WO2017034420A1 - Inhibitors of tryptophan dioxygenases (ido1 and tdo) and their use in therapy - Google Patents

Inhibitors of tryptophan dioxygenases (ido1 and tdo) and their use in therapy Download PDF

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Publication number
WO2017034420A1
WO2017034420A1 PCT/NZ2016/050135 NZ2016050135W WO2017034420A1 WO 2017034420 A1 WO2017034420 A1 WO 2017034420A1 NZ 2016050135 W NZ2016050135 W NZ 2016050135W WO 2017034420 A1 WO2017034420 A1 WO 2017034420A1
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Prior art keywords
optionally substituted
alkyl
group
independently selected
aryl
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PCT/NZ2016/050135
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French (fr)
Inventor
Brian Desmond Palmer
Lai-Ming Ching
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Auckland Uniservices Limited
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Publication date
Priority to CA2996681A priority Critical patent/CA2996681C/en
Priority to EP16839685.1A priority patent/EP3350188B1/en
Priority to JP2018511057A priority patent/JP7334041B2/en
Priority to CN201680063267.2A priority patent/CN108349997A/en
Priority to KR1020187008532A priority patent/KR20180048798A/en
Priority to US15/755,750 priority patent/US11414428B2/en
Application filed by Auckland Uniservices Limited filed Critical Auckland Uniservices Limited
Priority to AU2016312848A priority patent/AU2016312848A1/en
Publication of WO2017034420A1 publication Critical patent/WO2017034420A1/en
Priority to HK19101029.2A priority patent/HK1258665A1/en
Priority to AU2021212003A priority patent/AU2021212003B2/en
Priority to JP2021182007A priority patent/JP2022033753A/en
Priority to US17/888,281 priority patent/US20220411438A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed 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
    • A61K31/4353—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to 3-aminoisoxazolopyridines, to pharmaceutical compositions containing them and their use as medicaments, and more particularly to their use in cancer therapy, either alone or in combination with other agents, such as anti-cancer vaccines, other types of immunomodulatory therapies, radiation and other chemotherapeutic agents.
  • Indoleamine 2,3-dioxygenase 1 catalyses the first and rate limiting step of tryptophan conversion to kynurenine, and is expressed in a broad range of cancers to suppress the immune system (Uyttenhove et al., J. Nat. Med. 2003, 9, 1269). High IDOl expression in clinical tumours has been shown to correlate with poor patient prognosis in a wide range of cancers including lung, colorectal, breast, melanoma and gynecologic cancers.
  • Blocking downstream signalling of the IDOl enzyme with small molecule inhibitors also has the potential to synergise with other immunomodulatory approaches, such as anti-cancer vaccine administration, modulation of immune checkpoint proteins (such as CTLA4 and the PDl-4s) and the use of adoptive T-cell therapies (such as CART cells) (Mautina et al., Proceedings of the AACR Annual Meeting, 2014, Poster 5023).
  • immunomodulatory approaches such as anti-cancer vaccine administration, modulation of immune checkpoint proteins (such as CTLA4 and the PDl-4s) and the use of adoptive T-cell therapies (such as CART cells)
  • CART cells adoptive T-cell therapies
  • TDO Tryptophan 2,3-dioxygenase
  • TDO inhibitors may also have wide rangi ng therapeutic efficacy i n the treatment of cancer and other conditions.
  • the present invention provides a pharmaceutical composition comprising :
  • W is CR 1 , N or N-oxide
  • X is CR 2 , N or N-oxide
  • Y is CR 3 , N or N-oxide
  • Z is CR 4 , N or N-oxide
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the following groups : H, halo, R, -OH, -OR, -OC(0)H, -OC(0)R, -OC(0)NH 2 , -OC(0)NHR, -OC(0)NRR,-
  • R 1 and R 2 taken together, or R 2 and R 3 taken together, or R 3 and R 4 taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6- membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from 0, N and S, and the ring is optionally substituted independently with 1 to 4
  • each R is independently selected from any of the groups defined in
  • R 9 and R 10 are each independently selected from any of the g roups defined in paragraphs (a) to (d) below, with the proviso that at least one of R 9 and R 10 is selected from any of the groups defined in paragraphs (c) and (d) below:
  • each R 14 , R 15 and R 16 is independently selected from the group consisting of H, optionally substituted Ci-6 alkyi, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-7 cyclic alkyi, optionally substituted aryl, and optionally substituted heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S, and wherein the one or more optional substituents for each of said alkyi, alkenyl, alkynyl, cyclic alkyi, aryl and heteroaryl for R 14 , R 15 and R 16 are each independently selected
  • each R is independently selected from the groups defined above for R, and R 17 is optionally substituted aryl or optionally substituted heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S, and wherein the one or more optional substituents for each of said aryl and heteroaryl are independently selected from the same optional substituents as those defined in (a) above for R 9 and R 10 ; and -SO2R 18 , wherein R 18 is optionally substituted Ci ealkyl or optionally substituted C3-7 cyclic alkyi, wherein the one or more optional substituents for each of said alkyi and cyclic alkyi are each independently selected from those defined in (a) above for R 9 and R 10 ; and a pharmaceutically acceptable carrier.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in medicine.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a warm blooded animal, including a human.
  • the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament.
  • the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a warm blooded animal, including a human.
  • the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a warm blooded animal, including a human, wherein the treatment comprises administration of the compound of Formula I and one or more additional agents selected from the group consisting of chemotherapeutic agents, immune-modulating agents such as anti-cancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)), and radiotherapy, and wherein the additional agent is administered either before, during or after administration of the compound of Formula I.
  • the additional agent comprises an immune-modulating agent.
  • the invention provides a method of treating cancer in a warm blooded animal, including a human, comprising administering to the animal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of treating cancer in a warm blooded animal, including a human, wherein the method comprises
  • the method further includes the step of administering one or more additional agents selected from the group consisting of chemotherapeutic agents, immune-modulating agents such as anti-cancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)), and radiotherapy, and wherein the additional agent is administered either before, during or after administration of the compound of Formula I.
  • the additional agent comprises an immune-modulating agent.
  • the invention provides a method of inhibiting indoleamine 2,3-dioxygenase 1 (IDOl) in a warm blooded animal in need thereof, including a human, comprising administering to the animal a compound of Formula I or a pharmaceutically acceptable salt thereof having IDOl inhibitory activity, in an amount effective to inhibit IDOl .
  • IDOl indoleamine 2,3-dioxygenase 1
  • the invention provides a method of inhibiting
  • tryptophan2,3-dioxygenase in a warm blooded animal in need thereof, including a human, comprising administering to the animal a compound of Formula I or a pharmaceutically acceptable salt thereof, having TDO inhibitory activity, in an amount effective to inhibit TDO.
  • the invention provides a method of inhibiting IDOl and TDO in a warm blooded animal in need thereof, including a human, comprising administering to the animal a compound of Formula I or a pharmaceutically acceptable salt thereof having both IDOl and TDO inhibitory activity, in an amount effective to inhibit IDOl and TDO.
  • the invention provides a pharmaceutical combination or kit, comprising
  • chemotherapeutic agents include anti-cancer vaccines, modulators of immune checkpoint proteins and adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)).
  • immune-modulating agents such as anti-cancer vaccines, modulators of immune checkpoint proteins and adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)).
  • the invention provides a pharmaceutical combination or kit, for use in treating cancer, comprising
  • chemotherapeutic agents selected from the group consisting of chemotherapeutic agents, and immune-modulating agents such as anticancer vaccines, modulators of immune checkpoint proteins and adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)).
  • immune-modulating agents such as anticancer vaccines, modulators of immune checkpoint proteins and adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)).
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating a condition or disorder selected from the group consisting of: an inflammatory condition, an infectious disease, a central nervous system disease or disorder, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, a condition or disorder relating to female reproductive health, and cataracts.
  • a condition or disorder selected from the group consisting of: an inflammatory condition, an infectious disease, a central nervous system disease or disorder, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, a condition or disorder relating to female reproductive health, and cataracts.
  • the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a condition or disorder selected from the group consisting of: an inflammatory condition, an infectious disease, a central nervous system disease or disorder, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, a condition or disorder relating to female reproductive health, and cataracts.
  • a condition or disorder selected from the group consisting of: an inflammatory condition, an infectious disease, a central nervous system disease or disorder, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, a condition or disorder relating to female reproductive health, and cataracts.
  • the invention provides a method of treating a condition or disorder selected from the group consisting of: an inflammatory condition, an infectious disease, a central nervous system disease or disorder, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, a condition or disorder relating to female reproductive health, and cataracts, in a warm blooded animal, including a human, wherein the method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, halo, optionally substituted C1-C6 alkyl, -O-R wherein R is optionally substituted C1-C6 alkyl, an optionally substituted aryl, such as substituted phenyl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, halo, optionally substituted C1-C6 alkyl, -O-R wherein R is selected from optionally substituted C1-C6 alkyl and optionally substituted aryl (such as phenyl), -NHR wherein R is optionally substituted aryl, an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, halogen, -CF 3 , -CH F2, -OCF3, -OCH F2, Ci-e alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally
  • R 1 , R 2 , R 3 and R 4 where present, is H, and the others of R 1 , R 2 R 3 and R 4 that are not H are independently selected from the group consisting of halogen, - CF 3 , -CH F2, -OCF3, -OCH F2, Ci-e alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
  • each of R 2 and R 3 that is other than H is independently selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, -OR wherein R is selected from optionally substituted C1-C6 alkyl and optionally substituted aryl, -NHR wherein R is optionally substituted aryl; an optionally substituted aryl, such as substituted phenyl, and an optionally substituted heteroaryl group.
  • each of R 2 and R 3 that is other than H is independently selected from the group consisting of halogen, -CF3, -CH F2, -OCF3, -OCH F2, Ci-6 alkyi such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and - NHR wherein R is optionally substituted aryl.
  • R 9 and R 10 are selected from the group consisting of H and optionally substituted Ci-6 alkyi (such as C1-3 alkyi), for example, one of R 9 and R 10 is H, and the other of R 9 and R 10 is selected from any of the groups defined in (c) and (d).
  • R 9 and R 10 are selected from the group consisting of H and optionally substituted Ci-6 alkyi (such as C1-3 alkyi), and the other of R 9 and R 10 is selected from the group consisting of -C(0)R 14 , -C(0)OR 14 , -C(S)R 14 , and - C(S)OR 14 ; wherein each R 14 is independently selected from the group consisting of: (a) optionally substituted Ci-6 alkyi, for example Ci-6 alkyi wherein said alkyi is substituted by aryl and optionally one or two further substituents, and wherein said aryl is itself optionally substituted, and (b) optionally substituted aryl.
  • each R 14 is optionally substituted alkyi having the formula -(CH2) n (aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
  • R 9 and R 10 are selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R 9 and R 10 is -C(0)OR 14 .
  • R 9 and R 10 are selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R 9 and R 10 is selected from the group consisting of -C(0)NR 15 R 16 and -C(S)NR 15 R 16 , wherein each R 15 and R 16 is independently selected from the group consisting of (a) H, (b) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and, optionally, one or two further substituents, and wherein said aryl is itself optionally substituted, and (c) optionally substituted aryl.
  • each R 15 and R 16 is independently selected from the group consisting of (a) H and (b) optionally substituted alkyl having the formula -(CH2) n (aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
  • each R 14 is independently selected from the group consisting of: (a) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and, optionally, one or two further substituents, and wherein said aryl is itself optionally substituted, and (b) optionally substituted aryl.
  • R 14 is optionally substituted alkyl having the formula -(CH2) n (aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of H, halogen, -CF3, -CH F2, -OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and - NHR wherein R is optionally substituted aryl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of H, halogen, Ci-6 alkyl, such as methyl, substituted aryl, and substituted
  • R 1 , R 2 and R 3 are H, and the others of R 1 , R 2 and R 3 that are not H are independently selected from the g roup consisting of halogen, -CF3, -CH F2, - OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted
  • heteroaryl -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl .
  • R 1 is H
  • R 2 and R 3 is other than H
  • each of R 2 and R 3 that is not H is independently selected from the group consisting of halogen, -CF3, - CH F2, -OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl .
  • R 3 is selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl .
  • a compound of Formula I as defined in any one of paragraphs ( 1) to (30) above, or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 , R 2 , R 3 and R 4 , where present, is other than H or methyl, for example wherein at least one of R 1 , R 2 , R 3 and R 4 , where present, is other than H or alkyl, and with the proviso that the compound is not selected from the following compounds:
  • Certain compounds of the Formula I are novel . Accordingly, such compounds are provided as a further feature of the invention.
  • the invention provides a compound of Formula I, as defined in any one of paragraphs ( 1) to (30) above, or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 , R 2 , R 3 and R 4 , where present, is other than H or methyl, for example wherein at least one of R 1 , R 2 , R 3 and R 4 , where present, is other than H or alkyl, and with the proviso that the compound is not selected from the following compounds:
  • the invention provides a compound of Formula I, as defined in any of the paragraphs numbered (35) to (63) below.
  • W is CR 1 , N or N-oxide
  • X is CR 2 , N or N-oxide
  • Y is CR 3 , N or N-oxide
  • Z is CR 4 , N or N-oxide
  • R 1 and R 2 taken together, or R 2 and R 3 taken together, or R 3 and R 4 taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6- membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from 0, N and S, and the ring is optionally substituted independently with 1 to 4
  • each R is independently selected from any of the groups defined in
  • R 9 and R 10 are each independently selected from any of the groups defined in paragraphs (a) to (d) below, with the proviso that at least one of R 9 and R 10 is selected from any of the groups defined in paragraphs (c) and (d) below:
  • each R 14 , R 15 and R 16 is independently selected from the group consisting of H, optionally substituted Ci-6 alkyi, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-7 cyclic alkyi, optionally substituted aryl, and optionally substituted heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S, and wherein the one or more optional substituents for each of said alkyi, alkenyl, alkynyl, cyclic alkyi, aryl and heteroaryl for R 14 , R 15 and R 16 are each independently selected
  • each R is independently selected from the groups defined above for R, and R 17 is optionally substituted aryl or optionally substituted heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S, and wherein the one or more optional substituents for each of said aryl and heteroaryl are independently selected from the same optional substituents as those defined in (a) above for R 9 and R 10 ; and -SO2R 18 , wherein R 18 is optionally substituted Ci ealkyl or optionally substituted C3-7 cyclic alkyi, wherein the one or more optional substituents for each of said alkyi and cyclic alkyi are each independently selected from those defined in (a) above for R 9 and R 10 ; with the proviso that at least one of R 1 , R 2 , R 3 and R 4 , where present, is other
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, halo, optionally substituted C1-C6 alkyl, -O-R wherein R is selected from optionally substituted C1-C6 alkyl and optionally substituted aryl (such as phenyl), - N H R wherein R is optionally substituted aryl, an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S .
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, halogen, - CF3, -CH F2, -OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl.
  • R 1 , R 2 , R 3 and R 4 where present, is H, and the others of R 1 , R 2 , R 3 and R 4 that are not H are independently selected from the group consisting of halogen, -CF3, -CH F2, -OCF3, - OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl. (42).
  • R 3 is present and selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl.
  • Z is N or N-oxide, such as N
  • W is CR 1
  • X is CR 2 and Y is CR 3
  • R 3 is selected from the group consisting of halogen, -O-R wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl.
  • each of R 2 and R 3 that is other than H is independently selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, -OR wherein R is selected from optionally substituted C1-C6 alkyl and optionally substituted aryl, -N H R wherein R is optionally substituted aryl; an optionally substituted aryl, such as substituted phenyl, and an optionally substituted heteroaryl group.
  • each of R 2 and R 3 that is other than H is independently selected from the group consisting of halogen, -CF3, - CH F2, -OCF3, -OCH F2, Ci-6 alkyl such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl.
  • R 9 and R 10 are selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), for example one of one of R 9 and R 10 is H, and the other of R 9 and R 10 is selected from any of the groups defined in paragraphs (c) and (d).
  • R 9 and R 10 are selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R 9 and R 10 is selected from the group consisting of -C(0)R 14 , -C(0)OR 14 , -C(S)R 14 , and -C(S)OR 14 ; wherein each R 14 is independently selected from the group consisting of: (a) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and optionally one or two further substituents, and wherein said aryl is itself optionally substituted, and (b) optionally substituted aryl.
  • each R 14 is optionally substituted alkyl having the formula -(CH2) n (aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
  • R 9 and R 10 are selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R 9 and R 10 is selected from the group consisting of -C(0)NR 15 R 16 and -C(S)NR 15 R 16 , wherein each R 15 and R 16 is
  • each R 15 and R 16 is independently selected from the group consisting of (a) H and (b) optionally substituted alkyl having the formula -(CH2) n (aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted .
  • R 1 , R 2 and R 3 are each independently selected from the g roup consisting of H, halogen, -CF3, -CH F2, - OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl .
  • R 1 , R 2 and R 3 are each independently selected from the g roup consisting of H, halogen, Ci-6 alkyl, such as methyl, substituted aryl, and substituted heteroaryl .
  • Ci-6 alkyl such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
  • R 3 is selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
  • the invention further provides a compound of Formula I selected from the following:
  • Phenyl (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)carbamate (4) l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3- (trifluoromethyl)phenyl)urea (15)
  • Other aspects of the invention may include suitable combinations of embodiments disclosed herein. Also, as will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention.
  • radiotherapy means the use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body near cancer cells (internal radiation therapy). Systemic radiotherapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that travels in the blood to tissues throughout the body. The terms irradiation and radiation therapy have the same meaning. It is to be recognised that certain compounds of the present invention may exist in one or more different enantiomeric or diastereomeric forms. It is to be understood that the enantiomeric or diastereomeric forms are included in the above aspects of the invention.
  • halo or halogen group used throughout the specification is to be taken as meaning a fluoro, chloro, bromo or iodo group.
  • variables of the Formula I as defined above are optionally substituted by one or more imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl groups that the linkage to the relevant variable may be through either one of the available nitrogen or carbon ring atoms of these groups.
  • heteroaryl includes both monocyclic and bicyclic ring systems, unless the context requires otherwise.
  • aryl means an aromatic hydrocarbon such as phenyl or naphthyl.
  • C1-C6 alkyl or C2-C6 alkenyl group these groups may be unbranched or branched.
  • reference to a C1-C6 alkyl would include a tert-butyl (Me)3C- group.
  • treating cancer and 'treatment of cancer include methods that produce one or more anti-cancer effects which include, but are not limited to, anti-tumor effects, the response rate, the time to disease progression and the overall survival rate.
  • Anti-tumor effects include but are not limited to inhibition of tumor growth, tumor growth delay, regression of tumor, shrinkage of tumor, increased time to regrowth of tumor on cessation of treatment and slowing of disease progression.
  • “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a cancer, is sufficient to effect such treatment for the cancer.
  • the “effective amount” will vary depending on the cancer to be treated, the compound to be administered, the severity of the cancer treated, the age and relative health of the subject, the route and form of administration, whether the treatment is monotherapy or combination therapy, the judgement of the attending clinician, and other factors.
  • “Pharmaceutically acceptable” means: that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include:
  • hydrochloric acid hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid and the like; and
  • a metal ion e.g . an alkali metal ion, an alkaline earth ion, or an aluminium ion
  • Acceptable organic bases include ethanolamine, diethanolamine, N- methylglucamine, triethanolamine and the like.
  • Acceptable inorganic bases include aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • Warm blooded animal means any member of the mammalia class including, but not limited to humans, non-human primates such as chimpanzees and other apes and monkey species, farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the invention relates to pharmaceutical compositions containing compounds of the general Formula I, and the use of such compounds in therapy, and in particular cancer therapy.
  • Compounds of Formula I have been found to be inhibitors of indoleamine 2,3-dioxygenase 1 (IDOl) and/or tryptophan2,3-dioxygenase (TDO) .
  • the compounds of the present invention are expected to be useful in cancer therapy, either alone or in combination with other agents, such as anti-cancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)), radiation therapy and other chemotherapeutic agents.
  • the compounds of Formula I are also expected to be useful in the treatment of various other conditions besides cancer, as described in more detail in the Therapeutic Methods of the
  • Methods 1 to 8 below describe the preparation of precursor 3-amino compounds, which can be used as starting materials to prepare compounds of the formula I of the present invention, using the processes described in Methods 9 to 11 below, or using analogous processes.
  • Certain precursor 3-amino compounds may be prepared by reaction of an appropriately substituted halo-cyano pyridine with acetohydroxamic acid, in the presence of a base such as potassium tertr-butoxide, potassium carbonate or cesium carbonate (Method 1).
  • a base such as potassium tertr-butoxide, potassium carbonate or cesium carbonate (Method 1).
  • a range of solvents may be used for this reaction, including DMF, p-dioxane and /V-methylmorpholine.
  • Compounds bearing alkylamino substituents and/or arylamino substituents may be prepared by displacement of an activated halogen atom with amines and/or anilines (Method 2).
  • Such compounds may also be prepared by reaction of the primary amine wi an alkyl aldehyde, followed by a reducing agent such as sodium cyanoborohydhde, i a reductive amination process (Method 4).
  • Compounds bearing a pendant aryl or heteroaryl (Het) substituent may be prepared by reaction of an appropriately substituted halogen- or triflate-containing substrate with suitable aryl or heteroaryl boronic acids or esters, under palladium catalysis, in a Suzuki coupling reaction (Method 5).
  • Compounds bearing a pendant aryl or heteroaryl (Het) substituent may also be prepared by performing a palladium-catalysed Suzuki coupling reaction with an appropriately substituted halogen or O-triflate containing chemical intermediate, and suitable aryl or heteroaryl boronic acids or esters, followed by elaboration of the resultant aryl- or heteroarylated product to the final product (Method 6).
  • Method 6 hal
  • Compounds containing alkyl and/or aryl ether-linked substituents may be prepared by displacement of an activated halogen atom by alcohols and/or phenols, in the presence of a base such as sodium or sodium hydride or cesium carbonate (Method 7).
  • Compounds containing thioalkyi and/or thioaryl ether-linked substituents may be prepared by displacement of an activated halogen atom by thiols and/or thiophenols, in the presence of a base such as sodium or sodium hydride or cesium carbonate, or by direct reaction with the metal salt of a thiol or thiophenol.
  • the resultant thioalkyi or thiophenol derivatives may be oxidised to their corresponding sulfoxide or sulfone derivatives with suitable oxidising reagents such as hydrogen peroxide, peracids, metal complexes and oxaziridines (Method 8).
  • Compounds of Formula I according to the present invention containing urea functionality at the 3-position of the isoxazoiopyridine ring system, can be prepared by reaction of the corresponding 3-amino compound with an alkyl, aryl or heteroaryl isocyanate. In some instances the reaction can be mediated by the addition of a suitable catalyst, such as dibutyltin oxide (Method 9).
  • a suitable catalyst such as dibutyltin oxide (Method 9).
  • the corresponding thioureas may be similarly prepared by reacting the 3-aminoisoxazolopyridine with analogous isothiocyanates.
  • Compounds of Formula I according to the present invention containing carbamate functionality at the 3-position of the isoxazoiopyridine ring system, can be prepared by reaction of the corresponding 3-amino compound with an alkyl, aryl or heteroaryl chloroformate in the presence of a base, such as Et3N, pyridine, K2CO3 and the like (Method 10).
  • a base such as Et3N, pyridine, K2CO3 and the like
  • the corresponding thiocarbamates may be similarly prepared by reacting the 3-aminoisoxazolopyridine with analogous chlorothioformates.
  • the carbamates and thiocarbamates so-produced may further be used to prepare compounds containing urea and thiourea functionality, respectively at the 3-position of the isoxazoiopyridine ring system, by their reaction with alkyl amines, substituted anilines, or amino- substituted heterocycles (Method 10) .
  • the carbamates and thiocarbamates so- produced may also be reacted with alkyl thiols, substituted thiophenols and
  • Compounds of Formula I according to the present invention containing amide functionality at the 3-position of the isoxazoiopyridine ring system, may be prepared by reaction of an alkyl, or aryl, or heterocyclic carboxylic acid with an activating reagent such as thionyl chloride, ⁇ /,/V-carbonyldiinnidazole, EDCI and the like, followed by reaction of the resulting species with the 3-aminoisoxazolopyridine.
  • an activating reagent such as thionyl chloride, ⁇ /,/V-carbonyldiinnidazole, EDCI and the like
  • a base such as NaH, Et3N, pyridine, K2CO3 and the like may be used in both reaction steps, and a catalyst such as 4-/V / /V-(dimethylamino)pyridine may be used in the final coupling reaction (Method 11).
  • the amides so-produced may be converted into corresponding thioamides by thiiation with a suitable reagent, such as P4S10 or Lawesson's reagent, in a suitable solvent such as pyridine, tertrahydrofuran, benzene and the like.
  • Compounds of Formula I according to the present invention containing sulfonamide functionality at the 3-position of the isoxazoiopyridine ring system, can be prepared by reaction of the corresponding 3-amino compound with an alkyl, aryl or heteroaryl sulfonyl chloride in the presence of a base, such as EtjN, pyridine, K2CO3 and the like (Method 12).
  • a base such as EtjN, pyridine, K2CO3 and the like
  • Methods 9 to 12 can also be carried out on isoxazolopyridines where a mono-alkylamino group, or a mono-arylamino group, or a mono- heteroarylamino group has been introduced at the 3-position by the procedures, for example, of Methods 3 and 4, to give N-alkylated, N-arylated and N-heteroarylated derivatives of the 3-position amides, thioamides, carbamates, thiocarbamates, ureas, thioureas, dithiocarbamates and sulfonamides.
  • the compounds of Formula I of the invention may be inhibitors of IDOl or TDO, or both IDOl and TDO.
  • Compounds that are inhibitors of either IDOl or TDO, and compounds that are dual inhibitors of IDOl and TDO, are expected to be useful in cancer therapy. Accordingly, in certain embodiments, the present invention provides methods of treating cancer in warm blooded animals, including humans, by
  • the compounds of formula I are expected to be useful in restoring tumor immunity in cancer patients.
  • the compounds of the invention may be useful either alone, or in combination with other cancer therapies, including chemotherapeutic agents, radiation and/or immune modulating agents.
  • Immune modulating agents include, without limitation, anti-cancer vaccines, agents that modulate immune checkpoint proteins (such as CTLA4 and the PDl-4s, LAG3 and TIM3) and adoptive T-cell therapies (such as CARTs). Accordingly, the compound of Formula I can be administered either alone or in combination with one or more other such therapies, either simultaneously or sequentially dependent upon the particular condition to be treated.
  • the compound of Formula I may be administered in combination with one or more immunotherapies selected from Ipilimumab,
  • Tremelimumab both inhibitors of CTLA4
  • Nivolumab also known as Lambrolizumab
  • Pidilizumab all inhibitors of PD-1).
  • chemotherapeutic agents that can be administered in combination with a compound of Formula I include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 14 th Edition of the Merck Index (2006), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, proc
  • Additional anti-proliferative agents that can be administered in combination with a compound of Formula I include but are not limited to BCNU, CCNU, DTIC, and actinomycin D. Still further anti-proliferative agents include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Eleventh Edition), editor Molinoff et al., publ.
  • Additional anti-proliferative agents that can be administered in combination with a compound of Formula I include but are not limited to other molecular targeted agents, which block the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumour growth.
  • examples include small molecule protein and lipid kinase inhibitors, monoclonal antibodies, molecularly targeted humanised monoclonal antibodies and monoclonal antibody drug conjugates. Examples of such inhibitors include: Rituximab, Trastuzumab, Alemtuzumab,
  • cancers that may be treated in accordance with the present invention include but are not limited to: colorectal cancer, cancers of the breast, melanoma, reproductive organs, respiratory tract, brain, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophthalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallblader, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant),
  • cholangiocarcinoma intrahepatic bile duct carcinoma
  • mixed hepatocellular cholangiocarcinoma mixed hepatocellular cholangiocarcinoma
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to
  • Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. These disorders have been well characterized in man, but also exist with a similar etiology in other warm-blooded animals, and can be treated by the compounds of the present invention.
  • Therapeutic dosages will likely be in the range of 1 mg to 30 g per day.
  • the specific dose level selected for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy.
  • the invention provides a method of inhibiting IDOl and ID02 in a a warm blooded animal in need thereof, including a human, comprising administering to the animal a compound of Formula I or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit IDOl and ID02.
  • IDOl and ID02 inhibitors of IDO
  • TDO TDO
  • compounds that are inhibitors of IDO (IDOl and ID02) and/or TDO may have efficacy not only in the treatment of cancer, but also in the treatment of a range of other diseases or conditions, for example as discussed in PCT International Publication WO 2015/082499 and the references to scientific literature referred to therein, all of which are incorporated herein by reference.
  • such compounds may be useful in the treatment of inflammatory conditions, infectious diseases, central nervous system diseases or disorders, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, disease conditions or disorders relating to female reproductive health, and cataracts.
  • compounds of Formula I of the present invention may also be useful in the treatment of such diseases or conditions.
  • Formula I include conditions relating to immune B cell, T cell, dendritic cell, natural killer cell, macrophage, and /or neutrophil dysregulation.
  • infectious diseases that may be treated by compounds of Formula I include bacterial infections, viral infections such as gut infections, hepatitis C, sepsis, and sepsis induced hypotension.
  • central nervous system diseases or disorders that may be treated by compounds of Formula I include amyotrophic lateral sclerosis (AML), Huntington's disease, Alzheimer's disease, pain, psychiatric disorders including affective disorders such as depression, multiple sclerosis, Parkinson's disease, and HIV related
  • diseases or disorders relating to female reproductive health that may be treated by compounds of Formula I is endometriosis, and conditions relating to female reproductive health include contraception and abortion.
  • compositions of the invention are provided.
  • the invention includes pharmaceutical compositions including one or more compounds of Formula I of this invention, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser should be nontoxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration.
  • the compounds may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations.
  • administration by injection' includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques.
  • One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.
  • compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions.
  • Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • These compounds may also be prepared in solid, rapidly released form.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
  • the compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Pharmaceutical compositions of the invention may also be in the form of oil- in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • the compounds may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter and polyethylene glycols.
  • the prepared acyl chloride solution was added to a mixture of 1 (100 mg, 0.51 mmol, 1.0 eq ) and TEA (103 mg, 1.02 mmol, 2.0 eq) in THF (5 ml) at 0 °C, and the resulting mixture was stirred at RT overnight.
  • the reaction mixture was poured into water and extracted with EtOAc (25 ml_ x 3). The organic layers were combined and washed with saturated aqueous NaHCC solution and brine, then dried over Na2S04, filtered and concentrated . The residue was recrystallised from CH2CI2 to give the desired product.
  • Recombinant human IDOl (rhIDOl) was expressed and purified from cultures of EC538 strain of E. coli transformed with pREP4 and pQE9-IDO plasmid. Reaction mixes were set up in 384-well microplates containing 50 mM phosphate buffer, 10 mM ascorbic, 10 ⁇ methylene blue, 100 ⁇ g/mL catalase, 80 ⁇ TRP, 0.01% Tween 20 (v/v) mixed with rhIDOl (15 ⁇ _) at a final concentration of 9 nM in a total volume of 30 ⁇ _ assay medium.
  • Lewis Lung carcinoma cells transfected to express human IDOl (LLTC-hlDOl) or murine (LLTC-mlDOl) were cultured with test compounds at 37°C, 5% CO2 for 24 h.
  • Culture supernatant from each well was then transferred into a fresh, flat-bottomed 96-well plate, mixed with trichloroacetic acid (10% final concentration) and incubated for 20 min at 60°C. Plates were then centrifuged ( 10 min at 2500 g) and the supernatants were then transferred and mixed 1 : 1 with 4-(dimethylamino)benzaldehyde (20 mg/mL in acetic acid) in a new plate.
  • the absorbance of each well was read at 480 nm, and the concentration that inhibited 50% cellular enzyme activity was calculated.
  • the viability of the cells in each well in the same experiment was determined using the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colourimetric assay. After the removal of the supernatant for determination of IDOl inhibition, the cells were incubated with MTT (500 ⁇ g/mL) until crystal formation was observed. Plates were centrifuged for 15 min at 2500 g, and then all the supernatant in then wells was discarded. DMSO (100 ⁇ L/we ⁇ ) was added to dissolve the crystals and then the absorbance in each well was measured at 570 nm. Cell viability in each well was expressed as a percentage of untreated controls. Triplicate cultures were used for all experiments unless stated otherwise.
  • Activity IC 5 o ranges: A; ⁇ 1 ⁇ , B; 1-10 ⁇ , C; 10-100 ⁇ , D; > 100 ⁇ Cell-based assay for TDO inhibition
  • GL261 cells transfected to over- express full length human TDO were cultured with test compounds at 37°C, 5% CO2 for 24 h. Culture supernatant from each well was then transferred into a fresh, flat- bottomed 96-well plate, and kynurenine content was determined as described above for the IDOl assay, and the concentration that inhibited 50% cellular enzyme activity was calculated.
  • Activity IC50 ranges: A; ⁇ 1 ⁇ , B; 1-10 ⁇ , C; 10-100 ⁇ , D; > 100 ⁇

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Abstract

Pharmaceutical compositions comprising 3-aminoisoxazolopyridine compounds of the Formula I having IDO1 and/or TDO inhibitory activity are described, where W is CR1, N or N-oxide; X is CR2, N or N-oxide; Y is CR3, N or N-oxide; Z is CR4, N or N-oxide; and at least one of W, X, Y, and Z is N or N-oxide; and R9 and R10 are as defined. Also described are methods of using such compounds in the treatment of various conditions, such as cancer.

Description

INHIBITORS OF TRYPTOPHAN DIOXYGENASES (IDOl and TDO) AND THEIR USE IN THERAPY
TECHNICAL FIELD
The present invention relates to 3-aminoisoxazolopyridines, to pharmaceutical compositions containing them and their use as medicaments, and more particularly to their use in cancer therapy, either alone or in combination with other agents, such as anti-cancer vaccines, other types of immunomodulatory therapies, radiation and other chemotherapeutic agents.
BACKGROUND TO THE INVENTION
Indoleamine 2,3-dioxygenase 1 (IDOl) catalyses the first and rate limiting step of tryptophan conversion to kynurenine, and is expressed in a broad range of cancers to suppress the immune system (Uyttenhove et al., J. Nat. Med. 2003, 9, 1269). High IDOl expression in clinical tumours has been shown to correlate with poor patient prognosis in a wide range of cancers including lung, colorectal, breast, melanoma and gynecologic cancers. Silencing of the IDOl gene in a murine melanoma cell line resulted in reduced capacity of the cells to form tumours when implanted into mice (Zheng et a/., J. Immunol. 2006, 177, 5639), validating IDOl as a target for cancer intervention. A number of groups have pursued the development of small molecule inhibitors of IDOl as an approach for restoring tumour immunity in cancer patients. Such inhibitors should have potential to exhibit antitumour activity on their own, or in combination with other standard chemotherapies. Blocking downstream signalling of the IDOl enzyme with small molecule inhibitors also has the potential to synergise with other immunomodulatory approaches, such as anti-cancer vaccine administration, modulation of immune checkpoint proteins (such as CTLA4 and the PDl-4s) and the use of adoptive T-cell therapies (such as CART cells) (Mautina et al., Proceedings of the AACR Annual Meeting, 2014, Poster 5023). Early studies used derivatives of tryptophan such as 1-methyltryptophan (1-MT) as competitive inhibitors of IDOl (Cady and Sono, Arch. Biochem. Biophys. 1991, 291, 326) and provided proof of concept that IDOl would be an attractive target for pharmacological intervention of cancer (Hou et al. , Cancer Res. 2007, 614). Natural products, isolated from marine invertebrates, inhibit IDOl at considerably higher potencies than tryptophan derivatives. One of the most potent IDOl inhibitors that has been described to date, with activity at nM concentrations, is an exiguamine isolated from a marine sponge (Brastianos et al., J. Am. Chem. Soc, 2006, 128, 16046). Two annulins isolated from marine hydroids exhibited activity at nM concentrations, and stimulated a medicinal chemistry program that generated a series of IDO l inhibitory pyranonaphthoquinones with low nM potency (Pereira et al., J. Nat. Prod. 2006, 69, 1496; Kumar et al., J. Med. Chem. 2008, 51, 1706). High throughput screening of a compound library led to the discovery and optimisation of a structural class of hyd roxyamidine inhibitors of IDO l (Yue et al., J. Med. Chem. 2009, 52, 7364) . An optimised hydroxyamidine candidate with nM potency against the enzyme in cells and with oral bioavailability is currently in clinical trials (Newton et al., J Clin Oncol. 2012, 30, (SuppI ; abstract 2500)) . Another potent IDO inhibitor of the imidazoisoindole class is also currently in early stage clinical trials (Mautina et al., Proceedings of the AACR Annual Meeting, 2013) .
Tryptophan 2,3-dioxygenase (TDO) is another key enzyme in the tryptophan degradation pathway. TDO inhibitors may also have wide rangi ng therapeutic efficacy i n the treatment of cancer and other conditions.
It is an object of the present invention to provide 3-aminoisoxazolopyridine compounds and their use in medicine, for example in cancer therapy, or at least to provide the public with a useful choice.
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides a pharmaceutical composition comprising :
a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein :
10
Figure imgf000003_0001
I
W is CR1, N or N-oxide;
X is CR2, N or N-oxide;
Y is CR3, N or N-oxide;
Z is CR4, N or N-oxide;
and where at least one of W, X, Y, and Z is N or N-oxide;
R1, R2, R3 and R4 are each independently selected from the following groups : H, halo, R, -OH, -OR, -OC(0)H, -OC(0)R, -OC(0)NH2, -OC(0)NHR, -OC(0)NRR,-
OP(0)(OH)2, -OP(0)(OR)2, -NO2, -NH2, -NHR, -NRR, -N HC(0) H, -NHC(0)R, -NRC(0)R, -N HC(0) NH2, -NHC(0)N RR, -NRC(0)NHR, -SH, -SR, -S(0)H, -S(0)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -CN, -C≡CH, -C≡CR, -CH = CHR, -CH = CRR, -CR=CHR, -CR=CRR, -CO2H, -CO2R, -CHO, -C(0)R, -C(0)NH2, -C(0)NHR, - C(0)NRR, -CONHSO2H, -CONHSO2R, -CONRSO2R, cyclic C3-C7 alkylamino, imidazolyl, C1-C6 alkylpiperazinyl, morpholinyl and thiomorpholinyl;
or R1 and R2 taken together, or R2 and R3 taken together, or R3 and R4 taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6- membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from 0, N and S, and the ring is optionally substituted independently with 1 to 4
substituents selected from R;
each R is independently selected from any of the groups defined in
paragraphs (a) and (b) below:
(a) an optionally substituted Ci-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group and an optionally substituted C3-7 cyclic alkyl group; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and cyclic alkyl groups are each independently selected from the following groups: halo, -OH, -OR5, -OC(0)R5, -OC(0)NH2, -
OC(0)NHR5, -OC(0)NR5R5, -OP(0)(OH)2, -OP(0)(OR5)2, -NO2, -IMH2, -NHR5, -NR5R5, - N+(0 )R5R5, -NHC(0)H, -NHC(0)R5, -NR5C(0)R5, -NHC(0)NH2, -NHC(0)NR5R5, - NR5C(0)NHR5, -SH, -SR5, -S(0)H, -S(0)R5, -SO2R5, -SO2NH2, -SO2NHR5, -S02NR5R5, - CF3, -CHF2, -CH2F,-OCF3, -OCHF2, -CN, -CO2H, -CO2R5, -CHO, -C(0)R5, -C(0)NH2, - C(0)NHR5, -C(0)NR5R5, -CONHSO2H, -C(0)NHS02R5, -C(0)NR5S02R5, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more of the following groups: Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cyclic alkyl, halo, -OH, -OR7, -OC(0)R7, -
OC(0)NH2 -OC(0)NHR7, -OC(0)NR7R7, -OP(0)(OH)2, -OP(0)(OR7)2, -NO2, -NH2, -NHR7, -NR7R7, -N+(0") R7R7, -NHC(0)H, -NHC(0)R7, -NR7C(0)R7, -NHC(0)NH2, - NHC(0)NR7R7, -NR7C(0)NHR7, -SH, -SR7, -S(0)H, -S(0)R7, -SO2R7, -SO2NH2, - S02NHR7,-S02NR7R7, -CF3, -CHF2, -CH2F,-OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -CO2H, - CO2R7, -CHO, -C(0)R7, -C(0)NH2, -C(0)NHR7, -C(0)NR7R7, -CONHSO2H, -
C(0)NHS02R7, -C(0)NR7S02R7, an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S; and wherein the one or more optional substituents for each of said aryl and heteroaryl groups are each independently selected from the following groups: Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or C3-7 cyclic alkyl, halo, -OH, -OR8, -OC(0)R8, - OC(0)NH2, -OC(0)NHR8, -OC(0)NR8R8, -OP(0)(OH)2, -OP(0)(OR8)2, -NO2, -IMH2, - NHR8, -NR8R8, -N+(0 )R8R8, -NHC(0)H, -NHC(0)R8, -NR8C(0)R8, -NHC(0)NH2, - NHC(0)NR8R8, -NR8C(0)NHR8, -SH, -SR8, -S(0)H, -S(0)R8, -SO2R8, -SO2NH2, - S02NHR8,-S02NR8R8, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -CO2H, - CO2R8, -CHO, -C(0)R8, -C(0)NH2, -C(0)NHR8, -C(0)NR8R8, -CON HSO2H, - C(0)NHS02R8, and -C(0)NR8S02R8; wherein each R5, R7 and R8 is independently selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7 cyclic alkyl group; and
(b) an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S; and wherein the one or more optional substituents are each independently selected from the same optional substituents as those defined in (a) above for R;
R9 and R10 are each independently selected from any of the g roups defined in paragraphs (a) to (d) below, with the proviso that at least one of R9 and R10 is selected from any of the groups defined in paragraphs (c) and (d) below:
(a) H, an optionally substituted Ci-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, and an optionally substituted C3-7 cyclic alkyl group; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and cyclic alkyl are each independently selected from the following groups: halo, -OH, -OR11, -OC(0)Rn, -OC(0)NH2, -OC(0)NHRn, - OC(0)NRnRn, -OP(0)(OH)2, -OP(0)(ORn)2, -NO2, -IMH2, -NHR11, -NR11R11, -N+(0 " )RnRn, -NHC(0)H, -NHC(0)Rn, -NR11C(0)R11, -NHC(0)NH2, -NHC(0)NR11R11, - NR11C(0)NHR11, -SH, -SR11, -S(0)H, -S(0)Rn, -SO2R11, -SO2NH2, -SO2N HR11, - S02NRnRn, -CF3, -CHF2, -CH2F,-OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -CO2H, -CO2R11, - CHO, -C(0)Rn, -C(0)NH2, -C(0)NHRn, -C(0)NR11R11, -CONHSO2H, -C(0)NHS02Rn, - C(0)NR11S02R11, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, azetidinyl, aryl, and heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S; wherein each of the groups cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl azetidinyl, aryl and heteroaryl are optionally substituted by one or more of the following groups : Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cyclic alkyl, halo, -OH, -OR13, -OC(0)R13, -OC(0)NH2, -OC(0)NHR13, - OC(0)NR13R13, -OP(0)(OH)2, -OP(0)(OR13)2, -NO2, -NH2, -NHR13, -NR13R13 -N+(0 " )R13R13, -NHC(0)H, -NHC(0)R13, -NR13C(0)R13, -NHC(0)NH2, -NHC(0)NR13R13, - NR13C(0)NHR13, -SH, -SR13, -S(0)H, -S(0)R13, -SO2R13, -SO2NH2, -SO2N HR13,- S02NR13R13, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, ,-SCF3, -SCF2H, -CN, -CO2H, -CO2R13, - CHO, -C(0)R13, -C(0)NH2, -C(0)NHR13, -C(0)NR13R13, -CONHSO2H, -C(0)NHS02R13, and -C(0)NR13S02R13; wherein each Rn and R13 is independently selected from a Ci-6 alkyi group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7 cyclic alkyi group;
(b) an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S; and wherein the one or more optional substituents for each of said aryl and heteroaryl are each
independently selected from the same optional substituents as those defined in (a) above for R9 and R10;
(c) -C(0)R14, -C(0)OR14, -C(0)NR15R16, -C(0)SR14, -C(S)R14, -C(S)OR14 C(S)NR15R16, and -C(S)SR14, wherein each R14, R15 and R16 is independently selected from the group consisting of H, optionally substituted Ci-6 alkyi, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-7 cyclic alkyi, optionally substituted aryl, and optionally substituted heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S, and wherein the one or more optional substituents for each of said alkyi, alkenyl, alkynyl, cyclic alkyi, aryl and heteroaryl for R14, R15 and R16 are each independently selected from the same optional substituents as those defined in (a) above for R9 and R10; and
(d) -S02(CRR)nR17, wherein n is an integer of from 0 to 6, each R is independently selected from the groups defined above for R, and R17 is optionally substituted aryl or optionally substituted heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S, and wherein the one or more optional substituents for each of said aryl and heteroaryl are independently selected from the same optional substituents as those defined in (a) above for R9 and R10; and -SO2R18, wherein R18 is optionally substituted Ci ealkyl or optionally substituted C3-7 cyclic alkyi, wherein the one or more optional substituents for each of said alkyi and cyclic alkyi are each independently selected from those defined in (a) above for R9 and R10; and a pharmaceutically acceptable carrier.
In another aspect, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament.
In another aspect, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in medicine. In a further aspect, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.
In a further aspect, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a warm blooded animal, including a human.
In a further aspect, the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament.
In a further aspect, the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a warm blooded animal, including a human.
In a further aspect, the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a warm blooded animal, including a human, wherein the treatment comprises administration of the compound of Formula I and one or more additional agents selected from the group consisting of chemotherapeutic agents, immune-modulating agents such as anti-cancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)), and radiotherapy, and wherein the additional agent is administered either before, during or after administration of the compound of Formula I. In certain embodiments, the additional agent comprises an immune-modulating agent.
In a further aspect, the invention provides a method of treating cancer in a warm blooded animal, including a human, comprising administering to the animal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
In a further aspect, the invention provides a method of treating cancer in a warm blooded animal, including a human, wherein the method comprises
administering to the animal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and wherein the method further includes the step of administering one or more additional agents selected from the group consisting of chemotherapeutic agents, immune-modulating agents such as anti-cancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)), and radiotherapy, and wherein the additional agent is administered either before, during or after administration of the compound of Formula I. In certain embodiments, the additional agent comprises an immune-modulating agent. In a further aspect, the invention provides a method of inhibiting indoleamine 2,3-dioxygenase 1 (IDOl) in a warm blooded animal in need thereof, including a human, comprising administering to the animal a compound of Formula I or a pharmaceutically acceptable salt thereof having IDOl inhibitory activity, in an amount effective to inhibit IDOl .
In a further aspect, the invention provides a method of inhibiting
tryptophan2,3-dioxygenase (TDO) in a warm blooded animal in need thereof, including a human, comprising administering to the animal a compound of Formula I or a pharmaceutically acceptable salt thereof, having TDO inhibitory activity, in an amount effective to inhibit TDO.
In a further aspect, the invention provides a method of inhibiting IDOl and TDO in a warm blooded animal in need thereof, including a human, comprising administering to the animal a compound of Formula I or a pharmaceutically acceptable salt thereof having both IDOl and TDO inhibitory activity, in an amount effective to inhibit IDOl and TDO.
In a further aspect, the invention provides a pharmaceutical combination or kit, comprising
(a) a compound of Formula I or a pharmaceutically acceptable salt thereof, and
(b) one or more additional agents selected from the group consisting of chemotherapeutic agents, and immune-modulating agents such as anti-cancer vaccines, modulators of immune checkpoint proteins and adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)).
In a further aspect, the invention provides a pharmaceutical combination or kit, for use in treating cancer, comprising
(a) a compound of Formula I or a pharmaceutically acceptable salt thereof, and
(b) one or more additional agents selected from the group consisting of chemotherapeutic agents, and immune-modulating agents such as anticancer vaccines, modulators of immune checkpoint proteins and adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)).
In a further aspect, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating a condition or disorder selected from the group consisting of: an inflammatory condition, an infectious disease, a central nervous system disease or disorder, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, a condition or disorder relating to female reproductive health, and cataracts.
In a further aspect, the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a condition or disorder selected from the group consisting of: an inflammatory condition, an infectious disease, a central nervous system disease or disorder, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, a condition or disorder relating to female reproductive health, and cataracts.
In a further aspect, the invention provides a method of treating a condition or disorder selected from the group consisting of: an inflammatory condition, an infectious disease, a central nervous system disease or disorder, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, a condition or disorder relating to female reproductive health, and cataracts, in a warm blooded animal, including a human, wherein the method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
Certain embodiments of compounds of Formula I, that may be used in any of the compositions, methods, uses and other aspects of the invention as defined above, are described in the numbered paragraphs (1) to (30) below.
(1). A compound of Formula I or a pharmaceutically acceptable salt thereof, as defined above in the first aspect of the invention.
(2). A compound as defined in paragraph (1), wherein Z is N or N- oxide, such as N, W is CR1, X is CR2 and Y is CR3.
(3). A compound as defined in paragraph (1), wherein X is N or N- oxide, such as N, W is CR1, Y is CR3 and Z is CR4.
(4). A compound as defined in paragraph (1), wherein X and Z are both N or N-oxide, such as N, W is CR1 and Y is CR3.
(5). A compound as defined in any one of paragraphs (1) to (4), wherein R1, R2, R3 and R4, where present, are each independently selected from the group consisting of H, halo, optionally substituted C1-C6 alkyl, -O-R wherein R is optionally substituted C1-C6 alkyl, an optionally substituted aryl, such as substituted phenyl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S.
(6). A compound as defined in any one of paragraphs (1) to (4), wherein R1, R2, R3 and R4, where present, are each independently selected from the group consisting of H, halo, optionally substituted C1-C6 alkyl, -O-R wherein R is selected from optionally substituted C1-C6 alkyl and optionally substituted aryl (such as phenyl), -NHR wherein R is optionally substituted aryl, an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S.
(7) . A compound as defined in paragraph (6), wherein R1, R2, R3 and R4, where present, are each independently selected from the group consisting of H, halogen, -CF3, -CH F2, -OCF3, -OCH F2, Ci-e alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally
substituted aryl, and -NHR wherein R is optionally substituted aryl.
(8) . A compound as defined in paragraph (6), wherein one or two of R1, R2, R3 and R4, where present, is H, and the others of R1, R2 R3 and R4 that are not H are independently selected from the group consisting of halogen, - CF3, -CH F2, -OCF3, -OCH F2, Ci-e alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
(9) . A compound as defined in any one of paragraphs (6) to (8), wherein R3 is present and selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
(10) . A compound as defined in paragraph (2), wherein Z is N or N- oxide, such as N, W is CR1, X is CR2 and Y is CR3, and R3 is selected from the group consisting of halogen, -O-R wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
(11) . A compound as defined in paragraph (2), wherein Z is N or N- oxide, such as N, W is CR1, X is CR2 and Y is CR3, R1 is H, and one or both of R2 and R3 are other than H, for example, both R2 and R3 are other than H, or R2 is H and R3 is other than H, or R3 is H and R2 is other than H .
(12). A compound as defined in paragraph (11), wherein each of R2 and R3 that is other than H is independently selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, -OR wherein R is selected from optionally substituted C1-C6 alkyl and optionally substituted aryl, -NHR wherein R is optionally substituted aryl; an optionally substituted aryl, such as substituted phenyl, and an optionally substituted heteroaryl group.
(13). A compound as defined in paragraph (12), wherein each of R2 and R3 that is other than H is independently selected from the group consisting of halogen, -CF3, -CH F2, -OCF3, -OCH F2, Ci-6 alkyi such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and - NHR wherein R is optionally substituted aryl.
(14) . A compound as defined in any one of paragraphs (1) to (4), wherein R1 and R2 taken together, or R2 and R3 taken together, or R3 and R4 taken together form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from 0, N or S and the ring is optionally substituted with 1 to 4 substituents independently selected from R, and those of R1, R2, R3 and R4 that are not part of the ring, are independently selected from : H, halo, optionally substituted C1-C6 alkyi, O-R wherein R is optionally substituted C1-C6 alkyi, an optionally substituted aryl and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S.
(15) . A compound as defined in any one of paragraphs (1) to (14), wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyi (such as C1-3 alkyi), for example, one of R9 and R10 is H, and the other of R9 and R10 is selected from any of the groups defined in (c) and (d).
(16) . A compound as defined in any one of paragraphs (1) to (15), wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyi (such as C1-3 alkyi), and the other of R9 and R10 is selected from any of the groups defined in (c).
(17) . A compound as defined in any one of paragraphs (1) to (15), wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyi (such as C1-3 alkyi), and the other of R9 and R10 is selected from the group consisting of -C(0)R14, -C(0)OR14, -C(S)R14, and - C(S)OR14; wherein each R14 is independently selected from the group consisting of: (a) optionally substituted Ci-6 alkyi, for example Ci-6 alkyi wherein said alkyi is substituted by aryl and optionally one or two further substituents, and wherein said aryl is itself optionally substituted, and (b) optionally substituted aryl.
(18) . A compound as defined in paragraph (17), where each R14 is optionally substituted alkyi having the formula -(CH2)n(aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
(19) . A compound as defined in any one of paragraphs (16) to (18) , wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is -C(0)OR14.
(20) . A compound as defined in any one of paragraphs (1) to (15), wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is selected from the group consisting of -C(0)NR15R16 and -C(S)NR15R16, wherein each R15 and R16 is independently selected from the group consisting of (a) H, (b) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and, optionally, one or two further substituents, and wherein said aryl is itself optionally substituted, and (c) optionally substituted aryl.
(21) . A compound as defined in paragraph (20), wherein each R15 and R16 is independently selected from the group consisting of (a) H and (b) optionally substituted alkyl having the formula -(CH2)n(aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
(22) A compound as defined in claim (20) or (21), wherein one but not both of R15 and R16 is H.
(23) . A compound as defined in paragraph (2), wherein Z is N or N- oxide, such as N, W is CR1, X is CR2 and Y is CR3, one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as Ci-
3 alkyl), for example one of R9 and R10 is H, and the other of R9 and R10 is is - C(0)OR14, wherein each R14 is independently selected from the group consisting of: (a) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and, optionally, one or two further substituents, and wherein said aryl is itself optionally substituted, and (b) optionally substituted aryl.
(24) . A compound as defined in paragraph (23), wherein R14 is optionally substituted alkyl having the formula -(CH2)n(aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
(25) A compound as defined in paragraph (23) or (24), wherein R1, R2 and R3 are each independently selected from the group consisting of H, halogen, -CF3, -CH F2, -OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and - NHR wherein R is optionally substituted aryl.
(26). A compound as defined in paragraph (23) or (24), wherein R1, R2 and R3 are each independently selected from the group consisting of H, halogen, Ci-6 alkyl, such as methyl, substituted aryl, and substituted
heteroaryl .
(27) . A compound as defined in paragraph (23) or (24), wherein one or two of R1, R2 and R3 is H, and the others of R1, R2 and R3 that are not H are independently selected from the g roup consisting of halogen, -CF3, -CH F2, - OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted
heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl .
(28) . A compound as defined in paragraph (23) or (24), wherein R1 is H, and one of both of R2 and R3 is other than H, wherein each of R2 and R3 that is not H is independently selected from the group consisting of halogen, -CF3, - CH F2, -OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl .
(29) . A compound as defined in any one of parag raphs (23) to (28), wherein R3 is selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl .
(30) . A compound as defined in paragraph (23) or (24), wherein R1 is H, and R2 and R3 form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from 0, N and S and the ring is optionally substituted with 1 to 4 substituents independently selected from R.
(31) . A compound of Formula I, as defined in any one of paragraphs ( 1) to (30) above, or a pharmaceutically acceptable salt thereof, wherein at least one of R1, R2, R3 and R4, where present, is other than H or methyl, for example wherein at least one of R1, R2, R3 and R4, where present, is other than H or alkyl, and with the proviso that the compound is not selected from the following compounds:
2-Bromo-N-(5-chloro-4,6-di methyl isoxazolo[5,4-b] pyridin-3-yl)acetamide, N-(6-Phenyl-4-(trifluoromethyl)isoxazolo[5,4-b] pyridin-3- yl)cyclopropanecarboxamide, and
2-Phenyl-N-(6-phenyl-4-(trifluoromethyl)isoxazolo[5,4-b] pyridin-3- yl)acetamide. (32) . A compound as defined in paragraph ( 1), selected from the group consisting of: l-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4- (trifluoromethoxy) phenyl) urea (2)
l-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-cyanophenyl)urea (3)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b]pyridin-3-yl)-3-(2-chlorophenyl) urea
(6)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b]pyridin-3-yl)-3-(3-chlorophenyl) urea (7)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b]pyridin-3-yl)-3-(4-chlorophenyl) urea (8)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(2- (trifluoromethoxy) phenyl) urea (9)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3-
(trifluoromethoxy) phenyl) urea (10)
l-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2- methoxyphenyl)urea (11)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3- methoxyphenyl)urea (12)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(4- methoxyphenyl)urea (13)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(2-
(trifluoromethyl)phenyl)urea (14)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(4- (trifluoromethyl)phenyl)urea (16)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-phenyl urea (17)
N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-phenylacetamide (18) N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-(4- (trifluoromethoxy)phenyl)acetamide (19)
Phenyl (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)carbamate (4) l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3-
(trifluoromethyl)phenyl)urea (15)
4-Fluorophenyl (5-chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)carbamate (5)
N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)acetamide (20)
and pharmaceutically acceptable salts thereof.
(33). A compound as defined in any one of the preceding paragraphs (1) to (32), wherein the compound is an IDOl inhibitor. (34) . A compound as defined in any one of the preceding paragraphs ( 1) to (32), wherein the compound is a TDO inhibitor.
(35) . A compound as defined in any one of the preceding paragraphs ( 1) to (32), wherein the compound is both an IDO l inhibitor and a TDO inhibitor.
Certain compounds of the Formula I are novel . Accordingly, such compounds are provided as a further feature of the invention.
In a further aspect, the invention provides a compound of Formula I, as defined in any one of paragraphs ( 1) to (30) above, or a pharmaceutically acceptable salt thereof, wherein at least one of R1, R2, R3 and R4, where present, is other than H or methyl, for example wherein at least one of R1, R2, R3 and R4, where present, is other than H or alkyl, and with the proviso that the compound is not selected from the following compounds:
2-Bromo-N-(5-chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)acetamide, N-(6-Phenyl-4-(trifluoromethyl)isoxazolo[5,4-b] pyridin-3- yl)cyclopropanecarboxamide, and
2-Phenyl-N-(6-phenyl-4-(trifluoromethyl)isoxazolo[5,4-b] pyridin-3- yl)acetamide.
In certain embodiments, the invention provides a compound of Formula I, as defined in any of the paragraphs numbered (35) to (63) below.
(35) . A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein :
10
Figure imgf000015_0001
I
W is CR1, N or N-oxide;
X is CR2, N or N-oxide;
Y is CR3, N or N-oxide;
Z is CR4, N or N-oxide;
and where at least one of W, X, Y, and Z is N or N-oxide;
R1, R2, R3 and R4 are each independently selected from the following groups: H, halo, R, -OH, -OR, -OC(0)H, -OC(0)R, -OC(0)NH2, -OC(0)NHR, -OC(0)NRR,- OP(0)(OH)2, -OP(0)(OR)2, -NO2, -NH2, -NHR, -NRR, -NHC(0)H, -NHC(0)R, -NRC(0)R, -NHC(0)NH2, -NHC(0)NRR, -NRC(0)NHR, -SH, -SR, -S(0)H, -S(0)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -CN, -C≡CH, -C≡CR, -CH = CHR, -CH = CRR, -CR=CHR, -CR=CRR, -CO2H, -CO2R, -CHO, -C(0)R, -C(0)NH2, -C(0)NHR, - C(0)NRR, -CONHSO2H, -CONHSO2R, -CONRSO2R, cyclic C3-C7 alkylamino, imidazolyl, C1-C6 alkylpiperazinyl, morpholinyl and thiomorpholinyl;
or R1 and R2 taken together, or R2 and R3 taken together, or R3 and R4 taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6- membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from 0, N and S, and the ring is optionally substituted independently with 1 to 4
substituents selected from R;
each R is independently selected from any of the groups defined in
paragraphs (a) and (b) below:
(a) an optionally substituted Ci-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group and an optionally substituted C3-7 cyclic alkyl group; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and cyclic alkyl groups are each independently selected from the following groups: halo, -OH, -OR5, -OC(0)R5, -OC(0)NH2, - OC(0)NHR5, -OC(0)NR5R5, -OP(0)(OH)2, -OP(0)(OR5)2, -NO2, -INH2, -NHR5, -NR5R5, - N+(0")R5R5, -NHC(0)H, -NHC(0)R5, -NR5C(0)R5, -NHC(0)NH2, -NHC(0)NR5R5, -
NR5C(0)NHR5, -SH, -SR5, -S(0)H, -S(0)R5, -SO2R5, -SO2NH2, -SO2NHR5, -S02NR5R5, - CF3, -CHF2, -CH2F,-OCF3, -OCHF2, -CN, -CO2H, -CO2R5, -CHO, -C(0)R5, -C(0)NH2, - C(0)NHR5, -C(0)NR5R5, -CONHSO2H, -C(0)NHS02R5, -C(0)NR5S02R5, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more of the following groups: Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cyclic alkyl, halo, -OH, -OR7, -OC(0)R7, - OC(0)NH2 -OC(0)NHR7, -OC(0)NR7R7, -OP(0)(OH)2, -OP(0)(OR7)2, -NO2, -NH2, -NHR7, -NR7R7, -N+(0") R7R7, -NHC(0)H, -NHC(0)R7, -NR7C(0)R7, -NHC(0)NH2, -
NHC(0)NR7R7, -NR7C(0)NHR7, -SH, -SR7, -S(0)H, -S(0)R7, -SO2R7, -SO2NH2, - S02NHR7,-S02NR7R7, -CF3, -CHF2, -CH2F,-OCF3, -OCHF2, ,-SCF3, -SCF2H, -CN, -CO2H, - CO2R7, -CHO, -C(0)R7, -C(0)NH2, -C(0)NHR7, -C(0)NR7R7, -CONHSO2H, - C(0)NHS02R7, -C(0)NR7S02R7, an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S; and wherein the one or more optional substituents for each of said aryl and heteroaryl groups are each independently selected from the following groups: Ci-6 alkyl, C2-e alkenyl, C2-6 alkynyl or C3-7 cyclic alkyl, halo, -OH, -OR8, -OC(0)R8, - OC(0)NH2, -OC(0)NHR8, -OC(0)NR8R8, -OP(0)(OH)2, -OP(0)(OR8)2, -NO2, -NH2, - NHR8, -NR8R8, -N+(0 )R8R8, -NHC(0)H, -NHC(0)R8, -NR8C(0)R8, -NHC(0)NH2, - NHC(0)NR8R8, -NR8C(0)NHR8, -SH, -SR8, -S(0)H, -S(0)R8, -S02R8, -S02NH2, -
S02NHR8,-S02NR8R8, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -C02H, - C02R8, -CHO, -C(0)R8, -C(0)NH2, -C(0)NHR8, -C(0)NR8R8, -CONHS02H, - C(0)NHS02R8, and -C(0)NR8S02R8; wherein each R5, R7 and R8 is independently selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7 cyclic alkyl group; and
(b) an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S; and wherein the one or more optional substituents are each independently selected from the same optional substituents as those defined in (a) above for R;
R9 and R10 are each independently selected from any of the groups defined in paragraphs (a) to (d) below, with the proviso that at least one of R9 and R10 is selected from any of the groups defined in paragraphs (c) and (d) below:
(a) H, an optionally substituted Ci-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, and an optionally substituted C3-7 cyclic alkyl group; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and cyclic alkyl are each independently selected from the following groups: halo, -OH, -OR11, -OC(0)Rn, -OC(0)NH2, -OC(0)NHRn, - OC(0)NRnRn, -OP(0)(OH)2, -OP(0)(ORn)2, -NO2, -IM H2, -NHR11, -NR11R11, -N+(0 " )RnRn, -NHC(0)H, -NHC(0)Rn, -NR11C(0)R11, -NHC(0)NH2, -NHC(0)NR11R11, - NR11C(0)NHR11, -SH, -SR11, -S(0)H, -S(0)Rn, -S02Rn, -S02NH2, -S02NHR11, - S02NR11R11, -CF3, -CHF2, -CH2F,-OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -C02H, -C02Rn, - CHO, -C(0)Rn, -C(0)NH2, -C(0)NHRn, -C(0)NR11R11, -CONHS02H, -C(0)NHS02Rn, - C(0)NR11S02R11, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, azetidinyl, aryl, and heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S; wherein each of the groups cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl azetidinyl, aryl and heteroaryl are optionally substituted by one or more of the following groups: Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cyclic alkyl, halo, -OH, -OR13, -OC(0)R13, -OC(0)NH2, -OC(0)NHR13, - OC(0)NR13R13, -OP(0)(OH)2, -OP(0)(OR13)2, -NO2, -IM H2, -NHR13, -NR13R13 -N+(0 " )R13R13, -NHC(0)H, -NHC(0)R13, -NR13C(0)R13, -NHC(0)NH2, -NHC(0)NR13R13, - NR13C(0)NHR13, -SH, -SR13, -S(0)H, -S(0)R13, -SO2R13, -SO2NH2, -SO2NHR13,- S02NR13R13, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -CO2H, -CO2R13, - CHO, -C(0)R13, -C(0)NH2, -C(0)NHR13, -C(0)NR13R13, -CONHSO2H, -C(0)NHS02R13, and -C(0)NR13S02R13; wherein each Rn and R13 is independently selected from a Ci-6 alkyi group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7 cyclic alkyi group;
(b) an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S; and wherein the one or more optional substituents for each of said aryl and heteroaryl are each
independently selected from the same optional substituents as those defined in (a) above for R9 and R10;
(c) -C(0)R14, -C(0)OR14, -C(0)NR15R16, -C(0)SR14, -C(S)R14, -C(S)OR14 C(S)NR15R16, and -C(S)SR14, wherein each R14, R15 and R16 is independently selected from the group consisting of H, optionally substituted Ci-6 alkyi, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-7 cyclic alkyi, optionally substituted aryl, and optionally substituted heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S, and wherein the one or more optional substituents for each of said alkyi, alkenyl, alkynyl, cyclic alkyi, aryl and heteroaryl for R14, R15 and R16 are each independently selected from the same optional substituents as those defined in (a) above for R9 and R10; and
(d) -S02(CRR)nR17, wherein n is an integer of from 0 to 6, each R is independently selected from the groups defined above for R, and R17 is optionally substituted aryl or optionally substituted heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S, and wherein the one or more optional substituents for each of said aryl and heteroaryl are independently selected from the same optional substituents as those defined in (a) above for R9 and R10; and -SO2R18, wherein R18 is optionally substituted Ci ealkyl or optionally substituted C3-7 cyclic alkyi, wherein the one or more optional substituents for each of said alkyi and cyclic alkyi are each independently selected from those defined in (a) above for R9 and R10; with the proviso that at least one of R1, R2, R3 and R4 , where present, is other than H or methyl, and
with the further proviso that the compound is not selected from the following :
2-Bromo-N-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)acetamide, N-(6-Phenyl-4-(tnfluoromethyl)isoxazolo[5,4-b]pyridin-3-yl)cyclopropanecarboxamide, and
2-Phenyl-N-(6-phenyl-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-yl)acetannide. (36). A compound according to paragraph (35), wherein Z is N or N-oxide, such as N, W is CR1, X is CR2 and Y is CR3.
(37) . A compound according to paragraph (35), wherein X is N or N-oxide, such as N, W is CR1, Y is CR3 and Z is CR4.
(38) . A compound according to paragraph (35), wherein X and Z are both N or N- oxide, such as N, W is CR1 and Y is CR3.
(39) . A compound according to any one of paragraphs (35) to (38), wherein R1, R2, R3 and R4, where present, are each independently selected from the group consisting of H, halo, optionally substituted C1-C6 alkyl, -O-R wherein R is selected from optionally substituted C1-C6 alkyl and optionally substituted aryl (such as phenyl), - N H R wherein R is optionally substituted aryl, an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S .
(40) . A compound according to paragraph (39), wherein R1, R2, R3 and R4, where present, are each independently selected from the group consisting of H, halogen, - CF3, -CH F2, -OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl.
(41) . A compound according to paragraph (39), wherein one or two of R1, R2, R3 and R4, where present, is H, and the others of R1, R2 , R3 and R4 that are not H are independently selected from the group consisting of halogen, -CF3, -CH F2, -OCF3, - OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl. (42). A compound according to any one of paragraphs (39) to (41), wherein R3 is present and selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl. (43). A compound according to paragraph (36), wherein Z is N or N-oxide, such as N, W is CR1, X is CR2 and Y is CR3, and R3 is selected from the group consisting of halogen, -O-R wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl. (44). A compound according to paragraph (36), wherein Z is N or N-oxide, such as N, W is CR1, X is CR2 and Y is CR3, R1 is H, and one or both of R2 and R3 are other than H, for example, both R2 and R3 are other than H, or R2 is H and R3 is other than H, or R3 is H and R2 is other than H . (45). A compound according to paragraph (44), wherein each of R2 and R3 that is other than H is independently selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, -OR wherein R is selected from optionally substituted C1-C6 alkyl and optionally substituted aryl, -N H R wherein R is optionally substituted aryl; an optionally substituted aryl, such as substituted phenyl, and an optionally substituted heteroaryl group.
(46) . A compound according to paragraph (45), wherein each of R2 and R3 that is other than H is independently selected from the group consisting of halogen, -CF3, - CH F2, -OCF3, -OCH F2, Ci-6 alkyl such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl.
(47) . A compound according to any one of paragraphs (35) to (38), wherein R1 and R2 taken together, or R2 and R3 taken together, or R3 and R4 taken together, form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from O, N or S and the ring is optionally substituted with 1 to 4 substituents independently selected from R, and those of R1, R2, R3 and R4 that are not part of the ring, are independently selected from : H , halo, optionally substituted C1-C6 alkyl, O-R wherein R is optionally substituted C1-C6 alkyl, an optionally substituted aryl and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S. (48) . A compound according to any one of paragraphs (35) to (47), wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), for example one of one of R9 and R10 is H, and the other of R9 and R10 is selected from any of the groups defined in paragraphs (c) and (d).
(49) . A compound according to any one of paragraphs (35) to (48), wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is selected from any of the groups defined in paragraph (c).
(50) . A compound according to any one of paragraphs (35) to (48), wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is selected from the group consisting of -C(0)R14, -C(0)OR14, -C(S)R14, and -C(S)OR14; wherein each R14 is independently selected from the group consisting of: (a) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and optionally one or two further substituents, and wherein said aryl is itself optionally substituted, and (b) optionally substituted aryl.
(51) . A compound according to paragraph (50), where each R14 is optionally substituted alkyl having the formula -(CH2)n(aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted. (52). A compound according to any one of paragraphs (49) to (51), wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is -C(0)OR14.
(53). A compound according to any one of paragraphs (35) to (48), wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is selected from the group consisting of -C(0)NR15R16 and -C(S)NR15R16, wherein each R15 and R16 is
independently selected from the group consisting of (a) H, (b) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and, optionally, one or two further substituents, and wherein said aryl is itself optionally substituted, and (c) optionally substituted aryl. (54) . A compound according to parag raph (53), wherein each R15 and R16 is independently selected from the group consisting of (a) H and (b) optionally substituted alkyl having the formula -(CH2)n(aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted .
(55) . A compound according to parag raph (53) or (54), wherein one but not both of R15 and R16 is H .
(56) . A compound according to parag raph (36), wherein Z is N or N-oxide, such as N, W is CR1, X is CR2 and Y is CR3, one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), for example one of R9 and R10 is H, and the other of R9 and R10 is is -C(0)OR14, wherein each R14 is i ndependently selected from the group consisting of: (a) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and, optionally, one or two further substituents, and wherein said aryl is itself optionally substituted, and (b) optionally substituted aryl .
(57) . A compound according to parag raph (56), wherein R14 is optionally substituted alkyl having the formula -(CH2)n(aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted .
(58) . A compound according to parag raph (56) or (57), wherein R1, R2 and R3 are each independently selected from the g roup consisting of H, halogen, -CF3, -CH F2, - OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl .
(59) . A compound according to parag raph (56) or (57), wherein R1, R2 and R3 are each independently selected from the g roup consisting of H, halogen, Ci-6 alkyl, such as methyl, substituted aryl, and substituted heteroaryl .
(60) . A compound according to parag raph (56) or (57), wherein one or two of R1, R2 and R3 is H, and the others of R1, R2 and R3 that are not H are independently selected from the g roup consisting of halogen, -CF3, -CH F2, -OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl . (61) . A compound according to paragraph (56) or (57), wherein R1 is H, and one of both of R2 and R3 is other than H, wherein each of R2 and R3 that is not H is
independently selected from the group consisting of halogen, -CF3, -CHF2, -OCF3, - OCHF2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
(62) . A compound according to any one of paragraphs (56) to (61), wherein R3 is selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
(63) . A compound according to paragraph (56) or (57), wherein R1 is H, and R2 and R3 form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from 0, N and S and the ring is optionally substituted with 1 to 4 substituents independently selected from R.
By way of example, the invention further provides a compound of Formula I selected from the following:
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(4- (trifluoromethoxy)phenyl)urea (2)
l-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-cyanophenyl)urea (3)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b]pyridin-3-yl)-3-(2-chlorophenyl) urea
(6)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b]pyridin-3-yl)-3-(3-chlorophenyl) urea
(7)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b]pyridin-3-yl)-3-(4-chlorophenyl) urea
(8)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(2- (trifluoromethoxy)phenyl)urea (9)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3- (trifluoromethoxy) phenyl) urea (10)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(2- methoxyphenyl)urea (11)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3- methoxyphenyl)urea (12) l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(4- methoxyphenyl)urea (13)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(2- (trifluoromethyl)phenyl)urea (14)
l-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4- (trifluoromethyl)phenyl)urea (16)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-phenyl urea (17)
N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-phenylacetamide (18) N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-(4- (trifluoromethoxy)phenyl)acetamide (19)
Phenyl (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)carbamate (4) l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3- (trifluoromethyl)phenyl)urea (15)
4-Fluorophenyl (5-chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)carbamate (5)
N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)acetamide (20); and pharmaceutically acceptable salts thereof. Other aspects of the invention may include suitable combinations of embodiments disclosed herein. Also, as will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention.
While the invention is broadly as defined above, it is not limited thereto and also includes embodiments of which the following description provides examples. The invention will now be described in more detail.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the term "radiotherapy" means the use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body near cancer cells (internal radiation therapy). Systemic radiotherapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that travels in the blood to tissues throughout the body. The terms irradiation and radiation therapy have the same meaning. It is to be recognised that certain compounds of the present invention may exist in one or more different enantiomeric or diastereomeric forms. It is to be understood that the enantiomeric or diastereomeric forms are included in the above aspects of the invention.
The term halo or halogen group used throughout the specification is to be taken as meaning a fluoro, chloro, bromo or iodo group.
It is to be understood that where variables of the Formula I as defined above are optionally substituted by one or more imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl groups that the linkage to the relevant variable may be through either one of the available nitrogen or carbon ring atoms of these groups.
It is to be understood that the term "heteroaryl" includes both monocyclic and bicyclic ring systems, unless the context requires otherwise.
It is to be understood that the term "aryl" means an aromatic hydrocarbon such as phenyl or naphthyl.
It is to be understood that where a group is qualified as being "optionally substituted", this means that the group can be either (a) unsubstituted or (b) substituted by one or more of the defined substituents.
It is to be understood that where reference is made throughout the specification to a C1-C6 alkyl or C2-C6 alkenyl group, these groups may be unbranched or branched. For example, it is intended that reference to a C1-C6 alkyl would include a tert-butyl (Me)3C- group.
The expressions "treating cancer" and 'treatment of cancer" include methods that produce one or more anti-cancer effects which include, but are not limited to, anti-tumor effects, the response rate, the time to disease progression and the overall survival rate. "Anti-tumor" effects include but are not limited to inhibition of tumor growth, tumor growth delay, regression of tumor, shrinkage of tumor, increased time to regrowth of tumor on cessation of treatment and slowing of disease progression.
"Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a cancer, is sufficient to effect such treatment for the cancer. The "effective amount" will vary depending on the cancer to be treated, the compound to be administered, the severity of the cancer treated, the age and relative health of the subject, the route and form of administration, whether the treatment is monotherapy or combination therapy, the judgement of the attending clinician, and other factors.
"Pharmaceutically acceptable" means: that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes that which is acceptable for veterinary as well as human pharmaceutical use.
"Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include:
(a) acid addition salts formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid and the like; and
(b) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g . an alkali metal ion, an alkaline earth ion, or an aluminium ion; or coordinates with an organic or inorganic base. Acceptable organic bases include ethanolamine, diethanolamine, N- methylglucamine, triethanolamine and the like. Acceptable inorganic bases include aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
"Warm blooded animal" means any member of the mammalia class including, but not limited to humans, non-human primates such as chimpanzees and other apes and monkey species, farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
Compounds of the invention and methods of preparing them
As defined above, in broad terms the invention relates to pharmaceutical compositions containing compounds of the general Formula I, and the use of such compounds in therapy, and in particular cancer therapy. Compounds of Formula I have been found to be inhibitors of indoleamine 2,3-dioxygenase 1 (IDOl) and/or tryptophan2,3-dioxygenase (TDO) . As such, the compounds of the present invention are expected to be useful in cancer therapy, either alone or in combination with other agents, such as anti-cancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)), radiation therapy and other chemotherapeutic agents. The compounds of Formula I are also expected to be useful in the treatment of various other conditions besides cancer, as described in more detail in the Therapeutic Methods of the
Invention section, below. Certain methods for preparing compounds and pharmaceutically acceptable the compounds of Formula I are described below, with reference to Methods 1
Synthetic Schemes
Methods 1 to 8 below describe the preparation of precursor 3-amino compounds, which can be used as starting materials to prepare compounds of the formula I of the present invention, using the processes described in Methods 9 to 11 below, or using analogous processes.
Certain precursor 3-amino compounds may be prepared by reaction of an appropriately substituted halo-cyano pyridine with acetohydroxamic acid, in the presence of a base such as potassium tertr-butoxide, potassium carbonate or cesium carbonate (Method 1). A range of solvents may be used for this reaction, including DMF, p-dioxane and /V-methylmorpholine.
Method 1
Figure imgf000027_0001
Compounds bearing alkylamino substituents and/or arylamino substituents may be prepared by displacement of an activated halogen atom with amines and/or anilines (Method 2).
Method 2
Figure imgf000027_0002
or (Alkyl)2NH
or ArylNH2 or ArylNH- or ArylAlkylNH or ArylAlkyIN
Compounds containing alkyl substitution on the exocyclic amino group may be prepared by reaction of the primary amine with a trialkylorthoformate, followed by reduction with an appropriate reducing agent, such as sodium borohydride (Method3). Method 3
Figure imgf000028_0001
Such compounds may also be prepared by reaction of the primary amine wi an alkyl aldehyde, followed by a reducing agent such as sodium cyanoborohydhde, i a reductive amination process (Method 4).
Method 4
Figure imgf000028_0002
Y=H, Alkyl
Compounds bearing a pendant aryl or heteroaryl (Het) substituent may be prepared by reaction of an appropriately substituted halogen- or triflate-containing substrate with suitable aryl or heteroaryl boronic acids or esters, under palladium catalysis, in a Suzuki coupling reaction (Method 5).
Method 5
Figure imgf000028_0003
Compounds bearing a pendant aryl or heteroaryl (Het) substituent may also be prepared by performing a palladium-catalysed Suzuki coupling reaction with an appropriately substituted halogen or O-triflate containing chemical intermediate, and suitable aryl or heteroaryl boronic acids or esters, followed by elaboration of the resultant aryl- or heteroarylated product to the final product (Method 6). Method 6 hal
Figure imgf000029_0001
Dehydrating
reagent
Figure imgf000029_0002
Compounds containing alkyl and/or aryl ether-linked substituents may be prepared by displacement of an activated halogen atom by alcohols and/or phenols, in the presence of a base such as sodium or sodium hydride or cesium carbonate (Method 7).
Method 7
Figure imgf000029_0003
or ArylO- O
Compounds containing thioalkyi and/or thioaryl ether-linked substituents may be prepared by displacement of an activated halogen atom by thiols and/or thiophenols, in the presence of a base such as sodium or sodium hydride or cesium carbonate, or by direct reaction with the metal salt of a thiol or thiophenol. The resultant thioalkyi or thiophenol derivatives may be oxidised to their corresponding sulfoxide or sulfone derivatives with suitable oxidising reagents such as hydrogen peroxide, peracids, metal complexes and oxaziridines (Method 8).
Method 8
Figure imgf000029_0004
Compounds of Formula I according to the present invention, containing urea functionality at the 3-position of the isoxazoiopyridine ring system, can be prepared by reaction of the corresponding 3-amino compound with an alkyl, aryl or heteroaryl isocyanate. In some instances the reaction can be mediated by the addition of a suitable catalyst, such as dibutyltin oxide (Method 9). The corresponding thioureas may be similarly prepared by reacting the 3-aminoisoxazolopyridine with analogous isothiocyanates.
Method 9
Figure imgf000030_0001
Compounds of Formula I according to the present invention, containing carbamate functionality at the 3-position of the isoxazoiopyridine ring system, can be prepared by reaction of the corresponding 3-amino compound with an alkyl, aryl or heteroaryl chloroformate in the presence of a base, such as Et3N, pyridine, K2CO3 and the like (Method 10). The corresponding thiocarbamates may be similarly prepared by reacting the 3-aminoisoxazolopyridine with analogous chlorothioformates. The carbamates and thiocarbamates so-produced may further be used to prepare compounds containing urea and thiourea functionality, respectively at the 3-position of the isoxazoiopyridine ring system, by their reaction with alkyl amines, substituted anilines, or amino- substituted heterocycles (Method 10) . The carbamates and thiocarbamates so- produced may also be reacted with alkyl thiols, substituted thiophenols and
heterocyclic thiols to produce corresponding S-linked thiocarbamates and
dithiocarbamates, respectively.
Method 10
Figure imgf000030_0002
Compounds of Formula I according to the present invention, containing amide functionality at the 3-position of the isoxazoiopyridine ring system, may be prepared by reaction of an alkyl, or aryl, or heterocyclic carboxylic acid with an activating reagent such as thionyl chloride, Λ/,/V-carbonyldiinnidazole, EDCI and the like, followed by reaction of the resulting species with the 3-aminoisoxazolopyridine. A base such as NaH, Et3N, pyridine, K2CO3 and the like may be used in both reaction steps, and a catalyst such as 4-/V//V-(dimethylamino)pyridine may be used in the final coupling reaction (Method 11). The amides so-produced may be converted into corresponding thioamides by thiiation with a suitable reagent, such as P4S10 or Lawesson's reagent, in a suitable solvent such as pyridine, tertrahydrofuran, benzene and the like.
Method 11
Figure imgf000031_0001
Compounds of Formula I according to the present invention, containing sulfonamide functionality at the 3-position of the isoxazoiopyridine ring system, can be prepared by reaction of the corresponding 3-amino compound with an alkyl, aryl or heteroaryl sulfonyl chloride in the presence of a base, such as EtjN, pyridine, K2CO3 and the like (Method 12). Method 12
Figure imgf000031_0002
The procedures of Methods 9 to 12 can also be carried out on isoxazolopyridines where a mono-alkylamino group, or a mono-arylamino group, or a mono- heteroarylamino group has been introduced at the 3-position by the procedures, for example, of Methods 3 and 4, to give N-alkylated, N-arylated and N-heteroarylated derivatives of the 3-position amides, thioamides, carbamates, thiocarbamates, ureas, thioureas, dithiocarbamates and sulfonamides.
Those persons skilled in the art will understand that by using analogous procedures to those outlined above, other compounds of the Formula I can also be prepared . Therapeutic methods of the invention
The compounds of Formula I of the invention may be inhibitors of IDOl or TDO, or both IDOl and TDO. Compounds that are inhibitors of either IDOl or TDO, and compounds that are dual inhibitors of IDOl and TDO, are expected to be useful in cancer therapy. Accordingly, in certain embodiments, the present invention provides methods of treating cancer in warm blooded animals, including humans, by
administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I, or a pharmaceutical composition containing a compound of Formula I.
In particular aspects of the invention, the compounds of formula I are expected to be useful in restoring tumor immunity in cancer patients. The compounds of the invention may be useful either alone, or in combination with other cancer therapies, including chemotherapeutic agents, radiation and/or immune modulating agents.
Immune modulating agents include, without limitation, anti-cancer vaccines, agents that modulate immune checkpoint proteins (such as CTLA4 and the PDl-4s, LAG3 and TIM3) and adoptive T-cell therapies (such as CARTs). Accordingly, the compound of Formula I can be administered either alone or in combination with one or more other such therapies, either simultaneously or sequentially dependent upon the particular condition to be treated.
In particular embodiments, the compound of Formula I may be administered in combination with one or more immunotherapies selected from Ipilimumab,
Tremelimumab (both inhibitors of CTLA4), Nivolumab, Pembrolizumab (also known as Lambrolizumab), and Pidilizumab (all inhibitors of PD-1).
Additional chemotherapeutic agents that can be administered in combination with a compound of Formula I include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 14th Edition of the Merck Index (2006), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine. Additional anti-proliferative agents that can be administered in combination with a compound of Formula I include but are not limited to BCNU, CCNU, DTIC, and actinomycin D. Still further anti-proliferative agents include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Eleventh Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287 (2006), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5- fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N- phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.
Additional anti-proliferative agents that can be administered in combination with a compound of Formula I include but are not limited to other molecular targeted agents, which block the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumour growth. Examples include small molecule protein and lipid kinase inhibitors, monoclonal antibodies, molecularly targeted humanised monoclonal antibodies and monoclonal antibody drug conjugates. Examples of such inhibitors include: Rituximab, Trastuzumab, Alemtuzumab,
Tositumomab-1131, Cetuximab, Ibritumomab tiuxetan, Bevacizumab, Panitumumab, Ofatumumab, Ipilimumab, Brentuximab vedotin, Pertuzumab, Ado-Trastuzumab emtansine, Ramucirumab, Obinutuzumab, Nivolumab, Lambrolizumab, Dinutuximab, Imatinib, Gefitinib, Erlotinib, Sorafenib, Dasatinib, Sunitinib, Lapatinib, Nilotinib, Pazopanib, Crizotinib, Ruxolitinib, Vandetanib, Vemurafenib, Axitinib, Bosutinib, Cabozantinib, Ponatinib, Regorafenib, Tofacitinib, Afatinib, Dabrafenib, Ibrutinib and Trametinib.
A wide range of cancers may be treated by the compounds of the present invention. Cancers that may be treated in accordance with the present invention include but are not limited to: colorectal cancer, cancers of the breast, melanoma, reproductive organs, respiratory tract, brain, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to brain stem and hypophthalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallblader, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant),
cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to
laryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lip and oral cavity cancer. Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and
rhabdomyosarcoma. Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. These disorders have been well characterized in man, but also exist with a similar etiology in other warm-blooded animals, and can be treated by the compounds of the present invention.
It will be appreciated by those skilled in the art that a particular method of therapy will employ a selected route of administration which will in turn depend on a variety of factors, all of which are considered routinely when administering
therapeutics. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of this invention given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
Therapeutic dosages will likely be in the range of 1 mg to 30 g per day. The specific dose level selected for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy.
Certain compounds of Formula I, as well as being inhibitors of IDOl, may also inhibit ID02. Compounds that are dual inhibitors of IDOl and ID02 are also expected to be useful in cancer therapy. Accordingly, in another aspect, the invention provides a method of inhibiting IDOl and ID02 in a a warm blooded animal in need thereof, including a human, comprising administering to the animal a compound of Formula I or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit IDOl and ID02.
It has been reported that compounds that are inhibitors of IDO (IDOl and ID02) and/or TDO may have efficacy not only in the treatment of cancer, but also in the treatment of a range of other diseases or conditions, for example as discussed in PCT International Publication WO 2015/082499 and the references to scientific literature referred to therein, all of which are incorporated herein by reference. For example, such compounds may be useful in the treatment of inflammatory conditions, infectious diseases, central nervous system diseases or disorders, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, disease conditions or disorders relating to female reproductive health, and cataracts.
Accordingly, compounds of Formula I of the present invention may also be useful in the treatment of such diseases or conditions.
Examples of inflammatory conditions that may be treated by compounds of
Formula I include conditions relating to immune B cell, T cell, dendritic cell, natural killer cell, macrophage, and /or neutrophil dysregulation. Examples of infectious diseases that may be treated by compounds of Formula I include bacterial infections, viral infections such as gut infections, hepatitis C, sepsis, and sepsis induced hypotension.
Examples of central nervous system diseases or disorders that may be treated by compounds of Formula I include amyotrophic lateral sclerosis (AML), Huntington's disease, Alzheimer's disease, pain, psychiatric disorders including affective disorders such as depression, multiple sclerosis, Parkinson's disease, and HIV related
neurocognitive decline.
An example of diseases or disorders relating to female reproductive health that may be treated by compounds of Formula I is endometriosis, and conditions relating to female reproductive health include contraception and abortion.
Pharmaceutical compositions of the invention
The invention includes pharmaceutical compositions including one or more compounds of Formula I of this invention, and a pharmaceutically acceptable carrier.
The pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser should be nontoxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration.
The compounds may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term 'administration by injection' includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Pharmaceutical compositions of the invention may also be in the form of oil- in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
EXAMPLES
The following examples are representative of the compounds of the invention and methods for preparing them. However, the scope of the invention is not to be taken as being limited to these examples.
Synthetic Procedures
Starting materials not described explicitly were either available commercially or their synthesis has been described in the chemistry literature or the materials can be prepared by methods known to a person skilled in the art. Exemplar compounds were characterised by 1H NMR spectroscopy, APCI ionisation mass spectrometry, melting point, and combustion or HRMS analysis. Purity of the exemplar compounds was determined by HPLC analysis and found to be >95% for all compounds.
Silica gel 60 (S1O2) (0.040-0.063 mm) was used for all column
chromatography.
Abbreviations
NMR nuclear magnetic resonance ESI electrospray ionisation APCI atmospheric pressure chemical ionisation
HPLC high performance liquid chromatography
LCMS liquid chromatography-mass spectrometry
HRMS high resolution mass spectrometry mp melting point
DMF dimethylformamide
EtOAc ethyl acetate
DCM dichloromethane
MeOH methanol
THF tetrahydrofuran
HOAc acetic acid dppf 2-(di phenyl phosphino)ferrocene
EDCI l-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
TEA Triethylamine
Method 1. Representative example
5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (1)
Figure imgf000039_0001
To a solution of acetohydroxamic acid (0.22 g, 2.98 mmol) in dry DMF (5 ml) under nitrogen was added potassium tertr-butoxide (0.33 g, 2.98 mmol). The reaction mixture was stirred at 20 °C for 2 hr. 2,5-Dichloro-4,6-dimethylnicotinonitrile (0.50 g, 2.49 mmol) was then added and the resulting mixture was stirred at 20°C for 5 hr, then diluted with H2O (150 ml) and stirred for 1 hr. The resulting white precipitate was filtered and washed with water. The filtrate was extracted with EtOAc (30 ml x 3). Combined organic fractions were dried (Na2S04), and the solvent was evaporated under vacuum to give further material. Both the isolated solid and the extracted material were combined and chromatographed on S1O2 eluting with a 0-50 % gradient of petroleum ether/EtOAc. The column purified product was recrystallized from
DCM/petroleum ether to give (1) (0.22 g, 45% ) as a white solid, mp
(DCM/petroleum ether) 214-216 °C, *H NMR [(CD3)2SO] δ 6.25 (bs, 2H, N H2), 2.64 (s, 3H, CH3), 2.61 (s, 3H, CH3); LCMS [M + H] = 198; HPLC 99.8%; Anal calcd. for CsHsCI NsO : C, 48.6; H, 4.1; N, 21.4; found C, 48.8; H, 3.9, N, 21.4%.
Method 9. Representative procedure and further example
Method 9. Representative procedure l-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4- (trifluoromethoxy) phenyl) urea (2)
Figure imgf000040_0001
(2)
To a solution of 5-chloro-4,6-dimethylisoxazol[5,4-b)pyridine-3-amine (1) (125 mg, 0.60 mmol) in THF (1 ml) at 20 °C was added diisopropylethylamine (0.12 ml, 0.78 mmol, 1.3 eq) and l-isocyanato-4-(trifluoromethoxy)benzene (0.1 ml, 0.74 mmol, 1.23 eq). The reaction mixture was stirred at this temperature for 72 hr, then quenched with aq. KHCO3. The resulting precipitate was filtered and washed with l-hO.The filtrate was extracted with EtOAc to give further material after evaporation of the solvent. The combined solid material was triturated with diisopropyl ether for 3 days to give (2) (18mg, 7%), mp (diisopropyl ether) 205-208 °C; *H NMR
[(CD3)2SO] δ 9.55 (s, 1H), 9.47 (s, 1H), 7.60 (d, J = 9.1 Hz, 2H), 7.32 (d, J = 9.1 Hz, 2H), 2.69 (s, 3H), 2.58 (s, 3H); HPLC purity 84%; HRMS (ESI+) calcd. for Ci6H i2CI F3N4Na03 [M + Na] 423.0442, found 423.0440. l-(5-chloro-4,6-di methyl isoxazolo[5,4-b]pyridin-3-yl)-3-(4-cyanophenyl) urea (3)
Figure imgf000041_0001
(1 )
(3)
Similarly from 5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridine-3-amine and 4- isocyanatobenzonitrile to give (3) in 3.5% yield, mp (MeOH) 223-224 °C; *H NMR [(CD3)2SO] δ 9.86 (s, 1 H), 9.62 (s, 1H), 7.77 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 8.9 Hz, 2H), 2.69 (s, 3H), 2.57 (s, 3H); Anal, calcd. for C16H 12CI N5O2 : C, 56.2; H, 3.5; N, 20.5; found C, 56.2; H, 3.4; N, 20.4%.
Method 10. Representative example
Figure imgf000041_0002
D
General procedure
To a solution of 1 (1.5 g, 7.6 mmol, 1.0 eq) and TEA (1.5 g, 15.2 mmol, 2.0 eq) in THF (200 mL) at 0 °C was added phenyl chloroformate B (1.2 g, 76 mmol, 10.0 eq) drop-wise with stirring. The reaction mixture was stirred at room temperature under a N2 atmosphere overnight. The reaction mixture was poured into water and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with saturated aqueous NaHCC solution and brine, dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (pet. ether/EtOAc = 10/1-5/1) to give the product 4 (1.7 g, 71%) as a white solid.
Similar reaction of 1 with 4-fluorophenyl chloroformate gave 5 as a white solid (64%) following chromatography on silica (pet. ether/EtOAc (1 : 1).
To a solution of 4 (0.47 mmol, 1.0 eq) in THF (8.0 mL) were added TEA (0.94 mmol, 2.0 eq) and substituted aniline D (0.71 mmol, 1.5 eq). The reaction mixture was stirred at room temperature under a N2 atmosphere overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (CH2Cl2/MeOH = 100/1-80/1) to give the desired product. The following compounds were prepared using the methods described above:
Figure imgf000042_0001
Figure imgf000043_0001
Method 11. Representative examples
Figure imgf000043_0002
General experimental conditions A
To a solution of a substituted phenylacetic acid (0.56 mmol, 1.1 eq) in CH2CI2 (8.0 ml) was added oxalyl chloride (78 mg, 0.62 mmol, 1.2 eq) . The resulting mixture was stirred at room temperature under N2 for 2 h . The reaction
mixture was concentrated under reduced pressure to afford acid chloride B, which was dissolved in THF (2 ml) . The prepared acid chloride solution was added to a mixture of 1 (100 mg, 0.51 mmol, 1.0 eq) and NaH (24.8 mg, 0.62 mmol, 1.2 eq) in THF (5 ml) at 0 °C, and the resulting mixture was stirred at 40 °C overnight. The reaction mixture was poured into water and extracted with EtOAc (25 ml_ x 3). The organic layers were combined and washed with saturated aqueous NaHCC solution and brine, then dried over Na2S04, filtered and concentrated . The residue was purified by column chromatography (pet. ether/EtOAc = 5/1-3/1) to give the desired product.
General experimental conditions B
To a solution of a substituted phenylacetic acid, or acetic acid (5.1 mmol, 10 eq) in CH2CI2 (8.0 ml) was added oxalyl chloride (710 mg, 5.6 mmol, 11 eq) and DMF (2 drops, cat) . The resulting mixture was stirred at room temperature under N2 for 2 h. The reaction mixture was concentrated under reduced pressure to afford acid chloride B, which was dissolved in THF (2 ml) . The prepared acyl chloride solution was added to a mixture of 1 (100 mg, 0.51 mmol, 1.0 eq ) and TEA (103 mg, 1.02 mmol, 2.0 eq) in THF (5 ml) at 0 °C, and the resulting mixture was stirred at RT overnight. The reaction mixture was poured into water and extracted with EtOAc (25 ml_ x 3). The organic layers were combined and washed with saturated aqueous NaHCC solution and brine, then dried over Na2S04, filtered and concentrated . The residue was recrystallised from CH2CI2 to give the desired product.
The following compounds were prepared using the methods described above :
Compound Preparation
Structure [M + H] + *Η NMR
Number method
IH NMR (400 MHz,
315.9
DMSO) δ 12.30 (s, IH),
18 A
7.38 (d, J = 4.4 Hz, 5H),
317.8
4.42 (s, 2H), 2.34 (s,
3H), 2.06 (s, 3H).
IH NMR (400 MHz,
400.1 CD3OD) δ 7.49 (d, J = 8.4
19 Hz, 2H), 7.27 (d, J = 8.0 B
402.1 Hz, 2H), 3.86 (s, 2H),
2.70 (s, 3H), 2.35 (s,
3H).
Figure imgf000045_0001
Enzymatic Assay for IDOl activity
Recombinant human IDOl (rhIDOl) was expressed and purified from cultures of EC538 strain of E. coli transformed with pREP4 and pQE9-IDO plasmid. Reaction mixes were set up in 384-well microplates containing 50 mM phosphate buffer, 10 mM ascorbic, 10 μΜ methylene blue, 100 μg/mL catalase, 80 μΜ TRP, 0.01% Tween 20 (v/v) mixed with rhIDOl (15 μΙ_) at a final concentration of 9 nM in a total volume of 30 μΙ_ assay medium. The plates were incubated at 37°C for 30 min, and the enzymatic reaction was terminated by adding piperidine (200 mM) and heated at 65°C for 20 min. Fluorescence intensity was read at hex 400 nm and Aem 500 nm. Test compounds were dissolved in 100% DMSO and pre-diluted in assay medium prior to adding rhIDOl . IDOl inhibition (%) was calculated as
(\uninhibited enzyme assay signal\— \inhibited enzyme signal\)
x 100 y (\uninhibited enzyme assay signal\— \assay medium signal\) J
All experiments were carried out in triplicates, and statistical Analyses were conducted in Prism v5 (Graphpad Software, Inc., La Jolla, CA, USA).
Cell-based assay for IDOl inhibition
For the assay of inhibition of cellular IDOl activity, Lewis Lung carcinoma cells transfected to express human IDOl (LLTC-hlDOl) or murine (LLTC-mlDOl) were cultured with test compounds at 37°C, 5% CO2 for 24 h. Culture supernatant from each well was then transferred into a fresh, flat-bottomed 96-well plate, mixed with trichloroacetic acid (10% final concentration) and incubated for 20 min at 60°C. Plates were then centrifuged ( 10 min at 2500 g) and the supernatants were then transferred and mixed 1 : 1 with 4-(dimethylamino)benzaldehyde (20 mg/mL in acetic acid) in a new plate. The absorbance of each well was read at 480 nm, and the concentration that inhibited 50% cellular enzyme activity was calculated.
The viability of the cells in each well in the same experiment was determined using the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colourimetric assay. After the removal of the supernatant for determination of IDOl inhibition, the cells were incubated with MTT (500 μg/mL) until crystal formation was observed. Plates were centrifuged for 15 min at 2500 g, and then all the supernatant in then wells was discarded. DMSO (100 \ L/we\\) was added to dissolve the crystals and then the absorbance in each well was measured at 570 nm. Cell viability in each well was expressed as a percentage of untreated controls. Triplicate cultures were used for all experiments unless stated otherwise.
Results of the assays are shown in the table below. Compound activity
Figure imgf000046_0001
Activity IC5o ranges: A; < 1 μΜ, B; 1-10 μΜ, C; 10-100 μΜ, D; > 100 μΜ Cell-based assay for TDO inhibition
For the assay of inhibition of cellular TDO, GL261 cells transfected to over- express full length human TDO were cultured with test compounds at 37°C, 5% CO2 for 24 h. Culture supernatant from each well was then transferred into a fresh, flat- bottomed 96-well plate, and kynurenine content was determined as described above for the IDOl assay, and the concentration that inhibited 50% cellular enzyme activity was calculated.
The viability of the cells in each well in the same experiment was determined using the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colourimetric assay.
Results of the assay are shown in the table below.
Compound activity
Figure imgf000047_0001
Activity IC50 ranges: A; < 1 μΜ, B; 1-10 μΜ, C; 10-100 μΜ, D; > 100 μΜ
As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. In each instance herein any of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced with either of the other two terms.
When a group of materials, compositions, components or compounds is disclosed herein, it is understood that all individual members of those groups and all subgroups thereof are disclosed separately. When a Markush group or other grouping is used herein, all individual members of the group and all combinations and subcombinations possible of the group are intended to be individually included in the disclosure. Every formulation or combination of components described or exemplified herein can be used to practice the invention, unless otherwise stated . Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the disclosure. In the disclosure and the claims, "and/or" means additionally or alternatively. Moreover, any use of a term in the singular also encompasses plural forms.
All references cited herein are hereby incorporated by reference in their entirety to the extent that there is no inconsistency with the disclosure of this specification. Some references provided herein are incorporated by reference to provide details concerning sources of starting materials, additional starting materials, additional reagents, additional methods of synthesis, additional methods of analysis, additional biological materials, additional cells, and additional uses of the invention. All headings used herein are for convenience only. All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains, and are herein incorporated by reference to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. References cited herein are incorporated by reference herein in their entirety to indicate the state of the art as of their publication or filing date and it is intended that this information can be employed herein, if needed, to exclude specific embodiments that are in the prior art.

Claims

1. A pharmaceutical composition comprising :
a co I or a pharmaceutically acceptable salt thereof, wh
Figure imgf000049_0001
W is CR1, N or N-oxide;
X is CR2, N or N-oxide;
Y is CR3, N or N-oxide;
Z is CR4, N or N-oxide;
and where at least one of W, X, Y, and Z is N or N-oxide;
R1, R2, R3 and R4 are each independently selected from the following groups:
H, halo, R, -OH, -OR, -OC(0)H, -OC(0)R, -OC(0)NH2, -OC(0)NHR, -OC(0)NRR,- OP(0)(OH)2, -OP(0)(OR)2, -NO2, -N H2, -NHR, -NRR, -NHC(0)H, -NHC(0)R, -NRC(0)R, -NHC(0)NH2, -NHC(0)NRR, -NRC(0)NHR, -SH, -SR, -S(0)H, -S(0)R, -SO2R, -SO2N H2, -SO2N H R, -SO2N RR, -CF3, -CH F2, -CH2F, -OCF3, -OCH F2, -CN, -C≡CH, -C≡CR, -CH = CHR, -CH = CRR, -CR=CHR, -CR=CRR, -CO2H, -CO2R, -CHO, -C(0)R, -C(0)NH2, -C(0)NHR, - C(0)NRR, -CON HSO2H, -CON HSO2R, -CON RSO2R, cyclic C3-C7 alkylamino, imidazolyl, C1-C6 alkylpiperazinyl, morpholinyl and thiomorpholinyl;
or R1 and R2 taken together, or R2 and R3 taken together, or R3 and R4 taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6- membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from O, N and S, and the ring is optionally substituted independently with 1 to 4
substituents selected from R;
each R is independently selected from any of the groups defined in
paragraphs (a) and (b) below:
(a) an optionally substituted Ci-6 alkyi group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group and an optionally substituted C3-7 cyclic alkyi group; wherein the one or more optional substituents for each of said alkyi, alkenyl, alkynyl and cyclic alkyi groups are each independently selected from the following groups: halo, -OH, -OR5, -OC(0)R5, -OC(0)NH2, - OC(0)NHR5, -OC(0)NR5R5, -OP(0)(OH)2, -OP(0)(OR5)2, -NO2, -N H2, -NHR5, -NR5R5, - N+(0")R5R5, -NHC(0)H, -NHC(0)R5, -NR5C(0)R5, -NHC(0)NH2, -NHC(0)NR5R5, - NR5C(0)NHR5, -SH, -SR5, -S(0)H, -S(0)R5, -SO2R5, -SO2N H2, -SO2N H R5, -S02NR5R5, - CF3, -CH F2, -CH2F,-OCF3, -OCH F2, -CN, -CO2H, -CO2R5, -CHO, -C(0)R5, -C(0)NH2, - C(0)NHR5, -C(0)NR5R5, -CONHSO2H, -C(0)NHS02R5, -C(0)NR5S02R5, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more of the following groups: Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cyclic alkyl, halo, -OH, -OR7, -OC(0)R7, - OC(0)NH2 -OC(0)NHR7, -OC(0)NR7R7, -OP(0)(OH)2, -OP(0)(OR7)2, -NO2, -NH2, -NHR7, -NR7R7, -N+(0 ) R7R7, -NHC(0)H, -NHC(0)R7, -NR7C(0)R7, -NHC(0)NH2, - NHC(0)NR7R7, -NR7C(0)NHR7, -SH, -SR7, -S(0)H, -S(0)R7, -S02R7, -S02NH2, - S02NHR7,-S02NR7R7, -CF3, -CHF2, -CH2F,-OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -C02H, - C02R7, -CHO, -C(0)R7, -C(0)NH2, -C(0)NHR7, -C(0)NR7R7, -CONHS02H, - C(0)NHS02R7, -C(0)NR7S02R7, an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S; and wherein the one or more optional substituents for each of said aryl and heteroaryl groups are each independently selected from the following groups: Ci-6 alkyl, C2-e alkenyl, C2-e alkynyl or C3-7 cyclic alkyl, halo, -OH, -OR8, -OC(0)R8, - OC(0)NH2, -OC(0)NHR8, -OC(0)NR8R8, -OP(0)(OH)2, -OP(0)(OR8)2, -NO2, -IMH2, - NHR8, -NR8R8, -N+(0 )R8R8, -NHC(0)H, -NHC(0)R8, -NR8C(0)R8, -NHC(0)NH2, - NHC(0)NR8R8, -NR8C(0)NHR8, -SH, -SR8, -S(0)H, -S(0)R8, -S02R8, -S02NH2, -
S02NHR8,-S02NR8R8, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -C02H, - C02R8, -CHO, -C(0)R8, -C(0)NH2, -C(0)NHR8, -C(0)NR8R8, -CONHS02H, - C(0)NHS02R8, and -C(0)NR8S02R8; wherein each R5, R7 and R8 is independently selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7 cyclic alkyl group; and
(b) an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S; and wherein the one or more optional substituents are each independently selected from the same optional substituents as those defined in (a) above for R;
R9 and R10 are each independently selected from any of the groups defined in paragraphs (a) to (d) below, with the proviso that at least one of R9 and R10 is selected from any of the groups defined in paragraphs (c) and (d) below:
(a) H, an optionally substituted Ci-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, and an optionally substituted C3-7 cyclic alkyl group; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and cyclic alkyl are each independently selected from the following groups: halo, -OH, -OR11, -OC(0)Rn, -OC(0)NH2, -OC(0)NHRn, - OC(0)NRnRn, -OP(0)(OH)2, -OP(0)(ORn)2, -NO2, -NH2, -NHR11, -NR11R11, -N+(0 " )RnRn, -NHC(0)H, -NHC(0)Rn, -NR11C(0)R11, -NHC(0)NH2, -NHC(0)NR11R11, - NR11C(0)NHR11, -SH, -SR11, -S(0)H, -S(0)Rn, -SO2R11, -SO2NH2, -SO2NHR11, - S02NRnRn, -CF3, -CHF2, -CH2F,-OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -CO2H, -CO2R11, - CHO, -C(0)Rn, -C(0)NH2, -C(0)NHRn, -C(0)NR11R11, -CONHSO2H, -C(0)NHS02Rn, - C(0)NR11S02R11, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, azetidinyl, aryl, and heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S; wherein each of the groups cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl azetidinyl, aryl and heteroaryl are optionally substituted by one or more of the following groups: Ci-6 alkyi, C2-6 alkenyl, C2-6 alkynyl, C3-7 cyclic alkyi, halo, -OH, -OR13, -OC(0)R13, -OC(0)NH2, -OC(0)NHR13, - OC(0)NR13R13, -OP(0)(OH)2, -OP(0)(OR13)2, -NO2, -IMH2, -NHR13, -NR13R13 -N+(0 " )R13R13, -NHC(0)H, -NHC(0)R13, -NR13C(0)R13, -NHC(0)NH2, -NHC(0)NR13R13, - NR13C(0)NHR13, -SH, -SR13, -S(0)H, -S(0)R13, -SO2R13, -SO2NH2, -SO2NHR13,- S02NR13R13, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, ,-SCF3, -SCF2H, -CN, -CO2H, -CO2R13, - CHO, -C(0)R13, -C(0)NH2, -C(0)NHR13, -C(0)NR13R13, -CONHSO2H, -C(0)NHS02R13, and -C(0)NR13S02R13; wherein each Rn and R13 is independently selected from a Ci-6 alkyi group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7 cyclic alkyi group;
(b) an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S; and wherein the one or more optional substituents for each of said aryl and heteroaryl are each
independently selected from the same optional substituents as those defined in (a) above for R9 and R10;
(c) -C(0)R14, -C(0)OR14, -C(0)NR15R16, -C(0)SR14, -C(S)R14, -C(S)OR14 C(S)NR15R16, and -C(S)SR14, wherein each R14, R15 and R16 is independently selected from the group consisting of H, optionally substituted Ci-6 alkyi, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-7 cyclic alkyi, optionally substituted aryl, and optionally substituted heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S, and wherein the one or more optional substituents for each of said alkyi, alkenyl, alkynyl, cyclic alkyi, aryl and heteroaryl for R14, R15 and R16 are each independently selected from the same optional substituents as those defined in (a) above for R9 and R10; and
(d) -S02(CRR)nR17, wherein n is an integer of from 0 to 6, each R is independently selected from the groups defined above for R, and R17 is optionally substituted aryl or optionally substituted heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S, and wherein the one or more optional substituents for each of said aryl and heteroaryl are independently selected from the same optional substituents as those defined in (a) above for R9 and R10; and -SO2R18, wherein R18 is optionally substituted Ci ealkyl or optionally substituted C3-7 cyclic alkyl, wherein the one or more optional substituents for each of said alkyl and cyclic alkyl are each independently selected from those defined in (a) above for R9 and R10; and a pharmaceutically acceptable carrier.
2. A pharmaceutical composition according to claim 1, wherein Z is N or N-oxide, such as N, W is CR1, X is CR2 and Y is CR3.
3. A pharmaceutical composition according to claim 1, wherein X is N or N-oxide, such as N, W is CR1, Y is CR3 and Z is CR4.
4. A pharmaceutical composition according to claim 1, wherein X and Z are both N or N-oxide, such as N, W is CR1 and Y is CR3.
5. A pharmaceutical composition according to any one of claims 1 to 4, wherein R1, R2, R3 and R4, where present, are each independently selected from the group consisting of H, halo, optionally substituted C1-C6 alkyl, -O-R wherein R is selected from optionally substituted C1-C6 alkyl and optionally substituted aryl (such as phenyl), -NHR wherein R is optionally substituted aryl, an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S.
6. A pharmaceutical composition according to claim 5, wherein R1, R2, R3 and R4, where present, are each independently selected from the group consisting of H, halogen, -CF3, -CH F2, -OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl.
7. A pharmaceutical composition according to claim 5, wherein one or two of R1, R2, R3 and R4, where present, is H, and the others of R1, R2 , R3 and R4 that are not H are independently selected from the group consisting of halogen, -CF3, -CH F2, -OCF3, - OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl.
8. A pharmaceutical composition according to any one of claims 5 to 7, wherein R3 is present and selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl.
9. A pharmaceutical composition according to claim 2, wherein Z is N or N-oxide, such as N, W is CR1, X is CR2 and Y is CR3, and R3 is selected from the group consisting of halogen, -O-R wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl.
10. A pharmaceutical composition according to claim 2, wherein Z is N or N-oxide, such as N, W is CR1, X is CR2 and Y is CR3, R1 is H, and one or both of R2 and R3 are other than H, for example, both R2 and R3 are other than H, or R2 is H and R3 is other than H, or R3 is H and R2 is other than H .
11. A pharmaceutical composition according to claim 10, wherein each of R2 and R3 that is other than H is independently selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, -OR wherein R is selected from optionally
substituted C1-C6 alkyl and optionally substituted aryl, -N H R wherein R is optionally substituted aryl; an optionally substituted aryl, such as substituted phenyl, and an optionally substituted heteroaryl group.
12. A pharmaceutical composition according to claim 11, wherein each of R2 and R3 that is other than H is independently selected from the group consisting of halogen, - CF3, -CH F2, -OCF3, -OCH F2, Ci-6 alkyl such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -N H R wherein R is optionally substituted aryl.
13. A pharmaceutical composition according to any one of claims 1 to 4, wherein R1 and R2 taken together, or R2 and R3 taken together, or R3 and R4 taken together, form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from 0, N or S and the ring is optionally substituted with 1 to 4 substituents independently selected from R, and those of R1, R2, R3 and R4 that are not part of the ring, are independently selected from : H, halo, optionally substituted C1-C6 alkyl, O-R wherein R is optionally substituted C1-C6 alkyl, an optionally substituted aryl and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S.
14. A pharmaceutical composition according to any one of claims 1 to 13, wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is selected from any of the groups defined in paragraphs (c) and (d).
15. A pharmaceutical composition according to any one of claims 1 to 13, wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is selected from any of the groups defined in paragraph (c).
16. A pharmaceutical composition according to any one of claims 1 to 13, wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is selected from the group consisting of -C(0)R14, -C(0)OR14, -C(S)R14, and -C(S)OR14; wherein each R14 is independently selected from the group consisting of: (a) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and optionally one or two further substituents, and wherein said aryl is itself optionally substituted, and (b) optionally substituted aryl.
17. A pharmaceutical composition according to claim 16, where each R14 is optionally substituted alkyl having the formula -(CH2)n(aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
18. A pharmaceutical composition according to any one of claims 15 to 17, wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-e alkyl (such as C1-3 alkyl), and the other of R9 and R10 is -C(0)OR14.
19. A pharmaceutical composition according to any one of claims 1 to 13, wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is selected from the group consisting of -C(0)NR15R16 and -C(S)NR15R16, wherein each R15 and R16 is
independently selected from the group consisting of (a) H, (b) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and, optionally, one or two further substituents, and wherein said aryl is itself optionally substituted, and (c) optionally substituted aryl.
20. A pharmaceutical composition according to claim 19, wherein each R15 and R16 is independently selected from the group consisting of (a) H and (b) optionally substituted alkyl having the formula -(CH2)n(aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
21. A pharmaceutical composition according to claim 19 or claim 20, wherein one but not both of R15 and R16 is H.
22. A pharmaceutical composition according to claim 2, wherein Z is N or N-oxide, such as N, W is CR1, X is CR2 and Y is CR3, one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is is -C(0)OR14, wherein each R14 is independently selected from the group consisting of: (a) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and, optionally, one or two further
substituents, and wherein said aryl is itself optionally substituted, and (b) optionally substituted aryl.
23. A pharmaceutical composition according to claim 22, wherein R14 is optionally substituted alkyl having the formula -(CH2)n(aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
24. A pharmaceutical composition according to claim 22 or claim 23, wherein R1, R2 and R3 are each independently selected from the group consisting of H, halogen, -CF3, -CH F2, -OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
25. A pharmaceutical composition according to claim 22 or claim 23, wherein R1, R2 and R3 are each independently selected from the group consisting of H, halogen, Ci-6 alkyl, such as methyl, substituted aryl, and substituted heteroaryl.
26. A pharmaceutical composition according to claim 22 or claim 23, wherein one or two of R1, R2 and R3 is H, and the others of R1, R2 and R3 that are not H are independently selected from the group consisting of halogen, -CF3, -CH F2, -OCF3, - OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
27. A pharmaceutical composition according to claim 22 or claim 23, wherein R1 is H, and one of both of R2 and R3 is other than H, wherein each of R2 and R3 that is not H is independently selected from the group consisting of halogen, -CF3, -CH F2, -OCF3, - OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
28. A pharmaceutical composition according to any one of claims 22 to 27, wherein R3 is selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
29. A pharmaceutical composition according to claim 22 or claim 23, wherein R1 is H, and R2 and R3 form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from O, N and S and the ring is optionally substituted with 1 to 4 substituents independently selected from R.
30. A pharmaceutical composition according to claim 1, wherein the compound of formula 1 is selected from the group consisting of:
l-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4- (trifluoromethoxy)phenyl)urea (2)
l-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-cyanophenyl)urea (3)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b]pyridin-3-yl)-3-(2-chlorophenyl) urea
(6)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b]pyridin-3-yl)-3-(3-chlorophenyl) urea
(7) l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridin-3-yl)-3-(4-chlorophenyl) urea
(8)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(2- (trifluoromethoxy) phenyl) urea (9)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3-
(trifluoromethoxy) phenyl) urea ( 10)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(2- methoxyphenyl)urea ( 11)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3- methoxyphenyl)urea ( 12)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(4- methoxyphenyl)urea ( 13)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(2-
(trifluoromethyl)phenyl)urea ( 14)
l-(5-Chloro-4,6-di methylisoxazolo[5,4-b] pyridin-3-yl)-3-(4-
(trifluoromethyl)phenyl)urea ( 16)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-phenyl urea ( 17)
N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-2-phenylacetamide ( 18) N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-2-(4- (trifluoromethoxy)phenyl)acetamide ( 19)
Phenyl (5-chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)carbamate (4) l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3- (trifluoromethyl)phenyl)urea ( 15)
4-Fluorophenyl (5-chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)carbamate (5)
N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)acetamide (20)
and pharmaceutically acceptable salts thereof.
31. A pharmaceutical composition according to any one of the preceding claims, wherein the compound of Formula I is an IDO l inhibitor.
32. A pharmaceutical composition according to any one of claims 1 to 30, wherein the compound of Formula I is a TDO inhibitor.
33. A pharmaceutical composition according to any one of claims 1 to 30, wherein the compound is both an IDO l inhibitor and a TDO inhibitor.
34. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein :
Figure imgf000058_0001
W is CR1, N or N-oxide;
X is CR2, N or N-oxide;
Y is CR3, N or N-oxide;
Z is CR4, N or N-oxide;
and where at least one of W, X, Y, and Z is N or N-oxide;
R1, R2, R3 and R4 are each independently selected from the following groups: H, halo, R, -OH, -OR, -OC(0)H, -OC(0)R, -OC(0)NH2, -OC(0)NHR, -OC(0)NRR,-
OP(0)(OH)2, -OP(0)(OR)2, -NO2, -NH2, -NHR, -NRR, -N HC(0) H, -NHC(0)R, -NRC(0)R, -N HC(0) NH2, -NHC(0)N RR, -NRC(0)NHR, -SH, -SR, -S(0)H, -S(0)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -CN, -C≡CH, -C≡CR, -CH = CHR, -CH = CRR, -CR=CHR, -CR=CRR, -CO2H, -CO2R, -CHO, -C(0)R, -C(0)NH2, -C(0)NHR, - C(0)NRR, -CONHSO2H, -CONHSO2R, -CONRSO2R, cyclic C3-C7 alkylamino, imidazolyl, C1-C6 alkylpiperazinyl, morpholinyl and thiomorpholinyl ;
or R1 and R2 taken together, or R2 and R3 taken together, or R3 and R4 taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6- membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from O, N and S, and the ring is optionally substituted independently with 1 to 4
substituents selected from R;
each R is independently selected from any of the groups defined in
paragraphs (a) and (b) below:
(a) an optionally substituted Ci-6 alkyi group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group and an optionally substituted C3-7 cyclic alkyi group; wherein the one or more optional substituents for each of said alkyi, alkenyl, alkynyl and cyclic alkyi groups are each independently selected from the following groups : halo, -OH, -OR5, -OC(0)R5, -OC(0)NH2, - OC(0)NHR5, -OC(0)NR5R5, -OP(0)(OH)2, -OP(0)(OR5)2, -NO2, -NH2, -N HR5, -NR5R5, - N+(0")R5R5, -NHC(0)H, -NHC(0)R5, -NR5C(0)R5, -NHC(0)N H2, -NHC(0)NR5R5, -
NR5C(0)N HR5, -SH, -SR5, -S(0)H, -S(0)R5, -SO2R5, -SO2NH2, -SO2NHR5, -S02NR5R5, - CF3, -CHF2, -CH2F,-OCF3, -OCHF2, -CN, -CO2H, -CO2R5, -CHO, -C(0)R5, -C(0)NH2, - C(0)NHR5, -C(0)NR5R5, -CONHSO2H, -C(0)NHS02R5, -C(0)NR5S02R5, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more of the following groups: Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cyclic alkyl, halo, -OH, -OR7, -OC(0)R7, -
OC(0)NH2 -OC(0)NHR7, -OC(0)NR7R7, -OP(0)(OH)2, -OP(0)(OR7)2, -NO2, -NH2, -NHR7, -NR7R7, -N+(0") R7R7, -NHC(0)H, -NHC(0)R7, -NR7C(0)R7, -NHC(0)NH2, - NHC(0)NR7R7, -NR7C(0)NHR7, -SH, -SR7, -S(0)H, -S(0)R7, -S02R7, -S02NH2, - S02NHR7,-S02NR7R7, -CF3, -CHF2, -CH2F,-OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -C02H, - C02R7, -CHO, -C(0)R7, -C(0)NH2, -C(0)NHR7, -C(0)NR7R7, -CONHS02H, -
C(0)NHS02R7, -C(0)NR7S02R7, an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S; and wherein the one or more optional substituents for each of said aryl and heteroaryl groups are each independently selected from the following groups: Ci-6 alkyl, C2-e alkenyl, C2-e alkynyl or C3-7 cyclic alkyl, halo, -OH, -OR8, -OC(0)R8, - OC(0)NH2, -OC(0)NHR8, -OC(0)NR8R8, -OP(0)(OH)2, -OP(0)(OR8)2, -NO2, -IMH2, - NHR8, -NR8R8, -N+(0 )R8R8, -NHC(0)H, -NHC(0)R8, -NR8C(0)R8, -NHC(0)NH2, - NHC(0)NR8R8, -NR8C(0)NHR8, -SH, -SR8, -S(0)H, -S(0)R8, -S02R8, -S02NH2, - S02NHR8,-S02NR8R8, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -C02H, - C02R8, -CHO, -C(0)R8, -C(0)NH2, -C(0)NHR8, -C(0)NR8R8, -CONHS02H, - C(0)NHS02R8, and -C(0)NR8S02R8; wherein each R5, R7 and R8 is independently selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7
■ m Wb> ■ fie IS¾| ^H - ffiHrfi- (b) an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S; and wherein the one or more optional substituents are each independently selected from the same optional substituents as those defined in (a) above for R;
R9 and R10 are each independently selected from any of the groups defined in paragraphs (a) to (d) below, with the proviso that at least one of R9 and R10 is selected from any of the groups defined in paragraphs (c) and (d) below:
(a) H, an optionally substituted Ci-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, and an optionally substituted C3-7 cyclic alkyl group; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and cyclic alkyl are each independently selected from the following groups: halo, -OH, -OR11, -OC(0)Rn, -OC(0)NH2, -OC(0)NHRn, - OC(0)NRnRn, -OP(0)(OH)2, -OP(0)(ORn)2, -NO2, -NH2, -NHR11, -NR11R11, -N+(0 " )RnRn, -NHC(0)H, -NHC(0)Rn, -NR11C(0)R11, -NHC(0)NH2, -NHC(0)NR11R11, - NR11C(0)NHR11, -SH, -SR11, -S(0)H, -S(0)Rn, -SO2R11, -SO2NH2, -SO2NHR11, - S02NRnRn, -CF3, -CHF2, -CH2F,-OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -CO2H, -CO2R11, - CHO, -C(0)Rn, -C(0)NH2, -C(0)NHRn, -C(0)NR11R11, -CONHSO2H, -C(0)NHS02Rn, - C(0)NR11S02R11, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, azetidinyl, aryl, and heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S; wherein each of the groups cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl azetidinyl, aryl and heteroaryl are optionally substituted by one or more of the following groups: Ci-6 alkyi, C2-6 alkenyl, C2-6 alkynyl, C3-7 cyclic alkyi, halo, -OH, -OR13, -OC(0)R13, -OC(0)NH2, -OC(0)NHR13, - OC(0)NR13R13, -OP(0)(OH)2, -OP(0)(OR13)2, -NO2, -IMH2, -NHR13, -NR13R13 -N+(0 " )R13R13, -NHC(0)H, -NHC(0)R13, -NR13C(0)R13, -NHC(0)NH2, -NHC(0)NR13R13, - NR13C(0)NHR13, -SH, -SR13, -S(0)H, -S(0)R13, -SO2R13, -SO2NH2, -SO2NHR13,- S02NR13R13, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, ,-SCFa, -SCF2H, -CN, -CO2H, -CO2R13, - CHO, -C(0)R13, -C(0)NH2, -C(0)NHR13, -C(0)NR13R13, -CONHSO2H, -C(0)NHS02R13, and -C(0)NR13S02R13; wherein each Rn and R13 is independently selected from a Ci-6 alkyi group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7 cyclic alkyi group;
(b) an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S; and wherein the one or more optional substituents for each of said aryl and heteroaryl are each
independently selected from the same optional substituents as those defined in (a) above for R9 and R10;
(c) -C(0)R14, -C(0)OR14, -C(0)NR15R16, -C(0)SR14, -C(S)R14, -C(S)OR14 C(S)NR15R16, and -C(S)SR14, wherein each R14, R15 and R16 is independently selected from the group consisting of H, optionally substituted Ci-6 alkyi, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-7 cyclic alkyi, optionally substituted aryl, and optionally substituted heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S, and wherein the one or more optional substituents for each of said alkyi, alkenyl, alkynyl, cyclic alkyi, aryl and heteroaryl for R14, R15 and R16 are each independently selected from the same optional substituents as those defined in (a) above for R9 and R10; and (d) -S02(CRR)nR17, wherein n is an integer of from 0 to 6, each R is independently selected from the groups defined above for R, and R17 is optionally substituted aryl or optionally substituted heteroaryl having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from 0, N and S, and wherein the one or more optional substituents for each of said aryl and heteroaryl are independently selected from the same optional substituents as those defined in (a) above for R9 and R10; and -SO2R18, wherein R18 is optionally substituted Ci ealkyl or optionally substituted C3-7 cyclic alkyl, wherein the one or more optional substituents for each of said alkyl and cyclic alkyl are each independently selected from those defined in (a) above for R9 and R10; with the proviso that at least one of R1, R2, R3 and R4 , where present, is other than H or methyl, and
with the further proviso that the compound is not selected from the following : 2-Bromo-N-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)acetamide,
N-(6-Phenyl-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-yl)cyclopropanecarboxamide, and
2-Phenyl-N-(6-phenyl-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-yl)acetamide.
35. A compound according to claim 34, wherein Z is N or N-oxide, such as N, W is CR1, X is CR2 and Y is CR3.
36. A compound according to claim 34, wherein X is N or N-oxide, such as N, W is CR1, Y is CR3 and Z is CR4.
37. A compound according to claim 34, wherein X and Z are both N or N-oxide, such as N, W is CR1 and Y is CR3.
38. A compound according to any one of claims 34 to 37, wherein R1, R2, R3 and R4, where present, are each independently selected from the group consisting of H, halo, optionally substituted C1-C6 alkyl, -O-R wherein R is selected from optionally substituted C1-C6 alkyl and optionally substituted aryl (such as phenyl), -NHR wherein R is optionally substituted aryl, an optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S.
39. A compound according to claim 38, wherein R1, R2, R3 and R4, where present, are each independently selected from the group consisting of H, halogen, -CF3, -CH F2, -OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, - OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
40. A compound according to claim 38, wherein one or two of R1, R2, R3 and R4, where present, is H, and the others of R1, R2 , R3 and R4 that are not H are
independently selected from the group consisting of halogen, -CF3, -CH F2, -OCF3, - OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
41. A compound according to any one of claims 38 to 40, wherein R3 is present and selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
42. A compound according to claim 35, wherein Z is N or N-oxide, such as N, W is CR1, X is CR2 and Y is CR3, and R3 is selected from the group consisting of halogen, - O-R wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
43. A compound according to claim 35, wherein Z is N or N-oxide, such as N, W is CR1, X is CR2 and Y is CR3, R1 is H, and one or both of R2 and R3 are other than H, for example, both R2 and R3 are other than H, or R2 is H and R3 is other than H, or R3 is H and R2 is other than H.
44. A compound according to claim 43, wherein each of R2 and R3 that is other than H is independently selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, -OR wherein R is selected from optionally substituted C1-C6 alkyl and optionally substituted aryl, -NHR wherein R is optionally substituted aryl; an optionally substituted aryl, such as substituted phenyl, and an optionally substituted heteroaryl group.
45. A compound according to claim 44, wherein each of R2 and R3 that is other than H is independently selected from the group consisting of halogen, -CF3, -CH F2, - OCF3, -OCH F2, Ci-6 alkyl such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
46. A compound according to any one of claims 34 to 37, wherein R1 and R2 taken together, or R2 and R3 taken together, or R3 and R4 taken together, form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from 0, N or S and the ring is optionally substituted with 1 to 4 substituents independently selected from R, and those of R1, R2, R3 and R4 that are not part of the ring, are independently selected from : H, halo, optionally substituted C1-C6 alkyl, O-R wherein R is optionally substituted C1-C6 alkyl, an optionally substituted aryl and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system which are each independently selected from O, N and S.
47. A compound according to any one of claims 34 to 46, wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as Ci-3 alkyl), and the other of R9 and R10 is selected from any of the groups defined in paragraphs (c) and (d).
48. A compound according to any one of claims 34 to 46, wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as Ci-3 alkyl), and the other of R9 and R10 is selected from any of the groups defined in paragraph (c) .
49. A compound according to any one of claims 34 to 46, wherein
one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is selected from the group consisting of -C(0)R14, -C(0)OR14, -C(S)R14, and -C(S)OR14; wherein each R14 is independently selected from the group consisting of: (a) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and optionally one or two further substituents, and wherein said aryl is itself optionally substituted, and (b) optionally substituted aryl.
50. A compound according to claim 49, where each R14 is optionally substituted alkyl having the formula -(CH2)n(aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
51. A compound according to any one of claims 48 to 50, wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as Ci-3 alkyl), and the other of R9 and R10 is -C(0)OR14.
52. A compound according to any one of claims 34 to 46, wherein one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as Ci-3 alkyl), and the other of R9 and R10 is selected from the group consisting of -C(0)NR15R16 and -C(S)NR15R16, wherein each R15 and R16 is independently selected from the group consisting of (a) H, (b) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and, optionally, one or two further substituents, and wherein said aryl is itself optionally substituted, and (c) optionally substituted aryl.
53. A compound according to claim 52, wherein each R15 and R16 is independently selected from the group consisting of (a) H and (b) optionally substituted alkyl having the formula -(CH2)n(aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
54. A compound according to claim 52 or claim 53, wherein one but not both of R15 and R16 is H.
55. A compound according to claim 35, wherein Z is N or N-oxide, such as N, W is CR1, X is CR2 and Y is CR3, one of R9 and R10 is selected from the group consisting of H and optionally substituted Ci-6 alkyl (such as C1-3 alkyl), and the other of R9 and R10 is is -C(0)OR14, wherein each R14 is independently selected from the group consisting of: (a) optionally substituted Ci-6 alkyl, for example Ci-6 alkyl wherein said alkyl is substituted by aryl and, optionally, one or two further substituents, and wherein said aryl is itself optionally substituted, and (b) optionally substituted aryl.
56. A compound according to claim 55, wherein R14 is optionally substituted alkyl having the formula -(CH2)n(aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and said aryl is optionally substituted.
57. A compound according to claim 55 or claim 56, wherein R1, R2 and R3 are each independently selected from the group consisting of H, halogen, -CF3, -CHF2, -OCF3, - OCHF2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.
58. A compound according to claim 55 or claim 56, wherein R1, R2 and R3 are each independently selected from the group consisting of H, halogen, Ci-6 alkyl, such as methyl, substituted aryl, and substituted heteroaryl .
59. A compound according to claim 55 or claim 56, wherein one or two of R1, R2 and R3 is H, and the others of R1, R2 and R3 that are not H are independently selected from the g roup consisting of halogen, -CF3, -CH F2, -OCF3, -OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl .
60. A compound according to claim 55 or claim 56, wherein R1 is H, and one of both of R2 and R3 is other than H, wherein each of R2 and R3 that is not H is
i ndependently selected from the group consisting of halogen, -CF3, -CH F2, -OCF3, - OCH F2, Ci-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl .
61. A compound according to any one of claims 55 to 60, wherein R3 is selected from the g roup consisting of halogen, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl .
62. A compound according to claim 55 or claim 56, wherei n R1 is H, and R2 and R3 form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1 to 3 heteroatoms selected from O, N and S and the ring is optionally substituted with 1 to 4 substituents independently selected from R.
63. A compound according to claim 34, wherein the compound of formula 1 is selected from the group consisting of:
l-(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-3-(4- (trifluoromethoxy) phenyl) urea (2)
l-(5-chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-3-(4-cyanophenyl)urea (3)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridin-3-yl)-3-(2-chlorophenyl) urea (6)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridin-3-yl)-3-(3-chlorophenyl) urea
(7) l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridin-3-yl)-3-(4-chlorophenyl) urea
(8)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(2- (trifluoromethoxy) phenyl) urea (9)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3- (trifluoromethoxy) phenyl) urea ( 10)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(2- methoxyphenyl)urea ( 11)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3- methoxyphenyl)urea ( 12)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(4- methoxyphenyl)urea ( 13)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(2-
(trifluoromethyl)phenyl)urea ( 14)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(4- (trifluoromethyl)phenyl)urea ( 16)
l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-phenyl urea ( 17) N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-2-phenylacetamide ( 18) N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-2-(4- (trifluoromethoxy)phenyl)acetamide ( 19)
Phenyl (5-chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)carbamate (4) l-(5-Chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)-3-(3- (trifluoromethyl)phenyl)urea ( 15)
4-Fluorophenyl (5-chloro-4,6-di methyl isoxazolo[5,4-b] pyridi n-3-yl)carbamate (5)
N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)acetamide (20)
and pharmaceutically acceptable salts thereof.
64. A compound according to any one of claims 34 to 63, wherein the compound of Formula I is an IDO l inhibitor.
65. A compound according to any one of claims 34 to 63, wherein the compound of Formula I is a TDO inhibitor.
66. A compound according to any one of claims 34 to 63, wherein the compound is both an IDOl inhibitor and a TDO inhibitor.
67. The use of a compound of Formula I, as defined in any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament.
68. The use of a compound of Formula I, as defined in any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a warm blooded animal, including a human.
69. The use of a compound of Formula I, as defined in any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a warm blooded animal, including a human, wherein the treatment comprises administration of the compound of Formula I and one or more additional agents selected from the group consisting of chemotherapeutic agents, immune- modulating agents such as anti-cancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)), and radiotherapy, and wherein the additional agent is administered either before, during or after administration of the compound of Formula I.
70. The use according to claim 69, wherein the additional agent comprises an immune-modulating agent.
71. A method of treating cancer in a warm blooded animal, including a human, comprising administering to the animal a therapeutically effective amount of a compound of Formula I, as defined in any one of claims 1 to 66, or a
pharmaceutically acceptable salt thereof.
72. A method of treating cancer in a warm blooded animal, including a human, wherein the method comprises administering to the animal a therapeutically effective amount of a compound of Formula I, as defined in any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, and wherein the method further includes the step of administering one or more additional agents selected from the group consisting of chemotherapeutic agents, immune-modulating agents such as anti-cancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)), and radiotherapy, and wherein the additional agent is administered either before, during or after
administration of the compound of Formula I.
73. A method according to claim 72, wherein the additional agent comprises an immune-modulating agent.
74. A method of inhibiting indoleamine 2,3-dioxygenase 1 (IDOl) in a warm blooded animal in need thereof, including a human, comprising administering to the animal a compound of Formula I, as defined in any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, having IDOl inhibitory activity, in an amount effective to inhibit IDOl.
75. A method of inhibiting tryptophan 2,3-dioxygenase (TDO) in a warm blooded animal in need thereof, including a human, comprising administering to the animal a compound of Formula I, as defined in any one of claims 1 to 66, or a
pharmaceutically acceptable salt thereof, having TDO inhibitory activity, in an amount effective to inhibit TDO.
76. A method of inhibiting IDOl and TDO in a warm blooded animal in need thereof, including a human, comprising administering to the animal a compound of Formula I, as defined in any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof having both IDOl and TDO inhibitory activity, in an amount effective to inhibit IDOl and TDO.
77. A pharmaceutical combination or kit, comprising
(a) a compound of Formula I, as defined in any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, and
(b) one or more additional agents selected from the group consisting of chemotherapeutic agents, and immune-modulating agents such as anti-cancer vaccines, modulators of immune checkpoint proteins and adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)).
78. A pharmaceutical combination or kit, for use in treating cancer, comprising
(a) a compound of Formula I, as defined in any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, and
(b) one or more additional agents selected from the group consisting of chemotherapeutic agents, and immune-modulating agents such as anticancer vaccines, modulators of immune checkpoint proteins and adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)).
79. The use of a compound of Formula I, as defined in any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a condition or disorder selected from the group consisting of: an
inflammatory condition, an infectious disease, a central nervous system disease or disorder, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, a condition or disorder relating to female reproductive health, and cataracts.
80. A method of treating a condition or disorder selected from the group consisting of: an inflammatory condition, an infectious disease, a central nervous system disease or disorder, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, a condition or disorder relating to female reproductive health, and cataracts, in a warm blooded animal, including a human, wherein the method comprises administering to the animal a therapeutically effective amount of a compound of Formula I, as defined in any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof.
PCT/NZ2016/050135 2015-08-27 2016-08-25 Inhibitors of tryptophan dioxygenases (ido1 and tdo) and their use in therapy WO2017034420A1 (en)

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CN201680063267.2A CN108349997A (en) 2015-08-27 2016-08-25 Tryptophan dioxygenase（IDO1 and TDO）Inhibitor and its purposes in the treatment
KR1020187008532A KR20180048798A (en) 2015-08-27 2016-08-25 Inhibitors of tryptophan dioxygenase (IDO1 and TDO) and their use in therapy
US15/755,750 US11414428B2 (en) 2015-08-27 2016-08-25 Inhibitors of tryptophan dioxygenases (IDO1 and TDO) and their use in therapy
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