Combination for use in the treatment of glioma

Abstract

The invention relates to the use of a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase-2 (TDO2), in combination with temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, in the treatment of glioma. In particular, the present invention generally relates to the use of a dual inhibitor of IDO1 and TDO2, in combination with TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, in the treatment of glioblastoma. The present invention also relates to uses, combinations, combination products and kits thereof for treating glioma in a subject.

Description

[0001] COMBINATION FOR USE IN THE TREATMENT OF GLIOMA

[0002] RELATED APPLICATIONS

[0003] This application derives priority from Australian patent application number 2023902805, incorporated herein by reference.

[0004] TECHNICAL FIELD

[0005] The present invention generally relates to the use of a dual inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase-2 (TDO2), in combination with temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, in the treatment of glioma. In particular, the present invention generally relates to the use of a dual inhibitor of IDO1 and TDO2, in combination with temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, in the treatment of glioblastoma. The present invention also relates to uses, combinations, combination products and kits thereof for treating glioma in a subject.

[0006] BACKGROUND TO THE INVENTION

[0007] Glioblastoma multiforme is the most commonly occurring tumour of the central nervous system, accounting for up to 80% of primary malignant central cancers (Schwartzbaum JA et al., (2006). Nat Clin Pract Neurol, 2, 494-503) and is a deadly disease with extremely poor prognosis. Patients have a median survival of only 14-15 months from diagnosis following current best treatment approaches (Thakkar JP et al., (2014) Cancer Epidemiol Biomarkers Prev. 23: 1985-96). While surgery is often attempted it is not always possible and as glioblastomas are highly invasive, relapse following surgical excision occurs in 80% of cases close to the original tumour (lacob G et al., (2009). J Med Life 2: 386). Any surgery conducted is commonly followed by radiation treatment, which can extend survival in high grade gliomas (Scott J et al., (2011). Int J Radiat Oncol Biol Phys. 81 : 206-10), but is not always advantageous or indicated, leaving chemotherapy as the only recourse for many patients.

[0008] Temozolomide (TMZ), either used alone or in combination with radiotherapy, has become the standard-of-care chemotherapeutic drug for the treatment of glioblastomas (Reardon DA et al., (2006). Oncologist 11 : 52-164) on the basis of moderately prolonging survival (Stupp R et al., (2005) N Engl J Med 352: 987- 96). TMZ is an alkylating agent that works by methylating guanine bases in DNA at N7 and 06, leading to futile cycling of the DNA miss-match repair (MMR) system, cell cycle arrest, double-strand DNA breaks and apoptosis (Mojas, N et al., (2007). Genes Dev. 21 (24): 3342-3355). Unfortunately, most glioblastoma patients are, or become, resistant to TMZ due to high expression of the repair protein O6-methylguanine-DNA methyltransferase (MGMT) (Hegi ME et al., (2005). N Engl J Med 352: 997-1003) or due to rapid resistance development as a consequence of drug-induced damage to the MMR pathway (Sarkaria JN et al., (2008). Clin Cancer Res. 14: 2900-8).

[0009] There is an ongoing need for methods, uses, combinations, combination products, pharmaceutical combinations, compositions and kits for treating such gliomas and, more particularly, glioblastomas. It is an object of the present invention to go some way to meeting this need, and / or at least to provide the public with a useful choice.

[0010] Other objects of the invention may become apparent from the following description which is given by way of example only.

[0011] In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

[0012] SUMMARY OF THE INVENTION

[0013] In a first aspect, the present invention provides a method of treating glioma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase-2 (TDO2) and temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0014] In a second aspect, the present invention provides a use of a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase-2 (TDO2) in the manufacture of a medicament for treating glioma in a subject, wherein said medicament is to be administered in combination with temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0015] In a third aspect, the present invention provides a use of temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating glioma in a subject, wherein said medicament is to be administered in combination with a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase-2 (TDO2).

[0016] In a fourth aspect, the present invention provides a use of a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase-2 (TDO2) and temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating glioma in a subject. In a fifth aspect, the present invention provides a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase-2 (TDO2) and temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of glioma in a subject.

[0017] In a sixth aspect, the present invention provides a combination, such as a combination product or a pharmaceutical combination, for use in the treatment of glioma in a subject, wherein the pharmaceutical combination comprises (a) a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1 ) and tryptophan-2,3-dioxygenase-2 (TDO2) and (b) temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0018] In a seventh aspect, the present invention provides a kit for use in the treatment of glioma in a subject, wherein the kit comprises (a) a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1 ) and tryptophan-2,3-dioxygenase-2 (TDO2) and (b) temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0019] The following embodiments and preferences may relate alone or in any combination of any two or more to any of the above aspects.

[0020] In various embodiments, the glioma is astrocytoma, ependymoma or oligodendroglioma. In various embodiments, the glioma is astrocytoma. In various embodiments, the glioma is glioblastoma.

[0021] In various embodiments, the dual inhibitor of IDO1 and TDO2 is formulated as a pharmaceutical composition comprising the dual inhibitor of IDO1 and TDO2 and a pharmaceutically acceptable carrier.

[0022] In various embodiments, the dual inhibitor of IDO1 and TDO2 is formulated for oral or intravenous administration. In various embodiments, the dual inhibitor of IDO1 and TDO2 is formulated for oral administration. In various embodiments, the dual inhibitor of IDO1 and TDO2 is formulated for intravenous administration.

[0023] In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition comprising the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is formulated for oral or intravenous administration. In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is formulated for intravenous administration. In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is formulated for oral administration. In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof and the dual inhibitor of IDO1 and TDO2 are or are to be administered simultaneously, sequentially or separately. In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is or is to be administered orally or intravenously. In various embodiments, the dual inhibitor of IDO1 and TDO2 is or is to be administered orally or intravenously.

[0024] In various embodiments, the method comprises a step of administering 1 mg to 2000 mg of the dual inhibitor of IDO1 and TDO2 daily, or 1 mg to 2000 mg of the dual inhibitor of IDO1 and TDO2 every two days, every three days, every four days, every five days, every six days or every seven days. In various embodiments, the use, combination or kit comprise a dual inhibitor of IDO1 and TDO2 that is to be administered at a dose of 1 mg to 2000 mg per day, or to be administered at a dose of 1 mg to 2000 mg every two days, every three days, every four days, every five days, every six days or every seven days. In various embodiments, the dual inhibitor of IDO1 and TDO2 is administered or is to be administered in a single dose or as multiple doses throughout the day, for example in 2, 3, 4 or more separate doses.

[0025] In various embodiments, the method comprises a step of administering the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof at a dose of about 50 to 300 mg / m2(body surface area (BSA)) or 75 to 200 mg / m2(BSA), for example, 75, 150, or 200 mg / m2(BSA) on a once-daily basis. In various embodiments, the use, combination or kit comprise the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, that is to be administered at a dose of about 50 to 300 mg / m2(body surface area (BSA)) or 75 to 200 mg / m2(BSA), for example, 75, 150, or 200 mg / m2(BSA) on a once-daily basis.

[0026] In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is a compound of formula A:

[0027] Formula A wherein:

[0028] R1is hydrogen, or an alkyl group containing from 1 to 6 carbon atoms or an alkenyl or alkynyl group containing from 2 to 6 carbon atoms, or said an alkyl, alkenyl or alkynyl group substituted by from one to three substituents independently selected from halogen, alkoxy, alkylthio, a Ikylsulphinyl and alkylsulphonyl groups containing up to 4 carbon atoms, and phenyl substituted by alkoxy and alkyl groups containing from 1 to 4 carbon atoms or a nitro group; or R1is a cycloalkyl group containing from 3 to 8 carbon atoms; and R2is a carbamoyl group, or a carbamoyl group carrying on the nitrogen atom one or two groups selected from alkyl and alkenyl groups containing up to 4 carbon atoms, and cycloalkyl groups containing from 3 to 8 carbon atoms; or, when R1is hydrogen, an alkali metal salt thereof.

[0029] In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is a compound of formula A wherein R1is methyl. In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is a compound of formula A wherein R2is a carbamoyl group. In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is a compound of formula A wherein R1is methyl and wherein R2is a carbamoyl group.

[0030] In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1 - d]-as-tetrazine-8-carboxamide (TMZ): , or a pharmaceutically acceptable salt thereof.

[0031] In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1 - d]-as-tetrazine-8-carboxamide (TMZ):

[0032]

[0033] In various embodiments, the dual inhibitor of IDO1 and TDO2 has cellular TDO2 inhibitory activity that is greater than, or equal to, the cellular I DOI inhibitory activity. In various embodiments, the dual inhibitor of IDO1 and TDO2 has a cellular IDO1 IC50 of less than 100 pM as determined by a cell-based assay for IDO1 inhibition; and has a cellular TDO2 IC50 of less than 100 pM as determined by a cellbased assay for TDO2 inhibition. In various embodiments, the dual inhibitor of IDO1 and TDO2 has a cellular IDO1 IC50 of less than 10 pM as determined by a cell-based assay for IDO1 inhibition; and has a cellular TDO2 IC50 of less than 10 pM as determined by a cell-based assay for TDO2 inhibition. In various embodiments, the dual inhibitor of IDO1 and TDO2 has a cellular IDO1 IC50 of less than 1 pM as determined by a cell-based assay for IDO1 inhibition; and has a cellular TDO2 IC50 of less than 1 pM as determined by a cell-based assay for TDO2 inhibition.

[0034] In various embodiments, the dual inhibitor of IDO1 and TDO2 is as described in the numbered paragraphs (1) to (49) below.

[0035] (1) A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the compound is a dual inhibitor of IDO1 and TDO, and wherein:

[0036] W is CR1, N or N-oxide;

[0037] X is CR2, N or N-oxide;

[0038] Y is CR3, N or N-oxide;

[0039] 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, R3and R4are each independently selected from the following groups: H, halo, R, -OH, -OR, -OC(O)H, -OC(O)R, -OC(O)NH2, -OC(O)NHR, - CONHSO2R, -CONRSO2R, cyclic C3-C7 alkylamino, imidazolyl, Ci-Ce - alkylpiperazinyl, morpholinyl and thiomorpholinyl; or R1and R2taken together, or R2and R3taken together, or R3and R4taken 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:

[0040] (a) an optionally substituted C1-6 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(O)R5, -OC(O)NH2, -OC(O)NHR5, -OC(O)NR5R5, -OP(O)(OH)2, - OP(O)(OR5)2, -NO2, -NH2, -NHR5, -NR5R5, -N+(O )R5R5, -NHC(O)H, -NHC(O)R5, - NR5C(O)R5, -NHC(O)NH2, -NHC(O)NR5R5, -NR5C(O)NHR5, -SH, -SR5, -S(O)H, - S(O)R5, -SO2R5, -SO2NH2, -SO2NHR5, -SO2NR5R5, -CF3, -CHF2, -CH2F,-OCF3, - OCHF2, -CN, -CO2H, -CO2R5, -CHO, -C(O)R5, -C(O)NH2, -C(O)NHR5, -C(O)NR5R5, -CONHSO2H, -C(O)NHSO2R5, -C(O)NR5SO2R5, 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: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cyclic alkyl, halo, -OH, -OR7, -OC(O)R7, - OC(O)NH2-OC(O)NHR7, -OC(O)NR7R7, -OP(O)(OH)2, -OP(O)(OR7)2, -NO2, -NH2, -NHR7, -NR7R7, -N+(O ) R7R7, -NHC(O)H, -NHC(O)R7, -NR7C(O)R7, -NHC(O)NH2, -NHC(O)NR7R7, -NR7C(O)NHR7, -SH, -SR7, -S(O)H, -S(O)R7, -SO2R7, -SO2NH2, - SO2NHR7,-SO2NR7R7, -CF3, -CHF2, -CH2F,-OCF3, -OCHF2, -CN, -CO2H, -CO2R7, - CHO, -C(O)R7, -C(O)NH2, -C(O)NHR7, -C(O)NR7R7, -CONHSO2H, - C(O)NHSO2R7, -C(O)NR7SO2R7, 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: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or C3-7cyclic alkyl, halo, -OH, -OR8, -OC(O)R8, -OC(O)NH2, -OC(O)NHR8, -OC(O)NR8R8, -OP(O)(OH)2, -OP(O)(OR8)2, -NO2, -NH2, -NHR8, -NR8R8, -N+(O ’ )R8R8, -NHC(O)H, -NHC(O)R8, -NR8C(O)R8, -NHC(O)NH2, -NHC(O)NR8R8, - NR8C(O)NHR8, -SH, -SR8, -S(O)H, -S(O)R8, -SO2R8, -SO2NH2, -SO2NHR8,- SO2NR8R8, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -CN, -CO2H, -CO2R8, -CHO, - C(O)R8, -C(O)NH2, -C(O)NHR8, -C(O)NR8R8, -CONHSO2H, -C(O)NHSO2R8, and - C(O)NR8SO2R8; wherein each R5, R7and R8is independently selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7cyclic alkyl group; and

[0041] (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;

[0042] R9and R10are each independently selected from any of the groups defined in paragraphs (a) and (b) below:

[0043] (a) H, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, and an optionally substituted C3.7cyclic 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(O)R11, -OC(O)NH2, -OC(O)NHR11, -OC(O)NR11R11, -OP(O)(OH)2, - OP(O)(OR11)2, -NO2, -NH2, -NHR11, -NR11R11, -N+(O )R11R11, -NHC(O)H, - NHC(O)R11, -NR11C(O)R11, -NHC(O)NH2, -NHC(O)NR11R11, -NR11C(O)NHR11, - SH, -SR11, -S(O)H, -S(O)R11, -SO2R11, -SO2NH2, -SO2NHR11, -SO2NR11R11, -CF3, - CHF2, -CH2F,-OCF3. -OCHF2, -CN, -CO2H, -CO2R11, -CHO, -C(O)R11, -C(O)NH2, - C(O)NHR11, -C(O)NR11R11, -CONHSO2H, -C(O)NHSO2R11, -C(O)NR11SO2R11, cyclic C3-C7alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups cyclic C3-C7alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more of the following groups: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.7cyclic alkyl, halo, -OH, -OR13, -OC(O)R13, -OC(O)NH2, -OC(O)NHR13, - OC(O)NR13R13, -OP(O)(OH)2, -OP(O)(OR13)2, -NO2, -NH2, -NHR13, -NR13R13-N+(- O )R13R13, -NHC(O)H, -NHC(O)R13, -NR13C(O)R13, -NHC(O)NH2, - NHC(O)NR13R13, -NR13C(O)NHR13, -SH, -SR13, -S(O)H, -S(O)R13, -SO2R13, - SO2NH2, -SO2NHR13,-SO2NR13R13, -CF3, -CHF2, -CH2F -OCF3, .OCHF2, -CN, - CO2H, -CO2R13, -CHO, -C(O)R13, -C(O)NH2, -C(O)NHR13, -C(O)NR13R13, - CONHSO2H, -C(O)NHSO2R13, and -C(O)NR13SO2R13; wherein each R11and R13is independently selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7 cyclic alkyl group; and

[0044] (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 for each of said aryl and heteroaryl are each independently selected from the same optional substituents as those defined in (a) above for R9and R10; or

[0045] (c) R9and R10taken 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 O, 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 R9and R10.

[0046] (2). A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein W, X, Y, and Z are all as defined above in (1), and wherein:

[0047] R1, R2, R3and R4are each independently selected from the following groups: H, halo, R, -OH, -OR, -OC(O)H, -OC(O)R, -OC(O)NH2, -OC(O)NHR, - OC(O)NRR,-OP(O)(OH)2, -OP(O)(OR)2, -NO2, -NH2, -NHR, -NRR, -NHC(O)H, - NHC(O)R, -NRC(O)R, -NHC(O)NH2, -NHC(O)NRR, -NRC(O)NHR, -SH, -SR, - S(O)H, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, -CF3, -OCF3. -OCHF2, -CN, - CECH, -CECR, -CH=CHR, -CH = CRR, -CR=CHR, -CR=CRR, -CO2H, -CO2R, - CHO, -C(O)R, -C(O)NH2, -C(O)NHR, -C(O)NRR, -CONHSO2H, -CONHSO2R, - CONRSO2R, cyclic C3-Cy alkylamino, imidazolyl, Ci-Ce alkylpiperazinyl, morpholinyl and thiomorpholinyl; or R1and R2taken together, or R2and R3taken together, or R3and R4taken 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 the following groups defined in paragraphs (a) and (b) below:

[0048] (a) an optionally substituted C1-6 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(O)R5, -OC(O)NH2, - OC(O)NHR5, -OC(O)NR5R5, -OP(O)(OH)2, -OP(O)(OR5)2, -NO2, -NH2, - NHR5, -NR5R5, -N+(O )R5R5, -NHC(O)H, -NHC(O)R5, -NR5C(O)R5, - NHC(O)NH2, -NHC(O)NR5R5, -NR5C(O)NHR5, -SH, -SR5, -S(O)H, -S(O)R5, -SO2R5, -SO2NH2, -SO2NHR5, -SO2NR5R5, -CF3, -OCF3, -OCHF2, -CN, - CO2H, -CO2R5, -CHO, -C(O)R5, -C(O)NH2, -C(O)NHR5, -C(O)NR5R5, - CONHSO2H, -C(O)NHSO2R5, -C(O)NR5SO2R5, 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: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cyclic alkyl, halo, -OH, -OR7, -OC(O)R7, -OC(O)NH2-OC(O)NHR7, - OC(O)NR7R7, -OP(O)(OH)2, -OP(O)(OR7)2, -NO2, -NH2, -NHR7, -NR7R7, - N+(O ) R7R7, -NHC(O)H, -NHC(O)R7, -NR7C(O)R7, -NHC(O)NH2, - NHC(O)NR7R7, -NR7C(O)NHR7, -SH, -SR7, -S(O)H, -S(O)R7, -SO2R7, - SO2NH2, -SO2NHR7,-SO2NR7R7, -CF3, -OCF3, -OCHF2, -CN, -CO2H, - CO2R7, -CHO, -C(O)R7, -C(O)NH2, -C(O)NHR7, -C(O)NR7R7, -CONHSO2H, -C(O)NHSO2R7, -C(O)NR7SO2R7an 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: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cyclic alkyl, halo, -OH, -OR8, -OC(O)R8, - OC(O)NH2, -OC(O)NHR8, -OC(O)NR8R8, -OP(O)(OH)2, -OP(O)(OR8)2, - NO2, -NH2, -NHR8, -NR8R8, -N+(O )R8R8, -NHC(O)H, -NHC(O)R8, - NR8C(O)R8, -NHC(O)NH2, -NHC(O)NR8R8, -NR8C(O)NHR8, -SH, -SR8, - S(O)H, -S(O)R8, -SO2R8, -SO2NH2, -SO2NHR8,-SO2NR8R8, -CF3, -OCF3, - OCHF2, -CN, -CO2H, -CO2R8, -CHO, -C(O)R8, -C(O)NH2, -C(O)NHR8, - C(O)NR8R8, -CONHSO2H, -C(O)NHSO2R8, and -C(O)NR8SO2R8; wherein each R5, R7and R8is independently selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7 cyclic alkyl group; and

[0049] (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 for each aryl and heteroaryl are each independently selected from the same optional substituents as those defined in (a) above for R;

[0050] R9and R10are each independently selected from the following groups defined in paragraphs (a) and (b) below:

[0051] (a) H, an optionally substituted C1-6 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(O)R11, -OC(O)NH2, - OC(O)NHR11, -OC(O)NR11R11, -OP(O)(OH)2, -OP(O)(OR11)2, -NO2, -NH2, -NHR11, -NR11R11, -N+(O )R11R11, -NHC(O)H, -NHC(O)R11, -NR11C(O)R11, -NHC(O)NH2, -NHC(O)NR11R11, -NR11C(O)NHR11, -SH, -SR11, -S(O)H, - S(O)R11, -SO2R11, -SO2NH2, -SO2NHR11, -SO2NR11R11, -CF3, -OCF3, - OCHF2, -CN, -CO2H, -CO2R11, -CHO, -C(O)R11, -C(O)NH2, -C(O)NHR11, - C(O)NR11R11, -CONHSO2H, -C(O)NHSO2R11, -C(O)NR11SO2R11, cyclic C3- C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more of the following groups: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cyclic alkyl, halo, -OH, -OR13, - OC(O)R13, -OC(O)NH2, -OC(O)NHR13, -OC(O)NR13R13, -OP(O)(OH)2, - OP(O)(OR13)2, -NO2, -NH2, -NHR13, -NR13R13-N+(O )R13R13, -NHC(O)H, - NHC(O)R13, -NR13C(O)R13, -NHC(O)NH2, -NHC(O)NR13R13, - NR13C(O)NHR13, -SH, -SR13, -S(O)H, -S(O)R13, -SO2R13, -SO2NH2, - SO2NHR13,-SO2NR13R13, -CF3, OCF3, OCHF2, -CN, -CO2H, -CO2R13, - CHO, -C(O)R13, -C(O)NH2, -C(O)NHR13, -C(O)NR13R13, -CONHSO2H, - C(O)NHSO2R13, and -C(O)NR13SO2R13; wherein each R11and R13is independently selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7 cyclic alkyl group; and

[0052] (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 for each of said aryl and heteroaryl are each independently selected from the same optional substituents as those defined in (a) above for R9and R10; or (c) R9and R10taken 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 O, 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 R9and R10.

[0053] (3). A compound as defined in paragraph (1) or (2), wherein when

[0054] R9and R10are each independently selected from the following groups: an optionally substituted C1-6 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; 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, -OR11, -OC(O)R11, -OC(O)NH2, - OC(O)NHR11, -OC(O)NR11R11, -OP(O)(OH)2, -OP(O)(OR11)2, -NO2, -NH2, -NHR11, -NR11R11, -N+(O )R11R11, -NHC(O)H, -NHC(O)R11, -NR11C(O)R11, -NHC(O)NH2, - NHC(O)NR11R11, -NR11C(O)NHR11, -SH, -SR11, -S(O)H, -S(O)R11, -SO2R11, - SO2NH2, -SO2NHR11, -SO2NR11R11, -CF3, -CHF2, -CH2F,-OCF3, -OCHF2, -CN, - CO2H, -CO2R11, -CHO, -C(O)R11, -C(O)NH2, -C(O)NHR11, -C(O)NR11R11, - CONHSO2H, -C(O)NHSO2R11, and -C(O)NR11SO2R11; wherein each R11is independently selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-7 cyclic alkyl group.

[0055] (4). A compound as defined in any one of paragraphs (1) to (3), wherein Z is N or N-oxide, such as N, W is CR1, X is CR2and Y is CR3.

[0056] (5). A compound as defined in any one of paragraphs (1) to (3), wherein X is N or N-oxide, such as N, W is CR1, Y is CR3and Z is CR4.

[0057] (6). A compound as defined in any one of paragraphs (1) to (3), wherein X and Z are both N or N-oxide, such as N, W is CR1and Y is CR3.

[0058] (7). A compound as defined in any one of paragraphs (1) to (6), wherein R1, R2, R3and R4, where present, are each independently selected from the group consisting of H, halo, optionally substituted Ci-Ce alkyl, -O-R wherein R is optionally substituted Ci-Ce 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.

[0059] (8). A compound as defined in any one of paragraphs (1) to (6), wherein R1, R2, R3and R4, where present, are each independently selected from the group consisting of H, halo, optionally substituted Ci-Ce alkyl, -O-R wherein R is selected from optionally substituted Ci-Ce 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.

[0060] (9). A compound as defined in paragraph (8), wherein R1, R2, R3and

[0061] R4, where present, are each independently selected from the group consisting of H, halogen, -CFs, -CHF2, -OCF3, -OCHF2, C1-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

[0062] (10). A compound as defined in paragraph (8), wherein one or two of R1, R2, R3and R4, where present, is H, and the others of R1, R2R3and R4that are not H are independently selected from the group consisting of halogen, -CF3, -CHF2, -OCF3, -OCHF2, C1-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and - NHR wherein R is optionally substituted aryl.

[0063] (11). A compound as defined in any one of paragraphs (8) to (10), wherein R3is present and selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

[0064] (12). A compound as defined in paragraph (4), wherein Z is N or N- oxide, such as N, W is CR1, X is CR2and Y is CR3, and R3is selected from the group consisting of halogen, -O-R wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

[0065] (13). A compound as defined in paragraph (4), wherein Z is N or N- oxide, such as N, W is CR1, X is CR2and Y is CR3, R1is H, and one or both of R2and R3are other than H, for example, both R2and R3are other than H, or R2is H and R3is other than H, or R3is H and R2is other than H.

[0066] (14). A compound as defined in paragraph (13), wherein each of R2and R3that is other than H is independently selected from the group consisting of halogen, optionally substituted Ci-Ce alkyl, -OR wherein R is selected from optionally substituted Ci-Ce 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.

[0067] (15). A compound as defined in paragraph (14), wherein each of R2and R3that is other than H is independently selected from the group consisting of halogen, -CF3, -CHF2, -OCF3, -OCHF2, C1-6 alkyl such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

[0068] (16). A compound as defined in any one of paragraphs (1) to (6), wherein R1and R2taken together, or R2and R3taken together, or R3and R4taken 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, R3and R4that are not part of the ring, are independently selected from: H, halo, optionally substituted Ci-Ce alkyl, O-R wherein R is optionally substituted Ci- Ce 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.

[0069] (17). A compound as defined in any one of paragraphs (1) to (16), wherein R9and R10are independently selected from H, an optionally substituted C1-6 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 O, N and S.

[0070] (18). A compound as defined in any one of paragraphs (1) to (17), wherein R9and R10are both H.

[0071] (19). A compound as defined in paragraph (4), wherein Z is N or N- oxide, such as N, W is CR1, X is CR2and Y is CR3, and R9and R10are both H.

[0072] (20) A compound as defined in paragraph (19), wherein R1, R2and R3are each independently selected from the group consisting of H, halogen, - CFs, -CHF2, -OCF3, -OCHF2, C1-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

[0073] (21). A compound as defined in paragraph (19), wherein R1, R2and R3are each independently selected from the group consisting of H, halogen, C1-6 alkyl, such as methyl, substituted aryl, and substituted heteroaryl.

[0074] (22). A compound as defined in paragraph (19), wherein one or two of R1, R2and R3is H, and the others of R1, R2and R3that are not H are independently selected from the group consisting of halogen, -CF3, -CHF2, - OCF3, -OCHF2, C1-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

[0075] (23). A compound as defined in paragraph (19), wherein R1is H, and one or both of R2and R3is other than H, wherein each of R2and R3that is not H is independently selected from the group consisting of halogen, -CF3, - CHF2, -OCF3, -OCHF2, C1-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

[0076] (24). A compound as defined in any one of paragraphs (19) to (23), wherein R3is selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

[0077] (25). A compound as defined in paragraph (19), wherein R1is H, and R2and R3form 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.

[0078] (26) A compound as defined in any one of paragraphs (1) to (6) wherein W is CR1and R1is selected from H, halo, -CHF2, -CF3 or methyl; and Z is N or N-oxide, such as N, X is CR2and Y is CR3; X is N or N-oxide, such as N, Y is CR3and Z is CR4; or X and Z are both N or N-oxide, such as N, and Y is CR3.

[0079] (27) A compound as defined in any one of paragraphs (1) to (6) wherein W is CR1and R1is selected from H, halo, -CHF2, -CF3 or methyl; R9and R10are each H; and Z is N or N-oxide, such as N, X is CR2and Y is CR3; X is N or N-oxide, such as N, Y is CR3and Z is CR4; or X and Z are both N or N-oxide, such as N, and Y is CR3.

[0080] (28) A compound as defined in any one of paragraphs (1) to (6) wherein W is CR1and R1is selected from H, halo, -CHF2, -CF3 or methyl; R9and R10are each H; Z is N or N-oxide, such as N, X is CR2and Y is CR3; and R2and R3are each independently selected from: H, halogen, -CF3, -CHF2, -OCF3, - OCHF2, -NO2, C1-6 alkyl, such as methyl, optionally substituted aryl, optionally substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl; or R2and R3taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms and the ring is optionally substituted with 1 to 4 substituents independently selected from R.

[0081] (29) A compound as defined in any one of paragraphs (1) to (6) wherein W is CR1and R1is selected from H, halo, -CHF2, -CF3 or methyl.

[0082] (30) A compound as defined in paragraphs (1) to (6) and (26) to (29) wherein W is CR1and R1is H, F, -CHF2, -CF3 or methyl.

[0083] (31) A compound as defined in paragraph (1) to (6) and (26) or (30) wherein W is CR1and R1is H or F. (32) A compound as defined in any one of paragraphs (1) to (6) and (26) to (30) wherein W is CR1and R1is H or methyl.

[0084] (33) A compound as defined in any one of paragraphs (1) to (6) and (26) to (32) wherein W is CR1and R1is H.

[0085] (34) A compound as defined any one of paragraphs (1) to (6) and (29) to (33) wherein R9and R10are independently selected from H, an optionally substituted C1-6 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 O, N and S.

[0086] (35) A compound as defined in any one of paragraphs (1) to (6) and (29) to (34) wherein R9and R10are each H.

[0087] (36) A compound as defined in any one of paragraphs (26) to (35), wherein Z is N or N-oxide, such as N, X is CR2andY is CR3.

[0088] (37) A compound as defined in any one of paragraphs (26) to (35), wherein X is N or N-oxide, such as N, Y is CR3and Z is CR4.

[0089] (38) A compound as defined in any one of paragraphs (26) to (35), wherein X and Z are both N or N-oxide, such as N, and Y is CR3.

[0090] (39) A compound as defined in any one of paragraphs (1) to (6) and (29) to (36) wherein R2and R3are each independently selected from: H, halogen, -CFs, -CHF2, -OCF3, -OCHF2, -NO2, C1-6 alkyl, such as methyl, optionally substituted aryl, optionally substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl; or R2and R3taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms and the ring is optionally substituted with 1 to 4 substituents independently selected from R.

[0091] (40) A compound as defined in any one of paragraphs (1) to (6), (28) to (36), and (39) wherein R2and R3are each independently selected from: H, halogen, -CF3, -CHF2, -OCF3, -OCHF2, -NO2, C1-6 alkyl, such as methyl, optionally substituted aryl, optionally substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl; or R2and R3taken together can form a saturated or a partially saturated or a fully unsaturated 6-membered ring of carbon atoms and the ring is optionally substituted with 1 to 4 substituents independently selected from R.

[0092] (41) A compound as defined in any one of paragraphs (1) to (6), (28) to (36), (39), and (40) wherein R2and R3are each independently selected from: H, halogen, -CF3, -CHF2, -OCF3, -OCHF2, -NO2, C1-6 alkyl, such as methyl, optionally substituted aryl, optionally substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl; or R2and R3taken together can form a saturated or a partially saturated or a fully unsaturated 6-membered ring of carbon atoms.

[0093] (42) A compound as defined in any one of paragraphs (1) to (6), (28) to (36), and (39) to (41) wherein R2and R3are each independently selected from: H, halo, -CFs, -CHF2, -NO2, and methyl.

[0094] (43) A compound as defined in any one of paragraphs (1) to (6), (28) to (36), and (39) to (42) wherein R2and R3are each independently selected from: H, halo, -CF3, and -NO2.

[0095] (44) A compound as defined in any one of paragraphs (1) to (6), (28) to (35), and (38) to (43) wherein one of R2and R3is H and the other is a group other than H.

[0096] (45) A compound as defined in any one of paragraphs (1) to (3), wherein W is CR1and R1is H or F; R9and R10are each H; Z is N or N-oxide, such as N, X is CR2and Y is CR3; and R2and R3are each independently selected from: H, halo, -CF3, -CHF2, -NO2, and methyl.

[0097] (45) A compound as defined in any one of paragraphs (1) to (3), wherein W is CR1and R1is H; R9and R10are each H; Z is N or N-oxide, such as N, X is CR2and Y is CR3; and R2and R3are each independently selected from: H, halo, -CF3, and -NO2.

[0098] (46) A compound as defined in any one of paragraphs (1) to (3), (26), (27), (29) to (35) and (37), wherein X is N or N-oxide, such as N, Y is CR3and Z is CR4; and R3and R4are each independently selected from the group of substituents listed for R2and R3in any one of paragraphs (39) to (43).

[0099] (47) A compound as defined in any one of paragraphs (1) to (3), X and Z are both N or N-oxide, such as N, and Y is CR3; and R3is selected from the group of substituents listed for R2and R3in any one of paragraphs (39) to (43).

[0100] (46). A compound as defined in paragraph (1), selected from the group consisting of:

[0101] 5-Bromo-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (1) lsoxazolo[5,4-b]pyridin-3-amine (2) 5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (3)

[0102] 4.6-Dimethylisoxazolo[5,4-b]pyridin-3-amine (4)

[0103] 4.5.6-Trimethylisoxazolo[5,4-b]pyridin-3-amine (5) 5-Bromoisoxazolo[5,4-b]pyridin-3-amine (6) 6-Methylisoxazolo[5,4-b]pyridin-3-amine (7)

[0104] 5-Chloroisoxazolo[5,4-b]pyridin-3-amine (8) lsoxazolo[5,4-b]quinolin-3-amine (9) 5,6,7,8-Tetrahydroisoxazolo[5,4-b]quinolin-3-amine (10)

[0105] 6-Chloroisoxazolo[5,4-b]pyridin-3-amine (11) lsoxazolo[5,4-d]pyrimidin-3-amine (12)

[0106] 5-Fluoroisoxazolo[5,4-b]pyridin-3-amine (14)

[0107] 6-Phenylisoxazolo[5,4-b]pyridin-3-amine (15) 5-lodoisoxazolo[5,4-b]pyridin-3-amine (16) lsoxazolo[4,5-c]pyridin-3-amine (17) N6,N6-Dimethylisoxazolo[5,4-b]pyridine-3,6-diamine (18) N4,N4-Dimethylisoxazolo[5,4-b]pyridine-3,4-diamine (19) 5-(3-Methoxyphenyl)isoxazolo[5,4-b]pyridin-3-amine (22) 5-(2-Methoxyphenyl)isoxazolo[5,4-b]pyridin-3-amine (23) 5-Phenylisoxazolo[5,4-b]pyridin-3-amine (24) 5-(Pyridin-3-yl)isoxazolo[5,4-b]pyridin-3-amine (26) 5-(Pyridin-4-yl)isoxazolo[5,4-b]pyridin-3-amine (27) 2-(3-Aminoisoxazolo[5,4-b]pyridin-5-yl)phenol (28)

[0108] 4-(3-Aminoisoxazolo[5,4-b]pyridin-5-yl)phenol (29)

[0109] 5-(4-Fluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (30) 5-(3-Fluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (31) 5-(2,4-difluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (32) 5-(3,5-Difluoro-2-methoxyphenyl)isoxazolo[5,4-b]pyridin-3-amine (33) 5-(2,4-Dichlorophenyl)isoxazolo[5,4-b]pyridin-3-amine (34) 5-(2,3,4-Trichlorophenyl)isoxazolo[5,4-b]pyridin-3-amine (35) 5-(4-(Trifluoromethylphenyl)isoxazolo[5,4-b]pyridin-3-amine (36) 5-(3-Aminophenyl)isoxazolo[5,4-b]pyridin-3-amine (37)

[0110] Methyl 3-(3-aminoisoxazolo[5,4-b]pyridin-5-yl)benzoate (38) 5-(6-Fluoropyridin-3-yl)isoxazolo[5,4-b]pyridin-3-amine (39)

[0111] 5-(2-Chloro-4-(trifluoromethyl)phenyl)isoxazolo[5,4-b]pyridin-3-amine (40)

[0112] 6-Methoxyisoxazolo[5,4-b]pyridin-3-amine (41) 6-Chloro-4-methylisoxazolo[5,4-b]pyridin-3-amine (42) lsoxazolo[5,4-b]pyridine-3,6-diamine (43)

[0113] 5-Methylisoxazolo[5,4-b]pyridin-3-amine (44) 5,6-Dimethylisoxazolo[5,4-b]pyridin-3-amine (45)

[0114] 6-Methyl-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine (46) 6-(Trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine (47) 6-lsopropylisoxazolo[5,4-b]pyridin-3-amine (48) 5-Nitroisoxazolo[5,4-b]pyridin-3-amine (49)

[0115] Ethyl 3-amino-6-(trifluoromethyl)isoxazolo[5,4-b]pyridine-5-carboxylate (50) 4-Methoxyisoxazolo[5,4-b]pyridin-3-amine (51)

[0116] 5-(Difluoromethoxy)-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (52) Ethyl 3-amino-6-methylisoxazolo[5,4-b] pyridine-5-carboxylate (53)

[0117] Ethyl 3-amino-6-(difluoromethyl)isoxazolo[5,4-b]pyridine-5-carboxylate (54)

[0118] 5-Fluoro-6-morpholinoisoxazolo[5,4-b]pyridin-3-amine (55)

[0119] 6-(Furan-2-yl)isoxazolo[5,4-b]pyridin-3-amine (58) 6,7,8,9-Tetrahydro-5H-cyclohepta[b]isoxazolo[4,5-e]pyridin-3-amine (60)

[0120] 6.6-Dimethyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]quinolin-3-amine (61) 7,8-Dihydro-5H-isoxazolo[5,4-b]pyrano[3,4-e]pyridin-3-amine (62) 6-(Methylthio)isoxazolo[5,4-d]pyrimidin-3-amine (63) 6-Methylisoxazolo[5,4-d]pyrimidin-3-amine (64) 6-Chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66)

[0121] 5.6-Dichloroisoxazolo[5,4-b]pyridin-3-amine (67) 6-Chloro-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine (68)

[0122] 5-(3-Methoxyprop-1-yn-1 -yl)isoxazolo[5,4-b]pyridin-3-amine (69)

[0123] 6-(4-Fluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (71) 6-(2,4-Difluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (73) 6-(2-Thienyl)isoxazolo[5,4-b]pyridin-3-amine (74) 6-(Methylthio)isoxazolo[5,4-b]pyridin-3-amine (79) 6-(Methylsulfonyl)isoxazolo[5,4-b]pyridin-3-amine (80) Methyl 3-aminoisoxazolo[5,4-b]pyridine-6-carboxylate (82) 6-Phenoxyisoxazolo[5,4-b]pyridin-3-amine (83) 6-(2-Chlorophenoxy)isoxazolo[5,4-b]pyridin-3-amine (84) 6-(3-Chlorophenoxy)isoxazolo[5,4-b]pyridin-3-amine (85) 6-(4-Chlorophenoxy)isoxazolo[5,4-b]pyridin-3-amine (86) 6-(2-(Trifluoromethoxy)phenoxy)isoxazolo[5,4-b]pyridin-3-amine (87) 6-(3-(Trifluoromethoxy)phenoxy)isoxazolo[5,4-b]pyridin-3-amine (88) 6-(4-(Trifluoromethoxy)phenoxy)isoxazolo[5,4-b]pyridin-3-amine (89) 6-(2-Methoxyphenoxy)isoxazolo[5,4-b]pyridin-3-amine (90) 6-(3-Methoxyphenoxy)isoxazolo[5,4-b]pyridin-3-amine (91) 6-(4-Methoxyphenoxy)isoxazolo[5,4-b]pyridin-3-amine (92) 6-(3-(Trifluoromethyl)phenoxy)isoxazolo[5,4-b]pyridin-3-amine (93) N6-Phenylisoxazolo[5,4-b]pyridine-3,6-diamine (94) N6-(3-Methoxyphenyl)isoxazolo[5,4-b]pyridine-3,6-diamine (95) and N6-(4-Methoxyphenyl)isoxazolo[5,4-b]pyridine-3,6-diamine (96), and pharmaceutically acceptable salts thereof.

[0124] (47) A compound as defined in paragraph (1), selected from the group consisting of:

[0125] 6-Chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) 5-Bromoisoxazolo[5,4-b]pyridin-3-amine (6)

[0126] 5-Chloroisoxazolo[5,4-b]pyridin-3-amine (8)

[0127] 6-Chloroisoxazolo[5,4-b]pyridin-3-amine (11) 5-lodoisoxazolo[5,4-b]pyridin-3-amine (16) 5-Nitroisoxazolo[5,4-b]pyridin-3-amine (49)

[0128] 5.6-Dichloroisoxazolo[5,4-b]pyridin-3-amine (67)

[0129] 5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (3)

[0130] 4.6-Dimethylisoxazolo[5,4-b]pyridin-3-amine (4)

[0131] 4.5.6-Trimethylisoxazolo[5,4-b]pyridin-3-amine (5)

[0132] 6-Methylisoxazolo[5,4-b]pyridin-3-amine (7) 5-Phenylisoxazolo[5,4-b]pyridin-3-amine (24) 5-Bromo-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (1) lsoxazolo[5,4-b]quinolin-3-amine (9) 5-(4-Fluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (30) 5,6,7,8-Tetrahydroisoxazolo[5,4-b]quinolin-3-amine (10) lsoxazolo[5,4-d]pyrimidin-3-amine (12)

[0133] 5-Fluoroisoxazolo[5,4-b]pyridin-3-amine (14)

[0134] 6-Phenylisoxazolo[5,4-b]pyridin-3-amine (15) 6-(2-Thienyl)isoxazolo[5,4-b]pyridin-3-amine (74) 6-Methoxyisoxazolo[5,4-b]pyridin-3-amine (41) 6-(Trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine (47) 6-Chloro-4-methylisoxazolo[5,4-b]pyridin-3-amine (42)

[0135] 5.6-Dimethylisoxazolo[5,4-b]pyridin-3-amine (45)

[0136] 5-Methylisoxazolo[5,4-b]pyridin-3-amine (44)

[0137] 6-(2-Chlorophenoxy)isoxazolo[5,4-b]pyridin-3-amine (84) 6-(4-(Trifluoromethoxy)phenoxy)isoxazolo[5,4-b]pyridin-3-amine (89) N6-(3-Methoxyphenyl)isoxazolo[5,4-b]pyridine-3,6-diamine (95), and pharmaceutically acceptable salts thereof.

[0138] (48) A compound as defined in paragraph (1), selected from the group consisting of:

[0139] 6-Chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) 5-Bromoisoxazolo[5,4-b]pyridin-3-amine (6)

[0140] 5-Chloroisoxazolo[5,4-b]pyridin-3-amine (8)

[0141] 6-Chloroisoxazolo[5,4-b]pyridin-3-amine (11) 5-lodoisoxazolo[5,4-b]pyridin-3-amine (16) 5-Nitroisoxazolo[5,4-b]pyridin-3-amine (49)

[0142] 5.6-Dichloroisoxazolo[5,4-b]pyridin-3-amine (67), and pharmaceutically acceptable salts thereof. (49) A compound as defined in paragraph (1), wherein the compound is 6- Chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) or pharmaceutically acceptable salts thereof.

[0143] In various embodiments, the dual inhibitor of IDO1 and TDO2 is selected from the compounds as described in the numbered paragraphs (47) to (49) above and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1 -d]-as-tetrazine-8-carboxamide (TMZ): , or pharmaceutically acceptable salts thereof; and the glioma is glioblastoma.

[0144] In various embodiments, the dual inhibitor of IDO1 and TDO2 is 6-Chloro-5- fluoroisoxazolo[5,4~b]pyridin-3-amine (66):

[0145] , or a pharmaceutically acceptable salt thereof; the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8- carboxamide (TMZ): , or a pharmaceutically acceptable salt thereof; and the glioma is glioblastoma.

[0146] In various embodiments, the dual ID01 and TD02 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, are or are to be administered in combination with one or more additional agents selected from the group consisting of: anticancer agents, immune-modulating agents such as anticancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)), and radiotherapy. In various embodiments, the one or more additional gent is or is to be administered either before, during or after administration of the dual inhibitor of IDO1 and TDO2 and / or either before, during or after administration of the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0147] In various embodiments, the one or more additional agent is or is to be administered simultaneously or sequentially with the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, and / or simultaneously or sequentially with the dual inhibitor of IDO1 and TDO2.

[0148] In various embodiments, the dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, are formulated in a single composition. In various embodiments, the dual inhibitor of IDO1 and TDO2 and the temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, are formulated as separate compositions.

[0149] Also described herein in various aspects and embodiments are kits, compositions or combinations, such as combination products or pharmaceutical combinations, comprising the dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0150] Also described herein in various aspects and embodiments are kits, compositions or combinations, such as combination products or a pharmaceutical combinations, comprising the dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof; and optionally instructions for using the dual inhibitor and TMZ accordance with the methods or uses described in the various aspects or embodiments described herein.

[0151] Also described herein in various aspect and embodiments are kits, compositions or combinations, such as combination products or a pharmaceutical combinations, comprising the dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, for use in the methods or uses described in the various aspects or embodiments described herein.

[0152] 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. It is intended that reference to a range of numbers disclosed herein (for example, 1 to 10) also incorporates reference to all rational numbers within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7) and, therefore, all sub-ranges of all ranges expressly disclosed herein are hereby expressly disclosed. These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.

[0153] 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.

[0154] This invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, and any or all combinations of any two or more said parts, elements or features, and where specific integers are mentioned herein which have known equivalents in the art to which this invention relates, such known equivalents are deemed to be incorporated herein as if individually set forth.

[0155] 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.

[0156] BRIEF DESCRIPTION OF THE FIGURES

[0157] The present invention will be described with reference to the accompanying Figures, in which:

[0158] Figure 1 shows a graph demonstrating IDO1 and TDO2 enzyme inhibition in response to AT-0174 (at increasing mol / L (M) concentrations). LLTC-hlDO1 and GL261 -hTDO2 cells were incubated with AT-0174 for 24 hours, followed by analysis of supernatants for kynurenine content by colorimetric assay.

[0159] Figure 2 shows a graph demonstrating the effect of oral AT-0174 treatment on the kynurenine:tryptophan ratio (K:T ratio) in male C57BL / 6J mice 12 days after subcutaneous implantation of either GL261-hlDO1 or GL261-hTDO2 tumours.

[0160] Figure 3 shows an orthotopic glioblastoma study experimental design.

[0161] Figure 4 shows a graph demonstrating body weight of female C57BL / 6J mice with orthotopic GL261 (luc2) cell glioblastomas, expressed as a percentage of pretreatment weight for each group.

[0162] Figure 5A shows a graph demonstrating glioblastoma tumour size measured by luciferase bioluminescence, in female C57BL / 6J mice.

[0163] Figure 5B shows graphs demonstrating the effect size in tumor grade when compared between the control group (vehicle) and the treatment groups. A positive effect size signifies a favourable treatment outcome. The dashed line indicates a positive synergistic effect.

[0164] Figure 6 shows a Kaplan-Meier survival curve for female C57BL / 6J mice with orthotopic glioblastoma tumours, following treatment with repeat doses of vehicle control (5% DMSO, 10 ml / kg, PO), temozolomide (TMZ, 8 mg / kg, IP), AT-0174 (120 mg / kg, PO) or a combination of TMZ and AT-0174.

[0165] Figure 7 shows graphs demonstrating the effect of temozolomide (TMZ), AT- 0174 or a combination of TMZ and AT-0174 on the expression of Tcell subsets within GL261 (luc2) glioblastomas in C57BL / 6J mice.

[0166] Figure 8 shows a graph demonstrating the effect of temozolomide (TMZ), AT-0174 or a combination of TMZ and AT-0174 on the ratio of CD8+ to Treg cells.

[0167] DETAILED DESCRIPTION OF THE INVENTION

[0168] Definitions

[0169] 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. When interpreting each statement in this specification and claims that includes the term "comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner.

[0170] 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.

[0171] Unless otherwise stated, the singular forms "a," "an," and "the" include the plural reference.

[0172] In the disclosure and the claims, "and / or" means additionally or alternatively.

[0173] Moreover, any use of a term in the singular also encompasses plural forms.

[0174] 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.

[0175] The term "halo" or "halogen" as used throughout the specification is to be taken as meaning a fluoro, chloro, bromo or iodo group.

[0176] 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.

[0177] It is to be understood that the term "heteroaryl" includes both monocyclic and bicyclic ring systems, unless the context requires otherwise.

[0178] It is to be understood that the term "aryl" means an aromatic hydrocarbon such as phenyl or naphthyl.

[0179] 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 the defined substituents.

[0180] It is to be understood that where reference is made throughout the specification to a Cj-Ce alkyl, C2-C6 alkynyl group or C2-C6 alkenyl group, these groups may be unbranched or branched. For example, it is intended that reference to a Ci-Ce alkyl would include a tert-butyl group, i.e. (Me)sC-.

[0181] A "subject" refers to a warm-blooded animal. "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, deer, and swine; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Preferably, the subject is a human.

[0182] As used herein, the term "chemotherapy" means the use of one or more chemotherapeutic agent in the treatment or prevention of cancer, for example to kill cancer cells or shrink tumours.

[0183] 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 radiolabelled monoclonal antibody, that travels in the blood to tissues throughout the body. The terms irradiation and radiation therapy have the same meaning.

[0184] The expressions "treating glioma” and 'treatment of glioma" 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.

[0185] "Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a glioma, is sufficient to effect such treatment for the glioma. The "effective amount" will vary depending on the glioma to be treated, the compound to be administered, the severity of the glioma 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.

[0186] "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.

[0187] Also described herein are pharmaceutically acceptable salts. "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:

[0188] (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

[0189] (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.

[0190] Acceptable inorganic bases include aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

[0191] In one aspect, the present invention provides a method of treating glioma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a dual inhibitor of indoleamine-2,3-dioxygenase (I D01 ) and tryptophan-2,3-dioxygenase-2 (TDO2) and temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0192] In one aspect, the present invention provides a use of a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1 ) and tryptophan-2,3-dioxygenase-2 (TDO2) in the manufacture of a medicament for treating glioma in a subject, wherein said medicament is to be administered in combination with temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof. In one aspect, the present invention provides a use of temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating glioma in a subject, wherein said medicament is to be administered in combination with a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1 ) and tryptophan-2,3-dioxygenase-2 (TDO2).

[0193] In one aspect, the present invention provides a use of a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1 ) and tryptophan-2,3-dioxygenase-2 (TDO2) and temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating glioma in a subject.

[0194] In one aspect, the present invention provides a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1 ) and tryptophan-2,3-dioxygenase-2 (TDO2) and temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of glioma in a subject.

[0195] In one aspect, the present invention provides a combination, such as a combination product or a pharmaceutical combination, for use in the treatment of glioma in a subject, wherein the pharmaceutical combination comprises (a) a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase-2 (TDO2) and (b) temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0196] In one aspect, the present invention provides a kit for use in the treatment of glioma in a subject, wherein the kit comprises (a) a dual inhibitor of indoleamine-2,3- dioxygenase (IDO1) and tryptophan-2,3-dioxygenase-2 (TDO2) and (b) temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0197] As described in the examples, the inventors have surprisingly discovered that a dual inhibitor of IDO1 and TDO in combination with the first-line chemotherapeutic agent used in clinical glioma, temozolomide (TMZ), have a synergistic effect in the treatment of glioma, providing a decrease in tumor size and increase in survival.

[0198] The following embodiments and preferences may relate, alone or in any combination of any two or more, to any of the above aspects.

[0199] Glioma

[0200] Gliomas are brain tumors that begin in glial cells in the brain or spinal cord. Methods of determining or assessing glioma will be apparent to those skilled in the art. For example, the glioma may be a WHO CNS Grade 1, WHO CNS Grade 2, WHO CNS Grade 3 or WHO CNS Grade 4 glioma as graded according to the 2021 5th edition of the WHO Classification of Tumors of the Central Nervous System. In various embodiments, the glioma is a WHO CNS Grade 4 glioma. Examples of glioma include astrocytomas (such as astrocytomas grown from glial cells called astrocytes); oligodendrogliomas (such as oligodendrogliomas grown from glial cells called oligodendrocytes), ependymomas (such as ependymomas grown from glial cells called ependymal cells), oligoastrocytomas (such as oligoastrocytomas containing a mix of astrocytes and oligodendrocytes); and mixed neuronal-glial tumors (such as mixed neuronal-glial tumors containing a mix of neurons and glial cells).

[0201] Gliomas may be classified according to the 2021 5th edition of the WHO Classification of Tumors of the Central Nervous System as adult-type diffuse gliomas, pediatric-type diffuse low-grade gliomas, pediatric-type diffuse high-grade gliomas, circumscribed astrocytic gliomas or ependymal tumor. Examples of adult-type diffuse glioma include astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant and 1 p / 19q-codeleted; and glioblastoma, IDH-wildtype. Examples of pediatric-type diffuse low-grade glioma include diffuse astrocytoma, MYB- or MYBL1 -altered; angiocentric glioma; polymorphous low-grade neuroepithelial tumor of the young; and diffuse low-grade glioma, MAPK pathway-altered. Examples of pediatric-type diffuse high-grade glioma include diffuse midline glioma, H3 K27-altered; diffuse hemispheric glioma, H3 G34-mutant; diffuse pediatric-type high-grade glioma, H3- wildtype and IDH-wildtype; and Infant-type hemispheric glioma. Examples of circumscribed astrocytic glioma include pilocytic astrocytoma; high-grade astrocytoma with piloid features; pleomorphic xanthoastrocytoma; subependymal giant cell astrocytoma; chordoid glioma; and astroblastoma, MN 1 -altered. Examples of an ependymal tumor include supratentorial ependymoma; supratentorial ependymoma, ZFTA fusion-positive; supratentorial ependymoma, YAP1 fusionpositive; posterior fossa ependymoma; posterior fossa ependymoma, group PFA; posterior fossa ependymoma, group PFB; spinal ependymoma; spinal ependymoma, MYCN-amplified; myxopapillary ependymoma and subependymoma.

[0202] Glioma that may be treated in accordance with the present invention include, but are not limited to, astrocytoma, ependymoma or oligodendroglioma.

[0203] Astrocytoma are tumors which typically originate from astrocytes. Methods of determining or assessing astrocytoma will be apparent to those skilled in the art. For example, the astrocytoma may be an astrocytoma graded according to the 2021 5th edition of the WHO Classification of Tumors of the Central Nervous System - WHO CNS Grade 1, WHO CNS Grade 2, WHO CNS Grade 3 or WHO CNS Grade 4. In various embodiments, the astrocytoma is WHO CNS Grade 1, WHO CNS Grade 2, WHO CNS Grade 3 or WHO CNS Grade 4 according to the 2021 5th edition of the WHO Classification of Tumors of the Central Nervous System. Examples of astrocytoma include pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, anaplastic astrocytoma and glioblastoma.

[0204] Glioblastoma, also known as glioblastoma multiforme or GBM, is the most commonly occurring tumour of the central nervous system and is a deadly disease with extremely poor prognosis. Based on the 2021 5th edition of the WHO Classification of Tumors of the Central Nervous System glioblastoma are classified as WHO CNS Grade 4. In various embodiments, the glioma is a glioblastoma.

[0205] Methods of diagnosing, determining, grading, or assessing glioblastoma will be apparent to those skilled in the art. For example, the glioblastoma may be a glioblastoma, IDH-wildtype according to the 2021 5th edition of the WHO Classification of Tumors of the Central Nervous System.

[0206] In various embodiments, the present invention provides a method of treating glioma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a dual inhibitor of IDO1 and TDO2 and TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, wherein the glioma is a WHO CNS Grade 4 glioma. In various embodiments, the present invention provides a method of treating astrocytoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a dual inhibitor of IDO1 and TDO2 and TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof. In various embodiments, the astrocytoma is pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, anaplastic astrocytoma or glioblastoma. In various embodiments, the present invention provides a method of treating glioblastoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a dual inhibitor of IDO1 and TDO2 and TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0207] Temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof

[0208] Temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, useful in the invention includes compounds of formula A:

[0209] Formula A wherein:

[0210] R1is hydrogen, or an alkyl group containing from 1 to 6 carbon atoms or an alkenyl or alkynyl group containing from 2 to 6 carbon atoms, or said an alkyl, alkenyl or alkynyl group substituted by from one to three substituents independently selected from halogen, alkoxy, alkylthio, a Ikylsulphinyl and alkylsulphonyl groups containing up to 4 carbon atoms, and phenyl substituted by alkoxy and alkyl groups containing from 1 to 4 carbon atoms or a nitro group; or R1is a cycloalkyl group containing from 3 to 8 carbon atoms; and

[0211] R2is a carbamoyl group, or a carbamoyl group carrying on the nitrogen atom one or two groups selected from alkyl and alkenyl groups containing up to 4 carbon atoms, and cycloalkyl groups containing from 3 to 8 carbon atoms; or, when R1is hydrogen, an alkali metal salt thereof.

[0212] In various embodiments, the temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula A wherein R1is methyl, wherein R2is a carbamoyl group. In various embodiments, the temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula A wherein R1is methyl and R2is a carbamoyl group.

[0213] In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, is temozolomide (TMZ). TMZ is well known in the art and readily commercially available. Methods of synthesis of temozolomide are also well known in the art. The chemical name for TMZ is 3,4-dihydro-3-methyl-4- oxoimidazo[5,1 -d]-as-tetrazine-8-carboxamide. The structural formula for TMZ is:

[0214]

[0215] In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, is TMZ or a pharmaceutically acceptable salt thereof.

[0216] Methods of synthesis of TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof are well known. Such compounds are described in U.S. Pat. No. 5,260,291 (Lunt et al.), incorporated herein by reference. Methods of synthesis of such compounds are also described therein.

[0217] Dual inhibitors of IDO1 and TDO2

[0218] The term "dual inhibitor of IDO1 and TDO2", and similar terms such as "dual inhibitors of IDO1 and TDO2", means a compound that inhibits the enzyme activity of IDO1 and inhibits the enzyme activity of TDO2, in particular, a compound that inhibits the cellular enzyme activity of IDO1 and inhibits the cellular enzyme activity of TDO2, for example, a compound that has a cellular IDO1 IC50 of less than 100 pM and a cellular TDO2 IC50 of less than 100 pM.

[0219] Unless indicated otherwise, the inhibition of cellular enzyme activity of IDO1 and the inhibition of cellular enzyme activity of TDO2 are each as determined by a method described in the examples herein.

[0220] In various embodiments, the dual inhibitor of IDO1 and TDO2 has a cellular IDO1 IC50 of less than 100 pM as determined by a cell-based assay for IDO1 inhibition; and has a cellular TDO2 IC50 of less than 100 pM as determined by a cellbased assay for TDO2 inhibition. In various embodiments, the dual inhibitor of IDO1 and TDO2 described herein has an cellular IDO1 IC50 of less than 100 pM, less than 90 pM, less than 80 pM, less than 70 pM, less than 60 pM, less than 50 pM, less than 40 pM, less than 30 pM, less than 20 pM, less than 15 pM, less than 10 pM or less than 1 pM as determined by a cell-based assay for IDO1 inhibition described in the examples; and has a cellular TDO2 IC50 of less than 100 pM, less than 90 pM, less than 80 pM, less than 70 pM, less than 60 pM, less than 50 pM, less than 40 pM, less than 30 pM, less than 20 pM, less than 15 pM, less than 10 pM or less than 1 pM as determined by a cell-based assay for TDO2 inhibition described in the examples. In various embodiments, the dual inhibitor of IDO1 and TDO2 described herein has a cellular IDO1 IC50 of less 10 pM as determined by a cell-based assay for IDO1 inhibition described in the examples; and has a cellular TDO2 IC50 of less than 10 pM as determined by a cell-based assay for TDO2 inhibition described in the examples.

[0221] In various embodiments, the dual inhibitor of IDO1 and TDO2 described herein has a cellular IDO1 IC50 of less than 10 pM, less than 9 pM, less than 8 pM, less than 7 pM, less than 6 pM, less than 5 pM, less than 4 pM, less than 3 pM, less than 2 pM, less than 1 pM, less than 0.9 pM, less than 0.8 pM, less than 0.7 pM, less than 0.6 pM, less than 0.5 pM, less than 0.4 pM, less than 0.3 pM, less than 0.2 pM and / or less than 0.1 pM as determined by a cell-based assay for IDO1 inhibition described in the examples; and has a cellular TDO2 IC50 of less than 10 pM, less than 9 pM, less than 8 pM, less than 7 pM, less than 6 pM, less than 5 pM, less than 4 pM, less than 3 pM, less than 2 pM, less than 1 pM, less than 0.9 pM, less than 0.8 pM, less than 0.7 pM, less than 0.6 pM, less than 0.5 pM, less than 0.4 pM, less than 0.3 pM, less than 0.2 pM and / or less than 0.1 pM as determined by a cell-based assay for TDO2 inhibition described in the examples. In various embodiments, the dual inhibitor of IDO1 and TDO2 described herein has a cellular IDO1 IC50 of less 1 pM as determined by a cellbased assay for IDO1 inhibition described in the examples; and has a cellular TDO2 IC50 of less than 1 pM as determined by a cell-based assay for TDO2 inhibition described in the examples.

[0222] In various embodiments, the dual inhibitor of IDO1 and TDO2 described herein has a cellular IDO1 IC50 of less than 1 pM, less than 0.9 pM, less than 0.8 pM, less than 0.7 pM, less than 0.6 pM, less than 0.5 pM, less than 0.4 pM, less than 0.3 pM, less than 0.2 pM and / or less than 0.1 pM as determined by a cell-based assay for IDO1 inhibition described in the examples herein; and has a cellular TDO2 IC50 of less than 1 pM, less than 0.9 pM, less than 0.8 pM, less than 0.7 pM, less than 0.6 pM, less than 0.5 pM, less than 0.4 pM, less than 0.3 pM, less than 0.2 pM and / or less than 0.1 pM as determined by a cell-based assay for TDO2 inhibition described in the examples herein. In various embodiments, the dual inhibitor of IDO1 and TDO2 described herein has cellular TDO2 inhibitory activity that is greater than, or equal to, the cellular IDO1 inhibitory activity. In various embodiments, the dual inhibitor of IDO1 and TDO2 has a cellular IDO1 IC50 that is higher or equal to the cellular TDO2 IC50. The cellular IDO1 IC50 may be as determined by a cell-based assay for IDO1 inhibition described in the examples herein; and the cellular TDO2 IC50 may be as determined by a cell-based assay for TDO2 inhibition described in the examples herein.

[0223] As described in detail in PCT / IB2015 / 056129, which is incorporated herein by reference, compounds of Formula I have been found to be inhibitors of IDO1 and / or TDO2. In various embodiments, the dual inhibitor of IDO1 and TDO2 is a 3- aminoisosoxazoie, preferably a 3-aminoisosoxazole fused to a 6 membered aromatic ring comprising at least one ring nitrogen atom, such as certain compounds of Formula I as described herein.

[0224] In various embodiments, the dual IDO1 and TDO2 inhibitor is 6-Chloro-5- fluoroisoxazolo[5,4-b]pyridin-3-amine (also referred to herein as compound 66 or

[0225] AT-0174 is shown by the inventors in the examples to be essentially equipotent at IDO1 and TDO2 enzymes in cellular assays. Accordingly, in various embodiments, the dual inhibitor of IDO1 and TDO2 described herein has a cellular IDO1 ICso of less than 0.3 pM as determined by a cell-based assay for IDO1 inhibition described in the examples herein; and has a cellular TDO2 I Cso of less than 0.3 pM as determined by a cell-based assay for TDO2 inhibition described in the examples herein. In various embodiments, the dual inhibitor of IDO1 and TDO2 described herein has a cellular IDO1 ICso of less than 0.2 pM as determined by a cell-based assay for IDO1 inhibition described in the examples herein; and has a cellular TDO2 ICso of less than 0.3 pM as determined by a cell-based assay for TDO2 inhibition described in the examples herein.

[0226] As shown in the examples, AT-0174 exerted a synergistic antitumour effect when given in combination with TMZ, showing a statistically significant reduction in tumor growth compared to TMZ given alone by day 35 (p < 0.05). In various embodiments, the treatment of the glioma with the dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, decreases the glioma tumor size. In a particular embodiment, the decrease in tumor size is measured by a luciferase bioluminescence assay, such as the luciferase bioluminescence assay described in the examples herein.

[0227] In various embodiments, the dual inhibitor of IDO1 and TDO2 for use in the present invention is a compound of the general Formula I with IDO1 and TDO2 inhibitory activity.

[0228] Dual inhibitors of IDO1 and TDO2 include, for example, compounds as defined in paragraphs (1) to (49) of the summary of invention section and that have dual IDO1 and TDO2 inhibitory activity, may be used in any of the methods, uses and other aspects of the invention described herein. Accordingly, in various embodiments, the dual inhibitor of IDO1 and TDO2 is a compound as defined in paragraphs (1) to (49), and that has inhibitory IDO1 and TDO2 activity. The dual inhibitors of IDO1 and TDO2 as defined in paragraphs (46) to (49) in the summary of invention section., may be used in any of the methods, uses and other aspects of the invention described herein. Accordingly, in various embodiments, the dual inhibitor of IDO1 and TDO2 is a compound as defined in paragraphs (46) to (49) in the summary of invention section.

[0229] In various embodiments, the dual inhibitor of IDO1 and TDO2 is a compound as defined in paragraphs (48) to (49) in the summary of invention section.

[0230] In various embodiments, the dual inhibitor of IDO1 and TDO2 is 6-Chloro-5- fluoroisoxazolo[5,4-b]pyridin-3-amine (also referred to herein as compound 66 or

[0231] As explained in the examples, the inventors discovered that the dual inhibitor of IDO1 and TDO2 AT-0174 has excellent brain penetration, with much higher levels of AT-0174 detected in the mouse brain, compared to mouse plasma, after oral dosing. Without being bound by theory, the significant uptake into the brain suggests that AT-0174 would be ideal for use in the treatment of brain cancers such as glioma and, more specifically, glioblastoma.

[0232] As explained in the examples, the dual inhibitor of IDO1 and TDO2 AT-0174 had no significant effect on tumour growth or survival of mice when administered alone. The combination of AT-0174 with TMZ, on the other hand, surprisingly conferred clear efficacious synergy, suppressed tumour growth, and significantly improved survival.

[0233] The inventors also found, through Tcell analysis of glioma tumours, that AT- 0174 suppressed Treg numbers, while elevating activated CD8+ / CD25+Tcells. Depletion of Tregs has been linked to survival prolongation in mice with experimental gliomas (El Andaloussi et al., 2006., J Neurosurg. 105(3): 430-7), while CD4+ / CD257FoxP3+Treg infiltration positively correlates with clinical glioma tumour grade (El Andaloussi & Lesniak., 2006., Neuro Oncol. 8(3): 234-43). AT-0174 therefore appears to improve the immune profile in favour of the treatment of glioma. Without being bound to theory, the dual inhibitor of IDO1 and TDO2 described herein may have a dual effect when used in combination with TMZ in the treatment of glioma: (i) to down-regulate Treg expression, while promoting CD8+cell activation to engage an immune response to the glioma, and (ii) to block kynurenine-AhR- induced Pol K, improving prognosis in response to the TMZ. Overexpression of TDO2 in glioma, in addition to the Pol K-inducing effects of TMZ itself, may contribute to poor prognosis in glioma patients treated with TMZ. Glioblastomas are characterised by elevated expression of translesion DNA polymerases, including Pol K (Wang et al., 2010., Neuro Oncol. 12(7): 679-86). Wang et al (2010) also reports that increased Pol K and Pol i expression are highly correlated to increased glioblastoma disease stage severity and negatively correlated with survival. Peng et al. (2016) Cancer Res. 76(8): 2340-53 have also demonstrated that over-expression of Pol K in A172 glioma cells leads to a significantly worse outcome in response to TMZ treatment, and reports that Pol K is not only associated with glioblastoma outcome, but is induced directly by TMZ. Further, Bostian et al ((2016) Chem Res Toxicol. 29(1): 101-8) have reported that kynurenine signalling, through AhR also significantly increases the expression of Pol K, and that the AhR activation in glioblastoma cells (to increase Pol K) has been shown to result from TDO2 activity. As shown in the examples, AT-0174 dose-dependently reduced the intra-tumoural kynurenine:tryptophan (K:T) ratio, confirming that AT-0174 functionally acts as a dual inhibitor of IDO1 and TDO2 in vivo. By inhibiting IDO1 and TDO2, the AT-0174 may reduce kynurenine-AhR-induced Pol K and thereby contribute to improved prognosis of glioma patients in response to TMZ.

[0234] Gliomas can overexpress IDO1 and TDO2 and there are correlations between disease severity and IDO1 and TDO2 expression. Patients with strong IDO expression have been shown to have significantly worse overall survival rates than patients with weak IDO expression (Mitsuka et al, (2013) Neurosurgery. 72(6): 1031 -8). There is also evidence for a correlation between TDO2 expression and poor patient survival (Opitz CA et al., (2011) Nature 478(7368): 197-203). In various embodiments, the glioma may be characterized by an overexpression of TDO2 relative to normal background levels in healthy individuals. In various embodiments, the glioma may be characterized by an overexpression of IDO1 relative to normal background levels in healthy individuals. In various embodiments, the glioma may be characterized by an overexpression of IDO1 and TDO2 relative to normal background levels in healthy individuals.

[0235] Compounds of Formula I may be prepared by following the methods described in PCT International patent application number PCT / IB2015 / 056129 (published as WO2016024233), which is incorporated herein by reference, or procedures analogous thereto. The person skilled in the art would appreciate that other dual inhibitor of IDO1 and TDO2 are also suitable for use in the invention.

[0236] Other inhibitors of IDO1 and / or TDO2 and methods for their preparation are described in PCT International patent application number PCT / NZ2016 / 050135 (published as WO 2017034420), which is incorporated herein by reference. Compounds as described in PCT / NZ2016 / 050135 that are dual inhibitors of IDO1 and TDO are suitable for use in the present invention. For example, PCT / NZ2016 / 050135 discloses the following compounds:

[0237] 1 -(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-3-(4- (trifluoromethoxy)phenyl)urea (2B)

[0238] 1 -(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-3-(2-chlorophenyl)urea (6B)

[0239] 1 -(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-3-(3-chlorophenyl)urea (7B)

[0240] 1 -(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-3-(4-chlorophenyl)urea (SB)

[0241] 1 -(5~Chloro-4,6-dimethylisoxazolo[5,4~b] pyridin-3-yl)-3-(2- (trifluoromethoxy)phenyl)urea (9B)

[0242] 1 -(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-3-(3- (trifluoromethoxy)phenyl)urea (10B)

[0243] 1 -(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-3-(3- methoxyphenyi)urea (12B)

[0244] N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-2~phenylacetamide (18B)

[0245] N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-2-(4- (trifluoromethoxy)phenyl)acetamide (198)

[0246] Phenyl (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)carbamate (4B)

[0247] 1 -(5-Chloro-4,6-dimethylisoxazolo[5,4-b] pyridin-3-yl)-3-(3- (trifluoromethyl)phenyl)urea (15B)

[0248] 4-Fluorophenyl (5<hloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)carbamate (5B)

[0249] N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3~yl)acetamide (20B), and a pharmaceutically acceptance salts thereof.

[0250] Certain dual inhibitors of IDO1 and TDO described in PCT / NZ2016 / 050135 that may be suitable for use in the invention include Phenyl (5-chloro-4,6- dimethylisoxazolo[5,4-b]pyridin-3-yl)carbamate (4B) and 1 -(5-Chloro-4,6- dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-(trifluoromethyl)phenyl)urea (15B).

[0251] Administration

[0252] The dual inhibitor of IDO1 and TDO2, and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, may be administered as a single formulation or as separate formulations. In various embodiments, the dual inhibitor of IDO1 and TDO2, and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, are administered as separate formulations. In various embodiments, the dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, are administered as a single formulation.

[0253] In various embodiments, the dual inhibitor of IDO1 and TDO2 may be administered before, during or after administration of the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0254] In various embodiments, the dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, may be administered simultaneously, sequentially, or separately.

[0255] It will be appreciated by those skilled in the art that a particular method of therapy comprising administering the dual inhibitors of IDO1 and TDO2 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 that the optimal course of treatment or prevention, e.g., the formulation and the number and frequency of doses of the dual inhibitors of IDO1 and TDO2 given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.

[0256] Therapeutic dosages of the dual inhibitor of IDO1 and TDO2, as described herein, may be in the range of 1 mg to 2000 mg per day. In various embodiments, the therapeutic dosages of the dual inhibitors of IDO1 and TDO2, as described herein, may be in the range of 1 mg to 2000 mg per day and administered in a single dose or administered as multiple doses throughout the day, for example in 2, 3, 4 or more separate doses.

[0257] In various embodiments, the dose of the dual inhibitor of IDO1 and TDO2 is in the range of 1 to 100 mg per day, 100 to 200 mg per day, 200 to 300 mg per day, 300 to 400 mg per day, 400 to 500 mg per day, 500 to 600 mg per day, 600 to 700 mg per day, 700 to 800 mg per day, 800 to 900 mg per day, 900 to 1000 mg per day. In various embodiments, the dose of the dual inhibitor of IDO1 and TDO2 is in the range of 1000 to 1100 mg per day, 1100 to 1200 mg per day, 1200 to 1300 mg per day, 1300 to 1400 mg per day, 1400 to 1500 mg per day, 1500 to 1600 mg per day, 1600 to 1700 mg per day, 1700 to 1800 mg per day, 1800 to 1900 mg per day or 1900 to 2000 mg per day. In various embodiments, the dose of the dual inhibitor of IDO1 and TDO2 is in the range of 25 mg to 800 mg per day or 50 to 800 mg per day. In various embodiments, the dose of the dual inhibitor of IDO1 and TDO2 is in the range of 1 mg to 50 mg per day, 50 mg to 100 mg per day, 100 to 150 mg per day, 150 mg to 200 mg per day, 200 mg to 250 mg per day, 250 mg to 300 mg per day, 300 mg to 350 mg per day, 350 mg to 400 mg per day, 400 mg to 450 mg per day, 450 mg to 500 mg per day, 500 mg to 550 mg per day, 550 mg to 600 mg per day, 600 mg to 650 mg per day, 650 mg to 700 mg per day, 700 mg to 750 mg per day, 750 mg to 800 mg per day, 800 mg to 850 mg per day, 850 mg to 900 mg per day, 900 mg to 950 mg per day, 950 mg to 1000 mg per day.

[0258] In various embodiments, the therapeutic dosages of the dual inhibitors of IDO1 and TDO2, as described herein, may be in the range of 1 mg to 2000 mg administered every two days, every three days, every four days, every five days, every six days or every week, and administered in a single dose or administered as multiple doses throughout the day, for example in 2, 3, 4 or more separate doses in a single day.

[0259] In a various embodiments, the therapeutic dosages of the dual inhibitors of IDO1 and TDO2, as described herein, may be in the range of 1 mg to 50 mg, 50 mg to 100 mg, 100 to 150 mg per day, 150 mg to 200 mg per day, 200 mg to 250 mg, 250 mg to 300 mg, 50 to 300 mg, 300 mg to 350 mg, 350 mg to 400 mg, 50 to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 50 to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 50 to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 50 to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 50 to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 50 to 900 mg, 900 mg to 950 mg, 950 mg to 1000 mg administered every two days, every three days, every four days, every five days, every six days or every week.

[0260] It will also be appreciated by those skilled in the art that a particular method of therapy comprising administering temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, 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 that the optimal course of treatment or prevention, e.g., the formulation and the number and frequency of doses of the temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests. According to the method of the present invention, the dosage form of the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof and the method of administration thereof are not particularly limited.

[0261] Temozolomide may be commercially available for oral administration and for intravenous injection under the trade name "Temodar®" distributed by: Merck Sharp & Dohme LLC. The person skilled in the art will appreciate that the dose of the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof may be varied depending on the age and sex of a patient, and the severity of glioma. In various embodiments, the dose of TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is about 50 to 300 mg / m2body surface area (BSA) or 75 to 200 mg / m2(BSA), for example, 75, 150, or 200 mg / m2(BSA). In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is administered every day, every two days, every three days, every four days, every five days, every six days or once weekly. In various embodiments, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is administered every two days but every fifth administration is skipped (i.e. not administered). In various embodiments, the dose of TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is about 50 to 300 mg / m2(body surface area (BSA)) or 75 to 200 mg / m2(BSA), for example, 75, 150, or 200 mg / m2(BSA) on a once-daily basis.

[0262] In various embodiments, the methods and uses described herein comprise administering the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, at a dose of about 50 to 300 mg / m2(body surface area (BSA)) or 75 to 200 mg / m2(BSA), for example, 75, 150, or 200 mg / m2(BSA), and the dual inhibitor of IDO1 and TDO2 at a dose in the range of 1 mg to 2000 mg per day, for example, 1 to 100 mg per day, 100 to 200 mg per day, 200 to 300 mg per day, 50 to 400 mg per day, 300 to 400 mg per day, 50 to 500 mg per day, 400 to 500 mg per day, 500 to 600 mg per day, 50 to 700 mg per day, 600 to 700 mg per day, 50 to 800 mg per day, 700 to 800 mg per day, 800 to 900 mg per day, 900 to 1000 mg per day.

[0263] In various embodiments, the methods and uses described herein comprise administering the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, every day, every two days, every three days, every four days, every five days, every six days or once weekly at a dose of about 50 to 300 mg / m2(body surface area (BSA)) or 75 to 200 mg / m2(BSA), for example, 75, 150, or 200 mg / m2(BSA), and administering the dual inhibitor of IDO1 and TDO2 at a dose in the range of 1 mg to 2000 mg per day, for example, 1 to 100 mg per day, 100 to 200 mg per day, 200 to 300 mg per day, 50 to 400 mg per day, 300 to 400 mg per day, 50 to 500 mg per day, 400 to 500 mg per day, 500 to 600 mg per day, 50 to 700 mg per day, 600 to 700 mg per day, 50 to 800 mg per day, 700 to 800 mg per day, 800 to 900 mg per day, 900 to 1000 mg per day, every one or two days.

[0264] In various embodiments, the methods and uses described herein comprise at least one treatment cycle, wherein the at least one treatment cycle comprises administering the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof every day, every two days, every three days, every four days, every five days, every six days or every seven days, and administering the dual inhibitor of IDO1 and TD02 every day, every two days, every three days, every four days, every five days, every six days or every seven days.

[0265] In various embodiments, the methods and uses described herein comprise at least one treatment cycle, wherein the at least one treatment cycle comprises administering the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof every day or every two days, and administering the dual inhibitor of IDO1 and TDO2 every day or every two days. In various embodiments, the methods and uses described herein comprise at least one treatment cycle, wherein the at least one treatment cycle comprises administering the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof every two days, and administering the dual inhibitor of IDO1 and TDO2 every day or every two days. In various embodiments, the methods and uses described herein comprise at least one treatment cycle, wherein the at least one treatment cycle comprises administering the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof every day, every two days, every three days, every four days, every five days, every six days or every seven days at a dose of about 50 to 300 mg / m2 (body surface area (BSA)) or 75 to 200 mg / m2 (BSA), for example, 75, 150, or 200 mg / m2 (BSA), and administering the dual inhibitor of IDO1 and TDO2 daily at a dose in the range of 1 mg to 2000 mg per day, for example, 1 to 100 mg per day, 100 to 200 mg per day, 200 to 300 mg per day, 50 to 400 mg per day, 300 to 400 mg per day, 50 to 500 mg per day, 400 to 500 mg per day, 500 to 600 mg per day, 50 to 700 mg per day, 600 to 700 mg per day, 50 to 800 mg per day, 700 to 800 mg per day, 800 to 900 mg per day, 900 to 1000 mg per day.

[0266] In various embodiments, the at least one treatment cycle comprises from 1 to 100 days, for example, about 3 to 56 days, about 3 to 25 days, about 3 to 10 days, about 5 to 56 days, about 5 to 30 days, about 5 to 15 days, about 5 to 10 days, about 7 to 56 days, about 7 to 30 days, about 15 to 30 days, about 15 to 40 days, about 14 to 56 days, about 14 to 40 days, about 21 to 56 days, about 21 to 38 days, about 28 to 56 days, about 35 to 56 days, about 35 to 49 days, about 35 to 42 days, about 42 to 56 days, or about 42 to 49 days. In various embodiments, the at least one treatment cycle comprises at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 32 days, at least 33 days, at least 34 days, at least 35 days, at least 36 days, at least 37 days, at least 38 days, at least 39 days, at least 40 days, at least 41 days, at least 42 days, at least 43 days, at least 44 days, at least 45 days, at least 46 days, at least 47 days, at least 48 days, at least 49 days, at least 50 days, at least 51 days, at least 52 days, at least 53 days, at least 54 days, at least 55 days, at least 56 days, at least 57 days, at least 58 days, at least 59 days, at least 60 days, at least 61 days, at least 62 days, at least 63 days, at least 64 days, at least 65 days, at least 66 days, at least 67 days, at least 68 days, at least 69 days, at least 70 days, at least 71 days, at least 72 days, at least 73 days, at least 74 days, at least 75 days, at least 76 days, at least 77 days, at least 78 days, at least 79 days, at least 80 days, at least 81 days, at least 82 days, at least 83 days, at least 84 days, at least 85 days, at least 86 days, at least 87 days, at least 88 days, at least 89 days, at least 90 days, at least 91 days, at least 92 days, at least 93 days, at least 94 days, at least 95 days, at least 96 days, at least 97 days, at least 98 days, at least 99 days, or at least 100 days.

[0267] In various embodiments, the at least one treatment cycle comprises 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days,

[0268] 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 clays, 35 clays, 36 clays, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days,

[0269] 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 61 days,

[0270] 62 days, 63 days, 64 days, 65 days, 66 days, 67 days, 68 days, 69 days, 70 days, 71 days, 72 days, 73 days, 74 days, 75 days, 76 days, 77 days, 78 days, 79 days, 80 days,

[0271] 81 days, 82 days, 83 days, 84 days, 85 days, 86 days, 87 days, 88 days, 89 days, 90 days, 91 days, 92 days, 93 days, 94 days, 95 days, 96 days, 97 days, 98 days, 99 days, or 100 days. In various embodiments, the methods and uses described herein comprise the at least one treatment cycle and at least one repetition of the at least one treatment cycle. In various embodiments, the methods and uses described herein comprise the at least one treatment cycle and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 repetitions of the at least one treatment cycle.

[0272] In various embodiments, the methods and uses described herein comprise at least one treatment cycle, wherein the at least one treatment cycle comprises administering the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof once a day for at least 4, at least 5, at least 6, at least 7 or at least 8 consecutive days at a dose of about 50 to 300 mg / m2 (body surface area (BSA)) or 75 to 200 mg / m2 (BSA), for example, 75, 150, or 200 mg / m2 (BSA), and administering the dual inhibitor of IDO1 and TDO2 daily at a dose in the range of 1 mg to 2000 mg per day, for example, 1 to 100 mg per day, 100 to 200 mg per day, 200 to 300 mg per day, 50 to 400 mg per day, 300 to 400 mg per day, 50 to 500 mg per clay, 400 to 500 mg per day, 500 to 600 mg per day, 50 to 700 mg per day, 600 to 700 mg per day, 50 to 800 mg per day, 700 to 800 mg per day, 800 to 900 mg per day, 900 to 1000 mg per day, wherein the at least one treatment cycle comprises 21 to 56 days, and optionally wherein the at least one treatment cycle is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 times. In various embodiments, the methods and uses described herein comprise at least one treatment cycle, wherein the at least one treatment cycle comprises administering the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof once a day for at least 20 consecutive days at a dose of about 50 to 300 mg / m2 (body surface area (BSA)) or 75 to 200 mg / m2 (BSA), for example, 75, 150, or 200 mg / m2 (BSA), and administering the dual inhibitor of IDO1 and TDO2 daily at a dose in the range of 1 mg to 2000 mg per day, for example, 1 to 100 mg per day, 100 to 200 mg per day, 200 to 300 mg per day, 50 to 400 mg per day, 300 to 400 mg per day, 50 to 500 mg per day, 400 to 500 mg per day, 500 to 600 mg per day, 50 to 700 mg per day, 600 to 700 mg per day, 50 to 800 mg per day, 700 to 800 mg per day, 800 to 900 mg per day, 900 to 1000 mg per day, wherein the at least one treatment cycle comprises 20 to 56 days, for example, 30 to 50 days, 35 to 50 days, or 40 to 50 days, and optionally wherein the at least one treatment cycle is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 times.

[0273] In various embodiments, the methods and uses described herein comprise at least one treatment cycle, wherein the at least one treatment cycle comprises administering the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is administered every two days but every fifth administration is skipped (i.e. not administered) at a dose of about 50 to 300 mg / m2 (body surface area (BSA)) or 75 to 200 mg / m2 (BSA), for example, 75, 150, or 200 mg / m2 (BSA), and administering the dual inhibitor of IDO1 and TDO2 daily at a dose in the range of 1 mg to 2000 mg per day, for example, 1 to 100 mg per day, 100 to 200 mg per day, 200 to 300 mg per day, 50 to 400 mg per day, 300 to 400 mg per day, 50 to 500 mg per day, 400 to 500 mg per day, 500 to 600 mg per day, 50 to 700 mg per day, 600 to 700 mg per day, 50 to 800 mg per day, 700 to 800 mg per day, 800 to 900 mg per day, 900 to 1000 mg per day, wherein the at least one treatment cycle is 21 to 56 days, for example, 30 to 50 days, 35 to 50 days, or 40 to 50 days, and optionally wherein the at least one treatment cycle is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 times.

[0274] 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.

[0275] Dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to provide an amount of the active ingredient which is effective to achieve the desired therapeutic effect for a particular patient, composition, and mode of administration, without being toxic to the patient (an effective amount). Pharmaceutical compositions

[0276] The dual inhibitor of indoleamine-2,3-dioxygenase (I D01 ) and tryptophan- 2,3-dioxygenase-2 (TDO2), may be formulated or provided for use as a pharmaceutical composition comprising the dual inhibitor of IDO1 and TDO2, and a pharmaceutically acceptable carrier.

[0277] Similarly, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, may be formulated or provided for use as a pharmaceutical composition comprising the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0278] Alternatively, in various embodiments, the dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, can be formulated in a single composition.

[0279] The term “pharmaceutically acceptable carrier" refers to a carrier (e.g. adjuvant, buffer, stabiliser or vehicle) that may be administered to a subject together with the dual inhibitor of IDO1 and TDO2 and / or with the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, and which is generally safe. The pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser should be nontoxic and should not interfere with the efficacy of the active ingredient. The term "pharmaceutically acceptable carrier" also including carriers suitable in veterinary as well as human pharmaceutical use. The precise nature of the carrier or other material will depend on the route of administration.

[0280] The dual inhibitor of IDO1 and TDO2 and / or the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof may be administered by injection, orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term 'administered by injection' includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. The dual inhibitor of IDO1 and TDO2 and / or the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients. Compositions intended for intravenous use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions.

[0281] 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, flavouring agents, colouring 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 dual inhibitor of IDO1 and TDO2 and / or the temozolomide (TMZ) or derivative thereof, or pharmaceutically acceptable salt thereof, may also be prepared in solid, rapidly released form.

[0282] 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.

[0283] 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 colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0284] 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, flavouring and colouring agents, may also be present. The dual inhibitor of IDO1 and TD02 and / or the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof may also be in the form of nonaqueous 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 flavouring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0285] Pharmaceutical compositions comprising the dual inhibitor of IDO1 and TDO2 and / or the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof 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 flavouring agents.

[0286] 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 flavouring and colouring agents.

[0287] The dual inhibitor of IDO1 and TDO2 and / or the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof 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.

[0288] Additional agents

[0289] The dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof can be administered in combination with one or more additional anticancer agent and / or cancer therapy.

[0290] The dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, are also expected to be useful in treating glioma in combination with one or more additional anticancer agent and / or cancer therapy. In various embodiments, the methods described further comprise administering the dual inhibitor of IDO1 and TDO2, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, and one or more additional anticancer agent and / or cancer therapy. The dual inhibitor, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, and the one or more additional anticancer agent and / or cancer therapy may be administered simultaneously, sequentially, or separately and may be administered as a single formulation or as separate formulations, as appropriate.

[0291] In various embodiments, the anticancer agent is a platinum based chemotherapeutic agent selected from: carboplatin, cisplatin, lobaplatin, oxaliplatin, picoplatin, nedaplatin, phenanthriplatin and / or satraplatin, or another chemotherapeutic agent selected from the group comprising: alkaloids and natural products, including: camptothecin derivatives for example 9-aminocamptothecin, exatecan, irinotecan rubitecan and topotecan, podophyllum derivatives for example etoposide and teniposide, taxanes for example docetaxel, paclitaxel and paclitaxel poliglumex, vinca alkaloids for example vinblastine, vincristine, vindesine, vinflunine and vinorelbine, and others for example a plidine, elliptinium acetate, irofulven, ixabepilone, kahalalide F, midostaurin and trabectedin; alkylating agents, including alkyl sulfonates for example busulfan, improsulfan and piposulfan, aziridines for example carboquone, diaziquone, mitomycin-C and uredepa, ethylenimines and methylmelamines for example altretamine, triethylenemelamine, triethylenephosphoramide and triethylenethiophosphoramide, nitrogen mustards for example bendamustine, canfosfamide, chlorambucil, chlornaphazine, yclophosamide, cyclophosphamide estramustine, glufosfamide, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, perfosfamide, prenimustine, trichlormethine, trofosfamide, and uracil mustard, nitrosoureas for example carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine, and others for example dacarbazine, etoglucid, mitobronitol, mitolactol, pipobroman, procarbazine, and lomustine; antibiotics and analogs, including actinomycins for example cactinomycin and dactinomycin, anthracydines for example aclacinomycins, amrubicin, carubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, Valrubicin and zorubicin, and others for example bleomycins, mitomycins, peplomycin, plicamycin, porfiromycin, streptozocin, temsirolimus and zinostatin; antimetabolites, including folic add analogs and antagonists for example denopterin, edatrexate, methotrexate, nolatrexed, pemetrexed, piritrexi, pteropterin, raltitrexed and trimetrexate, purine analogs for example cladribine, clofarabine, fludarabine, fludarabine phosphate 6-mercaptopurine, nelarabine, thiamiprine, thioguanine and tiazofurine, and pyrimidine analogs for example ancitabine, azacitidine 6-azauridine, capecitabine, carmofur, cytarabine, decitabine, doxifluridine, enocitabine, floxuridine, fluorouracil, gemcitabine, tegafur andtroxacitabine; enzymes for example L- asparaginase and ranpirnase; farnesyl transferase inhibitors for example lonafarnib, tipifa rnib; immunomodulators for example aldesleukin, interferon -a, interferon- y, lentinan, mepact, oregovomab, propagermanium, PSK®, roquinimex, sipuleucel-T, sizofiran, teceleukin and ubenimex; immunotoxins for example cintredekin besudotox and denileukin diftitox; monoclonal antibodies for example alemtuzumab, bevacizumab, cetuximab, edrecolomab, epratuzumab, gemtuzumab, ozogamicin, oregovomab, panitumumab, rituximab, tositumomab131!, ofatumumab, ipilimumab, pertuzumab, ramucirumab, obinutuzumab, nivolumab, Pembrolizumab, dinutuximab and trastuzumab; antibody drug conjugates for example Ibritumomab tiuxetan, Brentuximab vedotin and Ado-Trastuzumab emtansine; oligonucleotides for example aprinocarsen and oblimersen sodium; retinoids and analogs for example alitretinoin, bexarotene, fenretinidem, mofarotene and tarnibarotene; tyrosine kinase inhibitors for example canertinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, sorafenib, sunitinib, axitinib, nilotinib, Pazopanib, Bosutinib, Cabozantinib, Ponatinib, Regorafenib and vatalanib; other inhibitors for example crizotinib, ruxolitinib, vandetanib, Vemurafenib Tofacitinib, Afatinib, Dabrafenib, Ibrutinib and Trametinib; and others for example amsacrine, arsenic trioxide, atrasentan, bisantrene, bortezomib, brostallicin, calcitriol, edotecarin, eflornithine, flavopiridol, gallium nitrate, hydroxyurea, liarozole, lonidamine, miltefosine, mitoguazone, mitoxantrone, nitracrine, pentostatin, perifosine, pixantrone, razoxane, seocalcitol, sobuzoxane, spirogermanium, tirapazamine and vorinostat. Such anticancer agents also include without limitation antineoplastic hormonal agents including androgens for example dromostanolone, epitiostanol, mepitiostane and testolactone; antiadrenals for example aminoglutethimide, mitotane, trilostane; antiandrogens, bicalutainide, flutamide and nilutamide; antiestrogens for example arzoxifene, droloxifene, fulvestrant, idoxifene, tamoxifen and toremifene; antiprogestins for example onapristone; aromatase inhibitors for example aminoglutethimide, anastrozole, exemestane, fadrozole, formestane, letrozole and vorozole; estrogens for example diethylstilbestrol, fosfestrol, hexestrol and polyestradiol phosphate; LH-RH analogs for example abarelix, buserelin, cetrorelix, goserelin, leuprolide and triptorelin; progestagens for example chlormadinone acetate, medroxyprogesterone and megestrol acetate; and somatostatin analogs for example lanreotide. Such anticancer agents also include without limitation antineoplastic photosensitisers for example 6- aminolevulinic acid, methyl aminolevulinate, motexafin lutetium, porfimer sodium, talaporfin and temoporfin; other anti-proliferative agents such as azathioprine, 5- azacytidine cladribine, 2',2'-difluorodeoxycytidine, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fluoxymesterone, hydroxyprogesterone caproate, N-phosphonoacetyl-L-aspartate (PALA), semustine, tenipdside, testosterone propionate, thiotepa, trimethylmelamine and uridine. Additional chemotherapeutic agents 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, mesna, prednisolone, prednisone, and raloxifen. For example, in various embodiments, the anticancer agent is a chemotherapeutic agent selected from: alkylating agents, including alkyl sulfonates, aziridines, ethylenimines and methylmelamines, nitrogen mustards for example cyclophosamide, mechlorethamine, mechlorethamine oxide hydrochloride, nitrosoureas; and anthracyclines.

[0292] In various embodiments, the cancer therapy comprises the administration of one or more anticancer agent and / or a radiotherapy.

[0293] In various embodiments, the cancer therapy comprises the administration of one or more anticancer agent, for example, an anticancer agent selected from: a chemotherapeutic agent and / or a radiotherapeutic agent. For example, in various embodiments, the one or more additional cancer therapy comprises the administration of one or more anticancer agent selected from the anticancer agents listed above.

[0294] In various embodiments, the cancer therapy is a radiotherapy. In various embodiments, the radiotherapy is external radiation treatment or internal radiation treatment. In various embodiments, the one or more additional anticancer agent and / or cancer therapy is selected from the group consisting of: chemotherapeutic agents, immune-modulating agents such as anticancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapies (for example chimeric antigen receptor T cells (CART cells)), and radiotherapy.

[0295] Other suitable anticancer agents will be apparent to those skilled in the art having regard, for example, to the glioma to be treated. Numerous anticancer agents are known in the art. Examples of suitable anticancer agents include those listed in Cancer: Principles and Practice of Oncology, 7thEdtion, Devita et al, Lippincott Williams & Wilkins, 2005, which is incorporated herein by reference.

[0296] In various embodiments, the anticancer agent induces an increase in ROS within cancer cells. In various embodiments, the one or more additional anticancer agent induces reactive oxygen species (ROS) dependent programmed cell death (PCD) in cancer cells.

[0297] In various embodiments, the anticancer agent is a chemotherapeutic agent selected from, but are not limited to, compounds listed on the cancer chemotherapy drug regimens in the 14thEdition 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.

[0298] In various embodiments, the anticancer agent is an anti-proliferative agent, selected from, 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, tenipdside, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.

[0299] In various embodiments, the anticancer agent is an anti-proliferative agents selected from 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, Pembrolizumab, 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.

[0300] In various embodiments, the anticancer agent is an immune modulating agent. For example, in various embodiments, the immune modulating agent is selected from, without limitation, anticancer vaccines, agents that modulate immune checkpoint proteins (such as CTLA4, PD1 -4s and PD-L1) and adoptive T-cell therapies (such as CARTs). In various embodiments, the one or more additional anticancer agent is an inhibitor of CTLA4, an anti-PD-1 antibody or an anti-PD-L1 antibody. For example, in various embodiments, the one or more additional anticancer agent is an inhibitor of CTLA4 such as Ipilimumab, an anti-PD-1 antibody such as Cemiplimab, Nivolumab and / or Pembrolizumab, or an anti-PD-L1 antibody such as Atezolizumab, Avelumab and / or Durvalumab.

[0301] The dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof may be administered simultaneously, sequentially, or separately with the one or more additional anticancer agents, therapy and / or an immune modulating agent. The dual inhibitor of IDO1 and TDO2, the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, and the one or more additional anticancer agents and / or an immune modulating agent may be administered as single formulation or as separate formulations.

[0302] Accordingly, the dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof can be administered in combination with one or more other such anticancer agents or therapies, either simultaneously or sequentially dependent upon the particular glioma to be treated.

[0303] In various embodiments, the one or more additional cancer therapy comprises a step of administering the one or more additional anticancer agent. In various embodiments, the one or more additional cancer therapy is a radiotherapy.

[0304] In various embodiments, the one or more additional cancer therapy is an immunotherapy selected from Ipilimumab (an inhibitor of CTLA4), Nivolumab and Pembrolizumab (both inhibitors of PD-1).

[0305] Kits

[0306] The dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, may be formulated or provided for use as a kit comprising the one or more dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof; and optionally instructions for use in accordance with the methods described herein.

[0307] The dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof may each independently be in the form of a pharmaceutical composition, and contained within separate containers. In other various embodiments, the dual inhibitor of IDO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, may be in the form of a pharmaceutical composition, and contained within the same contain container.

[0308] The container may be any vessel or other sealed or sealable apparatus that can hold the pharmaceutical composition. Examples include bottles, ampules, divided or multi-chambered holders bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition. The container can be in any conventional shape or form and is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag, or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed typically depends on the dosage form involved. More than one container can be used together in a single package for a single dosage form.

[0309] The kits may also comprise a device to administer or to measure out a unit dose of the dual inhibitor of IDO1 and TDO2 and / or the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof. The device may include, for example, an inhaler if the composition is an inhalable composition; a syringe and needle if the composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if the composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit.

[0310] In various embodiments, the kit may comprise one or more additional anticancer agent. In various embodiments, the one or more additional anticancer agent is an anticancer agent as described hereinabove.

[0311] In various embodiments, the kits may comprise, for example in a separate vessel or container, the one or more additional anticancer agent, typically in the form of a pharmaceutical composition comprising the one or more additional anticancer agent and a pharmaceutically acceptable carrier. The one or more additional anticancer agent may be selected from any of those indicated herein for coadministration with the dual inhibitor of IDO1 and TDO2 and temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof as described herein.

[0312] EXAMPLES

[0313] The following non-limiting examples are provided to illustrate the present invention and in no way limit the scope thereof.

[0314] EXAMPLE 1

[0315] Enzymatic Assay for ID01 activity

[0316] Recombinant human IDO1 (rhIDOI) 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 pM methylene blue, 100 pg / mL catalase, 80 pM TRP, 0.01% Tween 20 (v / v) mixed with rhIDOI (15 pL) at a final concentration of 9 nM in a total volume of 30 pL 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 Aex400 nm and Aem500 nm. Test compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and pre- diluted in assay medium prior to adding rhIDOI . IDO1 inhibition (%) was calculated as 100

[0317] All experiments were carried out in triplicates, and statistical Analyses were conducted in Prism v5 (Graphpad Software, Inc., La Jolla, CA, USA).

[0318] Cell-based assay for ID01 inhibition

[0319] For the assay of inhibition of cellular ID01 activity, Lewis Lung carcinoma cells transfected to express human ID01 (LLTC-hlDO1) or murine (LLTC-mlDO1) 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.

[0320] 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 IDO1 inhibition, the cells were incubated with MTT (500 pg / 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 pL / well) 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.

[0321] Cell-based assay for TDO2 inhibition

[0322] For the assay of inhibition of cellular TDO2, GL261 cells transfected to overexpress full length human TDO2 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 IDO1 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.

[0323] Results of the assays are shown in Table 1 below. RESULTS

[0324] Table 1 ts a v V 9 N Il 1 HN *Q

[0325] Activity IC50 ranges: A: < 1 pM, B: 1-10 pM, C: 10-100 pM, D: >100 pM

[0326] EXAMPLE 2

[0327] MATERIALS & METHODS

[0328] The structure and chemical name of the compound AT-0174 6 (also referred to herein as compound (66)) is shown below:

[0329] 6-Chloro-5-fluoroisoxazolo[5,4-b] pyridin-3-amine

[0330] Cellular IDO 7 Enzyme Inhibition Assay

[0331] Lewis-lung carcinoma cells adapted to tissue culture (LLTC) stably transfected with the expression vector F279-V5 / hlDO1 containing human IDO1 under the control of the CMV promoter, were used for a cell-based assay of IDO1 enzyme activity (LLTC-hlDO1). Test compounds, including AT-0174, were solubilised in 0.5% (v / v) dimethyl sulfoxide (DMSO) and incubated (24 h; 37°C) with 2x104LLTC-hlDO1 cells / well in oc-MEM (Minimum Essential Medium) medium (containing 10 % fetal calf serum, 10% penicillin (100 U / ml), streptomycin (100 pg / ml) and puromycin (2.5 pM) and 49 pM tryptophan). Incubation supernatants (120 pl) were treated for 20 min at 60°C with 10% trichloroacetic acid and spun (2500 g, 10 min) prior to mixing with para-dimethylaminobenzaldehyde (p-DMAB) (20 mg / mL in glacial acetic acid). After 10 min incubation in the dark, absorbance was read at 490 nm on a SpectraMax M2 (Molecular Devices) to assay kynurenine content. The concentration of kynurenine in the supernatants was determined from a calibration curve of kynurenine standard, to provide a measure of IDO1 enzyme inhibition in the cells. Cellular TD02 Enzyme Inhibition Assay

[0332] The murine glioma cell line GL261 was engineered to overexpress full-length human TDO2 under the control of a strong cytomegalovirus promoter (GL261 -hTDO cells). Test compounds, including AT-0174, were solubilised in 0.5% (v / v) DMSO and incubated for 24 h (37°C, 5% CO2) with 1x104GL261 -hTDO2 cells / well in oc-MEM medium containing 10 % fetal calf serum and 400 pM tryptophan. The incubation supernatant was treated for 20 min at 60°C in 40% trichloroacetic acid prior to treatment with Erhlich's Reagent (dark, room temperature, 10 min) and measurement of kynurenine was determined from absorbance at 500 nm (SpectraMax M2 (Molecular Devices), compared against a kynurenine standard curve, to provide a measure of TDO2 activity.

[0333] Effect of AT-0174 on Tryptophan and Kynurenine in Mice

[0334] To assess the pharmacodynamic effect of AT-0174 in vivo, changes in tumour tryptophan and kynurenine were assessed in mice with IDO1 - and TDO2- expressing tumours. Male C57BL / 6J mice were implanted subcutaneously with either GL261 -hlDO1 or GL261 -hTDO2 cells (1 xl 06per site) to produce syngeneic subcutaneous tumours that overexpressed IDO1 or TDO2 enzyme, respectively. 12 days following inoculation, mice were orally dosed with either vehicle control or AT- 0174 (60, 120 or 240 mg / kg gavage in 5% DMSO) and then sacrificed 2 h after oral gavage. Tumour tissue was dissected and prepared for the extraction and analysis of tryptophan and kynurenine content (high-performance liquid chromatography) to provide a pharmacodynamic measure of IDO1 and TDO2 enzyme inhibition.

[0335] Pharmacokinetics and Brain Penetration of AT-0174

[0336] Pharmacokinetic parameters were determined in male CD1 mice, which were administered AT-0174 either intravenously (10 mg / kg in 5 ml / kg 20% DMSO, 20% Kolliphor EL, 60% hydroxypropyl-cyclodextrin) or by oral gavage (60 mg / kg in 10 ml / kg 5% DMSO, 95% methylcellulose (0.5%)). Three mice per timepoint were sacrificed at 10, 20, 30, 60 and 120 minutes for blood sample collection and at 5, 10, 20, 30, 60 and 120 minutes post dosing for dissection of brain samples to assess central penetration of AT-0174. Plasma samples were prepared from blood collections and brain tissues were homogenised and spun down to enable assessment of AT-0174 in plasma and brain samples by liquid Chromatography with tandem mass spectrometry (LC / MS-MS). Pharmacokinetic parameters (including maximal concentration (Cmax), time post dose of maximum concentration (Tmax), area under the concentration / time curve (AUC), clearance (CL), volume of distribution (Vs), and Oral bioavailability) were calculated from AT-0174 content data. Glioblastoma Study Animals

[0337] All mice were housed in an A2 animal facility and all animal studies were carried out under protocols approved by the Institutional Animal Care and Use Committee at the University of Bordeaux. 7-week-old female C57BL / 6J mice were obtained from Charles River Laboratories and acclimated for 13 days prior to use at 9 weeks of age. Ventilation was 25 volumes / hour in temperature (21-22°C ) and humidity (~ 50%) controlled conditions under 12h / 12h light / dark. Free access to mouse pellet food and water was provided.

[0338] Glioblastoma Cell Inoculation

[0339] Murine glioma GL261 (Luc2) tumour cell line was cultured in vitro: Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 1% Penicillin-Streptomycin, 1 mM HEPES (4-(2-hydroxyethyl)-1 - piperazineethanesulfonic acid) and under selection pressure using G418 at 200 pg / mL. The cells were validated as mycoplasma-free. Before inoculation in mice, cell viability was assessed by flow cytometry and viable cell gating. A cell suspension was prepared according to the viable cell count. On the day of inoculation, analgesia was applied by intraperitoneal injection of 0.1 mg / kg buprenorphine. Mice were anesthetized using gas anaesthesia with 4% isoflurane for induction and 2% isoflurane for maintenance. The scalp was shaved and anesthetized with dermal cream and the scalp was incised to reveal Bregma. GL261 (Luc2) tumour cells were resuspended in sterile PBS and stereotaxically injected via Hamilton syringe (25,000 cells / pL) 2.02 mm left of Bregma, depth 3.04 mm (striatum). The injection site was cleaned with betadine gauze band the skin was stitched. The anesthetized mice were placed on a warming blanket and monitored until they woke up.

[0340] Treatment Groups and Dosing Schedule

[0341] On day 6 post tumour cell inoculation, randomization and group allocation were conducted based on the first bioluminescence imaging (see Animal Monitoring below). Animal groups, 15 mice per group in the main study and a further 6 per group for fluorescence activated cell sorting (FACS) analysis, were treated with either vehicle control (5% DMSO), temozolomide (TMZ) (Focus Biomolecules), AT-0174 (Antido Therapeutics), or TMZ + AT-0174. Dose regimen for each treatment group were as described in Table 2, while Figure 3 shows the overall study design methodology as a schematic.

[0342] Figure 3 shows an orthotopic glioblastoma study experimental design. Following acclimation for ~2 weeks, female C57BL / 6J mice were implanted with GL261(luc2) cells into the striatum under stereotaxic control, to provide syngeneic orthoptic glioblastomas. Drug treatments started on day 7, with temozolomide (TMZ; 8 mg / kg IP) and AT-0174 (120 mg / kg PO), given alone or in combination, on the days shown. Main study mice (n= 15 / treatment group) were assessed for body weight, tumour growth (bioluminescence measurement) and mortality, throughout the study. A satellite group of mice (n=6 / treatment group) received the same drug treatment regime but were sacrificed on day 16 for FACS analysis of T cell subsets to assess treatment effects on the intra-tumoural immune response.

[0343] Animal Monitoring

[0344] Starting from day 6 after tumour cell inoculation, all mice were monitored in vivo until Day 55 for tumour growth (assessed by bioluminescence and measured on day 6, 14, 21, 28, 35, 42, and 49), body weight (monitored 3 times per week until day 18, and then daily from day 19-55) and survival. Mice were sacrificed, according to the humane endpoints, when they showed reliable clinical signs such as respiratory distress, hunched posture or loss of > 15% body weight.

[0345] Immune Response Profiling

[0346] On day 16 post-tumour inoculation, satellite animals from each experimental group were sacrificed, and tumours were collected. Tumours were processed for organ dissociation using the GentleMACS system (Miltenyi Biotec) and myelin debris removal and homogenate purification and through a Percoll gradient. Tumour homogenates were then processed for immunostaining and profiling analysis by flow cytometry for the lymphoid component according to a marker panel of CD45+, CD3+, CD4+, CD8+, IFNy+, CD25+, and FoxP3+cells. Statistical Analysis

[0347] One-way ANOVA was conducted for the comparison of data of different groups followed by post hoc analysis. Dunnett's multiple comparisons post hoc analysis was used when comparing the mean of each treatment with the mean of controls in the orthotopic study. To assess the synergistic potential of AT-0174+TMZ, this study utilized the effect size of tumour grade differences between the control and treatment groups as a metric for treatment efficacy.

[0348] Effect size was calculated by dividing the mean difference of tumour grade between the Vehicle and treatment groups by the corresponding standard error

[0349] (Effect size ;represents the mean of tumor grade). Larger effect sizes indicate a more significant treatment effect. The effect sizes were calculated for TMZ, AT- 0174, and AT-0174+TMZ at Day 21, 28, 35, 42, and 49.

[0350] RESULTS

[0351] Enzyme Inhibition Potency & Selectivity

[0352] Analysis of IDO1 and TDO2 enzyme inhibition in recombinant cell systems indicated sub micromolar potency at both enzymes (see Figure 1).

[0353] Enzyme inhibition determined by colorimetry of kynurenine production in LLTC-hlDO1 cells revealed an inhibitory potency at IDO1 of 0.17 pM ICso- Potency at the TDO2 enzyme was similar in GL261 -hTDO2 cells, with the ICso determined to be 0.25 pM. Analysis of activity at related tryptophan and monoamine metabolic enzyme sites, revealed good selectivity for IDO1 and TDO2.

[0354] Effect on Kynurenine and Tryptophan in Mouse Xenograft Models

[0355] The dose-response relationship of AT-0174 on intra-tumoural kynurenine and tryptophan were examined in male mice given subcutaneous GL261 -hlDO1 or GL261 -hTDO2 tumours, which were grown for 12 days prior to dosing. Block of these enzymes would be expected to increase tryptophan and decrease kynurenine, reflected by a lowered kynurenine: tryptophan (K:T) ratio. AT-0174 was administered at 60, 120 or 240 mg / kg by oral gavage 2 hours prior to sacrifice and tumour tissue collection. Kynurenine and tryptophan were measured and the ratio of K:T was determined (expressed as a percentage of the K:T ratio in vehicle-treated animals). AT-0174 (60, 120 or 240 mg / kg, PO) dose-dependently reduced the K:T ratio in mice harboring subcutaneous tumours that over-expressed either IDO1 or TDO2 enzymes, measured 2 hours after oral gavage of the compound, when compared with the K:T ratio in mice administered only vehicle (Figure 2). Table 3: K:T ratio in hlDO1 - and hTDO2-expressing tumors in male mice 2 hours after oral treatment with AT-0174, expressed as a percentage of vehicle control-treated values

[0356] AT-0174 Pharmacokinetics

[0357] Intravenous administration of AT-0174 (10 mg / kg) to male CD-1 mice revealed a short half-life (16 min) and rapid elimination of the drug from the plasma, with a very high volume of distribution (Vss; 1595 ml), suggesting that the drug rapidly sequesters into tissues out of the plasma, rather than simply being rapidly metabolised and eliminated from the body. The half-life in plasma following oral administration was similarly short in mice and analysis of the area under the curve (AUC) from each route of administration indicates oral bioavailability is less than 10% in this species. However, despite the short half-life in plasma and the low oral bioavailability in mice, analysis of AT-0174 content in mouse brain after oral dosing demonstrates much higher central exposure than in the circulation (Table 4), in agreement with the high Vssof the compound.

[0358] Table 4: Pharmacokinetic parameters of AT-0174 in male CD1 mice

[0359] AT-0174 on body weight in Orthotopic Glioblastoma Mice

[0360] Mice were treated with repeat doses of vehicle control (5% DMSO, 10 ml / kg, PO), temozolomide (TMZ, 8 mg / kg, IP), AT-0174 (120 mg / kg, PO) or a combination of TMZ and AT-0174. In mice with orthotopic striatal GL261 (luc2) tumours, repeated treatment with TMZ appeared to induce a mild (though non-significant) drop in body weight compared to vehicle-treated animals (Figure 4), which appeared to be ameliorated by combination treatment with AT-0174. Neither AT-0174 administered alone or in combination with TMZ had any noticeable effect on body weight. Body weight gain during the study (typically in indicator of overall health) was greatest in animals that received the combination treatment.

[0361] Body weight measurements were taken through to day 55, but escalating mortality in different treatments groups beyond day 30 led to inaccuracy in the body weight measure and is therefore not shown.

[0362] Glioblastoma Tumour Growth

[0363] Mice were administered GL261 (luc2) cells into the striatum under stereotaxic control and tumour growth was measured each week from day 7 after inoculation. Tumour growth was measured by luciferase bioluminescence as an indicator of central GL261 (luc2) cell growth. Bioluminescence (BLI) readings showed a pronounced exponential increase in response to increased tumour size, with nonnormal distribution and was converted to a tumour growth grade according to the following scale: BLI (ph / s / sr) 0-10,000 Grade 1; 10,001 -50,000 Grade 2; 50,001- 250,000 Grade 3; 250,001-1,000,000 Grade 4; 1,000,001-5,000,000 Grade 5; above 5,000,000 Grade 6. For animals that died or were sacrificed due to morbidity between days 27 and 49 a last-observation-carried forward (LOCF) methodology was applied to the dataset.

[0364] AT-0174 treatment had no significant effect on tumour growth (Figure 5A). TMZ, in contrast, reduced tumour growth from day 28 onwards compared to tumour growth in vehicle-treated control mice (Figure 5A). Importantly, AT-0174 exerted a synergistic antitumour effect when given orally in combination with TMZ treatment (Figure 5A). Analysis of variance (ANOVA) at each time point showed a significant effect of treatment on tumour growth on test days 28, 25, 42 and 49 (# p<0.005, ## p<0.001). Combination treatment produced a statistically significant improvement over TMZ given alone by day 35 (p < 0.05). Post hoc analysis of treatment demonstrated a significant benefit of combining TMZ with AT-0174 to decrease tumour growth (* p < 0.05, TMZ compared with TMZ + AT-0174).

[0365] Table 5: Effect of AT-0174 or TMZ or AT-0174 and TMZ on glioblastoma tumour growth in mice

[0366] The combination of AT-0174+TMZ exhibited a notably larger positive treatment effect than TMZ alone, highlighting a clear and positive synergistic effect within the AT-0174+TMZ combination (see Figure 5B). As shown in Figure 5B, the combination of AT-0174+TMZ yielded a synergistic effect, as demonstrated by the effect size in tumor grade when compared between the control group (vehicle) and the treatment groups.

[0367] Survival of Mice with Orthotopic Glioblastomas

[0368] Vehicle-treated mice with GL261 (luc2) tumours in the striatum had a median survival duration of 36 days post-inoculation, with the first mortality recorded on day 29. As shown in Figure 6, median survival for each treatment was as follows: Vehicle = 36 days; AT-0174 = 40 days; TMZ = 54 days; AT-0174 + TMZ = undefined (73% survival at 54 days). Statistically significant survival benefit was conferred by combination treatment with TMZ plus AT-0174 (p < 0.01 compared with vehicle- treated group), but not with either drug treatment when given alone (see Figure 6).

[0369] Daily treatment with 120 mg / kg AT-0174 by oral gavage did not significantly affect survival, with the first death on day 30, and a median survival of 40 days (Figure 6).

[0370] TMZ, by comparison, improved median survival duration to 54 days, though the first death occurred as early as day 26. Combination treatment of TMZ plus AT- 0174 exerted the greatest survival benefit, with zero mortality recorded until day 44. A median survival duration could not be calculated for the combination treatment as more than 50% of the mice in the combination treatment group survived to the end of the study (74% survival on day 54). ANOVA assessment confirmed a statistically significant effect of the combination treatment on the survival of mice harbouring glioblastomas in this study (p< 0.01).

[0371] Table 6: Survival percentage of mice with orthotopic glioblastomas, following treatment with vehicle control, AT-0174, TMZ or AT-0174 plus TMZ.

[0372] (Initial group size = 15 mice).

[0373] _ Survival Percentage _ Vehicle TMZ AT-0174 TMZ + AT-0174

[0374]

[0375] Effect of Treatment on Immune Cell Infiltration

[0376] Analysis of Tcell subset populations within the GL261 tumours of mice were analysed by immune marker FACS analysis after 16 days of treatment (see Figure 7). Tregs (CD4+, CD25+, FoxP3+cells) accounted for 11.8% cells in vehicle- treated mouse tumours and was actually higher in TMZ-treated mice (18.0%). AT- 0174 suppressed Treg expression when given alone (5.1% Treg expression) or in combination with TMZ (6.0%), as shown in Figure 7 (top graph). AT-0174 or a combination of TMZ + AT-0174 significantly decreased Treg expression (effect of treatment by ANOVA, F3,2o=2.9O5, p=0.06).

[0377] As well as elevating Treg numbers, TMZ treatment also increased the number of activated cytotoxic Tcells (CD8+, CD25+, FoxP3" cells) compared with the activated Tcell count in vehicle-treated mouse tumours. All treatments increased the expression or infiltration of CD8+, CD25+, FoxP3" cells into the tumours, with AT-0174- treated mice showing the most consistent increase (p < 0.05; Figure 7, middle graph; effect of treatment by ANOVA, F3,2o=2.9O5, p=0.09). AT-0174 treatment led to the highest activated Tcell count (Figure 7, middle graph), significantly greater than the Tcell count in vehicle treated mouse tumours (p< 0.01). The pro-immune response of the mice to the tumours is perhaps best indicated by the ratio between activated CD8+ / CD25+Tcells and regulatory Tcells. This CD8+ / Treg ratio was 0.133 in vehicle- treated mouse tumours. TMZ treatment increased this ratio to 0.786, while AT-0174 treatment alone (ratio CD8+ / Treg of 2.000) or in combination with TMZ (1.382) had the most pronounced pro-immune effect, increasing CD8+numbers and decreasing Tregs to such a degree that CD8+cells outnumbered Tregs under these conditions (Figure 7, bottom graph). While the ratio of activated CD8+ / CD25+cells to regulatory Tcells is increased with TMZ, it increased to a greater degree with AT-0174 administered alone (p < 0.05 compared with vehicle), or as combination of TMZ + AT-0174 (effect of treatment by ANOVA, F3,2o=2.876, p=0.06).

[0378] Figure 8 shows the ratio of CD8+ to Treg cells. A pronounced pro-immune effect, with a 4-fold increase in the CD8+ / Treg ratio, was observed when comparing the combination treatment to the vehicle-treated mice (Figure 8). The pro-immune CD8+ to Treg ratio increases with AT-0174 administration alone, but demonstrates an even greater increase following administration of the combination TMZ + AT-0174 (effect of treatment by ANOVA, p=0.01).

[0379] 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.

[0380] 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. Although the invention has been described by way of example and with reference to particular embodiments, it is to be understood that modifications and / or improvements may be made without departing from the scope of the invention.

Claims

CLAIMS1. A method of treating glioma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase-2 (TDO2) and temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof.

2. Use of a dual inhibitor of indoleamine-2,3-dioxygenase (I DOI ) and tryptophan-2,3- dioxygenase-2 (TDO2) in the manufacture of a medicament for treating glioma in a subject, wherein said medicament is to be administered in combination with temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof.

3. Use of temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating glioma in a subject, wherein said medicament is to be administered in combination with a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase-2 (TDO2).

4. Use of a dual inhibitor of indoleamine-2,3-dioxygenase (I DOI ) and tryptophan-2,3- dioxygenase-2 (TDO2) and temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating glioma in a subject.

5. A combination, such as a combination product or a pharmaceutical combination, for use in the treatment of glioma in a subject, wherein the pharmaceutical combination comprises (a) a dual inhibitor of indoleamine-2,3-dioxygenase (I DOI ) and tryptophan-2,3-dioxygenase-2 (TDO2) and (b) temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof.

6. A kit for use in the treatment of glioma in a subject, wherein the kit comprises (a) a dual inhibitor of indoleamine-2,3-dioxygenase (I DOI ) and tryptophan-2,3- dioxygenase-2 (TDO2) and (b) temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof.

7. The method, use, combination or kit of any one of the preceding claims wherein the glioma is astrocytoma, ependymoma or oligodendroglioma.

8. The method, use, combination or kit of any one of the preceding claims wherein the glioma is astrocytoma.

9. The method, use, combination or kit of any one of the preceding claims wherein the glioma is glioblastoma.

10. The method, use, combination or kit of any one of the preceding claims wherein the dual inhibitor of IDO1 and TDO2 is formulated as a pharmaceutical composition comprising the dual inhibitor of IDO1 and TDO2 and a pharmaceutically acceptable carrier.

11. The method, use, combination or kit of claim 10 wherein the dual inhibitor of IDO1 and TDO2 is formulated for oral or intravenous administration.

12. The method, use, combination or kit of claim 11 wherein the dual inhibitor of IDO1 and TDO2 is formulated for oral administration.

13. The method, use, combination or kit of claim 11 wherein the dual inhibitor of IDO1 and TDO2 is formulated for intravenous administration.

14. The method, use, combination or kit of any one of the preceding claims wherein the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition comprising the TMZ and a pharmaceutically acceptable carrier.

15. The method, use, combination or kit of claim 14 wherein the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is formulated for oral or intravenous administration.

16. The method, use, combination or kit of claim 15 wherein the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is formulated for intravenous administration.

17. The method, use, combination or kit of claim 15 wherein the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is formulated for oral administration.

18. The method, use, combination or kit of any one of the preceding claims wherein the method comprises a step of administering the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof and the dual inhibitor of IDO1 and TDO2 simultaneously, sequentially or separately, or the use, combination or kit comprise TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof and a dual inhibitor of IDO1 and TDO2 that are to be administered simultaneously, sequentially or separately.

19. The method, use, combination or kit of any one of the preceding claims wherein the method comprises a step of administering the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof orally or intravenously, or the use, combination or kit comprise TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof that is to be administered orally or intravenously.

20. The method, use, combination or kit of any one of the preceding claims wherein the method comprises a step of administering the dual inhibitor of IDO1 and TDO2 orally or intravenously; or the use, combination or kit comprise a dual inhibitor of IDO1 and TDO2 that is to be administered orally or intravenously.

21. The method, use, combination or kit of any one of the preceding claims wherein the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is a compound of formula A:Formula A wherein:R1is hydrogen, or an alkyl group containing from 1 to 6 carbon atoms or an alkenyl or alkynyl group containing from 2 to 6 carbon atoms, or said an alkyl, alkenyl or alkynyl group substituted by from one to three substituents independently selected from halogen, alkoxy, alkylthio, alkylsulphinyl and alkylsul phonyl groups containing up to 4 carbon atoms, and phenyl substituted by alkoxy and alkyl groups containing from 1 to 4 carbon atoms or a nitro group; or R1is a cycloalkyl group containing from 3 to 8 carbon atoms; andR2is a carbamoyl group, or a carbamoyl group carrying on the nitrogen atom one or two groups selected from alkyl and alkenyl groups containing up to 4 carbon atoms, and cycloalkyl groups containing from 3 to 8 carbon atoms; or, when R1is hydrogen, an alkali metal salt thereof.

22. The method, use, combination or kit of claim 21 wherein R1is methyl, R2is a carbamoyl group, or R1is methyl and R2is a carbamoyl group.

23. The method, use, combination or kit of any one of the preceding claims wherein the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is 3,4- dihydro-3-methyl-4-oxoimidazo[5,1 -d]-as-tetrazine-8-carboxamide (TMZ):, or a pharmaceutically acceptable salt thereof.

24. The method, use, combination or kit of any one of the preceding claims wherein the dual inhibitor of I DOI and TDO2 has cellular TDO2 inhibitory activity that is greater than, or equal to, the cellular IDO1 inhibitory activity.

25. The method, use, combination or kit of any one of the preceding claims wherein the dual inhibitor of I DOI and TDO2 has a cellular i DOI IC50 of less than 10 pM as determined by a cell-based assay for IDO1 inhibition; and has a cellular TDO2 IC50 of less than 10 pM as determined by a cell-based assay for TDO2 inhibition.

26. The method, use, combination or kit of any one of the preceding claims wherein the dual inhibitor of I DOI and TDO2 has a cellular IDO1 IC50 of less than 1 pM as determined by a cell-based assay for IDO1 inhibition; and has a cellular TDO2 IC50 of less than 1 pM as determined by a cell-based assay for TDO2 inhibition.

27. The method, use, combination or kit of any one of the preceding claims wherein the dual inhibitor of IDO1 and TDO2 is a compound of Formula I or a pharmaceutically acceptable salt thereof,wherein: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, R3and R4are each independently selected from the following groups: H, halo, R, -OH, -OR, -OC(O)H, -OC(O)R, -OC(O)NH2, -OC(O)NHR, -OC(O)NRR,-OP(O)(OH)2, - OP(O)(OR)2, -NO2, -NH2, -NHR, -NRR, -NHC(O)H, -NHC(O)R, -NRC(O)R, -NHC(O)NH2, - N HC(O)N RR, -N RC(O)N HR, -SH, -SR, -S(O)H, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, - SO2N RR, -CF3, -CHF2. -CH2F, -OCF3, OCHF2, -CN, -C=CH, -C=CR, -CH=CHR, -CH=CRR, - CR=CHR, -CR=CRR, -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, -C(O)NRR, - CONHSO2H, -CONHSO2R, -CONRSO2R, cyclic C3-C7 alkylamino, imidazolyl, Ci -C6- alkyl piperazinyl, morpholinyl and thiomorpholinyl; or R1and R2taken together, or R2and R3taken together, or R3and R4taken 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-e alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-e aikynyl group and an optionally substituted C3-7 cyclic alkyl group; 'wherein the one or more optional substituents for each of said alkyl, alkenyl, aikynyl and cyclic alkyl groups are each independently selected from the following groups: halo, -OH, -OR5, -OC(O)R5, -OC(O)NH2, -OC(O)NHR5, -OC(O)NR5R5, - OP(O)(OH)2, -OP(O)(OR5)2, -NO2, -NHZ, -N HR5, -N R5R5, -N+(O )R5R5, -NHC(O)H, - NHC(O)R5, -NR5C(O)R5, -NHC(O)NH2, -NHC(O)N R5R5, -N R5C(O)NHR5, -SH, -SR5, -S(O)H, -S(O)R5, -SO2R5, -SO2N H2, -SO2NHR5, -SO2NR5R5, -CF3, -CHF2, -CH2F,-OCF3. -OCHF2, -CN, -CO2H, -CO2R5, -CHO, -C(O)R5, -C(O)N H2, -C(O)N HR5, -C(O)N R5R5, -CONHSO2H, - C(O)NHSO2R5, -C(O)N R5SO2R5, 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 e alkyl, C2e alkenyl, C2e aikynyl, C3-7 cyclic alkyl, halo, -OH, -OR7, -OC(O)R7, -OC(O)NH2-OC(O)NHR7, - OC(O)NR7R7, -OP(O)(OH)2, -OP(O)(OR7)2, -NO2, -NH2, -NHR7, -NR7R7, -N+(O ) R'R7, - N HC(O)H, -NHC(O)R7, -NR7C(O)R7, -NHC(O)NH2, -N HC(O)N R7R7, -N R7C(O)NHR7, -SH, - SR7, -S(O)H, -S(O)R7, -SO2R7, -SO2N H2, -SO2NHR7,-SO2NR7R7, -CF3, -CHF2J-CH2F,-OCF3, OCHF2, -CN, -CO2H, -CO2R7, -CHO, -C(O)R7, -C(O)NH2, -C(O)NHR7, -C(O)NR7R7, - CONHSOzH, -C(O)N HSO2R7, -C(O)NR7SO2R7, 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 andheteroaryl groups are each independently selected from the following groups: Cve alkyl, C2 e alkenyl, C2-6 alkynyl or C3 7 cyclic alkyl, halo, -OH, -OR8, -OC(O)R8, - OC(O)NH2, -OC(O)N HR8, -OC(O)NR8R8, -OP(O)(OH)2, -OP(O)(ORS)2, -NO2, -NH2, -N HR8, -N R8R8, -N+(O )R8R8, -NHC(O)H, -N HC(O)R8, -N R8C(O)R8, -NHC(O)NH2, -N HC(O)N R8RS, -N R8C(O)NHR8, -SH, -SR8, -S(O)H, -S(O)R8, -SO2R8, -SO2NH2, -SO2NHR8,-SO2NR8R8, -CF3, -CHF2 -CH2F, -OCFs, OCHF2, -CN, -CO2H, -CO2R8, -CHO, -C(O)R8, -C(O)NH2, -C(O)NHR8, -C(O)N R8R8, -CONHSO2H, -C(O)N HSO2R8, and -C(O)NR8SO2R8; wherein each R5, R7and R8is independently selected from a Ci-e alkyl group, a C2-6 alkenyl group, a C2 e 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 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;R9and R10are each independently selected from any of the groups defined in paragraphs (a) and (b) below:(a) H, an optionally substituted C1-6 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(O)R11, -OC(O)NH2, -OC(O)NHR11, -OC(O)NR11R11, - OP(O)(OH)2, -OP(O)(OR11)2, -NO2, -NH2, -NHR11, -NR11R11, -N+(O )R11R11, -NHC(O)H, - NHC(O)R11, -NR11C(O)R11, -NHC(O)NH2, -NHC(O)NR11R11, -NR11C(O)NHR11, -SH, -SR11, - S(O)H, -S(O)R11, -SO2R11, -SO2NH2, -SO2NHR11, -SO2N R11R1 1, -CF3, -CHF2, -CH2F,-OCF3, - OCHF2, -CN, -CO2H, -CO2R11, -CHO, -C(O)R11, -C(O)NH2, -C(O)NHR11, -C(O)NR11R11, - CONHSO2H, -C(O)N HSO2R11, -C(O)NR11SO2R11, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more of the following groups: C ve alkyl, C2 e alkenyl, C2 6alkynyl, C3 7 cyclic alkyl, halo, -OH, -OR13, -OC(O)R13, -OC(O)N H2, - OC(O)NHR13, -OC(O)N R13R13, -OP(O)(OH)2, -OP(O)(OR13)2, -NO2, -NH2, -NHR13, -NR13R13-N+(O )R13R13, -NHC(O)H, -N HC(O)R13, -NR13C(O)R13, -N HC(O)NH2, -NHC(O)N R13R13, - N R13C(O)NHR13, -SH, -SR13, -S(O)H, -S(O)R13, -SO2R13, -SO2NH2, -SO2NHR13,-SO2N R13R13, -CF3, -CHF2, -CH2F, -OCF3. -OCHF2, -CN, -CO2H, -CO2R13, -CHO, -C(O)R13, -C(O)NH2, - C(O)NHR13, -C(O)N R13R13, -CONHSO2H, -C(O)N HSO2R13, and -C(O)NR13SO2R13; wherein each R11and R13is independently selected from a C1-6 alkyl group, a C2 6 alkenyl group, a C2e 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 O, 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 R9and R10; or(c) R9and R10taken 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 O, 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 R9and R10; and a pharmaceutically acceptable carrier.

28. The method, use, combination or kit of claim 27, wherein Z is N or N-oxide, such as N, W is CR1, X is CR2and Y is CR3.

29. The method, use, combination or kit of claim 27, wherein X is N or N-oxide, such as N, W is CR1, Y is CR3and Z is CR4.

30. The method, use, combination or kit of claim 27, wherein X and Z are both N or N- oxide, such as N, W is CR1and Y is CR3.

31. The method, use, combination or kit of any one of claims 27 to 30, wherein R1, R2, R3and R4, where present, are each independently selected from the group consisting of H, halogen, optionally substituted Ci-Ce alkyl, -O-R wherein R is selected from optionally substituted G-Ce 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.

32. The method, use, combination or kit of claim 31 , wherein R1, R2, R3and R4, where present, are each independently selected from the group consisting of H, halogen, - CF3, -CHF2, -OCF3, -OCHF2, C1 6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

33. The method, use, combination or kit of claim 31 , wherein one or two of R1, R2, R3and R4, where present, is H, and the others of R1, R2, R3and R4that are not H are independently selected from the group consisting of halogen, -CFs, -CHF2, -OCF3, - OCHF2, C1-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -ORwherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted ary!-34. The method, use, combination or kit of any one of claims 31 to 33, wherein R3is present and selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

35. The method, use, combination or kit of claim 28, wherein Z is N or N-oxide, such as N, W is CR1, X is CR2and Y is CR3, and R3is selected from the group consisting of halogen, -O-R wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

36. The method, use, combination or kit of claim 28, wherein Z is N or N-oxide, such as N, W is CR1, X is CR2and Y is CR3, R1is H, and one or both of R2and R3are other than H.

37. The method, use, combination or kit of claim 36, wherein each of R2and R3that is other than H is independently selected from the group consisting of halogen, optionally substituted G-G alkyl, -OR wherein R is selected from optionally substituted G-Ce 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.

38. The method, use, combination or kit of claim 36, wherein each of R2and P? that is other than H is each independently selected from the group consisting of halogen, - CF3, -CHF2, -OCF3, -OCHF?, G 6 alkyl such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

39. The method, use, combination or kit of any one of claims 27 to 30, wherein R1and R4taken together, or R2and R3taken together, or R3and R4taken 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, R3and R4that are not part of the ring, are independently selected from: H, halo, optionally substituted G-Ce alkyl, O-R wherein R is optionally substituted G-Ce 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.

40. The method, use, combination or kit of any one of claims 27 to 39 wherein R9and R10are independently selected from the group consisting of H, an optionally substituted C i 6 alkyl group, an optionally substituted aryl, such as substituted phenyl, and anoptionally 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.

41. The method, use, combination or kit of any one of claims 27 to 40, wherein R9and R10are both H.

42. The method, use, combination or kit of claim 28, wherein Z is N or N-oxide, such as N, W is CR1, X is CR2and Y is CR3, and R9and R10are both H.

43. The method, use, combination or kit of claim 42, wherein R1, R2and R3are each independently selected from the group consisting of H, halogen, -CFj, -CHF2, -OCF3, - OCHF2, C-i-6 alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

44. The method, use, combination or kit of claim 42, wherein one or two of R1, R2and R3is H, and the others of R1, R2and R3that are not H are independently selected from the group consisting of halogen, -CF=, -CHF2, -OCF3, -OCHF2, Cre alkyl, such as methyl, substituted aryl, substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

45. The method, use, combination or kit of claim 42, wherein R!is H, and one of both of R3and R3is other than H, wherein each of R2and R3that 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.

46. The method, use, combination or kit of claim 42, wherein R3is selected from the group consisting of halogen, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl.

47. The method, use, combination or kit of claim 42, wherein R1is H, and R2and R3form 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.

48. The method, use, combination or kit of any one of claims 27 to 30 wherein W is CR1and R1is selected from H, halo, -CHF2, -CF3 or methyl; and Z is N or N-oxide, such as N, X is CR2and Y is CR3; X is N or N-oxide, such as N, Y is CR3and Z is CR4: or X and Z are both N or N-oxide, such as N, and Y is CR3.

49. The method, use, combination or kit of any one of claims 27 to 30 wherein W is CR1and R1is selected from H, halo, -CHF2, -CF3 or methyl; R9and R10are each H; and Z isN or N-oxide, such as N, X is CR2and Y is CR3; X is N or N-oxide, such as N, Y is CR3and Z is CR4; or X and Z are both N or N-oxide, such as N, and Y is CR3.

50. The method, use, combination or kit of any one of claims 27 to 30 wherein W is CR1and R1is selected from H, halo, -CHF2, -CF3 or methyl; R9and R10are each H; Z is N or N-oxide, such as N, X is CR2and Y is CR3; and R2and R3are each independently selected from: H, halogen, -CF3, -CHF?, -OCF3, -OCHF2, -NO2, Ci e alkyl, such as methyl, optionally substituted aryl, optionally substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl; or R2and R3taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms and the ring is optionally substituted with 1 to 4 substituents independently selected from R.

51. The method, use, combination or kit of any one of claims 27 to 30 wherein W is CR1and R1is selected from H, halo, -CHF2, -CF3 or methyl.

52. The method, use, combination or kit of any one of claims 27 to 30 and 48 to 51 wherein W is CR1and R1is H, F, -CHF2, -CF3 or methyl.

53. The method, use, combination or kit of any one of claims 27 to 30 and 48 or 52 wherein W is CR1and R1is H or F.

54. The method, use, combination or kit of any one of claims 27 to 30 and 48 to 52 wherein W is CR1and R1is H or methyl.

55. The method, use, combination or kit of any one of claims 27 to 30 and 48 to 54 wherein W is CR1and R1is H.

56. The method, use, combination or kit of any one of claims 27 to 30 and 51 to 55 wherein R9and R10are independently selected from H, an optionally substituted C1-6 allcyl 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 O, N and S.

57. The method, use, combination or kit of any one of claims 27 to 30 and 51 to 56 wherein R9and R10are each H.

58. The method, use, combination or kit of any one of claims 48 to 57, wherein Z is N or N-oxide, such as N, X is CR2and Y is CR3.

59. The method, use, combination or kit of any one of claims 48 to 57, wherein X is N or N-oxide, such as N, Y is CR5and Z is CR4.

60. The method, use, combination or kit of any one of claims 48 to 57, wherein X and Z are both N or N-oxide, such as N, and Y is CR3.

61. The method, use, combination or kit of any one of claims 27 to 30 and 51 to 58 wherein R2and R3are each independently selected from: H, halogen, -CF3, -CHF2, - OCF3, -OCHF2, -NO2, C1 6 alkyl, such as methyl, optionally substituted aryl, optionally substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl; or R2and R3taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered ring of carbon atoms and the ring is optionally substituted with 1 to 4 substituents independently selected from R.

62. The method, use, combination or kit of any one of claims 27 to 30, 50 to 58, and 61 wherein R2and R3are each independently selected from: H, halogen, -CF3, -CHF2, - OCF3, -OCHF2, -NO2, Ci 6 alkyl, such as methyl, optionally substituted aryl, optionally substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl; or R2and R3taken together can form a saturated or a partially saturated or a fully unsaturated 6-membered ring of carbon atoms and the ring is optionally substituted with 1 to 4 substituents independently selected from R.

63. The method, use, combination or kit of any one of claims 27 to 30, 50 to 58, 61 and62 wherein R2and R3are each independently selected from: H, halogen, -CF3, -CHF2, - OCF3, -OCHF2, -NO2, C1 6 alkyl, such as methyl, optionally substituted aryl, optionally substituted heteroaryl, -OR wherein R is optionally substituted aryl, and -NHR wherein R is optionally substituted aryl; or R2and R3taken together can form a saturated or a partially saturated or a fully unsaturated 6-membered ring of carbon atoms.

64. The method, use, combination or kit of any one of claims 27 to 30, 50 to 58 and 61 to63 wherein R2and R3are each independently selected from: H, halo, -CF3, -CHF2, - NO2, and methyl.

65. The method, use, combination or kit of any one of claims 27 to 30, 50 to 58, and 61 to 64 wherein R2and R3are each independently selected from: H, halo, -CF3, and - NO2.

66. The method, use, combination or kit of any one of claims 27 to 30, 50 to 57, and 60 to 65 wherein one of R2and R3is H and the other is a group other than H.

67. The method, use, combination or kit of claim 27, wherein W is CR1and R1is H or F; R9and R10are each H; Z is N or N-oxide, such as N, X is CR2and Y is CR3; and R2and R3are each independently selected from: H, halo, -CF3, -CHF2, -NO2, and methyl.

68. The method, use, combination or kit of claim 27, wherein W is CR1and R!is H; R9and R10are each H; Z is N or N-oxide, such as N, X is CR2and Y is CR3; and R2and R3are each independently selected from: H, halo, -CF3, and -NO2.

69. The method, use, combination or kit of claim 27, 48, 49, 51 to 57 and 59, wherein X is N or N-oxide, such as N, Y is CR3and Z is CR4; and R3and R4are each independently selected from the group of substituents listed for R2and R3in any one of claims 61 to 68.

70. The method, use, combination or kit of claim 27, wherein X and Z are both N or N- oxide, such as N, and Y is CR3; and R3is selected from the group of substituents listed for R2and R3in any one of claims 61 to 68.

71. The method, use, combination or kit of any one of claims 1 to 27 wherein the dual inhibitor of IDO1 and TDO2 is selected from the group consisting of:5-Bromo-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (1) lsoxazolo[5,4-b]pyridin-3-amine (2) 5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (3)4.6-Dimethylisoxazolo[5,4-b]pyridin-3-amine (4)4.5.6-Trimethylisoxazolo[5,4-b]pyridin-3-amine (5)5-Bromoisoxazolo[5,4-b]pyridin-3-amine (6)6-Methylisoxazolo[5,4-b]pyridin-3-amine (7)5-Chloroisoxazolo[5,4-b]pyridin-3-amine (8) lsoxazolo[5,4-b]quinolin-3-amine (9) 5,6,7,8-Tetrahydroisoxazolo[5,4-b]quinolin-3-amine (10)6-Chloroisoxazolo[5,4-b]pyridin-3-amine (11) lsoxazolo[5,4-d]pyrimidin-3-amine (12)5-Fluoroisoxazolo[5,4-b]pyridin-3-amine (14)6-Phenylisoxazolo[5,4-b]pyridin-3-amine (15) 5-lodoisoxazolo[5,4-b]pyridin-3-amine (16) lsoxazolo[4,5-c]pyridin-3-amine (17) N6,N6-Dimethylisoxazolo[5,4-b]pyridine-3,6-diamine (18) N4N4-Dimethylisoxazolo[5,4-b]pyridine-3,4-diamine (19) 5-(3-Methoxyphenyl)isoxazolo[5,4-b]pyridin-3-amine (22) 5-(2-Methoxyphenyl)isoxazolo[5,4-b]pyridin-3-amine (23) 5-Phenylisoxazolo[5,4-b]pyridin-3-amine (24) 5-(Pyridin-3-yl)isoxazolo[5,4-b]pyridin-3-amine (26) 5-(Pyridin-4-yl)isoxazolo[5,4-b]pyridin-3-amine (27) 2-(3-Aminoisoxazolo[5,4-b]pyridin-5-yl)phenol (28)4-(3-Aminoisoxazolo[5,4-b]pyridin-5-yl)phenol (29)5-(4-Fluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (30) 5-(3-Fluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (31) 5-(2,4-difluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (32) 5-(3,5-Difluoro-2-methoxyphenyl)isoxazolo[5,4-b]pyridin-3-amine (33)5-(2,4-Dichlorophenyl)isoxazolo[5,4-b]pyridin-3-amine (34) 5-(2,3,4-Trichlorophenyl)isoxazolo[5,4-b]pyridin-3-amine (35) 5-(4-(Trifluoromethylphenyl)isoxazolo[5,4-b]pyridin-3-amine (36) 5-(3-Aminophenyl)isoxazolo[5,4-b]pyridin-3-amine (37) Methyl 3-(3-aminoisoxazolo[5,4-b]pyridin-5-yl)benzoate (38) 5-(6-Fluoropyridin-3-yl)isoxazolo[5,4-b]pyridin-3-amine (39)5-(2-Chloro-4-(trifluoromethyl)phenyl)isoxazolo[5,4-b]pyridin-3-amine (40)6-Methoxyisoxazolo[5,4-b]pyridin-3-amine (41) 6-Chloro-4-methylisoxazolo[5,4-b]pyridin-3-amine (42) lsoxazolo[5,4-b]pyridine-3,6-diamine (43)5-Methylisoxazolo[5,4-b]pyridin-3-amine (44)5.6-Dimethylisoxazolo[5,4-b]pyridin-3-amine (45)6-Methyl-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine (46) 6-(Trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine (47) 6-lsopropylisoxazolo[5,4-b]pyridin-3-amine (48) 5-Nitroisoxazolo[5,4-b]pyridin-3-amine (49)Ethyl 3-amino-6-(trifiuoromethyl)isoxazolo[5,4-b]pyridlne-5-carboxylate (50)4-Methoxyisoxazolo[5,4-b]pyridin-3-amine (51)5-(Difluoromethoxy)-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (52) Ethyl 3-amino-6-methylisoxazolo[5,4-b]pyridine-5-carboxylate (53)Ethyl 3-amino-6-(difluoromethyl)isoxazolo[5,4-b]pyridine-5-carboxylate (54)5-Fluoro-6-morpholinoisoxazolo[5,4-b]pyridin-3-amine (55)6-(Furan-2-yl)isoxazolo[5,4-b]pyridin-3-amine (58) 6,7,8,9-Tetrahydro-5H-cyclohepta[b]isoxazolo[4,5-e]pyridin-3-amine (60)6.6-Dimethyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]quinolin-3-amine (61) 7,8-Dihydro-5H-isoxazolo[5,4-b]pyrano[3,4-e]pyridin-3-amine (62) 6-(Methylthio)isoxazolo[5,4-d]pyrimidin-3-amine (63) 6-Methyllsoxazolo[5,4-d]pyrimidln-3-amine (64)6-Chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66)5.6-Dichloroisoxazolo[5,4-b]pyridin-3-amine (67)6-Chloro-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine (68)5-(3-Methoxyprop-1 -yn-1 -yl)isoxazolo[5,4-b]pyridin-3-amine (69)6-(4-Fluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (71) 6-(2,4-Difluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (73) 6-(2-Thienyl)isoxazolo[5,4-b]pyridin-3-amine (74) 6-(Methylthio)isoxazolo[5,4-b]pyridin-3-amine (79) 6-(Methylsulfonyl)isoxazolo[5,4-b]pyridin-3-amine (80) Methyl 3-aminoisoxazolo[5,4-b]pyridine-6-carboxylate (82) 6-Phenoxyisoxazolo[5,4-b]pyridin-3-amine (83)6-(2-Chlorophenoxy)isoxazolo[5,4-b]pyridin-3-amine (84) 6-(3-Chlorophenoxy)isoxazolo[5,4-b]pyridin-3-amine (85) 6-(4-Chlorophenoxy)isoxazolo[5,4-b]pyridin-3-amine (86) 6-(2-(Trifluoromethoxy)phenoxy)isoxazolo[5,4-b]pyridin-3-amine (§7) 6-(3-(Trifluoromethoxy)phenoxy)isoxazolo[5,4-b]pyridin-3-amine (§8) 6-(4-(Trifluoromethoxy)phenoxy)isoxazolo[5,4-b]pyridin-3-amine (89) 6-(2-Methoxyphenoxy)isoxazolo[5,4-b]pyridin-3-amine (90) 6-(3-Methoxyphenoxy)isoxazolo[5,4-b]pyridin-3-amine (91) 6-(4-Methoxyphenoxy)isoxazolo[5,4-b]pyridin-3-amine (92) 6-(3-(Trifluoromethyl)phenoxy)isoxazolo[5,4-b]pyridin-3-amine (93) N6-Phenyiisoxazolo[5,4-b]pyridine-3,6-diamine (94) N6-(3-Methoxyphenyl)isoxazolo[5,4-b]pyridine-3,6-diamine (95) and N6-(4-Methoxyphenyl)isoxazolo[5,4-b]pyridine-3,6-diamine (96), and pharmaceutically acceptable salts thereof. and pharmaceutically acceptable salts thereof.

72. The method, use, combination or kit of any one of claims 1 to 27 wherein the dual inhibitor of IDO1 and TDO2 is selected from the group consisting of:6-Chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) 5-Bromoisoxazolo[5,4-b]pyridin-3-amine (6)5-Chloroisoxazolo[5,4-b]pyridin-3-amine (8)6-Chloroisoxazolo[5,4-b]pyridin-3-amine (1 1) 5-lodoisoxazolo[5,4-b]pyridin-3-amine (16) 5-Nitroisoxazolo[5,4-b]pyridin-3-amine (49)5.6-Dichloroisoxazolo[5,4-b]pyridin-3-amine (67)5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (3)4.6-Dimethylisoxazolo[5,4-b]pyridin-3-amine (4)4.5.6-Trimethylisoxazolo[5,4-b]pyridin-3-amine (5)6-Methylisoxazolo[5,4-b]pyridin-3-amine (7) 5-Phenylisoxazolo[5,4-b]pyridin-3-amine (24) 5-Bromo-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (1) lsoxazolo[5,4-b]quinolin-3-amine (9) 5-(4-Fluorophenyl)isoxazoio[5,4-b]pyridin-3-amine (30) 5,6,7,8-Tetrahydroisoxazolo[5,4-b]quinolin-3-amine (10) lsoxazolo[5,4-d]pyrimidin-3-amine (12)5-Fluoroisoxazolo[5,4-b]pyridin-3-amine (14)6-Phenylisoxazolo[5,4-b]pyridin-3-amine (15) 6-(2-Thienyl)isoxazolo[5,4-b]pyridin-3-amine (74) 6-Methoxyisoxazolo[5,4-b]pyridin-3-amine (41) 6-(Trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine (47)6-Chloro-4-methylisoxazolo[5,4-b]pyridin-3-amine (42)5.6-Dimethylisoxazolo[5,4-b]pyridin-3-amine (45)5-Methylisoxazolo[5,4-b]pyridin-3-amine (44)6-(2-Chlorophenoxy)isoxazolo[5,4-b]pyridin-3-amine (84) 6-(4-(Trifluoromethoxy)phenoxy)isoxazolo[5,4-b]pyridin-3-amine (89) N6-(3-Methoxyphenyl)isoxazolo[5,4-b]pyridine-3,6-diamine (95), and pharmaceutically acceptable salts thereof.

73. The method, use, combination or kit of any one of claims 1 to 27 wherein the dual inhibitor of IDO1 and TDO2 is selected from:6-Chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) 5-Bromoisoxazolo[5,4-b]pyridin-3-amine (6)5-Chloroisoxazolo[5,4-b]pyridin-3-amine (8)6-Chloroisoxazolo[5,4-b]pyridin-3-amine (11) 5-lodoisoxazolo[5,4-b]pyridin-3-amine (16) 5-Nitroisoxazolo[5,4-b]pyridin-3-amine (49)5.6-Dichloroisoxazolo[5,4-b]pyridin-3-amine (67), and pharmaceutically acceptable salts thereof.

74. The method, use, combination or kit of any one of claims 1 to 27 wherein the dual inhibitor of IDO1 and TDO2 is 6-Chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66):

75. The method, use, combination or kit of any one of claims 71 to 74 wherein the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is 3,4-dihydro-3- methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide (TMZ):pharmaceutically acceptable salt thereof; and wherein the glioma is glioblastoma.

76. The method, use, combination or kit of any one of the preceding claims wherein:« the dual inhibitor of IDO1 and TDO2 is 6-Chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66):, or a pharmaceutically acceptable salt thereof;® the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof is3,4-dihydro-3-methyl-4-oxoimidazo[5,1 -d]-as-tetrazine-8-carboxamide (TMZ):, or a pharmaceutically acceptable salt thereof; an<® the glioma is glioblastoma.

77. The method, use, combination or kit of any one of the preceding claims wherein the dual inhibitor of I DO1 and TDO2 and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, are formulated as separate compositions.

78. A kit, composition or combination, such as a combination product or a pharmaceutical combination, comprising the dual inhibitor of IDO1 and TDO2 of any one of the preceding claims and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, of any one of the preceding claims.

79. A kit, composition or combination, such as a combination product or a pharmaceutical combination, comprising the dual inhibitor of IDO1 and TDO2 of any one of the preceding claims and the TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, of any one of the preceding claims; and optionally instructions for using the dual inhibitor and TMZ in accordance with the method, use, combination or kit of the any one of the preceding claims.

80. A kit, composition or combination, such as a combination product or a pharmaceutical combination, comprising the dual inhibitor of IDO1 and TDO2 of any one of the preceding claims and the TMZ or a derivative thereof, or apharmaceutically acceptable salt thereof, of any one of the preceding claims, for use in the method, use, combination or kit of the any one of the preceding claims.

81. A kit, composition or combination, such as a combination product or a pharmaceutical combination, comprising a dual inhibitor of IDO1 and TDO2 and TMZ or a derivative thereof, or a pharmaceutically acceptable salt thereof, for use in the method of any one of claims 1 or 7 to 77.

82. The kit or combination of any one of claims 78 to 81 wherein the dual inhibitor of IDO1 and TDO2 and the temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, are formulated as separate compositions.

83. A dual inhibitor of IDO1 and TDO2 and temozolomide (TMZ) or a derivative thereof, or a pharmaceutically acceptable salt thereof, for use in a method of treating glioma in a subject, wherein the method is as described in any one of claims 1 or 7 to 77.

Images