WO2018136887A1 - Compounds - Google Patents

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Publication number
WO2018136887A1
WO2018136887A1 PCT/US2018/014725 US2018014725W WO2018136887A1 WO 2018136887 A1 WO2018136887 A1 WO 2018136887A1 US 2018014725 W US2018014725 W US 2018014725W WO 2018136887 A1 WO2018136887 A1 WO 2018136887A1
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Prior art keywords
alkyl
compound
independently selected
optionally substituted
imidazo
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PCT/US2018/014725
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French (fr)
Inventor
Richard T. Lewis
Philip Jones
Alessia Petrocchi
Naphtali REYNA
Matthew Hamilton
Jason Cross
Martin Tremblay
Paul Graham LEONARD
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Tesaro, Inc.
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Publication of WO2018136887A1 publication Critical patent/WO2018136887A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This disclosure relates to compounds useful as inhibitors of indoleamine 2,3 -di oxygenase and/or tryptophan dioxygenase, in particular to compounds having favourable activity and/or selectivity for use in the treatment of conditions such as cancers.
  • Indoleamine 2,3 -dioxygenase (IDOl and ID02) and tryptophan dioxygenase (TDO) belong to the family of heme-containing enzymes that mediate the degradation of the essential amino acid L-tryptophan (L-TRP) to N-formylkynurenine. This is the first and rate-limiting step of L-TRP oxidation in the kynurenine (KYN) pathway.
  • IDOl, ID02 and TDO all catalyse the same biochemical reaction, they share limited structural similarity.
  • TDO is a homotetrameric enzyme with high substrate specificity for L-TRP, whilst IDOl is a monomeric enzyme which recognises a broader range of substrates including L- and D-TRP, serotonin and tryptamine. ID02 shares 43% sequence identity with IDOl but is much less effective in catabolising L-TRP.
  • TDO is primarily expressed in the liver, and lower levels of the enzyme are also present in the brain.
  • IDOl is ubiquitous in the body, including in the placenta, lung, small and large intestines, colon, spleen, liver, kidney, stomach and brain.
  • ID02 is expressed in a subset of the tissues that express IDOl, primarily in the kidney, as well as in the epididymis, testis, liver, ovary, uterus, and placenta (Dounay et al, J. Med. Chem. (2015) 58:8762-8782).
  • the KYN pathway is thought to regulate immune responses to prevent excessive immune activity and immunopathology.
  • IDOl is believed to play a role in the protection of the foetus from rejection by the mother's immune system (Munn et al., Science (1998) 281 : 1191-1193), and is implicated in allergies, in autoimmunity, and in tolerance to allografts (Lovelace et al, Neuropharmacology (2017) 112:373-388).
  • L-TRP L-TRP derived metabolites
  • IDOl IDOl
  • ID02 IDOl
  • TDO L-TRP derived metabolites
  • KYN L-TRP derived metabolites
  • the generation of KYN and its metabolites, including quinolic acid (QUIN) also affects the synthesis of the coenzyme nicotinamide adenine dinucleotide (NAD + ).
  • NAD + plays an important role in DNA replication, and hence cell division, as well as in DNA repair, redox signalling, and mitochondrial function, all of which may be involved in cancer cell proliferation (Bostian et al., Chem. Res. Toxicol. (2016) 29: 1369-1380).
  • IDOl, ID02 and/or TDO are expressed by many human tumours.
  • the degree of IDOl expression in tumour cells is known to correlate with clinical prognosis (e.g. overall survival and progression-free survival) and increased IDOl levels have been linked with tumour cell resistance to immunotherapy, radiation therapy, and chemotherapy agents.
  • Tumour cell resistance is often accompanied by increased metastasis, due to the suppression of the patient's immune response to the invading cancer cells.
  • Aberrant KYN signalling has also been associated with a number of neurological diseases or disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis and Parkinson's disease (Bostian, 2016).
  • the interaction between immune activation and the metabolism of L-TRP via the kynurenine pathway has also been shown to be involved in neuropsychological diseases or disorders such as schizophrenia, anorexia and depression, including depressive and anxiety symptoms in the early puerperium (Lovelace, 2017).
  • Inhibitors of IDOl, ID02 and/or TDO are also believed to have utility in the treatment of cataracts; infectious diseases where the immune system is compromised (e.g. influenza virus, peritonitis, sepsis, chlamydia trachomatis, human immunodeficiency virus (HIV) and HIV- associated neurological disorders (HAND)); and autoimmune disorders such as arthritis, rheumatoid arthritis or multiple sclerosis (Lovelace, 2017).
  • infectious diseases where the immune system is compromised e.g. influenza virus, peritonitis, sepsis, chlamydia trachomatis, human immunodeficiency virus (HIV) and HIV- associated neurological disorders (HAND)
  • HAND HIV-associated neurological disorders
  • autoimmune disorders such as arthritis, rheumatoid arthritis or multiple sclerosis
  • the present inventors have discovered a family of compounds which are useful as inhibitors of IDOl, ID02 and/or TDO, especially IDOl . These compounds are suitable for use in pharmaceutical compositions as well as in medical treatments in which the KYN pathway needs to be modulated. In particular, the compounds of the invention are suitable for use in the treatment of cancers, immune system regulatory disorders and neurological disorders.
  • the invention provides a com ound characterised by formula (IA) or formula (IB),
  • Y 1 is selected from CR 1 and N;
  • Y 2 is selected from CR 3 and N;
  • A is selected from
  • heterocyclyl wherein said aryl or heterocyclyl is optionally substituted by one or more groups independently selected from R 8 ;
  • R 1 and R 2 are each independently selected from
  • alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is optionally substituted by one or more groups independently selected from halogen,
  • R 1 and R 2 taken together with the intervening carbon atoms form a 5-membered carbocyclic or heterocyclic group which is optionally substituted with one or more groups independently selected from halogen;
  • R 3 is selected from
  • R 4 and R 5 are each independently selected from H and NR a R b , wherein R a and R b are each independently selected from H and C 1-3 alkyl; is selected from
  • each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R 8a , and
  • R 7 is selected from
  • each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R ,
  • R 6 and R 7 taken together with the intervening nitrogen atom form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group which is optionally substituted by one or more groups independently selected from R 8 ; any pair of R groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group,
  • any pair of R 8a groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered carbocyclic or heterocyclic group,
  • any pair of R 8b groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered carbocyclic or heterocyclic group, and
  • R 8 , R 8a and/or R 8b groups are each independently selected from
  • each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J;
  • each said alkyl, alkenyl, alkynyl, aryl or heteroaryl is optionally substituted by one or more groups independently selected from halogen and hydroxy;
  • R 21 are each independently selected from
  • each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl is optionally substituted by one or more groups independently selected from halogen, OH and Ci-3-alkyl optionally substituted by one or more groups independently selected from halogen.
  • each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen.
  • At least one of Y 1 and Y 2 is N.
  • the compound is characterised by formula (IIA) or formula (IIB),
  • the compound is characterised by formula (IIIA) or formula (IIIB),
  • R 1 , R 2 , R 4 , R 5 and A are as defined hereinbefore.
  • R 1 and/or R 2 are independently selected from H, halogen, CN, and Ci-3-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen.
  • R 3 is selected from H, halogen, and methyl, wherein said methyl is optionally substituted by one or more groups independently selected from fluorine.
  • R 4 and R 5 are each independently selected from H and NH 2 .
  • R 2 is selected from H, CI and Ci-3-alkyl, wherein said alkyl is optionally substituted by 1, 2 or 3 fluorine atoms; and R 1 , R 3 , R 4 and R 5 , where present, are each independently selected from H. In embodiments, R 2 is selected from CI and CF 3 .
  • the compound is characterised by formula (VIIIA) or formula (VIIIB),
  • R 6 is selected from H, Ci-6-alkyl, C 2- 6-alkenyl, C 2- 6-alkynyl, (Co-6-alkyl)-cycloalkyl, (C 0 . 6 -alkyl)-cycloalkenyl, (C 0- 6-alkyl)-aryl, (C 0- 6-alkyl)-heterocycloalkyl, (C 0- 6-alkyl)- heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R 8a ; and
  • R 7 is selected from H, Ci -6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, (C 0- 6-alkyl)-cycloalkyl, (C 0 . 6 -alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)- heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R , and R 1 to R 5 , R 8a and R 8b are as defined hereinbefore.
  • the compound is characterised by formula (XIIA) or formula (XIIB),
  • XIIA (XIIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein: m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; n is 0, 1 or 2;
  • X 1 is selected from N, C, S and O; and at least one pair of R 8 groups, taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, wherein said carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J, and
  • R 1 to R 5 , R 8 and J are as defined hereinbefore.
  • the compound is characterised by formula (XVIA) or formula (XVIB),
  • any remaining groups R 22 to R 31 are each independently selected from H, halogen, oxo, OH, CN, d -6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, 0-(Ci -6 -alkyl), (C 0 - 6 -alkyl)-SO 2 R 9 , (C 0 -6-alkyl)-SO 2 N(R 10 ) 2 , (Co-e-alky - HSO.R 11 , N(R 12 )S0 2 N(R 13 ) 2 , N(R 14 )C(0)N(R 15 ) 2 , (C
  • R 22 , R 23 , R 30 and R 31 are each independently H; and R 24 , R 25 , R 28 and R 29 are each independently selected from H and Ci-6-alkyl, wherein said alkyl is optionally and independently substituted by one or more groups independently selected from J as defined hereinbefore.
  • R 26 and R 27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group, which cycloalkyl or heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined hereinbefore.
  • R and R together with the intervening atom form a 4- to 6-membered spiro heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined hereinbefore, wherein R 24 is selected from halogen and Ci-6-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen, and wherein R 22 , R 23 , R 25 , R 28 , R 29 , R 30 and R 31 are each H.
  • R 26 and R 27 together with the intervening atom form a 4- to 6-membered spiro heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined hereinbefore, wherein R 24 and R 25 are independently selected from halogen and Ci -6 -alkyl, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen, and wherein R 22 , R 23 , R 28 , R 29 , R 30 and R 31 are each H.
  • one pair of the groups R 22 to R 31 , taken together with the intervening atom forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined hereinbefore, and wherein another pair of the groups R 22 to R 31 , taken together with the intervening atoms, forms a 5- to 8-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined hereinbefore.
  • R 26 and R 27 taken together with the intervening atom, forms a 4- to 6- membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined hereinbefore, and wherein R 24 and R 28 , taken together with the intervening atoms, forms a 5- to 8-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined hereinbefore.
  • the compound is characterised by formula (XXA) or formula (XXB),
  • R" to R" and R ie to R J1 are each independently selected from H, halogen, oxo, OH, CN, Ci -6 -alkyl, C 2 - 6 -alkenyl, C 2-6 -alkynyl, 0-(Ci -6 -alkyl), (C 0 - 6 -alkyl)-SO 2 R 9 , (C 0-6 -alkyl)-SO 2 N(R 10 ) 2 , (Co-e-alky - HSC ⁇ R 11 , N(R 12 )S0 2 N(R 13 ) 2 , N(R 14 )C(0)N(R 15 ) 2 , (C 0 .
  • R 22 to R 31 is oxo, the corresponding geminal group is absent, and any remaining R 32 group is selected from H, OH, Ci-6-alkyl, C 2- 6-alkenyl, C 2- 6-alkynyl, 0-(Ci -6 -alkyl), (C 0- 6-alkyl)-SO 2 R 9 , (C 0- 6-alkyl)-SO 2 N(R 10 ) 2 , (Ci -6 -alkyl)- HS0 2 R u , (Ci -6 -alkyl)- R 16 R 17 , (Ci -6 -alkyl)- HC(0)R 18 , (C 0- 6-alkyl)-C(O)N(R 19 ) 2 , (C 0- 6-alkyl)-C
  • R 1 to R 5 , R 9 to R 21 and J are as defined hereinbefore.
  • R , R , R JU and R J1 are each independently H; and R , R , R and R 2y are each independently selected from H and Ci -6 -alkyl, wherein said alkyl is optionally and independently substituted by one or more groups independently selected from J as defined hereinbefore.
  • R 32 is selected from H, Ci -6 -alkyl, (C 0 -6-alkyl)-SO 2 R 9 and (C 0- 6-alkyl)-C(O)R 20 , wherein each said alkyl is optionally substituted by one or more groups independently selected from J, and wherein R 9 , R 20 and J are as defined hereinbefore.
  • A is selected from
  • X 2 is selected from H, N(d -5 alkyl), O, and C(R') 2 , wherein each R' is independently selected from H and Ci -5 alkyl;
  • R 33 , R 34 and R 36 are each independently selected from H, Ci-5-alkyl, C 2 -5-alkenyl,
  • R 35 is selected from H, Ci -5 -alkyl, C 2-5 -alkenyl, C 2-5 -alkynyl, (C 0 -4-alkyl)-SO 2 R 9 , (C 0 . 4 -alkyl)-SO 2 N(R 10 ) 2 , (Ci -4 -alkyl)- HCOR 18 , (C 0 - 4 -alkyl)-CON(R 19 ) 2 , (Co -4 -alkyl)-COR 20 , and (Co -4 -alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen and hydroxyl, and
  • R * to R , R ie to R iU and ⁇ to R , where present, are as defined hereinbefore.
  • A is selected from
  • A is C 6 -io-aryl substituted by at least two groups independently selected from R 8 as defined hereinbefore.
  • the compound is characterised by formula (XXIV A) or formula (XXIVB),
  • R to R are each independently selected from H, halogen, OH, CN, Ci-6-alkyl, C2- 6 -alkenyl, C2-6-alkynyl, 0-(Ci.
  • R 37 and R 41 are each independently H;
  • R 38 and R 40 are each independently selected from H, halogen, Ci -6 -alkyl, (C 0- 6-alkyl)-cycloalkyl, (C 0- 6-alkyl)-aryl, (C 0- 6-alkyl)- heterocycloalkyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more groups independently selected from J; and
  • R 39 is selected from H, Ci-6-alkyl, (Co-6-alkyl)-S0 2 R 9 , (Co-6-alkyl)- SO 2 N(R 10 ) 2 , (Co-e-alky - HSCbR 11 , (C 0 - 6 -alkyl)- HCOR 18 , (C 0-6 alkyl)-C(0)N(R 19 ) 2 , (
  • A is selected from
  • X 4 is selected from NH, N(d -6 alkyl), O, and CR' 2 ,
  • each R' is independently selected from Ci -6 alkyl
  • R 26 , R 32 , R 3 J 3 J and R 3 J 5 3 are each independently selected from: H,
  • R 28 and R 29 are each independently selected from:
  • R 28 and R 29 may together form a C 3 - 9-cycloalkyl or 3- to 9-membered heterocycloalkyl;
  • R 27 and R 34 are selected from:
  • each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally and independently substituted by one or more groups selected independently from J as defined hereinbefore, and wherein R 9 , R 10 , R 11 , R 18 , R 19 and R 20 are as defined hereinbefore.
  • the invention further provides a compound selected from the group consisting of Compounds 1 to 51 :
  • the compound is selected from the group consisting of Compound 1A, Compound 2, Compound 3, Compound 4, Compound 6, Compound 8, Compound 12, Compound 18B, Compound 19, Compound 23, Compound 25, Compound 27, Compound 27A, Compound 28, Compound 29, Compound 39A, Compound 39B, Compound 40, Compound 41B, Compound 42, Compound 44, Compound 46, Compound 47, Compound 49, and Compound 51; and the pharmaceutically acceptable salts or prodrugs thereof.
  • said compound has an inhibitory activity (measured as IC 50 value) against IDOl of less than 300 nM.
  • said compound is selective for IDOl over TDO by a value of at least 10 times.
  • the invention further provides a pharmaceutical composition comprising a compound of the invention, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises a further active agent selected from the group consisting of chemotherapeutic agents and immunotherapeutic agents.
  • the invention further provides a compound, or a pharmaceutical composition, of the invention for use in therapy.
  • the invention further provides a method for treating an IDOl, ID02 and/or TDO mediated condition in a subject, the method comprising administering to the subject an effective amount of a compound of the invention.
  • the IDOl, ID02 and/or TDO mediated condition is selected from a cancer; a neurological or neuropsychological disease or disorder; an autoimmune disease or disorder; an infection; a cataract; and a vascular disease.
  • the IDOl, ID02 and/or TDO mediated condition is characterised by the overexpression of IDOl, ID02 and/or TDO, respectively.
  • the IDOl , ID02 and/or TDO mediated condition is a cancer is selected from head and neck cancer, breast cancer (e.g. metastatic breast cancer), prostate cancer (e.g. metastatic prostate cancer), ovarian cancer, endometrial cancer, colon cancer, lung cancer (e.g. non-small cell lung cancer), bladder cancer, pancreatic cancer (e.g. metastatic pancreatic cancer), brain tumour (e.g. primary malignant brain tumour), gynaecological cancer, peritoneal cancer, skin cancer, thyroid cancer, oesophageal cancer, cervical cancer, gastric cancer, liver cancer, stomach cancer, renal cell cancer, biliary tract cancer, hematologic cancer, and blood cancer.
  • breast cancer e.g. metastatic breast cancer
  • prostate cancer e.g. metastatic prostate cancer
  • ovarian cancer endometrial cancer
  • colon cancer e.g. non-small cell lung cancer
  • lung cancer e.g. non-small cell lung cancer
  • bladder cancer pancreatic cancer (e
  • the cancer is associated with low levels of L-TRP and/or the cancer is associated with high levels of L-TRP metabolites.
  • the IDOl, ID02 and/or TDO mediated condition is a cancer
  • the method comprises administering said compound in combination with another therapeutic intervention for said cancer.
  • said another therapeutic intervention is immunotherapy, radiation therapy and/or chemotherapy.
  • the method is for treating a subject diagnosed as having a cancer or being at risk of developing a cancer.
  • the the IDO l, ID02 and/or TDO mediated condition is a neurological disease or disorder selected from Alzheimer' s disease, amyotrophic lateral sclerosis, Huntington' s disease, multiple sclerosis, Parkinson' s disease, and HIV-associated neurological disorders (HAND).
  • the IDOl, ID02 and/or TDO mediated condition is a neuropsychological disease or disorder selected from schizophrenia, anorexia, depression, and anxiety.
  • the IDOl, ID02 and/or TDO mediated condition is an autoimmune disease or disorder selected from arthritis, rheumatoid arthritis, and multiple sclerosis.
  • the IDOl, ID02 and/or TDO mediated condition is an infection selected from influenza virus infection, peritonitis, sepsis, chlamydia trachomatis infection, and human immunodeficiency virus (HIV).
  • the IDOl, ID02 and/or TDO mediated condition is a cataract.
  • the IDOl, ID02 and/or TDO mediated condition is a cardiovascular disease.
  • the invention further provides a compound of the invention for use in a method as defined hereinbefore.
  • the invention further provides the use of a compound of the invention in the manufacture of a medicament for use in a method as defined hereinbefore.
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives and the like.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure or process steps to produce a composition or achieve an intended result.
  • a "subject,” “individual” or “patient” is used interchangeably herein, and refers to a vertebrate, such as a mammal.
  • Mammals include, but are not limited to, rodents, farm animals, sport animals, pets and primates; for example murines, rats, rabbit, simians, bovines, ovines, porcines, canines, felines, equines, and humans.
  • the mammals include horses, dogs, and cats.
  • the mammal is a human.
  • administering is defined herein as a means of providing an agent or a composition containing the agent to a subject in a manner that results in the agent being inside the subject's body.
  • Such an administration can be by any route including, without limitation, oral, transdermal (e.g. by the vagina, rectum, or oral mucosa), by injection (e.g. subcutaneous, intravenous, parenteral, intraperitoneal, or into the central nervous system), or by inhalation (e.g. oral or nasal).
  • Pharmaceutical preparations are, of course, given by forms suitable for each administration route.
  • Treating" or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; and/or (3) relieving the disease, i.e. causing regression of the disease or its clinical symptoms.
  • the term "suffering” as it relates to the term “treatment” refers to a patient or individual who has been diagnosed with or is predisposed to the disease.
  • a patient may also be referred to being "at risk of suffering” from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease.
  • a patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease.
  • an “effective amount” or “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc.. It is understood, however, that specific dose levels of the therapeutic agents of the present invention for any particular subject depends upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration.
  • Treatment dosages generally may be titrated to optimize safety and efficacy.
  • dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on the proper doses for patient administration.
  • one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks.
  • the term "pharmaceutically acceptable excipient” encompasses any of the standard pharmaceutical excipients, including carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents. Pharmaceutical compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000).
  • the term “prodrug” means a pharmacological derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug.
  • prodrugs are variations or derivatives of the compounds described herein that have groups cleavable under certain metabolic conditions, which when cleaved, become the compounds described herein, e.g. a compound of formula (I). Such prodrugs then are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation.
  • Prodrug compounds herein may be called single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and the number of functionalities present in a precursor-type form.
  • Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, "The Organic Chemistry of Drug Design and Drug Action” pp. 352-401, Academic Press, San Diego, Calif, 1992).
  • Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of acid compounds with a suitable alcohol, amides prepared by reaction of acid compounds with an amine, basic groups reacted to form an acylated base derivative, etc..
  • Other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability.
  • those of skill in the art will appreciate that certain of the presently disclosed compounds having, for example, free amino or hydroxyl groups can be converted into prodrugs.
  • Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.
  • pharmaceutically acceptable salt means a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.
  • alkyl means a saturated linear or branched free radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms.
  • exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.
  • Other alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • the terms "Ci-3-alkyl”, “C4-8-alkyl”, etc. have equivalent meanings, i.e. a saturated linear or branched free radical consisting essentially of 1 to 3 (or 4 to 8) carbon atoms and a corresponding number of hydrogen atoms.
  • haloalkyl means an alkyl group which is substituted by one or more halogens.
  • exemplary haloalkyl groups include chlorom ethyl, dichloromethyl, trichloroethyl, etc..
  • fluoroalkyl is to be construed accordingly, i.e. to encompass fluoromethyl, difluoromethyl, trifluoroethyl, etc..
  • alkenyl means an unsaturated linear or branched free radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, prop-l-enyl, prop-2-enyl, isopropenyl, but-l-enyl, 2-methyl-prop-l-enyl, 2- methyl-prop-2-enyl, 1,2-propandien-l-yl, etc.
  • C2-6-alkenyl has an equivalent meaning, i.e. an unsaturated linear or branched free radical consisting essentially of 2 to 6 carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon double bond.
  • alkynyl means an unsaturated linear or branched free radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon triple bond.
  • exemplary alkynyl groups include ethynyl, prop-l-ynyl, prop-2-ynyl, but-l-ynyl, 3-methyl-but-l-ynyl, etc.
  • Other alkynyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • C2-6-alkynyl has an equivalent meaning, i.e. an unsaturated linear or branched free radical consisting essentially of 2 to 6 carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon triple bond.
  • cyclic group means a saturated, partially or fully unsaturated, or aromatic group having at least 3 to 9 atoms ⁇ i.e. ring atoms) that form a ring.
  • a cyclic group is defined as having a certain number of members, the term “members”, “membered” and the like is used to denote the number of ring atoms in said cyclic group.
  • a 5- membered cyclic group ⁇ e.g. a 5-membered heterocyclic group) contains 5 ring atoms.
  • a cyclic group may be part of a larger cyclic system; for example, bicyclo[4.3.0]nonane comprises two carbocyclic groups, namely a cyclohexane group and a cyclopentane group, which are fused to form the carbocyclic system which makes up the molecule.
  • the term "cyclic group” is intended to encompass both carbocyclic groups as well as heterocyclic groups.
  • the term “carbocyclic” refers to a group having at least 3 to 9 carbon atoms that form a ring.
  • carbocyclyl is used to mean a carbocyclic free radical.
  • heterocyclic refers to a group having at least 3 to 6 atoms that form a ring, wherein at least 1 to 5 of said ring atoms are carbon and the remaining at least 1 to 5 ring atom(s) (i.e. hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulphur and oxygen.
  • heterocyclyl is used to mean a heterocyclic free radical.
  • spiro as used herein in relation to cyclic groups denotes that a first cyclic group within a multi cyclic system is attached to a second cyclic group within said multi cyclic system, wherein the ring atoms of said first cyclic group and the ring atoms of said second cyclic group have only one atom in common, i.e. said first and second cyclic groups share only one common ring atom.
  • the spiro[5.5]undecanyl group comprises two cyclohexane rings which have a single carbon ring atom in common.
  • fused as used herein in relation to cyclic groups denotes that a first cyclic group within a multicyclic system is attached to a second cyclic group within said multicyclic system, wherein the ring atoms of said first cyclic group and the ring atoms of said second cyclic group have two adjacent atoms in common, i.e. said first and second cyclic groups share two common ring atoms.
  • the bicyclo[4.4.0]decanyl group comprises two cyclohexane rings which have two adjacent carbon ring atoms in common.
  • bridged as used herein in relation to cyclic groups denotes that a first cyclic group within a multicyclic system is attached to a second cyclic group within said multicyclic system, wherein the ring atoms of said first cyclic group and the ring atoms of said second cyclic group have more than two adjacent atoms in common, i.e. said first and second cyclic groups share three or more common ring atoms.
  • the bicyclo[3.3.1]nonanyl group comprises two cyclohexane rings which have three adjacent carbon ring atoms in common.
  • cycloalkyl means a saturated free radical having at least 3 to 9 carbon atoms (i.e. ring atoms) that form a ring.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It will be appreciated that the cycloalkyl group may be monocyclic or multicyclic (e.g. fused, bridged or spirocyclic systems). In the case of multicyclic cycloalkyl groups, there are further rings, e.g. 1, 2, 3, or more, further rings, all of which contain from 3 to 9 carbon atoms (i.e. ring atoms). Exemplary cycloalkyl groups having such further rings include decalinyl (bicyclo[4.4.0]decanyl) and spiro[5.5]undecanyl.
  • cycloalkenyl means a partially or fully unsaturated free radical having at least 3 to 9 carbon atoms (i.e. ring atoms) that form a ring.
  • cycloalkenyl is not intended to encompass cyclic groups having significant aromatic character.
  • Exemplary cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. It will be appreciated that the cycloalkenyl group may be monocyclic or multicyclic (e.g. fused, bridged or spirocyclic systems). In the case of multicyclic cycloalkenyl groups, there are further rings, e.g.
  • further rings all of which contain from 3 to 9 carbon atoms (i.e. ring atoms) and which may themselves be saturated or partially or fully unsaturated.
  • exemplary cycloalkenyl groups having such further rings include spiro[5.5]undecenyl and octahydronaphthalenyl .
  • aryl means an aromatic free radical having at least 6 carbon atoms (i.e. ring atoms) that form a ring. It will be appreciated that the aryl group may be monocyclic or multicyclic (e.g. fused, bridged or spirocyclic systems). In the case of multicyclic aryl groups, there are further rings, e.g. 1, 2, 3, or more, further rings, all of which contain at least 3 carbon atoms (i.e. ring atoms), which further rings may optionally be aromatic. Examples of aryl groups include phenyl and naphthalenyl, as well as indenyl and indanyl groups.
  • heterocycloalkyl means a saturated free radical having at least 3 to 6 atoms (i.e. ring atoms) that form a ring, wherein at least 1 to 5 of said ring atoms are carbon and the remaining at least 1 to 5 ring atom(s) (i.e. hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulphur and oxygen.
  • exemplary heterocyclic groups include aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl. In the case of multicyclic heterocyclic groups, there are further rings, e.g.
  • heterocycloalkenyl means a partially or fully unsaturated free radical having at least 3 to 6 atoms (i.e.
  • ring atoms that form a ring, wherein at least 1 to 5 of said ring atoms are carbon and the remaining at least 1 to 5 ring atom(s) (i.e. hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulphur and oxygen.
  • exemplary heterocycloalkenyl groups include tetrahydropyridyl.
  • further rings e.g. 1, 2, 3, or more, further rings, all of which contain from 3 to 8 ring atoms selected from carbon, nitrogen, sulphur and oxygen. Said further rings may be saturated, or partially or fully unsaturated.
  • Multicyclic heterocycloalkenyl groups include fused, bridged and spirocyclic ring systems.
  • Exemplary heterocycloalkenyl groups having such further rings include 2,3-dihydroindolyl and 5,6-dihydroindolyl.
  • heteroaryl means an aromatic free radical typically containing from 6 to 10 ring atoms, wherein 1 to 9 of said ring atoms are carbon and the remaining 1 to 9 ring atom(s) (i.e. hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulphur and oxygen.
  • the heteroaryl group may be monocyclic or multicyclic (e.g. fused, bridged and/or spirocyclic systems).
  • further rings e.g. 1, 2, 3, or more, further rings, all of which contain at least 3 atoms (i.e. ring atoms), which further rings may optionally be aromatic.
  • heteroaryl groups include monocyclic groups such as pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl and N-pyridin-4-onyl, as well as multicyclic groups such as benzofuranyl, benzothiophenyl, benzoxazolyl, indolyl, pyrrolopyridinyl, quinolinyl, pteridinyl and 2- oxob enzimi dazoly 1.
  • monocyclic groups such as pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl and N-pyridin-4-onyl
  • multicyclic groups such as benzofuranyl, benzothiophenyl, benzoxazolyl, indolyl, pyrrolopyridinyl, quinolinyl, pteridinyl and 2- oxob enzimi
  • CN mean a free radical having a carbon atom linked to a nitrogen atom via a triple bond.
  • the CN radical is attached via its carbon atom.
  • oxo means a free radical wherein an oxygen atom is connected to the atom bearing this radical via a double bond.
  • a carbon atom carries an oxo radical it forms a carbon-oxygen double bond. It will be appreciated that not all atoms within a given structure can be substituted by oxo, and that this will depend on the free valency of the atom to be substituted.
  • compositions and methods provided herein may be combined with one or more of any of the other compositions and methods provided herein.
  • ADDP l,l'-(azodicarbonyl)dipiperidine
  • AIBN azobisisobutyronitrile
  • Boc tert-butyloxycarbonyl
  • DIAD diisopropyl azodicarboxylate
  • DIBAL diisobutylaluminum hydride
  • DIEA N,N-diisopropylethylamine
  • DIPEA N,N-diisopropylethylamine
  • DTBAD (E)-di-tert-butyl diazene-l,2-dicarboxylate
  • EDC l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • HATU 1 bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
  • HIV human immunodeficiency virus
  • HOBt hydroxybenzotriazole
  • IDOl / ID02 indoleamine 2, 3 -di oxygenase
  • LAH Lithium aluminium hydride (LiAlH 4 )
  • L-TRP L-tryptophan
  • NBS N-bromosuccinimide
  • TBAF tetra- «-butylammonium fluoride
  • TBDPS tert-butyldiphenylsilyl
  • TDO tryptophan dioxygenase
  • TMZ temozolomide
  • the present invention relates to compounds useful as inhibitors of IDOl, ID02 and/or TDO.
  • the invention provides a compound characterised by formula (IA) or formula (IB),
  • Y 1 is selected from CR 1 and N;
  • Y 2 is selected from CR 3 and N;
  • A is selected from
  • aryl or heterocyclyl is optionally substituted by one or more groups independently selected from R 8 ;
  • R 1 and R 2 are each independently selected from
  • R 1 and R 2 taken together with the intervening carbon atoms form a 5-membered carbocyclic or heterocyclic group which is optionally substituted with one or more groups independently selected from halogen;
  • R 3 is selected from
  • R 4 and R 5 are each independently selected from H and NR a R b , wherein R a and R b are each independently selected from H and C 1-3 alkyl;
  • R 6 is selected from
  • each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R 8a , and
  • R 7 is selected from
  • each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R ,
  • R 6 and R 7 taken together with the intervening nitrogen atom form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group which is optionally substituted by one or more groups independently selected from R 8 ;
  • any pair of R 8 groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group,
  • any pair of R 8a groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered carbocyclic or heterocyclic group,
  • any pair of R 8b groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered carbocyclic or heterocyclic group, and
  • R 8 , R 8a and/or R 8b groups are each independently selected from
  • each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J;
  • each said alkyl, alkenyl, alkynyl, heteroaryl or aryl is optionally substituted by one or more groups independently selected from halogen and hydroxy; and R 9 to R 21 are each independently selected from
  • each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl is optionally substituted by one or more groups independently selected from halogen, OH and Ci -3 -alkyl optionally substituted by one or more groups independently selected from halogen.
  • diments, J in each case is independently selected from:
  • each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen.
  • the compound is not 8-phenylimidazo[l,5-a]pyridine.
  • At least one of Y 1 and Y 2 is N. In embodiments, one of Y 1 and Y 2 is N, and the other is CR 1 or CR 3 , respectively. In embodiments, no more than one of Y 1 and Y 2 is N. In one embodiment, Y 1 is N. In another embodiment Y 1 is CR 1 . In one embodiment, Y 2 is N. In another embodiment Y 2 is CR 3 .
  • the compound is characterised by formula (IIA) or formula (IIB),
  • the compound is characterised by formula (IIIA) or formula (IIIB),
  • the compound is characterised by formula (IV A) or formula (IVB),
  • A is C6- 10 -aryl or heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • A is C 6- io-aryl optionally substituted by one or more groups independently selected from R 8 as defined herein. In embodiments, A is phenyl optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • A is heterocyclyl optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • A is heterocyclyl, e.g. 3- to 10-membered, 5- to 8-membered, or 5- to 7-membered heterocyclyl.
  • A is selected from heterocycloalkyl, heterocycloalkenyl, and heteroaryl, each of which is optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • A is heterocycloalkyl optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • A is heterocycloalkenyl optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • A is heteroaryl optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • A is R 6 R 7 .
  • R 1 and R 2 are independently selected from H, halogen, CN, Ci. 3-alkyl, 0-(Ci-3-alkyl), C 2 -3-alkenyl, C 2 -3-alkynyl, C 3 -5-cycloalkyl, and C 3 -5-cycloalkenyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is optionally substituted by one or more groups independently selected from halogen.
  • R 1 and/or R 2 are independently selected from H, halogen, CN, methyl, CF 3 , ethyl, CH 3 CF 2 , z ' sopropyl, CF(CH 3 ) 2 , 0-CHF 2 , 2-propenyl, ethynyl, cyclopropyl, and cyclopenten-l-yl, wherein said cyclopropyl is optionally substituted by one or two fluorine atoms.
  • R 1 and/or R 2 are independently selected from H, halogen, CN, and Ci -3 -alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen.
  • R 1 and/or R 2 are independently selected from H, halogen, and Ci -3 -alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen.
  • R 1 and/or R 2 are independently selected from H, halogen, and Ci -3 -alkyl, wherein said alkyl is optionally substituted by one or more fluorine atoms.
  • R 2 is selected from CI and CF 3 .
  • R 1 is H.
  • R 1 , where present, is H
  • R 2 is selected from H, CI, and Ci -3 -alkyl, wherein said alkyl is optionally substituted by one or more fluorine atoms.
  • R 1 , where present, is H
  • R 2 is CI.
  • R 1 , where present, is H
  • R 2 is methyl optionally substituted by 1, 2 or 3 fluorine atoms.
  • R 1 and R 2 where present, are independently selected from H.
  • R 1 and R 2 taken together with the intervening carbon atoms form a 5-membered carbocyclic or heterocyclic group which is optionally substituted with one or more groups independently selected from halogen (e.g. fluorine).
  • halogen e.g. fluorine
  • R 3 is selected from H, halogen, and methyl, wherein said methyl is optionally substituted by one or more groups independently selected from halogen (e.g. fluorine).
  • halogen e.g. fluorine
  • R 3 is selected from H, CI, F, and methyl. In one embodiment where R 3 is present, it is H.
  • R 4 and R 5 are each independently selected from H and H 2 . In one embodiment, R 4 and R 5 are both independently selected from H. In other embodiments, one of R 4 and R 5 is H and the other is R a R b .
  • R a and R b are each independently selected from H and methyl. In embodiments, R a and/or R b are independently selected from H. In embodiments, R a and R b are each Ci-3 alkyl.
  • R 2 is selected from H, CI and Ci-3-alkyl, wherein said alkyl is optionally substituted by 1, 2 or 3 fluorine atoms; and R 1 , R 3 , R 4 and R 5 , where present, are each independently selected from H.
  • the invention provides a compound characterised by formula (VA) or formula (VB
  • the invention provides a compound characterised by formula (VIA) or formula (VIB),
  • VIA (VIA) (VIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R 2 to R 7 are as defined herein.
  • the invention provides a compound characterised by formula (VIIA) or formula (VIIB),
  • VIIA (VIIA) (VIIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1 , R 2 and R 4 to R 7 are as defined herein.
  • the invention provides a compound characterised by formula (VIIIA) or formula (VIIIB),
  • R 6 and R 7 taken together with the intervening nitrogen atom form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group which is substituted by at least two R 8 groups, wherein at least one pair of said R 8 groups, taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, wherein said carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • R 6 and R 7 taken together with the intervening nitrogen atom form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group which is substituted by at least two R 8 groups, and wherein at least one pair of said R 8 groups, taken together with the intervening atom, forms a 3- to 10-membered spiro carbocyclic or heterocyclic group, wherein said carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • R 6 and R 7 taken together with the intervening nitrogen atom do not form a heterocyclic group.
  • R 6 is selected from H, Ci-6-alkyl, C2- 6 -alkenyl, C2-6-alkynyl, (Co-6-alkyl)- cycloalkyl, (Co-6-alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (C 0 .
  • R 6 is selected from H, Ci-6-alkyl, (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)- cycloalkenyl, (C 0- 6-alkyl)-aryl, (C 0- 6-alkyl)-heterocycloalkenyl, (C 0- 6-alkyl)-heterocycloalkyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R 8a as defined herein.
  • R 6 is selected from H and Ci -6 -alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from R 8a as defined herein.
  • R 6 is selected from (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)-cycloalkenyl, (C 0 . 6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)- heteroaryl, wherein each said cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R 8a as defined herein.
  • R 7 is selected from H, Ci-6-alkyl, (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)- cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkenyl, (Co-6-alkyl)-heterocycloalkyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R as defined herein.
  • R 7 is selected from H and Ci-6-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from R as defined herein.
  • R 7 is selected from (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)-cycloalkenyl, (C 0 . 6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)- heteroaryl, wherein each said cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R 8b as defined herein.
  • R 6 and R 7 taken together with the intervening nitrogen atom form a heterocyclic group.
  • R 6 and R 7 taken together with the intervening nitrogen atom form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group which is optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • R 6 and R 7 taken together with the intervening nitrogen atom form a heterocycloalkyl group, e.g. a 3- to 10-membered, 3- to 8-membered, or 5- to 7-membered heterocycloalkyl group, which is optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • a heterocycloalkyl group e.g. a 3- to 10-membered, 3- to 8-membered, or 5- to 7-membered heterocycloalkyl group, which is optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • R 6 and R 7 taken together with the intervening nitrogen atom form a heterocycloalkyl group selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, 1,2,3-triazolidinyl, piped dinyl, piperazinyl, morpholinyl, 1,4-azathianyl, azepanyl, 1,4-oxaazepanyl, 1,4- thiazepanyl, 1,4-diazepanyl, and tropanyl, wherein said heterocycloalkyl group is optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • said heterocycloalkyl group is selected from piperidinyl and piperazinyl. In one embodiment, said heterocycloalkyl group is piperidinyl. In another embodiment, said heterocycloalkyl group is piperazinyl.
  • R 6 and R 7 taken together with the intervening nitrogen atom form a heterocycloalkenyl group, e.g. a 3- to 10-membered, 3- to 8-membered, or 5- to 7-membered heterocycloalkenyl group, which is optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • a heterocycloalkenyl group e.g. a 3- to 10-membered, 3- to 8-membered, or 5- to 7-membered heterocycloalkenyl group, which is optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • R 6 and R 7 taken together with the intervening nitrogen atom form a heterocycloalkenyl group selected from pyrrolinyl, pyrrazolinyl, imidazolinyl, isoxazolinyl, oxazolinyl, isothiazolinyl, and thiazolinyl, wherein said heterocycloalkenyl group is optionally substituted by one or more groups independently selected from R 8 as defined herein.
  • each R , R a and/or R group is independently selected from halogen, oxo, OH, CN, Ci-6-alkyl, C 2- 6-alkenyl, C 2-6 -alkynyl, 0-(Ci -6 -alkyl), (C 0- 6-alkyl)-SO 2 R 9 , (Co-e-alkyl)- SO 2 N(R 10 ) 2 , (Co-e-alky -NHSO.R 11 , N(R 12 )S0 2 N(R 13 ) 2 , N(R 14 )C(0)N(R 15 ) 2 , (Co-e-alkyl)- R 16 R 17 , (C 0 -6-alkyl)- HC(O)R 18 , (C 0- 6-alkyl)-C(O)N(R 19 ) 2 , (C 0- 6-alkyl)-C(O)R 20 , (Co-e-alkyl)- C(0)OR 21
  • each R 8 , R 8a and/or R 8b group is independently selected from halogen, oxo, OH, CN, Ci-6-alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, 0-(Ci -6 -alkyl), (C 0- 6-alkyl)-SO 2 R 9 , (Co-e-alkyl)- S0 2 NHR 10 , (Co-e-alky -NHSOzR 11 , N(R 12 )S0 2 NHR 13 , N(R 14 )C(0)NHR 15 , (C 0- 6-alkyl)-NR 16 R 17 , (C 0- 6-alkyl)-NHC(O)R 18 , (C 0- 6-alkyl)-C(O)NHR 19 , (C 0- 6-alkyl)-C(O)R 20 , (C 0- 6-alkyl)-C(O)OR 21 , (Co-6-alkyl)-
  • each R 8a and R 8b are independently selected from halogen, OH, C(0)OH, CN, (C 0 -6-alkyl)-SO 2 R 9 , (C 0 -6-alkyl)-SO 2 NHR 10 , (Co-6-alkyl)-NHS0 2 R u , N(R 14 )C(0)NHR 15 , (C 0 - 6-alkyl)-NR 16 R 17 , (C 0- 6-alkyl)-NHC(O)R 18 , and (C 0- 6-alkyl)-heteroaryl, wherein each said alkyl or heteroaryl is optionally substituted by one or more groups independently selected from J, and wherein R 9 to R 11 , R 14 to R 18 , and J are as defined herein.
  • each R 8 is independently selected from halogen, oxo, OH, Ci-6-alkyl, 0-(Ci. 6-alkyl), (C 0 - 6 -alkyl)-SO 2 R 9 , (C 0- 6-alkyl)-SO 2 NHR 10 , (Co-e-alky -NHSOzR 11 , N(R 12 )S0 2 NHR 13 , (C 0- 6-alkyl)-NHC(O)R 18 , (C 0- 6-alkyl)-C(O)NHR 19 , (C 0- 6-alkyl)-C(O)R 20 , (C 0- 6-alkyl)-aryl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, aryl or heteroaryl is optionally substituted by
  • each R , R a and R is independently selected from halogen, oxo, Ci-6-alkyl, (C 0-6 -alkyl)-SO 2 R 9 , (C 0 - 6 -alkyl)-SO 2 N(R 10 ) 2 , N(R 12 )S0 2 N(R 13 ) 2 , and (C 0-6 -alkyl)-C(O)R 20 wherein each said alkyl is optionally substituted by one or more groups independently selected from J, and wherein R 9', R 10 , R 12 , R 13 , R 2 z 0 u and J are as defined herein.
  • each R 8 , R 8a and R 8b is independently selected from halogen, OH, methyl, trifluoromethyl, S0 2 Me, S0 2 H 2 , HS0 2 Me, C(0)Me, and phenyl, wherein said phenyl is optionally substituted by one or more groups independently selected from J.
  • said 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group is a 3- to 10-membered spiro, fused or bridged carbocyclic group, e.g. a 3- to 8-membered, 5- to 8-membered, or 5- to 7- membered spiro, fused or bridged carbocyclic group.
  • said 3- to 10- membered spiro, fused or bridged carbocyclic or heterocyclic group is a 3- to 10-membered spiro, fused or bridged heterocyclic group, e.g. a 3- to 8-membered, 5- to 8-membered, or 5- to 7- membered spiro, fused or bridged heterocyclic group.
  • At least one pair of R 8 groups, taken together with the intervening atom independently forms a 3- to 10-membered spiro carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • at least one pair of R 8 groups, taken together with the intervening atoms independently form a 3- to 10-membered fused carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • At least one pair of R 8 groups, taken together with the intervening atoms independently forms a 3- to 10-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • one pair of R groups, taken together with the intervening atom forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • one pair of R 8 groups taken together with the intervening atom, forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein, and another R 8 group is selected from halogen and Ci-6-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen.
  • said another R 8 group is at a position vicinal to said spiro heterocyclic group.
  • one pair of R 8 groups taken together with the intervening atom, forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein, and another pair of R 8 groups is selected independently from halogen and Ci-6-alkyl, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen.
  • said another pair of R 8 groups is at a position vicinal to said spiro heterocyclic group.
  • said pair of R 8 groups is a geminal pair of groups which is preferably at a position vicinal to said spiro heterocyclic group.
  • one pair of R 8 groups, taken together with the intervening atom forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein, and another pair of R 8 groups, taken together with the intervening atoms, forms a 5- to 8-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • said bridged carbocyclic or heterocyclic group is formed from a pair of R 8 groups, at least one of which is positioned vicinal to said spiro heterocyclic group.
  • said bridged carbocyclic or heterocyclic group is formed from a pair of R 8 groups, both of which are positioned vicinal to said spiro heterocyclic group.
  • At least one pair of R 8a groups, taken together with the intervening atom or atoms, independently forms a 3- to 10-membered carbocyclic or heterocyclic group, e.g. a 3- to 8-membered, 5- to 8-membered, or 5- to 7- membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • at least one pair of R 8a groups, taken together with the intervening atom or atoms independently forms a 3- to 10-membered cycloalkyl or heterocycloalkyl group, e.g.
  • cycloalkyl or heterocycloalkyl group wherein said cycloalkyl or heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • cycloalkenyl or heterocycloalkenyl group wherein said cycloalkenyl or heterocycloalkenyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • At least one pair of R 8a groups taken together with the intervening atom or atoms, independently forms a 5- to 10-membered heteroaryl group, e.g. a 5- to 8-membered, or 6- to 7- membered heteroaryl group, wherein said heteroaryl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • At least one pair of R 8b groups, taken together with the intervening atom or atoms, independently forms a 3- to 10-membered carbocyclic or heterocyclic group, e.g. a 3- to 8-membered, 5- to 8-membered, or 5- to 7- membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • at least one pair of R 8b groups, taken together with the intervening atom or atoms independently forms a 3- to 10-membered cycloalkyl or heterocycloalkyl group, e.g.
  • cycloalkyl or heterocycloalkyl group wherein said cycloalkyl or heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • cycloalkenyl or heterocycloalkenyl group wherein said cycloalkenyl or heterocycloalkenyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • At least one pair of R 8b groups taken together with the intervening atom or atoms, independently forms a 5- to 10-membered heteroaryl group, e.g. a 5- to 8-membered, or 6- to 7- membered heteroaryl group, wherein said heteroaryl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • each J is independently selected from halogen, oxo, OH, Ci-s-alkyl, 0-(Ci. 4-alkyl), (C 0 -4-alkyl)-SO 2 R 9 , and (C 0- 4-alkyl)-C(O)R 20 , wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen.
  • each J is independently selected from halogen, OH, Ci-s-alkyl, 0-(Ci-4-alkyl), (Co-4-alkyl)-S0 2 R 9 , and (Co-4-alkyl)-C(0)R 20 , wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen.
  • each J is independently selected from halogen, oxo, Ci-5-alkyl, C 2- 5-alkenyl, C 2- 5-alkynyl, (C 0 -4-alkyl)-O-(Ci -4 -alkyl), (C 0 -4-alkyl)-SO 2 R 9 , and (C 0 - 4 -alkyl)-C(O)R 20 , wherein each said alkyl, alkenyl, or alkynyl is optionally substituted by one or more groups independently selected from halogen and hydroxy.
  • each J is independently selected from halogen, oxo, Ci -5 -alkyl, (C 0- 4-alkyl)-SO 2 R 9 , and (C 0- 4-alkyl)-C(O)R 20 , wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen.
  • each J is independently selected from halogen, Ci-s-alkyl, C 2- 5-alkenyl, (Co- 4-alkyl)-S0 2 R 9 , and (Co-4-alkyl)-C(0)R 20 , wherein each said alkyl, or alkenyl is optionally substituted by one or more groups independently selected from halogen and hydroxy.
  • each J is independently selected from halogen, Ci-s-alkyl, (Co-4-alkyl)-S0 2 R 9 , and (Co-4-alkyl)-C(0)R 20 , wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen.
  • each J is independently selected from CI, F, oxo, methyl, propan-l,2-dienyl, prop-2-ynyl, CF 3 , S0 2 Me, and C(0)Me. In embodiments, each J is independently selected from CI, F, oxo, methyl, CF 3 , S0 2 Me, and C(0)Me. In embodiments, each J is independently selected from oxo, methyl, S0 2 Me, and C(0)Me. In embodiments, each J is independently selected from CI, F, methyl, CF 3 , S0 2 Me, and C(0)Me. In embodiments, each J is independently selected from methyl, S0 2 Me, and C(0)Me.
  • R 9 to R 21 are each independently selected from H, Ci-6-alkyl, C 3 - 6-cycloalkyl, phenyl, 3- to 6-membered heterocycloalkyl, and 5- to 7-membered heteroaryl, wherein each said alkyl, cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen, OH and Ci -3 -alkyl optionally substituted by one or more groups independently selected from halogen.
  • R 9 to R 21 are each independently selected from H, Ci-6-alkyl, and phenyl, wherein each said alkyl, or phenyl is optionally substituted by one or more groups independently selected from halogen, OH and Ci -3 -alkyl optionally substituted by one or more groups independently selected from halogen.
  • R 9 to R 21 are each independently selected from H and Ci-6-alkyl, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen.
  • the compound is characterised by formula (IXA) or formula (IXB),
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • n 0, 1 or 2;
  • X 1 is selected from N, C, S and O, and
  • the compound is characterised b formula (XA) or formula (XB),
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • n 0, 1 or 2;
  • X 1 is selected from N, C, S and O, and
  • R 2 to R 5 and R 8 are as defined herein.
  • the compound is characterised b formula (XIA) or formula (XIB),
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • n 0, 1 or 2;
  • X 1 is selected from N, C, S and O, and
  • R 1 , R 2 , R 4 , R 5 and R 8 are as defined herein.
  • the compound is characterised by formula (XIIA) or formula
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
  • n 0, 1 or 2;
  • X 1 is selected from N, C, S and O, and
  • R 1 to R 5 and R 8 are as defined herein.
  • m is an integer from 2 to 12
  • m is an integer from 2 to 12, and at least one pair of R groups, taken together with the intervening atom, forms a 3- to 10-membered spiro carbocyclic or heterocyclic group, wherein said carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • m is 2, 3 or 4.
  • m is 2.
  • m is 3.
  • m is 4.
  • n is 0 or 1. In embodiments, n is 1 or 2. In one embodiment, n is 0. In another embodiment, n is 1.
  • X 1 is N, e.g. R 8 . In another embodiment, X 1 is C, e.g. CHR 8 . In another embodiment, X 1 is S. In another embodiment, X 1 is O.
  • the compound is characterised by formula (XIIIA) or formula (XIIIB
  • any pair of the groups R 22 to R 31 , taken together with the intervening atom or atoms, may independently form a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group,
  • each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • the compound is characterised by formula (XIVA) or formula (XIVB),
  • the compound is characterised by formula (XV A) or formula (XVB
  • R , R , R and R to R are as defined herein.
  • the compound is characterised by formula (XVIA) or formula
  • any remaining groups R 22 to R 31 are each independently selected from H, halogen, oxo, Ci-6-alkyl, (Co-6-alkyl)- S0 2 R 9 , (C 0 -6-alkyl)-SO 2 N(R 10 )2, N(R 12 )S0 2 N(R 13 ) 2 , and (C 0 -6-alkyl)-C(O)R 20 , wherein when any
  • R , R , R and R 20 are as defined herein, and wherein each said alkyl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • At least one pair of the groups R 22 to R 31 taken together with the intervening atom or atoms, forms a spiro, fused or bridged carbocyclic or heterocyclic group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered carbocyclic or heterocyclic group, which carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • At least one pair of the groups R 22 to R 31 taken together with the intervening atom or atoms, forms a spiro, fused or bridged cycloalkyl or cycloalkenyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered cycloalkyl or cycloalkenyl group, which cycloalkyl or cycloalkenyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • At least one pair of the groups R 22 to R 31 taken together with the intervening atom or atoms, forms a spiro, fused or bridged heterocycloalkyl or heterocycloalkenyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered heterocycloalkyl or heterocycloalkenyl group, which heterocycloalkyl or heterocycloalkenyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • At least one pair of the groups R 22 to R 31 taken together with the intervening atom or atoms, forms a spiro, fused or bridged heterocycloalkyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • At least one pair of the groups R 22 to R 31 taken together with the intervening atom, forms a spiro heterocycloalkyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8- membered, or 5- to 7-membered heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • a spiro heterocycloalkyl group e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8- membered, or 5- to 7-membered heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group e.g. a 3- to 8-membered spiro heterocycloalkyl group
  • a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group e.g. a 3- to 8-membered spiro heterocycloalkyl group
  • R 26 and R 27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group (e.g. a 3- to 8-membered spiro heterocycloalkyl group), which cycloalkyl or heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • R 26 and R 27 together with the intervening atom form a 4- to 6-membered spiro heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein, wherein R 24 is selected from halogen and Ci-6-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen, and wherein R 22 , R 23 , R 25 , R 28 , R 29 , R 30 and R 31 are each H.
  • R 26 and R 27 together with the intervening atom form a 4- to 6-membered spiro heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein, wherein R 24 and R 25 are independently selected from halogen and Ci. 6-alkyl, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen, and wherein R 22 , R 23 , R 28 , R 29 , R 30 and R 31 are each H.
  • one pair of the groups R 22 to R 31 , taken together with the intervening atom forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein, and wherein another pair of the groups R 22 to R 31 , taken together with the intervening atoms, forms a 5- to 8-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • R 26 and R 27 taken together with the intervening atom, forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein, and wherein R 24 and R 28 , taken together with the intervening atoms, forms a 5- to 8-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • said spiro heterocycloalkyl group is selected from imidazolinyl, piperidinyl, and azepanyl, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • said spiro heterocycloalkyl group is imidazolinyl, optionally substituted by one or more groups independently selected from J as defined herein.
  • said spiro heterocycloalkyl group is piperidinyl, optionally substituted by one or more groups independently selected from J as defined herein.
  • said spiro heterocycloalkyl group is azepanyl, optionally substituted by one or more groups independently selected from J as defined herein.
  • said spiro heterocycloalkyl group is imidazolidine-2,4-dionyl (hydantoinyl).
  • R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 and R 31 are each independently selected from H, Ci.6-alkyl, S0 2 (Ci -3 -alkyl), S0 2 H 2 , S0 2 H(Ci -6 -alkyl) and C(0)(Ci -6 -alkyl); and R 22 and R 23 are each independently selected from H, Ci -6 -alkyl, S0 2 (Ci -3 -alkyl), S0 2 H 2 , S0 2 H(Ci.
  • each said alkyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more groups independently selected from J as defined in herein.
  • R 22 , R 23 , R 26 , R 27 , R 28 , R 29 , R 30 and R 31 are each independently selected from H, Ci-e-alkyl, S0 2 (Ci -3 -alkyl), S0 2 H 2 , S0 2 H(Ci -6 -alkyl) and C(0)(Ci -6 -alkyl); and R 24 and R 25 are each independently selected from H, Ci-e-alkyl, S0 2 (Ci -3 -alkyl), S0 2 H 2 , S0 2 H(Ci.
  • each said alkyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more groups independently selected from J as defined herein.
  • R 22 , R 23 , R 30 and R 31 are each independently H;
  • R 26 , R 27 , R 28 and R 29 are each independently selected from H, Ci -6 -alkyl, S0 2 (Ci -3 -alkyl), S0 2 H 2 , S0 2 H(Ci -6 -alkyl) and C(0)(Ci-6-alkyl);
  • R 24 and R 25 are each independently selected from H, Ci-6-alkyl, S0 2 (Ci.
  • R 22 , R 23 , R 30 and R 31 are each H; R 24 , R 25 , R 28 and R 29 are each independently selected from H and Ci -6 alkyl; and R 26 and R 27 are each independently selected from H, Ci.
  • 6-alkyl S0 2 (Ci -3 -alkyl), S0 2 H 2 , S0 2 H(Ci -6 -alkyl) and C(0)(Ci -6 -alkyl), or R 26 and R 27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group; wherein each said alkyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more groups independently selected from J as defined herein.
  • R 24 and R 28 together with the intervening atoms form a 5- to 8-membered bridged cycloalkyl or heterocycloalkyl group
  • R 26 and R 27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group, wherein each said cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups independently selected from J as defined herein.
  • R 26 and R 27 together with the intervening atom do not form a carbocyclic or heterocyclic group.
  • R 22 , R 23 , R 30 and R 31 are each independently H;
  • R 24 , R 25 , R 28 and R 29 are each independently selected from H and Ci -6 alkyl; and
  • R 26 and R 27 are each independently selected from H, Ci -6 -alkyl, S0 2 (Ci -3 -alkyl), S0 2 H 2 , S0 2 H(Ci -6 -alkyl), and C(0)(Ci -6 -alkyl); wherein each said alkyl is optionally and independently substituted by one or more groups independently selected from J as defined herein.
  • R 22 , R 23 , R 30 and R 31 are each independently H.
  • R , R , R and R are each independently selected from H and Ci-6-alkyl, wherein said alkyl is optionally and independently substituted by one or more groups
  • R , R , R and R are each independently selected from H and methyl.
  • R 24 and R 25 are each methyl, and R 28 and R 29 are each independently H.
  • R 26 and R 27 are each independently selected from H, Ci -6 -alkyl, S0 2 (Ci. 3-alkyl), S0 2 H 2 , S0 2 H(Ci -6 -alkyl), and C(0)(Ci -6 -alkyl), wherein each said alkyl is optionally substituted by one or more groups independently selected from J as defined herein.
  • R 26 and R 27 are each independently selected from H, S0 2 Me, and C(0)Me.
  • R 26 is H, and R 27 is S0 2 Me or C(0)Me.
  • R 26 is H, and R 27 is S0 2 Me.
  • R 26 is H, and R 27 is C(0)Me.
  • R , R", R JU and R J1 are each independently H; R and R are each independently selected from H and methyl; and R 26 and R 27 together with the intervening atom form a 5- to 7-membered spiro heterocycloalkyl group, wherein said heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • R 1 is H;
  • R 2 is CI or CF 3 ;
  • R 3 to R 5 are each independently H;
  • R 22 , R 23 , R 28 , R 29 , R 30 and R 31 are each independently H;
  • R 24 and R 25 are each independently selected from H and methyl;
  • R 26 and R 27 together with the intervening atom form a 5- to 7-membered spiro heterocycloalkyl group, wherein said heterocycloalkyl group is optionally substituted by one or more groups independently selected from oxo, methyl, C(0)Me, and S0 2 Me.
  • the compound is characterised by formula (XVIIA) or formula (XVIIB),
  • any pair of the groups R 22 to R 25 and R 28 to R 32 , taken together with the intervening atom or atoms, may independently form a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group,
  • any remaining groups R 22 to R 25 and R 28 to R 31 are as defined herein, and wherein any remaining R 32 group is selected from
  • R 9 to R 11 , and R 16 to R 21 are as defined herein, and
  • each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • the compound is characterised by formula (XVIIIA) or formula (XVIIIB
  • R to R , R to R , and R to R 32 are as defined herein.
  • the compound is characterised by formula (XIXA) or formula (XIXB
  • the compound is characterised by formula (XXA) or formula (XXB).
  • R to R , R to R , and R to are as defined herein.
  • R" to R , and R ie to R are each independently selected from H, halogen, oxo, Ci-e-alkyl, (C 0-6 -alkyl)-SO 2 R 9 , (C 0 - 6 -alkyl)-SO 2 N(R 10 ) 2 , N(R 12 )S0 2 N(R 13 ) 2 , and (C 0 - 6 -alkyl)-
  • R 32 is selected from H, Ci-6-alkyl, (Co-6-alkyl)-S0 2 R 9 , (C 0 -6-alkyl)-SO 2 N(R 10 ) 2 , and (C 0 -6-alkyl)-C(O)R 20 , wherein R 9 , R 10 , R 12 , R 13 and R 20 are as defined herein, and wherein each said alkyl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
  • a spiro, fused or bridged heterocycloalkyl or heterocycloalkenyl group e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered heterocycloalkyl or heterocycloalkenyl group, which heterocycloalkyl or heterocycloalkenyl group is optionally substituted by one
  • a spiro, fused or bridged heterocycloalkyl group e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • At least one pair of the groups R to R , and R to R , taken together with the intervening atom forms a spiro heterocycloalkyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • R and R together with the intervening atom, and/or R and R together with the intervening atom independently form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group (e.g. a 3- to 8-membered spiro heterocycloalkyl group), which cycloalkyl or cycloalkenyl group is optionally and independently substituted by one or more groups independently selected from J as defined herein.
  • R and R together with the intervening atom, and/or R and R together with the intervening atom independently form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group (e.g. a 3- to 8-membered spiro heterocycloalkyl group), which cycloalkyl or cycloalkenyl group is optionally and independently substituted by one or more groups independently selected from J as defined herein.
  • said spiro heterocycloalkyl group is selected from imidazolinyl, piperidinyl, and azepanyl, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
  • said spiro heterocycloalkyl group is imidazolinyl, optionally substituted by one or more groups independently selected from J as defined herein.
  • said spiro heterocycloalkyl group is piperidinyl, optionally substituted by one or more groups independently selected from J as defined herein.
  • said spiro heterocycloalkyl group is azepanyl, optionally substituted by one or more groups independently selected from J as defined herein.
  • said spiro heterocycloalkyl group is imidazolidine-2,4-dionyl (hydantoinyl).
  • R 24 , R 25 , R 28 , R 29 , R 30 and R 31 are each independently selected from H, Ci.
  • R 32 is selected from H, Ci-e-alkyl, C(0)(Ci -6 -alkyl), S0 2 (Ci -6 -alkyl), (Co- 6 -alkyl)-cycloalkyl, (C 0 - 6 -alkyl)- cycloalkenyl, (C 0- 6-alkyl)-aryl, (C 0- 6-alkyl)-heterocycloalkyl, (C 0- 6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl; and R 22 and R 23 are each independently selected from H, Ci-6-alkyl, S0 2 (Ci -3 -alkyl), S0 2 H 2 , S0 2 H(Ci -6 -alkyl) and C(0)(Ci -6 -alkyl); R 32 is selected from H, Ci-e-alkyl, C(0)(Ci -6 -alkyl), S0 2 (Ci
  • R , R , R , R , R JU and R J1 are each independently selected from H, Ci. 6-alkyl, S0 2 (Ci -3 -alkyl), S0 2 H 2 , S0 2 H(Ci -6 -alkyl) and C(0)(Ci -6 -alkyl);
  • R 32 is selected from H, Ci-e-alkyl, C(0)(Ci -6 -alkyl), S0 2 (Ci -6 -alkyl), (C 0- 6-alkyl)-cycloalkyl, (C 0 - 6 -alkyl)- cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl; and R 22 and R 23 together with the intervening atom form a 3- to 8- membered
  • R 22 , R 23 , R 30 and R 31 are each independently H;
  • R 28 and R 29 are each independently selected from H, Ci-e-alkyl, S0 2 (Ci -3 -alkyl), S0 2 H 2 , S0 2 H(Ci -6 -alkyl) and C(0)(Ci -6 -alkyl);
  • R 32 is selected from H, Ci -6 -alkyl, C(0)(Ci -6 -alkyl), S0 2 (Ci -6 -alkyl), (C 0 .
  • R 24 and R 25 are each independently selected from H, Ci-e-alkyl, S0 2 (Ci -3 -alkyl), S0 2 H 2 , S0 2 H(Ci -6 -alkyl) and C(0)(Ci-6-alkyl), or R 24 and R 25 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group; wherein each said alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by
  • R 24 and R 28 together with the intervening atoms form a 5- to 8-membered bridged cycloalkyl or heterocycloalkyl group, wherein each said cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups independently selected from J as defined herein.
  • R 22 , R 23 , R 30 and R 31 are each independently H; R 24 , R 25 , R 28 and R 29 are each independently selected from H and Ci -6 alkyl; and R 32 is selected from H, Ci -6 -alkyl, C(0)(Ci. 6-alkyl), S0 2 (Ci-6-alkyl), (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)-cycloalkenyl and (Co-6-alkyl)-aryl; wherein each said alkyl, cycloalkyl, cycloalkenyl or aryl is optionally substituted by one or more groups independently selected from J as defined herein.
  • R 22 , R 23 , R 30 and R 31 are each independently H.
  • R 24 , R 25 , R 28 and R 29 are each independently selected from H and Ci. 6 -alkyl, wherein said alkyl is optionally and independently substituted by one or more groups independently selected from J as defined herein.
  • R 24 , R 25 , R 28 and R 29 are each independently selected from H and methyl.
  • R and R are each methyl, and R 28 and R 29 are each independently H.
  • R 32 is selected from H, Ci -6 -alkyl, (C 0 -6-alkyl)-SO 2 R 9 and (C 0- 6-alkyl)-C(O)R 20 , wherein each said alkyl is optionally substituted by one or more groups independently selected from J, and wherein R 9 , R 20 and J are as defined herein.
  • R 32 is selected from H, Ci -6 -alkyl, S0 2 (Ci -6 -alkyl), and C(0)(Ci -6 -alkyl), wherein each said alkyl is optionally substituted by one or more groups independently selected from J as defined herein.
  • R 32 is selected from H, S0 2 Me, and C(0)Me.
  • R , R , R 29 , R 30 and R 31 are each independently H; R 24 and R 25 are each independently selected from H and methyl; and R 32 is selected from C(0)Me and S0 2 Me.
  • R , R JU and R J1 are each independently H; R and R are each methyl; and R is selected from C(0)Me and S0 2 Me.
  • R 1 is H;
  • R 2 is CI or CF 3 ;
  • R 3 to R 5 are each independently H;
  • R 22 , R 23 , R 28 , R 29 , R 30 and R 31 are each independently H;
  • R 24 and R 25 are each methyl;
  • R 32 is selected from C(0)Me and S0 2 Me.
  • A is selected from
  • X 2 is selected from NH, N(Ci-5 alkyl), O, and CR' 2 , wherein each R' is independently selected from H and C alkyl;
  • R , R and R are each independently selected from
  • each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen and hydroxyl;
  • R 35 is selected from H
  • R 9 , R 10 , R 11 , R 18 , R 19 and R 20 are as defined herein, and
  • each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen and hydroxyl, and wherein R 24 to R 27 , where present, are as defined herein.
  • R 24 and R 25 together with the intervening atom, form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group, and/or
  • R 26 and R 27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group
  • any remaining groups R 24 to R 27 are each independently selected from
  • each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally and independently substituted by one or more groups independently selected from J as defined herein.
  • A is selected from
  • X 2 is selected from NH, N(Ci -5 alkyl), O, and CR' 2 , wherein each R' is independently selected from H and Ci -5 alkyl;
  • R 33 , R 34 and R 36 are each independently selected from
  • each said alkyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen;
  • R 35 is selected from
  • R 9 , R 10 , R 11 , R 18 , R 19 and R 20 are as defined herein, and
  • each said alkyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen, and wherein R 24 to R 27 , where present, are as defined herein.
  • R 24 and R 25 together with the intervening atom, form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group, and/or
  • R 26 and R 27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group
  • any remaining groups R 24 to R 27 are each independently selected from
  • each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally and independently substituted by one or more groups independently selected from J as defined herein.
  • A is selected from
  • R to R , R to R and X are as defined herein.
  • A is selected from
  • R to R are as defined herein.
  • A is selected from
  • R to R , R to R and X are as defined herein.
  • A is selected from
  • R to R , R to R and X are as defined herein.
  • X 2 is H. In other embodiments, X 2 is N(Ci -5 alkyl). In embodiments, X 2 is N(Ci-3 alkyl). In one embodiment, X 2 is Me. In another embodiment, X 2 is O.
  • X 2 is CR' 2 , wherein each R' is independently selected from H and Ci -5 - alkyl.
  • R 33 and R 34 are selected from H, Ci-s-alkyl, C 2- 5-alkenyl and C 2- 5-alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted by one or more groups independently selected from halogen and hydroxyl.
  • R 33 and R 34 are selected from H, C 2- 5-alkenyl and C 2- 5-alkynyl, wherein said alkenyl or alkynyl is optionally substituted by one or more groups independently selected from halogen.
  • R 33 and R 34 are selected from H and Ci -5 -alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen.
  • R 33 and R 34 are selected from H and methyl. In one embodiment, R 33 and R 34 are each H. In another embodiment, R 33 and R 34 are each methyl. In another embodiment, R 33 is H, and R 34 is methyl.
  • R 35 is selected from H, Ci-s-alkyl, S0 2 (Ci-3-alkyl), and C(0)(Ci-6-alkyl), wherein each said alkyl is optionally and independently substituted by one or more groups independently selected from halogen.
  • R 35 is independently selected from H, S0 2 Me and C(0)Me.
  • R 35 is independently selected from S0 2 Me and C(0)Me.
  • R is selected from H and Ci-5-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen.
  • R 36 is selected from H and methyl.
  • A is selected from
  • A is selected from
  • A is selected from In embodiments, A is selected from
  • A is selected from
  • A is selected from
  • A is selected from
  • A is C 6- io-aryl, optionally substituted by one or more groups independently selected from R 8 , wherein R 8 is as defined herein.
  • said C 6 . lo-aryl is phenyl.
  • A is C6- 10 -aryl substituted by at least one group independently selected from R 8 , wherein R 8 is as defined herein. In embodiments, A is C 6- io-aryl substituted by at least two groups independently selected from R 8 , wherein R 8 is as defined herein. In embodiments, A is C6-io-aryl substituted by at least three groups independently selected from R 8 , wherein R 8 is as defined herein. In embodiments, A is not unsubstituted phenyl. In other embodiments, A is not 4- (methyl sulfonyl)phenyl .
  • the compound is characterised by formula (XXIA) or formula (XXIB),
  • IT to R 4J are each independently selected from:
  • each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein, and
  • Y 1 , Y 2 , R 2 , R 4 and R 5 are as defined herein.
  • the compound is characterised by formula (XXIIA) or formula (XXIIB),
  • the compound is characterised by formula (XXIIIA) or formula (XXIIIB),
  • R and/or R are independently H.
  • R 38 and/or R 40 are independently selected from H, halogen, Ci-6-alkyl, (C 0 . 6-alkyl)-cycloalkyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more groups independently selected from J as defined herein.

Abstract

Compounds of formula (IA) and formula (IB), which are useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase, are provided. Also provided are pharmaceutical compositions, kits comprising said compounds, and methods and uses pertaining to said compounds.

Description

COMPOUNDS
This disclosure relates to compounds useful as inhibitors of indoleamine 2,3 -di oxygenase and/or tryptophan dioxygenase, in particular to compounds having favourable activity and/or selectivity for use in the treatment of conditions such as cancers. SUMMARY OF THE INVENTION
Indoleamine 2,3 -dioxygenase (IDOl and ID02) and tryptophan dioxygenase (TDO) belong to the family of heme-containing enzymes that mediate the degradation of the essential amino acid L-tryptophan (L-TRP) to N-formylkynurenine. This is the first and rate-limiting step of L-TRP oxidation in the kynurenine (KYN) pathway. Although IDOl, ID02 and TDO all catalyse the same biochemical reaction, they share limited structural similarity. TDO is a homotetrameric enzyme with high substrate specificity for L-TRP, whilst IDOl is a monomeric enzyme which recognises a broader range of substrates including L- and D-TRP, serotonin and tryptamine. ID02 shares 43% sequence identity with IDOl but is much less effective in catabolising L-TRP. In healthy patients, TDO is primarily expressed in the liver, and lower levels of the enzyme are also present in the brain. In contrast, IDOl is ubiquitous in the body, including in the placenta, lung, small and large intestines, colon, spleen, liver, kidney, stomach and brain. ID02 is expressed in a subset of the tissues that express IDOl, primarily in the kidney, as well as in the epididymis, testis, liver, ovary, uterus, and placenta (Dounay et al, J. Med. Chem. (2015) 58:8762-8782). The KYN pathway is thought to regulate immune responses to prevent excessive immune activity and immunopathology. For example, IDOl is believed to play a role in the protection of the foetus from rejection by the mother's immune system (Munn et al., Science (1998) 281 : 1191-1193), and is implicated in allergies, in autoimmunity, and in tolerance to allografts (Lovelace et al, Neuropharmacology (2017) 112:373-388). The catabolism of L-TRP by IDOl, ID02 and/or TDO, and the production of L-TRP derived metabolites such as KYN, has also been identified as one important immune effector pathway in tumour cells to escape potential immune responses, for example by suppressing antigen-specific T-cells and natural killer T-cells, while inducing the formation of regulatory T-cells which suppress immune cells (Qian et al., RSC Adv. (2016) 6:7575-7581). The generation of KYN and its metabolites, including quinolic acid (QUIN), also affects the synthesis of the coenzyme nicotinamide adenine dinucleotide (NAD+). NAD+ plays an important role in DNA replication, and hence cell division, as well as in DNA repair, redox signalling, and mitochondrial function, all of which may be involved in cancer cell proliferation (Bostian et al., Chem. Res. Toxicol. (2016) 29: 1369-1380).
IDOl, ID02 and/or TDO are expressed by many human tumours. The degree of IDOl expression in tumour cells is known to correlate with clinical prognosis (e.g. overall survival and progression-free survival) and increased IDOl levels have been linked with tumour cell resistance to immunotherapy, radiation therapy, and chemotherapy agents. Tumour cell resistance is often accompanied by increased metastasis, due to the suppression of the patient's immune response to the invading cancer cells. In particular, in vitro experiments have demonstrated the role of IDOl in tumour chem oresi stance to a variety of agents including cisplatin, olaparib, paclitaxel, pemetrexed, gemcitabine, and gamma radiation (Vareki et al., PLOS ONE (2015) 10(11), e0143435/l-22).
Aberrant KYN signalling has also been associated with a number of neurological diseases or disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis and Parkinson's disease (Bostian, 2016). The interaction between immune activation and the metabolism of L-TRP via the kynurenine pathway has also been shown to be involved in neuropsychological diseases or disorders such as schizophrenia, anorexia and depression, including depressive and anxiety symptoms in the early puerperium (Lovelace, 2017).
Inhibitors of IDOl, ID02 and/or TDO are also believed to have utility in the treatment of cataracts; infectious diseases where the immune system is compromised (e.g. influenza virus, peritonitis, sepsis, chlamydia trachomatis, human immunodeficiency virus (HIV) and HIV- associated neurological disorders (HAND)); and autoimmune disorders such as arthritis, rheumatoid arthritis or multiple sclerosis (Lovelace, 2017).
A number of structurally-diverse inhibitors of IDOl, ID02 and/or TDO have recently been developed. These include indoximod (NLG8189), which is being evaluated in clinical studies for metastatic breast cancer, metastatic melanoma, non-small cell lung cancer, primary malignant brain tumours, metastatic pancreatic cancer, as well as metastatic prostate cancer; epacadostat (INCB024360), which is being evaluated in clinical studies in gynaecological and peritoneal cancers, melanoma, malignant solid tumour, lymphoma, breast, lung, and renal cell cancers; and GDC-0919 ( LG919), which is being evaluated in trials for the treatment of advanced-stage solid tumours.
However, there remains a need for new inhibitors of IDOl, ID02 and/or TDO, especially inhibitors having high potency, high selectivity and/or beneficial in vivo properties such as pharmacokinetic properties. This need is met by the present invention.
The present inventors have discovered a family of compounds which are useful as inhibitors of IDOl, ID02 and/or TDO, especially IDOl . These compounds are suitable for use in pharmaceutical compositions as well as in medical treatments in which the KYN pathway needs to be modulated. In particular, the compounds of the invention are suitable for use in the treatment of cancers, immune system regulatory disorders and neurological disorders.
The invention provides a com ound characterised by formula (IA) or formula (IB),
Figure imgf000004_0001
(IA) (IB)
armaceutically acceptable salt or prodrug thereof, wherein:
Y1 is selected from CR1 and N;
Y2 is selected from CR3 and N;
A is selected from
R6R7,
Figure imgf000004_0002
heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted by one or more groups independently selected from R8;
R1 and R2 are each independently selected from
H,
halogen,
CN,
Ci.3-alkyl,
0-(Ci.3-alkyl),
C2-3-alkenyl,
C2-3-alkynyl,
C3-5-cycloalkyl, and
C3-5-cycloalkenyl,
wherein said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is optionally substituted by one or more groups independently selected from halogen,
or R1 and R2 taken together with the intervening carbon atoms form a 5-membered carbocyclic or heterocyclic group which is optionally substituted with one or more groups independently selected from halogen; R3 is selected from
H,
halogen,
C(0) H2, and
methyl optionally substituted by one or more groups independently selected from halogen;
R4 and R5 are each independently selected from H and NRaRb, wherein Ra and Rb are each independently selected from H and C1-3 alkyl; is selected from
H, Ci-e-alkyl,
C2-6-alkenyl,
C2-6-alkynyl,
(Co-6-alkyl)-cycloalkyl,
(Co-6-alkyl)-cycloalkenyl,
(C0-6-alkyl)-aryl,
(Co-6-alkyl)-heterocycloalkyl,
(Co-6-alkyl)-heterocycloalkenyl, and
(Co-6-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R8a, and
R7 is selected from
H,
Ci-e-alkyl,
C2-6-alkenyl,
C2-6-alkynyl,
(C0-6-alkyl)-cycloalkyl,
(C0-6-alkyl)-cycloalkenyl,
(Co-6-alkyl)-aryl,
(Co-6-alkyl)-heterocycloalkyl,
(Co-6-alkyl)-heterocycloalkenyl, and
(C0-6-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R ,
or R6 and R7 taken together with the intervening nitrogen atom form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group which is optionally substituted by one or more groups independently selected from R8; any pair of R groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group,
any pair of R8a groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered carbocyclic or heterocyclic group,
any pair of R8b groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered carbocyclic or heterocyclic group, and
any remaining R8, R8a and/or R8b groups are each independently selected from
halogen,
oxo,
OH,
CN,
Ci-e-alkyl,
C2-6-alkenyl,
C2-6-alkynyl,
0-(Ci-6-alkyl),
(C0-6-alkyl)-SO2R9,
(C0-6-alkyl)-SO2N(RiU)2,
(Co-e-alky - HSCbR11,
N(R12)S02N(R13)2,
N(Ri4)C(0)N(Ri:,)2,
(C0-6-alkyl)- R16R17,
(C0-6-alkyl)- HC(O)R ,
(C0-6-alkyl)-C(O)N(R19)2,
(Co-6-alkyl)-C(0)R20,
(C0-6-alkyl)-C(O)OR21,
(C0-6-alkyl)-cycloalkyl,
(Co-6-alkyl)-cycloalkenyl,
(Co-6-alkyl)-aryl,
(Co-6-alkyl)-heterocycloalkyl,
(C0-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J;
J in each case is independently selected from
halogen,
oxo,
OH,
CN,
Ci-s-alkyl,
C2-5-alkenyl,
C2-5-alkynyl,
(C0-4-alkyl)-O-(Ci-4-alkyl),
(C0-4-alkyl)-SO2R9,
(C0-4-alkyl)-SO2N(R10)2,
(Co^-alky - HSOzR11,
N(R14)C(0)N(R15)2,
(C0-4-alkyl)- R16R17,
(C0-4-alkyl)- HCOR18,
(C0-4-alkyl)-CON(R19)2,
(Co-4-alkyl)-C(0)R20,
C(0)OH,
C(0)0(Ci-4-alkyl),
(Co-4-alkyl)-aryl, and
(Co-4-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, aryl or heteroaryl is optionally substituted by one or more groups independently selected from halogen and hydroxy; and
R21 are each independently selected from
H, Ci-e-alkyl,
C2-6-alkenyl,
C2-6-alkynyl,
C3-6-cycloalkyl,
C3-6-cycloalkenyl,
phenyl,
3- to 6-membered heterocycloalkyl,
3- to 6-membered heterocycloalkenyl, and
5- to 7-membered heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl is optionally substituted by one or more groups independently selected from halogen, OH and Ci-3-alkyl optionally substituted by one or more groups independently selected from halogen.
diments, J in each case is independently selected from
halogen,
oxo,
OH,
CN,
Ci.s-alkyl,
C2-5-alkenyl,
C2-5-alkynyl,
0-(Ci-4-alkyl),
(C0-4-alkyl)-SO2R9,
(C0-4-alkyl)-SO2N(R10)2,
(Co-4-alkyl)- HS02Ru,
N(R14)C(0)N(R15)2,
(C0-4-alkyl)- R16R17,
(C0-4-alkyl)- HCOR18,
(C0-4-alkyl)-CON(R19)2,
(Co-4-alkyl)-C(0)R20,
C(0)OH, C(0)0(Ci.4-alkyl), and
(C0-4-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen.
In embodiments, at least one of Y1 and Y2 is N.
In embodiments, the compound is characterised by formula (IIA) or formula (IIB),
Figure imgf000010_0001
(IIA) (IIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R2 to R5 and A are as defined hereinbefore.
In embodiments, the compound is characterised by formula (IIIA) or formula (IIIB),
Figure imgf000010_0002
(IIIA) (IIIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, R4, R5 and A are as defined hereinbefore. In embodiments, R1 and/or R2 are independently selected from H, halogen, CN, and Ci-3-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen.
In embodiments, R3 is selected from H, halogen, and methyl, wherein said methyl is optionally substituted by one or more groups independently selected from fluorine.
In embodiments, R4 and R5 are each independently selected from H and NH2.
In embodiments, R2 is selected from H, CI and Ci-3-alkyl, wherein said alkyl is optionally substituted by 1, 2 or 3 fluorine atoms; and R1, R3, R4 and R5, where present, are each independently selected from H. In embodiments, R2 is selected from CI and CF3.
In embodiments, the compound is characterised by formula (VIIIA) or formula (VIIIB),
Figure imgf000011_0001
(VIIIA) (VIIIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R6 is selected from H, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, (Co-6-alkyl)-cycloalkyl, (C0. 6-alkyl)-cycloalkenyl, (C0-6-alkyl)-aryl, (C0-6-alkyl)-heterocycloalkyl, (C0-6-alkyl)- heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R8a; and
R7 is selected from H, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, (C0-6-alkyl)-cycloalkyl, (C0. 6-alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)- heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R , and R1 to R5, R8a and R8b are as defined hereinbefore.
In embodiments, the compound is characterised by formula (XIIA) or formula (XIIB),
Figure imgf000012_0001
(XIIA) (XIIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein: m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; n is 0, 1 or 2;
X1 is selected from N, C, S and O; and at least one pair of R8 groups, taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, wherein said carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J, and
R1 to R5, R8 and J are as defined hereinbefore.
In embodiments, the compound is characterised by formula (XVIA) or formula (XVIB),
Figure imgf000013_0001
(XVIA) (XVIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein: at least one pair of the groups R22 to R31, taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, wherein any remaining groups R22 to R31 are each independently selected from H, halogen, oxo, OH, CN, d-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, 0-(Ci-6-alkyl), (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2N(R10)2, (Co-e-alky - HSO.R11, N(R12)S02N(R13)2, N(R14)C(0)N(R15)2, (C0. 6-alkyl)- R16R17, (C0-6-alkyl)- HC(O)R18, (C0-6-alkyl)-C(O)N(R19)2, (C0-6-alkyl)-C(O)R20, (C0. 6-alkyl)-C(0)OR21, (C0-6-alkyl)-cycloalkyl, (C0-6-alkyl)-cycloalkenyl, (C0-6-alkyl)-aryl, (C0. 6-alkyl)-heterocycloalkyl, (C0-6-alkyl)-heterocycloalkenyl, and (C0-6-alkyl)-heteroaryl, wherein when any of R22 to R31 is oxo, the corresponding geminal group is absent, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J, and R1 to R5, R9 to R21 and J are as defined hereinbefore.
In embodiments, R22, R23, R30 and R31 are each independently H; and R24, R25, R28 and R29 are each independently selected from H and Ci-6-alkyl, wherein said alkyl is optionally and independently substituted by one or more groups independently selected from J as defined hereinbefore. In embodiments, R26 and R27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group, which cycloalkyl or heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined hereinbefore. In embodiments, R and R together with the intervening atom form a 4- to 6-membered spiro heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined hereinbefore, wherein R24 is selected from halogen and Ci-6-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen, and wherein R 22 , R 23 , R 25 , R 28 , R 29 , R 30 and R 31 are each H.
In embodiments, R26 and R27 together with the intervening atom form a 4- to 6-membered spiro heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined hereinbefore, wherein R24 and R25 are independently selected from halogen and Ci-6-alkyl, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen, and wherein R22, R23, R28, R29, R30 and R31 are each H.
In embodiments, one pair of the groups R22 to R31, taken together with the intervening atom, forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined hereinbefore, and wherein another pair of the groups R22 to R31, taken together with the intervening atoms, forms a 5- to 8-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined hereinbefore. In embodiments, R26 and R27, taken together with the intervening atom, forms a 4- to 6- membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined hereinbefore, and wherein R24 and R28, taken together with the intervening atoms, forms a 5- to 8-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined hereinbefore.
In embodiments, the compound is characterised by formula (XXA) or formula (XXB),
Figure imgf000015_0001
(XXA) (XXB) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
22 25 28 32
at least one pair of the groups R to R , and R to R , taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, any remaining groups 22 25 28 31
R" to R" and Rie to RJ1 are each independently selected from H, halogen, oxo, OH, CN, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, 0-(Ci-6-alkyl), (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2N(R10)2, (Co-e-alky - HSC^R11, N(R12)S02N(R13)2, N(R14)C(0)N(R15)2, (C0. 6-alkyl)- R16R17, (C0-6-alkyl)- HC(O)R18, (C0-6-alkyl)-C(O)N(R19)2, (C0-6-alkyl)-C(O)R20, (C0. 6-alkyl)-C(0)OR21, (C0-6-alkyl)-cycloalkyl, (C0-6-alkyl)-cycloalkenyl, (C0-6-alkyl)-aryl, (C0. 6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein when any of R22 to R31 is oxo, the corresponding geminal group is absent, and any remaining R32 group is selected from H, OH, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, 0-(Ci-6-alkyl), (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2N(R10)2, (Ci-6-alkyl)- HS02Ru, (Ci-6-alkyl)- R16R17, (Ci-6-alkyl)- HC(0)R18, (C0-6-alkyl)-C(O)N(R19)2, (C0-6-alkyl)-C(O)R20, (C0-6-alkyl)- C(0)OR21, (C0-6-alkyl)-cycloalkyl, (C0-6-alkyl)-cycloalkenyl, (C0-6-alkyl)-aryl, (C0-6-alkyl)- heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J, and
R1 to R5, R9 to R21 and J are as defined hereinbefore. In embodiments, R , R , RJU and RJ1 are each independently H; and R , R , R and R2y are each independently selected from H and Ci-6-alkyl, wherein said alkyl is optionally and independently substituted by one or more groups independently selected from J as defined hereinbefore. In embodiments, R32 is selected from H, Ci-6-alkyl, (C0-6-alkyl)-SO2R9 and (C0-6-alkyl)-C(O)R20, wherein each said alkyl is optionally substituted by one or more groups independently selected from J, and wherein R9, R20 and J are as defined hereinbefore.
In embodiments, A is selected from
Figure imgf000016_0001
wherein: X2 is selected from H, N(d-5 alkyl), O, and C(R')2, wherein each R' is independently selected from H and Ci-5 alkyl;
R 33 , R 34 and R 36 are each independently selected from H, Ci-5-alkyl, C2-5-alkenyl,
C2-5-alkynyl and (Co-4-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen and hydroxyl; and
R35 is selected from H, Ci-5-alkyl, C2-5-alkenyl, C2-5-alkynyl, (C0-4-alkyl)-SO2R9, (C0. 4-alkyl)-SO2N(R10)2,
Figure imgf000017_0001
(Ci-4-alkyl)- HCOR18, (C0-4-alkyl)-CON(R19)2, (Co-4-alkyl)-COR20, and (Co-4-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen and hydroxyl, and
9 11 18 20 24 27
R* to R , Rie to RiU and Έ to R , where present, are as defined hereinbefore. In embodiments, A is selected from
Figure imgf000018_0001
In embodiments, A is C6-io-aryl substituted by at least two groups independently selected from R8 as defined hereinbefore.
In embodiments, the compound is characterised by formula (XXIV A) or formula (XXIVB),
Figure imgf000019_0001
(XXIVA) (XXIVB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R to R are each independently selected from H, halogen, OH, CN, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, 0-(Ci. 6-alkyl), (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2N(R10)2, (Co-e-alky - HSO.R11, N(R12)S02N(R13)2, N(R14)C(0)N(R15)2, (C0-6-alkyl)- R16R17, (C0-6-alkyl)- HC(O)R18, (C0-6-alkyl)-C(O)N(R19)2, (C0-6-alkyl)-C(O)R20, (C0-6-alkyl)-C(O)OR21, (C0-6-alkyl)-cycloalkyl, (C0-6-alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)- heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J, and R1 to R5, R9 to R21 and J are as defined hereinbefore.
In embodiments: R37 and R41 are each independently H; R38 and R40 are each independently selected from H, halogen, Ci-6-alkyl, (C0-6-alkyl)-cycloalkyl, (C0-6-alkyl)-aryl, (C0-6-alkyl)- heterocycloalkyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more groups independently selected from J; and R39 is selected from H, Ci-6-alkyl, (Co-6-alkyl)-S02R9, (Co-6-alkyl)- SO2N(R10)2, (Co-e-alky - HSCbR11, (C0-6-alkyl)- HCOR18, (C0-6 alkyl)-C(0)N(R19)2, (C0. 6-alkyl)-cycloalkyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more groups independently selected from J, and R9, R10, R11, R18, R19 and J are as defined hereinbefore. In embodiments, A is selected from
Figure imgf000020_0001
wherein:
X4 is selected from NH, N(d-6 alkyl), O, and CR'2,
wherein each R' is independently selected from Ci-6 alkyl;
R 26 , R 32 , R 3J3J and R 3J53 are each independently selected from: H,
Ci-g-alkyl,
(Co-9-alkyl)-(C3-io-cycloalkyl),
(Co-9-alkyl)-(C6-io-aryl),
(Co-9-alkyl)-heterocycloalkyl, and
(C0-9-alkyl)-heteroaryl;
R28 and R29 are each independently selected from:
H,
Ci-9-alkyl,
(C0-9-alkyl)-(C3.io-cycloalkyl),
(Co-9-alkyl)-(C6-io-aryl),
(Co-9-alkyl)-heterocycloalkyl,
(Co-9-alkyl)-heteroaryl, or
R28 and R29 may together form a C3 -9-cycloalkyl or 3- to 9-membered heterocycloalkyl;
R27 and R34 are selected from:
H,
Ci.g-alkyl,
(C0-9-alkyl)-SO2R9,
(C0-9-alkyl)-SO2 HR10,
(Co-9-alkyl)- HS02Ru,
(C0-9-alkyl)- HCOR18,
(C0-9-alkyl)-CO HR19,
(C0-9-alkyl)-COR20,
(Co-9-alkyl)-(C3-io-cycloalkyl),
(Co-9-alkyl)-(C6-io-aryl),
(C0-9-alkyl)-heterocycloalkyl, and
(Co-9-alkyl)-heteroaryl,
wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally and independently substituted by one or more groups selected independently from J as defined hereinbefore, and wherein R9, R10, R11, R18, R19 and R20 are as defined hereinbefore.
The invention further provides a compound selected from the group consisting of Compounds 1 to 51 :
Figure imgf000022_0001
8-[4-methanesulfonyl-3-(trifluoromethyl)phenyl]imidazo[l,5-
Compound 11
a]pyridine
3-methanesulfonyl-9-[7-(trifluoromethyl)imidazo[l,5-
Compound 12
a]pyridin-5-yl]-3,9-diazaspiro[5.5]undecane l-{9-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3,9-
Compound 13
diazaspiro[5.5]undecan-3 -yl } ethan- 1 -one
3,6,64rimethyl-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 14
yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione
2,2-dimethyl-4-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 15
yl]piperazine-l -sulfonamide
N-(4-{2,2-dimethyl-4-[7-(trifluoromethyl)imidazo[l,5-
Compound 16
a]pyridin-5-yl]piperazin-l-yl}phenyl)methanesulfonamide
3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 17A
azabicyclo[3.3.1 ]nonan-9-ol
3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 17B
azabicyclo[3.3.1 ]nonan-9-ol bis(3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 18A
azaspiro[bicyclo[3.3.1]nonane-9,4'-imidazolidine]-2',5'-dione) bis(3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 18B
azaspiro[bicyclo[3.3.1]nonane-9,4'-imidazolidine]-2',5'-dione)
3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 19
azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
5-methanesulfonyl-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 20
a]pyridin-5-yl]-5,8-diazaspiro[3.5]nonane
5-{6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-
Compound 21
yl}imidazo[l,5-a]pyridine-7-carbonitrile l-methanesulfonyl-2-(trifluoromethyl)-4-[7-
Compound 22
(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]piperazine 8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,8-
Compound 23
triazaspiro[4.5]decane-2,4-dione
7-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,7-
Compound 24
triazaspiro[4.4]nonane-2,4-dione
1 l-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-5,7, 11-
Compound 25
triazadispiro[2.0.44.43]dodecane-6,8-dione
3-(2-hydroxyethyl)-6,6-dimethyl-8-[7-
Compound 26 (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,8- triazaspiro[4.5]decane-2,4-dione
6,6-difluoro-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-
Compound 27
l,3,8-triazaspiro[4.5]decane-2,4-dione
6,6-difluoro-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-
Compound 27A
l,3,8-triazaspiro[4.5]decane-2,4-dione (Enantiomer A)
6,6-difluoro-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-
Compound 27B
l,3,8-triazaspiro[4.5]decane-2,4-dione (Enantiomer B)
6-(trifluoromethyl)-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 28
a]pyridin-5-yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione l-methanesulfonyl-2,2-dimethyl-4-[6-
Compound 29
(trifluoromethyl)imidazo[l,5-a]pyridin-8-yl]piperazine
5-(4-methanesulfonyl-3,3-dimethylpiperazin-l-yl)imidazo[l,5-
Compound 30
a]pyridine-7-carbonitrile
3-benzyl-6,6-dimethyl-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 31
a]pyridin-5-yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione
4-{ 7-cyclopropylimidazo[ 1 , 5-a]pyridin-5-yl } - 1 -
Compound 32
methanesulfonyl-2,2-dimethylpiperazine l-{3,3-dimethyl-l-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-
Compound 33
5-yl]piperidin-4-yl}imidazolidin-2-one
3-ethyl-6,6-dimethyl-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 34
a]pyridin-5-yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione l-methanesulfonyl-2,2-dimethyl-4-[7-
Compound 35
(trifluoromethyl)imidazo[l,5-c]pyrimidin-5-yl]piperazine 3-(2-methoxyethyl)-6,6-dimethyl-8-[7-
Compound 36 (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,8- triazaspiro[4.5]decane-2,4-dione
4-{2-chloroimidazo[l,5-b]pyridazin-4-yl}-l-methanesulfonyl-
Compound 37
2,2-dimethylpiperazine
3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-
Compound 38
azabicyclo[3.2.1]octane-8-carboxamide
3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-
Compound 39A azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
(Enantiomer A)
3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-
Compound 39B azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
(Enantiomer B)
l'-(2-hydroxyethyl)-3-[7-(trifluoromethyl)imidazo[l,5-
Compound 40 a]pyridin-5-yl]-3-azaspiro[bicyclo[3.2.1]octane-8,4'- imidazolidine]-2',5'-dione
2-{3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-
Compound 41A
azabicyclo[3.2.1]octan-8-yl}acetamide (Enantiomer A)
2-{3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-
Compound 41B
azabicyclo[3.2. l]octan-8-yl}acetamide (Enantiomer B)
3-[7-(trifluoromethyl)imidazo[l,5-c]pyrimidin-5-yl]-3-
Compound 42
azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
6,6-dimethyl-8-[2-(trifluoromethyl)imidazo[l,5-a]pyrimidin-4-
Compound 43
yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione
6,6-dimethyl-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 44
y 1 ] - 1 , 3 , 8 -tri azaspiro [4.5 ] decan-2-one
2-{2',5'-dioxo-3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 45 yl]-3-azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-l'- yl}acetamide
1 '-(propa- 1 ,2-dien- 1 -yl)-3 - [7-(trifluoromethyl)imidazo[ 1 , 5 -
Compound 46 a]pyridin-5-yl]-3-azaspiro[bicyclo[3.2.1]octane-8,4'- imidazolidine]-2',5'-dione 1 '-(prop-2-yn- 1 -yl)-3 -[7-(trifluoromethyl)imidazo[ 1,5-
Compound 47 a]pyridin-5-yl]-3-azaspiro[bicyclo[3.2.1]octane-8,4'- imidazolidine]-2',5'-dione
r-[(lH-l,2,3-triazol-4-yl)methyl]-3-[7-
Compound 48 (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3- azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
6-fluoro-6-(trifluoromethyl)-8-[7-
Compound 49 (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,8- triazaspiro[4.5]decane-2,4-dione
9,9-dimethyl-7-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 50
yl]-l,3,7-triazaspiro[4.4]nonane-2,4-dione
6-fluoro-6-methyl-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 51
a]pyridin-5-yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione and the pharmaceutically acceptable salts or prodrugs thereof.
In embodiments, the compound is selected from the group consisting of Compound 1A, Compound 2, Compound 3, Compound 4, Compound 6, Compound 8, Compound 12, Compound 18B, Compound 19, Compound 23, Compound 25, Compound 27, Compound 27A, Compound 28, Compound 29, Compound 39A, Compound 39B, Compound 40, Compound 41B, Compound 42, Compound 44, Compound 46, Compound 47, Compound 49, and Compound 51; and the pharmaceutically acceptable salts or prodrugs thereof.
In embodiments, said compound has an inhibitory activity (measured as IC50 value) against IDOl of less than 300 nM.
In embodiments, said compound is selective for IDOl over TDO by a value of at least 10 times.
The invention further provides a pharmaceutical composition comprising a compound of the invention, and at least one pharmaceutically acceptable excipient.
In embodiments, the pharmaceutical composition comprises a further active agent selected from the group consisting of chemotherapeutic agents and immunotherapeutic agents.
The invention further provides a compound, or a pharmaceutical composition, of the invention for use in therapy. The invention further provides a method for treating an IDOl, ID02 and/or TDO mediated condition in a subject, the method comprising administering to the subject an effective amount of a compound of the invention.
In embodiments, the IDOl, ID02 and/or TDO mediated condition is selected from a cancer; a neurological or neuropsychological disease or disorder; an autoimmune disease or disorder; an infection; a cataract; and a vascular disease.
In embodiments, the IDOl, ID02 and/or TDO mediated condition is characterised by the overexpression of IDOl, ID02 and/or TDO, respectively.
In embodiments, the IDOl , ID02 and/or TDO mediated condition is a cancer is selected from head and neck cancer, breast cancer (e.g. metastatic breast cancer), prostate cancer (e.g. metastatic prostate cancer), ovarian cancer, endometrial cancer, colon cancer, lung cancer (e.g. non-small cell lung cancer), bladder cancer, pancreatic cancer (e.g. metastatic pancreatic cancer), brain tumour (e.g. primary malignant brain tumour), gynaecological cancer, peritoneal cancer, skin cancer, thyroid cancer, oesophageal cancer, cervical cancer, gastric cancer, liver cancer, stomach cancer, renal cell cancer, biliary tract cancer, hematologic cancer, and blood cancer.
In embodiments, the cancer is associated with low levels of L-TRP and/or the cancer is associated with high levels of L-TRP metabolites.
In embodiments, the IDOl, ID02 and/or TDO mediated condition is a cancer, and the method comprises administering said compound in combination with another therapeutic intervention for said cancer.
In embodiments, said another therapeutic intervention is immunotherapy, radiation therapy and/or chemotherapy.
In embodiments, the method is for treating a subject diagnosed as having a cancer or being at risk of developing a cancer. In embodiments, the the IDO l, ID02 and/or TDO mediated condition is a neurological disease or disorder selected from Alzheimer' s disease, amyotrophic lateral sclerosis, Huntington' s disease, multiple sclerosis, Parkinson' s disease, and HIV-associated neurological disorders (HAND). In embodiments, the IDOl, ID02 and/or TDO mediated condition is a neuropsychological disease or disorder selected from schizophrenia, anorexia, depression, and anxiety.
In embodiments, the IDOl, ID02 and/or TDO mediated condition is an autoimmune disease or disorder selected from arthritis, rheumatoid arthritis, and multiple sclerosis. In embodiments, the IDOl, ID02 and/or TDO mediated condition is an infection selected from influenza virus infection, peritonitis, sepsis, chlamydia trachomatis infection, and human immunodeficiency virus (HIV).
In embodiments, the IDOl, ID02 and/or TDO mediated condition is a cataract.
In embodiments, the IDOl, ID02 and/or TDO mediated condition is a cardiovascular disease. The invention further provides a compound of the invention for use in a method as defined hereinbefore.
The invention further provides the use of a compound of the invention in the manufacture of a medicament for use in a method as defined hereinbefore.
DETAILED DESCRIPTION Although specific embodiments of the present disclosure will now be described with reference to the description and examples, it should be understood that such embodiments are by way of example only and merely illustrative of but a small number of the many possible specific embodiments which can represent applications of the principles of the present disclosure. Various changes and modifications will be obvious to those of skill in the art given the benefit of the present disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.
Definitions
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of chemical synthesis, tissue culture, immunology, molecular biology, microbiology, cell biology and recombinant DNA, which are within the skill of the art. See, e.g., Michael R. Green and Joseph Sambrook, Molecular Cloning (4th ed., Cold Spring Harbor Laboratory Press 2012); the series Ausubel et al. eds. (2007) Current Protocols in Molecular Biology; the series Methods in Enzymology (Academic Press, Inc., N.Y.); MacPherson et al. (1991) PCR 1 : A Practical Approach (IRL Press at Oxford University Press); MacPherson et al. (1995) PCR 2: A Practical Approach; Harlow and Lane eds. (1999) Antibodies, A Laboratory Manual; Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique, 5th edition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Patent No. 4,683, 195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); Herzenberg et al. eds (1996) Weir's Handbook of Experimental Immunology; Manipulating the Mouse Embryo: A Laboratory Manual, 3rd edition (Cold Spring Harbor Laboratory Press (2002)); Sohail (ed.) (2004) Gene Silencing by RNA Interference: Technology and Application (CRC Press).
Numerical designations, e.g. pH, temperature, time, concentration, molecular weight, etc., including ranges, are approximations which are varied ( + ) or ( - ) by increments of 0.1 or 1.0, where appropriate. It is to be understood, although not always explicitly stated that all numerical designations are preceded by the term "about". It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such may be known in the art.
As used in the specification and claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures thereof. Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive. The term "including" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to".
As used herein, the term "comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives and the like. "Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure or process steps to produce a composition or achieve an intended result. Embodiments defined by each of these transition terms are within the scope of this invention. Use of the term "comprising" herein is intended to encompass, and to disclose, the corresponding statements in which the term "comprising" is replaced by "consisting essentially of or "consisting of.
A "subject," "individual" or "patient" is used interchangeably herein, and refers to a vertebrate, such as a mammal. Mammals include, but are not limited to, rodents, farm animals, sport animals, pets and primates; for example murines, rats, rabbit, simians, bovines, ovines, porcines, canines, felines, equines, and humans. In one embodiment, the mammals include horses, dogs, and cats. In a preferred embodiment, the mammal is a human.
"Administering" is defined herein as a means of providing an agent or a composition containing the agent to a subject in a manner that results in the agent being inside the subject's body. Such an administration can be by any route including, without limitation, oral, transdermal (e.g. by the vagina, rectum, or oral mucosa), by injection (e.g. subcutaneous, intravenous, parenteral, intraperitoneal, or into the central nervous system), or by inhalation (e.g. oral or nasal). Pharmaceutical preparations are, of course, given by forms suitable for each administration route.
"Treating" or "treatment" of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; and/or (3) relieving the disease, i.e. causing regression of the disease or its clinical symptoms.
The term "suffering" as it relates to the term "treatment" refers to a patient or individual who has been diagnosed with or is predisposed to the disease. A patient may also be referred to being "at risk of suffering" from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease. A patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease.
An "effective amount" or "therapeutically effective amount" is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc.. It is understood, however, that specific dose levels of the therapeutic agents of the present invention for any particular subject depends upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on the proper doses for patient administration. In general, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks. As used herein, the term "pharmaceutically acceptable excipient" encompasses any of the standard pharmaceutical excipients, including carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents. Pharmaceutical compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000). As used herein, the term "prodrug" means a pharmacological derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. For example, prodrugs are variations or derivatives of the compounds described herein that have groups cleavable under certain metabolic conditions, which when cleaved, become the compounds described herein, e.g. a compound of formula (I). Such prodrugs then are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds herein may be called single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and the number of functionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, "The Organic Chemistry of Drug Design and Drug Action" pp. 352-401, Academic Press, San Diego, Calif, 1992).
Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of acid compounds with a suitable alcohol, amides prepared by reaction of acid compounds with an amine, basic groups reacted to form an acylated base derivative, etc.. Other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability. As such, those of skill in the art will appreciate that certain of the presently disclosed compounds having, for example, free amino or hydroxyl groups can be converted into prodrugs. Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.
As used herein, the term "pharmaceutically acceptable salt" means a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.
As used herein, the term "alkyl" means a saturated linear or branched free radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. Other alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. The terms "Ci-3-alkyl", "C4-8-alkyl", etc., have equivalent meanings, i.e. a saturated linear or branched free radical consisting essentially of 1 to 3 (or 4 to 8) carbon atoms and a corresponding number of hydrogen atoms. The term "haloalkyl" means an alkyl group which is substituted by one or more halogens. Exemplary haloalkyl groups include chlorom ethyl, dichloromethyl, trichloroethyl, etc.. The term "fluoroalkyl" is to be construed accordingly, i.e. to encompass fluoromethyl, difluoromethyl, trifluoroethyl, etc..
As used herein, the term "alkenyl" means an unsaturated linear or branched free radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon double bond. Exemplary alkenyl groups include ethenyl, prop-l-enyl, prop-2-enyl, isopropenyl, but-l-enyl, 2-methyl-prop-l-enyl, 2- methyl-prop-2-enyl, 1,2-propandien-l-yl, etc. Other alkenyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. The term "C2-6-alkenyl" has an equivalent meaning, i.e. an unsaturated linear or branched free radical consisting essentially of 2 to 6 carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon double bond.
As used herein, the term "alkynyl" means an unsaturated linear or branched free radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon triple bond. Exemplary alkynyl groups include ethynyl, prop-l-ynyl, prop-2-ynyl, but-l-ynyl, 3-methyl-but-l-ynyl, etc. Other alkynyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. The term "C2-6-alkynyl" has an equivalent meaning, i.e. an unsaturated linear or branched free radical consisting essentially of 2 to 6 carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon triple bond.
As used herein, the term "cyclic group" means a saturated, partially or fully unsaturated, or aromatic group having at least 3 to 9 atoms {i.e. ring atoms) that form a ring. Where a cyclic group is defined as having a certain number of members, the term "members", "membered" and the like is used to denote the number of ring atoms in said cyclic group. For example, a 5- membered cyclic group {e.g. a 5-membered heterocyclic group) contains 5 ring atoms. It will be appreciated that a cyclic group may be part of a larger cyclic system; for example, bicyclo[4.3.0]nonane comprises two carbocyclic groups, namely a cyclohexane group and a cyclopentane group, which are fused to form the carbocyclic system which makes up the molecule. The term "cyclic group" is intended to encompass both carbocyclic groups as well as heterocyclic groups. The term "carbocyclic" refers to a group having at least 3 to 9 carbon atoms that form a ring. The term "carbocyclyl" is used to mean a carbocyclic free radical. The term "heterocyclic" refers to a group having at least 3 to 6 atoms that form a ring, wherein at least 1 to 5 of said ring atoms are carbon and the remaining at least 1 to 5 ring atom(s) (i.e. hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulphur and oxygen. The term "heterocyclyl" is used to mean a heterocyclic free radical.
The term "spiro" as used herein in relation to cyclic groups denotes that a first cyclic group within a multi cyclic system is attached to a second cyclic group within said multi cyclic system, wherein the ring atoms of said first cyclic group and the ring atoms of said second cyclic group have only one atom in common, i.e. said first and second cyclic groups share only one common ring atom. For example, the spiro[5.5]undecanyl group comprises two cyclohexane rings which have a single carbon ring atom in common. The term "fused" as used herein in relation to cyclic groups denotes that a first cyclic group within a multicyclic system is attached to a second cyclic group within said multicyclic system, wherein the ring atoms of said first cyclic group and the ring atoms of said second cyclic group have two adjacent atoms in common, i.e. said first and second cyclic groups share two common ring atoms. For example, the bicyclo[4.4.0]decanyl group comprises two cyclohexane rings which have two adjacent carbon ring atoms in common.
The term "bridged" as used herein in relation to cyclic groups denotes that a first cyclic group within a multicyclic system is attached to a second cyclic group within said multicyclic system, wherein the ring atoms of said first cyclic group and the ring atoms of said second cyclic group have more than two adjacent atoms in common, i.e. said first and second cyclic groups share three or more common ring atoms. For example, the bicyclo[3.3.1]nonanyl group comprises two cyclohexane rings which have three adjacent carbon ring atoms in common.
As used herein, the term "cycloalkyl" means a saturated free radical having at least 3 to 9 carbon atoms (i.e. ring atoms) that form a ring. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It will be appreciated that the cycloalkyl group may be monocyclic or multicyclic (e.g. fused, bridged or spirocyclic systems). In the case of multicyclic cycloalkyl groups, there are further rings, e.g. 1, 2, 3, or more, further rings, all of which contain from 3 to 9 carbon atoms (i.e. ring atoms). Exemplary cycloalkyl groups having such further rings include decalinyl (bicyclo[4.4.0]decanyl) and spiro[5.5]undecanyl.
As used herein, the term "cycloalkenyl" means a partially or fully unsaturated free radical having at least 3 to 9 carbon atoms (i.e. ring atoms) that form a ring. The term "cycloalkenyl" is not intended to encompass cyclic groups having significant aromatic character. Exemplary cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. It will be appreciated that the cycloalkenyl group may be monocyclic or multicyclic (e.g. fused, bridged or spirocyclic systems). In the case of multicyclic cycloalkenyl groups, there are further rings, e.g. 1, 2, 3, or more, further rings, all of which contain from 3 to 9 carbon atoms (i.e. ring atoms) and which may themselves be saturated or partially or fully unsaturated. Exemplary cycloalkenyl groups having such further rings include spiro[5.5]undecenyl and octahydronaphthalenyl .
As used herein, the term "aryl" means an aromatic free radical having at least 6 carbon atoms (i.e. ring atoms) that form a ring. It will be appreciated that the aryl group may be monocyclic or multicyclic (e.g. fused, bridged or spirocyclic systems). In the case of multicyclic aryl groups, there are further rings, e.g. 1, 2, 3, or more, further rings, all of which contain at least 3 carbon atoms (i.e. ring atoms), which further rings may optionally be aromatic. Examples of aryl groups include phenyl and naphthalenyl, as well as indenyl and indanyl groups. As used herein, the term "heterocycloalkyl" means a saturated free radical having at least 3 to 6 atoms (i.e. ring atoms) that form a ring, wherein at least 1 to 5 of said ring atoms are carbon and the remaining at least 1 to 5 ring atom(s) (i.e. hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulphur and oxygen. Exemplary heterocyclic groups include aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl. In the case of multicyclic heterocyclic groups, there are further rings, e.g. 1, 2, 3, or more, further rings, all of which contain from 3 to 6 ring atoms selected from carbon, nitrogen, sulphur and oxygen. Multicyclic heterocyclic rings include fused, bridged and spirocyclic ring systems. Exemplary heterocarbocyclic groups having such further rings include 2-azabicyclo[3.3.0]octanyl and 3,9- diazaspiro[5.5]undecanyl. As used herein, the term "heterocycloalkenyl" means a partially or fully unsaturated free radical having at least 3 to 6 atoms (i.e. ring atoms) that form a ring, wherein at least 1 to 5 of said ring atoms are carbon and the remaining at least 1 to 5 ring atom(s) (i.e. hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulphur and oxygen. Exemplary heterocycloalkenyl groups include tetrahydropyridyl. In the case of multi cyclic heterocycloalkenyl groups, there are further rings, e.g. 1, 2, 3, or more, further rings, all of which contain from 3 to 8 ring atoms selected from carbon, nitrogen, sulphur and oxygen. Said further rings may be saturated, or partially or fully unsaturated. Multicyclic heterocycloalkenyl groups include fused, bridged and spirocyclic ring systems. Exemplary heterocycloalkenyl groups having such further rings include 2,3-dihydroindolyl and 5,6-dihydroindolyl.
As used herein, the term "heteroaryl" means an aromatic free radical typically containing from 6 to 10 ring atoms, wherein 1 to 9 of said ring atoms are carbon and the remaining 1 to 9 ring atom(s) (i.e. hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulphur and oxygen. It will be appreciated that the heteroaryl group may be monocyclic or multicyclic (e.g. fused, bridged and/or spirocyclic systems). In the case of multicyclic heteroaryl groups, there are further rings, e.g. 1, 2, 3, or more, further rings, all of which contain at least 3 atoms (i.e. ring atoms), which further rings may optionally be aromatic. Examples of heteroaryl groups include monocyclic groups such as pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl and N-pyridin-4-onyl, as well as multicyclic groups such as benzofuranyl, benzothiophenyl, benzoxazolyl, indolyl, pyrrolopyridinyl, quinolinyl, pteridinyl and 2- oxob enzimi dazoly 1.
As used herein, the terms "halo" and "halogen" mean fluorine, chlorine, bromine, or iodine. These terms are used interchangeably and may refer to a halogen free radical group or to a halogen atom as such. Those of skill in the art will readily be able to ascertain the identification of which in view of the context in which this term is used in the present disclosure.
As used herein, the term "CN" mean a free radical having a carbon atom linked to a nitrogen atom via a triple bond. The CN radical is attached via its carbon atom.
As used herein, the term "oxo" means a free radical wherein an oxygen atom is connected to the atom bearing this radical via a double bond. For example, where a carbon atom carries an oxo radical it forms a carbon-oxygen double bond. It will be appreciated that not all atoms within a given structure can be substituted by oxo, and that this will depend on the free valency of the atom to be substituted.
The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
Compositions and methods provided herein may be combined with one or more of any of the other compositions and methods provided herein.
The following abbreviations are used herein: °C = Celsius
1H- MR = proton nuclear magnetic resonance
ADDP = l,l'-(azodicarbonyl)dipiperidine
AIBN = azobisisobutyronitrile
Boc = tert-butyloxycarbonyl
dba = dibenzylideneacetone
DCM = dichloromethane
DEAD = diethyl azodicarboxylate
DIAD = diisopropyl azodicarboxylate
DIBAL = diisobutylaluminum hydride
DIEA = N,N-diisopropylethylamine
DIPEA = N,N-diisopropylethylamine
DMA = Dimethylacetamide
DMF = dimethylformamide
DMSO = dimethyl sulfoxide
dppf = l, l'-Bis(diphenylphosphino)ferrocene
DTBAD = (E)-di-tert-butyl diazene-l,2-dicarboxylate
EDC = l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
ES+ = electrospray positive ionization
EtOAc = ethyl acetate
h = hour HAND = HIV-associated neurological disorders
HATU = 1 bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
HIV = human immunodeficiency virus
HOBt = hydroxybenzotriazole
HPLC = high pressure liquid chromatography
Hz = hertz
IDOl / ID02 = indoleamine 2, 3 -di oxygenase
IFN = interferon
KYN = kynurenine
LAH = Lithium aluminium hydride (LiAlH4)
L-TRP = L-tryptophan
M = molar
MeCN = acetonitrile
MHz = megahertz;
min = minute
MS = mass spectrometry
NBS = N-bromosuccinimide
QUIN = quinolic acid
rt / RT = room temperature
SFC = supercritical fluid chromatography
TBAF = tetra-«-butylammonium fluoride
TBDPS = tert-butyldiphenylsilyl
TEA = triethylamine
TDO = tryptophan dioxygenase
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TMZ = temozolomide
Compounds
The present invention relates to compounds useful as inhibitors of IDOl, ID02 and/or TDO. In one aspect, the invention provides a compound characterised by formula (IA) or formula (IB),
Figure imgf000039_0001
(IA) (IB) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Y1 is selected from CR1 and N;
Y2 is selected from CR3 and N;
A is selected from
R6R7,
Figure imgf000039_0002
heterocyclyl,
wherein said aryl or heterocyclyl is optionally substituted by one or more groups independently selected from R8;
R1 and R2 are each independently selected from
H,
halogen,
CN,
Ci.3-alkyl,
0-(Ci.3-alkyl),
C2-3-alkenyl,
C2-3-alkynyl,
C3-5-cycloalkyl, and
C3-5-cycloalkenyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is optionally substituted by one or more groups independently selected from halogen,
or R1 and R2 taken together with the intervening carbon atoms form a 5-membered carbocyclic or heterocyclic group which is optionally substituted with one or more groups independently selected from halogen;
R3 is selected from
H,
halogen,
C(0) H2, and
methyl optionally substituted by one or more groups independently selected from halogen;
R4 and R5 are each independently selected from H and NRaRb, wherein Ra and Rb are each independently selected from H and C1-3 alkyl;
R6 is selected from
H,
Ci-e-alkyl,
C2.6-alkenyl,
C2-6-alkynyl,
(C0-6-alkyl)-cycloalkyl,
(Co-6-alkyl)-cycloalkenyl,
(Co-6-alkyl)-aryl,
(Co-6-alkyl)-heterocycloalkyl,
(C0-6-alkyl)-heterocycloalkenyl, and
(Co-6-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R8a, and
R7 is selected from
H,
Ci-e-alkyl,
C2-6-alkenyl, C2.6-alkynyl,
(C0-6-alkyl)-cycloalkyl,
(Co-6-alkyl)-cycloalkenyl,
(Co-6-alkyl)-aryl,
(Co-6-alkyl)-heterocycloalkyl,
(C0-6-alkyl)-heterocycloalkenyl, and
(Co-6-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R ,
or R6 and R7 taken together with the intervening nitrogen atom form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group which is optionally substituted by one or more groups independently selected from R8;
any pair of R8 groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group,
any pair of R8a groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered carbocyclic or heterocyclic group,
any pair of R8b groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered carbocyclic or heterocyclic group, and
any remaining R8, R8a and/or R8b groups are each independently selected from
halogen,
oxo,
OH,
CN,
Ci-e-alkyl,
C2-6-alkenyl,
C2-6-alkynyl,
0-(Ci-6-alkyl),
(C0-6-alkyl)-SO2R9,
(C0-6-alkyl)-SO2N(R10)2, (Co-e-alky - HSOzR11,
N(R12)S02N(R1 )2,
N(R14)C(0)N(R15)2,
(C0-6-alkyl)- R16R17,
(C0-6-alkyl)- HC(O)R18,
(Co.6-alkyl)-C(0)N(R19)2,
(Co-6-alkyl)-C(0)R20,
(C0-6-alkyl)-C(O)OR21,
(Co-6-alkyl)-cycloalkyl,
(C0-6-alkyl)-cycloalkenyl,
(Co-6-alkyl)-aryl,
(Co-6-alkyl)-heterocycloalkyl,
(Co-6-alkyl)-heterocycloalkenyl, and
(Co-6-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J;
J in each case is independently selected from
halogen,
oxo,
OH,
CN,
Ci.5-alkyl,
C2-5-alkenyl,
C2 -5-alkynyl,
(C0-4-alkyl)-O-(C -alkyl),
(C0-4-alkyl)-SO2R9,
(C0-4-alkyl)-SO2N(R10)2,
(Co^-alky - HSOzR11,
N(R14)C(0)N(R15)2,
(C0-4-alkyl)- R16R17, (C0-4-alkyl)- HCOR ,
(C0-4-alkyl)-CON(R19)2,
(Co-4-alkyl)-C(0)R20,
C(0)OH,
C(0)0(Ci.4-alkyl),
(C0-4-alkyl)-aryl, and
(Co-4-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, heteroaryl or aryl is optionally substituted by one or more groups independently selected from halogen and hydroxy; and R9 to R21 are each independently selected from
H,
Ci-e-alkyl,
C2-6-alkenyl,
C2-6-alkynyl,
C3-6-cycloalkyl,
C3-6-cycloalkenyl,
phenyl,
3- to 6-membered heterocycloalkyl,
3- to 6-membered heterocycloalkenyl, and
5- to 7-membered heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl is optionally substituted by one or more groups independently selected from halogen, OH and Ci-3-alkyl optionally substituted by one or more groups independently selected from halogen. diments, J in each case is independently selected from:
halogen,
oxo,
OH,
CN,
Ci-s-alkyl,
C2-5-alkenyl, C2-5-alkynyl,
0-(C1-4-alkyl),
(C0-4-alkyl)-SO2R9,
(C0-4-alkyl)-SO2N(R10)2,
(Co^-alky - HSOzR11,
N(R14)C(0)N(R15)2,
(C0-4-alkyl)- R16R17,
(C0-4-alkyl)- HCOR18,
(C0-4-alkyl)-CON(R19)2,
(C0-4-alkyl)-C(O)R20,
C(0)OH,
C(0)0(Ci-4-alkyl),
(Co-4-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen.
In embodiments, the compound is not 8-phenylimidazo[l,5-a]pyridine.
In embodiments, at least one of Y1 and Y2 is N. In embodiments, one of Y1 and Y2 is N, and the other is CR1 or CR3, respectively. In embodiments, no more than one of Y1 and Y2 is N. In one embodiment, Y1 is N. In another embodiment Y1 is CR1. In one embodiment, Y2 is N. In another embodiment Y2 is CR3.
In aspects and embodiments, the compound is characterised by formula (IIA) or formula (IIB),
Figure imgf000045_0001
(IIA) (IIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R2 to R5 and A are as defined herein.
In aspects and embodiments, the compound is characterised by formula (IIIA) or formula (IIIB),
Figure imgf000045_0002
(IIIA) (IIIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, R4, R5 and A are as defined herein.
In aspects and embodiments, the compound is characterised by formula (IV A) or formula (IVB),
Figure imgf000046_0001
(IVA) (IVB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1 to R5 and A are as defined herein.
In embodiments, A is C6-10-aryl or heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted by one or more groups independently selected from R8 as defined herein.
In embodiments, A is C6-io-aryl optionally substituted by one or more groups independently selected from R8 as defined herein. In embodiments, A is phenyl optionally substituted by one or more groups independently selected from R8 as defined herein.
In other embodiments, A is heterocyclyl optionally substituted by one or more groups independently selected from R8 as defined herein. In embodiments, A is heterocyclyl, e.g. 3- to 10-membered, 5- to 8-membered, or 5- to 7-membered heterocyclyl. In embodiments, A is selected from heterocycloalkyl, heterocycloalkenyl, and heteroaryl, each of which is optionally substituted by one or more groups independently selected from R8 as defined herein. In embodiments, A is heterocycloalkyl optionally substituted by one or more groups independently selected from R8 as defined herein. In other embodiments, A is heterocycloalkenyl optionally substituted by one or more groups independently selected from R8 as defined herein. In other embodiments, A is heteroaryl optionally substituted by one or more groups independently selected from R8 as defined herein.
In embodiments, A is R6R7.
In embodiments, R1 and R2, where present, are independently selected from H, halogen, CN, Ci. 3-alkyl, 0-(Ci-3-alkyl), C2-3-alkenyl, C2-3-alkynyl, C3-5-cycloalkyl, and C3-5-cycloalkenyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is optionally substituted by one or more groups independently selected from halogen.
In embodiments, R1 and/or R2 are independently selected from H, halogen, CN, methyl, CF3, ethyl, CH3CF2, z'sopropyl, CF(CH3)2, 0-CHF2, 2-propenyl, ethynyl, cyclopropyl, and cyclopenten-l-yl, wherein said cyclopropyl is optionally substituted by one or two fluorine atoms.
In embodiments, R1 and/or R2 are independently selected from H, halogen, CN, and Ci-3-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen.
In embodiments, R1 and/or R2 are independently selected from H, halogen, and Ci-3-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen.
In embodiments, R1 and/or R2 are independently selected from H, halogen, and Ci-3-alkyl, wherein said alkyl is optionally substituted by one or more fluorine atoms.
In an embodiment, R2 is selected from CI and CF3.
In an embodiment, R1 is H.
In embodiments, R1, where present, is H, and R2 is selected from H, CI, and Ci-3-alkyl, wherein said alkyl is optionally substituted by one or more fluorine atoms. In embodiments, R1, where present, is H, and R2 is CI. In other embodiments, R1, where present, is H, and R2 is methyl optionally substituted by 1, 2 or 3 fluorine atoms. In other embodiments, R1 and R2, where present, are independently selected from H.
In other embodiments, R1 and R2 taken together with the intervening carbon atoms form a 5-membered carbocyclic or heterocyclic group which is optionally substituted with one or more groups independently selected from halogen (e.g. fluorine).
In embodiments where R3 is present, it is selected from H, halogen, and methyl, wherein said methyl is optionally substituted by one or more groups independently selected from halogen (e.g. fluorine). In embodiments where R3 is present, it is selected from H, CI, F, and methyl. In one embodiment where R3 is present, it is H.
In embodiments, R4 and R5 are each independently selected from H and H2. In one embodiment, R4 and R5 are both independently selected from H. In other embodiments, one of R4 and R5 is H and the other is RaRb.
In embodiments, Ra and Rb are each independently selected from H and methyl. In embodiments, Ra and/or Rb are independently selected from H. In embodiments, Ra and Rb are each Ci-3 alkyl.
In embodiments, R2 is selected from H, CI and Ci-3-alkyl, wherein said alkyl is optionally substituted by 1, 2 or 3 fluorine atoms; and R1, R3, R4 and R5, where present, are each independently selected from H.
In aspects and embodiments, the invention provides a compound characterised by formula (VA) or formula (VB
Figure imgf000048_0001
(VA) (VB)
or a pharmaceutically acceptable salt or prodrug thereof, wherein Y1, Y2, R2 and R4 to R7 are as defined herein.
In aspects and embodiments, the invention provides a compound characterised by formula (VIA) or formula (VIB),
Figure imgf000049_0001
(VIA) (VIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R2 to R7 are as defined herein.
In aspects and embodiments, the invention provides a compound characterised by formula (VIIA) or formula (VIIB),
Figure imgf000049_0002
(VIIA) (VIIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2 and R4 to R7 are as defined herein.
In aspects and embodiments, the invention provides a compound characterised by formula (VIIIA) or formula (VIIIB),
Figure imgf000050_0001
(VIIIA) (VIIIB) armaceutically acceptable salt or prodrug thereof, wherein R1 to R7 are as defined herein.
In embodiments where the compound is characterised by formula (VA) or formula (VB) (e.g. where the compound is characterised by formula (VIIIA) or formula (VIIIB)), R6 and R7 taken together with the intervening nitrogen atom form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group which is substituted by at least two R8 groups, wherein at least one pair of said R8 groups, taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, wherein said carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, where the compound is characterised by formula (VA) or formula (VB) (e.g. where the compound is characterised by formula (VIIIA) or formula (VIIIB)), R6 and R7 taken together with the intervening nitrogen atom form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group which is substituted by at least two R8 groups, and wherein at least one pair of said R8 groups, taken together with the intervening atom, forms a 3- to 10-membered spiro carbocyclic or heterocyclic group, wherein said carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, R6 and R7 taken together with the intervening nitrogen atom do not form a heterocyclic group.
In embodiments, R6 is selected from H, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, (Co-6-alkyl)- cycloalkyl, (Co-6-alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (C0. 6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R8a as defined herein; and R7 is selected from H, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, (Co-6-alkyl)-cycloalkyl, (C0. 6-alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)- heterocycloalkenyl, and (C0-6-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R as defined herein.
In embodiments, R6 is selected from H, Ci-6-alkyl, (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)- cycloalkenyl, (C0-6-alkyl)-aryl, (C0-6-alkyl)-heterocycloalkenyl, (C0-6-alkyl)-heterocycloalkyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R8a as defined herein.
In embodiments, R6 is selected from H and Ci-6-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from R8a as defined herein.
In embodiments, R6 is selected from (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)-cycloalkenyl, (C0. 6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)- heteroaryl, wherein each said cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R8a as defined herein.
In embodiments, R7 is selected from H, Ci-6-alkyl, (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)- cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkenyl, (Co-6-alkyl)-heterocycloalkyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R as defined herein.
In embodiments, R7 is selected from H and Ci-6-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from R as defined herein.
In embodiments, R7 is selected from (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)-cycloalkenyl, (C0. 6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)- heteroaryl, wherein each said cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R8b as defined herein.
In other embodiments, R6 and R7 taken together with the intervening nitrogen atom form a heterocyclic group.
In embodiments, R6 and R7 taken together with the intervening nitrogen atom form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group which is optionally substituted by one or more groups independently selected from R8 as defined herein.
In embodiments, R6 and R7 taken together with the intervening nitrogen atom form a heterocycloalkyl group, e.g. a 3- to 10-membered, 3- to 8-membered, or 5- to 7-membered heterocycloalkyl group, which is optionally substituted by one or more groups independently selected from R8 as defined herein.
In embodiments, R6 and R7 taken together with the intervening nitrogen atom form a heterocycloalkyl group selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, 1,2,3-triazolidinyl, piped dinyl, piperazinyl, morpholinyl, 1,4-azathianyl, azepanyl, 1,4-oxaazepanyl, 1,4- thiazepanyl, 1,4-diazepanyl, and tropanyl, wherein said heterocycloalkyl group is optionally substituted by one or more groups independently selected from R8 as defined herein. In embodiments, said heterocycloalkyl group is selected from piperidinyl and piperazinyl. In one embodiment, said heterocycloalkyl group is piperidinyl. In another embodiment, said heterocycloalkyl group is piperazinyl.
In embodiments, R6 and R7 taken together with the intervening nitrogen atom form a heterocycloalkenyl group, e.g. a 3- to 10-membered, 3- to 8-membered, or 5- to 7-membered heterocycloalkenyl group, which is optionally substituted by one or more groups independently selected from R8 as defined herein.
In embodiments, R6 and R7 taken together with the intervening nitrogen atom form a heterocycloalkenyl group selected from pyrrolinyl, pyrrazolinyl, imidazolinyl, isoxazolinyl, oxazolinyl, isothiazolinyl, and thiazolinyl, wherein said heterocycloalkenyl group is optionally substituted by one or more groups independently selected from R8 as defined herein. In embodiments, each R , R a and/or R group is independently selected from halogen, oxo, OH, CN, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, 0-(Ci-6-alkyl), (C0-6-alkyl)-SO2R9, (Co-e-alkyl)- SO2N(R10)2, (Co-e-alky -NHSO.R11, N(R12)S02N(R13)2, N(R14)C(0)N(R15)2, (Co-e-alkyl)- R16R17, (C0-6-alkyl)- HC(O)R18, (C0-6-alkyl)-C(O)N(R19)2, (C0-6-alkyl)-C(O)R20, (Co-e-alkyl)- C(0)OR21, (C0-6-alkyl)-cycloalkyl, (C0-6-alkyl)-cycloalkenyl, (C0-6-alkyl)-aryl, (C0-6-alkyl)- heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from J, and wherein R9 to R21 and J are as defined herein.
In embodiments, each R8, R8a and/or R8b group is independently selected from halogen, oxo, OH, CN, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, 0-(Ci-6-alkyl), (C0-6-alkyl)-SO2R9, (Co-e-alkyl)- S02NHR10, (Co-e-alky -NHSOzR11, N(R12)S02NHR13, N(R14)C(0)NHR15, (C0-6-alkyl)-NR16R17, (C0-6-alkyl)-NHC(O)R18, (C0-6-alkyl)-C(O)NHR19, (C0-6-alkyl)-C(O)R20, (C0-6-alkyl)-C(O)OR21, (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from J, and wherein R9 to R21 and J are as defined herein.
In embodiments, each R8a and R8b are independently selected from halogen, OH, C(0)OH, CN, (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2NHR10, (Co-6-alkyl)-NHS02Ru, N(R14)C(0)NHR15, (C0- 6-alkyl)-NR16R17, (C0-6-alkyl)-NHC(O)R18, and (C0-6-alkyl)-heteroaryl, wherein each said alkyl or heteroaryl is optionally substituted by one or more groups independently selected from J, and wherein R9 to R11, R14 to R18, and J are as defined herein.
In embodiments, each R8 is independently selected from halogen, oxo, OH, Ci-6-alkyl, 0-(Ci. 6-alkyl), (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2NHR10, (Co-e-alky -NHSOzR11, N(R12)S02NHR13, (C0-6-alkyl)-NHC(O)R18, (C0-6-alkyl)-C(O)NHR19, (C0-6-alkyl)-C(O)R20, (C0-6-alkyl)-aryl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, aryl or heteroaryl is optionally substituted by
9 13 18 20
one or more groups independently selected from J, and wherein R to R , R to R , and J are as defined herein. In embodiments, each R , R a and R is independently selected from halogen, oxo, Ci-6-alkyl, (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2N(R10)2, N(R12)S02N(R13)2, and (C0-6-alkyl)-C(O)R20 wherein each said alkyl is optionally substituted by one or more groups independently selected from J, and wherein R 9', R 10 , R 12 , R 13 , R 2z0u and J are as defined herein. In embodiments, each R8, R8a and R8b is independently selected from halogen, OH, methyl, trifluoromethyl, S02Me, S02 H2, HS02Me, C(0)Me, and phenyl, wherein said phenyl is optionally substituted by one or more groups independently selected from J.
In embodiments, at least one pair of R8 groups, taken together with the intervening atom or atoms, independently forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, said 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group is a 3- to 10-membered spiro, fused or bridged carbocyclic group, e.g. a 3- to 8-membered, 5- to 8-membered, or 5- to 7- membered spiro, fused or bridged carbocyclic group. In other embodiments, said 3- to 10- membered spiro, fused or bridged carbocyclic or heterocyclic group is a 3- to 10-membered spiro, fused or bridged heterocyclic group, e.g. a 3- to 8-membered, 5- to 8-membered, or 5- to 7- membered spiro, fused or bridged heterocyclic group.
In embodiments, at least one pair of R8 groups, taken together with the intervening atom, independently forms a 3- to 10-membered spiro carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein. In other embodiments, at least one pair of R8 groups, taken together with the intervening atoms, independently form a 3- to 10-membered fused carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein. In other embodiments, at least one pair of R8 groups, taken together with the intervening atoms, independently forms a 3- to 10-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, one pair of R groups, taken together with the intervening atom, forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, one pair of R8 groups, taken together with the intervening atom, forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein, and another R8 group is selected from halogen and Ci-6-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen. In one embodiment, said another R8 group is at a position vicinal to said spiro heterocyclic group. In embodiments, one pair of R8 groups, taken together with the intervening atom, forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein, and another pair of R8 groups is selected independently from halogen and Ci-6-alkyl, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen. In one embodiment, said another pair of R8 groups is at a position vicinal to said spiro heterocyclic group. In one embodiment, said pair of R8 groups is a geminal pair of groups which is preferably at a position vicinal to said spiro heterocyclic group.
In embodiments, one pair of R8 groups, taken together with the intervening atom, forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein, and another pair of R8 groups, taken together with the intervening atoms, forms a 5- to 8-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein. In one embodiment, said bridged carbocyclic or heterocyclic group is formed from a pair of R8 groups, at least one of which is positioned vicinal to said spiro heterocyclic group. In one embodiment, said bridged carbocyclic or heterocyclic group is formed from a pair of R8 groups, both of which are positioned vicinal to said spiro heterocyclic group.
In embodiments, at least one pair of R8a groups, taken together with the intervening atom or atoms, independently forms a 3- to 10-membered carbocyclic or heterocyclic group, e.g. a 3- to 8-membered, 5- to 8-membered, or 5- to 7- membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, at least one pair of R8a groups, taken together with the intervening atom or atoms, independently forms a 3- to 10-membered cycloalkyl or heterocycloalkyl group, e.g. a 3- to 8-membered, 5- to 8-membered, or 5- to 7- membered cycloalkyl or heterocycloalkyl group, wherein said cycloalkyl or heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, at least one pair of R8a groups, taken together with the intervening atom or atoms, independently forms a 3- to 10-membered cycloalkenyl or heterocycloalkenyl group, e.g. a 3- to 8-membered, 5- to 8-membered, or 5- to 7- membered cycloalkenyl or heterocycloalkenyl group, wherein said cycloalkenyl or heterocycloalkenyl group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, at least one pair of R8a groups, taken together with the intervening atom or atoms, independently forms a C6-io-aryl group, e.g. a phenyl group, wherein said aryl group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, at least one pair of R8a groups, taken together with the intervening atom or atoms, independently forms a 5- to 10-membered heteroaryl group, e.g. a 5- to 8-membered, or 6- to 7- membered heteroaryl group, wherein said heteroaryl group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, at least one pair of R8b groups, taken together with the intervening atom or atoms, independently forms a 3- to 10-membered carbocyclic or heterocyclic group, e.g. a 3- to 8-membered, 5- to 8-membered, or 5- to 7- membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, at least one pair of R8b groups, taken together with the intervening atom or atoms, independently forms a 3- to 10-membered cycloalkyl or heterocycloalkyl group, e.g. a 3- to 8-membered, 5- to 8-membered, or 5- to 7- membered cycloalkyl or heterocycloalkyl group, wherein said cycloalkyl or heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, at least one pair of R8b groups, taken together with the intervening atom or atoms, independently forms a 3- to 10-membered cycloalkenyl or heterocycloalkenyl group, e.g. a 3- to 8-membered, 5- to 8-membered, or 5- to 7- membered cycloalkenyl or heterocycloalkenyl group, wherein said cycloalkenyl or heterocycloalkenyl group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, at least one pair of R8b groups, taken together with the intervening atom or atoms, independently forms a C6-io-aryl group, e.g. a phenyl group, wherein said aryl group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, at least one pair of R8b groups, taken together with the intervening atom or atoms, independently forms a 5- to 10-membered heteroaryl group, e.g. a 5- to 8-membered, or 6- to 7- membered heteroaryl group, wherein said heteroaryl group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, each J is independently selected from halogen, oxo, OH, Ci-s-alkyl, 0-(Ci. 4-alkyl), (C0-4-alkyl)-SO2R9, and (C0-4-alkyl)-C(O)R20, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen. In embodiments, each J is independently selected from halogen, OH, Ci-s-alkyl, 0-(Ci-4-alkyl), (Co-4-alkyl)-S02R9, and (Co-4-alkyl)-C(0)R20, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen. In embodiments, each J is independently selected from halogen, oxo, Ci-5-alkyl, C2-5-alkenyl, C2- 5-alkynyl, (C0-4-alkyl)-O-(Ci-4-alkyl), (C0-4-alkyl)-SO2R9, and (C0-4-alkyl)-C(O)R20, wherein each said alkyl, alkenyl, or alkynyl is optionally substituted by one or more groups independently selected from halogen and hydroxy. In embodiments, each J is independently selected from halogen, oxo, Ci-5-alkyl, (C0-4-alkyl)-SO2R9, and (C0-4-alkyl)-C(O)R20, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen. In embodiments, each J is independently selected from halogen, Ci-s-alkyl, C2-5-alkenyl, (Co- 4-alkyl)-S02R9, and (Co-4-alkyl)-C(0)R20, wherein each said alkyl, or alkenyl is optionally substituted by one or more groups independently selected from halogen and hydroxy. In embodiments, each J is independently selected from halogen, Ci-s-alkyl, (Co-4-alkyl)-S02R9, and (Co-4-alkyl)-C(0)R20, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen.
In embodiments, each J is independently selected from CI, F, oxo, methyl, propan-l,2-dienyl, prop-2-ynyl, CF3, S02Me, and C(0)Me. In embodiments, each J is independently selected from CI, F, oxo, methyl, CF3, S02Me, and C(0)Me. In embodiments, each J is independently selected from oxo, methyl, S02Me, and C(0)Me. In embodiments, each J is independently selected from CI, F, methyl, CF3, S02Me, and C(0)Me. In embodiments, each J is independently selected from methyl, S02Me, and C(0)Me.
In embodiments, R9 to R21 are each independently selected from H, Ci-6-alkyl, C3 -6-cycloalkyl, phenyl, 3- to 6-membered heterocycloalkyl, and 5- to 7-membered heteroaryl, wherein each said alkyl, cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen, OH and Ci-3-alkyl optionally substituted by one or more groups independently selected from halogen.
In embodiments, R9 to R21 are each independently selected from H, Ci-6-alkyl, and phenyl, wherein each said alkyl, or phenyl is optionally substituted by one or more groups independently selected from halogen, OH and Ci-3-alkyl optionally substituted by one or more groups independently selected from halogen.
In embodiments, R9 to R21 are each independently selected from H and Ci-6-alkyl, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen.
In as ects and embodiments, the compound is characterised by formula (IXA) or formula (IXB),
Figure imgf000058_0001
(IXA) (IXB)
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
n is 0, 1 or 2; and
X1 is selected from N, C, S and O, and
and R are as defined herein. In as ects and embodiments, the compound is characterised b formula (XA) or formula (XB),
Figure imgf000059_0001
(XA) (XB)
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
n is 0, 1 or 2; and
X1 is selected from N, C, S and O, and
R2 to R5 and R8 are as defined herein.
In as ects and embodiments, the compound is characterised b formula (XIA) or formula (XIB),
Figure imgf000059_0002
or a pharmaceutically acceptable salt or prodrug thereof, wherein
m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
n is 0, 1 or 2; and
X1 is selected from N, C, S and O, and
R1, R2, R4, R5 and R8 are as defined herein. In aspects and embodiments, the compound is characterised by formula (XIIA) or formula
(XIIB
Figure imgf000060_0001
(XIIA) (XIIB)
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
n is 0, 1 or 2; and
X1 is selected from N, C, S and O, and
R1 to R5 and R8 are as defined herein.
In connection with formulae (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA) and (XIIB), and as will be appreciated, when X1 is selected from N, this denotes that said N may be substituted by H, or by a group selected from R8 as defined herein. Similarly, when X1 is selected from C, this denotes that said C may be substituted by one or two H and/or by one or two groups independently selected from R8 as defined herein. Likewise, when X1 is selected from S, this denotes that said S may either be unsubstituted, or be substituted by one or two oxo groups, e.g. it may denote a sulfide, a sulfoxide or a sulfone.
In embodiments where the compound is characterised by formula (IXA) or formula (IXB) (e.g. where the compound is characterised by formula (XIIA) or formula (XIIB)), m is an integer from 2 to 12, and at least one pair of R8 groups, taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, wherein said carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, where the compound is characterised by formula (IXA) or formula (IXB) (e.g. where the compound is characterised by formula (XIIA) or formula (XIIB)), m is an integer from 2 to 12, and at least one pair of R groups, taken together with the intervening atom, forms a 3- to 10-membered spiro carbocyclic or heterocyclic group, wherein said carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, m is 2, 3 or 4. In one embodiment, m is 2. In another embodiment, m is 3. In another embodiment, m is 4.
In embodiments, n is 0 or 1. In embodiments, n is 1 or 2. In one embodiment, n is 0. In another embodiment, n is 1.
In one embodiment, X1 is N, e.g. R8. In another embodiment, X1 is C, e.g. CHR8. In another embodiment, X1 is S. In another embodiment, X1 is O.
In aspects and embodiments, the compound is characterised by formula (XIIIA) or formula (XIIIB
Figure imgf000061_0001
(XIIIA) (XIIIB)
or a pharmaceutically acceptable salt or prodrug thereof, wherein Y1, Y2, R2, R4 and R5 are as defined herein, and wherein:
any pair of the groups R22 to R31, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group,
wherein any remaining groups R22 to R31 are each independently selected from
H,
halogen, oxo,
OH,
CN,
Ci-e-alkyl,
C2-6-alkenyl,
C2-6-alkynyl,
0-(Ci-6-alkyl),
(Co-6-alkyl)-S02R9,
(C0.6-alkyl)-SO2N(R10)2,
(Co.6-alkyl)- HS02Ru,
N(R12)S02N(R13)2,
N(R14)C(0)N(R15)2,
(Co-6-alkyl)- R16R17,
(C0-6-alkyl)-NHC(O)R18,
(Co-6-alkyl)-C(0)N(R19)2,
(Co-6-alkyl)-C(0)R20,
(C0-6-alkyl)-C(O)OR21,
(C0-6-alkyl)-cycloalkyl,
(C0-6-alkyl)-cycloalkenyl,
(Co-6-alkyl)-aryl,
(Co-6-alkyl)-heterocycloalkyl,
(Co-6-alkyl)-heterocycloalkenyl, and
(Co-6-alkyl)-heteroaryl,
wherein when any of R22 to R31 is oxo, the corresponding geminal group is absent, wherein R9 to R21 are as defined herein, and
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
In aspects and embodiments, the compound is characterised by formula (XIVA) or formula (XIVB),
Figure imgf000063_0001
(XIVA) (XIVB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R2 to R5 and R22 to R31 are as defined herein.
In aspects and embodiments, the compound is characterised by formula (XV A) or formula (XVB
Figure imgf000063_0002
(XV A) (XVB)
1 2 4 5 22 31 or a pharmaceutically acceptable salt or prodrug thereof, wherein R , R , R , R and R to R are as defined herein.
In aspects and embodiments, the compound is characterised by formula (XVIA) or formula
(xvm),
Figure imgf000064_0001
In embodiments where the compound is characterised by formula (XIIIA) or formula (XIIIB) (e.g. where the compound is characterised by formula (XVIA) or formula (XVIB)), at least one pair of the groups R22 to R31, taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, wherein each said carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments where the compound is characterised by formula (XIIIA) or formula (XIIIB) (e.g. where the compound is characterised by formula (XVIA) or formula (XVIB)), at least one pair of the groups R22 to R31, taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, and any remaining groups R22 to R31 are each independently selected from H, halogen, oxo, Ci-6-alkyl, (Co-6-alkyl)- S02R9, (C0-6-alkyl)-SO2N(R10)2, N(R12)S02N(R13)2, and (C0-6-alkyl)-C(O)R20, wherein when any
22 31 9 10 12 13 of R" to RJ i is oxo then the corresponding geminal group is absent, wherein R , R , R , R and R20 are as defined herein, and wherein each said alkyl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, at least one pair of the groups R22 to R31, taken together with the intervening atom or atoms, forms a spiro, fused or bridged carbocyclic or heterocyclic group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered carbocyclic or heterocyclic group, which carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, at least one pair of the groups R22 to R31, taken together with the intervening atom or atoms, forms a spiro, fused or bridged cycloalkyl or cycloalkenyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered cycloalkyl or cycloalkenyl group, which cycloalkyl or cycloalkenyl group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, at least one pair of the groups R22 to R31, taken together with the intervening atom or atoms, forms a spiro, fused or bridged heterocycloalkyl or heterocycloalkenyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered heterocycloalkyl or heterocycloalkenyl group, which heterocycloalkyl or heterocycloalkenyl group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, at least one pair of the groups R22 to R31, taken together with the intervening atom or atoms, forms a spiro, fused or bridged heterocycloalkyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, at least one pair of the groups R22 to R31, taken together with the intervening atom, forms a spiro heterocycloalkyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8- membered, or 5- to 7-membered heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, R 22 and R 23 together with the intervening atom, and/or R 30 and R 31 together with the intervening atom, independently form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group (e.g. a 3- to 8-membered spiro heterocycloalkyl group), which cycloalkyl or cycloalkenyl group is optionally and independently substituted by one or more groups independently selected from J as defined herein.
In embodiments, R 24 and R 25 together with the intervening atom, and/or R 28 and R 29 together with the intervening atom, independently form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group (e.g. a 3- to 8-membered spiro heterocycloalkyl group), which cycloalkyl or cycloalkenyl group is optionally and independently substituted by one or more groups independently selected from J as defined herein.
In embodiments, R26 and R27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group (e.g. a 3- to 8-membered spiro heterocycloalkyl group), which cycloalkyl or heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments where the compound is characterised by formula (XIIIA) or formula (XIIIB) (e.g. where the compound is characterised by formula (XVIA) or formula (XVIB)), R26 and R27 together with the intervening atom form a 4- to 6-membered spiro heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein, wherein R24 is selected from halogen and Ci-6-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen, and wherein R22, R23, R25, R28, R29, R30 and R31 are each H. In embodiments where the compound is characterised by formula (XIIIA) or formula (XIIIB) (e.g. where the compound is characterised by formula (XVIA) or formula (XVIB)), R26 and R27 together with the intervening atom form a 4- to 6-membered spiro heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein, wherein R24 and R25 are independently selected from halogen and Ci. 6-alkyl, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen, and wherein R22, R23, R28, R29, R30 and R31 are each H.
In embodiments where the compound is characterised by formula (XIIIA) or formula (XIIIB) (e.g. where the compound is characterised by formula (XVIA) or formula (XVIB)), one pair of the groups R22 to R31, taken together with the intervening atom, forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein, and wherein another pair of the groups R22 to R31, taken together with the intervening atoms, forms a 5- to 8-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments where the compound is characterised by formula (XIIIA) or formula (XIIIB) (e.g. where the compound is characterised by formula (XVIA) or formula (XVIB)), R26 and R27, taken together with the intervening atom, forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein, and wherein R24 and R28, taken together with the intervening atoms, forms a 5- to 8-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, said spiro heterocycloalkyl group is selected from imidazolinyl, piperidinyl, and azepanyl, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein. In one embodiment, said spiro heterocycloalkyl group is imidazolinyl, optionally substituted by one or more groups independently selected from J as defined herein. In another embodiment, said spiro heterocycloalkyl group is piperidinyl, optionally substituted by one or more groups independently selected from J as defined herein. In another embodiment, said spiro heterocycloalkyl group is azepanyl, optionally substituted by one or more groups independently selected from J as defined herein. In one embodiment, said spiro heterocycloalkyl group is imidazolidine-2,4-dionyl (hydantoinyl).
In embodiments, R24, R25, R26, R27, R28, R29, R30 and R31 are each independently selected from H, Ci.6-alkyl, S02(Ci-3-alkyl), S02 H2, S02 H(Ci-6-alkyl) and C(0)(Ci-6-alkyl); and R22 and R23 are each independently selected from H, Ci-6-alkyl, S02(Ci-3-alkyl), S02 H2, S02 H(Ci. 6-alkyl) and C(0)(Ci-6-alkyl), or R22 and R23 together with the intervening atom form a 3- to 8- membered spiro cycloalkyl or heterocycloalkyl group; wherein each said alkyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more groups independently selected from J as defined in herein. In embodiments, R22, R23, R26, R27, R28, R29, R30 and R31 are each independently selected from H, Ci-e-alkyl, S02(Ci-3-alkyl), S02 H2, S02 H(Ci-6-alkyl) and C(0)(Ci-6-alkyl); and R24 and R25 are each independently selected from H, Ci-e-alkyl, S02(Ci-3-alkyl), S02 H2, S02 H(Ci. 6-alkyl) and C(0)(Ci-6-alkyl), or R24 and R25 together with the intervening atom form a 3- to 8- membered spiro cycloalkyl or heterocycloalkyl group; wherein each said alkyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more groups independently selected from J as defined herein.
In embodiments, R22, R23, R30 and R31 are each independently H; R26, R27, R28 and R29 are each independently selected from H, Ci-6-alkyl, S02(Ci-3-alkyl), S02 H2, S02 H(Ci-6-alkyl) and C(0)(Ci-6-alkyl); and R24 and R25 are each independently selected from H, Ci-6-alkyl, S02(Ci. 3-alkyl), S02 H2, S02 H(Ci-6-alkyl) and C(0)(Ci-6-alkyl), or R24 and R25 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group; wherein each said alkyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more groups independently selected from J as defined herein. In embodiments, R22, R23, R30 and R31 are each H; R24, R25, R28 and R29 are each independently selected from H and Ci-6 alkyl; and R26 and R27 are each independently selected from H, Ci. 6-alkyl, S02(Ci-3-alkyl), S02 H2, S02 H(Ci-6-alkyl) and C(0)(Ci-6-alkyl), or R26 and R27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group; wherein each said alkyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more groups independently selected from J as defined herein.
In embodiments, R24 and R28 together with the intervening atoms form a 5- to 8-membered bridged cycloalkyl or heterocycloalkyl group, and/or R26 and R27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group, wherein each said cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, R26 and R27 together with the intervening atom do not form a carbocyclic or heterocyclic group.
In embodiments, R22, R23, R30 and R31 are each independently H; R24, R25, R28 and R29 are each independently selected from H and Ci-6 alkyl; and R26 and R27 are each independently selected from H, Ci-6-alkyl, S02(Ci-3-alkyl), S02 H2, S02 H(Ci-6-alkyl), and C(0)(Ci-6-alkyl); wherein each said alkyl is optionally and independently substituted by one or more groups independently selected from J as defined herein.
In one embodiment, R 22 , R 23 , R 30 and R 31 are each independently H. In embodiments, R , R , R and R are each independently selected from H and Ci-6-alkyl, wherein said alkyl is optionally and independently substituted by one or more groups
24 25 28 29
independently selected from J as defined herein. In embodiments, R , R , R and R are each independently selected from H and methyl. In embodiments, R24 and R25 are each methyl, and R28 and R29 are each independently H.
In embodiments, R26 and R27 are each independently selected from H, Ci-6-alkyl, S02(Ci. 3-alkyl), S02 H2, S02 H(Ci-6-alkyl), and C(0)(Ci-6-alkyl), wherein each said alkyl is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, R26 and R27 are each independently selected from H, S02Me, and C(0)Me. In embodiments, R26 is H, and R27 is S02Me or C(0)Me. In one embodiment, R26 is H, and R27 is S02Me. In another embodiment, R26 is H, and R27 is C(0)Me.
In embodiments where the compound is characterised by formula (XIIIA) or formula (XIIIB) (e.g. where the compound is characterised by formula (XVIA) or formula (XVIB)), R22, R23,
28 29 30 31 24 25
R , R", RJU and RJ1 are each independently H; R and R are each independently selected from H and methyl; and R26 and R27 together with the intervening atom form a 5- to 7-membered spiro heterocycloalkyl group, wherein said heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments where the compound is characterised by formula (XIIIA) or formula (XIIIB) (e.g. where the compound is characterised by formula (XVIA) or formula (XVIB)), R1 is H; R2 is CI or CF3; R3 to R5 are each independently H; R22, R23, R28, R29, R30 and R31 are each independently H; R24 and R25 are each independently selected from H and methyl; and R26 and R27 together with the intervening atom form a 5- to 7-membered spiro heterocycloalkyl group, wherein said heterocycloalkyl group is optionally substituted by one or more groups independently selected from oxo, methyl, C(0)Me, and S02Me.
In aspects and embodiments, the compound is characterised by formula (XVIIA) or formula (XVIIB),
Figure imgf000070_0001
(XVIIA)
or a pharmaceutically acceptable salt or prodrug thereof, wherein Y1, Y2, R2, R4 and R5 are as defined herein, and wherein:
any pair of the groups R22 to R25 and R28 to R32, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group,
wherein any remaining groups R22 to R25 and R28 to R31 are as defined herein, and wherein any remaining R32 group is selected from
H,
OH,
C1-6-alkyl,
C2-6-alkenyl,
C2-6-alkynyl,
0-(Ci-6-alkyl),
(C0-6-alkyl)-SO2R9,
(Co-6-alkyl)-S02N(R10)2,
(Ci-e-alky -NHSOzR11,
(Ci-6-alkyl)- R16R17,
(Ci-6-alkyl)- HC(0)R18,
(Co-6-alkyl)-C(0)N(R1 )2,
(Co-6-alkyl)-C(0)R20,
(C0-6-alkyl)-C(O)OR21,
(C0-6-alkyl)-cycloalkyl,
(Co-6-alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl,
(C0-6-alkyl)-heterocycloalkyl,
(Co-6-alkyl)-heterocycloalkenyl, and
(Co-6-alkyl)-heteroaryl,
wherein R9 to R11, and R16 to R21 are as defined herein, and
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
In aspects and embodiments, the compound is characterised by formula (XVIIIA) or formula (XVIIIB
Figure imgf000071_0001
(XVIIIA) (XVIIIB)
2 5 22 25 28 or a pharmaceutically acceptable salt or prodrug thereof, wherein R to R , R to R , and R to R32 are as defined herein.
In aspects and embodiments, the compound is characterised by formula (XIXA) or formula (XIXB
Figure imgf000071_0002
(XIXA) (XIXB) 1 2 4 5 22 25 or a pharmaceutically acceptable salt or prodrug thereof, wherein R , R , R , R , R to R , and R28 to R32 are as defined herein.
In aspects and embodiments, the compound is characterised by formula (XXA) or formula (XXB
Figure imgf000072_0001
(XXA) (XXB)
1 5 22 25 28 or a pharmaceutically acceptable salt or prodrug thereof, wherein R to R , R to R , and R to are as defined herein.
In embodiments where the compound is characterised by formula (XVIIA) or formula (XVIIB) (e.g. where the compound is characterised by formula (XXA) or formula (XXB)), at least one
22 25 28 32
pair of the groups R to R , and R to R , taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, wherein each said carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments where the compound is characterised by formula (XVIIA) or formula (XVIIB) (e.g. where the compound is characterised by formula (XXA) or formula (XXB)), at least one
22 25 28 32
pair of the groups R to R , and R to R , taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group; any
22 25 28 31
remaining groups R" to R , and Rie to R , are each independently selected from H, halogen, oxo, Ci-e-alkyl, (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2N(R10)2, N(R12)S02N(R13)2, and (C0-6-alkyl)-
20 22 25 28 31
C(0)R , wherein when any of R" to R" and Rzo to RJ i is oxo then the corresponding geminal group is absent; and any remaining group R32 is selected from H, Ci-6-alkyl, (Co-6-alkyl)-S02R9, (C0-6-alkyl)-SO2N(R10)2, and (C0-6-alkyl)-C(O)R20, wherein R9, R10, R12, R13 and R20 are as defined herein, and wherein each said alkyl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
22 25 28 32
In embodiments, at least one pair of the groups R to R , and R to R , taken together with the intervening atom or atoms, forms a spiro, fused or bridged carbocyclic or heterocyclic group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered carbocyclic or heterocyclic group, which carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein.
22 25 28 31
In embodiments, at least one pair of the groups R to R , and R to R , taken together with the intervening atom or atoms, forms a spiro, fused or bridged cycloalkyl or cycloalkenyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered cycloalkyl or cycloalkenyl group, which cycloalkyl or cycloalkenyl group is optionally substituted by one or more groups independently selected from J as defined herein.
22 25 28 32
In embodiments, at least one pair of the groups R to R , and R to R , taken together with the intervening atom or atoms, forms a spiro, fused or bridged heterocycloalkyl or heterocycloalkenyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered heterocycloalkyl or heterocycloalkenyl group, which heterocycloalkyl or heterocycloalkenyl group is optionally substituted by one or more groups independently selected from J as defined herein.
22 25 28 32
In embodiments, at least one pair of the groups R to R , and R to R , taken together with the intervening atom or atoms, forms a spiro, fused or bridged heterocycloalkyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein.
22 25 28 31
In embodiments, at least one pair of the groups R to R , and R to R , taken together with the intervening atom, forms a spiro heterocycloalkyl group, e.g. a 3- to 10-membered, 3- to 8-membered, 5- to 8-membered, or 5- to 7-membered heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, R and R together with the intervening atom, and/or R and R together with the intervening atom, independently form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group (e.g. a 3- to 8-membered spiro heterocycloalkyl group), which cycloalkyl or cycloalkenyl group is optionally and independently substituted by one or more groups independently selected from J as defined herein.
24 25 28 29
In embodiments, R and R together with the intervening atom, and/or R and R together with the intervening atom, independently form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group (e.g. a 3- to 8-membered spiro heterocycloalkyl group), which cycloalkyl or cycloalkenyl group is optionally and independently substituted by one or more groups independently selected from J as defined herein.
In embodiments, said spiro heterocycloalkyl group is selected from imidazolinyl, piperidinyl, and azepanyl, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined herein. In one embodiment, said spiro heterocycloalkyl group is imidazolinyl, optionally substituted by one or more groups independently selected from J as defined herein. In another embodiment, said spiro heterocycloalkyl group is piperidinyl, optionally substituted by one or more groups independently selected from J as defined herein. In another embodiment, said spiro heterocycloalkyl group is azepanyl, optionally substituted by one or more groups independently selected from J as defined herein. In one embodiment, said spiro heterocycloalkyl group is imidazolidine-2,4-dionyl (hydantoinyl). In embodiments, R24, R25, R28, R29, R30 and R31 are each independently selected from H, Ci. 6-alkyl, S02(Ci-3-alkyl), S02 H2, S02 H(Ci-6-alkyl) and C(0)(Ci-6-alkyl); R32 is selected from H, Ci-e-alkyl, C(0)(Ci-6-alkyl), S02(Ci-6-alkyl), (Co-6-alkyl)-cycloalkyl, (C0-6-alkyl)- cycloalkenyl, (C0-6-alkyl)-aryl, (C0-6-alkyl)-heterocycloalkyl, (C0-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl; and R22 and R23 are each independently selected from H, Ci-6-alkyl, S02(Ci-3-alkyl), S02 H2, S02 H(Ci-6-alkyl) and C(0)(Ci-6-alkyl), or R22 and R23 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group; wherein each said alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from J as defined in herein. 24 25 28 29 30 31
In embodiments, R , R , R , R , RJU and RJ1 are each independently selected from H, Ci. 6-alkyl, S02(Ci-3-alkyl), S02 H2, S02 H(Ci-6-alkyl) and C(0)(Ci-6-alkyl); R32 is selected from H, Ci-e-alkyl, C(0)(Ci-6-alkyl), S02(Ci-6-alkyl), (C0-6-alkyl)-cycloalkyl, (C0-6-alkyl)- cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl; and R22 and R23 together with the intervening atom form a 3- to 8- membered spiro cycloalkyl or heterocycloalkyl group; wherein each said alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from J as defined in herein.
In embodiments, R 22 , R 23 , R 30 and R 31 are each independently H; R 28 and R 29 are each independently selected from H, Ci-e-alkyl, S02(Ci-3-alkyl), S02 H2, S02 H(Ci-6-alkyl) and C(0)(Ci-6-alkyl); R32 is selected from H, Ci-6-alkyl, C(0)(Ci-6-alkyl), S02(Ci-6-alkyl), (C0. 6-alkyl)-cycloalkyl, (Co-6-alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl; and R24 and R25 are each independently selected from H, Ci-e-alkyl, S02(Ci-3-alkyl), S02 H2, S02 H(Ci-6-alkyl) and C(0)(Ci-6-alkyl), or R24 and R25 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group; wherein each said alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, R24 and R28 together with the intervening atoms form a 5- to 8-membered bridged cycloalkyl or heterocycloalkyl group, wherein each said cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, R22, R23, R30 and R31 are each independently H; R24, R25, R28 and R29 are each independently selected from H and Ci-6 alkyl; and R32 is selected from H, Ci-6-alkyl, C(0)(Ci. 6-alkyl), S02(Ci-6-alkyl), (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)-cycloalkenyl and (Co-6-alkyl)-aryl; wherein each said alkyl, cycloalkyl, cycloalkenyl or aryl is optionally substituted by one or more groups independently selected from J as defined herein.
In one embodiment, R 22 , R 23 , R 30 and R 31 are each independently H.
In embodiments, R 24 , R 25 , R 28 and R 29 are each independently selected from H and Ci.6-alkyl, wherein said alkyl is optionally and independently substituted by one or more groups independently selected from J as defined herein. In embodiments, R 24 , R 25 , R 28 and R 29 are each independently selected from H and methyl. In embodiments, R and R are each methyl, and R28 and R29 are each independently H.
In embodiments, R32 is selected from H, Ci-6-alkyl, (C0-6-alkyl)-SO2R9 and (C0-6-alkyl)-C(O)R20, wherein each said alkyl is optionally substituted by one or more groups independently selected from J, and wherein R9, R20 and J are as defined herein.
In embodiments, R32 is selected from H, Ci-6-alkyl, S02(Ci-6-alkyl), and C(0)(Ci-6-alkyl), wherein each said alkyl is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, R32 is selected from H, S02Me, and C(0)Me.
In embodiments where the compound is characterised by formula (XVIIA) or formula (XVIIB)
22 23 28 (e.g. where the compound is characterised by formula (XXA) or formula (XXB)), R , R , R , R29, R30 and R31 are each independently H; R24 and R25 are each independently selected from H and methyl; and R32 is selected from C(0)Me and S02Me.
In embodiments where the compound is characterised by formula (XVIIA) or formula (XVIIB)
22 23 28
(e.g. where the compound is characterised by formula (XXA) or formula (XXB)), R , R , R ,
29 30 31 24 25 32
R , RJU and RJ1 are each independently H; R and R are each methyl; and R is selected from C(0)Me and S02Me.
In embodiments where the compound is characterised by formula (XVIIA) or formula (XVIIB) (e.g. where the compound is characterised by formula (XXA) or formula (XXB)), R1 is H; R2 is CI or CF3; R3 to R5 are each independently H; R22, R23, R28, R29, R30 and R31 are each independently H; R24 and R25 are each methyl; and R32 is selected from C(0)Me and S02Me.
In embodiments, A is selected from
Figure imgf000077_0001
wherein:
X2 is selected from NH, N(Ci-5 alkyl), O, and CR'2, wherein each R' is independently selected from H and C alkyl;
R , R and R are each independently selected from
H,
Ci-5-alkyl,
C2-5-alkenyl,
C2-5-alkynyl and
(C0-4-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen and hydroxyl; and
R35 is selected from H,
Ci.s-alkyl,
C2-5-alkenyl,
C2-5-alkynyl,
(C0-4-alkyl)-SO2R9,
(C0-4-alkyl)-SO2N(R10)2,
Figure imgf000078_0001
(Ci.4-alkyl)- HCOR18,
(C0-4-alkyl)-CON(R19)2,
(C0-4-alkyl)-COR20, and
(Co-4-alkyl)-heteroaryl,
wherein R9, R10, R11, R18, R19 and R20 are as defined herein, and
wherein each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen and hydroxyl, and wherein R24 to R27, where present, are as defined herein.
In embodiments,
R24 and R25 together with the intervening atom, form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group, and/or
R26 and R27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group, and
any remaining groups R24 to R27 are each independently selected from
H,
halogen,
oxo,
Ci-e-alkyl,
(C0-6-alkyl)-SO2R9,
(C0-6-alkyl)-SO2N(R10)2,
Co-e-alky - HSOzR11,
N(R12)S02N(R13)2,
(C0-6-alkyl)- HCOR18, (C0-6-alkyl)-CON(Er)2,
(C0-6-alkyl)-C(O)R20,
(Co-6-alkyl)-cycloalkyl,
(Co-6-alkyl)-aryl,
(Co-6-alkyl)-heterocycloalkyl, and
(C0-6-alkyl)-heteroaryl,
wherein when any of R24 to R27 is oxo, the corresponding geminal group is absent, wherein R9 to R11 and R18 to R20 are as defined herein, and
wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally and independently substituted by one or more groups independently selected from J as defined herein.
In embodiments, A is selected from
Figure imgf000079_0001
wherein: X2 is selected from NH, N(Ci-5 alkyl), O, and CR'2, wherein each R' is independently selected from H and Ci-5 alkyl;
R 33 , R 34 and R 36 are each independently selected from
H,
Ci-5-alkyl, and
(Co-4-alkyl)-heteroaryl,
wherein each said alkyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen; and
R35 is selected from
H,
Ci-s-alkyl,
(C0-4-alkyl)-SO2R9,
(C0-4-alkyl)-SO2N(R10)2,
(CM-alky - HSOiR11,
(Ci.4-alkyl)- HCOR18,
(C0-4-alkyl)-CON(R19)2,
(C0-4-alkyl)-COR20, and
(Co-4-alkyl)-heteroaryl,
wherein R9, R10, R11, R18, R19 and R20 are as defined herein, and
wherein each said alkyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen, and wherein R24 to R27, where present, are as defined herein.
In embodiments,
R24 and R25 together with the intervening atom, form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group, and/or
R26 and R27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group, and
any remaining groups R24 to R27 are each independently selected from
H,
halogen, oxo,
C1-6-alkyl,
(C0.6-alkyl)-SO2R9,
(Co-6-alkyl)-S02N(R10)2,
C0-6-alkyl)- HSO2R11,
N(R12)S02N(R1 )2,
(C0-6-alkyl)-NHCOR18,
(C0-6-alkyl)-CON(R19)2,
(Co-6-alkyl)-C(0)R20,
(C0-6-alkyl)-cycloalkyl,
(C0-6-alkyl)-aryl,
(Co-6-alkyl)-heterocycloalkyl, and
(Co-6-alkyl)-heteroaryl,
wherein when any of R24 to R27 is oxo, the corresponding geminal group is absent, wherein R9 to R13 and R18 to R20 are as defined herein, and
wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally and independently substituted by one or more groups independently selected from J as defined herein.
In embodiments, A is selected from
Figure imgf000081_0001
24 27 33 35 2
wherein R to R , R to R and X , where present, are as defined herein. In embodiments, A is selected from
Figure imgf000082_0001
wherein R to R , where present, are as defined herein.
In embodiments, A is selected from
Figure imgf000082_0002
24 27 33 35 2
wherein R to R , R to R and X , where present, are as defined herein. In embodiments, A is selected from
Figure imgf000083_0001
24 27 33 35 2
wherein R to R , R to R and X , where present, are as defined herein.
In one embodiment, X2 is H. In other embodiments, X2 is N(Ci-5 alkyl). In embodiments, X2 is N(Ci-3 alkyl). In one embodiment, X2 is Me. In another embodiment, X2 is O.
In other embodiments, X2 is CR'2, wherein each R' is independently selected from H and Ci-5- alkyl.
In embodiments, R33 and R34 are selected from H, Ci-s-alkyl, C2-5-alkenyl and C2-5-alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted by one or more groups independently selected from halogen and hydroxyl. In embodiments, R33 and R34 are selected from H, C2-5-alkenyl and C2-5-alkynyl, wherein said alkenyl or alkynyl is optionally substituted by one or more groups independently selected from halogen. In embodiments, R33 and R34 are selected from H and Ci-5-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen. In embodiments, R33 and R34 are selected from H and methyl. In one embodiment, R 33 and R 34 are each H. In another embodiment, R 33 and R 34 are each methyl. In another embodiment, R33 is H, and R34 is methyl.
In embodiments, R35 is selected from H, Ci-s-alkyl, S02(Ci-3-alkyl), and C(0)(Ci-6-alkyl), wherein each said alkyl is optionally and independently substituted by one or more groups independently selected from halogen. In embodiments, R35 is independently selected from H, S02Me and C(0)Me. In embodiments, R35 is independently selected from S02Me and C(0)Me. In embodiments, R is selected from H and Ci-5-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen. In embodiments, R36 is selected from H and methyl.
In embodiments, A is selected from
Figure imgf000085_0001
In embodiments, A is selected from
Figure imgf000086_0001
In embodiments, A is selected from
Figure imgf000086_0002
In embodiments, A is selected from
Figure imgf000087_0001
In embodiments, A is selected from
Figure imgf000087_0002
In embodiments, A is selected from
Figure imgf000088_0001
In embodiments, A is selected from
Figure imgf000088_0002
In aspects and embodiments, A is C6-io-aryl, optionally substituted by one or more groups independently selected from R8, wherein R8 is as defined herein. In one embodiment, said C6. lo-aryl is phenyl.
In embodiments, A is C6-10-aryl substituted by at least one group independently selected from R8, wherein R8 is as defined herein. In embodiments, A is C6-io-aryl substituted by at least two groups independently selected from R8, wherein R8 is as defined herein. In embodiments, A is C6-io-aryl substituted by at least three groups independently selected from R8, wherein R8 is as defined herein. In embodiments, A is not unsubstituted phenyl. In other embodiments, A is not 4- (methyl sulfonyl)phenyl .
In aspects and embodiments, the compound is characterised by formula (XXIA) or formula (XXIB),
Figure imgf000089_0001
(XXIA) (XXIB) pharmaceutically acceptable salt or prodrug thereof,
IT to R4J are each independently selected from:
H,
halogen,
OH,
CN,
Ci-e-alkyl,
C2-6-alkenyl,
C2-6-alkynyl,
0-(C1-6-alkyl),
(C0-6-alkyl)-SO2R9,
(C0-6-alkyl)-SO2N(R10)2,
(Co-e-alky - HSO.R11,
N(R12)S02N(R13)2,
N(R14)C(0)N(R15)2,
(C0-6-alkyl)- R16R17,
(C0-6-alkyl)-NHC(O)R18,
(C0-6-alkyl)-C(O)N(R19)2,
(Co-6-alkyl)-C(0)R20,
(C0-6-alkyl)-C(O)OR21,
(Co-6-alkyl)-cycloalkyl,
(Co-6-alkyl)-cycloalkenyl,
(C0-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl,
(C0-6-alkyl)-heterocycloalkenyl, and
(Co-6-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined herein, and
Y1, Y2, R2, R4 and R5 are as defined herein.
In aspects and embodiments, the compound is characterised by formula (XXIIA) or formula (XXIIB),
Figure imgf000090_0001
(XXIIA) (XXIIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R2 to R5 and R37 to R41 are as defined herein.
In aspects and embodiments, the compound is characterised by formula (XXIIIA) or formula (XXIIIB),
Figure imgf000090_0002
(XXIIIA) (XXIIIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, R4, R5 and R37 to R41 are as defined herein.
Accordingly, the invention provides a compound characterised by formula (XXIV A) or formula (XXIVB),
Figure imgf000091_0001
(XXIVA) (XXIVB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1 to R5 and R37 to R41 are as defined herein.
In embodiments, R and/or R are independently H. In embodiments, R38 and/or R40 are independently selected from H, halogen, Ci-6-alkyl, (C0. 6-alkyl)-cycloalkyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, R38 and/or R40 are independently selected from H, halogen and Ci-6-alkyl, wherein each said alkyl is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, R38 and/or R40 are independently selected from H, halogen and Ci-6-alkyl, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen.
In embodiments, R39 is selected from H, Ci-6-alkyl, (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2N(R10)2, (Co-e-alky - HSC^R11, (C0-6-alkyl)- HCOR18, (C0-6 alkyl)-C(0)N(R19)2, (Co-e-alkyl)- cycloalkyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, and (Co-6-alkyl)-heteroaryl, wherein R9, R10, R11, R18 and R19 are as defined herein, and wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, R is selected from Ci-6-alkyl, (Co-6-alkyl)- S02R9, (C0-6-alkyl)-SO2N(R10)2, (Co-e-alky - HSC^R11, (C0-6-alkyl)- HCOR18, (C0-6 alkyl)- C(0)N(R19)2, (C0-6-alkyl)-cycloalkyl, (C0-6-alkyl)-aryl, (C0-6-alkyl)-heterocycloalkyl, and (C0. 6-alkyl)-heteroaryl, wherein R9, R10, R11, R18 and R19 are as defined herein, and wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more groups independently selected from J as defined herein. In embodiments, R39 is selected from S02(Ci-6-alkyl), e.g. S02(C2-6-alkyl). In embodiments, R39 is not S02Me.
In embodiments, R37 and R41 are each independently H; R38 and R40 are each independently selected from H, halogen, Ci-6-alkyl, (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)- heterocycloalkyl, and (C0-6-alkyl)-heteroaryl; and R39 is selected from H, Ci-6-alkyl, (C0-6-alkyl)- S02R9, (C0-6-alkyl)-SO2N(R10)2, (Co-e-alky - HSO.R11, (C0-6-alkyl)- HCOR18, (C0-6 alkyl)- C(0)N(R19)2, (C0-6-alkyl)-cycloalkyl, (C0-6-alkyl)-aryl, (C0-6-alkyl)-heterocycloalkyl, and (C0. 6-alkyl)-heteroaryl, wherein R9, R10, R11, R18 and R19 are as defined herein, and wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more groups independently selected from J as defined herein.
In embodiments, R37, R38 and R41 are each H, and R39 and R40 are as defined herein. In other embodiments, R37, R40 and R41 are each H, and R38 and R39 are as defined herein. In other embodiments, R37, R39 and R41 are each H, and R38 and R40 are as defined herein.
In embodiments, R37, R38 and R41 are independently H, and R39 and R40 are each independently selected from halogen, Ci-6-alkyl, (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2N(R10)2, N(R12)S02N(R13)2, and (C0-6-alkyl)-C(O)R20 wherein each said alkyl is optionally substituted by one or more groups independently selected from J, and wherein R 9 , R 10 , R 12 , R 13 , R 20 and J are as defined herein.
In embodiments, R37, R38 and R41 are independently H; R40 is halogen or Ci-6-alkyl; and R39 is selected from Ci-6-alkyl, (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2N(R10)2, (Co-e-alky - HSC^R11, (C0-6-alkyl)- HCOR18, (C0-6 alkyl)-C(0)N(R19)2, (C0-6-alkyl)-cycloalkyl, (C0-6-alkyl)-aryl, (C0. 6-alkyl)-heterocycloalkyl, and (C0-6-alkyl)-heteroaryl, wherein R9, R10, R11, R18 and R19 are as defined herein; wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more groups independently selected from J as defined herein. mbodiments, A is selected from
Figure imgf000093_0001
wherein:
X4 is selected from NH, N(d-6 alkyl), O, and CR'2,
wherein each R' is independently selected from Ci-6 alkyl;
R 26 , R 32 , R 3J3J and R 3J53 are each independently selected from:
H, Ci-9-alkyl,
(C0-9-alkyl)-(C3.io-cycloalkyl),
(Co-9-alkyl)-(C6-io-aryl),
(Co-9-alkyl)-heterocycloalkyl, and
(Co-9-alkyl)-heteroaryl;
R28 and R29 are each independently selected from:
H,
Ci-9-alkyl,
(Co-9-alkyl)-(C3-io-cycloalkyl),
(Co.9-alkyl)-(C6.io-aiyl),
(Co-9-alkyl)-heterocycloalkyl,
(Co-9-alkyl)-heteroaryl, or
R28 and R29 may together form a C3-9-cycloalkyl or 3- to 9-membered heterocycloalkyl;
R27 and R34 are selected from:
H,
Ci-9-alkyl,
(C0-9-alkyl)-SO2R9,
(C0-9-alkyl)-SO2 HR10,
(Co-9-alkyl)- HS02Ru,
(C0-9-alkyl)- HCOR18,
(C0-9-alkyl)-CO HR19,
(C0-9-alkyl)-COR20,
(Co-9-alkyl)-(C3-io-cycloalkyl),
(Co-9-alkyl)-(C6-io-aryl),
(Co-9-alkyl)-heterocycloalkyl, and
(C0-9-alkyl)-heteroaryl,
wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally and independently substituted by one or more groups selected independently from J as defined herein, and
wherein R9, R10, R11, R18, R19 and R20 are as defined herein. In one aspect and embodiment, the compound is selected from the group consisting of Compounds 1 to 51 :
Figure imgf000095_0001
8-[4-methanesulfonyl-3-(trifluoromethyl)phenyl]imidazo[l,5-
Compound 11
a]pyridine
3-methanesulfonyl-9-[7-(trifluoromethyl)imidazo[l,5-
Compound 12
a]pyridin-5-yl]-3,9-diazaspiro[5.5]undecane l-{9-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3,9-
Compound 13
diazaspiro[5.5]undecan-3 -yl } ethan- 1 -one
3,6,64rimethyl-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 14
yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione
2,2-dimethyl-4-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 15
yl]piperazine-l -sulfonamide
N-(4-{2,2-dimethyl-4-[7-(trifluoromethyl)imidazo[l,5-
Compound 16
a]pyridin-5-yl]piperazin-l-yl}phenyl)methanesulfonamide
3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 17A
azabicyclo[3.3.1 ]nonan-9-ol
3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 17B
azabicyclo[3.3.1 ]nonan-9-ol bis(3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 18A
azaspiro[bicyclo[3.3.1]nonane-9,4'-imidazolidine]-2',5'-dione) bis(3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 18B
azaspiro[bicyclo[3.3.1]nonane-9,4'-imidazolidine]-2',5'-dione)
3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 19
azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
5-methanesulfonyl-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 20
a]pyridin-5-yl]-5,8-diazaspiro[3.5]nonane
5-{6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-
Compound 21
yl}imidazo[l,5-a]pyridine-7-carbonitrile l-methanesulfonyl-2-(trifluoromethyl)-4-[7-
Compound 22
(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]piperazine 8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,8-
Compound 23
triazaspiro[4.5]decane-2,4-dione
7-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,7-
Compound 24
triazaspiro[4.4]nonane-2,4-dione
1 l-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-5,7, 11-
Compound 25
triazadispiro[2.0.44.43]dodecane-6,8-dione
3-(2-hydroxyethyl)-6,6-dimethyl-8-[7-
Compound 26 (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,8- triazaspiro[4.5]decane-2,4-dione
6,6-difluoro-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-
Compound 27
l,3,8-triazaspiro[4.5]decane-2,4-dione
6,6-difluoro-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-
Compound 27A
l,3,8-triazaspiro[4.5]decane-2,4-dione (Enantiomer A)
6,6-difluoro-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-
Compound 27B
l,3,8-triazaspiro[4.5]decane-2,4-dione (Enantiomer B)
6-(trifluoromethyl)-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 28
a]pyridin-5-yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione l-methanesulfonyl-2,2-dimethyl-4-[6-
Compound 29
(trifluoromethyl)imidazo[l,5-a]pyridin-8-yl]piperazine
5-(4-methanesulfonyl-3,3-dimethylpiperazin-l-yl)imidazo[l,5-
Compound 30
a]pyridine-7-carbonitrile
3-benzyl-6,6-dimethyl-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 31
a]pyridin-5-yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione
4-{ 7-cyclopropylimidazo[ 1 , 5-a]pyridin-5-yl } - 1 -
Compound 32
methanesulfonyl-2,2-dimethylpiperazine l-{3,3-dimethyl-l-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-
Compound 33
5-yl]piperidin-4-yl}imidazolidin-2-one
3-ethyl-6,6-dimethyl-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 34
a]pyridin-5-yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione l-methanesulfonyl-2,2-dimethyl-4-[7-
Compound 35
(trifluoromethyl)imidazo[l,5-c]pyrimidin-5-yl]piperazine 3-(2-methoxyethyl)-6,6-dimethyl-8-[7-
Compound 36 (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,8- triazaspiro[4.5]decane-2,4-dione
4-{2-chloroimidazo[l,5-b]pyridazin-4-yl}-l-methanesulfonyl-
Compound 37
2,2-dimethylpiperazine
3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-
Compound 38
azabicyclo[3.2.1]octane-8-carboxamide
3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-
Compound 39A azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
(Enantiomer A)
3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-
Compound 39B azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
(Enantiomer B)
l'-(2-hydroxyethyl)-3-[7-(trifluoromethyl)imidazo[l,5-
Compound 40 a]pyridin-5-yl]-3-azaspiro[bicyclo[3.2.1]octane-8,4'- imidazolidine]-2',5'-dione
2-{3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-
Compound 41A
azabicyclo[3.2.1]octan-8-yl}acetamide (Enantiomer A)
2-{3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-
Compound 41B
azabicyclo[3.2. l]octan-8-yl}acetamide (Enantiomer B)
3-[7-(trifluoromethyl)imidazo[l,5-c]pyrimidin-5-yl]-3-
Compound 42
azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
6,6-dimethyl-8-[2-(trifluoromethyl)imidazo[l,5-a]pyrimidin-4-
Compound 43
yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione
6,6-dimethyl-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 44
y 1 ] - 1 , 3 , 8 -tri azaspiro [4.5 ] decan-2-one
2-{2',5'-dioxo-3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 45 yl]-3-azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-l'- yl}acetamide
1 '-(propa- 1 ,2-dien- 1 -yl)-3 - [7-(trifluoromethyl)imidazo[ 1 , 5 -
Compound 46 a]pyridin-5-yl]-3-azaspiro[bicyclo[3.2.1]octane-8,4'- imidazolidine]-2',5'-dione 1 '-(prop-2-yn- 1 -yl)-3 -[7-(trifluoromethyl)imidazo[ 1,5-
Compound 47 a]pyridin-5-yl]-3-azaspiro[bicyclo[3.2.1]octane-8,4'- imidazolidine]-2',5'-dione
r-[(lH-l,2,3-triazol-4-yl)methyl]-3-[7-
Compound 48 (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3- azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
6-fluoro-6-(trifluoromethyl)-8-[7-
Compound 49 (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,8- triazaspiro[4.5]decane-2,4-dione
9,9-dimethyl-7-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 50
yl]-l,3,7-triazaspiro[4.4]nonane-2,4-dione
6-fluoro-6-methyl-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 51
a]pyridin-5-yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione and the pharmaceutically acceptable salts or prodrugs thereof.
In embodiments, the compound is selected from the group consisting of: Compounds 1 A, 2, 3, 4, 6, 8, 12, 18B, 19, 23, 25, 27, 27A, 28, 29, 39A, 39B, 40, 41B, 42, 44, 46, 47, 49, and 51; and the pharmaceutically acceptable salts or prodrugs thereof.In other embodiments, the compound is selected from the group consisting of: Compounds 1A, 2, 3, 4, 8, 19, 27, 27A, 39B, 46, 47, and 49; and the pharmaceutically acceptable salts or prodrugs thereof. In other embodiments, the compound is selected from the group consisting of: Compounds 1A, 2, 27A, 39B, 46, and 49; and the pharmaceutically acceptable salts or prodrugs thereof.
In embodiments, the compound is selected from the group consisting of: Compounds 1 A, 3, 4, 5, 6, 7, 15, 17A, 18B, 19, 22, 25, 26, 27, 32, 34, 36, 38, 39A, 40, 41A, 41B, and 44; and the pharmaceutically acceptable salts or prodrugs thereof. In embodiments, the compound is selected from the group consisting of: Compounds 1A, 4, 6, 7, 17A, 18B, 19, 25, 27, 39A, 40, 41A, and 4 IB; and the pharmaceutically acceptable salts or prodrugs thereof.
In embodiments, the compound is selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 8, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17A, Compound 17B, Compound 18 A, Compound 19, Compound 20, Compound 21; and the pharmaceutically acceptable salts or prodrugs thereof. In an embodiment, the compound is selected from the group consisting of: Compounds 1, 2, 3, 4, 5, 6, 8, 12 and 13; and the pharmaceutically acceptable salts or prodrugs thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 2, 3, 4, 5, 6 and 8; and the pharmaceutically acceptable salts or prodrugs thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 2, 3 and 4; and the pharmaceutically acceptable salts or prodrugs thereof.
The compounds of the invention are useful as inhibitors of IDOl, ID02 and/or TDO. In particular, compounds of the invention are useful as inhibitors of IDOl . Assays for determining the inhibitory activity of compounds against IDOl (e.g. against mouse or human IDO l, or a fragment thereof having catalytic activity) are known in the art and are also set out in the following Examples. The activity values listed below may, for example, be determined according to an assay as set out in the following Examples, e.g. as set out in Example 43 and/or Example 44.
In embodiments, compounds of the invention have an IC50 value (e.g. an inhibitory activity against IDOl in a cell-based assay) of less than 10 μΜ, less than 5 μΜ, less than 2 μΜ, less than 1 μΜ, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 150 nM, less than 100 nM, less than 75 nM or less than 50 nM.
The compounds of the invention may be selective for IDOl and/or ID02 over TDO. In particular, the compounds of the invention may be selective for IDOl over TDO. Assays for determining the selectivity of a compound for IDOl (or ID02) over TDO are known in the art and are illustrated in the following Examples.
In embodiments, the compounds of the invention are selective for IDO l over TDO. In embodiments, the compounds of the invention are selective for IDOl over TDO by a value of at least 10 times, at least 20 times, at least 50 times or at least 100 times. By "selective" is meant that the concentration of compound which results in 50% maximal inhibition (IC50) of TDO is at least the stated factor more than the concentration of compound which results in 50% maximal inhibition of IDOl . Thus, a compound having an IC50 value of 50 nM against IDOl, and having an IC50 value of 50 μΜ against TDO, is selective for IDOl over TDO by a value of 1000 times.
Salts Presently disclosed compounds that are basic in nature are generally capable of forming a wide variety of different salts with various inorganic and/or organic acids. Although such salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds can be readily prepared using conventional techniques, e.g. by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as, for example, methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained. Presently disclosed compounds that are positively charged, e.g. containing a quaternary ammonium, may also form salts with the anionic component of various inorganic and/or organic acids.
Acids which can be used to prepare pharmaceutically acceptable salts of compounds are those which can form non-toxic acid addition salts, e.g. salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, malate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e. Ι, Γ-methylene- bis-(2-hydroxy-3-naphthoate)] salts. Presently disclosed compounds that are acidic in nature, e.g. compounds containing a carboxylic acid or tetrazole moiety, are generally capable of forming a wide variety of different salts with various inorganic and/or organic bases. Although such salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and subsequently convert the free acid to a pharmaceutically acceptable base addition salt. These base addition salts can be readily prepared using conventional techniques, e.g. by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, e.g. under reduced pressure. Alternatively, they also can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents may be employed in order to ensure completeness of reaction and maximum product yields of the desired solid salt. Bases which can be used to prepare the pharmaceutically acceptable base addition salts of compounds are those which can form non-toxic base addition salts, e.g. salts containing pharmacologically acceptable cations, such as, alkali metal cations (e.g. potassium and sodium), alkaline earth metal cations (e.g. calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine (meglumine), lower alkanolammonium, and other such bases of organic amines.
Prodrugs
Pharmaceutically acceptable prodrugs for use according to the present disclosure are derivatives of IDOl inhibitors, e.g. compounds characterized by formula (I), which can be converted in vivo into the compounds described herein. The prodrugs, which may themselves have some activity, become fully pharmaceutically active in vivo when they undergo, for example, solvolysis under physiological conditions or through enzymatic degradation. Methods for preparing prodrugs of compounds as described herein would be apparent to one of skill in the art based on the present disclosure.
Stereochemistry Stereoisomers (e.g. cis and trans isomers) and all optical isomers of a presently disclosed compound (e.g. R- and S- enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.
For example, where the group A contains one or more chiral carbon atoms, the compounds of the invention may exist predominantly as a single enantiomer (or diastereomer), or as a mixture of isomers (e.g. enantiomers or diastereomers).
In embodiments, the compounds of the invention are present as a racemic mixture, e.g. said R- and S- isomers (or all enantiomers or diastereomers) are present in approximately equal amounts. By way of example, in embodiments Compound 1, or a pharmaceutically acceptable salt or prodrug thereof, is provided as a racemic mixture. In other embodiments the compounds of the invention are present as a mixture of isomers in which one enantiomer (or diastereomer) is present in an enantiomeric excess of at least about 5%, 10%, 25%, 40%, 70%, 80%, 90%, 95%, 97%, 98% or 99%, e.g. about 100%.
Methods for preparing enantioenriched and/or enantiopure compounds would be apparent to the person of skill in the art based on the present disclosure. Examples of such methods include chemical resolution (e.g. crystallization) and chiral chromatography.
The compounds presently disclosed may exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, all tautomers are within the scope of the present disclosure.
Other forms
Pharmaceutically acceptable hydrates, solvates, polymorphs, etc., of the compounds described herein are also within the scope of the present disclosure. Compounds as described herein may be in an amorphous form and/or in one or more crystalline forms.
Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an "isotopically-labeled compound" refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35 S, 18F, and 36C1, respectively. Within the ambit of isotopically-labelled compounds, deuterated compounds, e.g. compounds of the invention which have one or more hydrogen atoms replaced by deuterium, are preferred.
Pharmaceutical compositions
The present disclosure provides pharmaceutical compositions comprising at least one compound of the invention, e.g. a compound characterized by formula (I), and at least one pharmaceutically acceptable excipient, e.g. for use according to the methods disclosed herein. The pharmaceutically acceptable excipient can be any such excipient known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). Pharmaceutical compositions of the compounds presently disclosed may be prepared by conventional means known in the art including, for example, mixing at least one presently disclosed compound with a pharmaceutically acceptable excipient.
A pharmaceutical composition or dosage form of the invention can include an agent and another carrier, e.g. compound or composition, inert or active, such as a detectable agent, label, adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like. Carriers also include pharmaceutical excipients and additives, for example, proteins, peptides, amino acids, lipids, and carbohydrates (e.g. sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1 to 99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid/antibody components, which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. Carbohydrate excipients are also intended within the scope of this invention, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol.
Carriers which may be used include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers. Additional carriers include polymeric excipients/additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g. cyclodextrins, such as 2-hydroxypropyl-P-cyclodextrin), polyethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g. polysorbates such as "TWEEN 20" and "TWEEN 80"), lipids (e.g. phospholipids, fatty acids), steroids (e.g. cholesterol), and chelating agents (e.g. EDTA).
The present disclosure also provides pharmaceutical compositions, and kits comprising said compositions, which contain at least one compound as described herein, e.g. a compound characterized by formula (I), and at least one further pharmaceutically-active agent. These pharmaceutical compositions and kits may be adapted to allow simultaneous, subsequent and/or separate administration of the compound and the further active agent. For example, the compound and the further active agent may be formulated in separate dosage forms, e.g. in separate tablets, capsules, lyophilisates or liquids, or they may be formulated in the same dosage form, e.g. in the same tablet, capsule, lyophilisate or liquid. Where the compound and the further active agent are formulated in the same dosage form, the compound and the further active agent may be present substantially in admixture, e.g. within the core of a tablet, or they may be present substantially in discrete regions of the dosage form, e.g. in separate layers of the same tablet.
A further aspect of the present invention provides a pharmaceutical composition comprising: (i) a compound as described herein, e.g. a compound characterized by formula (I); (ii) a further active agent; and (iii) a pharmaceutically acceptable excipient.
Another aspect of the present invention provides a kit comprising (i) a compound as described herein, e.g. a compound characterized by formula (I); (ii) instructions for the use of the compound in therapy, e.g. in a method as described herein; and (iii) optionally a further active agent.
In one embodiment, said further active agent is a chemotherapeutic agent or an immunotherapeutic agent. Examples of such further active agents are provided below.
The pharmaceutical compositions can be formulated so as to provide slow, extended, or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. The pharmaceutical compositions can also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner, e.g. by using an enteric coating. Examples of embedding compositions include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more pharmaceutically acceptable carriers, excipients, or diluents well known in the art (see, e.g., Remington's). The compounds presently disclosed may be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in United States Patents 3, 119,742; 3,492,397; 3,538,214; 4,060,598; and 4, 173,626.
Chemical synthesis
An illustrative synthetic scheme (Scheme I) is shown below for the preparation of compounds characterised by formula (IA) wherein R4 and R5 are each H, and Y1, Y2 and R2 are as defined herein:
Figure imgf000106_0001
Scheme I
In step (i) of Scheme I, the compound A in which X is halogen, e.g. CI, (which may be commercially available, or prepared according to general synthetic methodology known to the person of skill in the art) is brominated, e.g. using a Wohl-Ziegler reaction ( BS and AIBN in CCU) to yield intermediate B. In step (ii), nucleophilic substitution with a highly hindered alkylamine, e.g. 1,3,5,7-tetraazaadamantane as shown in the scheme above, leads to intermediate C. In step (iii), intermediate C is decomposed to form the corresponding primary amine D, e.g. using acidic hydrolysis or ethanolysis according to the Delepine reaction. In step (iv), intermediate D is treated with a formylating agent, e.g. ethyl formate, under basic conditions, e.g. using trimethylamine, to form the intermediary formamide, and subsequent cyclisation, e.g. using POCI3, leads to compound E. In final step (v), a reactant that comprises group A (which may be protected if necessary, e.g. if substituted) participates in a nucleophilic substitution or coupling reaction, e.g. using Pd catalysis, to give the target compound F. Another illustrative synthetic scheme (Scheme II) is shown below for the preparation of compounds characterised by formula (IB), wherein R4 and R5 are each H, and Y1, Y2 and R2 are as defined herein:
Figure imgf000107_0001
G H
Scheme II
In step (i) of Scheme II, the compound G in which X is halogen, e.g. Br, (which may be commercially available, or prepared according to general synthetic methodology known to the person of skill in the art) is cyclised, e.g. using formic acid and acetic anhydride, to yield intermediate H. In step (ii), a reactant that comprises group A (which may be protected if necessary, e.g. if substituted) participates in a nucleophilic substitution or coupling reaction, e.g. using Pd catalysis, to give the target compound I.
The above synthetic schemes I and II may be modified to provide compounds of the present invention in which R4 or R5 is l¾. Scheme III below illustrates the synthesis of such compounds:
(IIIA)
Figure imgf000107_0002
(ii
Figure imgf000107_0003
H H' K
Scheme III In step (i) of Schemes IIIA and IIIB, the intermediate E or H is nitrated, e.g. using HNO3 in H2S04 and AcOH at 100 °C, to yield compound E' or H', respectively. In step (ii), the nitrated compound is coupled with a reactant that comprises group A, e.g. using the method of Scheme I, step (v) or Scheme II, step (ii) to yield the corresponding nitrated compound F' or I', respectively. In step (iii) of Schemes IIIA and IIIB, F' or I' is reduced to the corresponding amine, J or K, e.g. using NaBH4, which compound may then optionally be N-alkylated.
The illustrative synthetic schemes below (Schemes IV and V) show the preparation of exemplary compounds useful for introducing group A in the synthetic schemes above. Scheme IV illustrates
22 25 28 31
the synthesis of piperidin-4-yl compounds in which R to R and R to R are as defined herein:
Figure imgf000108_0001
M
In step (i) of Scheme IV, the compound L (in which P denotes a protecting group, e.g. Boc) is reacted to introduce the spiro-hydantoin moiety of compound M, e.g. using potassium cyanide and ammonium carbonate (the Bucherer-Bergs reaction). In step (ii), the protecting group is removed to yield the free amine compound N. Where the protecting group is acid-labile, e.g. in the case where P denotes Boc, the deprotection may be effected with HCl, in which case the compound N may be obtained as the hydrochloride salt.
22 25 28
Scheme V illustrates the synthesis of piperazin-4-yl compounds in which R to R and R to R32 are as defined herein:
Figure imgf000109_0001
O Q R
Scheme V
In step (i) of Scheme V, the compound O (in which P denotes a protecting group, e.g. Boc) is reacted with an electrophilic derivative of R32, e.g. a compound R32-C1 where the CI can act as a leaving group in a nucleophilic substitution reaction, to yield intermediate Q. For example, when R32 is methanesulfonyl (-S02Me), compound O may be reacted with methanesulfonyl chloride under basic conditions, e.g. in triethylamine. In step (ii), the protecting group is removed to yield the free amine compound R. Where the protecting group is acid-labile, e.g. in the case where P denotes Boc, the deprotection may be effected with HCl, in which case the compound R may be obtained as the hydrochloride salt.
Alternative methods for the synthesis of compounds of the present disclosure would be apparent to the skilled person on the basis of their common general knowledge and the teaching of the present application.
Medical indications The compounds described herein, and pharmaceutical compositions thereof, are useful in therapy, in particular in the therapeutic treatment of IDOl, ID02 and/or TDO mediated conditions in a subject, and especially in the therapeutic treatment of IDOl mediated conditions in a subject. Subjects to be treated according to the methods described herein include vertebrates, such as mammals. In preferred embodiments the mammal is a human patient. The present invention provides a method for treating an IDOl, ID02 and/or TDO mediated condition {e.g. an IDOl mediated condition) in a subject, the method comprising administering to the subject an effective amount of a compound as defined herein, e.g. a compound characterised by formula (I). Also provided is a compound as defined herein, e.g. a compound characterised by formula (I), for use in a method of treating an IDOl, ID02 and/or TDO mediated condition {e.g. an IDOl mediated condition) in a subject. Further provided is the use of a compound as defined herein, e.g. a compound characterised by formula (I), in the manufacture of a medicament for use in a method of treating an IDOl, ID02 and/or TDO mediated condition (e.g. an IDOl mediated condition) in a subject.
The KYN pathway has been implicated in a number of conditions, including: cancers; neurological and neuropsychological diseases and disorders; autoimmune diseases and disorders; infections; and cataracts.
In embodiments, the IDOl, ID02 and/or TDO mediated condition (e.g. the IDOl mediated condition) is selected from a cancer; a neurological or neuropsychological disease or disorder; an autoimmune disease or disorder; an infection; a cataract; and a vascular disease. In embodiments, the IDOl, ID02 and/or TDO mediated condition (e.g. the IDOl mediated condition) is characterised by the overexpression of IDOl, ID02 and/or TDO, respectively (e.g. by the overexpression of IDOl).
In embodiments, the treatment of the IDOl, ID02 and/or TDO mediated condition (e.g. the IDOl mediated condition) comprises administering a compound of the invention in combination with another therapeutic intervention for said condition. The other therapeutic intervention may be performed before, during and/or after administering the compound of the invention.
Cancers
Overexpression of IDOl, ID02 and/or TDO occurs in a significant number of cancer types, including breast cancer, prostate cancer, colon cancer, colorectal carcinoma, head and neck carcinoma, glioblastoma, astrocytoma, lung carcinoma, bladder carcinoma, hepatocarcinoma, lymphocytic leukaemia, melanoma, mesothelioma, neuroblastoma, and brain tumour. For example, the deregulation of IDOl in tumour cells has been shown to be linked to the cancer suppressive gene bridging integrator 1 (Binl), which is a down-regulator of IDOl. Clinical observations suggest that high expression levels of IDOl and loss or attenuation of Binl are frequent in a number of cancers including advanced breast cancer, prostate cancer, melanoma, astrocytoma, neuroblastoma, lymphocytic leukaemia and colon cancer.
Furthermore, metabolites of KYN such as QUIN affect the biosynthesis of NAD+, which may be involved in cancer cell proliferation. For example, in glioblastoma multiforme, genotoxic anticancer drugs such as temozolomide (TMZ), hydroxyurea, procarbazine, cisplatin, and nitrosamines, such as carmustine, lomustine, and nimustine, in combination with radiation are used to kill tumour cells which remain following surgery. However, the effectiveness of these drugs can be weakened by the tolerance of the tumour cells to DNA repair/damage. It is thought that modulation of the KYN pathway can enhance genotoxic treatment by diminishing the ability of the cancer cells to repair damaged DNA and/or to bypass the cytotoxic effects of DNA damage. Thus, treatment with a compound as defined herein in combination with immunotherapy, radiation therapy and/or chemotherapy is expected to enhance the efficacy of said therapy.
Accordingly, in one embodiment the IDOl, ID02 and/or TDO mediated condition (e.g. the IDOl mediated condition) is a cancer. In embodiments, the cancer is associated with low levels of L-TRP. In embodiments, the tumour microenvironment is depleted in L-TRP (e.g. below normal levels). In embodiments, the cancer is associated with high levels of L-TRP metabolites, e.g. KYN and/or QUIN. In embodiments, the concentration of said L-TRP metabolites in cells of the tumour are above normal levels for cells of that tissue type. In embodiments, the cancer is associated with overexpression of IDOl, ID02 and/or TDO, e.g. overexpression of IDOl .
In embodiments the cancer is selected from head and neck cancer, breast cancer (e.g. metastatic breast cancer), prostate cancer (e.g. metastatic prostate cancer), ovarian cancer, endometrial cancer, colon cancer, lung cancer (e.g. non-small cell lung cancer), bladder cancer, pancreatic cancer (e.g. metastatic pancreatic cancer), brain tumour (e.g. primary malignant brain tumour), gynecological cancer, peritoneal cancer, skin cancer, thyroid cancer, oesophageal cancer, cervical cancer, gastric cancer, liver cancer, stomach cancer, renal cell cancer, biliary tract cancer, hematologic cancer, and blood cancer. In embodiments, the cancer is selected from colorectal carcinoma, large intestinal colon carcinoma, head and neck carcinoma, lung carcinoma, lung adenocarcinoma, bladder carcinoma, Barret's adenocarcinoma, renal carcinoma, and hepatocarcinoma. In embodiments, the cancer is selected from glioblastoma, astrocytoma, melanoma (e.g. metastatic melanoma), mesothelioma, neuroblastoma, histiocytic lymphoma, and lymphocytic leukaemia. In embodiments, the cancer is a solid tumour (e.g. a malignant solid tumour) which may be an advanced-stage solid tumour.
In embodiments, the treatment of said IDOl, ID02 and/or TDO mediated condition (e.g. said IDOl mediated condition) as disclosed herein comprises administering a compound of the invention in combination with another therapeutic intervention for said condition. The other therapeutic intervention may be performed before, during and/or after administering the compound of the invention. Thus, in embodiments the subject is receiving (or has received, or will receive) said another therapeutic intervention for said IDOl, ID02 and/or TDO mediated condition.
In embodiments, said another therapeutic intervention is immunotherapy, radiation therapy and/or chemotherapy. In embodiments, said another therapeutic intervention is immunotherapy. In embodiments, said another therapeutic intervention is radiation therapy. In embodiments, said another therapeutic intervention is chemotherapy. In embodiments, said another therapeutic intervention comprises radiation therapy and further comprises treatment with immunotherapy and/or with chemotherapy.
In embodiments, said radiotherapy comprises treatment with gamma radiation.
In embodiments, said immunotherapy comprises treatment with an immunotherapeutic agent selected from therapeutic antibodies. In embodiments, the therapeutic antibody is a humanised monoclonal antibody. In embodiments, said immunotherapy comprises treatment with an immunotherapeutic agent selected from vaccines. In embodiments, the vaccine is a gene therapy vaccine.
In embodiments, said chemotherapy comprises treatment with a chemotherapeutic agent selected from alkylating agents, alkyl sulfonates, aziridines, ethylenimines and methylamelamines, nitrogen mustards, nitrosureas, bisphosphonates, purine analogs, pyrimidine analogs, taxoids, platinum analogs, anti-hormonal agents, aromatase inhibitors, antiandrogens, protein kinase inhibitors, lipid kinase inhibitors, antisense oligonucleotides, ribozymes, anti-retroviral protease inhibitors, anti-angiogenic agents, and topoisomerase 1 inhibitors.
In embodiments, said cancer is partially or totally resistant to treatment with at least one chemotherapeutic and/or immunotherapeutic agent (e.g. as defined herein).
In embodiments, administration of the compounds as disclosed herein can treat subjects diagnosed as having said cancer or being at risk of developing said cancer. In embodiments, administration of compounds as disclosed herein improves prognosis, reduces angiogenesis, reduces the catabolism of L-TRP, decreases growth of malignant cells, and/or prevents or reduces tumour progression.
Neurological and neuropsychological diseases and disorders
IDOl is present in numerous cell types within the body, in particular in microglia, the macrophage-like cells located in the central nervous system. Expression of IDOl is induced by proinflammatory cytokines and molecules, in particular by interferon gamma (IFN-γ) and, to a lesser extent, by IFN-a, IFN-β, interleukines, and tumor necrosis factors (TNF). TDO is present in small amount in the brain, where its expression is induced by corticosteroids and glucagon.
Increased levels of KYN, and its metabolites, have been observed in a number of neurological and neuropsychological diseases and disorders including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and Parkinson's disease (Bostian, 2016; Lovelace, 2017). Decreasing the production of neurotoxic metabolites of KYN, which include QUIN and 3 -hydroxy kynurenine, may reduce neuronal loss and atrophy in various neurological disorders and diseases. Furthermore, the interaction between immune activation and the metabolism of L-TRP (which is a precursor of serotonin) via the KYN pathway is implicated in neuropsychological diseases and disorders such as schizophrenia, anorexia, and depression, including depressive and anxiety symptoms in the early puerperium (Lovelace, 2017).
Accordingly, in one embodiment, the IDOl, ID02 and/or TDO mediated condition {e.g. the IDOl mediated condition) is a neurological or neuropsychological disease or disorder. In embodiments, said condition is a neurological disease or disorder. In other embodiments, said condition is a neuropsychological disease or disorder.
In embodiments, the neurological or neuropsychological disease or disorder is associated with low levels of L-TRP. In embodiments, the cerebrospinal fluid and/or the serum of the subject is depleted in L-TRP {e.g. below normal levels). In embodiments, the neurological or neuropsychological disease or disorder is associated with high levels of L-TRP metabolites, e.g. KYN, QUIN and/or 3 -hydroxy kynurenine. In embodiments, the concentration of said L-TRP metabolites in microglia of the subject are above normal levels. In embodiments, the neurological or neuropsychological disease or disorder is associated with overexpression of IDOl, ID02 and/or TDO, e.g. overexpression of IDOl . In embodiments, the neurological disease or disorder is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, Parkinson's disease, and HAND. In embodiments, the neuropsychological disease or disorder is selected from schizophrenia, anorexia, depression, and anxiety (e.g. depressive and anxiety symptoms in the early puerperium).
Autoimmune diseases and disorders
Catabolism of L-TRP may prevent normal proliferation in various cell types, and may increase the susceptibility of cells to apoptosis. In particular, antigen-specific T-cells have been shown to be susceptible to L-TRP deprivation. In addition, L-TRP catabolism leads to the formation of metabolites which have been shown to increase apoptosis of helper T-cells and natural killer T- cells. Further, KYN induces the formation of regulatory T-cells which may suppress immune cells. Furthermore, L-TRP levels in rheumatoid arthritis patients have been shown to be lower than in healthy patients, this may be due to overexpression of IDOL
Accordingly, in one embodiment, the IDOl, ID02 and/or TDO mediated condition (e.g. the IDOl mediated condition) is an autoimmune disease or disorder.
In embodiments, the autoimmune disease or disorder is associated with low levels of L-TRP. In embodiments, the serum of the subject is depleted in L-TRP (e.g. below normal levels). In embodiments, the autoimmune disease or disorder is associated with high levels of L-TRP metabolites, e.g. KYN, QUIN and/or 3-hydroxykynurenine. In embodiments, the autoimmune disease or disorder is associated with overexpression of IDOl, ID02 and/or TDO, e.g. overexpression of IDO 1.
In embodiments, the autoimmune disease or disorder is selected from arthritis, rheumatoid arthritis, and multiple sclerosis.
Infections Antigen-specific T-cells have been shown to be susceptible to L-TRP deprivation. In addition, L- TRP catabolism leads to the formation of metabolites which have been shown to increase apoptosis of helper T-cells and natural killer T-cells. Further, KYN induces the formation of regulatory T-cells which may suppress immune cells. Thus, IDOl, ID02 and/or TDO may influence the progression of infectious diseases in which the immune system is compromised. In particular, HIV infections may be caused by CD4+ T-cell depletion, combined with chronic immune activation and inflammation responses. Elevated levels of KYN metabolites and IFN-γ are commonly found in HIV patients, and catabolism of L-TRP may be a factor in HIV disease progression, through immune suppression and/or the generation of neurotoxic KYN metabolites. Elevated levels of KYN neurotoxic metabolites such as QUIN in HIV infected patients have also been linked to the progression of HAND. Those KYN metabolites may be produced in the central nervous system, possibly by microglia, in response to peripheral immune and inflammatory signals.
IDOl activity is elevated in sepsis and has been associated with disease severity. Further, IDOl activity has been shown to correlate with hypotension in cases of human septic shock. In this regard, KYN is thought to be a vasodilator which may contribute to the hypotension observed in septic shock.
Accordingly, in embodiments the infection is selected from influenza virus infection, peritonitis, sepsis, chlamydia trachomatis infection, and HIV. In embodiments, the infection is associated with low levels of L-TRP. In embodiments, the plasma of the subject is depleted in L-TRP (e.g. below normal levels). In embodiments, the infection is associated with high levels of L-TRP metabolites, e.g. KYN, QUIN and/or 3- hydroxykynurenine. In embodiments, the plasma of the subject has a ratio of KYN to L-TRP above normal levels. In embodiments, the infection is associated with overexpression of IDOl, ID02 and/or TDO, e.g. overexpression of IDOl .
In embodiments, the treatment of said infection comprises administering a compound of the invention in combination with another therapeutic intervention for said infection. Said another therapeutic intervention may be performed before, during and/or after administering the compound of the invention. Thus, in embodiments the subject is receiving (or has received, or will receive) said another therapeutic intervention for said infection.
In embodiments, the infection is a viral infection and said another therapeutic intervention is treatment with an antiviral agent. In embodiments, the infection is HIV infection and said another therapeutic intervention is treatment with an antiretroviral agent. In embodiments, the infection is a bacterial infection and said another therapeutic intervention is treatment with an antibacterial agent.
Other conditions
The KYN pathway has also been implicated in other conditions. For example, elevated lenticular levels of IDOl and KYN metabolites have been observed in association with cataracts. IDOl activity has also been shown to correlate with carotid artery intima/media thickness, which is an early marker of atherosclerosis (a leading cause of cardiovascular diseases). Elevated levels of KYN have also been associated with the risk of acute myocardial infarction.
Accordingly, in one embodiment, the IDOl, ID02 and/or TDO mediated condition {e.g. the IDOl mediated condition) is a cataract. In embodiments, the cataract is age related, or is associated with diabetes in the subject.
In another embodiment, the IDOl, ID02 and/or TDO mediated condition {e.g. the IDOl mediated condition) is a vascular disease. In embodiments, the vascular disease is a cardiovascular disease. In embodiments, the IDOl, ID02 and/or TDO mediated condition {e.g. the IDOl mediated condition) is atherosclerosis. In embodiments, the IDOl, ID02 and/or TDO mediated condition {e.g. the IDOl mediated condition) is myocardial infarction, in particular acute myocardial infarction.
Administration and dosages
A presently disclosed compound can be formulated as a pharmaceutical composition for oral, buccal, parenteral {e.g. intravenous, intraperitoneal, intramuscular or subcutaneous), topical, rectal or intranasal administration or in a form suitable for administration by inhalation or insufflation. In one embodiment, the compound or pharmaceutical composition is formulated for systemic administration, e.g. via a non-parenteral route. In another embodiment, the compound or pharmaceutical composition is formulated for oral administration, e.g. in solid form. Such modes of administration and the methods for preparing appropriate pharmaceutical compositions are described, for example, in Gibaldi's Drug Delivery Systems in Pharmaceutical Care (1st ed., American Society of 15 Health-System Pharmacists 2007).
In solid dosage forms for oral administration {e.g. capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, excipients, or diluents, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose, calcium phosphate and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatine, pregelatinized maize starch, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, sodium starch glycolate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, sodium lauryl sulphate, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, silica, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) colouring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions can also comprise buffering agents. Solid compositions of a similar type can also be prepared using fillers in soft and hard-filled gelatine capsules, and excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet can be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (for example, gelatine or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- actives, and/ or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art.
In embodiments, the pharmaceutical compositions are administered orally in a liquid form. Liquid dosage forms for oral administration of an active ingredient include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid preparations for oral administration may be presented as a dry product for constitution with water or other suitable vehicle before use. In addition to the active ingredient, the liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilising agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (e.g. cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the liquid pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavouring, colouring, perfuming and preservative agents, and the like. Suspensions, in addition to the active ingredient(s) can contain suspending agents such as, but not limited to, ethoxylated isostearyl alcohols, poly oxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Suitable liquid preparations may be prepared by conventional means with a pharmaceutically acceptable additive(s) such as a suspending agent (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g. lecithin or acacia); non-aqueous vehicle (e.g. almond oil, oily esters or ethyl alcohol); and/or preservative (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid). The active ingredient(s) can also be administered as a bolus, electuary, or paste.
For buccal administration, the composition may take the form of tablets or lozenges formulated in a conventional manner.
In embodiments, the pharmaceutical compositions are administered by non-oral means such as by topical application, transdermal application, injection, and the like. In related embodiments, the pharmaceutical compositions are administered parenterally by injection, infusion, or implantation (e.g. intravenous, intramuscular, intra-arterial, subcutaneous, and the like).
Presently disclosed compounds may be formulated for parenteral administration by injection, including using conventional catheterisation techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain a formulating agent such as a suspending, stabilising and/or dispersing agent recognised by those of skill in the art. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The pharmaceutical compositions can be in the form of sterile injections. The pharmaceutical compositions can be sterilised by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilising agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. To prepare such a composition, the active ingredient is dissolved or suspended in a parenterally acceptable liquid vehicle. Exemplary vehicles and solvents include, but are not limited to, water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution. The pharmaceutical composition can also contain one or more preservatives, for example, methyl, ethyl or n-propyl p-hydroxybenzoate. To improve solubility, a dissolution enhancing or solubilising agent can be added or the solvent can contain 10-60% w/w of propylene glycol or the like.
The pharmaceutical compositions can contain one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which can be reconstituted into sterile injectable solutions or dispersions just prior to use. Such pharmaceutical compositions can contain antioxidants; buffers; bacteriostats; solutes, which render the formulation isotonic with the blood of the intended recipient; suspending agents; thickening agents; preservatives; and the like.
Examples of suitable aqueous and nonaqueous carriers, which can be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, in order to prolong the effect of an active ingredient, it is desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the active ingredient then depends upon its rate of dissolution which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered active ingredient is accomplished by dissolving or suspending the compound in an oil vehicle. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatine.
Controlled release parenteral compositions can be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, emulsions, or the active ingredient can be incorporated in biocompatible carrier(s), liposomes, nanoparticles, implants or infusion devices. Materials for use in the preparation of microspheres and/or microcapsules include, but are not limited to, biodegradable/bioerodible polymers such as polyglactin, poly- (isobutyl cyanoacrylate), poly(2-hydroxyethyl-L-glutamine) and poly(lactic acid). Biocompatible carriers which can be used when formulating a controlled release parenteral formulation include carbohydrates such as dextrans, proteins such as albumin, lipoproteins or antibodies. Materials for use in implants can be non-biodegradable, e.g. polydimethylsiloxane, or biodegradable such as, e.g., poly(caprolactone), poly(lactic acid), poly(gly colic acid) or poly(ortho esters).
For topical administration, a presently disclosed compound may be formulated as an ointment or cream. Presently disclosed compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, presently disclosed compounds may be conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurised container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container or nebulizer may contain a solution or suspension of the presently disclosed compound. Capsules and cartridges (made, for example, from gelatine) for use in an inhaler or insufflator may be formulated containing a powder mix of a presently disclosed compound and a suitable powder base such as lactose or starch.
Generally, the agents and compositions described herein are administered in an effective amount or quantity sufficient to inhibit IDOl, ID02 and/or TDO in the subject receiving the agent or composition. Typically, the dose can be adjusted based on, e.g., age, physical condition, body weight, sex, diet, time of administration, and other clinical factors. The effective amount may also vary depending on the mode of administration, e.g. intravenous versus oral, as well as on the nature of the composition, e.g. rapidly disintegrating versus slow release compositions. Determination of an effective amount is within the capability of those skilled in the art. Generally, an effective amount for administration to a subject is in the range of about 0.1 to 1000 mg/kg.
In other aspects, the invention provides a dosage form or pharmaceutical composition as described herein for use in therapy, e.g. for use in a method as defined herein.
Having been generally described herein, the follow non-limiting examples are provided to further illustrate this invention.
EXAMPLES
Chemical synthesis Intermediate 1: 6, 6-dimethyl-l,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride
Step 1:
To a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-l-carboxylate (1 g, 4.40 mmol) in EtOH (18 ml) was added potassium cyanide (0.859 g, 13.2 mmol) and ammonium carbonate (1.52 g, 15.84 mmol) and the resulting mixture was stirred at 90 °C overnight, then water was added and the mixture was diluted with EtOAc. The aqueous phase was back extracted with EtOAc (x2) and then the organic phase was washed with brine and dried over Na2S04 to afford tert-butyl 6,6- dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate as a yellow solid. MS (ES+) Ci4H23N304 requires: 297, found: 298 [M+H]+.
Step 2: To a solution of tert-butyl 6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate (1140 mg, 3.83 mmol) in DCM (10 ml) was added HC1 4M in dioxane (4.79 ml, 19.17 mmol) at 0 °C and the mixture was left at this temperature for 15 min and then at RT for 48 h. The suspension was filtered and washed with diethyl ether to recover 6,6-dimethyl-l,3,8- triazaspiro[4.5]decane-2,4-dione hydrochloride as an off-white solid. MS (ES+) C9H15N3O2 requires: 197, found: 198 [M+H]+.
Intermediate 2: 2,2-dimethyl-l-(methylsulfonyl)piperazine hydrochloride
Step 1:
To a solution of tert-butyl 3,3-dimethylpiperazine-l-carboxylate (500 mg, 2.333 mmol) in DCM (11 ml) at 0 °C was added TEA (0.976 ml, 7.00 mmol) and methanesulfonyl chloride (321 mg, 2.80 mmol) and the resulting mixture was stirred RT for 3 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (5 - 100 % EtOAc in hexanes) to give tert-butyl 3,3-dimethyl-4-(methylsulfonyl)piperazine-l-carboxylate (600 mg, 2.052 mmol, 88 % yield) as a colorless liquid. MS (ES+) C^H^C^S requires: 292, found: 293 [M+H] +.
Step 2:
To a solution of 3,3-dimethyl-4-(methylsulfonyl)piperazine-l-carboxylate in DCM 4N HCl in dioxane (1.75 ml, 7.00 mmol) was added and the mixture was stirred at RT overnight. A white precipitate was formed and filtered off to yield the final product 2,2-dimethyl-l- (methylsulfonyl)piperazine hydrochloride (440 mg, 1.924 mmol, 82% yield). MS (ES+) C7H16N2O2S requires: 192, found: 193 [M+H]+.
Intermediate 3: N-( 4-( 2, 2 -dimethylpiperazin- 1 -yl)phenyl)methane sulfonamide
hydrochloride
Step 1:
To a suspension of tert-butyl 3,3-dimethylpiperazine-l-carboxylate (150 mg, 0.700 mmol) in dioxane (2 mL) were added dicyclohexyl(2',6'-diisopropoxy-[l,l'-biphenyl]-2-yl)phosphine (Ruphos; 65.3 mg, 0.140 mmol) and N-(4-bromophenyl)methanesulfonamide (193 mg, 0.770 mmol), Ruphos Pd G4 (119 mg, 0.140 mmol), sodium tert-butoxide (336 mg, 3.50 mmol) and the resulting mixture was stirred at 65°C for 4 h. The mixture was concentrated and the residue was purified via silica gel chromatography (20 - 100 % EtOAc in hexanes) to give tert-butyl 3,3- dimethyl-4-(4-(methylsulfonamido)phenyl)piperazine-l-carboxylate (173 mg, 0.451 mmol, 64 % yield) as a brown amorphous material. MS (ES+) C18H29N3O4S requires: 383, found: 384 [M+H]+.
Step 2:
To a solution of tert-butyl 3,3-dimethyl-4-(4-(methylsulfonamido)phenyl)piperazine-l- carboxylate (173 mg, 0.451 mmol) in dioxane (2 mL) were added 4M HC1 in dioxane (0.338 mL, 1.353 mmol) and the resulting mixture was stirred at RT for 48 h. The reaction mixture was filtered through sintered glass funnel, and the solid was collected and used as such in the next step. MS (ES+) C13H21N3O2S requires: 283, found: 284 [M+H]+.
Intermediate 4: 5-(methylsulfonyl)-5,8-diazaspiro[3.5]nonane hydrochloride
To a solution of tert-butyl 5,8-diazaspiro[3.5]nonane-8-carboxylate (100 mg, 0.442 mmol) in DCM (2 mL) at 0°C were added TEA (185 μΐ, 1.326 mmol) and methanesulfonyl chloride (60.7 mg, 0.530 mmol) and the resulting mixture was stirred RT overnight. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (5 - 100 % EtOAc in hexanes and the residue was dissolved in DCM and 4N HC1 in dioxane (331 μΐ, 1.326 mmol) and stirred at RT overnight. The volatiles were removed under reduced pressure to yield 5-(methylsulfonyl)-5,8-diazaspiro[3.5]nonane hydrochloride (103 mg, 0.428 mmol, 97 % yield). MS (ES+) C8Hi6N202S requires: 204, found: 205 [M+H]+.
Intermediate 5: l-(methylsulfonyl)-2-(trifluoromethyl)piperazine 2,2,2-trifluoroacetate
Step 1: To a solution of 2-(trifluoromethyl)piperazine (135 mg, 0.876 mmol) in DCM (6 ml) were added di-tert-butyl dicarbonate (0.224 ml, 0.963 mmol) and the resulting mixture was stirred at RT for 3 h, then concentrated and the residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give tert-butyl 3 -(trifluoromethyl)piperazine-l -carboxylate (200 mg, 0.787 mmol, 90 % yield) as a pale yellow solid. MS (ES+) C10H17F3N2O2 requires: 254, found: 155 [M+H]+- Boc group.
Step 2:
To a solution of tert-butyl 3 -(trifluoromethyl)piperazine-l -carboxylate (50 mg, 0.197 mmol) in pyridine (0.5 ml) were added methanesulfonyl chloride (0.023 ml, 0.295 mmol) and the resulting mixture was stirred at RT for 1 h, saturated NH4C1 was added and the solution was extracted with EtOAc and the organic phase was dried. The residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give tert-butyl 4-(methylsulfonyl)-3- (trifluoromethyl)piperazine-l-carboxylate (45 mg, 0.135 mmol, 69 % yield) as a white solid. MS (ES+) C11H19F3N2O4S requires: 332, found: 233 [M+H]+- Boc group. Step 3:
To a solution of tert-butyl 4-(methylsulfonyl)-3-(trifluoromethyl)piperazine-l-carboxylate (45 mg, 0.135 mmol) in DCM (0.8 ml) were added TFA (0.209 ml, 2.71 mmol) and the resulting mixture was stirred at RT 1 h, then concentrated and used as such in the next step. MS (ES+) C6H11F3N2O2S requires: 232, found: 233 [M+H]+. Intermediate 6: 5, 7, 1 l-triazadispiro[ 2.0.44.43]dodecane-6, 8-dione hydrochloride
To a solution of benzyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylate (300 mg, 1.157 mmol) in ethanol (5 ml) were added potassium cyanide (226 mg, 3.47 mmol) and ammonium carbonate (400 mg, 4.17 mmol) and the resulting mixture was stirred at 90 °C for 48 h in a pressured vial. The mixture was diluted with H20, taken up in EtOAc and the aqueous phase was back extracted with EtOAc (x2) and then the organic phase was washed with brine and dried over Na2S04 to recover a brown solid (200 mg, 0.607 mmol). MS (ES+) C17H19N3O4 requires: 329, found: 330 [M+H]+. This residue was charged in a reaction vessel and was dissolved MeOH (3 ml), treated with 6N HC1 (0.101 ml, 0.607 mmol) and subjected under an atmosphere of N2. 10% Pd-C (64.6 mg, 0.061 mmol) was added to the mixture and the suspension was degassed with N2 and purged with H2. The reaction mixture was stirred under an atmosphere of H2 at 1 atm overnight. The reaction mixture was purged with N2, and filtered through on a pad of Celite and the filtrate concentrated under reduced pressure to yield 5,7,1 l-triazadispiro[2.0.44.43]dodecane-6,8-dione (100 mg, 5.1 mmol, 84%) as a white solid. Used as is in next step. MS (ES+) C9H13N3O2 requires: 195, found: 196 [M+H]+. Intermediate 7: 6, 6-difluoro-l,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride
Prepared as Intermediate 1 using tert-butyl 3,3-difluoro-4-oxopiperidine-l-carboxylate to give 6,6-difluoro-l,3,8-triazaspiro[4.5]decane-2,4-dione. MS (ES+) C7H9F2N3O2 requires: 205, found: 206 [M+H]+.
Intermediate 8: 6-(trifluoromethyl)-l, 3, 8-triazaspirof 4.5 Jdecane-2, 4-dione Prepared as Intermediate 1 using tert-butyl 4-oxo-3-(trifluoromethyl)piperidine-l-carboxylate to give 6-(trifluoromethyl)-l,3,8-triazaspiro[4.5]decane-2,4-dione. MS (ES+) C8Hi0F3N3O2 requires: 237, found: 238 [M+H]+.
Intermediate 9: N-( ( 6-chloro-4-( trifluoromethyl)pyridin-2-yl)methyl)formamide
To a solution of 2-(bromomethyl)-6-chloro-4-(trifluoromethyl)pyridine (1.11 g, 2.85 mmol) (Example 1, Step 1) in DMF (3 ml) were added sodium diformylamide (0.406 g, 4.28 mmol) and the resulting mixture was stirred at RT for 30 min and MeOH (7 ml), formic acid (0.396 ml, 10.31 mmol) and water (0.111 ml, 6.19 mmol) were added and the resulting mixture was stirred at 70°C overnight. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (20 - 100 % EtOAc in hexanes to give N-((6-chloro-4- (trifluoromethyl)pyridin-2-yl)methyl)formamide (598 mg, 2.506 mmol, 61 % yield) as a white solid. MS (ES+) C8H6C1F3N20 requires: 238, found: 239 [M+H]+.
Example 1 : Synthesis of imidazorL5-a1pyridin-5-yl heterocycloalkyl compounds Compound 1: 6,6-dimethyl-8-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-l,3,8- triazaspirof 4.5 ]decane-2, 4-dione
Figure imgf000125_0001
Step 1:
To a solution of 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.514 ml, 10.2 mmol) in CC14 (30 ml) was added BS (2730 mg, 15.3 mmol) and AIBN (168 mg, 1.02 mmol) and the resulting mixture was stirred at 90 °C overnight, then filtered and the solution was evaporated and purified via silica gel chromatography (0 - 10 % EtOAc in hexanes to give a mixture of 2-chloro-6- methyl-4-(trifluoromethyl)pyridine, 2-(bromomethyl)-6-chloro-4-(trifluoromethyl)pyridine and 2-chloro-6-(dibromomethyl)-4-(trifluoromethyl)pyridine (1812 mg, 3.30 mmol, 32% yield, -50% monobromo) as an orange liquid. MS (ES+) C7H4BrClF3N requires: 274, found: 274, 276 [M+H]+.
Step 2:
To a solution of the mixture coming from the previous step (1812 mg, 3.30 mmol, -50% monobromo) in DCM (10 ml) was added 1,3,5,7-tetraazaadamantane (555 mg, 3.96 mmol) and the resulting mixture was stirred at RT overnight. The product was collected by filtration, to afford 1 -((6-chloro-4-(trifluoromethyl)pyridin-2-yl)methyl)- 1 ,3 , 5,7-tetraazaadamantan- 1 -ium bromide (1369 mg, 3.30 mmol, 100% yield) as a white solid. MS (ES+) Ci3Hi6ClF3N5 + requires: 334, found: 335 [M+H]+. Step 3:
To a suspension of l-((6-chloro-4-(trifluoromethyl)pyridin-2-yl)methyl)-l, 3, 5,7- tetraazaadamantan- 1 -ium bromide (1369 mg, 3.30 mmol) in EtOH (20 ml) was added concentrated HC1 (0.566 ml, 6.90 mmol) and the resulting mixture was stirred at 45 °C overnight. The mixture was filtered and the filtrate was evaporated to afford 6-chloro-4- (trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (852 mg, 3.45 mmol) which was used as such in the next step without further purification. MS (ES+) C7H6C1F3N2 requires: 210, found: 211 [M+H]+.
Step 4:
To a solution of (6-chloro-4-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (852 mg, 3.45 mmol) in EtOH (15 mL) was added TEA (1.44 mL, 10.35 mmol) and ethyl formate (1.40 mL, 17.2 mmol) and the resulting mixture was stirred at 90 °C overnight. The volatiles were evaporated and POCl3 (1.93 mL, 20.6 mmol) was added to the residue, and the mixture was heated at 90 °C for 30 min. The mixture was concentrated and then neutralised by slow dropwise addition of saturated aqueous NaHC03; with stirring and cooling in an ice bath. The mixture was extracted with EtOAc and the organic phase was washed with brine, dried over Na2S04. The aqueous phase was back extracted (x2) and the organic layers were combined and concentrated. The residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give 5- chloro-7-(trifluoromethyl)imidazo[l,5-a]pyridine (180 mg, 0.816 mmol, 24 % yield) as a dark yellow solid. MS (ES+) C8H4C1F3N2 requires: 220, found: 221 [M+H]+. Step 5:
To a solution of 5-chloro-7-(trifluoromethyl)imidazo[l,5-a]pyridine (60 mg, 0.272 mmol) in dioxane (1.5 ml) was added Ruphos Pd G4 (46 mg, 0.054 mmol), dicyclohexyl(2',6'- diisopropoxy-[l, l'-biphenyl]-2-yl)phosphine (Ruphos; 25 mg, 0.054 mmol), sodium 2- methylpropan-2-olate (131 mg, 1.360 mmol), and 6,6-dimethyl-l,3,8-triazaspiro[4.5]decane-2,4- dione hydrochloride (Intermediate 1) (70 mg, 0.299 mmol). The mixture was degassed under N2 and then heated overnight at 65 °C. The volatiles were evaporated and the residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes followed by 25% of MeOH in EtOAc) to give 6,6-dimethyl-8-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-l,3,8- triazaspiro[4.5]decane-2,4-dione (27 mg, 0.071 mmol, 26 % yield) as a brown solid. 10 mg was further purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 20 - 60%; 20 min; Column: C18) to give 6,6-dimethyl-8-(7- (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-l,3,8-triazaspiro[4.5] decane-2,4-dione 2,2,2- trifluoroacetate (5 mg, 10.09 μιηοΐ, 3.7 % yield) as a white solid. MS (ES+) Ci7Hi8ClF3N502 requires: 381, found: 382 [M+H]+. 1H MR (600 MHz, METHANOL-d4) δ: 8.98 (s, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 6.62 (s, 1H), 3.59-3.46 (m, 2H), 3.37-3.29 (m, 1H), 3.03 (d, J = 12.7, 1H), 2.36-2.11 (m, 2H), 1.24 (s, 3H), 1.14 (s, 3H).
Compounds 1A and IB: R or S 6,6-dimethyl-8-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)- 1, 3, 8-triazaspirof 4.5 ]decane-2, 4-dione 2, 2, 2-trifluoroacetate 6,6-dimethyl-8-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-l,3,8-triazaspiro[4.5]decane-2,4- dione 2,2,2-trifluoroacetate was separated by SFC method (C02, co-solvent methanol with 0.25%) isopropylamine; Isocratic gradient: 30%> co-solvent; Column: 2.1 x 25.0 cm Chiralcel OX-H from Chiral Technologies (West Chester, PA)). The 2 isomers were analyzed by analytical SFC (C02, co-solvent methanol with 0.1%> isopropylamine; Isocratic gradient: 25%> Co-solvent; Column: 4.6 x 100 mm Chiralcel OX-H from Chiral Technologies (West Chester, PA)) and Enantiomer A (Compound 1A) eluted with rt = 1.02 min and Enantiomer B (Compound IB) rt =2.3 min.
The compounds shown in Table 1 were prepared analogously to Compound 1 : Table 1:
Figure imgf000128_0002
Example 2: Synthesis of imidazo|T,5-a1pyridin-8-yl heterocvcloalkyl compounds
Compound 6: 6-chloro-8-(3, 3-dimethyl-4-(methylsulfonyl)piperazin-l-yl)imidazo[ 1, 5-aJ pyridine 2,2,2-trifluoroacetate
Figure imgf000128_0001
Step 1:
To a suspension of (3-bromo-5-chloropyridin-2-yl)methanamine hydrochloride (900 mg, 3.49 mmol) was added formic acid (736 μΐ, 19.19 mmol) and acetic anhydride (1811 μΐ, 19.19 mmol) previously mixed together and the resulting mixture was stirred at 65 °C for 2 h, then evaporated and the residue diluted with DCM. The organic phase was washed with saturated aqueous NaHC03, the aqueous phase was removed and the solid present in the organic phase was filtered to afford 420 mg of 8-bromo-6-chloroimidazo[l,5-a]pyridine as a white solid. The filtrate was evaporated, dissolved with DCM and MeOH and purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give additional product (total 740 mg, 3.20 mmol, 92 % yield). MS (ES+) C7H4BrClN2 requires: 231, found: 232 [M+H]+.
Step 2:
To a solution of 8-bromo-6-chloroimidazo[l,5-a]pyridine (17 mg, 0.073 mmol) in dioxane (0.5 ml), 2,2-dimethyl-l-(methylsulfonyl)piperazine hydrochloride (Intermediate 2, 22 mg, 0.095 mmol), dicyclohexyl(2',6'-diisopropoxy-[l,l'-biphenyl]-2-yl)phosphine (RuPhos; 6.85 mg, 0.015 mmol), sodium tert-butoxide (35.3 mg, 0.367 mmol) and Ruphos Pd G4 (12.4 mg, 0.015 mmol) were added and the mixture was degassed under N2 and then heated overnight at 65 °C. Solvents were evaporated, and the residue was dissolved in DMSO and purified by reverse phase preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 20 - 60%; 20 min; Column: C18) to give 6-chloro-8-(3,3-dimethyl-4-(methylsulfonyl)piperazin-l- yl)imidazo[l,5-a]pyridine 2,2,2-trifluoroacetate (0.8 mg, 1.751 μπιοΐ, 2 % yield) as a white solid. MS (ES+) C14H19CIN4O2S requires: 342, found: 343 [M+H]+. 1H MR (500 MHz, DMSO-d6) δ 8.52 (brs, 1H), 8.26 (s, 1H), 7.61 (s, 1H), 6.10 (s, 1H), 3.60-3.54 (m, 2H), 3.41-3.34 (m, 2H), 3.18 (s, 2H), 3.03 (s, 3H), 1.51 (s, 6H).
The compounds shown in Table 2 were prepared analogously to Compound 6: Table 2:
Figure imgf000130_0002
Example 3 : Synthesis of imidazo[L5-alpyridin-8-yl aryl compounds
Compound 9: 6-chloro-8-(3-chloro-4-(methylsulfonyl)phenyl)imidazo 2,2,2- trifluoroacetate
Figure imgf000130_0001
To a solution of 8-bromo-6-chloroimidazo[l,5-a]pyridine (17 mg, 0.073 mmol) in dioxane (0.5 ml) was added cesium carbonate (72 mg, 0.22 mmol) and (3-chloro-4- (methylsulfonyl)phenyl)boronic acid (24.3 mg, 0.095 mmol) and PdCl2(dppf)-CH2Cl2Adduct (6 mg, 7.34 μηιοΐ) and the resulting mixture was stirred at 90 °C overnight. The mixture was evaporated and the residue was filtered and purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give 6-chloro-8-(3-chloro-4-(methylsulfonyl)phenyl)imidazo[l,5- a]pyridine (1 mg, 2.93 μηιοΐ, 4% yield) as a yellow solid. The impure fractions collected were repurified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA MeCN; Gradient: B = 20 - 60%; 20 min; Column: CI 8) to give 6-chloro-8-(3-chloro-4- (methylsulfonyl)phenyl)imidazo[l,5-a]pyridine 2,2,2-trifluoroacetate (1.7 mg, 3.73 μιηοΐ, 5 % yield) as a yellow solid. MS (ES+) C14H10CI2N2O2S requires: 341, found: 342 [M+H]+. 1H MR (600 MHz, DMSO-d5) δ 8.77 (s, 1H), 8.55 (s, 1H), 8.18 (d, J = 8.2, 1H), 8.11 (d, J = 1.7, 1H), 8.04 (dd, J= 8.0, J= 1.7, 1H), 7.62 (s, 1H), 7.19 (d, J= 1.7, 1H), 3.44 (s, 3H).
The compounds shown in Table 3 were prepared analogously to Compound 9:
Table 3:
Figure imgf000131_0002
Example 4: Synthesis of 5-(9-(methylsulfonyl)-3,9-diazaspiror5.51undecan-3-yl)-7- (trifluoromethyl) imidazorL5-a1pyridine 2,2,2-trifluoroacetate (Compound 12)
Figure imgf000131_0001
To a solution of tert-butyl 9-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (prepared as in Example 1) in DCM (0.4 ml) was added 0.1 ml of TFA and the mixture was stirred overnight. The volatiles were stripped at reduced pressure, and the residue used without further purification. To a solution of 5-(3,9-diazaspiro[5.5]undecan-3-yl)-7-(trifluoromethyl)imidazo[l,5-a]pyridine 2,2,2-trifluoroacetate (10 mg, 0.022 mmol) in DCM (0.5 ml) was added TEA (9.24 μΐ, 0.066 mmol) and methansulfonyl chloride (2.58 μΐ, 0.033 mmol) and the resulting mixture was stirred at RT for 1 h. The mixture was evaporated and the residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 20 - 60%; 20 min; Column: C18) to give 5-(9-(methylsulfonyl)-3,9-diazaspiro[5.5]undecan-3-yl)-7- (trifluoromethyl)imidazo[l,5-a]pyridine 2,2,2-trifluoroacetate (1.2 mg, 2.262 μπιοΐ, 10 % yield) as a colorless amorphous material. MS (ES+) C18H23F3N4O2S requires: 416, found: 417 [M+H]+. 1H MR (600 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 6.37 (s, 1H), 3.17-3.10 (m, 8H), 2.88 (s, 3H), 1.75-1.71 (m, 4H), 1.66-1.61 (m, 4H).
Example 5: Synthesis of l-(9-(7-(trifluoromethyl)imidazo[L5-alpyridin-5-yl)-3,9- diazaspiror5.51undecan-3-yl)ethanone 2,2,2-trifluoroacetate (Compound 13)
Figure imgf000132_0001
To a solution of tert-butyl 9-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (prepared as in Example 1) in DCM (0.4 ml) was added 0.1 ml of TFA and the mixture was stirred overnight. The mixture was then evaporated and used as such.
To a solution of 5-(3,9-diazaspiro[5.5]undecan-3-yl)-7-(trifluoromethyl)imidazo[l,5-a]pyridine 2,2,2-trifluoroacetate (10 mg, 0.022 mmol) in DCM (0.5 ml) was added TEA (9.24 μΐ, 0.066 mmol) and acetyl chloride (2.358 μΐ, 0.033 mmol) and the resulting mixture was stirred at RT overnight. The mixture was evaporated and the residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 20 - 60%; 12 min; Column: C18) to give l-(9-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-3,9- diazaspiro[5.5]undecan-3-yl)ethanone 2,2,2-trifluoroacetate (2.5 mg, 5.06 μπιοΐ, 23 % yield) as a colorless amorphous material. MS (ES+) C19H23F3N4O requires: 380, found: 381 [M+H]+. 1H MR (600 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 6.39 (s, 1H), 3.49-3.44 (m, 2H), 3.44-3.39 (m, 2H), 3.16-3.09 (m, 4H), 2.00 (s, 3H), 1.75-1.70 (m, 4H), 1.57-1.52 (m, 2H), 1.50-1.44 (m, 2H).
Example 6: Synthesis of 3,6,6-trimethyl-8-(7-(trifluoromethyl)imidazorL5-a1pyridin-5-yl)- L3,8-triazaspiror4.51decane-2,4-dione (Compound 14)
Figure imgf000133_0001
To a solution of 6,6-dimethyl-8-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-l,3,8- triazaspiro[4.5]decane-2,4-dione (8.8 mg, 0.023 mmol) in DMF (0.3 ml) was added potassium carbonate (3.51 mg, 0.025 mmol) and dimethyl sulfate (2.205 μΐ, 0.023 mmol) and the resulting mixture was stirred at RT for 2 h then directly purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 20 - 60%; 12 min; Column: C18) to give 3,6,6-trimethyl-8-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-l,3,8- triazaspiro[4.5]decane-2,4-dione 2,2,2-trifluoroacetate (1.9 mg, 3.73 μπιοΐ, 16 % yield) as a pale yellow solid. MS (ES+)
Figure imgf000133_0002
requires: 395, found: 396 [M+H]+. 1H NMR (600 MHz, DMSO-de) δ: 8.61-8.54 (brs, 2H), 7.91 (s, 1H), 7.79 (s, 1H), 6.33 (s, 1H), 3.41-3.18 (m, 3H), 3.05 (d, J= 12.0, 1H), 2.85 (s, 3H), 2.26-1.98 (m, 2H), 1.05 (brs, 6H).
3,6,6-trimethyl-8-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-l,3,8-triazaspiro[4.5]decane- 2,4-dione was prepared analogously to 3,6,6-trimethyl-8-(7-(trifluoromethyl)imidazo[l,5- a]pyridin-5-yl)-l,3,8-triazaspiro[4.5]decane-2,4-dione 2,2,2-trifluoroacetate. Example 7: Synthesis of 2,2-dimethyl-4-(7-(trifluoromethyl)imidazorL5-a1pyridin-5- vDpiperazine-l -sulfonamide 2,2,2-trifluoroacetate (Compound 15)
Figure imgf000134_0001
To a solution of 5-(3,3-dimethylpiperazin-l-yl)-7-(trifluoromethyl)imidazo[l,5-a]pyridine hydrochloride (53 mg, 0.158 mmol; prepared as Step 2, Example 2 reacting with tert-butyl 2,2- dimethylpiperazine-l-carboxylate, followed by Boc-deprotection with 4N HCl (30 eq) in dioxane) in DCM (1 mL) were added TEA (0.066 mL, 0.475 mmol) and sulfurisocyanatidic chloride (22.41 mg, 0.158 mmol), tBuOH (0.015 mL, 0.158 mmol) and the resulting mixture was stirred overnight at RT. The mixture was washed with water and the organic phase was evaporated and 0.7 mL of DCM and TFA (0.3 mL) was added and the mixture was stirred 1 h, then evaporated and the residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 20 - 60%; 20 min; Column: C18) to give 2,2-dimethyl-4-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)piperazine-l- sulfonamide 2,2,2-trifluoroacetate (14 mg, 0.028 mmol, 18 % yield) as a white solid. MS (ES+) Ci4Hi8F3N502S requires: 377, found: 378 [M+H]+. 1HNMR (600 MHz, METHANOL-d4) δ: 8.95 (s, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 6.61 (s, 1H), 3.71 (t, J = 4.8, 2H), 3.28-3.24 (m, 2H), 3.06 (s, 2H), 1.64 (brs, 6H).
Example 8: Synthesis of N-(4-(2,2-dimethyl-4-(7-(trifluoromethyl)imidazo[L5-alpyridin-5- vDpiperazin-lyDphenvDmethanesulfonamide 2,2,2-trifluoroacetate (Compound 16)
Figure imgf000134_0002
Prepared as Example 1 step 5 using Intermediate 3 and purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 20 - 60%; 20 min; Column: CI 8) to give N-(4-(2,2-dimethyl-4-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5- yl)piperazin-l-yl)phenyl)methanesulfonamide (1.75 mg, 3.74 μπιοΐ, 4.1 % yield). MS(ES+) C2iH24F3N502S requires: 467, found: 468 [M+H]+. 1HNMR (600 MHz, METHANOL-d4) δ 8.97 (s, 1H), 7.97 (s, 2H), 7.48 (d, J = 8.5, 2H), 7.38 (d, J = 8.5, 2H), 6.67 (s, 1H), 3.50 (brs, 2H), 3.35-3.28 (m, 2H), 3.44 (s, 2H), 3.04 (s, 3H), 1.41 (s, 6H).
Example 9: Synthesis of 3-(6-chloroimidazorL5-a1pyridin-8-yl)-3-azabicyclor3.3.11nonan-9-ol (Compound 17A) and 3-{6-chloroimidazorL5-a1pyridin-8-yl|-3-azabicvclor3.3.11nonan-9-ol
(Compound 17B)
Figure imgf000135_0001
A B
Step 1:
3 -b enzy 1 - 1 , 5 , 3 -di oxazepane
Figure imgf000135_0002
To a solution of phenylmethanamine (20 g, 186.65 mmol, 20.4 mL) in toluene (80 mL) was added ethylene glycol (23.17 g, 373.3 mmol, 20.87 mL) and paraformaldehyde (33.63 g, 373.3 mmol). The mixture was stirred at 110 °C for 3 h when about 6 mL water was separated from the reaction via a Dean Stark trap. The residue was poured into water (200 mL), extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine, and concentrated as colorless liquid. The residue was used for next step without any further purification. (30 g, 155.2 mmol, 83% yield). 1H MR (400MHz, CDC13) δ: 7.38 - 7.32 (m, 5H), 4.51 (s, 4H), 4.05 (s, 2H), 3.92 (s, 4H).
Step 2:
3'-benzylspiro[l,3-dioxolane-2,9'-3-azabicyclo[3.3.1]nonane]
Figure imgf000136_0001
To a solution of Nal (15.27 g, 101.9 mmol) in acetonitrile (50 mL) was added TMSC1 (11.07 g, 101.9 mmol, 12.87 mL). The mixture was stirred at 0 °C for 20 min. Then to the mixture was added cyclohexanone (5.00 g, 50.9 mmol, 5.26 mL). The reaction was stirred at 0 °C for 20 min. 3-benzyl-l,5,3-dioxazepane (11.81 g, 61.14 mmol) was added to the mixture and it was stirred at 35 °C for 4 h. The residue was poured into saturated aqueous NaHC03 solution (200 mL), extracted with EtOAc (100 mLx2). The combined organic layers were concentrated and purified by column chromatography on silica gel (Eluent Petroleum ether :EtOAc=100: l) to give the desired product as colorless oil (7.2 g, 20.81 mmol, 41% yield). MS (ES+) C17H23NO2 requires: 273, found: 274 [M+H]+.
Step 3:
spiro[ 1 ,3 -dioxolane-2,9'-3 -azabicyclo[3.3.
Figure imgf000136_0002
To a solution of 3'-benzylspiro[l,3-dioxolane-2,9'-3-azabicyclo[3.3.1]nonane] (7.2 g, 26.34 mmol) in MeOH (100 mL) was added Pd/C (5 g, 26.34 mmol, 10%) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 50 °C under H2 (50 Psi) for 16 h. The reaction was filtered and the filtrate was concentrated to give a white solid. This was purified by column chromatography on silica gel (eluent
DCM:MeOH=10: l) to give desired product (2.5 g, 13.37 mmol, 51% yield).1H MR (400MHz, METHANOL-d4) δ: 3.98 (s, 4H), 3.33-3.31 (m, 1H), 3.30-3.27 (m, 1H), 3.13-3.06 (m, 2H), 2.18 - 2.07 (m, 2H), 2.01-1.92 (m, 1H), 1.86-1.78 (m, 2H), 1.69 (s, 2H), 1.57 (td,
Figure imgf000137_0001
1H).
Step 4:
3'-(6-chloroimidazo[l,5-a]pyridin-8-yl)spiro[l,3-dioxolane-2,9'-3-azabicyclo[3.3.1]nonane]
I
Figure imgf000137_0002
To a solution of spiro[l,3-dioxolane-2,9'-3-azabicyclo[3.3.1]nonane] (593.7 mg, 3.24 mmol) in dioxane (15 mL) was added 8-bromo-6-chloro-imidazo[l,5-a]pyridine (500 mg, 2.16 mmol, prepared as Example 2, step 1), Xphos-Pd-G3 (182.8 mg, 216 umol) and t-BuONa (622.7 mg, 6.48 mmol). The mixture was stirred at 90 °C for 16 h under N2. The residue was poured into water (50 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were concentrated. The residue was purified by column chromatography on silica gel, (eluent Petroleum ether : EtOAc = 1 : 1) to give the desired product as yellow oil (470 mg, 591.35 umol, 27% yield). MS (ES+) C17H20N3CIO2 requires: 333 and 335, found: 334 and 336 [M+H]+.
Step 5:
3-(6-chloroimidazo[l,5-a]pyridin-8-yl)-3-azabicyclo[3.3.1]nonan-9-one
I
Figure imgf000137_0003
To a solution of 3'-(6-chloroimidazo[l,5-a]pyridin-8-yl)spiro[l,3-dioxolane-2,9'-3- azabicyclo[3.3.1]nonane] (470 mg, 1.41 mmol) in H20 (11 mL) and dioxane (11 mL) was added HC1 (12 M, 1.00 mL). The mixture was stirred at 100 °C for 16 h. The residue was poured into water (20 mL), extracted with EtOAc (10 mL x 2). The aqueous layer was adjusted pH to 7 and extracted with EtOAc (10 mL x 2). The combined organic layers were concentrated. The residue was used for next step without any further purification. MS (ES+) C15H16N3OCI requires: 289 and 291, found: 290 and 292 [M+H]+.
Step 6:
3-(6-chloroimidazo[l,5-a]pyridin-8-yl)-3-azabicyclo[3.3.1]nonan-9-ol and 3-(6- chloroimidazo[l,5-a]pyridin-8-yl)-3-azabicyclo[3.3.1]nonan-9-ol
Figure imgf000138_0001
A B
To a solution of 3-(6-chloroimidazo [1,5-a] pyridin-8-yl)-3-azabicyclo [3.3.1] nonan-9-one (50 mg, 172.5 umol) in MeOH (2 mL) was added NaBH4 (13.06 mg, 345.12 umol). The mixture was stirred at 25 °C for 5 min. The residue was quenched with H20 (20 mL), extracted with EtOAc (10 mL x 2). The combined organic layers were concentrated as yellow oil which was purified by prep-HPLC (Mobile phase: A= H20 (0.05% ammonia hydroxide v/v), B=MeCN; Gradient B = 25 - 55%; 12 min; Column: CI 8) and freeze-dried to give desired product. Two products were obtained.
Compound 17A was collected as a white solid (3-(6-chloroimidazo[l,5-a]pyridin-8-yl)-3- azabicyclo[3.3.1]nonan-9-ol (1.0 mg, 3.39 umol, 2 % yield)). MS (ES+) Ci5Hi8N3OCl requires: 291 found: 292 [M+H]+. 1H MR (400 MHz, METHANOL-d4) δ: 8.26 (s, 1H), 8.00 (s, 1H), 7.48 (s, 1H), 6.03 (s, 1H), 3.95 - 3.85 (m, 3H), 3.19 - 3.11 (m, 2H), 2.43 (td, J= 6.6, 13.2 Hz, 1H), 2.29 - 2.19 (m, 2H), 2.00 (br s, 2H), 1.73 (br dd, J= 5.2, 13.5 Hz, 2H), 1.56 - 1.49 (m, 1H). Compound 17B was collected as a white solid (3-(6-chloroimidazo[l,5-a]pyridin-8-yl)-3- azabicyclo[3.3.1]nonan-9-ol (1.0 mg, 3.29 umol, 2 % yield)). MS (ES+) Ci5Hi8N3OCl requires: 291 found: 292 [M+H]+. 1H NMR (400 MHz, METHANOL-d4) δ: 8.25 (s, 1H), 7.98 (s, 1H), 7.48 (s, 1H), 6.02 (s, 1H), 3.87 (t, J=3.3 Hz, 1H), 3.60 - 3.53 (m, 2H), 3.49 - 3.45 (m, 2H), 2.44 - 2.39 (m, 1H), 2.11 - 2.07 (m, 2H), 2.01 (s, 2H), 1.91 - 1.84 (m, 2H), 1.54 - 1.47 (m, 1H).
Example 10: Synthesis of. 3-(6-chloroimidazorL5-a1pyridin-8-yl)spiror3-azabicvclo r3.3.11nonane-9,5'-imidazolidine1-2',4'-dione and 3-(6-chloroimidazorL5-a1pyridin-8-yl)spiro Γ3- azabicyclor3.3.11nonane-9,5'-imidazolidine1-2',4'-dione (Compounds 18A and 18B)
Figure imgf000139_0001
To a solution of 3-(6-chloroimidazo [l,5-a]pyridin-8-yl)-3-azabicyclo [3.3.1] nonan-9-one (50 mg, 172.56 umol) in EtOH (3.6 mL) and H20 (1 mL) was added NaCN (19.96 mg, 407.24 umol) and ( H4)2C03 (315.04 mg, 3.28 mmol, 350.04 uL) in a sealed tube, then it was stirred at 85 °C for 16 h. The residue was poured into water (20 mL), extracted with EtOAc (10 mL x 2). The combined organic layers were concentrated. The aqueous layer was quenched by aqueous NaCIO solution maintaining pH>l 1. The yellow oil was purified by prep-HPLC (Mobile phase: A= H20 (0.1%TFA), B= MeCN], Gradient B = 8 - 38%, 13 min; Column: C18) and freeze-dried to give the desired product. Two products were obtained:
Product A: 3-(6-chloroimidazo[l,5-a]pyridin-8-yl)spiro[3-azabicyclo[3.3.1]nonane-9,5'- imidazolidine]-2',4'-dione (1.6 mg, 4.31 umol, 3 % yield) was collected as a white solid. MS (ES+) Ci7Hi8N502Cl requires: 359 found: 360 [M+H]+. 1H MR (400 MHz, METHANOL-d4) δ: 8.83 (s, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 6.25 (s, 1H), 4.08 (d, J=12.0 Hz, 2H), 3.76 (d, J=11.9 Hz, 2H), 2.60 - 2.29 (m, 1H), 2.12 (s, 4H), 2.01 - 1.92 (m, 2H), 1.66 - 1.57 (m, 1H).
Product B: 3-(6-chloroimidazo[l,5-a]pyridin-8-yl)spiro[3-azabicyclo[3.3.1]nonane-9,5'- imidazolidine]-2',4'-dione (1.2 mg, 5.17e-l umol, 0.3 % yield) was collected as a white solid. MS (ES+) Ci7Hi8N502Cl requires: 359 found: 360 [M+H]+. 1H NMR (400MHz, METHANOL- d4) δ: 8.70 (s, 1H), 8.11 (s, 1H), 7.78 (s, 1H), 6.23 (s, 1H), 3.78 (d, 7=11.5 Hz, 2H), 3.52 - 3.45 (m, 2H), 2.70 (br d, 7=14.1 Hz, 2H), 2.50 - 2.29 (m, 1H), 2.12 (s, 2H), 2.01 - 1.84 (m, 2H), 1.62 (d, 7=6.8 Hz, 1H). Example 11 : Synthesis of 3 -{ 6-chloroimidazor 1 , 5-a1pyridin-8-yl I -3 -azaspiro rbicyclor3.2.11octane-8,4'-imidazolidine1-2',5'-dione (Compound 19)
o
Figure imgf000140_0001
Figure imgf000140_0002
Step 1:
3'-benzylspiro[l,3-dioxolane-2,8'-3-azabicyclo[3.2.1]octane]
Figure imgf000140_0003
To a solution of Nal (14.25 g, 95.10 mmol) in MeCN (48 mL) was added dropwise TMSC1 (10.33 g, 95.10 mmol, 12.01 mL) at 0 °C under N2. The mixture was stirred for 20 min. Then cyclopentanone (4.00 g, 47.55 mmol, 4.21 mL) was added and stirred for 20 min at 0 °C. A solution of 3-benzyl-l,5,3-dioxazepane (9.19 g, 47.55 mmol, Example 8, step 1) in MeCN (30 mL) was added dropwise at 0 °C. The mixture was heated to 40 °C and stirred for 6 h under N2. The reaction solution was poured into saturated NaHC03 solution (100 mL) at 0 °C and the mixture was extracted with EtOAc (80 mL><3) and washed with brine (100 mL><2). The organic layer was dried over Na2S04. After filtration, the filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluent Petroleum Ether /EtOAc =1/0 to 20: 1) to give the desired product 3'-benzylspiro[l,3-dioxolane-2,8'-3- azabicyclo[3.2.1]octane] (5.39 g, 20.78 mmol, 43 % yield) as a colorless oil. 1H NMR (400MHz, METHANOL-d4) δ: 7.34 - 7.23 (m, 4H), 7.23 - 7.16 (m, 1H), 3.95-3.87 (m, 4H), 3.50 (s, 2H), 2.60 - 2.49 (m, 4H), 1.74 (s, 6H).
Step 2: spiro[l,3-dioxolane-2,8'-3-azabicyclo[3.2.1]octane]
Figure imgf000141_0001
To a solution of 3'-benzylspiro[l,3-dioxolane-2,8'-3-azabicyclo[3.2.1]octane] (2.5 g, 9.64 mmol, 1.00 eq) in MeOH (20 mL) was added Pd/C (400 mg, 9.64 mmol) and AcOH (57.89 mg, 963.99 umol, 55.13 uL) under N2 at 25 °C. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 40 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent DCM: MeOH = 50: 1 to 10: 1) to give the desired product spiro[l,3-dioxolane-2,8'-3-azabicyclo[3.2.1]octane] (1.44 g, 8.51 mmol, 88 % yield) as a colorless oil. 1H MR (400 MHz, METHANOL-d4) δ: 3.98 - 3.88 (m, 4H), 3.09 (d, J =12.8, 2H), 2.61 (dd, J= 3.1, 13.4, 2H), 1.92 - 1.69 (m, 4H), 1.66 - 1.49 (m, 2H) Step 3:
3'-(6-chloroimidazo[l,5-a]pyridin-8-yl)spiro[l,3-dioxolane-2,8'-3-azabicyclo[3.2.1]octane]
I
Figure imgf000141_0002
To a solution of spiro[l,3-dioxolane-2,8'-3-azabicyclo[3.2.1]octane] (520 mg, 3.07 mmol) in dioxane (8 mL) was added 8-bromo-6-chloro-imidazo[l,5-a]pyridine (677 mg, 2.93 mmol), t- BuONa (1.41 g, 14.63 mmol), RuPhos (273.13 mg, 585.32 umol) and RuPhos Pd G2 (200 mg, 257.49 umol) at 15 °C. The suspension was degassed under vacuo and purged with N2 several times. The mixture was heated to 95 °C and stirred for 16 h under N2. To the mixture was added water (5 mL) at 0 °C and the aqueous phase was extracted with EtOAc (10 mL><3). The organic layer was dried over Na2S04. After filtration, the filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel, (eluent DCM: MeOH = 75: 1 to 10: 1) to give the desired product 3'-(6-chloroimidazo[l,5-a]pyridin-8-yl)spiro[l,3-dioxolane- 2,8'-3-azabicyclo[3.2.1]octane] (414 mg, 1.29 mmol, 44 % yield) as yellow solid. MS (ES+) Ci6Hi8ClN302 requires: 319, found: 320 [M+H]+.
Step 4: 3-(6-chloroimidazo[l,5-a]pyridin-8-yl)-3-azabicyclo[3.2.1]octan-8-one
I
Figure imgf000142_0001
To a solution of 3'-(6-chloroimidazo [l,5-a]pyridin-8-yl) spiro [1,3-dioxolane -2,8'-3- azabicyclo[3.2.1]octane] (414.00 mg, 1.29 mmol) in dioxane (16 mL) and H20 (4 mL) was added PTSA (155.5 mg, 903.00 umol) at 15 °C. The solution was heated to 100 °C and stirred for 16 h. The mixture was adjusted to pH 9 with IN NaOH solution (2 mL) at 0°C. Then the mixture was extracted with EtOAc (5 mL><3). The organic layer was dried over Na2S04. After filtration, the filtrate was concentrated in vacuo and the residue was purified by Prep-TLC on silica gel (eluent DCM:MeOH=10: l) to give desired product 3-(6-chloroimidazo[l,5-a]pyridin- 8-yl)-3-azabicyclo[3.2.1]octan-8-one (51 mg, 184.96 umol, 14 % yield) as a red oil. MS (ES+) Ci4Hi4N3OCl requires: 275, found: 276 [M+H]+.
Step 5:
3-(6-chloroimidazo[l,5-a]pyridin-8-yl)spiro[3-azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'- dione
Figure imgf000142_0002
To a solution of 3-(6-chloroimidazo [1,5-a] pyridin-8-yl)-3-azabicyclo [3.2.1]octan-8-one (51 mg, 184.96 umol) in EtOH (4 mL) and H20 (lmL) was added ( H4)2C03 (337.68 mg, 3.51 mmol, 375.20 uL) and NaCN (36.26 mg, 739.84 umol) at 15 °C. The mixture was heated to 85 °C and stirred for 16 h. To the mixture was added EtOAc (10 mL) at 15°C and the mixture was extracted with brine (6 mL><3). The organic layer was dried over Na2S04. After filtration, the filtrate was concentrated in vacuo and the residue was purified by Prep-TLC on silica gel (eluent DCM: MeOH=10: l) to give crude product (40 mg) as a light yellow oil. The crude product was repurified by Prep-HPLC (column: Boston pH-lex 150*25 lOum; mobile phase: [H20 (0.1%TFA)-MeCN]; B%: 14%-44%, lOmin) and dried by lyophilization to give desired product 3-(6-chloroimidazo[l,5-a]pyridin-8-yl)spiro[3-azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'- dione (1.8 mg, 4.95 umol, 3% yield) as a yellow solid. MS (ES+) Ci6Hi6N5C102 requires: 345, found: 346 [M+H]+. 1H MR (400 MHz, METHANOL-d4) δ: 9.10 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 6.41 (d, J=1.3, 1H), 3.62 (dd, J= 3.3, 12.5, 2H), 3.38 (d, J=12.3, 2H), 2.52 - 2.29 (m, 4H), 1.97 - 1.87 (m, 2H).
Example 12: Synthesis of 5-(5-(methylsulfonyl)-5,8-diazaspiro[3.51nonan-8-yl)-7-
(trifluoromethyl) imidazorL5-a1pyridine 2,2,2-trifluoroacetate (Compound 20)
Figure imgf000143_0001
Prepared by the method of Example 1 step 5 using the product of Example 1 step 4 together with Intermediate 4 (preparation described below) The product was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 10 - 40%; 20 min; Column: C18) to give 5-(5-(methylsulfonyl)-5,8-diazaspiro[3.5]nonan-8-yl)-7- (trifluoromethyl)imidazo[l,5-a]pyridine (0.7 mg, 1.802 μιηοΐ, 3 % yield) MS (ES+) Ci6Hi9F3N402S requires: 388, found: 389 [M+H]+. 1HNMR (600 MHz, METHANOL-d4) δ 9.01 (s, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 6.68 (s, 1H), 3.68-3.61 (m, 2H), 3.39 (s, 2H), 3.20-3.12 (m, 2H), 3.09 (s, 3H), 2.67-2.55 (m, 2H), 2.38-2.28 (m, 2H), 1.98-1.89 (m, 1H), 1.88-1.78 (m, 1H).] Example 13 : Synthesis of 5-(6,6-dimethyl-2,4-dioxo-L3,8-triazaspiror4.51decan-8-yl) imidazorL5-a1pyridine-7-carbonitrile 2,2,2-trifluoroacetate (Compound 21)
Figure imgf000144_0001
To a solution of 5-chloroimidazo[l,5-a]pyridine-7-carbonitrile (25 mg, 0.141 mmol; prepared as Example 1, step 4) in DMSO (0.6 mL) were added cesium fluoride (21.38 mg, 0.141 mmol) and DIPEA (0.049 mL, 0.282 mmol) and 6,6-dimethyl-l,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (41 mg, 0.176 mmol) and the resulting mixture was stirred at 120 °C for 7 days and then concentratred and directly purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 10 - 40%; 20 min; Column: C18) to give 5-(6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)imidazo[l,5-a]pyridine-7- carbonitrile 2,2,2-trifluoroacetate as an orange solid. MS (ES+) Ci7Hi8N602 requires: 338, found: 339 [M+H]+. 1HNMR (600 MHz, METHANOL-d4) δ 8.78 (s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 6.55 (s, 1H), 3.55-3.46 (m, 2H), 3.36-3.27 (m, 1H), 3.01 (d, J = 11.2, 1H), 2.35-2.10 (m, 2H), 1.23 (s, 3H), 1.13 (brs, 3H).
Example 14: Synthesis of 5-(4-(methylsulfonyl)-3-(trifluoromethyl)piperazin-l-yl)-7- (trifluoromethyl)imidazorL5-a1pyridine (Compound 22)
Figure imgf000144_0002
To a suspension of 5-chloro-7-(trifluoromethyl)imidazo[l,5-a]pyridine (20 mg, 0.091 mmol) in Dioxane (0.5 ml) were added l-(methylsulfonyl)-2-(trifluoromethyl)piperazine 2,2,2- trifluoroacetate (Intermediate 5; 47 mg, 0.136 mmol), Ru(Phos)G4- Precatalyst (11.5 mg, 0.014 mmol) and dicyclohexyl(2',6'-diisopropoxy-[l,l'-biphenyl]-2-yl)phosphine (RuPhos) (6.3 mg, 0.014 mmol) and the resulting mixture was stirred ovenight at 65 °C 12 h, then at 90 °C for 8 h. The solution was filtered and purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 20 - 60%; 20 min; Column: C18) to give 5-(4-(methylsulfonyl)-3-(trifluoromethyl)piperazin-l-yl)-7-(trifluoromethyl)imidazo[l,5- a]pyridine 2,2,2-trifluoroacetate (1.3 mg, 2.451 μπιοΐ, 3 % yield) as a yellow solid. MS (ES+) C14H14F6N4O2S requires: 416, found: 417 [M+H]+. 1HNMR (600 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.01 (s, 1H), 7.82 (s, 1H), 6.49 (s, 1H), 4.89 - 4.82 (m, 1H), 3.90 (d, J= 14.2, 1H), 3.72 (t, J = 12.6, 1H), 3.62 (d, J= 13.3, 1H), 3.45 (d, J= 11.5, 2H), 3.21 (s, 3H), 2.95 (t, J= 11.1, 1H).
Example 15: Synthesis of 8-(7-(trifluoromethyl)imidazorL5-a1pyridin-5-yl)-L3,8- triazaspiror4.51decane-2,4-dione (Compound 23)
Figure imgf000145_0001
Prepared as Example 1 step 5 using Intermediate 1 and purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 10 - 40%; 20 min; Column: C18) to give 8-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-l,3,8- triazaspiro[4.5]decane-2,4-dione 2,2,2-trifluoroacetate (0.4 mg, 0.361 mmol, 1 % yield). MS(ES+) C15H14F3N5O2 requires: 353, found: 354 [M+H]+. 1HNMR (600 MHz, DMSO-d6) δ 10.75-10.61 (m, 1H), 8.55-8.40 (m, 1H), 7.90-7.84 (m, 2H), 7.73 (s, 1H), 6.26 (s, 1H), 3.47 - 3.26 (m, 2H), 3.19 - 3.04 (m, 2H), 2.18 (t, J= 10.9, 2H), 1.77 (d, J= 13.6, 2H).
Example 16: Synthesis of. 7-(7-(trifluoromethyl)imidazorL5-a1pyridin-5-yl)-L3,7- triazaspiror4.41nonane-2,4-dione (Compound 24)
Figure imgf000146_0001
To a solution of N-((6-chloro-4-(trifluoromethyl)pyridin-2-yl)methyl)formamide (Intermediate 9; 43 mg, 0.180 mmol) in DMSO (0.5 ml) were added DIPEA (0.031 ml, 0.180 mmol) and cesium fluoride (32.9 mg, 0.216 mmol) and l,3,7-triazaspiro[4.4]nonane-2,4-dione (28.0 mg, 0.180 mmol) and the resulting mixture was stirred at 100 °C for 5 h. The mixture was taken up in EtOAc and washed with water, then the residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give N-((6-(2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)-4- (trifluoromethyl)pyridin-2-yl)methyl)formamide as an orange solid. This solid was then treated with 100 μΙ_, of POCl3 and heated at 100 °C for 15 min, then quenched with saturated slution of NaHC03 and taken up in EtOAc. The organic phase was then evaporated and the residue purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 10 - 40%; 20 min; Column: CI 8) to give 7-(7- (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-l,3,7-triazaspiro[4.4]nonane-2,4-dione 2,2,2- trifluoroacetate (4.5 mg, 9.9 μπιοΐ, 5.5 % yield) as a white solid. MS (ES+) Ci4Hi2F3N502 requires: 339, found: 340 [M+H]+. 1HNMR (600 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.78 (s, 1H), 8.57 (s, 1H), 7.81 (s, 1H), 7.79 (s, 1H), 6.27 (s, 1H), 3.79 (d, J = 10.3, 1H), 3.79 - 3.74 (m, 1H), 3.59 (d, 7= 10.3, 1H), 3.56 - 3.50 (m, 1H), 2.45 - 2.39 (m, 1H), 2.20 - 2.15 (m, 1H). Example 17: Synthesis of 1 l-(7-(trifluoromethyl)imidazorL5-a1pyridin-5-yl)-5,7,l 1- triazadispiror2.0.44.431dodecane-6,8-dione (Compound 25)
Figure imgf000147_0001
Prepared as Example 1 step 5 using Intermediate 6 and purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 20 - 60%; 20 min; Column: C18) to give 1 l-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-5,7,l 1- triazadispiro[2.0.44.43]dodecane-6,8-dione 2,2,2-trifluoroacetate as a white solid. MS (ES+) C17H16F3N5O2 requires: 379, found: 380 [M+H]+. 1H MR (600 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.52 (s,lH), 8.19 (s, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 6.32 (s, 1H), 3.53 - 3.44 (m, 2H), 3.42 - 3.33 (m, 1H), 3.00 - 2.94 (m, 1H), 2.25 - 2.17 (m, 1H), 2.12 - 2.02 (m, 1H), 0.75 - 0.60 (m, 2H), 0.54 (s, 2H).
Example 18: Synthesis of 3-(2-hvdroxyethyl)-6,6-dimethyl-8-(7-(trifluoromethyl)imidazo Γ1,5- a1pyridin-5-yl)-L3,8-triazaspiror4.51decane-2,4-dione (Compound 26)
Figure imgf000147_0002
To a solution of 6,6-dimethyl-8-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-l,3,8- triazaspiro[4.5]decane-2,4-dione 2,2,2-trifluoroacetate (30 mg, 0.06 mmol) in DMF (0.5 ml) were added CS2CO3 (39.5 mg, 0.12 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (17.39 mg, 0.073 mmol) and the resulting mixture was stirred at 90 °C for lh. The reaction mixture was diluted with H20 and taken up in EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc (3x) and the combined organic layers were concentrated under reduced pressure. MS (ES+) C25H36F3N5O3S1 requires: 539, found: 540 [M+H]+. The residue was treated with 4N HCl in dioxane (0.5 ml, 2.0 mmol) and stirred overnight at RT. The volatiles were removed under reduced pressure and the residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 10 - 50%; 20 min; Column: C18) to give 3-(2-hydroxyethyl)-6,6-dimethyl-8-(7-(trifluoromethyl)imidazo[l,5- a]pyridin-5-yl)-l,3,8-triazaspiro[4.5]decane-2,4-dione (13.5 mg, 0.025 mmol, 41 % yield) as a white solid. MS (ES+) C19H22F3N5O3 requires: 425, found: 426 [M+H]+. 1H MR (600 MHz, DMSO-de) δ 8.72 (s, 1H), 8.54 (s, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 6.39 (s, 1H), 3.52 - 3.47 (m, 2H), 3.46 - 3.41 (m, 2H), 3.40 - 3.32 (m, 2H), 3.31 - 3.16 (m, 2H), 3.06 (d, J = 11.7, 1H), 2.30 - 1.96 (m, 2H), 1.05 (s, 6H).
Example 19: Synthesis of 6,6-difluoro-8-(7-(trifluoromethyl)imidazo[L5-alpyridin-5-yl)-L3,8- triazaspiror4.51decane-2,4-dione (Compound 27)
Figure imgf000148_0001
Prepared as Example 16 using Intermediate 7 and purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B =10 - 40%; 20 min; Column: C18). MS (ES+) Ci5Hi2F5N502 requires: 389, found: 390 [M+H]+. 1H NMR (600 MHz, DMSO-de) δ 11.18 (s, 1H), 8.76 (s, 1H), 8.47 (s, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 6.55 (s, 1H), 3.86-3.76 (m, 2H), 3.52-3.39 (m, 2H), 2.40-2.34 (m, 1H), 2.30-2.22 (m, 1H).
Compounds 27 A and 27B: R or S 6, 6-difluoro-8-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5- yl)-l, 3, 8-triazaspirof 4.5 ]decane-2, 4-dione
Compounds coming from Example 16 were not purified by mass-triggered preparative HPLC but precipitated from EtOH and then chirally separated. 6,6-difluoro-8-(7- (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-l,3,8-triazaspiro[4.5]decane-2,4-dione was separated by SFC method (C02, co-solvent ethanol with 0.25% isopropylamine; Isocratic gradient: 24% Co-solvent; Column: 2.1 x 25.0 cm Chiralcel OX-H from Chiral Technologies (West Chester, PA)). The 2 isomers were analyzed by analytical SFC (C02, co-solvent ethanol with 0.25% isopropyl amine; Isocratic gradient: 25% co-solvent; Column: 4.6 x 100 mm Chiralcel OX-H from Chiral Technologies (West Chester, PA)) and Compound 27A eluted with rt= 0.79 min and Compound 27B with rt=1.06 min.
Example 20: Synthesis of 6-(trifluoromethyl)-8-(7-(trifluoromethyl)imidazo[L5-alpyridin-5- yl)-L3,8-triazaspiror4.51decane-2,4-dione (Compound 28)
Figure imgf000149_0001
Prepared as Example 16 using Intermediate 8 and purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B =10 - 40%; 20 min; Column: C18). MS (ES+) Ci6Hi3F6N502 requires: 421, found: 422 [M+H]+. 1H NMR (600 MHz, MeOH-d4) δ 8.98 (s, 1H), 7.96 (s, 2H), 6.63 (s, 1H), 3.74 - 3.69 (m, 1H), 3.58 - 3.47 (m, 2H), 3.26 - 3.20 (m, 1H), 3.13 - 3.06 (m, 1H), 2.48 - 2.41 (m, 1H), 1.99 - 1.94 (m, 1H).
Example 21 : Synthesis of 8-(3,3-dimethyl-4-(methylsulfonyl)piperazin-l-yl)-6-
(trifluoromethyl)imidazorL5-a1pyridine (Compound 29)
Figure imgf000149_0002
Prepared as Example 1 step 5 using Intermediate 1 and purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 10 - 40%; 20 min; Column: C18) to give 8-(3,3-dimethyl-4-(methylsulfonyl)piperazin-l-yl)-6- (trifluoromethyl)imidazo[l,5-a]pyridine 2,2,2-trifluoroacetate as a brown solid. MS (ES+) C15H19F3N4O2S requires: 376, found: 377 [M+H]+. 1H MR (600 MHz, MeOH-d4) δ 8.89 (s, 1H), 8.52 (s, 1H), 7.79 (s, 1H), 6.33 (s, 1H), 3.74 - 3.68 (m, 2H), 3.45 - 3.40 (m, 2H), 3.22 (s, 2H), 3.03 (s, 3H), 1.62 (s, 6H).
Example 22: Synthesis of 5-(3,3-dimethyl-4-(methylsulfonyl)piperazin-l-yl)imidazorL5- alpyridine-7-carbonitrile (Compound 30)
Figure imgf000150_0001
Prepared as Example 1 step 5 using Intermediate 1 and purified by mass-triggered preparative
HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 10 - 40%; 20 min; Column: C18) to give 5-(3,3-dimethyl-4-(methylsulfonyl)piperazin-l-yl)imidazo[l,5- a]pyridine-7-carbonitrile. MS (ES+) C15H19N5O2S requires: 333, found: 334 [M+H]+. 1H NMR (600 MHz, DMSO-de) δ 8.57 (s, 1H), 8.16 (s, 1H), 7.82 (s, 1H), 6.48 (s, 1H), 3.65 - 6.61 (m, 2H), 3.18 - 3.11 (m, 2H), 3.05 (s, 3H), 3.02 (s, 2H), 1.54 (s, 6H).
Example 23 : Synthesis of 3-benzyl-6,6-dimethyl-8-r7-(trifluoromethyl)imidazorL5-a1pyridin- 5-vH-L3,8-triazaspiror4.51decane-2,4-dione (Compound 31)
Figure imgf000150_0002
Step 1:
To a solution of tert-butyl 6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate (Intermediate 1, step 1; 200 mg, 672.6 umol) in DMF (0.5 mL) was added NaH (28.2 mg, 706.2 umol, 60% in mineral oil) at 0 °C, the mixture was stirred for 10 min, then benzyl bromide (103 mg, 605.3 umol) was added. The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with H20 (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si02, Petroleum ether/EtOAc =5/1 to 3/1) to afford tert-butyl 3-benzyl-6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate (200 mg, 495.5 umol, 74% yield) as a colorless oil. MS (ES+) C2iH29N304 requires: 387, found: 288 [M+H-100]+.
Step 2:
To a solution of tert- butyl 3-benzyl-6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decane-8- carboxylate (200 mg, 516.1 umol) in EtOAc (5 mL) was added HCl/EtO Ac (4 M, 3 mL). The mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried under high vacuum to afford 3-benzyl-6,6-dimethyl-l,3,8-triazaspiro[4.5]decane-2,4-dione (150 mg, 458.5 umol, 88% yield) as a white solid. MS (ES+) Ci6H2iN302 requires: 287, found: 288 [M+H]+.
Step 3: To a solution of 3-benzyl-6,6-dimethyl-l,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (60 mg, 185.2 umol) in DMF (1 mL) was added Cs2C03 (120.7 mg, 370.5 umol) and 5- chloro-7- (trifluoromethyl)imidazo[l,5-a]pyridine (27.2 mg, 123.5 umol). The mixture was stirred at 120 °C for 15 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex synergi CI 8 150*25 * 10um; mobile phase: [H20 (0.1% TFA) - MeCN]; B%: 30%-60%), the fraction was concentrated and freeze dried to afford 3-benzyl-6,6-dimethyl-8-[7-(trifluoromethyl)imidazo [l,5-a]pyridin-5-yl]-l,3,8- triazaspiro[4.5]decane-2,4-dione (4.9 mg, 8.2 umol, 7 % yield) as a black brown solid. MS (ES+) C24H24N502F3 requires: 471, found: 472 [M+H]+. 1H MR (400 MHz, MeOH-d4) δ: 9.01 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.38 - 7.24 (m, 5H), 6.64 (s, 1H), 4.65 (s, 2H), 3.55 - 3.51 (m, 2H), 3.37-3.35 (m, 1H), 3.03 - 3.00 (m, 1H), 2.31 - 2.16 (m, 1H), 2.12 - 2.00 (m, 1H), 1.20 (s, 3H), 0.99 (s, 3H). Example 24: Synthesis of 7-cyclopropyl-5-(3,3-dimethyl-4-methylsulfonyl-piperazin-l- yl)imidazorL5-a1pyridine (Compound 32)
m-CPBA
DCM
Figure imgf000152_0001
Figure imgf000152_0002
Figure imgf000152_0003
Step 1:
To a solution of 4-bromopyridine hydrochloride (8.9 g, 45.77 mmol) in dioxane (100 mL) and H20 (12.5 mL) was added cyclopropylboronic acid (5.8 g, 68.1 mmol), Pd(dppf)Cl2 (2.0 g, 2.75 mmol) and potassium phosphate (27.9 g, 131.8 mmol) under N2. The mixture was stirred at 90 °C for 16 h. Water (100 mL) was added, filtered and the residue was extracted with EtOAc (100 mLx3), dried over Na2S04, filtered and concentrated in vacuum. To the residue was added HCl (5 mol/L, 50 mL), extracted with DCM (50 mL x3), the aqueous layer was basified with NaOH (5 mol/L, 100 mL) and extracted with DCM (50 mL x4), dried over Na2S04, filtered and concentrated in vacuum to afford 4-cyclopropylpyridine (4.1 g, 27.0 mmol, 59 % yield) as a black oil. MS (ES+) C8H9N requires: 119, found 120 [M+H]+. Step 2:
To a solution of 4-cyclopropylpyridine (2.0 g, 16.7 mmol) in DCM (10 mL) was added m- CPBA (7.24 g, 33.56 mmol) at 0 °C and the mixture was stirred at 55 °C for 4 h. The reaction mixture was quenched by saturated Na2S203 (20 mL) at 0 °C and extracted with EtOAc (20 mL x4), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (Si02, from EtOAc 5% to 100% in Petroleum ether) to afford 4-cyclopropyl-l-oxido-pyridin-l-ium (1.57 g, 7.9 mmol, 47 % yield) as a yellow solid. 1H MR (400 MHz, DMSO-d6) δ: 8.07 - 8.04 (m, 2H), 7.13 - 7.09 (m, 2H), 1.99 - 1.95 (m, 1H), 1.06 - 1.03 (m, 2H), 0.76 - 0.74 (m, 2H). Step 3:
To a solution of 4-cyclopropyl-l-oxido-pyridin-l-ium (870 mg, 6.44 mmol) in MeCN (8 mL) was added TEA (1.04 g, 10.3 mmol, 1.43 mL) and TMSCN (1.66 g, 16.74 mmol, 2.1 mL). The mixture was stirred at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure. H20 (10 mL) was added and extracted with EtOAc (15 mL x3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (Si02, from EtOAc 4% to 20% in Petroleum ether) to afford 4- cyclopropylpyridine-2-carbonitrile (190 mg, 1.32 mmol, 20% yield) as a yellow liquid. MS (ES+) C9H8N2 requires: 144, found 145 [M+H]+.
Step 4: To a solution of 4-cyclopropyl-l,2-dihydropyridine-2-carbonitrile (190 mg, 1.30 mmol) in DCM (3 mL) was added m-CPBA (448.5 mg, 2.60 mmol), the mixture was stirred at 70 °C for 1 h. The reaction mixture was quenched by saturated Na2S203 (20 mL) at 0 °C and extracted with EtOAc (20 mL x4), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si02, from EtOAc 1% to 25% in Petroleum ether) to afford 4-cyclopropyl-l-oxido-pyridin-l-ium-2-carbonitrile (201 mg, 1.1 mmol, 91 yield) as a white solid. MS (ES+) C9H8N20, requires 160, found 161 [M+H]+.
Step 5:
To a flask was added 4-cyclopropyl-l-oxido-pyridin-l-ium-2-carbonitrile (201 mg, 1.1 mmol) and POCl3 (4.9 g, 32.28 mmol, 3.00 mL), the mixture was stirred at 85 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (Si02, from EtOAc 1% to 90% in Petroleum ether) to afford 6-chloro-4- cyclopropyl-pyridine-2-carbonitrile (150 mg, 814.5 μπιοΐ, 68 % yield) as a white solid. MS (ES+) C9H7N2CI requires 178, found 179 [M+H]+. Step 6:
To a solution of 6-chloro-4-cyclopropyl-pyridine-2-carbonitrile (150 mg, 839.7 umol) in THF (10 mL) was added Raney-Ni (100 mg, 1.17 mmol) and Boc20 (219 mg, 1.01 mmol) under N2, The suspension was degassed under vacuum and purged with H2 several times, the mixture was stirred at 30 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove solvent to afford tert-butyl N-[(6-chloro-4-cyclopropyl-2-pyridyl)methyl]carbamate (440 mg, 824.70 μιηοΐ, 98 % yield) as a light yellow liquid. MS (ES+) C14H19N2CIO2 requires 282, found 283 [M+H]+.
Step 7:
To a solution of tert-butyl N-[(6-chloro-4-cyclopropyl-2-pyridyl)methyl]carbamate (440 mg, 824.7 umol) in EtOAc (1 mL) was added HCl/EtOAc (4 M, 206 μί) at 0°C, then the mixture was warmed to RT and stirred for 1 h. The mixture was filtered and the filter cake was washed with EtOAc (20 mLx3), the solid was dried under reduced pressure to afford (6-chloro-4- cyclopropyl-2-pyridyl)methanamine (170 mg, 775.8 μπιοΐ, 94 % yield) as a white solid.
Step 8: A solution of (6-chloro-4-cyclopropyl-2-pyridyl)methanamine (170 mg, 775.8 umol) in formic acid (3 mL) was warmed to 70 °C, then Ac20 (3.5 g, 34.25 mmol) was added, the mixture was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Si02, DCM/MeOH= 100/1 to 20/1) to afford 5-chloro-7-cyclopropyl-imidazo[l,5-a]pyridine (42 mg, 213.6 μπιοΐ, 27 % yield) as a light yellow liquid. MS (ES+) Ci0H9N2Cl requires: 192, found 193 [M+H]+.
Step 9:
To a solution of 5-chloro-7-cyclopropyl-imidazo[l,5-a]pyridine (30 mg, 155.7 μπιοΐ) in dioxane (2 mL) was added sodium tert-butoxide (2 M, 233 uL), Ruphos-Pd-G4 (13.2 mg, 15.5 umol) and 2,2-dimethyl-l-methylsulfonyl-piperazine hydrochloride (44.9 mg, 196.3 umol) under N2. The mixture was stirred at 90 °C for 16 h. To the mixture was added water (10 mL), extracted with EtOAc (10 mLx2) dried over Na2S04, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25 * 10um; mobile phase: [H20 (0.1 % TFA) - MeCN]; B%: 12% - 42%), and concentrated under reduced pressure to remove solvent then freeze dried to afford 7-cyclopropyl-5-(3,3-dimethyl-4-methylsulfonyl-piperazin-l- yl)imidazo[l,5-a]pyridine (0.01 g, 28.7 μιηοΐ, 18 % yield) as a solid. MS (ES+) Ci7H2402SN4 requires: 348, found 349 [M+H]+. 1H NMR (400 MHz, MeOH-d4) δ: 9.20 (s, 1H), 7.83 (s, 1H), 7.30 (s, 1H), 6.51 (s, 1H), 3.76 - 3.73 (m, 2H), 3.19 - 3.18 (m, 2H), 3.08 - 3.07 (m, 5H), 2.03 - 2.00 (m, 1H), 1.67 (s, 6H), 1.09 - 1.07 (m, 2H), 0.88 - 0.85 (m, 2H).
Example 25: Synthesis of l-(3,3-dimethyl-l-(7-(trifluoromethyl)imidazo[L5-alpyridin-5- vDpiperidin-4-yl)imidazolidin-2-one (Compound 33)
Figure imgf000155_0001
Step 1: To a solution of tert-butyl 3,3-dimethyl-4-oxo-piperidine-l-carboxylate (5 g, 22 mmol) in EtOAc (20 mL) was added HCl/EtOAc (4 M, 20 mL). The mixture was stirred at RT for 16 h. The residue was concentrated in vacuo and used in the next step without any further purification. The product was collected as a yellow solid 3,3-dimethylpiperidin-4-one (3.6 g, 22.0 mmol, 100 % yield). 1H NMR (400 MHz, MeOH-d4) δ: 3.57 (t, J= 6.5, 1H), 3.37 (s, 1H), 3.23 - 3.13 (m, 1H), 3.01 (s, 1H), 2.78 (t, J= 6.5, 1H), 2.07 - 2.01 (m, 1H), 1.26 (s, 3H), 1.10 (d, J= 14.1, 3H). Step 2:
To a solution of 3,3-dimethylpiperidin-4-one hydrochloride (3.6 g, 22.0 mmol, 22.0 mL) in THF (22 mL) was added K2C03 (3 M, 14.6 mL) dissolved in H20 (15 mL). Then the mixture was cooled to 0 °C and benzyl chloroformate (4.13 g, 24.2 mmol) was added dropwise. The reaction was stirred at 25 °C for 2 h. The residue was poured into water (50 mL), extracted with EtOAc (50 mLx2). The combined organic layer was concentrated as a yellow liquid to afford benzyl 3,3- dimethyl-4-oxo-piperidine-l-carboxylate (5.80 g, 21.09 mmol, 96 % yield). MS (ES+) Ci5Hi9N03 requires: 261, found: 262 [M+H]+. 1H MR (400 MHz, MeOH-d4) δ: 7.42 - 7.35 (m, 5H), 5.19 (s, 2H), 3.78 (s, 2H), 3.53 (s, 2H), 2.50 (t, J= 6.5, 2H), 1.06 (s, 6H). Step 3:
To a solution of benzyl 3,3-dimethyl-4-oxo-piperidine-l-carboxylate (5.8 g, 22.2 mmol) in MeOH (50 mL) was added tert-butyl (2-aminoethyl)carbamate (3.5 g, 22.2 mmol) and AcOH (66.6 mg, 1.11 mmol, 63 μΕ). The mixture was stirred at 25 °C for 1 h. Then to the mixture was added NaBH3CN (4.19 g, 66.6 mmol) and was stirred at RT for 3 h. The residue was poured into water (100 mL), extracted with EtOAc (50 mL x2). The combined organic layer was concentrated and purified by column chromatography on silica (Petroleum Ether:EtOAc=l : l) and concentrated in vacuo to give benzyl 4-[2-(tert-butoxycarbonylamino)ethylamino]-3,3- dimethyl-piperidine-l-carboxylate (3.5 g, 6.04 mmol, 27 % yield) as a yellow oil. MS (ES+) C22H35N304 requires: 405, found: 406 [M+H]+. 1H MR (400 MHz, MeOH-d4) δ: 7.42-7.30 (m, 5H), 5.13 (s, 2H), 3.72 (d, J= 13.3, 1H), 3.41 - 3.29 (m, 1H), 3.27 - 3.10 (m, 2H), 2.97 - 2.56 (m, 4H), 2.40 - 2.22 (m, 1H), 1.81 (d, J = 11.7, 1H), 1.45 (s, 9H), 1.38 (dd, J = 4.1, 12.2, 1H), 0.98 (d, J= 6.4, 3H), 0.84 (d, J= 6.4, 3H).
Step 4:
To a solution of benzyl 4-[2-(tert-butoxycarbonylamino)ethylamino]-3,3-dimethyl-piperidine-l- carboxylate (3.5 g, 8.6 mmol) in EtOAc (20 mL) was added HCl/EtOAc (4 M, 20 mL). The mixture was stirred at 25 °C for 16 h. The residue was concentrated as white solid and used for next step without any further purification. MS (ES+) Ci7H27N302 requires: 305, found: 306 [M+H]+. Step 5:
To a solution of benzyl 4-(2-aminoethylamino)-3,3-dimethyl-piperidine-l-carboxylate (1.45 g, 4.75 mmol) in MeCN (100 mL) was added DBU (1.59 g, 10.44 mmol, 1.57 mL) and CDI (846 mg, 5.22 mmol). The mixture was stirred at 25 °C for 16 h. The residue was poured into water (200 mL), extracted with EtOAc (100 mLx2). The combined organic layer was concentrated as yellow oil. The yellow oil was purified by column chromatography on silica (DCM:MeOH=40: l) and concentrated in vacuo to give desired product. The product was collected as a yellow oil (benzyl 3,3-dimethyl-4-(2-oxoimidazolidin-l-yl)piperidine-l- carboxylate (870.00 mg, 1.71 mmol, 35% yield). MS (ES+) Ci8H25N303 requires: 331, found: 332 [M+H]+ 1H MR (400 MHz, MeOH-d4) δ: 7.41 -7.33 (m, 5H), 5.19 - 5.05 (m, 2H), 4.30 (td, Jl = 13.4, 72 = 2.4, 1H), 3.81 (d, J = 13.6, 1H), 3.67 (dd, Jl = 12.7, 72 = 4.0, 1H), 3.57 - 3.44 (m, 2H), 3.41 - 3.35 (m, 2H), 3.03 - 2.82 (m, 1H), 2.81 - 2.62 (m, 1H), 1.96 (dd, Jl = 12.8, 72 = 4.9, 1H), 1.49 (d, 7= 11.8, 1H), 0.94 (d, 7= 9.0, 6H).
Step 6: To a solution of benzyl 3,3-dimethyl-4-(2-oxoimidazolidin-l-yl)piperidine-l-carboxylate (870 mg, 2.63 mmol) in MeOH (20 mL) was added 10 % Pd/C (500 mg) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 40 °C under H2 (50 Psi) for 16 h. The residue was filtrated and the filtrate was concentrated as a yellow oil. The yellow oil was purified by column chromatography on silica (DCM:MeOH=5: l) and concentrated in vacuo to give (l-(3,3-dimethyl-4-piperidyl)imidazolidin-2-one as a yellow solid (300 mg, 1.37 mmol, 52% yield). 1H MR (400 MHz, MeOH-d4) δ: 3.69 (dd, Jl = 12.7, 72 = 3.8, 1H), 3.62-3.47 (m, 2H), 3.45 - 3.39 (m, 1H), 3.33 (d, 7 = 1.0, 1H), 3.28 - 3.21 (m, 1H), 2.84 - 2.70 (m, 2H), 2.67 - 2.53 (m, 1H), 2.10 - 1.91 (m, 1H), 1.55 (d, 7= 13.7, 1H), 1.10 (s, 3H), 0.95 (s, 3H). Step 7:
To a solution of l-(3,3-dimethyl-4-piperidyl)imidazolidin-2-one (53.6 mg, 272.0 umol) in DMF (2 mL) was added 5-chloro-7-(trifluoromethyl)imidazo[l,5-a]pyridine (50 mg, 226.68 μπιοΐ), CsF (34.4 mg, 226.6 umol) and Cs2C03 (73.8 mg, 226 umol). The mixture was stirred at 120 °C for 16 h and poured into water (20 mL), extracted with EtOAc (10 mL x2). The combined organic layer was concentrated and purified by prep-HPLC (column: Phenomenex Synergi C18 150*25* 10um; mobile phase: [H20 (0.1 % TFA) - MeCN]; B%: 16% - 46%, 13 min) and freeze- dried to give l-[3,3-dimethyl -l-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-4- piperidyl]imidazolidin-2-one (5.2 mg, 13.2 μmol, 5 % yield) as colourless oil. MS (ES+) Ci8H22N5OF3 requires: 381, found: 382 [M+H]+. 1H MR (400 MHz, MeOH-d4) δ: 9.16 (s, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 6.70 (d, J = 1.0, 1H), 3.80 (dd, J = 4.1, 12.7, 1H), 3.75-3.57 (m, 3H), 3.51 - 3.40 (m, 2H), 3.12 (dd, J = 2.3, 11.7, 1H), 2.99 - 2.86 (m, 2H), 2.56 - 2.43 (m, 1H), 1.78 - 1.66 (m, 1H), 1.31 (s, 3H), 1.06 (s, 3H).
Example 26: Synthesis of 3-ethyl-6,6-dimethyl-8-r7-(trifluoromethyl)imidazorL5-a1pyridin-5- yl1-L3,8-triazaspiror4.51decane-2,4-dione (Compound 34)
Figure imgf000158_0001
Step 1:
To a solution of tert-butyl 6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate (Intermediate 1; 500 mg, 1.68 mmol) in DMF (1 mL) was added NaH (134.5 mg, 3.36 mmol, 60% in mineral oil) at 0 °C , then 1-iodoethane (285.5 mg, 1.68 mmol, 164 μΐ.) was added and stirred at 20 °C for 1.5 h. The reaction mixture was quenched by H20 (10 mL) at 0 °C, and then extracted with EtOAc (10 mL x3). The combined organic layers were concentrated under reduced pressure to give a residue which was purified by column chromatography (Si02, Petroleum ether/EtOAc=2/l to 1/1) to afford tert-butyl 3-ethyl-6,6-dimethyl-2,4-dioxo-l,3,8- triazaspiro[4.5]decane-8-carboxylate (200 mg, 553.1 μπιοΐ, 33 % yield) as a colorless oil. 1H MR (400 MHz, CHCl3-d) δ: 6.23 (br, 1H), 3.78 - 4.05 (m, 1H), 3.35 - 3.60 (m, 5H), 1.70 - 1.78 (m, 2H), 1.40 (s, 9H), 1.06 - 1.19 (m, 3H), 0.91 (s, 3H), 0.86 (s, 3H).
Step 2:
To a solution of tert-butyl 3-ethyl-6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decane-8- carboxylate (200 mg, 614.6 μιηοΐ) in EtOAc (5.00 mL) was added HCl/EtOAc (4 M, 3.57 mL) and the mixture was stirred at 20 °C for 1 h. The precipitate was collected by filtration and dried under high vacuum to afford 3-ethyl-6,6-dimethyl-l,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (120 mg, 316.3 umol, 52 % yield) was collected as a white solid which was used into the next step without further purification. MS (ES+) C11H19N3O2 requires: 225, found: 226 [M+H]+. Step 3:
To a solution of 3-ethyl-6,6-dimethyl-l,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (50 mg, 221.9 μιηοΐ) in DMF (1 mL) was added Cs2C03 (144.6 mg, 443.8 umol), CsF (33.7 mg, 221.9 umol) and 5-chloro-7-(trifluoromethyl)imidazo[l,5-a]pyridine (48.9 mg, 221.9 μπιοΐ). The mixture was stirred at 120 °C for 15 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm* 10um; mobile phase: [H20 (0.05% ammonium hydroxide v/v) - MeCN]; B%: 42% - 60%), 10 min), the fraction was concentrated and freeze dried to afford 3-ethyl-6,6-dimethyl-8-[7- (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,8- triazaspiro[4.5]decane-2,4-dione (4.9 mg, 11.8 μιηοΐ, 5 % yield) as a white solid. MS (ES+) Ci9H22F3N502 requires: 409, found: 410 [M+H]+. 1H MR (400 MHz, CHCl3-d) δ: 8.29 (s, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 6.28 (d, J = 1.25, 1H), 5.54 - 5.35 (m, 1H), 3.71 - 3.50 (m, 4H), 3.38 (brs, 1H), 3.03 - 3.0 (d, 1H), 2.27 (brs, 1H), 2.08 (brs, 1H), 1.34 (s, 3H), 1.27 - 1.24 (t, J= 8.0, 3H), 1.06 (brs, 3H).
Example 27: Synthesis of l-methanesulfonyl-2,2-dimethyl-4-r7-(trifluoromethyl)imidazo Γ1,5- clpyrimidin-5-vHpiperazine (Compound 35)
Figure imgf000159_0001
2 4
Figure imgf000159_0002
5 6 Step 1:
To a 0 °C solution of 2,4-dichloro-6-(trifluoromethyl)pyrimidine (200 mg, 921.7 umol, 200 μΙ_/) in H20 (0.4 mL) and DMF (2 mL) was added DAB CO (10.3 mg, 92.1 μιηοΐ, 10 uL) and NaCN (54.2 mg, 1.1 mmol). The mixture was stirred at 0 °C for 1 h. The residue was poured into H20 (20 mL), extracted with EtOAc (10 mLx2). The combined organic layer was concentrated to afford 2-chloro-6-(trifluoromethyl)pyrimidine-4-carbonitrile (360 mg, crude) as a yellow oil.
Step 2:
To a solution of 2-chloro-6-(trifluoromethyl)pyrimidine-4-carbonitrile (360 mg, 1.73 mmol) in dioxane (4 mL) was added 2,2-dimethyl-l-methylsulfonyl-piperazine hydrochloride (476.1 mg, 2.0 mmol) and TEA (526.5 mg, 5.2 mmol, 724 μί). The mixture was stirred at 80 °C for 16 h. The residue was poured into water (20 mL), extracted with EtOAc (10 mL x2). The combined organic layer was concentrated as yellow oil. The resisue was purified by prep-TLC (Petroleum Ether:EtOAc=l : l) and concentrated in vacuo to give 2-(3,3-dimethyl-4-methylsulfonyl- piperazin-l-yl)-6-(trifluoromethyl)pyrimidine-4-carbonitrile as a green oil (130 mg, 304.1 μπιοΐ, 17 % yield). MS (ES+) C13H16N5SO2F3 requires: 363, found: 364 [M+H]+. 1H MR (400 MHz, MeOH-d4) δ: 7.39 (s, 1H), 3.92 - 3.87 (m, 4H), 3.72 - 3.67 (m, 2H), 3.02 (s, 3H), 1.53 (s, 6H).
Step 3:
To a solution of 2-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl)-6-(trifluoromethyl) pyrimidine-4-carbonitrile (130 mg, 357.7 μπιοΐ) in THF (10 mL) was added Boc20 (156.1 mg, 715.5 μπιοΐ) and Raney-Ni (100 mg, 1.17 mmol) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 30 °C under H2 (50 Psi) for 16 h. The residue was filtrated and the filtrate was concentrated in vacuo and used for next step without any further purification. The product was collected as colorless oil (tert-butyl N-[[2-(3,3- dimethyl-4-methylsulfonyl-piperazin-l-yl)-6-(trifluoromethyl) pyrimidin-4-yl]methyl]carbamate (100 mg, 181.8 μιηοΐ, 51 % yield)). MS (ES+) d^NsSC^ requires: 467, found: 468 [M+H]+.
Step 4:
To a solution of tert-butyl N-[[2-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl)-6- (trifluoromethyl)pyrimidin-4-yl]methyl]carbamate (100 mg, 213.9 μπιοΐ) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 20 °C for 2 h. The residue was concentrated as white solid and used for next step without any further purification. The product was collected as white solid ([2-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl)-6- (trifluoromethyl)pyrimidin-4-yl]methanamine (80 mg, 154.5 umol, 72 % yield)). MS (ES+) C13H20N5SO2F3 requires: 367, found: 368 [M+H]+.
Step 5:
To HCO2H (2 mL) was added [2-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl)-6- (trifluoromethyl)pyrimidin-4-yl]methanamine hydrochloride (80 mg, 198.0 μπιοΐ). The mixture was stirred at 80 °C for 30 min. Then Ac20 (1.98 g, 19.43 mmol, 1.82 mL) was added and the mixture was stirred at 80 °C for 1 h. The mixture was concentrated and POCI3 was added (9.54 g, 62.22 mmol, 5.78 mL). The reaction was stirred at 80 °C for 1 h. The residue was concentrated as yellow oil and POCI3 was slowly quenched with water and taken up in EtOAc. The organic phase was separated and concentrated and the residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25* 10 urn; mobile phase: [H20 (0.1 %TFA) - MeCN]; B%: 32% - 62%, 13 min) and freeze-dried to give (5-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl)-7- (trifluoromethyl)imidazo[l,5-c]pyrimidine as a white solid (31 mg, 79.6 μπιοΐ, 40 % yield). MS (ES+) Ci4Hi8N5S02F3 requires: 377, found: 378 [M+H]+. 1H MR (400 MHz, MeOH-d4) δ: 8.78 (s, 1H), 7.76 (s, 1H), 7.67 (s, 1H), 3.82 - 3.74 (m, 4H), 3.55 (s, 2H), 3.07 (s, 3H), 1.63 (s, 6H).
Example 28: Synthesis of 3-(2-methoxyethyl)-6,6-dimethyl-8-[7-(trifluoromethyl) imidazo[l,5- a1pyridin-5-vH-L3,8-triazaspiror4.51decane-2,4-dione (Compound 36)
Figure imgf000161_0001
Step 1:
To a solution of tert-butyl 6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate (200 mg, 672.6 μιηοΐ) in MeCN (2 mL) was added KOH (75.4 mg, 1.35 mmol) at 0 °C for 30 min and l-bromo-2-methoxy-ethane (93.4 mg, 672.6 μπιοΐ, 63 μΕ) was added. The mixture was stirred at 20 °C for 1.5 h. The reaction mixture was quenched by H20 (10 mL) at 0 °C, and then extracted with EtOAc (10 mL x3). The combined organic layers concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Synergi CI 8 150*25* 10um;mobile phase: [H20 (0.1 %TFA) - MeCN]; B%: 25% - 55%, 12 min) to afford tert-butyl 3-(2-methoxyethyl)-6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decane-8-carboxylate (32 mg, 82.8 μιηοΐ, 12 % yield) as a colorless oil. MS (ES+) ^Η29Ν305 requires: 355, found: 356 [M+H]+.
Step 2:
To a solution of tert-butyl 3-(2-methoxyethyl)-6,6-dimethyl-2,4-dioxo-l,3,8- triazaspiro[4.5]decane-8-carboxylate (30 mg, 84.4 μπιοΐ) in EtOAc (1 mL) was added HCl/EtOAc (4 M, 1 mL). The mixture was stirred at RT for 30 min. The precipitate was collected by filtration and dried under high vacuum to afford 3-(2-methoxyethyl)-6,6-dimethyl-l,3,8- triazaspiro[4.5]decane-2,4-dione (22 mg, 67.8 μπιοΐ, 80 % yield) as a white solid which was used in the next step without further purification. MS (ES+) Ci2H2iN303 requires: 255, found: 256 [M+H]+.
Step 3:
To a solution of 3-(2-methoxyethyl)-6,6-dimethyl-l,3,8-triazaspiro[4.5]decane-2,4-dione (22 mg, 75.40 μπιοΐ) in DMSO (1.0 mL) was added 5-chloro-7-(trifluoromethyl)imidazo[l,5- a]pyridine (16.6 mg, 75.40 μιηοΐ), Cs2C03 (49.1 mg, 150.8 μιηοΐ) and CsF (11.4 mg, 75.4 μιηοΐ). The mixture was stirred at 120 °C for 15 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Synergi CI 8 150*25* 10 um;mobile phase: [H20 (0.1% TFA) - MeCN]; B%: 18% - 48%), the fraction was concentrated then freeze dried to afford 3-(2-methoxyethyl)-6,6-dimethyl-8-[7- (trifluoromethyl)imidazo[l,5-a]pyridine-5-yl]-l,3,8-triazaspiro[4.5]decane -2,4-dione (3.2 mg, 5.49 μιηοΐ) as a black brown solid. MS (ES+) C20H24F3N5O3 requires:439, found: 440 [M+H]+. 1H NMR (400 MHz, MeOH-d4) δ: 8.98 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 6.64 (s, 1H), 3.77-3.50 (m, 7H), 3.34 (s, 3H), 3.07 (d, J = 11.5, 1H), 2.38 - 2.26(m, 1H), 2.23 - 2.12 (m, 1H), 1.26 (s, 3H), 1.12 (s, 3H). Example 29: Synthesis of 2-chloro-4-(3,3-dimethyl-4-methylsulfonyl-piperazin-l- yl)imidazorL5-b1pyridazine (Compound 37)
Figure imgf000163_0001
Figure imgf000163_0002
6 7
Step 1:
To a solution of 3,4,6-trichloropyridazine (2.92 g, 15.90 mmol) and 2,2-dimethyl-l- methylsulfonyl-piperazine hydrochloride (4.0 g, 17.4 mmol) in DMA (40 mL) was added Na2CC"3 (3.37 g, 31.79 mmol), the mixture was stirred at 25 °C for 2 h. To the mixture was added water (20 mL), extracted with EtOAc (10 mL x3), the combined organic layers were washed with brine (15 mL x2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/EtOAc=20/l to 3/1), to afford 3,6-dichloro-4-(3,3-dimethyl-4-methylsulfonyl-piperazin-l- yl)pyridazine (4.8 g, 10.61 mmol, 67 % yield) as a green solid. MS (ES+) CnHi6N4Cl202S requires: 338, found 339 [M+H]+.
Step 2:
To benzyl alcohol (10 mL) was added Na (357.8 mg, 15.5 mmol, 368.8 μΕ) under N2, to the mixture was added 3,6-dichloro-4-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl) pyridazine (4.8 g, 14.1 mmol) and then stirred at 60 °C for 30 min. The mixture was poured into ice water (15 mL) slowly and extracted with EtOAc (15 mL x2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/EtOAc=25/l to 10/1) to afford a colorless liquid (1.92 g) which was further purified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50mm* 10 urn; mobile phase: [H20 (0.1%TFA)-MeCN]; B%: 40% - 65%, 8 min), concentrated and freeze dried to afford 3-chloro-4-(3,3-dimethyl-4-methylsulfonyl-piperazin-l- yl)-6-benzyloxy-pyridazine (0.732 g, 1.84 mmol, 13 % yield) as a white solid. MS (ES+) Ci8H23N4C103S requires: 410, found 411 [M+H]+. Step 3:
To a solution of 6-benzyloxy-3-chloro-4-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl) pyridazine (276 mg, 510.4 μιηοΐ), Zn(CN)2 (179.8 mg, 1.53 mmol, 97 μί) in DMF (1 mL) was added Pd2(dba)3 (93.4 mg, 102.0 μιηοΐ) and dppf (56.6 mg, 102.09 μιηοΐ) under N2, the mixture was stirred at 100 °C for 16 h. To the mixture was added water (5 mL), extracted with EtOAc (10 mL x2), dried over Na2S04, filtered and concentrated in vacuum. The residue was purified by column chromatography (Si02, Petroleum ether/EtOAc=20/l to 1/1) to afford 6-benzyloxy-4- (3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl)pyridazine-3-carbonitrile (0.189 g, 371.9 μπιοΐ, 72 % yield) as a yellow solid. MS (ES+) Ci9H23N5S03 requires 401, found 402 [M+H]+.
Step 4: To a solution of 6-benzyloxy-4-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl)pyridazine-3- carbonitrile (0.189 g, 470.7 μιηοΐ) in THF (5.0 mL) was added Raney-Ni (125.8 mg, 1.47 mmol) and Boc20 (123.2 mg, 564.9 μπιοΐ) under N2. The suspension was degassed under vacuum and purged with H2 several times, the mixture was stirred at 30 °C under 50 psi for 16 h. The mixture was filtered and to the filtrate was added Pd(OH)2 (198.3 mg, 1.41 mmol), the suspension was degassed under vacuum and purged with H2 for three times, the mixture was stirred at 30 °C under 50 psi for 16 h. The mixture was filtered and concentrated under reduced pressure to afford tert-butyl N-[[4-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl)-6-hydroxy-pyridazin-3- yl]methyl]carbamate (0.13 g, 178.3 μπιοΐ, 38 % yield) as a black brown liquid. MS (ES+) Ci7H29N5S05 requires 415, found 416 [M+H]+. Step 5:
A solution of tert-butyl N-[[4-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl)-6-hydroxy- pyridazin-3-yl]methyl]carbamate (0.065 g, 156.4 μηιοΐ) in EtOAc (15 mL) was cooled to 0 °C, then HCl/EtOAc (4 M, 391 μΐ was added and the mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filter cake was washed with EtOAc (10 mL x3) to afford 6- (aminomethyl)-5-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl)pyridazin-3-ol hydrochloride (0.054 g, 153.47 umol, 98 % yield) as a white solid.
Step 6:
A solution of 6-(aminomethyl)-5-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl)pyridazin-3-ol hydrochloride (53.7 mg, 170.5 μπιοΐ) in formic acid (770 uL) was warmed to 70 °C, then Ac20 (902.84 mg, 8.84 mmol, 828.2 uL) was added, the mixture was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (Si02, EtOAc/MeOH = 10/1) to afford 4-(3,3-dimethyl-4-methylsulfonyl- piperazin-l-yl)imidazo[l,5-b]pyridazin-2-ol (0.025 g, 63.0 μπιοΐ, 37 % yield) as a black brown solid. MS (ES+) C13H19N5O3S requires: 325, found 326 [M+H]+.
Step 7:
To a flask was added 4-(3,3-dimethyl-4-methylsulfonyl-piperazin-l-yl)imidazo[l,5-b]pyridazin- 2-ol (0.025 g, 76.83 μπιοΐ) and POCI3 (1.65 g, 10.76 mmol, 1 mL), the mixture was stirred at 145 °C for 54 h. The reaction mixture was concentrated under reduced pressure to remove solvent, then quenched slowly with water and the mixture was purified by prep-HPLC (column: Venusil XBP C8 150*25* 10um;mobile phase: [H20 (0.25% formic acid) - MeCN]; B%: 20% - 50%), 10 min), and concentrated under reduced pressure to afford 2-chloro-4-(3,3-dimethyl-4- methylsulfonyl-piperazin-l-yl)imidazo[l,5-b]pyridazine as a formate salt (1.3 mg, 2.83 μηιοΐ, 4 % yield) as a light black brown solid. MS (ES+) CI3HI802SC1N5 requires: 343, found 344 [M+H]+. 1H MR (400 MHz, MeOH-d4) δ: 8.41 (s, 1H), 7.76 (s, 1H), 5.94 (s, 1H), 3.94 - 3.92 (m, 2H), 3.81 (s, 4H), 3.04 (s, 3H), 1.58 (s, 6H). Example 30: Synthesis of 3-r7-(trifluoromethyl)imidazorL5-a1pyridin-5-yl1-3-azabicvclo r3.2.11octane-8-carboxamide (Compound 38)
Figure imgf000166_0001
9 10
Figure imgf000166_0002
Step 1: To a solution of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (500 mg, 2.32 mmol) in dimethoxyethane (18.5 mL) was added tosylmethyl isocyanide (816.17 mg, 4.18 mmol), t-BuOK (912.12 mg, 8.13 mmol) and ethanol (0.3 mL, 5.34 mmol) at 0 °C. The mixture was stirred at 50 °C for 10 h. The residue was poured into water (100 mL), extracted with EtOAc (100 mL x2). The combined organic layer was concentrated to afford a yellow oil which was purified by column chromatography on silica (Petroleum Ether:EtOAc=50: l) and concentrated in vacuo to give (3-benzyl-3-azabicyclo[3.2.1]octane-8-carbonitrile (300 mg, 1.29 mmol, 55 % yield) as a yellow oil. MS (ES+) Ci5Hi8N2 requires: 226, found: 227 [M+H]+. 1H MR (400 MHz, MeOH- d4) δ 7.42-7.09 (m, 5H), 3.51 (d, J = 20.0, 2H), 2.78 - 2.62 (m, 3H), 2.52 - 2.34 (m, 3H), 2.13 (d, J= 11.0, 1H), 1.95 - 1.85 (m, 3H), 1.70 - 1.75 (m, 1H). Step 2:
To a solution of 3-benzyl-3-azabicyclo[3.2.1]octane-8-carbonitrile (300 mg, 1.33 mmol) in DCM (3 mL) was added H2S04 (98%, 3.68 g, 37.52 mmol, 2 mL). The mixture was stirred at 0 °C for 20 min, then the mixture was warmed to 20 °C and stirred at this temperature 16 h. The residue was added dropwise to aqueous ammonia (28%, 9 mL) under ice-cooling. To the mixture was added water (6 mL) and the mixture was extracted with DCM (20 mL x2). The organic layer was dried over Na2S04, filtered, concentrated in vacuo to afford 3-benzyl-3-azabicyclo[3.2.1]octane- 8-carboxamide (430 mg, crude) as a white solid. MS (ES+) C15H20N2O requires: 244, found: 245 [M+H]+. 1H MR (400 MHz, MeOH-d4) δ: 7.35-7.19 (m, 5H), 3.53-3.44 (m, 2H), 2.76 (dd, Jl = 10.9, J2=4.0, 1H), 2.56 - 2.47 (m, 2H), 2.46 - 2.38 (m, 2H), 2.29 (s, 1H), 2.17 (d, J = 10.5, 1H), 1.91 - 1.83 (m, 1H), 1.78 - 1.71 (m, 3H)
Step 3:
To a solution of 3-benzyl-3-azabicyclo[3.2.1]octane-8-carboxamide (430 mg, 1.76 mmol) in MeOH (10 mL) was added 10 % Pd/C (400 mg) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 50 °C under H2 (50 Psi) for 16 h. The residue was filtered and the filter cake was washed with MeOH, the filtrate was concentrated to afford 3-azabicyclo[3.2.1]octane-8-carboxamide (240 mg, 1.56 mmol, 88 % yield) a colorless oil. MS (ES+) C8Hi4N20 requires: 154, found: 155 [M+H]+. 1H MR (400 MHz, MeOH-d4) δ: 3.59 (d, J = 12.5, 1H), 3.09 - 3.04 (m, 2H), 2.97 (dd, Jl = 13.1, J2 = 2.6, 1H), 2.70-2.64 (m, 1H), 2.63 - 2.53 (m, 2H), 2.07 - 1.97 (m, 2H), 1.89 - 1.80 (m, 1H), 1.76 - 1.67 (m, 1H).
Step 4:
To a solution of 3-azabicyclo[3.2.1]octane-8-carboxamide (80 mg, 518.7 μπιοΐ) in DMSO (3 mL) was added 5-chloro-7-(trifluoromethyl)imidazo[l,5-a]pyridine (Example 1, step 5; 60 mg, 272.0 μιηοΐ), CsF (78.8 mg, 518.7 μιηοΐ) and Cs2C03 (202.8 mg, 622.5 μιηοΐ). The mixture was stirred at 120 °C for 16 h. The residue was poured into water (20 mL), extracted with EtOAc (10 mL x2). The combined organic layer was concentrated to afford a yellow oil which was purified by prep-TLC (DCM:MeOH=10: l) to afford two isomers followed by prep-HPLC (column: Boston pH-lex 150*25 10um;mobile phase: [H20 (0.1%TFA)-MeCN]; B%: 15% - 45%, 10 min) respectively, then freeze-dried to afford:
Peak A: (1.7 mg, 3.53 umol, 0.7 % yield) as a colorless oil. MS (ES+) Ci6Hi7N4OF3 requires: 338, found: 339 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.46 (s, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.40 (s, 1H), 7.05 - 6.96 (m, 1H), 6.21 (s, 1H), 3.30 (d, J = 11.3, 1H), 3.20 - 3.09 (m, 2H), 2.83-2.74 (m, 1H), 2.70 - 2.64 (m, 2H), 2.43 - 2.27 (m, 1H), 1.98 -1.77 (m, 4H); and
Peak B (Compound 38): (2.8 mg, 2.88 umol, 1 % yield) as a colorless oil. MS (ES+) Ci6Hi7N4OF3 requires: 338, found: 339 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.45 (s, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.34 (s, 1H), 6.84 (s, 1H), 6.33 (s, 1H), 3.37 - 3.32 (m, 3H), 2.95 (d, J = 10.8, 2H), 2.80 - 2.62 (m, 2H), 1.88 - 1.65 (m, 4H). (Note: the H adjacent to amide peak around 2.5 ppm overlaps with solvent peak).
Example 31 : Synthesis of. 3-[7-(trifluoromethyl)imidazo[L5-alpyridin-5-yllspiro[3- azabicyclor3.2.11octane-8,5'-imidazolidine1-2',4'-dione (Compound 39)
Figure imgf000168_0001
5
Step 1:
To a solution of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (1.8 g, 8.36 mmol) in EtOH (32 mL) and H20 (8 mL) was added (NH4)2C03 (15.2 g, 158.8 mmol) and NaCN (1.64 g, 33.44 mmol) at 15 °C. The mixture was heated to 85 °C and stirred for 16 h. To the mixture was added H20 (100 mL) at 15°C. Then the mixture was extracted with EtOAc (150 mL x2). The organic layer was dried over Na2S04. After filtration, the filtrate was concentrated in vacuo to get a crude product 3-benzylspiro[3-azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (1.88 g, 6.59 mmol, 79 % yield) as a white solid. The crude product was used in next step directly. 1H NMR (400 MHz, DMSO-dg) δ: 10.57 (brs, 1H), 8.35 (s, 1H), 7.38 - 7.26 (m, 5H), 3.55 (s, 2H), 2.59 - 2.52 (m, 2H), 2.48 - 2.34 (m, 2H), 2.14 - 2.00 (m, 2H), 1.96 - 1.90 (m, 2H), 1.75 - 1.58 (m, 2H).
Step 2:
To a solution of 3-benzylspiro[3-azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (1 g, 3.50 mmol) in MeOH (25 mL) was added AcOH (21 mg, 350.4 μιηοΐ, 20 μί) and 10% Pd/C (200 mg, 3.50 mmol) under N2 at 15 °C. The suspension was degassed under vacuum and purged with H2 (x 3). The mixture was stirred under H2 (50 psi) at 40 °C for 16 h. To the mixture was added 10% Pd/C (200 mg, 3.50 mmol) and DMF (15 mL) at 15 °C under N2. The suspension was degassed under vacuum and purged with N2 for three times. The mixture was stirred under H2 (50 psi) at 40 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford crude product spiro[3-azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (225 mg, crude) as a gray solid. The crude product was used in next step directly. 1H NMR (400 MHz, DMSO-dg) δ: 8.34 (br, 1H), 7.29 (br, 1H), 6.71 (br, 1H), 3.01 - 2.53 (m, 2H), 2.45 - 2.25 (m, 4H), 1.53 - 1.47 (m, 4H).
Step 3:
To a solution of N-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]methyl]formamide (Intermediate 9; 50 mg, 209.5 μιηοΐ) in DMSO (1 mL) was added DIPEA (27 mg, 209.5 μιηοΐ, 36.5 μί), spiro[3- azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (45 mg, 230.5 μπιοΐ) and CsF (31.8 mg, 209.5 μπιοΐ, 7.73 ιΌ) at 15 °C. The mixture was heated to 100 °C and stirred for 16 h. The reaction was heated to 100 °C and stirred for 48 h. The mixture was taken up in EtOAc (5 mL) and washed with brine (4 mL χ3). The organic layer was dried over Na2S04, filtered, concentrated in vacuo to afford a crude product (132 mg) as a light yellow oil. The crude product was purified by prep-TLC (Si02, DCM: MeOH = 10: 1) to afford N-[[6-(2',5'-dioxospiro[3- azabicyclo[3.2.1]octane-8,4'-imidazolidine]-3-yl)-4-(trifluoromethyl)-2- pyridyl]methyl]formamide (25 mg, 62.9 μπιοΐ, 30% yield) as a light yellow solid. MS (ES+) Ci7Hi8N503F3 requires: 397, found: 398 [M+H]+. Step 4:
To N-[[6-(2',5'-dioxospiro[3-azabicyclo[3.2.1]octane-8,4'-imidazolidine]-3-yl)-4- (trifluoromethyl)-2-pyridyl]methyl]formamide (25 mg, 62.9 μπιοΐ) was added POCl3 (825 mg, 5.38 mmol, 500 μΕ) at 15 °C. The mixture was heated to 50 °C and stirred for 2 h. To the mixture was added water (3 mL) at 0 °C, then the mixture was adjusted to pH 7 with IN NaOH solution (8 mL). The solution was extracted with EtOAc (5 mL x3). The organic layer was dried over Na2S04, filtered, concentrated in vacuo to get a crude product (32 mg) as light yellow oil. The crude product was purified by Prep-HPLC (column: Phenomenex Gemini CI 8 250*50mm* 10 um; mobile phase: [H20 (0.05% ammonium hydroxide v/v)-MeCN] and dried by lyophilization to afford two peaks: Product A (3.7 mg, 9.75 μπιοΐ, 15 % yield; product A) as a white solid and product B (1.1 mg, 2.90 μηιοΐ, 5 % yield) as a white solid. MS (ES+) Ci7Hi6N502F3 requires: 379, found: 380 [M+H]+.
Product A (Compound 39A): 1H NMR (400 MHz, DMSO-d6) δ: 8.66 (s, 1H), 8.44 (s, 1H), 7.91 (s, 1H), 7.74 (s, 1H), 6.58 (s, 1H), 3.29 - 3.25 (m, 2H), 3.20 - 3.10 (m, 2H), 2.30 - 2.17 (m, 4H), 2.01 - 1.57 (m, 2H).
Product B (Compound 39B): 1H NMR (400 MHz, DMSO-d6) δ: 8.66 (s, 1H), 8.44 (s, 1H), 7.91 (s, 1H), 7.74 (s, 1H), 6.58 (s, 1H), 3.27 (s, 2H), 3.20 - 3.11 (m, 2H), 2.29 - 2.18 (m, 4H), 2.01 - 1.88 (m, 2H).
Example 32: Synthesis of 3'-(2-hvdroxyethyl)-3-r7-(trifluoromethyl)imidazorL5-a1pyridin-5- yl1spiror3-azabicyclor3.2.11octane-8,5'-imidazolidine1-2',4'-dione (Compound 40)
Figure imgf000170_0001
To a solution of 3-[7-(trifluoromethyl)imidazo[l,5-a]pyridine-5-yl]spiro[3- azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (50 mg, 131.8 μιηοΐ) in DMSO (0.5 mL) was added 2-bromoethoxy-tert-butyl-dimethyl-silane (34.6 mg, 144.9 μιηοΐ) and Cs2C03 (107.3 mg, 329.5 μπιοΐ) at 15 °C. The mixture was heated to 100 °C and stirred for 16 h. To the mixture was added water (1 mL) at 0 °C. Then the mixture was extracted with EtOAc (4 mL χ3). The organic layer was dried over Na2S04, filtered, concentrated in vacuo to obtain a crude product (91 mg) as a yellow oil, which was purified by Prep-HPLC (column: Phenomenex Synergi C18 150*25* 10um;mobile phase: [H20 (0.1%TFA) - MeCN]; B%: 19% - 40%, 10 min) and dried by lyophilization to afford 3'-(2-hydroxyethyl)-3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5- yl]spiro[3-azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (34 mg, 51.4 μπιοΐ, 39% yield) as a light yellow oil. MS (ES+) Ci9H20N5O3F3 requires: 423, found: 424 [M+H]+. 1H NMR (400 MHz, DMSO-de) δ: 8.94 (s, 1H), 8.07 (s, 2H), 6.82 (s, 1H), 4.55 (t, J=5.0 Hz, 0.5 H), 3.78 (t, J = 4.8 Hz, 0.5 H), 3.58 - 3.38 (m, 3H), 3.36 - 3.26 (m, 2H), 3.23 - 3.12 (m, 2H), 2.31 - 2.17 (m, 4H), 2.06 - 1.91 (m, 2H). Example 33 : Synthesis of. 2- { 3 7-(trifluoromethyl)imidazor 1 ,5 -a1pyridin-5-yl1-3 - azabicyclor3.2.11octan-8-yl|acetamide (Compounds 41A and 41B)
Figure imgf000171_0001
9 Step 1:
A solution of methyl 2-(diethoxyphosphoryl)acetate (2.34 g, 11.15 mmol) in THF (10 mL) was added dropwise while stirring to a solution of t-BuOK (2.08 g, 18.58 mmol) in THF (20 mL) at 0 °C and then stirred for 1 h. Then a solution of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (2 g, 9.29 mmol) in THF (10 mL) was added dropwise to the solution at 0 °C. The solution was stirred for 2 h at 15 °C. To the mixture was added IN HC1 (5 mL) at 0 °C. Then the mixture was extracted with EtOAc (40 mL χ2). The organic layer was dried over Na2S04, filtered, concentrated in vacuo to afford a crude product (5.2 g) as a light yellow oil which was purified by column chromatography (Si02, Petroleum ether/EtOAc=50/l to EA/MeOH=10/l) to afford methyl 2-(3-benzyl-3-azabicyclo[3.2.1]octan-8-ylidene)acetate (1.27 g, 3.98 mmol, 43 % yield) as a colorless oil. MS (ES+) Ci7H2iN02 requires: 271, found: 272 [M+H]+.
Step 2:
To a solution of methyl 2-(3-benzyl-3-azabicyclo[3.2.1]octan-8-ylidene)acetate (0.6 g, 2.21 mmol) in EtOAc (10 mL) was added 10% Pd/C (100 mg, 93.97 μιηοΐ) under N2 at 15 °C. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 15 °C for 2 h. The mixture was filtrated, and the filtrate was concentrated in vacuo to afford crude product methyl 2-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)acetate (523 mg, crude) as a light yellow oil which was used in next step directly. MS (ES+) C17H23NO2 requires: 273, found: 274 [M+H]+.
Step 3:
To a solution of methyl 2-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)acetate (423 mg, 1.55 mmol) in DMF (2 mL) was added formamide (236.9 mg, 5.26 mmol, 209.7 μΐ,) at 15 °C. The mixture was heated to 100 °C. Fresh prepared sodium methoxide (58.5 mg, 1.08 mmol) was added in portions and stirring was continued for 1 h at 100 °C. The mixture was concentrated in vacuo to afford crude product 2-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)acetamide (543 mg, crude) as a light yellow solid. The crude product was used in next step directly. MS (ES+) Ci6H22N20 requires: 258, found: 259 [M+H]+.
Step 4: To a solution of 2-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)acetamide (493 mg, 1.91 mmol) in MeOH (8 mL) and DMF (8 mL) was added AcOH (1 1.4 mg, 190.8 μιηοΐ, 10.9 iV) and 10% Pd/C (200 mg, 187.9 μπιοΐ) at 15 °C. The suspension was degassed and purged with N2 three times, then purged with H2 three times. The mixture was stirred under H2 (50 psi) at 60 °C for 16 h. The mixture was filtered, the filtrate was concentrated in vacuo to afford a crude product 2-(3- azabicyclo[3.2.1]octan-8-yl)acetamide (450 mg, crude) as a colorless oil which was used in next step directly. MS (ES+) C9Hi6N20 requires: 168, found: 169 [M+H]+.
Step 5:
To a solution of N-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]methyl]formamide (Intermediate 9; 322.3 mg, 1.35 mmol) in DMSO (2 mL) was added DIPEA (174.5 mg, 1.35 mmol, 235 μL·), 2- (3-azabicyclo[3.2.1]octan-8-yl)acetamide (250 mg, 1.49 mmol) and CsF (205.2 mg, 1.35 mmol, 49.8 \iL) at 15 °C. The mixture was heated to 100 °C for 44 h, EtOAc (5 mL) was added and washed with brine (4 mL χ3). The organic layer was dried over Na2S04, filtered, concentrated in vacuo to afford a crude product (217 mg) as brown oil which was purified by prep-TLC (Si02, EtOAc: MeOH = 10: 1) to afford 2-[3-[6-(formamidomethyl)-4-(trifluoromethyl)-2-pyridyl]-3- azabicyclo[3.2.1]octan-8-yl]acetamide (27 mg, 72.9 μηιοΐ, 5 % yield; Peak A) as a light yellow oil and 2-[3-[6-(formamidomethyl)-4-(trifluoromethyl)-2-pyridyl]-3-azabicyclo[3.2.1]octan-8- yl]acetamide (14 mg, 37.80 μιηοΐ, 3 % yield; Peak B) as a light yellow solid. MS (ES+) C17H21N4O2F3 requires: 370, found: 371 [M+H]+. Step 6A: In the synthesis of Compound 41A
To 2-[3-[6-(formamidomethyl)-4-(trifluoromethyl)-2-pyridyl]-3-azabicyclo[3.2.1]octan-8- yl]acetamide (27 mg, 72.90 μιηοΐ, Peak A) was added POCI3 (825 mg, 5.38 mmol, 500 μί) at 15 °C. The mixture was heated to 50 °C and stirred for 4 h, The solution was concentrated in vacuo to remove POCI3. To the mixture was added EtOAc (2 mL). Then the mixture was quenched by saturated H4C1 solution (1 mL), and adjusted to pH 7 with NaOH solution (IN, 1 mL). Then the solution was extracted with EtOAc (2 mL χ2). The organic layer was dried over Na2SC>4, filtered, concentrated in vacuo to afford a crude product 2-[3-[7-(trifluoromethyl) imidazo[l,5-a] pyridin-5-yl]-3-azabicyclo[3.2.1]octan-8-yl]acetonitrile (28 mg, crude) as a yellow oil which was used in next step directly. MS (ES+) C17H17N4F3 requires: 334, found: 335 [M+H]+. Step 7A: In the synthesis of Compound 41 A
To a solution of 2-[3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-azabicyclo [3.2.1]octan- 8-yl]acetonitrile (28 mg, 83.7 μιηοΐ) in DCM (0.5 mL) was added H2S04 (98%, 552 mg, 5.63 mmol, 0.3 mL) at 0 °C. The solution was stirred for 16 h at 25 °C. The mixture was adjusted to pH 8 with ammonium hydroxide (2 mL) at 0 °C. Then the mixture was extracted with DCM (2 mL x3). The organic layer was dried over Na2SC>4, filtered, concentrated in vacuo to obtain a crude product (20 mg) as yellow oil which was purified by Prep-HPLC (column: Phenomenex Gemini 150*25mm* 10um;mobile phase: [H20 (0.05% ammonium hydroxide v/v)-MeCN]; B%: 30%-60%, 12min) and dried by lyophilization to afford 2-{3-[7-(trifluoromethyl)imidazo[l,5- a]pyridin-5-yl]-3-azabicyclo[3.2.1]octan-8-yl}acetamide (Compound 41A) (10.2 mg, 28.6 μιηοΐ, 34 % yield) as a white solid. MS (ES+) C17H19N4F3O requires: 352, found: 353 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.38 (s, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 7.39 (br, 1H), 6.87 (s, 1H), 6.42 (d, J = 1.5, 1H), 3.25 - 3.15 (m, 2H), 3.12 - 3.02 (m, 2H), 2.52 - 2.41 (m, 2H), 2.22 - 2.05 (m, 3H), 1.98 - 1.75 (m, 4H). Step 6B: In the synthesis of Compound 41B
To 2-[3-[6-(formamidomethyl)-4-(trifluoromethyl)-2-pyridyl]-3-azabicyclo[3.2.1]octan-8- yl]acetamide (Peak B; from step 5; 14 mg, 37.80 μπιοΐ) was added POCl3 (825 mg, 5.38 mmol, 500 μΐ.) at 15 °C. The mixture was heated to 50 °C and stirred for 4 h. The solution was concentrated in vacuo to remove POCI3. To the mixture was added EtOAc (2 mL), washed with saturated H4CI solution (1 mL), adjusted to pH 7 with NaOH solution (IN, 1 mL) and extracted with EtOAc (2 mL χ2) and the organic layer was dried over Na2S04, filtered, concentrated in vacuo to afford a crude product 2-[3-[7-(trifluoromethyl) imidazo[l,5-a]pyridine-5-yl]-3- azabicyclo[3.2.1]octan-8-yl]acetonitrile (20 mg, crude) as a green oil which was used in next step directly. MS (ES+) Ci7Hi7N4F3 requires: 334, found: 335 [M+H]+.
Step 7B: In the synthesis of Compound 41B
To a solution of 2-[3-[7-(trifluoromethyl)imidazo[l,5-a]pyridine-5-yl]-3-azabicyclo[3.2.1]octan- 8-yl]acetonitrile (20 mg, 59.8 μιηοΐ) in DCM (0.5 mL) was added H2S04 (552 mg, 5.6 mmol, 0.3 mL) at 0 °C. The solution was stirred for 16 h at 25 °C. The mixture was adjusted to pH 8 with ammonium hydroxide (2 mL) at 0 °C. Then the mixture was extracted with DCM (2 mL x3). The organic layer was dried over Na2S04, filtered, concentrated in vacuo to afford a crude product (15 mg) as a green oil which was purified by Prep-HPLC(column: Phenomenex Gemini 150*25mm* 10um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 30% - 60%), 12min) and dried by lyophilization to afford 2-{3-[7-(trifluoromethyl)imidazo[l,5- a]pyridin-5-yl]-3-azabicyclo[3.2.1]octan-8-yl}acetamide (Compound 41B) (2.3 mg, 6.46 μπιοΐ, 11 % yield) as a white solid. MS (ES+) Ci7Hi9N4F30 requires: 352, found: 353 [M+H]+ 1H NMR (400 MHz, DMSO-de) δ: 8.39 (s, 1H), 7.85 (s, 1H), 7.71 (s, 1H), 7.33 (br s, 1H), 6.80 (br s, 1H), 6.32 (d, J = 1.5, 1H), 3.30 (d, J= 3.7, 2H), 2.91 (d, J = 10.8, 2H), 2.19 - 2.09 (m, 3H), 2.00 (d, J = 7.6, 2H), 1.83 (s, 4H). Example 34: Synthesis of 3-r7-(trifluoromethyl)imidazorL5-c1pyrimidin-5-yl1-3-azaspiro rbicyclor3.2.11octane-8,4'-imidazolidine1-2',5'-dione (Compound 42)
Figure imgf000175_0001
3
Figure imgf000175_0002
Figure imgf000175_0003
Step 1:
To a solution of 2,4-dichloro-6-(trifluoromethyl)pyrimidine (2 g, 9.22 mmol, 2.00 mL) in H20 (2 mL) and DMF (20 mL) was added DABCO (103.39 mg, 921.7 μιηοΐ, 101.3 μί) and NaCN (0.3 g, 6.12 mmol). The mixture was stirred at 20 °C for 16 h. The residue was poured into water (50 mL), extracted with EtOAc (50 mL x2). The aqueous layer was quenched with aqueous NaCIO and adjusted pH to 11 and the combined organic layer was concentrated as yellow oil (2-chloro- 6-(trifluoromethyl)pyrimidine-4-carbonitrile (1.9 g, crude)) and used as such in the next step.
Step 2:
To a solution of 2-chloro-6-(trifluoromethyl)pyrimidine-4-carbonitrile (1.9 g, 9.15 mmol) in THF (20 mL) was added Raney-Ni (1.57 g, 18.31 mmol) and Boc20 (4.00 g, 18.31 mmol) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 30 °C under H2 (50 Psi) for 16 h. The residue was filtered and the filtrate was concentrated and then purified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50mm* 10 urn; mobile phase: [H20 (0.225% formic acid)-MeCN]; B%: 40%- 70% MeCN) and concentrated to give a yellow oil (tert-butyl N-[[2-chloro-6-(trifluoromethyl)pyrimidin-4- yl]methyl]carbamate (230 mg, 590.33 μιηοΐ, 6 % yield)). MS (ES+) Ci6Hi6N7OF3 requires: 311 and 313, found: 256 and 258 [M+H-56]+. 1H MR (400 MHz, MeOH-d4) δ: 7.74 (s, 1H), 4.44 (s, 2H), 1.49 (s, 9H).
Step 3:
To a solution of tert-butyl N-[[2-chloro-6-(trifluoromethyl)pyrimidin-4-yl]methyl]carbamate (230 mg, 737.92 μιηοΐ) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 °C for 16 h. The residue was concentrated as a yellow oil and used for next step without any further purification. ([2-chloro-6-(trifluoromethyl)pyrimidin-4-yl]methanamine (180 mg, 645.88 umol, 87% yield)). MS (ES+) C6H5N3CIF3 requires: 211 and 213, found: 212 and 214 [M+H]+.
Step 4: To HC02H (5 mL) was added [2-chloro-6-(trifluoromethyl)pyrimidin-4-yl]methanamine (180 mg, 850.7 μπιοΐ) and the mixture was stirred at 80 °C for 1 h. Then to the mixture was added Ac20 (5.45 g, 53.38 mmol, 5 mL) and the mixture was stirred at 80 °C for 1 h. The mixture was concentrated and POCI3 (8.81 g, 57.46 mmol, 5.34 mL) was added. The mixture was stirred at 80 °C for 1 h. The residue was concentrated in vacuo then purified by column chromatography on silica (DCM:MeOH=10: l) and concentrated to afford (5-chloro-7-(trifluoromethyl)imidazo[l,5- c]pyrimidine (150 mg, 663.4 μιηοΐ, 78% yield) as a yellow oil. MS (ES+) C7H3N3CIF3 requires: 221 and 223, found: 222 and 224 [M+H]+. 1H MR (400 MHz, DMSO-d6) δ: 8.85 (s, 1H), 8.33 (s, 1H), 7.87 (s, 1H).
Step 5: To a solution of 3-benzylspiro[3-azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (400 mg, 1.40 mmol) in MeOH (10 mL) and DMF (10 mL) was added 10% Pd/C (400 mg) and AcOH (8.42 mg, 140.18 umol, 8.0 μΕ) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 40 °C under H2 (50 Psi) for 16 h. The residue was filtered and the filtrate was concentrated in vacuo. The residue was used for next step without any further purification. The product was collected as white solid (spiro[3- azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (150 mg, 760.69 μιηοΐ, 54 % yield). MS (ES+) C9H13N3O2 requires: 195, found: 196 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 8.37 (s, 1H), 7.33 (s, 1H), 5.72 (s, 1H), 2.93 (d, J = 12.8, 2H), 2.48 - 2.33 (m, 3H), 2.10 - 2.03 (m, 1H), 1.68 - 1.50 (m, 3H), 1.40 - 1.21 (m, 1H).
Step 6:
To a solution of 5-chloro-7-(trifluoromethyl)imidazo[l,5-c]pyrimidine (75 mg, 338.5 μπιοΐ) in DMF (3 mL) was added TEA (102.76 mg, 1.02 mmol, 141 μΐ,) and spiro[3- azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (75 mg, 384.19 μπιοΐ). The mixture was stirred at 100 °C for 16 h. The residue was adjust pH to ~7 without further treatment and purified by prep-HPLC (column: Boston pH-lex 150*25 10 urn ;mobile phase: [H20 (0.1%TFA) - MeCN]; B%: 28%-58%,10 min), then two peaks were collected and freeze-dried to afford:
Peak A (Compound 42): (24.2 mg, 48.46 μιηοΐ, 14 % yield) was collected as a yellow solid. MS (ES+) C16H15N6O2F3 requires: 380, found: 381 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ: 10.73 (s, 1H), 8.61 (s, 2H), 7.65 (d, J = 3.4, 2H), 3.98 (dd, Jl = 13.1, 72 = 2.9, 2H), 3.62 (d, J = 12.8, 2H), 2.27 (s, 2H), 2.22 - 2.13 (m, 2H), 1.85 - 1.74 (m, 2H);
Peak B: (1.7 mg, 3.2 μιηοΐ, 0.9 % yield) was collected as a yellow solid. MS (ES+) C16H15N6O2F3 requires: 380, found: 381 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 10.87 (s, 1H), 8.62 (s, 1H), 8.19 (d, 7 =1.1, 1H), 7.65 (d, 7= 8.4, 2H), 4.04 - 3.95 (m, 2H), 3.85 (dd, Jl = 12.8, 72 = 3.0, 2H), 2.41 (s, 2H), 1.95 - 1.76 (m, 4H).
Example 35: Synthesis of 6,6-dimethyl-8-r7-(trifluoromethyl)imidazorL5-clpyrimidin-5-yll-
L3,8-triazaspiror4.51decane-2,4-dione (Compound 43)
Figure imgf000177_0001
Prepared as Example 1 step 5, using the product of step 4 of Example 34, and purified by mass- triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 10 - 40%; 20 min; Column: CI 8) to give 6,6-dimethyl-8-(2- (trifluoromethyl)imidazo[l,5-a]pyrimidin-4-yl)-l,3,8-triazaspiro[4.5]decane-2,4-dione. MS (ES+) C16H17N6O2F3 requires: 382, found: 383 [M+H]+. 1H MR (600 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.09 (s, 1H), 3.88 - 3.76 (m, 2H), 3.69 - 3.59 (m, 2H), 1.98 - 1.92 (m, 1H), 1.86 - 1.79 (m, 1H), 0.97 (s, 3H), 0.89 (s, 3H).
Example 36: Synthesis of 6,6-dimethyl-8-(7-(trifluoromethyl)imidazorL5-a1pyridin-5-yl)- L3,8-triazaspiror4.51decan-2-one (Compound 44)
Figure imgf000178_0001
To a flask containing aluminum chloride (69.9 mg, 0.524 mmol) cooled at 0 °C was slowly added a solution of LAH (393 μΐ, 0.393 mmol, 1 M in THF). The resulting mixture was stirred at 0 °C for 15 min. At 0 °C a solution of 6,6-dimethyl-8-(7-(trifluoromethyl)imidazo[l,5-a]pyridin- 5-yl)-l,3,8-triazaspiro[4.5]decane-2,4-dione (Example 1; 50 mg, 0.131 mmol) in THF (874 μΐ) was added and the resulting mixture was allowed to stir at 25 °C for 48 h. The resulting solution was cooled to 0 °C and water (0.5 mL) was added slowly, followed by NaOH (1 mL, 10% aq. solution), and then water (1.5 mL). The resulting mixture was diluted with EtOAc (5 mL), filtered through Celite, and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 30 - 70%; 12 min; Column: CI 8) to give 6,6-dimethyl-8-(7- (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-l,3,8-triazaspiro[4.5]decan-2-one (8 mg, 0.022 mmol, 16 % yield) as a colorless liquid. MS (ES+) Ci7H20F3N5O requires: 367, found: 368 [M+H]+. 1H NMR (600 MHz, MeOH-d4) δ 8.41 (s, 1H), 7.76 (d, J = 1.9, 1H), 7.70 (s, 1H), 6.37 (d, J = 1.5, 1H), 3.66 (d, J = 9.5, 1H), 3.35 (s, 2H), 3.24 - 3.18 (m, 2H), 3.01 (d, J = 12.0, 1H), 2.92 (d, J= 12.1, 1H), 2.23 - 2.01 (m, 2H), 1.20 (s, 3H), 1.12 (s, 3H).
Example 37: Synthesis of 2-{2',5'-dioxo-3-[7-(trifluoromethyl)imidazo[L5-alpyridin-5-yll-3- azaspirorbicvclor3.2.11octane-8,4'-imidazolidine1- -yl|acetamide (Compound 45)
Figure imgf000179_0001
To a solution of 3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]spiro[3- azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (Example 31; 40 mg, 105.4 μιηοΐ) in DMSO (0.5 mL) was added 2-chloroacetamide (14.79 mg, 158.1 μιηοΐ) and Cs2C03 (85.8 mg, 263.6 μπιοΐ) at 15 °C. The mixture was heated to 100 °C and stirred for 16 h. To the mixture was added water (1 mL) at 0 °C and the mixture was extracted with EtOAc (4 mL χ3) and washed with brine (10 mL χ2). The organic layer was dried over Na2S04. After filtration, the filtrate was concentrated in vacuo to obtain a crude product (60 mg) as a yellow oil. The crude product was purified by Prep-HPLC (column: Gemini 150*25 5u; mobile phase: [water (0.05% ammonium hydroxide v/v) - MeCN]; B%: 25% - 55%, 10 min) and dried by lyophilization to afford 2-[2',5'- dioxo-3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]spiro[3-azabicyclo[3.2.1]octane-8,4'- imidazolidine]-l'-yl]acetamide (6.5 mg, 13.7 μπιοΐ, 13% yield) as a white solid. MS (ES+) Ci9Hi9N603F3 requires: 436, found: 437 [M+H]+. 1H MR (400 MHz, DMSO-d6) δ: 8.98 (s, 1H), 8.45 (s, 1H), 7.92 (s, 1H), 7.74 (s, 1H), 7.58 (s, 1H), 7.16 (s, 1H), 6.58 (d, J= 1.3, 1H), 3.93 (s, 2H), 3.30 - 3.18 (m, 4H), 2.29 - 2.17 (m, 4H), 2.04 - 1.92 (m, 2H).
Example 38: Synthesis of 3'-propa-L2-dienyl-3-r7-(trifluoromethyl)imidazorL5-a1pyridin-5- yl1spiror3-azabicyclor3.2.11octane-8,5'-imidazolidine1-2',4'-dione (Compound 46); and 3'-prop- 2-ynyl-3-[7-(trifluoromethyl)imidazo[L5-alpyridin-5-yllspiro[3-azabicyclo[3.2.11octane-8,5'- imidazolidine1-2',4'-dione (Compound 47)
Figure imgf000180_0001
To a solution of 3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]spiro[3- azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (Example 31; 150 mg, 395.4 μιηοΐ) in DMSO (3 mL) was added 3-bromoprop-l-yne (70.5 mg, 593.1 μιηοΐ, 51 μΐ.) and Cs2C03 (257.68 mg, 790.8 μιηοΐ). The mixture was stirred at 100 °C for 16 h. To the mixture was added water (20 mL) and the mixture was extracted with EtOAc (20 mL x2). The combined organic layer was dried over Na2S04, filtered, concentrated to afford a yellow oil which was purified by prep-TLC Petroleum Ether : EtOAc = 1 : 1) to obtain two compounds with the same mass. The more apolar compound was purified by prep-HPLC (column: UniSil 120*30* 10um;mobile phase: [H20 (0.1%TFA) - MeCN]; B%: 28% - 58%, 7 min) and freeze-dried to afford Compound 47. The other peak was collected and MeOH (3 mL) was added. The mixture was stirred for 5 min, filtered and the filter cake was collected to afford Compound 46.
Compound 46: (3'-propa-l,2-dienyl-3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]spiro[3- azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (1.6 mg). MS (ES+) C20Hi8N5O2F3 requires: 417, found: 418 [M+H]+. 1H MR (400 MHz, DMSO-d6) δ: 9.24 (s, 1H), 8.60 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 6.66 (s, 1H), 6.63 (t, J= 6.7, 1H), 5.48 (d, J= 6.7, 2H), 3.34 - 3.28 (m, 2H), 3.19 (dd, Jl = 11.9, J2 = 3.1, 2H), 2.36 - 2.32 (m, 2H), 2.29 - 2.21 (m, 2H), 2.04 - 1.96 (m, 2H).
Compound 47: 3'-prop-2-ynyl-3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]spiro[3- azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (1.6 mg). MS (ES+) C20Hi8N5O2F3 requires: 417, found: 418 [M+H]+. 1H MR (400 MHz, DMSO-d6) δ: 9.11 (s, 1H), 8.45 (s, 1H), 7.93 (s, 1H), 7.75 (s, 1H), 6.59 (s, 1H), 4.17 (d, J= 2.3, 2H), 3.29 - 3.28 (m, 1H), 3.25 - 3.16 (m, 4H), 2.31 - 2.21 (m, 4H), 2.06 - 1.95 (m, 2H). Example 39: Synthesis of 3'-(lH riazol-4-ylmethyl)-3-r7-(trifluoromethyl)imidazorL5-a1 pyridin-5-yllspiro[3-azabicyclo[3.2.11octane-8,5'-imidazolidinel-2',4'-dione (Compound 48)
Figure imgf000181_0001
To a solution of 3'-prop-2-ynyl-3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]spiro[3- azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (60 mg, 143.75 μηιοΐ) in DMF (4 mL), H20 (2 mL) and toluene (0.03 mL) was added CuS04*5H20 (7.18 mg, 28.75 μιηοΐ) and L- ascorbic acid sodium salt (56.9 mg, 287.5 μιηοΐ). The mixture was heated to 90 °C and TMSN3 (132.49 mg, 1.15 mmol, 151 μΕ) was added to the mixture dropwise. The solution was stirred at 90 °C for 3 h. To the mixture was added H20 (20 mL) and the mixture was extracted with EtOAc (20 mL x2). The combined organic layer was dried over Na2S04, filtered, concentrated as a yellow liquid which was purified by prep-HPLC (column: Boston pH-lex 150*25 10um;mobile phase: [H20 (0.1%TFA)-MeCN]; B%: 20% - 50%, 10 min) and freeze-dried to afford 3'-(lH- triazol-4-ylmethyl)-3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]spiro[3- azabicyclo[3.2.1]octane-8,5'-imidazolidine]-2',4'-dione (2.6 mg, 3.6 μπιοΐ, 2 % yield, TFA salt) as a white solid. MS (ES+) C20Hi9N8O2F3 requires: 460, found: 461 [M+H]+. 1H MR (400 MHz, DMSO-de) δ: 9.06 (s, 1H), 8.55 (s, 1H), 7.96 (s, 1H), 7.87 - 7.69 (m, 2H), 6.63 (s, 1H), 4.66 (s, 2H), 3.35 - 3.29 (m, 2H), 3.24 - 3.16 (m, 2H), 2.32 - 2.22 (m, 4H), 2.05 - 1.95 (m, 2H).
Example 40: Synthesis of 6-fluoro-6-(trifluoromethyl)-8-r7-(trifluoromethyl)imidazorL5- a1pyridin-5-vH-L3,8-triazaspiror4.51decane-2,4-dione (Compound 49)
Figure imgf000182_0001
Step 1: To a solution of tert-butyl 4-oxo-3-(trifluoromethyl)piperidine-l-carboxylate (1050 mg, 3.93 mmol) in Toluene (11 ml) were added TEA (1.314 ml, 9.43 mmol) and trimethylsilyl trifluoromethanesulfonate (0.852 ml, 4.71 mmol) dropwise at -15 °C (acetone, dry ice bath) and the resulting mixture was stirred at -15°C for 1 h, then toluene was evaporated, MeCN (10 ml) was added and selectfluor (1531 mg, 4.32 mmol) at 0 °C and the mixture was stirred at RT 48 h, then evaporated and purified twice via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give tert-butyl 3-fluoro-4-oxo-3-(trifluoromethyl)piperidine-l-carboxylate (522 mg, 1.830 mmol, 47% yield) as a yellow liquid. MS (ES+) C11H15NO3F4 requires: 285, found: 186 [M+H]+- Boc.
Step 2: To a solution of tert-butyl 3-fluoro-4-oxo-3-(trifluoromethyl)piperidine-l-carboxylate (522 mg, 1.830 mmol) in EtOH (6 ml) were added KCN (357 mg, 5.49 mmol) and ammonium carbonate (633 mg, 6.59 mmol) and the resulting mixture was stirred at 90°C 16 h in a pressure vial. Saturated NaHC03 was added to the mixture and then diluted with EtOAc. The aqueous phase was back extracted with EtOAc (x2) and then the organic phase was washed with brine and dried over Na2S04 to recover a brown solid. The residue was purified via silica gel chromatography (10 - 100 % EtOAc in hexanes) to give tert-butyl 6-fluoro-2,4-dioxo-6-(trifluoromethyl)-l,3,8- triazaspiro[4.5]decane-8-carboxylate as two separate diasteroisomers. MS (ES+) Ci3Hi7F4N304 requires: 355, found: 356 [M+H]+: A: 1H MR (500 MHz, DMSO-d6) δ: 11.17 (brs, 1H), 8.98 (brs, 1H), 4.35 - 4.11 (m, 1H), 3.97 - 3.86 (m, 1H), 3.76 - 3.62 (m, 0.5H), 3.56 - 3.39 (m, 0.5H), 3.25 - 3.13 (m, 1H), 2.1 1 - 2.02 (m, 1H), 1.78 (brd, J= 14.0, 1H), 1.40 (s, 9H). (140 mg, 0.39 mmol, 21 % yield); and
B 1H MR (500 MHz, DMSO-d6) δ: 9.29 (s, 1H), 8.52 (s, 1H), 4.54 - 4.26 (m, 1H), 4.16 - 3.99 (m, 1H), 3.69 - 3.35 (m, 1H), 3.18 - 2.88 (m, 1H), 2.33 - 2.18 (m, 1H), 1.82 (brd, J = 14.6, 1H), 1.42 (s, 9H). (22 mg, 0.062 mmol, 3 % yield).
Step 3: tert-butyl 6-fluoro-2,4-dioxo-6-(trifluoromethyl)-l,3,8-triazaspiro[4.5]decane-8-carboxylate (140 mg, 0.39 mmol, diastereomer A) was treated with 4N HC1 in dioxane (0.985 ml, 3.9 mmol) and the solution was stirred for 2 h at RT and then concentrated to yield 6-fluoro-6-(trifluoromethyl)- l,3,8-triazaspiro[4.5]decane-2,4-dione (115 mg, 0.39 mmol, 100% yield). MS (ES+)
Figure imgf000183_0001
requires: 255, found: 256 [M+H]+.
Step 4:
To a solution of 6-fluoro-6-(trifluoromethyl)-l,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (115 mg, 0.394 mmol) in DMSO (1 mL) were added DIPEA (0.076 mL, 0.434 mmol) and cesium fluoride (71.9 mg, 0.473 mmol) and N-((6-chloro-4-(trifluoromethyl)pyridin- 2-yl)methyl)formamide (Intermediate 9; 103 mg, 0.434 mmol) and the resulting mixture was stirred at 100 °C for 72 h then poured into water and extracted with EtOAc. The organic phase was evaporated and the residue was directly purified via silica gel chromatography (0 - 100 % EtOAc in hexanes to give N-((6-(6-fluoro-2,4-dioxo-6-(trifluoromethyl)-l,3,8- triazaspiro[4.5]decan-8-yl)-4-(trifluoromethyl)pyridin-2-yl)methyl)formamide (32 mg, 0.070 mmol, 18 % yield) as a yellow solid. MS (ES+) C16H14F7N5O3 requires: 457, found: 458 [M+H]+.
Step 5:
To N-((6-(6-fluoro-2,4-dioxo-6-(trifluoromethyl)-l,3,8-triazaspiro[4.5]decan-8-yl)-4- (trifluoromethyl)pyridin-2-yl)methyl)formamide (32 mg, 0.070 mmol) were added POCI3 (65.2 μΐ, 0.700 mmol) and the resulting mixture was stirred at 80 °C for 30 min. The volatiles were removed under reduced pressure. The reaction mixture was cooled to 0 °C saturated NaHC03 was added until pH = 7, EtOAc was added and the layers were separated. The aqueous phase was extracted with EtOAc (3x), the combined organic layers were concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B = 5 - 40%; 30 min; Column: C18) to give 6- fluoro-6-(trifluoromethyl)-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,8- triazaspiro[4.5]decane-2,4-dione (5.4 mg, 0.009 mmol, 14% yield) as a white solid. MS (ES+) Ci6Hi2F7N502 requires: 439, found: 440 [M+H]+. 1H MR (600 MHz, MeOH-d4) δ: 8.76 (brs, 1H), 7.98 (s, 1H), 6.71 (s, 1H), 4.01 - 3.94 (m, 1H), 3.70 - 3.56 (m, 3H), 2.74 - 2.64 (m, 1H), 2.21 - 2.11 (m, 1H).
Example 41 : Synthesis of 9,9-dimethyl-7-r7-(trifluoromethyl)imidazorL5-a1pyridin-5-yl1- L3,7-triazaspiror4.41nonane-2,4-dione (Compound 50)
Figure imgf000184_0001
9,9-dimethyl-7-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,7-triazaspiro[4.4]nonane-2,4- dione was prepared by SNAr reaction following the procedure of Example 40 using Intermediate 9 and 9,9-dimethyl-l,3,7-triazaspiro[4.4]nonane-2,4-dione hydrochloride (prepared analogously to Intermediate 1) and then closing with POCI3. MS (ES+) Ci6Hi602F3 requires:367, found 368 [M+H]+. 1HNMR (400 MHz, MeOH-d4) δ: 9.32 (s, 1H), 8.07 (s, 1H), 7.71 (s, 1H), 6.50 (s, 1H), 4.03 (dd, Jl = 12.2, 72 = 9.8, 2H), 3.84 (d, 7= 10.4, 1H), 3.43 (d, 7= 9.2, 1H), 1.30 (s, 3H), 1.19 (s, 3H).
Example 42: Synthesis of 6-fluoro-6-methyl-8-r7-(trifluoromethyl)imidazorL5-a1pyridin-5-yl1- L3,8-triazaspiror4.51decane-2,4-dione (Compound 51)
Figure imgf000185_0001
Prepared according to Example 40 starting from tert-butyl 3-methyl-4-oxopiperidine-l- carboxylate and purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H20, B = 0.1% TFA/MeCN; Gradient: B =10 - 40%; 20 min; Column: CI 8) to afford a mixture of diasterosiomers (ratio 3 : 1). MS (ES+) Ci6Hi5F4N502 requires: 385, found: 386 [M+H]+. 1H MR (600 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.48 (s, 2H), 7.92 (s, 1H), 7.80 (s, 1H), 6.44 (s, 1H), 3.72 - 3.63 (m, 1H), 3.54 - 3.46 (m, 1H), 3.43 - 3.28 (m, 2H), 2.33 - 2.20 (m, 1H), 2.16 - 2.03 (m, 1H), 1.54 - 1.26 (m, 3H).
Example 43 : IDOl cell-based assay
HeLa cells were obtained from the American Type Culture Collection (ATCC) and maintained in DMEM media containing 10% FBS. Cells (7,000/well) were seeded onto a 384 well plate in 50 μΐ of media and incubated at 37 °C, 5% C02 overnight. Cell media was aspirated, fresh media containing lOng/mL IFNgamma was added, and cells were incubated in absence or presence of various concentrations of test compound (final 0.5 % DMSO) for 24 hours. Aliquots of the cell conditioned media were removed from the cell plate, and mixed with an equal volume of 200mM ZnS04 to precipitate media containing protein. Two volumes of acetonitrile were added, mixed, and samples were then centrifuged at 2250G for 20 minutes at 4 °C. Aliquots of the supernatant were diluted 1 : 10 in 0.1% formic acid containing 3μΜ of deuterated Tryptophan as an internal standard.
Samples were analyzed via RFMS to quantify N-Formyl Kynurenine (AUC) and L-tryptophan (AUC). A C18 cartridge was used with mobile phases of 0.1% Formic Acid and 80% ACN/0.1% Formic Acid under isocratic conditions. Dose-response curves were analyzed using IC50 regression curve fitting (GeneData Screener). Curves were plotted as percent of control and normalized by high controls without inhibitor (100%), and low controls (0%) containing 1 μΜ of epacadostat, a potent cell-permeable IDOl inhibitor. Cell viability was also assessed using the Cell Titer Glo Kit (Promega) following manufacturer recommendation.
Table 4 below summarises the results of the IDOl cell-based assay, in which the IC50 values are indicated for each compound as: (A) less than 150 nM; (B) 150 nM to 300 nM; (C) 300 nM to 750 nM; (D) 750 nM to 1.5 μΜ; and (E) greater than 1.5 μΜ.
Table 4:
Figure imgf000186_0001
Compound IC50
23 B
24 E
25 B
26 C
27 B
27A A
27B D
28 B
29 C
30 E
31 E
32 E
33 E
34 D
35 C
36 E
37 D
38 C
39A B
39B A
40 B
41A D
41B C
42 C
43 E
44 B
45 E
46 A
47 B
48 D
49 A
50 D
51 C
Example 44: IDOl enzyme assay
Inhibition of recombinant human His-tagged IDOl enzyme (R&D Systems, catalog # 6030-AO) was assessed by measuring the conversion of L-tryptophan to N-Formyl Kynurenine using Rapid Fire Mass Spectrometry (RFMS) system (Agilent Technologies). IDOl enzyme (InM) was incubated in absence or presence of various concentrations of compounds in assay buffer (40mM Tris, pH 7.0, 15μΜ Tween-20, containing 5mM sodium ascorbate, 5μΜ methylene blue, and 0.5μΜ catalase) in a 384 well plate. After 10 minutes at room-temperature, L-tryptophan (6μΜ) was added to a final volume of 60 μΐ per well, and the reaction plate was incubated at room- temperature for 1 hour. Reactions were quenched by addition of 30μΙ. 0.24% formic acid containing 15μΜ deuterated tryptophan as an internal standard.
Samples were analyzed via RFMS to quantify N-Formyl Kynurenine (AUC) and L-tryptophan (AUC). A C18 cartridge was used with mobile phases of 0.1% Formic Acid and 80% ACN/0.1% Formic Acid under isocratic conditions. Dose-response curves were analyzed using IC50 regression curve fitting (GeneData Screener). Curves were plotted as percent of control and normalized by high controls without inhibitor (100%), and low controls without substrate (0%).
Table 5 below summarises the results of the IDOl enzyme assay, in which the IC50 values are indicated for each compound as: (A) less than 100 nM; (B) 100 nM to 250 nM; (C) 250 nM to 500 nM; (D) 500 nM to 1 μΜ; and (E) greater than 1 μΜ.
Table 5:
Figure imgf000188_0001
Compound IC50
21 D
22 A
24 E
25 A
26 A
27 A
27 A
29 C
32 A
33 D
34 A
35 C
36 A
37 E
38 A
39A A
40 A
41A A
41B A
42 B
44 A
51 B
The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.
While the present invention has particularly been shown and described with reference to exemplary embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the sprit and scope of the invention encompassed by the appended claims.

Claims

1. A com ound characterised by formula (IA) or formula (IB),
Figure imgf000190_0001
(IA) (IB)
larmaceutically acceptable salt or prodrug thereof, wherein:
Y1 is selected from CR1 and N;
Y2 is selected from CR3 and N;
A is selected from
NR6R7,
Figure imgf000190_0002
heterocyclyl,
wherein said aryl or heterocyclyl is optionally substituted by groups independently selected from R8;
R1 and R2 are each independently selected from halogen,
CN,
Ci-3-alkyl,
0-(Ci.3-alkyl),
C2-3-alkenyl,
C2-3-alkynyl,
C3-5-cycloalkyl, and
C3-5-cycloalkenyl,
wherein said alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is optionally substituted by one or more groups independently selected from halogen, or R1 and R2 taken together with the intervening carbon atoms form a 5-membered carbocyclic or heterocyclic group which is optionally substituted with one or more groups independently selected from halogen;
R3 is selected from
H,
halogen,
C(0)NH2, and
methyl optionally substituted by one or more groups independently selected from halogen;
R4 and R5 are each independently selected from H and NRaRb, wherein Ra and Rb are each independently selected from H and C1-3 alkyl;
R6 is selected from
H,
Ci-e-alkyl,
C2-6-alkenyl,
C2-6-alkynyl,
(Co-6-alkyl)-cycloalkyl,
(Co-6-alkyl)-cycloalkenyl,
(Co-6-alkyl)-aryl,
(Co-6-alkyl)-heterocycloalkyl,
(Co-6-alkyl)-heterocycloalkenyl, and
(Co-6-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R8a, and
R7 is selected from
H,
Ci-e-alkyl,
C2-6-alkenyl,
C2-6-alkynyl, (Co-6-alkyl)-cycloalkyl,
(Co-6-alkyl)-cycloalkenyl,
(Co-6-alkyl)-aryl,
(Co-6-alkyl)-heterocycloalkyl,
(Co-6-alkyl)-heterocycloalkenyl, and
(Co-6-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R ,
or R6 and R7 taken together with the intervening nitrogen atom form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group which is optionally substituted by one or more groups independently selected from R8; any pair of R8 groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group,
any pair of R8a groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered carbocyclic or heterocyclic group,
any pair of R8b groups, taken together with the intervening atom or atoms, may independently form a 3- to 10-membered carbocyclic or heterocyclic group, and
any remaining R8, R8a and/or R8b groups are each independently selected from
halogen,
oxo,
OH,
CN,
Ci-e-alkyl,
C2-6-alkenyl,
C2-6-alkynyl,
0-(Ci-6-alkyl),
(Co-6-alkyl)-S02R9,
(Co-6-alkyl)-S02N(R10)2,
(Co-e-alky -NHSO.R11,
N(R12)S02N(R1 )2, N(R14)C(0)N(R15)2,
(Co-6-alkyl)-NR16R17,
(C0-6-alkyl)-NHC(O)R18,
(C0-6-alkyl)-C(O)N(R19)2,
(Co-6-alkyl)-C(0)R20,
(C0-6-alkTl)-C(O)OR21,
(Co-6-alkyl)-cycloalkyl,
(Co-6-alkyl)-cycloalkenyl,
(C0-6-alkyl)-aiyl,
(Co-6-alkyl)-heterocycloalkyl,
(Co-6-alkyl)-heterocycloalkenyl, and
(Co-6-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl. heteroan l. carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J;
J in each case is independently selected from
halogen,
oxo,
OH,
CN,
Ci-5-alkyl,
C2-5-alkenyl,
C2-5-alkynyl,
(C0-4-alkyl)-O-(Ci.4-alkyl),
(C0-4-alkyl)-SO2R9,
(Co-4-alkyl)-S02N(R10)2,
(Co^-alky -NHSOzR11,
N(R14)C(0)N(R15)2,
(C0-4-alkyl)-NR16R17,
(Co-4-alkyl)-NHCOR18.
(C0-4-alkyl)-CON(R19)2,
(Co-4-alkyl)-C(0)R20, C(0)OH,
C(0)0(Ci-4-alkyl),
(Co-4-alkyl)-aryl, and
(Co-4-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, aryl or heteroaryl is optionally substituted by one or more groups independently selected from halogen and hydroxy; and
R9 to R21 are each independently selected from
H,
Ci-e-alkyl,
C2-6-alkenyl,
C2-6-alkynyl,
C3-6-cycloalkyl,
C3-6-cycloalkenyl,
phenyl,
3- to 6-membered heterocycloalkyl,
3- to 6-membered heterocycloalkenyl, and
5- to 7-membered heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl is optionally substituted by one or more groups independently selected from halogen, OH and Ci-3-alkyl optionally substituted by one or more groups independently selected from halogen.
2. The compound of claim 1, wherein J in each case is independently selected from
halogen,
oxo,
OH,
CN,
Ci.s-alkyl,
C2-5-alkenyl,
C2-5-alkynyl,
0-(Ci-4-alkyl), (Co-4-alkyl)-S02R9,
(Co-4-alkyl)-S02N(R10)2,
(Co^-alky -NHSOzR11,
N(R14)C(0)N(R15)2,
(Co-4-alkyl)-NR16R17,
(Co-4-alkyl)-NHCOR18,
(Co-4-alkyl)-CON(R19)2,
(Co-4-alkyl)-C(0)R20,
C(0)OH,
C(0)0(C -alkyl), and
Figure imgf000195_0001
wherein each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by more groups independently selected from halogen.
The compound of claim 1 or claim 2, wherein at least one of Y1 and Y2 is N.
4. The compound of any one of claims 1 to 3, characterised by formula (IIA) or formula (IIB),
Figure imgf000195_0002
defined in any of the preceding claims.
5. The compound of any one of claims 1 to 3, characterised by formula (IIIA) or formula (IIIB),
Figure imgf000196_0001
(IIIA) (IIIB)
or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, R4, R5 and A are as defined in any of the preceding claims.
6. The compound of any one of claims 1 to 5, wherein R1 and/or R2 are independently selected from H, halogen, CN, and Ci-3-alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from halogen.
7. The compound of any one of claims 1 to 4 and 6, wherein R3 is selected from H, halogen, and methyl, wherein said methyl is optionally substituted by one or more groups independently selected from fluorine.
8. The compound of any one of claims 1 to 7, wherein R4 and R5 are each independently selected from H and NH2.
9. The compound of any one of claims 1 to 8, wherein R2 is selected from H, CI and Ci-3-alkyl, wherein said alkyl is optionally substituted by 1, 2 or 3 fluorine atoms; and R1, R3, R4 and R5, where present, are each independently selected from H.
10. The compound of claim 9, wherein R2 is selected from CI and CF3.
11. The compound of any one of claims 1-2 and 6-10, characterised by formula (VIIIA) or formula (VIIIB),
Figure imgf000197_0001
(VIIIA) (VIIIB)
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R6 is selected from H, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)- heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R8a; and
R7 is selected from H, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)- heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is optionally substituted by one or more groups independently selected from R , and
R1 to R5, R8a and R8b are as defined in any of the preceding claims.
12. The compound of any one of claims 1 -2 and 6-10, characterised by formula (XIIA) or formula XIIB),
Figure imgf000197_0002
(XIIA) (XIIB)
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; n is 0, 1 or 2;
X1 is selected from N, C, S and O; and
at least one pair of R8 groups, taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, wherein said carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J, and
R1 to R5, R8 and J are as defined in any of the preceding claims.
The com ound of claim 12, characterised by formula (XVIA) or formula (XVIB),
Figure imgf000198_0001
(XVIA) (XVIB) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
at least one pair of the groups R22 to R31, taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group, wherein any remaining groups R22 to R31 are each independently selected from H, halogen, oxo, OH, CN, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, 0-(Ci-6-alkyl), (Co-6-alkyl)- S02R9, (C0-6-alkyl)-SO2N(R10)2, (Co-e-alky -NHSChR11, N(R12)S02N(R1 )2, N(R14)C(0)N(R15)2, (C0-6-alkyl)-NR16R17, (C0-6-alkyl)-NHC(O)R18, (C0-6-alkyl)-C(O)N(R19)2, (C0-6-alkyl)-C(O)R20, (C0-6-alkyl)-C(O)OR21, (C0-6-alkyl)-cycloalkyl, (Co-e-alkyl)- cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein when any of R22 to R31 is oxo, the corresponding geminal group is absent,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J, and
R1 to R5, R9 to R21 and J are as defined in any of the preceding claims. 22 23 30 31
14. The compound of claim 13, wherein R , R , R and R are each independently H;
24 25 28 29
and R , R , Ri0 and R^ are each independently selected from H and Ci-6-alkyl, wherein said alkyl is optionally and independently substituted by one or more groups independently selected from J as defined in any of the preceding claims.
15. The compound of claim 13 or claim 14, wherein R26 and R27 together with the intervening atom form a 3- to 8-membered spiro cycloalkyl or heterocycloalkyl group, which cycloalkyl or heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined in any of the preceding claims.
16. The compound of any one of claims 13 to 15, wherein R26 and R27 together with the intervening atom form a 4- to 6-membered spiro heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined in any of the preceding claims, wherein R24 is selected from halogen and Ci-6-alkyl, wherein said alkyl is optionally substituted by one or more groups
22 23 25 28 29 30 31 independently selected from halogen, and wherein R , R , R , R , R , R and R are each H.
17. The compound of any one of claims 13 to 15, wherein R26 and R27 together with the intervening atom form a 4- to 6-membered spiro heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more groups independently selected from J as defined in any of the preceding claims, wherein R24 and R25 are independently selected from halogen and Ci-6-alkyl, wherein each said alkyl is optionally substituted by one or more groups independently selected from halogen, and wherein R22, R23, R28, R29, R30 and R31 are each H.
18. The compound of claim 13, wherein one pair of the groups R22 to R31, taken together with the intervening atom, forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined in any of the preceding claims, and wherein another pair of the groups R22 to R31, taken together with the intervening atoms, forms a 5- to 8- membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined in any of the preceding claims.
19. The compound of claim 18, wherein R26 and R27, taken together with the intervening atom, forms a 4- to 6-membered spiro heterocyclic group, wherein said heterocyclic group is optionally substituted by one or more groups independently selected from J as defined in any of the preceding claims, and wherein R24 and R28, taken together with the intervening atoms, forms a 5- to 8-membered bridged carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more groups independently selected from J as defined in any of the preceding claims.
20. The compound of claim 12, characterised by formula (XXA) or formula (XXB),
Figure imgf000200_0001
(XXA) (XXB) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
22 25 28 32
at least one pair of the groups R to R , and R to R , taken together with the intervening atom or atoms, forms a 3- to 10-membered spiro, fused or bridged carbocyclic or heterocyclic group,
any remaining groups R to R and R to R are each independently selected from H, halogen, oxo, OH, CN, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, 0-(Ci-6-alkyl), (Co-6-alkyl)- S02R9, (C0-6-alkyl)-SO2N(R10)2, (C-e-alky -NHSO.R11, N(R12)S02N(R1 )2, N(R14)C(0)N(R15)2, (C0-6-alkyl)-NR16R17, (C0-6-alkyl)-NHC(O)R18, (C0-6-alkyl)-C(O)N(R19)2, (C0-6-alkyl)-C(O)R20, (C0-6-alkyl)-C(O)OR21, (C0-6-alkyl)-cycloalkyl, (Co-e-alkyl)- cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein when any of R22 to R31 is oxo, the corresponding geminal group is absent, and
any remaining R32 group is selected from H, OH, Ci-6-alkyl, C2-6-alkenyl, C2- 6-alkynyl, 0-(Ci-6-alkyl), (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2N(R10)2, (Ci-6-alkyl)- NHSO2R11, (Ci-6-alkyl)-NR16R17, (Ci-6-alkyl)-NHC(0)R18, (C0-6-alkyl)-C(O)N(R19)2, (C0- 6-alkyl)-C(0)R20, (C0-6-alkyl)-C(O)OR21, (C0-6-alkyl)-cycloalkyl, (C0-6-alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)-heterocycloalkenyl, and (Co- 6-alkyl)-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J, and
R1 to R5, R9 to R21 and J are as defined in any of the preceding claims.
22 23 30 31
21. The compound of claim 20, wherein R , R , R and R are each independently H;
24 25 28 29
and R , R , Ri0 and R" are each independently selected from H and Ci-6-alkyl, wherein said alkyl is optionally and independently substituted by one or more groups independently selected from J as defined in any of the preceding claims.
22. The compound of claim 20 or claim 21, wherein R32 is selected from H, Ci-6-alkyl, (Co-6-alkyl)-S02R9 and (Co-6-alkyl)-C(0)R20, wherein each said alkyl is optionally substituted by one or more groups independently selected from J, and wherein R9, R20 and J are as defined in any of the preceding claims.
23. The compound of any one of claims 1 to 10, wherein A is selected from
Figure imgf000202_0001
wherein:
X2 is selected from NH, N(Ci-5 alkyl), O, and C(R')2, wherein each R' is independently selected from H and C1-5 alkyl;
R33, R34 and R36 are each independently selected from H, Ci-5-alkyl, C2- 5-alkenyl, C2-5-alkynyl, and (Co-4-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen and hydroxyl; and
R35 is selected from H, Ci-5-alkyl, C2-5-alkenyl, C2-5-alkynyl, (C0-4-alkyl)-SO2R9, (C0-4-alkyl)-SO2N(R10)2,
Figure imgf000202_0002
(Ci-4-alkyl)-NHCOR18, (C0-4-alkyl)- CON(R19)2, (Co-4-alkyl)-COR20, and (Co-4-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl or heteroaryl is optionally substituted by one or more groups independently selected from halogen and hydroxyl, and
Ry to R , Rie to RiU and R" to R , where present, are as defined in any of the preceding claims.
Figure imgf000203_0001
202
25. The compound of any one of claims 1 to 10, wherein A is C6-io-aryl substituted by at least two groups independently selected from R8 as defined in any of the preceding claims.
26. The compound of claim 25, characterised by formula (XXIV A) or formula (XXIVB),
Figure imgf000204_0001
(XXIVA) (XXIVB) or a pharmaceutically acceptable salt or prodrug thereof, wherein R37 to R41 are each independently selected from H, halogen, OH, CN, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, O- (Ci-6-alkyl), (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2N(R10)2, (C-e-alky -NHSO.R11, N(R12)S02N(R1 )2, N(R14)C(0)N(R15)2, (C0-6-alkyl)-NR16R17, (C0-6-alkyl)-NHC(O)R18, (C„. 6-alkyl)-C(0)N(R19)2, (C0-6-alkyl)-C(O)R20, (C0-6-alkyl)-C(O)OR21, (C0-6-alkyl)-cycloalkyl, (Co-6-alkyl)-cycloalkenyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, (Co-6-alkyl)- heterocycloalkenyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by one or more groups independently selected from J, and R1 to R5, R9 to R21 and J are as defined in any of the preceding claims.
27. The compound of claim 25 or claim 26, wherein:
R37 and R41 are each independently H;
R38 and R40 are each independently selected from H, halogen, Ci-6-alkyl, (C0- 6-alkyl)-cycloalkyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, and (Co-6-alkyl)- heteroaryl, wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more groups independently selected from J; and
R39 is selected from H, Ci-6-alkyl, (C0-6-alkyl)-SO2R9, (C0-6-alkyl)-SO2N(R10)2, (C0- 6-alkyl)-NHS02Rn, (C0-6-alkyl)-NHCOR18, (Co-β alkyl)-C(0)N(R19)2, (Co-6-alkyl)-cycloalkyl, (Co-6-alkyl)-aryl, (Co-6-alkyl)-heterocycloalkyl, and (Co-6-alkyl)-heteroaryl, wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one groups independently selected from J, and
R9, R10, R", R18, R19 and J are as defined in any of the preceding claims.
28. The compound of any one of the claims 1 to 10, wherein A is selected from
Figure imgf000205_0001
wherein:
X4 is selected from NH, N(Ci-6 alkyl), O, and CR'2,
wherein each R' is independently selected from Ci-6 alkyl;
26 32 33 35
are each independently selected from: H,
Ci-9-alkyl,
(Co-9-alkyl)-(C3-io-cycloalkyl),
(Co-9-alkyl)-(C6-io-aryl),
(Co-9-alkyl)-heterocycloalkyl, and
(Co-9-alkyl)-heteroaryl;
R28 and R29 are each independently selected from:
H,
Ci-9-alkyl,
(Co-9-alkyl)-(C3-io-cycloalkyl),
(Co-9-alkyl)-(C6-io-aryl),
(Co-9-alkyl)-heterocycloalkyl,
(Co-9-alkyl)-heteroaryl, or
R28 and R29 may together form a C3-9-cycloalkyl or 3- to 9-membered heterocycloalkyl; and
R27 and R34 are selected from:
H,
Ci-9-alkyl,
(Co-9-alkyl)-S02R9,
(Co-9-alkyl)-S02NHR10,
(Co-g-alky -NHSOzR11,
(C0-9-alkyl)-NHCOR18,
(C0-9-alkyl)-CONHR19,
(Co-9-alkyl)-COR20,
(C0-9-alkyl)-(C3-io-cycloalkyl),
(Co-9-alkyl)-(C6-io-aryl),
(Co-9-alkyl)-heterocycloalkyl, and
(Co-9-alkyl)-heteroaryl,
wherein each said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally and independently substituted by one or more groups selected independently from J as defined in any one of the preceding claims, and
wherein R9, R10, R11, R18, R19 and R20 are as defined in any one of the preceding claims. A compound selected from the group consisting of Compounds 1 to 51
Figure imgf000207_0001
l-{9-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3,9-
Compound 13
diazaspiro [5.5] undecan-3 -yl } ethan- 1 -one
3,6,6-trimethyl-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 14
yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione
2,2-dimethyl-4- [7-(trifluoromethy l)imidazo [ 1 ,5-a] py ridin-5 -
Compound 15
yljpiperazine- 1 -sulfonamide
N-(4-{2,2-dimethyl-4-[7-(trifluoromethyl)imidazo[l,5-
Compound 16
a] py ridin-5 -yl] piperazin- 1 -yl } phenyl)methanesulfonamide
3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 17A
azabicyclo[3.3. l]nonan-9-ol
3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 17B
azabicyclo[3.3. l]nonan-9-ol bis(3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 18A
azaspiro[bicyclo[3.3.1]nonane-9,4'-imidazolidine]-2',5'-dione) bis(3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 18B
azaspiro[bicyclo[3.3.1]nonane-9,4'-imidazolidine]-2',5'-dione)
3-{6-chloroimidazo[l,5-a]pyridin-8-yl}-3-
Compound 19
azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
5-methanesulfonyl-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 20
a]pyridin-5-yl]-5,8-diazaspiro[3.5]nonane
5-{6,6-dimethyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-
Compound 21
yl}imidazo[l,5-a]pyridine-7-carbonitrile l-methanesulfonyl-2-(trifluoromethyl)-4-[7-
Compound 22
(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]piperazine
8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,8-
Compound 23
triazaspiro [4.5] decane-2,4-dione
7-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,7-
Compound 24
triazaspiro[4.4]nonane-2,4-dione
1 l-(7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl)-5,7,l 1-
Compound 25
triazadispiro[2.0.44.4 ]dodecane-6,8-dione 3-(2-hydroxyethyl)-6,6-dimethyl-8-[7-
Compound 26 (trifluoromethyl)imidazo[ 1 ,5 -a] py ridin-5-y 1] - 1 ,3 , 8- triazaspiro [4.5] decane-2,4-dione
6,6-difluoro-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-
Compound 27
l,3,8-triazaspiro[4.5]decane-2,4-dione
6,6-difluoro-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-
Compound 27A
l,3,8-triazaspiro[4.5]decane-2,4-dione (Enantiomer A)
6,6-difluoro-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-
Compound 27B
l,3,8-triazaspiro[4.5]decane-2,4-dione (Enantiomer B)
6-(trifluoromethyl)-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 28
a]pyridin-5 -y 1] - 1 ,3 , 8-triazaspiro[4.5] decane-2,4-dione l-methanesulfonyl-2,2-dimethyl-4-[6-
Compound 29
(trifluoromethyl)imidazo[l,5-a]pyridin-8-yl]piperazine
5-(4-methanesulfonyl-3,3-dimethylpiperazin-l-yl)imidazo[l,5-
Compound 30
a]pyridine-7-carbonitrile
3-benzyl-6,6-dimethyl-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 31
a]pyridin-5 -y 1] - 1 ,3 , 8-triazaspiro[4.5] decane-2,4-dione
4-{7-cyclopropylimidazo[l,5-a]pyridin-5-yl}-l-
Compound 32
methanesulfonyl-2,2-dimethylpiperazine l-{3,3-dimethyl-l-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-
Compound 33
5 -y l]piperidin-4-yl } imidazolidin-2-one
3-ethyl-6,6-dimethyl-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 34
a]pyridin-5 -y 1] - 1 ,3 , 8-triazaspiro[4.5] decane-2,4-dione l-methanesulfonyl-2,2-dimethyl-4-[7-
Compound 35
(trifluoromethyl)imidazo[l,5-c]pyrimidin-5-yl]piperazine
3-(2-methoxyethyl)-6,6-dimethyl-8-[7-
Compound 36 (trifluoromethyl)imidazo[ 1 ,5 -a] py ridin-5-y 1] - 1 ,3 , 8- triazaspiro [4.5] decane-2,4-dione
4- {2-chloroimidazo [ 1 ,5-b] py ridazin-4-yl } - 1 -methanesulfony 1-
Compound 37
2,2-dimethylpiperazine
3 - [7 -(trifluoromethy l)imidazo [ 1 , 5 -a] py ridin-5 -y 1] -3 -
Compound 38
azabicyclo[3.2.1]octane-8-carboxamide
3 - [7 -(trifluoromethy l)imidazo [ 1 , 5 -a] py ridin-5 -y 1] -3 -
Compound 39A azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
(Enantiomer A) 3 - [7 -(trifluoromethy l)imidazo [ 1 , 5 -a] py ridin-5 -y 1] -3 -
Compound 39B azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
(Enantiomer B)
l'-(2 -hydroxy ethyl)-3-[7-(trifluoromethyl)imidazo[l, 5-
Compound 40 a]pyridin-5-yl]-3-azaspiro[bicyclo[3.2.1]octane-8,4'- imidazolidine]-2',5'-dione
2-{3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-
Compound 41A
azabicyclo[3.2.1]octan-8-yl}acetamide (Enantiomer A)
2-{3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-3-
Compound 41B
azabicyclo[3.2.1]octan-8-yl}acetamide (Enantiomer B)
3 -[7-(trifluoromethy l)imidazo [ 1 ,5 -c]pyrimidin-5 -yl] -3 -
Compound 42
azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
6,6-dimethyl-8-[2-(trifluoromethyl)imidazo[l,5-a]pyrimidin-4-
Compound 43
yl]-l,3,8-triazaspiro[4.5]decane-2,4-dione
6,6-dimethyl-8-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 44
yl] - 1 ,3,8-triazaspiro[4.5] decan-2-one
2-{2',5'-dioxo-3-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 45 yl] -3-azaspiro [bicy clo [3.2.1 ] octane-8,4'-imidazolidine] - 1 '- yl}acetamide
l'-(propa-l,2-dien-l-yl)-3-[7-(trifluoromethyl)imidazo[l,5-
Compound 46 a]pyridin-5-yl]-3-azaspiro[bicyclo[3.2.1]octane-8,4'- imidazolidine]-2',5'-dione
1 '-(prop-2-yn- 1 -y l)-3 -[7-(trifluoromethy l)imidazo[ 1 ,5 -
Compound 47 a]pyridin-5-yl]-3-azaspiro[bicyclo[3.2.1]octane-8,4'- imidazolidine]-2',5'-dione
r-[(lH-l,2,3-triazol-4-yl)methyl]-3-[7-
Compound 48 (trifluoromethy l)imidazo [ 1 ,5-a] py ridin-5 -yl] -3 - azaspiro[bicyclo[3.2.1]octane-8,4'-imidazolidine]-2',5'-dione
6-fluoro-6-(trifluoromethyl)-8-[7-
Compound 49 (trifluoromethyl)imidazo[l,5-a]pyridin-5-yl]-l,3,8- triazaspiro [4.5] decane-2,4-dione
9,9-dimethyl-7-[7-(trifluoromethyl)imidazo[l,5-a]pyridin-5-
Compound 50
yl]-l,3,7-triazaspiro[4.4]nonane-2,4-dione
6-fluoro-6-methyl-8-[7-(trifluoromethyl)imidazo[l,5-
Compound 51
a]pyridin-5 -y 1] - 1 ,3 , 8-triazaspiro[4.5] decane-2,4-dione and the pharmaceutically acceptable salts or prodrugs thereof.
30. The compound of claim 29, selected from the group consisting of Compound 1A, Compound 2, Compound 3, Compound 4, Compound 6, Compound 8, Compound 12, Compound 18B, Compound 19, Compound 23, Compound 25, Compound 27, Compound 27A, Compound 28, Compound 29, Compound 39A, Compound 39B, Compound 40, Compound 4 IB, Compound 42, Compound 44, Compound 46, Compound 47, Compound 49, and Compound 51; and the pharmaceutically acceptable salts or prodrugs thereof.
31. The compound of any one of claims 1 to 30, wherein said compound has an inhibitory activity (measured as IC50 value) against IDOl of less than 300 nM.
32. The compound of any one of the claims 1 to 31, wherein said compound is selective for IDOl over TDO by a value of at least 10 times.
33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32 and at least one pharmaceutically acceptable excipient.
34. The pharmaceutical composition of claim 33 comprising a further active agent selected from the group consisting of chemotherapeutic agents and immunotherapeutic agents.
35. A compound according to any one of claims 1 to 32, or a pharmaceutical composition according to claim 33 or claim 34, for use in therapy.
36. A method for treating an IDOl, ID02 and/or TDO mediated condition in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 32.
37. The method of claim 36, wherein the IDOl, ID02 and/or TDO mediated condition is selected from a cancer; a neurological or neuropsychological disease or disorder; an autoimmune disease or disorder; an infection; a cataract; and a vascular disease.
38. The method of claim 36 or claim 37, wherein the IDOl, ID02 and/or TDO mediated condition is characterised by the overexpression of IDOl, ID02 and/or TDO, respectively.
39. The method of any one of claims 36 to 38, wherein the IDOl, ID02 and/or TDO mediated condition is a cancer is selected from head and neck cancer, breast cancer (e.g. metastatic breast cancer), prostate cancer (e.g. metastatic prostate cancer), ovarian cancer, endometrial cancer, colon cancer, lung cancer (e.g. non-small cell lung cancer), bladder cancer, pancreatic cancer (e.g. metastatic pancreatic cancer), brain tumour (e.g. primary malignant brain tumour), gynecological cancer, peritoneal cancer, skin cancer, thyroid cancer, oesophageal cancer, cervical cancer, gastric cancer, liver cancer, stomach cancer, renal cell cancer, biliary tract cancer, hematologic cancer, and blood cancer.
40. The method of claim 39, wherein the cancer is associated with low levels of L-TRP and/or the cancer is associated with high levels of L-TRP metabolites.
41. The method of any one of claims 36 to 40, wherein the IDOl, ID02 and/or TDO mediated condition is a cancer, and wherein the method comprises administering said compound in combination with another therapeutic intervention for said cancer.
42. The method of claim 41, wherein said another therapeutic intervention is immunotherapy, radiation therapy and/or chemotherapy.
43. The method of any one of claims 39 to 42, for treating a subject diagnosed as having a cancer or being at risk of developing a cancer.
44. The method of any one of claims 36 to 38, wherein the IDOl, ID02 and/or TDO mediated condition is a neurological disease or disorder selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, Parkinson's disease, and HIV-associated neurological disorders (HAND).
45. The method of any one of claims 36 to 38, wherein the IDOl, ID02 and/or TDO mediated condition is a neuropsychological disease or disorder selected from schizophrenia, anorexia, depression, and anxiety.
46. The method of any one of claims 36 to 38, wherein the IDOl, ID02 and/or TDO mediated condition is an autoimmune disease or disorder selected from arthritis, rheumatoid arthritis, and multiple sclerosis.
47. The method of any one of claims 36 to 38, wherein the IDOl, ID02 and/or TDO mediated condition is an infection selected from influenza virus infection, peritonitis, sepsis, chlamydia trachomatis infection, and human immunodeficiency virus (HIV).
48. The method of any one of claims 36 to 38, wherein the IDOl, ID02 and/or TDO mediated condition is a cataract.
49. The method of any one of claims 36 to 38, wherein the IDOl, ID02 and/or TDO mediated condition is a cardiovascular disease.
50. A compound according to any one of claims 1 to 32, for use in a method as defined in any one of claims 36 to 49.
51. Use of a compound according to any one of claims 1 to 32 in the manufacture of a medicament for use in a method as defined in any one of claims 36 to 49.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109053693A (en) * 2018-09-20 2018-12-21 周银平 The preparation and its application of pyridazine aminated compounds
WO2019034725A1 (en) 2017-08-17 2019-02-21 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
WO2019138107A1 (en) 2018-01-15 2019-07-18 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
WO2021005222A1 (en) 2019-07-11 2021-01-14 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
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
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
WO2023118011A1 (en) 2021-12-22 2023-06-29 Syngenta Crop Protection Ag Microbiocidal aza-heterobiaryl derivatives

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070078156A1 (en) * 2003-09-19 2007-04-05 Fletcher Stephen R Derivatives of n-(1h-indazolyl)-and n-(1h-indolyl)-urea as well as related compounds as modulators of the vanilloid-1 receptor (vr1) for treatment of pain

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070078156A1 (en) * 2003-09-19 2007-04-05 Fletcher Stephen R Derivatives of n-(1h-indazolyl)-and n-(1h-indolyl)-urea as well as related compounds as modulators of the vanilloid-1 receptor (vr1) for treatment of pain

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM 6 January 2011 (2011-01-06), XP055505594, Database accession no. 103905401 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2019034725A1 (en) 2017-08-17 2019-02-21 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
US11267824B2 (en) 2017-08-17 2022-03-08 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
WO2019138107A1 (en) 2018-01-15 2019-07-18 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
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
CN109053693A (en) * 2018-09-20 2018-12-21 周银平 The preparation and its application of pyridazine aminated compounds
WO2021005222A1 (en) 2019-07-11 2021-01-14 Idorsia Pharmaceuticals Ltd Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
WO2023118011A1 (en) 2021-12-22 2023-06-29 Syngenta Crop Protection Ag Microbiocidal aza-heterobiaryl derivatives

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