmol)._1H NMR: 1.55—1.98 (m, 8H), 2.36—2.41 (s, 1H), 3.56—3.66 (, 1H), 3.67 (s, 3H), 4.51 (s, 2H), 7.28—7.35 (m, 5H).

Example 18 General ure for the Reaction of Methyl Piperidinecarboxylate hydrochloride with Acid Chlorides mm i-Pr2NEt o 0 + r 0— R CI H34 To a suspension of methyl piperidinecarboxylate hydrochloride (5.6 mmol) in CHzClz (20 mL) at 0 CC was added diisopropylethyl amine (16.7 mmol) and the sion was d for 10 minutes. Appropriate acid chloride (8.4 mmol) was added dropwise and the solution was d to warm to rt and stirred overnight. The reaction was diluted with water (15 mL) and CHzClz (15 mL). The organic layer was collected and the aqueous layer was extracted with CHzClz (2 x 20 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduce pressure to afford the following compounds.

# Compound Name Yield (%) methyl loylpiperidine—4-carboxylate 1H NMR 1.21 (s, 9H) 1.65—1.53 (m, 2H), 1.87—1.92 (m, 2H), 2.48—2.52 (m, 1H), 2.89—2.93 (m, 2H), 3.63 (s, 3H), 4.18—4.22 (m, 1H), 4.24—4.27 (m, 1H) methyl l-(thiophenecarbonyl)piperidine carboxylate 1H NMR 1.69—1.79 (m, 2H), 1.89—1.95 (m, 2H), 2.56—2.63 (m, 1H), 3.12 (t, 2H, .1: 12.0 Hz), 3.68 (s, 3H), 4.28—4.31 (m, 2H), 70—702 (m, 1H), 7.24—7.26 (m, 1H), 7.40—7.42 (m, methyl 1-(2-phenylacetyl)piperidine carboxylate 1H NMR 1.30—1.95 (m, 4H), 2.35—2.55(m, 1H), .85 (m, 1H), 2.95—3.10 (m, 1H), 3.62 (s, 3H), 3.70 (s, 2H), 3.70-3.85(m, 1H), 4.30—4.40 (m, 1H), 7.15—7.35 (m, 5H) Example 19 Methyl 2—bromo—3—ﬂuorobenzoate F F Br Br SOCI2 0“ MeOH 0\ o o To a suspension of 2—bromo—3—ﬂuorobenzoic acid (300 mg, 1.37 mmol) in methanol (10 mL) at rt, was added SOClz (0.11 mL, 1.51 mmol) and the mixture was d at rt for 18 h. The solvent was distilled off under reduced pressure. The crude was basiﬁed by adding saturated aqueous NaHCO3 solution and the s layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over NaZSO4, ﬁltered and concentrated. The obtained crude product was used in the next step t further puriﬁcation.

Example 20 Methyl 3 -ﬂuoro( 1 -trityl- lH-imidazolyl)benzoate Trt‘ EtMg B r Trt\ N_\\ "‘\_\\N \ N S/ o A OMe + F Br OMe Pd<PPh3)4 o To a stirred solution of 4-iodo-l-trityl- lH-imidazole (436 mg, 1.0 mmol) in ous THF (6 mL) was added EtMgBr (3.0 M in THF, 1.20 mmol, 0.40 mL) under an atmosphere of N2. The resulting on was allowed to stir for 90 min and ZnClz (0.5 M in 2012/033245 THF, 2.40 mL, 1.20 mmol) was added. The ing white sion was allowed to stir for 90 min and a solution of methyl 2-bromofluorobenzoate (280 mg, 1.20 mmol) in THF (1 mL) was added followed by the immediate addition of Pd(PPh3)4 (58 mg, 0.05 mmol).

The reaction mixture was allowed to stir at 90 CC for 18 h under an atmosphere of N2. After cooling to room temperature, the solution was diluted with CHzClz (20 mL) and the organic layer was washed with an EDTA (aq) buffer (pH = 9) (2 x 5 mL) and brine. The organic layer was dried 4) and concentrated under reduced pressure. The crude residue was d by ﬂash column chromatography to afford the desired product as yellow oil (190 mg, 41 %). 1H NMR: 3.93 (s, 3H), 7.12—7.59 (m, 18H), 7.56 (s, 1H), 7.73—7.75 (m, 1H).

Example 21 3 -Fluoro(1-trityl-1H-imidazolyl)benzaldehyde N’\\ DIBAL—H To a solution of methyl 3-fluoro(1-trityl-1H-imidazolyl)benzoate (62 mg, 0.134 mmol) in toluene (4 mL) at -78 CC was added dropwise a solution DIBAH (1 M, 0.161 mL, 0.161 mmol) Stirring was continued at for 10 min. At this temperature, dry methanol was added. The e was poured into saturated s NH4Cl (5 mL), diluted with EtOAc (15 mL), shaken vigorously for 3 min, added brine (5 mL), shaken again, the phases ted and the organic layer dried over NaZSO4, filtered, and evaporated to give the desired aldehyde which was used without further purification.

Example 22 General Procedure for the Synthesis of Dimethyl (2-oxo)phosphonates O o 1 ' I. )n-BuLI —P—0Me RJK/R\\ IOMe (IDM i OMe e 2) R OMe To a stirred solution of dimethyl methylphosphonate (3.14 g, 25.3 mmol) in 20 ml of anhydrous tetrahydrofuran at -78 0C was added dropwise a solution of n-butyl lithium (10.13 mL, 25.3 mmol, 2.5 M in hexanes) under an atmosphere of N2, and the mixture was stirred for 30 minutes. To this reaction mixture was added dropwise a solution of the appropriate commercially available methyl or ethyl ester or 19-26, 91 or 115-121 (12.7 mmol) as a solution in THF (5 mL). After being stirred for 30 minutes, the reaction e was allowed 2012/033245 to warm to 0 0C, and stirred for l h. The solvent was distilled off and the crude was diluted with ted NH4Cl (10 mL) and 10 ml of water. The mixture was extracted with ethyl acetate (2 x 40 mL). The combined ethyl acetate layers were washed with water (1 x 20 mL), brine (l x 20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and trated under reduced pressure to afford the crude product. The crude was purified by column chromatography to afford the ing compounds.

# Compound Name Yield (%) O O “ ,OMe dimethyl (2-(2,5-dimethylfuranyl)—2- I P\OM 52 e oxoethM)l hosphonate 27 0 1H NMR 2.23 (s, 3H), 2.53 (s, 3H), 3.31 (d, 2H, J: 22.5 Hz), 3.75 (s, 3H), 3.79 (s, 3H), 6.24 (s, 1H) m90 d1methyl (2—(furan—2—yl)—2—- O P—OMe | oxoethyl)phosphonate 28 OMe 1H NMR 3.52 (d, 2H, J: 22.6 Hz), 3.75 (s, 3H), 3.78 (s, 3H), 6.56 (d, 1H, J: 1.6 Hz), 7.29 (s, 1H), 7.62 (s, 1H) dimethyl (2-( 1 -methyl- lH-imidazol yl)—2-oxoethyl)phosphonate 1H NMR 3.80 (s, 3H), 3.83 (s, 3H), 3.88 (d, 2H, J: 22.2 Hz), 4.01 (s, 3H), 7.07 (s, 1H), 7.18 (s, 1H) 0 O . . \\ ,0 Me yl (2-oxo(th1azol SVV‘OMe yl)ethyl)phosphonate 1H NMR 3.76 (s, 3H), 3.79 (s, 3H), 3.90 (d, 2H, J: 22.8 Hz), 8.32 (s, 1H), 8.85 (s, 1H) 9’ dimethy12-(4,4-difluorocyclohexyl)—2- F 82 Ifo\ oxoethylphosphonate 31 O 1H NMR , .7213} (16,411), 1.96—1.93 (m, 2H), 3.11—2.13 (m, 2H). 2.63—2.71) (m, 1H), 314 (d, 211,11: 2.2.4 Hz), 3.79 (61, (3&1: 11.2 Hz) d1meth. y12- 4-meth( ylenecyclohexy)l 32 ﬂ? 67 ﬁ—O\ oxoethylphosphonate WO 42237 H NMR 1.43—1.53 (m, 2H), 1.95—2.13 (m, 4H), 2.37—2.41 (m, 2H), 2.72—2.78 (m, 1H), 3.18 (d, 2H, J: 22.5 Hz), 3.82 (d, 6H, J: 11.3 Hz), 4.68 (s, 2H) [OWE-O0 o dimethyl 2-0x0(1,4- dioxaspiro[4.5]decan—8— 72 ' \ 33 O y1)ethy1phosph0nate 1H NMR 1.31—1.39 (m, 2H), 1.70—1.85 (m, 5H), 1.85—1.98 (m, 2H), 3.15 (d, 2H, J= 11.2 Hz), 3.77 (d, J= 18 Hz, 6H), 3.92 (m, 4H) ~O—gO dimethyl 2—(4—methylcyclohexyl)—2— O:P\—O Me oxoethylphosphonate 1H NMR 0.88—0.90 (m, 3H), 1.20—1.50 (m, 2H), 1.50—1.65 (m, 5H), 1.80—1.95 (m, 2H), 2.62—2.71 (m, 2H), 3.13 (d, J: 22.8 Hz, 2H), 3.73 and 3.80 (two 8, 6H) dimethyl 2-(4- (iodomethylene)cyc10hexy1)—2— 47 oxoethylphosphonate 1H NMR 1.20-1.52 (m, 2H), 1.93-2.10 (m, 4H), 2.30-2.36 (m, 1H), 2.49-2.58 (m, 4H), 3.07—3.10(m, 2H), 3.73—3.76 (m, 6H), 4.60 (s, 1H) > O O _ (LE—o dimethyl (4-(propan | ylidene)cyc10hexy1)ethy1)ph0sphonate 36 OMe 1H NMR 1.28—1.42 (m, 2H), 1.63 (s, 6H), 1.72—1.96 (m, 4H), 2.65—2.75 (m, 3H), 3.12 (d, 1H, J: 21.0 Hz), 3.75 (d, 6H, J: 12.0 Hz) O dimethyl (2—(4— P (cyclopropylmethylene)cyclohexyl)—2— 68 oxoethy1)phosph0nate H NMR 0.24 (s, 2H), 0.67 (d, 2H, J= 7.8 Hz), 1.39—1.43 (m, 3H), 1.86-2.07 (m, 4H), .21 (m, 1H), 2.71—2.79 (m, 2H), 3.13 (d, 2H, J: 22.5 Hz), 3.77 (d, 6H, J= 11.2 Hz), 4.50 (d, 1H, J= 9.3 Hz) O O 72~N [lo dimethyl (2-0x0(1-piva10y1piperidin- 38 4-y1)ethy1)phosph0nate 1H NMR 1.23 (s, 9H), 1.51 (m, 1H, 1.87 (m, 3H), 2.85 (m, 3H), 3.02 (s, 1H), 3.14 (s, 1H), -3.75 (d, 6H, .1: 11.2 Hz), 4.34 (m, 1H), 4.37 (m, 1H) N O 1M00 dimethy1 (2- l-meth( yl-lH-imidazol-S- /P\ 0xoethyl)phosph0nate 39 MeO OMe 1H NMR 3.35 (d, 2H, .1: 22.8 Hz), 3.74 (d, 6H, .1: 11.2 Hz), 3.86 (s, 3H), 7.54 (s, 1H), 7.78 (s, 1H) F dimethyl (2—(1—methy1—1H—imidazol—4— / O /N Pl, 29 l \ Y)1 _2 _0X06thly)phOSp onaeh t 40 MeO OMe 1H NMR 3.66—3.74 (s, 3H merged with d, 2H, .1: 22.5 Hz), 3.78 (d, 6H, .1: 11.2 Hz), 7.44 (s, 1H), 7.63 (s, 1H) dimethyl (2-0x0(thiazol 41 y1)ethy1)phosph0nate dimethyl (2-(1-acetylpiperidiny1)—2- oxoethyl)phosph0nate 1H NMR 1.44—1.69 (m, 2H), .89 (m, 2H), 2.07 (s, 3H), 2.66—2.73 (m, 1H), 2.79—2.85 (m, 1H), 3.03—3.22 (m, 3H), 3.72—3.83 (m, 1H overlapping with d, 6H, J: 11.2 Hz), 4.53 (d,1H, J: 13.4 Hz) O O dimethyl (2-0x0(1-(thiophene N O Pg] yl)piperidin 59 \ S MeO 0 Me y1)ethy1)phosph0nate 1H NMR 1.63 (m, 2H), 1.95 (m, 2H), 2.89 (s, 1H), 3.07 (m, 2H), 3.10 (s, 1H), 3.18 (s, 1H), 3.77 (d, 6H, J: 11.2 Hz), 4.38 (m, 2H), 7.02 (dd, 1H, J: 5.0 Hz, 3.7 Hz), 7.25 (dd, 1H, .1 = 3.7 Hz, 1.1 Hz), 7.42 (dd, 1H, .1: 5.1 Hz, 1.2 Hz) o o dimethyl 2-0x0(1-(2- O}N 6’0 phenylacetyl)piperidin—4— 39 MeO OMe y1)ethy1phosph0nate 1H NMR 1.20—1.90 (m, 4H), 1.67 (d, 1H, .1: 10.2 Hz), 1.84 (d, 1H, .1: 9.6 Hz), 2.55—2.75 (m, 2H), 2.90—3.15 (m, 2H) 3.70 (d, 6H, .1: 11.2 Hz), 3.90 (d, 1H, J = 10.2 , 3.65(s, 2H) , Hz), 4.48 (d, 1H, J = 9.9 Hz), 7.10—7.30 (m, 5H) _—<% O O\/ dimethy13 0hexy12- O 70 P\\/ \ oxopropylphosphonate 45 o 1H NMR 0.60—1.15 (m, 5H), 1.35—1.71 (m, 5H), 2.28 (d, 2H, J: 8.8 Hz), 2.83 (s, 1H), 2.91 (s, 1H), 3.55 (s, 3H), 3.59 (s, 1H) TrtoMOO / dlmethyl (2—0x0—2-(4—.

F'>—o 79 ('5 \ (trityloxy)cyc10hexy1)ethy1)phosph0nate 1H NMR (mixture of cis and trans isomers) 1.08-1.36 (m, 5H), 1.59—1.91 (m, 3H), 2.41— 2.52 (m, 1H), 3.03 and 3.13 (two d, 2H, J = 20.0 Hz), 3.35—3.79 (m, 1H), 3.73—3.79 (m, 6H), 7.22—7.29 (m, 9H), 7.49—7.51 (m, 6H) (tranS)—methy1 4-(2- (dimethoxyphosphoryl)acety1)cyc10hexa 70 —OMe 122 Meogl OMe necarboxylate 1H NMR 1.31—1.53 (m, 4H), 2.00—2.20 (m, 4H), 2.23—2.31 (m, 1H), .61 (m, 1H), 3.13 (d, 2H, J: 22.6 Hz), 3.67 (s, 3H), 3.79 (d, 6H, J: 11.2 Hz) — dimethyl (2-0x0(4-(propan 0¢ 70 ylidene)cyc10hexy1)ethy1)ph0sphonate 124 O,P\O/ 1H NMR 1.28—1.42 (m, 2H), 1.63 (s, 6H), 1.72—1.96 (m, 4H), 2.65—2.75 (m, 3H), 3.12 (d, 1H, J: 21.0 Hz), 3.75 (d, 6H, J= 12.0 Hz) mO0 dimethyl (2-0x0(spiro[2.5]0ctan—6— PI/ 77 y1)ethy1)phosph0nate 125 Med \OMe H NMR 0.13—0.27 (m, 4H), .95 (m, 2H), 1.40—2.06 (m, 6H), 2.52—2.58 (m, 1H), 3.11 (d, 2H, J = 24.0 Hz), 3.75 (d, 6H, J =12.0 Hz) dimethyl (2-((trans)—4-((tert- butyldimethylsilyl)0xy)cyc10hexy1)—2— 96 oxoethy1)phosph0nate 1H NMR 0.11 (s, 6H), 0.82 (s, 9H), 1.19—1.32 (m, 4H), 1.85—1.88 (m, 4H), 2.41—2.47 (m, W7.) -1H), 3.08 (d, 2H, J = 24.0 Hz), 3.72 (s, 3H), 3.74 (s, 3H) dimethyl (2—((trans)-4_ (benzyloxy)cyclohexy1)—2- 16 127 y1)phosph0nate 1H NMR 1.13—1.41 (m, 4H), 1.93—2.02 (m, 2H), 2.12—2.15 (m, 2H), 2.51—2.56 (m, 1H), 3.11 (d, 2H J = 24 Hz), 3.27—3.32 (m, 1H), 3.75 (d, 6H, J = 12 Hz), .32 (m, 5H) dimethyl (2-(cis—4— benzamidocyclohexyI)—2— 83 oxoethy1)phosph0nate 1H NMR 1.76-1.85 (m, 8H), 2.78-2.79 (m, 1H), 3.18 (d, 2H, J= 22.8 Hz), 3.82 (d, 6H, J= 11.2 Hz), 4.21—4.25 (m, 1H), .52 (m, 3H), 7.76-7.78 (m, 2H) dimethyl (2—(trans—4— benzamidocyclohexy1) 54 oxoethy1)phosph0nate H NMR 1.29 (dq, 2H, .1: 3.1, 12.1 Hz), 1.54 (dq, 2H, .1: 3.0, 11.5 Hz), 2.04 (d, 2H, J= 12.9 Hz), 2.12 (dd, 2H, .1: 3.0, 12.6 Hz), 2.60 (n, 1H, .1: 3.4, 12.0 Hz), 3.15 (d, 2H, .1: 22.6 Hz), 3.79 (d, 6H, .1: 11.2 Hz), 3.93—3.99 (m, 1H), 5.98 (d, 1H, .1: 7.7 Hz), 7.41—7.45 (m, 2H), 7.48—7.52 (m, 2H), 7.74 (d, 2H, .1: 7.1 Hz) Flk dimethyl (2-0x0-2—(4-(2- loxy)ethylidene)cyc10hexy1)ethy1)p 42 0 Ph OkPhPh hosphonite 1H NMR 1.26—1.60 (m, 2H), 1.35—1.37 (m, 1H), 1.80—2.30 (m, 3H), 2.25—2.40 (m, 2H), 2.70-2.76 (m, 1H), 3.05 (d, J = 27 Hz, 2H), 3.57-3.61 (m, 2H), 3.71—3.75 (d, J = 12 Hz, 2H), 7.19—7.32 (m, 9H), 7.44—7.51 (m, 6H) tert—butyl 3 -(2— 131 (dimethoxyphosphoryl)acety1)azetidine- 99 1-carb0xy1ate - HNMR 1.43 (s, 9H), 3.11 (d, J: 24 Hz, 2H), 3.68—3.82 (m, 7H), 3.81—4.12 (m, 4H) O '/O\ I: dlmethyl (pyr1d1n. . .

O 56 N/ yl)ethyl)phosphonate 132 I 1H NMR 3.69—3.77 (m, 6H), 3.96—4.04 (m, 2H), 7.45—7.48 (m, 1H), 7.80—7.85 (m, 1H), .09 (m, 1H), 8.66—8.69 (m, 1H) O |,O I: \ dlmethyl (2—oxo(pyr1d1n. . .

O 65 | yl)ethyl)phosphonate 1H NMR 3.60—3.80 (m, 8H), 7,41—7.45 (m, 1H), 8.26—8.29 (m, 1H), 8.78—8.79 (m, 1H), 9.18 (m, 1H) 0 (ID/WMe E dlmethyl (2—oxo(4-. (triﬂuoromethyl)cyclohexyl)ethyl)phosp 30 134 honate 1H NMR 1.55—1.64 (m, 4H), 1.75—1.77 (m, 2H), 204—216 (m, 3H), 2.83—2.84 (m, 1H), 3.14 (d, J = 22.4 Hz, 2H), 3.78 (d, J = 11.2 Hz, 6H) dimethyl (2—((ls,4s)—4— (benzyloxy)cyclohexyl) 17 oxoethyl)phosphonate H NMR 1.47—1.55 (m, 2H), 1.66—1.71 (m, 2H), .85 (m, 2H), 1.95—1.99 (m, 2H), 2.58—2.62 (m, 1H), 3.14 (d, 2H, J = 22.4 Hz), 3.60—3.63 (m, 1H), 3.78 (d, 6H, J = 11.2 Hz), 4.48 (s, 2H), 7.24—7.33 (m, 5H) Example 23 General ure for the Synthesis of 2-(5H—imidazo[5,l-a]isoindol-5— yl)ethanones by Homer—Wadsworth-Emmons Reaction Followed by Cyclization. \\ 2 \ /OMe R\\ O R1 I 1)R1 \ / H OMe \ / \ 2 N N )AcOH / L z) N\ N To a suspension of 95% NaH (17.4 mg, 0.7 mmol) in THF (3 mL) at 0 0C was added the appropriate phosponate t 27-46, 89, 90 or 5 (0.75 mmol) as a solution in THF (2 mL) and the mixture was stirred for 40 min. The appropriate 2-(l-trityl-lH-imidazol- 4—yl)benzaldehyde was added as a solution in THF (3 mL) drop wise over a period of 3 min.

The reaction was allowed to warm to RT and stirred overnight. The solvent was removed under reduced pressure and the crude was diluted with saturated NH4C1 (10 mL) and water (10 mL). The aqueous layer was extracted with CHzClz (2 x 20 mL) and the combined organic fractions were washed with brine (15 mL), dried over NaZSO4 and concentrated under reduced pressure to afford the crude product. To the crude residue was added AcOH (1 mL) and MeOH (3 mL) and the solution was stirred at 90 0C for 2 h. After cooling to rt, the solvent was distilled off and the crude was stirred in a mixture of sat’d K2C03 (5 mL) and EtOAc (5 mL). The c layer was separated and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water, brine and dried (NaZSO4) and the solvent evaporated under reduced pressure. The crude residue was purified by ﬂash column tography on silica gel to afford the following compounds.

Yield # nd Name l—(cyclohexen- 1 —(5H— imidazo[5, l -a] isoindolyl)ethanone 1H NMR 1.64—1.68 (m, 4H), 2.23—2.33 (m, 4H), 3.12 (dd, 1H, J= 9.8, 17.8 Hz), 3.36 (dd, 1H, J= 3.2, 18.0 Hz), 5.72 (dd, 1H, J= 3.6, 7.6 Hz), 6.86—6.88 (m, 1H), 7.17 (s, 1H), 7.32 (d, 1H, J= 7.6 Hz), 7.38 (t, 1H, J= 7.4 Hz), 7.55 (d, 1H, .1 = 7.2 Hz), 7.65 (s, Compound 1-(2,5-dimethylfuran-3 -y1)—2-(6- ﬂuoro—SH—imidazo[5, 1—a]isoind01—5— y1)ethan0ne H NMR 2.22 (s, 3H), 2.60 (s, 3H), 2.97 (dd, 1H, .1: 10.8, 18.4 Hz), 3.72 (d, 1H, .1: 18.2Hz), 5.86 (d, 1H, .1: 10.7 Hz), 6.11 (s, 1H), 6.93 (t, 1H, .1: 8.5 Hz), 7.16 (s, 1H), .37 (m, 2H). 7.74 (s, 1H) 2—(6—ﬂuoro-5H-imidazo[5, 1- a]isoind01—5-y1)—1—(furan-2— y1)ethan0ne H NMR 3.16 (dd, 1H, .1: 10.5, 18.4 Hz), 3.85 (d, 1H, .1: 18.4 Hz), 5.86 (d, 1H, .1: .5 Hz), 6.54 (s, 1H), 6.92 (t, 1H, .1: 8.9 Hz), 7.14 (s, 1H), 7.24—7.35 (m, 3H), 7.57 (s, 1H), 7.74 (s, 1H) 2—(6—ﬂuoro-5H-imidazo[5, 1- a]isoind01—5—y1)(1—methy1—1H— imidazol-Z-y1)ethan0ne 1H NMR 3.56 (dd, 1H, J: 12.0, 20.0 Hz), 4.07 (s, 3H), 4.13 (d, 1H, J: 20.0 Hz), 5.86 (d, 1H, J: 12.0 Hz), 6.92 (t, 1H, J: 8.0 Hz), 7.09 (d, 1H, J: 8.0 Hz), 7.15 (s, 1H), 7.31—7.34 (m, 3H), 7.71 (s, 1H) imidazo[5, 1-a]isoind01—5 -y1)— 1 — (thiazolyl)ethan0ne 1H NMR 3.62 (dd, 1H, J: 9.7, 18.8 Hz), 3.92 (dd, 1H, J: 3.0, 18.9 Hz), 5.79 (d, 1H, 9.5 Hz), 7.18 (s, 1H), 7.26—7.28 (m, 1H overlap with CHC13), 7.36—7.40 (m, 2H), 7.55 (d, 1H, J: 7.4 Hz), 7.75 (s, 1H), 8.38 (s, 1H), 8.82 (s, 1H) WO 42237 Yield 1-(4,4-diﬂuorocyc10hexy1)—2—(6— ﬂuoro—SH—imidazo[5, 1 —a]isoind01—5— y1)ethan0ne H NMR 1.65 1.82 (m, 4H), 1.902.01 (m, 2H), 2.11—2.16 (m, 2H), 2.44—2.48 (m, 1H), 2.79 (dd, 1H, .1: 10.4 Hz, 18.4 Hz), 3.52 (dd, 1H, .1: 2 Hz, 18.4 Hz), 5.72 (d, 1H, .1: .4 Hz), 6.92 (t, 1H, .1: 8.8 Hz), 7.15 (s, 1H), 7.28—7.35 (m, 2H), 7.58 (s, 1H) 1-(4,4-diﬂuorocyclohexy1)(5H- imidazo[5,1-a]isoind01—5 -y1)ethan0ne H NMR 1.73—1.80 (m, 4H), 1.91—1.95 (m, 2H), .14 (m, 2H), 2.41—2.47 (m, 1H), 2.90 (dd, 1H, J= 9.4 Hz, 18.8 Hz), 3.21 (dd, 1H, J= 3.6 Hz, 18.4 Hz), 5.60 (dd, 1H, J= 3.4 Hz, 9.4 Hz), 7.13 (s, 1H), 7.22—7.28 (m, 2H), 7.36 (t, 1H, J= 7.2 Hz), 7.51 (d, 1H, J ——7.6 Hz), 7.57 (s, 1H) 2-(5H—imidazo[5, 1-a]isoind01—5 -y1)— 1 — (4-methylenecyc10hexy1)ethan0ne 1H NMR 1.30—1.50 (m, 2H), 1.80—2.05 (m, 3H), 2.20—2.32 (m, 2H), 2.40—2.50 (m, 1H), 2.58—2.67 (m, 1H), 2.78—2.88 (m, 1H), 3.16—3.17 (m, 1H), 5.50—5.54 (m, 1H), 7.13—7.17 (m, 1H), 7.20—7.30 (m, 2H), 7.43—7.45 (m, 1H), 7.52 (s, 1H) 2—(6—ﬂuoro—5H-imidazo[5, 1 - a]isoind01—5—y1)-1—(4— methylenecyc10hexy1)ethan0ne 1H NMR 1.30—1.60 (m, 2H), 1.90—2.10 (m, 3H), 2.32—2.35 (m, 2H), 2.50—2.60 (m, 1H), 2.60—2.72 (m, 1H), 2.76—2.84 (m, 1H), 3.52 (d, J: 18.4 Hz, 1H), 4.63 (s, 2H), 5.73 (d, J =10.4 Hz, 1H), 6.91—6.96 (m, 1H), 7.20—7.30 (m, 2H), 7.43—7.45 (m, 1H), 7.52 (s, 1H) Yield Compound 2—(6—ﬂuoro-5H-imidazo[5, 1- OO] a]isoind01—5—y1)(1,4- dioxaspiro[4.5]decan—8—y1)ethan0ne H NMR (013301)) 1.48 1.91 (m, 6H), 2.35—2.65 (m, 2H), 3.58—3.65 (m, 1H), 3.91 (s, 4H), 5.79—5.82 (m, 1H), 7.01—7.07 (m, 1H), 7.16 (m, 1H), 7.42—7.45 (m, 2H), 7.70 (s, 1H) 2—(6—ﬂuoro-5H-imidazo[5, 1- a]isoind01—5—y1)—1—(4— methylcyclohexyl)ethanone 1H NMR 0.80-0.95 (m, 3H), 1.24—1.40 (m, 2H), 1.40—1.68 (m, 5H), 1.70—2.00 (m, 2H), 2.40—2.55 (m, 1H), 2.72—2.84 (m, 1H), 3.48 (d, J= 18.4 Hz, 1H), 5.75 (d, J= 10.4 Hz, 1H), .95 (m, 1H), 7.15 (s, 1H), 7.26—7.38 (m, 2H), 7.62 (s, 1H) 2—(6—ﬂuoro-5H-imidazo[5, 1- a]isoind01—5—y1)—1—(4— (iodomethylene)cyc10hexy1)ethan0ne H NMR (CD3OD) 1.20—1.52 (m, 2H), 1.80—2.20 (m, 4H), 2.30—2.36 (m, 1H), 2.45—2.80 (m, 3H), 2.90—3.02 (m, 1H), .64 (m, 1H), 4.63 (s, 1H), 5.75—5.80 (m, 1H), 7.02— 7.08 (m, 1H), 7.15 (s, 1H), 7.42—7.47 (m, 2H), 7.65 (s, 1H). uoro-5H-imidazo[5, 1- a]isoind01—5 —y1)—1—(4— methylcyclohexy1)ethan0ne H NMR (CD3OD) 0.80—0.95 (m, 3H), 1.24—1.40 (m, 2H), 1.40-1.68 (m, 5H), 1.70—2.00 (m, 2H), 2.40—2.55 (m, 1H), .84 (m, 1H), 3.48 (d, J= 18.4 Hz, 1H), 5.49—5.59 (m, 1H), 7.10—7.18 (m, 2H), 7.60—8.00 (m, 1H) Yield Compound 2—(6—ﬂuoro-5H-imidazo[5, 1 - a]isoind01—5—y1)—1—(4—(propan—2— e)cyc10hexyl)ethanone H NMR 1.30— 1.52 (m, 2H), 1.64 (s, 6H), 1.70—1.81 (m, 2H), .98 (m, 2H), 2.52— 2.62 (m, 1H), 2.68—2.74 (m, 2H), 2.80 (dd, 1H, J: 18.5 Hz, 10.6 Hz), 3.50 (dd, 1H, J: 18.5 Hz, 2.2 Hz), 5.75 (d, 1H, J: 9.27 Hz), 6.90—6.96 (m, 1H), 7.17 (s, 1H), 7.32—7.36 (m, 2H), 7.59 (s, 1H) 1 (4- (cyclopropylmethylene)cyclohexyl)— 2—(6—ﬂuoro-5H-imidazo[5, 1 - a]isoind01—5—y1)ethan0ne 1H NMR 0.24 (s, 2H), 0.67 (d, 2H, J= 7.8 Hz), 1.43-1.49 (m, 3H), 1.82-2.15 (m, 3H), .28 (m, 1H), 2.50-2.62 (m, 1H), 2.75-2.85 (m, 2H), 3.52 (d, 1H, J= 18.6 Hz), 4.52 (d, 1H, J= 9.3 Hz), 5.75 (d, 1H J= 10.2 Hz), 6.89-6.95 (m, 1H), 7.16 (s, 1H), 7.25-7.36 (m, 3H), 7.59 (s, 1H) 1—(4—(2—(5H—imidazo[5,1—a]isoind01— —y1)acety1)piperidiny1)—2,2- dimethylpropan0ne 1H NMR 1.26 (s, 9H), 1.60 (m, 2H), 1.88 (m, 2H), 2.61 (m, 1H), 2.84 (m, 2H), 2.89 (dd, 1H, J: 9.39 Hz, 18.6 Hz), 3.22 (dd, 1H, J: 3.6 Hz, 18.3 Hz), 4.41 (m, 2H), 5.62 (dd, 1H, .1: 3.54 Hz, 9.45 Hz), 7.16 (s, 1H), 7.24 (m, 2H), 7.37 (m, 1H), 7.53 (d, 1H, J= 7.56 Hz), 7.59 (s, 1H) 2—(6—ﬂuoro-5H-imidazo[5, 1 - a]isoind01—5 -y1)— 1 -( 1 -methyl- 1H- imidazol-S -y1)ethan0ne H NMR 3.13—3.20 (m, 1H), 3.85—3.89 (m, 1H), 4.0 (s, 3H), 5.79 and 5.89 (two d, 1H, J Yield # Compound Name = 10.4 Hz), 6.96 (t, 1H, J= 8.8 Hz), 7.20 (s, 1H), 7.33-7.38 (m, 2H), 7.62 (s, 1H), 7.74 and 7.81 (two 8, 3H) N=\ 2—(5H—imidazo[5,1-a]isoind01—5-y1) ( 1 -methyl- 1H-imidazoly1)ethan0ne 1H NMR 3.42 (d, 1H, J: 9.9 Hz), 3.48 (d, 1H, J: 8.7 Hz), 3.75 (s, 3H), 5.75 (dd, 1H, J = 3.4 Hz, 9.8 Hz), 7.26-7.19 (m, 1H), 7.14 (s, 1H), 7.35 (m, 2H), 7.41 (d, 1H, .1: 1.0 Hz), 7.52 (dd, 1H, J: 1.2 Hz, 7.35 Hz), 7.71 (s, 1H), 7.67 (d, 1H, .1: 1.2 Hz), imidazo[5, 1 -a]isoind01—5 -y1) (thiazol-S-yl)ethan0ne H NMR 3.40 (dd, 1H, .1: 9.6 Hz, 18.4 Hz), 3.71 (dd, 1H, .1: 3.2 Hz, 18.0 Hz), 5.80 (dd, 1H, .1: 2.8 Hz, 9.2 Hz), 7.21 (s, 1H), 7.29 (d, 1H, .1: 7.2 Hz), .41 (m, 2H), 7.57 (d, 1H, .1: 8.0 Hz), 8.41 (s, 1H), 7.73 (s, 1H), 9.0 (s, 1H), 1-(1-acety1piperidinyl)(5H— imidazo [5 ,1-a]isoindol-S-yl)ethan0ne 1H NMR 1.57 (m, 2H), 1.90 (m, 2H), 2.09 (s, 3H), 2.60 (m, 2H), 2.91 (m, 1H), 3.07—3.26 (m, 2H), 3.82 (m, 1H), 4.58 (m, 1H), 5.62 (m, 1H), 7.16 (s, 1H) 7.29 (m, 2H), 7.37 (m, 1H), 7.53 (d, 1H,J=10.4 Hz), 7.58 (d, 1H, J: 4.8 Hz) 2-(5H—imidazo[5, 1-a]isoind01—5 -y1)— 1 — (1 -(thiophenecarb0ny1)piperidin y1)ethan0ne 2012/033245 Compound 1—(4—(2—(5H-imidazo[5,1—a]isoind01— —y1)acety1)piperidiny1) phenylethanone 1H NMR 1.20—1.90 (m, 4H), 2.40—3.33(m, 5H), 3.73(s, 2H), 3.89 (d, 1H, .1: 13.5 Hz), 4.59 (d, 1H, .1: 13.5 Hz), 5.50—5.70 (m, 1H), 7.15—7.45 (m, 9H), 7.53 (d, 1H, .1: 7.5 Hz), 7.68 (d, 1H, .1: 7.8 Hz) 1—Cyclohexy1—3-(5H—imidazo[5, 1- a]isoind01—5 -y1)propan—2—0ne H NMR 0.85—1.35 (m, 5H), 1.55—1.175 (m, 5H), 1.80—1.95 (m, 1H), 2.25—2.38 (m, 2H), 2.70—2.80 (m, 1H), 3.16 (dd, 1H, J= 2.4, 14.8 Hz), 5.50—5.60 (m, 1H), 7.16 (s, 1H), 7.20—7.30 (m, 3H), 7.35 (t, 1H, J= 5.4 Hz), 7.41 (d, 1H, J= 5.4 Hz), 7.73 (s, 1H) 1—cyclohexy1—3—(6—ﬂuoro—5H- imidazo[5,1-a]isoind01—5-y1)propan- / N 78 g] 2—0ne N 0 1H NMR 0.80—1.40 (m, 5H), 1.45—2.00 (m, 6H), 2.32 (t, 2H, .1: 9.3Hz), 2.80—2.60 (m, 1H), 3.46 (d, 1H, .1: 18.6 Hz), 5.72 (d, 1H, .1: 10.5 Hz), 6.92 (t, 1H, .1: 9.3 Hz), 7.18 (s, 1H), .40 (m, 2H), 7.71 (s, 1H) 2—(6—ﬂuoro-5H-imidazo[5, 1 - a]isoind01—5 —y1)— 1 —(4— hydroxycyc10hexy1)ethan0ne H NMR (mixture of cis and trans isomers) 1.25—1.77 (m, 6H), 1.90—2.06 (m, 3H), 2.34— 2.42 (m, 1H), 2.80 (dd, 1H, J = 10.8 8 Hz), 3.51 (d, 1H, J = 18.8 Hz), 3.60—3.62 and 3.97—4.01 (m, 1H), 5.73—5.76 (m, 1H), 6.93 (t, 1H, J = 8.4 Hz), 7.17 (s, 1H), 7.30— 7.37 (m, 2H), 7.59 and 7.62 (two 8, 1H) Compound 1-cyclohexy1(SH-imidazo [5 ,1- a]isoindol-5 —y1)ethanone 1H NMR 1.25 (m, 5H), 1.79 (m, 5H), 2.38 (m, 1H), 2.89 (dd, 1H, J: 18.0 Hz, 9.0 Hz), 3.18 (dd, 1H, J: 18 Hz, 3.0 Hz), 5.63 (m, 1H), 7.16 (s, 1H), 7.21-7.28 (m, 2H), 7.37 (t, 1H, J: 7.5 Hz), 7.53 (d, 1H, J: 6 Hz), 7.60 (s, 1H) aThe compound was not characterized and was used as such for the next synthetic step 1-cyclohexy1(5H—imidazo[5 ,1- a]isoindol—S—y1idene)ethanone 136 H NMR Indistinguishable mixture of E/Z isomers 1.26—1.48 (m, 8.9H), .94 (m, 13.7H), 2.58—2.62 (m, 0.6H), .38 (m, 1H), 6.40 (s, 0.4H), 6.60 (s, 0.53H), 7.15 (d, 0.8 Hz, J: 6.0 Hz), 7.25—7.28 (m merged with CHC13, 0.8H), 7.43—7.49 (m, 3H), 7.63— 7.67 (m, 2H), .77 (m, 3H), 7.93 (s, 1H), 8.06 (d, 1H, J: 8.0 Hz), 9.25 (s, 0.4H), 9.43 (s, 0.8 H) (trans)-methy1 4-(2-(5H—imidazo[5, 1 - a]isoindol—5— y1)acety1)cyclohexanecarboxylate 1H NMR 1.38—1.49 (m, 4H), 1.95—2.11 (m, 4H), 2.27—2.32 (m, 1H), 2.27—2.42 (m, 1H), 2.91 (dd, J: 9.5, 18.5 Hz, 1H), 3.21 (dd, J: 3.5, 18.5 Hz, 1H), 3.67 (s, 3H), 5.63 (dd, J = 3.3, 9.5 Hz), 7.17 (s, 1H), 7.22—7.29 (m, 2H), 7.38 (t, 1H, J: 7.5 Hz), 7.54 (d, 1H, J: 7.6 Hz), 7.60 (s, 1H) 2—(6—ﬂuoro-5H—imidazo[5, 1- a]isoindol-5 —y1)—1—(4—(propan—2— N o / ,> y1idene)cyclohexy1)ethanone 1H NMR 1.30—1.52 (m, 2H), 1.64 (s, 6H), 1.70—1.81 (m, 2H), 1.85—1.98 (m, 2H), 2.52— 2.62 (m, 1H), 2.68—2.74 (m, 2H), 2.80 (dd, 1H, J = 18.5 Hz, 10.6), 3.50 (dd, 1H, J = 18.5 Yield Compound Name Hz, 2.2 Hz), 5.75 (d, 1H, J = 9.27 Hz), 6.90—6.96 (m, 1H), 7.17 (s, 1H), .36 (m, 2H), 7.59 (s, 1H) 2-(5H—imidaz0[5, oind01—5 —y1)— 1-(spiro[2.5]octany1)ethan0ne 1H NMR 0.18—0.30 (m, 4H), 0.90—0.98 (m, 2H), .87 (m, 6H), 2.38—2.53 (m, 1H), 2.91 (dd, 1H, J = 18.4, 9.60 Hz), 3.20 (dd, 1H, J = 18.47, 3.6 Hz), 5.58—5.65 (m, 1H), 7.15 (s, 1H), 7.21—7.27 (m, 2H), 7.36 (t, 1H, J = 7.60 Hz), 7.52 (d, 1H J = 7.60 Hz), 7.61 (s, 1H) 1—((trans)—4—((tert— butyldimethylsilyl)0xy)cyclohexyl)- 2—(6—ﬂuoro-5H-imidaz0[5,1- 141 nd01—5—y1)ethan0ne 1H NMR 0.028 ( s, 6H), 0.88 (s, 9H), 11.27—1.96 (m, 8H), 2.32—2.38 (m, 1H), 2.80 (dd, 1H, J = 18.8, 10.6 Hz), 3.48-3.57 (m, 2H), 5.75 (d, J = 9.3 Hz), 6.91-6.95 (m, 1H), 7.17 (s, 1H), 7.23—7.39 (m, 2H), 7.59 and 7.64 (two 5, 1H) 1—((trans)—4—(benzy10xy)cyclohexyl)- 2—(6—ﬂuoro-5H-imidaz0[5, 1 - a]isoind01—5—y1)ethan0ne 142 1H NMR 1.15—1.54 (m, 4H), 1.91—2.20 (m, 4H), 2.37—2.43 (m, 1H), 2.80 (dd, 1H, J = 18.5, 10.5 Hz), 3.31—3.36 (m, 1H), 3.51 (d, 1H, J = 18.6 Hz), 4.55 (s, 2H), 5.74 (d, 1H, J = 10.3 Hz), 6.93 (t, 1H, J = 8.0 Hz), 7.17 (s, 1H), 7.29—7.39 (m, 7H), 7.59 and 7.78 (two , 1H) 1—((trans)—4—(benzy10xy)cyclohexyl)- 2-(5H—imidaz0[5,1—a]isoind01—5— y1)ethan0ne H NMR 1.14—1.50 (m, 4H), 1.92—2.01 (m, 2H), 2.15—2.19(m, 2H), 2.34—2.43 (m, 1H), 2.90 (dd, 1H, J =18, 9 Hz), 3.19 (dd, 1H, J = 24, 6 Hz), 3.30—3.37 (m, 1H), 4.49 and 4.55 (two 5, 2H), 5.61 (dd, 1H, J =10.5, 4.5 Hz), 7.16—7.39 (m, 9H), 7.53 (d, 1H, J = 9 Hz), Yield # Compound Name -7.62 (s, 1H) N—((cis)—4—(2—(5H-imidazo[5, 1- a]isoindol—5— yl)acetyl)cyclohexyl)benzamide 1H NMR 1.25—1.34 (m, 2H), 1.53—1.63 (m, 2H), 1.98—2.08 (m, 2H), 2.20 (t, 2H, J: 11.6 Hz), 2.36 (t, 1H, J: 12.2 Hz), 2.90 (dd, 1H, J= 9.4, 18.6 Hz), 3.25 (dd, 1H, J= 3.2, 18.4 Hz), 3.93-4.00 (m, 1H), 5.63 (dd, 1H, J= 3.2, 9.2 Hz), 6.32 (d, 1H, J= 6.8 Hz), 7.19 (s, 1H), 7.26—7.35 (m, 2H, merged with form), 7.3 8—7.43 (m, 3H), 7.48 (d, 1H, J= 7.2 Hz), 7.55 (d, 1H, J= 7.6 Hz), 7.71 (s, 1H), 7.76 (d, 2H, J= 7.6 Hz) N—((trans)—4—(2—(5H-imidazo[5, 1 - a]isoindol—5— yl)acetyl)cyclohexyl)benzamide 1H NMR 1.19—1.36 (m, 2H), 1.48—1.65 (m, 2H), .07 (m, 2H), 2.18—2.23 (m, 2H), 2.35 (tt, 1H, J = 3.2, 12.2 Hz), 2.90 (dd, 1H, J= 9.5, 18.4 Hz), 3.22 (dd, 1H, J= 3.6, 18.4 Hz), 3.92-3.99 (m, 1H), 5.62 (dd, 1H, J= 3.4, 9.4 Hz), 6.23 (d, 1H, J= 7.6 Hz), 7.23- 7.32 (m, 3H, merged with chloroform), 7.34—7.42 (m, 3H), 7.46—7.50 (m, 1H), 7.54 (d, 1H, J= 7.6 Hz), 7.63 (s, 1H), 7.76 (d, 2H, J= 7.6 Hz) 1—(4—(2— hydroxyethylidene)cyclohexyl) (5H—imidazo[5,1—a]isoindol—5— yl)ethanone 1H NMR 1.26—1.50_(m, 2H), 1.70—2.30 (m, 4H), 2.31—2.40 (m, 1H), 2.41—2.75 (m, 2H), 2.76-2.90 (m, 1H), 3.15-3.25 (m, 1H), .13 (m, 1H), 5.25-5.40 (m, 1H), 5.51-5.60 (m, 1H), 7.12 (s, 1H), 7.13-7.40 (m, 2H), 7.48-7.60 (m, 3H) O tert—butyl 3 —(2-(5H—imidazo[5, 1 - NJ40 a]isoindol—5—yl)acetyl)azetidine— 1 - k carboxylate 1H NMR 1.38 (s, 9H), 2.85—2.92 (m, 1H), 3.20—3.25 (m, 1H), 3.44—3.48 (m, 1H), 3.65— Yield # Compound Name 3.70 (m, 2H), 4.01—4.28 (m, 2H), 5.63—5.66 (m, 1H), 7.16 (s, 1H),7.21-7.31 (m, 2H), 7.36—7.40 (m, 1H), 7.53—7.55 (m, 1H), 7.66 (s, 1H) imidazo[5, 1 -a]isoind01—5 —y1)_ 1 _ (pyridinyl)ethan0ne 1H NMR 3.60 (dd, J = 10, 19.2Hz, 1H), 3.91 (dd, J = 3.2, 19.2Hz, 1H), 5.65 (dd, J = 3.2, Hz, 1H), 7.08 (s, 1H), 7.13—7.17 (m, 1H), 7.25—7.30 (m, 2H), 7.38—7.45 (m, 2H), 7.66 (s, 1H), 7.78—7.80 (m, 1H), 8.05 (d, J = 8 Hz, 1H), 8.51—8.53 (m, 1H) 2-(5H—imidazo[5, 1 -a]isoind01—5 —y1)_ 1 _ (pyridin-3 -y1)ethan0ne H NMR 3.57—3.67 (m, 1H), 3.80—3.95 (m, 1H), 6.01—6.05 (m, 1H), 7.27—7.73 (m, 6H), 8.29—8.36 (m, 1H), 8.61(s, 1H), 8.86 (d, J = 3 Hz, 1H), 9.18 (s, 1H) 2-(5H—imidazo[5, 1 -a]isoind01—5 —y1)_ 1 _ iny1)ethan0ne 1H NMR .49 (dd, J = 9.2, 18.8 Hz, 1H), 3.76 (dd, J = 3.6, , 1H), 5.83 (dd, J = 3.2, 9.2 Hz, 1H), 7.20 (s, 1H), 7.28—7.32 (m, 1H), 7.38—7.45 (m, 2H), 7.58—7.60 (m, 1H), 7.74—7.75(m, 2H), 7.81 (s, 1H), 8.84—8.86 (m, 2H) 2-(5H—imidazo[5, 1 -a]isoind01—5 -y1)— 1 — (triﬂuoromethyl)cyc10hexy1)ethan0ne H NMR 1.55—1.81 (m, 5H),_2.08—2.29 (m, 4H), 2.58-2.62 (m, 1H), 2.94 (dd, J = 9, 18 Hz, 1H), 3.22 (dd, J = 6, 18 Hz, 1H), 5.68 (dd, J = 6, 9 Hz, 1H), 7.18-7.57 (m, 5 H), 7.81 and 7.83 (two 8, 1H) Yield Compound 2—(6—ﬂuoro-5H—imidazo[5, l- a]isoindol—5—yl)— 1 —(4— 53 (triﬂuoromethyl)cyclohexyl)ethanone H NMR 1.51 1.83 (m, 6H), 1.952.21 (m, 3H), 2.58—2.62 (m, 1H), 2.79 (dd, J = 9, 18 Hz, 1H), 3.46—3.55 (m, 1H), 5.73—5.79 (m, 1H), 6.89—6.98 (m, 1H), 7.20—7.38 (m, 4H), 7.71 (s, 1H) 1—((cis)—4—(benzyloxy)cyclohexyl) (6—ﬂuoro—5H—imidazo[5, l—a]isoindol— -yl)ethanone H NMR 1.67—2.04 (m, 8H), 2.39—2.45 (m, 1H), 2.79 (dd, 1H, J = 18.6, 10.6 Hz), 3.50 (dd, 1H, J = 16.4, 2.4 Hz), 3.60—3.65 (m, 1H), 4.49 and 4.55 (two s, 1H), 5.76 (d, 1H, J = 8.8 Hz), 6.91—6.95 (m, 1H), 7.17 (s, 1H), 7.26—7.35 (m, 7H), 7.63 (s, 1H) Example 24 l-(Cyclohex-3 -enyl)(6-ﬂuoro-5H-imidazo[5, l -a] isoindol-5 -yl)ethanone F F PTSA OH O —> ‘ /N3 716 /N3 0 71 (270 mg, 0.86 mmol) was ved in benzene (7 mL) and p—toluenesulfonic acid (444 mg, 2.58 mmol) was added. The reaction mixture was heated at 100 CC for 48 h and concentrated. The residue was basiﬁed with aqueous potassium carbonate on (5 mL).

The aqueous solution was extracted with ethyl e (2 x 20 mL). The combined organic layers were washed with water, brine, dried over NaZSO4, ﬁltered and concentrated. The residue was puriﬁed by ﬂash column chromatography to afford the title compound 155 as yellow gel (218 mg, 86%). 1H NMR: .71 (m, 1H), 1.88—2.40 (m, 5H), 2.62—2.67 (m, 1H), 2.74—2.87 (m, 1H), 3.47—3.58 (m, 1H), 5.66—5.75 (m, 3H), 6.91 (t, 1H, J= 8.9 Hz), 7.15 (s, 1H), 7.26—7.35 (m, 2H), 7.62 (d, 1H, J= 9.8 Hz).

Example 25 General Procedure for the Reduction of imidazo[5,l-a]isoindol yl)ethanones to 2-(5H-imidazo[5, l-a]isoindolyl)ethanols.

X\\ X\\ \ / \ / R R N N HO / O ,) / /) N N To a solution of the appropriate ketone (9-18, 47-72, 136-153, 155, 1256, 1287, 1300, 1306, 1326, 1328, 1334, 1348 or 1353) (0.25 mmol) in MeOH (2 mL) at 0 0C, was added NaBH4 (0.75 mmol) and the solution was allowed to stir for l h. The solvent was removed under reduced pressure and 2M HCl (2 mL) was added to the crude. The solution was allowed to stir for 10 min and was made basic by satd. K2CO3 solution. The aqueous layer was extracted with CH2C12 (3 x 5 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure to afford the crude residue. The crude was purified by column chromatography using 1—10% MeOH:DCM nt to afford the following compounds.

Yield Compound Name 2-(6-chloro-5H-imidazo[5, l - a] isoindolyl)— l -cyclohexylethanol 1H NMR (a mixture of diastereomers) 0.96—1.35 (m, 6H), 1.60—1.86 (m, 5H), 2.10 (m, 1H), .69 (m, 1H), 3.58—3.69 (m, 1H), 5.31 and 5.59 (two dd, 1H, J]: 6.0 Hz, 2.80 Hz, J2 = 10.4 Hz, 2.80 Hz), .19 (m, 2H), 7.28 (m, 1H), 7.41 (t, 1H, J: 5.4 Hz), 7.82 and 7.94 (two s, 1H) l-cyclohexyl(5H-imidazo[5, l - N OH a] isoindolyl)ethanol 1304 N 1H NMR (a mixture of reomers) 1.10—1.37 (m, 6H), 1.66—1.80 (m, 5H), 2.05 (m, 2H), 2.15 (m, 1H), 3.72 (m, 1H), 5.36 and 5.46 (two m, 1H), 7.16 (s, 1H), 7.25 (m,lH), 7.34 (m, 1H), 7.43 (d, 1H, J: 7.6 Hz), 7.54 (d, 1H, J: 7.6 Hz), 7.80 (s, 1H) Yield # Compound Name (I)- o”N+ O O 2—(5H—imidazo[5,1—a]isoindol—5—y1)—1— (2-mtropheny1)ethanol N OH 1327 I /> 1H NMR (a mixture of diastereomers) 2.29 (m, 1H), 2.61 (m, 1H), 5.44 (m, 1H), 5.71 (dd, 1H, J: 9.0 Hz, 4.5 Hz), 7.08 (s, 1H), 7.27 (m, 2H), 7.34 (m,1H), .53 (m, 3H), 7.68 (m, 1H), 7.95 (m, 2H) 0 ON+O- 2-(5H-imidazo[5,1-a]isoindoly1)-1— I N) OH ('3' (3-nitropheny1)ethanol 1307 N 1H NMR (a mixture of diastereomers) 2.32-2.40 (m, 1H), 2.48—2.58 (m, 1H), 5.06—5. 11 (m, 1H), 5.41 and 5.61 (two m, 1H), 7.09 (s, 1H), 7.30—7.43 (m, 2H), 7.48—7.57 (m, 3H), 7.64—7.72 (m, 2H), 8.12—8.19 (m, 2H) tert-butyl hydroxy(5H— o[5,1-a]isoindol—5— 50 y1)ethy1)pheny1)carbamate 1329 H NMR (a mixture of diastereomers) 1.50 and 1.55 (two 5, 9H), 2.50 and 2.78 (two m,. . 2H), 5.02 and 5.07 (two m, 1H), 5.19 and 5.56 (two m, 1H), 6.93—7.02 (m, 2H), 7.12 (d, 1H, J: 8.0 Hz), 7.24 (m, 2H), 7.36 (m, 2H), 7.49 (d, 1H, J: 7.6 Hz), 7.71 (br s, 1H), 7.80 and 7.85 (two 5, 1H, J= 8.0 Hz), 8.12 and 8.45 (two 5, 1H) O O \ﬂ/OK tert—butyl (4—(1—hydroxy—2—(5H— imidazo[5,1-a]isoindol—5— 81 N> OH I y1)ethy1)pheny1)carbamate 1302 / 1H NMR (a mixture of diastereomers) 1.50 (s, 9H), 2.28—2.41 (m, 2H), 4.98—5.03 (m, 1H), 5.25 and 5.55 (two m, 1H), 6.55 and 6.61 (two 5, 1H), 7.12—7.54 (m, 7H), 7.66 and 7.78 (two 5, 1H) WO 42237 Yield Compound Name go”W0 tert-butyl (3-(1 -hydroxy(5H- imidazo[5, 1 a—jlisoindol—5— 52 N OH I / y1)ethy1)pheny1)carbamate 1367 ON> 1H NMR (a e of diastereomers) (MeOH—d4) 1.51 (s, 9H), 2.33—2.57 (m, 2H), 4.93— 4.96 (m, 1H), 5.36 and 5.49 (two m, 1H), 7.00—7.06 (m, 2H), 7.19—7.40 (m, 4H), 7.48 (s, 1H), 7.53—7.57 (m, 2H), 7.72 (s, 1H) 0 O imidazo[5,1-a]isoindoly1) N OH phenylethanol 1349 l /> H NMR (a mixture of diastereomers) 2.30 (m, 1H), 2.41 (m, 1H), 5.08 (m, 1H), 5.31 (m, 1H), 7.08 (m, 1H), 7.20—7.51 (m, 9 H), 7.63 (s, 1H). tert-butyl 4-(1-hydroxy(5H— imidazo[5,1—a]isoindol—5— 83 I N> OH y1)ethy1)piperidinecarboxy1ate 1363 1H NMR (a mixture of diastereomers) 1.26 (m, 2H), 1.44 (s, 9 H), 1.47-1.59 (m, 2H), 1.76 (m, 1H), 206—2.11 (m, 1H), 2.14—2.20 (m, 1H), 2.64 (m, 2H), 3.73 and 3.80 (two m, 1H), 4.16 (m, 2H), 5.37 and 5.51 (two m, 1H), 7.16 (s, 1H), 7.22 (m, 1H), 7.32—7.41 (m, 2H), 7.54 (d, 1H, J: 4.0 Hz), 7.79 and 7.81 (two 5, 1H) 1—cyclohexy1—2—(6—ﬂuoro—5H— 85 OH imidazo[5,1-a]isoindoly1)ethanol 1357 1H NMR (a mixture of diastereomers) 0.98—1.39 (m, 6H), 1.65—1.79 (m, 5H), .07 (m, 1H) 2.34—2.50 (m, 2H), 3.54—3.73 (m, 1H), 5.46 and 5.67 (two dd, 1H, J; =, 3.0, 8.0 Hz, J2 = 3.0, 10.4 Hz), 6.93 (t, 1H, J: 8.0 Hz), 7.17 (d, 1H, J: 7.17 Hz), 7.30—7.37 (m, 2H), 7.82, 7.88 (two 5, 1H) Yield # Compound Name 2-(7-chloro-5H-imidazo[5,1- OH a]isoindoly1)—1-cyclohexy1ethanol I NV} 1359 1H NMR (a mixture of diastereomers)1.00-1.28 (m, 5H), 1.37—1.40 (m, 1H), 1.66—2.01 (m, 5H), .0 (m, 1H) 2.12—2.23 (m, 1H), 3.71—3.75 (m, 1H), 7.15 (s, 1H), 7.33 (d, 1H, J: 8.0 Hz), 7.45 (d, 1H, J: 8.0 Hz), 7.79, 7.82 (two 5, 1H) 1-cyclopenty1—2-(5H—imidazo[5,1- / '1) HO a]isoindoly1)ethanol 1362 1H NMR (a mixture of diastereomers) 1.11-1.41 (m, 2H), .70 (m, 4H), 1.83—2.17 (m, 4H), 3.74—3.79 (m, 1H), 5.38, 5.49 (one t and one d, 1H, J]: 6.0 Hz, J2 = 6.0 Hz), 7.18 (s, 1H), 7.25 (d merged with CHC13, 1H), 7.38 (t, 1H, J: 7.2 Hz), 7.46 (d, 1H, J = 7.6 Hz), 7.55 (d, 1H, J: 7.6 Hz), 7.84 (s, 1H) 1—(cyclohex— 1 -en- 1 —y1)(5H- I N> imidazo[5,1-a]isoindoly1)ethanol 1375 H NMR (a mixture of diastereomers) 1.47—1.68 (m, 3H), 1.73—1.82 (m, 1H), 1.93—2.14 (m, 4H), 2.18—2.22 (m, 1H), 2.33—2.40 (m, 2H), 4.36 (t, 1H, J: 7.0 Hz), 5.26, 5.44 (onet and one dd, 1H, J2 = 6.0 Hz, J2 = 10.0 Hz), 5.71, 5.72 (two 5, 1H), 7.15, 7.18 (two, 5, 1H), 7.2—7.26 (m, 1H), 7.34, 7.38 (two d, 1H, J]: 6.8 Hz, J2 = 7.27 Hz), 7.43 (d, 1H, J: 7.6 Hz), 7.54 (d, 1H, J: 7.6 Hz), 7.81, 7.86 (two 5, 1H) 1-(3 opheny1)(5H—imidazo[5 ,1- a]1somdol—5—y1)ethanol 1343 / 3 HO 1H NMR (a mixture of diastereomers) 2.18-2.52 (m, 2H), 5.25—5.40 (m, 1H), 5.46—5.60 (m, 1H), 7.07 (s, 1H), 7.15—7.55 (m, 7H), 7.69 (d, 1H, J: 8.0 Hz), 7.79 (s, 1H) 2012/033245 Yield Compound Name 1-(2-chloropheny1)(5H—imidazo[5 1- / HO a]isoindoly1)ethanol 1336 N 1H NMR (a mixture of diastereomers) 2.20—2.50 (m, 2H), 5.0—5.08 (m, 1H), 5.26—5.38 (m, 1H), 7.05 (s, 1H), 7.20—7.45 (m, 7H), 7.45 (d, 1H, J: 7.6 Hz), 7.52 (d, 1H, J: 7.6 Hz) 7.68 (s, 1H) 2-(8-chloro-5H-imidazo[5,1- N OH a] isoindoly1)— 1 -cyclohexy1ethanol 1374 / /> 1H NMR (a mixture of reomers) (MeOH—d4) 1.00—2.30 (m, 13H), 3.60—3.70 (m, 1H), 5.35 and 5.50 (two m, 1H), 6.95—7.08 (m, 1H), 7.16—7.88 (m, 4H) 1—cyclohexy1—2—(8—ﬂuoro—5H— / N> OH o[5,1-a]isoindoly1)ethanol 1376 N “H NMR (a mixture of diastereomers) (MeOH—d4) 1.00—2.30 (m, 13H), 3.50—3.57 (m, 1H), 5.35 and 5.50 (m, 1H), 7.18—7.50 (m, 3H), 7.60—7.65 (m, 1H), 7.92 and 7.98 (two 5, F ;> 2—(6—ﬂuoro-5H—imidazo[5, 1- a]isoindolyl)(1,4— 90 / 3 OH dioxaspiro[4.5]decan-8—y1)ethanol 1378 1H NMR (a mixture of diastereomers) (MeOH—d4) 1.31-1.52 (m, 5H), 1.60—1.63 (m, 1H), 1.71—1.78 (m, 3H), 1.86—2.07 (m, 1H), 2.43—2.48 (m, 1H), 3.48—3.64 (m, 1H), 3.90 (s, 4H), .57 and 5.69 (two m, 1H), 7.00—7.06 (m, 1H), 7.18 (d, 1H, J = 11.6 Hz), 7.41—7.44 (m, 2H), 7.94—8.00 (m, 2H) 2012/033245 Yield Compound Name 2-(5H-imidazo[5,1-a]isoindoly1) / N (tetrahydro-2H-pyrany1)ethanol 1358 1H NMR (a mixture of diastereomers)1.39-1.51 (m, 2H), 1.59—1.65 (m, 1H), 1.71—1.75 (m, 1H), 2.11—2.17 (m, 1H), 3.32—3.39 (m, 3H), 3.69—3.73 (m, 1H), .05 (m, 3H), .39 and 5.49 (two m, 1H), 7.17 (s, 1H), 7.23—7.28 (m, 1H), 7.33—7.44 (m, 2H), 7.55 (d, 1H, J: 8 Hz), 7.84 (s, 1H) \O 1-cyclohexy1(9-methoxy-5H— / N imidazo[5,1-a]isoindoly1)ethanol 1372 H NMR (a mixture of diastereomers) (CD3OD) 1.05-1.11 (m, 1H), 1.13-1.33 (m, 4H), .81 (m, 5H), 2.01—2.08 (m, 1H), 3.57 and 3.67 (two m, 1H), 3.95 (s, 3H), 5.40 and .47 (two m, 1H), 6.81 and 6.83 (two d, 1H, J= 8 Hz), 6.90 and 6.97 (two d, 1H, J= 7.6 Hz), 7.04 and 7.05 (two 5, 1H), 7.12—7.17 (m, 1H), 7.92 and 7.99 (two 5, 1H). 1-(2,5-dimethy1furan-3 -y1)(6—ﬂuoro— 5H—imidazo[5,1-a]isoindol—5— 81 anol 1352 1H NMR (a mixture of diastereomers)1.89—1.96, 2.37—2.45, 2.53—2.59, 2.77—2.83 (four m, 2H), 2.11, 2.17 (s, 3H), 2.20, 2.22 (two 5, 3H), 4.79—4.88 (m, 1H), 5.36—5.68, 5.63—5.64 (two m, 1H), 5.94, 5.97 (two 5, 1H), 6.87—6.97 (m, 1H), 7.15, 7.21 (two 5, 1H), 7.32—7.38 (m, 2H), 7.74, 7.88 (two 5, 1H) O 2-(6-ﬂuoro-5H—imidazo[5, 1 - 1393 \ 88 N a] isoindol-5 -y1)(furany1)ethanol Yield # Compound Name 1H NMR (a mixture of diastereomers)1.99—2.06, 2.36—2.43 (two m, 1H), 2.77—2.80, 2.92— 2.98 (two m, 1H), 3.72 (d, 1H, J: 11.0 Hz), 5.02—5.08 (m, 1H), 5.39—5.40, 5.67—5.69 (two m, 1H), 6.27 (t, 1H, J: 6.4 Hz), 6.31 (s, 1H), 6.93 (s, 1H, J: 9.2 Hz), 7.08 (d, 1H, J: 12.2 Hz), 7.26—7.36 (m, 2H), 7.77, 7.86 (two 5, 1H) 2—(6—ﬂuoro-5H—imidazo[5, 1- OH a]isoindoly1)—1-(1-methy1—1H- 81 / N / N / imidazoly1)ethanol 1394 N N— 1H NMR (a e of diastereomers)2.43-2.51, 2.81—2.85, 2.99—3. 15 (three m, 2H), 3.69 (s, 3H), 5.00—5.08 (m, 1H), 5.38—5.40, 5.67—5.69 (two m, 1H), 6.77 (s, 1H), 6.79 (s, 1H), 6.91 (t, 1H, J: 8.9 Hz), 7.07 (s, 1H), 7.28—7.33 (m, 2H), 7.79 (s, 1H) \ S 2-(5H—imidazo[5,1-a]isoindol-5—y1)—1— / HO (thiazoly1)ethanol 1390 N 1H NMR(a mixture of reomers)2.14-2.21, 2.49—2.58, 2.68—2.82 (m, 2H), 5.23—5.53 (m, 2H), 7.11 (s, 1H), 7.21 (s, 1H), 7.25-7.28 (m, 1H, overlap with CHC13), 7.37 (t, 1H, J = 7.5 Hz), 7.47—7.54 (m, 2H), 7.74 (s, 1H), 8.79 (s, 1H) 1-(4,4-diﬂuorocyclohexy1)(5H— / N imidazo[5,1-a]isoindoly1)ethanol N?! F 1407 1H NMR (a mixture of diastereomers)1.26—1.36 (m, 3H), 1.63—1.97 (m, 5H), .08 (m, 3H), 3.69—3.72 (m, 1H), 5.02 and 5.12 (two d, 1H, J= 6.0 Hz), 5.34—5.53 and 5.41— .43 (two m, 1H), 7.10 and 7.12 (two 5, 1H), 7.25 (t, 1H, J= 7.4 Hz), 7.36 (t, 1H, J= 7.4 Hz), 7.54—7.58 (m, 2H), 7.91 and 7.93 (two 5, 1H —diﬂuorocyclohexy1)—2—(6—ﬂuoro— 5H—imidazo[5,1—a]isoindol—5— 78 y1)ethanol 1H NMR (a mixture of diastereomers) d6): 1.21-1.29 (m, 3H), 1.56-1.72 (m, 4H), 1.88—1.96 (m, 3H), 2.28 and 2.32 (two t, 1H, J= 5Hz), 3.41—3.44 and 3.62—3.65 (two m, 1H), 4.73 and 5.17 (two d, 1H, J= 8.2 Hz), 5.56—5.59 and 5.61—5.64 (two m, 1H), 7.03— 7.17 (m, 2H), 7.39—7.44 (m, 2H), 7.91 and 7.95 (two 5, 1H) ‘ 1—(cyclohex—3—eny1)—2—(6-ﬂuoro-5H- imidazo[5 ,1-a]isoindol-5 -y1)ethanol 1414 1H NMR (a mixture of diastereomers)1.21-1.42 (m, 2H), 1.62-1.83 (m, 4H), 1.93—2.15 (m, 7H), 2.30—2.44 (m, 1H), 2.6 (br s 3.67—3.72 (m, 1H), 3.77—3.82 (m, 1H), 5.49 (q, , 1H), 1H, J: 5.3 Hz), 5.64—5.70 (m, 3H), 6.92—6.96 (m, 2H), 7.16—7.19 (m, 2H), 7.31—7.38 (m, 3H), 7.77—7.79 (m, 1H), 7.88 (d, 1H, J: 3.6 Hz), 7.91 (s, 1H) imidazo[5, 1 -a]isoindoly1)— 1 — (4-methy1enecyclohexy1)ethanol H NMR (a mixture of diastereomers)1.11-1.20 (m, 2H), 1.49-1.55 (m, 1H), 1.74—1.78 (m, 1H), 1.90—2.10 (m, 4H), 2.16—2.23 (m, 1H), 2.31—2.38 (m, 2H), 3.74—3.77 and 3.80— 3.85 (two m, 1H), 4.62 (d, 2H, J= 0.8 Hz), 5.37 and 5.48(t and dd, 1H, J= 6 Hz and J= 3 Hz, 10.4 Hz), 7.18 (s, 1H), 7.23 (dd, 1H, J= 1.2 Hz, 7.6 Hz), 7.37 (t, 1H, J= 7.6 Hz), 7.43 (d, 1H, J= 7.6 Hz), 7.55 (d, 1H, J= 7.6 Hz), 7.77 and 7.79 (two 5, 1H) uoro-5H—imidazo[5, 1- a]isoindoly1)—1—(1,4— 90 dioxaspiro[4.5]decany1)ethanol N HO 1381 H NMR (a mixture of diastereomers) (CD3OD) .00 (m, 2H), 1.3 8—1.60 (m, 1H), 1.70—1.80 (m, 1H), 1.87—2.09 (m, 6H), 3.30—3.34 and 3.53—3.78 (two m, 1H), 5.56—5.58 and 5.69—5.71 (two m, 1H), 7.00—7.04 (m, 1H), 7.42 and 7.62 (m and s, 2H), 7.93 and 8.00 (two 5, 1H) 2012/033245 Yield Compound Name 2—(6—ﬂuoro-5H—imidazo[5, 1- a]isoindol—5—yl)—1—(4— 68 methylcyclohexy1)ethanol 1387 H NMR (a mixture of diastereomers)0.81—0.95 (m, 3H), 1.20—1.83 (m, 10H), 1.85—2.03 (m, 1H), 2.35—2.52 (m, 1H), 3.45—3.80 (m, 1H), .60 and 5.65—5.71 (two m, 1H), .06 (m, 1H), 7.14 and 7.18 (two 5, 1H), 7.30—7.42 (m, 2H), 7.93 and 7.98 (two 5, 2—(6—ﬂuoro-5H—imidazo[5, 1- ' a]isoindol—5—yl)—1—(4— 77 / /N HO (iodomethylene)cyclohexy1)ethanol 1398 N 1H NMR (a mixture of diastereomers)0.92-1.45 (m, 2H), 1.54-1.76 (m, 2H), 1.80-2.11 (m, 3H), 2.33—3.10(m, 4H), 3.59—3.90 (m, 1H), 4.60 (s, 1H), 5.45—5.81 (m, 1H), 6.91—6.95 (m, 1H), 7.16 (s, 1H), 7.26—7.31 (m, 2H), 7.81—7.83 (m, 1H) 2—(9—ﬂuoro-5H—imidazo[5,1- F a]isoindol—5—y1)—1—(4— 35 / N ,) HO cyclohexy1)ethanol 1413 N H NMR (a mixture of reomers) ) 0.75—0.96 (m, 3H), 1.00—1.25 (m, 1H), 1.28—1.74 (m, 9H), 2.01—2.14(m, 2H), 3.67—3.80 (m, 1H), 5.49—5.59 (m, 1H), 7.10—7.18 (m, 2H), 7.60—8.00 (m, 1H) F 2—(6—ﬂuoro-5H—imidazo[5, 1- a]isoindoly1)(4-(propan-2— / N) HO ylidene)cyclohexy1 N/ )ethanol 1411 H NMR (a mixture of diastereomers)1.01-1.06 (m, 2H), 1.46—1.57 (m, 2H), 1.63 (s, 6H), 1.68—1.75 (m, 2H), 1.82—1.96 (two m, 1H), 2.03—2.11 (m, 1H), 2.32—2.39 (two m , 1H), 2.45—2.51 and 2.66—2.75 (two m, 2H), 3.65—3.75 (m, 1H), 5.44—5.65 (two m, 1H), 6.91 (t, 1H, J= 8.7 Hz),7.16 and 7.17 (two 5, 1H), 7.28—7.36 (m, 2H), 7.80 and 7.87 (two 5, 1H) Yield # Compound Name F 1—(4— / (cyclopropylmethylene)cyclohexy1)—2— / N (6—ﬂuoro—5H—imidazo[5,1-a]isoindol- N/ 5—y1)ethanol 1410 H NMR(a mixture of diastereomers)0.24 (s, 2H), 0.65 (d, 2H, J = 7.4 Hz), 1.12-1.20 (m, 2H), 1.44—1.54 (m, 2H), 1.71—2.03 (m, 6H), 2.34—2.54 (two m ,1H), 2.72—2.84 (m, 1H), 3.63—3.80 (m, 1H), 4.48 (d, 1H, J: 9.0 Hz), 5.43—5.67 (two m, 1H), 6.81—6.94 (m, 1H), 7.15 (s, 1H), .30 (m, 3H), 7.80 and 7.88 (two 5, 1H) NJS< 1—(4—(1—hydroxy—2—(5H—imidazo[5,1— a] isoindol-5 -y1)ethy1)piperidiny1)- 77 / '1) HO 2,2-dimethy1propanone 1392 H NMR(a mixture of reomers)1.24 (s, 9H), 1.28 (m, 2H), 1.60 (m, 2H), 2.13—1.86 (m, 3H), 2.70 (m, 2H), 3.78 (m, 1H), 4.46 (m, 2H), 5.53 and 5.38 (two m, 1H), 7.12 (s, 1H), 7.21 (m, 1H), 7.33 (m, 1H), 7.42 (d, 1H, J: 7.5 Hz), 7.52 (d, 1H, J: 7.5 Hz), 7.81 and 7.79 (two 5, 1H), \ 2—(6—ﬂuoro-5H—imidazo[5, 1- \:7LN ahyﬁndthad}1{1qnmhyL1hL 44 / AN HO ol—5—y1)ethanol 1409 1H NMR(a mixture of diastereomers)1.92-2.42 (three m, 1H), 2.72-3.10 (three m, 1H), 3.72 (s, 3H), 4.90—5.10 (three m, 1H), 5.42—5.76 (three m, 1H), 6.77—6.92 (m, 2H), 7.07 and 7.13 (two 5, 1H), 7.25—7.37 (m, 3H), 7.82, 7.88 and 7.94 (three 5, 1H) N=\ 2-(5H-imidazo[5,1-a]isoindoly1) \ N\ (1-methy1—1H—1m1dazoly1)ethanol. . 1389 H NMR (a mixture of diastereomers)2.01, 2.51, 2.67 (three m, 2H), 3.61 (s, 3H), 5.09 and 5.00 (two m, 1H), 5.53 and 5.33 (two m, 1H), 6.75 and 6.70 (two 5 7.11 , 1H), (s, 1H), 7.25—7.16(m, 2H), 7.32 (m, 1H), 7.37 (s, 1H), 7.49 (t, 1H, J= 7.80 Hz), 7.88 and 7.67 (two 5, 1H), Yield # nd Name :WN imidazo[5,1-a]isoindoly1) / 3 (thiazoly1)ethanol 1391 N 1H NMR (a mixture of diastereomers)1.84, 2.03, 2.45, 2.51, 2.66, (ﬁve m, 2H), 5.29 5.41, .55 (three m, 2H), 7.06—7.28 (m, 2H), 7.37 (t, 1H, J: 7.5 Hz), 7.41 (d, 1H, J: 7. 5H2), 7.52 (d, 1H, J: 7.5 Hz), 7.71, 7.73 (two 5, 1H), 7.83 (s, 1H), 8.70, 8.71 (two 5, 1H), 0 1-(4-(1-hydroxy(5H-imidazo[5, 1- N a] isoindoly1)ethy1)piperidin 93 / 5 HO y1)ethanone 1385 1H NMR (a mixture of diastereomers) 1.28 (m, 2H), 1.62 (m, 2H), 1.83 (m, 1H), 2.04 and 2.06 (two 5, 3H), 2.19 (m, 1H), 2.47 (t, 1H, J: 12.4 Hz), 3.00 (t, 1H, J: 13.1 Hz), 3.74 (m, 1H), 3.84 (t, 1H, J: 15.5 Hz), 4.68 (d, 1H, J: 14.6 Hz), 5.37 and 5.51 (two m, 1H), 7.15 (s, 1H), 7.23 (m, 1H), 7.39 (m, 2H), 7.54 (d, 1H, J: 7.5 Hz), 7.80 (s, 1H) N%S (4-(1-hydroxy(5H—imidazo[5, 1- a] isoindoly1)ethy1)piperidin 72 y1)(thiopheny1)methanone 1384 W 1H NMR (a mixture of diastereomers)1.39 (m, 2H), 1.66 (m, 2H), 2.07 (m, 1H), 2.17 (m, 1H), 2.89 (m, 2H), 3.76 (m, 1H), 5.37 and 5.51 (m, 1H), 7.01 (t, 1H, J: 4.3 Hz), 7.16 (s, 1H), 7.24 (m, 2H), 7.31—7.40 (m, 3H), 7.54 (d, 1H, J: 7.6 Hz), 7.81 (s, 1H) 1-(4-(1-hydroxy(5H-imidazo[5,1- a]isoindoly1)ethy1)piperidiny1) 68 / '1) HO phenylethanone 1405 N 1H NMR(a mixture of diastereomers)1.00-2.25 (m, 6H), 2.47 (t, 1H, J = 9.8 Hz), 2.47 (t, 1H, J: 9.8 Hz), 2.89 (t, 1H, J: 12.0 Hz), 3.70 (m, 3H), 3.90 (t, 1H, J: 12.6 Hz), 3.90 (t, 1H, J: 12.3 Hz), 5.25—5.50 (m, 1H), 7.10—7.30 (m, 9H), 7.36 (t, 1H, J: 9.6 Hz), 7.53 (d, 1H, J: 7.8 Hz) Yield Compound Name 3? 1—Cyclohexy1(5H—imidazo[5, 1- / N a]isoind01-5 -y1)pr0pan—2—01 1404 N/ HO H NMR(a mixture of diastereomers)0.8085 (m, 14H), 2.00—2.20 (m, 1H), 4.20—4.50 (m, 1H), 5.30—5.60 (m, 1H), 7.14 (s, 1H), 7.20—7.39 (m, 2H), 7.43 (d, 1H, J: 7.2 Hz), 7.43 (d, 1H, J: 7.2 Hz), 7.91 (s, 1H) 1—cyclohexy1—3—(6—ﬂu0r0—5H— imidazo[5,1-a]isoind01y1)pr0pan—2— 55 9’ 01 1403 N HO H NMR (a mixture of reomers)0.55—1.75 (m, 13H), 2.00—2.50 (m, 2H), . 10 (m, 1H), 5.30—5.75 (m, 1H), 6.85—7.00 (m, 1H), 7.10—7.25 (m, 2H), 7.25—7.40 (m, 2H), 7.93 (s, 1H) 1-cyclohexy1(5H-imidazo[5,1- / N a]isoind01y1idene)ethan01 1419 1H NMR mixture ofE/Z isomers: 1.15-1.30 (m, 10H), 1.66—1.83 (m, 10H), 2.00—2.12 (m, 2H), 4.56 (t, 1H, J = 6.4 Hz), 4.66 (d, 1H, J = 7.4 Hz), 6.02 (d, 1H, J = 8.3 Hz), 6.76 (s, 1H), 7.07 (s, 1H), 7.33—7.48 (m, 4H), 7.56 (d, 2H, J = 7.8 Hz), 7.82 (s, 1H), 7.98 (d, 1H, J = 7.9 Hz), 8.04 (s, 1H), 8.42 (s, 1H). (tranS)-methy1 4-((1R)—1-hydr0xy (5H—imidazo[5, 1—a]isoind01—5— 87 y1)cyclohexanecarboxylate 1426 H NMR (a mixture of diastereomers) 1.05 — 1.20 (m, 2H), 1.42 (qt, J = 12.7, 4.0 Hz, 3H), 1.63 — 1.82 (m, 1H), 1.92 — 2.10 (m, 4H), 2.11 — 2.31 (m, 2H), 3.65 (s, 3H), 3.72 — 3.83 (m, 1H), 5.36 (t, J: 6.2 Hz, 0.7H), 5.52 (dd, J=10.8, 3.1 Hz, 0.3H), 7.14 (s, 1H), 7.23 (t, J: 7.4 Hz, 1H), 7.31 — 7.40 (m, 1H), 7.42 (d, J: 7.7 Hz, 1H), 7.53 (d, J: 7.6 Hz, 1H), 7.83 (s, 1H) Yield # Compound Name 2-(5H—imidazo[5, 1 -a]isoindoly1)— 1 - N) HO / (spiro[2.5]octany1)ethanol 1438 1H NMR (a mixture of diastereomers) 0.14-0.28 (m, 4H), 0.89 (t, 2H, J = 12.0 Hz), 1.19— 2.938(m, 9H), 2.81 (br s, 1H), 3.80—3.82 (m, 1H), 5.36—5.39 and 5.50—5.53 (two m, 1H), 7.16 (s, 1H), 7.21—7.25 (m, 1H), 7.33 (t, 1H, J = 7.6 Hz), 7.44 (d, 1H, J = 7.6 Hz), 7.53 (d, 1H, J = 7.6 Hz), 7.80 and 7.81 (two s, 1H ) (trans)—4—(2—(6—ﬂuoro-5H—imidazo[5, 1- a]isoindol—5-y1)—1— 92 / N OH 9I hydroxyethy1)cyclohexanol HO H 1475 N H NMR (a mixture of diastereomers) 1.07-2.52 (m, 11H), 3.48—3.68 (two m, 2H), 5.45 (t, 1H, J = 6.0 Hz), 5.65 (dd, 1H, J = 9.0, 3.0 Hz), .96 (m, 1H), 7.16 (s, 1H), 7.29— 7.38 (m, 2H), 7.80 and 7.88 (two s, 1H) F (1R)((trans)—4— H OCHZPh (benzyloxy)cyclohexy1)—2—(6—ﬂuoro— N 5H—imidazo[5,1—a]isoindol—5— / ) HO N/ y1)ethanol 1499 1H NMR (a mixture of diastereomers) 1.04-1.33 (m, 5H), 1.71—2.32 (m, 5H), 2.75—2.51 (two m, 1H), 3.24—3.29 (m, 1H), 3.65—3.69 (m, 1H), 4.54 (s, 2H), 5.43 (t, 1H, J =4.7 Hz, isomer), 5.65 (dd, 1H, J = 10.4, 2.4 Hz, isomer), 6.92 (t, 1H, J = 8.8 Hz), 7.14 (s, 1H), 7.26—7.33 (m, 7H), 7.79 and 7.88 (two s, 1H) -((trans)—4— H OCH Ph2 loxy)cyclohexyl)—2—(5H— 78 HO imidazo[5,1-a]isoindoly1)ethanol 1498 /N/) H NMR (a mixture of diastereomers) 1.15-2.20 (m, 11H), 3.22—3.31 (m, 1H), 3.65—3.75 (m, 1H), 4.48 and 4.54 (two s, 2H), 5.35 (t, 1H, J = 8.0 Hz, ), 5.48 (dd, 1H, J = 16.0, 4.0 Hz, isomer), 7.15—7.55 (m, 10H), 7.77 and 7.79 and 7.81 (three s, 1H) Yield # Compound Name N—((CiS)—4—(1—hydroxy—2—(5H— >—ph imidazo[5,1—a]isoindol—5— 63 / N NH y1)cyclohexy1)benzam1de. g] HO H 1492 1H NMR (a mixture of diastereomers) (CD3OD) 1.27—1.46 (m, 5H), 1.79 (d, 1H, J = 12.0 Hz), 2.04—2.22 (m, 5H), 3.78—3.88 (m, 2H), 5.47—5.49 and 5.53—5.54 (two m, 1H), 7.16 and 7.19 (two 5, 1H), 7.35 (t, 1H, J= 7.4 Hz), 7.42—7.49 (m, 3H), 7.53 (d, 1H, J= 7.2 Hz), 7.59 (d, 1H, J= 7.6 Hz), 7.64 (d, 1H, J= 7.6 Hz), 7.82 (d, 2H, J= 7.6 Hz), 7.97 and 8.01 (two 5, 1H) N—((trans)—4—(1-hydroxy(5H— imidazo[5,1-a]isoindol—5— 57 y1)ethy1)cyclohexy1)benzamide 1505 H NMR (a mixture of diastereomers) 1.14-1.45 (m, 4H), 1.74 (d, 1H, J = 10.6 Hz), 1.97 (d, 1H, J: 10.6 Hz), 2.09—2.20 (m, 4H), 3.71—3.82 (m, 1H), 3.85—3.95 (m, 1H), 5.3—5.40 and 5.48—5.59 (two m, 1H), 6.03 (d, 1H, J= 7.6 Hz), 7.17 (s, 1H), 7.21—7.30 (m, 1H, merged with chloroform), 7.31—7.51 (m, 5H), 7.55 (d, 1H, J= 7.4 Hz), 7.74 (d, 2H, J= 7.6 Hz), 7.83 (s, 1H) 1—(4—(2— OH hydroxyethylidene)cyclohexy1)—2—(5H— 59 / 5 HO imidazo[5,1-a]isoindoly1)ethanol 1441 H NMR (a mixture of diastereomers) 1.00-1.30 (m, 2H), 1.40-1.60 (m, 1H), 1.62—1.81 (m, 2H), 1.82—2.13 (m, 3H), 2.60—2.75 (m, 1H), 3.60—3.75 (m, 1H), 3.90—4.10 (m, 2H), .25—5.31 (m, 1H), 5.33—5.48 (m, 1H), 7.13 (s, 1H), .43 (m, 2H), .60 (m, 2H), 7.97 (s, 1H) 0 tert—butyl 3—(1—hydroxy(5H— 1460 N40 imidazo[5,1—a]isoindol—5— 43 / A HO k y1)ethy1)azetidinecarboxy1ate 1H NMR (a mixture of diastereomers) 1.42 (s, 9H), 1.92—2.23 (m, 2H), 2.50—2.63 (m, 1H), 3.61—3.80 (m, 2H), 3.90—4.02 (m, 3H), 4.20—4.58 (br, 1H), 5.33—5.41 and 5.52—5.58 (two m, 1H), 7.13 (s, 1H), 7.21—7.28 (m, , 7.30—7.39 (m, 1.33H), 7.41—7.48 (m, 0.8H), 7.58 (d, J = 14.3 Hz, 1H), 7.93 and 7.99 (two 5, 1H) / \ 2-(5H—imidazo[5,1-a]isoindoly1)—1- / 5 N’ (pyridiny1)ethanol 1502 N 1H NMR (a mixture of diastereomers) 2.25—2.33 (m, 2H), 5.06—5.07 (m, 1H), 5.09 (br s, 1H), .38 and 5.46—5.49 (two m, 1H), 7.02 (s, 1H), 7.13—7.24 (m, 4H), 7.44—7.48 (m, 2H), 7.57—7.62 (m, 2H), 8.46—8.47 (m, 1H) %2-(5H—imidazo[5, 1 -a]isoindoly1)— 1 — 69 / 5 (pyridin-3 -y1)ethanol 1474 N 1H NMR (a e of diastereomers) 1.75—2.43 (m, 2H), 5.07—5.12 (m, 1H), 5.38—5.40 and 5.56—5.58 (two m, 2H), 6.98 and 7.11 (two 5, 1H), 7.19—7.33 (m, 3H), 7.43—7.49 (m, 2H), 7.43—7.79 (m, 2H), 83—851 (m, 2H) N 2-(5H—imidazo[5, 1 -a]isoindoly1)— 1 — N / (pyridiny1)ethanol 1501 /N/) H NMR (a mixture of diastereomers) 1.98—2.32 (m, 2H), 3.59 (br, 1H), 5.03—5.06 (m, 1H), 5.42—5.45 and .58 (two m, 1H), 7.20—7.23 (m, 1H), 7.24—7.25 (m, 4H), 7.34 (t, J = 7.0 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 8.44—8.46 (m, 2H) 2-(5H—imidazo[5, 1 -a]isoindoly1)— 1 - (4-(triﬂuoromethy1)cyclohexy1)ethanol 1509 /;I\1 CF3 1H NMR (a mixture of diastereomers) 1.53-2.22 (m, 12H), 3.92-3.98 (m, 1H), 4.12 (br s, 1H), 5.39—5.43 and 5.50—5.60 (two m, 1H), 7.14 (s, 1H), 7.23—7.54 (m, 5H), 7.94 (s, 1H) Yield # Compound Name 2—(6—ﬂuoro-5H-imidazo[5, 1 - a]isoindol—5—y1)—1—(4— 61 / /) HO (triﬂuoromethy1)cyclohexyl)ethanol 1508 N H NMR (a e of diastereomers) 1.40-1.70 (m, 7H), 1.70—1.90 (m, 2H), 1.91—2.04 (m, 1H), 2.09—2.28 (m, 1H), 2.38—2.48 (m, 1H), 3.80—3.98 (br, 2H), 5.43—5.71 (two m, 1H), .94 (m, 1H), 7.14 (s, 1H), 7.29—7.38 (m, 2H), 7.93 and 7.97 (two 5, 1H) 1—((cis)—4—(benzyloxy)cyclohexy1) OCHZPh (6-ﬂuoro-5H—imidazo[5,1—a]isoindol— 87 —y1)ethanol 1473 1H NMR (a mixture of diastereomers) 1.39-2.42 (m, 12 H), 3.39—3.78 (m, 2H), 4.47 and 4.48 (two 5, 2H), 5.44 (t, 1H, J = 5.1 Hz), 5.67 (dd, 1H, J = 10.2, 2.8 Hz), 6.88—6.94 (m, 1H), 7.25—7.36 (m, 8H), 7.80, 7.82, 7.88 and 7.90 (four 5, 1H) Example 26 Preparation of 1469-1472 0 0 N40% N40% / 3 OH / S (5H N/ N/ 1469 1470 .m NJ?0% ..\\ NJ? /N 2:0 /N QH/C/ 0% N) N) 1471 1472 The pure diastereomers were obtained from the racemic mixture of 1363 using preparative chiral ritical ﬂuid chromatography (SFC) technique, using a AD-H column (Regis Technologies, Inc.) in methanol:COz (24:76).

Example 27 General Procedure for the Removal of Boc ting Group n N’Boc * _, * n NH.HC| / N N) HO n /N/) HO n .HCI n=Oor1 n=Oor1 To a solution of the appropriate Boc ted amine 1363, 1469, 1470, 1471, 1472 or 1460 (1.13 mmol) in dichloromethane (10 mL) was added triﬂuoroacetic acid (33.8 mmol). The resulting solution was stirred at RT for 2 h and concentrated. The crude was dissolved in methanol (4 mL) and hydrogen chloride (4M in dioxane) (3.39 mmol) was added. The mixture was concentrated and dried under high vacuum to give the desired product as a dihydrochloride salt which was directly used in the next step without r puriﬁcation.

Example 28 General Procedure for the Synthesis of 1423, 1424, 1425, 1437, 1439, 1448, 1450, 1458, 1480, 1481, 1490, 1493, 1500 and 1511 Using HATU Coupling. .. nNH.HCI , .. nN’/< /NHO N) n /N )HO n .HCI n=Oor1 n:00r1 To a vial containing appropriate amine salt obtained from Example 27 (0.25 mmol) in DMF (4 mL) was added the ponding carboxylic acid (0.26 mmol), DIPEA (1.5 mmol) and HATU (0.28 mmol). The reaction e was stirred at rt for 18 h and poured into water (10 mL) and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), dried over , and concentrated.

The crude product was puriﬁed by ﬂash column chromatography to afford 1423, 1424, 1425, 1437, 1439, 1448, 1450, 1458, 1480, 1481, 1490, 1493 or 1500.

Example 29 General Procedure for the synthesis of 1449, 1459, 1476, 1477, 1478 and 1479. * nNH.HCI * nN/K //) N HO n //) H HO n N N .HCI n=Oor1 n=oor1 To a Vial containing appropriate amine salt obtained from Example 19 (0.25 mmol) in dichloromethane (4 mL) was added DIPEA (1.0 mmol) and phenylisocyanate (0.25 mmol).

The reaction mixture was stirred at rt for 30 min and concentrated. The residue was ved in romethane (30 mL) and washed with water (3 x 10 mL). The c layer was dried over NaZSO4 and concentrated. The crude product was purified by ﬂash column chromatography to afford ureas 1449, 1459, 1476, 1477, 1478 and 1479.

Example 30 General Procedure for the Synthesis of 1495, 1496, 1497, 1503, 1504, 1507, 1512. * n NH.HC| * n N4 R / N W ,) H0 n /) HO n N N/ .HCI “=00“ n=Oor1 To a solution of appropriate amine (0.3 mmol) in CHzClz (3 mL) was added carbonyldiimidazole (0.35 mmol) and ethyl diisopropylamine (2.0 mmol) at 0 0C under an atmosphere of N2 and the mixture was stirred for 1 h. The appropriate amine salt obtained from Example 19 (0.25 mmol) was added and the mixture was d to stir overnight. The solution was partitioned with water in a separatory funnel and the organic layer was collected. The s layer was extracted with dichloromethane (3 x 10 mL) and the combined organic fractioned were dried (NaZSO4). The crude was puriﬁed by ﬂash column chromatography to afford 1495, 1496, 1497, 1503, 1504 or 1507.

Yield # Compound Name D 1—(4—(1—hydroxy—2—(5H— \ N o[5,1—a]isoindol—5— N 76 N yl)ethy1)piperidiny1) /N) HO (pyrimidiny1)ethanone 1H NMR (a mixture of diastereomers) 1.30-1.41 (m, 3H), 1.63-1.72 (m, 2H), 1.87—2.22 1423 (m, 2H), 2.56 (t, 1H, J = 12.4 Hz), 3.01—3.15 (m, 2H), 3.67 (d, 1H, J = 6.0 Hz), 3.83—3.85 (m, 1H), 3.96 (t, 1H, J = 14.6 Hz), 4.66 (t, 1H, J = 14.6 Hz), 5.44—5.46 and 5.62—5.65 (two m, 1H), 7.17 and 7.19 (two 5, 1H), 7.26—7.30 (m, 1H, merged with chloroform), 7.39 (t, 1H, J = 7.4 Hz), 7.46 (d, 1H, J = 7.6 Hz), 7.56 (d, 1H, J = 7.2 Hz), 8.14 (d, 1H, J = 13.2 Hz), 8.63 (d, 2H, J = 4.4 Hz), 9.08—9.10 (m, 1H) 2—(3 ,4-diﬂuoropheny1)— 1 -(4-(1- hydroxy(5H—imidazo[5, 1- a]isoindol-5 —y1)ethy1)piperidin— 1 - yl)ethanone 1424 H NMR (a e of diastereomers) .33 (m, 2H), 1.61-1.64 (m, 3H), 1.84—1.92 (m, 1H), .15 (m, 1H), 2.53 (t, 1H, J =12.8 Hz), 2.98 (t, 1H, J = 12.8 Hz), 3.67 (d, 2H, J = 4.0 Hz), 3.76—3.78 (m, 1H), 3.90 (t, 1H, J = 13.6 Hz), 4.19 (br s, 1H), 4.70 (t, 1H, J = 13.6 Hz), 5.32—5.36 and 5.49—5.53 (two m, 1H), 6.94 (s, 1H), 7.06—7.13 (m, 2H), 7.14 (s, 1H), 7.24—7.30 (m, 1H), 7.34—7.42 (m, 2H), 7.56 (d, 1H, J = 6.8 Hz), 7.81—7.85 (m, cyclohexy1(4-(1-hydroxy(5H— N imidazo[5,1-a]isoindol 44 / 5 HO yl)ethy1)piperidiny1)methanone 1425 1H NMR (a mixture of diastereomers) 1.20—1.34 (m, 6H), .77 (m, 10H), 1.87-1.97 (m, 1H), 2.03—2.08 (m, 1H), 2.16—2.20 (m, 1H), 2.46 (t, 2H, J = 12.0 Hz), 3.76—3.79 (m, 1H), 3.97 (t, 1H, J = 16.2 Hz), 4.70 (t, 1H, J = 14.2 Hz), 5.38—5.41 and 5.51—5.56 (two m, 1H), 7.15 (s, 1H), 7.23-7.27 (m, 1H, merged with chloroform), 7.37 (t, 1H, J = 7.8 Hz), 7.44 (d, 1H, J = 7.6 Hz), 7.54 (d, 1H, J = 7.6 Hz), 7.79 and 7.82 (two 5, 1H) 2012/033245 # Yield Compound Name l—(4—(l —hydroxy—2—(5H— N/(Q/N imidazo[5,1—a]isoindol—5— yl)ethyl)piperidinyl)—2- 49 idineyl)ethanone 1437 1H NMR (a mixture of diastereomers) 1.08—1.16 (m, 1H), .33 (m, 1H), 1.57—1.65 (m, 2H), 1.86 (t, 1H, J = 14.0 Hz), 1.99—2.17 (m, 2H), 2.52 (dt, 1H, J = 2.4, 12.8 Hz), 2.97 (dt, 1H, J = 4.0, 12.8 Hz), 3.70 (d, 2H, J = 7.2 Hz), 3.70-3.76 (m, 1H, merged with doublet at 3.70), 3.83 (t, 1H, J = 13.8 Hz), 4.30 (br s, 1H), 4.69 (t, 1H, J = 14.0 Hz), 5.32— .36 and 5.51—5.53 (two m, 1H), 7.10 and 7.12 (two 5, 1H), 7.16—7.25 (m, 3H), 7.35—7.41 (m, 2H), 7.54 (d, 1H, J = 7.6 Hz), 7.76 (d, 1H, J = 4.4 Hz), 8.49—8.52 (m, 2H) 2-(4-ﬂuorophenyl)- 1-(4-(1- y(5H—imidazo[5, 1- N a]isoindol—5 —yl)ethyl)piperidin— 1— N/ HO yl)ethanone 1H NMR (a mixture of diastereomers) 1.08-1.13 (m, 1H), 1.23—1.30 (m, 1H), 1.54—1.63 1439 (m, 2H), 1.78 and 1.86 (two d, 1H, J = 13.0 Hz), 1.99—2.12 (m, 2H), 2.49 (dt, 1H, J = 2.4, 12.8 Hz), 2.93 (dt, 1H, J = 3.0, 12.8 Hz), 3.66 (d, 2H, J = 4.4 Hz), 3.71—3.73 (m, 2H, merged with broad singlet of OH), 3.90 (t, 1H, J = 15.2 Hz), 4.68 (t, 1H, J = 13.6 Hz), .30—5.37 and 5.47—5.50 (two m, 1H), 6.94—7.00 (m, 2H), 7.13 (s, 1H), 7.15—7.20 (m, 2H), 7.22-7.31 (m, 1H, merged with chloroform), 7.35—7.41 (m, 2H), 7.54 (d, 1H, J = 7.6 Hz), 7.84 (d, 1H, J = 5.2 Hz) (3—ﬂuoro—2—h-ydroxyphenyl)(4(1— hydroxy(5H—imidazo[5, 1- a]isoindol—5 y—l)ethyl)piperidin— 1— yl)methanone 1448 1H NMR .47 (m, 2H), 1.66—1.70 (m, 2H), 1.86—2.15 (m, 7H), 2.89 (m, 1H), 4.31 (br s, 1H), 5.43-5.47 and 5.53-5.59 (two m, 1H), 6.78-6.84 (m, 1H), 6.99 (d, 1H, J = 7.6 Hz), 7.11 (t, 1H, J = 9.4 Hz), 7.19 (s, 1H), 7.33 (d, 1H, J = 7.2 Hz), 7.37-7.47 (m, 2H), 7.58 (d, 1H, J = 7.2 Hz), 8.03 and 8.13 (two 5, 1H) 2012/033245 Yield Compound Name 4-(1-hydroxy-2—(5H—imidazo[5, 1- a]isoind01—5—y1)ethy1)—N— 62 phenylpiperidinecarb0xamide 1449 1H NMR (CD3OD) 1.33—1.43 (m, 2H), 1.59—1.71 (m, 2H), 1.92—1.95 (m, 1H), 2.10—2.22 (m, 2H), 2.87 (t, 2H, J = 11.8 Hz), 3.79—3.83 (m, 1H), 4.25 (t, 2H, J = 15.2 Hz), 5.48 and 552—555 (t, J = 6.0 Hz and m, 1H), 7.03 (t, 1H, J = 7.4 Hz), 7.16 and 7.19 (two 5, 1H), 7.28 (t, 2H, J = 8.0 Hz), 7.33—7.37 (m, 3H), 7.43 (t, 1H, J = 7.4 Hz), 7.62 (dd, 2H, J = 7.6, 21.6 Hz), 7.94 and 7.97 (two 5, 1H), 8.01 (s, 1H) 0 (4-ﬂuorophenyl)(4-(1-hydroxy-2— (5H—imidazo[5,1—a]isoind01—5- 29 /N/) OH yl)ethy1)piperidiny1)methan0ne 1450 F H NMR 1.29—1.37 (m, 3H), 1.57—1.87 (m, 3H), 2.18—2.36 (m, 2H), 3.73—3.86 (m, 4H), 4.74 (br s, 1H), 5.44—5.49 and 5.58—5.63 (two m, 1H), 7.08 (t, 2H, J = 7.2 Hz), 7.23 (s, 1H), 7.31—7.48 (m, 5H), 7.59 (d, 1H, J = 7.2 Hz), 8.20 an d 8.27 (two 5 , 1H) 1—(3 —(1—hydroxy—2—(5H— imidazo[5,1—a]isoind01—5— N 55 /N/ yl)ethy1)azet1d1ny1)-2—. .

N phenylethanone 1458 1H NMR (a mixture of diastereomers)1.79-2.13 (m, 2H), 2.44-2.48 (m, 1H), 3.33—3.42 (m, 2H), 3.67—3.93 (m, 2H), 3.97—4.04 (m, 2H), 4.12—4.19 (m, 1H), 5.23—5.31 and 5.34— 542 (two m, 1H), .37 (m, 9H), .48 (m, 1 H), 7.93 and 8.07 (two d, J = 7.6 Hz, 1H) 3 -(1-hydroxy-2—(5H—imidazo[5, 1- 1459 ndoly1)ethy1)—N— 19 phenylazetidinecarb0xamide Yield # Compound Name 1H NMR (a mixture of diastereomers) 1.95-2.20 (m, 2H), 2.64—2.68 (m, 1H), 3.76—3.81 (m, 1H), 3.98—4.10(m, 4H), .46 and 5.51—5.57 (two m, 1H), 6.97—7.14 (m, 1H), 7.22 and 7.24 (two 8, 1H), 7.26-7.38 (m, 3.3H), 7.40-7.42 (m, 3H), 7.57-7.62 (m, 1.7H), 7.99 and 8.00 (two 8, 1H) O 4—((S)—1—hydroxy—2—((R)—5H— N4N@ imidazo[5,1-a]isoindol—5—yl)ethyl)— 67 / H 9 OH N—phenylpiperidine-l-carboxamide 1476 H NMR .41 (m, 2H), 1.51—1.57 (m, 1H), 1.61 (d, 1H, J = 12.4 Hz), 1.83 (d, 1H, J = 12.4 Hz), 2.00—2.14 (m, 2H), 2.78 (t, 2H, J = 12.0 Hz), 3.74—3.76 (m, 1H), 4.15—4.18 (m, 2H), 4.42 (br s, 1H), 5.32 (t,1H, J = 6.0 Hz), 6.98 (t, 1H, J = 7.4 Hz), 7.15 (d, 2H, J = 14.4 Hz), 7.20—7.25 (m, 3H), 7.35—7.37 (m, 3H), 7.40 (d, 1H, J = 7.6 Hz), 7.52 (d, 1H, J = 7.6 Hz), 7.86 (s, 1H) 4—((R)—1—hydroxy—2—((R)—5H— imidazo[5,1-a]isoindolyl)ethyl)— 78 N—phenylpiperidinecarboxamide 1477 1H NMR 1.15—1.61 (m, 6 H), 1.86 (d, 1H, J = 12.8 Hz), 2.17—2.22 (t, 1H, J = 11.2 Hz), 2.66—2.75 (m, 2H), 3.68—3.76 (m, 1H), 4.04—4.08 (m, 2H), 4.60 (br,2H), 5.47 (d, 1H, J = 8.8 Hz), 6.86—6.90 (t, 1H, J = 11.2 Hz), 6.94 (s, 1H), 7.09—7.31 (m, 7H), 7.45 (d, 1H, J = 7.2 Hz), 8.24 (s, 1H) 4—((R)—1—hydroxy—2—((S)—5H— imidazo[5,1-a]isoindoly1)ethy1)— 74 N-pheny1piperidinecarboxamide 1478 H NMR .61 (m, 4H), 1.81 (d, 1H, J =12.5 Hz), 2.01—2.15 (m, 2H), 2.77 (t, 2H, J = 12.4 Hz), 3.68—3.73 (m, 1H), 408—4. 14 (m, 2H), 5.31 (t, 1H, J = 4.0 Hz), 6.92 (s, 1H), 6.97 (t, 1H, J = 6.0 Hz), 7.12 (s, 1H), 7.21—7.38 (m, 6H), 7.51 (d, 1H, J = 7.4 Hz), 7.87 (s, Yield 4—((1S§— 1 —hydroxy—2—((S)—5H— imidazo[5,1-a]isoind01—5-y1)ethy1)— 78 N-pheny1piperidinecarb0xamide 1H NMR 1.15—1.61 (m, 6 H), 1.86 (d, 1H, J = 12.8 Hz), 2.17—2.22 (t, 1H, J = 11.2 Hz), 2.66—2.75 (m, 2H), .76 (m, 1H), 4.04—4.08 (m, 2H), 4.60 (br,2H), 5.47 (d, 1H, J = 8.8 Hz), 6.86—6.90 (t, 1H, J = 11.2 Hz), 6.94 (s, 1H), 7.09—7.31 (m, 7H), 7.45 (d, 1H, J = 7.2 Hz), 8.24 (s, 1H) 1—(4—((R)—1—hydroxy—2—((S)—5H— imidazo[5,1—a]isoind01—5— N WVC/NW5 . . . 1 y1)2 / ) yl)ethy1)p1perld1n_ _ _ _ N/ phenylethanone 1H NMR 10—214 (m, 8H), 2.46 (t, 1H, J = 12 Hz), 2.91 (t, 1H, J =12 Hz), 3.65—3.72 (m, 3H), 3.91 (t, 1H, J =16 Hz), 4.71 (t, 1H, J = 12 Hz), 7.15—7.56 (m, 9H), 7.55 (d, 1H, J = 7.51 Hz), 7.91 (d, 1H, J = 7.7 Hz) 1—(4—((S)—1—hydroxy—2—((1S§—5H— ”HE/0NW imidazo[5,1—a]isoind01—5— N y1)p1perld1n. . . / _ 1 y1)2_ _ _ /) OH N phenylethanone 1H NMR 1.04—1.27 (m, 2H), 1.51—1.67 (m, 3H), 1.81—1.89 (m, 1H), 2.19—2.25 (m, 1H), 2.46—2.52 (m, 1H), 2.90 (t, 1H, J = 12.8 Hz), .74 (m, 3H), 3.90 (t, 1H, J = 16.0 Hz), 4.62—4.70 (m, 1H), 5.23 (br s, 1H), 5.49 (dd, 1H, J = 2.2, 10.2 Hz), 7.12 (s, 1H), 7.18— 7.37 (m, 8H), 7.53 (d, 1H, J = 7.5 Hz), 7.92 (d, 1H, J = 3.0 Hz) O 1-(4-((S)—1—hydroxy—2—((S)—5H— ...uﬁ/C/NW0 imidazo[5,1—a]isoind01—5— / 5 yl)ethy1)piperidiny1)—2- N (tetrahydro-2H-pyranyl)ethan0ne Yield # nd Name 1H NMR (CD3OD) 5 1.06 —1.46 (m, 4H), 1.56 — 1.73 (m, 3H), 1.82 — 2.08 (m, 3H), 2.32 (t, J: 6.4 Hz, 2H), 2.39 (dd, J: 18.4, 7.2 Hz, 1H), 2.54 (t, J= 13.0 Hz, 1H), 3.03 (t, J= 12.9 Hz, 1H), 3.40 (t, J: 11.7 Hz, 2H), 3.48— 3.59 (m, 1H), 3.90 (d, J= 11.5 Hz, 2H), 3.94 — 4.06 (m, 1H), 4.57 (t, .1: 14.8 Hz, 1H), 5.71 (d, .1: 6.5 Hz, 1H), 7.41 —7.52 (m, 2H), 7.55 (d, .1: 7.3 Hz, 1H), 7.73 (d, .1: 7.1 Hz, 1H), 7.90 (s, 1H), 8.57 (s, 1H) 1—(4—((S)—1—hydroxy—2—((R)—5H— NW imidaz0[5,1—a]isoind01—5— N yl)ethy1)p1perld1n. . . / _ 1 y1)2_ _ _ /) OH N phenylethanone 1493 1H NMR 0.49—1.21 (m, 4H), 1.44—1.56 (m, 1H), .05 (m, 2H), 2.38—2.47 (m, 1H), 2.80—2.86 (m, 1H), 3.58—3.64 (m, 2H), 3.83 (t, J = 13.2 Hz, 1H), 4.62 (t, J = 13.2 Hz, 1H), .25—5.30 (m, 1H), 7.13—7.24 (m, 7H), 7.29—7.34 (m, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.94 (br s, 1H) 4—((R)—1—hydroxy—2—((S)—5H— O imidaz0[5,1-a]isoind01—5-y1)ethy1)— .1” N4 "‘OH N N—((tranS)—4— 56 N _ / A : H OH hydroxycyc10hexy1)piperidine carboxamide 1495 H NMR (CD3OD) 1.21—1.43 (m, 7H), 1.48—1.66 (m, 2H), .01 (m, 5H), 2.14 (ddd, 2H, J: 4.4, 8.4, 10.4 Hz), 2.71 (t, 2H, J: 11.7 Hz), 3.49—3.55 (m, 2H), 3.74—3.79 (m, 1H), 4.08 (t, 1H, J: 13.6 Hz), 5.46 (t, 1H, J: 6.2 Hz), 7.16 (s, 1H), 7.34 (t, 1H, J: 7.5 Hz), 7.43 (t, 1H, J: 7.3 Hz), 7.57 (d, 1H, J: 7.6 Hz), 7.64 (d, 1H, J: 7.6 Hz), 8.00 (s, 0 4—((S)—1—hydroxy—2—((S)—5H— ...uYC/N”(N/CO imidaz0[5,1—a]isoind01—5-y1)ethy1)— H N (tetrahydro 2H pyran 4 / 5 _ _ _ _ _ N yl)piperidinecarb0xamide 1496 1H NMR 1.16—1.74 (m, 6H), 1.78— 2.00 (m, 2H), 2.18 — 2.37 (m, 1H), 2.70 (t, J= 12.7 Hz, 2H), 3.33 — 3.51 (m, 2H), 3.71— 4.13 (m, 5H), 4.76 (d, J= 7.4 Hz, 1H), 5.54 (dd merged with br s, J= 10.6, 2.3 Hz, 3H), 7.13 (s, 1H), 7.20 — 7.38 (m, 3H), 7.51 (d, J= 7.5 Hz, 1H), 7.90 (s, 1H) Yield # Compound Name 4—((S)—1—h—ydroxy2—((S)—5H— NAN0’ imidazo[5, 1 a—jlisoindoly1)ethy1)- N—((tranS)—4— 65 [5)N/> hydroxycyclohexy1)piperidine carboxamide 1497 1H NMR 1.08 — 1.44 (m, 6H), 1.57 (t,J= 12.5 Hz, 2H), 1.67— 1.80 (m, 1H), 1.90 (dd,J = 24.8, 9.8 Hz, 4H), 2.29 (ddd, J = 14.3, 11.0, 3.1 Hz, 1H), 2.69 (t, J = 12.8 Hz, 2H), 3.35 (s, 1H), 3.49 (d, J = 4.4 Hz, 2H), 3.63— 3.77 (m, 1H), 3.95— 4.19 (m, 2H), 5.50 (dd, J = 9.7, 3.0 Hz, 1H), 6.05 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H), 7.31 (td, J = 7.5, 1.0 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, (R)—1—hydroxy—2—((S)—5H— ”\fC/NJz/CO imidazo[5,1-a]isoindol—5— /N) y1)ethy1)piperidiny1) (tetrahydro-2H—pyrany1)ethanone 1500 H NMR 1.19—1.42 (m, 4H), .67 (m, 4H), 1.86—1.90 (m, 1H), 2.08—2.25 (m, 4H), 2.43—2.51 (m, 1H), 2.92—3.01 (m, 1H), 3.39 (t, 2H, J = 11.8 Hz), 3.72—3.76 (m, 1H), 3.90— 3.99 (m, 3H), 4.70 (m, 1H, J = 9.75 Hz), 5.35—5.40 (m, 1H), 7.13 (s, 1H), .27 (m, 1H), 7.35—7.43 (m, 2H), 7.54 (d, 1H, J = 7.4 Hz), 7.80 (s, 1H) 4—((R)—1—hydroxy—2—((S)—5H— “VON/“’00 imidazo[5,1—a]isoindol—5—y1)ethy1)— / 5 (5H H N—(retr'th‘ydro—2H—pyran y1)p1per1d1necarboxam1de 1H NMR1.29—1.33(m, 1H), 1.41—1.47 (m, 2H), 1.51—1.61(m, 1H), 1.62 (d, 1H, J: 12.7 1503 Hz), 1.83 (d, 1H, J: 12.4 Hz), 1.91 (d, 2H, J: 12.4 Hz), 2.07—2.26 (m, 2H), 2.73 (t, 2H, J: 12.2 Hz), 3.46 (t, 2H, J= 10.8 Hz), 3.73-3.78 (m, 1H), 3.81-3.89 (m, 1H), 3.93-4.05 (m, 4H), 4.40 (d, 1H, J: 7.5 Hz), 4.61 (br s, 2H), 5.41 (t, 1H, J= 5.9 Hz), 7.18 (s, 1H), 7.24—7.30 (m, 1H, merged with chloroform), 7.39 (t, 1H, J= 7.5 Hz), 7.44 (d, 1H, J= 7.6 Hz), 7.56 (d, 1H, J= 7.6 Hz), 7.92 (s, 1H) Yield # Compound Name N—cyclohexy1—4—((R)—1—hydroxy—2— ((S)—5H—imidazo[5, 1—a]isoind01—5— 77 yl)ethy1)piperidinecarb0xamide 1H NMR 0.97—1.23 (m, 3H), 1.26—1.36 (m, 4H), 1.48—1.70 (m, 5H), 1.82 (d, J: 13.1 Hz, 1504 1H), 1.93 (d, J: 10.3 Hz, 2H), 2.07 (ddd, J: 14.3, 6.8, 2.7 Hz, 1H), 2.14 — 2.27 (m, 1H), 2.70 (td, J: 12.8, 2.5 Hz, 2H), 3.57—3.65 (m, 1H), 3.71 — 3.81 (m, 1H), 3.97 (t, J: 13.2 Hz, 2H), 4.31 (d, J: 7.6 Hz, 1H), 5.39 (t, J: 6.0 Hz, 1H), 7.16 (s, 1H), 7.24 (dd, J: 7.6, 1.0 Hz, 1H), 7.37 (t, J: 7.4 Hz, 1H), 7.43 (d, J: 7.6 Hz, 1H), 7.55 (d, J: 7.6 Hz, 1H), 7.80 (s, 1H) N—cyclopenty1—4—((R)—1—hydroxy-2— H—imidazo[5, 1 —a]isoind01—5— 87 1507 yl)ethy1)piperidinecarb0xamide ER"I“ 1—(4—((R)—1—hydroxy—2—((S)—5H— NWCFa imidazo[5,1-a]isoind01—5— 69 N = / y1)piperidiny1)(4- N/ (triﬂuoromethy1)pheny1)ethan0ne 1511 H NMR 1.03 — 1.26 (m, 2H),1.28 — 1.39 (m, 2H), 1.56 (q, J: 13.9, 13.1 Hz, 2H), 1.75 (d, J: 13.0 Hz, 1H), 1.91 — 2.10 (m, 2H), 2.45 (t, J: 13.4 Hz,1H), 2.90 (t, J=13.0 Hz, 1H), 3.68 (d, J: 6.5 Hz, 2H), 3.83 (t, J: 13.9 Hz, 1H), 4.59 (t, J: 11.5 Hz, 1H), 4.94 (br s, 1H), 5.35 (q, J: 6.6 Hz, 1H), 7.06 (d, J: 7.6 Hz, 1H), 7.21 — 7.40 (m, 5H), 7.42 — 7.56 (m, 3H), 8.16 (d, J: 17.3 Hz, 1H). 4—((R)— 1——hydroxy2—((S)—SH— 1512 ijVC/N/qms/Q/CF imidazo[5,1 a—jlisoindolyl)ethy1)— (SH N—(4-(triﬂuoromethyl)phenyl) piperidinecarb0xamide 1H NMR 1.15—1.61 (m, 6 H), 1.86 (d, 1H, .1: 12.8 Hz), 2.17—2.22 (t, 1H, .1: 11.2 Hz), 2.66—2.75 (m, 2H), 3.68—3.76 (m, 1H), 4.04—4.08 (m, 2H), 4.60 (br,2H), 5.47 (d, 1H, .1: 8.8 Hz), 6.86—6.90 (t, 1H, J= 11.2 Hz), 6.94 (s, 1H), 7.09—7.31 (m, 7H), 7.45 (d, 1H, J= 7.2 Hz), 8.24 (s, 1H) (4—((R)— l —hydroxy—2—((S)—5H— imidazo[5,1—a]isoindol—5— yl)ethyl)piperidinyl)(1H- imidazolyl)methanone 1513 H NMR 1.44—1.54 (m, 2H), 1.65—1.68 (m, 1H), 1.73 (d, 1H, J= 12.8 Hz), 1.98 (d, 1H, J = 13.0 Hz), 2.05—2.14 (m, 1H), 2.18—2.25 (m, 1H), 2.99 (t, 2H, J= 12.0 Hz), 3.82—3.87 (m, 1H), 4.16 (t, 2H, .1: 10.7 Hz), 4.80 (br s, 1H), 5.41 (t, 1H, J= 5.9 Hz), 7.07 (s, 1H), 7.14 (s, 1H), 7.18 (s, 1H), .28 (m, 1H, merged with chloroform), 7.38 (t, 1H, J= 7.5 Hz), 7.43 (d, 1H, J= 7.6 Hz), 7.55 (d, 1H, J= 7.6 Hz), 7.84 (s, 1H), 7.86 (s, 1H).

Example 31 1-( 1 -(benzylsulfonyl)piperidinyl)—2-(5H—imidazo [5 ,1-a]isoindol-5— yl)ethanol %CNHHCI N,§=o /N/) N O / /) HO HCI N 1442 To a Vial 2-(5H—imidazo[5,1-a]isoindolyl)(piperidinyl)ethanol ochloride (0.12 g, 0.34 mmol) in CHzClz (3 mL) was added ethyl diisopropylamine (0.35 mL, 2.0 mmol) and benzyl yl chloride (67 mg, 0.35 mmol). The reaction mixture was stirred at RT for 18 h and concentrated. The residue was dissolved in dichloromethane (30 mL) and washed with water (3 x 10 ml). The organic layer was dried over NaZSO4 and concentrated. The crude product was puriﬁed by ﬂash column chromatography to afford 1442 as white solid (85 mg, 58%).1H NMR (a mixture of diastereomers) 1.21-1.29 (m, 2H), 1.34-1.36 (m, 1H), 1.57—1.60 (m, 1H), 1.79—1.90 (m, 2H), .10 (m, 1H), 2.52—2.66 (m, 2H), .63 (m, 2H), 3.67— 3.71(m, 1H), 4.38 (s, 2H), 5.03 and 5.14 (two d, 1H, J = 6.0 Hz, OH), 5.39 (t, 1H, J = 6.8 Hz), 7.13 and 7.16 (two s, 1H), 7.29 (t, 1H, J = 7.2 Hz), 7.37-7.42 (m, 6H), 7.60 (dd, 2H, J = 7.8, 14.2 Hz), 7.92 and 7.95 (two s, 1H).

Example 32 2—(5H—imidazo[5,1—a]isoindol—5—yl)acetic acid OEt OH N O N O I ,9 I ,9 N N 1256 1258 To a solution of 1256 (0.41 mmol) in tetrahydrofuran (2 mL) at rt was added LiOH°H20 (0.45 mmol) and water (0.5 mL) the solution was stirred overnight. The solvent was distilled off and the crude was ved in methanol (1.5 mL) followed by the addition of ethyl acetate (2.5 mL), the precipitated white solid was filtered, washed with ethylacetate and dried under reduced pressure to afford 1258 (68 mg, 75%). 1H NMR: 2.10 (dd, 1H, J = 18.0 Hz, 9.0 Hz), 2.66 (dd, 1H, J= 15.0 Hz, 3.0 Hz), 5.43—5.47 (m, 1H), 7.05 (s, 1H), 7.20 (t, 1H, J= 9.0 Hz), 7.32 (t, 1H, J= 9.0 Hz), 7.50—7.54 (m, 2H), 7.90 (s, 1H).

Example 33 2-(5H—imidazo[5,1-a]isoindolyl)ethanol OEt 0“ N o ______,. N I ,9 | 9 N N 1256 1254 To a solution of 1256 (3.51 mmol) in a 1:2 mixture of THF:EtOH (24 mL) at rt, was added NaBH4 (12.28 mmol) and LiCl (12.28 mmol). After stirring overnight, the solvents were distilled off and the crude was diluted with satd. NH4Cl (20 mL). The s layer was extracted with CHzClz (3 x 40 mL). The combined organic extracts were dried over MgSO4 and the t distilled off under reduced pressure to afford a crude e. The crude product was purified by silica ﬂash chromatography to afford 1254 (638 mg, 91%). 1H NMR: 2.04—2.08 (m, 1H), .40 (m, 1H), 3.84 (t, 2H, J: 6.3 Hz), 5.37—5.41 (m, 1H), 7.17 (s, 1H), 7.25—7.28 (m, 1H), 7.35 (d, 1H, J= 6.90 Hz), 7.38 (d, 1H, J= 7.2 Hz), 7.54 (d, 1H, J= 7.5 Hz), 7.76 (s, 1H).

Example 34 2-(5H—imidazo[5,1-a]isoindolyl)-N-methylacetamide OEt N\ N O N O I —’ ,> I /> N N 1256 1259 To a solution of 1256 (0.124 mmol) in tetrahydrofuran (1.5 mL) at rt, was added the methylamine solution (1.24 mmol, 0.62 mL, 2M in THF) and the solution was stirred at 60 0C overnight. After cooling to rt the solvent was distilled off under reduced pressure and the crude was purified by column tography to afford 1259 (21 mg, 75%). 1H NMR: 2.43 (dd, 1H, J= 20.0 Hz, 12.8 Hz), 2.91 (d, 3H, J= 4.8 Hz), 2.94 (dd, 1H, J= 20.0 Hz, 6.0 Hz) .69 (dd, 1H, J=12.8 Hz, 5.60 Hz), 5.81 (br s, 1H), 7.13 (s, 1H), 7.22—7.26 (m, 1H), 7.33 (d, 1H, J= 8.4 Hz), 7.38 (d, 1H, J= 7.2 Hz), 7.53 (d, 1H, J= 7.80 Hz), 7.67 (s, 1H). e 35 2—(5H—imidazo[5,1—a]isoindol—5—yl)acetaldehyde \7 N\ OH \7\l _> \o 1254 74 To a solution of 1254 (0.5 mmol) in dichloromethane (5 mL) at 0 0C was added pyridinium chlorochromate (0.6 mmol) and the solution was allowed to warm to rt. After stirring for 4 h, the solvent was distilled off under d pressure and the crude was purified by column chromatography to afford 74 (63 mg, 64%). 1H NMR: 2.99 (dd, 1H, J = 7.5 Hz, 6.0 Hz), 3.28 (dd, 1H, J= 12.0 Hz), 5.61—5.65 (m, 1H), 7.18 (s, 1H), 7.26—7.30 (m, 1H), 7.32 (d, 1H, J= 6.0 Hz), 7.39 (t, 1H, J= 6.0 Hz), 7.55 (d, 1H, J= 6.0 Hz), 7.68 (s, 1H), 9.80 (s, 1H).

Example 36 (E)(2-bromostyryl)-5H—imidazo[5,1-a]isoindole \ O \ O N 74 1273 To a on of 74 (1.21 mmol) in tetrahydrofuran (4 mL) at -20 0C was added iPngCl°LiCl (1.21 mmol, 1.3 M in THF) se. After stirring for 1 h at -20 CC, 2-(5H— imidazo[5,1—a]isoindolyl)acetaldehyde was added as a solution in tetrahydrofuran (2 mL) and the reaction was allowed to warm to -10 0C. After stirring for 2 h at -10 0C the reaction was quenched by adding sat’d NH4Cl solution (2 mL) and water (2 mL). The aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic extract was dried over NaZSO4 and concentrated under reduced pressure to afford the crude reside. Chromatographic cation of the crude using MeOH (98:2) afforded 1273 (42 mg, 21%). 1H NMR .77 (d, 1H, J: 6.0 Hz), 6.26 (dd, 1H, J: 15.0 Hz, Hz, 6.0 Hz), 6.97 (d, 1H, J: 15.0 Hz), 7.13—7.17 (m, 2H), 7.26—7.33 (m, 2H), 7.47—7.65 (m, 5H).

Example 37 2-(5H—imidazo[5,1-a]isoindolyl)ethyl 2-(((1R,2R,5 S)isopropyl methylcyclohexyl)oxy)acetate \ 7“ OH 0 v“ —> \HAO E N O /\ l /> 1254 1288 To a solution of 1254 (110 mg, 0.55 mmol) in CHzClz at 0 °C was added diisopropylethylamine (110 mg, 0.824 mmol). The mixture was allowed to stir for 5 min and 2-(((1S,2S,5R)isopropylmethylcyclohexyl)oxy)acetyl chloride (129 mg, 0.55 mmol) was added. The solution was allowed to warm to rt and stirred for 4 h. The reaction mixture was diluted with water (10 mL) and the organic layer was collected. The aqueous layer was ted with CH2Clz (3 x 15 mL). The combined organic extract was dried (MgSO4) and concentrated under reduced pressure to afford the crude product. The crude residue was purified by ﬂash chromatography to afford 1288 (200 mg, 92%). 1H NMR: 0.77 (d, 3H, J = 3.0 Hz), .25 (m, 7H) 1.23—1.31 (m, 2H), 1.54-1.72 (m, 3H), 1.98-2.03 (m, 1H), 2.20- 2.28 (m, 2H), 2.50-2.54 (m, 1H), .14 (m, 1H), 3.97—4.15 (m, 2H), 4.27 (t, 2H, J: 4.5 Hz), 5.26—5.31 (m, 1H), 7.19 (s, 1H), 7.26—7.30 (m, 1H), 7.35 (d, 1H, J= 6.0 Hz), 7.39 (d, 1H, J= 6.0 Hz), 7.55 (d, 1H, J= 6.0 Hz), 7.75 (s, 1H).

Example 38 1-Cyclohexyl(5H—imidazo[5,1-a]isoindolyl)ethanamine and (E)—5-(2- CyclohexylVinyl)-5H-imidazo[5,1-a]isoindole WO 42237 1) DEAD, PPh3 phthalimide —> \ 2) NH NH 'H o / N N 2 2 2 (aN H N2 / Ho N» Na 1304 1388 1412 To a solution of triphenylphosphine (255 mg, 0.97 mmol) in THF (10 mL) at 0 CC was added phthalimide (143 mg, 0.97 mmol) and 1304 (250 mg, 0.885 mmol) followed by the se addition of DEAD (0.44 mL, 0.97 mmol). The reaction e was allowed to warm to room temperature and stirred overnight. The solvent was distilled off under reduced pressure, diluted with CHzClz (30 mL) and washed successively with 10% aq NaOH (2 x 15 mL), water and brine. The organic layer was dried (NaZSO4) and the solvent was evaporated under reduced pressure to afford an off—white solid. The solid was dissolved in EtOH (5 mL) and ine monohydrate (0.09 mL, 1.77 mmol) was added. The mixture was heated at 80 CC overnight. The solution was cooled to rt and the solvent was distilled off under reduced pressure. The crude was diluted with CHzClz (20 mL) and the organic phase was washed with water (10 mL). The organic layer was dried (NaZSO4) and the solvent was evaporated under reduced pressure to afford a crude residue that was ed by column chromatography to afford 1388 as a white solid (50 mg, 14%) and an eliminated side product 1412 (30 mg). 1388 1H NMR: 0.97—1.24 (m, 7H), 1.62—1.71 (m, 6H), 2.0 (m, 1H), 2.89 (m, 1H), 5.34 (dd, 1H, J= 8.4 Hz, 15.6 Hz), 5.38 and 5.49 (two m, 1H), 7.15 (s, 1H), 7.24 (m, 1H), 7.31—7.52 (m, 3H), 7.77 and 7.81 (two s, 1H). 1412 1H NMR: 1.11-1.28 (m, 5H), 1.55—1.75 (m, 5H), 2.01-2.11 (m, 1H), 5.47 (d, 1H, J= 8.0 Hz), 6.01 (dd, 1H, J= 6.8 Hz, 15.0 Hz), 7.18 (s, 1H), 7.26 (m, 2H), 7.36 (m, 1H), 7.52 (d, 1H, J= 7.6 Hz), 7.64 (s, 1H).

Example 39 4-(2-(6-fluoro-5H—imidazo[5, 1-a]isoindolyl) hydroxyethyl)cyclohexanone F F —» o / N A HO / /) HO N N 1378 1379 To a on of 1378 (186 mg, 0.52 mmol) in THF (5 mL) was added 2M HCl (5 mL) and the solution was stirred at room temperature overnight. The solvent was removed in vacuo and ing solution basiﬁed with 2M aqueous NaOH (6 mL) to pH > 8.0. The aqueous solution was extracted with dichloromethane (2 x 50 mL) and the combined organic layers were dried (NaZSO4) and concentrated in vacuo to give 1379 as a white solid (155 mg, 95%). 1H NMR: (CD3OD) 1.23—2.51 (m, 11H), 3.53—3.77 (m, 2H), 5.60—5.75 (m, 1H), 7.03—7.08 (m, 1H), 7.26—7.27 (m, 1H), 7.43—7.44 (m, 1H), 8.13 and 8.21 (two s, 1H).

Example 40 1-(4-(Hydroxymethyl)cyclohexyl)(5H—imidazo[5,1-a]isoindolyl)etanol (1383) 1) 2 2) OH / N aq. NaOH N 2 HO H202 //) H0 N N 1386 1383 To a solution of 1386 (121 mg, 0.41 mmol) in dry THF (10 mL) at 0 0C was added BH3° SMez (0.05 mL, 0.53 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight under an atmosphere of N2. The solution was diluted with water (10 mL) and cooled to 0 °C. 3M NaOH (0.55 mL, 1.64 mmol) and 30% (w/w) hydrogen de solution (0.19 mL, 1.64 mmol) were added sequentially. The on mixture was allowed to stir overnight at room temperatura. The aqueous layer was extracted with CHzClz (3 x 40 mL). The combined organic layers were 4) and concentrated under reduced pressure. The crude residue was puriﬁed by ﬂash column chromatography to afford 1383 as a white solid (45 mg, 35%). 1H NMR MeOH—d4: 1.20—1.78 (m, 11H), 2.02— 2.22 (m, 2H), 3.46—3.51 (m, 2H), 3.78—3.88 (m, 2H), .44 (m, 1H), 7.12 and 7.14 (two s, 1H), 7.27—7.46 (m, 2H), 7.52—7.61 (m, 2H), 7.92 and 7.95 (two s, 1H).

Example 41 1-(5H—imidazo[5,1-a]isoindolyl)methylpropanol (N —> N / Nlr/ 1256 1335 To a stirred solution of 1256 (48 mg, 0.20 mmol) in THF at 0 0C was added MeMgBr 1.0 M in THF (0.4 mL,) dropwise. The resulting solution was allowed to stir at rt for 2h. The reaction was quenched by the careful addition of methanol to the reaction mixture. The crude mixture was trated, absorbed in silica gel and purified by column chromatography to afford 1335 (24 mg, 52%). 1H NMR 1.43 (s, 3H), 1.49 (s, 3H), 2.05—2.30 (m, 2H), 5.30—5.35 (m, 1H), 7.14 (s, 1H), 7.20—7.40 (m, 3H), 7.52 (d, 1H, J: 9.6 Hz), 8.02 (s, 1H). e 42 4-(2-(6-Fluoro-5H—imidazo[5,1-a]isoindol-5 -yl)hydroxyethyl)cyclohexanol NaBH4 OH O —> /5 HO /N/)N HO 1379 1371 To a e of 1379 (38 mg, 0.12 mmol) in anhydrous MeOH at 0 0C, was added NaBH4 (0.36 mmol) and the solution was allowed to stir for 2 h at rt. The solvent was distilled off under reduced pressure and the residue was partitioned between CHzClz (15 mL) and satd. NH4C1 (5 mL). The organic layer was collected and the aqueous layer was extracted with CH2Clz (2 x 10 mL). The ed c extract was washed with brine, dried (NaZSO4) and the solvent evaporated. The crude was puriﬁed by column chromatography (25% MeOH in EtOAc) to afford 1371 (29 mg, 76%). 1H NMR MeOH—d4 (mixture of diastereomers): 1.00—1.40 (m, 5H), 1.40—2.10 (m, 5H), 2.37—2.47 (m, 1H), 3.39—3.57 (m, 2H), .54 and 5.72 (two m, 1H) 6.98—7.06 (m, 1H), 7.15-7.18 (m, , 1H), 7.37—7.42 (m, 2H), 7.93— 7.99 (m, 1H).

Example 43 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethanone oxime N N N O —> "‘q I /> I /> OH 86 1360 To a solution of 86 (160 mg, 0.57 mmol) in EtOH (3 mL) at rt was added 50% aq NHZOH (1.71 mmol) and the solution was stirred at 50 0C overnight. After cooling to rt, the solvent was removed under reduced re and the crude was puriﬁed by ﬂash column chromatography to afford 1360 (120 mg, 71%). 1H NMR .15 (m, 5 H), 1.45—1.72 (m, 6 H), 2.43 and 2.58 (two m, 1H), 2.70 and 2.91 (m, 1H), 4.69 (m, 1H), 7.23-7.29 (m, 3H), 7.40 and 7.46 (two m, 1H), 7.53 and 7.58 (two m, 1H), 7.75 and 7.76 (two s, 1H), 10.34 and 10.41 (two s, 1H).

Example 44 1-cyclohexyl(5H-imidazo[5,1-a]isoindol-5 -yl)ethanamine I 5) NmOH I 51> NH2 N N 1360 1364 To a solution of 1360 (100 mg, 0.34 mmol) in 1:1 EtOH/AcOH (4 mL) was added zinc powder (67 mg, 1.0 mmol) and the mixture was d overnight at rt. The solvent was removed under reduced re and the mixture was suspended in 1:1 MeOH/DCM (10 mL) and ﬁltered. The ﬁltrate was collected and concentrated under reduced pressure. The crude was purified by ion-exchange chromatography using water and NH4OH as the eluent to afford 1364 (25 mg, 26%). 1H NMR (mixture of diastereomers) 0.89-1.75 (m, 11H), 2.24 and 2.42 (two m, 1H), 2.62 (m, 1H), 4.52 (m, 1H), 7.09 (t, 1H, .1: 9.2 Hz), 7.29 (m, 2H), 7.38 (m, 1H), 7.47 (m, 1H), 7.60 (d, 1H, J= 9.2 Hz).

Example 45 General Procedure for the Removal the BOC ting Group from Substituted Anilines and Amines RN11 k —’0 R-NH2 To a solution of 17, 1300, 1328 or 1363 (66.0 umol) in dichloromethane (2 mL) was added triﬂuoroacetic acid (0.2 mL, 2.66 mmol) and the mixture was stirred at rt for 2 h. The solvents were distilled off under reduced pressure and the on was basifled with satd.

NaHCO3. The aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water, brine and dried (NaZSO4). The on as filtered and the solvent removed under reduced pressure. The crude residue was purified by column chromatography to afford the following compounds. 1-(2-amin0pheny1)—2-(5H- o[5,1-a]isoind01—5— y1)ethan0ne H NMR 3.40 (dd, 1H, J: 18.0 Hz, 9.6 Hz), 3.70 (dd, 1H, J: 18.0 Hz, 3.3 Hz), .81 (dd, 1H, J: 6.3 Hz, J: 3.3 Hz), 6.43 (br s, 2H), 6.60 (t, 1H, J: 7.5 Hz), 6.68 (d, 1H, J: 8.4 Hz), 7.18 (s, 1H), 7.29 (m, 2H), 7.36 (d, 2H, J: 7.8 Hz), 7.55 (d, 2H, J: 7.5 Hz), 7.74 (s, 1H) 2—(5H-imidazo[5, 1 -a]isoind01—5— y1)(piperidiny1)ethan01 H NMR (Mixture of diasteromers) 1.66-1.87 (m, 6 H), 2.20 (s, 1H), 2.75 (m, 2H), 3.40 (m, 2H), 3.84 (m, 2H), 5.27 and 5.34 (two m, 1H), 7.05 (s, 1H), 7.19 (t, 1H, J: 4.0 Hz), 7.30 (t, 1H, J: 8.0 Hz), 7.38 (d, 1H, J: 8.0 Hz), 7.46 (d, 1H, J: 8.0 Hz), 8.06 and 8.12 (two 8, 1H) 1-(4-amin0pheny1)—2-(5H- imidazo[5,1-a]isoind01—5— y1)ethan0ne 1H NMR 3.35 (dd, 1H, J =18.6 Hz, 9.6 Hz), 3.61 (dd, 1H, J = 18.6 Hz, 9.6 Hz), 4.13 (br s, 2H), 5.84 (dd, 1H, J =18.6 Hz, 9.6 Hz), 6.65 (d, 2H, J = 8.7 Hz), 7.18 (s, 1H), .29 (m, 1H), 7.37—7.58 (m, 3H), 7.74—7.82 (m, 3H) 0 O 1-(3 -amin0pheny1)—2-(5H- N H2 imidazo[5,1-a]isoind01—5— N CH I /> y1)ethan01 (MeOH-d4) 2.32 (t, 2H, J = 6.3 Hz), 4.89—4.94 (m, 1H), 5.30 and 5.38 (two m, 1H), 6.64 (d, 1H, J: 7.8 Hz), 6.71—6.77 (m, 2H), 7.05—7.10 (m, 1H), 7.28—7.41 (m, 2H), 7.51—7.58 (m, 2H), 7.66 (s, 1H) Example 46 5-(2-Cyc10hexy1—2-hydroxyethy1)—5H-imidazo[5,1-a]isoind01—9-01 O HO N N //) HO //) HO N N 1372 1373 To a solution of 1372 (28 mg, 0.09 mmol) in DCM (3 mL) at 0 CC was added BBr3 (1 M in DCM, 0.27 mL, 0.27 mmol) dropwise and the mixture was allowed to stir at 0 CC for 2 h. Saturated aqueous NaHCO3 was added and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were dried (Na2S04) and concentrated under reduced pressure. The residue was puriﬁed by ﬂash column chromatography to afford 1373 (15 mg, 56%). 1H NMR MeOH-d4: (mixture of reomers) 1.04-1.12 (m, 1H), .33 (m, 4H), 1.62-1.86 (m, 5H), 2.00—2.07 (m, 1H), 3.55 and 3.70 (two m, 1H), 5.38 and 5.44 (two m, 1H), 6.80 and 6.81 (two d, 1H, J= 8.0 Hz), 6.90 and 6.99 (two d, 1H, J= 7.6 Hz), 7.03 and 7.05 (two s, 1H), 7.12—7.16(m, 1H), 7.93 and 7.99 (two s, 1H).

Scheme 3. Enantioselective sis of (S)—1—cyc10hexy1—2—((S)—5H-imidazo[5,1—a]isoindol— than01 (1417) and (R)cyc10hexy1-2—((S)—5H-imidazo[5, 1 -a]isoind01y1)ethan01 (1418) 0*+*0 | O OH LDA THF DMAP, TBSCI -78 °C to -40 °C, 3 h DMF, rt, 18 h | O OTBS (S)—-CBS MGM—13.

I OH OTBS | OH OTBS THF, 18 h 106 (1R, 38) (1R, BR) 107 108 (separate by column chromatography) Et3N TSCI, CHchZ * * DMAP reflux, 18 h | OTs OTBS E \> NaH, DMF, 60 °C 14 h 1. Pd(OAC)2, F’Ph3, CyZNMe * * DMF, 95 °C, 5 h _ —> * (JN OTBS 2.1% HCI, EtOH, 50 °C, 3 h NMYC / /) OH (13, as) 109 (13, 23) 1417 (1S,3R)111 (1R, 28)1418 SCHEME 3 Example 47 3 -Cyclohexy1-3 -hydroxy(2—iodopheny1)propanone @* . 00—» *W To a solution of diisopropylamine (1.6 mL, 11.1 mmol) in THF (38 mL) at 0 CC was added n—BuLi (4.1 mL, 10.2 mmol) under an atmosphere of N2. After 30 min the solution was cooled to —30 CC and a solution of odophenyl)ethanone (2.27 g, 9.23 mmol) in THF (6 mL) was added dropwise to the mixture and was stirred for 45 min at -30 CC. The mixture was cooled to —78 CC and cyclohexylcarboxaldehyde (1.2 mL, 9.69 mmol) was added dropwise and the mixture was allowed to warm to -40 CC over 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl. The aqueous layer was ted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried (NaZSO4), ed and concentrated. The residue was puriﬁed by ﬂash column chromatography to afford the title compound as yellow oil (2.56 g, 78%). 1H NMR: 1.02-1.27 (m, 4H), 1.41-1.49 (m, 1H), 1.66—1.76 (m, 4H), 1.89 (d, 1H, J: 12.4 Hz), 2.88 (d, 1H, J: 3.2 Hz), 2.98 (dd, 1H, J: 9.2 Hz, 17.2 Hz), 3.13 (dd, 1H, J: 2.0 Hz, 17.2 Hz), 3.99—4.01 (m, 1H), 7.11—7.15 (m, 1H), 7.42 (d, 2H, J: 4.4 Hz), 7.93 (d, 1H, J: 8.0 Hz).

Example 48 3 -(tert-Butyldimethylsilyloxy)-3 -cyclohexyl(2-iodophenyl)propanone | O OTBS To a on of 3-Cyclohexy1—3—hydroxy—1—(2—iodophenyl)propan—1—one (2.56 g, 7.15 mmol) and DMAP (1.05 g, 8.58 mmol) in DMF (40 mL) was added TBSCl (1.62, 10.7). The reaction mixture was stirred at rt for 18 h and poured into water (40 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with water (2 x 20 mL), brine (10 mL), dried (NaZSO4), filtered and concentrated. The crude was puriﬁed by ﬂash column chromatography to afford 106 as clear oil (3.15 g, 93%). 1H NMR: 0.01 (s, 3H), 0.08 (s, 3H), 0.86 (s, 9H), 1.12—1.24 (m, 6H), 1.43—1.52 (dt, 1H, J: 3.6 Hz, 15.2 Hz), 1.65—1.76 (m, 4H), 2.91 (dd, 1H, J: 6.8 Hz, 22.0 Hz), 3.1 (dd, 1H, J: 9.4 Hz, 22.0 Hz), 4.19—4.24 (m, 1H), 7.11 (dt, 1H, J: 2.4 Hz, 10.0 Hz), 7.40 (t, 1H, J= 9.6 Hz), 7.48 (dd, 1H, J = 2.4 Hz, 10.4 Hz), 7.92 (d, 1H, J: 10.4 Hz). e 49 (1R,3R)—3 -(tert—Butyldimethylsilyloxy)-3 -cyclohexyl(2-iodophenyl)propan- 1—01 and (lR,3S)—3 —(tert—butyldimethylsilyloxy)—3 hexyl— l —(2— iodophenyl)propanol WO 42237 2012/033245 OTBS | OH OTBS | OH OTBS 107 108 (separated by normal phase column chromatography) A mixture of 106 (3.15 g, 6.67 mmol), BH3°SMe2 (0.63 mL, 6.67 mmol) and S—2— methyl-CBS-oxazaborolidine (370 mg, 1.33 mmol) in THF (50 ml) was stirred at room temperature for 16 h. Aqueous 6 M HCl (4 mL) was added and the mixture was stirred for 5 minutes. The mixture was poured into water (20 mL) and the aqueous layer was ted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine (20 mL), dried 4), ﬁltered and concentrated. The residue was puriﬁed by ﬂash column chromatography (3%—6% EtOAc/hexanes gradient). The two diastereomers 107 and 108 were separated in this manner. The stereochemistry was conﬁrmed by ping 107 and 108 on a normal phase analytical silica gel TLC plate against an authentic sample of 108. An authentic sample of 108 was prepared independently by an enantioselective aldol reaction as outlined in Scheme 4. 1H NMR: (1R,3S): 0.15 (s, 3H), 0.18 (s, 3H), 0.87 (s, 9H), 1.08—1.27 (m, 5H), 1.52—1.68 (m, 4H), 1.75—1.89 (m, 4H), 4.02—4.10 (m, 1H), 4.91 (d, 1H, J: 9.6 Hz), 6.95 (t, 1H, J= 6.8 Hz), 7.37 (t, 1H, J= 7.4 Hz), 7.61 (d, 1H, J= 6.8 Hz), 7.78 (d, 1H, J= 7.2 Hz). 1H NMR: (1R,3R): 0.12 (s, 3H), 0.16 (s, 3H), 0.88—0.93 (m, 2H), 0.97 (s, 9H), 1.12— 1.17 (m, 1H), 1.27—1.31 (m ,2H), 1.57—1.79 (m, 5H), 1.91—2.07 (m, 3H), 3.70—3.72 (m, 1H), 4.19 (s, 1H), 5.20 (d, 1H, J= 10.4 Hz), 6.94 (t, 1H, J= 6.8 Hz), 7.38 (t, 1H, J= 7.4 Hz), 7.60 (d, 1H, J= 7.2 Hz), 7.77 (d, 1H, J= 7.2 Hz).

Example 50 (1R,3S)-3 -(tert—Butyldimethylsilyloxy)-3 -cyclohexyl(2- iodophenyl)propyl4-methylbenzenesulfonate | OH OTBS | OTS OTBS To a solution of 107 or 108 (300 mg, 0.63 mmol) in dichloromethane (5 mL) was added triethylamine (0.18 mL, 1.26 mmol) and DMAP (85 mg, 0.70 mmol. The reaction mixture was stirred at room temperature for 5 min and p-toluenesulfonyl de (145 mg, 0.76 mmol) was added. The reaction mixture was reﬂuxed for 18 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (30 ml) and the organic layer was washed with water (10 ml), satd aq NaHC03 (15 mL) and brine. The organic layer was WO 42237 dried (NaZSO4), ﬁltered and concentrated. The title compound was used in the next step without further puriﬁcation.

Example 51 (lR,3R)—3 -(tert—Butyldimethylsilyloxy)-3 -cyclohexyl- l -(2- iodophenyl)propyl4-methylbenzenesulfonate We _ I OH OTBS | OTs (:DTBS (lR,3R)-3 —Butyldimethylsilyloxy)-3 -cyclohexyl- l -(2-iodophenyl)propyl4- methylbenzenesulfonate was prepared as described in the above procedure. The title compound was used in the next step without further puriﬁcation.

Example 52 l-(( lS,3S)(tert—Butyldimethylsilyloxy)-3 -cyclohexyl- l -(2- iodophenyl)propyl)- lH—imidazole W+t§>—>©w© | OTS OTBS | N OTBS To a suspension of NaH (55 mg, 2.17 mmol) in dry DMF (4 mL) was added imidazole (148 mg, 2.17 mmol). The solution was stirred for 2 h and a solution of (lR,3S)-3— (tert—butyldimethylsilyloxy)-3 -cyclohexyl- l -(2-iodophenyl)propyl 4-methylbenzenesulfonate (341 mg, 0.54 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 60 CC for 14 h. The reaction mixture was poured into water (10 mL) and the s layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), brine (10 mL), dried (NaZSO4), ﬁltered and trated. The residue was puriﬁed by ﬂash column chromatography to afford 109 as clear gel (130 mg, 46%). 1H NMR: (1S, 3S) 0.03 (s, 3H), 0.05 (s, 3H), 0.97 (s, 9H), 1.11—1.31 (m, 5H), .59 (m, 2H), 1.68—1.79 (m, 4H), 2.20—2.23 (m, 2H), 3.59—3.62 (m, 1H), 5.75—5.79 (m, 1H), 7.01—7.13 (m, 3H), 7.17 (s, 1H), 7.34—7.37 (m, 1H), 7.73 (s, 1H), 7.93 (d, 1H, J: 7.8 Hz).

Example 53 l-(( lS,3R)(tert—Butyldimethylsilyloxy)cyclohexyl- l -(2- iodophenyl)propyl)- lH—imidazole (7 8) Wri>—»©.W© | OTS OTBS | EN] OTBS Compound 111 was prepared as described for compound 109 in the above procedure. 111 was isolated as a clear gel (42% over two steps). 1H NMR: (18, 3R) 0.05 (s, 3H), 0.07 (s, 3H), 0.97 (s, 9H), 1.12-1.29 (m, 5H), 1.47-1.50 (m, 1H), 1.69-1.77 (m, 3H), 1.82-1.85 (m, 2H), 2.20—2.28 (m, 1H), 2.39—2.47 (m, 1H), 3.56-3.60 (m, 1H), 5.63 (t, 1H, J= 7.4 Hz), 6.97- 6.98 (m, 1H), 7.04-7.11 (m, 2H), 7.31-7.34 (m, 2H), 7.45 (dt, 1H, J= 1.0 Hz, 7.6 Hz), 7.64 (s, 1H), 7.96 (dd, 1H, J= 1.2 Hz, 8.0 Hz).

Example 54 (S)((S)(tert—Butyldimethylsilyloxy)cyclohexylethyl)-5H-imidazo[5, l- a]isoindole (_7 OTBS TBS 109 109a To a Vial containing 109 (65 mg, 0.12 mmol) was added ohexylmethylamine (0.04 mL, 0.19 mmol), PPh3 (13 mg, 0.05 mmol) and DMF (4 mL). The mixture was ed for 10 min and Pd(OAc)2 (6 mg, 25 umol) was added. The mixture was heated at 95 CC for 5 h. After cooling to rt, the mixture was diluted with ethyl acetate (15 mL) and passed h a Celite pad. The ﬁlter cake was washed with ethyl acetate. The organic layer was washed with water (3 x 10 mL), brine (10 mL), dried (NaZSO4), ﬁltered and concentrated.

The crude residue was used directly in the next step.

Example 55 (S)((R)—2-((tert-butyldimethylsilyl)oxy)cyclohexylethyl)-5H- imidazo[5,1—a]isoindole ICE OTBS OTBS 111 111a Compound 11121 was prepared as described in the above procedure. The crude residue was used ly in the next step.

Example 56 (53c-yclohexyl2-((S)—5H—imidazo[5 1--a]]isoindolyl)ethanol (1417) 109a )1417 To a Vial containing crude 10921 (60 mg, 0.15 mmol) was added 1% HCl in ethanol (2 mL). The reaction mixture was heated at 50 CC for 3 h and poured into saturated aqueous NaHC03 (5 mL). The aqueous layer was extracted with dichloromethane (2 x 15 mL). The combined organic layers were dried (NaZSO4), ﬁltered and trated. The residue was puriﬁed by ﬂash column chromatography to afford 1417 as a white solid (17 mg, 47% over 2 steps). 1H NMR: (1S, 2S) .28 (m, 5H), 1.40-1.42 (m, 1H), 1.67—1.83 (m, 4H), 1.91 (d, 1H, J: 12.4 Hz), .30 (m, 1H), 2.82 (br s, 1H), 3.80—3.83 (m, 1H), 5.52 (dd, 1H, J= 3.0 Hz, 10.8 Hz), 7.20 (s, 1H), 7.25—7.29 (m, 1H), 7.36—7.40 (m, 2H), 7.56 (d, 1H, J= 7.6 Hz), 7.84 (s, 1H). Absolute conﬁguration of this diasteromer was conﬁrmed by X—ray crystallography of HBr: 1417 salt crystals (Figure 1).

Example 57 (R)cyclohexyl((S)-5H-imidazo [5 ,1-a]isoindol-5 -yl)ethanol (1418) / S 6TBS N N/) 111a 1418 Compound 1418 was prepared as described for compound 11121 in the above procedure. 1418 was isolated as a colorless solid (42% over 2 steps). 1H NMR: (1S, 2R) 0.97-1.26 (m, 5H), 1.32-1.39 (m, 1H), .67 (m, 2H), 1.71-1.80 (m, 3H), 2.00-2.06 (m, 1H),2.10—2.18(m, 1H), 2.55 (br s, 1H), 3.70-3.74 (m, 1H), 5.35 (t, 1H, J = 7.6 Hz), 7.14 (s, 1H), 7.19—7.23 (m, 1H), 7.34 (t, 1H, J = 7.6 Hz), 7.42 (d, 1H, J = 7.4 Hz), 7.52 (d, 1H, J = 7.4 Hz), 7.78 (s, 1H). e 58 )hydroxy(5H—imidazo[5 ,1-a]isoindolyl)ethyl) cyclohexanecarboxylic acid (143 6) LiOH H20 -,,I N—\\ If N "(OH \ N O \—\\N (I) 1436 To a solution of 1426 (268 mg, 0.79 mmol) in ter 3:1 (4 mL) was added lithium hydroxide monohydrate (99 mg, 2.36 mmol). The solution was allowed to stir for 18 h. The THF was removed under reduced pressure and the solution was neutralized to pH = 5 with 1M HCl. The solution was concentrated under reduced pressure and to the remaining residue was added 20% MeOH/DCM. The residue was ﬁltered through a plug of silica gel and the plug was eluted with 200 mL 20% CM. The solution was concentrated to afford the NLG-1436 as a light yellow solid 193 mg (75%). 1H NMR (DMSO—d6): 0.83—0.85 (m, 1H), 1.05—1.25 (m, 4H), 1.41—1.45 (m, 2H), 1.85—1.88 (m, 3H), 2.03—2.21 (m, 2H), 3.61— 3.64 (m, 1H), 5.35—5.42 (m, 1H), 7.11 and 7.13 (two s, 1H), 7.27 (t, 1H, J= 7.0 Hz), 7.37 (t, 1H, J= 7.4 Hz), 7.49 and 7.56 (two d, 1H, J= 7.5 Hz), 7.59 (d, 1H, J= 7.5 Hz), 7.88 and 7.92 (two s, 1H), 11.98 (br s, 1H).

Example 59 1-((trans)(hydroxymethyl)cyclohexyl)(5H—imidazo [5 ,1-a]isoindol-5 - yl)ethanol (NLG- 1 43 0) 1430 To a solution of 1426 (100 mg, 0.30 mmol) in THF:EtOH (3 mL, 1:2 ratio) at rt, was added NaBH4 (48.1 mg, 1.27 mmol) and LiCl (53.9 mg, 1.27 mmol). The reaction mixture was stirred overnight. The solvents were removed under reduced pressure and the crude residue was diluted with sat’d NH4C1 (20 mL). The product was extracted with EtOAc (3 x mL). The combined c extract was dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was puriﬁed by silica ﬂash chromatography to afford 1430 (78 mg, 85%). 1H NMR (a mixture of reomers) 0.94-1.13 (m, 4H), 1.14- 2.18 (m, 10H), 3.45 (d, J= 6.3 Hz, 2H), 3.73-3.78 (m, 1H), 5.30—5.38 (m, 1H), 7.17 (s, 1H), 7.22—7.27 (m merged with CHCl3, 1H), 7.33-7.44 (m, 2H), 7.54 (d, J= 7.6 Hz, 1H), 7.83 (d, J= 10.4 Hz, 1H).

Example 60 (trans)hydroxy(5H-imidazo [5 ,1-a]isoindolyl)ethyl)-N—(2- methylsulfonamido)ethyl)cyclohexanecarboxamide (1432) o o ..1\/< ”HM O“ ’ N N ZMe //) HO //) HO N N 1432 To a vial containing N-(2-aminoethyl)methanesulfonamide dihydrochloride (56.4 mg, 0.27 mmol) in DMF (4 mL) was added 1436 (83 mg, 0.25 mmol), DIPEA (197 mg, 1.53 mmol) and HATU (106 mg, 0.28 mmol). The reaction was stirred at RT for 18 h and trated. The residue was puriﬁed by column tography on silica gel using hexanes/EtOAc 10%—>60% gradient. The compound was isolated as a light yellow solid 72 mg (64%). 1H NMR: (CD3OD) 1.04—1.14 (m, 2H), 1.38—1.46 (m, 3H), 1.73—1.96 (m, 4H), 2.11—217 (m, 2H), 2.32—2.38 (m, 1H), 2.93 and 2.97 (two s, 3H), 3.15 (t, 1.7H, J= 6.4 Hz), 3.29—3.31 (m overlap with, 1H), 3.54—3.58 and 3.78—3.80 (two m, 1H), 5.57—5.66 (t and dd, 1H, J= 6.3 and J= 2.6, 9.2 H), 7.33-7.47 (m, 3H), 7.52 and 7.60 (two d, 1H, J= 7.6 Hz), 7.68-7.71 (m, 0.8 H), 7.91 (s, 0.4 H), 8.21 (dd, 0.6 H, J= 1.1, 8.4 Hz), 8.44 (s, 0.4 H), 8.53- 8.57 (m, 1H).

Example 61 (cis)(2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl) hydroxyethyl)cyclohexanol F F 0 ..\OH / N) HO HO / / N) / N N 1379 1465 To a on of 79 (60 mg, (0.19 mmol) in dry THF (5 mL) at -78 0C under a nitrogen atmosphere was added lithium trisiamylborohydride solution (1.0 M in THF) (0.38 mL, 0.38 mmol). The resulting mixture was stirred vigorously for 3 h at —78 °C and then allowed to warm to room temperature (1 h). The reaction mixture was quenched with 1:1 HZO/EtOH (4 mL). The reaction was acidified with 6 N HCl followed by basif1cation with sat’d K2CO3 solution. The s layer was extracted with dichloromethane (5 x 15 mL).

The combined organic layers were dried over NaZSO4, filtered and concentrated under reduced pressure to afford a crude residue. The residue was purified by column tography to afford 1465 35 mg (58 %). e of diastereomers 1H NMR: .15 (m, 10H), 2.35-2.51 (m, 1H), 3.66-3.79 (two m, 1H), 4.03 (br s, 1H), 5.48 (t, 1H, J = 5.1 Hz, isomer), 5.67 (dd, 1H, J = 10.6, 2.8 Hz), 6.91—6.95 (m, 1H), 7.19 (d, 1H, J = 5.4 Hz), 7.25— 7.39 (m, 2H), 7.88 (two, s, 1H).

The mixtures of four diastereomers (1465) were ted by preparative chiral super critical ﬂuid chromatography (SFC) to afford the pure diasteromers 1482-1485. SFC was performed on RegisPack 5 column in isopropanol/CO2: 0.2%DEA.

H lI‘OH N "'OH //) HO 1482 1483 F F N ..\\\BO...OH:' N ...1>H)O.HOH // Ho //) HO N N 1484 1485 1482 and 1484 1H NMR 1)) 5 1.16 (d, .1: 6.1 Hz, 1H), 1.23 (d, .1: 17.8 Hz, 2H), 1.28 (s, 1H), .65 (m, 6H), 1.73 (s, 2H), 1.90— 2.14 (m, 1H), 2.48 (d, J= 15.2 Hz, 1H), 3.55 (s, 1H), 3.90 (s, 1H), 5.58 (s, 1H), 6.91— 7.08 (m, 1H), 7.16 (s, 1H), 7.41 (s, 2H), 7.96 (d, J= 28.8 Hz, 1H). 1483 and 1485 1H NMR: (013301)) 5 1.15 (d, J: 6.4 Hz, 1H), 1.26 (d, J = 24.4 Hz, 2H) 1.41—1.79 (m, 8H) 2.35 —2.50 (m, 1H), 3.65 (d, J= 7.8 Hz, 1H), 3.90 (s, 1H), 5.69 (dd, J= .1, 2.4 Hz, 1H), 6.93 —7.08 (m, 1H), 7.18 (s, 1H), 7.41 (dd, J= 5.2, 3.5 Hz, 2H), 7.94 (s, 1H).

Example 62 2—(6-ﬂuoro-5H-imidazo[5,1-a]isoindol—5—y1)—1—((trans)—4— hydroxycyclohexy1)ethanone F 0Y1?“ F CHO ‘ O + 1)NaH /_//N 2)AcOH,MeOH / N OH Trt’N OTBS 3) HCI NA 0 H 4 126 154 To a suspension of NaH (1.11 g, 46.2 mmol) in THF (150 mL) at -10 0C was added a solution of 126 (18.5 g, 50.8 mmol) in THF (75 mL) dropwise and the mixture was stirred for 45 min at 0 0C. Aldehyde 4 (20.0 g, 46.4 mmol) was added as a solution in THF (120 mL) dro wise over ap period of 15 min. After stirring for 1 h at 0 °C the reaction mixture was allowed to warm to rt and was stirred overnight. The solvent was distilled off under reduced pressure and the crude was diluted with sat’d NH4Cl (80 mL), water (100 mL) and EtOAc (100 mL). The solution was partitioned in a separatory funnel and the organic layer was collected. The aqueous layer was extracted with EtOAc (3 x 150 mL) and the combined organic fractions were washed with brine and dried over NaZSO4. The solution was ﬁltered and concentrated under d pressure to afford the crude product. The crude was stirred in a mixture of acetic acid (20 mL) and MeOH (170 mL) at 90 CC for 1.5 h. After cooling to 50 0C the reaction mixture was treated with 6N HCl (20 mL) and stirred for 30 s. After g to rt the solvent was distilled off and sat’d NaHC03 (200 mL) was added to the residue followed by CHzClz (200 mL). The layers were separated and the aqueous layer was extracted with CHzClz (2 x 100 mL). The combined organic layers were dried over Na2SO4 and the solvent evaporated under reduced re to afford the crude product which was purified by using ﬂash silica gel column chromatography to afford 154 (13.8 g, 95%).

Example 63 (trans)(2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl) hydroxyethyl)cyclohexanol (1475) NaBH4 N O H N9! HO H 154 1475 To a solution of 154 (13.8 g, 43.9 mmol) in MeOH (150 mL) at -10 to 0 0C, was added NaBH4 (4.98 g, 131.71 mmol) in small portions and the solution was allowed to stir for 4 h. The solvent was distilled off under reduced re and the mixture was d by addition of saturated NH4Cl solution (200 mL) and dichloromethane (200 mL) and the mixture was stirred for 25 min. The organic layer was separated and the aqueous layer was extracted with a mixture of 5% 2,2,2-triﬂuorethanol in CHzClz (5 x 75 mL). The combined organic extract was washed with brine, dried (MgSO4) and concentrated under d pressure to afford the crude. Purification by column chromatography afforded 1475 as a white solid (13.24 g, 95%). 1H NMR (a mixture of diastereomers): .52 (m, 11H), 3.48— 3.68 (two m, 2H), 5.45 (t, 1H, J = 6.0 Hz), 5.65 (dd, 1H, J = 9.0, 3.0 Hz), 6.89—6.96 (m, 1H), 7.16 (s, 1H), 7.29—7.38 (m, 2H), 7.80 and 7.88 (two s, 1H). 2012/033245 The mixtures of the four diasteromers were separated by preparative chiral super critical ﬂuid chromatography to afford the pure diasteromers 1486-1489. Separation by SFC was performed by a first passage through an AD-H column (Regis Technologies, Inc.) to te compounds 1487, 1486 + 1488 and 1489. The peak comprising a mixture of 1486 + 1488 was separated by SFC in a Whelk—Ol column (Regis Technologies, Inc). All separations were done in isopropanol:CO2 (10:90) + DEA 0.1%.

F F ‘IWBO‘OH H OH N N / HO / ) HO N N/ 1486 1487 1488 1489 86 and NLG—1489 1H NMR: 1.03-1.26 (m, 6H), 1.43-1.47 (m, 2H), 1.93-1.96 (m, 2H), 2.45—2.50 (m, 3H), 3.48 (s, 1H), 3.61 (s, 1H), 5.62 (d, J= 8.9 Hz, 1H), 6.91 (t, J= 8.6 Hz, 1H), 7.12 (s, 1H), 7.26-7.30 (m merged with CHCl3, 2H), 7.79 (s, 1H).

NLG—1487 and 88 1H NMR: 0.95-1.33 (m, 6H), 1.61-1.64 (m, 1H), 1.79—1.82 (m, 1H), 1.91—2.04 (m, 4H), 2.28 (d, J: 14.4 Hz, 1H), 3.42—3.45 (m, 1H), 3.62 (s, 1H), 5.37 (t, J = 4.9 Hz, 1H), 6.88 (t, J= 8.9 Hz), 7.05 (s, 1H), 7.24-7.31 (m merged with CHCl3, 2H), 7.84 (s, 1H).

Synthesis of ProDrugs of 1304 Example 64 Sodium 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethyl phosphate (1434) N N / 2 0“ /N/) O\P,ONa "\ONa 1304 o 1434 To a solution of 1304 (150 mg, 0.53 mmol) and pyridine (85.7 uL, 1.1 mmol) in dichloromethane (4 mL) at 0 °C was added POCl3 (99.3 uL, 1.06 mmol) and the solution was allowed to warm to rt. After stirring overnight the reaction was quenched with NaHCO3 sat’d (5mL), and stirred for 15 minutes. The solvents were evaporated under reduced pressure and the solid was washed with THF (2 x 15 mL). The t was removed under reduced pressure to afford the crude residue. The e was dissolved in DCM (5 mL) and passed through a plug of NaZSO4 to remove water. The solvent was evaporated under reduced pressure to afford 1434. (33%). 1H NMR (a mixture of diastereomers): (CD3OD) 1.15-1.41 (m, 6H), 1.59-1.82 (m, 5H), 1.98—2.04 (m, 1H), 2.56—2.86 (two m, 1H), 3.57—3.58 and 4.08—4.11 (two m, 1H), 5.29 — .54 (two m, 1H), 7.11 and 7.16 (two s, 1H), 7.25—7.47 (m, 3H), .60 (m, 1H), 7.83 and 7.95 (two s, 1H).

Example 65 l-cyclohexyl(5H—imidazo[5, l -a]isoindolyl)ethyl acetate A solution of 1304 (80 mg, 0.28 mmol) and 4-dimethylaminopyridine (1.04 mg, 8.5 umol) in ne (3 ml) was treated with acetic anhydride (32 ”L, 0.34 mmol) at RT and the on was stirred overnight. The solution was concentrated in vacuo and the residue was dissolved in dichloromethane (10 ml) and washed successively with water (3 x 10 ml) and dried over NaZSO4. The solution was concentrated and the crude was purified by ﬂash column chromatography to afford the desired product as yellow gel (75 mg, 82%). 1H NMR(a mixture of diastereomers): 0.76—1.25 (m, 5H), 1.30—1.75 (m, 6H), 1.78—2.20 (m, 4H), 2.26—2.40 (m, 1H), 4.96—5.12 (m, 2H), .39 (m, 4H), 7.51—7.53 (m, 1H), 7.71 and 8.00 (two s, 1H).

Example 66 4-(1-cyclohexyl(5H—imidazo[5,1-a]isoindolyl)ethoxy)oxobutanoic acid (142 8) / ﬂ HO / B o o N/ N N 1304 O OH 1428 A solution of 1304 (48 mg, 0.17 mmol) and 4-dimethylaminopyridine (0.83 mg, 6.8 umol) in dichloromethane (3 ml) was treated with succinic anhydride (19 mg, 0.19 mmol) and DIPEA (33 ”L, 0.19 mmol) at RT and the reaction was d overnight. The solution was poured into saturated NH4C1 (10 mL) and extracted with dichloromethane (3 x 10 ml).

The combined organic layers were dried over NaZSO4 and concentrated. The crude product was crystallized from ethanol/chloroform (1:4) to afford 1428 as white solid (62 mg, 95%). 1H NMR(a mixture of diastereomers): 0.93-1.65 (m, 11H), 1.90—2.32 (m, 1H), .90 (m, 3H), 2.92—3.05 (m, 1H), 3.57 and 3.73 (m, 1H), 5.20—5.22 (m, 1H), 5.29—5.33 (m, 1H), 6.41— 6.78 (m, 1H), 7.16—8.00 (m, 5H), 12.20—12.80 (br s, 1H).

Example 67 1-cyclohexyl(5H—imidazo[5,1-a]isoindolyl)ethyl te (1431) N O //) HO / /) O N N 1304 1431 A solution of 1304 (76 mg, 0.27 mmol) and 4-dimethylaminopyridine (1.0 mg, 8.1 umol) in pyridine (3 ml) was treated with c ide (73 mg, 0.32 mmol) at RT and the reaction was stirred overnight. The on was concentrated in vacuo and the residue was dissolved in dichloromethane (10 ml) and washed successively with saturated NaHCO3 (10 mL), water (10 ml) and dried over NaZSO4. The solution was concentrated and the crude was purified by ﬂash column chromatography to afford 1431 (25 mg, 23%). 1H NMR (a mixture of diastereomers): 0.88—1.25 (m, 7H), 1.62—1.90 (m, 4H), 2.15—2.25 (m, 1H), 2.49-2.58 (m, 1H), 5.19-5.21 (m, 1H), 5.34—5.37 (m, 1H), 7.16—7.28 (m, 4H), 7.40—7.64 (m, 4H), 7.80 (s, 1H), 8.00—8.02 (d, J = 6.3 Hz, 1H), 8.12—8.14(d, J = 5.7 Hz, 1H).

Example 68 1-cyclohexyl(5H—imidazo[5,1-a]isoindolyl)ethyl phenylcarbamate (1427) N N / ) HO / J o H / / N N N (2], \Ph 1304 1427 To a on of 1304 (40 mg, 0.14 mmol) in THF (5 mL) was added triethylamine (43 ”L, 0.31 mmol) followed by phenylisocyanate (17 ”L, 0.16 mmol). The reaction mixture was d at RT for 18 h and concentrated. The crude t was purified using ﬂash column chromatography (4:1 EtOAc:MeOH) to afford 1427 as colorless gel (19 mg, 34%). 1H NMR (a mixture of diastereomers): 1.02-1.04 (m, 5H), 1.56-1.70 (m, 6H), 2.10—2.14 (m, 1H), 2.31—2.40 (m, 1H), 5.02—5.10 (m, 1H), 5.18—5.24 (m, 1H), 7.04—7.08 (m, 1H), 7.18—7.35 (m, 6H), 7.39—7.41 (m, 2H), 7.50 (d, J = 4 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.74 (s, 1H) Example 69 l Procedure for the Synthesis of Prodrugs of 1304 To a Vial containing 1304 (0.5 mmol) in dichloromethane (5 mL) was added the appropriate carboxylic acid (1.1 mmol), diisopropylethyl amine (3.0 mmol) and HATU (1.3 mmol). The reaction mixture was d at rt for 48 h and poured into saturated aqueous NaHCO3 (10 mL) and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over NaZSO4, and concentrated. The crude product was dissolved in dichloromethane (6 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated. The residue was dissolved in water and solid K2CO3 was added until the on was basic. The aqueous solution was extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over NaZSO4, filtered and concentrated to afford 1433, 1440, 1442 and 1443. (2S)—1-cyclohexy1—2-(5H—imidazo[5, 1- a]isoindoly1)ethy1 2-aminopropanoate H NMR (a mixture of diastereomers) 0.96-1.06 (m, 2H), . 19 (m, 3H), 1.27 and 1.30 (two d, 3H, J = 7.0 Hz), 1.41—1.53 (m, 3H), 1.63—1.77 (m, 5H), 2.10-2.16 and 2.23— 2.26 (two m, 1H), 2.37—2.45 (m, 1H), 3.21 and 3.50 (two q, 1H, J = 7.0 Hz), 4.86—4.90, .06—5.09 and 5.15—5.17 (three m, 2H), 7.19 (d, 1H, J = 3.2 Hz), 7.24-7.27 (m, 1H, merged with form), 7.37 (dt, 1H, J = 2.8, 7.6 Hz), 7.49—7.55 (m, 2H), 7.69 (s, 1H) (2S)—1-cyclohexy1—2-(5H—imidazo[5, 1- a]isoindoly1)ethy1 pyrrolidine 77 carboxylate dihydrochloride 1442 1H NMR (a mixture of diastereomers) (CD3OD) 0.90—1. 17 (m, 5H), 1.4—1.75 (m, 10H), 2.11—2.18 (m, 2H), 2.36—2.42 (m, 1H), 2.82 (br s, 1H), 2.89-3.0 (m, 2H), 3.54-3.60 and 3.72—3.75 and 3.81—3.83 (three m, 1H), 4.93—5.25 (four m, 2H), 7.16 (s, 1H, J = 3.6 Hz), 7.22-7.16 (m, 1H), 7.35 (t, 1H, J = 7.40 Hz), 7.48-7.52 (m, 2H), 7.69 (d, 1H, J = 8.40 Hz) (2S)-5 -(1-cyclohexy1—2-(5H—imidazo[5 ,1- ndol-5 hy1) 1-methy1 2- 73 aminopentanedioate dihydrochloride 1443 NH2 HCI 1H NMR (a mixture of diastereomers) (DMOS-d6) 0.85—0.88 (m, 2H), 1.02—1. 12 (m, 3H), 1.34—1.38 (m, 1H), 1.53—1.67 (m, 5H), .20 (m, 2H), 2.60—2.73 (m, 2H), 3.41—3.53 (m, 2H), 3.74 and 3.87 (two 5, 3H), 4.44—4.52 (m, 1H), 5.81—5.3 (m, 1H), 7.50—7.53 (m, 2H), 7.69—7.70 (m, 1H), 7.81—7.72 (m, 1H), 7.95 (d, 1H, J: 6.4 Hz), 8.66 (br s, 3H), 9.52 (s, 1H) Yield (%) (2S)(1-cyclohexyl(5H—imidazo[5 ,1- a]isoindol—5—yl)ethoxy)—3—methyl— 1 - 40 oxobutanaminium de hydrochloride 1H NMR (a mixture of diastereomers) (DMOS-d6) 0.86—0.98 (m, 6H), 1.01—1.12 (m, 4H), 1.42 and 1.44 (two s, 9H), .87 (m, 6H), 2.0—2.16(m, 2H), 2.33—2.43 (m, 1H), 4.04— 4.07 and 4.08—4.15 (two m, 1H), 4.91—5.29 (three m, 3H), 7.17 (s, 1H), 7.21—7.28 (m, 2H), 7.31—7.40 (m, 2H), 7.70 (s, 1H) Biological Example 1 Human IDO protein cloning, expression and ation Expression vectors for human indoleamine-2,3-dioxygenase (IDO) protein were prepared by amplification of a 1219 bp fragment of the sequence present in vector phIDO6His cDNA with primers 5’-ggagcatgctaATGGCACACGCTATGGAAAAC-3’ and ’-gagagatctACCTTCCTTCAAAAGGGATTTC-3’ and cloning the SphI—BglII 1213 bp fragment into pQE70 (Qiagen), to yield vector pQE70-hIDO. This construct adds 2 extra amino acids and a 6-Histidine tag to the inus of the natural human IDO protein while preserving intact the natural start codon and N—terminus amino acid sequence. The amplified allele of human IDO shows two polymorphisms with t to the ce deposited in accession file P14902 of SwissProt database. These polymorphisms result in a P110S and E119G amino acid changes.

Plasmid pQE70-hIDO was transformed into M15(pREP4) cells (Qiagen) and clones were selected in LB-agar plates supplemented with carbenicillin 50 ug/mL and kanamycin 30 ug/mL. Protein expression was carried out by growing an overnight culture of the M15pREP4/pQE70-hIDO clone in 100 mL LB supplemented with 100 ug/mL carbenicillin, 50 ug/mL kanamycin and 50 ug/mL of L-tryptophan (LBCKT ). 40 mL of this e were inoculated into 750 mL of LBCKT for 4 hours at 37 °C. This culture was diluted 1:10 into LBCKT medium and cultured for another 2 hours at 37 0C until OD600 was higher than 0.8. At this point the cultures were inoculated with Hemin to 7 uM and L-Tryptophan to 75 ug/mL and incubated at 37 °C for 2 h. Induction of protein expression was carried out by supplementing the cultures with IPTG to 1 mM, PMSF to 200 uM, EDTA to 1 mM and L-tryptophan to 50 ug/mL. tion was continued for additional 16 h at 25 °C. Cells were 2012/033245 collected by centrifugation, and the cell s were washed with PBS buffer supplemented with 200 ”M PMSF and 1 mM EDTA and stored at -80 0C until protein puriﬁcation.

The equivalent of 16 L of e were processed in one batch of puriﬁcation. Cell pellets were thawed, ended in 50 mM potassium phosphate buffer pH 7.0, 200 uM PMSF, 1 mM EDTA, 1 mg/mL lysozyme to 10 mL per liter of bacterial culture and incubated minutes on ice. Cells were then lysed by sonication. Cell lysates were centrifuged 20 min at 20000 g and the supernatant was ﬁltered through 0.45 pm ﬁlters. The ﬁltered supernatant was loaded onto a 60 mL phosphocellulose column equilibrated with 50 mM potassium phosphate buffer pH 6.5 (KPB) at 1-3 mL/min. The column was washed with 3 volumes of 50 mM KPB, 3 volumes of 100 mM KPB and the protein was eluted with 15 volumes of a linear gradient of 100-500 mM KPB. Fractions were collected and IDO activity assay was performed by measuring kynurenine production. This was carried out by mixing 50 uL of each fraction with 100 ”L of reaction mix to yield a ﬁnal concentration of 50 mM KPB buffer, 20 mM ascorbic acid, 200 ug/mL catalase, 20 ”M methylene blue and 400 ”M L-tryptophan. Fractions demonstrating IDO activity were loaded onto a Ni-NTA puriﬁcation column (15 mL). This afﬁnity puriﬁcation column was washed with 10 volumes of 250 mM KPB, 150 mM NaCl, 50 mM imidazole pH 8, and eluted with 10 volumes of buffer containing 250 mM KPB, 150 mM NaCl and a 50 to 250 mM ole linear gradient.

Collected fractions were d by IDO enzymatic assay described above and the positive fractions were pooled and trated by ultraﬁltration and ed against a buffer containing 250 mM KPB, 50% glycerol. This process yields ~ 8—10 mg of pure protein (>98%) with a speciﬁc activity of 170 umol/h/mg.

Biological Example 2 g of IDO inhibitory compounds by enzymatic IDO assay The IC50 values for each compound were determined by testing the activity of IDO in a mixture containing 50 mM potassium phosphate buffer at pH 6.5; 70 nM puriﬁed human IDO protein, 200 ”M L-tryptophan, 20 mM ate, 20 ”M methylene blue, 0.1% DMSO.

The inhibitors were initially diluted in DMSO at 100 mM and were diluted in potassium phosphate 50 mM, added to the reaction mixture at ﬁnal concentrations raging from 1 mM to nM and ubated with the enzyme for 5 min at 25 OC. The reaction was started by addition of L—tryptophan to 200 ”M and incubated 15 min at 37 °C. The reaction was stopped by addition of 0.5 vol of 30% trichloroacetic acid and incubated 30 min at 60 0C to hydrolyze N—formylkynurenine to kynurenine. The reaction was centrifuged at 3400 g for 5 min to remove precipitated protein and the supernatant was d with 2% (w/v) of p-dimethylaminobenzaldehyde in acetic acid. The reaction was incubated 10 min at 25 OC and read at 480 nm in a spectrophotometer. Control samples with no IDO inhibitor, or with no IDO enzyme or with the reference inhibitors 1-methyl-tryptophan (200 uM) and menadione (1.2 uM) were used as controls to set the ters for the non-linear regressions necessary for determination of the IC50 for each compound. Nonlinear regressions and determination of the IC50 values were performed using the GraphPad Prism 4 software. nds with an IC50 of less than 500 ”M were considered as active tors in this assay.

Biological Example3 Determination of IDO inhibitory activity and toxicity in cell based nurenine assay 293—T-RExTM cells (Invitrogen) constitutively express a tet operator binding repressor protein and are maintained in DMEM, 10 % FBS, 1X Penicillin+Streptomycin, 2 mM L-glutamine, 5 ug/mL blasticidin at 37 0C with a 5% C02 in air atmosphere and typically split prior to conﬂuency. Cells were passed by splitting the culture 1/10- by ng media by aspiration, washing 1X with PBS, incubating with 0.25% trypsin/EDTA until the cells detach, sing the cells in fresh growth media, and g at 1/ 10 dilutions in fresh growth media. For long term eservation, cells are detached from the plate as described above, collected by centrifugation, resuspended in freeze medium (growth medium, %DMSO), stored in 1.8 mL cyropreservation vials (~ 2-5 X 106 cells per vial), in liquid nitrogen vapor storage tanks.

IDOl— expressing RexTM cell lines were generated by stable transfection of plasmid pcDNA-tetO-IDO expressing human IDO or murine IDO under the control of the doxycycline—inducible CMV—tet promoter. Transfected cells were selected in DBZ medium (DMEM, 10 % FBS, 1X Penicillin + Streptomycin, 2 mM L-glutamine, 5 ug/mL blasticidin and 25 ug/mL Zeocin) at 37 °C with a 5% C02 in air atmosphere. Individual clones were isolated by limiting dilution cloning from these tions. These clones were assayed for IDO activity and the clones that showed the highest levels of IDO activity inducible by doxycycline were used for subsequent cell based IDO assays.

To setup an IDO cell based activity assay, IDO—293—T—Rex cells were ted and ended in DBZ media at 106 mL, and split into -lysine coated l plates at 100,000 cells per well. 100 uL of Neutral medium (DBZ medium, 200 uM L—tryptophan) or Induction media (Neutral medium mented with 5 uM doxycycline) are added to the cells and incubated 28 h at 37 °C. After the IDO induction period, medium is removed and replaced with ion or Neutral medium containing different concentrations of each inhibitor (1 mM to 0.5 nM). The cells incubated in Neutral medium serve as negative control of the assay. The cells incubated in Induction medium and without inhibitor serve as the positive control of the assay. The incubation is carried out for 16 h at 37 0C in a cell culture incubator. 200 uL of medium are transferred to U-bottom polypropylene 96—well plates ning 25 uL of 30% TCA, incubated 30 s at 60 °C and centrifuged at 3400 g for 5 minutes. 150 uL of the clear supernatant is transferred to a polystyrene 96-well plate containing 50 uL of 4% (w/v) of p-dimethylaminobenzaldehyde in acetic acid, incubated for min. Kynurenine concentration is determined by measuring the absorbance at 480 nm.

To measure the toxicity of each compound after 16 h incubation with cells, cell viability is measured via a WST-l assay (Roche) according to instructions from the manufacturer. Brieﬂy, after the incubation with each compound, medium is aspirated and replaced with 100 mL of WST—l reagent, and incubated 30 min at 37 °C. Absorbance at 540 nm is correlated with the number of viable cells. Determination of IC50 (Kynurenine assay) or LD50 (WST-l assay) is performed via non-linear sion analysis using GraphPad Prism Biological Example 4 Reversal of IDO-Mediated Suppression of T- Cell Proliferation by IDO Inhibitors.

Human monocytes were collected from peripheral mononuclear cells by leukoapheresis and cultured overnight at 106 cells/well in a 96—well plate in RPMI 1640 medium supplemented with 10% fetal calf serum and 2 mM L-glutamine. Adherent cells were retained and cultured for 7 days with 200 ng/ml IL—4, 100 ng/ml . Cells were matured for 2 days with a cytokine cocktail containing TNF-oc, IL-1I3, IL-6 and PGE2 for additional 2 days to induce dendritic cell maturation. At the end of maturation, loosely adherent cells were detached by gentle aspiration and plated in V-bottom 96 well plates, at 5000 cells/well. These cells are >80% IDO+ dendritic cells. Human allogeneic T cells ) from normal donors were resuspended in RPMI 1640 supplemented with 100—200 U/mL IL-2 and 100 ng/mL anti-CD3 antibody and added to the wells. Serial dilutions of IDO compounds dissolved in phenol red —free RPMI was added to yield a final concentration of IDOi between 500 and l LLM. After incubation for 2-4 days, T cell proliferation was measured by BrdU incorporation assay after an overnight pulse with BrdU labeling mix (Roche Molecular Biochemicals). At the en of the pulse, the cells were ﬁxed and incubated with 100 u L/well anti-BrdU-POD antibody following the instructions from the manufacturer. Plates were read in a microplate reader.

Alternatively, testing of IDO inhibitors in an in vitro mouse model of diated suppression of T cell proliferation is performed by the following procedure. C57bl6 mice are inoculated with 1x106 GMCSF tumor cells in the right ﬂank. After 10-12 days, tumor draining lymph nodes are ted and cells are stained with anti-CDllc and anti-B220 monoclonal antibodies. Cells are sorted by high—speed ﬂuorescence activated cell sorting and the CD1 20+ plasmacytoid dendritic cells are collected and seeded at 2000 well in 96 well V—bottom plates. Splenocytes are collected from BM3 transgenic mice (in CBA background) and collected by nylon wool ment. BM3 T cells (105 cells/well) are added to each well in 200 u L of RPMI, 10% FCS, 50 u M [3-mercaptoetanol. Alternatively, T cells are obtained from spleens of OT-I transgenic mice and added to the culture in ation with OVA peptide. IDO inhibitors are added dissolved in RPMI at final concentrations ranging from 1 mM to 10 nM. After 3 days of stimulation, cells are pulsed by 16 h with BrdU or 3H-thymidine. Cells are collected, ﬁxed and tested for BrdU incorporation ing the instructions from the BrdU labeling kit cturer (Roche Diagnostics). If 3H-tymidine is used to measure T cell proliferation, cells are harvested and dpm counts are measured in a scintillation counter following procedures widely known in the art. Control CDllc+ cells taken from the contralateral lymph node or CD1 lc+/ B220" cells (IDO' population) from the TDLN are used as positive control for proliferation.

Biological Example 5 Pharmacological Value Pharmacological values for compounds tested according to one or more of the preceding examples are reported in the following table, including, Human IDO IC50: this is the concentration of the compound at which we observe 50% of enzymatic activity using recombinant human IDO under the assay conditions described in one of the examples; IC50 values are reported in ranges: A: < 1 LLM, B: 1 - 10 ”M, C: 10 - 100 ”M; D: > 100 uM.

Structure 2-(5H-imidazo[5, 1-a]isoind01y1)ethan01 B ethyl 2-(5H-imidazo[5,1-a]isoind01—5— y1)acetate 2—(5H—imidazo[5, 1-a]isoind01—5—y1)acetic acid 2-(5H-imidazo[5,1-a]isoind01—5—y1)—N— methylacetamide (2-br0mostyry1)-5H-imidazo[5,1- a]isoind01e 2—(6-ch10r0-5H-imidazo[5,1-a]isoind01—5— y1)cyclohexy1ethan01 2—(6-ch10r0-5H-imidazo[5,1-a]isoind01—5— y1)-1 -cyclohexy1ethan0ne 2012/033245 2-(5H-imidazo[5, 1 -a]isoind01—5 -y1)ethy1 2—(((1R,2R,5 sopr0py1—5— methylcyc10hexy1)0xy)acetate 2—(6-ch10r0-5H-imidazo[5,1-a]isoind01—5— 1299 N y1)—1—cyclohexylethan01 tert-butyl (4-(2—(5H-imidazo[5, 1- 1300 a] isoindol-S -y1)acety1)pheny1)carbamate 1-(4-amin0pheny1)-2—(SH-imidazo [5 ,1- 1301 ’. a] isoindol-S-y1)ethan0ne tert-butyl (4-(1-hydr0xy(5H- 1302 A imidazo[5,1-a]isoind01—5- y1)ethy1)pheny1)carbamate 1-(4-amin0pheny1)-2—(SH-imidazo [5 ,1- 1303 N a]isoind01—5 —y1)ethan01 1-cyc10hexy1—2—(5H-imidazo[5, 1- 1304 a]isoind01—5 -y1)ethan01 imidazo[5, 1-a]isoind01—5—y1)—1—(3 — nitropheny1)ethan0ne 2—(5H-imidazo[5, 1-a]isoind01—5—y1)—1—(3 — nitropheny1)ethan01 2-(5H-imidazo[5,1-a]isoind01y1)(2- nitropheny1)ethan0ne 2-(5H-imidazo[5,1-a]isoind01y1)(2- nitropheny1)ethan01 tert-butyl (2—(2—(5H-imidazo[5, 1- a]isoindol-S-y1)acety1)pheny1)carbamate tert-butyl (2—(1-hydr0xy(5H- o[5,1-a]isoind01—5— y1)ethy1)pheny1)carbamate 1-(2-amin0pheny1)(5H-imidazo[5,1- a]isoind01—5-y1)ethan0ne .0—O1-(2-amin0pheny1)(5H-imidazo[5,1- a]isoind01—5 -y1)ethan01 1-(2—ch10r0pheny1)-2—(5H-imidazo[5, 1- a]isoind01—5-y1)ethan0ne 1-(5H-imidazo[5,1-a]isoind01—5-y1)-2— methylpropan-Z-ol 1-(2—ch10r0pheny1)-2—(5H-imidazo[5, 1- a]isoind01—5 -y1)ethan01 1-(3-ch10r0pheny1)-2—(5H-imidazo[5, 1- a]isoind01—5 han01 imidazo[5,1-a]isoind01y1) phenylethanone 2—(5H-imidazo[5,1-a]isoind01y1) phenylethanol 1-(2,4-dimethylfuran-3 -y1)-2—(6—ﬂu0r0— 5H-imidazo[5,1-a]isoindol-S-y1)ethan01; 1-(3-ch10r0pheny1)-2—(5H-imidazo[5, 1- a]isoind01—5-y1)ethan0ne 1-cyclohexy1-2—(6-ﬂu0r0-5H-imidazo[5, 1- a]isoind01—5-y1)ethan0ne 1-cyclohexy1-2—(6-ﬂu0r0-5H-imidazo[5, 1- a]isoind01—5 -y1)ethan01 2—(5H-imidazo[5,1-a]isoind01y1) (tetrahydro-ZH-pyrany1)ethan01 h10r0-5H-imidazo[5,1-a]isoind01—5— y1)cyclohexylethan01 (Z)—1-cyclohexy1(5H-imidazo[5 ,1- a]isoind01y1)ethan0ne oxime 1-cyclopenty1(5H-imidazo[5, 1- a]isoind01—5 -y1)ethan01 tert-butyl 4-(1-hydr0xy(5H- imidazo[5,1-a]isoind01—5— y1)ethy1)piperidinecarb0xy1ate 1-cyclohexy1(5H-imidazo[5,1- 1364 a]isoind01—5 hanamine tert-butyl (3 -(1-hydr0xy(5H- 1367 imidazo[5,1-a]isoind01 yl)ethy1)pheny1)carbamate 1-(3 -amin0pheny1)(5H-imidazo[5, 1- a]isoind01—5 -y1)ethan01 2—(5H-imidazo[5,1-a]isoind01y1) (piperidiny1)ethan01 6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01y1)hydr0xyethy1)cyclohexano1; 1-cyc10hexy1-2—(9-meth0xy-5H- imidazo[5,1-a]isoind01y1)ethan01 —(2—Cyclohexy1—2—hydr0xyethy1)—5H- imidazo[5,1—a]isoind01—9—01 2—(8-ch10r0-5H-imidazo[5,1-a]isoind01—5— y1)cyclohexylethan01; 1—(cyclohexeny1)(5H- imidazo[5,1-a]isoindol-S-y1)ethan01; 1-cyclohexy1-2—(8-ﬂu0r0-5H-imidazo[5, 1- a]isoind01-5 -y1)ethan01; 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01—5— y1)—1—(1,4—di0xaspir0[4.5]decan—8— y1)ethan01; 6-ﬂu0r0-5H-imidazo[5, oind01- -y1)hydr0xyethy1)cyclohexanone; 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01—5— y1)(4-methylenecyclohexy1)ethanol; 1—(cyclohex—3 —en—1—y1)—2—(5H— imidazo[5,1-a]isoindol-S-y1)ethan01; 1-(4-(hydroxymethy1)cyc10hexy1)-2—(5H- 13 83 o[5,1-a]isoindol-S-y1)ethan01; (4-(1-hydr0xy(5H-imidazo[5,1- a]is0ind01—5-y1)ethy1)piperidin y1)(thi0pheny1)methan0ne; 1-(4-(1-hydr0xy-2—(5H-imidazo[5, 1- a]isoind01y1)ethy1)piperidin y1)ethan0ne; 2—(5H-imidazo[5,1-a]isoind01y1)(4- methylenecyclohexyl)ethanol; 2-(6-ﬂu0r0-5H-imidazo[5,1-a]isoind01—5— y1)- 1-(4-methylcyc10hexy1)ethan01; 1-cyclohexy1(5H-imidazo[5,1- a]isoind01—5 -y1)ethanamine 2-(5H-imidazo[5,1-a]isoind01y1)(1- methyl-1H-imidazoly1)ethan01; 2—(5H-imidazo[5,1-a]isoind01y1) (thiazoly1)ethan01; imidazo[5,1-a]isoind01y1) (thiazol-S-y1)ethan01; 1-(4-(1-hydr0xy-2—(5H-imidazo[5, 1- a]isoind01y1)ethy1)piperidiny1)-2,2— dimethylpropan0ne; 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01—5— y1)(furany1)ethan01; 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01—5— y1)(1-methy1—1H-imidazol y1)ethan01; u0r0-5H-imidazo[5,1-a]isoind01—5— y1)—1—(4— (iodomethylene)cyclohexyl)ethanol; 1-cyclohexy1(5H-imidazo[5,1- a] isoindol-S -y1)pr0pan01; 2—(5H—imidazo[5, 1 -a]isoind01—5— y1)acet0nitrile; 2012/033245 1—cyclohexy1—3—(6—ﬂu0r0—5H—imidazo[5, 1- a]isoind01—5 -y1)pr0pan01; 1—Cyclohexy1—3-(5H-imidazo[5, 1- a]isoind01-5 -y1)pr0pan01; 1-(4-(1-hydr0xy-2—(5H-imidazo[5, 1- a]isoindol-S-y1)ethy1)piperidiny1) phenylethanone; —diﬂuorocyclohexy1)—2—(6—ﬂu0r0— 5H-imidazo[5,1-a]isoindol-S-y1)ethan01; 1-(4,4-diﬂuorocyc10hexy1)-2—(5H- imidazo[5,1-a]isoindol-S-y1)ethan01; 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01—5— y1)(1-methy1—1H-imidazol y1)ethan01; 1-(4-(cyc10propylmethylene)cyclohexyl)- 2-(6-ﬂu0r0-5H-imidazo[5, 1-a]isoind01—5— y1)ethan01; Structure F 2-(6-ﬂu0r0-5H-imidazo[5,1-a]isoind01—5— 141 1 y1)(4-(pr0pan \ ylidene)cyc10hexy1)ethan01; \ (E)—5—(2—cyclohexy1viny1)-5H- 1412 N imidazo[5,1—a]isoindole; 2-(9-ﬂu0r0-5H-imidazo[5, 1-a]isoind01—5— 1413 y1)(4-methylcyclohexy1)ethanol; F \ » F OH 1-(cyclohexen-1—y1)—2—(6—ﬂu0r0—5H— 1414 O N imidazo [5 ,1-a]isoind01—5 han01; \ 7 9/ (R)cyclohexy1—2-((R)-5H-imidazo[5, 1- 141 5 a]isoind01—5 -y1)ethan01 (S)—1—cyclohexy1—2-((R)-5H-imidazo[5, 1- 1416 a]isoind01—5 -y1)ethan01 (S)—1—Cyclohexy1—2—((S)—5H—imidaz0[5,1- 141 7 .. a]isoind01—5 -y1)ethan01 cyc10hexy1—2—((S)-5H-imidazo[5 ,1- 1418 ” a]isoind01—5 -y1)ethan01 1-cyc10hexy1—2—(5H-imidazo[5, 1- 1419 / N . . .

/ A a]1somd01 5 e)ethan01_ _ 1-c clohex 1-2— 5H-imidazo 5,1- y ( [ 1420 E539 y.

/ A . o d01—5-y1)ethy1 acetate N )7/ 1—(4—(2— 142 1 (benzyloxy)ethylidene)cyclohexy1)—2— (5H-imidazo[5,1-a]isoind01—5-y1)ethan01 1-(1-(benzylsulfony1)piperidiny1)—2— 1422 (SH-imidazo [5 ,1-a]isoind01—5-y1)ethan01 1 -(4-(1-hydr0xy-2—(5H-imidazo[5, 1- 1423 a]isoindol-S-y1)ethy1)piperidiny1) (pyrimidin-S -y1)ethan0ne 2-(3 ,4-diﬂu0r0pheny1)(4-(1-hydr0xy-2— 1424 (5H-imidazo[5,1-a]isoind01—5— y1)ethy1)piperidiny1)ethan0ne cyclohexy1(4-(1-hydr0xy(5H- imidazo[5,1-a]isoind01—5— y1)ethy1)piperidiny1)methan0ne methyl 4-(1-hydr0xy(5H-imidazo[5,1- 1426 a]isoind01—5— y1)ethy1)cyclohexanecarboxylate 1-cyclohexy1(5H-imidazo[5,1- a]isoind01-5 -y1)ethy1 phenylcarbamate 4-(1-cyclohexy1(5H-imidazo[5, 1 - a]isoind01—5 -y1)eth0xy)0x0butan0ic acid 4-(1-hydr0xy(5H-imidazo[5,1- nd01—5 -y1)ethy1)cyclohexan01 1-(4-(hydroxymethy1)cyc10hexy1)-2—(5H- imidazo[5,1-a]isoind01y1)ethan01 1-cyclohexy1(5H-imidazo[5,1- a]isoind01—5-y1)ethy1 te 4-(1-hydr0xy(5H-imidazo[5,1- NH a]1somd01 5 y1)ethy1) N (2- - _ _ _ _ _ 1432 N / B N) HO (methylsulfonamido)ethy1)cyclohexanecar HN ,0 . ‘3’ boxamlde 0” \ (2 S)—1-(1-cyclohexy1—2-(5H-imidazo[5 ,1- a]isoindol-S-y1)eth0xy)methy1—1- oxobutan-Z-aminium chloride sodium 1—cyclohexy1—2—(5H—imidazo[5, 1- 1434 a]isoind01—5-y1)ethy1 phosphate 4-(1-hydr0xy(5H-imidazo[5,1- 143 6 a]isoind01—5— y1)ethy1)cyclohexanecarboxylic acid 1-(4-(1-hydr0xy-2—(5H-imidazo[5, 1- ndol-S-y1)ethy1)piperidiny1) (pyridiny1)ethan0ne 2—(5H-imidazo[5, 1 ind01—5 -y1) (Spiro[2.5]octan—6—y1)ethan01 2-(4-ﬂu0r0pheny1)(4-(1-hydr0xy-2— 143 9 (5H-imidazo[5,1-a]isoind01—5- y1)ethy1)piperidiny1)ethan0ne (ZS c) yclohexy1—2- 5H-imidazo 5,1-( [ 1440 N C / A O O a]isoind01—5-y1)ethy1 2-aminopr0pan0ate H2NWt 1-(4-(2-hydr0xyethylidene)cyclohexy1)—2- (5H-imidazo[5, 1-a]isoind01y1)ethan01 -cyclohexy1—2-(5H-imidazo[5 ,1- a]isoind01—5-y1)ethy1 pyrrolidine-Z- carboxylate (2 S)—5—( 1 —cyclohexy1(5H-imidazo[5, 1- a]isoind01—5-y1)ethy1) l-methyl 2- aminopentanedioate 1—(4—((S)—1-hydr0xy-2—((S)-5H- imidazo[5,1-a]isoind01—5— yl)ethy1)piperidiny1)phenylethan0ne (3—ﬂu0r0—2-hydr0xypheny1)(4-(1- hydroxy-Z-(SH-imidazo[5,1-a]isoind01—5— y1)piperidiny1)methan0ne 4-(1-hydr0xy(5H-imidazo[5,1- a]isoind01-5 -y1)ethy1)-N— phenylpiperidinecarb0xamide (4-ﬂu0r0pheny1)(4-(1-hydr0xy-2—(5H- o[5,1-a]isoind01—5— y1)ethy1)piperidiny1)methan0ne (ZS)amin0(4-(1-hydr0xy(5H- imidazo[5,1-a]isoind01—5— yl)ethy1)piperidiny1)-3 -pheny1pr0pan- l—one (4-(1-hydr0xy(5H-imidazo[5,1- a] isoindol-S -y1)ethy1)piperidiny1)((S)- pyrrolidiny1)methan0ne (1R,4s)—4—(2—((S)—6—ﬂu0r0—5H— o[5,1-a]isoind01—5-yl) hydroxyethyl)cyclohexy1 benzoate (1R,4s)—4—(2—((S)—6—ﬂu0r0—5H— imidazo[5,1-a]isoind01—5-yl) hydroxyethy1)cyclohexanol 1-(3 -(1-hydr0xy-2—(5H-imidazo[5, 1- a]isoind01—5 -y1)ethy1)azetidiny1) phenylethanone 3-(1-hydr0xy(5H-imidazo[5,1- a]isoind01—5 -y1)ethyl)—N-pheny1azetidine- l-carboxamide tert—butyl 3 -(1-hydr0xy(5H- imidazo[5,1-a]isoind01—5— yl)ethy1)azetidine-l-carboxylate tidiny1)(5H-imidazo[5,1- a]isoind01—5 -y1)ethan01 tert—butyl 4—((S)—1—hydr0xy—2—((R)—5H— imidazo[5,1-a]isoind01—5— y1)ethy1)piperidinecarb0xy1ate tert—butyl 4—((R)—1—hydr0xy—2—((R)—5H— o[5,1-a]isoind01—5— y1)ethy1)piperidinecarb0xy1ate tert—butyl 4—((R)—1—hydr0xy—2—((S)—5H— imidazo[5,1-a]isoind01—5— y1)ethy1)piperidinecarb0xy1ate tert—butyl 4—((S)—1—hydr0xy—2—((S)—5H— imidazo[5,1-a]isoind01—5— y1)ethy1)piperidinecarb0xy1ate 1-((1s,4s)—4-(benzy10xy)cyclohexy1)(6— ﬂuoro-SH-imidazo[5,1-a]isoind01—5— y1)ethan01 2—(5H—imidazo[5, 1 ind01—5_y1)_ 1- (pyridin-3 -y1)ethan01 (1r,4r)(2-(6-ﬂu0r0-5H-imidazo[5, 1— a]isoind01y1)— 1- hydroxyethy1)cyclohexanol 4-((S)hydr0xy((R)-5H-imidazo[5,1- a]isoind01—5 -y1)ethy1)-N— phenylpiperidinecarb0xamide 4-((R)—1-hydr0xy((R)-5H-imidazo[5 ,1- nd01—5 -y1)ethy1)-N— phenylpiperidinecarb0xamide 4-((R)—1-hydr0xy((S)-5H-imidazo[5, 1- nd01—5 -y1)ethy1)-N— phenylpiperidinecarb0xamide 4-((S)hydr0xy((S)-5H-imidazo[5,1- a]isoind01—5 -y1)ethy1)-N— phenylpiperidinecarb0xamide 1—(4—((R)—1—hydr0xy—2—((S)—5H— 1480 imidazo[5,1-a]isoind01—5- y1)ethy1)piperidiny1)phenylethan0ne 1—(4—((S)—1—hydr0xy—2—((S)—5H— imidazo[5,1-a]isoind01—5— y1)ethy1)piperidiny1)phenylethan0ne (1R,4s)—4—((S)—2—((R)—6—ﬂu0r0—5H— imidazo[5,1-a]isoind01—5-y1) hydroxyethy1)cyclohexanol (1 S,4s)—4—((R)—2—((R)—6—ﬂu0r0—5H— imidazo[5,1-a]isoind01—5-y1) hydroxyethy1)cyclohexanol (1 4—((R)—2—((S)—6—ﬂu0r0—5H— imidazo[5,1-a]isoind01—5-y1) hydroxyethy1)cyclohexanol (1R,4s)—4—((S)—2—((S)—6—ﬂu0r0—5H— imidazo[5,1-a]isoind01—5-y1) hydroxyethy1)cyclohexanol (1 S,4r)—4—((S)—2—((S)—6—ﬂuor0—5H— imidazo[5,1-a]isoind01—5-y1) hydroxyethy1)cyclohexanol (1 S,4r)—4—((S)—2—((R)—6—ﬂuor0—5H— imidazo[5,1-a]isoind01—5-y1) hydroxyethy1)cyclohexanol (1R,4r)—4—((R)—2—((S)—6—ﬂu0r0—5H— imidazo[5,1-a]isoind01—5-y1) hydroxyethy1)cyclohexanol (1R,4r)—4—((R)—2—((R)—6—ﬂu0r0—5H— imidazo[5,1-a]isoind01—5-y1) hydroxyethy1)cyclohexanol 1—(4—((S)—1—hydr0xy—2—((S)—5H— imidazo[5,1-a]isoind01—5— y1)ethy1)piperidiny1)(tetrahydr0-2H- 4-y1)ethan0ne 1—(4—((R)—1—hydr0xy—2—((R)—5H— imidazo[5,1-a]isoind01—5— y1)ethy1)piperidiny1)phenylethan0ne H45 N—((1s,4s)(1-hydr0xy-2—(5H- 1492 O imidazo[5,1-a]isoind01—5- y1)ethy1)cyc10hexy1)benzamide 1—(4—((S)—1—hydr0xy—2—((R)—5H— imidazo[5,1-a]isoind01—5— y1)ethy1)piperidiny1)phenylethan0ne 2-(5H-imidazo[5,1-a]isoind01—5-y1)(1- (phenylcarbam0y1)piperidiny1)ethy1 phenylcarbamate —1-hydr0xy((S)-5H-imidazo[5, 1- a]is0ind01—5-y1)ethy1)-N—((1r,4R) hydroxycyc10hexy1)piperidine-1 - carboxamide 4-((S)hydr0xy((S)-5H-imidazo[5,1- a]isoind01—5 -y1)ethy1)-N-(tetrahydr0-2H- pyrany1)piperidinecarb0xamide 4-((S)hydr0xy((S)-5H-imidazo[5,1- a]isoindol-S-y1)ethy1)-N—((1r,4S) hydroxycyc10hexy1)piperidine carboxamide 1 -((1r,4r)(benzyloxy)cyclohexy1)—2- 1498 O A N HO (5H-1m1dazo[5,1-a]1somd01—5-y1)ethan01. . . .

WO 42237 (G 1 -(( 1r,4r)(benzy10xy)cyc10hexy1)—2—(6— ﬂu0r0-5H-imidazo[5,1-a]isoind01—5— / 3 H HO y1)ethan01 1—(4—((R)—1—hydr0xy—2—((S)—5H— imidazo[5,1-a]isoind01—5— 1500 y1)ethy1)piperidiny1)(tetrahydr0-2H- pyrany1)ethan0ne 2—(5H-imidazo[5,1-a]isoind01—5-y1) 1501 (pyridiny1)ethan01 2—(5H-imidazo[5,1-a]isoind01—5—y1)_1_ 1502 (pyridiny1)ethan01 4-((R)—1-hydr0xy((S)-5H-imidazo[5, 1- 1503 a]isoind01—5 -y1)ethy1)-N-(tetrahydr0-2H- pyrany1)piperidinecarb0xamide ohexy1((R)hydr0xy((S)- 1504 .= 5H-imidazo[5,1-a]isoind01—5- y1)ethy1)piperidinecarb0xamide N—((1r,4r)(1-hydr0xy(5H- 1505 imidazo[5,1-a]isoind01—5- yl)ethy1)cyc10hexy1)benzamide 1 -((1r,4r)(benzyloxy)cyclohexy1)—2- 1506 (SH-imidazo [5 ,1-a]isoind01—5-y1)ethan01 O N—cyclopentyl-4—((R)— 1 —hydroxy—2—((S)— 5H—imidazo[5, 1 indol—5— yl)ethyl)piperidine- l -carboxamide uoro-5H-imidazo[5, l-a]isoindol-5— y1)—1—(4— (triﬂuoromethyl)cyclohexyl)ethanol 2—(5H-imidazo[5, l-a]isoindolyl)- l -(4- (triﬂuoromethyl)cyclohexyl)ethanol l—(4—((R)— l —hydroxy—2—((S)—5H— imidazo[5, oindol—5— yl)ethyl)piperidin- l -yl)(4- (triﬂuoromethyl)phenyl)ethanone 4-((R)- l -hydroxy((S)-5H—imidazo[5, l- a]isoindol—5—yl)ethyl)—N—(4— (triﬂuoromethyl)phenyl)piperidine- l - carboxamide (4-((R)- l -hydroxy((S)—5H—imidazo[5, l - a]isoindolyl)ethyl)piperidin- l -yl)(lH- imidazol- l thanone Biological Example 6 In Vivo Testing of IDO Inhibitors for Antitumor Activity in Combination with Chemotherapeutic Agents In vivo anti-tumor efﬁcacy can be tested using modiﬁed tumor allograft ols. For instance, it has been described in the literature that IDO inhibition can syngerize with cytotoxic chemotherapy in immune-competent mice. Due to different susceptibilities of different tumor cell lines to chemotherapeutic drugs and to immune mediated rejection, each IDO inhibitor is tested alone and in combination with 2 different chemotherapeutic drugs in 4 different animal tumor models, represented by 4 ent mouse tumor cell lines, of different tissue origin (colorectal, bladder, y and lung carcinoma), implanted subcutaneously in syngeneic strains of mice. These cell lines have been selected based on their known susceptibility to chemotherapeutic drugs, their partial response to IDO inhibitors as single agents, their presumed pattern of IDO expression according to their tissue of origin, and their ability to elicit an immune on.

For every animal tumor model, 2 ent chemotherapeutic drugs are tested in te groups of mice according to the following list: 1] LLC tumor: cyclophosphamide and paclitaxel; 2] EMT6 tumor: cyclophosphamide and paclitaxel; 3] CT26 tumor: cyclophosphamide and doxorubicin; and 4] MB49 tumor: cyclophosphamide and gemcitabine.

The following chemotherapeutic drugs are used, at the indicated doses. The maximum tolerated dose for the ing chemotherapeutic agents in mice depends on the formulation, concentration, frequency of administration, route of administration and number of doses. The chemotherapeutic drugs administered in ction with each IDO inhibitor drug are: 1] Paclitaxel: 20 mg/kg/day i.p, every 4 days, 4 times (q4dx4) (in Cremophor); 2] Doxorubicin: 5 mg/kg, once a week for 3 weeks (q7dx3); 3] Cyclophosphamide (CTX): 100 mg/kg, I.P., every 4 days, 4 times (q4dx4); 4] Gemcitabine: 80 mg/kg every 4 days, 4 times, i.p.

All animals receive a subcutaneous injection of a tumor forming dose of live tumor cells (~ 50000 - 1000000 cells) ded in 0.1 mL of PBS or saline on day 1. Subcutaneous injection forms a localized tumor that allows monitoring tumor growth over time.

To mimic the effect of IDO inhibitor drugs as therapeutic compositions, administration of IDO inhibitor drugs begins at day 5-8 after tumor inoculation. Dosing, route of stration, dosing frequency varies depending on the toxicity and pharmacokinetics profile of each drug. Duration of the treatment is 2 weeks. Most preferably, drug is administered continuously via oral gavage or dissolution in the drinking water. Alternatively, subcutaneous slow release pellets or osmotic pumps containing 100 mg of each drug are implanted under the AH26(9298372_1):RTK skin by surgical ure. IDO inhibitor drug are administered at the maximum tolerated dose or at a concentration corresponding to the LD50.

To test the antitumor activity of compounds 1357 and 1304, 200000 LLC murine tumor cells were injected subcutaneously into eic C57Bl6 mice on day 0. Each treatment group consists of 10 mice. On day 7, once the tumor is established and IDO expression is induced in plasmacytoid dendritic cells at the tumor draining lymph nodes, a group of 10 mice were surgically implanted (subcutaneously and on the opposite flank to the tumor), with osmotic pumps loaded with 200 uL of a 30 mg/mL solution of compounds 1357 or 1304 in cremaphor:EtOH:saline (10:10:80). These pumps release 1 uL of solution per hour for a period of 8 days, achieving a steady state plasma concentration of drug of ~ 0.5-3 micromolar. From days 15 to 24 compound administrations continued via two s.c. daily doses of 1 mg each. In the case of compound 1304, mice were optionally treated with cyclophosphamide 100 mg/kg by eritoneal injection on days 9, 13 and 15 post-tumor innoculation, either as a single agent or in combination with nd 1304. The results of these tests indicate that compounds 1357 and 1304 have a significant antitumor effect either as a single agent or when administered in combination with chemotherapy. The eutic effect is observed as a d rate of tumor growth, which has an impact on median survival time and in overall survival on.

The average tumor volume over time of two groups of 10 mice each was studied.

The control group was treated with vehicle, while the ent groups received osmotic pumps with compound 1357 as described above. The tumor volumes were fitted to an exponential growth equation and the fitted parameters were compared using GraphPad software. The data te a tically significant differences between the two curves (p<0.0001).

A survival plot of the same groups of mice described immediately above was generated. The logrank test indicates a statistically significant difference in median survival time when animals were treated with compound 1357 as a single agent.

The average tumor volume over time of four groups of 10 mice each was studied.

The control group was treated with vehicle, while the treatment groups received either cyclophosphamide chemotherapy, osmotic pumps with compound 1304, or a combination therapy of hosphamide with compound 1304. The data shows that this tumor is very AH26(9298372_1):RTK sensitive to the effects of treatment with nd 1304 either as a single agent or in combination with chemotherapy.

A al plot of the same groups of mice described immediately above was generated. The logrank test indicated a statistically significant difference in median survival time when animals were treated with compound 1304, either as a single agent or in combination with cyclophosphamide. The long term survival fraction observed for treatment with 1304 is exceptionally high, with 70-80% of the mice being tumor free after 60 days.

AH26(9298372_1):RTK WE

Claims

CLAIM 1.:

1. A compound of the formula, (R1)n or a pharmaceutically acceptable salt thereof, wherein bond α is a single or double bond; n is 0, 1, 2, 3, or 4; each R1 is independently halogen, cyano, nitro, C1-6alkyl, C1-6haloalkyl, -OR, -N(R)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)2R, OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)C(O)N(R)2; R2 is –C1-4alkyl-RA or –C2-4alkenyl-R3 when bond α is a single bond; and R2 is =C(H)RA when bond α is a double bond; wherein RA is –CN, –C(O)R3, –C(O)OR3, (R3)(RC), –C(ORB)(R3)(RC), -C(NHRB)(R3)(RC), or ORC)R3, wherein RB is hydrogen, C1-6alkyl, C1-6haloalkyl, -C1-6alkyl-RB1, -C(O)R3, -C(O)N(H)R3, or -S(O)2R3, -C(O)(CH2)1-4COOR, -C(O)(CH2)1-4(NR)COOR, – C(O)CH(NH2)(RD), -S(O)2OR3, -S(O)2N(R3)2, -CH2-OP(O)2(OR)2, or – P(O)(OR3)2, wherein RB1 is cyano, nitro, C1-6alkyl, C1-6haloalkyl, -OR, -N(R)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)2R, OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, (O)OR, or -N(R)C(O)N(R)2; RD is hydrogen, methyl, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), benzyl, 4-hydroxybenzyl, -indolyl), -CH2SH, -CH2CH2SCH3, -CH2OH, -CH(CH3)OH, -(CH2)4-NH2, -(CH2)3-N(H)C(=NH)NH2, -CH2(4-imidazolyl), OH, -CH2CH2COOH, -CH2CONH2, -CH2CH2CONH2; AH26(9298372_1):RTK each R3 is ndently hydrogen, C1-6alkyl, C1-6haloalkyl, aryl, heteroaryl, C3-8cycloalkyl, C3-8cycloalkenyl, 3-10 membered heterocyclyl, arylC1-6alkyl-, heteroarylC1-6 alkyl-, C3-8cycloalkylC1-6alkyl-, C3-8cycloalkenylC1-6alkyl-, (3-10 membered heterocyclyl)C1-6alkyl-, or (heteroaryl)-(3-10 membered heterocyclyl)-, wherein the alkyl, cloalkyl, cloalkenyl, 3-10 membered cyclyl, C3-8cycloalkylC1-6alkyl-, C3-8cycloalkenylC1-6alkyl-, (3-10 ed heterocyclyl)C1-6alkyl-, and (heteroaryl)-(3-10 membered cyclyl)-, are each optionally and independently substituted by one =R32 group and each optionally substituted and ndently by one, two, three, or four R31 groups; the aryl, heteroaryl, arylC1-6alkyl-, and heteroarylC1-6alkyl- groups, are each optionally substituted by one, two, three, or four R31 groups; wherein each R31 is independently halogen, cyano, nitro, C1-6alkyl, -C1-6alkyl-R33, C1-6haloalkyl, -OR, -N(R)2, -SR, -C(O)OR, -C(O)N(R)2, - C(O)N(OH)R, -C(O)R, -C(NR11)R, -C(NR11)N(R11)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)N(R)2, wherein R33 is cyano, -OR, -N(R)2, -SR, -C(O)OR, -C(O)N(R)2, , -S(O)R, -S(O)OR, -S(O)N(R)2, R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)C(O)N(R)2; R32 is =O, =S, =N(R), =N(OR), =C(R34)2, =(spiro-C3-8cycloalkyl), or =(spiro-(3-10 membered heterocyclyl)), n each R34 is independently hydrogen, halogen, cyano, C1-6alkyl, - C1-6alkyl-OR, C1-6haloalkyl, C3-8cycloalkyl, or 3-10 membered heterocyclyl; or both R34 taken er with the atom to which they are both attached form a monocyclic C3-8cycloalkyl or monocyclic 3-8 membered heterocyclyl; RC is hydrogen or C1-6alkyl; AH26(9298372_1):RTK each R is independently en or R10, wherein R10 is C1-6alkyl, C1-6haloalkyl, aryl, heteroaryl, C3-8cycloalkyl, C3-8cycloalkenyl, 3-10 membered cyclyl, arylC1-6alkyl, heteroarylC1-6alkyl-, C3-8 cycloalkylC1-6alkyl-, C3-8cycloalkenylC1-6alkyl-, or (3-10 membered heterocyclyl)C1-6alkyl-, each R10 optionally tuted by one, two, three, or four groups that are each independently halogen, cyano, nitro, C1-6alkyl, C1-6haloalkyl, -OR11, -N(R11)2, -SR11, -C(O)OR11, -C(O)N(R11)2, -C(O)R11, -S(O)R11, -S(O)OR11, -S(O)N(R11)2, -S(O)2R11, -S(O)2OR11, -S(O)2N(R11)2, -OC(O)R11, OR11, -OC(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2R11, or – C(O)-(3-10 membered heterocyclyl), wherein each R11 is independently hydrogen or C1-6alkyl.

2. The compound of claim 1 wherein bond α is a single bond.

3. The compound of claim 1 or 2, wherein R2 is lkyl-RA.

4. The compound of claim 1 or 2, wherein R2 is –CH2-RA, –CH2CH2-RA, -C(H)(CH3)CH2-RA, or -C(H)=C(H)R3.

5. The nd of claim 1 or 2, wherein R2 is –CH2-RA.

6. The compound of any one of claims 1 – 5, wherein RA is –C(O)R3 or –C(ORB)(R3)(RC).

7. The compound of any one of claims 1 – 5, wherein RA is -C(NHRB)(R3)(RC), or -C(=N-ORC)R3.

8. The compound of any one of claims 1 – 5, wherein RA is -C(NHRB)(R3)(RC), wherein RB is hydrogen, C1-6alkyl, or -C(O)C1-6alkyl.

9. The compound of any one of claims 1 – 5, wherein RA is -C(NH2)(R3)(RC).

10. The compound of any one of claims 1 – 5, wherein RA is –C(O)R3.

11. The nd of any one of claims 1 – 5, wherein RA is )(R3)(RC).

12. The compound of any one of claims 1 – 5, wherein RA is –CH(OH)(R3). AH26(9298372_1):RTK

13. The compound of any one of claims 1 – 12, n R3 is hydrogen, C1-6alkyl, aryl, heteroaryl, C3-8cycloalkyl, C3-8cycloalkenyl, 3-10 ed heterocyclyl, or C3-8cycloalkylC1-6alkyl-, wherein the C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkenyl, 3-10 ed heterocyclyl, and C3-8cycloalkylC1-6alkyl-, are each optionally substituted by one =R32 group and one or two R31 groups; and the aryl and heteroaryl , are each optionally substituted by one or two R31 groups.

14. The compound of any one of claims 1 – 12, wherein R3 is aryl, heteroaryl, C3-8cycloalkyl, C3-8cycloalkenyl, 3-10 membered heterocyclyl, or C3-8cycloalkylC1-6alkyl-, wherein the C3-8cycloalkyl, C3-8cycloalkenyl, 3-10 membered heterocyclyl, and C3-8cycloalkylC1-6 alkyl-, are each optionally and ndently substituted by one =R32 group and each optionally and independently tuted by one or two R31 groups; and the aryl and heteroaryl groups, are each optionally substituted by one or two R31 groups.

15. The compound of any one of claims 1 – 12, wherein R3 is phenyl, a five or six membered heteroaryl, monocyclic C5-8cycloalkyl, monocyclic C5-8cycloalkenyl, a five or six membered monocyclic cyclyl, or (monocyclic C5-8cycloalkyl)C1-6 alkyl-, n the C5-8cycloalkyl, C5-8cycloalkenyl, 5 - 6 membered cyclyl, and C5-8cycloalkylC1-6 alkyl-, are each optionally and independently substituted by one =R32 group and each optionally and ndently substituted by one or two R31 groups; and the phenyl and heteroaryl groups, are each optionally substituted by one or two R31 groups.

16. The compound of any one of claims 1 – 12, wherein R3 is phenyl or a five or six membered heteroaryl, each optionally substituted by one or two R31 groups.

17. The compound of any one of claims 1 – 12, wherein R3 is clic C5-8cycloalkyl, monocyclic C5-8cycloalkenyl, a five or six membered monocyclic heterocyclyl, or (monocyclic C5-8cycloalkyl)C1-6alkyl-, each optionally substituted by one =R32 group and one or two R31 groups. (R31)m

18. The compound of any one of claims 1 – 12, wherein R3 is p , wherein bond a is a single bond or a double bond; m is 0, 1, or 2; AH26(9298372_1):RTK p is 0 or 1; and when bond a is a single bond, then Z is –C(R36)2-, –C(=R32)-, -N(R35)-, or –O-, wherein R35 is en, C1-6alkyl, -C(O)R, -S(O)2R, -C(O)OR, -C(O)N(R)2, -S(O)2OR, or -S(O)2N(R)2; and when bond a is a double bond, then Z is –C(R36)= or –N=; each R36 is independently hydrogen or R31.

19. The compound of claim 18, wherein when bond a is a single bond, then Z is –C(R36)2- or -C(=R32)-; and when bond a is a double bond, then Z is )= or –N=.

20. The compound of claim 18, wherein bond a is a single bond; and Z is –C(R36)2- or -C(=R32)-.

21. The compound of claim 18, wherein bond a is a single bond; and Z is -N(R35)- or –O-.

22. The compound of claim 2, wherein n is 0 or 1; each R1 is independently halogen, -OR, -N(R)2, or -SR; R2 is –CH2-RA, –CH2CH2-RA, or -C(H)=C(H)R3; and wherein RA is –C(O)R3, or –C(ORB)(R3)(RC), wherein RB is hydrogen; each R3 is independently hydrogen, C1-6alkyl, aryl, heteroaryl, C3-8cycloalkyl, C3-8cycloalkenyl, 3-10 membered cyclyl, or C3-8cycloalkylC1-6alkyl-, the C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkenyl, 3-10 membered heterocyclyl, and C3-8cycloalkylC1-6alkyl-, are each optionally and independently substituted by one =R32 group and each optionally and independently substituted by one or two R31 groups; the aryl and heteroaryl groups, are each optionally substituted by one or two R31 groups; wherein each R31 is independently halogen, cyano, nitro, C1-6alkyl, -C1-6alkyl-R33, C1-6haloalkyl, -OR, , -SR, R, -C(O)N(R)2, -C(O)R, AH26(9298372_1):RTK -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)N(R)2, wherein R33 is -OR, -N(R)2, or -SR; R32 is oxo, =C(R34)2, =(spiro-C3-8cycloalkyl), or =(spiro-(3-10 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, C1-6alkyl, or C3-8cycloalkyl; and RC is hydrogen or kyl.

23. The compound of claim 22 of the formula, (R1)n N .

24. The compound of claim 23, wherein R3 is aryl, heteroaryl, cloalkyl, C3-8cycloalkenyl, or 3-10 membered heterocyclyl, wherein the C3-8cycloalkyl, C3-8cycloalkenyl, and 3-10 membered cyclyl are each optionally substituted by one =R32 group and one, two, three, or four R31 ; and the aryl and heteroaryl are each optionally substituted by one, two, three, or four R31 groups.

25. The compound of claim 24 of the formula, (R1)n N RC (R31)m Z p , wherein bond a is a single bond or a double bond; m is 0, 1, or 2; p is 0 or 1; and AH26(9298372_1):RTK when a is a single bond, then Z is –C(R36)2-, –C(=R32)-, -N(R35)-, or –O-, wherein R35 is hydrogen, C1-6alkyl, -C(O)R, -S(O)2R, -C(O)OR, -C(O)N(R)2, -S(O)2OR, or -S(O)2N(R)2; and when a is a double bond, then Z is –C(R36)= or –N=; and each R36 is independently hydrogen or R31.

26. The compound of any one of claims 1-22 of the formula, (R1)n n the stereoisomeric configuration of -1 (C-1) and carbon-3 (C-3) are respectively (R, R).

27. The compound of any one of claims 1-22 of the formula, (R1)n wherein the stereoisomeric configuration of carbon-1 and carbon-3 are tively (R, S).

28. The compound of any one of claims 1-22 of the formula, (R1)n wherein the stereoisomeric configuration of -1 and carbon-3 are respectively (S, R).

29. The compound of any one of claims 1-22 of the formula, AH26(9298372_1):RTK (R1)n wherein the stereoisomeric configuration of carbon-1 and carbon-3 are respectively (S, S).

30. The compound of any one of claims 1-22 of the formula, (R1)n wherein the stereoisomeric configuration of carbon-1 and carbon-3 are respectively (S, R) or (S,S), and wherein R3 is cyclohexyl and R31 is OR

31. The compound of any one of claims 1-22 of the a, (R1)n wherein the stereoisomeric configuration of carbon-1 and carbon-3 are respectively (S, R), or (S,S) and wherein R3 is piperidine and R31 is -C(O)R or -C(O)(NHR).

32. The nd of claim 1 that is 2-(5H-imidazo[5,1-a]isoindolyl)ethanol; ethyl 2-(5H-imidazo[5,1-a]isoindolyl)acetate; (E)(2-bromostyryl)-5H-imidazo[5,1-a]isoindole; 2-(6-chloro-5H-imidazo[5,1-a]isoindolyl)cyclohexylethanol; 2-(6-chloro-5H-imidazo[5,1-a]isoindolyl)cyclohexylethanone; 2-(5H-imidazo[5,1-a]isoindolyl)ethyl2-(((1R,2R,5S)isopropyl methylcyclohexyl)oxy)acetate; utyl (5H-imidazo[5,1-a]isoindolyl)acetyl)phenyl)carbamate; 1-(4-aminophenyl)(5H-imidazo[5,1-a]isoindolyl)ethanone; tert-butyl (4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)phenyl)carbamate; AH26(9298372_1):RTK 1-(4-aminophenyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)(3-nitrophenyl)ethanone; 2-(5H-imidazo[5,1-a]isoindolyl)(3-nitrophenyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)(2-nitrophenyl)ethanone; 2-(5H-imidazo[5,1-a]isoindolyl)(2-nitrophenyl)ethanol; tert-butyl (2-(2-(5H-imidazo[5,1-a]isoindolyl)acetyl)phenyl)carbamate; tert-butyl (2-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)phenyl)carbamate; 1-(2-aminophenyl)(5H-imidazo[5,1-a]isoindolyl)ethanone; 1-(2-aminophenyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 1-(2-chlorophenyl)(5H-imidazo[5,1-a]isoindolyl)ethanone; 1-(5H-imidazo[5,1-a]isoindolyl)methylpropanol; 1-(2-chlorophenyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 1-(3-chlorophenyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)phenylethanone; 2-(5H-imidazo[5,1-a]isoindolyl)phenylethanol; -dimethylfuranyl)(6-fluoro-5H-imidazo[5,1-a]isoindolyl)ethanol; 1-(3-chlorophenyl)(5H-imidazo[5,1-a]isoindolyl)ethanone; ohexyl(6-fluoro-5H-imidazo[5,1-a]isoindolyl)ethanone; 1-cyclohexyl(6-fluoro-5H-imidazo[5,1-a]isoindolyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)(tetrahydro-2H-pyranyl)ethanol; 2-(7-chloro-5H-imidazo[5,1-a]isoindolyl)cyclohexylethanol; (Z)cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethanone oxime; opentyl(5H-imidazo[5,1-a]isoindolyl)ethanol; tert-butyl 4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidine carboxylate; 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethanamine; tert-butyl (3-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)phenyl)carbamate; 1-(3-aminophenyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)hydroxyethyl)cyclohexanol; 1-cyclohexyl(9-methoxy-5H-imidazo[5,1-a]isoindolyl)ethanol; 5-(2-cyclohexylhydroxyethyl)-5H-imidazo[5,1-a]isoindolol; 2-(8-chloro-5H-imidazo[5,1-a]isoindolyl)cyclohexylethanol; 1-(cyclohexenyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; AH26(9298372_1):RTK 1-cyclohexyl(8-fluoro-5H-imidazo[5,1-a]isoindolyl)ethanol; 2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)(1,4-dioxaspiro[4.5]decan anol; 4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)hydroxyethyl)cyclohexanone; 2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)(4-methylenecyclohexyl)ethanol; 1-(cyclohexenyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 1-(4-(hydroxymethyl)cyclohexyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; (4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)(thiophen hanone; 1-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)ethanone; 2-(5H-imidazo[5,1-a]isoindolyl)(4-methylenecyclohexyl)ethanol; 2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)(4-methylcyclohexyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)(thiazolyl)ethanol; imidazo[5,1-a]isoindolyl)(thiazolyl)ethanol; 1-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)-2,2- dimethylpropanone; 2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)(furanyl)ethanol; (1S)cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethanol; (1R)cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethanol; 2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)(4- (iodomethylene)cyclohexyl)ethanol; 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)propanol; 2-(5H-imidazo[5,1-a]isoindolyl)acetonitrile; 1-cyclohexyl(6-fluoro-5H-imidazo[5,1-a]isoindolyl)propanol; 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)propanol; 1-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) phenylethanone; 1-(4,4-difluorocyclohexyl)(6-fluoro-5H-imidazo[5,1-a]isoindolyl)ethanol; 1-(4,4-difluorocyclohexyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)(1-methyl-1H-imidazolyl)ethanol; 1-(4-(cyclopropylmethylene)cyclohexyl)(6-fluoro-5H-imidazo[5,1-a]isoindol yl)ethanol; 2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)(4-(propan ylidene)cyclohexyl)ethanol; AH26(9298372_1):RTK (E)(2-cyclohexylvinyl)-5H-imidazo[5,1-a]isoindole; 2-(9-fluoro-5H-imidazo[5,1-a]isoindolyl)(4-methylcyclohexyl)ethanol; 1-(cyclohexenyl)(6-fluoro-5H-imidazo[5,1-a]isoindolyl)ethanol; cyclohexyl((R)-5H-imidazo[5,1-a]isoindolyl)ethanol; (R)cyclohexyl((R)-5H-imidazo[5,1-a]isoindolyl)ethanol; (R)cyclohexyl((S)-5H-imidazo[5,1-a]isoindolyl)ethanol; (S)cyclohexyl((S)-5H-imidazo[5,1-a]isoindolyl)ethanol; 1-cyclohexyl(5H-imidazo[5,1-a]isoindolylidene)etanol; 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethyl acetate; 2-(benzyloxy)ethylidene)cyclohexyl)(5H-imidazo[5,1-a]isoindol yl)ethanol; 1-(1-(benzylsulfonyl)piperidinyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 1-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) (pyrimidinyl)ethanone; 2-(3,4-difluorophenyl)(4-(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)piperidinyl)ethanone; cyclohexyl(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidin yl)methanone; methyl 4-(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexanecarboxylate; 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethyl phenylcarbamate; 4-(1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethoxy)oxobutanoic acid; 4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)cyclohexanol; 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethyl benzoate; 4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)-N-(2- (methylsulfonamido)ethyl)cyclohexanecarboxamide; (2S)cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethylamino butanoate; 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethyl dihydrogen phosphate; 4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)cyclohexanecarboxylic acid; 1-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)(pyridin- 4-yl)ethanone; imidazo[5,1-a]isoindolyl)(spiro[2.5]octanyl)ethanol; 2-(4-fluorophenyl)(4-(1-hydroxy(5H-imidazo[5,1-a]isoindol AH26(9298372_1):RTK yl)piperidinyl)ethanone; (2S)cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethyl 2-aminopropanoate; 1-(4-(2-hydroxyethylidene)cyclohexyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; (2S)cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethyl pyrrolidine carboxylate; (2S)(1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethyl) 1-methyl 2- aminopentanedioate; 1-(4-((S)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) phenylethanone; (3-fluorohydroxyphenyl)(4-(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)piperidinyl)methanone; 4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)-N-phenylpiperidine carboxamide; (4-fluorophenyl)(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidin yl)methanone; (2S)amino(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidin yl)phenylpropanone; (4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)((S)- pyrrolidinyl) methanone; (1R,4s)(2-((S)fluoro-5H-imidazo[5,1-a]isoindolyl)hydroxyethyl) cyclohexyl benzoate; (1R,4s)(2-((S)fluoro-5H-imidazo[5,1-a]isoindolyl)hydroxyethyl) cyclohexanol; 1-(3-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)azetidinyl) phenylethanone; 3-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)-N-phenylazetidine amide; tert-butyl ydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)azetidine carboxylate 1-(azetidinyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; tert-butyl 4-((S)hydroxy((R)-5H-imidazo[5,1-a]isoindolyl)ethyl)piperidine- 1-carboxylate; tert-butyl 4-((R)hydroxy((R)-5H-imidazo[5,1-a]isoindolyl)ethyl)piperidine- 1-carboxylate; AH26(9298372_1):RTK tert-butyl 4-((R)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)piperidine- 1-carboxylate; tert-butyl 4-((S)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)piperidine- 1-carboxylate; 1-((1s,4s)(benzyloxy)cyclohexyl)(6-fluoro-5H-imidazo[5,1-a]isoindol anol; imidazo[5,1-a]isoindolyl)(pyridinyl)ethanol; (1r,4r)(2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl) hydroxyethyl)cyclohexanol; 4-((S)hydroxy((R)-5H-imidazo[5,1-a]isoindolyl)ethyl)-N-phenylpiperidine- 1-carboxamide; 4-((R)hydroxy((R)-5H-imidazo[5,1-a]isoindolyl)ethyl)-N-phenylpiperidine- 1-carboxamide; 4-((R)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)-N-phenylpiperidine- 1-carboxamide; 4-((S)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)-N-phenylpiperidine- 1-carboxamide; 1-(4-((R)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) phenylethanone; (1R,4s)((S)((R)fluoro-5H-imidazo[5,1-a]isoindolyl) hydroxyethyl)cyclohexanol; )((R)((R)fluoro-5H-imidazo[5,1-a]isoindolyl) hydroxyethyl)cyclohexanol; (1S,4s)((R)((S)fluoro-5H-imidazo[5,1-a]isoindolyl) hydroxyethyl)cyclohexanol; (1R,4s)((S)((S)fluoro-5H-imidazo[5,1-a]isoindolyl) hydroxyethyl)cyclohexanol; (1S,4r)((S)((S)fluoro-5H-imidazo[5,1-a]isoindolyl) hydroxyethyl)cyclohexanol; (1S,4r)((S)((R)fluoro-5H-imidazo[5,1-a]isoindolyl) hydroxyethyl)cyclohexanol; (1R,4r)((R)((S)fluoro-5H-imidazo[5,1-a]isoindolyl) hydroxyethyl)cyclohexanol; (1R,4r)((R)((R)fluoro-5H-imidazo[5,1-a]isoindolyl) AH26(9298372_1):RTK hydroxyethyl)cyclohexanol; 1-(4-((S)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) hydro-2H-pyranyl)ethanone; 1-(4-((R)hydroxy((R)-5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) phenylethanone; N-((1s,4s)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)benzamide; 1-(4-((S)hydroxy((R)-5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) phenylethanone; 2-(5H-imidazo[5,1-a]isoindolyl)(1-(phenylcarbamoyl)piperidinyl)ethyl phenylcarbamate; 4-((R)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)-N-((1r,4R) ycyclohexyl)piperidinecarboxamide; 4-((S)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)-N-(tetrahydro-2H- pyranyl)piperidinecarboxamide; 4-((S)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)-N-((1r,4S) hydroxycyclohexyl)piperidinecarboxamide; 1-((1r,4r)(benzyloxy)cyclohexyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 1-((1r,4r)(benzyloxy)cyclohexyl)(6-fluoro-5H-imidazo[5,1-a]isoindol yl)ethanol; 1-(4-((R)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) (tetrahydro-2H-pyranyl)ethanone; 2-(5H-imidazo[5,1-a]isoindolyl)(pyridinyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)(pyridinyl)ethanol; 4-((R)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)-N-(tetrahydro-2H- pyranyl)piperidinecarboxamide; N-cyclohexyl((R)hydroxy((S)-5H-imidazo[5,1-a]isoindol yl)ethyl)piperidinecarboxamide; N-((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)benzamide; N-cyclopentyl((R)hydroxy((S)-5H-imidazo[5,1-a]isoindol yl)ethyl)piperidinecarboxamide; luoro-5H-imidazo[5,1-a]isoindolyl)(4- (trifluoromethyl)cyclohexyl)ethanol; AH26(9298372_1):RTK 2-(5H-imidazo[5,1-a]isoindolyl)(4-(trifluoromethyl)cyclohexyl)ethanol; (R)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) (4-(trifluoromethyl)phenyl)ethanone; 4-((R)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)-N-(4- (trifluoromethyl)phenyl)piperidinecarboxamide; (4-((R)hydroxy((S)-5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)(1H- imidazolyl)methanone; 1-(5H-imidazo[5,1-a]isoindolyl)methylbutanol; 2-(5H-imidazo[5,1-a]isoindolyl)(tetrahydro-2H-pyranyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)(piperidinyl)ethanol; 1-cyclohexyl((R)-5H-imidazo[5,1-a]isoindolyl)ethanol; ohexyl((S)-5H-imidazo[5,1-a]isoindolyl)ethanol; 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)propanol; 1-cyclohexyl(9-fluoro-5H-imidazo[5,1-a]isoindolyl)ethanol; N-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)phenyl)(tetrahydro-2H- pyranyl)acetamide; 2-(5H-imidazo[5,1-a]isoindolyl)(1H-imidazolyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)(1H-imidazolyl)ethanol; 2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)(thiazolyl)ethanol; (5S)(2-cyclohexylhydroxyethyl)-5H-imidazo[5,1-a]isoindolol; 1-(2-aminocyclohexyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; N-(1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)ethyl)acetamide; N-(2-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)cyclohexyl)acetamide; 1-cyclohexyl(5H-imidazo[5,1-a]isoindolyl)-N-methylethanamine; 2-((1-cyclohexyl((S)-5H-imidazo[5,1-a]isoindol yl)amino)ethanesulfonamide; 2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)(1-methylpiperidinyl)ethanol; 1-(4-aminocyclohexyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; N-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)cyclohexyl)acetamide; 1-(4-(aminomethyl)cyclohexyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)cyclohexanecarboxamide; 1-(3-aminocyclohexyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)((1r,4r)(pyridin AH26(9298372_1):RTK ylmethoxy)cyclohexyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)((1r,4r)(pyridin ylmethoxy)cyclohexyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)((1r,4r)(pyridin ylmethoxy)cyclohexyl)ethanol; 1-((1r,4r)((2-aminopyridinyl)methoxy)cyclohexyl)(5H-imidazo[5,1- a]isoindolyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)((1r,4r)(pyrazin ylmethoxy)cyclohexyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)((1r,4r)(pyrimidin ylmethoxy)cyclohexyl)ethanol; 1-((1r,4r)((6-aminopyridinyl)methoxy)cyclohexyl)(5H-imidazo[5,1- a]isoindolyl)ethanol; 1-((1r,4r)((6-aminopyridinyl)methoxy)cyclohexyl)(5H-imidazo[5,1- ndolyl)ethanol; 1-((1r,4r)((3-aminopyridinyl)methoxy)cyclohexyl)(5H-imidazo[5,1- a]isoindolyl)ethanol; 1-((1r,4r)((2-aminopyrimidinyl)methoxy)cyclohexyl)(5H-imidazo[5,1- a]isoindolyl)ethanol; 1-((1r,4r)((4-aminopyrimidinyl)methoxy)cyclohexyl)(5H-imidazo[5,1- ndolyl)ethanol; 1-((1r,4r)((5-aminopyridinyl)methoxy)cyclohexyl)(5H-imidazo[5,1- a]isoindolyl)ethanol; 4-((((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)cyclohexyl)oxy)methyl)-N,N-dimethylbenzamide; 3-((((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)oxy)methyl)-N,N-dimethylbenzamide; 2-((((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)oxy)methyl)-N,N-dimethylbenzamide; 4-((((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)oxy)methyl)benzenesulfonamide; 3-((((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)oxy)methyl)benzenesulfonamide; 2-((((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol AH26(9298372_1):RTK yl)ethyl)cyclohexyl)oxy)methyl)benzenesulfonamide; 4-((((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)oxy)methyl)benzamide; 3-((((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)oxy)methyl)benzamide; 2-((((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)oxy)methyl)benzamide; methyl 4-((((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)oxy)methyl)benzoate; methyl 3-((((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)oxy)methyl)benzoate; methyl 2-((((1r,4r)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)oxy)methyl)benzoate; 2-(5H-imidazo[5,1-a]isoindolyl)((1r,4r)methoxycyclohexyl)ethanol; 1-((1r,4r)ethoxycyclohexyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)((1r,4r)isopropoxycyclohexyl)ethanol; ,4r)(cyclopropylmethoxy)cyclohexyl)(5H-imidazo[5,1-a]isoindol yl)ethanol; 1-((1r,4r)(cyclopentylmethoxy)cyclohexyl)(5H-imidazo[5,1-a]isoindol yl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)((1r,4r)(thiophen oxy)cyclohexyl)ethanol; 1-((1r,4r)((1H-indolyl)oxy)cyclohexyl)(5H-imidazo[5,1-a]isoindol yl)ethanol; 1-((1r,4r)((1H-indolyl)oxy)cyclohexyl)(5H-imidazo[5,1-a]isoindol yl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)(4-((tetrahydro-2H-pyran yl)methoxy)cyclohexyl)ethanol; 4-(((4-(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexyl)oxy)methyl)benzenesulfonamide; 2-(5H-imidazo[5,1-a]isoindolyl)(4-(oxazolylmethoxy)cyclohexyl)ethanol; imidazo[5,1-a]isoindolyl)(4-(thiazolylmethoxy)cyclohexyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)(1-(1-iminophenylethyl)piperidin yl)ethanol; AH26(9298372_1):RTK 4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)-N-phenylpiperidine carboximidamide; 4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)-N-(pyridinyl)piperidine- 1-carboximidamide; 4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)-N-(tetrahydro-2H-pyran yl)piperidinecarboximidamide; N-(4-cyanophenyl)(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)piperidinecarboxamide; N-(tert-butyl)(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidine carboxamide; N-(tert-butyl)(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidine amide; 1-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)(3- hydroxyphenyl)ethanone; 2-(1-(azetidinecarbonyl)piperidinyl)hydroxy(4-(1-hydroxy(5H- imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)ethanone; 2-cyclopentyl(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidin yl)ethanone; 1-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)(2- methylthiazolyl)ethanone; N-cyclohexyl-N-hydroxy(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)piperidinecarboxamide; N-(4-(2-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) oxoethyl)phenyl)methanesulfonamide; N-cyclopropyl-N-hydroxy(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)piperidinecarboxamide; 3,3-difluoro(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidin yl)butanone; 1-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)(ptolyl )ethanone; 1-(1-(4-aminopyrimidinyl)piperidinyl)(5H-imidazo[5,1-a]isoindol yl)ethanol; 1-(1-(2-aminopyrimidinyl)piperidinyl)(5H-imidazo[5,1-a]isoindol yl)ethanol; AH26(9298372_1):RTK N-cyclopropyl(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidine carboxamide; 2-cyclopropyl(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidin yl)ethanone; 2-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)ethyl)cyclohexylidene)acetonitrile; 4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)-N-(4- (trifluoromethyl)thiazolyl)piperidinecarboxamide; 4-(2-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) oxoethyl)benzamide; 1-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)(4- (methylsulfonyl)phenyl)ethanone; 4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)-N-((1r,4r) methylcyclohexyl)piperidinecarboxamide; 1-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl)-3,3- dimethylbutanone; 4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) oxoethyl)benzenesulfonamide; N-(tert-butyl)(2-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindol yl)piperidinyl)oxoethyl)benzenesulfonamide; 4-(2-(4-(1-hydroxy(5H-imidazo[5,1-a]isoindolyl)ethyl)piperidinyl) oxoethyl)benzoic acid; 1-(4-(difluoromethylene)cyclohexyl)(5H-imidazo[5,1-a]isoindolyl)ethanol; 2-(5H-imidazo[5,1-a]isoindolyl)(4-(2,2,2- trifluoroethylidene)cyclohexyl)ethanol; N-benzyl(2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl) hydroxyethyl)cyclohexanecarboxamide; 6-fluoro-5H-imidazo[5,1-a]isoindolyl)hydroxyethyl)-N- phenylcyclohexanecarboxamide; N-(4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl) hydroxyethyl)cyclohexyl)benzamide; 1-(4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)hydroxyethyl)cyclohexyl) phenylurea; N-(4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindolyl)hydroxyethyl)cyclohexyl) AH26(9298372_1):RTK phenylacetamide; or a pharmaceutically acceptable salt thereof.

33. The nd according to claim 1 that is 4-((R)hydroxy((S)-5H-imidazo[5,1- a]isoindolyl)ethyl)-N-phenylpiperidinecarboxamide or a pharmaceutically acceptable salt thereof.

34. The compound according to claim 1 that is 1-(4-((R)hydroxy((S)-5H-imidazo[5,1- a]isoindolyl)ethyl)piperidinyl)phenylethanone or a pharmaceutically acceptable salt thereof.

35. The compound according to claim 1 that is 1-(4-((S)hydroxy((S)-5H-imidazo[5,1- a]isoindolyl)ethyl)piperidinyl)phenylethanone or a ceutically able salt thereof.

36. The compound according to claim 1 that is (S)cyclohexyl((S)-5H-imidazo[5,1- a]isoindolyl)ethanol or a pharmaceutically able salt thereof.

37. The compound of claim 1 that is(1R,4r)((R)((S)fluoro-5H-imidazo[5,1- a]isoindolyl)hydroxyethyl)cyclohexanol or a pharmaceutically acceptable salt thereof.

38. A pharmaceutical composition comprising a compound according to any one of claims 1 – 37 and a pharmaceutically acceptable t, excipient, or r.

39. A kit comprising a compound ing to any one of claims 1 – 37.

40. The kit according to claim 39, further comprising a second therapeutic agent.

41. The kit according to claim 40, wherein the second therapeutic agent is an anti-viral agent.

42. The kit according to claim 41, wherein the anti-viral agent is a nucleoside or nucleotide reverse transcriptase inhibitor (NRTI).

43. The kit according to claim 42, wherein the NRTI is zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); ir dipivoxil AH26(9969527_1):JJC [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emitricitabine TC]; beta-LFD4 ; DAPD, or lodenosine (FddA).

44. The kit ing to claim 41, wherein the anti-viral agent is an NNRTI.

45. The kit according to claim 44, wherein the NNRTI is nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1- (ethoxy-methyl)(1-methylethyl)(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); or (+)- calanolide A (NSC-675451) or B.

46. The kit according to claim 41, wherein the anti-viral agent is a protease inhibitor.

47. The kit according to claim 46, wherein the protease inhibitor is avir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); 0; BMS-2322623; ABT-378; or AG-1549.

48. The kit according to claim 41, wherein the anti-viral agent is hydroxyurea, ribavirin, IL-2, IL-12, pentafuside or Yissum Project No. 11607.

49. The kit according to claim 40, wherein the second therapeutic agent is a chemotherapeutic or other anticancer agent.

50. The kit according to claim 49, wherein the herapeutic or other anticancer agent is an alkylating agent.

51. The kit ing to claim 50 wherein the alkylating agent is a nitrogen mustard, an ethylenimine derivative, an alkyl sulfonate, a nitrosourea, or a triazene.

52. The kit according to claim 50 wherein the alkylating agent is uracil mustard, ethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene- melamine, ylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, or lomide.

53. The kit according to claim 49, wherein the chemotherapeutic or other ncer agent is an antimetabolite. AH26(9969527_1):JJC

54. The kit according to claim 53 wherein the tabolite is an folic acid antagonist, a pyrimidine analog, a purine analog, or an adenosine deaminase inhibitor.

55. The kit according to claim 49, wherein the chemotherapeutic or other anticancer agent is rexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, or gemcitabine.

56. The kit according to claim 49, n the chemotherapeutic or other anticancer agent is a vinca alkaloid, an antitumor antibiotic, an enzyme, a lymphokine, or an epipodophyllotoxin.

57. The kit according to claim 49, wherein the chemotherapeutic or other ncer agent is vinblastine, stine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel ™), docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, or teniposide.

58. The kit according to claim 40, n the second therapeutic agent is a cytotoxic agent.

59. The kit according to claim 58, wherein the cytotoxic agent is navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, or droloxafine.

60. The kit according to claim 58, wherein the cytotoxic agent is an antineoplastic enzyme; a topoisomerase inhibitor; a platinum coordination complex; a ical response modifier; a growth inhibitor; an antihormonal therapeutic agent; or a haematopoietic growth factor.

61. The kit according to claim 58, wherein the cytotoxic agent is epidophyllotoxin; procarbazine; ntrone; cisplatin, carboplatin; leucovorin; or tegafur.

62. The kit according to claim 49, wherein the chemotherapeutic or other anticancer agent is an dy to a costimulatory molecule or cytokine.

63. The kit according to claim 62, wherein the cytokine is IL-10 or TGF-β.

64. The kit according to claim 62, wherein the chemotherapeutic or other ncer agent is an antibody to the costimulatory molecule CTLA-4,4-1BB or PD-1. AH26(9969527_1):JJC

65. The kit according to claim 62, wherein the chemotherapeutic or other anticancer agent is an antibody to the cytokine IL-10 or TGF-β.

66. The kit according to claim 49, wherein the chemotherapeutic or other anticancer agent is trastuzumab.

67. The kit according to claim 49, wherein the chemotherapeutic or other anticancer agent blocks immune cell ion.

68. The kit according to claim 67, wherein the herapeutic or other anticancer agent is an antagonist of a chemokine receptor.

69. The kit according to claim 68, wherein the chemokine receptor is CCR2, CCR4, or CCR6.

70. The kit according to claim 49, wherein the chemotherapeutic or other anticancer agent is a vaccine.

71. The kit according to claim 70, wherein the vaccine comprises a dendritic cell, a synthetic peptide, a DNA vaccine, or a recombinant virus.

72. The kit according to any of claims 39 - 71, r comprising an adjuvant for augmenting the immune system. NewLink cs Corporation By the Attorneys for the Applicant SPRUSON & FERGUSON Per: AH26(9969527_1):JJC WO 42237