Tryptophan dioxygenase (IDO1 and TDO) inhibitors and their use in therapy

Abstract

Disclosed is a pharmaceutical composition comprising a 3-aminoisoxazolopyridine compound of Formula I, said 3-aminoisoxazolopyridine compound having IDO1 and / or TDO inhibitory activity, wherein 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; and R 9 and R 10 are as defined herein. Also described is a method of using such compounds for treating various conditions such as cancer.

Description

Technical Field

[0001] The present invention relates to 3-aminoisoxazolopyridine, to pharmaceutical compositions containing the same and to its use as a medicament, and more particularly to its use in cancer treatment, either alone or in combination with other agents such as anti-cancer vaccines, other types of immunomodulatory therapeutic agents, radiotherapy agents and other chemotherapeutic agents. Background Art

[0002] Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the first and rate-limiting step in the conversion of tryptophan to kynurenine and is expressed in a wide range of cancers to suppress the immune system (Uyttenhove et al., J. Nat. Med. 2003, 9, 1269). High IDO1 expression in clinical tumors has been shown to be associated with poor patient prognosis in a wide range of cancers including lung cancer, colorectal cancer, breast cancer, melanoma, and gynecological cancers. Silencing of the IDO1 gene in murine melanoma cell lines when implanted in mice results in a reduced ability of the cells to form tumors (Zheng et al., J. Immunol. 2006, 177, 5639), thus confirming IDO1 as a target for cancer intervention. Many research groups have worked on developing small molecule inhibitors of IDO1 as a means to restore tumor immunity in cancer patients. These inhibitors should have the potential to exhibit anti-tumor activity either alone or in combination with other standard chemotherapies. Blocking downstream IDO1 enzyme signaling using small molecule inhibitors may also act synergistically with other immunomodulatory approaches such as the administration of anti-cancer vaccines, modulation of immune checkpoint proteins (such as CTLA4 and PD1-4s), and the use of adoptive T cell therapies (such as CART cells) (Mautina et al., Proceedings of the AACR Annual Meeting, 2014, Poster 5023). Early studies used tryptophan derivatives such as 1-methyltryptophan (1-MT) as competitive inhibitors of IDO1 (Cady and Sono, Arch. Biochem. Biophys. 1991, 291, 326) and provided evidence for the notion that IDO1 would be an attractive target for cancer pharmaceutical intervention (Hou et al., Cancer Res. 2007, 614). Natural products isolated from marine invertebrates inhibit IDO1 with potencies significantly higher than tryptophan derivatives. One of the most potent IDO1 inhibitors described to date with activity in the nM concentration range is Exiguamine isolated from a marine sponge (Brastianos et al., J. Am. Chem. Soc., 2006, 128, 16046). Two Annulins isolated from a marine hydrozoan exhibit activity in the nM concentration range and have stimulated medicinal chemistry programs that have produced a series of IDO1-inhibitory Pyranonaphthoquinones with low nM potencies (Pereira et al., J. Nat. Prod. 2006, 69, 1496; Kumar et al., J. Med. Chem. 2008, 51, 1706). High throughput screening of compound libraries has identified and optimized hydroxamidine inhibitors of IDO1 that structurally belong to a class (Yue et al., J. Med. Chem. 2009, 52, 7364).An optimized hydroxamidine candidate with nM potency against enzymes in cells and with oral bioavailability is currently in clinical trials (Newton et al., J Clin Oncol. 2012, 30, (suppl; abstr 2500)). Another potent imidazoisoindole IDO inhibitor is also currently in the early stages of clinical trials (Mautina et al., Proceedings of the AACR Annual Meeting, 2013).

[0003] Tryptophan 2,3-dioxygenase (TDO) is another important enzyme in the tryptophan degradation pathway. TDO inhibitors can also have broad therapeutic efficacy in the treatment of cancer and other conditions.

[0004] The object of the present invention is to provide 3-aminoisoxazolopyridine compounds and their use in medicine, such as in the treatment of cancer, or at least to provide a useful option for the public. Summary of the Invention

[0005] In a first aspect, the present invention provides a pharmaceutical composition comprising:

[0006] a compound of formula I or a pharmaceutically acceptable salt thereof, wherein:

[0007]

[0008] W is CR 1 , N or N-oxide;

[0009] X is CR 2 , N or N-oxide;

[0010] Y is CR 3 , N or N-oxide;

[0011] Z is CR 4 , N or N-oxide;

[0012] and wherein at least one of W, X, Y and Z is N or N-oxide;

[0013] R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of: H, halogen, 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 , -NO2 、 -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 alkylpiperazinyl, morpholinyl and thiomorpholinyl;

[0014] Or R 1 and R 2 together, or R 2 and R 3 together, or R 3 and R 4 together may form a saturated or partially saturated or fully unsaturated 5 - or 6 - membered carbon atom ring, which optionally includes 1 to 3 heteroatoms selected from O, N, and S, and the ring is optionally independently substituted by 1 to 4 substituents selected from R;

[0015] Each R is independently selected from any group defined in paragraphs (a) and (b) below:

[0016] (a) Optionally substituted C1 - 6 alkyl, optionally substituted C2 - 6 alkenyl, optionally substituted C2 - 6 alkynyl, and optionally substituted C3 - 7 cycloalkyl; wherein one or more optional substituents of each of the alkyl, alkenyl, alkynyl, and cycloalkyl are independently selected from the following groups: halogen, -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 R5 and cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, and azetidinyl; wherein said imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, and azetidinyl are each optionally substituted with one or more of the following groups: C 1 -- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, halogen, -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 , -OCHF2 , -SCF 3 , -SCF 2 H, -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 , an optionally substituted aryl, and an optionally substituted heteroaryl, the heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N, and S; and wherein one or more optional substituents of each of the aryl and heteroaryl are each independently selected from the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-7 cycloalkyl, halogen, -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)R8 、-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 、-SCF 3 、-SCF 2 H, -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 R 5 , R 7 and R 8 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-7 Cycloalkyl; and

[0017] (b) optionally substituted aryl and optionally substituted heteroaryl, said heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N and S; and wherein the one or more optional substituents are each independently selected from the same optional substituents as those defined for R in (a) above;

[0018] R 9 and R 10 are each independently selected from any of the groups defined in paragraphs (a) to (d) below, provided that R 9 and R 10 At least one of the following groups is selected from any of the groups defined in paragraphs (c) and (d):

[0019] (a) H, optionally substituted C 1-6alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 3-7 cycloalkyl; wherein one or more optional substituents of each of said alkyl, alkenyl, alkynyl, and cycloalkyl are each independently selected from the group consisting of: halogen, -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 , -SO 11 R 11 , -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -SCF 3 , -SCF 2 , -CN, -CO 2 , -CO 2 R 11 , -CHO, -C(O)R 11 , -C(O)NH2 、 -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, azetidinyl, aryl and heteroaryl, said heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N and S; wherein cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, azetidinyl, aryl and heteroaryl are each optionally substituted by one or more of the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, halogen, -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)R13 , -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 , -SCF 3 , -SCF 2 , -CN, -CO 2 , -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 , -C(O)NHSO 2 R 13 and -C(O)NR 13 SO 2 R 13 ; wherein R 11 and R 13 are each independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-7 cycloalkyl;

[0020] (b) Optionally substituted aryl and optionally substituted heteroaryl, said heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N, and S; and wherein one or more optional substituents of each of said aryl and heteroaryl are each independently selected from the same optional substituents as defined above for R 9 and R 10 ;

[0021] (c) -C(O)R 14 , -C(O)OR 14 , –C(O)NR 15 R 16 , -C(O)SR 14 , -C(S)R 14 , -C(S)OR 14 C(S)NR15 R 16 and -C(S)SR 14 wherein R 14 、R 15 and R 16 are each independently selected from the group consisting of: H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, said heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N, and S, and wherein for R 14 、R 15 and R 16 the one or more optional substituents of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl are each independently selected from the same optional substituents as defined for R 9 and R 10 above in (a); and

[0022] (d) –SO 2 (CRR) n R 17 where n is an integer from 0 to 6, each R is independently selected from the groups defined above for R, and R 17 is optionally substituted aryl or optionally substituted heteroaryl, said heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N, and S, and wherein the one or more optional substituents of said aryl and heteroaryl are independently selected from the same optional substituents as defined for R 9 and R 10 above in (a); and -SO 2 R 18 where R 18 is optionally substituted C 1-6 alkyl or optionally substituted C 3-7 cycloalkyl, wherein the one or more optional substituents of said alkyl and cycloalkyl are each independently selected from those defined for R 9 and R 10 above in (a);

[0023] and a pharmaceutically acceptable carrier.

[0024] In another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use as a medicament.

[0025] On the other hand, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in medicine.

[0026] In yet another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

[0027] In yet another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of cancer in warm-blooded animals, including humans.

[0028] In yet another aspect, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.

[0029] In yet another aspect, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer in warm-blooded animals, including humans.

[0030] In yet another aspect, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer in warm-blooded animals, including humans, wherein the treatment comprises administering a compound of formula I and one or more additional agents selected from the group consisting of: chemotherapeutic agents, immunomodulators (such as anti-cancer vaccines, immune checkpoint protein modulators, adoptive T cell immunotherapy (such as chimeric antigen receptor T cells (CAR T cells))), and radiotherapy, and wherein the additional agent is administered before, during, or after the administration of the compound of formula I. In certain embodiments, the additional agent comprises an immunomodulator.

[0031] In yet another aspect, the present invention provides a method for treating cancer in warm-blooded animals, including humans, which comprises administering to the animal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0032] In yet another aspect, the present invention provides a method for treating cancer in warm-blooded animals, including humans, wherein the method comprises administering to the animal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and wherein the method further comprises the step of administering one or more additional agents selected from the group consisting of: chemotherapeutic agents, immunomodulators (such as anti-cancer vaccines, immune checkpoint protein modulators, adoptive T cell immunotherapy (such as chimeric antigen receptor T cells (CAR T cells))), and radiotherapy, and wherein the additional agent is administered before, during, or after the administration of the compound of formula I. In certain embodiments, the additional agent comprises an immunomodulator.

[0033] In yet another aspect, the present invention provides a method for inhibiting indoleamine-2,3-dioxygenase 1 (IDO1) in warm-blooded animals (including humans) in need thereof, which comprises administering to the animal a compound of formula I having IDO1 inhibitory activity or a pharmaceutically acceptable salt thereof in an amount effective to inhibit IDO1.

[0034] In yet another aspect, the present invention provides a method for inhibiting tryptophan 2,3-dioxygenase (TDO) in warm-blooded animals (including humans) in need thereof, which comprises administering to the animal a compound of formula I having TDO inhibitory activity or a pharmaceutically acceptable salt thereof in an amount effective to inhibit TDO.

[0035] In yet another aspect, the present invention provides a method for inhibiting IDO1 and TDO in warm-blooded animals (including humans) in need thereof, which comprises administering to the animal a compound of formula I having IDO1 and TDO inhibitory activity or a pharmaceutically acceptable salt thereof in an amount effective to inhibit IDO1 and TDO.

[0036] In yet another aspect, the present invention provides a pharmaceutical combination or kit, which comprises

[0037] (a) a compound of formula I or a pharmaceutically acceptable salt thereof, and

[0038] (b) one or more additional agents selected from the group consisting of: chemotherapeutic agents, and immunomodulators such as anti-cancer vaccines, immune checkpoint protein modulators, and adoptive T cell immunotherapy (such as chimeric antigen receptor T cells (CAR T cells)).

[0039] In yet another aspect, the present invention provides a pharmaceutical combination or kit for treating cancer, which comprises

[0040] (a) a compound of formula I or a pharmaceutically acceptable salt thereof, and

[0041] (b) one or more additional agents selected from the group consisting of: chemotherapeutic agents, and immunomodulators such as anti-cancer vaccines, immune checkpoint protein modulators, and adoptive T cell immunotherapy (such as chimeric antigen receptor T cells (CAR T cells)).

[0042] In yet another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for treating conditions or disorders selected from the group consisting of: inflammatory conditions, infectious diseases, central nervous system diseases or disorders, coronary heart disease, chronic renal failure, postanesthetic cognitive dysfunction, conditions or disorders related to female reproductive health, and cataracts.

[0043] In yet another aspect, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition or disorder selected from the group consisting of: inflammatory conditions, infectious diseases, central nervous system diseases or disorders, coronary heart disease, chronic renal failure, postanesthetic cognitive dysfunction, conditions or disorders related to female reproductive health, and cataracts.

[0044] In yet another aspect, the present invention provides a method for treating a condition or disorder selected from the group consisting of: inflammatory conditions, infectious diseases, central nervous system diseases or disorders, coronary heart disease, chronic renal failure, postanesthetic cognitive dysfunction, conditions or disorders related to female reproductive health, and cataracts in warm-blooded animals including humans, wherein the method comprises administering to the animal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0045] Certain embodiments of the compound of formula I useful in any of the compositions, methods, uses, and other aspects of the present invention as defined above are described in paragraphs (1) to (30) numbered below.

[0046] (1). A compound of formula I or a pharmaceutically acceptable salt thereof as defined in the first aspect of the present invention above.

[0047] (2). The compound as defined in paragraph (1), wherein Z is N or N-oxide, such as N, W is CR 1 , X is CR 2 , and Y is CR 3 .

[0048] (3). The compound as defined in paragraph (1), wherein X is N or N-oxide, such as N, W is CR 1 , Y is CR 3 , and Z is CR 4 .

[0049] (4). The compound as defined in paragraph (1), wherein both X and Z are N or N-oxide, such as N, W is CR 1 , and Y is CR 3 .

[0050] (5). The compound as defined in any one of paragraphs (1) to (4), wherein R 1 , R 2 , R 3 and R 4 (when present) are each independently selected from the group consisting of: H; halogen; optionally substituted C 1 -C 6 alkyl; -O-R, wherein R is optionally substituted C 1 -C6 alkyl; optionally substituted aryl, such as substituted phenyl; and optionally substituted heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N, and S.

[0051] (6). A compound as defined in any one of paragraphs (1) to (4), wherein R 1 , R 2 , R 3 and R 4 (when present) are each independently selected from the group consisting of: H; halogen; optionally substituted C 1 -C 6 alkyl; -O-R, wherein R is selected from optionally substituted C 1 -C 6 alkyl and optionally substituted aryl (such as phenyl); -NHR, wherein R is optionally substituted aryl; optionally substituted aryl; and optionally substituted heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N, and S.

[0052] (7). A compound as defined in paragraph (6), wherein R 1 , R 2 , R 3 and R 4 (when present) are each independently selected from the group consisting of: H; halogen; -CF 3 ; -CHF 2 ; -OCF 3 ; -OCHF 2 ; C 1-6 alkyl, such as methyl; substituted aryl; substituted heteroaryl; -OR, wherein R is optionally substituted aryl; and -NHR, wherein R is optionally substituted aryl.

[0053] (8). A compound as defined in paragraph (6), wherein one or two of R 1 , R 2 , R 3 and R 4 (when present) are H, and the other groups among R 1 , R 2 , R 3 and R 4 that are not H are independently selected from the group consisting of: halogen; -CF 3 ; -CHF 2 ; -OCF 3 ; -OCHF 2 ; C 1-6Alkyl, such as methyl; substituted aryl; substituted heteroaryl; -OR, where R is optionally substituted aryl; and -NHR, where R is optionally substituted aryl.

[0054] (9). A compound as defined in any one of paragraphs (6) to (8), wherein R 3 is present and selected from the group consisting of: halogen; -OR, where R is optionally substituted aryl; and -NHR, where R is optionally substituted aryl.

[0055] (10). A compound as defined in paragraph (2), wherein Z is N or N-oxide, such as N, W is CR 1 , X is CR 2 , and Y is CR 3 , and R 3 is selected from the group consisting of: halogen; -O-R, where R is optionally substituted aryl; and -NHR, where R is optionally substituted aryl.

[0056] (11). A compound as defined in paragraph (2), wherein Z is N or N-oxide, such as N, W is CR 1 , X is CR 2 , and Y is CR 3 , R 1 is H, and one or both of R 2 and R 3 are not H. For example, both R 2 and R 3 are not H, or R 2 is H but R 3 is not H, or R 3 is H but R 2 is not H.

[0057] (12). A compound as defined in paragraph (11), wherein each of R 2 and R 3 that is not H is independently selected from the group consisting of: halogen; optionally substituted C 1 -C 6 alkyl; -OR, where R is selected from optionally substituted C 1 -C 6 alkyl and optionally substituted aryl; -NHR, where R is optionally substituted aryl; optionally substituted aryl, such as substituted phenyl; and optionally substituted heteroaryl.

[0058] (13). A compound as defined in paragraph (12), wherein each of R 2 and R 3 that is not H is independently selected from the group consisting of: halogen; -CF3 ; -CHF 2 ; -OCF 3 ; -OCHF 2 ; C 1-6 alkyl, such as methyl; substituted aryl; substituted heteroaryl; -OR, where R is an optionally substituted aryl; and -NHR, where R is an optionally substituted aryl.

[0059] (14). A compound as defined in any one of paragraphs (1) to (4), wherein R 1 and R 2 together, or R 2 and R 3 together, or R 3 and R 4 together form a saturated or partially saturated or fully unsaturated 5 - or 6 - membered carbon atom ring, which optionally includes 1 to 3 heteroatoms selected from O, N or S, and the ring is optionally substituted with 1 to 4 substituents independently selected from R, and R 1 , R 2 , R 3 and R 4 that are not part of the ring are independently selected from: H; halogen; optionally substituted C 1 -C 6 alkyl; O - R, where R is an optionally substituted C 1 -C 6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl, the heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms independently selected from O, N and S.

[0060] (15). A compound as defined in any one of paragraphs (1) to (14), wherein one of R 9 and R 10 is selected from the group consisting of: H and optionally substituted C 1-6 alkyl (such as C 1-3 alkyl), for example, one of R 9 and R 10 is H, and the other of R 9 and R 10 is selected from any of the groups defined in (c) and (d).

[0061] (16). A compound as defined in any one of paragraphs (1) to (15), wherein one of R 9 and R 10 is selected from the group consisting of: H and optionally substituted C 1-6 alkyl (such as C 1-3 alkyl), and R 9 and R10 Another one selected from any of the groups defined in (c).

[0062] (17). A compound as defined in any one of paragraphs (1) to (15), wherein R 9 and R 10 One of them is selected from the group consisting of: H and optionally substituted C 1-6 alkyl (such as C 1-3 alkyl), and R 9 and R 10 The other one is selected from the group consisting of: -C(O)R 14 , -C(O)OR 14 , -C(S)R 14 and -C(S)OR 14 ; wherein each R 14 is independently selected from the group consisting of: (a) optionally substituted C 1-6 alkyl, such as C 1-6 alkyl, wherein the alkyl is substituted by an aryl and optionally substituted by one or two more substituents, and wherein the aryl itself is optionally substituted, and (b) optionally substituted aryl.

[0063] (18). A compound as defined in paragraph (17), wherein each R 14 is an optionally substituted alkyl having the chemical formula -(CH 2 ) n (aryl), where n is an integer from 0 to 3, such as 0 or 1, and the aryl is optionally substituted.

[0064] (19). A compound as defined in any one of paragraphs (16) to (18), wherein R 9 and R 10 One of them is selected from the group consisting of: H and optionally substituted C 1-6 alkyl (such as C 1-3 alkyl), and R 9 and R 10 The other one is -C(O)OR 14 .

[0065] (20). A compound as defined in any one of paragraphs (1) to (15), wherein R 9 and R 10 One of them is selected from the group consisting of: H and optionally substituted C 1-6 alkyl (such as C 1-3 alkyl), and R 9 and R 10 The other one is selected from the group consisting of: –C(O)NR 15 R16 and –C(S)NR 15 R 16 , wherein R 15 and R 16 are each independently selected from the group consisting of: (a) H, (b) optionally substituted C 1-6 alkyl, such as C 1-6 alkyl, wherein the alkyl is substituted with an aryl and optionally substituted with one or two or more substituents, and wherein the aryl itself is optionally substituted, and (c) optionally substituted aryl.

[0066] (21). A compound as defined in paragraph (20), wherein R 15 and R 16 are each independently selected from the group consisting of: (a) H and (b) optionally substituted alkyl having the formula -(CH 2 ) n (aryl), where n is an integer from 0 to 3, such as 0 or 1, and the aryl is optionally substituted.

[0067] (22). A compound as defined in paragraph (20) or (21), wherein one but not both of R 15 and R 16 is H.

[0068] (23). A compound as defined in paragraph (2), wherein Z is N or N-oxide, such as N, W is CR 1 , X is CR 2 , and Y is CR 3 , R 9 and R 10 one of which is selected from the group consisting of: H and optionally substituted C 1-6 alkyl (such as C 1-3 alkyl), for example one of R 9 and R 10 is H, and the other of R 9 and R 10 is -C(O)OR 14 , wherein each R 14 is independently selected from the group consisting of: (a) optionally substituted C 1-6 alkyl, such as C 1-6 alkyl, wherein the alkyl is substituted with an aryl and optionally substituted with one or two or more substituents, and wherein the aryl itself is optionally substituted, and (b) optionally substituted aryl.

[0069] (24). A compound as defined in paragraph (23), wherein R 14 is optionally substituted alkyl having the formula -(CH2 ) n (aryl), where n is an integer from 0 to 3, such as 0 or 1, and the aryl is optionally substituted.

[0070] (25). A compound as defined in paragraph (23) or (24), wherein R 1 , R 2 and R 3 are each independently selected from the group consisting of: H; halogen; -CF 3 ; -CHF 2 ; -OCF 3 ; -OCHF 2 ; C 1-6 alkyl, such as methyl; substituted aryl; substituted heteroaryl; -OR, where R is an optionally substituted aryl; and -NHR, where R is an optionally substituted aryl.

[0071] (26). A compound as defined in paragraph (23) or (24), wherein R 1 , R 2 and R 3 are each independently selected from the group consisting of: H, halogen, C 1-6 alkyl such as methyl, substituted aryl, and substituted heteroaryl.

[0072] (27). A compound as defined in paragraph (23) or (24), wherein one or two of R 1 , R 2 and R 3 are H, and the other groups among R 1 , R 2 and R 3 that are not H are independently selected from the group consisting of: halogen; -CF 3 ; -CHF 2 ; -OCF 3 ; -OCHF 2 ; C 1-6 alkyl, such as methyl; substituted aryl; substituted heteroaryl; -OR, where R is an optionally substituted aryl; and -NHR, where R is an optionally substituted aryl.

[0073] (28). A compound as defined in paragraph (23) or (24), wherein R 1 is H, and one or two of R 2 and R 3 are not H, wherein each group among R 2 and R 3 that is not H is independently selected from the group consisting of: halogen; -CF 3 ; -CHF2 ; -OCF 3 ; -OCHF 2 ; C 1-6 alkyl, such as methyl; substituted aryl; substituted heteroaryl; -OR, where R is optionally substituted aryl; and -NHR, where R is optionally substituted aryl.

[0074] (29). A compound as defined in any one of paragraphs (23) to (28), wherein R 3 is selected from the group consisting of: halogen; -OR, where R is optionally substituted aryl; and -NHR, where R is optionally substituted aryl.

[0075] (30). A compound as defined in paragraph (23) or (24), wherein R 1 is H, and R 2 and R 3 form a saturated or partially saturated or fully unsaturated 5 - or 6 - membered carbon atom ring, which optionally includes 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.

[0076] (31). A compound of formula I as defined in any one of the above paragraphs (1) to (30), or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 , R 2 , R 3 and R 4 (when present) is not H or methyl, for example, wherein at least one of R 1 , R 2 , R 3 and R 4 (when present) is not H or alkyl, and the condition is that the compound cannot be selected from the following compounds:

[0077] 2 - bromo - N-(5 - chloro - 4,6 - dimethylisoxazolo[5,4 - b]pyridin - 3 - yl)acetamide, N-(6 - phenyl - 4-(trifluoromethyl)isoxazolo[5,4 - b]pyridin - 3 - yl)cyclopropanecarboxamide, and 2 - phenyl - N-(6 - phenyl - 4-(trifluoromethyl)isoxazolo[5,4 - b]pyridin - 3 - yl)acetamide.

[0078] (32). A compound as defined in paragraph (1), which is selected from the group consisting of:

[0079] 1-(5 - chloro - 4,6 - dimethylisoxazolo[5,4 - b]pyridin - 3 - yl)-3-(4-(trifluoromethoxy)phenyl)urea (2)

[0080] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-cyanophenyl)urea (3)

[0081] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-chlorophenyl)urea (6)

[0082] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-chlorophenyl)urea (7)

[0083] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-chlorophenyl)urea (8)

[0084] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-(trifluoromethoxy)phenyl)urea (9)

[0085] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-(trifluoromethoxy)phenyl)urea (10)

[0086] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-methoxyphenyl)urea (11)

[0087] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-methoxyphenyl)urea (12)

[0088] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-methoxyphenyl)urea (13)

[0089] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-(trifluoromethyl)phenyl)urea (14)

[0090] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (16)

[0091] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-phenylurea (17)

[0092] N-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-phenylacetamide (18)

[0093] N-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide (19)

[0094] (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)phenylcarbamate (4)

[0095] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-(trifluoromethyl)phenyl)urea (15)

[0096] (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl) 4-fluorophenylcarbamate (5)

[0097] N-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)acetamide (20)

[0098] and pharmaceutically acceptable salts thereof.

[0099] (33). A compound as defined in any one of paragraphs (1) to (32) above, wherein the compound is an IDO1 inhibitor.

[0100] (34). A compound as defined in any one of paragraphs (1) to (32) above, wherein the compound is a TDO inhibitor.

[0101] (35). A compound as defined in any one of paragraphs (1) to (32) above, wherein the compound is an IDO1 inhibitor and a TDO inhibitor.

[0102] Certain compounds of formula I are novel. Accordingly, these compounds are provided as a further feature of the invention.

[0103] In yet another aspect, the present invention provides a compound of formula I as defined in any one of paragraphs (1) to (30) above, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 and R 4 at least one of (when present) is not H or methyl, for example wherein R 1 、R 2 、R 3 and R 4 at least one of (when present) is not H or alkyl, and provided that the compound is not selected from the following compounds:[[]]

[0104] 2-Bromo-N-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)acetamide, N-(6-phenyl-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-yl)cyclopropanecarboxamide, and 2-phenyl-N-(6-phenyl-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-yl)acetamide.

[0105] In certain embodiments, the present invention provides a compound of formula I as defined in any one of paragraphs numbered (35) to (63) below.

[0106] (35). A compound of formula I or a pharmaceutically acceptable salt thereof, wherein:

[0107]

[0108] W is CR 1 , N or N-oxide;

[0109] X is CR 2 , N or N-oxide;

[0110] Y is CR 3 , N or N-oxide;

[0111] Z is CR 4 , N or N-oxide;

[0112] and wherein at least one of W, X, Y and Z is N or N-oxide;

[0113] R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of: H, halogen, 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, -CF3 、 -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;

[0114] or R 1 and R 2 together, or R 2 and R 3 together, or R 3 and R 4 together may form a saturated or partially saturated or fully unsaturated 5 - or 6 - membered carbon atom ring, optionally including 1 to 3 heteroatoms selected from O, N, and S, and said ring is optionally independently substituted with 1 to 4 substituents selected from R;

[0115] Each R independently is selected from any of the groups defined in paragraphs (a) and (b) below:

[0116] (a) Optionally substituted C1 - 6 alkyl, optionally substituted C2 - 6 alkenyl, optionally substituted C2 - 6 alkynyl, and optionally substituted C3 - 7 cycloalkyl; wherein one or more optional substituents of each of said alkyl, alkenyl, alkynyl, and cycloalkyl are each independently selected from the following groups: halogen, -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 、 -NR5 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; wherein the imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, and azetidinyl are each optionally substituted with one or more of the following groups: C 1 -- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-7 Cycloalkyl, halogen, -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 、-SCF 3 、-SCF 2 H、-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 2H, -C(O)NHSO 2 R 7 , -C(O)NR 7 SO 2 R 7 , optionally substituted aryl, and optionally substituted heteroaryl, said heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N, and S; and wherein one or more optional substituents of each of said aryl and heteroaryl are each independently selected from the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-7 cycloalkyl, halogen, -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 ,, -SCF 3 , -SCF 2 H, -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 R 5 , R 7 and R 8 each independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-7 cycloalkyl; and

[0117] (b) Optionally substituted aryl and optionally substituted heteroaryl, said heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N, and S; and wherein one or more of the optional substituents are each independently selected from the same optional substituents defined for R in (a) above;

[0118] R 9 and R 10 each independently selected from any of the groups defined in paragraphs (a) through (d) below, provided that at least one of R 9 and R 10 is selected from any of the groups defined in paragraphs (c) and (d) below:

[0119] (a) H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 3-7 cycloalkyl; wherein one or more of the optional substituents of each of said alkyl, alkenyl, alkynyl, and cycloalkyl are each independently selected from the following groups: halogen, -OH, -OR 11 , -OC(O)R 11 , -OC(O)NH 2 , -OC(O)NHR 11 , -OC(O)NR 11 R11 、 -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 、 -SCF 3 、 -SCF 2 H, -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 7Alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, azetidinyl, aryl and heteroaryl, wherein the heteroaryl has up to 12 carbon atoms in its ring system and has one or more heteroatoms each independently selected from O, N and S; wherein said cyclic C 3 -C 7 Alkylamino, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, azetidinyl, aryl and heteroaryl are each optionally substituted with one or more of the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, halogen, -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, -OCF3 , -OCHF 2 , -SCF 3 , -SCF 2 H, -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 R 11 and R 13 are each independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-7 cycloalkyl;

[0120] (b) Optionally substituted aryl and optionally substituted heteroaryl, said heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N, and S; and wherein one or more optional substituents of each of said aryl and heteroaryl are each independently selected from the same optional substituents as defined above for R 9 and R 10 ;

[0121] (c) -C(O)R 14 , -C(O)OR 14 , –C(O)NR 15 R 16 , -C(O)SR 14 , -C(S)R 14 , -C(S)OR 14 C(S)NR 15 R 16 and -C(S)SR 14 , wherein R 14 , R 15 and R 16 are each independently selected from the group consisting of: H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-7A cycloalkyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group, the heteroaryl group having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N, and S, and wherein for R 14 , R 15 and R 16 each of the one or more optional substituents of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl groups is independently selected from the same optional substituents as defined for R 9 and R 10 in (a) above; and

[0122] (d) –SO 2 (CRR) n R 17 , where n is an integer from 0 to 6, each R is independently selected from the groups defined above for R, and R 17 is an optionally substituted aryl group or an optionally substituted heteroaryl group, the heteroaryl group having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N, and S, and wherein each of the one or more optional substituents of said aryl and heteroaryl groups is independently selected from the same optional substituents as defined for R 9 and R 10 in (a) above; and -SO 2 R 18 , where R 18 is an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-7 cycloalkyl group, wherein each of the one or more optional substituents of said alkyl and cycloalkyl groups is independently selected from those defined for R 9 and R 10 in (a) above;

[0123] provided that at least one of R 1 , R 2 , R 3 and R 4 (when present) is not H or methyl, and further provided that the compound cannot be selected from the following:

[0124] 2 - Bromo - N-(5 - chloro - 4,6 - dimethylisoxazolo[5,4 - b]pyridin - 3 - yl)acetamide, N-(6 - phenyl - 4 - (trifluoromethyl)isoxazolo[5,4 - b]pyridin - 3 - yl)cyclopropanecarboxamide, and 2 - phenyl - N-(6 - phenyl - 4 - (trifluoromethyl)isoxazolo[5,4 - b]pyridin - 3 - yl)acetamide.

[0125] (36). A compound according to paragraph (35), wherein Z is N or N - oxide, such as N, W is CR1 , X is CR 2 , and Y is CR 3 .

[0126] (37). The compound according to paragraph (35), wherein X is N or N-oxide, such as N, W is CR 1 , Y is CR 3 , and Z is CR 4 .

[0127] (38). The compound according to paragraph (35), wherein both X and Z are N or N-oxide, such as N, W is CR 1 , and Y is CR 3 .

[0128] (39). The compound according to any one of paragraphs (35) to (38), wherein R 1 , R 2 , R 3 , and R 4 (when present) are each independently selected from the group consisting of: H; halogen; optionally substituted C 1 -C 6 alkyl; -O-R, wherein R is selected from optionally substituted C 1 -C 6 alkyl and optionally substituted aryl (such as phenyl); -NHR, wherein R is optionally substituted aryl; optionally substituted aryl; and optionally substituted heteroaryl, said heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N, and S.

[0129] (40). The compound according to paragraph (39), wherein R 1 , R 2 , R 3 , and R 4 (when present) are each independently selected from the group consisting of: H; halogen; -CF 3 ; -CHF 2 ; -OCF 3 ; -OCHF 2 ; C 1-6 alkyl, such as methyl; substituted aryl; substituted heteroaryl; -OR, wherein R is optionally substituted aryl; and -NHR, wherein R is optionally substituted aryl.

[0130] (41). The compound according to paragraph (39), wherein one or two of R 1 , R 2 , R 3 , and R 4 (when present) are H, and R 1 , R2 , R 3 and R 4 Other groups in that are not H independently select from the group consisting of: halogen; -CF 3 ; -CHF 2 ; -OCF 3 ; -OCHF 2 ; C 1-6 alkyl, such as methyl; substituted aryl; substituted heteroaryl; -OR, where R is an optionally substituted aryl; and -NHR, where R is an optionally substituted aryl.

[0131] (42). A compound according to any one of paragraphs (39) to (41), wherein R 3 is present and selects from the group consisting of: halogen; -OR, where R is an optionally substituted aryl; and -NHR, where R is an optionally substituted aryl.

[0132] (43). A compound according to paragraph (36), wherein Z is N or N-oxide, such as N, W is CR 1 , X is CR 2 , and Y is CR 3 , and R 3 selects from the group consisting of: halogen; -O-R, where R is an optionally substituted aryl; and -NHR, where R is an optionally substituted aryl.

[0133] (44). A compound according to paragraph (36), wherein Z is N or N-oxide, such as N, W is CR 1 , X is CR 2 , and Y is CR 3 , R 1 is H, and one or both of R 2 and R 3 are not H. For example, neither R 2 nor R 3 is H, or R 2 is H but R 3 is not H, or R 3 is H but R 2 is not H.

[0134] (45). A compound according to paragraph (44), wherein each of R 2 and R 3 that is not H independently selects from the group consisting of: halogen; optionally substituted C 1 -C 6 alkyl; -OR, where R is selected from optionally substituted C 1 -C 6Alkyl and optionally substituted aryl; -NHR, where R is optionally substituted aryl; optionally substituted aryl, such as substituted phenyl; and optionally substituted heteroaryl.

[0135] (46). A compound according to paragraph (45), wherein R 2 and R 3 each independently of the other which is not H is selected from the group consisting of: halogen; -CF 3 ; -CHF 2 ; -OCF 3 ; -OCHF 2 ; C 1-6 alkyl, such as methyl; substituted aryl; substituted heteroaryl; -OR, where R is optionally substituted aryl; and -NHR, where R is optionally substituted aryl.

[0136] (47). A compound according to any one of paragraphs (35) to (38), wherein R 1 and R 2 together, or R 2 and R 3 together, or R 3 and R 4 together form a saturated or partially saturated or fully unsaturated 5- or 6-membered carbon atom ring which optionally includes 1 to 3 heteroatoms selected from O, N or S, and the ring is optionally substituted by 1 to 4 substituents independently selected from R, and R 1 , R 2 , R 3 and R 4 which are not part of the ring are independently selected from: H; halogen; optionally substituted C 1 -C 6 alkyl; O-R, where R is optionally substituted C 1 -C 6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl, the heteroaryl having up to 12 carbon atoms in its ring system and having one or more heteroatoms each independently selected from O, N and S.

[0137] (48). A compound according to any one of paragraphs (35) to (47), wherein one of R 9 and R 10 is selected from the group consisting of: H and optionally substituted C 1-6 alkyl (such as C 1-3 alkyl), for example one of R 9 and R 10 is H, and the other of R 9 and R 10 is selected from any of the groups defined in paragraphs (c) and (d).

[0138] (49). A compound according to any one of paragraphs (35) to (48), wherein one of R 9 and R 10 is selected from the group consisting of: H and optionally substituted C 1-6 alkyl (such as C 1-3 alkyl), and the other of R 9 and R 10 is selected from any of the groups defined in paragraph (c).

[0139] (50). A compound according to any one of paragraphs (35) to (48), wherein

[0140] one of R 9 and R 10 is selected from the group consisting of: H and optionally substituted C 1-6 alkyl (such as C 1-3 alkyl), and the other of R 9 and R 10 is selected from the group consisting of: -C(O)R 14 , -C(O)OR 14 , -C(S)R 14 , and -C(S)OR 14 ; wherein each R 14 is independently selected from the group consisting of: (a) optionally substituted C 1-6 alkyl, such as C 1-6 alkyl, wherein the alkyl is substituted with an aryl and optionally substituted with one or two more substituents, and wherein the aryl itself is optionally substituted, and (b) optionally substituted aryl.

[0141] (51). The compound according to paragraph (50), wherein each R 14 is an optionally substituted alkyl having the chemical formula -(CH 2 ) n (aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and the aryl is optionally substituted.

[0142] (52). The compound according to any one of paragraphs (49) to (51), wherein one of R 9 and R 10 is selected from the group consisting of: H and optionally substituted C 1-6 alkyl (such as C 1-3 alkyl), and the other of R 9 and R 10 is -C(O)OR 14 .

[0143] (53). A compound according to any one of paragraphs (35) to (48), wherein one of R 9 and R 10 is selected from the group consisting of: H and optionally substituted C 1-6 alkyl (such as C 1-3 alkyl), and the other of R 9 and R 10 is selected from the group consisting of: –C(O)NR 15 R 16 and –C(S)NR 15 R 16 , wherein each of R 15 and R 16 is independently selected from the group consisting of: (a) H, (b) optionally substituted C 1-6 alkyl, such as C 1-6 alkyl, wherein the alkyl is substituted with an aryl and optionally substituted with one or two or more additional substituents, and wherein the aryl itself is optionally substituted, and (c) optionally substituted aryl.

[0144] (54). A compound according to paragraph (53), wherein each of R 15 and R 16 is independently selected from the group consisting of: (a) H and (b) optionally substituted alkyl having the chemical formula -(CH 2 ) n (aryl), wherein n is an integer from 0 to 3, such as 0 or 1, and the aryl is optionally substituted.

[0145] (55). A compound according to paragraph (53) or (54), wherein one but not both of R 15 and R 16 is H.

[0146] (56). A compound according to paragraph (36), wherein Z is N or N-oxide, such as N, W is CR 1 , X is CR 2 , and Y is CR 3 , one of R 9 and R 10 is selected from the group consisting of: H and optionally substituted C 1-6 alkyl (such as C 1-3 alkyl), for example one of R 9 and R 10 is H, and the other of R 9 and R 10 is -C(O)OR 14 , wherein each R 14Independently selected from the group consisting of: (a) optionally substituted C 1-6 alkyl, such as C 1-6 alkyl, wherein the alkyl is substituted with an aryl and optionally substituted with one or two or more substituents, and wherein the aryl itself is optionally substituted, and (b) optionally substituted aryl.

[0147] (57). The compound according to paragraph (56), wherein R 14 is optionally substituted alkyl having the chemical formula -(CH 2 ) n (aryl), where n is an integer from 0 to 3, such as 0 or 1, and the aryl is optionally substituted.

[0148] (58). The compound according to paragraph (56) or (57), wherein R 1 , R 2 and R 3 are each independently selected from the group consisting of: H; halogen; -CF3; -CHF 2 ; -OCF 3 ; -OCHF 2 ; C 1-6 alkyl, such as methyl; substituted aryl; substituted heteroaryl; -OR, where R is optionally substituted aryl; and -NHR, where R is optionally substituted aryl.

[0149] (59). The compound according to paragraph (56) or (57), wherein R 1 , R 2 and R 3 are each independently selected from the group consisting of: H, halogen, C 1-6 alkyl like methyl, substituted aryl, and substituted heteroaryl.

[0150] (60). The compound according to paragraph (56) or (57), wherein one or two of R 1 , R 2 and R 3 are H, and the other groups among R 1 , R 2 and R 3 that are not H are independently selected from the group consisting of: halogen; -CF 3 ; -CHF 2 ; -OCF 3 ; -OCHF 2 ; C 1-6 alkyl, such as methyl; substituted aryl; substituted heteroaryl; -OR, where R is optionally substituted aryl; and -NHR, where R is optionally substituted aryl.

[0151] (61). A compound according to paragraph (56) or (57), wherein R 1 is H, and one or both of R 2 and R 3 are not H, and each group that is not H in R 2 and R 3 is independently selected from the group consisting of: halogen; -CF 3 ; -CHF 2 ; -OCF 3 ; -OCHF 2 ; C 1-6 alkyl, such as methyl; substituted aryl; substituted heteroaryl; -OR, wherein R is optionally substituted aryl; and -NHR, wherein R is optionally substituted aryl.

[0152] (62). A compound according to any one of paragraphs (56) to (61), wherein R 3 is selected from the group consisting of: halogen; -OR, wherein R is optionally substituted aryl; and -NHR, wherein R is optionally substituted aryl.

[0153] (63). A compound according to paragraph (56) or (57), wherein R 1 is H, and R 2 and R 3 form a saturated or partially saturated or fully unsaturated 5- or 6-membered carbon atom ring, which optionally includes 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.

[0154] The present invention further provides, by way of example, compounds of formula I selected from the following:

[0155] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea (2)

[0156] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-cyanophenyl)urea (3)

[0157] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-chlorophenyl)urea (6)

[0158] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-chlorophenyl)urea (7)

[0159] 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-chlorophenyl)urea (8)

[0160] 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-(trifluoromethoxy)phenyl)urea (9)

[0161] 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-(trifluoromethoxy)phenyl)urea (10)

[0162] 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-methoxyphenyl)urea (11)

[0163] 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-methoxyphenyl)urea (12)

[0164] 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-methoxyphenyl)urea (13)

[0165] 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-(trifluoromethyl)phenyl)urea (14)

[0166] 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (16)

[0167] 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-phenylurea (17)

[0168] N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-phenylacetamide (18)

[0169] N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide (19)

[0170] (5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)phenylcarbamate (4)

[0171] 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-(trifluoromethyl)phenyl)urea (15)

[0172] 4-Fluorophenyl (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)carbamate (5)

[0173] N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)acetamide (20);

[0174] and its pharmaceutically acceptable salts.

[0175] Other aspects of the invention may include suitable combinations of the embodiments disclosed herein. Additionally, those skilled in the art will understand that the features and preferred embodiments of one aspect of the invention will also be suitable for other aspects of the invention.

[0176] Although the invention has been broadly defined above, it is not limited thereto and also includes various embodiments, examples of which are provided in the following description. The invention will now be described in more detail. Detailed Description

[0177] Definitions

[0178] As used herein, the term "radiotherapy" means the use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. The radiation can come from an external machine (external beam radiation therapy), or it can come from radioactive material placed near the cancer cells inside the body (internal radiotherapy). Systemic radiotherapy uses radioactive materials such as radiolabeled monoclonal antibodies that move through the bloodstream to tissues throughout the body. The term irradiation therapy has the same meaning as radiation therapy.

[0179] It should be recognized that certain compounds of the invention can exist in one or more different enantiomeric or diastereomeric forms. It is understood that the above aspects of the invention include enantiomeric or diastereomeric forms.

[0180] The term halo or halogen as used throughout the specification means fluorine, chlorine, bromine, or iodine.

[0181] It should be understood that when the variables of formula I as described above are optionally substituted by one or more imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, azepanyl, pyrrolidinyl, and azetidinyl groups, the linkage to the relevant variable can be through any of the available nitrogen or carbon ring atoms of these groups.

[0182] It should be understood that the term "heteroaryl" includes monocyclic and bicyclic ring systems unless the context requires otherwise.

[0183] It is to be understood that the term "aryl" means an aromatic hydrocarbon such as phenyl or naphthyl.

[0184] It is to be understood that when a group is eligible to be "optionally substituted", this means that the group can be (a) unsubstituted or (b) substituted with one or more of the defined substituents.

[0185] It is to be understood that throughout the specification, references to C 1 -C 6 alkyl or C 2 -C 6 alkenyl mean that these groups can be unbranched or branched. For example, reference to C 1 -C 6 alkyl is intended to include tert-butyl (Me) 3 C-.

[0186] Expressions such as "treating cancer" and "treatment of cancer" include methods that produce one or more anti-cancer effects, said anti-cancer effects including (but not limited to) anti-tumor effects, response rate, time to disease progression, and overall survival. "Anti-tumor" effects include (but not limited to) inhibiting tumor growth, delaying tumor growth, tumor regression, tumor atrophy, increasing the time to tumor regrowth upon cessation of treatment, and slowing disease progression.

[0187] "Therapeutically effective amount" means the amount of a compound that is sufficient to effect such treatment of cancer when administered to a subject for the treatment of cancer. The "effective amount" will vary depending on the cancer to be treated, the compound to be administered, the severity of the cancer being treated, the age and relative health of the subject, the route and form of administration (whether the treatment is a single treatment or a combination treatment), the judgment of the attending physician, and other factors.

[0188] "Pharmaceutically acceptable" means that it can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, neither biologically nor otherwise undesirable, and includes those that are acceptable for veterinary as well as human pharmaceutical use.

[0189] "Pharmaceutically acceptable salt" of a compound means a pharmaceutically acceptable salt as defined herein and having the desired pharmacological activity of the parent compound. Such salts include:

[0190] (a) addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or addition salts formed with organic acids such as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, etc.; and

[0191] (b) Salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth ions, or aluminum ions), or coordinated with organic or inorganic bases. Acceptable organic bases include ethanolamine, diethanolamine, N-methylglucosamine, triethanolamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0192] "Warm-blooded animal" means any member of the class Mammalia, including (but not limited to): humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs, etc.

[0193] The compounds of the present invention and methods for preparing them

[0194] As defined above, broadly speaking, the present invention relates to pharmaceutical compositions comprising compounds of general formula I, and the use of these compounds in therapy, particularly in the treatment of cancer. It has been found that the compounds of formula I are inhibitors of indoleamine-2,3-dioxygenase 1 (IDO1) and / or tryptophan 2,3-dioxygenase (TDO). Accordingly, it is expected that the compounds of the present invention can be used alone for the treatment of cancer, or in combination with other agents (such as anti-cancer vaccines, immune checkpoint protein modulators, adoptive T cell immunotherapy (such as chimeric antigen receptor T cells (CAR T cells))), radiotherapy agents, and other chemotherapeutic agents for the treatment of cancer. As described in more detail in the treatment methods section of the present invention below, in addition to cancer, it is also expected that the compounds of formula I can be used for the treatment of various other conditions.

[0195] With reference to Methods 1 to 11, certain methods for preparing the compounds of formula I and pharmaceutically acceptable salts thereof are described below.

[0196] Synthesis scheme

[0197] The following Methods 1 to 8 describe the preparation of precursor 3-amino compounds, which can be used as starting materials to prepare the compounds of formula I of the present invention using the methods described in the following Methods 9 to 11 or using similar methods.

[0198] Certain precursor 3-amino compounds can be prepared by reacting appropriately substituted halo-cyanopyridine with acetohydroxamic acid in the presence of a base such as potassium tert-butoxide, potassium carbonate, or cesium carbonate (Method 1). This reaction can use a series of solvents, including DMF, dioxane, and N-methylmorpholine.

[0199] Method 1

[0200]

[0201] Compounds with alkylamino substituents and / or arylamino substituents can be prepared by using amines and / or anilines to replace the activated halogen atoms (Method 2).

[0202] Method 2

[0203]

[0204] Compounds containing an alkyl-substituted exocyclic amino group can be prepared by reacting a primary amine with a trialkyl orthoformate followed by reduction with a suitable reducing agent such as sodium borohydride (Method 3).

[0205] Method 3

[0206]

[0207] Such compounds can also be prepared by reacting a primary amine with an alkyl aldehyde followed by reaction with a reducing agent such as sodium cyanoborohydride in a reductive amination method (Method 4).

[0208] Method 4

[0209]

[0210] Compounds with pendant aryl or heteroaryl (Het) substituents can be prepared by reacting a suitably substituted substrate containing a halogen or a trifluoromethanesulfonate group with a suitable aryl or heteroaryl boronic acid or boronate ester in a palladium-catalyzed Suzuki coupling reaction (Method 5).

[0211] Method 5

[0212]

[0213] Compounds with pendant aryl or heteroaryl (Het) substituents can also be prepared as follows: A suitably substituted chemical intermediate containing a halogen or an O-trifluoromethanesulfonate group is subjected to a palladium-catalyzed Suzuki coupling reaction with a suitable aryl or heteroaryl boronic acid or boronate ester, and then the resulting arylated or heteroarylated product is processed to obtain the final product (Method 6).

[0214] Method 6

[0215]

[0216] Compounds containing substituents with alkyl and / or aryl ether linkages can be prepared by replacing the activated halogen atom with an alcohol and / or a phenol in the presence of a base such as sodium, sodium hydride, or cesium carbonate (Method 7).

[0217] Method 7

[0218]

[0219] Compounds containing substituents linked by thioalkyl and / or thioaryl ethers can be prepared by replacing an activated halogen atom with a thiol and / or thiophenol in the presence of a base such as sodium, sodium hydride or caesium carbonate, or by direct reaction with a metal salt of a thiol or thiophenol. The resulting thioalkyl or thiophenol derivatives can be oxidized to their corresponding sulfoxide or sulfone derivatives using a suitable oxidizing agent such as hydrogen peroxide, peracids, metal complexes and aziridines (Method 8).

[0220] Method 8

[0221]

[0222] The compounds of formula I according to the invention containing a urea functional group at the 3-position of the isoxazolo[4,5-b]pyridine ring system can be prepared by reacting the corresponding 3-amino compound with an alkyl, aryl or heteroaryl isocyanate. In some cases, the reaction can be controlled by adding a suitable catalyst such as dibutyltin oxide (Method 9). The corresponding thioureas can be prepared analogously by reacting 3-aminoisoxazolo[4,5-b]pyridine with a similar isothiocyanate.

[0223] Method 9

[0224]

[0225] The compounds of formula I according to the invention containing a carbamate functional group at the 3-position of the isoxazolo[4,5-b]pyridine ring system can be prepared by reacting the corresponding 3-amino compound with an alkyl chloroformate, aryl chloroformate or heteroaryl chloroformate in the presence of a base such as Et 3 N, pyridine, K 2 CO 3 etc. (Method 10). The corresponding thiocarbamates can be prepared analogously by reacting 3-aminoisoxazolo[4,5-b]pyridine with a similar thiol chloroformate. The carbamates and thiocarbamates thus produced can be further used to prepare compounds containing urea and thiourea functional groups respectively at the 3-position of the isoxazolo[4,5-b]pyridine ring system by reacting them with alkylamines, substituted anilines, or amino-substituted heterocycles (Method 10). The carbamates and thiocarbamates thus produced can also be reacted with alkyl thiols, substituted thiophenols and heterocyclic thiols to produce the corresponding S-linked thiocarbamates and dithiocarbamates respectively.

[0226] Method 10

[0227]

[0228] The compounds of formula I according to the invention containing an amide functional group at the 3-position of the isoxazolo[4,5 - b]pyridine ring system can be prepared by reacting an alkyl, or aryl, or heterocyclic carboxylic acid with an activating reagent such as thionyl chloride, N,N'-carbonyldiimidazole, EDCI, etc., and then reacting the resulting substance with 3 - aminoisoxazolo[4,5 - b]pyridine. Bases such as NaH, Et 3 N, pyridine, K 2 CO 3 etc. can all be used in the two - step reaction, and a catalyst such as 4 - N,N-(dimethylamino)pyridine can be used in the final coupling reaction (Method 11). The amide thus produced can be converted to the corresponding thioamide by thionation using a suitable reagent such as P 4 S 10 or Lawesson's reagent in a suitable solvent such as pyridine, tetrahydrofuran, benzene, etc.

[0229] Method 11

[0230]

[0231] The compounds of formula I according to the invention containing a sulfonamide functional group at the 3 - position of the isoxazolo[4,5 - b]pyridine ring system can be prepared by reacting the corresponding 3 - amino compound with an alkyl, aryl or heteroaryl sulfonyl chloride in the presence of a base such as Et 3 N, pyridine, K 2 CO 3 etc. (Method 12).

[0232] Method 12

[0233]

[0234] The steps of Methods 9 to 12 can also be carried out on the isoxazolo[4,5 - b]pyridine, where a monoalkylamino, or monoarylamino, or monoheteroarylamino is introduced to the 3 - position by the steps of Methods 3 and 4 (for example), to obtain N - alkylated, N - arylated and N - heteroarylated derivatives of amide, thioamide, carbamate, thiocarbamate, urea, thiourea, dithiocarbamate and sulfonamide at the 3 - position.

[0235] Those skilled in the art will understand that other compounds of formula I can also be prepared by using steps similar to those listed above.

[0236] The therapeutic methods of the present invention

[0237] The compound of formula I of the present invention can be an inhibitor of IDO1 or TDO, or an inhibitor of both IDO1 and TDO. It is expected that inhibitor compounds of IDO1 or TDO and dual inhibitor compounds of IDO1 and TDO can be used for cancer treatment. Accordingly, in certain embodiments, the present invention provides a method for treating cancer in warm-blooded animals (including humans) by administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I, or a pharmaceutical composition comprising a compound of formula I.

[0238] In a particular aspect of the present invention, it is expected that the compound of formula I can be used to restore tumor immunity in cancer patients. The compounds of the present invention can be used alone or in combination with other cancer therapies, including chemotherapeutic agents, radiation, and / or immunomodulators.

[0239] Immunomodulators include, without limitation, anti-cancer vaccines, agents that modulate immune checkpoint proteins (such as CTLA4 and PD1-4s, LAG3, and TIM3), and adoptive T cell therapies (such as CART). Accordingly, the compound of formula I can be administered alone or in combination with one or more of these other therapies, either simultaneously or sequentially depending on the particular condition to be treated.

[0240] In certain embodiments, the compound of formula I can be administered in combination with one or more immunotherapies selected from ipilimumab, tremelimumab (both CTLA4 inhibitors), nivolumab, pembrolizumab (also known as Lambrolizumab), and pidilizumab (all PD-1 inhibitors).

[0241] Additional chemotherapeutic agents that can be administered in combination with the compound of formula I include, but are not limited to, the compounds listed in the cancer chemotherapy drug regimens of the 14th edition of the Merck Index (2006), such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, L-asparaginase, cyclophosphamide, cytarabine, dacarbazine, actinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisone, prednisolone, procarbazine, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine, the Merck Index being incorporated herein by reference.

[0242] Additional anti-proliferative agents that can be administered in combination with the compounds of Formula I include, but are not limited to, BCNU, CCNU, DTIC, and actinomycin D. Still other anti-proliferative agents include, but are not limited to, those compounds identified for the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th Edition (2006), pages 1225-1287, edited by Molinoff et al. and published by McGraw-Hill, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2′,2′-difluorodeoxycytidine, docetaxel, red-9-(2-hydroxy-3-nonyl)adenine, ethinylestradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine, the Goodman and Gilman's The Pharmacological Basis of Therapeutics being incorporated herein by reference.

[0243] Additional anti-proliferative agents that can be administered in combination with the compounds of Formula I include, but are not limited to, other molecular targeting agents that block cancer cell growth by interfering with specific targeted molecules required for cancer development and tumor growth. Examples include small molecule protein and lipid kinase inhibitors, monoclonal antibodies, molecularly targeted humanized monoclonal antibodies, and monoclonal antibody-drug conjugates. Examples of such inhibitors include: rituximab, trastuzumab, alemtuzumab, tositumomab-I131, cetuximab, ibritumomab, bevacizumab, panitumumab, ofatumumab, ipilimumab, brentuximab, pertuzumab, trastuzumab, ramucirumab, atezolizumab, nivolumab, Lambrolizumab, dinutuximab, imatinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapatinib, nilotinib, pazopanib, crizotinib, loxo-101, vandetanib, vemurafenib, axitinib, bosutinib, cabozantinib, ponatinib, regorafenib, tofacitinib, afatinib, dacomitinib, ibrutinib, and trametinib.

[0244] The compounds of the present invention can be used to treat a variety of cancers. Cancers that can be treated according to the present invention include (but are not limited to): colorectal cancer, breast cancer, melanoma, cancer of the reproductive organs, respiratory cancer, brain cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and their distant metastases. Those disorders also include lymphoma, sarcoma, and leukemia.

[0245] Examples of breast cancer include (but are not limited to) invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0246] Examples of respiratory cancer include (but are not limited to) small cell and non-small cell lung cancer, as well as bronchial adenoma and pleuropulmonary blastoma.

[0247] Examples of brain cancer include (but are not limited to) brainstem and Hypophthalmic gliomas, cerebellar and cerebral astrocytomas, medulloblastoma, ependymoma, and neuroectodermal and pineal tumors.

[0248] Male reproductive organ tumors include (but are not limited to) prostate cancer and testicular cancer.

[0249] Female reproductive organ tumors include (but are not limited to) endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, and vulvar cancer, as well as uterine sarcoma.

[0250] Digestive tract 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.

[0251] Urinary tract tumors include (but are not limited to) bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureteral cancer, and urethral cancer.

[0252] Eye cancer includes (but is not limited to) intraocular melanoma and retinoblastoma.

[0253] Examples of liver cancer include (but are not limited to) hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variant), cholangiocarcinoma of the liver (intrahepatic bile duct cancer), and mixed hepatocellular cholangiocarcinoma.

[0254] Skin cancer includes (but is not limited to) squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0255] Head and neck cancer includes (but is not limited to) laryngeal cancer / hypopharyngeal cancer / nasopharyngeal cancer / oropharyngeal cancer, as well as lip cancer and oral cancer. Lymphoma includes (but is not limited to) AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and central nervous system lymphoma.

[0256] Sarcomas include (but are not limited to) soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcomas, and rhabdomyosarcomas. Leukemias include (but are not limited to) acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0257] These disorders have been well characterized in humans, but similar etiologies exist in other warm-blooded animals and can be treated by the compounds of the present invention.

[0258] Those skilled in the art will understand that a particular treatment method will employ a selected route of administration, which in turn will depend on various factors that are all routinely considered when administering a therapeutic agent. Those skilled in the art will further understand that those skilled in the art can use routine therapeutic testing to determine the optimal course of treatment, i.e., the mode of treatment and the number of daily administrations of the compounds of the present invention given for a specified number of days.

[0259] Therapeutic doses may range from 1 mg to 30 g per day. The specific dose level selected for any particular patient will depend on various factors, including the activity of the specific compound employed, age, weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination, and the severity of the condition being treated.

[0260] Certain compounds of Formula I are also inhibitors of IDO1 and can also inhibit IDO2. Compounds that are also desired to be dual inhibitors of IDO1 and IDO2 can be used in cancer treatment. Accordingly, in another aspect, the present invention provides a method of inhibiting IDO1 and IDO2 in warm-blooded animals (including humans) in need thereof, which comprises administering to the animal a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to inhibit IDO1 and IDO2.

[0261] It has been reported that compounds that are inhibitors of IDO (IDO1 and IDO2) and / or TDO may be effective not only in cancer treatment but also in the treatment of a range of other diseases or conditions, e.g., as discussed in PCT International Publication WO2015 / 082499 and the references to scientific literature incorporated herein by reference in their entirety. For example, such compounds can be used to treat inflammatory conditions, infectious diseases, central nervous system diseases or disorders, coronary heart disease, chronic renal failure, post-anesthetic cognitive disorders, disease conditions or disorders related to female reproductive health, and cataracts. Accordingly, the compounds of Formula I of the present invention can also be used to treat these diseases or conditions.

[0262] Examples of inflammatory conditions treatable by a compound of formula I include conditions associated with abnormal immune B cells, T cells, dendritic cells, natural killer cells, macrophages, and / or neutrophils.

[0263] Examples of infectious diseases treatable by a compound of formula I include bacterial infections, viral infections such as enteric infections, hepatitis C, sepsis, and sepsis-induced hypotension.

[0264] Examples of central nervous system diseases or disorders treatable by a compound of formula I include amyotrophic lateral sclerosis (AML), Huntington's disease, Alzheimer's disease, pain, mental disorders (including affective disorders such as depression), multiple sclerosis, Parkinson's disease, and HIV-associated neurocognitive decline.

[0265] An example of a disease or disorder related to female reproductive health treatable by a compound of formula I is endometriosis, and conditions related to female reproductive health include contraception and abortion.

[0266] The pharmaceutical composition of the present invention

[0267] The present invention includes a pharmaceutical composition comprising one or more compounds of formula I of the present invention and a pharmaceutically acceptable carrier.

[0268] 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 exact nature of the carrier or other materials will depend on the route of administration.

[0269] The compounds can be administered in unit dosage forms by oral, topical, parenteral, inhalation, or spray or rectal routes. The term 'administered by injection' includes intravenous, intramuscular, subcutaneous, and parenteral injections, as well as the use of infusion techniques. One or more compounds can be present in combination with one or more pharmaceutically acceptable non-toxic carriers and (if desired) other active ingredients.

[0270] Compositions intended for oral use may be prepared by any suitable method known in the art for manufacturing pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents, and preservatives in order to provide a palatable preparation. Tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients suitable for the manufacture of tablets. These excipients may be, for example: inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; and binders such as magnesium stearate, stearic acid or talc. Tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, delayed release substances such as glyceryl monostearate or glyceryl distearate may be used. These compounds may also be formulated in solid fast release forms.

[0271] Preparations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

[0272] Aqueous suspensions contain the active material in admixture 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 may be: naturally occurring phosphatides such as lecithin; or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate; 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 hexitol anhydrides such as polyoxyethylene sorbitan monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as n-propyl p-hydroxybenzoate or ethyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

[0273] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening agents, flavoring agents and coloring agents may also be present.

[0274] The compound can also be in the form of a non-aqueous liquid preparation, such as an oily suspension, which can be formulated by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or groundnut oil) or a mineral oil such as liquid paraffin. The oily suspension can contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents (such as those listed above) and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by adding an antioxidant such as ascorbic acid.

[0275] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (such as olive oil or peanut oil), or a mineral oil (such as liquid paraffin) or a mixture thereof. Suitable emulsifying agents can be naturally occurring gums (such as gum arabic or tragacanth), naturally occurring phospholipids (such as soy bean, 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 polyoxyethylene sorbitan monooleate). The emulsion can also contain sweetening agents and flavoring agents.

[0276] Syrups and elixirs can be formulated using sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations can also contain demulcents, preservatives, and flavoring and coloring agents.

[0277] The compound can also be administered in the form of a suppository for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0278] Examples

[0279] The following examples are representative of the compounds of the present invention and methods for preparing them. However, the scope of the present invention should not be considered limited to these examples.

[0280] Synthetic procedures

[0281] Starting materials not specifically described are commercially available, or their synthesis has been described in the chemical literature, or the individual materials can be prepared by methods known to those skilled in the art. The exemplary compounds are characterized by 1 H NMR spectroscopy, APCI ionization mass spectrometry, melting point, and combustion or HRMS analysis. The purity of the exemplary compounds was determined by HPLC analysis and all compounds were found to be >95%.

[0282] All column chromatography was performed using silica gel 60 (SiO 2 )(0.040 - 0.063 mm).

[0283] Abbreviation

[0284] NMR Nuclear Magnetic Resonance

[0285] ESI Electrospray Ionization

[0286] APCI Atmospheric Pressure Chemical Ionization

[0287] HPLC High Performance Liquid Chromatography

[0288] LCMS Liquid Chromatography - Mass Spectrometry

[0289] HRMS High Resolution Mass Spectrometry

[0290] mp Melting Point

[0291] DMF Dimethylformamide

[0292] EtOAc Ethyl Acetate

[0293] DCM Dichloromethane

[0294] MeOH Methanol

[0295] THF Tetrahydrofuran

[0296] HOAc Acetic Acid

[0297] dppf 2-(Diphenylphosphino)ferrocene

[0298] EDCI 1-Ethyl-(3-dimethylaminopropyl)carbodiimide Hydrochloride

[0299] TEA Triethylamine

[0300] Method 1. Representative Example

[0301] 5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine (1)

[0302]

[0303] Under nitrogen, potassium tert-butoxide (0.33 g, 2.98 mmol) was added to a solution of acetohydroxamic acid (0.22 g, 2.98 mmol) in dry DMF (5 ml). The reaction mixture was stirred at 20 °C for 2 hours. Then 2,5-dichloro-4,6-dimethylnicotinonitrile (0.50 g, 2.49 mmol) was added and the resulting mixture was stirred at 20 °C for 5 hours and then diluted with H 2 O (150 ml) and stirred for 1 hour. The resulting white precipitate was filtered and washed with water. The filtrate was extracted with EtOAc (30 ml x 3). The combined organic portions were dried (Na 2 SO 4), The solvent was evaporated under reduced pressure to obtain more substances. The separated solid and the extracted substances were combined and chromatographically purified on SiO 2 and eluted with a 0 - 50% gradient of petroleum ether / EtOAc. The product purified by column was recrystallized from DCM / petroleum ether to give a white solid (1) (0.22 g, 45%), mp (DCM / petroleum ether) was 214 - 216 °C, 1 1H NMR [(CD 3 ) 2 SO] δ 6.25 (bs, 2H, NH 2 ), 2.64 (s, 3H, CH 3 ), 2.61 (s, 3H, CH 3 ); LCMS [M + H] = 198; HPLC 99.8%; Anal. calcd for C 8 H 8 ClN 3 O: C, 48.6; H, 4.1; N, 21.4; found: C, 48.8; H, 3.9, N, 21.4%.

[0304] Method 9. Representative Steps and Further Examples

[0305] Method 9. Representative Steps

[0306] 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea (2)

[0307]

[0308] To a solution of 5-chloro-4,6-dimethylisoxazolo[5,4-b)pyridin-3-amine (1) (125 mg, 0.60 mmol) in THF (1 ml) at 20 °C was added diisopropylethylamine (0.12 ml, 0.78 mmol, 1.3 eq) and 1-isocyanato-4-(trifluoromethoxy)benzene (0.1 ml, 0.74 mmol, 1.23 eq). The reaction mixture was stirred at this temperature for 72 h and then quenched with an aqueous solution of KHCO 3 . The resulting precipitate was filtered and washed with H 2 O. The filtrate was extracted with EtOAc and the solvent was evaporated to obtain more substances. The combined solid material was triturated with diisopropyl ether for 3 days to give (2) (18 mg, 7%), mp (diisopropyl ether) was 205 - 208 °C; 1 1H NMR [(CD 3 ) 2SO] δ 9.55 (s, 1H), 9.47 (s, 1H), 7.60 (d, J = 9.1 Hz, 2H), 7.32 (d, J = 9.1 Hz, 2H), 2.69 (s, 3H), 2.58 (s, 3H); HPLC purity: 84%; C 16 H 12 ClF 3 N 4 NaO 3 [M+Na] HRMS (ESI + ) Calculated for: 423.0442, Found: 423.0440.

[0309] 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-cyanophenyl)urea (3)

[0310]

[0311]

[0312] Similar to 5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-amine and 4-isocyanatobenzonitrile, (3) was obtained in 3.5% yield, mp (MeOH) 223 - 224 °C; 1 H NMR [(CD 3 ) 2 SO] δ 9.86 (s, 1H), 9.62 (s, 1H), 7.77 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 8.9 Hz, 2H), 2.69 (s, 3H), 2.57 (s, 3H); C 16 H 12 ClN 5 O 2 Anal. Calcd for C, 56.2; H, 3.5; N, 20.5; Found: C, 56.2; H, 3.4; N, 20.4%.

[0313] Method 10. Representative Example

[0314]

[0315] General procedure

[0316] To a solution of 1 (1.5 g, 7.6 mmol, 1.0 eq) and TEA (1.5 g, 15.2 mmol, 2.0 eq) in THF (200 mL) at 0 °C with stirring was added dropwise phenyl chloroformate B (1.2 g, 76 mmol, 10.0 eq). The reaction mixture was stirred at room temperature and N 2Stir overnight under the atmosphere. Pour the reaction mixture into water and extract with EtOAc (25 mL x 3). Wash the combined organic layers with saturated NaHCO 3 aqueous solution and brine, and dry over Na 2 SO 4 . Filter and concentrate. Purify the residue by column chromatography (petroleum ether / EtOAc = 10 / 1 - 5 / 1) to obtain the product 4 as a white solid (1.7 g, 71%).

[0317] Perform a similar reaction with 4-fluorophenyl chloroformate for 1, and after purification by silica chromatography (petroleum ether / EtOAc (1:1)), obtain 5 as a white solid (64%).

[0318] Add TEA (0.94 mmol, 2.0 eq) and substituted aniline D (0.71 mmol, 1.5 eq) to a solution of 4 (0.47 mmol, 1.0 eq) in THF (8.0 mL). Stir the reaction mixture overnight at room temperature and under N 2 atmosphere. Concentrate the reaction mixture under reduced pressure and purify the residue by column chromatography (CH 2 Cl 2 / MeOH = 100 / 1 - 80 / 1) to obtain the target product.

[0319] The following compounds were prepared using the method described below:

[0320]

[0321]

[0322]

[0323] Method 11. Representative Example

[0324]

[0325] General test condition A

[0326] Add oxalyl chloride (78 mg, 0.62 mmol, 1.2 eq) to a solution of substituted phenylacetic acid (0.56 mmol, 1.1 eq) in CH 2 Cl 2 (8.0 ml). Stir the resulting mixture at room temperature and under N 2Stir for 2 hours. Concentrate the reaction mixture under reduced pressure to obtain acyl chloride B, which is dissolved in THF (2 ml). Add the prepared acyl chloride solution to a mixture of 1 (100 mg, 0.51 mmol, 1.0 eq) and NaH (24.8 mg, 0.62 mmol, 1.2 eq) in THF (5 ml) at 0 °C, and stir the resulting mixture at 40 °C overnight. Pour the reaction mixture into water and extract with EtOAc (25 mL x 3). Combine the organic layers and wash with saturated NaHCO 3 aqueous solution and brine, then use Na 2 SO 4 to dry, filter and concentrate. Purify the residue by column chromatography (petroleum ether / EtOAc = 5 / 1 - 3 / 1) to obtain the target product.

[0327] General test condition B

[0328] Add oxalyl chloride (710 mg, 5.6 mmol, 11 eq) and DMF (2 drops, catalytic amount) to a solution of substituted phenylacetic acid or acetic acid (5.1 mmol, 10 eq) in CH 2 Cl 2 (8.0 ml). Stir the resulting mixture at room temperature and N 2 for 2 hours. Concentrate the reaction mixture under reduced pressure to obtain acyl chloride B, which is dissolved in THF (2 ml). Add the prepared acyl chloride solution to a mixture of 1 (100 mg, 0.51 mmol, 1.0 eq) and TEA (103 mg, 1.02 mmol, 2.0 eq) in THF (5 ml) at 0 °C, and stir the resulting mixture at room temperature overnight. Pour the reaction mixture into water and extract with EtOAc (25 mL x 3). Combine the organic layers and wash with saturated NaHCO 3 aqueous solution and brine, then use Na 2 SO 4 to dry, filter and concentrate. Recrystallize the residue from CH 2 Cl 2 to obtain the target product.

[0329] The following compounds were prepared using the methods described below:

[0330]

[0331]

[0332] Enzyme test for IDO1 activity

[0333] Recombinant human IDO1 (rhIDO1) was expressed and purified from a culture of Escherichia coli strain EC538 transformed with pREP4 and pQE9-IDO plasmids. The reaction mixture was dispensed into 384-well microplates 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), with a final concentration of 9 nM, and the total volume of the test medium was 30 μL. The plates were incubated at 37 °C for 30 minutes, and the enzyme reaction was terminated by adding piperidine (200 mM) and heating at 65 °C for 20 minutes. At λ ex 400 nm and λ em 500 nm, the fluorescence intensity was read. The test compounds were dissolved in 100% DMSO and pre-diluted in the test medium before adding rhIDO1. IDO1 inhibition (%) was calculated as follows:

[0334]

[0335] All assays were performed in triplicate and statistical analysis was performed in Prism v5 (Graphpad Software, Inc., La Jolla, CA, USA).

[0336] Cell-based IDO1 inhibition assay

[0337] For the inhibition assay of cell IDO1 activity, Lewis lung cancer cells transfected to express human IDO1 (LLTC-hIDO1) or murine (LLTC-mIDO1) were cultured with the test compounds at 37 °C and 5% CO 2 for 24 hours. Then, the culture supernatant of each well was transferred to a new flat-bottom 96-well plate, mixed with trichloroacetic acid (10% final concentration), and incubated at 60 °C for 20 minutes. Then the plates were centrifuged (10 min, 2500 g), and the supernatant was transferred to a new plate together with 4-(dimethylamino)benzaldehyde (20 mg / mL, in acetic acid) and mixed with 4-(dimethylamino)benzaldehyde at 1:1. The absorbance of each well was read at 480 nm, and the concentration that inhibited 50% of the cell enzyme activity was calculated.

[0338] Cell viability in each well of the same experiment was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. For the determination of IDO1 inhibition, after removing the supernatant, the cells were incubated with MTT (500 μg / mL) until crystal formation was observed. The plates were centrifuged at 2500 g for 15 minutes, and then all the supernatant in each well was discarded. DMSO (100 μL / well) was added to dissolve the crystals, and then the absorbance in each well was measured at 570 nm. The cell viability in each well was expressed as a percentage of the untreated control. All experiments were performed using triplicate cultures, unless otherwise indicated.

[0339] The test results are shown in the following table.

[0340] Compound Activity

[0341]

[0342]

[0343] Activity IC 50 Range: A; <1 μM, B; 1 - 10 μM, C; 10 - 100 μM, D; >100 μM

[0344] Cell-based assay for TDO inhibition

[0345] For the inhibition assay of cellular TDO, GL261 cells transfected to overexpress full-length human TDO were cultured with the test compound at 37 °C and 5% CO 2 for 24 hours. Then the culture supernatant in each well was transferred to a new flat-bottom 96-well plate, and the kynurenine content was determined as described above for the IDO1 test, and the concentration that inhibited 50% of the cellular enzyme activity was calculated.

[0346] Cell viability in each well of the same experiment was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay.

[0347] The test results are shown in the following table.

[0348] Compound activity

[0349] Compound Number <![CDATA[Cell IC 50 > <![CDATA[Cytotoxic IC 50 > 1 B D 4 C D 15 C D

[0350] Activity IC 50 Range: A; <1 μM, B; 1 - 10 μM, C; 10 - 100 μM, D; >100 μM

[0351] As used herein, "comprising" is synonymous with "including", "containing", or "characterized by", and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" does not include any element, step, or ingredient not specifically recited in the claimed 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, each of the terms "comprising", "consisting essentially of", and "consisting of" may be replaced by either of the other two terms.

[0352] When a group of materials, compositions, components, or compounds is disclosed herein, it is to be understood that all individual members of those groups and all subgroups thereof are separately disclosed. When Markush groups or other groupings are used herein, the disclosure is intended to include separately all individual members of the group as well as all possible combinations and subcombinations of the group. Each formulation or combination of the components described or exemplified herein may be used to practice the invention, unless otherwise indicated. Whenever a range is given in the specification, such as a temperature range, a time range, or a composition range, the disclosure is intended to include all intermediate ranges and subranges, as well as all individual values included in the given range. In the present disclosure and claims, "and / or" means additionally or alternatively. In addition, any use of a singular term also includes the plural form.

[0353] All references cited herein are incorporated herein by reference in their entirety to the extent not inconsistent with the disclosure of this specification. Some of the references provided herein are incorporated by reference to provide details regarding the source of materials, additional materials, additional reagents, additional synthetic methods, additional analytical methods, additional biomaterials, additional cells, and additional uses of the present invention. All headings used herein are for convenience only. All patents and publications mentioned in the specification indicate the state of the art of those skilled in the art to which the present invention pertains and are incorporated herein by reference to the extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference. The references cited herein are incorporated by reference in their entirety to indicate the state of the art as of their publication or filing date, and if desired, it is expected that this information may be used herein to exclude specific embodiments of the prior art.

Claims

1. A pharmaceutical composition, comprising: a compound of formula I or a pharmaceutically acceptable salt thereof, wherein: Z is N or N-oxide, W is CR 1 , X is CR 2 and Y is CR 3 ; R 1 、R 2 、 and R 3 each independently selected from the group consisting of: H, halogen, and C 1 -C 6 alkyl; R 9 and R 10 One of them is selected from the groups defined in the following paragraph (a), and R 9 and R 10 The other one is selected from any of the groups defined in the following paragraph (b): (a) H; (b)-C(O)R 14 、-C(O)OR 14 、-C(O)NR 15 R 16 、-C(S)R 14 、-C(S)OR 14 和C(S)NR 15 R 16 , wherein R 14 is a group having the formula -(CH 2 )n(phenyl), where n is an integer from 0 to 3, and the phenyl is optionally substituted, and R 15 and R 16 are each independently selected from the group consisting of: (a) H and (b) a group having the formula -(CH 2 )n(phenyl), where n is an integer from 0 to 3, and the phenyl is optionally substituted, provided that one but not both of R 15 and R 16 is H and wherein for R 14 、R 15 and R 16 each of one or more optional substituents of each said phenyl group is independently selected from the following groups: halogen, -OH, -OR 11 、-NO 2 、-NH 2 、-NHR 11 、-NR 11 R 11 、-SH、-SR 11 、-CF 3 、-CHF 2、 -CH 2 F、-OCF 3 、-OCHF 2 、-SCF 3 、-SCF 2 H、-CN; where each R 11 is independently selected from C 1-6 alkyl; and Provided that at least one of R 1 , R 2 and R 3 is not H; and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1, wherein for R 14 , R 15 and R 16 , each of the one or more optional substituents of each of the phenyl groups is independently selected from the following groups: halogen, -OH, -OR 11 , -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 and -CN.

3. The pharmaceutical composition according to claim 1, wherein for each of the phenyl groups of R 14 , R 15 and R 16 , the one or more optional substituents are each independently selected from the group consisting of: halogen, -OR 11 , -CF 3 , -OCF 3 and -CN.

4. The pharmaceutical composition according to claim 1, wherein R 1 , R 2 , and R 3 are each independently selected from the group consisting of: halogen and C 1 -C 6 alkyl.

5. The pharmaceutical composition according to claim 1, wherein one or two of R 1 , R 2 and R 3 are H, and the other groups among R 1 , R 2 and R 3 that are not H are independently selected from the group consisting of: halogen and C 1-6 alkyl.

6. The pharmaceutical composition according to claim 1, wherein R 3 is selected from halogen.

7. The pharmaceutical composition according to claim 1, wherein R 1 is H, and one or both of R 2 and R 3 are not H.

8. The pharmaceutical composition according to claim 1, wherein each group in R 2 and R 3 that is not H is independently selected from the group consisting of halogen and C 1-6 alkyl.

9. The pharmaceutical composition according to claim 1, wherein one of R 9 and R 10 is H, and the other of R 9 and R 10 is selected from the group consisting of: -C(O)R 14 , -C(O)OR 14 , -C(S)R 14 , and -C(S)OR 14 .

10. The pharmaceutical composition according to claim 9, wherein each R 14 is an optionally substituted alkyl group having the chemical formula -(CH 2 ) n (phenyl), where n is an integer of 0 or 1, and the phenyl group is optionally substituted.

11. The pharmaceutical composition according to claim 1, wherein one of R 9 and R 10 is H, and the other of R 9 and R 10 is selected from the group consisting of: -C(O)NR 15 R 16 and -C(S)NR 15 R 16 .

12. The pharmaceutical composition according to claim 11, wherein R 15 and R 16 are each independently selected from the group consisting of: (a) H and (b) optionally substituted alkyl having the chemical formula -(CH 2 ) n (phenyl), where n is an integer of 0 or 1, and the phenyl is optionally substituted.

13. The pharmaceutical composition according to claim 1, wherein one of R 9 and R 10 is H, and the other of R 9 and R 10 is -C(O)OR 14 .

14. The pharmaceutical composition according to claim 13, wherein R 14 is an optionally substituted alkyl group having the chemical formula -(CH 2 ) n (phenyl), where n is an integer of 0 or 1, and the phenyl group is optionally substituted.

15. The pharmaceutical composition according to claim 13, wherein R 1 , R 2 and R 3 are each independently selected from the group consisting of: halogen; and C 1-6 alkyl.

16. The pharmaceutical composition according to claim 13, wherein one or two of R 1 , R 2 and R 3 are H, and the other groups among R 1 , R 2 and R 3 that are not H are independently selected from the group consisting of: halogen and C 1-6 alkyl.

17. The pharmaceutical composition according to claim 13, wherein R 1 is H, and one or both of R 2 and R 3 are not H, wherein each group that is not H in R 2 and R 3 is independently selected from the group consisting of: halogen and C 1-6 alkyl.

18. The pharmaceutical composition according to claim 13, wherein R 3 is selected from halogen.

19. The pharmaceutical composition according to claim 1, wherein the compound of formula 1 is selected from the group consisting of: 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea (2) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-cyanophenyl)urea (3) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-chlorophenyl)urea (6) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-chlorophenyl)urea (7) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-chlorophenyl)urea (8) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-(trifluoromethoxy)phenyl)urea (9) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-(trifluoromethoxy)phenyl)urea (10) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-methoxyphenyl)urea (11) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-methoxyphenyl)urea (12) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-methoxyphenyl)urea (13) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-(trifluoromethyl)phenyl)urea (14) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (16) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-phenylurea (17) (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)phenylcarbamate (4) 1-(5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-(trifluoromethyl)phenyl)urea (15) (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)phenylcarbamate 4-fluorophenyl (5) and pharmaceutically acceptable salts thereof.

20. The pharmaceutical composition according to claim 1, wherein the compound of formula I is an IDO1 inhibitor.

21. The pharmaceutical composition according to claim 1, wherein the compound of formula I is a TDO inhibitor.

22. The pharmaceutical composition according to claim 1, wherein the compound is an IDO1 inhibitor and a TDO inhibitor.

23. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein: Z is N or an N-oxide, W is CR 1 , X is CR 2 and Y is CR 3 ; R 1 、 R 2 and R 3 each independently selected from the group consisting of: H, halogen, and C 1 -C 6 -alkyl; R 9 and R 10 one of which is selected from the groups defined in paragraph (a) below, and R 9 and R 10 the other of which is selected from any of the groups defined in paragraph (b) below: (a) H; (b)-C(O)R 14 、-C(O)OR 14 、-C(O)NR 15 R 16 、-C(S)R 14 、-C(S)OR 14 和C(S)NR 15 R 16 , where each R 14 is a group having the formula -(CH 2 )n(phenyl), where n is an integer from 0 to 3, and the phenyl is optionally substituted, and each R 15 and R 16 are independently selected from the group consisting of: (a) H and (b) a group having the formula -(CH 2 )n(phenyl), where n is an integer from 0 to 3, and the phenyl is optionally substituted, provided that one but not both of R 15 and R 16 is H and wherein for R 14 、R 15 and R 16 each of one or more optional substituents of each of said phenyl groups is independently selected from the following groups: halogen, -OH, -OR 11 、-NO 2 、-NH 2 、-NHR 11 、-NR 11 R 11 、-SH、-SR 11 、-CF 3 、-CHF 2、 -CH 2 F、-OCF 3、 -OCHF 2 、-SCF 3 、-SCF 2 H、-CN; where each R 11 is independently selected from C 1-6 alkyl; and The condition is that R 1 , R 2 and R 3 at least one of which is not H or methyl, and a further condition is that the compound is not selected from the following: 2-Phenyl-N-(6-phenyl-4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-yl)acetamide.

24. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein for R 14 、R 15 and R 16 each of the one or more optional substituents of each phenyl group is independently selected from the following groups: halogen, -OH, -OR 11 、-CF 3 、-CHF 2 、-CH 2 F、-OCF 3 、-OCHF 2 and -CN.

25. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein for each of the one or more optional substituents of each phenyl group of R 14 , R 15 and R 16 are each independently selected from the group consisting of: halogen, -OR 11 , -CF 3 , -OCF 3 and -CN.

26. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 3 are each independently selected from the group consisting of halogen and C 1 -C 6 alkyl.

27. The compound according to claim 23, wherein one or two of R 1 , R 2 and R 3 are H, and the other groups that are not H among R 1 , R 2 and R 3 are independently selected from the group consisting of: halogen and C 1-6 alkyl.

28. The compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein R 3 is present and is selected from halogen.

29. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein R 1 is H, and one or both of R 2 and R 3 are not H.

30. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, wherein each of R 2 and R 3 that is not H is independently selected from the group consisting of halogen and C 1-6 alkyl.

31. The compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein R 9 and R 10 one of which is H, and R 9 and R 10 the other of which is selected from the group consisting of: -C(O)R 14 、-C(O)OR 14 、-C(S)R 14 、and -C(S)OR 14 .

32. The compound or a pharmaceutically acceptable salt thereof according to claim 31, wherein each R 14 is an optionally substituted alkyl group having the formula -(CH 2 ) n (phenyl), where n is an integer of 0 or 1, and the phenyl is optionally substituted.

33. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein one of R 9 and R 10 is H, and the other of R 9 and R 10 is selected from the group consisting of: -C(O)NR 15 R 16 and -C(S)NR 15 R 16 .

34. The compound or a pharmaceutically acceptable salt thereof according to claim 33, wherein each R 15 and R 16 is independently selected from the group consisting of: (a) H and (b) optionally substituted alkyl having the chemical formula -(CH 2 ) n (phenyl), where n is an integer of 0 or 1, and the phenyl is optionally substituted.

35. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein one of R 9 and R 10 is H, and the other of R 9 and R 10 is -C(O)OR 14 .

36. The compound or a pharmaceutically acceptable salt thereof according to claim 35, wherein R 14 is an optionally substituted alkyl group having the formula -(CH 2 ) n (phenyl), where n is an integer of 0 or 1, and the phenyl is optionally substituted.

37. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and R 3 are each independently selected from the group consisting of: halogen; and C 1-6 alkyl.

38. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein one or two of R 1 , R 2 and R 3 are H, and the other groups that are not H among R 1 , R 2 and R 3 are independently selected from the group consisting of: halogen and C 1-6 alkyl.

39. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein R 1 is H, and one or both of R 2 and R 3 are not H, wherein each group that is not H in R 2 and R 3 is independently selected from the group consisting of halogen and C 1-6 alkyl.

40. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from halogen.

41. The compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein the compound of formula 1 is selected from the group consisting of: 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea (2) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-cyanophenyl)urea (3) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-chlorophenyl)urea (6) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-chlorophenyl)urea (7) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-chlorophenyl)urea (8) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-(trifluoromethoxy)phenyl)urea (9) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-(trifluoromethoxy)phenyl)urea (10) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-methoxyphenyl)urea (11) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-methoxyphenyl)urea (12) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-methoxyphenyl)urea (13) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(2-(trifluoromethyl)phenyl)urea (14) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (16) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-phenylurea (17) N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-phenylacetamide (18) N-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide (19) (5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)phenylcarbamate (4) 1-(5-Chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)-3-(3-(trifluoromethyl)phenyl)urea (15) 4-Fluorophenyl (5-chloro-4,6-dimethylisoxazolo[5,4-b]pyridin-3-yl)carbamate (5) and its pharmaceutically acceptable salts.

42. The compound or its pharmaceutically acceptable salt according to claim 23, wherein the compound of formula I is an IDO1 inhibitor.

43. The compound or its pharmaceutically acceptable salt according to claim 23, wherein the compound of formula I is a TDO inhibitor.

44. The compound or its pharmaceutically acceptable salt according to claim 23, wherein the compound is an IDO1 inhibitor and a TDO inhibitor.

45. Use of the compound of formula I as defined in any one of claims 23 to 44 or the compound of formula I as defined in the pharmaceutical composition according to any one of claims 1 to 22, or its pharmaceutically acceptable salt, in the manufacture of a medicament for treating cancer in warm-blooded animals by inhibiting IDO1 and / or TDO.

46. The use according to claim 45, wherein the warm-blooded animal is a human.

47. Use of the compound of formula I as defined in any one of claims 23 to 44 or the compound of formula I as defined in the pharmaceutical composition according to any one of claims 1 to 22, or its pharmaceutically acceptable salt, in the manufacture of a medicament for treating cancer in warm-blooded animals by inhibiting IDO1 and / or TDO, wherein the treatment comprises administering the compound of formula I and one or more additional agents selected from the group consisting of chemotherapeutic agents, immunomodulators, immune checkpoint protein modulators, adoptive T cell immunotherapeutic agents, and radiotherapy agents, and wherein the additional agents are administered before, during, or after the administration of the compound of formula I.

48. The use according to claim 47, wherein the warm-blooded animal is a human.

49. The use according to claim 47, wherein the additional agent comprises an immunomodulator.

50. Use of the compound of formula I as defined in any one of claims 23 to 44 or the compound of formula I as defined in the pharmaceutical composition according to any one of claims 1 to 22, or its pharmaceutically acceptable salt, in the manufacture of a medicament for inhibiting indoleamine-2,3-dioxygenase 1 (IDO1) in warm-blooded animals in need thereof, wherein the compound has IDO1 inhibitory activity.

51. Use of the compound of formula I as defined in any one of claims 23 to 44 or the compound of formula I as defined in the pharmaceutical composition according to any one of claims 1 to 22, or its pharmaceutically acceptable salt, in the manufacture of a medicament for inhibiting tryptophan 2,3-dioxygenase (TDO) in warm-blooded animals in need thereof, wherein the compound has TDO inhibitory activity.

52. Use of the compound of formula I as defined in any one of claims 23 to 44 or the compound of formula I as defined in the pharmaceutical composition according to any one of claims 1 to 22, or its pharmaceutically acceptable salt, in the manufacture of a medicament for inhibiting IDO1 and TDO in warm-blooded animals in need thereof, wherein the compound has IDO1 and TDO inhibitory activity.

53. Use according to any one of claims 50 - 52, wherein the warm-blooded animal is a human.

54. A pharmaceutical combination or kit, comprising (a) a compound of formula I according to any one of claims 23 to 44 or a compound of formula I as defined in the pharmaceutical composition according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and (b) one or more additional agents selected from the group consisting of: chemotherapeutic agents, and immunomodulators, immune checkpoint protein modulators, and adoptive T cell immunotherapeutic agents.

55. Use of a compound of formula I according to any one of claims 23 to 44 or a compound of formula I as defined in the pharmaceutical composition according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition or disorder by inhibiting IDO1 and / or TDO, wherein the condition or disorder is selected from the group consisting of: inflammatory conditions, infectious diseases, central nervous system diseases or disorders, coronary heart disease, chronic renal failure, postanesthetic cognitive dysfunction, conditions or disorders related to female reproductive health, and cataracts.

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