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  • 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
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • 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
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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 Tryptophan2,3-dioxygenase
• TDO inhibitors may also have wide ranging therapeutic efficacy in 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,- OP(0)(OH) 2 , -OP(0)(OR) 2 , -N0 2 , -NH 2 , -NHR, -NRR, -NHC(0)H, -NHC(0)R, -NRC(0)R, -NHC(0)NH 2 , -NHC(0)NRR, -NRC(0)NHR, -SH, -SR, -S(0)H, -S(0)R, -S0 2 R, -S0 2 NH 2 , -S0 2 NHR, -S0 2 NRR, -CF 3 , -CHF 2 -CH 2 F -OCF 3 _OCHF 2 , -CN, -C ⁇ CH, -
• 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
• C(0)NR 7 S0 2 R 7 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, C 2 . 6 alkenyl, C 2 . 6 alkynyl or C 3 .
• R 9 and R 10 are each independently selected from any of the groups defined in paragraphs (a) and (b) below:
• R 9 and R 10 taken together can form 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 can be optionally substituted independently with 1 to 5 substituents selected from the same optional substituents as those defined in (a) above for R 9 and R 10 ;
• 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
• 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
• a compound of Formula I or a pharmaceutically acceptable salt thereof (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)).
• chemotherapeutic 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)).
• 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
• 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
• 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 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 substituents selected from R;
• each R is independently selected from the following groups defined in paragraphs (a) and (b) below:
• each R 5 , R 7 and R 8 is independently selected from a Ci- 6 alkyl group, a C 2 -6 alkenyl group, a C 2 - 6 alkynyl group and a C 3 - 7 cyclic alkyl group;
• R 9 and R 10 are each independently selected from the following groups definedaphs (a) and (b) below:
• R 9 and R 10 taken together can form 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 can be optionally substituted independently with 1 to 5 substituents selected from the same optional substituents as those defined in (a) above for R 9 and R 10 .
• R 9 and R 10 are each independently selected from the following groups: an optionally substituted Ci- 6 alkyl group, an optionally substituted C 2 - 6 alkenyl group, an optionally substituted C 2 - 6 alkynyl group, and an optionally substituted C 3 - 7 cyclic alkyl group; then 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, -OR 11 , -OC(0)R n , -OC(0)NH 2 , - OC(0)NHR n , -OC(0)NR n R n , -OP(0)(OH) 2 , -OP(0)(OR n ) 2 , -N0 2 , -NH 2 , -NHR 11 , -NR 11 R 11 , -N + (0 )R n R n
• R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, halo, optionally substituted Ci-C 6 alkyl, -O-R wherein R is optionally substituted Ci-C 6 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 0, 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 Ci-C 6 alkyl, -O-R wherein R is selected from optionally substituted Ci-C 6 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 , -CHF 2 , -OCF 3 , -OCHF 2 , Ci-e alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally
• 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 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 Ci-C 6 alkyl, -OR wherein R is selected from optionally substituted Ci-C 6 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, -CF 3 , -CH F 2 , -OCF 3 , -OCH F 2 , Ci- 6 alkyl such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -
• R is optionally substituted aryl
• Ci- 6 alkyl group 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 0, N and S.
• aryl such as substituted phenyl
• 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 and R 3 are each independently selected from the group consisting of H, halogen, -CF 3 , -CHF 2 , -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 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 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, -CF 3 , -CHF 2 , - 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.
• 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.
• Certain compounds of the Formula I are novel. Accordingly, such compound: are provided as a further feature of the invention.
• the invention further provides a compound of Formula I selected from the following:
• * and ** denotes significance (p ⁇ 0.05, p ⁇ 0.01, respectively) by one-way ANOVA and Sidak's multiple comparisons compared to DMSO controls.
• Figure 3 shows survival to humane ethical end point of a study with mice with sc GL261-hID01 tumours treated with vehicle (A); Compound 3 at 75 mg/kg (B) IP daily, beginning 8 days after tumor implantation; anti-immune checkpoint antibodies (C) against anti-PDl (Top: 250 pg/mouse IP on days 8, 11 and 14 after tumor implantation) or anti-CTLA4 (Bottom : 1 mg/mouse IP 6 days after tumor implantation); or a combination (D) of Compound 3 plus immune checkpoint antibody.
• P-values indicate significant difference by Log-rank analysis compared to vehicle survival curves. Coloured arrowheads indicate dosing schedule.
• 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.
• 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. It is to be understood that the term “aryl” means an aromatic hydrocarbon such as phenyl or naphthyl.
• Ci-C 6 alkyl or C 2 -C 6 alkenyl group these groups may be unbranched or branched.
• reference to a Ci-C 6 alkyl would include a tert-butyl (Me) 3 C- 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:
• 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.
• 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
• Certain compounds of Formula I may be prepared by reaction of an
• 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 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).
• Compounds containing alkyl and/or aryl ether-linked substituents may be prepared by displacement of an activated halogen atom by alcohols and/or phenols, the presence of a base such as sodium or sodium hydride or cesium carbonate (Method 7).
• Compounds containing thioalkyl 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 thioalkyl 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).
• 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) 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 (an inhibitor of CTLA4), Nivolumab and Lambrolizumab (both inhibitors of PD-1).
• immunotherapies selected from Ipilimumab (an inhibitor of CTLA4), Nivolumab and Lambrolizumab (both 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), 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
• 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.
• 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.
• 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.
• 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 rectaiiy 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.
• 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.
• 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 .
• 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.
• 6-Methylisoxazolo[5,4-b]pyridin-3-amine (48 mg, 0.32 mmol) was dissolved in concentrated H 2 S0 4 (5 mL) at 0°C, then Cr0 3 (160 mg, 1.6 mmol) was added and stirring was continued for 20 hr at 20°C. The mixture was then stirred in ice, and the resulting precipitate was filtered, washed with H 2 0, and a 1 : 1 mixture of pet.
• 6-Methylisoxazolo[5,4-b] pyridin-3-amine (248 mg, 1.66 mmol) was dissolved i n cooled concentrated H 2 S0 4 ( 10 ml) at 0°C then Cr0 3 (350 mg, 3.5 mmol) was added and the mixture was stirred at 20°C for 3 days. After cooling to 0°C MeOH ( 1 ml) was added and stirring was continued at 20°C for 20 hr. The mixture was diluted with water and extracted into EtOAc.
• Recombinant human IDOl (rhIDO l) 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 rhIDO l ( 15 ⁇ ) at a fi nal concentration of 9 nM in a total volume of 30 [ L assay medium .
• Lewis Lung carcinoma cells transfected to express human IDOl (LLTC-hlDO l) or murine (LLTC-mlDO l) were cultured with test compounds at 37°C, 5% C0 2 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 ICso 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% C0 2 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 ICso ranges: A; ⁇ 1 ⁇ , B; 1-10 ⁇ , C; 10-100 ⁇ , D; > 100 ⁇
• Tumours were implanted subcutaneously into syngeneic C57BI/6 mice and allocated into different treatment groups when tumours had reached approximately 3x3 mm in size. Compounds were dissolved in DMSO and the dose in a volume of 50 ml was administered by daily injection either ip or sc. Tumours were measured every second day and mice were monitored until humane ethical endpoint was reached.
• K:T ratios in plasma and tumours from mice with 16 day subcutaneous GL- 261-hIDOl tumours (tumour size 15-20 mm), were determined by analytical HPLC 0.25h, lh, 2h, 4h, 6h and 24h following treatment with 150 mg/kg Compound 3, n 3 per time point.
• DMSO vehicle control group (n 21) pooled from 3 mice, 0.25h, lh, 2h, 4h, 6h and 24h following treatment with DMSO. * and ** denotes significance (p ⁇ 0.05, p ⁇ 0.01, respectively) by one-way ANOVA and Sidak's multiple comparisons compared to DMSO controls.
• Figure 3 shows survival to humane ethical end point of a study with mice with sc GL261-hID01 tumours treated with vehicle (A); Compound 3 at 75 mg/kg (B) IP daily, beginning 8 days after tumor implantation; anti-immune checkpoint antibodies (C) against anti-PDl (Top: 250 pg/mouse IP on days 8, 11 and 14 after tumor implantation) or anti-CTLA4 (Bottom : 1 mg/mouse IP 6 days after tumor

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