Dual inhibitors of tryptophan dioxygenase (ido1 and tdo) and their use in therapy

Abstract

The present invention relates generally to the use of dual inhibitors of indoleamine 2,3-dioxygenase I (IDOI) and tryptophan-2,3-dioxygenase (TDO), alone or in combination with other agents, and pharmaceutical compositions comprising same for the treatment or prevention of refractory cancers, and for the manufacture of medicaments for the treatment or prevention of refractory cancers.

Description

[Technical field]

[0001] Related Applications This application benefits from U.S. Patent Application No. 63 / 316,740, which is incorporated herein by reference.

[0002] Technical Field The present invention relates generally to dual inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase (TDO), alone or in combination with other agents, and their use in the treatment or prevention of refractory cancers, as well as pharmaceutical compositions comprising same in the manufacture of a medicament for the treatment or prevention of refractory cancers. [Background technology]

[0003] 2. Background of the Invention The essential amino acid tryptophan is primarily degraded by two closely related enzymes, indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase (TDO), which catalyze the rate-limiting conversion of tryptophan to N-formylkynurenine and its subsequent degradation to kynurenine in the kynurenine pathway.

[0004] Indoleamine 2,3-dioxygenase 1 (IDO1) is naturally expressed at low levels throughout the body, but is expressed in a wide range of cancers to suppress the immune system (Uyttenhove et al., J. Nat. Med. 2003, 9, 1269). High expression of IDO1 in clinical tumors has been shown to correlate with poor patient prognosis in a wide range of cancers, including lung, colorectal, breast, melanoma, and gynecological cancers. Silencing the IDO1 gene in mouse melanoma cell lines reduced their tumorigenicity when transplanted into mice (Zheng et al., J. Immunol. 2006, 177, 5639), supporting IDO1 inhibition as a method of cancer intervention. Many groups are developing small molecule inhibitors of IDO1 as an approach to restore tumor immunity in cancer patients.

[0005] Unlike IDO1, tryptophan-2,3-dioxygenase (TDO) has high levels of natural expression, primarily in the liver, but like IDO1, it has also been shown to be elevated in tumors, making it a potential additional target for anticancer drugs (Pilotte et al PNAS 2012, 109, 2497).

[0006] Common cancer treatments such as radiation therapy, chemotherapy, and immunotherapy often have limited effectiveness due to the development of resistance, and many cancers remain with extremely poor prognoses. There is a constant demand for methods to treat and prevent the onset of such intractable cancers.

[0007] It is an object of the present invention to fulfill this need in part and / or at least provide the public with a useful choice.

[0008] Other objects of the present invention will become apparent from the following description, which is given by way of example only.

[0009] References herein to patents, other external documents, or other sources of information are generally intended to provide a context for discussing features of the present invention, and unless specifically noted otherwise, the reference to such external documents shall not be construed as an admission that such documents or sources are prior art or form part of the general knowledge in the art in any jurisdiction. Summary of the Invention

[0010] In a first particular aspect, the present invention broadly relates to a method for treating or preventing the occurrence of refractory cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a dual inhibitor of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO).

[0011] In a second particular aspect, the present invention broadly comprises the use of a dual inhibitor of IDO1 and TDO in the manufacture of a medicament for treating a refractory cancer or preventing the onset of a refractory cancer in a subject.

[0012] In a third particular aspect, the present invention broadly consists of a dual inhibitor of IDO1 and TDO for use in the treatment of refractory cancer or for preventing the onset of refractory cancer in a subject.

[0013] In a fourth particular aspect, the present invention broadly comprises a method for treating refractory cancer cells or preventing the development of refractory cancer cells, comprising administering to said cancer cells a dual inhibitor of IDO1 and TDO.

[0014] In a fifth particular aspect, the present invention broadly comprises the use of a dual inhibitor of IDO1 and TDO in the manufacture of a medicament for treating refractory cancer cells or preventing the development of refractory cancer cells.

[0015] In a sixth particular aspect, the present invention broadly relates to a dual inhibitor, including a dual inhibitor of IDO1 and TDO, for use in treating refractory cancer cells or preventing the development of refractory cancer cells.

[0016] In a seventh particular aspect, the present invention provides a kit comprising a dual inhibitor of IDO1 and TDO; and optionally one or more additional therapeutic agents; and instructions for using the dual inhibitor in a method of the first or fourth aspect.

[0017] The following embodiments and preferences may be relevant to any of the above aspects, either alone or in any two or more combinations.

[0018] In various embodiments, the method, use or dual inhibitor is for treating a refractory cancer in a subject in need thereof. In various embodiments, the method, use or dual inhibitor is for preventing the onset of a refractory cancer in a subject in need thereof.

[0019] In various embodiments, the method, use or dual inhibitor is for treating refractory cancer cells. In various embodiments, the method, use or dual inhibitor is for preventing the development of refractory cancer cells.

[0020] In various embodiments, the refractory cancer cells are in vitro or in vivo.

[0021] In various embodiments, the refractory cancer or cancer cells are refractory to anti-cancer drugs.

[0022] In various embodiments, the refractory cancer or cancer cells are refractory to a cancer treatment, for example, in various embodiments, the cancer treatment comprises administering one or more anti-cancer agents and / or radiation therapy.

[0023] In various embodiments, the subject or the refractory cancer cells have previously been administered an anti-cancer agent, and the refractory cancer or cancer cells are refractory to said anti-cancer agent.

[0024] In various embodiments, the refractory cancer or cancer cells are refractory to a cancer treatment. In various embodiments, the subject or the refractory cancer cells have previously been administered a cancer therapy, and the refractory cancer or cancer cells are refractory to said cancer therapy. In various embodiments, the cancer treatment comprises administering one or more anti-cancer agents. In various embodiments, the cancer treatment is radiation therapy.

[0025] In various embodiments, the anti-cancer agent is selected from a chemotherapeutic agent or a radiotherapeutic agent.

[0026] In various embodiments, the chemotherapeutic agent is a platinum-based chemotherapeutic agent. In various embodiments, the platinum-based chemotherapeutic agent is selected from carboplatin, cisplatin, lobaplatin, oxaliplatin, picoplatin, nedaplatin, phenanthriplatin, and satraplatin. In various embodiments, the platinum-based chemotherapeutic agent is cisplatin, carboplatin, or oxaliplatin. In various embodiments, the platinum-based chemotherapeutic agent is cisplatin or oxaliplatin.

[0027] In various embodiments, the anti-cancer agent induces ROS accumulation in cancer cells.

[0028] In various embodiments, the anticancer drug induces ROS accumulation in cancer cells, and the refractory cancer or refractory cancer cells are resistant to the ROS accumulation in cancer cells.For example, in various embodiments, the refractory cancer or refractory cancer cells are resistant to ROS-induced cell death.For example, in various embodiments, the refractory cancer or refractory cancer cells are resistant to ROS-dependent programmed cell death (PCD) in cancer cells.

[0029] In various embodiments, the refractory cancer or refractory cancer cells are colon cancer, breast cancer, melanoma, reproductive cancer, respiratory cancer, brain cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and / or distant metastases thereof.

[0030] In various embodiments, the refractory cancer or refractory cancer cell is a lymphoma, a sarcoma, or a leukemia.

[0031] In various embodiments, the refractory cancer or refractory cancer cells are selected from the group consisting of refractory breast cancer selected from invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ; refractory cancers of the respiratory system selected from small cell lung cancer and non-small cell lung cancer, bronchial adenoma, and pleuropulmonary blastoma. In various embodiments, the refractory cancer is selected from refractory brain cancers, selected from glioblastoma, brain stem and low tension glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor, and pineal tumor; refractory tumors of the male reproductive organs, selected from prostate cancer and testicular cancer; refractory tumors of the female reproductive organs, selected from endometrial cancer, cervical cancer, ovarian cancer, ovarian adenocarcinoma, vaginal cancer, vulvar cancer, and uterine sarcoma; refractory tumors of the digestive tract, selected from anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer; refractory tumors of the urinary tract, selected from bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, and urethral cancer; refractory eye cancers, selected from intraocular melanoma and retinoblastoma; hepatocellular carcinoma, with or without fibrolamellar variants. refractory liver cancer selected from squamous cell carcinoma, cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular-cholangiocarcinoma; refractory skin cancer selected from squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer; refractory head and neck cancer selected from laryngeal / hypopharyngeal / nasopharyngeal / oral cancer, lip and oral cavity cancer; refractory lymphoma selected from AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system; refractory sarcoma selected from sarcoma of soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma; and refractory leukemia selected from acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, and / or distant metastasis thereof.

[0032] In various embodiments, the refractory cancer or refractory cancer cells are selected from lung cancer, pancreatic cancer, breast cancer, and ovarian cancer.

[0033] In various embodiments, the anti-cancer agent is a platinum-based chemotherapy agent and the refractory cancer is selected from lung cancer, pancreatic cancer, breast cancer, and ovarian cancer, e.g., in various embodiments, the anti-cancer agent is selected from cisplatin, carboplatin, or oxaliplatin.

[0034] The refractory cancer may be a solid tumor or a liquid tumor. In various embodiments, the refractory cancer is a solid tumor.

[0035] In various embodiments, dual inhibitors of IDO1 and TDO that may be used in any of the methods or uses as described herein (including any use in the manufacture of a medicament as described herein, and any inhibitor of IDO1 and TDO for use as described herein) are described in numbered paragraphs (1) to (49) below.

[0036] (1) A compound of formula I or a pharma- ceutically acceptable salt thereof, which is a dual inhibitor of IDO1 and TDO.

[0037] [ka]

[0038] In the formula, W is CR 1 , N or N-oxide; X is CR 2 , N or N-oxide; Y is CR 3 , N or N-oxide; Z is CR 4 , N or N-oxide; At least one of W, X, Y and Z is N or N-oxide; R 1 , R 2 , R 3 and R 4 are each independently one of the following groups: H, halo, R, -OH, -OR, -OC(O)H, -OC(O)R, -OC(O)NH 2, -OC(O)NHR, -OC(O)NRR, -OP(O)(OH) 2 , -OP(O)(OR) 2 , -NO 2 , -NH 2 , -NHR, -NRR, -NHC(O)H, -NHC(O)R, -NRC(O)R, -NHC(O)NH 2 , -NHC(O)NRR, -NRC(O)NHR, -SH, -SR, -S(O)H, -S(O)R, -SO 2 R, -SO 2 NH 2 , -SO 2 NHR, -SO 2 NRR, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -CN, -C≡CH, -C≡CR, -CH=CHR, -CH=CRR, -CR=CHR, -CR=CRR, -CO 2 H, -CO 2 R, -CHO, -C(O)R, -C(O)NH 2 , -C(O)NHR, -C(O)NRR, -CONHSO 2 H, -CONHSO 2 R,-CONRSO 2 R, cyclic C 3 -C 7 Alkylamino, imidazolyl, C 1 -C 6 Selected from alkylpiperazinyl, morpholinyl, and thiomorpholinyl; Or R 1 and R 2 together, or R 2 and R 3 together, or R 3 and R 4 may together form a saturated or partially saturated or fully unsaturated 5- or 6-membered ring of carbon atoms, optionally containing 1 to 3 heteroatoms selected from O, N and S, the ring being optionally substituted independently with 1 to 4 substituents selected from R.

[0039] Each R is independently a group defined in paragraphs (a) and (b) below: (a) optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl groups and optionally substituted C 3-7 Cyclic alkyl groups, wherein one or more optional substituents for each of the alkyl, alkenyl, alkynyl and cyclic alkyl groups are each independently selected from the following groups: halo, -OH, -OR 5 , -OC(O)R 5 , -OC(O)NH 2 , -OC(O)NHR 5 , -OC(O)NR 5 R 5 , -OP(O)(OH) 2 , -OP(O)(OR 5 ) 2 , -NO 2 , -NH 2 , -NHR 5 , -NR 5 R 5 , -N + (O-)R 5 R 5 , -NHC(O)H, -NHC(O)R 5 , -NR 5 C(O)R 5 , -NHC(O)NH 2 , -NHC(O)NR 5 R 5 , -NR 5 C(O)NHR 5 , -SH, -SR 5 , -S(O)H, -S(O)R 5 , -SO 2 R 5 , -SO 2 NH 2 , -SO 2 NHR 5 , -SO 2 NR 5 R 5 , -CF 3 , -CHF 2 , -CH 2 F,-OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO2 R 5 , -CHO, -C(O)R 5 , -C(O)NH 2 , -C(O)NHR 5 , -C(O)NR 5 R 5 , -CONHSO 2 H, -C(O)NHSO 2 R 5 , -C(O)NR 5 SO 2 R 5 , cyclic C 3 -C 7 and wherein each of the imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl groups is selected from the group: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cyclic alkyl, halo, -OH, -OR 7 , -OC(O)R 7 , -OC(O)NH 2 , -OC(O)NHR 7 , -OC(O)NR 7 R 7 , -OP(O)(OH) 2 , -OP(O)(OR 7 ) 2 , -NO 2 , -NH 2 , -NHR 7 , -NR 7 R 7 , -N + (O-)R 7 R 7 , -NHC(O)H, -NHC(O)R 7 , -NR 7 C(O)R 7 , -NHC(O)NH 2 , -NHC(O)NR 7 R 7 , -NR 7 C(O)NHR 7 , -SH, -SR 7, -S(O)H, -S(O)R 7 , -SO 2 R 7 , -SO 2 NH 2 , -SO 2 NHR 7 ,-SO 2 NR 7 R 7 , -CF 3 , -CHF 2 , -CH 2 F,-OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 7 , -CHO, -C(O)R 7 , -C(O)NH 2 , -C(O)NHR 7 , -C(O)NR 7 R 7 , -CONHSO 2 H, -C(O)NHSO 2 R 7 , -C(O)NR 7 SO 2 R 7 and optionally substituted aryl groups, and optionally substituted heteroaryl groups having up to 12 carbon atoms and having one or more heteroatoms in their ring system each independently selected from O, N and S; wherein one or more optional substituents on each of said aryl and heteroaryl groups are each independently selected from the following groups: 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-7 Cyclic alkyl, halo, -OH, -OR 8 , -OC(O)R 8 , -OC(O)NH 2 , -OC(O)NHR 8 , -OC(O)NR 8 R 8 , -OP(O)(OH) 2 , -OP(O)(OR 8 ) 2 , -NO 2 , -NH 2 , -NHR8 , -NR 8 R 8 , -N + (O)R 8 R 8 , -NHC(O)H, -NHC(O)R 8 , -NR 8 C(O)R 8 , -NHC(O)NH 2 , -NHC(O)NR 8 R 8 , -NR 8 C(O)NHR 8 , -SH, -SR 8 , -S(O)H, -S(O)R 8 , -SO 2 R 8 , -SO 2 NH 2 , -SO 2 NHR 8 ,-SO 2 NR 8 R 8 , -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 8 , -CHO, -C(O)R 8 , -C(O)NH 2 , -C(O)NHR 8 , -C(O)NR 8 R 8 , -CONHSO 2 H, -C(O)NHSO 2 R 8 , and -C(O)NR 8 SO 2 R 8 where each R 5 , R 7 and R 8 is independently 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups, and C 3-7 cyclic alkyl groups; and

[0040] (b) optionally substituted aryl groups, and optionally substituted heteroaryl groups having up to 12 carbon atoms and having one or more heteroatoms in its ring system, each independently selected from O, N and S, where the one or more optionally substituted groups are each independently selected from the same optionally substituted groups as defined in (a) above for R.

[0041] R 9 and R 10 are each independently a group defined in paragraphs (a) and (b) below: (a) H, optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl groups and optionally substituted C 3-7 Cyclic alkyl groups, wherein one or more optional substituents for each of said alkyl, alkenyl, alkynyl and cyclic alkyl are each independently selected from the following groups: halo, -OH, -OR 11 , -OC(O)R 11 , -OC(O)NH 2 , -OC(O)NHR 11 , -OC(O)NR 11 R 11 , -OP(O)(OH) 2 , -OP(O)(OR 11 ) 2 , -NO 2 , -NH 2 , -NHR 11 , -NR 11 R 11 , -N + (O)R 11 R 11 , -NHC(O)H, -NHC(O)R 11 , -NR 11 C(O)R 11 , -NHC(O)NH 2 , -NHC(O)NR 11 R 11 , -NR 11 C(O)NHR 11 , -SH, -SR 11, -S(O)H, -S(O)R 11 , -SO 2 R 11 , -SO 2 NH 2 , -SO 2 NHR 11 , -SO 2 NR 11 R 11 , -CF 3 , -CHF 2 , -CH 2 F,-OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 11 , -CHO, -C(O)R 11 , -C(O)NH 2 , -C(O)NHR 11 , -C(O)NR 11 R 11 , -CONHSO 2 H, -C(O)NHSO 2 R 11 , -C(O)NR 11 SO 2 R 11 , cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; 3 -C 7 Alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are each independently selected from the following groups: 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cyclic alkyl, halo, -OH, -OR 13 , -OC(O)R 13 , -OC(O)NH 2 , -OC(O)NHR 13 , -OC(O)NR 13 R 13 , -OP(O)(OH) 2 , -OP(O)(OR 13 )2 , -NO 2 , -NH 2 , -NHR 13 , -NR 13 R 13 , -N + (O)R 13 R 13 , -NHC(O)H, -NHC(O)R 13 , -NR 13 C(O)R 13 , -NHC(O)NH 2 , -NHC(O)NR 13 R 13 , -NR 13 C(O)NHR 13 , -SH, -SR 13 , -S(O)H, -S(O)R 13 , -SO 2 R 13 , -SO 2 NH 2 , -SO 2 NHR 13 ,-SO 2 NR 13 R 13 , -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 13 , -CHO, -C(O)R 13 , -C(O)NH 2 , -C(O)NHR 13 , -C(O)NR 13 R 13 , -CONHSO 2 H, -C(O)NHSO 2 R 13 , and -C(O)NR 13 SO 2 R 13 wherein each R 11 and R 13 is independently 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups and C 3-7cyclic alkyl groups; and

[0042] (b) optionally substituted aryl groups and optionally substituted heteroaryl groups having up to 12 carbon atoms and one or more heteroatoms in their ring system, each independently selected from O, N and S, wherein the one or more optional substituents for each of the aryl and heteroaryl are each independently selected from R 9 and R 10 selected from the same optional substituents as defined in (a) above for or (c)R 9 and R 10 can be joined together to form a partially saturated or fully unsaturated 5- or 6-membered ring of carbon atoms, optionally containing 1 to 3 heteroatoms selected from O, N, and S, and the ring is 9 and R 10 may be optionally substituted independently with 1 to 5 substituents selected from any of the same substituents as defined in (a) above.

[0043] (2) A compound of formula I or a pharma- ceutically acceptable salt thereof, wherein W, X, Y, and Z are all as de?ned in (1) above; Here, R 1 , R 2 , R 3 and R 4 are each independently selected from the following groups: H, halo, R, -OH, -OR, -OC(O)H, -OC(O)R, -OC(O)NH 2 , -OC(O)NHR, -OC(O)NRR, -OP(O)(OH) 2 , -OP(O)(OR) 2 , -NO 2 , -NH 2 , -NHR, -NRR, -NHC(O)H, -NHC(O)R, -NRC(O)R, -NHC(O)NH 2 , -NHC(O)NRR, -NRC(O)NHR, -SH, -SR, -S(O)H, -S(O)R, -SO 2 R, -SO 2 NH2 , -SO 2 NHR, -SO 2 NRR, -CF 3 , -OCF 3 , -OCHF 2 , -CN, -C≡CH, -C≡CR, -CH=CHR, -CH=CRR, -CR=CHR, -CR=CRR, -CO 2 H, -CO 2 R, -CHO, -C(O)R, -C(O)NH 2 , -C(O)NHR, -C(O)NRR, -CONHSO 2 H, -CONHSO 2 R,-CONRSO 2 R, cyclic C 3 -C 7 Alkylamino, imidazolyl, C 1 -C 6 alkylpiperazinyl, morpholinyl and thiomorpholinyl; Or R 1 and R 2 together, or R 2 and R 3 together, or R 3 and R 4 may together form a saturated or partially saturated or fully unsaturated 5- or 6-membered ring of carbon atoms, optionally containing 1 to 3 heteroatoms selected from O, N and S, the ring being optionally substituted independently with 1 to 4 substituents selected from R.

[0044] Each R is independently selected from the groups defined in paragraphs (a) and (b) below: (a) optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl groups and optionally substituted C 3-7 cyclic alkyl groups; wherein 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, -OR 5 , -OC(O)R 5 , -OC(O)NH 2, -OC(O)NHR 5 , -OC(O)NR 5 R 5 , -OP(O)(OH) 2 , -OP(O)(OR 5 ) 2 , -NO 2 , -NH 2 , -NHR 5 , -NR 5 R 5 , -N + (O-)R 5 R 5 , -NHC(O)H, -NHC(O)R 5 , -NR 5 C(O)R 5 , -NHC(O)NH 2 , -NHC(O)NR 5 R 5 , -NR 5 C(O)NHR 5 , -SH, -SR 5 , -S(O)H, -S(O)R 5 , -SO 2 R 5 , -SO 2 NH 2 , -SO 2 NHR 5 , -SO 2 NR 5 R 5 , -CF 3 , -OCF 3 , -OCHF 2 , -CN, -CO 2 , -CO 2 R 5 , -CHO, -C(O)R 5 , -C(O)NH 2 , -C(O)NHR 5 , -C(O)NR 5 R 5 , -CONHSO 2 , -C(O)NHSO 2 R 5 , -C(O)NR 5 , -SO 2 R 5 , cyclic C 3 , -C 7and wherein each of the imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl groups is selected from the group: alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; and wherein each of the imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl groups is selected from the group: 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cyclic alkyl, halo, -OH, -OR 7 , -OC(O)R 7 , -OC(O)NH 2 , -OC(O)NHR 7 , -OC(O)NR 7 R 7 , -OP(O)(OH) 2 , -OP(O)(OR 7 ) 2 , -NO 2 , -NH 2 , -NHR 7 , -NR 7 R 7 , -N + (O-)R 7 R 7 , -NHC(O)H, -NHC(O)R 7 , -NR 7 C(O)R 7 , -NHC(O)NH 2 , -NHC(O)NR 7 R 7 , -NR 7 C(O)NHR 7 , -SH, -SR 7 , -S(O)H, -S(O)R 7 , -SO 2 R 7 , -SO 2 NH 2 , -SO 2 NHR 7 -SO 2 NR 7 R 7 , -CF 3 , -OCF3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 7 , -CHO, -C(O)R 7 , -C(O)NH 2 , -C(O)NHR 7 , -C(O)NR 7 R 7 , -CONHSO 2 H, -C(O)NHSO 2 R 7 , -C(O)NR 7 SO 2 R 7 and optionally substituted aryl groups, and optionally substituted heteroaryl groups having up to 12 carbon atoms and having one or more heteroatoms in their ring system each independently selected from O, N and S; wherein one or more optional substituents on each of said aryl and heteroaryl groups are each independently selected from the following groups: 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-7 Cyclic alkyl, halo, -OH, -OR 8 , -OC(O)R 8 , -OC(O)NH 2 , -OC(O)NHR 8 , -OC(O)NR 8 R 8 , -OP(O)(OH) 2 , -OP(O)(OR 8 ) 2 , -NO 2 , -NH 2 , -NHR 8 , -NR 8 R 8 , -N + (O)R 8 R 8 , -NHC(O)H, -NHC(O)R 8 , -NR 8 C(O)R 8 , -NHC(O)NH 2 , -NHC(O)NR 8 R 8 , -NR 8C(O)NHR 8 , -SH, -SR 8 , -S(O)H, -S(O)R 8 , -SO 2 R 8 , -SO 2 NH 2 , -SO 2 NHR 8 ,-SO 2 NR 8 R 8 , -CF 3 , -OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 8 , -CHO, -C(O)R 8 , -C(O)NH 2 , -C(O)NHR 8 , -C(O)NR 8 R 8 , -CONHSO 2 H, -C(O)NHSO 2 R 8 , and -C(O)NR 8 SO 2 R 8 where each R 5 , R 7 and R 8 is independently 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups, and C 3-7 cyclic alkyl groups; and (b) optionally substituted aryl groups, and optionally substituted heteroaryl groups having up to 12 carbon atoms and having one or more heteroatoms in their ring system each independently selected from O, N and S, where the one or more optionally substituted substituents for each aryl and heteroaryl are each independently selected from the same optionally substituted substituents defined in (a) above for R.

[0045] R 9 and R 10 are each independently a group defined in paragraphs (a) and (b) below: (a) H, optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl groups and optionally substituted C 3-7 Cyclic alkyl groups, wherein one or more optional substituents for each of said alkyl, alkenyl, alkynyl and cyclic alkyl are each independently selected from the following groups: halo, -OH, -OR 11 , -OC(O)R 11 , -OC(O)NH 2 , -OC(O)NHR 11 , -OC(O)NR 11 R 11 , -OP(O)(OH) 2 , -OP(O)(OR 11 ) 2 , -NO 2 , -NH 2 , -NHR 11 , -NR 11 R 11 , -N + (O)R 11 R 11 , -NHC(O)H, -NHC(O)R 11 , -NR 11 C(O)R 11 , -NHC(O)NH 2 , -NHC(O)NR 11 R 11 , -NR 11 C(O)NHR 11 , -SH, -SR 11 , -S(O)H, -S(O)R 11 , -SO 2 R 11 , -SO 2 NH 2 , -SO 2 NHR 11 , -SO 2 NR 11 R 11 , -CF 3 , -OCF 3 , -OCHF 2 , CN, -CO 2 H, -CO 2 R 11 , -CHO, -C(O)R11 , -C(O)NH 2 , -C(O)NHR 11 , -C(O)NR 11 R 11 , -CONHSO 2 H, -C(O)NHSO 2 R 11 , -C(O)NR 11 SO 2 R 11 , cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; 3 -C 7 Alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are each independently selected from the following groups: 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cyclic alkyl, halo, -OH, -OR 13 , -OC(O)R 13 , -OC(O)NH 2 , -OC(O)NHR 13 , -OC(O)NR 13 R 13 , -OP(O)(OH) 2 , -OP(O)(OR 13 ) 2 , -NO 2 , -NH 2 , -NHR 13 , -NR 13 R 13 , -N + (O)R 13 R 13 , -NHC(O)H, -NHC(O)R 13 , -NR 13 C(O)R 13 , -NHC(O)NH 2 , -NHC(O)NR 13 R 13 , -NR 13 C(O)NHR 13 , -SH, -SR 13, -S(O)H, -S(O)R 13 , -SO 2 R 13 , -SO 2 NH 2 , -SO 2 NHR 13 ,-SO 2 NR 13 R 13 , -CF 3 , OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 13 , -CHO, -C(O)R 13 , -C(O)NH 2 , -C(O)NHR 13 , -C(O)NR 13 R 13 , -CONHSO 2 H, -C(O)NHSO 2 R 13 , and -C(O)NR 13 SO 2 R 13 each R 11 and R 13 is independently 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups and C 3-7 cyclic alkyl groups; and

[0046] (b) optionally substituted aryl groups and optionally substituted heteroaryl groups having up to 12 carbon atoms and one or more heteroatoms in their ring system, each independently selected from O, N and S, wherein the one or more optional substituents for each of the aryl and heteroaryl are each independently selected from R 9 and R 10 selected from the same optional substituents as defined above in (a) for (c)R 9 and R 10can be joined together to form a partially saturated or fully unsaturated 5- or 6-membered ring of carbon atoms, optionally containing 1 to 3 heteroatoms selected from O, N, and S, and the ring is 9 and R 10 may be optionally substituted independently with 1 to 5 substituents selected from any of the same substituents as defined in (a) above.

[0047] (3) A compound as defined in paragraph (1) or (2) comprising R 9 and R 10 each independently represents the following group: optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl groups and optionally substituted C 3-7 When selected from cyclic alkyl groups, 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, -OR 11 , -OC(O)R 11 , -OC(O)NH 2 , -OC(O)NHR 11 , -OC(O)NR 11 R 11 , -OP(O)(OH) 2 , -OP(O)(OR 11 ) 2 , -NO 2 , -NH 2 , -NHR 11 , -NR 11 R 11 , -N + (O)R 11 R 11 , -NHC(O)H, -NHC(O)R 11 , -NR 11 C(O)R 11 , -NHC(O)NH 2 , -NHC(O)NR 11 R 11 , -NR 11 C(O)NHR 11 , -SH, -SR 11 , -S(O)H, -S(O)R 11 , -SO2 R 11 , -SO 2 NH 2 , -SO 2 NHR 11 , -SO 2 NR 11 R 11 , -CF 3 , -CHF 2 , -CH 2 F,-OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 11 , -CHO, -C(O)R 11 , -C(O)NH 2 , -C(O)NHR 11 , -C(O)NR 11 R 11 , -CONHSO 2 H, -C(O)NHSO 2 R 11 , and -C(O)NR 11 SO 2 R 11 where each R 11 is independently 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups, and C 3-7 The alkyl group is selected from cyclic alkyl groups.

[0048] (4) Z is N or N-oxide, e.g., N, and W is CR 1 and X is CR 2 and Y is CR 3 3. A compound as defined in any one of paragraphs (1) to (3),

[0049] (5) X is N or N-oxide, e.g., N, and W is CR 1 and Y is CR 3 and Z is CR 4 3. A compound as defined in any one of paragraphs (1) to (3),

[0050] (6) X and Z are both N or N-oxide, e.g., N, and W is CR1 and Y is CR 3 3. A compound as defined in any one of paragraphs (1) to (3),

[0051] (7)R 1 , R 2 , R 3 and R 4 each independently, if present, is H, halo, optionally substituted C 1 -C 6 Alkyl, -OR (R is optionally substituted C 1 -C 6 a substituted aryl, e.g., substituted phenyl, optionally substituted aryl groups having up to 12 carbon atoms and having one or more heteroatoms in its ring system, each independently selected from O, N and S;

[0052] (8)R 1 , R 2 , R 3 and R 4 each independently, if present, is H, halo, optionally substituted C 1 -C 6 alkyl, -OR (R is optionally substituted C 1 -C 6 The compound as defined in any one of paragraphs (1) through (6), wherein the compound is selected from the group consisting of alkyl and optionally substituted aryl (such as phenyl), -NHR (wherein R is optionally substituted aryl), optionally substituted aryl, and optionally substituted heteroaryl groups having up to 12 carbon atoms and having one or more heteroatoms in their ring system each independently selected from O, N, and S.

[0053] (9)R 1 , R 2 , R 3 and R 4 each independently, if present, is H, halogen, -CF 3 , -CHF 2 , -OCF 3, -OCHF 2 , C 1-6 The compound as defined in paragraph (8) is selected from the group consisting of alkyl, e.g., methyl, substituted aryl, substituted heteroaryl, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl).

[0054] (10) If present, R 1 , R 2 , R 3 and R 4 One or two of R are H and R is not H. 1 , R 2 , R 3 and R 4 The others are independently halogen, -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , C 1-6 The compound as defined in paragraph (8) is selected from the group consisting of alkyl, e.g., methyl, substituted aryl, substituted heteroaryl, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl).

[0055] (11)R 3 is present and is selected from the group consisting of halogen, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl).

[0056] (12) Z is N or N-oxide, e.g., N, and W is CR 1 and X is CR 2 and Y is CR 3 and R 3 is selected from the group consisting of halogen, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl).

[0057] (13) Z is N or N-oxide, e.g., N, and W is CR 1 and X is CR 2 and Y is CR 3 and R 1 is H and R 2 and R 3 One or both of are other than H, e.g., R 2 and R 3 are other than H, or R 2 is H and R 3 is other than H or R 3 is H and R 2 is other than H.

[0058] (14) R other than H 2 and R 3 each independently represents a halogen, an optionally substituted C 1 -C 6 alkyl, -OR (R is optionally substituted C 1 -C 6 alkyl and optionally substituted aryl), -NHR, where R is an optionally substituted aryl; substituted aryl, e.g., substituted phenyl, and optionally substituted heteroaryl groups.

[0059] (15) R other than H 2 and R 3 each independently is a halogen, -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , C 1-6 The compound as defined in paragraph (14) is selected from the group consisting of alkyl, e.g., methyl, substituted aryl, substituted heteroaryl, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl).

[0060] (16)R 1 and R 2 are combined or R2 and R 3 are combined or R 3 and R 4 together form a saturated, partially saturated or fully unsaturated 5- or 6-membered ring of carbon atoms, optionally containing 1-3 heteroatoms selected from O, N or S, the ring being optionally substituted with 1-4 substituents independently selected from R, and any R that is not part of the ring 1 , R 2 , R 3 and R 4 are independently selected from H, halo, optionally substituted C 1 -C 6 alkyl, OR (R is optionally substituted C 1 -C 6 a compound as defined in any one of paragraphs (1) through (6) selected from optionally substituted aryl, optionally substituted aryl, and optionally substituted heteroaryl groups having up to 12 carbon atoms and having one or more heteroatoms in their ring system, each independently selected from O, N, and S.

[0061] (17)R 9 and R 10 are independently H, optionally substituted C 1-6 The compound according to any one of paragraphs (1) to (16), wherein the aryl group is selected from alkyl, optionally substituted aryl, e.g., substituted phenyl, and optionally substituted heteroaryl groups having up to 12 carbon atoms and having one or more heteroatoms in its ring system, each independently selected from O, N and S.

[0062] (18)R 9 and R 10 and (17) are both H.

[0063] (19) Z is N or N-oxide, e.g., N, and W is CR 1 and X is CR 2 and Y is CR 3 and R 9 and R 10A compound as defined in paragraph (4), wherein

[0064] (20)R 1 , R 2 and R 3 each independently represents H, halogen, or -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , C 1-6 The compound as defined in paragraph (19) is selected from the group consisting of alkyl, e.g., methyl, substituted aryl, substituted heteroaryl, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl).

[0065] (21)R 1 , R 2 and R 3 are each independently H, halogen, or C 1-6 The compound as defined in paragraph (19), wherein the aryl is selected from the group consisting of alkyl, e.g., methyl, substituted aryl, and substituted heteroaryl.

[0066] (22)R 1 , R 2 and R 3 One or two of R are H and R is not H. 1 , R 2 and R 3 The others are independently halogen, -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , C 1-6 The compound as defined in paragraph (19) is selected from the group consisting of alkyl, e.g., methyl, substituted aryl, substituted heteroaryl, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl).

[0067] (23)R 1 is H and R 2 and R 3 One or both of are other than H, and R is not H.2 and R 3 each independently represents a halogen, -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , C 1-6 The compound as defined in paragraph (19) is selected from the group consisting of alkyl, e.g., methyl, substituted aryl, substituted heteroaryl, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl).

[0068] (24)R 3 is selected from the group consisting of halogen, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl).

[0069] (25)R 1 is H and R 2 and R 3 forms a saturated or partially saturated or fully unsaturated 5- or 6-membered ring of carbon atoms, optionally containing 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.

[0070] (26) W is CR 1 and R 1 H, halo, -CHF 2 , -CF 3 or methyl; Z is N or N-oxide, e.g., N, and X is CR 2 and Y is CR 3 X is N or N-oxide, e.g., N, and Y is CR 3 and Z is CR 4 or X and Z are both N or N-oxide, e.g., N, and Y is CR 3 3. The compound as defined in any one of paragraphs (1) to (6),

[0071] (27) W is CR 1and R 1 H, halo, -CHF 2 , -CF 3 or methyl; R 9 and R 10 are each H; Z is N or N-oxide, e.g., N; X is CR 2 and Y is CR 3 X is N or N-oxide, e.g., N, and Y is CR 3 and Z is CR 4 or X and Z are both N or N-oxide, e.g., N, and Y is CR 3 3. The compound as defined in any one of paragraphs (1) to (6),

[0072] (28) W is CR 1 and R 1 H, halo, -CHF 2 , -CF 3 or methyl; R 9 and R 10 are each H; Z is N or N-oxide, e.g., N; X is CR 2 and Y is CR 3 ;R 2 and R 3 are each independently H, halogen, or -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -NO 2 , C 1-6 alkyl, e.g., methyl, optionally substituted aryl, optionally substituted heteroaryl, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl); or R 2 and R 3 may together form a saturated or partially saturated or fully unsaturated 5- or 6-membered ring of carbon atoms, the ring being optionally substituted with 1 to 4 substituents independently selected from R.

[0073] (29) W is CR 1 and R1 H, halo, -CHF 2 , -CF 3 or methyl.

[0074] (30) W is CR 1 and R 1 H, F, -CHF 2 , -CF 3 or methyl.

[0075] (31) W is CR 1 and R 1 is H or F.

[0076] (32) W is CR 1 and R 1 is H or methyl.

[0077] (33) W is CR 1 and R 1 is H.

[0078] (34)R 9 and R 10 are independently H, optionally substituted C 1-6 The compound defined in any one of paragraphs (1) to (6) and (29) to (33) is selected from an alkyl group, an optionally substituted aryl, e.g., a substituted phenyl, and an optionally substituted heteroaryl group having up to 12 carbon atoms and having one or more heteroatoms in its ring system, each independently selected from O, N, and S.

[0079] (35)R 9 and R 10 The compound defined in any one of (1) to (6) and (29) to (34), wherein each of

[0080] (36) Z is N or N-oxide, e.g., N, and X is CR 2 and Y is CR 3 A compound as defined in any one of paragraphs (26) to (35),

[0081] (37) X is N or N-oxide, e.g., N, and Y is CR 3 and Z is CR 4 A compound as defined in any one of paragraphs (26) to (35),

[0082] (38) X and Z are both N or N-oxide, e.g., N, and Y is CR 3 A compound as defined in any one of paragraphs (26) to (35),

[0083] (39)R 2 and R 3 are each independently H, halogen, or -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -NO 2 , C 1-6 alkyl, e.g., methyl, optionally substituted aryl, optionally substituted heteroaryl, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl); or R 2 and R 3 may together form a saturated or partially saturated or fully unsaturated 5- or 6-membered ring of carbon atoms, the ring being optionally substituted with 1 to 4 substituents independently selected from R.

[0084] (40)R 2 and R 3 are each independently H, halogen, or -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -NO 2 , C 1-6alkyl, e.g., methyl, optionally substituted aryl, optionally substituted heteroaryl, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl); or R 2 and R 3 may together form a saturated or partially saturated or fully unsaturated 5- or 6-membered ring of carbon atoms, the ring being optionally substituted with 1 to 4 substituents independently selected from R,

[0085] (41)R 2 and R 3 are each independently H, halogen, or -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -NO 2 , C 1-6 alkyl, e.g., methyl, optionally substituted aryl, optionally substituted heteroaryl, -OR (wherein R is an optionally substituted aryl), and -NHR (wherein R is an optionally substituted aryl); or R 2 and R 3 may together form a saturated, partially saturated or fully unsaturated 5- or 6-membered ring of carbon atoms, as defined in any one of paragraphs (1) to (6), (28) to (36), (39) and (40).

[0086] (42)R 2 and R 3 each independently represents H, halo, -CF 3 , -CHF 2 , -NO 2 and methyl.

[0087] (43)R 2 and R 3 each independently represents H, halo, -CF 3 , and -NO 2The compound defined in any one of paragraphs (1) to (6), (28) to (36), and (39) to (42) is selected from the group consisting of

[0088] (44)R 2 and R 3 A compound as defined in any one of paragraphs (1) to (6), (28) to (35), and (38) to (43), wherein one of is H and the other is a group other than H.

[0089] (45) W is CR 1 and R 1 is H or F; R 9 and R 10 are each H; Z is N or N-oxide, e.g., N; X is CR 2 and Y is CR 3 ;R 2 and R 3 each independently represents H, halo, -CF 3 , -CHF 2 , -NO 2 and methyl.

[0090] (45) W is CR 1 and R 1 is H;R 9 and R 10 are each H; Z is N or N-oxide, e.g., N; X is CR 2 and Y is CR 3 ;R 2 and R 3 each independently represents H, halo, -CF 3 , and -NO 2 The compound as defined in any one of paragraphs (1) to (3), selected from:

[0091] (46) X is N or N-oxide, e.g., N, and Y is CR 3 and Z is CR 4 ;R 3 and R 4 R in any one of paragraphs (39) to (43) 2 and R3 The compound defined in any one of paragraphs (1) to (3), (26), (27), (29) to (35) and (37), wherein the substituent is selected from the group of substituents recited for

[0092] (47) X and Z are both N or N-oxide, e.g., N, and Y is CR 3 ;R 3 In any one of paragraphs (39) to (43), 2 and R 3 The compound defined in any one of paragraphs (1) to (3), wherein the substituent is selected from the group of substituents listed for

[0093] (46) 5-Bromo-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (1) Isoxazolo[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) Isoxazolo[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) Isoxazolo[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-Iodoisoxazolo[5,4-b]pyridin-3-amine (16) Isoxazolo[4,5-c]pyridin-3-amine (17) N 6 ,N 6 Dimethylisoxazolo[5,4-b]pyridine-3,6-diamine (18) N 4 ,N 4 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]pyridine-3-a (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) Isoxazolo[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-Isopropylisoxazolo[5,4-b]pyridin-3-amine (48) 5-Nitroisoxazolo[5,4-b]pyridin-3-amine (49) Ethyl 3-amino-6-(trifluoromethyl)isoxazolo[5,4-b]pyridine-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-Methylisoxazolo[5,4-d]pyrimidin-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 (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) N 6 -Phenylisoxazolo[5,4-b]pyridine-3,6-diamine (94) N 6 -(3-Methoxyphenyl)isoxazolo[5,4-b]pyridine-3,6-diamine (95) and N 6 -(4-Methoxyphenyl)isoxazolo[5,4-b]pyridine-3,6-diamine (96), and pharma- ceutically acceptable salts thereof.

[0094] (47) 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-Iodoisoxazolo[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) Isoxazolo[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) Isoxazolo[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) N 6 -(3-Methoxyphenyl)isoxazolo[5,4-b]pyridine-3,6-diamine (95), and pharma- ceutically acceptable salts thereof.

[0095] (48) 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-Iodoisoxazolo[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 pharma- ceutically acceptable salts thereof.

[0096] (49) The compound defined in paragraph (1), wherein the compound is 6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) or a pharma- ceutically acceptable salt thereof.

[0097] In various embodiments relating to the treatment, prevention or kit, the dual inhibitor of IDO1 and TDO is 6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) or a pharma- ceutically acceptable salt thereof, and the refractory cancer to be treated or prevented is refractory to a platinum-based chemotherapeutic agent. For example, in various embodiments, the platinum-based chemotherapeutic agent is selected from carboplatin, cisplatin, lobaplatin, oxaliplatin, picoplatin, nedaplatin, phenanthriplatin and / or satraplatin. In a further example, the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin, and / or oxaliplatin.

[0098] In various embodiments relating to the treatment, prevention or kit, the dual inhibitor of IDO1 and TDO is 6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) or a pharma- ceutically acceptable salt thereof, and the refractory cancer being treated or prevented is refractory to platinum-based chemotherapy. For example, in various embodiments, the platinum-based chemotherapy comprises administering a chemotherapeutic agent selected from carboplatin, cisplatin, lobaplatin, oxaliplatin, picoplatin, nedaplatin, phenanthriplatin and / or satraplatin.

[0099] In various embodiments related to the treatment, prevention or kit, the dual inhibitor of IDO1 and TDO is 6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) or a pharma- ceutically acceptable salt thereof, and the cancer to be treated or prevented is selected from lung cancer, pancreatic cancer, breast cancer and ovarian cancer, and is refractory to platinum-based chemotherapeutic agents. For example, in various embodiments, the platinum-based chemotherapeutic agent is selected from carboplatin, cisplatin, lobaplatin, oxaliplatin, picoplatin, nedaplatin, phenanthriplatin and / or satraplatin. In further examples, the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin and / or oxaliplatin.

[0100] In various embodiments relating to the treatment, prevention or kit, the dual inhibitor of IDO1 and TDO is 6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) or a pharma- ceutically acceptable salt thereof, and the cancer to be treated or prevented is selected from lung cancer, pancreatic cancer, breast cancer and ovarian cancer and is refractory to platinum-based chemotherapy. For example, in various embodiments, the platinum-based chemotherapy comprises administering a chemotherapeutic agent selected from carboplatin, cisplatin, lobaplatin, oxaliplatin, picoplatin, nedaplatin, phenanthriplatin and / or satraplatin.

[0101] In various embodiments, the dual inhibitor of IDO1 and TDO has a cellular IDO1 IC of less than 100 μM as determined by a cell-based assay for IDO1 inhibition. 50 has a cellular TDO IC of less than 100 μM as determined by a cell-based assay for TDO inhibition 50 In various embodiments, the dual inhibitors of IDO1 and TDO described herein have a cellular IDO1 IC of less than 10 μM as determined by a cell-based assay for IDO1 inhibition. 50 has a cellular TDO IC of less than 10 μM as determined by a cell-based assay for TDO inhibition 50 In various embodiments, the dual inhibitors of IDO1 and TDO described herein have a cellular IDO1 IC of less than 1 μM as determined by a cell-based assay for IDO1 inhibition. 50 and has a cellular TDO IC of less than 1 μM as determined by a cell-based assay for TDO inhibition. 50 has.

[0102] In various embodiments, the dual inhibitor of IDO1 and TDO is formulated with a suitable pharma- ceutically acceptable carrier, such as an excipient, diluent, adjuvant, or combination thereof.

[0103] In various embodiments, the dual inhibitor of IDO1 and TDO is formulated or provided as a pharmaceutical composition comprising a dual inhibitor of IDO1 and TDO and a pharma- ceutically acceptable carrier.

[0104] In various embodiments, the dual inhibitor of IDO1 and TDO is formulated or provided for oral administration as a pharmaceutical composition comprising a dual inhibitor of IDO1 and TDO and a pharma- ceutically acceptable carrier.

[0105] In various embodiments, the dual inhibitor of IDO1 and TDO is administered orally.

[0106] In various embodiments, the method, use or dual inhibitor for preventing the development of a refractory cancer or refractory cancer cells comprises administering a dual inhibitor of IDO1 and TDO to a subject or cell in combination with an anti-cancer drug and / or cancer treatment to which the cancer or cancer cells are to be prevented from becoming refractory, and optionally the method, use or dual inhibitor further comprises treating the cancer or cancer cells at risk of becoming refractory to the anti-cancer drug and / or treatment.

[0107] In various embodiments, the method, use or dual inhibitor for preventing the development of refractory cancer refractory to anti-cancer agents and / or cancer therapies comprises administering to a subject in need thereof a dual inhibitor of IDO1 and TDO in combination with an anti-cancer agent and / or cancer therapy. In various embodiments, the dual inhibitor of IDO1 and TDO and the anti-cancer agent and / or cancer therapy are administered simultaneously, sequentially or separately. In various embodiments, the dual inhibitor of IDO1 and TDO and the anti-cancer agent and / or cancer therapy are administered as a single formulation or as separate formulations.

[0108] In various embodiments, the method, use or dual inhibitor further comprises administering one or more additional agents selected from the group consisting of anti-cancer drugs, immunomodulators such as anti-cancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapy (e.g., chimeric antigen receptor T cells (CART cells)), and radiation therapy, where the additional agents are administered either before, during, or after administration of the dual inhibitor of IDO1 and TDO. In various embodiments, the one or more additional agents are immunomodulators selected from inhibitors of CTLA4, anti-PD-1 antibodies, or anti-PD-L1 antibodies. For example, in various embodiments, the one or more additional agents are selected from ipilimumab, semipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab.

[0109] In various embodiments, the one or more additional agents are administered simultaneously, sequentially, or separately with the dual inhibitor of IDO1 and TDO. In various embodiments, the dual inhibitor of IDO1 and TDO and the one or more additional agents are administered in a single formulation or in separate formulations.

[0110] When ranges are given herein, e.g., temperature ranges, time ranges, composition ranges, etc., all intermediate and subranges, as well as all individual values ​​contained within the given ranges, are intended to be included in the disclosure. Reference to a range of numbers disclosed herein (e.g., 1-10) is intended to incorporate reference to all rational numbers within that range (e.g., 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9, 10), and any range of rational numbers within that range (e.g., 2-8, 1.5-5.5, 3.1-4.7), and thus all subranges of every range explicitly 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 and highest values ​​recited are to be considered as being equally expressly intended in this application.

[0111] Other aspects of the invention may include suitable combinations of the embodiments disclosed herein, and, as will be appreciated by those skilled in the art, features and preferred embodiments of one aspect of the invention may also relate to other aspects of the invention.

[0112] The present invention may also be broadly described as consisting of the parts, elements and features referred to or illustrated in this specification, individually or collectively, and any or all combinations of any two or more of said parts, elements or features, and where reference is made herein to a particular integer that has a known equivalent in the art to which the invention pertains, such known equivalent is deemed to be incorporated herein as if individually set forth.

[0113] The present invention is broadly as defined above, but is not limited thereto, and includes the embodiments exemplified in the following description. The present invention will now be described in more detail.

[0114] The present invention will now be described with reference to the accompanying drawings. [Brief description of the drawings]

[0115] [Figure 1] FIG. 1 is a graph showing the cell viability of human-derived cisplatin-sensitive lung cancer cell lines B, S, and A, and cisplatin-resistant lung cancer cell lines BC, SC, and ALC after incubation with AT-0174. [Figure 2A] Figure 2 shows the antitumor activity of the selective IDO1 inhibitor Epacadostat or the dual inhibitor AT-0174 in a syngeneic mouse model of lung cancer. (A) LLC-CR has higher basal levels of T-reg (CD4+CD25+) cell populations and lower basal levels of natural killer (NK; CD3-CD49b+) cell populations compared to parental tumors. [Figure 2B](B) Antitumor activity of Epacadostat or AT-0174 in parental versus cisplatin-resistant cell xenografts. Tumor growth was significantly inhibited in the cisplatin-resistant tumor groups treated with EPA or AT-0174 (*P=0.042, **P=0.014; using one-way ANOVA with Tukey's multiple comparison test; n=5). [Figure 2C] (C) A significant reduction in tumor weight was observed in mice treated with AT-0174; *p=0.002 (n=5). [Diagram 3] Figure 3 shows that both Epacadostat (EPA) and AT-0174 (AT) suppressed T-regs and increased NK cell activity in CR tumors. However, the dual inhibitor AT-0174 was more potent in enhancing immune activity in the tumor microenvironment. The AT-0174-treated group had higher NK cell activity and lower Treg populations compared to Epacadostat (p=0.035, p=0.02 (n=5), respectively). [Figure 4] Figure 4 shows kynurenine (KYN) and tryptophan (TRP) levels in mouse serum after treatment with Epacadostat or AT-0174. (A) LLC-CR mice have a high basal KYN / TRP ratio. Importantly, treatment of mice bearing cisplatin-resistant tumors with AT-0174 significantly suppressed the KYN / TRP ratio (A; *p=0.002; n=5) and KYN (B; **p=0.03) and increased TRP (C; ***p=0.02). [Diagram 5] FIG. 5 shows the body weight of mice treated with vehicle, oxaliplatin, or oxaliplatin plus AT-1074 in the mouse Pan02 syngeneic model of pancreatic cancer. [Figure 6] FIG. 6 shows the tumor burden in mice treated with vehicle, oxaliplatin, or oxaliplatin plus AT-1074 in the mouse Pan02 syngeneic model of pancreatic cancer. [Figure 7]FIG. 7 shows the relative tumor burden in mice treated with vehicle, oxaliplatin, or oxaliplatin plus AT-1074 in the mouse Pan02 syngeneic model of pancreatic cancer. [Figure 8] FIG. 8 shows changes in immune cell populations within Pan02 tumors in mice treated with either vehicle, oxaliplatin, or oxaliplatin and AT-1074. [Figure 9] FIG. 9 shows the percentage of immunophenotypic expression in Pan02 tumors. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0116] definition As used herein, "comprising" is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended and does not exclude additional, implied elements or method steps. When interpreting each statement containing the term "comprising" in this specification and claims, there may be other features present than the term or terms preceded by the term. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner.

[0117] As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. In each instance herein, any of the terms "consisting of," "consisting essentially of," and "consisting of" may be replaced with either of the other two terms.

[0118] Unless otherwise specified, the singular forms "a", "an" and "the" include plural references.

[0119] In this disclosure and claims, "and / or" means additionally or alternatively.

[0120] Additionally, terms used in the singular will also encompass the plural.

[0121] It will be appreciated that certain compounds of the present invention may exist in one or more different enantiomeric or diastereomeric forms, and it will be understood that the enantiomeric or diastereomeric forms are included in the above aspects of the invention.

[0122] The term "halo" or "halogen" as used throughout this specification is intended to mean a fluoro, chloro, bromo or iodo group.

[0123] When the variables of formula I defined above are optionally substituted with one or more imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl groups, it is understood that linkage to the associated variable may be through any available nitrogen or carbon ring atom of these groups.

[0124] The term "heteroaryl", unless the context indicates otherwise, is understood to include monocyclic and bicyclic ring systems.

[0125] The term "aryl" should be understood to mean an aromatic hydrocarbon such as phenyl or naphthyl.

[0126] When a group is modified as "optionally substituted," this is understood to mean that the group is either (a) unsubstituted, or (b) substituted with the defined substituents.

[0127] Throughout this specification, C 1 -C 6 When referring to an alkyl group or a C2-C6 alkenyl group, it is understood that these groups may be unbranched or branched. For example, C 1 -C 6Reference to alkyl is intended to include the group tert-butyl (Me)3C-.

[0128] "Subject" refers to a warm-blooded animal. By "warm-blooded animal" is meant animals belonging to the class Mammalia, including, but not limited to, humans, non-human primates such as apes, such as chimpanzees, and monkeys, domestic animals, such as cows, horses, sheep, goats, deer, and pigs, domestic animals, such as rabbits, dogs, and cats, and laboratory animals, including rodents, such as rats, mice, and guinea pigs. Preferably, the subject is a human.

[0129] As used herein, the term "chemotherapy" refers to the use of one or more chemotherapeutic agents in the treatment or prevention of cancer, eg, to kill cancer cells or shrink tumors.

[0130] In this specification, the term "radiotherapy" refers to the use of high-energy radiation such as X-rays, gamma rays, neutrons, and protons to kill cancer cells and shrink tumors. Radiation can be irradiated from a machine outside the body (external beam radiation therapy) or by placing a radioactive substance inside the body near the cancer cells (internal beam radiation therapy). Total body radiation therapy uses radioactive substances such as monoclonal antibodies labeled with radioisotopes, which travel through the bloodstream to tissues throughout the body. Radiation irradiation and radiation therapy have the same meaning.

[0131] As used herein, phrases such as "treating refractory cancer," "treatment of refractory cancer," "treating refractory cancer cells," "treatment of refractory cancer cells," and the like generally relate to treatments in which a desired therapeutic effect is achieved. The therapeutic effect can be, for example, suppression, reduction, amelioration, cessation, or prevention (e.g., growth) of the refractory cancer. For example, in some embodiments, the therapeutic effect can be inhibiting, reducing, preventing, or stopping a cancer or cancer cell that is refractory to platinum-based chemotherapy (including inhibiting, reducing, preventing, or stopping a cancer or cancer cell that is refractory to platinum-based chemotherapy). The phrases include methods that result in one or more anti-cancer effects. "Anti-cancer effect" includes, but is not limited to, anti-tumor effect, response rate, time to disease progression, overall survival rate, and the like. "Anti-tumor" effect includes, but is not limited to, inhibition of tumor growth, delay of tumor growth, tumor regression, tumor shrinkage, increase in time to tumor regrowth upon cessation of treatment, delay of disease progression, and the like.

[0132] As used herein, the terms "preventing refractory cancer", "preventing the development of refractory cancer", "preventing the development of refractory cancer cells", "preventing the development of cancer or cancer cells refractory to anticancer agents and / or cancer treatments" and similar expressions refer to preventing or inhibiting the development of cancer or cancer cells refractory to a particular anticancer agent and / or cancer treatment from cancer or cancer cells that are not refractory to the anticancer agent and / or cancer treatment, or preventing or reducing the likelihood of the development or recurrence of refractory cancer or refractory cancer cells, and / or delaying the development of refractory cancer or refractory cancer cells. For example, in some embodiments, the terms relate to preventing or inhibiting the development of refractory cancer that is refractory to a particular platinum-based chemotherapeutic agent from cancer that is not refractory to the particular platinum-based chemotherapeutic agent. Also included are terms delaying the onset or recurrence of refractory cancer, or delaying the onset or recurrence of symptoms of refractory cancer.

[0133] "Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating or preventing a refractory cancer, is sufficient to treat or prevent the refractory cancer. The "effective amount" will vary depending on the refractory cancer being treated, the compound being administered, the severity of the refractory cancer being treated, the age and relative health of the subject, the route and form of administration, whether the treatment is a monotherapy or combination therapy, the judgment of the attending physician, and other factors.

[0134] As used herein, the phrase "refractory cancer" or "refractory to (anticancer drugs and / or cancer treatments)" and similar terms refer to a particular cancer or cancer cells that do not respond favorably or are resistant to a particular anticancer drug and / or cancer treatment, or that recur or relapse after responding favorably to a particular anticancer drug and / or cancer treatment. Thus, for example, a cancer that is "refractory to platinum-based chemotherapy" refers to a cancer that does not respond favorably or is resistant to platinum-based chemotherapy, or a cancer that recurs or relapses after responding favorably to such treatment.

[0135] Methods for determining or assessing refractory cancer or refractory cancer cells will be clear to those skilled in the art. For example, to detect or identify refractory or resistant cancers, subjects undergoing cancer treatment or therapy can be closely monitored for signs of resistance, non-responsiveness, recurrence or relapse of the cancer. This can be achieved by monitoring the subject's cancer response to the treatment. The response, lack of response, recurrence or relapse of the cancer to a therapy, e.g., an initial therapy, can be determined by any suitable method practiced in the art. For example, this can be achieved by evaluating one or more anti-cancer effects, the lack of which indicates that the cancer is not responding to the cancer therapy or that a relapse has occurred. For example, this can be achieved by evaluating the size or number of tumors. An increase in tumor size or an increase in the number of tumors indicates that the tumor is not responding to chemotherapy or that a relapse has occurred. The decision can be made according to the "RECIST" criteria detailed in Eisenhauer, EA et al. European journal of cancer (Oxford, England : 1990) vol. 45,2 (2009): 228-47.

[0136] "Pharmaceutically acceptable" means something that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes something that is acceptable for veterinary use as well as for human pharmaceutical use.

[0137] Also included within the scope of the present invention are pharma- ceutically acceptable salts of the compounds of the present invention. A "pharmaceutically acceptable salt" of a compound means a salt that is pharma- ceutically acceptable, as defined herein, and that possesses the desired pharmacological activity of the parent compound. Such salts include the following: (a) Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, etc.; and (b) Salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, an aluminum ion, or coordinated with an organic or inorganic base. Organic bases that can be used include ethanolamine, diethanolamine, N-methylglucamine, triethanolamine, etc. Inorganic bases that can be used include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0138] The present inventors have surprisingly discovered that dual inhibitors of IDO1 and TDO are useful for the treatment and prevention of refractory cancers.

[0139] In one aspect, the present invention provides a treatment for refractory cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a dual inhibitor of IDO1 and TDO.

[0140] In another aspect, the present invention provides for the prevention of the onset of refractory cancer, comprising administering a therapeutically effective amount of a dual inhibitor of IDO1 and TDO to a subject in need thereof.

[0141] In another aspect, the present invention provides a method of treating refractory cancer cells, comprising administering a dual inhibitor of IDO1 and TDO to said cancer cells. In various embodiments, the refractory cancer cells are in vitro or in vivo.

[0142] In another aspect, the invention provides a method for preventing the development of refractory cancer cells, the method comprising administering a dual inhibitor of IDO1 and TDO to said cancer cells. In various embodiments, the cancer cells are in vitro or in vivo.

[0143] In various embodiments, the refractory cancer or cancer cells are refractory to anti-cancer drugs and / or cancer treatments.

[0144] Refractory cancer Refractory cancers that can be treated or prevented according to the present invention include, but are not limited to, cancers that are resistant to anticancer drugs. Refractory cancer cells that can be treated or prevented according to the present invention include, but are not limited to, cancer cells that are refractory to anticancer drugs.

[0145] Anti-cancer drugs will be clear to those skilled in the art, for example, for the refractory cancer or cancer cells to be treated or prevented. Many anti-cancer drugs are known in the art. Examples of suitable anti-cancer drugs include those listed in Cancer: Principles and Practice of Oncology, 7th Edition, Devita et al, Lippincott Williams & Wilkins, 2005, which is incorporated herein by reference.

[0146] In various embodiments, the refractory cancer or cancer cells are refractory to a platinum-based chemotherapeutic agent, e.g., a platinum complex. In various embodiments, the platinum-based chemotherapeutic agent is selected from carboplatin, cisplatin, lobaplatin, oxaliplatin, picoplatin, nedaplatin, phenanthriplatin, and / or satraplatin. For example, in various embodiments, the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin, and / or oxaliplatin.

[0147] Thus, in various embodiments, the refractory cancer or cancer cells to be treated or prevented are refractory to a platinum-based chemotherapeutic agent selected from carboplatin, cisplatin, lobaplatin, oxaliplatin, picoplatin, nedaplatin, phenanthriplatin, and satraplatin. For example, in various embodiments, the platinum-based chemotherapeutic agent is cisplatin, carboplatin, or oxaliplatin.

[0148] In various other embodiments, the refractory cancers to be treated or prevented according to the present invention include, but are not limited to, alkaloids and natural products, including camptothecin derivatives such as 9-aminocamptothecin, exatecan, irinotecan, rubitecan, topotecan, etc., podophyllum derivatives such as etoposide, teniposide, taxanes such as docetaxel, paclitaxel, paclitaxel poliglumex, vinca alkaloids, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, etc., as well as aplidine, elliptinium acetate, irofulven, ixabepilone, kahalalide F, midostaurin, trabectedin, etc. Alkylating agents, alkylsulfonates (busulfan, improsulfan, piposulfan, etc.), aziridines (carboquone, diaziquone, mitomycin C, uredepa, etc.), ethyleneimines and methylmelamines (altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, etc.), nitrogen mustards (bendamustine, canfosfamide, chlorambucil, chlornaphazine, cyclophosphamide, cyclophosphamide, estramustine, glufosfamide, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, perfosfamide, prenimustine, trichlormethine, trofosfamide, uracil mustard, etc. ), nitrosoureas (such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine), ranimustine, and other antibiotics such as dacarbazine, etoglucide, mitobronitol, mitolactol, pipobroman, procarbazine, lomustine, temozolomide, actinomycins such as cactinomycin, dactinomycin, anthracyclines such as aclacinomycin, amrubicin, carubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, zorubicin, and other antibiotics and analogues such as bleomycin, mitomycin, peplomycin, plicamycin, porfiromycin, streptozocin, temsirolimus, zinostatin.Antimetabolites, for example folic acid analogues and folic acid antagonists such as denopterin, edatrexate, methotrexate, nolatrexed, pemetrexed, piritrexy, pteropterin, raltitrexed and trimetrexate, for example cladribine, clofarabine, fludarabine, fludarabine phosphate, purine analogues such as 6-mercaptopurine, nelarabine, thiamiprine, thioguanine and tiazofurin, and pyrimidine analogues such as ancitabine, azacitidine 6-azauridine, capecitabine, carmofur, cytarabine, decitabine, doxifluridine, enocitabine, floxuridine, fluorouracil, gemcitabine, tegafur and troxacitabine; enzymes, for example L-asparaginase, rampirnur azeta, farnesyltransferase inhibitors such as lonafarnib, tipifarnib, immunomodulators such as aldesleukin, interferon-α, interferon-γ, lentinan, mepact, oregovomab, propagermanium, PSK®, roquinimex, sipuleucel-T, sizofiran, teceleukin, ubenimex, immunotoxins such as syntredekin, besudotox, denileukin, diftitox. Monoclonal antibodies such as alemtuzumab, bevacizumab, cetuximab, edrecolomab, epratuzumab, gemtuzumab, ozogamicin, oregovomab, panitumumab, rituximab, tositumomab 131I, ofatumumab, ipilimumab, pertuzumab, ramucirumab, obinutuzumab, nivolumab, pembrolizumab, dinutuximab and trastuzumab. Antibody drug conjugates such as ibritumomab tiuxetan, brentuximab vedotin and Ado-trastuzumab emtansine; oligonucleotides such as aprinocarsen and oblimersen sodium. Retinoids and analogues such as alitretinoin, bexarotene, fenretinide, mofalotene and talnibarotene.Tyrosine kinase inhibitors, such as canertinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, sorafenib, sunitinib, axitinib, nilotinib, pazopanib, bosutinib, cabozantinib, ponatinib, regorafenib and vatalanib; other inhibitors, such as crizotinib, ruxolitinib, vandetanib, vemurafenib, tofacitinib, afatinib, dabrafenib, ibrutinib and trametinib; others, such as amsacrine, arsenic trioxide, a The disease is refractory to anticancer drugs, including chemotherapeutic agents selected from the group including trasentan, 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 anti-cancer agents also include, but are not limited to, antineoplastic hormones, such as androgens, e.g., dromostanolone, epithiostanol, mepitiostane, and testolactone; antiadrenergics, e.g., aminoglutethimide, mitotane, trilostane; antiandrogens, e.g., bicalutamide, flultamide, and nilutamide; antiestrogens, e.g., arzoxifene, droxifene, fulvestrant, idoxifene, tamoxifen, and toremifene; antiprogestins, e.g., onapristone; aromatase inhibitors, e.g., azotamide, bromobutane ... minoglutethimide, anastrozole, exemestane, fadrozole, formestane, letrozole and vorozole; estrogens such as diethylstilbestrol, fosfestrol, hexestrol and polyestradiol phosphate; LH-RH analogues such as abarelix, buserelin, cetrorelix, goserelin, leuprolide and triptorelin; progestogens such as chlormadinone acetate, medroxyprogesterone and megestrol acetate; and somatostatin analogues such as lanreotide.Such anti-cancer agents also include, but are not limited to, antineoplastic photosensitizers such as 6-aminolevulinic acid, methyl aminolevulinate, motexafin lutetium, porfimer sodium, talaporfin, and temoporfin; 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-aspartic acid (PALA), semustine, tenipside, testosterone propionate, thiotepa, trimethylmelamine, and uridine. Additional chemotherapeutic agents include, but are not limited to, compounds listed in The Merck Index, 14th Edition (2006), Cancer Chemotherapy Drug Regimens, which is incorporated herein by reference, such as mesna, prednisolone, prednisone, raloxifene, etc.For example, in various embodiments, the anti-cancer agent is a chemotherapeutic agent selected from the following: alkylating agents, such as alkylsulfonates, e.g., busulfan, improsulfan, and piposulfan; aziridines, e.g., carboquone, diaziquone, mitomycin-C, and uredepa; ethylenimines and methylmelamines, e.g., altretamine, triethylenemelamine, triethylenephosphoramide, and triethyleneethyphosphoramide; nitrogen mustards, e.g., bendamustine, canfosfamide, chlorambucil, chlornaphazine, cyclophosphamide, estramustine, glufosfamide, ifosfamide, methylmelamine ... Chlorethamine, mechlorethamine oxide hydrochloride, melphalan, perfosfamide, prenimustine, trichlormethine, trofosfamide, uracil mustard, nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, dacarbazine, etoglucide, mitobronitol, mitolactol, pipobroman, procarbazine, lomustine, and temozolomide; anthracyclines such as aclacinomycin, amrubicin, carubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, barubicin, and zorubicin.

[0149] In various embodiments, the refractory cancer to be treated or prevented is refractory to a cancer treatment, such as, in various embodiments, a cancer treatment that includes administration of one or more anti-cancer agents and / or radiation therapy.

[0150] In various embodiments, the cancer treatment comprises administration of one or more anti-cancer agents, e.g., anti-cancer agents selected from chemotherapeutic agents and / or radiotherapeutic agents. For example, in various embodiments, the cancer treatment comprises administration of one or more anti-cancer agents, where the anti-cancer agents are selected from those mentioned in the discussion above in the context of anti-cancer agent-resistant cancers.

[0151] In various embodiments, the cancer treatment is platinum-based chemotherapy consisting of administering one or more platinum-based chemotherapeutic agents, optionally in combination with one or more other anti-cancer agents. For example, in various embodiments, the platinum-based chemotherapy can include administering one or more platinum-based chemotherapeutic agents selected from carboplatin, cisplatin, lobaplatin, oxaliplatin, picoplatin, nedaplatin, phenanthriplatin, and satraplatin. In various embodiments, the platinum-based chemotherapy includes administering carboplatin, cisplatin, and / or oxaliplatin.

[0152] In various embodiments, the cancer treatment is radiation therapy. Thus, in various embodiments, the refractory cancer or cancer cells to be treated or prevented are refractory to radiation therapy.

[0153] In various embodiments, the radiation therapy is external radiation therapy or internal radiation therapy.

[0154] Without being bound by theory, reactive oxygen species (ROS) can be increased after exposure to physical factors such as UV radiation and heat, as well as after chemotherapy and radiotherapy. There are multiple mechanisms by which ROS can be increased, including direct generation of ROS and interference with the antioxidant system.

[0155] Without being bound by theory, long-term cancer treatment with anticancer drugs induces ROS accumulation. One mechanism by which chemotherapy-resistant cells tolerate high ROS levels is by activating the kynurenine (KYN) pathway upon excessive oxidative stress to alleviate ROS-induced damage. Again, without being bound by theory, high ROS levels are a hallmark of cisplatin-resistant (CR) lung cancer cells.

[0156] Without being bound by theory, one mechanism by which the dual IDO1 and TDO inhibitor of the present invention may exert a therapeutic effect is to cause further ROS accumulation in refractory cancer cells, resulting in ROS-induced cell death in the cells.

[0157] In various embodiments, the mechanism of resistance of the refractory cancer or cancer cells to be treated or prevented is resistance to ROS-induced cell death, for example ROS-dependent programmed cell death (PCD).

[0158] Thus, the methods and uses described herein may be useful for the treatment or prevention of refractory cancers, which are refractory to anti-cancer agents and / or cancer therapies that induce ROS accumulation in cancer cells, such as anti-cancer agents and / or cancer therapies that induce ROS-dependent programmed cell death (PCD) in cancer cells. In various embodiments, the anti-cancer agents and / or cancer therapies are characterized by inducing ROS accumulation in cancer cells, and the refractory cancers are characterized by being resistant to said ROS accumulation.

[0159] The dual inhibitor of IDO1 and TDO of the present invention can treat or prevent a wide range of refractory cancers or cancer cells. Refractory cancers or cancer cells that can be treated or prevented according to the present invention include, but are not limited to, colon cancer, breast cancer, melanoma, reproductive cancer, respiratory cancer, brain tumor, digestive cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and / or distant metastasis thereof. These diseases also include lymphoma, sarcoma, and leukemia.

[0160] Examples of refractory breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0161] Examples of refractory cancers of the respiratory tract include, but are not limited to, small cell lung cancer, non-small cell lung cancer, bronchial adenoma, and pleuropulmonary blastoma.

[0162] Examples of refractory brain tumors include, but are not limited to, glioblastoma, brainstem / low tension glioma, cerebellar / cerebral astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor, and pineal tumor.

[0163] Refractory tumors of the male reproductive system include, but are not limited to, prostate cancer and testicular cancer.

[0164] Refractory tumors of the female reproductive tract include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, ovarian adenocarcinoma, vaginal cancer, vulvar cancer, and uterine sarcoma.

[0165] Refractory gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

[0166] Refractory urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, and urethral cancer.

[0167] Refractory eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0168] Examples of refractory liver cancer include, but are not limited to, hepatocellular carcinoma (with or without fibrotrabecular variant), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular-cholangiocarcinoma.

[0169] Refractory skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0170] Refractory head and neck cancers include, but are not limited to, laryngeal / hypopharyngeal / nasopharyngeal / oral cavity cancer, and lip / oral cavity cancer.Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.

[0171] Refractory sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0172] The refractory cancer may be a solid cancer or a liquid cancer. In various embodiments, the refractory cancer is a solid cancer.

[0173] Although these diseases are well characterized in humans, they also exist in other warm-blooded animals with similar etiology and can be treated with the compounds of the present invention.

[0174] Thus, in various embodiments, the present invention provides methods of treating or preventing a refractory cancer, or cells thereof, wherein the cancer is selected from one or more of the cancers listed above and is refractory to anti-cancer agents and / or cancer treatments.

[0175] In various embodiments, the refractory cancer or refractory cancer cell is refractory breast cancer, refractory respiratory cancer, refractory brain tumor, refractory male reproductive tumor, refractory female reproductive tumor, refractory gastrointestinal tumor, refractory urinary tract tumor, refractory eye cancer, refractory liver cancer, refractory skin cancer, refractory head and neck cancer, refractory lymphoma, refractory sarcoma, or refractory leukemia, such as those listed above. In various embodiments, the cancer is a solid tumor. In another embodiment, the cancer is a liquid tumor.

[0176] In various embodiments, the present invention provides methods of treating or preventing refractory lung cancer, refractory pancreatic cancer, refractory ovarian cancer, or refractory breast cancer.

[0177] In various embodiments, in the methods of treating a refractory cancer or a refractory cancer cell, the subject or cancer cells have previously been administered an anti-cancer agent, and the refractory cancer or cancer cells are refractory to said anti-cancer agent.

[0178] The dual inhibitors of IDO1 and TDO described herein are also useful for preventing the development of refractory cancers or refractory cancer cells, e.g., in various embodiments, preventing the development of refractory cancers or refractory cancer cells from cancers or cancer cells that are not refractory to the anti-cancer agents and / or treatments.

[0179] In various embodiments, a method for preventing the development of cancer or cancer cells refractory to anti-cancer agents and / or cancer treatments comprises administering a dual inhibitor of IDO1 and TDO in combination with an anti-cancer agent and / or cancer treatment, where the dual inhibitor and the anti-cancer agent and / or cancer treatment may be administered simultaneously, sequentially, or separately, and may be administered in a single formulation or in separate formulations, as appropriate.

[0180] In various embodiments, the method of preventing the development of a refractory cancer or refractory cancer cells further comprises administering one or more additional anti-cancer agents and / or cancer treatments in combination with the dual inhibitor of IDO1 and TDO and the anti-cancer agent and / or cancer treatment against which it is desired to prevent the cancer or cancer cells from becoming refractory. The dual inhibitor, the anti-cancer agent and / or cancer therapeutic, and the one or more additional anti-cancer agents and / or cancer therapeutics may be administered simultaneously, sequentially, or separately, and may be administered in a single formulation or in separate formulations, as appropriate.

[0181] For example, in various embodiments, the present invention provides a method for preventing the development of cancer or cancer cells refractory to a platinum-based chemotherapy agent, comprising administering a dual inhibitor of IDO1 and TDO in combination with a platinum-based chemotherapy agent.

[0182] In another aspect, the present invention provides a method for increasing the effectiveness of an anti-cancer agent and / or cancer therapy, comprising administering to a subject with cancer therapeutically effective amounts of (a) a dual inhibitor of IDO1 and TDO, and (b) the anti-cancer agent and / or therapy.

[0183] In another aspect, the present invention provides a method for increasing the sensitivity of a refractory cancer or refractory cancer cells to an anti-cancer agent and / or cancer treatment, the method comprising administering to a subject or refractory cancer cells an effective amount of (a) a dual inhibitor of IDO1 and TDO, and (b) an anti-cancer agent and / or cancer treatment.

[0184] The dual inhibitors of IDO1 and TDO described herein are also expected to be useful in preventing the development of refractory cancer in a subject having a cancer at risk of becoming refractory to an anti-cancer agent and / or cancer treatment. Accordingly, in some embodiments, the present invention provides a method of preventing the development of refractory cancer in a subject having a cancer at risk of becoming refractory to an anti-cancer agent and / or cancer treatment, comprising administering to the subject therapeutically effective amounts of (a) a dual inhibitor of IDO1 and TDO, and (b) an anti-cancer agent and / or cancer treatment.

[0185] Cancer or cancer cells at risk of becoming refractory to anticancer drugs and / or anticancer drug treatment include cancer or cancer cells with a significant high risk or probability of becoming refractory to anticancer drugs and / or anticancer drug treatment.For example, it is understood that in certain cancers treated with platinum-based chemotherapeutic agents, there is a high risk of the cancer becoming refractory to said platinum-based chemotherapeutic agents.In such a situation, it would be advantageous to administer the dual inhibitor of IDO1 and TDO of the present invention in combination with platinum-based chemotherapeutic agents to prevent the occurrence of refractory cancer.

[0186] The methods of preventing the development of refractory cancers or refractory cancer cells described herein thus provide or enable the treatment of cancers or cancer cells at risk of becoming refractory to anti-cancer agents and / or treatments with anti-cancer agents. In various embodiments, the methods of preventing the development of refractory cancers further comprise treating cancers or cancer cells at risk of becoming refractory to anti-cancer agents and / or treatments.

[0187] For example, in various embodiments, the method is for preventing the development of a refractory cancer in a subject having a cancer at risk of becoming refractory to a platinum-based chemotherapeutic agent, comprising administering to the individual therapeutically effective amounts of (a) a dual inhibitor of IDO1 and TDO and (b) a platinum-based chemotherapeutic agent.

[0188] In various embodiments, a method for preventing the development of a refractory cancer comprises administering to a subject or cancer cells a dual inhibitor of IDO1 and TDO in combination with an anti-cancer agent and / or cancer treatment, wherein the respective amounts of the dual inhibitor of IDO1 and TDO and the anti-cancer agent and / or cancer treatment are effective to prevent or delay the development of cellular resistance to the anti-cancer agent and / or cancer treatment.

[0189] In various embodiments, a method of treating a refractory cancer or a refractory cancer cell refractory to an anti-cancer agent and / or cancer treatment comprises administering a dual inhibitor of IDO1 and TDO in combination with an anti-cancer agent and / or cancer treatment. The dual inhibitor and the anti-cancer agent and / or cancer treatment may be administered simultaneously, sequentially, or separately, and may be administered in a single formulation or in separate formulations, as appropriate.

[0190] In various embodiments, the anti-cancer agent and / or cancer therapy administered in combination with the dual inhibitor of IDO1 and TDO is an anti-cancer agent and / or cancer therapy as mentioned in the above discussion in the context of cancer refractory to the anti-cancer agent and / or cancer therapy.

[0191] In various embodiments, the dual inhibitor of IDO1 and TDO and the anti-cancer and / or cancer therapeutic agent can optionally be administered in combination with one or more additional anti-cancer and / or cancer therapeutic agents.

[0192] The dual inhibitors of IDO1 and TDO described herein are also expected to be useful in treating refractory cancers, either alone or in combination with one or more anti-cancer agents and / or cancer treatments. Thus, in various embodiments, a method of treating a refractory cancer or refractory cancer cells comprises administering a dual inhibitor of IDO1 and TDO in combination with one or more additional anti-cancer agents and / or cancer treatments. The dual inhibitor and the one or more additional anti-cancer agents and / or cancer treatments can be administered simultaneously, sequentially, or separately, and can be administered in a single formulation or in separate formulations, as appropriate.

[0193] In various embodiments, the one or more additional anti-cancer agents and / or cancer therapies are, for example, as mentioned in the above discussion in the context of refractory cancer. For example, in various embodiments, the one or more additional anti-cancer agents may be platinum-based chemotherapeutic agents, such as platinum complexes. For example, in various embodiments, the platinum-based chemotherapeutic agents are selected from carboplatin, cisplatin, lobaplatin, oxaliplatin, picoplatin, nedaplatin, phenanthriplatin, and / or satraplatin. In certain examples, the platinum-based chemotherapeutic agents are selected from cisplatin, carboplatin, and / or oxaliplatin.

[0194] Dual IDO1 and TDO inhibitors can also be administered in combination with radiation therapy or radiotherapeutic agents.

[0195] In various embodiments, the one or more additional anti-cancer agents and / or cancer therapies are selected from the group consisting of chemotherapeutic agents, immunomodulatory agents such as anti-cancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapy (e.g., chimeric antigen receptor T cells (CART cells)), and radiation therapy.

[0196] Suitable one or more additional anti-cancer drugs will be clear to those skilled in the art, for example, considering the cancer to be treated.Many anti-cancer drugs are known in the art.Examples of suitable anti-cancer drugs include those listed in Cancer: Principles and Practice of Oncology, 7th Edition, Devita et al, Lippincott Williams & Wilkins, 2005, which is incorporated herein by reference.

[0197] In various embodiments, the one or more additional anti-cancer agents induce an increase in ROS in the cancer cells. In various embodiments, the one or more additional anti-cancer agents induce reactive oxygen species (ROS)-dependent programmed cell death (PCD) in the cancer cells.

[0198] In various embodiments, the one or more additional anti-cancer agents include, but are not limited to, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, collaps, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomus. The chemotherapeutic agent is selected from the compounds listed in The Merck Index, 14th Edition (2006), Cancer Chemotherapy Drug Regimens, which is incorporated herein by reference, such as rifampin, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.

[0199] In various embodiments, the one or more additional anti-cancer agents are anti-proliferative agents, selected from, but not limited to, BCNU, CCNU, DTIC, and actinomycin D. Additional anti-proliferative agents include, but are not limited to, compounds approved for use in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Eleventh Edition), editors Molinoff et al., publ. by McGraw-Hill, pages 1225-1287 (2006), which is incorporated herein by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinylestradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate fluoro. Darabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartic acid (PALA), plicamycin, semustine, tenipuzide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.

[0200] In various embodiments, the one or more additional anti-cancer agents are anti-proliferative agents selected from, but not limited to, other molecular targeted agents that inhibit the proliferation of cancer cells by inhibiting specific target molecules required for carcinogenesis and tumor growth, such as small molecule protein and lipid kinase inhibitors, monoclonal antibodies, molecular targeted humanized monoclonal antibodies, monoclonal antibody drug conjugates, etc. Examples of such inhibitors include: rituximab, trastuzumab, alemtuzumab, tositumomab-I131, cetuximab, ibritumomab tiuxetan, bevacizumab, panitumumab, ofatumumab, ipilimumab, brentuximab vedotin, pertuzumab, Ado-trastuzumab emtansine, ramucirumab, obinutuzumab, nivolumab, penicillin, ribozyme ... Brolizumab, dinutuximab, imatinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapatinib, nilotinib, pazopanib, crizotinib, ruxolitinib, vandetanib, vemurafenib, axitinib, bosutinib, cabozantinib, ponatinib, regorafenib, tofacitinib, afatinib, dabrafenib, ibrutinib, trametinib.

[0201] In various embodiments, the one or more additional anti-cancer agents are immunomodulatory agents. For example, in various embodiments, the immunomodulatory agent is selected from, but not limited to, an anti-cancer vaccine, an agent that modulates immune checkpoint proteins (such as CTLA4, PD1-4s, PD-L1), and adoptive T cell therapy (such as CART). In various embodiments, the one or more additional anti-cancer agents are CTLA4 inhibitors, anti-PD-1 antibodies, or anti-PD-L1 antibodies. For example, in various embodiments, the one or more additional anti-cancer agents are CTLA4 inhibitors, such as ipilimumab, anti-PD-1 antibodies, such as cemipramab, nivolumab, and / or pembrolizumab, or anti-PD-L1 antibodies, such as atezolizumab, avelumab, and / or durvalumab.

[0202] The dual inhibitor of IDO1 and TDO may be administered simultaneously, sequentially, or separately with one or more additional anti-cancer agents, therapeutic agents, and / or immunomodulatory agents. The dual inhibitor of IDO1 and TDO and the one or more additional anti-cancer agents and / or immunomodulatory agents may be administered in a single formulation or in separate formulations.

[0203] Thus, dual inhibitors of IDO1 and TDO can be administered alone or in combination with one or more other anti-cancer agents or therapies, either simultaneously or sequentially depending on the particular cancer being treated.

[0204] In various embodiments, the one or more additional cancer therapies comprises administering one or more additional anti-cancer agents, hi various embodiments, the one or more additional cancer treatments is radiation therapy.

[0205] In various embodiments, the one or more additional cancer therapies is an immunotherapy selected from ipilimumab (an inhibitor of CTLA4), nivolumab, and pembrolizumab (both inhibitors of PD-1).

[0206] Dual inhibitor of IDO1 and TDO Broadly, the present invention relates to the use of dual inhibitors of IDO1 and TDO for the treatment or prevention of refractory cancers.

[0207] The term "dual inhibitor of IDO1 and TDO" and similar terms such as "dual inhibitor of IDO1 and TDO" refer to a compound that inhibits the enzymatic activity of IDO1 and inhibits the enzymatic activity of TDO, particularly a compound that inhibits the cellular enzymatic activity of IDO1 and inhibits the cellular enzymatic activity of TDO, e.g., ... 50 , and a cellular TDO IC of less than 100 μM 50 The compound having the formula:

[0208] Unless otherwise specified, the inhibition of the intracellular enzyme activity of IDO1 and the inhibition of the intracellular enzyme activity of TDO were measured by the methods described in the Examples of this specification.

[0209] In various embodiments, the dual inhibitors of IDO1 and TDO described herein have a cellular IDO1 IC of less than 100 μM, less than 90 μM, less than 80 μM, less than 70 μM, or less than 60 μM as determined by the cell-based assay for IDO1 inhibition described in the Examples. 50 having a cellular IDO1 IC of less than 50 μM, less than 40 μM, less than 30 μM, less than 20 μM, less than 15 μM, less than 10 μM, or less than 1 μM 50 has a cellular TDO IC of less than 100 μM, less than 90 μM, less than 80 μM, less than 70 μM, less than 60 μM, less than 50 μM, less than 40 μM, less than 30 μM, less than 20 μM, less than 15 μM, less than 10 μM, or less than 1 μM as determined by the cell-based assay for TDO inhibition described in the Examples; 50 In various embodiments, the dual IDO1 and TDO inhibitors described herein have a cellular IDO1 IC of less than 10 μM, as determined by the cell-based assay for IDO1 inhibition described in the Examples. 50 has a cellular TDO IC of less than 10 μM as determined by the cell-based assay for TDO inhibition described in the Examples; 50 has.

[0210] In various embodiments, the dual IDO1 and TDO inhibitors described herein have a cellular IDO1 IC of less than 10 μM, less than 9 μM, less than 8 μM, less than 7 μM, less than 6 μM, less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM and / or less than 0.1 μM as determined by a cell-based assay for IDO1 inhibition described in the Examples. 50has a cellular TDO IC of less than 10 μM, less than 9 μM, less than 8 μM, less than 7 μM, less than 6 μM, less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM and / or less than 0.1 μM as determined by a cell-based assay for TDO inhibition described in the Examples; 50 In various embodiments, the dual inhibitors of IDO1 and TDO described herein have a cellular IDO1 IC of less than 1 μM, as determined by the cell-based assay for IDO1 inhibition described in the Examples. 50 has a cellular TDO IC of less than 1 μM as determined by the cell-based assay for TDO inhibition described in the Examples; 50 has.

[0211] In various embodiments of the invention, the dual inhibitors of IDO1 and TDO described herein have a cellular IDO1 IC of less than 1 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM and / or less than 0.1 μM as determined by the cell-based assay for IDO1 inhibition described in the Examples herein. 50 has a cellular TDO IC of less than 1 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM and / or less than 0.1 μM as determined by a cell-based assay for TDO inhibition described in the Examples herein; 50 Yes.

[0212] In various embodiments, the dual inhibitors of IDO1 and TDO described herein have a cellular TDO inhibitory activity that is greater than or equal to the IDO1 inhibitory activity. In certain embodiments, the dual inhibitors of IDO1 and TDO have a cellular TDO IC 50 Higher or equal cellular IDO1 IC 50 has.

[0213] In various embodiments, the dual inhibitor of IDO1 and TDO is a 3-aminoisoxazole, preferably a 3-aminoisoxazole fused to a 6-membered aromatic ring containing at least one ring nitrogen atom, such as certain compounds of formula I as described herein.

[0214] As described in detail in PCT / IB2015 / 056129, which is incorporated herein by reference, the compounds of formula I have been found to be inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and / or tryptophan 2,3-dioxygenase (TDO).

[0215] In various embodiments, the dual inhibitors of IDO1 and TDO used in the present invention are compounds of general formula I having IDO1 and TDO inhibitory activity.

[0216] A compound as defined in paragraphs (1) to (49) of the Summary of the Invention, which has dual IDO1 and TDO inhibitory activity, can be used in any of the methods, uses and other aspects of the invention described herein. Thus, in various embodiments of the invention, a dual IDO1 and TDO inhibitor is a compound as defined in paragraphs (1) to (49), which has IDO1 and TDO inhibitory activity.

[0217] A dual IDO1 and TDO inhibitor as defined in paragraphs (46) to (49) of the Summary of the Invention can be used in any of the methods, uses and other aspects of the invention described herein. Thus, in various embodiments, the dual IDO1 and TDO inhibitor is a compound as defined in paragraphs (46) to (49).

[0218] In various embodiments, the dual inhibitor of IDO1 and TDO is a compound defined in paragraphs (48)-(49).

[0219] In various embodiments, the dual inhibitor of IDO1 and TDO is 6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (also referred to herein as compound (66) or AT-0174).

[0220] Compounds of formula I can be prepared according to the methods described in PCT International Patent Application No. PCT / IB2015 / 056129 (published as WO2016024233), which is incorporated herein by reference, or procedures analogous thereto. Those skilled in the art will appreciate that other dual inhibitors of IDO1 and TDO are also suitable for use in the present invention.

[0221] Other inhibitors of IDO1 and / or TDO and methods for their preparation are described in PCT International Patent Application No. PCT / NZ2016 / 050135 (published as WO2017034420), which is incorporated herein by reference.

[0222] Compounds 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: 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea (2B) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-chlorophenyl)urea (6B) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-chlorophenyl)urea (7B) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-chlorophenyl)urea (8B) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-(trifluoromethoxy)phenyl)urea (9B) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-(trifluoromethoxy)phenyl)urea (10B) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-methoxyphenyl)urea (12B) N-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-phenylacetamide (18B) N-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide (19B) Phenyl (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)carbamate (4B) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-(trifluoromethyl)phenyl)urea (15B) 4-Fluorophenyl (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)carbamate (5B) N-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)acetamide (20B), and pharma-ceutically acceptable salts thereof.

[0223] Dual inhibitors of IDO1 and TDO suitable for use in the present 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).

[0224] Administration Those skilled in the art will understand that a particular treatment method for administering the dual inhibitors of IDO1 and TDO described herein will employ a selected route of administration, which will depend on various factors routinely considered when administering therapeutic agents. It will further be understood that the optimal course of treatment or prophylaxis, i.e., the mode of treatment and the number of daily doses of the compounds of the present invention administered over a specified number of days, can be ascertained by those skilled in the art using conventional treatment trials.

[0225] Therapeutic doses of the dual IDO1 and TDO inhibitors described herein will likely range from 1 mg to 2000 mg per day.

[0226] In various embodiments, the dose of the dual inhibitor of IDO1 and TDO ranges from 1-100 mg per day, 100-200 mg per day, 200-300 mg per day, 300-400 mg per day, 400-500 mg per day, 500-600 mg per day, 600-700 mg per day, 700-800 mg per day, 800-900 mg per day, or 900-1000 mg per day. In various embodiments, the dose of the dual inhibitor of IDO1 and TDO is in the range of 1000-1100 mg per day, 1100-1200 mg per day, 1200-1300 mg per day, 1300-1400 mg per day, 1400-1500 mg per day, 1500-1600 mg per day, 1600-1700 mg per day, 1700-1800 mg per day, 1800-1900 mg per day, or 1900-2000 mg per day.

[0227] In various embodiments, the dose of the dual inhibitor of IDO1 and TDO ranges from 1 mg to 50 mg / day, 50 mg to 100 mg / day, 201 mg to 250 mg / day, 250 mg to 300 mg / day, 300 mg to 350 mg / day, 350 mg to 400 mg / day, 400 mg to 450 mg / day, 450 mg to 500 mg / day, 500 mg to 550 mg / day, 550 mg to 600 mg / day, 600 mg to 650 mg / day, 650 mg to 700 mg / day, 700 mg to 750 mg / day, 750 mg to 800 mg / day, 800 mg to 850 mg / day, 850 mg to 900 mg / day, 900 mg to 950 mg / day, or 950 mg to 1000 mg / day.

[0228] The specific dose level selected for a particular patient will depend on a variety of factors, such as the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the condition being treated.

[0229] The dosage of the active ingredient in the pharmaceutical composition can be varied to provide an amount of the active ingredient effective to achieve the desired therapeutic effect for a particular patient, composition, and mode of administration, without causing toxicity to the patient (an effective amount).

[0230] Pharmaceutical Compositions A dual inhibitor of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO) may be formulated or presented for use as a pharmaceutical composition comprising a dual inhibitor of IDO1 and TDO and a pharma- ceutically acceptable carrier.

[0231] "Pharmaceutically acceptable carrier" refers to a generally safe carrier (such as an adjuvant, buffer, stabilizer, vehicle, etc.) that may be administered to a subject together with a dual inhibitor of IDO1 and TDO. A pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabilizer should be non-toxic and should not interfere with the efficacy of the active ingredient. The term "pharmaceutically acceptable carrier" includes carriers suitable for veterinary use as well as human pharmaceutical use. The exact nature of the carrier or other material will depend on the route of administration.

[0232] The dual inhibitors of IDO1 and TDO can be administered orally, topically, parenterally, by inhalation or aerosol, or rectally in a dosage unit formulation. The term "administration by injection" includes intravenous, intramuscular, subcutaneous, and parenteral injections, as well as the use of infusion techniques. The compound or compounds can be present in association with one or more non-toxic pharmaceutically acceptable carriers and, optionally, other active ingredients.

[0233] Compositions intended for oral use can be prepared according to any suitable method known in the art for the manufacture of pharmaceutical compositions. Such compositions can contain one or more agents selected from the group consisting of diluents, sweeteners, flavoring agents, coloring agents, and preservatives to provide a palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharma- ceutically acceptable excipients suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch, alginic acid; and binding agents such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be employed. These compounds can also be prepared in a solid, fast-release form.

[0234] Oral formulations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0235] Aqueous suspensions contain the active substances mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents are naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearates, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0236] 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, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0237] Compounds may also be in the form of non-aqueous liquid preparations, for example, oily suspensions, which are prepared by suspending active ingredients in vegetable oils, such as arachis oil, olive oil, sesame oil, peanut oil, or mineral oils, such as liquid paraffin.Oily suspensions may contain thickening agents, such as beeswax, hard paraffin, cetyl alcohol, etc. In order to provide a palatable oral preparation, sweeteners, flavorings, as mentioned above, may be added.These compositions may be preserved by the addition of antioxidants, such as ascorbic acid.

[0238] The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylenesorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0239] Syrups and elixirs may contain sweetening agents, for example glycerol, propylene glycol, sorbitol, sucrose, etc. Such preparations may also contain an anti-inflammatory agent, a preservative, a flavoring or a coloring agent.

[0240] The compound can also be administered in the form of a suppository for rectal administration of the drug. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0241] kit Dual inhibitors of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO) may be formulated or provided for use as kits that include one or more dual inhibitors of IDO1 and TDO; and optionally one or more additional therapeutic agents; and instructions for using the dual inhibitors in the described methods. In various embodiments, the therapeutic agent is an anti-cancer agent as described herein.

[0242] The dual inhibitor of IDO1 and TDO is usually in the form of a pharmaceutical composition and is contained in a container. The container may be any container or other closed or sealable device capable of holding a pharmaceutical composition. Examples include bottles, ampoules, divided or multi-chambered holder bottles, each division or chamber constituting a single dose of the composition, divided foil packets, each division constituting a single dose of the composition, or dispensers that dispense single doses of the composition. The container may be of any conventional shape or form, made of pharma- ceutically acceptable material, for example, a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag, or a blister pack with individual doses for pushing out of the pack according to the treatment schedule. The container employed usually depends on the dosage form involved. For one dosage form, multiple containers may be used together in one package.

[0243] The kit may also include a device for administering or measuring a unit dose of the pharmaceutical composition, which 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 container with or without volume label if the composition is an oral liquid composition, or other measuring or delivery device appropriate to the dosage form of the composition present in the kit.

[0244] In various embodiments, the kit can include, for example, in a separate container or containers, one or more additional therapeutic agents, typically in the form of a pharmaceutical composition including the additional therapeutic agent and a pharma- ceutically acceptable carrier. The additional therapeutic agent can be selected from those indicated herein for co-administration with the dual inhibitors of IDO1 and TDO described herein.

[0245] The above methods should in no way be considered limiting, and suitable modifications and alternatives will be apparent to those skilled in the art. EXAMPLES

[0246] The following non-limiting examples are offered to illustrate the present invention and are not intended to limit its scope in any way.

[0247] Example 1 Enzymatic assay of IDO1 activity Recombinant human IDO1 (rhIDO1) was expressed and purified from cultures of E. coli EC538 transformed with pREP4 and pQE9-IDO plasmids. 15 μL of rhIDO1 (9 nM final concentration) was mixed in a total volume of 30 μL of assay solution in a 384-well microplate containing 50 mM phosphate buffer, 10 mM ascorbic acid, 10 μM methylene blue, 100 μg / mL catalase, 80 μM TRP, 0.01% Tween® 20 (v / v). The plate was incubated at 37°C for 30 min, the enzyme reaction was stopped by adding piperidine (200 mM) and heated at 65°C for 20 min. Fluorescence intensity was read at λex 400 nm and λem 500 nm. Test compounds were dissolved in 100% DMSO and pre-diluted in assay medium before adding rhIDO1. The IDO1 inhibition rate (%) was calculated as follows:

[0248]

number

[0249] All experiments were performed in triplicate, and statistical analysis was performed using Prism v5 (Graphpad Software, Inc, La Jolla, CA, USA).

[0250] Cell-based assay for IDO1 inhibition To assay inhibition of cellular IDO1 activity, Lewis lung carcinoma cells transfected to express human IDO1 (LLTC-hIDO1) or mouse IDO1 (LLTC-mIDO1) were incubated with test compounds at 37°C, 5% CO. 2 The cells were cultured at 480 nm for 24 h. The culture supernatant from each well was transferred to a new flat-bottom 96-well plate, mixed with trichloroacetic acid (final concentration 10%), and incubated at 60°C for 20 min. The plate was then centrifuged (2500 g for 10 min), and the supernatant was 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% of the cellular enzyme activity was calculated.

[0251] The viability of cells in each well in the same experiment was measured using a 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. After removing the supernatant to measure IDO1 inhibition, the cells were incubated with MTT (500 μg / mL) until crystal formation was observed. The plates were centrifuged at 2500 g for 15 min, and all the supernatant in the wells was discarded. DMSO (100 μL / well) was added to dissolve the crystals, and the absorbance of each well was measured at 570 nm. The cell viability of each well was expressed as a percentage of the untreated control. Triplicate cultures were used for all experiments unless otherwise noted.

[0252] Cell-based assay for TDO inhibition To assay cellular TDO inhibition, GL261 cells transfected to overexpress full-length human TDO were incubated with test compounds at 37°C, 5% CO 2The cells were cultured at 4°C for 24 hours. Then, the culture supernatant from each well was transferred to a new flat-bottom 96-well plate, and the kynurenine content was measured in the same manner as in the IDO1 assay described above, and the concentration required for 50% inhibition of cellular enzyme activity was calculated.

[0253] The viability of cells in each well in the same experiment was measured using a 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay.

[0254] The results of the assay are shown in Table 1 below.

[0255] Compound activity

[0256] [Table 1-1]

[0257] [Table 1-2]

[0258] [Table 1-3]

[0259] [Table 1-4]

[0260] Example 2 - In vitro efficacy against parental and cisplatin-resistant human-derived lung cancer cells In this study, three different human-derived lung cancer cell lines were exposed to vehicle control (parental cells B, S, A) or long-term culture with cisplatin (BC, SC, ALC cells). Long-term culture with cisplatin induced cisplatin resistance in BC, SC, and ALC cell lines. AT-0174 killed cisplatin-treated cells with greater efficacy and potency than parental cells, indicating that AT-0174 is more effective in patients with acquired cisplatin resistance (see Table 2 and Figure 1).

[0261] method Growth inhibition and cytotoxicity assays Cells were seeded in 24-well dishes and treated with various concentrations of inhibitors (i.e., Epacadostat or AT-0174). Briefly, culture medium and trypsinized cells were harvested, and the mixture was centrifuged at 400 × g for 5 min. The supernatant was discarded and resuspended in 1 mL of Hank's buffer, and live and dead cells were measured using trypan blue exclusion.

[0262] statistical analysis Data from in vitro experiments were from three separate biological replicates, which were isolated and analyzed in technical triplicate, measured separately using two-tailed t-tests, and results are expressed as mean ± standard deviation.

[0263] result

[0264] [Table 2]

[0265] Example 3 - Inhibiting the kynurenine pathway in vivo using a dual IDO1 / TDO inhibitor (AT-0174) to alleviate immune suppression in the tumor microenvironment of cisplatin-resistant lung cancer In this study, we investigated and compared the in vivo antitumor effects of the selective IDO1 inhibitor Epacadostat and the dual IDO1 / TDO inhibitor AT-1074 against cisplatin-resistant (CR) cell tumors in a syngeneic mouse model of lung cancer.

[0266] method Cell lines and reagents Cisplatin-resistant mouse cell lines (LLC-CR) were derived from LLC (Mouse Lewis Lung Carcinoma (Epidermoid Carcinoma), ATCC) by intermittent treatment with increasing doses of cisplatin. LLC-CR clones had half the GI 50 Briefly, parental LLC cells were seeded in 6-well plates (4 × 10 4 ), 50% growth inhibition (GI 50 ) for 24 hours. Cultures were monitored daily and allowed to grow until they reached initial cell density. 50 A 1-2-fold increase in the concentration was observed within 1-2 weeks. After the cells had recovered from cisplatin toxicity, they were again treated with increasing doses of cisplatin for 24 hours. These cells were seeded at 500-1000 cells per dish and cultured for 5-7 days. Clones were selected, expanded, and their sensitivity to cisplatin was also tested. Similar exposures were repeated a third and fourth time to generate more resistant clones. Finally, resistant clones (LLC-CR) were cultured at 1 μg / ml (half GI 50 LLC-CR cells were maintained in medium supplemented with cisplatin at 1000 x 1000 μg / ml (1.3 μg / ml). LLC-CR cells were developed to be 3-5-fold resistant to cisplatin and carboplatin (~2 μg / ml and 1.3 μg / ml, respectively) and to have concurrent elevated IDO1 activity and sensitivity to IDO1 inhibitors (Nguyen DJM et al., Mol Cancer Res. 2020;18(1):105-117).

[0267] animal research LLC or LLC-CR(1×10 6 ) cells were injected subcutaneously into the flanks of C57B6 / J male and female mice (5 mice per group, 6-8 weeks old, Jackson laboratory) and allowed to grow for 3 days (mean tumor size = 50 mm 3). Then, the selective IDO1 inhibitor Epacadostat was administered at 200 mg / kg / day, or AT-0174 (a dual inhibitor of IDO1 and TDO enzymes) was administered at 170 mg / kg / day. Both compounds were administered orally (PO), diluted in 95% water + 5% methylcellulose (0.5%) and stored at -20°C. Compounds were prepared every 5 days. Methylcellulose (95 + 5%) was used as a control ("Veh"). Tumor growth was assessed by measuring tumor volume with a caliper every 2 days according to the following formula: tumor volume = width 2 × length × 0.5. After the study was completed, the mice were sacrificed and blood, tumors, and lymph nodes were collected for the measurement of KYN and tryptophan (TRP) and for the evaluation of immune cells, respectively.

[0268] Flow cytometry immune cell analysis Tumors or lymph nodes were harvested from mice and homogenized using a syringe plunger. A mesh filter (40 μM) was placed in a 15 mL or 50 mL tube to filter the tissue suspension. The cell filtrate was spun down at 1000 g. Red blood cell lysis buffer (1% ammonium oxalate) was added to the cell pellet and resuspended. The cell pellet was washed with PBS and separated. Tumors were isolated using the EasySep™ Mouse TIL (CD45) Positive Selection Kit (Stemcell Technologies). To detect regulatory T cells (T-regs) or natural killer cells (NKs), the EasySep™ Mouse CD25 Regulatory T Cell Positive Selection Kit and the EasySep™ Mouse CD49b Positive Selection Kit were used, respectively. The isolated cells were stained according to the manufacturer's instructions. Cells were also fixed with 2% paraformaldehyde and analyzed using a CytoFLEX flow cytometer (Beckman). All flow antibodies were obtained from Biolegend.

[0269] Measurement of KYN and TRP Blood samples were taken from sacrificed mice by cardiac puncture and the samples were analyzed for free amino acids using a Biochrom 30 amino acid analyzer (using ion exchange chromatography). Briefly, 200 μL of serum extract was mixed with an equal volume of 30% v / v deproteinizer (sulfosalicylic acid) and vortexed for 10 s. Samples were then incubated at 55 °C for 20 min and spun down at 2500 g for 20 min at 4 °C. The supernatant was collected, filtered through a 0.22 μm filter and injected into the Biochrom 30. Values ​​were reported relative to the normal range of the control group. Samples used in ion exchange chromatography are analytically separated using an ion exchange column and buffers of increasing pH and ionic strength. Chromatographically separated amino acids were detected after post-column derivatization with ninhydrin and recording of colorimetric intensities at 570 nm and 440 nm. Amino acid concentrations were calculated by comparing the peak area of ​​a particular amino acid to that of an internal standard-AEC of known concentration and multiplying by the specific response factor from the calibration curve.

[0270] result IDO1 inhibition or dual IDO1 / TDO inhibition affects tumor growth in syngeneic mouse models In this example, the Lewis lung mouse cell line (LLC; see Methods) LLC-CR was used to investigate the effect of IDO1 inhibition or dual IDO1 / TDO inhibition on tumor growth in vivo. Mice were inoculated with LLC or LLC-CR and treated with Epacadostat (200 mg / kg PO1 / day) or AT-0174 (170 mg / kg PO1 / day). C57B6 / J mice engrafted with LLC-CR showed increased T-reg (CD4 + CD25 + ) population, indicating a role for the kynurenine pathway (KP) and immunosuppressive tumor microenvironment (TME) in CR tumors (n=5; p<0.02) (Figure 2A).

[0271] Selective IDO1 inhibition with epacadostat reduced total tumor weight and suppressed tumor growth in CR xenografts compared to LLC mouse tumors (Table 3 and Figure 2B). However, AT-0174 significantly reduced tumor size (Table 3 and Figure 2B) and tumor weight (Figure 2C) in LLC-CR xenografted mice. Collectively, these data indicate that IDO1 / TDO inhibitors are superior to selective IDO1 inhibitors in inhibiting the kynurenine pathway.

[0272] [Table 3-1]

[0273] [Table 3-2]

[0274] Evaluation of tumor immune cells and TRP / KYN Antitumor immunity relies on checks and balances between cytotoxic cells (e.g., NK) and immune suppressive cells (e.g., T-reg). As shown in Figure 2A, LLC-CR had a significantly higher frequency of T-regs, suggesting that LLC-CR has adapted to evade immune surveillance. To examine whether inhibition of the kynurenine pathway could restore antitumor immunity in the CR tumor model, we measured T-effector, T-reg and NK populations after Epacadostat (EPA) or AT-0174 (AT) administration. The population of T-regs (CD4 + CD25 + FoxP3 + ) was significantly decreased in LLC-CR; however, it was notable that T-effector cells (CD3 + CD8 + ) and activated NK cells (CD3 - CD49b + NKG2D +) were found to be significantly higher in the treatment groups (Table 4 and Figure 3). In all cases, AT-1074 demonstrated greater immunostimulatory effects on these immune cell populations than the selective IDO1 inhibitor Epacadostat.

[0275] [Table 4]

[0276] This is important because kynurenine not only plays a key role in reprogramming naive T cells into T-reg cells, but it has also been shown that kynurenine impairs the ability of NK cells to kill target cells (Della Chiesa M, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, et al. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood. 2006;108(13):4118-25). Thus, AT-0174 was clearly shown to enhance NK cell activity by modulating NKG2D receptors in cisplatin-resistant cells.

[0277] Consistent with this finding, serum KYN / TRP ratio, a biomarker of IDO1 activity, was significantly decreased in LLC-CR treated with AT-0174 (Figure 4). At the same time, serum TRP levels were elevated in AT-0174 compared with epacadostat, confirming sustained inhibition of TDO-induced Trp degradation in normal tissues in vivo.

[0278] [Table 5]

[0279] Example 4 - Effect of AT-0174 on survival of mice bearing cisplatin-resistant synthetic syngeneic lung cancer tumors with or without co-treatment with anti-PD-1 antibody To investigate the synergistic effect of the dual IDO1 / TDO inhibitor AT-0174 and immune checkpoint inhibitors on the immune response against tumors, we performed a study using mice with cisplatin-resistant lung cancer, with and without an anti-PD1 antibody.

[0280] LLC-CR(1×10 6 ) cells were injected subcutaneously into the flank of C57B6 / J mice (6 mice per group, 8 weeks old) and allowed to grow for 3 days (mean tumor size = 50 mm 3 ). The IDO1 inhibitor Epacadostat was then administered at 200 mg / kg (supramaximal dose) or AT-0174 at 170 mg / kg daily. Both compounds were administered orally (PO) in 95% water + 5% methylcellulose (0.5%). Anti-mouse PD-1 MAb clone RMP1-14 was used as a checkpoint inhibitor and was injected intraperitoneally at 10 mg / kg every 3 days.

[0281] Comparing the effects of the dual inhibitor AT-0174 and the selective IDO1 inhibitor Epacadostat administered alone, we observed that AT-0174 extended survival more than the selective agent (Table 6 and Figure 5A). Administration of anti-PD1 antibody alone showed a similar survival improvement effect as AT-0174 or Epacadostat, but only showed a significant synergistic effect with AT-0174 (Figure 5B), and less synergistic effect with Epacadostat (Figure 5C). These data indicate that the previously observed effects on tumor growth and immune cell changes due to the tumor microenvironment translate into survival benefit in the same chemotherapy-resistant mouse model.

[0282] [Table 6]

[0283] Example 5 - Evaluation of the in vivo efficacy of AT-0174 in the mouse subcutaneous Pan02 syngeneic model of pancreatic cancer In this study, the efficacy of the test compound AT-0174 in combination with oxaliplatin was evaluated in the treatment of the Pan02 syngeneic model in female C57BL / 6 mice.

[0284] Methods and Materials Abbreviation Medication schedule 〇Qd Every day 〇B / W twice a week Route of Administration (ROA) 〇ip intraperitoneal 〇po Oral ●BW Weight ●BWL weight loss

[0285] research materials ●Oxaliplatin (Action: Positive control; Storage conditions: Room temperature) ●AT-0174 (Action: Test product; Storage conditions: 2~8℃) ● 5% glucose (Function: Vehicle for oxaliplatin) ●5% DMSO + 95% water (Action: Vehicle for AT-0174)

[0286] animal Female C57BL / 6 mice were used in the study and had free access to mouse food and water during the study period.

[0287] Cell culture and inoculation Mouse pancreatic Pan02 cancer cells were cultured in DMEM medium supplemented with 10% FBS under 5% CO 2 The cells were cultured in a 37°C incubator containing 1 × 10 6 PANC02 cells were placed in 100 µL of serum-free medium mixed with Matrigel (v / v 1:1) and inoculated subcutaneously into the right flank of each mouse while the mice were anesthetized with 2–5% isoflurane prior to inoculation.

[0288] Treatment group The dosing regimen is shown in Table 7.

[0289] [Table 7]

[0290] Dosage volume: Dosage volume was adjusted according to body weight (10 μL / g)

[0291] Preparation of test article dosing solutions

[0292] [Table 8]

[0293] Clinical Observations After grouping, the mice were observed daily for four weeks for general appearance and behavioral changes. After treatment was completed, the mice were observed for another week.

[0294] Measurement results Body weight: After group allocation, mice were weighed and recorded three times a week. Animals that died accidentally or were euthanized due to moribund conditions were also weighed.

[0295] Tumor volume: Tumor volume (V) was calculated as follows: V = (length × width) 2 After group allocation, tumor volumes were measured and recorded three times a week.

[0296] Individual relative tumor volumes (RTV) were calculated as follows: RTV=Vt / V0, where Vt is the volume on each day and V0 is the volume at the start of treatment.

[0297] FACS analysis On day 34, all tumor-bearing mice were sacrificed and tumors were harvested for FACS analysis. The FACS panel is as follows: Panel A: L / D, CD45, CD3, CD4, CD8, CD11b, CD25, IFN-γ, Foxp3. Panel B: L / D, CD45, CD3, CD11b, NKG2D, F4 / 80.

[0298] Flow cytometry was performed using standard methods using a Beckman Cytoflex LX and antibodies from Thermofisher and Biolegend.

[0299] statistics Comparisons between two groups were performed using Dunnett's multiple comparison test, and p<0.05 was considered significant.

[0300] result Body weight and clinical observations All animals tolerated the treatment well. Slight weight loss was observed when oxaliplatin was administered alone, but recovered after the 14th day. Mouse weights are shown in Table 8 and Figure 6. These results confirmed that mice tolerated oxaliplatin and oxaliplatin + AT-0174 administration without significant weight loss compared to the control.

[0301] [Table 9]

[0302] Tumor volume (TV) and relative tumor volume (RTV) The results of tumor volume in tumor-bearing mice are shown in Table 9 and Figure 7. The results of relative tumor volume in tumor-bearing mice are shown in Table 10 and Figure 8. These data indicate that compared with the vehicle group, chemotherapy oxaliplatin at 6 mg / kg BIW showed little antitumor effect during the treatment period, and the slight effect seen early in the treatment period disappeared after day 12. Compared with the vehicle group, the test compound AT-0174 at 120 mg / kg QD in combination with oxaliplatin 6 mg / kg BIW showed a significant reduction in tumor volume by day 32.

[0303] [Table 10]

[0304] [Table 11]

[0305] FACS analysis results The immune phenotype in Pan02 tumors is shown in Table 11 and Figure 9. The data show that oxaliplatin + AT-0174 combination therapy had a greater effect on immune cell changes than oxaliplatin monotherapy, significantly attenuating Treg expression.

[0306] [Table 12]

[0307] When a group of materials, compositions, ingredients, or compounds is disclosed herein, it is understood that each individual member of that group and all subgroups thereof are separately disclosed. When a Markush group or other grouping is used herein, each individual member of that group and all possible combinations and subcombinations of that group are intended to be included individually in the disclosure. Any formulation or combination of ingredients described or exemplified herein can be used to practice the present invention, unless otherwise specified.

[0308] All documents cited herein are incorporated by reference in their entirety, unless inconsistent with the disclosure herein. Some references provided herein are incorporated by reference to provide details regarding sources of starting materials, additional starting materials, additional reagents, additional synthetic methods, additional analytical methods, additional biological materials, additional cells, and additional uses of the present invention. All headings used herein are for convenience only. All patents and publications mentioned herein are indicative of the level of skill of those skilled in the art to which the present invention pertains, and are 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. It is intended that documents cited herein are incorporated by reference in their entirety to indicate the state of the art as of their publication or filing date, and that this information may be employed herein, if necessary, to exclude certain embodiments that are in the prior art.

[0309] Although the invention has been described by way of example and with reference to specific embodiments, it will be appreciated that modifications and / or improvements can be made without departing from the scope of the invention.

Claims

1. A dual inhibitor of indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO) for use in treating refractory cancer or preventing the onset of refractory cancer in a subject, comprising: wherein the dual inhibitor of IDO1 and TDO has a cellular IDO1 IC50 of less than 100 μM when determined by a cell-based assay for IDO1 inhibition; and has a cellular TDO IC50 of less than 100 μM when determined by a cell-based assay for TDO inhibition; A dual inhibitor of IDO1 and TDO is represented by Formula I: 【Chemistry 1】 [During the ceremony, (a) Z is N or N-oxide, for example N, W is CR 1 , X is CR 2 and Y is CR 3 ; or (b) X is N or N-oxide, for example N, W is CR 1 , Y is CR 3 and Z is CR 4 ; or (c) X and Z are both N or N-oxide, for example N, W is CR 1 and Y is CR 3 ; R 1 is selected from H, halo, —CHF 2 , —CF 3 or methyl; R 2 , R 3 and R 4 are each independently one of the following groups: H, halo, R, —OH, —OR, —OC(O)H, —OC(O)R, —OC(O)NH 2 , —OC(O)NHR, —OC(O)NRR, —OP(O)(OH) 2 , —OP(O)(OR) 2 , —NO 2 , —NH 2 , —NHR, —NRR, —NHC(O)H, —NHC(O)R, —NRC(O)R, —NHC(O)NH 2 , —NHC(O)NRR, —NRC(O)NHR, —SH, —SR, —S(O)H, —S(O)R, —SO 2 R, —SO 2 NH 2 , —SO 2 . selected from NHR, —SO 2 NRR, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —CN, —C≡CH, —C≡CR, —CH═CHR, —CH═CRR, —CR═CHR, —CR═CRR, —CO 2 H, —CO 2 R, —CHO, —C(O)R, —C(O)NH 2 , —C(O)NHR, —C(O)NRR, —CONHSO 2 H, —CONHSO 2 R, —CONRSO 2 R, cyclic C 3 -C 7 alkylamino, imidazolyl, C 1 -C 6 alkylpiperazinyl, morpholinyl and thiomorpholinyl; Alternatively, R 2 and R 3 together, or R 3 and R 4 together, may form a saturated, partially saturated, or fully unsaturated 5- or 6-membered ring of carbon atoms, optionally containing 1 to 3 heteroatoms selected from O, N, and S, the ring being optionally substituted independently with 1 to 4 substituents selected from R; Each R is independently a group defined in paragraphs (a) and (b) below: (a) optionally substituted C 1-6 alkyl groups, optionally substituted C 2-6 alkenyl groups, optionally substituted C 2-6 alkynyl groups, and optionally substituted C 3-7 cyclic alkyl groups; wherein one or more optional substituents on each of said alkyl groups, alkenyl groups, alkynyl groups, and cyclic alkyl groups are each independently selected from the following groups: halo, —OH, —OR 5 , —OC(O)R 5 , —OC(O)NH 2 , —OC(O)NHR 5 , —OC(O)NR 5 R 5 , —OP(O)(OH) 2 , —OP(O)(OR 5 ) 2 , —NO 2 , —NH 2 , —NHR 5 , —NR 5 R 5 , —N+(O—)R 5 R 5 , -NHC(O)H, -NHC(O)R 5 , -NR 5 C(O)R 5 , -NHC(O)NH 2 , -NHC(O)NR 5 R 5 , -NR 5 C(O)NHR 5 , -SH, -SR 5 , -S(O)H, -S(O)R 5 , -SO 2 R 5 , -SO 2 NH 2 , -SO 2 NHR 5 , -SO 2 NR 5 R 5 , -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 5 , -CHO, -C(O)R 5 , -C(O)NH 2 , —C(O)NHR 5 , —C(O)NR 5 R 5 , —CONHSO 2 H, —C(O)NHSO 2 R 5 , —C(O)NR 5 SO 2 R 5 , cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, and azetidinyl;Here, each of the imidazolyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, piperidinyl group, azepanyl group, pyrrolidinyl group and azetidinyl group is selected from the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cyclic alkyl, halo, —OH, —OR 7 , —OC(O)R 7 , —OC(O)NH 2 , —OC(O)NHR 7 , —OC(O)NR 7 R 7 , —OP(O)(OH) 2 , —OP(O)(OR 7 ) 2 , —NO 2 , —NH 2 , —NHR 7 , —NR 7 R 7 , —N + (O—)R 7 R 7 , -NHC(O)H, -NHC(O)R 7 , -NR 7 C(O)R 7 , -NHC(O)NH 2 , -NHC(O)NR 7 R 7 , -NR 7 C(O)NHR 7 , -SH, -SR 7 , -S(O)H, -S(O)R 7 , -SO 2 R 7 , -SO 2 NH 2 , -SO 2 NHR 7 , -SO 2 NR 7 R 7 , -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 7 , -CHO, -C(O)R 7 , -C(O)NH 2 , —C(O)NHR 7 , —C(O)NR 7 R 7 , —CONHSO 2 H, —C(O)NHSO 2 R 7 , —C(O)NR 7 SO 2 R 7 , optionally substituted aryl groups, and optionally substituted heteroaryl groups having up to 12 carbon atoms and having one or more heteroatoms each independently selected from O, N and S in their ring system;wherein one or more optional substituents for each of the aryl and heteroaryl groups are each independently selected from the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-7 cyclic alkyl, halo, —OH, —OR 8 , —OC(O)R 8 , —OC(O)NH 2 , —OC(O)NHR 8 , —OC(O)NR 8 R 8 , —OP(O)(OH) 2 , —OP(O)(OR 8 ) 2 , —NO 2 , —NH 2 , —NHR 8 , —NR 8 R 8 , —N + (O)R 8 R 8 , —NHC(O)H, —NHC(O)R 8 , —NR 8 C(O)R 8 , -NHC(O)NH 2 , -NHC(O)NR 8 R 8 , -NR 8 C(O)NHR 8 , -SH, -SR 8 , -S(O)H, -S(O)R 8 , -SO 2 R 8 , -SO 2 NH 2 , -SO 2 NHR 8 , -SO 2 NR 8 R 8 , -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 8 , -CHO, -C(O)R 8 , -C(O)NH 2 , -C(O)NHR 8 , -C(O)NR 8 R 8 , -CONHSO 2 H, -C(O)NHSO 2 R 8 , and -C(O)NR 8 SO; 2 R 8 ; wherein each R 5 , R 7 and R 8 is independently selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, and a C 3-7 cyclic alkyl group; and (b) optionally substituted aryl groups and optionally substituted heteroaryl groups having up to 12 carbon atoms and one or more heteroatoms in their ring system, each independently selected from O, N, and S, wherein the one or more optionally substituted groups are each independently selected from the same optionally substituted groups defined for R in (a) above. selected from any of the following: R 9 and R 10 are each independently a group defined in paragraphs (a) and (b) below: (a) H, optionally substituted C 1-6 alkyl groups, optionally substituted C 2-6 alkenyl groups, optionally substituted C 2-6 alkynyl groups, and optionally substituted C 3-7 cyclic alkyl groups, wherein one or more optional substituents for each of said alkyl, alkenyl, alkynyl, and cyclic alkyl are each independently selected from the following groups: halo, —OH, —OR 11 , —OC(O)R 11 , —OC(O)NH 2 , —OC(O)NHR 11 , —OC(O)NR 11 R 11 , —OP(O)(OH) 2 , —OP(O)(OR 11 ) 2 , —NO 2 , —NH 2 , —NHR 11 , —NR 11 R 11 , —N + (O)R 11 R 11 , -NHC(O)H, -NHC(O)R 11 , -NR 11 C(O)R 11 , -NHC(O)NH 2 , -NHC(O)NR 11 R 11 , -NR 11 C(O)NHR 11 , -SH, -SR 11 , -S(O)H, -S(O)R 11, -SO2R11, -SO2NH2, -SO2NHR11, -SO2NR11R11, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -CN, -CO2H, -CO2 R 11 , -CHO, -C(O)R 11 , —C(O)NH 2 , —C(O)NHR 11 , —C(O)NR 11 R 11 , —CONHSO 2 H, —C(O)NHSO 2 R 11 , —C(O)NR 11 SO 2 R 11 , cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl;wherein each of the groups cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl includes the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cyclic alkyl, halo, —OH, —OR 13 , —OC(O)R 13 , —OC(O)NH 2 , —OC(O)NHR 13 , —OC(O)NR 13 R 13 , —OP(O)(OH) 2 , —OP(O)(OR 13 ) 2 , —NO 2 , —NH 2 , —NHR 13 , —NR 13 R 13 , —N + (O)R 13 R 13 , -NHC(O)H, -NHC(O)R 13 , -NR 13 C(O)R 13 , -NHC(O)NH 2 , -NHC(O)NR 13 R 13 , -NR 13 C(O)NHR 13 , -SH, -SR 13 , -S(O)H, -S(O)R 13 , -SO 2 R 13 , -SO 2 NH 2 , -SO 2 NHR 13 , -SO 2 NR 13 R 13 , -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 13 , —CHO, —C(O)R 13 , —C(O)NH 2 , —C(O)NHR 13 , —C(O)NR 13 R 13 , —CONHSO 2 H, —C(O)NHSO 2 R 13 , and —C(O)NR 13 SO 2 R 13 ; each R 11 and R 13 is independently selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, and a C 3-7 cyclic alkyl group; and (b) optionally substituted aryl groups and optionally substituted heteroaryl groups having up to 12 carbon atoms and having one or more heteroatoms in their ring system, each independently selected from O, N, and S, wherein the one or more optional substituents for each of the aryl and heteroaryl are each independently selected from the same optional substituents as defined in (a) above for R 9 and R 10 ; or (c) R 9 and R 10 may together form a partially saturated or fully unsaturated 5- or 6-membered ring of carbon atoms, optionally containing 1 to 3 heteroatoms selected from O, N, and S, which ring may be independently optionally substituted with 1 to 5 substituents selected from any of the same substituents defined for R 9 and R 10 in (a) above. or a pharmaceutically acceptable salt thereof.

2. The dual inhibitor described in claim 1, wherein (a) the refractory cancer is refractory to anticancer drugs and / or cancer therapy, and optionally the refractory cancer is refractory to cancer therapy including the step of administering one or more anticancer drugs, or (b) the refractory cancer is refractory to radiation therapy.

3. 3. The dual inhibitor of claim 2, wherein the anti-cancer agent is a platinum-based chemotherapeutic agent, optionally wherein the platinum-based chemotherapeutic agent is selected from carboplatin, cisplatin, lobaplatin, oxaliplatin, picoplatin, nedaplatin, phenanthriplatin, and satraplatin.

4. The dual inhibitor of claim 3, wherein the platinum-based chemotherapeutic agent is cisplatin, carboplatin, or oxaliplatin.

5. Intractable cancer, (a) colorectal cancer, breast cancer, melanoma, reproductive cancer, respiratory cancer, brain cancer, digestive cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and distant metastases thereof; (b) lymphomas, sarcomas, and leukemias; and (c) refractory breast cancer selected from invasive ductal carcinoma, invasive lobular carcinoma, in situ ductal carcinoma, and in situ lobular carcinoma; refractory cancer of the respiratory system selected from small cell lung cancer and non-small cell lung carcinoma, bronchial adenoma, and pleuropulmonary blastoma; refractory brain cancer selected from glioblastoma, brainstem and low-pressure glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor, and pineal tumor; refractory male reproductive cancer selected from prostate cancer and testicular cancer. refractory tumors of the female reproductive organs selected from endometrial cancer, cervical cancer, ovarian cancer, ovarian adenocarcinoma, vaginal cancer, vulvar cancer, and uterine sarcoma; refractory tumors of the digestive tract selected from anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer; refractory tumors of the urinary tract selected from bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, and urethral cancer; intraocular melanoma and omental cancer Refractory eye cancer selected from mesoblastoma; refractory liver cancer selected from hepatocellular carcinoma (with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular-cholangiocarcinoma; refractory skin cancer selected from squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer; or refractory skin cancer selected from laryngeal cancer / hypopharyngeal cancer / nasopharyngeal cancer / oral cancer, lip cancer, and oral cavity cancer refractory head and neck cancers selected from the group consisting of: AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphomas of the central nervous system; refractory sarcomas selected from sarcoma of soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma; and acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, and distant metastases thereof.

2. The dual inhibitor of claim 1, selected from the group consisting of:

6. (a) the refractory cancer is selected from lung cancer, pancreatic cancer, breast cancer, and ovarian cancer; and / or (b) The method according to claim 1, wherein the refractory cancer is a solid tumor.

7. R １ is H, F, -CHF ２ , -CF ３ or methyl.

8. R １ The dual inhibitor of claim 7, wherein is H or methyl.

9. R ９ and R １０ are independently H, optionally substituted C １－６ 7. A dual inhibitor according to any one of claims 1 to 6, wherein the group is selected from alkyl groups, optionally substituted aryl, such as substituted phenyl, and optionally substituted heteroaryl groups having up to 12 carbon atoms and having one or more heteroatoms in its ring system, each independently selected from O, N and S.

10. R ９ and R １０ The dual inhibitor of claim 9 , wherein each is H. (a) Z is N or N-oxide, e.g., N, and X is CR ２ and Y is CR ３ R 2 and R 3 are each independently selected from H, halogen, —CF 3 , —CHF 2 , —OCF 3 , —OCHF 2 , —NO 2 , C 1-6 alkyl, such as methyl, optionally substituted aryl, optionally substituted heteroaryl, —OR (R is optionally substituted aryl), and —NHR (R is optionally substituted aryl); or R 2 and R 3 may together form a saturated, partially saturated, or fully unsaturated 5- or 6-membered ring of carbon atoms, which ring is optionally substituted with 1 to 4 substituents independently selected from R; or (b) X is N or N-oxide, e.g., N, Y is CR 3 , and Z is CR 4 ; R 3 and R 4 are each independently selected from H, halogen, —CF 3 , —CHF 2 , —OCF 3 , —OCHF 2 , —NO 2 , C 1-6 alkyl, e.g., methyl, optionally substituted aryl, optionally substituted heteroaryl, —OR (where R is optionally substituted aryl), and —NHR (where R is optionally substituted aryl); or (c) A dual inhibitor according to any one of claims 1 to 6, wherein X and Z are both N or N-oxide, e.g., N, and Y is CR 3 ; and R 3 is selected from H, halogen, —CF 3 , —CHF 2 , —OCF 3 , —OCHF 2 , —NO 2 , C 1-6 alkyl, e.g., methyl, optionally substituted aryl, optionally substituted heteroaryl, —OR (wherein R is optionally substituted aryl), and —NHR (wherein R is optionally substituted aryl).

12. A dual inhibitor according to any one of claims 1 to 6, wherein Z is N or N-oxide, for example N, X is CR 2 and Y is CR 3 .

13. Dual inhibitors of IDO1 and TDO are 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-Iodoisoxazolo[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) 5-Phenylisoxazolo[5,4-b]pyridin-3-amine (24) 5-Bromo-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (1) Isoxazolo[5,4-b]quinolin-3-amine (9) 5,6,7,8-Tetrahydroisoxazolo[5,4-b]quinolin-3-amine (10) Isoxazolo[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) N ６ -(3-methoxyphenyl)isoxazolo[5,4-b]pyridine-3,6-diamine (95), and pharmaceutically acceptable salts thereof, wherein the compound is a dual inhibitor of IDO1 and TDO.

14. Dual inhibitors of IDO1 and TDO are 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-Iodoisoxazolo[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), The dual inhibitor of any one of claims 1 to 6, selected from:

15. The dual inhibitor of IDO1 and TDO according to any one of claims 1 to 6, wherein the dual inhibitor is 6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) or a pharmaceutically acceptable salt thereof.

16. further comprising administering one or more additional agents selected from the group consisting of anti-cancer agents, immunomodulators, e.g., anti-cancer vaccines, modulators of immune checkpoint proteins, adoptive T cell immunotherapy (e.g., chimeric antigen receptor T cells (CAR T cells)), and radiation therapy, wherein the additional agent is administered either before, during, or after administration of the dual inhibitor of IDO1 and TDO; (a) the one or more additional agents are anticancer agents selected from the anticancer agents of claim 3 or 4; (b) the one or more additional agents is an immunomodulatory agent selected from a CTLA4 inhibitor, an anti-PD-1 antibody, or an anti-PD-L1 antibody; or (c) the one or more additional agents are selected from ipilimumab, semipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab.

17. A dual inhibitor of IDO1 and TDO for use in treating or preventing the onset of refractory cancer in a subject, wherein the dual inhibitor of IDO1 and TDO is 6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) or a pharmaceutically acceptable salt thereof, and the refractory cancer is refractory to an anticancer agent, and the anticancer agent is a platinum-based chemotherapeutic agent.

18. Use of a dual inhibitor of IDO1 and TDO in the manufacture of a medicament for treating refractory cancer or preventing the onset of refractory cancer in a subject, wherein the dual inhibitor of IDO1 and TDO is 6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine (66) or a pharmaceutically acceptable salt thereof, the refractory cancer is refractory to an anticancer agent, and the anticancer agent is a platinum-based chemotherapeutic agent.

19. A dual inhibitor of IDO1 and TDO, having a cellular IDO1 IC50 of less than 100 μM when determined by a cell-based assay for IDO1 inhibition; and having a cellular TDO IC50 of less than 100 μM when determined by a cell-based assay for TDO inhibition; A dual inhibitor of IDO1 and TDO is represented by Formula I: 【Chemistry 2】 [During the ceremony, (a) Z is N or N-oxide, for example N, W is CR 1 , X is CR 2 and Y is CR 3 ; or (b) X is N or N-oxide, for example N, W is CR 1 , Y is CR 3 and Z is CR 4 ; or (c) X and Z are both N or N-oxide, for example N, W is CR 1 and Y is CR 3 ; R 1 is selected from H, halo, —CHF 2 , —CF 3 or methyl; R 2 , R 3 and R 4 are each independently one of the following groups: H, halo, R, —OH, —OR, —OC(O)H, —OC(O)R, —OC(O)NH 2 , —OC(O)NHR, —OC(O)NRR, —OP(O)(OH) 2 , —OP(O)(OR) 2 , —NO 2 , —NH 2 , —NHR, —NRR, —NHC(O)H, —NHC(O)R, —NRC(O)R, —NHC(O)NH 2 , —NHC(O)NRR, —NRC(O)NHR, —SH, —SR, —S(O)H, —S(O)R, —SO 2 R, —SO 2 NH 2 , —SO 2 . selected from NHR, —SO 2 NRR, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —CN, —C≡CH, —C≡CR, —CH═CHR, —CH═CRR, —CR═CHR, —CR═CRR, —CO 2 H, —CO 2 R, —CHO, —C(O)R, —C(O)NH 2 , —C(O)NHR, —C(O)NRR, —CONHSO 2 H, —CONHSO 2 R, —CONRSO 2 R, cyclic C 3 -C 7 alkylamino, imidazolyl, C 1 -C 6 alkylpiperazinyl, morpholinyl and thiomorpholinyl; Alternatively, R 2 and R 3 together, or R 3 and R 4 together, may form a saturated, partially saturated, or fully unsaturated 5- or 6-membered ring of carbon atoms, optionally containing 1 to 3 heteroatoms selected from O, N, and S, the ring being optionally substituted independently with 1 to 4 substituents selected from R; Each R is independently a group defined in paragraphs (a) and (b) below: (a) optionally substituted C 1-6 alkyl groups, optionally substituted C 2-6 alkenyl groups, optionally substituted C 2-6 alkynyl groups, and optionally substituted C 3-7 cyclic alkyl groups; wherein one or more optional substituents on each of said alkyl groups, alkenyl groups, alkynyl groups, and cyclic alkyl groups are each independently selected from the following groups: halo, —OH, —OR 5 , —OC(O)R 5 , —OC(O)NH 2 , —OC(O)NHR 5 , —OC(O)NR 5 R 5 , —OP(O)(OH) 2 , —OP(O)(OR 5 ) 2 , —NO 2 , —NH 2 , —NHR 5 , —NR 5 R 5 , —N+(O—)R 5 R 5 , -NHC(O)H, -NHC(O)R 5 , -NR 5 C(O)R 5 , -NHC(O)NH 2 , -NHC(O)NR 5 R 5 , -NR 5 C(O)NHR 5 , -SH, -SR 5 , -S(O)H, -S(O)R 5 , -SO 2 R 5 , -SO 2 NH 2 , -SO 2 NHR 5 , -SO 2 NR 5 R 5 , -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 5 , -CHO, -C(O)R 5 , -C(O)NH 2 , —C(O)NHR 5 , —C(O)NR 5 R 5 , —CONHSO 2 H, —C(O)NHSO 2 R 5 , —C(O)NR 5 SO 2 R 5 , cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, and azetidinyl;Here, each of the imidazolyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, piperidinyl group, azepanyl group, pyrrolidinyl group and azetidinyl group is selected from the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cyclic alkyl, halo, —OH, —OR 7 , —OC(O)R 7 , —OC(O)NH 2 , —OC(O)NHR 7 , —OC(O)NR 7 R 7 , —OP(O)(OH) 2 , —OP(O)(OR 7 ) 2 , —NO 2 , —NH 2 , —NHR 7 , —NR 7 R 7 , —N + (O—)R 7 R 7 , -NHC(O)H, -NHC(O)R 7 , -NR 7 C(O)R 7 , -NHC(O)NH 2 , -NHC(O)NR 7 R 7 , -NR 7 C(O)NHR 7 , -SH, -SR 7 , -S(O)H, -S(O)R 7 , -SO 2 R 7 , -SO 2 NH 2 , -SO 2 NHR 7 , -SO 2 NR 7 R 7 , -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 7 , -CHO, -C(O)R 7 , -C(O)NH 2 , —C(O)NHR 7 , —C(O)NR 7 R 7 , —CONHSO 2 H, —C(O)NHSO 2 R 7 , —C(O)NR 7 SO 2 R 7 , optionally substituted aryl groups, and optionally substituted heteroaryl groups having up to 12 carbon atoms and having one or more heteroatoms each independently selected from O, N and S in their ring system;wherein one or more optional substituents for each of the aryl and heteroaryl groups are each independently selected from the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-7 cyclic alkyl, halo, —OH, —OR 8 , —OC(O)R 8 , —OC(O)NH 2 , —OC(O)NHR 8 , —OC(O)NR 8 R 8 , —OP(O)(OH) 2 , —OP(O)(OR 8 ) 2 , —NO 2 , —NH 2 , —NHR 8 , —NR 8 R 8 , —N + (O)R 8 R 8 , —NHC(O)H, —NHC(O)R 8 , —NR 8 C(O)R 8 , -NHC(O)NH 2 , -NHC(O)NR 8 R 8 , -NR 8 C(O)NHR 8 , -SH, -SR 8 , -S(O)H, -S(O)R 8 , -SO 2 R 8 , -SO 2 NH 2 , -SO 2 NHR 8 , -SO 2 NR 8 R 8 , -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 8 , -CHO, -C(O)R 8 , -C(O)NH 2 , -C(O)NHR 8 , -C(O)NR 8 R 8 , -CONHSO 2 H, -C(O)NHSO 2 R 8 , and -C(O)NR 8 SO; 2 R 8 ; wherein each R 5 , R 7 and R 8 is independently selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, and a C 3-7 cyclic alkyl group; and (b) optionally substituted aryl groups and optionally substituted heteroaryl groups having up to 12 carbon atoms and one or more heteroatoms in their ring system, each independently selected from O, N, and S, wherein the one or more optionally substituted groups are each independently selected from the same optionally substituted groups defined for R in (a) above. selected from any of the following: R 9 and R 10 are each independently a group defined in paragraphs (a) and (b) below: (a) H, optionally substituted C 1-6 alkyl groups, optionally substituted C 2-6 alkenyl groups, optionally substituted C 2-6 alkynyl groups, and optionally substituted C 3-7 cyclic alkyl groups, wherein one or more optional substituents for each of said alkyl, alkenyl, alkynyl, and cyclic alkyl are each independently selected from the following groups: halo, —OH, —OR 11 , —OC(O)R 11 , —OC(O)NH 2 , —OC(O)NHR 11 , —OC(O)NR 11 R 11 , —OP(O)(OH) 2 , —OP(O)(OR 11 ) 2 , —NO 2 , —NH 2 , —NHR 11 , —NR 11 R 11 , —N + (O)R 11 R 11 , -NHC(O)H, -NHC(O)R 11 , -NR 11 C(O)R 11 , -NHC(O)NH 2 , -NHC(O)NR 11 R 11 , -NR 11 C(O)NHR 11 , -SH, -SR 11 , -S(O)H, -S(O)R 11, -SO2R11, -SO2NH2, -SO2NHR11, -SO2NR11R11, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -CN, -CO2H, -CO2 R 11 , -CHO, -C(O)R 11 , —C(O)NH 2 , —C(O)NHR 11 , —C(O)NR 11 R 11 , —CONHSO 2 H, —C(O)NHSO 2 R 11 , —C(O)NR 11 SO 2 R 11 , cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl;wherein each of the groups cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl includes the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cyclic alkyl, halo, —OH, —OR 13 , —OC(O)R 13 , —OC(O)NH 2 , —OC(O)NHR 13 , —OC(O)NR 13 R 13 , —OP(O)(OH) 2 , —OP(O)(OR 13 ) 2 , —NO 2 , —NH 2 , —NHR 13 , —NR 13 R 13 , —N + (O)R 13 R 13 , -NHC(O)H, -NHC(O)R 13 , -NR 13 C(O)R 13 , -NHC(O)NH 2 , -NHC(O)NR 13 R 13 , -NR 13 C(O)NHR 13 , -SH, -SR 13 , -S(O)H, -S(O)R 13 , -SO 2 R 13 , -SO 2 NH 2 , -SO 2 NHR 13 , -SO 2 NR 13 R 13 , -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -CN, -CO 2 H, -CO 2 R 13 , —CHO, —C(O)R 13 , —C(O)NH 2 , —C(O)NHR 13 , —C(O)NR 13 R 13 , —CONHSO 2 H, —C(O)NHSO 2 R 13 , and —C(O)NR 13 SO 2 R 13 ; each R 11 and R 13 is independently selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, and a C 3-7 cyclic alkyl group; and (b) optionally substituted aryl groups and optionally substituted heteroaryl groups having up to 12 carbon atoms and having one or more heteroatoms in their ring system, each independently selected from O, N, and S, wherein the one or more optional substituents for each of the aryl and heteroaryl are each independently selected from the same optional substituents as defined in (a) above for R 9 and R 10 ; or (c) R 9 and R 10 may together form a partially saturated or fully unsaturated 5- or 6-membered ring of carbon atoms, optionally containing 1 to 3 heteroatoms selected from O, N, and S, which ring may be independently optionally substituted with 1 to 5 substituents selected from any of the same substituents defined for R 9 and R 10 in (a) above. or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating refractory cancer or preventing the onset of refractory cancer in a subject.

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