WO2012142237A1 - Fused imidazole derivatives useful as ido inhibitors - Google Patents

Fused imidazole derivatives useful as ido inhibitors Download PDF

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Publication number
WO2012142237A1
WO2012142237A1 PCT/US2012/033245 US2012033245W WO2012142237A1 WO 2012142237 A1 WO2012142237 A1 WO 2012142237A1 US 2012033245 W US2012033245 W US 2012033245W WO 2012142237 A1 WO2012142237 A1 WO 2012142237A1
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Prior art keywords
imidazo
isoindol
ethyl
cyclohexyl
ethanol
Prior art date
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PCT/US2012/033245
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French (fr)
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WO2012142237A8 (en
Inventor
Mario Mautino
Sanjeev Kumar
Jesse Waldo
Firoz Jaipuri
Tanay Kesharwani
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Newlink Geneticks Corporation
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Filing date
Publication date
Priority to RS20160285A priority Critical patent/RS54723B1/en
Priority to CA2833296A priority patent/CA2833296C/en
Priority to EP17205515.4A priority patent/EP3348558A1/en
Priority to NZ616457A priority patent/NZ616457B2/en
Priority to MEP-2016-82A priority patent/ME02417B/en
Priority to ES12715295.7T priority patent/ES2569665T3/en
Priority to EP12715295.7A priority patent/EP2697227B1/en
Priority to MX2013012021A priority patent/MX340442B/en
Priority to SI201230515A priority patent/SI2697227T1/en
Priority to JP2014505274A priority patent/JP2014511876A/en
Priority to AU2012242871A priority patent/AU2012242871C1/en
Priority to DK12715295.7T priority patent/DK2697227T3/en
Priority to RU2013150811A priority patent/RU2613579C2/en
Priority to BR112013026494A priority patent/BR112013026494A2/en
Application filed by Newlink Geneticks Corporation filed Critical Newlink Geneticks Corporation
Priority to KR1020137030438A priority patent/KR102164443B1/en
Priority to CN201280018684.7A priority patent/CN103547579B/en
Publication of WO2012142237A1 publication Critical patent/WO2012142237A1/en
Publication of WO2012142237A8 publication Critical patent/WO2012142237A8/en
Priority to US14/053,440 priority patent/US9260434B2/en
Priority to IL228862A priority patent/IL228862A/en
Priority to HK14107271.9A priority patent/HK1193822A1/en
Priority to US14/794,193 priority patent/US9388191B2/en
Priority to IL241846A priority patent/IL241846A/en
Priority to HRP20160369TT priority patent/HRP20160369T1/en
Priority to SM201600130T priority patent/SMT201600130B/en
Priority to US15/181,062 priority patent/US9850248B2/en
Priority to IL246515A priority patent/IL246515B/en
Priority to US15/800,190 priority patent/US10233190B2/en
Priority to US16/269,681 priority patent/US20190225618A1/en

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Definitions

  • the present disclosure relates to compounds and methods for inhibition of indoleamine 2,3-dioxygenase; further the disclosure relates to method of treatment of diseases and disorders mediated by indoleamine 2,3-dioxygenase.
  • Tryptophan is an essential amino acid required for the biosynthesis of proteins, niacin and the neurotransmitter 5-hydroxytryptamine (serotonin).
  • the enzyme indoleamine 2,3-dioxygenase also known as INDO or IDO
  • IDO indoleamine 2,3-dioxygenase
  • IFN-y stimulation induces activation of IDO, which leads to a depletion of Trp, thereby arresting the growth of Trp-dependent 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 vivo during rejection of allogeneic tumors, indicating a possible role for this enzyme in the tumor rejection process.
  • 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 diarrhea and possibly immunosuppression of AIDS patients (Brown, et ah, 1991, Adv. Exp. Med. Biol, 294: 425-35).
  • IDO inhibition can enhance the levels of virus-specific T cells and, concomitantly, reduce the number of virally infected macrophages in a mouse model of HIV (Portula et ah, 2005, Blood, 106:2382-90).
  • IDO is believed to play a role in the immunosuppressive processes that prevent fetal rejection in utero. More than 40 years ago, it was observed that, during pregnancy, the genetically disparate mammalian conceptus survives in spite of what would be predicted by tissue transplantation immunology (Medawar, 1953, Symp. Soc. Exp. Biol. 7: 320-38). Anatomic separation of mother and fetus and antigenic immaturity of the fetus cannot fully explain fetal allograft survival. Recent attention has focused on immunologic tolerance of the mother.
  • the mammalian conceptus appears to suppress T-cell activity and defends itself against rejection, and blocking tryptophan catabolism during murine pregnancy allows maternal T cells to provoke fetal allograft rejection (Munn, et al, 1998, Science 281 : 1 191-3).
  • IDO inhibitor 1-MT
  • chemotherapeutic agents 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 (Muller et ah, 2005, Nature Med., 1 1 :312-9).
  • One mechanism contributing to immunologic unresponsiveness toward tumors may be presentation of tumor antigens by tolerogenic host APCs.
  • APCs human IDO-expressing antigen-presenting cells (APCs) that coexpressed CD 123 (IL3RA) and CCR6 and inhibited T-cell proliferation have also been described.
  • TDLNs mouse tumor-draining lymph nodes
  • pDCs plasmacytoid dendritic cells
  • IDO degrades the indole moiety of tryptophan, serotonin and melatonin, and initiates the production of neuroactive and immunoregulatory metabolites, collectively known as kynurenines.
  • kynurenines neuroactive and immunoregulatory metabolites
  • IDO expressed by dendritic cells (DCs) can greatly affect T-cell proliferation and survival. IDO induction in DCs could be a common mechanism of deletional tolerance driven by regulatory T cells.
  • tryptophan 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 diseases such as those described above.
  • PCT Publication WO 99/29310 reports methods for altering T cell-mediated immunity comprising altering local extracellular concentrations of tryptophan and tryptophan metabolites, using an inhibitor of 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).
  • IDO Inhibitors of IDO can be used to activate T cells and therefore enhance T cell activation when the T cells are suppressed by pregnancy, malignancy or a virus such as HIV. Inhibition of 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.
  • the invention com rises compounds according to the formula (I),
  • R 1 , R 2 , n and a are each defined herein.
  • the invention comprises compounds according to the formula (II),
  • R 1 , R 3 , R c , and n are each defined herein.
  • compositions comprising a pharmaceutically acceptable excipient, diluent, or carrier, and a compound according to formula (I) or (II).
  • methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of a compound according 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 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); (c) treating a medical condition that benefits from the inhibition of
  • Figure 1 shows the absolute configuration of a diasteromer of the HBr salt of compound 1417 as confirmed by X-ray crystallography.
  • the invention provides com ounds of formula (I),
  • bond a is a single or double bond
  • n 0, 1 , 2, 3, or 4;
  • each R 1 is independently halogen, cyano, nitro, Ci- 6 alkyl, -OR, -N(R) 2 , -SR, -C(0)OR, -C(0)N(R) 2 , -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R) 2 , -S(0) 2 R, -S(0) 2 OR, -S(0) 2 N(R) 2 , -OC(0)R, -OC(0)OR, -OC(0)N(R) 2 , -N(R)C(0)R, -N(R)C(0)OR, or -N(R)C(0)N(R) 2 ;
  • R 2 is -Ci_4alkyl-R A or -C 2 _4alkenyl-R 3 when bond a is a single bond;
  • R B is hydrogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -Ci_ 6 alkyl-R B1 , -C(0)R 3 , or -S(0) 2 R 3 , -C(0)(CH 2 ) ! . 4 COOR, -C(0)CH(NH 2 )(R D ), -S(0) 2 OR 3 , -S(0) 2 N(R 3 ) 2 , -CH 2 - OP(0) 2 (OR) 2 , or -P(0)(OR 3 ) 2 , wherein
  • R B1 is cyano, nitro, d_ 6 alkyl, Ci_ 6 haloalkyl, -OR, -N(R) 2 , -SR, -C(0)OR, -C(0)N(R) 2 , -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R) 2 , -S(0) 2 R, -S(0) 2 OR, -S(0) 2 N(R) 2 , -OC(0)R, -OC(0)OR, -OC(0)N(R) 2 , -N(R)C(0)R, -N(R)C(0)OR, or -N(R)C(0)N(R) 2 ;
  • R D is hydrogen, methyl, -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), benzyl, 4-hydroxybenzyl, -CH 2 (3-indolyl), -CH 2 SH
  • each R 3 is independently hydrogen, Ci- 6 alkyl, aryl, heteroaryl, C 3 _ 8 cycloalkyl, C 3 _ 8 cycloalkenyl, 3- 10 membered heterocyclyl, arylCi- 6 alkyl-, heteroarylCi-6 alkyl-, C 3 _ 8 cycloalkylCi_ 6 alkyl-, C 3 _ 8 cycloalkenylCi_ 6 alkyl-, or (3- 10 membered heterocyclyl)Ci_ 6 alkyl-,
  • aryl, heteroaryl, arylCi_ 6 alkyl-, and heteroarylCi_ 6 alkyl- groups are each optionally substituted by one, two, three, or four R 31 groups;
  • each R 31 is independently halogen, cyano, nitro, Ci- 6 alkyl, -Ci_ 6 alkyl-R 33 , Ci_ 6 haloalkyl, -OR, -N(R) 2 , -SR, -C(0)OR, -C(0)N(R) 2 , -C(0)R,- -S(0)R, -S(0)OR, -S(0)N(R) 2 , -S(0) 2 R, -S(0) 2 OR, -S(0) 2 N(R) 2 , -OC(0)R, -OC(0)OR, -OC(0)N(R) 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)N(R) 2 , wherein
  • R 33 is cyano, -OR, -N(R) 2 , -SR, -C(0)OR, -C(0)N(R) 2 , -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R) 2 , -S(0) 2 R, -S(0) 2 OR, -S(0) 2 N(R) 2 , -OC(0)R, -OC(0)OR, -OC(0)N(R) 2 , -N(R)C(0)R, -N(R)C(0)OR, or -N(R)C(0)N(R) 2 ;
  • each R 34 is independently hydrogen, halogen, Ci_ 6 alkyl,
  • R c is hydrogen or Ci- 6 alkyl
  • each R is independently hydrogen or R , wherein
  • R 10 is Ci- 6 alkyl, aryl, heteroaryl, C3- 8 cycloalkyl, C3_ 8 cycloalkenyl, 3-10 membered heterocyclyl, arylCi- 6 alkyl, heteroarylCi_ 6 aikyl-, C3-8 cycloalkylCi- 6 alkyl-, C3- 8 cycloalkenylCi_ 6 alkyl-, or (3-10 membered heterocyclyl)Ci_ 6 alkyl-, each R 10 optionally substituted by one, two, three, or four groups that are each independently halogen, cyano, nitro, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -OR 11 , -N(R U ) 2 , -SR 11 , -C(0)OR n , -C(0)N(R n ) 2 , -C(0)R u , -S(0)R n , -S(0)OR n
  • R B is additionally -C(0)N(H)R 3 or -C(0)(CH 2 )!_ 4 (NR)COOR;
  • R 3 is additionally (heteroaryl)-(3-10 membered heterocyclyl)-,
  • R 34 is additionally cyano or - Ci- 6 alkyl-OR; and/or
  • R 10 is additionally optionally substituted by -N(R u )S(0)2R n or -C(O)-(3-10 membered heterocyclyl);
  • the invention further comprises subgenera of formula (I) and formula ( ⁇ ) in which the substituents are selected as any and all combinations of one or more of structural formula
  • Structural Formula I is one of formulae (la) - (Ih);
  • n and R 1 are selected from one of the following groups (la) - (lu);
  • n is 1, 2, 3, or 4, and each R 1 is as defined for formula (I).
  • (lb) n is 0, 1, 2, or 3, and each R 1 is as defined for formula (I).
  • n 0, 1, or 2 and each R 1 is independently halogen, -OR, -N(R) 2 , or -SR.
  • n 0, 1, or 2 and each R 1 is independently halogen, -OR 0 , -N(R°) 2 , or -SR°, wherein each R° is independently hydrogen or Ci- 6 alkyl.
  • n is 0, 1, or 2 and each R 1 is independently fluoro, chloro, hydroxy, or methoxy.
  • n is 0, 1, or 2 and each R 1 is independently halogen,
  • (lh) n is 0, 1, or 2 and each R 1 is independently fluoro or chloro.
  • n 0 or 1 and R 1 is as defined for formula (I),
  • (lj) n is 0 or 1 and R 1 is halogen, -OR, -N(R) 2 , or -SR.
  • (Ik) n is 0 or 1 and R 1 is halogen, -OR 0 , -N(R°) 2 , or -SR°;wherein each R° is independently hydrogen or Ci_ 6 alkyl.
  • n is 0 or 1 and R 1 is fluoro, chloro, hydroxy, or methoxy.
  • n 0 or 1 and R 1 is fluoro or chloro.
  • (lp) n is 1 and R 1 is halogen, -OR, -N(R) 2 , or -SR;
  • n 1 and R 1 is halogen, -OR 0 , -N(R°) 2 , or -SR°;wherein each R° is independently hydrogen or Ci_ 6 alkyl.
  • (lr) n is 1 and R 1 is fluoro, chloro, hydroxy, or methoxy.
  • R 2 is selected from one of the following groups (2a) - (21);
  • R 2 is -Ci_ 4 alkyl-R A .
  • R 2 is -Ci_ 2 alkyl-R A .
  • R 2 is -CH 2 -R A , -CH 2 CH 2 -R A , or -C(H)(CH 3 )CH 2 -R A .
  • R 2 is -CH 2 -R A .
  • R 2 is -CH 2 CH 2 -R A .
  • R 2 is -C(H)(CH 3 )CH 2 -R A
  • R A is selected from one of the following groups (3a) - (3n);
  • R A is -CN, -C(0)OR 3 , or -C(0)N(R 3 )(R c ).
  • R A is -C(0)R 3 or -C(OR B )(R 3 )(R c ).
  • R A is -C( HR B )(R 3 )(R C ), wherein R B is hydrogen, C 1-6 alkyl, or -C(0)Ci_ 6 alkyl.
  • R A is -C( H 2 )(R 3 )(R C ).
  • R A is -C(0)OR 3 .
  • R A is -C(0)N(R 3 )(R c ).
  • R A is -C(0)R 3 .
  • R A is -C(OR B )(R 3 )(R c ).
  • R A is -C(OH)(R 3 )(R c ).
  • R A is -CH(OH)(R 3 ).
  • R A is -CN, -C(0)R 3 , -C(0)OR 3 , -C(0)N(R 3 )(R c ), -C(OR B )(R 3 )(R c ),
  • R A is -C(0)R 3 or -C(OR B )(R 3 )(R c ), wherein R B is hydrogen and R c is hydrogen or
  • R A is -C(OR B )(R 3 )(R c ), wherein R B is hydrogen and R c is hydrogen or Ci- 6 alkyl.
  • R B is selected from one of the following groups (4a) - (4k);
  • R B is hydrogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -Ci_ 6 alkyl-R B1 , -C(0)(CH 2 ) ! _ 4 COOR B2 , -C(0)C(NH 2 )R D , -P(0 3 )(R B2 ) 2 , -CH 2 -OP(0) 2 (OR) 2 , wherein R D is the side chain of natural alpha amino acids , -C(0)R 3 , or -S(0) 2 R 3 , wherein R B1 is cyano, nitro, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -OR B2 , -N(R B2 ) 2 , -SR B2 , -C(0)OR B2 , -C(0)N(R B2 ) 2 , -C(0)R B2 , -S(0)R B2 , -S(0)OR B2 , -S(0)N(R B2 ,
  • R B is hydrogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -Ci_ 6 alkyl-R B1 , -C(0)R 3 , or -S(0) 2 R 3 , wherein R B1 is cyano, nitro, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -OR B2 , -N(R B2 ) 2 , -SR B2 , -C(0)OR B2 , -C(0)N(R B2 ) 2 , -C(0)R B2 , -S(0)R B2 , -S(0)OR B2 , -S(0)N(R B2 ) 2 , -S(0) 2 R B2 , -S(0) 2 OR B2 , -S(0) 2 N(R B2 ) 2 , -OC(0)R B2 , -OC(0)OR B2 , -OC(0)N(R B2 ) 2 , -N(R B2 )C ,
  • R B is hydrogen, Ci_ 6 alkyl, or -Ci- 6 alkyl-R B1 , wherein R B1 is cyano, nitro, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -OR B2 , -N(R B2 ) 2 , -SR B2 , -C(0)OR B2 , -C(0)N(R B2 ) 2 , -C(0)R B2 , -S(0)R B2 , -S(0)OR B2 , -S(0)N(R B2 ) 2 , -S(0) 2 R B2 , -S(0) 2 OR B2 , -S(0) 2 N(R B2 ) 2 , -OC(0)R B2 , -OC(0)OR B2 , -OC(0)N(R B2 ) 2 , -N(R B2 )C(0)R B2 , -N(R B2 )C(0)OR B2 , or -N(
  • R B is hydrogen, Ci- 6 alkyl, or -Ci- 6 alkyl-R B1 , wherein R B1 is cyano,
  • each R B2 is independently hydrogen or Ci- 6 alkyl.
  • R B is -Ci_ 6 alkyl-R B1 , wherein R B1 is cyano, -C(0)OR B2 , -C(0)N(R B2 ) 2 , -C(0)R B2 ,
  • each R B2 is independently hydrogen or Ci- 6 alkyl.
  • R B is hydrogen, Ci- 6 alkyl, Ci- 6 haloalkyl, -Ci- 6 alkyl-R B1 , -C(0)R B2 , or -S(0) 2 R B2 , wherein R B1 is -C(0)OR B3 , -C(0)N(R B3 ) 2 , -S(0) 2 OR B3 , or -S(0) 2 N(R 3 ) 2 , R B2 is Ci_ 6 alkyl; and R B3 is hydrogen or Ci_6 alkyl.
  • R B is hydrogen, Ci- 6 alkyl, or Ci_ 6 haloalkyl.
  • R B is hydrogen or Ci_ 6 alkyl
  • R B is hydrogen
  • R B is d-ealkyl
  • R B is hydrogen, -C(0)R B2 , -C(0)(CH 2 ) ! _ 4 COOR B2 , -C(0)C( H 2 )R D , -P(0)(OR B2 ) 2 , -CH 2 -OP(0) 2 (OR) 2 , -S(0) 2 R B2 , -C(0)N(R B2 ) 2 , -S(0) 2 OR B2 , -S(0) 2 N(R 3 ) 2 , wherein and R B2 is hydrogen or Ci_6 alkyl.
  • R c is selected from one of the following groups (5a) - (5g);
  • R c is hydrogen or Ci_ 4 alkyl.
  • R c is hydrogen or Ci- 2 alkyl.
  • R is hydrogen or methyl.
  • R c is hydrogen
  • R c is Ci_ 6 alkyl.
  • R c is Ci_ 4 alkyl.
  • R 3 is selected from one of the following groups (6a) - (6z);
  • R 3 is phenyl or a five or six membered heteroaryl, each optionally substituted by one or two R 31 groups.
  • R 3 is , wherein bond a is a single bond or a double bond; m is 0, 1, or 2; p is 0 or 1 ; and wherein
  • R 35 is hydrogen, Ci_ 6 alkyl, -C(0)R, -S(0) 2 R, -C(0)OR, -C(0)N(R) 2 , -S(0) 2 OR, or -S(0) 2 N(R) 2 ;
  • R 35 is hydrogen, Ci_ 6 alkyl, -C(0)R, -S(0) 2 R, -C(0)OR, -C(0)N(R) 2 , -S(0) 2 OR, or -S(0) 2 N(R) 2 ;
  • R 3 is hydrogen, Ci- 6 alkyl, aryl, heteroaryl, C3_ 8 cycloalkyl, C3_ 8 cycloalkenyl, 3-10 membered heterocyclyl, or C3_ 8 cycloalkylCi- 6 alkyl, wherein
  • the aryl and heteroaryl groups are each optionally substituted by one or two R 31 groups;
  • each R 31 is independently halogen, cyano, nitro, Ci- 6 alkyl, -Ci_ 6 alkyl-R 33 , Ci_ 6 haloalkyl, -OR, -N(R) 2 , -SR, -C(0)OR, -C(0)N(R) 2 , -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R) 2 , -S(0) 2 R, -S(0) 2 OR, -S(0) 2 N(R) 2 , -OC(0)R, -OC(0)OR, -OC(0)N(R) 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)N(R) 2 , wherein R 33 is -OR, -N(R) 2 , or -SR; and
  • R 3 is hydrogen, Ci_ 6 alkyl, aryl, heteroaryl, C3_ 8 cycloalkyl, C3_ 8 cycloalkenyl, 3-10 membered heterocyclyl, or C3_ 8 cycloalkylCi_ 6 alkyl-, wherein
  • the aryl and heteroaryl groups are each optionally substituted by one or two R 31 groups;
  • each R is independently halogen, cyano, nitro, Ci- 6 alkyl, -Ci- 6 alkyl-R , Ci_ 6 haloalkyl, -OR, -N(R) 2 , -SR, -C(0)OR, -C(0)N(R) 2 , -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R) 2 , -S(0) 2 R, -S(0) 2 OR, -S(0) 2 N(R) 2 , -OC(0)R, -OC(0)OR, -OC(0)N(R) 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)N(R) 2 , wherein R 33 is -OR, -N(R) 2 , or -SR; and
  • the aryl and heteroaryl are each optionally substituted by one, two, three, or four R 31 groups.
  • R 3 is phenyl, cyclopentyl, cyclohexyl, cyclohex-l-en-l-yl, cyclohex-3-en-l-yl, furan-
  • each R is independently hydrogen, Ci_ 6 alkyl, Ci- 6 haloalkyl, aryl, heteroaryl, C3_ 8 cycloalkyl, C3_ 8 cycloalkenyl, 3-10 membered heterocyclyl, arylCi- 6 alkyl, heteroarylCi_ 6 alkyl-, C3-8 cycloalkylCi- 6 alkyl-, C 3 _ 8 cycloalkenylCi_ 6 alkyl-, or (3-10 membered heterocyclyl)Ci_ 6 alkyl-.
  • each R is independently hydrogen, Ci_ 6 alkyl, Ci- 6 haloalkyl, phenyl, 5- or 6-membered heteroaryl, C3_ 8 cycloalkyl, C3_ 8 cycloalkenyl,
  • Particular embodiments of this aspect of the invention include compounds of any one of the formulae (I), ( ⁇ ), and (la) - (Id), each as defined in each of the following rows, wherein each entry is a group number as defined above (e.g., (Is) refers to n is 1 and each R 1 is halogen), and a dash "-" indicates that the variable is as defined for formula (I) or ( ⁇ ) or defined according to any one of the applicable variable definitions (la)-(6z) [e.g., when R c is a dash, it can be either as defined for Formula (I) or ( ⁇ ) or any one of definitions (5a)-(5g)] :
  • the invention rovides the compound according to formula (II),
  • n 0 or 1 ;
  • each R 1 is independently halogen, -OR, -N(R) 2 , or -SR;
  • the aryl and heteroaryl groups are each optionally substituted by one or two R 31 groups;
  • each R 31 is independently halogen, cyano, nitro, Ci- 6 alkyl,
  • -Ci_ 6 alkyl-R C 1-6 haloalkyl, -OR, -N(R) 2 , -SR, -C(0)OR, -C(0)N(R) 2 , -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R) 2 , -S(0) 2 R, -S(0) 2 OR, -S(0) 2 N(R) 2 , -OC(0)R, -OC(0)OR, -OC(0)N(R) 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)N(R) 2 , wherein R 33 is -OR, -N(R) 2 , or -SR;
  • R is hydrogen or Ci_ 6 alkyl
  • each R is independently hydrogen or R 10 , wherein
  • R 10 is Ci- 6 alkyl, aryl, heteroaryl, C3_ 8 cycloalkyl, C3_ 8 cycloalkenyl, 3-10 membered heterocyclyl, arylCi- 6 alkyl, heteroarylCi- 6 alkyl-, C3-8 cycloalkylCi- 6 alkyl-, C3- 8 cycloalkenylCi_ 6 alkyl-, or (3-10 membered heterocyclyl)Ci_ 6 alkyl-, each R 10 optionally substituted by one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6 alkyl, Ci_ 6 haloalkyl, -OR 11 , -N(R U ) 2 , -SR 11 , -C(0)OR n , -C(0)N(R n ) 2 , -C(0)R u , -S(0)R n , -S(0)OR n ,
  • the compounds of formula (II) further include those compounds where,
  • R 3 is additionally (heteroaryl)-(3-10 membered heterocyclyl)-;
  • R 34 is additionally cyano or - Ci- 6 alkyl-OR; and/or
  • R 10 is additionally optionally substituted by -N(R u )S(0) 2 R n or -C(O)-(3-10 membered heterocyclyl);
  • the invention further comprises subgenera of formula (II) or ( ⁇ ) in which the substituents are selected as any and all combinations of one or more of structural formula (II), n, R 1 , R 3 , and R c as defined herein, including without limitation, the following:
  • Structural Formula II is on f formulae (Ila) - (lid):
  • n and R 1 are selected from one of the following groups (7a) - (7i):
  • n is 0 or 1 and R 1 is halogen, -OR 0 , -N(R°) 2 , or -SR°; wherein each R° is independently hydrogen or C h alky 1.
  • n is 0 or 1 and R 1 is fluoro, chloro, hydroxy, or methoxy.
  • n is 0 or 1 and R 1 is halogen.
  • n is 0 or 1 and R 1 is fluoro or chloro.
  • n is 1 and R 1 is halogen, -OR 0 , -N(R°) 2 , or -SR°; wherein each R° is independently hydrogen or
  • n is 1 and R 1 is fluoro, chloro, hydroxy, or methoxy.
  • n 1 and R 1 is fluoro or chloro.
  • R c is selected from one of the following groups (8a) - (8g):
  • R c is hydrogen or Ci- 4 alkyl.
  • R c is hydrogen or
  • R c is hydrogen or methyl.
  • R c is hydrogen
  • R c is Ci-ealkyl.
  • R is Ci-4 lkyl.
  • R 3 is selected from one of the following groups (9a) - (9x);
  • R 3 is phenyl or a five or six membered heteroaryl, each optionally substituted by one or two R 31 groups.
  • R 3 is , wherein bond a is a single bond or a double bond; m is 0, 1, or 2; p is 0 or 1 ; and wherein
  • R 35 is hydrogen, Ci_ 6 alkyl, -C(0)R, -S(0) 2 R, -C(0)OR, -C(0)N(R) 2 , -S(0) 2 OR, or -S(0) 2 N(R) 2 ;
  • R 35 is hydrogen, Ci_ 6 alkyl, -C(0)R, -S(0) 2 R, -C(0)OR, -C(0)N(R) 2 , -S(0) 2 OR, or -S(0) 2 N(R) 2 ;
  • each R 36 is independently hydrogen, halogen, Ci_ 6 alkyl,
  • the aryl and heteroaryl groups are each optionally substituted by one or two R 31 groups;
  • each R 31 is independently halogen, cyano, nitro, Ci_ 6 alkyl, -Ci_ 6 alkyl-R 33 , Ci_ 6 haloalkyl, -OR, -N(R) 2 , -SR, -C(0)OR, -C(0)N(R) 2 , -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R) 2 , -S(0) 2 R, -S(0) 2 OR, -S(0) 2 N(R) 2 , -OC(0)R, -OC(0)OR, -OC(0)N(R) 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)N(R) 2 , wherein R 33 is -OR, -N(R) 2 , or -SR; and
  • the aryl and heteroaryl are each optionally substituted by one, two, three, or four R 31 groups.
  • each R is independently hydrogen, Ci_ 6 alkyl, Ci- 6 haloalkyl, aryl, heteroaryl, C3_ 8 cycloalkyl, C3_ 8 cycloalkenyl, 3-10 membered heterocyclyl, arylCi- 6 alkyl, heteroarylCi_ 6 alkyl-, C3-8 cycloalkylCi- 6 alkyl-, C3- 8 cycloalkenylCi_ 6 alkyl-, or (3-10 membered heterocyclyl)Ci_ 6 alkyl-.
  • each R is independently hydrogen, Ci- 6 alkyl, Ci_ 6 haloalkyl, phenyl, 5- or 6-membered heteroaryl, C3_ 8 cycloalkyl, C3_ 8 cycloalkenyl, 3-8 membered heterocyclyl, benzyl, (5- or 6-membered heteroaryl)Ci_ 6 alkyl-, C3-8 cycloalkylCi_ 6 alkyl-, C3- 8 cycloalkenylCi- 6 alkyl-, or (3-8 membered heterocyclyl)Ci- 6 alkyl-.
  • Particular embodiments of this aspect of the invention include compounds of any one of the formulae (II), (IF), and (Ha) - (Ild), each as defined in each of the following rows, wherein each entry is a group number as defined above and a dash "-" indicates that the variable is as defined for formula (II), or ( ⁇ ), or defined according to any one of the applicable variable definitions (7a)-(9t) [e.g., when R c is a dash, it can be either as defined for Formula (II), or (IF), or any one of definitions (8a)-(8g)]:
  • the present disclosure provides compounds that are 1 - -methyl-
  • the present disclosure provides compounds and pharmaceutical compositions comprising the compounds according to any one of the preceding aspects of the invention or any embodiment thereof, together with a pharmaceutically acceptable excipient, diluent, or carrier.
  • the invention provides methods 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 embodiment thereof.
  • IDO indoleamine 2,3-dioxygenase
  • the immunosuppression is associated with an infectious disease, or cancer.
  • the immunosuppression 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).
  • HCV hepatitis C virus
  • HPV human papilloma virus
  • CMV cytomegalovirus
  • EBV Epstein-Barr virus
  • poliovirus varicella zoster virus
  • coxsackie virus coxsackie virus
  • human immunodeficiency virus HCV
  • the immunosuppression is immunosupression associated with HIV-1 infection.
  • the immunosuppression is associated with a cancer.
  • the immunosuppression is tumor-specific immunosuppression associated with cancer.
  • 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.
  • the invention provides the use of compounds described by any one of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament for the treatment of medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase.
  • Medical conditions contemplated in this aspect include all the conditions described herein.
  • the invention provides a use of compounds described by any one of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament to stimulate T cell proliferation or to reverse an immunologic state of anergy or immunosuppression.
  • the anergy or immunosuppression is caused by expression of the enzyme indoleamine-2,3 -dioxygenase.
  • the invention provides the use of compounds described by any one of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament for the treatment of immunosuppression associated with cancer, infectious diseases, or viral infections.
  • the invention provides the use of compounds described in to any one of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament for the treatment of tumor-specific immunosuppression associated with cancer.
  • the cancer is cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, or head and neck, lymphoma, leukemia, melanoma, and the like.
  • 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 infectious disease is a viral infection.
  • 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).
  • alkyl group can be both a monovalent radical or divalent radical; in the latter case, it would be apparent to one skilled in the art that an additional hydrogen atom is removed from a monovalent alkyl radical to provide a suitable divalent moiety.
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond.
  • alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl.
  • alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec -butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
  • alkyl group is a linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CHC(CH 3 )-, -CH 2 CH(CH 2 CH 3 )CH 2 -.
  • aryl means a phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system.
  • the bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl.
  • the bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the phenyl portion of the bicyclic system, or any carbon atom with the napthyl or azulenyl ring.
  • the fused monocyclic cycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl are optionally substituted with one or two oxo and/or thia groups.
  • bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-l-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl,
  • the bicyclic aryl is (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • arylalkyl means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
  • cycloalkyl as used herein, means a monocyclic or a bicyclic cycloalkyl ring system.
  • Monocyclic ring systems 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. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings.
  • Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH 2 )w-, where w is 1, 2, or 3).
  • bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]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 attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring.
  • Cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • 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 refers to a monocyclic or a bicyclic cycloalkenyl ring system.
  • Monocyclic ring systems 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. Examples of monocyclic ring systems include cyclopentenyl and cyclohexenyl.
  • Bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings.
  • Bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH 2 ) W -, where w is 1, 2, or 3).
  • alkylene bridge of between one and three additional carbon atoms
  • bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct-2-enyl.
  • Fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring.
  • Cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • halo or halogen as used herein, means -CI, -Br, -I or -F.
  • haloalkyl means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • heteroaryl means a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring.
  • the monocyclic heteroaryl can be a 5 or 6 membered ring.
  • the 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom.
  • the 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms.
  • the 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl.
  • monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.
  • the bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted with one or two groups which are independently oxo or thia.
  • the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring
  • 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.
  • the bicyclic heteroaryl is a monocyclic heteroaryl fused to a phenyl ring or a monocyclic heteroaryl, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon atom or nitrogen atom within the bicyclic ring system.
  • bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl,
  • 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.
  • heteroarylalkyl and "-alkylheteroaryl” as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heteroarylalkyl include, but are not limited to, fur-3-ylmethyl, lH-imidazol-2-ylmethyl, lH-imidazol-4-ylmethyl, l-(pyridin-4-yl)ethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidin-5-ylmethyl, 2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl.
  • heterocyclyl as used herein, means a monocyclic heterocycle or a bicyclic heterocycle.
  • the monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic.
  • the 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S.
  • the 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle.
  • monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazol
  • the bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl.
  • the bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.
  • bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-l-yl, indolin-2-yl, indolin-3-yl, 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.
  • the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia.
  • hydroxy as used herein, means an -OH group.
  • nitro as used herein, means a -N0 2 group.
  • saturated means the referenced chemical structure does not contain any multiple carbon-carbon bonds.
  • a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like.
  • spiro refers to a cyclic moiety formed by the subsituted atom and two available substitutable postions on that same atom.
  • spiro-cyclopentyl group is the R group attached to the parent cyclohexyl ring by two single bonds.
  • R is a spiro-heterocyclyl group
  • such compounds include where the spiro-l,3-dioxolanyl ring is the R group attached to the parent cyclohexyl ring by two single bonds.
  • unsaturated means the referenced chemical structure contains at least one multiple carbon-carbon bond, but is not aromatic.
  • a unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "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 preparation containing the IDO enzyme.
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • a therapeutically effective amount can be an amount suitable for (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; or
  • 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.
  • treatment means (i) ameliorating the referenced disease state, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or improving the pathology and/or symptomatology) such as decreasing the severity of disease; or (ii) eliciting the referenced biological effect (e.g., IDO modulation or tryptophan degradation inhibition).
  • ameliorating the referenced disease state for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or improving the pathology and/or symptomatology) such as decreasing the severity of disease; or (ii) eliciting the referenced biological effect (e.g., IDO modulation or tryptophan degradation inhibition).
  • Manifestation of amelioration of a disease 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.
  • additional therapeutic agents such as antineoplastic agents in the case of cancer, or antiretroviral agents in the case of viral diseases.
  • administration of IDO inhibitors for the treatment of cancer does not always produce a direct antitumor effect when used as a single agent.
  • chemotherapeutic drugs antagonistineoplastic
  • the antitumor effect observed is higher than the sum of effects of each agent alone.
  • catalytic pocket As used herein, the terms “catalytic pocket”, “catalytic site”, “active site” collectively and indistinctly refer to a region of the enzyme that contains amino acid residues responsible for the substrate binding (charge, hydrophobicity, steric hindrance) and catalytic amino acid residues which act as proton donors or acceptors or are responsible for binding a cofactor and participate in the catalysis of a chemical reaction.
  • pharmaceutically acceptable salt refers to both pharmaceutically acceptable acid and base addition salts and solvates.
  • Such pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC-(CH 2 ) n -COOH where n is 0-4, and the like.
  • Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
  • the compounds and pharmaceutical compositions described herein can modulate activity of the enzyme indoleamine-2,3-dioxygenase (IDO).
  • IDO indoleamine-2,3-dioxygenase
  • modulate is meant to refer to an ability to decrease activity of an enzyme or receptor.
  • compounds described herein can be used in methods of modulating IDO by contacting the enzyme with any one or more of the compounds or compositions described herein.
  • the compounds described herein can act as inhibitors of IDO.
  • 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 modulating (e.g., inhibiting) amount of a compound described herein.
  • methods 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 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.
  • IDO-mediated immunosuppression has been associated with, for example, cancers, tumor growth, metastasis, infectious diseases (e.g., viral infection), viral replication, etc.
  • Example tumor-specific immunosuppression associated with cancers treatable by the methods herein include immunosuppression associated with cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head and neck, lymphoma, leukemia, melanoma, and the like.
  • a patient undergoing or having completed a course of chemotherapy and/or radiation therapy for the treatment of a disease state can benefit from administering to the patient a therapeutically effective amount of a compound or composition recited herein for inhibiting immunosuppression resulting from the disease state and/or treatment thereof.
  • IDO-mediated immunosuppression 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, varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV).
  • 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, varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV).
  • Example diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the IDO enzyme, such as over expression or abnormal activity.
  • An IDO-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating enzyme activity.
  • IDO-associated diseases include cancer, viral infection such as HIV infection, depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (e.g., organ transplant rejection), and autoimmune diseases including asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis and systemic lupus erythematosus or.
  • Example cancers treatable by the methods herein include cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head and neck, lymphoma, leukemia, melanoma, and the like.
  • One or more additional pharmaceutical agents for treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and/or tyrosine kinase inhibitors can be used in combination with the compounds 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 simultaneously or sequentially as separate dosage forms.
  • Therapeutic agents that constitute the standard of care for a particular cancer type or infectious disease are expected to benefit when combined with IDO inhibitors of the present invention.
  • the tumor is sensitive to the cytotoxic effects of the chemotherapeutic agent in order to stimulate the release of antigens that will eventually mediate an immune response that will be enhanced by addition of 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.
  • NRTIs nucleoside and nucleotide reverse transcriptase inhibitors
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • protease inhibitors and other antiviral drugs.
  • Example suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH- 10652; emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-L-2',3'-dicleoxy-5-fluoro-cytidene); DAPD, ((-)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).
  • Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266
  • protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549.
  • Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.
  • Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoure
  • Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.
  • antimetabolites including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TaxolTM), docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide.
  • certain natural products and their derivatives for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins
  • vinblastine vincristine, vindesine
  • bleomycin dactinomycin
  • cytotoxic agents include navelbene, CPT-1 1, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.
  • cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cis-platin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.
  • anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4,4-lBB and PD-1, or antibodies to cytokines (IL-10, TGF- ⁇ , etc.).
  • trastuzumab Herceptin
  • costimulatory molecules such as CTLA-4,4-lBB and PD-1
  • cytokines IL-10, TGF- ⁇ , etc.
  • anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2, CCR4 and CCR6.
  • anti-cancer 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 recombinant viruses.
  • compositions described herein generally comprise a combination of a compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient. Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application.
  • the composition if the compound is dissolved or suspended in water, the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient.
  • the pharmaceutical compositions described herein are solid pharmaceutical compositions (e.g., tablet, capsules, etc.).
  • compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral.
  • topical including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal
  • ocular oral or parenteral.
  • Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • 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.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound in preparing a formulation, 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.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • 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.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein.
  • a solid preformulation composition containing a homogeneous mixture of a compound described herein.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of a compound described herein.
  • the tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • 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 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the compounds described herein can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like.
  • 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 vivo, 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 provided are IDO enzyme assays that contain such labeled compounds.
  • isotopically-labeled compounds of the compounds described herein are isotopically-labeled compounds of the compounds described herein.
  • An “isotopically” or “radio-labeled” compound is a compound described herein where one or more atoms are replaced 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), n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 C1, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro IDO enzyme labeling and competition assays, compounds that incorporate H, C, Br, I, I, S or will generally be most useful. For radio-imaging applications n C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br will generally be most useful.
  • a "radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1, 35 S and 82 Br.
  • a radio-labeled compound described herein can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • 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.
  • kits useful for example, 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.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • l H NMR spectra were obtained with a Bruker DRX400, Varian VXR400 or VXR300. l H NMR spectra were reported in parts per million ( ⁇ ) relative to TMS (0.0), DMSO-d 6 (2.50) or CD 3 OD (4.80) as an internal reference. All *H NMR spectra were taken in CDCI 3 unless otherwise indicated.
  • the following starting materials were prepared according to their literature procedures: E)-ethyl 3-(2-iodophenyl)acrylate (Synth. Comm. 2007, 37, 2989-2994), 2-chloro-6-iodobenzaldehyde (J. Agric. Food Chem.
  • intermediate A can be achieved by allowing 2-iodobenzaldehydes to react with substituted methyl ketones in the presence of a base to afford 3-(2-iodophenyl)prop-2-en-l- ones. Negishi cross-coupling of the resulting 3-(2-iodophenyl)prop-2-en-l-ones with 4- iodo-l-trityl-lH- imidazole, also leads to intermediate A.
  • the solvent was distilled off under reduced pressure and the crude was partitioned between CH2CI2 (50 mL) and satd. NH4CI (30 mL). The organic layer was collected and the aqueous layer was extracted with CH2CI2 (2 x 30 mL). The organic layer was washed with brine, dried (Na 2 S0 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%).
  • the solution was stirred at 50 °C overnight.
  • the solvent was distilled off under reduced pressure and the crude was partitioned between CH2CI2 (50 mL) and satd. NH4CI (30 mL).
  • the organic layer was collected and the aqueous layer was extracted with CH2CI2 (2 x 30 mL).
  • the organic layer was washed with brine, dried (Na 2 S0 4 ) and concentrated under reduced pressured to obtain the crude product.
  • the crude was purified by column chromatography on silica gel to afford 22 as colorless oil (800 mg, 65%).
  • the pure diastereomers were obtained from the racemic mixture of 1363 using preparative chiral supercritical fluid chromatography (SFC) technique, using a AD-H column (Regis Technologies, Inc.) in methanohCC (24:76).
  • SFC preparative chiral supercritical fluid chromatography
  • Example 52 1 -(( 15,35)-3 -(tert-Butyldimethylsilyloxy)-3 -cyclohexyl- 1 -(2- iodophenyl)propyl)-lH- imidazole
  • the solvent was distilled off under reduced pressure and the crude was diluted with sat'd NH 4 C1 (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 Na 2 S0 4 . The solution was filtered and concentrated under reduced pressure to afford the crude product. The crude was stirred in a mixture of acetic acid (20 mL) and MeOH (170 mL) at 90 °C for 1.5 h.
  • 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 phID06His cDNA with primers 5 '-ggagcatgctaATGGCACACGCTATGGAAAAC-3 ' and 5 ' -gagagatctACCTTCCTTCAAAAGGGATTTC-3 ' and cloning the Sphl-Bglll 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 C-terminus 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 respect to the sequence deposited in accession file P14902 of SwissProt database. These polymorphisms result in a P1 10S and El 19G 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 ⁇ g/mL and kanamycin 30 ⁇ g/mL. Protein expression was carried out by growing an overnight culture of the M15pREP4/pQE70-hIDO clone in 100 mL LB supplemented with 100 ⁇ g/mL carbenicillin, 50 ⁇ g/mL kanamycin and 50 ⁇ g/mL of L-tryptophan (LBCKT medium). 40 mL of this culture 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 °C until OD600 was higher than 0.8. At this point the cultures were inoculated with Hemin to 7 ⁇ and L-Tryptophan to 75 ⁇ g/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 ⁇ , EDTA to 1 mM and L-tryptophan to 50 ⁇ g/mL. Incubation was continued for additional 16 h at 25 °C. Cells were collected by centrifugation, and the cell pellets were washed with PBS buffer supplemented with 200 ⁇ PMSF and 1 mM EDTA and stored at -80 °C until protein purification.
  • 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.
  • KPB potassium phosphate buffer pH 6.5
  • 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.
  • the IC5 0 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 ⁇ L-tryptophan, 20 mM ascorbate, 20 ⁇ 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 5 nM and preincubated with the enzyme for 5 min at 25 °C.
  • the reaction was started by addition of L-tryptophan to 200 ⁇ 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 °C to hydrolyze N-formylkynurenine to kynurenine.
  • the reaction was centrifuged at 3400 g for 5 min to remove precipitated protein and the supernatant was reacted with 2% (w/v) of p-dimethylaminobenzaldehyde in acetic acid.
  • the reaction was incubated 10 min at 25 °C 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 ⁇ ) and menadione (1.2 ⁇ ) were used as controls to set the parameters for the non-linear regressions necessary for determination of the IC5 0 for each compound.
  • Nonlinear regressions and determination of the IC5 0 values were performed using the GraphPad Prism 4 software. Compounds with an IC5 0 of less than 500 ⁇ were considered as active inhibitors in this assay.
  • 293-T-RExTM cells constitutively express a tet operator binding repressor protein and are maintained in DMEM, 10 % FBS, IX Penicillin+Streptomycin, 2 mM L-glutamine, 5 ⁇ g/mL blasticidin at 37 °C with a 5% CO 2 in air atmosphere and typically split prior to confluency.
  • Cells were passed by splitting the culture 1/10- by removing media by aspiration, washing IX with PBS, incubating with 0.25% trypsin/EDTA until the cells detach, disbursing the cells in fresh growth media, and plating at 1/10 dilutions in fresh growth media.
  • cells are detached from the plate as described above, collected by centrifugation, resuspended in freeze medium (growth medium, 10%DMSO), stored in 1.8 mL cyropreservation vials ( ⁇ 2-5 X 106 cells per vial), in liquid nitrogen vapor storage tanks.
  • freeze medium growth medium, 10%DMSO
  • IDOl- expressing 293-T-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, IX Penicillin + Streptomycin, 2 mM L-glutamine, 5 ⁇ g/mL blasticidin and 25 ⁇ g/mL Zeocin) at 37 °C with a 5% CO 2 in air atmosphere. Individual clones were isolated by limiting dilution cloning from these populations.
  • IDO-293-T-Rex cells were harvested and resuspended in DBZ media at 10 6 cells/mL, and split into poly-D-lysine coated 96-well plates at 100,000 cells per well. 100 ⁇ , of Neutral medium (DBZ medium, 200 ⁇ L-tryptophan) or Induction media (Neutral medium supplemented with 5 ⁇ doxycycline) are added to the cells and incubated 28 h at 37 °C.
  • medium is removed and replaced with Induction 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 °C in a cell culture incubator. 200 ⁇ ⁇ of medium are transferred to U-bottom polypropylene 96-well plates containing 25 ⁇ , of 30% TCA, incubated 30 minutes at 60 °C and centrifuged at 3400 g for 5 minutes.
  • cell viability is measured via a WST-1 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-1 reagent, and incubated 30 min at 37 °C. Absorbance at 540 nm is correlated with the number of viable cells. Determination of IC5 0 (Kynurenine assay) or LD5 0 (WST-1 assay) is performed via non-linear regression analysis using GraphPad Prism software.
  • Human monocytes were collected from peripheral mononuclear cells by leukoapheresis and cultured overnight at 10 6 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 GM-CSF. Cells were matured for 2 days with a cytokine cocktail containing TNF-a, IL- ⁇ , IL-6 and PGE2 for additional 2 days to induce dendritic cell maturation.
  • 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 ⁇ L/well anti-BrdU-POD antibody following the instructions from the manufacturer. Plates were read in a microplate reader.
  • testing of IDO inhibitors in an in vitro mouse model of IDO-mediated suppression of T cell proliferation is performed by the following procedure.
  • C57bl6 mice are inoculated with lxlO 6 B78H1-GMCSF tumor cells in the right flank. After 10-12 days, tumor draining lymph nodes are collected and cells are stained with anti-CD 1 1c and anti-B220 monoclonal antibodies. Cells are sorted by high-speed fluorescence activated cell sorting and the CDl lc+/B220+ plasmacytoid dendritic cells are collected and seeded at 2000 cells/well in 96 well V-bottom plates.
  • Splenocytes are collected from BM3 transgenic mice (in CBA background) and collected by nylon wool enrichment.
  • BM3 T cells (10 5 cells/well) are added to each well in 200 ⁇ L of RPMI, 10% FCS, 50 ⁇ M ⁇ -mercaptoetanol.
  • T cells are obtained from spleens of OT-I transgenic mice and added to the culture in combination 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 3 H-thymidine.
  • Human IDO IC5 0 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; [0210] IC 50 values are reported in ranges: A: ⁇ 1 ⁇ , B: 1 - 10 ⁇ , C: 10 - 100 ⁇ ; D: > 100 ⁇ .
  • In vivo anti-tumor efficacy can be tested using modified tumor allograft protocols. 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 different mouse tumor cell lines, of different tissue origin (colorectal, bladder, mammary 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 reaction.
  • the following chemotherapeutic drugs are used, at the indicated doses.
  • the maximum tolerated dose for the following chemotherapeutic agents in mice depends on the formulation, concentration, frequency of administration, route of administration and number of doses.
  • the chemotherapeutic drugs administered in conjunction 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, LP., every 4 days, 4 times (q4dx4); 4] Gemcitabine: 80 mg/kg every 4 days, 4 times, i.p. (q4dx4).
  • All animals receive a subcutaneous injection of a tumor forming dose of live tumor cells ( ⁇ 50000 - 1000000 cells) suspended in 0.1 mL of PBS or saline on day 1. Subcutaneous injection forms a localized tumor that allows monitoring tumor growth over time.
  • IDO inhibitor drugs begins at day 5-8 after tumor inoculation. Dosing, route of administration, 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 skin by surgical procedure. IDO inhibitor drug are administered at the maximum tolerated dose or at a concentration corresponding to the LD5 0 .
  • FIG. 1-2 An example of antitumor activity is shown in Figures 1-2 (for Cpd# 1357) and Figures 3-4 (for Cpd# 1304).
  • 200000 LLC murine tumor cells were injected subcutaneously into syngeneic C57B16 mice on day 0.
  • Each treatement group consists of 10 mice.
  • mice were optionally treated with cyclophosphamide 100 mg/kg by intraperitoneal injection on days 9, 13 and 15 post-tumor innoculation, either as a single agent or in combination with compound 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 therapeutic effect is observed as a reduced rate of tumor growth, which has an impact on median survival time and in overall survival fraction.
  • Figure 1 shows the average tumor volume over time of two groups of 10 mice each.
  • the control group was treated with vehicle, while the treatment 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 indicate a statistically significant differences between the two curves (pO.0001).
  • Figure 2 shows the survival plot of the same groups of mice described in Figure 1. The logrank test indicates a statistically significant difference in median survival time when animals were treated with compound 1357 as a single agent.
  • Figure 3 shows the average tumor volume over time of four groups of 10 mice each.
  • 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 cyclophosphamide with compound 1304.
  • the data shows that this tumor is very sensitive to the effects of treatment with compound 1304 either as a single agent or in combination with chemotherapy.
  • Figure 4 shows the survival plot of the same groups of mice described in Figure 3.
  • 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.

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.

Description

FUSED IMIDAZOLE DERIVATIVES USEFUL AS IDO INHIBITORS
Cross-Reference to Related Applications
[0001] This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 61/475,788, filed April 15, 2011, which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] The present disclosure relates to compounds and methods for inhibition of indoleamine 2,3-dioxygenase; further the disclosure relates to method of treatment of diseases and disorders mediated by indoleamine 2,3-dioxygenase.
Summary of the Related Art
[0003] Tryptophan (Trp) is an essential amino acid required for the biosynthesis of proteins, niacin and the neurotransmitter 5-hydroxytryptamine (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 Trp-dependent 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 vivo during rejection of allogeneic tumors, indicating a possible role for this enzyme in the tumor rejection process.
[0004] It has been observed that HeLa cells co-cultured with peripheral blood lymphocytes (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 1 -methyl-tryptophan (1MT), 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).
[0005] 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 diarrhea and possibly immunosuppression of AIDS patients (Brown, et ah, 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 macrophages in a mouse model of HIV (Portula et ah, 2005, Blood, 106:2382-90).
[0006] IDO is believed to play a role in the immunosuppressive processes that prevent fetal rejection in utero. More than 40 years ago, it was observed that, during pregnancy, the genetically disparate mammalian conceptus survives in spite of what would be predicted by tissue transplantation immunology (Medawar, 1953, Symp. Soc. Exp. Biol. 7: 320-38). Anatomic separation of mother and fetus and antigenic immaturity of the fetus cannot fully explain fetal allograft survival. Recent attention has focused on immunologic tolerance of the mother. Because 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 exposed to 1MT, and a rapid, T cell-induced rejection of all allogeneic concepti was observed. Thus, by catabolizing tryptophan, the mammalian conceptus appears to suppress T-cell activity and defends itself against rejection, and blocking tryptophan catabolism during murine pregnancy allows maternal T cells to provoke fetal allograft rejection (Munn, et al, 1998, Science 281 : 1 191-3).
[0007] Further evidence for a tumoral immune resistance mechanism based on tryptophan degradation 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 treatment of mice with an inhibitor of IDO, in the absence of noticeable toxicity. Thus, it was suggested that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO inhibitor (Uyttenhove et ah, 2003, Nature Med., 9: 1269-74). It has also been shown that the IDO inhibitor, 1-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 (Muller et ah, 2005, Nature Med., 1 1 :312-9). [0008] 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 CD 123 (IL3RA) and CCR6 and inhibited T-cell proliferation have also been described. Both mature and immature CD 123 -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 tumor-draining lymph nodes (TDLNs) contain 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 presented by nonsuppressive APCs. Within the population of pDCs, the majority of the functional IDO-mediated suppressor activity segregated with a novel subset of pDCs coexpressing the B-lineage marker CD19. Thus, it was hypothesized that IDO-mediated 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., 1 14(2): 280-90).
[0009] 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 expressed by dendritic cells (DCs) can greatly affect T-cell proliferation and survival. IDO induction in DCs could be a common mechanism of deletional tolerance driven by regulatory T cells. Because such tolerogenic responses can be expected to operate in a variety of physiopathological conditions, tryptophan metabolism and kynurenine production might represent a crucial interface between the immune and nervous systems (Grohmann, et al, 2003, Trends Immunol, 24: 242-8).
[0010] Small molecule inhibitors of IDO are being developed to treat or prevent IDO-related diseases such as those described above. For example, PCT Publication WO 99/29310 reports methods for altering T cell-mediated immunity comprising altering local extracellular concentrations of tryptophan and tryptophan metabolites, using an inhibitor of 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 reported in WO 2004/094409; and U.S. Patent Application Publication No. 2004/0234623 is directed to methods of treating a subject with a cancer or an infection by the administration of an inhibitor of indoleamine-2,3-dioxygenase in combination with other therapeutic modalities.
[0011] In light of the experimental data indicating a role for IDO in immunosuppression, tumor resistance and/or rejection, chronic infections, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhea), autoimmune diseases or disorders (such as rheumatoid arthritis), and immunologic tolerance and prevention of fetal rejection in utero, therapeutic agents aimed at suppression of tryptophan degradation by inhibiting 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 suppressed 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 INVENTION
[0012] In one aspect, the invention com rises compounds according to the formula (I),
Figure imgf000006_0001
wherein R1, R2, n and a are each defined herein.
[0013] In another aspect, the invention comprises compounds according to the formula (II),
Figure imgf000006_0002
wherein R1, R3, Rc, and n are each defined herein.
[0014] In another aspect pharmaceutical compositions are provided comprising a pharmaceutically acceptable excipient, diluent, or carrier, and a compound according to formula (I) or (II). [0015] In another aspect methods are provided for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of a compound according 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 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); (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 compound according to formula (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 according to formula (I) or (II); and (f) treating immunosupression associated with an infectious disease, e.g., HIV-1 infection, 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).
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 shows the absolute configuration of a diasteromer of the HBr salt of compound 1417 as confirmed by X-ray crystallography.
DETAILED DESCRIPTION OF THE INVENTION
[0017] In one aspect, the invention provides com ounds of formula (I),
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof, wherein
bond a is a single or double bond;
n is 0, 1 , 2, 3, or 4;
each R1 is independently halogen, cyano, nitro, Ci-6alkyl,
Figure imgf000008_0001
-OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, or -N(R)C(0)N(R)2;
R2 is -Ci_4alkyl-RA or -C2_4alkenyl-R3 when bond a is a single bond; and
R2 is =C(H)RA when bond a is a double bond;
wherein
RA is -CN, -C(0)R3, -C(0)OR3, -C(0)N(R3)(Rc), -C(ORB)(R3)(Rc), -C(NHRB)(R3)(RC), or -C(=N-ORc)R3, wherein
RB is hydrogen, Ci_6alkyl, Ci_6haloalkyl, -Ci_6alkyl-RB1, -C(0)R3, or -S(0)2R3, -C(0)(CH2)!.4COOR, -C(0)CH(NH2)(RD), -S(0)2OR3, -S(0)2N(R3)2, -CH2- OP(0)2(OR)2, or -P(0)(OR3)2, wherein
RB1 is cyano, nitro, d_6alkyl, Ci_6haloalkyl, -OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, or -N(R)C(0)N(R)2; RD is hydrogen, methyl, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), benzyl, 4-hydroxybenzyl, -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, Ci-6alkyl,
Figure imgf000008_0002
aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3- 10 membered heterocyclyl, arylCi-6alkyl-, heteroarylCi-6 alkyl-, C3_8cycloalkylCi_6alkyl-, C3_8cycloalkenylCi_6alkyl-, or (3- 10 membered heterocyclyl)Ci_6alkyl-,
wherein
the alkyl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, C3_8cycloalkylCi_6alkyl-, C3_8cycloalkenylCi_6alkyl-, and (3- 10 membered heterocyclyl)Ci_6alkyl- 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, arylCi_6alkyl-, and heteroarylCi_6alkyl- groups, are each optionally substituted by one, two, three, or four R31 groups; wherein
each R31 is independently halogen, cyano, nitro, Ci-6alkyl, -Ci_6alkyl-R33, Ci_6haloalkyl, -OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)R,- -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)N(R)2, wherein
R33 is cyano, -OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, or -N(R)C(0)N(R)2;
R32 is =0, =S, =N(R), =N(OR), =C(R34)2, =(spiro-C3-8cycloalkyl), or =(spiro-(3-10 membered heterocyclyl)), wherein
each R34 is independently hydrogen, halogen, Ci_6alkyl,
Ci-6haloalkyl, 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 Ci-6alkyl;
and
each R is independently hydrogen or R , wherein
R10 is Ci-6alkyl,
Figure imgf000009_0001
aryl, heteroaryl, C3-8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, arylCi-6alkyl, heteroarylCi_6aikyl-, C3-8 cycloalkylCi-6alkyl-, C3-8cycloalkenylCi_6alkyl-, or (3-10 membered heterocyclyl)Ci_6alkyl-, each R10 optionally substituted by one, two, three, or four groups that are each independently halogen, cyano, nitro, Ci_6alkyl, Ci_6haloalkyl, -OR11, -N(RU)2, -SR11, -C(0)ORn, -C(0)N(Rn)2, -C(0)Ru, -S(0)Rn, -S(0)ORn, -S(0)N(Ru)2, -S(0)2Rn, -S(0)2ORu, -S(0)2N(Ru)2, -OC(0)Rn, -OC(0)ORu, -OC(0)N(Rn)2, -N(Rn)C(0)Rn, -N(Ru)C(0)ORu, -N(Ru)C(0)N(Rn)2, wherein each R11 is independently hydrogen or Ci-6alkyl. [0018] In one embodiment, the compounds of formula (I) further include those compounds where,
RB is additionally -C(0)N(H)R3 or -C(0)(CH2)!_4(NR)COOR;
R3 is additionally (heteroaryl)-(3-10 membered heterocyclyl)-,
R31 is additionally -C(0)N(OH)R, -C(N=Rn)R, or -C(N=Rn)N(Rn)R;
R34 is additionally cyano or - Ci-6alkyl-OR; and/or
R10 is additionally optionally substituted by -N(Ru)S(0)2Rn or -C(O)-(3-10 membered heterocyclyl);
such compounds are referred to as compounds of formula (Γ).
[0019] The invention further comprises subgenera of formula (I) and formula (Γ) in which the substituents are selected as any and all combinations of one or more of structural formula
(I), n, R 1 , R 2 , R 3 , R A , R B , and R C , as defined herein, including without limitation, the following:
[0020] Structural Formula I is one of formulae (la) - (Ih);
Figure imgf000010_0001
n and R1 are selected from one of the following groups (la) - (lu);
n is 1, 2, 3, or 4, and each R1 is as defined for formula (I). (lb) n is 0, 1, 2, or 3, and each R1 is as defined for formula (I).
(lc) n is 0, 1, or 2 and each R1 is as defined for formula (I).
(Id) n is 0, 1, or 2 and each R1 is independently halogen, -OR, -N(R)2, or -SR.
(le) n is 0, 1, or 2 and each R1 is independently halogen, -OR0, -N(R°)2, or -SR°, wherein each R° is independently hydrogen or Ci-6alkyl.
(If) n is 0, 1, or 2 and each R1 is independently fluoro, chloro, hydroxy, or methoxy. (lg) n is 0, 1, or 2 and each R1 is independently halogen,
(lh) n is 0, 1, or 2 and each R1 is independently fluoro or chloro.
(li) 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.
(Ik) n is 0 or 1 and R1 is halogen, -OR0, -N(R°)2, or -SR°;wherein each R° is independently hydrogen or Ci_6alkyl.
(11) n is 0 or 1 and R1 is fluoro, chloro, hydroxy, or methoxy.
(lm) n is 0 or 1 and R1 is halogen.
(In) n is 0 or 1 and R1 is fluoro or chloro.
(lo) n is 1 and R1 is as defined for formula (I),
(lp) n is 1 and R1 is halogen, -OR, -N(R)2, or -SR;
(lq) n is 1 and R1 is halogen, -OR0, -N(R°)2, or -SR°;wherein each R° is independently hydrogen or Ci_6alkyl.
(lr) n is 1 and R1 is fluoro, chloro, hydroxy, or methoxy.
(Is) n is 1 and R1 is halogen.
(It) n is 1 and R1 is fluoro or chloro.
(lu) n is O.
[0022] R2 is selected from one of the following groups (2a) - (21);
(2a) R2 is -Ci_4alkyl-RA.
(2b) R2 is -Ci_2alkyl-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.
(2e) R2 is -C(H)=C(H)R30, wherein R30 is phenyl optionally substituted by one or two R31 groups.
(2f) 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 -C(H)(CH3)CH2-RA.
(2h) R2 is -CH2-RA, -CH2CH2-RA, or -C(H)=C(H)R3.
(2i) R2 is -CH2-RA.
(2j) R2 is -CH2CH2-RA.
(2k) R2 is -C(H)(CH3)CH2-RA
(21) R2 is -CH2-RA, -CH2CH2-RA, or -C(H)=C(H)R3.
[0023] RA is selected from one of the following groups (3a) - (3n);
(3a) RA is -CN, -C(0)OR3, or -C(0)N(R3)(Rc).
(3b) RA is -C(0)R3 or -C(ORB)(R3)(Rc).
(3c) RA is -C( HRB)(R3)(RC), or -C(=N-ORc)R3.
(3d) RA is -C( HRB)(R3)(RC), wherein RB is hydrogen, C1-6alkyl, or -C(0)Ci_6alkyl.
(3e) RA is -C( H2)(R3)(RC).
(3f) RA is -C(0)OR3.
(3g) RA is -C(0)N(R3)(Rc).
(3h) RA is -C(0)R3.
(3i) RA is -C(ORB)(R3)(Rc).
(3j) RA is -C(OH)(R3)(Rc).
(3k) RA is -CH(OH)(R3).
(31) RA is -CN, -C(0)R3, -C(0)OR3, -C(0)N(R3)(Rc), -C(ORB)(R3)(Rc),
-C(NHRB)(R3)(RC), or -C(=N-ORc)R3.
(3m) RA is -C(0)R3 or -C(ORB)(R3)(Rc), wherein RB is hydrogen and Rc is hydrogen or
Ci-6alkyl.
(3n) RA is -C(ORB)(R3)(Rc), wherein RB is hydrogen and Rc is hydrogen or Ci-6alkyl.
[0024] RB is selected from one of the following groups (4a) - (4k);
(4a) RB is hydrogen, Ci_6alkyl, Ci_6haloalkyl, -Ci_6alkyl-RB1, -C(0)(CH2)!_4COORB2, -C(0)C(NH2)RD, -P(03)(RB2)2, -CH2-OP(0)2(OR)2, wherein RD is the side chain of natural alpha amino acids , -C(0)R3, or -S(0)2R3, wherein RB1 is cyano, nitro, Ci_6alkyl, Ci_6haloalkyl, -ORB2, -N(RB2)2, -SRB2, -C(0)ORB2, -C(0)N(RB2)2, -C(0)RB2, -S(0)RB2, -S(0)ORB2, -S(0)N(RB2)2, -S(0)2RB2, -S(0)2ORB2, -S(0)2N(RB2)2, -OC(0)RB2, -OC(0)ORB2, -OC(0)N(RB2)2, -N(RB2)C(0)RB2, -N(RB2)C(0)OR , or -N(RBZ)C(0)N(R )¾ wherein each R is independently hydrogen or Ci-6alkyl.
(4b) RB is hydrogen, Ci_6alkyl, Ci_6haloalkyl, -Ci_6alkyl-RB1, -C(0)R3, or -S(0)2R3, wherein RB1 is cyano, nitro, Ci_6alkyl, Ci_6haloalkyl, -ORB2, -N(RB2)2, -SRB2, -C(0)ORB2, -C(0)N(RB2)2, -C(0)RB2, -S(0)RB2, -S(0)ORB2, -S(0)N(RB2)2, -S(0)2RB2, -S(0)2ORB2, -S(0)2N(RB2)2, -OC(0)RB2, -OC(0)ORB2, -OC(0)N(RB2)2, -N(RB2)C(0)RB2, -N(RB2)C(0)ORB2, or -N(RB2)C(0)N(RB2)2, wherein each RB2 is independently hydrogen or Ci_6alkyl.
(4c) RB is hydrogen, Ci_6alkyl,
Figure imgf000013_0001
or -Ci-6alkyl-RB1, wherein RB1 is cyano, nitro, Ci_6alkyl, Ci_6haloalkyl, -ORB2, -N(RB2)2, -SRB2, -C(0)ORB2, -C(0)N(RB2)2, -C(0)RB2, -S(0)RB2, -S(0)ORB2, -S(0)N(RB2)2, -S(0)2RB2, -S(0)2ORB2, -S(0)2N(RB2)2, -OC(0)RB2, -OC(0)ORB2, -OC(0)N(RB2)2, -N(RB2)C(0)RB2, -N(RB2)C(0)ORB2, or -N(RB2)C(0)N(RB2)2, wherein each RB2 is independently hydrogen or Ci-6alkyl.
(4d) RB is hydrogen, Ci-6alkyl,
Figure imgf000013_0002
or -Ci-6alkyl-RB1, wherein RB1 is cyano,
-C(0)ORB2, -C(0)N(RB2)2, -C(0)RB2, -S(0)2RB2, -S(0)2ORB2, or -S(0)2N(RB2)2, wherein each RB2 is independently hydrogen or Ci-6alkyl.
(4e) RB is -Ci_6alkyl-RB1, wherein RB1 is cyano, -C(0)ORB2, -C(0)N(RB2)2, -C(0)RB2,
-S(0)2RB2, -S(0)2ORB2, or -S(0)2N(RB2)2, wherein each RB2 is independently hydrogen or Ci-6alkyl.
(4f) RB is hydrogen, Ci-6alkyl, Ci-6haloalkyl, -Ci-6alkyl-RB1, -C(0)RB2, or -S(0)2RB2, wherein RB1 is -C(0)ORB3, -C(0)N(RB3)2, -S(0)2ORB3, or -S(0)2N(R 3)2, RB2 is Ci_6 alkyl; and RB3 is hydrogen or Ci_6 alkyl.
(4g) RB is hydrogen, Ci-6alkyl, or Ci_6haloalkyl.
(4h) RB is hydrogen or Ci_6alkyl;
(4i) RB is hydrogen.
(4j) RB is d-ealkyl.
(4k) RB is hydrogen, -C(0)RB2, -C(0)(CH2)!_4COORB2, -C(0)C( H2)RD, -P(0)(ORB2)2, -CH2-OP(0)2(OR)2, -S(0)2RB2, -C(0)N(RB2)2, -S(0)2ORB2, -S(0)2N(R 3)2, wherein and RB2 is hydrogen or Ci_6 alkyl.
[0025] Rc is selected from one of the following groups (5a) - (5g);
(5a) Rc is hydrogen or Ci_4alkyl.
(5b) Rc is hydrogen or Ci-2alkyl. (5c) R is hydrogen or methyl.
(5d) Rc is hydrogen.
(5e) Rc is Ci_6alkyl.
(5f) Rc is Ci_4alkyl.
(5g) Rc is methyl.
[0026] R3 is selected from one of the following groups (6a) - (6z);
(6a) R3 is hydrogen, Ci-6alkyl, aryl, heteroaryl, C3-8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, or C3-8cycloalkylCi_6alkyl-, wherein the
Figure imgf000014_0001
C3-8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, and C3-8cycloalkylCi-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_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, or C3-8cycloalkylCi-6alkyl-, wherein the C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, and C3_8cycloalkylCi_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.
(6c) R3 is phenyl, a five or six membered heteroaryl, monocyclic Cs-scycloalkyl, monocyclic Cs-scycloalkenyl, a five or six membered monocyclic heterocyclyl, or (monocyclic C5_8cycloalkyl)Ci_6 alkyl-, wherein the Cs-scycloalkyl, Cs-scycloalkenyl, 5 - 6 membered heterocyclyl, and C5_8cycloalkylCi_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.
(6e) R3 is monocyclic Cs-scycloalkyl, monocyclic Cs-scycloalkenyl, a five or six membered monocyclic heterocyclyl, or (monocyclic C5-8cycloalkyl)Ci_6alkyl-, each optionally substituted by one =R32 group and one or two R31 groups. (6f) R3 is
Figure imgf000015_0001
, wherein bond a is a single bond or a double bond; m is 0, 1, 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 -0-, wherein each R36 is independently hydrogen or R31; and
R35 is hydrogen, Ci_6alkyl, -C(0)R, -S(0)2R, -C(0)OR, -C(0)N(R)2, -S(0)2OR, or -S(0)2N(R)2;
or -N=.
Figure imgf000015_0002
double bond; m is 0, 1, 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 -0-, wherein each R36 is independently hydrogen or R31; and
R35 is hydrogen, Ci_6alkyl, -C(0)R, -S(0)2R, -C(0)OR, -C(0)N(R)2, -S(0)2OR, or -S(0)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 -C(=R32)-
; 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=.
(6j) As group (6g), wherein bond a is a single bond; and Z is -C(R36)2- or -C(=R32)-. (6k) As group (6g), wherein 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)-.
(6m) As group (6g), wherein m is 0; bond a is a single bond; and Z is -C(R36)2- or -
C(=R3 .
(6n) As group (6g), wherein m is 0; bond a is a single bond; and Z is -C(R )2-.
(6o) 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 -C(=R32)-, wherein each R36 is independently hydrogen, halogen, Ci-6alkyl, -Ci_6alkyl-OH,
Ci-6haloalkyl, or -OH, wherein R is =0, =C(R )2, =(spiro-C3_8cycloalkyl), or =(spiro-(3-8 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, Ci-6alkyl, Ci_6haloalkyl, C3_8cycloalkyl, or 3-8 membered heterocyclyl.
(6q) 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, halogen, Ci_6alkyl, -Ci_6alkyl-OH, Ci_6haloalkyl, or -OH, wherein
R32 is =0,
Figure imgf000016_0001
=(spiro-C3-8cycloalkyl), or =(spiro-(3-8 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, Ci_6alkyl, Ci-6haloalkyl, C3-8cycloalkyl, or 3-8 membered heterocyclyl.
(6r) As group (6g), wherein bond a is a single bond; and Z is -N(R35)- or -0-.
(6s) R3 is hydrogen, Ci-6alkyl, aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, or C3_8cycloalkylCi-6alkyl, wherein
the Ci-6alkyl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, and C3-8cycloalkylCi-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, Ci-6alkyl, -Ci_6alkyl-R33, Ci_6haloalkyl, -OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)N(R)2, wherein R33 is -OR, -N(R)2, or -SR; and
R32 is oxo, =C(R34)2, =(spiro-C3-8cycloalkyl), or =(spiro-(3-10 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, Ci_6alkyl, or C3-8cycloalkyl.
(6t) R3 is hydrogen, Ci_6alkyl, aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, or C3_8cycloalkylCi_6alkyl-, wherein
the Ci_6alkyl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, and C3-8cycloalkylCi-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 R is independently halogen, cyano, nitro, Ci-6alkyl, -Ci-6alkyl-R , Ci_6haloalkyl, -OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)N(R)2, wherein R33 is -OR, -N(R)2, or -SR; and
R32 is oxo, =C(R34)2, =(spiro-C3_8cycloalkyl), or =(spiro-(3-10 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, Ci-6alkyl, or C3_8cycloalkyl.
(6u) R3 is aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, or 3-10 membered heterocyclyl, wherein the C3_8cycloalkyl, C3_8cycloalkenyl, and 3-10 membered heterocyclyl are each optionally 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.
(6v) 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.
(6w) R3 is phenyl, cyclopentyl, cyclohexyl, cyclohex-l-en-l-yl, cyclohex-3-en-l-yl, furan-
2- yl, furan-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 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, Ci_6alkyl, Ci-6haloalkyl, aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, arylCi-6alkyl, heteroarylCi_6alkyl-, C3-8 cycloalkylCi-6alkyl-, C3_8cycloalkenylCi_6alkyl-, or (3-10 membered heterocyclyl)Ci_6alkyl-.
(6y) Any one of groups (6a) - (6w), wherein each R is independently hydrogen, Ci_6alkyl, Ci-6haloalkyl, phenyl, 5- or 6-membered heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl,
3- 8 membered heterocyclyl, benzyl, (5- or 6-membered heteroaryl)Ci_6alkyl-, C3-8 cycloalkylCi-6alkyl-, C3_8cycloalkenylCi_6alkyl-, or (3-8 membered heterocyclyl)Ci-6alkyl-. (6z) Any one of groups (6a) - (6w), wherein each R is independently hydrogen or Ci-6alkyl.
[0027] Particular embodiments of this aspect of the invention include compounds of any one of the formulae (I), (Γ), and (la) - (Id), each as defined in each of the following rows, wherein each entry is a group number as defined above (e.g., (Is) refers to n is 1 and each R1 is halogen), and a dash "-" indicates that the variable is as defined for formula (I) or (Γ) 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 (Γ) or any one of definitions (5a)-(5g)] :
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
[0028] In another aspect, the invention rovides the compound according to formula (II),
Figure imgf000024_0001
(II)
or a pharmaceutically acceptable salt thereof, wherein
n is 0 or 1 ;
each R1 is independently halogen, -OR, -N(R)2, or -SR;
each R3 is independently hydrogen, Ci-6alkyl, aryl, heteroaryl, C3-scycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, or C3_8cycloalkylCi_6alkyl-, wherein the Ci-6alkyl, C3-8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, and C3-8cycloalkylCi-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, Ci-6alkyl,
-Ci_6alkyl-R , C1-6haloalkyl, -OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)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, Ci_6alkyl, or C3_8cycloalkyl; and
R is hydrogen or Ci_6alkyl; and
each R is independently hydrogen or R10, wherein
R10 is Ci-6alkyl,
Figure imgf000024_0002
aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, arylCi-6alkyl, heteroarylCi-6alkyl-, C3-8 cycloalkylCi-6alkyl-, C3-8cycloalkenylCi_6alkyl-, or (3-10 membered heterocyclyl)Ci_6alkyl-, each R10 optionally substituted by one, two, three, or four groups that are each independently halogen, cyano, nitro, C1-6alkyl, Ci_6haloalkyl, -OR11, -N(RU)2, -SR11, -C(0)ORn, -C(0)N(Rn)2, -C(0)Ru, -S(0)Rn, -S(0)ORn, -S(0)N(Ru)2, -S(0)2Rn, -S(0)2ORu, -S(0)2N(Ru)2, -OC(0)Rn, -OC(0)ORu, -OC(0)N(Rn)2, -N(Rn)C(0)Rn, -N(Ru)C(0)ORu, -N(Ru)C(0)N(Rn)2, wherein each R11 is independently hydrogen or Ci_6alkyl.
[0029] In one embodiment, the compounds of formula (II) further include those compounds where,
R3 is additionally (heteroaryl)-(3-10 membered heterocyclyl)-;
R31 is additionally -C(0)N(OH)R, -C(N=Rn)R, or -C(N=Rn)N(Rn)R;
R34 is additionally cyano or - Ci-6alkyl-OR; and/or
R10 is additionally optionally substituted by -N(Ru)S(0)2Rn or -C(O)-(3-10 membered heterocyclyl);
such compounds are referred to as compounds of formula (ΙΓ).
[0030] The invention further comprises subgenera of formula (II) or (ΙΓ) in which the substituents are selected as any and all combinations of one or more of structural formula (II), n, R1, R3, and Rc as defined herein, including without limitation, the following:
[0031] Structural Formula II is on f formulae (Ila) - (lid):
Figure imgf000025_0001
[0032] (Ila): wherein the stereoisomeric configuration of carbon-1 (C-l) and carbon-3 (C-3) of formula (II) are respectively (R, R).
[0033] (lib): wherein the stereoisomeric configuration of carbon-1 and carbon-3 are of formula (II) respectively (R, S).
[0034] (He): wherein the stereoisomeric configuration of carbon-1 and carbon-3 are of formula (II) respectively (S, R).
[0035] (lid): wherein the stereoisomeric configuration of carbon-1 and carbon-3 are of formula (II) respectively (S, S). [0036] Structural Formula II is one of formulae Tile) - (Ilh):
Figure imgf000026_0001
[0037] (He): wherein the stereoisomeric configuration of carbon-1 (C-1) and carbon-3 (C-3) of formula (II) are respectively (R, R).
[0038] (Ilf): wherein the stereoisomeric configuration of carbon-1 and carbon-3 are of formula (II) respectively (R, S).
[0039] (Hg): wherein the stereoisomeric configuration of carbon-1 and carbon-3 are of formula (II) respectively (S, R).
[0040] (Ilh): wherein the stereoisomeric configuration of carbon-1 and carbon-3 are of formula (II) respectively (S, S).
[0041] n and R1 are selected from one of the following groups (7a) - (7i):
(7a) n is 0 or 1 and R1 is halogen, -OR0, -N(R°)2, or -SR°; wherein each R° is independently hydrogen or Chalky 1.
(7b) n is 0 or 1 and R1 is fluoro, chloro, hydroxy, or methoxy.
(7c) n is 0 or 1 and R1 is halogen.
(7d) n is 0 or 1 and R1 is fluoro or chloro.
(7e) n is 1 and R1 is halogen, -OR0, -N(R°)2, or -SR°; wherein each R° is independently hydrogen or
Figure imgf000026_0002
(7f) n is 1 and R1 is fluoro, chloro, hydroxy, or methoxy.
(7g) n is 1 and R1 is halogen.
(7h) n is 1 and R1 is fluoro or chloro.
(7i) n is O.
[0042] Rc is selected from one of the following groups (8a) - (8g):
(8a) Rc is hydrogen or Ci-4alkyl.
(8b) Rc is hydrogen or
Figure imgf000026_0003
(8c) Rc is hydrogen or methyl.
(8d) Rc is hydrogen.
(8e) Rc is Ci-ealkyl. (8f) R is Ci-4 lkyl.
(8g) Rc is methyl.
[0043] R3 is selected from one of the following groups (9a) - (9x);
(9a) R3 is aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, or C3_8cycloalkylCi-6alkyl-, wherein the C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, and C3_8cycloalkylCi_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 Cs-scycloalkyl, monocyclic Cs-scycloalkenyl, a five or six membered monocyclic heterocyclyl, or (monocyclic C5_8cycloalkyl)Ci_6 alkyl-, wherein the Cs-scycloalkyl, Cs-scycloalkenyl, 5 - 6 membered heterocyclyl, and C5_8cycloalkylCi_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 substituted by one or two R31 groups.
(9d) R3 is monocyclic Cs-scycloalkyl, monocyclic Cs-scycloalkenyl, a five or six membered monocyclic heterocyclyl, or (monocyclic C5_8cycloalkyl)Ci-6alkyl-, each optionally substituted by one =R32 group and one or two R31 groups.
(9e) R3 is
Figure imgf000027_0001
, wherein bond a is a single bond or a double bond; m is 0, 1, 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 -0-, wherein each R36 is independently hydrogen or R31; and
R35 is hydrogen, Ci_6alkyl, -C(0)R, -S(0)2R, -C(0)OR, -C(0)N(R)2, -S(0)2OR, or -S(0)2N(R)2;
or -N=.
(9f) R3
Figure imgf000027_0002
ouble bond; m is 0, 1, 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 -0-, wherein each R36 is independently hydrogen or R31; and
R35 is hydrogen, Ci_6alkyl, -C(0)R, -S(0)2R, -C(0)OR, -C(0)N(R)2, -S(0)2OR, or -S(0)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 -C(=R32)-
; 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)-. (9j) 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)-.
(9m) As group (9f), wherein m is 0; bond a is a single bond; and Z is -C(R36)2-.
(9n) As group (9f), wherein m is 0; bond a is a single bond; and Z is -C(=R32)-.
(9o) As group (9f), wherein bond a is a single bond; and Z is -C(R36)2- or -C(=R32)-, wherein each R36 is independently hydrogen, halogen, Ci-6alkyl, -Ci_6alkyl-OH,
Ci-6haloalkyl, or -OH, wherein
R32 is =0, =C(R34)2, =(spiro-C3-8cycloalkyl), or =(spiro-(3-8 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, Ci_6alkyl,
Ci-6haloalkyl, C3-8cycloalkyl, 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, Ci_6alkyl,
-Ci_6alkyl-OH, Ci_6haloalkyl, or -OH, wherein
R32 is =0, =C(R34)2, =(spiro-C3-8cycloalkyl), or =(spiro-(3-8 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, Ci-6alkyl,
Ci-6haloalkyl, C3-8cycloalkyl, or 3-8 membered heterocyclyl.
(9q) As group (9f), wherein bond a is a single bond; and Z is -N(R35)- or -0-.
(9r) R3 is hydrogen, Ci-6alkyl, aryl, heteroaryl, C3-8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, or C3_8cycloalkylCi_6alkyl, wherein the Ci_6alkyl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, and C3-8cycloalkylCi_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, Ci_6alkyl, -Ci_6alkyl-R33, Ci_6haloalkyl, -OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)N(R)2, wherein R33 is -OR, -N(R)2, or -SR; and
R32 is oxo, =C(R34)2, =(spiro-C3-8cycloalkyl), or =(spiro-(3-10 membered heterocyclyl)), wherein each R34 is independently hydrogen, halogen, Ci-6alkyl, or C3-8cycloalkyl.
(9s) R3 is aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, or 3-10 membered heterocyclyl, wherein the C3_8cycloalkyl, C3_8cycloalkenyl, and 3-10 membered heterocyclyl are each optionally 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.
(9u) R3 is phenyl, cyclopentyl, cyclohexyl, cyclohex-l-en-l-yl, cyclohex-3-en-l-yl, furan- 2-yl, furan-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 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.
(9v) Any one of groups (9a) - (9u), wherein each R is independently hydrogen, Ci_6alkyl, Ci-6haloalkyl, aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, arylCi-6alkyl, heteroarylCi_6alkyl-, C3-8 cycloalkylCi-6alkyl-, C3-8cycloalkenylCi_6alkyl-, or (3-10 membered heterocyclyl)Ci_6alkyl-. (9w) Any one of groups (9a) - (9u), wherein each R is independently hydrogen, Ci-6alkyl, Ci_6haloalkyl, phenyl, 5- or 6-membered heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-8 membered heterocyclyl, benzyl, (5- or 6-membered heteroaryl)Ci_6alkyl-, C3-8 cycloalkylCi_6alkyl-, C3-8cycloalkenylCi-6alkyl-, or (3-8 membered heterocyclyl)Ci-6alkyl-.
(9x) Any one of groups (9a) - (9u), wherein each R is independently hydrogen or Ci-6alkyl.
[0044] Particular embodiments of this aspect of the invention include compounds of any one of the formulae (II), (IF), and (Ha) - (Ild), each as defined in each of the following rows, wherein each entry is a group number as defined above and a dash "-" indicates that the variable is as defined for formula (II), or (ΙΓ), or defined according to any one of the applicable variable definitions (7a)-(9t) [e.g., when Rc is a dash, it can be either as defined for Formula (II), or (IF), or any one of definitions (8a)-(8g)]:
Figure imgf000030_0001
Figure imgf000030_0002
(Π) n & R1 R R> (II) n & R1 R R>
(2)-37 lib Vg 9e 8c (2)-68 lie 7h 9e 8d
(2)-38 lie Vg 9e 8c (2)-69 Ild 7h 9e 8d
(2)-39 Ild Vg 9e 8c (2)-70 Ilf 7h 9e 8g
(2)-40 Ilf Vg 9e 8d (2)-71 iig 7h 9e 8g
(2)-41 iig Vg 9e 8d (2)-72 Ilh 7h 9e 8g
(2)-42 Ilh Vg 9e 8d (2)-73 lib 7h 9v 8c
(2)-43 lib Vg 9e 8g (2)-74 lie 7h 9v 8c
(2)-44 lie Vg 9e 8g (2)-75 Ild 7h 9v 8c
(2)-45 Ild Vg 9e 8g (2)-76 Ilf 7h 9v 8d
(2)-46 Ilf Vg 9v 8c (2)-77 iig 7h 9v 8d
(2)-47 iig Vg 9v 8c (2)-78 Ilh 7h 9v 8d
(2)-48 Ilh Vg 9v 8c (2)-79 lib 7h 9v 8g
(2)-49 lib Vg 9v 8d (2)-80 He 7h 9v 8g
(2)-50 He Vg 9v 8d (2)-81 Ild 7h 9v 8g
(2)-51 Ild Vg 9v 8d (2)-82 Ilf 7i 9b 8c
(2)-52 Ilf Vg 9v 8g (2)-83 iig 7i 9b 8c
(2)-53 iig Vg 9v 8g (2)-84 Ilh 7i 9b 8c
(2)-54 Ilh Vg 9v 8g (2)-85 lib 7i 9b 8d
(2)-55 lib 7h 9b 8c (2)-86 lie 7i 9b 8d
(2)-56 He 7h 9b 8c (2)-87 Ild 7i 9b 8d
(2)-57 Ild 7h 9b 8c (2)-88 Ilf 7i 9b 8g
(2)-58 Ilf 7h 9b 8d (2)-89 iig 7i 9b 8g
(2)-59 iig 7h 9b 8d (2)-90 Ilh 7i 9b 8g
(2)-60 Ilh 7h 9b 8d (2)-91 lib 7i 9e 8c
(2)-61 lib 7h 9b 8g (2)-92 He 7i 9e 8c
(2)-62 He 7h 9b 8g (2)-93 Ild 7i 9e 8c
(2)-63 Ild 7h 9b 8g (2)-94 Ilf 7i 9e 8d
(2)-64 Ilf 7h 9e 8c (2)-95 iig 7i 9e 8d
(2)-65 iig 7h 9e 8c (2)-96 Ilh 7i 9e 8d
(2)-66 Ilh 7h 9e 8c (2)-97 lib 7i 9e 8g
(2)-67 lib 7h 9e 8d (2)-98 lie 7i 9e 8g (Π) n & R1 R R> (II) n & R1 R R>
(2)-99 Ild 7i 9e 8g (2)-130 - Vg 9b 8d
(2)-100 Ilf 7i 9v 8c (2)-131 - Vg 9e 8d
(2)-101 ng 7i 9v 8c (2)-132 - Vg 9v 8d
(2)-102 Ilh 7i 9v 8c (2)-133 - Vg 9b 8g
(2)-103 lib 7i 9v 8d (2)-134 - Vg 9e 8g
(2)-104 lie 7i 9v 8d (2)-135 - Vg 9v 8g
(2)-105 Ild 7i 9v 8d (2)-136 - 7h 9b 8c
(2)-106 Ilf 7i 9v 8g (2)-137 - 7h 9e 8c
(2)-107 ng 7i 9v 8g (2)-138 - 7h 9v 8c
(2)-108 Ilh 7i 9v 8g (2)-139 - 7h 9b 8d
(2)-109 - - 9b 8c (2)-140 - 7h 9e 8d
(2)-110 - - 9e 8c (2)-141 - 7h 9v 8d
(2)-lll - - 9v 8c (2)-142 - 7h 9b 8g
(2)-112 - - 9b 8d (2)-143 - 7h 9e 8g
(2)-113 - - 9e 8d (2)-144 - 7h 9v 8g
(2)-114 - - 9v 8d (2)-145 - 7i 9b 8c
(2)-115 - - 9b 8g (2)-146 - 7i 9e 8c
(2)-116 - - 9e 8g (2)-147 - 7i 9v 8c
(2)-117 - - 9v 8g (2)-148 - 7i 9b 8d
(2)-118 - 7a 9b 8c (2)-149 - 7i 9e 8d
(2)-119 - 7a 9e 8c (2)-150 - 7i 9v 8d
(2)-120 - 7a 9v 8c (2)-151 - 7i 9b 8g
(2)-121 - 7a 9b 8d (2)-152 - 7i 9e 8g
(2)-122 - 7a 9e 8d (2)-153 - 7i 9v 8g
(2)-123 - 7a 9v 8d (2)-154 - 7a - 8c
(2)-124 - 7a 9b 8g (2)-155 - 7a - 8d
(2)-125 - 7a 9e 8g (2)-156 - 7a - 8g
(2)-126 - 7a 9v 8g (2)-157 - Vg - 8c
(2)-127 - Vg 9b 8c (2)-158 - Vg - 8d
(2)-128 - Vg 9e 8c (2)-159 - Vg - 8g
(2)-129 - Vg 9v 8c (2)-160 - 7h - 8c
Figure imgf000033_0001
[0045] In another aspect, the present disclosure provides compounds that are
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
1 - -methyl-
-
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Ν' ^ aminopentanedioate
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
// \ HO carboxamide
Figure imgf000053_0001
ructure Name
1 -(5H-imidazo [5, 1 -a] isoindol-5 -yl)-3 - methylbutan-2-ol
N
2-(5H-imidazo[5, l-a]isoindol-5-yl)-l- (tetrahydro-2H-pyran-3-yl)ethanol
2-(5H-imidazo [5, 1 -a] isoindol-5 -yl)- 1 -(piperidin- 3-yl)ethanol
l-cyclohexyl-2-((R)-5H-imidazo[5, l-a]isoindol- 5-yl)ethanol
l-cyclohexyl-2-((S)-5H-imidazo[5, l-a]isoindol- 5-yl)ethanol
(l S)-l-cyclohexyl-2-(5H-imidazo[5, l-a]isoindol- 5-yl)ethanol
( 1 R)- 1 -cyclohexyl-2-(5H-imidazo [5, 1- a]isoindol-5-yl)ethanol
1 -cyclohexyl-3 -(5H-imidazo[5, 1 -a] isoindol-5 - yl)propan-l-ol
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
H2N^N^ a] is oindol-5 -y l)ethanol
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
mide
Figure imgf000062_0001
Figure imgf000063_0001
oxoethyl)phenyl)methanesulfonamide
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
[0046] In another aspect, the present disclosure provides compounds and pharmaceutical compositions comprising the compounds according to any one of the preceding aspects of the invention or any embodiment thereof, together with a pharmaceutically acceptable excipient, diluent, or carrier.
[0047] In another aspect, the invention provides methods 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 embodiment thereof.
[0048] In one embodiment, the immunosuppression is associated with an infectious disease, or cancer.
[0049] In another embodiment, the immunosuppression 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).
[0050] In another embodiment, the immunosuppression is immunosupression associated with HIV-1 infection.
[0051] In another embodiment, the immunosuppression is associated with a cancer.
[0052] In an embodiment, the immunosuppression is tumor-specific immunosuppression associated with cancer.
[0053] 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.
[0054] In another aspect, the invention provides the use of compounds described by any one of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament for the treatment of medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase. Medical conditions contemplated in this aspect include all the conditions described herein.
[0055] In another aspect, the invention provides a use of compounds described by any one of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament to stimulate T cell proliferation or to reverse an immunologic state of anergy or immunosuppression.
[0056] In one embodiment, the anergy or immunosuppression is caused by expression of the enzyme indoleamine-2,3 -dioxygenase.
[0057] In another aspect, the invention provides the use of compounds described by any one of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament for the treatment of immunosuppression associated with cancer, infectious diseases, or viral infections.
[0058] In one embodiment, the invention provides the use of compounds described in to any one of the preceding aspects (and any embodiment thereof), as defined above, for the preparation of a medicament for the treatment of tumor-specific immunosuppression associated with cancer. Preferably, the cancer is cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, or head and neck, lymphoma, leukemia, melanoma, and the like.
[0059] In another embodiment, 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 infectious 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
[0060] Terms used herein may be preceded and/or followed by a single dash, or a double dash, "=", to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond or a pair of single bonds in the case of a spiro-substituent. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read "left to right" unless a dash indicates otherwise. For example, Ci-C6alkoxycarbonyloxy and -OC(0)Ci-C6alkyl indicate the same functionality; similarly arylalkyl, arylalkyl-, and -alkylaryl indicate the same functionality.
[0061] Further, certain terms herein may be used as both monovalent and divalent linking radicals as would be familiar to those skilled in the art, and by their presentation linking between two other moieties. For example, an alkyl group can be both a monovalent radical or divalent radical; in the latter case, it would be apparent to one skilled in the art that an additional hydrogen atom is removed from a monovalent alkyl radical to provide a suitable divalent moiety.
[0062] The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl. [0063] The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
[0064] The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec -butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2.2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an "alkyl" group is a linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to -CH2-, -CH2CH2-, -CH2CH2CHC(CH3)-, -CH2CH(CH2CH3)CH2-.
[0065] The term "aryl," as used herein, means a phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the phenyl portion of the bicyclic system, or any carbon atom with the napthyl or azulenyl ring. The fused monocyclic cycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl are optionally substituted with one or two oxo and/or thia groups. Representative examples of the bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-l-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl,
2.3- dihydroindol-7-yl, inden-l-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen- 1 -yl, 5,6,7,8-tetrahydronaphthalen-l-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo[d][l,3]dioxol-4-yl, benzo[d][l,3]dioxol-5-yl, 2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl, 2H-chromen-2-on-7-yl, 2H-chromen-2-on-8-yl, isoindoline-l,3-dion-4-yl, isoindoline-l,3-dion-5-yl, inden-l-on-4-yl, inden-l-on-5-yl, inden-l-on-6-yl, inden-l-on-7-yl, 2,3-dihydrobenzo[b][l,4]dioxan-5-yl, 2,3-dihydrobenzo[b][l,4]dioxan-6-yl, 2H-benzo[b][l,4]oxazin3(4H)-on-5-yl, 2H-benzo [b] [ 1 ,4] oxazin3 (4H)-on-6-yl, 2H-benzo[b] [1,4] oxazin3 (4H)-on-7-yl, 2H-benzo[b][l,4]oxazin3(4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl, benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl, benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl, quinazolin-4(3H)-on-6-yl, quinazolin-4(3 H)-on-7-yl, quinazolin-4(3 H)-on-8-yl, quinoxalin-2( 1 H)-on-5 -yl, quinoxalin-2(lH)-on-6-yl, quinoxalin-2(lH)-on-7-yl, quinoxalin-2(lH)-on-8-yl, benzo[d]thiazol-2(3H)-on-4-yl, benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and, benzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic aryl is (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.
[0066] The term "arylalkyl," "-alkylaryl," and "arylalkyl-" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
[0067] The terms "cyano" and "nitrile" as used herein, mean a -CN group.
[0068] The term "cycloalkyl" as used herein, means a monocyclic or a bicyclic cycloalkyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In certain embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH2)w-, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]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 attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia.
[0069] "Cycloalkenyl" as used herein refers to a monocyclic or a bicyclic cycloalkenyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon-carbon double bond), but not aromatic. Examples of monocyclic ring systems include cyclopentenyl and cyclohexenyl. Bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH2)W-, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct-2-enyl. Fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. Cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia.
[0070] The term "halo" or "halogen" as used herein, means -CI, -Br, -I or -F.
[0071] The term "haloalkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
[0072] The term "heteroaryl," as used herein, means a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring. The monocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted with one or two groups which are independently oxo or thia. When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon or nitrogen atom contained within the monocyclic heteroaryl portion of the bicyclic ring system. When the bicyclic heteroaryl is a monocyclic heteroaryl fused to a phenyl ring or a monocyclic heteroaryl, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon atom or nitrogen atom within the bicyclic ring system. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl,
5.6- dihydroisoquinolin-l-yl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-l-yl, thienopyridinyl, 4,5,6,7 -tetrahy drobenzo [c] [ 1 ,2 ,5 ] oxadiazoly 1, and
6.7- dihydrobenzo[c][l,2,5]oxadiazol-4(5H)-onyl. In certain embodiments, the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroaryl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.
[0073] The term "heteroarylalkyl" and "-alkylheteroaryl" as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, fur-3-ylmethyl, lH-imidazol-2-ylmethyl, lH-imidazol-4-ylmethyl, l-(pyridin-4-yl)ethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidin-5-ylmethyl, 2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl.
[0074] The term "heterocyclyl" as used herein, means a monocyclic heterocycle or a bicyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1, 1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-l-yl, indolin-2-yl, indolin-3-yl, 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 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia.
[0075] The term "hydroxy" as used herein, means an -OH group.
[0076] The term "nitro" as used herein, means a -N02 group.
[0077] The term "oxo" as used herein means a =0 group.
[0078] The term "saturated" as used herein means the referenced chemical structure does not contain any multiple carbon-carbon bonds. For example, a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like. [0079] 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 as
Figure imgf000074_0001
, where R is a spiro-cycloalkyl= group includes compounds such as
where the spiro-cyclopentyl group is the R group attached to the parent cyclohexyl ring by two single bonds. Similarly, where R is a spiro-heterocyclyl group, such compounds include
Figure imgf000074_0002
where the spiro-l,3-dioxolanyl ring is the R group attached to the parent cyclohexyl ring by two single bonds.
[0080] The term "thia" as used herein means a =S group.
[0081] 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.
[0082] 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.
[0083] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" the 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 preparation containing the IDO enzyme.
[0084] As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
[0085] As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
[0086] In certain embodiments, a therapeutically effective amount can be an amount suitable for (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
[0087] (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; or
[0088] (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.
[0089] As used here, the terms "treatment" and "treating" means (i) ameliorating the referenced disease state, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or improving the pathology and/or symptomatology) such as decreasing the severity of disease; or (ii) eliciting the referenced biological effect (e.g., IDO modulation or tryptophan degradation inhibition).
[0090] Manifestation of amelioration of a disease 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.
[0091] As used herein, the terms "catalytic pocket", "catalytic site", "active site" collectively and indistinctly refer to a region of the enzyme that contains amino acid residues responsible for the substrate binding (charge, hydrophobicity, steric hindrance) and catalytic amino acid residues which act as proton donors or acceptors or are responsible for binding a cofactor and participate in the catalysis of a chemical reaction.
[0092] As used herein, the phrase "pharmaceutically acceptable salt" refers to both pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC-(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
[0093] 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. Accordingly, compounds described herein can be used in methods of modulating 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 modulating (e.g., inhibiting) amount of a compound described herein.
[0094] Further provided are methods 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) extracellular tryptophan levels in a mammal comprise administering an effective amount of a compound or pharmaceutical composition provided herein. Methods of measuring tryptophan levels and tryptophan degradation are routine in the art.
[0095] 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 example, cancers, tumor growth, metastasis, infectious diseases (e.g., viral infection), viral replication, etc.
[0096] Further provided are methods for treating tumor-specific immunosuppression associated with cancer in a patient by administering to the patient an effective amount of a compound or composition recited herein. Example tumor-specific immunosuppression associated with cancers treatable by the methods herein include immunosuppression associated with cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head and neck, lymphoma, leukemia, melanoma, and the like. [0097] For example, a patient undergoing or having completed a course of chemotherapy and/or radiation therapy for the treatment of a disease state, such as a cancer, can benefit from administering to the patient a therapeutically effective amount of a compound or composition recited herein for inhibiting immunosuppression resulting from the disease state and/or treatment thereof.
[0098] 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.
[0099] For example, IDO-mediated immunosuppression 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, varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV).
[00100] Further provided are methods of treating diseases associated with activity or expression, including abnormal activity and/or overexpression, of IDO in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound described herein or a pharmaceutical composition thereof. Example diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the IDO enzyme, such as over expression or abnormal activity. An IDO-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating enzyme activity.
[00101] Examples of IDO-associated diseases include cancer, viral infection such as HIV infection, depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (e.g., organ transplant rejection), and autoimmune diseases including asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis and systemic lupus erythematosus or. Example cancers treatable by the methods herein include cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head and neck, lymphoma, leukemia, melanoma, and the like.
Combination Therapy
[00102] One or more additional pharmaceutical agents for treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and/or tyrosine kinase inhibitors can be used in combination with the compounds 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 simultaneously or sequentially as separate dosage forms.
[00103] Therapeutic agents that constitute the standard of care for a particular cancer type or infectious disease are expected to benefit when combined with IDO inhibitors of the present invention. For example, for the case of tumors, is it preferable that the tumor is sensitive to the cytotoxic effects of the chemotherapeutic agent in order to stimulate the release of antigens that will eventually mediate an immune response that will be enhanced by addition of 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.
[0100] 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.
[0101] Example suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH- 10652; emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-L-2',3'-dicleoxy-5-fluoro-cytidene); DAPD, ((-)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721 ; AG-1549; MKC-442
(l-(ethoxy-methyl)-5-(l-methylethyl)-6-(phenylmethyl)-(2,4(lH,3H)-pyrimid- i nedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.
[0102] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
[0103] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.
[0104] Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide.
[0105] Other cytotoxic agents include navelbene, CPT-1 1, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.
[0106] Also suitable are cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cis-platin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.
[0107] Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4,4-lBB and PD-1, or antibodies to cytokines (IL-10, TGF-β, etc.).
[0108] Other anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2, CCR4 and CCR6.
[0109] Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.
[0110] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
[0111] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, N.J.), the disclosure of which is incorporated herein by reference as if set forth in its entirety.
Pharmaceutical Formulations and Dosage Forms
[0112] The pharmaceutical compositions described herein generally comprise a combination of a compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient. Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application. In some embodiments of this aspect, if the compound is dissolved or suspended in water, the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient. In other embodiments, the pharmaceutical compositions described herein are solid pharmaceutical compositions (e.g., tablet, capsules, etc.).
[0113] These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
[0114] Also, pharmaceutical compositions can contain, as the active ingredient, one or more of the compounds described herein above in combination with one or more pharmaceutically acceptable carriers. In making the compositions described herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
[0115] In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
[0116] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
[0117] 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.
[0118] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
[0119] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of a compound described herein.
[0120] The tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
[0121] The liquid forms in which the compounds and compositions can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
[0122] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
[0123] The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
[0124] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
[0125] The therapeutic dosage of the compounds can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds described herein can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
[0126] The compounds described herein can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like.
Labeled Compounds and Assay Methods
[0127] 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 vivo, 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 provided are IDO enzyme assays that contain such labeled compounds.
[0128] Further provided are isotopically-labeled compounds of the compounds described herein. An "isotopically" or "radio-labeled" compound is a compound described herein where one or more atoms are replaced 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), nC, 13C, 14C, 13N, 15N, 150, 170, 180, 18F, 35S, 36C1, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and 131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro IDO enzyme labeling and competition assays, compounds that incorporate H, C, Br, I, I, S or will generally be most useful. For radio-imaging applications nC, 18F, 125I, 123I, 124I, 131I, 75Br, 76Br or 77Br will generally be most useful.
[0129] 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.
[0130] Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds described herein and are well known in the art.
[0131] A radio-labeled compound described herein can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified 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. Accordingly, 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.
Kits
[0132] Also included are pharmaceutical kits useful, for example, 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 include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
[0133] The following examples are offered for illustrative purposes, and are not intended to limit the disclosure in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results. The example compounds below were found to be inhibitors of IDO according to one or more of the assays described herein.
EXAMPLES
All reagents and solvents were purchased fr m commercial sources. All commercial reagents and solvents were used as received without further purification. The reactions were monitored using analytical thin layer chromatography (TLC) with 0.25 mm EM Science silica gel plates (60F-254). The developed TLC plates were visualized by short wave UV light (254 nm) or immersion in potassium permanganate solution followed by heating on a hot plate. Flash chromatography was performed with Selecto Scientific silica gel, 32-63 μπι particle sizes. All reactions were performed in flame or oven-dried glassware under a nitrogen atmosphere. All reactions were stirred magnetically at ambient temperature unless otherwise indicated. lH NMR spectra were obtained with a Bruker DRX400, Varian VXR400 or VXR300. lH NMR spectra were reported in parts per million (δ) relative to TMS (0.0), DMSO-d6 (2.50) or CD3OD (4.80) as an internal reference. All *H NMR spectra were taken in CDCI3 unless otherwise indicated. The following starting materials were prepared according to their literature procedures: E)-ethyl 3-(2-iodophenyl)acrylate (Synth. 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)-2-oxoethyl)phosphonate (Phosphorus, Sulfur Silicon Relat. Elem., 1999, 155, 67-80), dimethyl (2-cyclohexyl-2-oxo)ethylphosphonate (Patent: US5807892 Al, 1998), ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate (Patent: US2008/306084 Al, 2008), (trans)-Qthyl 4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate
(Patent: US2006/25383 Al, 2006), ethyl spiro[2.5]octane-6-carboxylate (Bioorg. Med.
Chem. Lett. 2008, 18, 5280-5284), ethyl 4-(cyclopropylmethylene)cyclohexanecarboxylate (Patent: US4584013 Al, 1986), [0134] The aforementioned compounds are assigned compound identification numbers 86- 91 and 113-115 respectively for future reference in this patent. (4.80) as an internal reference. All spectra are recorded in CDCI3 unless otherwise indicated.
[0135] 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-lH- imidazole with phenylboronic acids gives rise to 2-(l-trityl-lH-imidazol-4-yl)benzaldehydes. The resulting 2-(l-trityl-lH-imidazol-4-yl)benzaldehydes are affected by aldol condensations or Horner- Wadsworth reactions to afford intermediate A. Alternatively, the synthesis of intermediate A can be achieved by allowing 2-iodobenzaldehydes to react with substituted methyl ketones in the presence of a base to afford 3-(2-iodophenyl)prop-2-en-l- ones. Negishi cross-coupling of the resulting 3-(2-iodophenyl)prop-2-en-l-ones with 4- iodo-l-trityl-lH- imidazole, also leads to intermediate A. Subjecting intermediate A to trityl deprotection 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. Synthesis of (£)-3-(2-(l-trityl-lH-imidazol-4-yl)phenyl)prop-2-en-l-ones
Intermediate A)
Figure imgf000086_0001
Scheme 2. Synthesis of 2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanones and Their
Corresponding 2-(5H-imidazo [5 , 1 -a] isoindol-5 -yl)ethanols
Figure imgf000087_0001
Example 1 General Procedure for the Synthesis of 3-(2-Iodophenyl)prop-2-en-l-ones by
Aldol Condensation
Figure imgf000087_0002
[0136] To a solution of the appropriate commercially available benzaldehyde or 87 (4.31 mmol) in anhydrous 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 diluted with satd. NH4C1 (20 mL). The aqueous layer was extracted with CH2CI2 (3 x 20 mL) and the combined organic extracts were dried (MgS04) 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.
Figure imgf000087_0003
Figure imgf000088_0001
Example 2 General Procedure for the Synthesis of 2-(5H-imidazo[5,l-a]isoindol-5- yl)ethanones by Palladium-Catalyzed Negishi Cross-Coupling of Aryl Iodides
-Iodo-l-Trityl-lH- imidazole.
Figure imgf000088_0002
[0137] To a stirred 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 ZnC . (0.5 mmol, 68.2 mg) was added. The resulting white suspension was allowed 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 addition of Pd(PPh3)4 (56 mg, 0.05 mmol). The reaction mixture was allowed to stir at 70 °C for 12 h under an atmosphere of N2. After cooling to room temperature, the solution was diluted with CH2CI2 (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 (Na2S04) 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 °C 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.
Figure imgf000089_0001
Example 3 Suzuki Cross-Coupling of 4-Iodo-l-trityl-lH- imidazole with Phenylboronic
Acids
Figure imgf000089_0002
[0138] A suspension of 4-iodo-l-trytyl-lH- imidazole (6.88 mmol ), the appropriate 2-formyl boronic acid derivative (10.31 mmol) and K3PO4 (20.63 mmol) in N,N-dimethylformamide (30 mL) and water (6 mL) was purged with nitrogen 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 °C for 16 h under an atmosphere of 2.The solution 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 organic extracts were washed with water (2 x 25 mL), brine and dried ( a2S04). The solution was filtered and the solvent was removed under reduced pressure to afford the crude product which was purified by flash column chromatography on silica gel to provide the following compounds.
Figure imgf000090_0001
# Compound Name Yield (%)
JH 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-2-(l-trityl-lH-imidazol-4-yl)benzaldehyde
Figure imgf000091_0001
[0139] 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 μιηοΐ) in DMF (10 mL) was stirred at 80 °C 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 concentrated. The crude product was used without further purification. A suspension of 4-iodo-l-trityl-lH- imidazole (400 mg, 0.917 mmol), 3-methoxy-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzaldehyde (288 mg, 1.10 mmol), K2C03 (444 mg, 3.21 mmol), Pd(dppf)Cl2*CH2Ci2 complex (150 mg, 0.18 mmol) in DMSO (10 mL) was heated at 80 °C 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%). H 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 Synthesis of 2-(5H-imidazo[5,l-a]isoindol-5- yl)ethanones by Aldol Condensation of 2-(l-trityl-lH-imidazol-4- yl)benzaldehydes with Methyl Ketones Followed by Cyclization
Figure imgf000092_0001
[0140] To a solution of the appropriate 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 allowed to stir 3 h at rt. The solvent was distilled off and the crude was diluted with saturated NH4C1 (10 mL) and the aqueous layer was extracted with dichloromethane (3 x 20 mL). The combined organic extracts were washed with brine, dried over Na2S04 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 °C 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.
Figure imgf000092_0002
J-
Hz, (s, IH),
5.83 (t,
18.5 Hz), IH)
18.9 (m,
Figure imgf000093_0001
Compound Name Yield (%)
2-(8-chloro-5H-imidazo[5,l- a]isoindol-5-yl)-l- 21 cyclohexylethanone
N
JH NMR (MeOH-d4) 1.10-1.90 (m, 10Η), 2.42-2.48 (m, 1Η), 2.99 (dd, 1] H, J= 18.9 Hz, 9 Hz), 3.40 (dd, IH, J= 18.9 Hz, 3.6 Hz), 5.58-5.62 (m, IH), 6.95-7.38 (m, 1Η), 7.16-7.88 (m, 4H)
CI
2-(7-chloro-5H-imidazo[5,l- a]isoindol-5-yl)-l- 43 cyclohexylethanone
N
¾ NMR 1.19-1.46 (m, 5H), 1.68-1.70 (m, IH), 1.78-1.91 (m, 5H), 2.35-2.43 (m, IH), 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 = 4.0, 8.0 Hz), 7.15 (s, IH), 7.28 (s, IH), 7.35 (d, IH, J= 8.0 Hz), 7.45 (d, IH, J= 8.0 Hz), 7.60 (s, IH)
1 -cyclohexyl-2-(6-fluoro-5H- imidazo[5,l-a]isoindol-5- 50 yl)ethanone
N
'H NMR 1.20-1.48 (m, 5H), 1.66-1.69 (m, 1H)1.78-1.92 (m, 5H), 2.36-2.44 (m, IH), 2.79 (dd, J= 12.0, 20.0 Hz), 3.50 (dd, IH, J= 4.0, 20.0 Hz), 5.77 (d, IH, J= 8.0 Hz), 6.94 (t, IH, J= 8.0 Hz), 7.18 (s, IH), 7.31-7.37 (m, 2H), 7.62 (s, IH)
1 -cyclohexyl-2-(9-methoxy-5H- imidazo[5,l-a]isoindol-5- 41
Figure imgf000094_0001
yl)ethanone
N
'H NMR 1.32-1.42 (m, 2H), 1.66-1.69 (m, IH), 1.78-1.90 (m, 4H), 2.35-2.38 (m, IH), 2.88 (dd, IH, J= 18.4 Hz, 10 Hz), 3.17 (dd, IH, J= 13.8 Hz, 3.2 Hz), 3.96 (s, 3H), 5.60-5.64 (m, IH), 6.88 (d, 2H, J= 8 Hz), 7.15 (s, IH), 7.21 (t, IH, J= 8 Hz), 7.59 (s, IH),
Figure imgf000095_0001
# Compound Name Yield (%)
JH NMR 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), 7.93(t, 1H, J= 2.4 Hz) aThe compound was not characterized and was used as such for the next synthetic step
Example 6 Ethyl 4-meth lenecyclohexanecarboxylate
Figure imgf000096_0001
19
[0141] To a suspension of methyltriphenylphosphonium bromide (1.57 g, 4.41 mmol) in THF (9 mL) at -10 °C was added w-BuLi (2.5 M in hexanes, 1.65 mL, 4.11 mmol) dropwise and the solution was allowed to stir for lh. 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), filtered and concentrated. The crude was purified by flash column chromatography to afford 19 as clear oil (419 mg, 85%). H 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 Eth l 4-(iodomethylene)cyclohexanecarboxylate
Figure imgf000096_0002
[0142] 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 combined organic layers were dried over anhydrous MgS04 and concentrated to obtain the crude product. The crude residue was purified by column chromatography to obtain 20 as light pink oil (207 mg, 24%). H 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 4-(propan-2-ylidene)cyclohexanecarboxylate
Figure imgf000097_0001
21
[0143] To a suspension of isopropyltriphenylphosphonium iodide (3.81g, 8.81 mmol) in anhydrous THF (20 mL) at 0 °C was added a solution of ?-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 °C, 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 CH2CI2 (50 mL) and satd. NH4CI (30 mL). The organic layer was collected and the aqueous layer was extracted with CH2CI2 (2 x 30 mL). The organic layer was washed with brine, dried (Na2S04) 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%). H 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 4-(cyclopropylmethylene)cyclohexanecarboxylate
Figure imgf000097_0002
22
[0144] To a suspension of cyclopropylmethyltriphenylphosphonium iodide (3.5 g, 8.81 mmol) in anhydrous THF (20 mL) at 0 °C was added a solution of ?-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 °C, 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 CH2CI2 (50 mL) and satd. NH4CI (30 mL). The organic layer was collected and the aqueous layer was extracted with CH2CI2 (2 x 30 mL). The organic layer was washed with brine, dried (Na2S04) and concentrated under reduced pressured to obtain the crude product. The crude was purified by column chromatography on silica gel to afford 22 as colorless oil (800 mg, 65%). H NMR: CDCI3 0.22-0.26 (m, 2H), 0.62-0.68 (m, 2H), 1.22 (t, 3H, J = 12 Hz), 1.39-1.47 (m, 3H), 1.75-2.04 (m, 4H), 2.14-2.20 (m, 1H), 2.37-2.46 (m, 1H), 2.67-2.75 (m, 1H), 4.10 (q, 2H, J = 7.2 Hz), 4.49 (d, 1H, J= 9.3 Hz).
Example 10 Eth l 4-(trityloxy)cyclohexanecarboxylate
Figure imgf000098_0001
[0145] To a solution of triphenylmethyl chloride (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 (Na2S04) and concentrated under reduced pressure. The crude was purified by flash column chromatography to afford 23 as colorless oil (714 mg, 59%). HNMR: (mixture of cis and trans isomers (1 : 1.4)) 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), 2.1 1-2.22 (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 CHC13), 7.49-7.51 (m, 13H).
Example 11 Methyl cz's-4-aminocyclohexanecarboxylate hydrochloride
Figure imgf000099_0001
115
A solution of cz's-4-aminocyclohexanecarboxylic acid (1.04 g, 7.26 mmol) in 10 mL of methanol was cooled to 0 °C and thionyl 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 colorless crystals (1.3 g, 92%). H NMR (CD3OD): 1.73-1.77 (m, 4H), 1.92-1.96 (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 cz's-4-benzamidocyclohexanecarboxylate
Figure imgf000099_0002
116
[0146] To a suspension of methyl cz's-4-aminocyclohexanecarboxylate hydrochloride (0.63 g, 3.26 mmol) in CH2CI2 (10 mL) at 0 °C 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 allowed to warm to rt and stirred overnight. The reaction was diluted with water (15 mL) and CH2CI2 (15 mL), the organic layer was collected and the aqueous layer was extracted with CH2CI2 (2 x 25 mL). The combined organic extracts were dried over Na2S04 and concentrated under reduce pressure to afford 116 as a clear gel (850 mg, 100%). H 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), 4.14-4.20 (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 iraws-4-aminocyclohexanecarboxylate hydrochloride
Figure imgf000100_0001
CI
117
A solution of £ra«s-4-aminocyclohexanecarboxylic acid (1.24 g, 8.66 mmol) in 12 mL of methanol was cooled to 0 °C and thionyl chloride (1.89 mL, 25.98 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 117 as colorless crystals (1.61 g, 95%). H 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 £ra«s-4-benzamidocyclohexanecarboxylate
Figure imgf000100_0002
118
[0147] To a suspension of methyl ?ra«s-4-aminocyclohexanecarboxylate hydrochloride, 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 allowed to warm to rt and stirred overnight. The reaction was diluted with water (15 mL) and CH2CI2 (15 mL), the organic layer was separated and the aqueous layer was extracted with CH2CI2 (2 x 25 mL). The combined organic extract was dried over Na2S04 and concentrated under reduce pressure to afford 118 as a white solid (200 mg, 24%). H 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-l,3-dicarboxylate
Figure imgf000101_0001
119
[0148] l-(t-butoxycarbonyl)azetidine-3-carboxylic acid (2.03 g, 10.09 mmol) was dissolved in MeOH (10 ml) and DCM (10 mL) and then cooled to 0 °C. A 2M solution of trimethylsilyldiazomethane in ether (7.57 ml, 15.1 mmol) was then added drop-wise over 5 minutes. The solution was stirred for 10 minutes at 0 °C 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 purification. H NMR: 1.44 (s, 9H), 3.35 (m, 1H), 3.75 (s, 3H), 4.10 (d, 4H, J = 7.6 Hz).
Example 16 Methyl cz's-4-hydroxycyclohexanecarboxylate
Figure imgf000101_0002
120
[0149] To a solution of cz's-4-hydroxycyclohexanecarboxylic acid (5.0 g, 34.7 mmol) in dry MeOH (40 mL) at RT, was added concentrated H2SO4 (0.2 mL, 3.47 mmol) and the solution was stirred at 65 °C for 16 h. The solvent was distilled off and the crude was dissolved in EtOAc (40 mL) and the solution was washed with sat'd aHC03 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 Na2S04 and concentrated under reduced 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 cz's-4-(benzyloxy)cyclohexanecarboxylate
Figure imgf000102_0001
121
To a solution of methyl e¾-4-hydroxycyclohexaneearboxylate (4.80 g, 30.3 mmol) in hexane/CHC13 2: 1 (60 mL) was added benzyl trichloroacetimidate (9.19 g, 36.4 mmol) and trifluoromethanesulfonic acid (683 mg, 4.55 mmol) at 23 C. The reaction mixture was stirred for 18 h and diluted with EtOAc (300 mL). The mixture was washed with saturated aqueous NaHC03, water and brine. The organic layer was dried over anhydrous Na2S04 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)._ H 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 Procedure for the Reaction of Methyl Piperidine-4-carboxylate hydrochloride with Acid Chlorides
Figure imgf000102_0002
[0150] To a suspension of methyl piperidine-4-carboxylate hydrochloride (5.6 mmol) in CH2CI2 (20 mL) at 0 °C was added diisopropylethyl amine (16.7 mmol) and the suspension was stirred for 10 minutes. Appropriate acid chloride (8.4 mmol) was added dropwise and the solution was allowed to warm to rt and stirred overnight. The reaction was diluted with water (15 mL) and CH2CI2 (15 mL). The organic layer was collected and the aqueous layer was extracted with CH2CI2 (2 x 20 mL). The combined organic extracts were dried ( a2S04) and concentrated under reduce pressure to afford the following compounds.
Figure imgf000102_0003
# Compound Name Yield (%) methyl 1 -(thiophene-2-carbonyl)piperidine-4-
91 carboxylate
x 0
25
1H NMR 1.69-1.79 (m, 2H), 1.89-1.95 (m, 2H), 2.56-2.63 (m, 1H), 3.12 (t, 2H, J= 12.0
Hz), 3.68 (s, 3H), 4.28-4.31 (m, 2H), 7.0-7.02 (m, 1H), 7.24-7.26 (m, 1H), 7.40-7.42 (m,
1H)
methyl 1 -(2-phenylacetyl)piperidine-4-
44 carboxylate
26
1H NMR 1.30-1.95 (m, 4H), 2.35-2.55(m, 1H), 2.70-2.85 (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
Figure imgf000103_0001
[0151] To a suspension of 2-bromo-3-fluorobenzoic acid (300 mg, 1.37 mmol) in methanol (10 mL) at rt, was added SOCI2 (0.11 mL, 1.51 mmol) and the mixture was stirred at rt for 18 h. The solvent was distilled off under reduced pressure. The crude was basified by adding saturated aqueous NaHCC>3 solution and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over a2S04, filtered and concentrated. The obtained crude product was used in the next step without further purification.
Example 20 Meth l 3-fluoro-2-(l-trityl-lH-imidazol-4-yl)benzoate
Figure imgf000103_0002
[0152] To a stirred solution of 4-iodo-l-trityl-lH- imidazole (436 mg, 1.0 mmol) in anhydrous THF (6 mL) was added EtMgBr (3.0 M in THF, 1.20 mmol, 0.40 mL) under an atmosphere of N2. The resulting solution was allowed to stir for 90 min and ZnCl2 (0.5 M in THF, 2.40 niL, 1.20 mmol) was added. The resulting white suspension was allowed to stir for 90 min and a solution of methyl 2-bromo-3-fluorobenzoate (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 °C for 18 h under an atmosphere of N2. After cooling to room temperature, the solution was diluted with CH2CI2 (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 ( a2S04) and concentrated under reduced pressure. The crude residue was purified by flash column chromatography to afford the desired product as yellow oil (190 mg, 41 %). H 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-2-(l-trityl-lH-imidazol-4-yl)benzaldehyde
Figure imgf000104_0001
[0153] To a solution of methyl 3-fluoro-2-(l-trityl-lH-imidazol-4-yl)benzoate (62 mg, 0.134 mmol) in toluene (4 mL) at -78 °C 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 mixture was poured into saturated aqueous NH4C1 (5 mL), diluted with EtOAc (15 mL), shaken vigorously for 3 min, added brine (5 mL), shaken again, the phases separated and the organic layer dried over Na2S04, 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
Figure imgf000104_0002
[0154] To a stirred solution of dimethyl methylphosphonate (3.14 g, 25.3 mmol) in 20 ml of anhydrous tetrahydrofuran at -78 °C 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 mixture was allowed to warm to 0 °C, and stirred for 1 h. The solvent was distilled off and the crude was diluted with saturated NH4C1 (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 (1 x 20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to afford the crude product. The crude was purified by column chromatography to afford the following compounds.
Figure imgf000105_0001
Figure imgf000106_0001
Compound Name Yield (%)
3.75 (d, 6H, J= 1 1.2 Hz), 4.34 (m, IH), 4.37 (m, IH)
/
dimethyl (2-( 1 -methyl- lH-imidazol-5 -
36
A yl)-2-oxoethyl)phosphonate
MeO OMe
H NMR 3.35 (d, 2H, J= 22.8 Hz), 3.74 (d, 6H, J= 1 1.2 Hz), 3.86 (s, 3H), 7.54 (s, IH),
7.78 (s, IH)
dimethyl (2-( 1 -methyl- lH-imidazol-4-
29
A yl)-2-oxoethyl)phosphonate
MeO OMe
H NMR 3.66-3.74 (s, 3H merged with d, 2H, J= 22.5 Hz), 3.78 (d, 6H, J= 1 1.2 Hz), 7.44
(s, IH), 7.63 (s, IH)
dimethyl (2-oxo-2-(thiazol-5-
18
A yl)ethyl)phosphonate
MeO OMe
H NMR 3.53 (s, IH), 3.61 (s, IH), 3.73 (d, 6H, J = 11.2 Hz), 8.52 (s, IH), 9.04 (s, IH) dimethyl (2-( 1 -acetylpiperidin-4-yl)-2-
64
A oxoethyl)phosphonate
MeO OMe
H NMR 1.44-1.69 (m, 2H), 1.83-1 89 (m, 2Η), 2.07 (s, 3Η), 2.66-2.73 (m, 1Η), 2.79-2.85
(m, IH), 3.03-3.22 (m, 3H), 3.72-3.83 (m, IH overlapping with d, 6H, J= 1 1.2 Hz), 4.53
(d, 1H, J= 13.4 Hz)
dimethyl (2-oxo-2-( 1 -(thiophene-2- carbonyl)piperidin-4- 59
MeO OMe yl)ethyl)phosphonate
H NMR 1.63 (m, 2H), 1.95 (m, 2H ), 2.89 (s, 1Η), 3.07 (m, 2Η), 3.10 (s, 1Η), 3.18 (s, 1Η),
3.77 (d, 6H, J= 1 1.2 Hz), 4.38 (m, 2H), 7.02 (dd, IH, J= 5.0 Hz, 3.7 Hz), 7.25 (dd, IH, J
= 3.7 Hz, 1.1 Hz), 7.42 (dd, 1H, J = 5.1 Hz, 1.2 Hz)
dimethyl 2-oxo-2-(l-(2- phenylacetyl)piperidin-4- 39
MeO OMe yl)ethylphosphonate
H NMR 1.20-1.90 (m, 4H) , 1.67 (d, IH, J= 10.2 Hz), 1.84 (d, IH, J= 9.6 Hz), 2.55-2.75 (m, 2H), 2.90-3.15 (m, 2H) , 3.65(s, 2H) , 3.70 (d, 6H, J= 1 1.2 Hz), 3.90 (d, 1H, J = 10.2
Hz), 4.48 (d, IH, J = 9.9 Hz), 7.10-7.30 (m, 5H)
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Example 23 General Procedure for the Synthesis of 2-(5H-imidazo[5,l-a]isoindol-5- yl)ethanones by Horner- Wadsworth-Emmons Reaction Followed by Cyclization.
Figure imgf000111_0001
[0155] To a suspension of 95% NaH (17.4 mg, 0.7 mmol) in THF (3 mL) at 0 °C was added the appropriate phosponate reagent 27-46, 89, 90 or 122-135 (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 CH2CI2 (2 x 20 mL) and the combined organic fractions were washed with brine (15 mL), dried over Na2S04 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 °C for 2 h. After cooling to rt, the solvent was distilled off and the crude was stirred in a mixture of sat'd K2CO3 (5 mL) and EtOAc (5 mL). The organic 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 ( a2S04) and the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to afford the following compounds.
Figure imgf000111_0002
Figure imgf000112_0001
Yield
Compound Name
(%)
1 -(4,4-difluorocyclohexyl)-2-(6- fluoro-5H-imidazo[5,l-a]isoindol-5- 81 yl)ethanone H NMR 1.65-1.82 (m, 4H), 1.90-2.01 (m, 2Η), 2.11-2.16 (m, 2Η), 2.44-2.48 (m, 1Η), 2.79 (dd, IH, J= 10.4 Hz, 18.4 Hz), 3 52 (dd, 1Η, J= 2 Hz, 18.4 Hz), 5.72 (d, IH, J = 10.4 Hz), 6.92 (t, 1H, J= 8.8 Hz), 7. If 5 (s, IH), 7.28-7.35 (m, 2H), 7.58 (s, IH) l-(4,4-difluorocyclohexyl)-2-(5H-
96 imidazo[5,l-a]isoindol-5-yl)ethanone
XH NMR 1.73-1.80 (m, 4H), 1.91-1.95 (m, 2H), 2.10-2.14 (m, 2H), 2.41-2.47 (m, IH), 2.90 (dd, IH, J= 9.4 Hz, 18.8 Hz), 3.21 (dd, IH, J= 3.6 Hz, 18.4 Hz), 5.60 (dd, IH, J= 3.4 Hz, 9.4 Hz), 7.13 (s, IH), 7.22-7.28 (m, 2H), 7.36 (t, IH, J= 7.2 Hz), 7.51 (d, IH, J = 7.6 Hz), 7.57 (s, IH)
2-(5H-imidazo [5 , 1 -a]isoindol-5 -yl)- 1 -
93 (4-methylenecyclohexyl)ethanone H NMR 1.30-1.50 (m, 2H), 1.80-2.05 (m, 3H), 2.20-2.32 (m, 2H), 2.40-2.50 (m, IH), 2.58-2.67 (m, IH), 2.78-2.88 (m, IH), 3.16-3.17 (m, IH), 5.50-5.54 (m, IH), 7.13-7.17 (m, IH), 7.20-7.30 (m, 2H), 7.43-7.45 (m, IH), 7.52 (s, IH)
2-(6-fluoro-5H-imidazo[5,l- a]isoindol-5-yl)-l-(4- 64 methylenecyclohexyl)ethanone H NMR 1.30-1.60 (m, 2H), 1.90-2.10 (m, 3H), 2.32-2.35 (m, 2H), 2.50-2.60 (m, IH), 2.60-2.72 (m, IH), 2.76-2.84 (m, IH), 3.52 (d, J= 18.4 Hz, IH), 4.63 (s, 2H), 5.73 (d, J = 10.4 Hz, IH), 6.91-6.96 (m, IH), 7.20-7.30 (m, 2H), 7.43-7.45 (m, IH), 7.52 (s, IH) Yield
Compound Name
(%)
2-(6-fluoro-5H-imidazo[5, l- a]isoindol-5-yl)-l-(l,4- 84 dioxaspiro [4.5 ]decan-8-yl)ethanone
N O H NMR (CD3OD) 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, l- a]isoindol-5-yl)-l-(4- 87 methylcyclohexyl)ethanone
N H 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), 6.89-6.95 (m, 1H), 7.15 (s, 1H), 7.26-7.38 (m, 2H), 7.62 (s, 1H)
2-(6-fluoro-5H-imidazo[5, l- a]isoindol-5-yl)- 1 -(4- 46 (iodomethylene)cyclohexyl)ethanone
N
XH 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), 3.59-3.64 (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).
2-(9-fluoro-5H-imidazo[5, l- a] isoindol-5 -yl)- 1 -(4- 55 methylcyclohexyl)ethanone
N 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), 2.72-2.84 (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)
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
7.37 (m, 2H), 7.59 and 7.62 (two s, 1H) Hz),
7.37 (t, step
(m, 7.15 (d, 7.63- 0.4H),
(m, 1H), (dd, J 1H, J =
2.52- J = 18.5
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
and 7.83 (two s, IH)
Figure imgf000122_0001
Example 24 -(Cyclohex-3-enyl)-2-(6-fluoro-5H-imidazo[5, l-a]isoindol-5-yl)ethanone
Figure imgf000122_0002
[0156] 71 (270 mg, 0.86 mmol) was dissolved in benzene (7 mL) and -toluenesulfonic acid (444 mg, 2.58 mmol) was added. The reaction mixture was heated at 100 °C for 48 h and concentrated. The residue was basified with aqueous potassium carbonate solution (5 mL). The aqueous solution was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water, brine, dried over Na2S04, filtered and concentrated. The residue was purified by flash column chromatography to afford the title compound 155 as yellow gel (218 mg, 86%). H NMR: 1.35-1.71 (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 2-(5H-imidazo[5, l-a]isoindol-5- yl)
Figure imgf000123_0001
[0157] 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 °C, was added NaBH4 (0.75 mmol) and the solution was allowed to stir for 1 h. The solvent was removed under reduced pressure and 2M HC1 (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 CH2CI2 (3 x 5 mL). The combined organic layers were washed with brine, dried (MgS04) and concentrated under reduced pressure to afford the crude residue. The crude was purified by column chromatography using 1-10% MeOH:DCM gradient to afford the following compounds.
Figure imgf000123_0002
Figure imgf000124_0001
7.78 (two s, IH)
Figure imgf000125_0001
2H), 7.82, 7.88 (two s, 1H)
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Yield
# Compound Name
(%) H NMR (a mixture of diastereomers)l .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 s, 1H)
2-(6-fluoro-5H-imidazo [5, 1-
V ' -O H a]isoindol-5-yl)- 1 -( 1 -methyl- 1H- 81 imidazol-2-yl)ethanol
1394 N l^N-
1H NMR (a mixture 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)
2-(5H-imidazo[5, 1 -a]isoindol-5-yl)- 1 -
34 (thiazol-4-yl)ethanol
1390 N
H NMR(a mixture of diastereomers)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) l-(4,4-difluorocyclohexyl)-2-(5H-
61 imidazo[5 , 1 -a] isoindol-5 -yl)ethanol
1407
H NMR (a mixture of diastereomers)1.26-1.36 (m, 3H), 1.63-1.97 (m, 5H), 2.02-2.08 (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- 5.43 (two m, 1H), 7.10 and 7.12 (two s, 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 s, 1H l-(4,4-difluorocyclohexyl)-2-(6-fluoro-
1406 5H-imidazo [5 , 1 -a] isoindol-5- 78 yl)ethanol
Figure imgf000130_0001
(two s, 1H)
Figure imgf000131_0001
Figure imgf000132_0001
7.67 (two s, IH),
Figure imgf000133_0001
Hz),
2Η),
(m, (s, (d, IH, J
Hz, 3.72- IH), Hz,
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
IH), 7.25-7.36 (m, 8H), 7.80, 7.82, 7.88 and 7.90 (four s, IH)
Figure imgf000138_0002
Figure imgf000138_0003
The pure diastereomers were obtained from the racemic mixture of 1363 using preparative chiral supercritical fluid chromatography (SFC) technique, using a AD-H column (Regis Technologies, Inc.) in methanohCC (24:76).
Example
Figure imgf000139_0001
To a solution of the appropriate Boc protected 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 further purification.
Example 28 General Procedure for the Synthesis of 1423, 1424, 1425, 1437, 1439, 1448, 1450, 145
Figure imgf000139_0002
To a vial containing appropriate amine salt obtained from Example 27 (0.25 mmol) in DMF (4 mL) was added the corresponding carboxylic acid (0.26 mmol), DIPEA (1.5 mmol) and HATU (0.28 mmol). The reaction mixture 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 Na2S04, 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.
Figure imgf000140_0001
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 dissolved in dichloromethane (30 mL) and washed with water (3 x 10 mL). The organic layer was dried over Na2S04 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.
Figure imgf000140_0002
To a solution of appropriate amine (0.3 mmol) in CH2C12 (3 mL) was added carbonyldiimidazole (0.35 mmol) and ethyl diisopropylamine (2.0 mmol) at 0 °C under an atmosphere of 2 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 allowed to stir overnight. The solution was partitioned with water in a separatory funnel and the organic layer was collected. The aqueous layer was extracted with dichloromethane (3 x 10 mL) and the combined organic fractioned were dried ( a2S04). The crude was purified by flash column chromatography to afford 1495, 1496, 1497, 1503, 1504 or 1507.
Figure imgf000141_0001
7.44 (d, IH, J = 7.6 Hz), 7.54 (d, IH, J = 7.6 Hz), 7.79 and 7.82 (two s, IH)
Hz), 2.97 5.32-
J = 2.4, 2H, Hz), (m, 2H), Hz),
4.31 (br = 7.6 Hz),
Figure imgf000142_0001
7.58 (d, IH, J = 7.2 Hz), 8.03 and 8.13 (two s, IH)
Figure imgf000143_0001
C V\ OH H phenylazetidine- 1 -carboxamide
Figure imgf000144_0001
Figure imgf000145_0001
V (tetrahydro-2H-pyran-4-yl)ethanone
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
piperidine- 1 -carboxamide Yield
# Compound Name
(%)
'H 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= 1 1.2 Hz), 6.94 (s, 1H), 7.09-7.31 (m, 7H), 7.45 (d, 1H, J = 7.2 Hz), 8.24 (s, 1H)
0
(4-((R)- 1 -hydroxy-2-((5)-5H- imidazo[5, l-a]isoindol-5-
50 yl)ethyl)piperidin- 1 -yl)( 1 Η-
N imidazol- 1 -yl)methanone
1513 ¾ 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, J= 10.7 Hz), 4.80 (br s, 1H), 5.41 (t, lH, J= 5.9 Hz), 7.07 (s, 1H), 7.14 (s, 1H), 7.18 (s, 1H), 7.24-7.28 (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 l-(l-(benzylsulfonyl)piperidin-4-yl)-2-(5H-imidazo[5, l-a]isoindol-5- yl)ethanol
Figure imgf000149_0001
1442
To a vial 2-(5H-imidazo[5, l-a]isoindol-5-yl)-l-(piperidin-4-yl)ethanol dihydrochloride (0.12 g, 0.34 mmol) in CH2CI2 (3 mL) was added ethyl diisopropylamine (0.35 mL, 2.0 mmol) and benzyl sulfonyl 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 Na2S04 and concentrated. The crude product was purified by flash column chromatography to afford 1442 as white solid (85 mg, 58%). H 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), 2.03-2.10 (m, 1H), 2.52-2.66 (m, 2H), 3.55-3.63 (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-(5 -imidazo[5, l-a]isoindol-5-yl)acetic acid
Figure imgf000150_0001
1256 -I258
[0158] 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 dissolved 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%). H 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-(5 -imidazo[5, l-a]isoindol-5-yl)ethanol
Figure imgf000150_0002
1256 1254
[0159] 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. NH4C1 (20 mL). The aqueous layer was extracted with CH2CI2 (3 x 40 mL). The combined organic extracts were dried over MgS04 and the solvent distilled off under reduced pressure to afford a crude residue. The crude product was purified by silica flash chromatography to afford 1254 (638 mg, 91%). H NMR: 2.04-2.08 (m, 1H), 2.36-2.40 (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, l-a]isoindol-5-yl)-N-methylacetamide
Figure imgf000151_0001
1256 1259
[0160] 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 °C overnight. After cooling to rt the solvent was distilled off under reduced pressure and the crude was purified by column chromatography to afford 1259 (21 mg, 75%). H 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) 5.69 (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).
Example 35 2-(5H-
Figure imgf000151_0002
[0161] To a solution of 1254 (0.5 mmol) in dichloromethane (5 mL) at 0 °C 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 reduced pressure and the crude was purified by column chromatography to afford 74 (63 mg, 64%). H 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,l-a]isoindole
Figure imgf000151_0003
[0162] To a solution of 74 (1.21 mmol) in tetrahydrofuran (4 mL) at -20 °C was added iPrMgCl'LiCl (1.21 mmol, 1.3 M in THF) dropwise. After stirring for 1 h at -20 °C, 2-(5H- imidazo[5, l-a]isoindol-5-yl)acetaldehyde was added as a solution in tetrahydrofuran (2 mL) and the reaction was allowed to warm to -10 °C. After stirring for 2 h at -10 °C the reaction was quenched by adding sat'd NH4C1 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 a2S04 and concentrated under reduced pressure to afford the crude reside. Chromatographic purification of the crude using EtOAc:MeOH (98:2) afforded 1273 (42 mg, 21%). H NMR 5.77 (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, l-a]isoindol-5-yl)ethyl 2-(((lR,2R,5S)-2-isopropyl-5- methylcyclohexyl)oxy)acetate
Figure imgf000152_0001
1254 1288
[0163] To a solution of 1254 (110 mg, 0.55 mmol) in CH2C12 at 0 °C was added diisopropylethylamine (1 10 mg, 0.824 mmol). The mixture was allowed to stir for 5 min and 2-(((lS,2S,5R)-2-isopropyl-5-methylcyclohexyl)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 extracted with CH2CI2 (3 x 15 mL). The combined organic extract was dried (MgS04) and concentrated under reduced pressure to afford the crude product. The crude residue was purified by flash chromatography to afford 1288 (200 mg, 92%). H NMR: 0.77 (d, 3H, J = 3.0 Hz), 0.75-1.25 (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), 3.09-3.14 (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 l-Cyclohexyl-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanamine and (E)-5-(2- Cyclohexylvinyl)-5H-imidazo[5, 1 -a]isoindole
Figure imgf000153_0001
[0164] To a solution of triphenylphosphine (255 mg, 0.97 mmol) in THF (10 mL) at 0 °C was added phthalimide (143 mg, 0.97 mmol) and 1304 (250 mg, 0.885 mmol) followed by the dropwise addition of DEAD (0.44 mL, 0.97 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was distilled off under reduced pressure, diluted with (¾(¾ (30 mL) and washed successively with 10% aq NaOH (2 x 15 mL), water and brine. The organic layer was dried (Na2S04) and the solvent was evaporated under reduced pressure to afford an off-white solid. The solid was dissolved in EtOH (5 mL) and hydrazine monohydrate (0.09 mL, 1.77 mmol) was added. The mixture was heated at 80 °C overnight. The solution was cooled to rt and the solvent was distilled off under reduced pressure. The crude was diluted with (¾(¾ (20 mL) and the organic phase was washed with water (10 mL). The organic layer was dried (Na2S04) and the solvent was evaporated under reduced pressure to afford a crude residue that was purified by column chromatography to afford 1388 as a white solid (50 mg, 14%) and an eliminated side product 1412 (30 mg). 1388 H 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 H 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, l-a]isoindol-5-yl)-l- hydroxyethyl cyclohexanone
Figure imgf000153_0002
1378 1379
[0165] To a solution of 1378 (186 mg, 0.52 mmol) in THF (5 mL) was added 2M HC1 (5 mL) and the solution was stirred at room temperature overnight. The solvent was removed in vacuo and remaining 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 ( a2S04) and concentrated in vacuo to give 1379 as a white solid (155 mg, 95%).
H NMR: (CD3OD) 1.23-2.51 (m, 1 1H), 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 l-(4-(Hydroxymethyl)cyclohexyl)-2-(5H-imidazo[5, l-a]isoindol-5-yl)etanol
Figure imgf000154_0001
1386 1383
[0166] To a solution of 1386 (121 mg, 0.41 mmol) in dry THF (10 mL) at 0 °C was added ΒΗ3· SMe2 (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 peroxide solution (0.19 mL, 1.64 mmol) were added sequentially. The reaction mixture was allowed to stir overnight at room temperatura. The aqueous layer was extracted with CH2CI2 (3 x 40 mL). The combined organic layers were ( a2S04) and concentrated under reduced pressure. The crude residue was purified by flash column chromatography to afford 1383 as a white solid (45 mg, 35%). H NMR MeOH-d4: 1.20-1.78 (m, 1 1Η), 2.02- 2.22 (m, 2Η), 3.46-3.51 (m, 2Η), 3.78-3.88 (m, 2Η), 5.38-5.44 (m, 1Η), 7.12 and 7.14 (two s, 1Η), 7.27-7.46 (m, 2Η), 7.52-7.61 (m, 2Η), 7.92 and 7.95 (two s, 1Η).
Example 41 l-(5H-imidazo[5, l-a]isoindol-5-yl)-2-methylpropan-2-ol
Figure imgf000154_0002
1256 1335 [0167] To a stirred solution of 1256 (48 mg, 0.20 mmol) in THF at 0 °C 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 concentrated, absorbed in silica gel and purified by column chromatography to afford 1335 (24 mg, 52%). H 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).
Example 42 4- 2-(6-Fluoro-5H-imidazo[5, l-a]isoindol-5-yl)-l-hydroxyethyl)cyclohexanol
Figure imgf000155_0001
[0168] To a mixture of 1379 (38 mg, 0.12 mmol) in anhydrous MeOH at 0 °C, 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 CH2CI2 (15 mL) and satd. NH4C1 (5 mL). The organic layer was collected and the aqueous layer was extracted with CH2CI2 (2 x 10 mL). The combined organic extract was washed with brine, dried ( a2S04) and the solvent evaporated. The crude was purified by column chromatography (25% MeOH in EtOAc) to afford 1371 (29 mg, 76%). H NMR MeOH-d4 (mixture of diastereomers): 1.00-1.40 (m, 5Η), 1.40-2.10 (m, 5Η), 2.37-2.47 (m, 1Η), 3.39-3.57 (m, 2Η), 5.54 and 5.72 (two m, 1Η) , 6.98-7.06 (m, 1Η), 7.15-7.18 (m, 1Η), 7.37-7.42 (m, 2Η), 7.93- 7.99 (m, 1Η).
Example 43 l-cyclohexyl-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanone oxime
Figure imgf000155_0002
86 1360
[0169] To a solution of 86 (160 mg, 0.57 mmol) in EtOH (3 mL) at rt was added 50% aq NH2OH (1.71 mmol) and the solution was stirred at 50 °C overnight. After cooling to rt, the solvent was removed under reduced pressure and the crude was purified by flash column chromatography to afford 1360 (120 mg, 71%). H NMR 0.99-1.15 (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 l-cyclohexyl-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanamine
Figure imgf000156_0001
1360 1364
[0170] 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 stirred overnight at rt. The solvent was removed under reduced pressure 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%). H NMR (mixture of diastereomers) 0.89-1.75 (m, 1 1H), 2.24 and 2.42 (two m, 1H), 2.62 (m, 1H), 4.52 (m, 1H), 7.09 (t, 1H, J = 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 Protecting Group from
Substituted Anilines and Amines
0 I TFA
R-
N O R-N H2
H
[0171] To a solution of 17, 1300, 1328 or 1363 (66.0 μιηοΐ) 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 solution was basified with satd. aHC03. The aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water, brine and dried ( a2S04). The solution as filtered and the solvent removed under reduced pressure. The crude residue was purified by column chromatography to afford the following compounds.
Figure imgf000156_0002
Figure imgf000157_0001
Example 46 5-(2-Cyclohexyl-2-hydroxyethyl)-5H-imidazo[5, l-a]isoindol-9-ol
Figure imgf000158_0001
1372 1373
[0172] To a solution of 1372 (28 mg, 0.09 mmol) in DCM (3 mL) at 0 °C was added BBr3 (1 M in DCM, 0.27 mL, 0.27 mmol) dropwise and the mixture was allowed to stir at 0 °C for 2 h. Saturated aqueous aHC03 was added and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were dried ( a2S04) and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 1373 (15 mg, 56%). H NMR MeOH-d4: (mixture of diastereomers) 1.04-1.12 (m, 1Η), 1.15-1.33 (m, 4Η), 1.62-1.86 (m, 5Η), 2.00-2.07 (m, 1Η), 3.55 and 3.70 (two m, 1Η), 5.38 and 5.44 (two m, 1Η), 6.80 and 6.81 (two d, 1Η, 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. Enantios elective Synthesis of (5')-l-cyclohexyl-2-((5,)-5H-imidazo[5, l-a]isoindol- 5-yl)ethanol (1417) and (R)-l-cyclohexyl-2-((5)-5H-imidazo[5, l-a]isoindol-5-yl)ethanol
Figure imgf000159_0001
(separate by column chromatography)
Figure imgf000159_0002
("I S, 3S) 109 ("I S, 2S) 1417 ("I S, 3R) 111 (1 R, 2S) 1418
SCHEME 3
Example 4 -Cyclohexyl-3 -hydroxy- l-(2-iodophenyl)propan-l -one
Figure imgf000159_0003
[0173] To a solution of diisopropylamine (1.6 mL, 1 1.1 mmol) in THF (38 mL) at 0 °C was added w-BuLi (4.1 mL, 10.2 mmol) under an atmosphere of N2. After 30 min the solution was cooled to -30 °C and a solution of l-(2-iodophenyl)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 °C. The mixture was cooled to -78 °C and cyclohexylcarboxaldehyde (1.2 mL, 9.69 mmol) was added dropwise and the mixture was allowed to warm to -40 °C over 2 h. The reaction was quenched by the addition of saturated aqueous NH4C1. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated. The residue was purified by flash column chromatography to afford the title compound as yellow oil (2.56 g, 78%). H 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), 7.1 1-7.15 (m, 1H), 7.42 (d, 2H, J= 4.4 Hz), 7.93 (d, 1H, J= 8.0 Hz).
Example 48 -(tert-Butyldimethylsilyloxy)-3 -cyclohexyl- 1 -(2-iodophenyl)propan- 1 -one
Figure imgf000160_0001
106
[0174] To a solution of 3 -Cyclohexyl-3 -hydroxy- l-(2-iodophenyl)propan-l -one (2.56 g, 7.15 mmol) and DMAP (1.05 g, 8.58 mmol) in DMF (40 mL) was added TBSC1 (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 ( a2S04), filtered and concentrated. The crude was purified by flash column chromatography to afford 106 as clear oil (3.15 g, 93%). H NMR: 0.01 (s, 3H), 0.08 (s, 3H), 0.86 (s, 9H), 1.12-1.24 (m, 6H), 1.43-1.52 (dt, lH, 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), 7.1 1 (dt, 1H, J= 2.4 Hz, 10.0 Hz), 7.40 (t, lH, J= 9.6 Hz), 7.48 (dd, 1H, J = 2.4 Hz, 10.4 Hz), 7.92 (d, 1H, J= 10.4 Hz).
Example 49 ( lR,3R)-3 -(tert-Butyldimethylsilyloxy)-3 -cyclohexyl- 1 -(2-iodophenyl)propan- 1 -ol and ( lR,35)-3 -(tert-butyldimethylsilyloxy)-3 -cyclohexyl- 1 -(2- iodophenyl)propan- 1 -ol
Figure imgf000161_0001
106 107 108
(separated by normal phase column chromatography)
[0175] A mixture of 106 (3.15 g, 6.67 mmol), BH3'SMe2 (0.63 mL, 6.67 mmol) and 5-2- methyl-CBS-oxazaborolidine (370 mg, 1.33 mmol) in THF (50 ml) was stirred at room temperature for 16 h. Aqueous 6 M HC1 (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 extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine (20 mL), dried (Na2S04), 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 developing 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. H NMR: (1R,35): 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). H 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 ( lR,35)-3 -(tert-Butyldimethylsilyloxy)-3 -cyclohexyl- 1 -(2- iodophenyl)propyl4-methylbenzenesulfonate
Figure imgf000161_0002
107
[0176] 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 -toluenesulfonyl chloride (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 aHC03 (15 mL) and brine. The organic layer was dried ( a2S04), filtered and concentrated. The title compound was used in the next step without further purification.
Example 51 ( lR,3R)-3 -(tert-Butyldimethylsilyloxy)-3 -cyclohexyl- 1 -(2- iodophenyl)propyl4-methylbenzenesulfonate
Figure imgf000162_0001
(lR,3R)-3-(tert-Butyldimethylsilyloxy)-3-cyclohexyl-l-(2-iodophenyl)propyl4- methylbenzenesulfonate was prepared as described in the above procedure, compound was used in the next step without further purification.
Example 52 1 -(( 15,35)-3 -(tert-Butyldimethylsilyloxy)-3 -cyclohexyl- 1 -(2- iodophenyl)propyl)-lH- imidazole
Figure imgf000162_0002
109
[0177] 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,35)-3- (tert-butyldimethylsilyloxy)-3 -cyclohexyl- 1 -(2-iodophenyl)propyl 4-methylbenzenesulfonate (341 mg, 0.54 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 60 °C for 14 h. The reaction mixture was poured into water (10 mL) and the aqueous 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 (Na2S04), filtered and concentrated. The residue was purified by flash column chromatography to afford 109 as clear gel (130 mg, 46%). H NMR: (I S,
3S) 0.03 (s, 3H), 0.05 (s, 3H), 0.97 (s, 9H), 1.11-1.31 (m, 5H), 1.53-1.59 (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-((15',3R)-3-(tert-Butyldimethylsilyloxy)-3-cyclohexyl-l-(2- iodophenyl)propyl)-lH- imidazole (78)
Figure imgf000163_0001
111
[0178] Compound 111 was prepared as described for compound 109 in the above procedure. Ill was isolated as a clear gel (42% over two steps). H NMR: (I S, 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 (5)-5-((5)-2-(tert-Butyldimethylsilyloxy)-2-cyclohexylethyl)-5H-imidazo[5, 1-
Figure imgf000163_0002
109 109a
[0179] To a vial containing 109 (65 mg, 0.12 mmol) was added dicyclohexylmethylamine (0.04 mL, 0.19 mmol), PPh3 (13 mg, 0.05 mmol) and DMF (4 mL). The mixture was degassed for 10 min and Pd(OAc)2 (6 mg, 25 μιηοΐ) was added. The mixture was heated at 95 °C for 5 h. After cooling to rt, the mixture was diluted with ethyl acetate (15 mL) and passed through 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 (Na2S04), filtered and concentrated. The crude residue was used directly in the next step.
Example 55 (S)-5-((R)-2-((tert-butyldimethylsilyl)oxy)-2-cyclohexylethyl)-5H-
Figure imgf000163_0003
111 111a [0180] Compound 111a was prepared as described in the above procedure. The crude residue was used directly in the next step.
Example 56 (5 -l-cyclohexyl-2-((5')-5H-imidazo[5,l-a]isoindol-5-yl)ethanol (1417)
Figure imgf000164_0001
[0181] To a vial containing crude 109a (60 mg, 0.15 mmol) was added 1% HQ in ethanol (2 mL). The reaction mixture was heated at 50 °C for 3 h and poured into saturated aqueous aHC03 (5 mL). The aqueous layer was extracted with dichloromethane (2 x 15 mL). The combined organic layers were dried ( a2S04), filtered and concentrated. The residue was purified by flash column chromatography to afford 1417 as a white solid (17 mg, 47% over 2 steps). H NMR: (IS, 2S) 1.02-1.28 (m, 5H), 1.40-1.42 (m, 1H), 1.67-1.83 (m, 4H), 1.91 (d, 1H, J= 12.4 Hz), 2.22-2.30 (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).
[0182]
Example 57 ( -l-cyclohexyl-2-((5')-5H-imidazo[5, l-a]isoindol-5-yl)ethanol (1418)
Figure imgf000165_0001
[0183] Compound 1418 was prepared as described for compound 111a in the above procedure. 1418 was isolated as a colorless solid (42% over 2 steps). 1H NMR: (IS, 2R) 0.97-1.26 (m, 5H), 1.32-1.39 (m, 1H), 1.63-1.67 (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).
Example 58 (?ra«s)-l-hydroxy-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethyl)
cyclohexanecarboxylic acid (1436)
Figure imgf000165_0002
1436
[0184] To a solution of 1426 (268 mg, 0.79 mmol) in THF: Water 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 HC1. 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% MeOH/DCM. The solution was concentrated to afford the NLG-1436 as a light yellow solid 193 mg (75%). H 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), 1 1.98 (br s, 1H).
Example 59 l-((?ra«s)-4-(hydroxymethyl)cyclohexyl)-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethanol ( LG-1430)
Figure imgf000166_0001
1430
[0185] To a solution of 1426 (100 mg, 0.30 mmol) in THF:EtOH (3 niL, 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 10 mL). The combined organic extract was dried over Na2S04 and the solvent was removed under reduced pressure. The crude product was purified by silica flash chromatography to afford 1430 (78 mg, 85%). H NMR (a mixture of diastereomers) 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 CHC13, 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)-l-hydroxy-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethyl)-N-(2- methylsulfonamido)ethyl)cyclohexanecarboxamide (1432)
Figure imgf000166_0002
[0186] 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 concentrated. The residue was purified by column chromatography on silica gel using hexanes/EtOAc 10%->60% gradient. The compound was isolated as a light yellow solid 72 mg (64%). H 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 (c«)-4-(2-(6-fluoro-5H-imidazo [5 , 1 -a] isoindol-5 -yl)- 1 - hydroxyethyl)cyclohexanol
Figure imgf000167_0001
1379 1465
[0187] To a solution of NLG-1379 (60 mg, (0.19 mmol) in dry THF (5 mL) at -78 °C 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 H20/EtOH (4 mL). The reaction was acidified with 6 N HC1 followed by basification with sat'd K2CO3 solution. The aqueous layer was extracted with dichloromethane (5 x 15 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to afford a crude residue. The residue was purified by column chromatography to afford 1465 35 mg (58 %). Mixture of diastereomers H NMR: 1.45-2.15 (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).
[0188] The mixtures of four diastereomers (1465) were separated by preparative chiral super critical fluid chromatography (SFC) to afford the pure diasteromers 1482-1485. SFC was performed on RegisPack 5 column in isopropanol/C02: 0.2%DEA.
Figure imgf000168_0001
Figure imgf000168_0002
1484 1485
1482 and 1484 ^ MR CCDsOD) δ 1.16 (d, J= 6.1 Hz, 1H), 1.23 (d, J= 17.8 Hz, 2H), 1.28 (s, 1H), 1.37-1.65 (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 XH NMR: (CD3OD) δ 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 = 10.1, 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 -yl)- 1 -((trans)-4- hydroxycyclohexyl)ethanone
Figure imgf000168_0003
126 154
[0189] To a suspension of NaH (1.1 1 g, 46.2 mmol) in THF (150 mL) at -10 °C 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 °C. Aldehyde 4 (20.0 g, 46.4 mmol) was added as a solution in THF (120 mL) dropwise over a 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 NH4C1 (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 Na2S04. The solution was filtered and concentrated under reduced pressure to afford the crude product. The crude was stirred in a mixture of acetic acid (20 mL) and MeOH (170 mL) at 90 °C for 1.5 h. After cooling to 50 °C the reaction mixture was treated with 6N HC1 (20 mL) and stirred for 30 minutes. After cooling to rt the solvent was distilled off and sat'd aHC03 (200 mL) was added to the residue followed by CH2CI2 (200 mL). The layers were separated and the aqueous layer was extracted with CH2CI2 (2 x 100 mL). The combined organic layers were dried over a2S04 and the solvent evaporated under reduced pressure to afford the crude product which was purified by using flash silica gel column chromatography to afford 154 (13.8 g, 95%).
Example 63 (?ra«s)-4-(2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l- hydroxyethyl)cyclohexanol (1475)
Figure imgf000169_0001
154 1475
[0190] To a solution of 154 (13.8 g, 43.9 mmol) in MeOH (150 mL) at -10 to 0 °C, 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 pressure and the mixture was diluted by addition of saturated NH4C1 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 CH2CI2 (5 x 75 mL). The combined organic extract was washed with brine, dried (MgS04) and concentrated under reduced pressure to afford the crude. Purification by column chromatography afforded 1475 as a white solid (13.24 g, 95%). H NMR (a mixture of diastereomers): 1.07-2.52 (m, 1 1H), 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). [0191] 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 separate 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:C02 (10:90) + DEA 0.1%.
Figure imgf000170_0001
1488 1489
NLG-1486 and NLG-1489 XH 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 CHC13, 2H), 7.79 (s, 1H).
NLG-1487 and NLG-1488 XH 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 CHC13, 2H), 7.84 (s, 1H).
[0192] Synthesis of ProDrugs of 1304
Example 64 Sodium l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl phosphate (1434)
Figure imgf000171_0001
[0193] To a solution of 1304 (150 mg, 0.53 mmol) and pyridine (85.7 μΐ,, 1.1 mmol) in dichloromethane (4 niL) at 0 °C was added POCI3 (99.3 μΐ,, 1.06 mmol) and the solution was allowed to warm to rt. After stirring overnight the reaction was quenched with NaHC03 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 solvent was removed under reduced pressure to afford the crude residue. The residue was dissolved in DCM (5 mL) and passed through a plug of a2S04 to remove water. The solvent was evaporated under reduced pressure to afford 1434.
(33%). H 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 4.08-4.1 1 (two m, 1H), 5.29 - 5.54 (two m, 1H), 7.11 and 7.16 (two s, 1H), 7.25-7.47 (m, 3H), 7.53-7.60 (m, 1H), 7.83 and 7.95 (two s, 1H).
Example 65 l-cyclohexyl-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethyl acetate
Figure imgf000171_0002
[0194] A solution of 1304 (80 mg, 0.28 mmol) and 4-dimethylaminopyridine (1.04 mg, 8.5 μιηοΐ) in pyridine (3 ml) was treated with acetic anhydride (32μΙ., 0.34 mmol) at RT and the reaction 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 Na2S04. The solution was concentrated and the crude was purified by flash column chromatography to afford the desired product as yellow gel (75 mg, 82%). H 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), 7.17-7.39 (m, 4H), 7.51-7.53 (m, 1H), 7.71 and 8.00 (two s, 1H). Example 66 4-(l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethoxy)-4-oxobutanoic acid (1428)
Figure imgf000172_0001
[0195] A solution of 1304 (48 mg, 0.17 mmol) and 4-dimethylaminopyridine (0.83 mg, 6.8 μιηοΐ) in dichloromethane (3 ml) was treated with succinic anhydride (19 mg, 0.19 mmol) and DIPEA (33 μί, 0.19 mmol) at RT and the reaction was stirred 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 Na2S04 and concentrated. The crude product was crystallized from ethanol/chloroform (1 :4) to afford 1428 as white solid (62 mg, 95%). H NMR(a mixture of diastereomers): 0.93-1.65 (m, 11H), 1.90-2.32 (m, 1H), 2.50-2.90 (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 l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl benzoate (1431)
Figure imgf000172_0002
A solution of 1304 (76 mg, 0.27 mmol) and 4-dimethylaminopyridine (1.0 mg, 8.1 μιηοΐ) in pyridine (3 ml) was treated with benzoic anhydride (73 mg, 0.32 mmol) at RT and the reaction was stirred overnight. The solution was concentrated in vacuo and the residue was dissolved in dichloromethane (10 ml) and washed successively with saturated aHC03 (10 mL), water (10 ml) and dried over Na2S04. The solution was concentrated and the crude was purified by flash column chromatography to afford 1431 (25 mg, 23%). H 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 l-cyclohexyl-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethyl phenylcarbamate (1427)
Figure imgf000173_0001
[0196] To a solution of 1304 (40 mg, 0.14 mmol) in THF (5 mL) was added triethylamine (43 μϊ^, 0.31 mmol) followed by phenylisocyanate (17 μϊ^, 0.16 mmol). The reaction mixture was stirred at RT for 18 h and concentrated. The crude product was purified using flash column chromatography (4: 1 EtOAc:MeOH) to afford 1427 as colorless gel (19 mg, 34%). H 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).
[0197]
Example 69 General 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 stirred at rt for 48 h and poured into saturated aqueous aHC03 (10 mL) and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over Na2S04, 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 solution was basic. The aqueous solution was extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over a2S04, filtered and concentrated to afford 1433, 1440, 1442 and 1443.
Figure imgf000174_0001
Figure imgf000175_0001
Biological Example 1 Human IDO protein cloning, expression and purification
[0198] 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 phID06His cDNA with primers 5 '-ggagcatgctaATGGCACACGCTATGGAAAAC-3 ' and 5 ' -gagagatctACCTTCCTTCAAAAGGGATTTC-3 ' and cloning the Sphl-Bglll 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 C-terminus 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 respect to the sequence deposited in accession file P14902 of SwissProt database. These polymorphisms result in a P1 10S and El 19G amino acid changes.
[0199] Plasmid pQE70-hIDO was transformed into M15(pREP4) cells (Qiagen) and clones were selected in LB-agar plates supplemented with carbenicillin 50 μg/mL and kanamycin 30 μg/mL. Protein expression was carried out by growing an overnight culture of the M15pREP4/pQE70-hIDO clone in 100 mL LB supplemented with 100 μg/mL carbenicillin, 50 μg/mL kanamycin and 50 μg/mL of L-tryptophan (LBCKT medium). 40 mL of this culture 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 °C until OD600 was higher than 0.8. At this point the cultures were inoculated with Hemin to 7 μΜ and L-Tryptophan to 75 μg/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 μΜ, EDTA to 1 mM and L-tryptophan to 50 μg/mL. Incubation was continued for additional 16 h at 25 °C. Cells were collected by centrifugation, and the cell pellets were washed with PBS buffer supplemented with 200 μΜ PMSF and 1 mM EDTA and stored at -80 °C until protein purification.
[0200] The equivalent of 16 L of culture were processed in one batch of purification. Cell pellets were thawed, resuspended in 50 mM potassium phosphate buffer pH 7.0, 200 μΜ PMSF, 1 mM EDTA, 1 mg/mL lysozyme to 10 mL per liter of bacterial culture and incubated 30 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 μιη 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 μϊ^ of each fraction with 100 μϊ^ of reaction mix to yield a final concentration of 50 mM KPB buffer, 20 mM ascorbic acid, 200 μg/mL catalase, 20 μΜ methylene blue and 400 μΜ 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 imidazole linear gradient. Collected fractions were assayed by IDO enzymatic assay described above and the positive fractions were pooled and concentrated by ultrafiltration and dialyzed 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 μιηοΐ/h/mg.
Biological Example 2 Testing of IDO inhibitory compounds by enzymatic IDO assay
[0201] 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 μΜ L-tryptophan, 20 mM ascorbate, 20 μΜ 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 5 nM and preincubated with the enzyme for 5 min at 25 °C. The reaction was started by addition of L-tryptophan to 200 μΜ 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 °C to hydrolyze N-formylkynurenine to kynurenine. The reaction was centrifuged at 3400 g for 5 min to remove precipitated protein and the supernatant was reacted with 2% (w/v) of p-dimethylaminobenzaldehyde in acetic acid. The reaction was incubated 10 min at 25 °C 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 μΜ) and menadione (1.2 μΜ) were used as controls to set the parameters 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. Compounds with an IC50 of less than 500 μΜ were considered as active inhibitors in this assay.
Biological Example 3 Determination of IDO inhibitory activity and toxicity in cell based IDO/Kynurenine assay
[0202] 293-T-REx™ cells (Invitrogen) constitutively express a tet operator binding repressor protein and are maintained in DMEM, 10 % FBS, IX Penicillin+Streptomycin, 2 mM L-glutamine, 5 μg/mL blasticidin at 37 °C with a 5% CO2 in air atmosphere and typically split prior to confluency. Cells were passed by splitting the culture 1/10- by removing media by aspiration, washing IX with PBS, incubating with 0.25% trypsin/EDTA until the cells detach, disbursing the cells in fresh growth media, and plating at 1/10 dilutions in fresh growth media. For long term cryopreservation, cells are detached from the plate as described above, collected by centrifugation, resuspended in freeze medium (growth medium, 10%DMSO), stored in 1.8 mL cyropreservation vials (~ 2-5 X 106 cells per vial), in liquid nitrogen vapor storage tanks.
[0203] IDOl- expressing 293-T-Rex™ 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, IX Penicillin + Streptomycin, 2 mM L-glutamine, 5 μg/mL blasticidin and 25 μg/mL Zeocin) at 37 °C with a 5% CO2 in air atmosphere. Individual clones were isolated by limiting dilution cloning from these populations. 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. [0204] To setup an IDO cell based activity assay, IDO-293-T-Rex cells were harvested and resuspended in DBZ media at 106 cells/mL, and split into poly-D-lysine coated 96-well plates at 100,000 cells per well. 100 μΐ, of Neutral medium (DBZ medium, 200 μΜ L-tryptophan) or Induction media (Neutral medium supplemented with 5 μΜ doxycycline) are added to the cells and incubated 28 h at 37 °C. After the IDO induction period, medium is removed and replaced with Induction 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 °C in a cell culture incubator. 200 μϊ^ of medium are transferred to U-bottom polypropylene 96-well plates containing 25 μΐ, of 30% TCA, incubated 30 minutes at 60 °C and centrifuged at 3400 g for 5 minutes. 150 μϊ^ of the clear supernatant is transferred to a polystyrene 96-well plate containing 50 μϊ^ of 4% (w/v) of p-dimethylaminobenzaldehyde in acetic acid, incubated for 10 min. Kynurenine concentration is determined by measuring the absorbance at 480 nm.
[0205] To measure the toxicity of each compound after 16 h incubation with cells, cell viability is measured via a WST-1 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-1 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-1 assay) is performed via non-linear regression analysis using GraphPad Prism software.
Biological Example 4 Reversal of IDO-Mediated Suppression of T- Cell Proliferation by IDO Inhibitors.
[0206] 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 GM-CSF. Cells were matured for 2 days with a cytokine cocktail containing TNF-a, IL-Ιβ, 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 (3xl05) from normal donors were resuspended in RPMI 1640 supplemented with 100-200 U/mL IL-2 and 100 ng/niL 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 1 μΜ. 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 μ L/well anti-BrdU-POD antibody following the instructions from the manufacturer. Plates were read in a microplate reader.
[0207] Alternatively, testing of IDO inhibitors in an in vitro mouse model of IDO-mediated suppression of T cell proliferation is performed by the following procedure. C57bl6 mice are inoculated with lxlO6 B78H1-GMCSF tumor cells in the right flank. After 10-12 days, tumor draining lymph nodes are collected and cells are stained with anti-CD 1 1c and anti-B220 monoclonal antibodies. Cells are sorted by high-speed fluorescence activated cell sorting and the CDl lc+/B220+ plasmacytoid dendritic cells are collected and seeded at 2000 cells/well in 96 well V-bottom plates. Splenocytes are collected from BM3 transgenic mice (in CBA background) and collected by nylon wool enrichment. BM3 T cells (105 cells/well) are added to each well in 200 μ L of RPMI, 10% FCS, 50 μ M β-mercaptoetanol. Alternatively, T cells are obtained from spleens of OT-I transgenic mice and added to the culture in combination 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 following the instructions from the BrdU labeling kit manufacturer (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 CDl lc+ cells taken from the contralateral lymph node or CD 1 1c / B220" cells (IDO" population) from the TDLN are used as positive control for proliferation.
Biological Example 5 Pharmacological Value
[0208] Pharmacological values for compounds tested according to one or more of the preceding examples are reported in the following table, including,
[0209] 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; [0210] IC50 values are reported in ranges: A: < 1 μΜ, B: 1 - 10 μΜ, C: 10 - 100 μΜ; D: > 100 μΜ.
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
yl)ethanol;
Figure imgf000190_0001
Figure imgf000191_0001
<NJ HO o- yl)ethyl)cyclohexanecarboxylate
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
N 1-one
Figure imgf000195_0001
Figure imgf000196_0001
V phenylpiperidine- 1 -carboxamide
Figure imgf000197_0001
y roxyet y)cyco exano
Figure imgf000198_0001
yl)ethyl)piperidin- 1 -yl)-2-phenylethanone
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Biological Example 6 In Vivo Testing of IDO Inhibitors for Antitumor Activity in
Combination with Chemotherapeutic Agents
[0211] In vivo anti-tumor efficacy can be tested using modified tumor allograft protocols. 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 different mouse tumor cell lines, of different tissue origin (colorectal, bladder, mammary 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 reaction.
[0212] For every animal tumor model, 2 different chemotherapeutic drugs are tested in separate 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.
[0213] The following chemotherapeutic drugs are used, at the indicated doses. The maximum tolerated dose for the following chemotherapeutic agents in mice depends on the formulation, concentration, frequency of administration, route of administration and number of doses. The chemotherapeutic drugs administered in conjunction 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, LP., every 4 days, 4 times (q4dx4); 4] Gemcitabine: 80 mg/kg every 4 days, 4 times, i.p. (q4dx4).
[0214] All animals receive a subcutaneous injection of a tumor forming dose of live tumor cells (~ 50000 - 1000000 cells) suspended in 0.1 mL of PBS or saline on day 1. Subcutaneous injection forms a localized tumor that allows monitoring tumor growth over time.
[0215] 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 administration, 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 skin by surgical procedure. IDO inhibitor drug are administered at the maximum tolerated dose or at a concentration corresponding to the LD50.
[0216] An example of antitumor activity is shown in Figures 1-2 (for Cpd# 1357) and Figures 3-4 (for Cpd# 1304). In this test, 200000 LLC murine tumor cells were injected subcutaneously into syngeneic C57B16 mice on day 0. Each treatement 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, achieveing 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 Figures 3-4, mice were optionally treated with cyclophosphamide 100 mg/kg by intraperitoneal injection on days 9, 13 and 15 post-tumor innoculation, either as a single agent or in combination with compound 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 therapeutic effect is observed as a reduced rate of tumor growth, which has an impact on median survival time and in overall survival fraction.
[0217] Figure 1 shows the average tumor volume over time of two groups of 10 mice each. The control group was treated with vehicle, while the treatment 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 indicate a statistically significant differences between the two curves (pO.0001).
[0218] Figure 2 shows the survival plot of the same groups of mice described in Figure 1. The logrank test indicates a statistically significant difference in median survival time when animals were treated with compound 1357 as a single agent.
[0219] Figure 3 shows the average tumor volume over time of four groups of 10 mice each. 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 cyclophosphamide with compound 1304. The data shows that this tumor is very sensitive to the effects of treatment with compound 1304 either as a single agent or in combination with chemotherapy.
[0220] Figure 4 shows the survival plot of the same groups of mice described in Figure 3. 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.

Claims

A compound of the formula,
Figure imgf000205_0001
or a pharmaceutically acceptable salt thereof, wherein
bond a is a single or double bond;
n is 0, 1, 2, 3, or 4;
each R1 is independently halogen, cyano, nitro, Ci-6alkyl, Ci-6haloalkyl, -OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, or -N(R)C(0)N(R)2;
R2 is -Ci_4alkyl-RA or -C2_4alkenyl-R3 when bond a is a single bond; and
R2 is =C(H)RA when bond a is a double bond;
wherein
RA is -CN, -C(0)R3, -C(0)OR3, -C(0)N(R3)(Rc), -C(ORB)(R3)(Rc), -C(NHRB)(R3)(RC), or -C(=N-ORc)R3, wherein
RB is hydrogen, Ci_6alkyl, Ci_6haloalkyl, -Ci_6alkyl-RB1, -C(0)R3, -C(0)N(H)R3, or -S(0)2R3, -C(0)(CH2)!_4COOR, -C(0)(CH2)!_4(NR)COOR, - C(0)CH(NH2)(RD), -S(0)2OR3, -S(0)2N(R3)2, -CH2-OP(0)2(OR)2, or - P(0)(OR3)2, wherein
RB1 is cyano, nitro, Ci_6alkyl, Ci_6haloalkyl, -OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, or -N(R)C(0)N(R)2; RD is hydrogen, methyl, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), benzyl, 4-hydroxybenzyl, -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, Ci-6alkyl, Ci-6haloalkyl, aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, arylCi_6alkyl-, heteroarylCi-6 alkyl-, C3-8cycloalkylCi_6alkyl-, C3-8cycloalkenylCi-6alkyl-, (3- 10 membered heterocyclyl)Ci_6aikyl-, or (heteroaryl)-(3-10 membered heterocyclyl)-,
wherein
the alkyl, C3-8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, C3_8cycloalkylCi_6alkyl-, C3_8cycloalkenylCi_6alkyl-, (3-10 membered heterocyclyl)Ci_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, arylCi_6alkyl-, and heteroarylCi_6alkyl- groups, are each optionally substituted by one, two, three, or four R31 groups; wherein
each R31 is independently halogen, cyano, nitro, Ci-6alkyl, -Ci_6alkyl-R33, Ci_6haloalkyl, -OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)N(OH)R, -C(0)R, -C( Rn)R, -C( Rn)N(Rn)R, -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)N(R)2, wherein
R33 is cyano, -OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, or -N(R)C(0)N(R)2;
R32 is =0, =S, =N(R), =N(OR), =C(R34)2, =(spiro-C3-8cycloalkyl), or =(spiro-(3-10 membered heterocyclyl)), wherein
each R34 is independently hydrogen, halogen, cyano, Ci-6alkyl, - Ci-6alkyl-OR,
Figure imgf000206_0001
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 Ci-6alkyl; independently hydrogen or R10, wherein R is Ci_6alkyl,
Figure imgf000207_0001
aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, arylCi-6alkyl, heteroarylCi_6aikyl-, C3-8 cycloalkylCi-6alkyl-, C3-8cycloalkenylCi_6alkyl-, or (3-10 membered heterocyclyl)Ci_6alkyl-, each R10 optionally substituted by one, two, three, or four groups that are each independently halogen, cyano, nitro, C1-6alkyl, Ci_6haloalkyl, -OR11, -N(RU)2, -SR11, -C(0)ORn, -C(0)N(Rn)2, -C(0)Ru, -S(0)Rn, -S(0)ORn, -S(0)N(Ru)2, -S(0)2Rn, -S(0)2ORu, -S(0)2N(Ru)2, -OC(0)Rn, -OC(0)ORu, -OC(0)N(Rn)2, -N(Rn)C(0)Rn, -N(Ru)C(0)ORu, -N(Rn)C(0)N(Rn)2, -N(Ru)S(0)2Rn, or -C(O)-(3-10 membered heterocyclyl), wherein each R11 is independently hydrogen or Ci_6alkyl.
2. The compound of claim 1 wherein bond a is a single bond.
3. The compound of claim 1 or 2, wherein R2 is -Ci_4alkyl-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 compound of claim 1 or 2, wherein R2 is -CH2-RA.
6. The compound of any one of claims 1 - 5, wherein RA is -C(0)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( HRB)(R3)(RC), wherein RB is hydrogen, d_6alkyl, or -C(0)Ci_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(0)R3.
11. The compound of any one of claims 1 - 5, wherein RA is -C(ORB)(R3)(Rc).
12. The compound of any one of claims 1 - 5, wherein RA is -CH(OH)(R3).
13 The compound of any one of claims 1 - 12, wherein R3 is hydrogen, Ci_6alkyl, aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, or C3-8cycloalkylCi-6alkyl-, wherein the Ci-6alkyl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, and C3_8cycloalkylCi-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.
14. The compound of any one of claims 1 - 12, wherein R3 is aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, or C3-8cycloalkylCi-6alkyl-, wherein the C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, and C3-8cycloalkylCi-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.
The compound of any one of claims 1 - 12, wherein R3 is phenyl, a five or six membered heteroaryl, monocyclic Cs-scycloalkyl, monocyclic Cs-scycloalkenyl, a five or six membered monocyclic heterocyclyl, or (monocyclic C5_8cycloalkyl)Ci_6 alkyl-, wherein
the C5_8cycloalkyl, Cs-scycloalkenyl, 5 - 6 membered heterocyclyl, and C5-8cycloalkylCi-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.
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.
The compound of any one of claims 1 - 12, wherein R3 is monocyclic Cs-scycloalkyl, monocyclic Cs-scycloalkenyl, a five or six membered monocyclic heterocyclyl, or (monocyclic C5_8cycloalkyl)Ci-6alkyl-, each optionally substituted by one =R32 group and one or two R31 groups.
18. The compound of any one of claims 1 - 12, wherein R is
Figure imgf000208_0001
, wherein bond a is a single bond or a double bond;
m is 0, 1, or 2;
p is 0 or 1 ; and
when bond a is a single bond, then Z is -C(R36)2-, -C(=R32)-, -N(R35)-, or -0-, wherein R35 is hydrogen, Ci_6alkyl, -C(0)R, -S(0)2R, -C(0)OR, -C(0)N(R)2, -S(0)2OR, or
-S(0)2N(R)2; and
when bond a is a double bond, then Z is -C(R )= or -N=;
each R36 is independently hydrogen or
19. The compound of claim 18, wherein when bond a is a single bond, then Z is -C(R )2- or -C(=R32)-; and when bond a is a double bond, then Z is -C(R33)= 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 -0-.
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(0)R3, or -C(ORB)(R3)(Rc), wherein
RB is hydrogen;
each R3 is independently hydrogen, Ci-6alkyl, aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, 3-10 membered heterocyclyl, or C3_8cycloalkylCi_6alkyl-, wherein
the Ci_6alkyl, C3-8cycloalkyl, C3_8cycloalkenyl, 3- 10 membered heterocyclyl, and C3-8cycloalkylCi_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, Ci-6alkyl, -Ci_6alkyl-R33, Ci_6haloalkyl, -OR, -N(R)2, -SR, -C(0)OR, -C(0)N(R)2, -C(0)R, -S(0)R, -S(0)OR, -S(0)N(R)2, -S(0)2R, -S(0)2OR, -S(0)2N(R)2, -OC(0)R, -OC(0)OR, -OC(0)N(R)2, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)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, Ci-6alkyl, or C3_8cycloalkyl; and
Rc is hydrogen or Ci-6alkyl.
23. The compound of claim 22 of the formula,
Figure imgf000210_0001
24. The compound of claim 23, wherein
R3 is aryl, heteroaryl, C3_8cycloalkyl, C3_8cycloalkenyl, or 3-10 membered heterocyclyl, wherein
the C3-8cycloalkyl, C3_8cycloalkenyl, and 3-10 membered heterocyclyl are each optionally 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.
25. The compound of claim 24 of the formula
Figure imgf000210_0002
wherein
bond a is a single bond or a double bond;
m is 0, 1, or 2;
p is 0 or 1 ; and
when a is a single bond, then Z is -C(R36)2-, -C(=R32)-, -N(R35)-, or -0-, wherein R35 is hydrogen, Ci_6alkyl, -C(0)R, -S(0)2R, -C(0)OR, -C(0)N(R)2, -S(0)2OR, or -S(0)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.
The compound of any one of claims 1-22 of the formula,
Figure imgf000211_0001
wherein the stereoisomeric configuration of carbon- 1 (C-l) and carbon-3 (C-3) are respectively (R, R).
27. The compound of any one of claim 1-22 of the formula,
Figure imgf000211_0002
wherein the stereoisomeric configuration of carbon- 1 and carbon-3 are respectively (R, S).
The compound of any one of claims 1-22 of the formula,
Figure imgf000211_0003
wherein the stereoisomeric configuration of carbon- 1 and carbon-3 are respectively (S, R).
The compound of any one of claims 1-22 of the formula,
Figure imgf000211_0004
wherein the stereoisomeric configuration of carbon- 1 and carbon-3 are respectively (S, S).
The compound of any one of claims 1-22 of the formula,
Figure imgf000211_0005
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 formula,
Figure imgf000212_0001
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(0)R or -C(0)( HR).
32. The compound of claim 1 that is
2-(5H-imidazo [5 , 1 -a] isoindol-5-yl)ethanol;
ethyl 2-(5H-imidazo[5, l-a]isoindol-5-yl)acetate;
(E)-5 -(2-bromostyryl)-5H-imidazo [5 , 1 -a] isoindole;
2-(6-chloro-5H-imidazo[5, l-a]isoindol-5-yl)-l-cyclohexylethanol;
2-(6-chloro-5H-imidazo[5, l-a]isoindol-5-yl)-l-cyclohexylethanone;
2-(5H-imidazo [5 , 1 -a] isoindol-5 -yl)ethyl2-((( 1 R,2R,5 S)-2-isopropyl-5 - methylcyclohexyl)oxy)acetate;
tert-butyl (4-(2-(5H-imidazo[5, 1 -a] isoindol-5 -yl)acetyl)phenyl)carbamate;
l-(4-aminophenyl)-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanone;
tert-butyl (4-(l -hydroxy -2-(5H-imidazo[5, l-a]isoindol-5-yl)ethyl)phenyl)carbamate; l-(4-aminophenyl)-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanol;
1- cyclohexyl-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanol;
2- (5H-imidazo [5 , 1 -a] isoindol-5-yl)- 1 -(3 -nitrophenyl)ethanone;
2-(5H-imidazo [5 , 1 -a] isoindol-5-yl)- 1 -(3 -nitrophenyl)ethanol;
2-(5H-imidazo[5, l-a]isoindol-5-yl)-l-(2-nitrophenyl)ethanone;
2-(5H-imidazo[5, l-a]isoindol-5-yl)-l-(2-nitrophenyl)ethanol;
tert-butyl (2-(2-(5H-imidazo[5, 1 -a] isoindol-5 -yl)acetyl)phenyl)carbamate;
tert-butyl (2-(l -hydroxy -2-(5H-imidazo[5, l-a]isoindol-5-yl)ethyl)phenyl)carbamate; l-(2-aminophenyl)-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanone;
l-(2-aminophenyl)-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanol;
l-(2-chlorophenyl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanone; l-(5H-imidazo[5,l-a]isoindol-5-yl)-2-methylpropan-2-ol;
l-(2-chlorophenyl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
1- (3-chlorophenyl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
2- (5H-imidazo[5,l-a]isoindol-5-yl)-l-phenylethanone;
2-(5H-imidazo[5,l-a]isoindol-5-yl)-l-phenylethanol;
l-(2,4-dimethylfuran-3-yl)-2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)ethanol; l-(3-chlorophenyl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanone;
l-cyclohexyl-2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)ethanone;
1- cyclohexyl-2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
2- (5H-imidazo[5,l-a]isoindol-5-yl)-l-(tetrahydro-2H-pyran-4-yl)ethanol;
2-(7-chloro-5H-imidazo[5,l-a]isoindol-5-yl)-l-cyclohexylethanol;
(Z)- 1 -cyclohexyl-2-(5H-imidazo[5, 1 -a]isoindol-5-yl)ethanone oxime;
l-cyclopentyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
tert-butyl 4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidine-l- carboxylate;
l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanamine;
tert-butyl (3-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)phenyl)carbamate; l-(3-aminophenyl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
4- (2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l-hydroxyethyl)cyclohexanol;
1- cyclohexyl-2-(9-methoxy-5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
5- (2-cyclohexyl-2-hydroxyethyl)-5H-imidazo[5,l-a]isoindol-9-ol;
2- (8-chloro-5H-imidazo[5,l-a]isoindol-5-yl)-l-cyclohexylethanol;
1 -(cyclohex- 1 -en- 1 -yl)-2-(5H-imidazo [5 , 1 -a] isoindol-5-yl)ethanol;
1- cyclohexyl-2-(8-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
2- (6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l-(l,4-dioxaspiro[4.5]decan-8- yl)ethanol;
4-(2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l-hydroxyethyl)cyclohexanone; 2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l-(4-methylenecyclohexyl)ethanol; 1 -(cyclohex-3 -en- 1 -yl)-2-(5H-imidazo [5 , 1 -a] isoindol-5-yl)ethanol;
l-(4-(hydroxymethyl)cyclohexyl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
(4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)(thiophen-2- yl)methanone;
l-(4-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)ethanone; 2-(5H-imidazo[5,l-a]isoindol-5-yl)-l-(4-methylenecyclohexyl)ethanol;
2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l-(4-methylcyclohexyl)ethanol;
2-(5H-imidazo[5,l-a]isoindol-5-yl)-l-(thiazol-4-yl)ethanol;
2-(5H-imidazo[5,l-a]isoindol-5-yl)-l-(thiazol-5-yl)ethanol;
1- (4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2,2- dimethylpropan- 1 -one;
2- (6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l-(furan-2-yl)ethanol;
(lS)-l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
(lR)-l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l-(4-
(iodomethylene)cyclohexyl)ethanol;
1- cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)propan-l-ol;
2- (5H-imidazo[5,l-a]isoindol-5-yl)acetonitrile;
l-cyclohexyl-3-(6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)propan-2-ol;
l-cyclohexyl-3-(5H-imidazo[5,l-a]isoindol-5-yl)propan-2-ol;
l-(4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2- phenylethanone;
l-(4,4-difluorocyclohexyl)-2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
1- (4,4-difluorocyclohexyl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
2- (6-fluoro-5H-imidazo[5, 1 -a]isoindol-5-yl)- 1 -( 1 -methyl- 1 H-imidazol-5-yl)ethanol;
1- (4-(cyclopropylmethylene)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5- yl)ethanol;
2- (6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l-(4-(propan-2- ylidene)cyclohexyl)ethanol;
(E)-5-(2-cyclohexylvinyl)-5H-imidazo[5,l-a]isoindole;
2-(9-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l-(4-methylcyclohexyl)ethanol;
1 -(cyclohex-3 -en- 1 -yl)-2-(6-fluoro-5H-imidazo[5, 1 -a]isoindol-5-yl)ethanol;
(S)-l-cyclohexyl-2-((R)-5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
(R)-l-cyclohexyl-2-((R)-5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
(R)-l-cyclohexyl-2-((S)-5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
(S)-l-cyclohexyl-2-((S)-5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-ylidene)etanol;
l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl acetate; l-(4-(2-(benzyloxy)ethylidene)cyclohexyl)-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethanol;
l-(l-(benzylsulfonyl)piperidin-4-yl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
1- (4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2-
(pyrimidin-5-yl)ethanone;
2- (3,4-difluorophenyl)-l-(4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- y l)ethyl)piperidin- 1 -yl)ethanone;
cyclohexyl(4-(l -hydroxy-2-(5H-imidazo[5, 1 -a]isoindol-5-yl)ethyl)piperidin- 1 - yl)methanone;
methyl 4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)cyclohexanecarboxylate;
l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl phenylcarbamate;
4-(l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethoxy)-4-oxobutanoic acid; 4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)cyclohexanol;
l-(4-(hydroxymethyl)cyclohexyl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl benzoate;
4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-(2-
(methylsulfonamido)ethyl)cyclohexanecarboxamide;
(2S)-l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl-2-amino-3- methylbutanoate;
l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl dihydrogen phosphate;
4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)cyclohexanecarboxylic acid;
1- (4-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2-(pyridin-
4-yl)ethanone;
2- (5H-imidazo [5 , 1 -a]isoindol-5-yl)- 1 -(spiro [2.5] octan-6-yl)ethanol;
2-(4-fluorophenyl)-l-(4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- y l)ethyl)piperidin- 1 -yl)ethanone;
(2S)-l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl 2-aminopropanoate; l-(4-(2-hydroxyethylidene)cyclohexyl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol; (2S)-l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl pyrrolidine-2- carboxylate;
(2S)-5-(l-cyclohexyl-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl) 1-methyl 2- aminopentanedioate; 1 -(4-((S)- 1 -hydroxy-2-((S)-5H-imidazo [5 , 1 -a] isoindol-5 -yl)ethyl)piperidin- 1 -yl)-2- phenylethanone;
(3-fluoro-2-hydroxyphenyl)(4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)piperidin- 1 -yl)methanone;
4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-l- carboxamide;
(4-fluorophenyl)(4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l- yl)methanone;
(2 S)-2-amino- l-(4-(l -hydroxy-2-(5H-imidazo [5 , 1 -a] isoindol-5 -yl)ethyl)piperidin- 1 - yl)-3-phenylpropan-l-one;
(4-( 1 -hydroxy-2-(5H-imidazo [5 , 1 -a] isoindol-5 -yl)ethyl)piperidin- 1 -yl)((S)- pyrrolidin-2-yl) methanone;
(lR,4s)-4-(2-((S)-6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l-hydroxyethyl)
cyclohexyl benzoate;
(lR,4s)-4-(2-((S)-6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l-hydroxyethyl)
cyclohexanol;
1 -(3 -( 1 -hydroxy -2-(5H-imidazo[5, 1 -a] isoindol-5 -yl)ethyl)azetidin- 1 -yl)-2- phenylethanone;
3-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-phenylazetidine-l- carboxamide;
tert-butyl 3-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)azetidine-l- carboxylate
l-(azetidin-3-yl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
tert-butyl 4-((S)-l-hydroxy-2-((R)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidine- 1-carboxylate;
tert-butyl 4-((R)- 1 -hydroxy-2-((R)-5H-imidazo[5, 1 -a]isoindol-5-yl)ethyl)piperidine- 1-carboxylate;
tert-butyl 4-((R)- 1 -hydroxy-2-((S)-5H-imidazo[5, 1 -a]isoindol-5-yl)ethyl)piperidine- 1-carboxylate;
tert-butyl 4-((S)-l-hydroxy-2-((S)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidine- 1-carboxylate;
1 -(( 1 s,4s)-4-(benzyloxy)cyclohexyl)-2-(6-fluoro-5H-imidazo[5 , 1 -a] isoindol-5 - yl)ethanol; 2-(5H-imidazo [5 , 1 -a] isoindol-5-yl)- 1 -(pyridin-3 -yl)ethanol;
( 1 r,4r)-4-(2-(6-fluoro-5H-imidazo [5 , 1 -a] isoindol-5-yl)- 1 - hydroxyethyl)cyclohexanol;
4-((S)-l-hydroxy-2-((R)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-
1 -carboxamide;
4-((R)-l-hydroxy-2-((R)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-phenylpiperidine- 1 -carboxamide;
4-((R)-l-hydroxy-2-((S)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-phenylpiperidine- 1 -carboxamide;
4-((S)-l-hydroxy-2-((S)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-phenylpiperidine- 1 -carboxamide;
l-(4-((R)-l-hydroxy-2-((S)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2- phenylethanone;
1 -(4-((S)- 1 -hydroxy-2-((S)-5H-imidazo [5 , 1 -a] isoindol-5 -yl)ethyl)piperidin- 1 -yl)-2- phenylethanone;
(lR,4s)-4-((S)-2-((R)-6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l- hydroxyethyl)cyclohexanol;
(1 S,4s)-4-((R)-2-((R)-6-fluoro-5H-imidazo[5, 1 -a]isoindol-5-yl)- 1 - hydroxyethyl)cyclohexanol;
( 1 S,4s)-4-((R)-2-((S)-6-fluoro-5H-imidazo [5 , 1 -a] isoindol-5 -yl)- 1 - hydroxyethyl)cyclohexanol;
(lR,4s)-4-((S)-2-((S)-6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l- hydroxyethyl)cyclohexanol;
(lS,4r)-4-((S)-2-((S)-6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l- hydroxyethyl)cyclohexanol;
(lS,4r)-4-((S)-2-((R)-6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l- hydroxyethyl)cyclohexanol;
( 1 R,4r)-4-((R)-2-((S)-6-fluoro-5H-imidazo [5 , 1 -a] isoindol-5 -yl)- 1 - hydroxyethyl)cyclohexanol;
( 1 R,4r)-4-((R)-2-((R)-6-fluoro-5H-imidazo [5 , 1 -a]isoindol-5 -yl)- 1 - hydroxyethyl)cyclohexanol;
1 -(4-((S)- 1 -hydroxy-2-((S)-5H-imidazo [5 , 1 -a] isoindol-5 -yl)ethyl)piperidin- 1 -yl)-2-
(tetrahydro-2H-pyran-4-yl)ethanone; l-(4-((R)-l-hydroxy-2-((R)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2- phenylethanone;
N-(( 1 s,4s)-4-( 1 -hydroxy-2-(5H-imidazo [5 , 1 -a] isoindol-5- yl)ethyl)cyclohexyl)benzamide;
1- (4-((S)-l-hydroxy-2-((R)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2- phenylethanone;
2- (5H-imidazo[5,l-a]isoindol-5-yl)-l-(l-(phenylcarbamoyl)piperidin-4-yl)ethyl phenylcarbamate;
4-((R)-l-hydroxy-2-((S)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-((lr,4R)-4- hydroxycyclohexyl)piperidine- 1 -carboxamide;
4-((S)-l-hydroxy-2-((S)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-(tetrahydro-2H- pyran-4-yl)piperidine- 1 -carboxamide;
4-((S)-l-hydroxy-2-((S)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-((lr,4S)-4- hydroxycyclohexyl)piperidine- 1 -carboxamide;
1 -(( 1 r,4r)-4-(benzyloxy)cyclohexyl)-2-(5H-imidazo [5 , 1 -a] isoindol-5 -yl)ethanol; l-((lr,4r)-4-(benzyloxy)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5- yl)ethanol;
1- (4-((R)-l-hydroxy-2-((S)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2-
(tetrahydro-2H-pyran-4-yl)ethanone;
2- (5H-imidazo[5,l-a]isoindol-5-yl)-l-(pyridin-4-yl)ethanol;
2-(5H-imidazo[5,l-a]isoindol-5-yl)-l-(pyridin-2-yl)ethanol;
4-((R)-l-hydroxy-2-((S)-5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-(tetrahydro-2H- pyran-4-yl)piperidine- 1 -carboxamide;
N-cyclohexyl-4-((R)-l-hydroxy-2-((S)-5H-imidazo[5,l-a]isoindol-5- yl)ethyl)piperidine- 1 -carboxamide;
N-((lr,4r)-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)cyclohexyl)benzamide;
1 -(( 1 r,4r)-4-(benzyloxy)cyclohexyl)-2-(5H-imidazo [5 , 1 -a] isoindol-5 -yl)ethanol; N-cyclopentyl-4-((R)-l-hydroxy-2-((S)-5H-imidazo[5,l-a]isoindol-5- yl)ethyl)piperidine- 1 -carboxamide;
2-(6-fluoro-5H-imidazo [5 , 1 -a] isoindol-5 -yl)- 1 -(4-
(trifluoromethyl)cyclohexyl)ethanol;
2-(5H-imidazo[5,l-a]isoindol-5-yl)-l-(4-(trifluoromethyl)cyclohexyl)ethanol; l-(4-((R)- l-hydroxy-2-((S)-5H-imidazo[5, 1 -a]isoindol-5-yl)ethyl)piperidin- 1 -yl)-2-
(4-(trifluoromethyl)phenyl)ethanone;
4-((R)-l -hydroxy-2-((5')-5H-imidazo[5, l-a]isoindol-5-yl)ethyl)-N-(4-
(trifluoromethyl)phenyl)piperidine- 1 -carboxamide;
(4-((R) -hydroxy-2-((5)-5H midazo[5, l -a]isoindol-5-yl)ethyl)piperidin- l-yl)(lH- imidazol- 1 -yl)methanone;
1- (5H-imidazo[5, l-a]isoindol-5-yl)-3-methylbutan-2-ol;
2- (5H-imidazo[5, l-a]isoindol-5-yl)- l-(tetrahydro-2H-pyran-3-yl)ethanol;
2-(5H-imidazo[5, l-a]isoindol-5-yl)- l-(piperidin-3-yl)ethanol;
l-cyclohexyl-2-((R)-5H-imidazo[5, l -a]isoindol-5-yl)ethanol;
l-cyclohexyl-2-((S)-5H-imidazo[5, l -a]isoindol-5-yl)ethanol;
(l S)- l -cyclohexyl-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanol;
(lR)-l -cyclohexyl-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanol;
1 -cyclohexyl-3 -(5H-imidazo[5, 1 -a] isoindol-5 -yl)propan- 1 -ol;
1- cyclohexyl-2-(9-fluoro-5H-imidazo[5, l -a]isoindol-5-yl)ethanol;
N-(4-(l-hydroxy-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethyl)phenyl)-2-(tetrahydro-2H- pyran-4-yl)acetamide;
2- (5H-imidazo[5, l-a]isoindol-5-yl)-l -(lH-imidazol-2-yl)ethanol;
2-(5H-imidazo [5 , 1 -a] isoindol-5-yl)- 1 -( 1 H-imidazol-4-yl)ethanol;
2-(6-fluoro-5H-imidazo[5, l -a]isoindol-5-yl)- l-(thiazol-2-yl)ethanol;
(5S)-5-(2 -cyclohexyl-2 -hydroxy ethyl)-5H-imidazo[5, l-a]isoindol-6-ol;
l-(2-aminocyclohexyl)-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanol;
N-(l-cyclohexyl-2-(5H-imidazo[5, l -a]isoindol-5-yl)ethyl)acetamide;
N-(2-(l -hydroxy-2-(5H-imidazo[5, 1 -a]isoindol-5-yl)ethyl)cyclohexyl)acetamide;
1- cyclohexyl-2-(5H-imidazo[5, l -a]isoindol-5-yl)-N-methylethanamine;
2- ((l-cyclohexyl-2-((S)-5H-imidazo[5, l-a]isoindol-5- yl)ethyl)amino)ethanesulfonamide;
2-(6-fluoro-5H-imidazo[5, l -a]isoindol-5-yl)- l-(l-methylpiperidin-4-yl)ethanol; l-(4-aminocyclohexyl)-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanol;
N-(4-(l -hydroxy-2-(5H-imidazo[5, 1 -a]isoindol-5-yl)ethyl)cyclohexyl)acetamide; l-(4-(aminomethyl)cyclohexyl)-2-(5H-imidazo[5, l -a]isoindol-5-yl)ethanol;
4-(l -hydroxy-2-(5H-imidazo[5, 1 -a] isoindol-5 -yl)ethyl)cyclohexanecarboxamide; l-(3-aminocyclohexyl)-2-(5H-imidazo[5, l-a]isoindol-5-yl)ethanol; (5H-imidazo[5,l-a]isoindol-5-yl)-l-(piperidin-3-yl)ethanol;
(5H-imidazo [5 , 1 -a] isoindol-5-yl)- 1 -(tetrahydro-2H-pyran-3 -yl)ethanol; (5H-imidazo [5 , 1 -a] isoindol-5-yl)- 1 -(( 1 r,4r)-4-(pyridin-2- ylmethoxy)cyclohexyl)ethanol;
(5H-imidazo [5 , 1 -a] isoindol-5-yl)- 1 -(( 1 r,4r)-4-(pyridin-3 - ylmethoxy)cyclohexyl)ethanol;
(5H-imidazo [5 , 1 -a] isoindol-5-yl)- 1 -(( 1 r,4r)-4-(pyridin-4- ylmethoxy)cyclohexyl)ethanol;
((lr,4r)-4-((2-aminopyridin-4-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,l- a]isoindol-5-yl)ethanol;
(5H-imidazo [5 , 1 -a] isoindol-5 -yl)- 1 -(( 1 r,4r)-4-(pyrazin-2- ylmethoxy)cyclohexyl)ethanol;
(5H-imidazo [5 , 1 -a] isoindol-5 -yl)- 1 -(( 1 r,4r)-4-(pyrimidin-5- ylmethoxy)cyclohexyl)ethanol;
((lr,4r)-4-((6-aminopyridin-2-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,l- a] isoindol-5 -yl)ethanol;
((lr,4r)-4-((6-aminopyridin-3-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,l- a] isoindol-5 -yl)ethanol;
(( 1 r,4r)-4-((3 -aminopyridin-2-yl)methoxy)cyclohexyl)-2-(5H-imidazo [5,1- a]isoindol-5-yl)ethanol;
((lr,4r)-4-((2-aminopyrimidin-5-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,l a]isoindol-5-yl)ethanol;
((lr,4r)-4-((4-aminopyrimidin-5-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,l a]isoindol-5-yl)ethanol;
((lr,4r)-4-((5-aminopyridin-2-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,l- a]isoindol-5-yl)ethanol;
(((( 1 r,4r)-4-( 1 -hydroxy-2-(5H-imidazo [5, 1 -a] isoindol-5 - yl)ethyl)cyclohexyl)oxy)methyl)-N,N-dimethylbenzamide;
(((( 1 r,4r)-4-( 1 -hydroxy-2-(5H-imidazo [5, 1 -a] isoindol-5 - yl)ethyl)cyclohexyl)oxy)methyl)-N,N-dimethylbenzamide;
(((( 1 r,4r)-4-( 1 -hydroxy-2-(5H-imidazo [5, 1 -a] isoindol-5 - yl)ethyl)cyclohexyl)oxy)methyl)-N,N-dimethylbenzamide;
(((( 1 r,4r)-4-( 1 -hydroxy-2-(5H-imidazo [5, 1 -a] isoindol-5 - yl)ethyl)cyclohexyl)oxy)methyl)benzenesulfonamide;
3- ((((lr,4r)-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)cyclohexyl)oxy)methyl)benzenesulfonamide;
2- ((((lr,4r)-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)cyclohexyl)oxy)methyl)benzenesulfonamide;
4- ((((lr,4r)-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)cyclohexyl)oxy)methyl)benzamide;
3- ((((lr,4r)-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)cyclohexyl)oxy)methyl)benzamide;
2-((((lr,4r)-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)cyclohexyl)oxy)methyl)benzamide;
methyl 4-((((lr,4r)-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)cyclohexyl)oxy)methyl)benzoate;
methyl 3-((((lr,4r)-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)cyclohexyl)oxy)methyl)benzoate;
methyl 2-((((lr,4r)-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)cyclohexyl)oxy)methyl)benzoate;
2-(5H-imidazo[5,l-a]isoindol-5-yl)-l-((lr,4r)-4-methoxycyclohexyl)ethanol;
1- ((lr,4r)-4-ethoxycyclohexyl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
2- (5H-imidazo[5,l-a]isoindol-5-yl)-l-((lr,4r)-4-isopropoxycyclohexyl)ethanol; l-((lr,4r)-4-(cyclopropylmethoxy)cyclohexyl)-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethanol;
1- ((lr,4r)-4-(cyclopentylmethoxy)cyclohexyl)-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethanol;
2- (5H-imidazo [5 , 1 -a] isoindol-5 -yl)- 1 -(( 1 r,4r)-4-(thiophen-2- ylmethoxy)cyclohexyl)ethanol;
1 -(( 1 r,4r)-4-(( 1 H-indol-3 -yl)oxy)cyclohexyl)-2-(5H-imidazo[5 , 1 -a] isoindol-5 - yl)ethanol;
1 -(( 1 r,4r)-4-(( 1 H-indol-5 -yl)oxy)cyclohexyl)-2-(5H-imidazo[5 , 1 -a] isoindol-5 - yl)ethanol;
2-(5H-imidazo[5,l-a]isoindol-5-yl)-l-(4-((tetrahydro-2H-pyran-4- yl)methoxy)cyclohexyl)ethanol;
4- (((4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)cyclohexyl)oxy)methyl)benzenesulfonamide;
2-(5H-imidazo[5,l-a]isoindol-5-yl)-l-(4-(oxazol-2-ylmethoxy)cyclohexyl)ethanol; 2-(5H-imidazo[5,l-a]isoindol-5-yl)-l-(4-(thiazol-2-ylmethoxy)cyclohexyl)ethanol; 2-(5H-imidazo [5 , 1 -a] isoindol-5-yl)- 1 -( 1 -( 1 -imino-2-phenylethyl)piperidin-4- yl)ethanol;
4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-l- carboximidamide;
4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-( yridin-4-yl)piperidine- 1 -carboximidamide;
4-(l -hydroxy-2-(5H-imidazo[5, 1 -a]isoindol-5-yl)ethyl)-N-(tetrahydro-2H-pyran-4- yl)piperidine- 1 -carboximidamide;
N-(4-cyanophenyl)-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- y l)ethyl)piperidine- 1 -carboxamide;
N-(tert-butyl)-4-(l -hydroxy -2-(5H-imidazo[5, 1 -a]isoindol-5-yl)ethyl)piperidine- 1 - carboxamide;
N-(tert-butyl)-4-(l -hydroxy-2-(5H-imidazo[5, 1 -a]isoindol-5-yl)ethyl)piperidine- 1 - sulfonamide;
1- (4-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2-(3- hydroxyphenyl)ethanone;
2- ( 1 -(azetidine- 1 -carbonyl)piperidin-4-yl)-2-hydroxy- 1 -(4-( 1 -hydroxy-2-(5H- imidazo[5, 1 -a]isoindol-5-yl)ethyl)piperidin- l-yl)ethanone;
2-cyclopentyl-l-(4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l- yl)ethanone;
l-(4-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2-(2- methylthiazol-5-yl)ethanone;
l-(4-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2-(2- methylthiazol-5-yl)ethanone;
N-cyclohexyl-N-hydroxy-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- y l)ethyl)piperidine- 1 -carboxamide;
N-(4-(2-(4-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2- oxoethyl)phenyl)methanesulfonamide;
N-cyclopropyl-N-hydroxy-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- y l)ethyl)piperidine- 1 -carboxamide; 3,3-difluoro-l-(4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l- yl)butan-l-one;
l-(4-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2-(p- tolyl)ethanone;
l-(l-(4-aminopyrimidin-2-yl)piperidin-4-yl)-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethanol;
1- (l-(2-aminopyrimidin-4-yl)piperidin-4-yl)-2-(5H-imidazo[5,l-a]isoindol-5- yl)ethanol;
N-cyclopropyl-4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidine-l- carboxamide;
2- cyclopropyl- 1 -(4-( 1 -hydroxy -2-(5H-imidazo [5 , 1 -a] isoindol-5 -yl)ethyl)piperidin- 1 - yl)ethanone;
2-(4-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5- yl)ethyl)cyclohexylidene)acetonitrile;
4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-(4-
(trifluoromethyl)thiazol-2-yl)piperidine- 1 -carboxamide;
4-(2-(4-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2- oxoethyl)benzamide;
l-(4-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2-(4-
(methylsulfonyl)phenyl)ethanone;
4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)-N-((lr,4r)-4- methylcyclohexyl)piperidine- 1 -carboxamide;
1 -(4-( 1 -hydroxy-2-(5H-imidazo [5, 1 -a] isoindol-5 -yl)ethyl)piperidin- 1 -yl)-3 ,3 - dimethylbutan- 1 -one;
4-(2-(4-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2- oxoethyl)benzenesulfonamide ;
N-(tert-butyl)-4-(2-(4-(l-hydroxy-2-(5H-imidazo[5,l-a]isoindol-5- y l)ethyl)piperidin- 1 -yl)-2-oxoethyl)benzenesulfonamide;
4-(2-(4-(l -hydroxy -2-(5H-imidazo[5,l-a]isoindol-5-yl)ethyl)piperidin-l-yl)-2- oxoethyl)benzoic acid;
1- (4-(difluoromethylene)cyclohexyl)-2-(5H-imidazo[5,l-a]isoindol-5-yl)ethanol;
2- (5H-imidazo[5,l-a]isoindol-5-yl)-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;
4-(2-(6-fluoro-5H-imidazo[5, l-a]isoindol-5-yl)-l-hydroxyethyl)-N- phenylcyclohexanecarboxamide;
N-(4-(2-(6-fluoro-5H-imidazo[5, l-a]isoindol-5-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-5-yl)-l-hydroxyethyl)cyclohexyl)-2- phenylacetamide;
or a pharmaceutically aceptable salt thereof.
33. A pharmaceutical composition comprising a compound according to any one of claims 1 - 32 and a pharmaceutically acceptable diluent, excipient, or carrier.
34. A method 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 according to any one of claims 1 - 32 or a pharmaceutical composition according to claim 33.
35. The method of claim 34, wherein the immunosuppression is associated with an infectious disease, or cancer.
36. The method of claim 35, wherein the infectious disease is 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, varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV).
37. The method of claim 35, wherein the immunosuppression is associated with a cancer.
38. The method of claim 37, wherein the cancer is colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head, or neck cancer, or lymphoma, leukemia, or melanoma.
PCT/US2012/033245 2011-04-15 2012-04-12 Fused imidazole derivatives useful as ido inhibitors WO2012142237A1 (en)

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KR1020137030438A KR102164443B1 (en) 2011-04-15 2012-04-12 Fused imidazole derivatives useful as ido inhibitors
CA2833296A CA2833296C (en) 2011-04-15 2012-04-12 Ido inhibitors
NZ616457A NZ616457B2 (en) 2011-04-15 2012-04-12 Fused imidazole derivatives useful as ido inhibitors
MEP-2016-82A ME02417B (en) 2011-04-15 2012-04-12 Fused imidazole derivatives useful as ido inhibitors
ES12715295.7T ES2569665T3 (en) 2011-04-15 2012-04-12 Condensed imidazole derivatives useful as IDO inhibitors
EP12715295.7A EP2697227B1 (en) 2011-04-15 2012-04-12 Fused imidazole derivatives useful as ido inhibitors
MX2013012021A MX340442B (en) 2011-04-15 2012-04-12 Fused imidazole derivatives useful as ido inhibitors.
SI201230515A SI2697227T1 (en) 2011-04-15 2012-04-12 Fused imidazole derivatives useful as ido inhibitors
JP2014505274A JP2014511876A (en) 2011-04-15 2012-04-12 IDO inhibitor
AU2012242871A AU2012242871C1 (en) 2011-04-15 2012-04-12 Fused imidazole derivatives useful as IDO inhibitors
DK12715295.7T DK2697227T3 (en) 2011-04-15 2012-04-12 DEHYDRATED imidazole USED AS IDO INHIBITORS
RU2013150811A RU2613579C2 (en) 2011-04-15 2012-04-12 Ido inhibitors
BR112013026494A BR112013026494A2 (en) 2011-04-15 2012-04-12 compound, pharmaceutical composition, method for treating condition
RS20160285A RS54723B1 (en) 2011-04-15 2012-04-12 Fused imidazole derivatives useful as ido inhibitors
EP17205515.4A EP3348558A1 (en) 2011-04-15 2012-04-12 Compositions comprising fused imidazole derivatives useful as ido inhibitors
CN201280018684.7A CN103547579B (en) 2011-04-15 2012-04-12 Fused imidazole derivatives useful as ido inhibitors
IL228862A IL228862A (en) 2011-04-15 2013-10-14 נגזרות אימידאזול ממוזגות לשימוש כמונעי ido
US14/053,440 US9260434B2 (en) 2011-04-15 2013-10-14 Fused imidazole derivatives useful as IDO inhibitors
HK14107271.9A HK1193822A1 (en) 2011-04-15 2014-07-16 Fused imidazole derivatives useful as ido inhibitors ido
US14/794,193 US9388191B2 (en) 2011-04-15 2015-07-08 Fused imidazole derivatives useful as IDO inhibitors
IL241846A IL241846A (en) 2011-04-15 2015-09-24 Fused imidazole derivatives useful as ido inhibitors
HRP20160369TT HRP20160369T1 (en) 2011-04-15 2016-04-12 Fused imidazole derivatives useful as ido inhibitors
SM201600130T SMT201600130B (en) 2011-04-15 2016-05-04 USEFUL IMIDAZOLIC DERIVATIVES USEFUL AS IDO INHIBITORS
US15/181,062 US9850248B2 (en) 2011-04-15 2016-06-13 IDO inhibitors
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Cited By (200)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103382187A (en) * 2013-08-06 2013-11-06 信实生物医药（上海）有限公司 3-chloro-7(5)-bromo-benzo-isoxazole compounding method
WO2014159248A1 (en) 2013-03-14 2014-10-02 Newlink Genetics Corporation Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
WO2015100282A1 (en) 2013-12-24 2015-07-02 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
WO2015187835A2 (en) 2014-06-06 2015-12-10 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
US9260434B2 (en) 2011-04-15 2016-02-16 Newlink Genetics Corporation Fused imidazole derivatives useful as IDO inhibitors
WO2016037026A1 (en) * 2014-09-05 2016-03-10 Merck Patent Gmbh Cyclohexyl-ethyl substituted diaza- and triaza-tricyclic compounds as indole-amine-2,3-dioxygenase (ido) antagonists for the treatment of cancer
WO2016051181A1 (en) * 2014-10-01 2016-04-07 Redx Pharma Plc 4h-imidazo[1,5-a]indole derivatives and their use as indoleamine 2,3-dioxygenase (ido) and/or tryptophan 2,3-dioxygenase (td02) modulators
WO2016059412A1 (en) * 2014-10-15 2016-04-21 Redx Pharma Plc 6,7-heterocyclic fused 5h-pyrrolo[1,2-c]imidazole derivatives and their use as indoleamine 2,3-dioxygenase (ido) and/or tryptophan 2,3-dioxygenase (td02) modulators
WO2016081748A2 (en) 2014-11-21 2016-05-26 Bristol-Myers Squibb Company Antibodies against cd73 and uses thereof
JP2016518329A (en) * 2013-03-14 2016-06-23 キュラデブ ファーマ プライベート リミテッド Inhibitors of the kynurenine pathway
WO2016106266A1 (en) 2014-12-22 2016-06-30 Bristol-Myers Squibb Company TGFβ RECEPTOR ANTAGONISTS
WO2016127052A1 (en) 2015-02-05 2016-08-11 Bristol-Myers Squibb Company Cxcl11 and smica as predictive biomarkers for efficacy of anti-ctla4 immunotherapy
WO2016131381A1 (en) * 2015-02-16 2016-08-25 Shanghai De Novo Pharmatech Co. Ltd. Fused-ring compounds, pharmaceutical composition and uses thereof
WO2016140884A1 (en) 2015-03-02 2016-09-09 Rigel Pharmaceuticals, Inc. TGF-β INHIBITORS
WO2016161269A1 (en) 2015-04-03 2016-10-06 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer
WO2016162505A1 (en) 2015-04-08 2016-10-13 F-Star Biotechnology Limited Her2 binding agent therapies
WO2016165613A1 (en) 2015-04-12 2016-10-20 Hangzhou Innogate Pharma Co., Ltd. Heterocycles useful as ido and tdo inhibitors
WO2016168149A1 (en) 2015-04-13 2016-10-20 Five Prime Therapeutics, Inc. Combination therapy for cancer
WO2016169421A1 (en) * 2015-04-21 2016-10-27 江苏恒瑞医药股份有限公司 Imidazo isoindole derivative, preparation method therefor and medical use thereof
WO2016183114A1 (en) 2015-05-11 2016-11-17 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
WO2016183118A1 (en) 2015-05-12 2016-11-17 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
WO2016183115A1 (en) 2015-05-12 2016-11-17 Bristol-Myers Squibb Company 5h-pyrido[3,2-b]indole compounds as anticancer agents
WO2016196228A1 (en) 2015-05-29 2016-12-08 Bristol-Myers Squibb Company Antibodies against ox40 and uses thereof
WO2017004016A1 (en) 2015-06-29 2017-01-05 The Rockefeller University Antibodies to cd40 with enhanced agonist activity
WO2017009842A2 (en) 2015-07-16 2017-01-19 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
WO2017019757A1 (en) 2015-07-28 2017-02-02 Bristol-Myers Squibb Company Tgf beta receptor antagonists
WO2017019175A1 (en) 2015-07-24 2017-02-02 Newlink Genetics Corporation Salts and prodrugs of 1-methyl-d-tryptophan
WO2017035118A1 (en) 2015-08-25 2017-03-02 Bristol-Myers Squibb Company Tgf beta receptor antagonists
WO2017079117A1 (en) 2015-11-02 2017-05-11 Five Prime Therapeutics, Inc. Cd80 extracellular domain polypeptides and their use in cancer treatment
WO2017087678A2 (en) 2015-11-19 2017-05-26 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
WO2017091580A1 (en) 2015-11-23 2017-06-01 Five Prime Therapeutics, Inc. Predicting response to cancer treatment with fgfr2 inhibitors
WO2017106291A1 (en) 2015-12-15 2017-06-22 Bristol-Myers Squibb Company Cxcr4 receptor antagonists
WO2017107979A1 (en) 2015-12-24 2017-06-29 Genentech, Inc. Tdo2 inhibitors
WO2017134555A1 (en) 2016-02-02 2017-08-10 Emcure Pharmaceuticals Limited Derivatives of pyrroloimidazole or analogues thereof which are useful for the treatment of inter alia cancer
WO2017140835A1 (en) 2016-02-19 2017-08-24 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of obesity
WO2017140272A1 (en) * 2016-02-19 2017-08-24 正大天晴药业集团股份有限公司 Tricyclic compound acting as immunomodulator
WO2017152085A1 (en) 2016-03-04 2017-09-08 Bristol-Myers Squibb Company Combination therapy with anti-cd73 antibodies
WO2017149469A1 (en) 2016-03-03 2017-09-08 Emcure Pharmaceuticals Limited Heterocyclic compounds useful as ido and/or tdo modulators
CN107176956A (en) * 2017-05-31 2017-09-19 成都海博锐药业有限公司 A kind of IDO inhibitor compound, Pharmaceutical composition, purposes
GB2548542A (en) * 2015-06-16 2017-09-27 Redx Pharma Plc Compounds
WO2017184619A2 (en) 2016-04-18 2017-10-26 Celldex Therapeutics, Inc. Agonistic antibodies that bind human cd40 and uses thereof
WO2017197055A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Heterocyclic degronimers for target protein degradation
WO2017197036A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Spirocyclic degronimers for target protein degradation
WO2017197046A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
WO2017198159A1 (en) * 2016-05-16 2017-11-23 鲁南制药集团股份有限公司 Imidazole derivative containing bridge ring
WO2017213919A1 (en) 2016-06-10 2017-12-14 Eli Lilly And Company 1-tetrahydropyranylcarbonyl-2,3-dihydro-1h-indole compounds for treating cancer
WO2018013818A2 (en) 2016-07-14 2018-01-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
WO2018017633A1 (en) 2016-07-21 2018-01-25 Bristol-Myers Squibb Company TGF Beta RECEPTOR ANTAGONISTS
WO2018054365A1 (en) 2016-09-24 2018-03-29 Beigene, Ltd. NOVEL 5 or 8-SUBSTITUTED IMIDAZO [1, 5-a] PYRIDINES AS SELECTIVE INHIBITORS OF INDOLEAMINE AND/OR TRYPTOPHANE 2, 3-DIOXYGENASES
WO2018071873A2 (en) 2016-10-13 2018-04-19 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
WO2018083635A2 (en) 2016-11-04 2018-05-11 Auckland Uniservices Limited Tricyclic heterocyclic derivatives and uses thereof
WO2018132279A1 (en) 2017-01-05 2018-07-19 Bristol-Myers Squibb Company Tgf beta receptor antagonists
WO2018175954A1 (en) 2017-03-23 2018-09-27 F. Hoffmann-La Roche Ag Synthesis of imidazo[5,1-a]isoindole derivative useful as ido inhibitors
WO2018183608A1 (en) 2017-03-31 2018-10-04 Five Prime Therapeutics, Inc. Combination therapy for cancer using anti-gitr antibodies
WO2018187613A2 (en) 2017-04-07 2018-10-11 Bristol-Myers Squibb Company Anti-icos agonist antibodies and uses thereof
WO2018195397A2 (en) 2017-04-21 2018-10-25 Kyn Therapeutics Indole ahr inhibitors and uses thereof
WO2018201014A1 (en) 2017-04-28 2018-11-01 Five Prime Therapeutics, Inc. Methods of treatment with cd80 extracellular domain polypeptides
WO2018209049A1 (en) 2017-05-12 2018-11-15 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN108884103A (en) * 2016-02-19 2018-11-23 正大天晴药业集团股份有限公司 Three and cycle compound as immunomodulator
WO2019006047A1 (en) 2017-06-28 2019-01-03 Genentech, Inc. Tdo2 and ido1 inhibitors
WO2019006283A1 (en) 2017-06-30 2019-01-03 Bristol-Myers Squibb Company Amorphous and crystalline forms of ido inhibitors
WO2019005559A1 (en) 2017-06-28 2019-01-03 Genentech, Inc. Tdo2 and ido1 inhibitors
WO2019023459A1 (en) 2017-07-28 2019-01-31 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
WO2019029507A1 (en) * 2017-08-08 2019-02-14 江苏恒瑞医药股份有限公司 Preparation method for imidazoisoindole derivatives
WO2019034725A1 (en) 2017-08-17 2019-02-21 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
WO2019046498A1 (en) 2017-08-31 2019-03-07 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
WO2019046496A1 (en) 2017-08-31 2019-03-07 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
WO2019046500A1 (en) 2017-08-31 2019-03-07 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
WO2019074822A1 (en) 2017-10-09 2019-04-18 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2019074824A1 (en) 2017-10-09 2019-04-18 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2019074887A1 (en) 2017-10-10 2019-04-18 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
WO2019075090A1 (en) 2017-10-10 2019-04-18 Tilos Therapeutics, Inc. Anti-lap antibodies and uses thereof
WO2019079261A1 (en) 2017-10-16 2019-04-25 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
WO2019089921A1 (en) 2017-11-01 2019-05-09 Bristol-Myers Squibb Company Immunostimulatory agonistic antibodies for use in treating cancer
WO2019090198A1 (en) 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Isofuranone compounds useful as hpk1 inhibitors
US10323004B2 (en) 2016-05-04 2019-06-18 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2019133747A1 (en) 2017-12-27 2019-07-04 Bristol-Myers Squibb Company Anti-cd40 antibodies and uses thereof
WO2019136112A1 (en) 2018-01-05 2019-07-11 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2019138107A1 (en) 2018-01-15 2019-07-18 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
WO2019140229A1 (en) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
WO2019160884A1 (en) 2018-02-13 2019-08-22 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
TWI671302B (en) * 2016-12-20 2019-09-11 大陸商深圳微芯生物科技有限責任公司 Fused imidazole compounds that may inhibit indoleamine 2,3-dioxygenase
WO2019173587A1 (en) 2018-03-08 2019-09-12 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
WO2019183040A1 (en) 2018-03-21 2019-09-26 Five Prime Therapeutics, Inc. ANTIBODIES BINDING TO VISTA AT ACIDIC pH
WO2019200256A1 (en) 2018-04-12 2019-10-17 Bristol-Myers Squibb Company Anticancer combination therapy with cd73 antagonist antibody and pd-1/pd-l1 axis antagonist antibody
WO2019204257A1 (en) 2018-04-16 2019-10-24 Arrys Therapeutics, Inc. Ep4 inhibitors and use thereof
WO2019213340A1 (en) 2018-05-03 2019-11-07 Bristol-Myers Squibb Company Uracil derivatives as mer-axl inhibitors
US10508085B2 (en) 2016-09-22 2019-12-17 Plexxikon Inc. Compounds and methods for IDO and TDO modulation, and indications therefor
WO2019243832A1 (en) 2018-06-22 2019-12-26 Bicycletx Limited Bicyclic peptide ligands specific for nectin-4
WO2020006016A1 (en) 2018-06-27 2020-01-02 Bristol-Myers Squibb Company Naphthyridinone compounds useful as t cell activators
WO2020006018A1 (en) 2018-06-27 2020-01-02 Bristol-Myers Squibb Company Substituted naphthyridinone compounds useful as t cell activators
US10525035B2 (en) 2014-12-18 2020-01-07 Lankenau Institute For Medical Research Methods and compositions for the treatment of retinopathy and other ocular diseases
WO2020010177A1 (en) 2018-07-06 2020-01-09 Kymera Therapeutics, Inc. Tricyclic crbn ligands and uses thereof
WO2020014327A2 (en) 2018-07-11 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to vista at acidic ph
WO2020014132A2 (en) 2018-07-09 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to ilt4
US10544099B2 (en) 2016-05-04 2020-01-28 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2020023355A1 (en) 2018-07-23 2020-01-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2020023356A1 (en) 2018-07-23 2020-01-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN110872289A (en) * 2015-04-10 2020-03-10 百济神州(北京)生物科技有限公司 Novel 8-substituted imidazo [1,5-a ] pyridines as IDO1 and/or TDO inhibitors
WO2020051424A1 (en) 2018-09-07 2020-03-12 Pic Therapeutics Eif4e inhibitors and uses thereof
WO2020076969A2 (en) 2018-10-10 2020-04-16 Tilos Therapeutics, Inc. Anti-lap antibody variants and uses thereof
US10633342B2 (en) 2016-05-04 2020-04-28 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2020102501A1 (en) 2018-11-16 2020-05-22 Bristol-Myers Squibb Company Anti-nkg2a antibodies and uses thereof
EP3670659A1 (en) 2018-12-20 2020-06-24 Abivax Biomarkers, and uses in treatment of viral infections, inflammations, or cancer
WO2020132561A1 (en) 2018-12-20 2020-06-25 C4 Therapeutics, Inc. Targeted protein degradation
US10696650B2 (en) 2017-08-17 2020-06-30 Ikena Oncology, Inc. AHR inhibitors and uses thereof
US10696648B2 (en) 2016-05-04 2020-06-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2020187998A1 (en) 2019-03-19 2020-09-24 Fundació Privada Institut D'investigació Oncològica De Vall Hebron Combination therapy with omomyc and an antibody binding pd-1 or ctla-4 for the treatment of cancer
US10793563B2 (en) 2018-01-29 2020-10-06 Merck Patent Gmbh GCN2 inhibitors and uses thereof
WO2020201753A1 (en) 2019-04-02 2020-10-08 Bicycletx Limited Bicycle toxin conjugates and uses thereof
WO2020231766A1 (en) 2019-05-13 2020-11-19 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
WO2020231713A1 (en) 2019-05-13 2020-11-19 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
WO2020243423A1 (en) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US10874743B2 (en) 2017-12-26 2020-12-29 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
WO2021005222A1 (en) 2019-07-11 2021-01-14 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
WO2021026179A1 (en) 2019-08-06 2021-02-11 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
WO2021041588A1 (en) 2019-08-28 2021-03-04 Bristol-Myers Squibb Company Substituted pyridopyrimidinonyl compounds useful as t cell activators
WO2021055698A1 (en) 2019-09-19 2021-03-25 Bristol-Myers Squibb Company Antibodies binding to vista at acidic ph
US10959986B2 (en) 2018-08-29 2021-03-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US10988477B2 (en) 2018-01-29 2021-04-27 Merck Patent Gmbh GCN2 inhibitors and uses thereof
WO2021101919A1 (en) 2019-11-19 2021-05-27 Bristol-Myers Squibb Company Compounds useful as inhibitors of helios protein
US11021481B2 (en) 2019-09-13 2021-06-01 Nimbus Saturn, Inc. Substituted isoindolin-1-ones and 2,3-dihydro-1h-pyrrolo[3,4-c]pyridin-1-ones as HPK1 antagonists
WO2021108528A1 (en) 2019-11-26 2021-06-03 Ikena Oncology, Inc. Polymorphic carbazole derivatives and uses thereof
WO2021108288A1 (en) 2019-11-26 2021-06-03 Bristol-Myers Squibb Company Salts/cocrystals of (r)-n-(4-chlorophenyl)-2-((1s,4s)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide
US11046649B2 (en) 2018-07-17 2021-06-29 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
WO2021133750A1 (en) 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted bicyclic piperidine derivatives useful as t cell activators
WO2021133749A1 (en) 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted piperazine derivatives useful as t cell activators
WO2021133751A1 (en) 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted quinazolinyl compounds useful as t cell activators
WO2021133752A1 (en) 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted heteroaryl compounds useful as t cell activators
WO2021133748A1 (en) 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted quinolinonyl piperazine compounds useful as t cell activators
WO2021141907A1 (en) 2020-01-06 2021-07-15 Hifibio (Hong Kong) Limited Anti-tnfr2 antibody and uses thereof
WO2021139682A1 (en) 2020-01-07 2021-07-15 Hifibio (Hk) Limited Anti-galectin-9 antibody and uses thereof
US11066383B2 (en) 2016-05-04 2021-07-20 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2021146370A1 (en) 2020-01-15 2021-07-22 Blueprint Medicines Corporation Map4k1 inhibitors
WO2021178488A1 (en) 2020-03-03 2021-09-10 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
US11117889B1 (en) 2018-11-30 2021-09-14 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
WO2021183428A1 (en) 2020-03-09 2021-09-16 Bristol-Myers Squibb Company Antibodies to cd40 with enhanced agonist activity
WO2021194914A1 (en) 2020-03-23 2021-09-30 Bristol-Myers Squibb Company Substituted oxoisoindoline compounds for the treatment of cancer
WO2021207449A1 (en) 2020-04-09 2021-10-14 Merck Sharp & Dohme Corp. Affinity matured anti-lap antibodies and uses thereof
US11149011B2 (en) 2018-03-20 2021-10-19 Plexxikon Inc. Compounds and methods for IDO and TDO modulation, and indications therefor
US11173145B2 (en) 2017-01-17 2021-11-16 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
WO2021231732A1 (en) 2020-05-15 2021-11-18 Bristol-Myers Squibb Company Antibodies to garp
WO2021258010A1 (en) 2020-06-19 2021-12-23 Gossamer Bio Services, Inc. Oxime compounds useful as t cell activators
US11242393B2 (en) 2018-03-23 2022-02-08 Bristol-Myers Squibb Company Antibodies against MICA and/or MICB and uses thereof
WO2022033419A2 (en) 2020-08-10 2022-02-17 Shanghai Xbh Biotechnology Co., Ltd. Compositions and methods for treating autoimmune diseases and cancers by targeting igsf8
US11253525B2 (en) 2018-08-29 2022-02-22 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2022038158A1 (en) 2020-08-17 2022-02-24 Bicycletx Limited Bicycle conjugates specific for nectin-4 and uses thereof
WO2022081718A1 (en) 2020-10-14 2022-04-21 Five Prime Therapeutics, Inc. Anti-c-c chemokine receptor 8 (ccr8) antibodies and methods of use thereof
US11351164B2 (en) 2016-08-26 2022-06-07 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2022120353A1 (en) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2022120354A1 (en) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11358948B2 (en) 2017-09-22 2022-06-14 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
WO2022133083A1 (en) 2020-12-16 2022-06-23 Gossamer Bio Services, Inc. Compounds useful as t cell activators
WO2022148979A1 (en) 2021-01-11 2022-07-14 Bicycletx Limited Methods for treating cancer
WO2022169921A1 (en) 2021-02-04 2022-08-11 Bristol-Myers Squibb Company Benzofuran compounds as sting agonists
WO2022167457A1 (en) 2021-02-02 2022-08-11 Liminal Biosciences Limited Gpr84 antagonists and uses thereof
WO2022167445A1 (en) 2021-02-02 2022-08-11 Liminal Biosciences Limited Gpr84 antagonists and uses thereof
WO2022171745A1 (en) 2021-02-12 2022-08-18 F. Hoffmann-La Roche Ag Bicyclic tetrahydroazepine derivatives for the treatment of cancer
EP4052705A1 (en) 2021-03-05 2022-09-07 Universität Basel Vizerektorat Forschung Compositions for the treatment of ebv associated diseases or conditions
WO2022184930A2 (en) 2021-03-05 2022-09-09 Universität Basel Compositions for the treatment of ebv associated diseases or conditions
WO2022192145A1 (en) 2021-03-08 2022-09-15 Blueprint Medicines Corporation Map4k1 inhibitors
WO2022197641A1 (en) 2021-03-15 2022-09-22 Rapt Therapeutics, Inc. 1h-pyrazolo[3,4-d]pyrimidin-6-yl-amine derivatives as hematopoietic progenitor kinase 1 (hpk1) modulators and/or inhibitors for the treatment of cancer and other diseases
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
WO2022216644A1 (en) 2021-04-06 2022-10-13 Bristol-Myers Squibb Company Pyridinyl substituted oxoisoindoline compounds
WO2022216573A1 (en) 2021-04-05 2022-10-13 Bristol-Myers Squibb Company Pyridinyl substituted oxoisoindoline compounds for the treatment of cancer
US11472788B2 (en) 2017-11-25 2022-10-18 Beigene, Ltd. Benzoimidazoles as selective inhibitors of indoleamine 2,3-dioxygenases
WO2022221866A1 (en) 2021-04-16 2022-10-20 Ikena Oncology, Inc. Mek inhibitors and uses thereof
US11485743B2 (en) 2018-01-12 2022-11-01 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US11485750B1 (en) 2019-04-05 2022-11-01 Kymera Therapeutics, Inc. STAT degraders and uses thereof
US11512080B2 (en) 2018-01-12 2022-11-29 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
WO2023288254A1 (en) 2021-07-14 2023-01-19 Blueprint Medicines Corporation Heterocyclic compounds as map4k1 inhibitors
WO2023288264A1 (en) 2021-07-15 2023-01-19 Blueprint Medicines Corporation Map4k1 inhibitors
US11591332B2 (en) 2019-12-17 2023-02-28 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
WO2023028235A1 (en) 2021-08-25 2023-03-02 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
WO2023028238A1 (en) 2021-08-25 2023-03-02 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
US11623932B2 (en) 2017-09-22 2023-04-11 Kymera Therapeutics, Inc. Protein degraders and uses thereof
WO2023114984A1 (en) 2021-12-17 2023-06-22 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11685750B2 (en) 2020-06-03 2023-06-27 Kymera Therapeutics, Inc. Crystalline forms of IRAK degraders
WO2023122772A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Oxime derivatives useful as t cell activators
WO2023122778A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Pyridazinone derivatives useful as t cell activators
WO2023122777A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Oxime derivatives useful as t cell activators
US11707457B2 (en) 2019-12-17 2023-07-25 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
WO2023150186A1 (en) 2022-02-01 2023-08-10 Arvinas Operations, Inc. Dgk targeting compounds and uses thereof
WO2023173053A1 (en) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2023173057A1 (en) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Mek inhibitors and uses thereof
EP4249066A2 (en) 2014-12-23 2023-09-27 Bristol-Myers Squibb Company Antibodies to tigit
WO2023211889A1 (en) 2022-04-25 2023-11-02 Ikena Oncology, Inc. Polymorphic compounds and uses thereof
WO2023230205A1 (en) 2022-05-25 2023-11-30 Ikena Oncology, Inc. Mek inhibitors and uses thereof
US11857535B2 (en) 2020-07-30 2024-01-02 Kymera Therapeutics, Inc. Methods of treating mutant lymphomas
WO2024028364A1 (en) 2022-08-02 2024-02-08 Liminal Biosciences Limited Aryl-triazolyl and related gpr84 antagonists and uses thereof
WO2024028363A1 (en) 2022-08-02 2024-02-08 Liminal Biosciences Limited Heteroaryl carboxamide and related gpr84 antagonists and uses thereof
WO2024028365A1 (en) 2022-08-02 2024-02-08 Liminal Biosciences Limited Substituted pyridone gpr84 antagonists and uses thereof
WO2024033458A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydroazepine derivatives
WO2024033388A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033457A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024036101A1 (en) 2022-08-09 2024-02-15 Bristol-Myers Squibb Company Tertiary amine substituted bicyclic compounds useful as t cell activators
WO2024036100A1 (en) 2022-08-08 2024-02-15 Bristol-Myers Squibb Company Substituted tetrazolyl compounds useful as t cell activators
WO2024033389A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
US11926625B2 (en) 2021-03-05 2024-03-12 Nimbus Saturn, Inc. HPK1 antagonists and uses thereof
US11932624B2 (en) 2020-03-19 2024-03-19 Kymera Therapeutics, Inc. MDM2 degraders and uses thereof

Families Citing this family (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9693957B2 (en) 2011-07-08 2017-07-04 The University Of North Carolina At Chapel Hill Metal bisphosphonate nanoparticles for anti-cancer therapy and imaging and for treating bone disorders
GB201311888D0 (en) 2013-07-03 2013-08-14 Glaxosmithkline Ip Dev Ltd Novel compounds
GB201311891D0 (en) 2013-07-03 2013-08-14 Glaxosmithkline Ip Dev Ltd Novel compound
CN106256830B (en) * 2015-06-18 2019-03-08 成都海创药业有限公司 A kind of deuterated IDO inhibitor and its preparation method and application
CN105037371A (en) * 2015-06-30 2015-11-11 西华大学 Deuterated indoleamine-2,3-dioxygenase inhibitor
GB201511790D0 (en) 2015-07-06 2015-08-19 Iomet Pharma Ltd Pharmaceutical compound
EP3337476A4 (en) 2015-08-19 2019-09-04 Arvinas, Inc. Compounds and methods for the targeted degradation of bromodomain-containing proteins
CN106478634B (en) * 2015-09-01 2020-05-22 尚华医药科技(江西)有限公司 Fused imidazole compounds, preparation method, pharmaceutical composition and use thereof
US10308647B2 (en) 2015-10-29 2019-06-04 Scifluor Life Sciences, Inc. Fused imidazole derivatives as IDO/TDO inhibitors
WO2017080934A1 (en) * 2015-11-09 2017-05-18 F. Hoffmann-La Roche Ag Screening assay to identify id01 and/or tdo modulators
CN107056785B (en) * 2016-01-02 2021-06-22 杭州英创医药科技有限公司 Heterocyclic compounds as IDO and TDO inhibitors
CN105732643A (en) * 2016-04-18 2016-07-06 苏州大学 Conjugate and preparation method thereof and application to preparation of IDO enzyme inhibitor and non-steroidal anti-inflammatory drugs
CN107312005B (en) * 2016-04-27 2021-12-17 上海翰森生物医药科技有限公司 Fused imidazole derivative with IDO/TDO inhibitory activity and preparation method and application thereof
CN107556316B (en) * 2016-06-30 2021-11-12 鲁南制药集团股份有限公司 Bridged ring-containing imidazole derivatives
CN107383012B (en) * 2016-05-16 2021-09-28 鲁南制药集团股份有限公司 Bicyclic imidazole alcohol derivatives
CN105902542A (en) * 2016-05-16 2016-08-31 张阳 Application of conjugate in preparation of medicine for treating cardiovascular diseases
CN106957318B (en) * 2016-05-19 2019-12-10 中国科学院上海有机化学研究所 Condensed polycyclic indoline compound, preparation method, pharmaceutical composition and application thereof
US11246877B2 (en) 2016-05-20 2022-02-15 The University Of Chicago Nanoparticles for chemotherapy, targeted therapy, photodynamic therapy, immunotherapy, and any combination thereof
CN107488179A (en) * 2016-06-11 2017-12-19 鲁南制药集团股份有限公司 Imidazoles 01 derivatives containing bridged ring
CN107556315B (en) * 2016-06-30 2021-08-31 鲁南制药集团股份有限公司 Imidazole derivatives containing four-membered rings
CN107663159A (en) * 2016-07-29 2018-02-06 上海迪诺医药科技有限公司 Polycyclic compound, its pharmaceutical composition and application
WO2018028491A1 (en) * 2016-08-09 2018-02-15 苏州国匡医药科技有限公司 Indoleamine2,3-dioxygenase inhibitors and uses thereof in pharmacy
WO2018045966A1 (en) * 2016-09-12 2018-03-15 广州必贝特医药技术有限公司 Imidazole-containing fused tricyclic compounds and applications thereof
CN108778332B (en) * 2016-10-21 2019-10-18 苏州盛迪亚生物医药有限公司 PD-1 antibody is combined with IDO inhibitor is preparing the purposes in anti-tumor drug
TW201815793A (en) * 2016-10-21 2018-05-01 江蘇恆瑞醫藥股份有限公司 Crystalline form of free alkali of imidazo isoindole derivative and a preparation method thereof
CN106474468B (en) * 2016-11-23 2020-03-27 中国医学科学院医学生物学研究所 Compound adjuvant, vaccine containing compound adjuvant and preparation method of vaccine
WO2018106579A1 (en) * 2016-12-06 2018-06-14 Albert Einstein College Of Medicine, Inc. Drug targeting of human indoleamine 2,3-dioxygenase
DK3559009T3 (en) 2016-12-22 2021-05-03 Calithera Biosciences Inc COMPOSITIONS AND METHODS FOR INHIBITATION OF ARGINASE ACTIVITY
CN108239091B (en) * 2016-12-26 2021-08-13 中国医学科学院药物研究所 Resolution of 1-cyclohexyl-2- (5H-imidazo [5,1-a ] isoindol) ethyl-1-one
JP7364552B2 (en) 2017-08-02 2023-10-18 ザ ユニバーシティ オブ シカゴ Nanoscale metal-organic layers and metal-organic nanoplates for X-ray-induced photodynamic therapy, radiotherapy, radiodynamic therapy, chemotherapy, immunotherapy, and any combination thereof
CN109384791B (en) * 2017-08-09 2020-09-11 江苏恒瑞医药股份有限公司 Crystal form of imidazo isoindole derivative free alkali and preparation method thereof
US11236107B2 (en) 2017-08-18 2022-02-01 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Crystal of tricyclic compound
CN107501272B (en) * 2017-09-05 2020-03-31 中国药科大学 Imidazoisoindole IDO1 inhibitor, and preparation method and application thereof
JP2020534289A (en) 2017-09-14 2020-11-26 ランケナー インスティテュート フォー メディカル リサーチ Methods and compositions for the treatment of cancer
WO2019141095A1 (en) * 2018-01-19 2019-07-25 四川科伦博泰生物医药股份有限公司 Amidine and guanidine derivative, preparation method therefor and medical use thereof
KR20210066857A (en) * 2018-09-27 2021-06-07 쉔젠 칩스크린 바이오사이언스 씨오., 엘티디. Quinoline derivatives having indoleamine-2,3-dioxygenase inhibitory activity
CN111333653A (en) * 2019-12-16 2020-06-26 山东大学 ICD inducer-IDO inhibitor conjugate, preparation method and application
WO2021133920A1 (en) 2019-12-23 2021-07-01 Kymera Therapeutics, Inc. Smarca degraders and uses thereof
CN111803635B (en) * 2020-06-17 2023-03-14 中国医学科学院基础医学研究所 Application of small molecule inhibitor in treating respiratory viral pneumonia
US11839659B2 (en) 2020-07-02 2023-12-12 Northwestern University Proteolysis-targeting chimeric molecules (PROTACs) that induce degradation of indoleamine 2,3-dioxygenase (IDO) protein
WO2022174269A1 (en) 2021-02-15 2022-08-18 Kymera Therapeutics, Inc. Irak4 degraders and uses thereof

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4584013A (en) 1983-05-18 1986-04-22 Ciba-Geigy Corporation Cyclohexanedionecarboxylic acid derivatives with herbicidal and plant growth regulating properties
US5807892A (en) 1994-09-30 1998-09-15 Alcon Laboratories, Inc. Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension
WO1999029310A2 (en) 1997-12-05 1999-06-17 Medical College Of Georgia Research Institute, Inc. Regulation of t cell-mediated immunity by tryptophan and its analogs
WO2003087347A1 (en) 2002-04-12 2003-10-23 Medical College Of Georgia Research Institute, Inc. Antigen-presenting cell populations and their use as reagents for enhancing or reducing immune tolerance
WO2004094409A1 (en) 2003-03-27 2004-11-04 Lankenau Institute For Medical Research Novel ido inhibitors and methods of use
US20040234623A1 (en) 2003-04-01 2004-11-25 Medical College Of Georgia Research Institute, Inc. Use of inhibitors of indoleamine-2,3-dioxygenase in combination with other therapeutic modalities
US20060025383A1 (en) 2004-02-03 2006-02-02 Neil Wishart Aminobenzoxazoles as therapeutic agents
US20080306084A1 (en) 2007-04-30 2008-12-11 Gruenenthal Gmbh Substituted Amide Compounds
WO2009132238A2 (en) * 2008-04-24 2009-10-29 Newlink Genetics Ido inhibitors

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2606783C (en) * 2005-05-10 2014-03-25 Incyte Corporation Modulators of indoleamine 2,3-dioxygenase and methods of using the same
US7705022B2 (en) 2005-10-27 2010-04-27 Lankenau Institute For Medical Research IDO inhibitors and methods of use thereof
JP5294874B2 (en) 2005-12-20 2013-09-18 インサイト・コーポレイション N-hydroxyamidino heterocycle as modulator of indoleamine 2,3-dioxygenase
US8389568B2 (en) 2007-03-16 2013-03-05 Lankenau Institute For Medical Research IDO inhibitors and methods of use thereof
WO2009073620A2 (en) 2007-11-30 2009-06-11 Newlink Genetics Ido inhibitors
WO2009085185A1 (en) 2007-12-19 2009-07-09 Amgen Inc. Fused pyridine, pyrimidine and triazine compounds as cell cycle inhibitors
PT2824100T (en) 2008-07-08 2018-05-10 Incyte Holdings Corp 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
ES2601226T3 (en) 2009-10-28 2017-02-14 Newlink Genetics Corporation Imidazole derivatives as IDO inhibitors
NO2694640T3 (en) * 2011-04-15 2018-03-17
AU2013348167A1 (en) 2012-11-20 2015-05-28 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
WO2014141110A2 (en) 2013-03-14 2014-09-18 Curadev Pharma Pvt. Ltd. Aminonitriles as kynurenine pathway inhibitors
HUE039473T2 (en) 2013-03-14 2019-01-28 Curadev Pharma Private Ltd Inhibitors of the kynurenine pathway
EP2976332B1 (en) 2013-03-14 2018-01-31 Newlink Genetics Corporation Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization.
JP6313416B2 (en) 2013-03-15 2018-04-18 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ IDO inhibitor
WO2014150646A1 (en) 2013-03-15 2014-09-25 Bristol-Myers Squibb Company Ido inhibitors
ES2719327T3 (en) 2013-07-01 2019-07-09 Bristol Myers Squibb Co IDO inhibitors
CN105517999B (en) 2013-07-11 2019-06-28 百时美施贵宝公司 IDO inhibitor

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4584013A (en) 1983-05-18 1986-04-22 Ciba-Geigy Corporation Cyclohexanedionecarboxylic acid derivatives with herbicidal and plant growth regulating properties
US5807892A (en) 1994-09-30 1998-09-15 Alcon Laboratories, Inc. Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension
WO1999029310A2 (en) 1997-12-05 1999-06-17 Medical College Of Georgia Research Institute, Inc. Regulation of t cell-mediated immunity by tryptophan and its analogs
WO2003087347A1 (en) 2002-04-12 2003-10-23 Medical College Of Georgia Research Institute, Inc. Antigen-presenting cell populations and their use as reagents for enhancing or reducing immune tolerance
EP1501918A1 (en) 2002-04-12 2005-02-02 Medical College Of Georgia Research Institute, Inc. Antigen-presenting cell populations and their use as reagents for enhancing or reducing immune tolerance
WO2004094409A1 (en) 2003-03-27 2004-11-04 Lankenau Institute For Medical Research Novel ido inhibitors and methods of use
US20040234623A1 (en) 2003-04-01 2004-11-25 Medical College Of Georgia Research Institute, Inc. Use of inhibitors of indoleamine-2,3-dioxygenase in combination with other therapeutic modalities
US20060025383A1 (en) 2004-02-03 2006-02-02 Neil Wishart Aminobenzoxazoles as therapeutic agents
US20080306084A1 (en) 2007-04-30 2008-12-11 Gruenenthal Gmbh Substituted Amide Compounds
WO2009132238A2 (en) * 2008-04-24 2009-10-29 Newlink Genetics Ido inhibitors

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
"Physicians' Desk Reference", 1996, MEDICAL ECONOMICS COMPANY
BIOORG. MED. CHEM. LETT., vol. 18, 2008, pages 5280 - 5284
BROWN ET AL., ADV. EXP. MED. BIOL., vol. 294, 1991, pages 425 - 35
CHEM. - EUR. J., vol. 10, 2004, pages 5233 - 5242
GROHMANN ET AL., TRENDS IMMUNOL., vol. 24, 2003, pages 242 - 8
J. AGRIC. FOOD CHEM., vol. 56, 2008, pages 5247 - 5253
KUMAR S ET AL: "Structure based development of phenylimidazole-derived inhibitors of indoleamine 2,3-dioxygenase", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 51, no. 16, 28 August 2008 (2008-08-28), pages 4968 - 4977, XP002558480, ISSN: 0022-2623, [retrieved on 20080730], DOI: 10.1021/JM800512Z *
LOGAN ET AL., IMMUNOLOGY, vol. 105, 2002, pages 478 - 87
MEDAWAR, SYMP. SOC. EXP. BIOL., vol. 7, 1953, pages 320 - 38
MULLER, NATURE MED., vol. 11, 2005, pages 312 - 9
MUNN ET AL., J. CLIN. INVEST., vol. 114, no. 2, 2004, pages 280 - 90
MUNN ET AL., SCIENCE, vol. 281, 1998, pages 1191 - 3
MUNN ET AL., SCIENCE, vol. 297, 2002, pages 1867 - 70
PHOSPHORUS, SULFUR SILICON RELAT. ELEM., vol. I55, 1999, pages 67 - 80
PORTULA ET AL., BLOOD, vol. 106, 2005, pages 2382 - 90
SYNTH. COMM., vol. 37, 2007, pages 2989 - 2994
UYTTENHOVE ET AL., NATURE MED., vol. 9, 2003, pages 1269 - 74

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US10233190B2 (en) 2011-04-15 2019-03-19 Newlink Genetics Corporation IDO inhibitors
US9850248B2 (en) 2011-04-15 2017-12-26 Newlink Genetics Corporation IDO inhibitors
CN105189466A (en) * 2013-03-14 2015-12-23 新联基因公司 Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
JP2016519056A (en) * 2013-03-14 2016-06-30 ニューリンク ジェネティクス コーポレイション Inhibitors of immunosuppression mediated by tryptophan metabolism
EP3366678A1 (en) 2013-03-14 2018-08-29 Newlink Genetics Corporation Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
US9981973B2 (en) 2013-03-14 2018-05-29 Newlink Genetics Corporation Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
RU2667509C2 (en) * 2013-03-14 2018-09-21 Ньюлинк Джинетикс Корпорейшин Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
AU2014241079C1 (en) * 2013-03-14 2017-07-06 Newlink Genetics Corporation Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
US9815811B2 (en) 2013-03-14 2017-11-14 Curadev Pharma, Pvt. Ltd. Inhibitors of the kynurenine pathway
US10294212B2 (en) 2013-03-14 2019-05-21 Curadev Pharma, Pvt. Ltd. Inhibitors of the kynurenine pathway
US9617272B2 (en) 2013-03-14 2017-04-11 Newlink Genetics Corporation Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
JP2016518329A (en) * 2013-03-14 2016-06-23 キュラデブ ファーマ プライベート リミテッド Inhibitors of the kynurenine pathway
JP2017052786A (en) * 2013-03-14 2017-03-16 ニューリンク ジェネティクス コーポレイション Inhibitor of immunosuppression mediated by tryptophan metabolism
AU2014241079A1 (en) * 2013-03-14 2015-09-03 Newlink Genetics Corporation Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
EP2970173A4 (en) * 2013-03-14 2016-08-03 Curadev Pharma Private Ltd Inhibitors of the kynurenine pathway
WO2014159248A1 (en) 2013-03-14 2014-10-02 Newlink Genetics Corporation Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
AU2014241079B2 (en) * 2013-03-14 2016-12-15 Newlink Genetics Corporation Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
CN103382187B (en) * 2013-08-06 2015-06-03 信实生物医药（上海）有限公司 3-chloro-7(5)-bromo-benzo-isoxazole compounding method
CN103382187A (en) * 2013-08-06 2013-11-06 信实生物医药（上海）有限公司 3-chloro-7(5)-bromo-benzo-isoxazole compounding method
EP3466949A1 (en) 2013-12-24 2019-04-10 Bristol-Myers Squibb Company Tricyclic compound as anticancer agents
WO2015100282A1 (en) 2013-12-24 2015-07-02 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
EP3610924A1 (en) 2014-06-06 2020-02-19 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
WO2015187835A2 (en) 2014-06-06 2015-12-10 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
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US10329297B2 (en) 2014-09-05 2019-06-25 Merck Patent Gmbh Compounds for the inhibition of indoleamine-2,3-dioxygenase
AU2015311826B2 (en) * 2014-09-05 2019-05-23 Merck Patent Gmbh Cyclohexyl-ethyl substituted diaza- and triaza-tricyclic compounds as indole-amine-2,3-dioxygenase (IDO) antagonists for the treatment of cancer
CN107074859A (en) * 2014-09-05 2017-08-18 默克专利有限公司 Indoleamine 2, the diaza and three aza-tricycle compounds of the cyclohexyl-ethyl substitution of 3 dioxygenases (IDO) antagonist are used as treating cancer
US9771370B2 (en) 2014-09-05 2017-09-26 Merck Patent Gmbh Compounds for the inhibition of indoleamine-2,3-dioxygenase
WO2016037026A1 (en) * 2014-09-05 2016-03-10 Merck Patent Gmbh Cyclohexyl-ethyl substituted diaza- and triaza-tricyclic compounds as indole-amine-2,3-dioxygenase (ido) antagonists for the treatment of cancer
WO2016051181A1 (en) * 2014-10-01 2016-04-07 Redx Pharma Plc 4h-imidazo[1,5-a]indole derivatives and their use as indoleamine 2,3-dioxygenase (ido) and/or tryptophan 2,3-dioxygenase (td02) modulators
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EP3725808A1 (en) 2014-11-21 2020-10-21 Bristol-Myers Squibb Company Antibodies against cd73 and uses thereof
WO2016081748A2 (en) 2014-11-21 2016-05-26 Bristol-Myers Squibb Company Antibodies against cd73 and uses thereof
US10525035B2 (en) 2014-12-18 2020-01-07 Lankenau Institute For Medical Research Methods and compositions for the treatment of retinopathy and other ocular diseases
US11564907B2 (en) 2014-12-18 2023-01-31 Lankenau Institute For Medical Research Methods and compositions for the treatment of retinopathy and other ocular diseases
US11376236B2 (en) 2014-12-18 2022-07-05 Lankenau Institute For Medical Research Methods and compositions for the treatment of retinopathy and other ocular diseases
US11564906B2 (en) 2014-12-18 2023-01-31 Lankenau Institute For Medical Research Methods and compositions for the treatment of retinopathy and other ocular diseases
WO2016106266A1 (en) 2014-12-22 2016-06-30 Bristol-Myers Squibb Company TGFβ RECEPTOR ANTAGONISTS
EP4249066A2 (en) 2014-12-23 2023-09-27 Bristol-Myers Squibb Company Antibodies to tigit
WO2016127052A1 (en) 2015-02-05 2016-08-11 Bristol-Myers Squibb Company Cxcl11 and smica as predictive biomarkers for efficacy of anti-ctla4 immunotherapy
AU2016222140B2 (en) * 2015-02-16 2019-10-24 Shanghai De Novo Pharmatech Co., Ltd. Fused-ring compounds, pharmaceutical composition and uses thereof
WO2016131381A1 (en) * 2015-02-16 2016-08-25 Shanghai De Novo Pharmatech Co. Ltd. Fused-ring compounds, pharmaceutical composition and uses thereof
WO2016140884A1 (en) 2015-03-02 2016-09-09 Rigel Pharmaceuticals, Inc. TGF-β INHIBITORS
WO2016161269A1 (en) 2015-04-03 2016-10-06 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer
US9790169B2 (en) 2015-04-03 2017-10-17 Bristol-Myers Squibb Company IDO inhibitors
US10399933B2 (en) 2015-04-03 2019-09-03 Bristol-Myers Squibb Company Inhibitors of indoleamine-2,3-dioxygenase for the treatment of cancer
US10167254B2 (en) 2015-04-03 2019-01-01 Bristol-Myers Squibb Company IDO inhibitors
WO2016161279A1 (en) 2015-04-03 2016-10-06 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer
US10399932B2 (en) 2015-04-03 2019-09-03 Bristol-Myers Squibb Company Inhibitors of indoleamine-2,3-dioxygenase for the treatment of cancer
WO2016162505A1 (en) 2015-04-08 2016-10-13 F-Star Biotechnology Limited Her2 binding agent therapies
TWI698435B (en) * 2015-04-10 2020-07-11 英屬開曼群島商百濟神州有限公司 NOVEL 5 or 8-SUBSTITUTED IMIDAZO[1,5-a]PYRIDINES AS INDOLEAMINE AND/OR TRYPTOPHANE 2,3-DIOXYGENASES
CN110872289A (en) * 2015-04-10 2020-03-10 百济神州(北京)生物科技有限公司 Novel 8-substituted imidazo [1,5-a ] pyridines as IDO1 and/or TDO inhibitors
US10358451B2 (en) 2015-04-12 2019-07-23 Hangzhou Innogate Pharma Co., Ltd. Heterocycles useful as IDO and TDO inhibitors
WO2016165613A1 (en) 2015-04-12 2016-10-20 Hangzhou Innogate Pharma Co., Ltd. Heterocycles useful as ido and tdo inhibitors
EP3964527A2 (en) 2015-04-13 2022-03-09 Five Prime Therapeutics, Inc. Combination therapy for cancer
WO2016168149A1 (en) 2015-04-13 2016-10-20 Five Prime Therapeutics, Inc. Combination therapy for cancer
WO2016169421A1 (en) * 2015-04-21 2016-10-27 江苏恒瑞医药股份有限公司 Imidazo isoindole derivative, preparation method therefor and medical use thereof
RU2717577C2 (en) * 2015-04-21 2020-03-24 Цзянсу Хэнжуй Медицин Ко., Лтд. Imidazoisoindole derivative, method for production thereof and medical use
US10899764B2 (en) 2015-04-21 2021-01-26 Jiangsu Hengrui Medicine Co., Ltd. Imidazo isoindole derivative, preparation method therefor and medical use thereof
WO2016183114A1 (en) 2015-05-11 2016-11-17 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
WO2016183115A1 (en) 2015-05-12 2016-11-17 Bristol-Myers Squibb Company 5h-pyrido[3,2-b]indole compounds as anticancer agents
WO2016183118A1 (en) 2015-05-12 2016-11-17 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
WO2016196228A1 (en) 2015-05-29 2016-12-08 Bristol-Myers Squibb Company Antibodies against ox40 and uses thereof
GB2548542A (en) * 2015-06-16 2017-09-27 Redx Pharma Plc Compounds
WO2017004016A1 (en) 2015-06-29 2017-01-05 The Rockefeller University Antibodies to cd40 with enhanced agonist activity
WO2017009842A2 (en) 2015-07-16 2017-01-19 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
EP3943098A2 (en) 2015-07-16 2022-01-26 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
EP3744340A2 (en) 2015-07-16 2020-12-02 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
EP3954369A1 (en) 2015-07-24 2022-02-16 Lumos Pharma, Inc. Salts and prodrugs of 1-methyl-d-tryptophan
US11485705B2 (en) 2015-07-24 2022-11-01 Lumos Pharma, Inc. Salts and prodrugs of 1-methyl-d-tryptophan
US10207990B2 (en) 2015-07-24 2019-02-19 Newlink Genetics Corporation Salts and prodrugs of 1-methyl-D-tryptophan
US9732035B2 (en) 2015-07-24 2017-08-15 Newlink Genetics Corporation Salts and prodrugs of 1-methyl-D-tryptophan
WO2017019175A1 (en) 2015-07-24 2017-02-02 Newlink Genetics Corporation Salts and prodrugs of 1-methyl-d-tryptophan
EP3613420A1 (en) 2015-07-24 2020-02-26 Newlink Genetics Corporation Salts and prodrugs of 1-methyl-d-tryptophan
WO2017019757A1 (en) 2015-07-28 2017-02-02 Bristol-Myers Squibb Company Tgf beta receptor antagonists
WO2017035118A1 (en) 2015-08-25 2017-03-02 Bristol-Myers Squibb Company Tgf beta receptor antagonists
WO2017079117A1 (en) 2015-11-02 2017-05-11 Five Prime Therapeutics, Inc. Cd80 extracellular domain polypeptides and their use in cancer treatment
WO2017087678A2 (en) 2015-11-19 2017-05-26 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
WO2017091577A1 (en) 2015-11-23 2017-06-01 Five Prime Therapeutics, Inc. Fgfr2 inhibitors alone or in combination with immune stimulating agents in cancer treatment
WO2017091580A1 (en) 2015-11-23 2017-06-01 Five Prime Therapeutics, Inc. Predicting response to cancer treatment with fgfr2 inhibitors
WO2017106291A1 (en) 2015-12-15 2017-06-22 Bristol-Myers Squibb Company Cxcr4 receptor antagonists
JP7227005B2 (en) 2015-12-24 2023-02-21 ジェネンテック， インコーポレイテッド TDO2 inhibitor
WO2017107979A1 (en) 2015-12-24 2017-06-29 Genentech, Inc. Tdo2 inhibitors
US10800780B2 (en) 2015-12-24 2020-10-13 Genentech, Inc. TDO2 Inhibitors
US20190016726A1 (en) * 2015-12-24 2019-01-17 Genentech, Inc. TDO2 Inhibitors
JP2019504039A (en) * 2015-12-24 2019-02-14 ジェネンテック， インコーポレイテッド TDO2 inhibitor
US20220306635A1 (en) * 2015-12-24 2022-09-29 Genentech, Inc. TDO2 Inhibitors
CN110072864A (en) * 2015-12-24 2019-07-30 基因泰克公司 TDO2 inhibitor
CN109071548A (en) * 2016-02-02 2018-12-21 埃姆库瑞医药品有限公司 It can be used for treating the pyrroles's benzimidazole derivative or its analog of especially cancer
WO2017134555A1 (en) 2016-02-02 2017-08-10 Emcure Pharmaceuticals Limited Derivatives of pyrroloimidazole or analogues thereof which are useful for the treatment of inter alia cancer
EP3418282A4 (en) * 2016-02-19 2019-01-09 Chai Tai Tianqing Pharmaceutical Group Co., Ltd. Tricyclic compound serving as immunomodulator
WO2017140835A1 (en) 2016-02-19 2017-08-24 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of obesity
WO2017140272A1 (en) * 2016-02-19 2017-08-24 正大天晴药业集团股份有限公司 Tricyclic compound acting as immunomodulator
US10487088B2 (en) 2016-02-19 2019-11-26 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Tricyclic compound serving as immunomodulator
CN108884103A (en) * 2016-02-19 2018-11-23 正大天晴药业集团股份有限公司 Three and cycle compound as immunomodulator
CN108884104B (en) * 2016-02-19 2021-01-15 正大天晴药业集团股份有限公司 Tricyclic compounds as immunomodulators
CN108884103B (en) * 2016-02-19 2021-01-15 正大天晴药业集团股份有限公司 Tricyclic compounds as immunomodulators
CN108884104A (en) * 2016-02-19 2018-11-23 正大天晴药业集团股份有限公司 Three and cycle compound as immunomodulator
TWI743088B (en) * 2016-02-19 2021-10-21 大陸商正大天晴藥業集團股份有限公司 Triadic compounds as immunomodulators
WO2017149469A1 (en) 2016-03-03 2017-09-08 Emcure Pharmaceuticals Limited Heterocyclic compounds useful as ido and/or tdo modulators
WO2017152085A1 (en) 2016-03-04 2017-09-08 Bristol-Myers Squibb Company Combination therapy with anti-cd73 antibodies
WO2017184619A2 (en) 2016-04-18 2017-10-26 Celldex Therapeutics, Inc. Agonistic antibodies that bind human cd40 and uses thereof
US10544099B2 (en) 2016-05-04 2020-01-28 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11066383B2 (en) 2016-05-04 2021-07-20 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US10323004B2 (en) 2016-05-04 2019-06-18 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US10696648B2 (en) 2016-05-04 2020-06-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US10633342B2 (en) 2016-05-04 2020-04-28 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2017197055A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Heterocyclic degronimers for target protein degradation
WO2017197036A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Spirocyclic degronimers for target protein degradation
WO2017197046A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
WO2017198159A1 (en) * 2016-05-16 2017-11-23 鲁南制药集团股份有限公司 Imidazole derivative containing bridge ring
TWI671294B (en) * 2016-06-10 2019-09-11 美商美國禮來大藥廠 2,3-dihydro-1h-indole compounds
US9872853B2 (en) 2016-06-10 2018-01-23 Eli Lilly And Company 2,3-dihydro-1H-indole compounds
WO2017213919A1 (en) 2016-06-10 2017-12-14 Eli Lilly And Company 1-tetrahydropyranylcarbonyl-2,3-dihydro-1h-indole compounds for treating cancer
US10759786B2 (en) 2016-06-10 2020-09-01 Eli Lilly And Company 1-tetrahydropyranylcarbonyl-2,3-dihydro-1H-indole compounds for treating cancer
WO2018013818A2 (en) 2016-07-14 2018-01-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
WO2018017633A1 (en) 2016-07-21 2018-01-25 Bristol-Myers Squibb Company TGF Beta RECEPTOR ANTAGONISTS
US11351164B2 (en) 2016-08-26 2022-06-07 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US10508085B2 (en) 2016-09-22 2019-12-17 Plexxikon Inc. Compounds and methods for IDO and TDO modulation, and indications therefor
US10882856B2 (en) 2016-09-24 2021-01-05 Beigene, Ltd. 5 or 8-substituted imidazo [1,5-a] pyridines as selective inhibitors of indoleamine and/or tryptophane 2,3-dioxygenases
WO2018054365A1 (en) 2016-09-24 2018-03-29 Beigene, Ltd. NOVEL 5 or 8-SUBSTITUTED IMIDAZO [1, 5-a] PYRIDINES AS SELECTIVE INHIBITORS OF INDOLEAMINE AND/OR TRYPTOPHANE 2, 3-DIOXYGENASES
US11896615B2 (en) 2016-10-13 2024-02-13 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
EP4190335A1 (en) 2016-10-13 2023-06-07 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
WO2018071873A2 (en) 2016-10-13 2018-04-19 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
WO2018083635A2 (en) 2016-11-04 2018-05-11 Auckland Uniservices Limited Tricyclic heterocyclic derivatives and uses thereof
US11028064B2 (en) 2016-11-04 2021-06-08 Auckland Uniservices Limited Tricyclic heterocyclic derivatives and uses thereof
TWI671302B (en) * 2016-12-20 2019-09-11 大陸商深圳微芯生物科技有限責任公司 Fused imidazole compounds that may inhibit indoleamine 2,3-dioxygenase
EP3560928A4 (en) * 2016-12-20 2020-09-16 Shenzhen Chipscreen Biosciences Co., Ltd. Fused imidazole compound having indoleamine 2,3-dioxygenase inhibitory activity
WO2018132279A1 (en) 2017-01-05 2018-07-19 Bristol-Myers Squibb Company Tgf beta receptor antagonists
US11173145B2 (en) 2017-01-17 2021-11-16 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
WO2018175954A1 (en) 2017-03-23 2018-09-27 F. Hoffmann-La Roche Ag Synthesis of imidazo[5,1-a]isoindole derivative useful as ido inhibitors
WO2018183608A1 (en) 2017-03-31 2018-10-04 Five Prime Therapeutics, Inc. Combination therapy for cancer using anti-gitr antibodies
WO2018187613A2 (en) 2017-04-07 2018-10-11 Bristol-Myers Squibb Company Anti-icos agonist antibodies and uses thereof
WO2018195397A2 (en) 2017-04-21 2018-10-25 Kyn Therapeutics Indole ahr inhibitors and uses thereof
US11358969B2 (en) 2017-04-21 2022-06-14 Ikena Oncology, Inc. Indole AHR inhibitors and uses thereof
US10570138B2 (en) 2017-04-21 2020-02-25 Kyn Therapeutics Indole AHR inhibitors and uses thereof
US10689388B1 (en) 2017-04-21 2020-06-23 Ikena Oncology, Inc. Indole AHR inhibitors and uses thereof
WO2018201014A1 (en) 2017-04-28 2018-11-01 Five Prime Therapeutics, Inc. Methods of treatment with cd80 extracellular domain polypeptides
US11066392B2 (en) 2017-05-12 2021-07-20 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2018209049A1 (en) 2017-05-12 2018-11-15 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN107176956B (en) * 2017-05-31 2019-11-12 成都海博锐药业有限公司 A kind of IDO inhibitor compound, Pharmaceutical composition, purposes
CN107176956A (en) * 2017-05-31 2017-09-19 成都海博锐药业有限公司 A kind of IDO inhibitor compound, Pharmaceutical composition, purposes
WO2019006047A1 (en) 2017-06-28 2019-01-03 Genentech, Inc. Tdo2 and ido1 inhibitors
US11827639B2 (en) 2017-06-28 2023-11-28 Genentech, Inc. TDO2 and IDO1 inhibitors
WO2019005559A1 (en) 2017-06-28 2019-01-03 Genentech, Inc. Tdo2 and ido1 inhibitors
WO2019006283A1 (en) 2017-06-30 2019-01-03 Bristol-Myers Squibb Company Amorphous and crystalline forms of ido inhibitors
US11236049B2 (en) 2017-06-30 2022-02-01 Bristol-Myers Squibb Company Amorphous and crystalline forms of IDO inhibitors
WO2019023459A1 (en) 2017-07-28 2019-01-31 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
CN109983019A (en) * 2017-08-08 2019-07-05 江苏恒瑞医药股份有限公司 A kind of preparation method of imidazo isoindoles derivative
WO2019029507A1 (en) * 2017-08-08 2019-02-14 江苏恒瑞医药股份有限公司 Preparation method for imidazoisoindole derivatives
CN109983019B (en) * 2017-08-08 2021-12-21 江苏恒瑞医药股份有限公司 Preparation method of imidazo isoindole derivative
US11555026B2 (en) 2017-08-17 2023-01-17 Ikena Oncology, Inc. AHR inhibitors and uses thereof
WO2019034725A1 (en) 2017-08-17 2019-02-21 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
US10696650B2 (en) 2017-08-17 2020-06-30 Ikena Oncology, Inc. AHR inhibitors and uses thereof
US11267824B2 (en) 2017-08-17 2022-03-08 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
WO2019046498A1 (en) 2017-08-31 2019-03-07 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
WO2019046500A1 (en) 2017-08-31 2019-03-07 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
WO2019046496A1 (en) 2017-08-31 2019-03-07 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
US11623932B2 (en) 2017-09-22 2023-04-11 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US11358948B2 (en) 2017-09-22 2022-06-14 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
WO2019074822A1 (en) 2017-10-09 2019-04-18 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11649212B2 (en) 2017-10-09 2023-05-16 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2019074824A1 (en) 2017-10-09 2019-04-18 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11203592B2 (en) 2017-10-09 2021-12-21 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2019075090A1 (en) 2017-10-10 2019-04-18 Tilos Therapeutics, Inc. Anti-lap antibodies and uses thereof
WO2019074887A1 (en) 2017-10-10 2019-04-18 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
US11230601B2 (en) 2017-10-10 2022-01-25 Tilos Therapeutics, Inc. Methods of using anti-lap antibodies
WO2019079261A1 (en) 2017-10-16 2019-04-25 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
WO2019089921A1 (en) 2017-11-01 2019-05-09 Bristol-Myers Squibb Company Immunostimulatory agonistic antibodies for use in treating cancer
WO2019090198A1 (en) 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Isofuranone compounds useful as hpk1 inhibitors
US11472788B2 (en) 2017-11-25 2022-10-18 Beigene, Ltd. Benzoimidazoles as selective inhibitors of indoleamine 2,3-dioxygenases
US10874743B2 (en) 2017-12-26 2020-12-29 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11318205B1 (en) 2017-12-26 2022-05-03 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11723980B2 (en) 2017-12-26 2023-08-15 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
WO2019133747A1 (en) 2017-12-27 2019-07-04 Bristol-Myers Squibb Company Anti-cd40 antibodies and uses thereof
US11306149B2 (en) 2017-12-27 2022-04-19 Bristol-Myers Squibb Company Anti-CD40 antibodies and uses thereof
US11952427B2 (en) 2017-12-27 2024-04-09 Bristol-Myers Squibb Company Anti-CD40 antibodies and uses thereof
US11447449B2 (en) 2018-01-05 2022-09-20 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2019136112A1 (en) 2018-01-05 2019-07-11 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2019140229A1 (en) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
US11485743B2 (en) 2018-01-12 2022-11-01 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US11512080B2 (en) 2018-01-12 2022-11-29 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
WO2019138107A1 (en) 2018-01-15 2019-07-18 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
US10988477B2 (en) 2018-01-29 2021-04-27 Merck Patent Gmbh GCN2 inhibitors and uses thereof
US10793563B2 (en) 2018-01-29 2020-10-06 Merck Patent Gmbh GCN2 inhibitors and uses thereof
WO2019160884A1 (en) 2018-02-13 2019-08-22 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
WO2019173587A1 (en) 2018-03-08 2019-09-12 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
US11149011B2 (en) 2018-03-20 2021-10-19 Plexxikon Inc. Compounds and methods for IDO and TDO modulation, and indications therefor
WO2019183040A1 (en) 2018-03-21 2019-09-26 Five Prime Therapeutics, Inc. ANTIBODIES BINDING TO VISTA AT ACIDIC pH
US11242393B2 (en) 2018-03-23 2022-02-08 Bristol-Myers Squibb Company Antibodies against MICA and/or MICB and uses thereof
WO2019200256A1 (en) 2018-04-12 2019-10-17 Bristol-Myers Squibb Company Anticancer combination therapy with cd73 antagonist antibody and pd-1/pd-l1 axis antagonist antibody
WO2019204257A1 (en) 2018-04-16 2019-10-24 Arrys Therapeutics, Inc. Ep4 inhibitors and use thereof
WO2019213340A1 (en) 2018-05-03 2019-11-07 Bristol-Myers Squibb Company Uracil derivatives as mer-axl inhibitors
WO2019243832A1 (en) 2018-06-22 2019-12-26 Bicycletx Limited Bicyclic peptide ligands specific for nectin-4
US11912792B2 (en) 2018-06-22 2024-02-27 Bicycletx Limited Bicyclic peptide ligands specific for nectin-4
US11180531B2 (en) 2018-06-22 2021-11-23 Bicycletx Limited Bicyclic peptide ligands specific for Nectin-4
US11453702B2 (en) 2018-06-22 2022-09-27 Bicycletx Limited Bicyclic peptide ligands specific for Nectin-4
WO2019243833A1 (en) 2018-06-22 2019-12-26 Bicycletx Limited Bicyclic peptide ligands specific for nectin-4
WO2020006018A1 (en) 2018-06-27 2020-01-02 Bristol-Myers Squibb Company Substituted naphthyridinone compounds useful as t cell activators
WO2020006016A1 (en) 2018-06-27 2020-01-02 Bristol-Myers Squibb Company Naphthyridinone compounds useful as t cell activators
US11897882B2 (en) 2018-07-06 2024-02-13 Kymera Therapeutics, Inc. Tricyclic crbn ligands and uses thereof
WO2020010177A1 (en) 2018-07-06 2020-01-09 Kymera Therapeutics, Inc. Tricyclic crbn ligands and uses thereof
US11292792B2 (en) 2018-07-06 2022-04-05 Kymera Therapeutics, Inc. Tricyclic CRBN ligands and uses thereof
WO2020014132A2 (en) 2018-07-09 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to ilt4
US11401328B2 (en) 2018-07-09 2022-08-02 Five Prime Therapeutics, Inc. Antibodies binding to ILT4
WO2020014327A2 (en) 2018-07-11 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to vista at acidic ph
US11046649B2 (en) 2018-07-17 2021-06-29 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
WO2020023355A1 (en) 2018-07-23 2020-01-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2020023356A1 (en) 2018-07-23 2020-01-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US10959986B2 (en) 2018-08-29 2021-03-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11253525B2 (en) 2018-08-29 2022-02-22 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2020051424A1 (en) 2018-09-07 2020-03-12 Pic Therapeutics Eif4e inhibitors and uses thereof
WO2020076969A2 (en) 2018-10-10 2020-04-16 Tilos Therapeutics, Inc. Anti-lap antibody variants and uses thereof
US11130802B2 (en) 2018-10-10 2021-09-28 Tilos Therapeutics, Inc. Anti-lap antibody variants
WO2020102501A1 (en) 2018-11-16 2020-05-22 Bristol-Myers Squibb Company Anti-nkg2a antibodies and uses thereof
US11352350B2 (en) 2018-11-30 2022-06-07 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11807636B2 (en) 2018-11-30 2023-11-07 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11117889B1 (en) 2018-11-30 2021-09-14 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
EP3670659A1 (en) 2018-12-20 2020-06-24 Abivax Biomarkers, and uses in treatment of viral infections, inflammations, or cancer
WO2020127853A1 (en) 2018-12-20 2020-06-25 Abivax Biomarkers, and uses in treatment of viral infections, inflammations, or cancer
WO2020132561A1 (en) 2018-12-20 2020-06-25 C4 Therapeutics, Inc. Targeted protein degradation
WO2020187998A1 (en) 2019-03-19 2020-09-24 Fundació Privada Institut D'investigació Oncològica De Vall Hebron Combination therapy with omomyc and an antibody binding pd-1 or ctla-4 for the treatment of cancer
WO2020201753A1 (en) 2019-04-02 2020-10-08 Bicycletx Limited Bicycle toxin conjugates and uses thereof
US11485750B1 (en) 2019-04-05 2022-11-01 Kymera Therapeutics, Inc. STAT degraders and uses thereof
US11746120B2 (en) 2019-04-05 2023-09-05 Kymera Therapeutics, Inc. Stat degraders and uses thereof
WO2020231713A1 (en) 2019-05-13 2020-11-19 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
WO2020231766A1 (en) 2019-05-13 2020-11-19 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
WO2020243423A1 (en) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2021005222A1 (en) 2019-07-11 2021-01-14 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
WO2021026179A1 (en) 2019-08-06 2021-02-11 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
WO2021041588A1 (en) 2019-08-28 2021-03-04 Bristol-Myers Squibb Company Substituted pyridopyrimidinonyl compounds useful as t cell activators
US11021481B2 (en) 2019-09-13 2021-06-01 Nimbus Saturn, Inc. Substituted isoindolin-1-ones and 2,3-dihydro-1h-pyrrolo[3,4-c]pyridin-1-ones as HPK1 antagonists
US11034694B2 (en) 2019-09-13 2021-06-15 Nimbus Saturn, Inc. Substituted isoindolin-1-ones and 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-ones as HPK1 antagonists
US11548890B1 (en) 2019-09-13 2023-01-10 Nimbus Saturn, Inc. HPK1 antagonists and uses thereof
US11078201B2 (en) 2019-09-13 2021-08-03 Nimbus Saturn, Inc. Substituted isoindolin-1-ones and 2,3-dihydro-1H-pyrrol[3,4-c]pyridin-1-ones as HPK1 antagonists
US11028085B2 (en) 2019-09-13 2021-06-08 Nimbus Saturn, Inc. Substituted isoindolin-1-ones and 2,3-dihydro-1h-pyrrolo[3,4-c]pyridin-1-ones as hpk1 antagonists
WO2021055698A1 (en) 2019-09-19 2021-03-25 Bristol-Myers Squibb Company Antibodies binding to vista at acidic ph
WO2021101919A1 (en) 2019-11-19 2021-05-27 Bristol-Myers Squibb Company Compounds useful as inhibitors of helios protein
WO2021108288A1 (en) 2019-11-26 2021-06-03 Bristol-Myers Squibb Company Salts/cocrystals of (r)-n-(4-chlorophenyl)-2-((1s,4s)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide
US11591339B2 (en) 2019-11-26 2023-02-28 Ikena Oncology, Inc. Solid forms of (R)-N-(2-(5-fluoropyridin-3-yl)-8-isopropylpyrazolo[ 1,5-a][1,3,5]triazin-4-yl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine maleate as aryl hydrocarbon receptor (AHR) inhibitors
WO2021108528A1 (en) 2019-11-26 2021-06-03 Ikena Oncology, Inc. Polymorphic carbazole derivatives and uses thereof
US11779578B2 (en) 2019-12-17 2023-10-10 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11707457B2 (en) 2019-12-17 2023-07-25 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11591332B2 (en) 2019-12-17 2023-02-28 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
WO2021133750A1 (en) 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted bicyclic piperidine derivatives useful as t cell activators
WO2021133752A1 (en) 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted heteroaryl compounds useful as t cell activators
WO2021133748A1 (en) 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted quinolinonyl piperazine compounds useful as t cell activators
WO2021133751A1 (en) 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted quinazolinyl compounds useful as t cell activators
WO2021133749A1 (en) 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted piperazine derivatives useful as t cell activators
WO2021141907A1 (en) 2020-01-06 2021-07-15 Hifibio (Hong Kong) Limited Anti-tnfr2 antibody and uses thereof
WO2021139682A1 (en) 2020-01-07 2021-07-15 Hifibio (Hk) Limited Anti-galectin-9 antibody and uses thereof
WO2021146370A1 (en) 2020-01-15 2021-07-22 Blueprint Medicines Corporation Map4k1 inhibitors
WO2021178488A1 (en) 2020-03-03 2021-09-10 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
WO2021183428A1 (en) 2020-03-09 2021-09-16 Bristol-Myers Squibb Company Antibodies to cd40 with enhanced agonist activity
US11932624B2 (en) 2020-03-19 2024-03-19 Kymera Therapeutics, Inc. MDM2 degraders and uses thereof
WO2021194914A1 (en) 2020-03-23 2021-09-30 Bristol-Myers Squibb Company Substituted oxoisoindoline compounds for the treatment of cancer
WO2021207449A1 (en) 2020-04-09 2021-10-14 Merck Sharp & Dohme Corp. Affinity matured anti-lap antibodies and uses thereof
WO2021231732A1 (en) 2020-05-15 2021-11-18 Bristol-Myers Squibb Company Antibodies to garp
US11685750B2 (en) 2020-06-03 2023-06-27 Kymera Therapeutics, Inc. Crystalline forms of IRAK degraders
WO2021258010A1 (en) 2020-06-19 2021-12-23 Gossamer Bio Services, Inc. Oxime compounds useful as t cell activators
US11857535B2 (en) 2020-07-30 2024-01-02 Kymera Therapeutics, Inc. Methods of treating mutant lymphomas
WO2022033419A2 (en) 2020-08-10 2022-02-17 Shanghai Xbh Biotechnology Co., Ltd. Compositions and methods for treating autoimmune diseases and cancers by targeting igsf8
WO2022038158A1 (en) 2020-08-17 2022-02-24 Bicycletx Limited Bicycle conjugates specific for nectin-4 and uses thereof
WO2022081718A1 (en) 2020-10-14 2022-04-21 Five Prime Therapeutics, Inc. Anti-c-c chemokine receptor 8 (ccr8) antibodies and methods of use thereof
WO2022120353A1 (en) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2022120354A1 (en) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2022133083A1 (en) 2020-12-16 2022-06-23 Gossamer Bio Services, Inc. Compounds useful as t cell activators
WO2022148979A1 (en) 2021-01-11 2022-07-14 Bicycletx Limited Methods for treating cancer
WO2022167445A1 (en) 2021-02-02 2022-08-11 Liminal Biosciences Limited Gpr84 antagonists and uses thereof
WO2022167457A1 (en) 2021-02-02 2022-08-11 Liminal Biosciences Limited Gpr84 antagonists and uses thereof
WO2022169921A1 (en) 2021-02-04 2022-08-11 Bristol-Myers Squibb Company Benzofuran compounds as sting agonists
WO2022171745A1 (en) 2021-02-12 2022-08-18 F. Hoffmann-La Roche Ag Bicyclic tetrahydroazepine derivatives for the treatment of cancer
EP4052705A1 (en) 2021-03-05 2022-09-07 Universität Basel Vizerektorat Forschung Compositions for the treatment of ebv associated diseases or conditions
WO2022184930A2 (en) 2021-03-05 2022-09-09 Universität Basel Compositions for the treatment of ebv associated diseases or conditions
US11926625B2 (en) 2021-03-05 2024-03-12 Nimbus Saturn, Inc. HPK1 antagonists and uses thereof
WO2022192145A1 (en) 2021-03-08 2022-09-15 Blueprint Medicines Corporation Map4k1 inhibitors
WO2022197641A1 (en) 2021-03-15 2022-09-22 Rapt Therapeutics, Inc. 1h-pyrazolo[3,4-d]pyrimidin-6-yl-amine derivatives as hematopoietic progenitor kinase 1 (hpk1) modulators and/or inhibitors for the treatment of cancer and other diseases
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
WO2022216573A1 (en) 2021-04-05 2022-10-13 Bristol-Myers Squibb Company Pyridinyl substituted oxoisoindoline compounds for the treatment of cancer
WO2022216644A1 (en) 2021-04-06 2022-10-13 Bristol-Myers Squibb Company Pyridinyl substituted oxoisoindoline compounds
WO2022221866A1 (en) 2021-04-16 2022-10-20 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2023288254A1 (en) 2021-07-14 2023-01-19 Blueprint Medicines Corporation Heterocyclic compounds as map4k1 inhibitors
WO2023288264A1 (en) 2021-07-15 2023-01-19 Blueprint Medicines Corporation Map4k1 inhibitors
WO2023028238A1 (en) 2021-08-25 2023-03-02 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
WO2023028235A1 (en) 2021-08-25 2023-03-02 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
WO2023114984A1 (en) 2021-12-17 2023-06-22 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2023122777A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Oxime derivatives useful as t cell activators
WO2023122778A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Pyridazinone derivatives useful as t cell activators
WO2023122772A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Oxime derivatives useful as t cell activators
WO2023150186A1 (en) 2022-02-01 2023-08-10 Arvinas Operations, Inc. Dgk targeting compounds and uses thereof
WO2023173053A1 (en) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2023173057A1 (en) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2023211889A1 (en) 2022-04-25 2023-11-02 Ikena Oncology, Inc. Polymorphic compounds and uses thereof
WO2023230205A1 (en) 2022-05-25 2023-11-30 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2024028363A1 (en) 2022-08-02 2024-02-08 Liminal Biosciences Limited Heteroaryl carboxamide and related gpr84 antagonists and uses thereof
WO2024028364A1 (en) 2022-08-02 2024-02-08 Liminal Biosciences Limited Aryl-triazolyl and related gpr84 antagonists and uses thereof
WO2024028365A1 (en) 2022-08-02 2024-02-08 Liminal Biosciences Limited Substituted pyridone gpr84 antagonists and uses thereof
WO2024036100A1 (en) 2022-08-08 2024-02-15 Bristol-Myers Squibb Company Substituted tetrazolyl compounds useful as t cell activators
WO2024036101A1 (en) 2022-08-09 2024-02-15 Bristol-Myers Squibb Company Tertiary amine substituted bicyclic compounds useful as t cell activators
WO2024033389A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033457A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033388A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033458A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydroazepine derivatives

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