Pyridazinylthiazolecarboxamides

Abstract

The present invention relates to pyridazinyl thiazole carboxamide compounds. The present invention provides compounds useful as active ingredients of pharmaceutical compositions for the treatment of cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. The present inventors have studied compounds useful as active ingredients of pharmaceutical compositions for the treatment of cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, and confirmed that pyridazinyl thiazole carboxamide compounds have DGKζ (DGKzeta) inhibitory effects, thereby completing the present invention. The pyridazinyl thiazole carboxamide compounds of the present invention have DGKζ inhibitory effects and can be used as therapeutic agents for cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

Description

[0001] This application is a divisional application of the invention patent application with the application date of December 24, 2020, application number 202080011114.X (international application number PCT / JP2020 / 048337), and invention name "Pyridazinylthiazolecarboxamide compounds". Technical Field

[0002] The present invention relates to pyridazinylthiazolecarboxamide compounds that are expected to be useful as pharmaceutical compositions and diacylglycerol kinase zeta (DGKzeta) inhibitors, for example, pyridazinylthiazolecarboxamide compounds that are expected to be useful as active ingredients in pharmaceutical compositions for treating cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly cancers associated with immune cell activation that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. Background Art

[0003] Cancer immunotherapy is gaining attention as the fourth pillar of cancer treatment, following existing surgical treatment, radiotherapy, and cancer drug therapy (chemotherapy, molecularly targeted drugs). The path forward is paved by anti-cytotoxic T lymphocyte antigen (CTLA)-4 antibodies (ipilimumab) and anti-PD-1 antibodies (nivolumab, pembrolizumab). CTLA-4 and PD-1 are known as immune checkpoint molecules, functioning as co-stimulatory molecules that receive inhibitory signals. Currently, anti-PD-1 antibodies have been shown to be clinically effective against a variety of cancers, including melanoma and non-small cell lung cancer, and their application is expanding. Furthermore, in recent years, the development of antibodies targeting checkpoint molecules other than CTLA-4 and PD-1 has become increasingly active worldwide.

[0004] DGK is an enzyme that phosphorylates diacylglycerol (DAG) and converts it into phosphatidic acid (PA). In mammals, there are 10 subtypes, which are roughly divided into five categories based on their structural characteristics. These subtypes are type I (α, β, γ), type II (δ, η, κ), type III (ε), type IV (ζ, ι), and type V (θ). All subtypes have a highly homologous catalytic domain at the C-terminus and a C1 domain within the molecule that is homologous to protein kinase C (PKC). The C1 domain is believed to be the domain that binds to phorbol ester / DAG (Int. J. Mol. Sci. 2013, 14:6649-6673).

[0005] In T cells, phospholipase Cγ1 (PLCγ1), activated by antigen stimulation, generates DAG and inositol triphosphate (IP3) from phosphatidylinositol-4,5-bisphosphate (PIP2). The generated DAG activates multiple downstream signaling pathways including RAS, NF-κB, and AKT, leading to T cell activation. On the other hand, IP3 is activated by Ca from the endoplasmic reticulum. 2+ The release of NFAT signaling activates the nuclear factor of activated T cells (NFAT), which not only participates in T cell activation but also in the induction of anergy. T cell anergy refers to an incomplete activation state caused by reduced or suppressed co-stimulation (CD28 signaling) during antigen recognition, resulting in a state of inability to respond even to restimulation.

[0006] DGKα and DGKζ are two major isoforms in T cells. These isoforms regulate the intensity of DAG signaling downstream of antigen stimulation to prevent excessive T cell activation. In addition, DGKα and DGKζ promote T cell anergy and play an important role in T cell immune tolerance (J Cell Sci. 2013, 126: 2176-2186., Crit Rev Immunol. 2013, 33: 97-118., Immunol Rev. 2008, 224: 249-264).

[0007] Furthermore, it has been reported that activated T cells lacking DGKζ are resistant to PD-1-mediated inhibitory signals and to PD-1-independent immunosuppressive factors such as transforming growth factor (TGF)-β, adenosine, and PGE2 (Cancer Res. 2017, 77:5676-5686; Front Cell Dev Biol. 2016, 4:108). It has also been reported that T cells overexpressing PD-1 become extremely exhausted, rendering anti-PD-1 antibodies ineffective in this state. Furthermore, immunosuppressive factors such as TGF-β are thought to be a mechanism of resistance to anti-PD-1 therapy (Cancer Treatment Reviews 2017, 52:71-81). It has been reported that DGKζ negatively controls NK cell activation caused by activating receptor stimulation in NK cells, and the proliferation of major histocompatibility complex (MHC) class I-deficient tumors is suppressed in DGKζKO mice (J Immunol. 2016, 197: 934-941).

[0008] Therefore, the development of DGKζ inhibitors is expected to leverage anti-tumor effects through immune cell activation, particularly T cell activation. Furthermore, the objective efficacy of anti-PD-1 antibody therapy has been reported to be approximately 30%, although this varies depending on the type of cancer (Front Immunol. 2016, 7:550). Therefore, DGKζ inhibitors are expected to be useful in patients resistant to such anti-PD-1 antibody therapy.

[0009] Patent Document 1 discloses that R59022 and R59499 have a DGK inhibitory effect, alleviate T cell anergy, and enhance immune response.

[0010]

[0011] Patent Document 2 discloses that the compound represented by the following general formula has a trkA receptor inhibitory activity and is useful for treating or preventing urinary frequency, urinary urgency, and the like associated with overactive bladder.

[0012]

[0013] (For the meaning of the symbols in the formula, please refer to the bulletin)

[0014] However, Patent Document 2 does not specifically disclose the use for cancer treatment or the compound of the present invention containing a phenyl group having four consecutive adjacent substituents as essential constituents.

[0015] Patent Document 3 discloses that the compound represented by the following general formula is useful as a protein kinase inhibitor such as cyclin-dependent kinase (CDK) for treating or preventing proliferative diseases, etc. Patent Document 3 also discloses the compound of Example 199 (hereinafter referred to as Compound C).

[0016]

[0017] (For the meaning of the symbols in the formula, please refer to the bulletin)

[0018] However, Patent Document 3 does not specifically disclose DGK or the compound of the present invention containing a phenyl group having four consecutive adjacent substituents as essential constituents.

[0019] Prior art literature

[0020] Patent Literature

[0021] Patent Document 1: U.S. Patent No. 7,381,401

[0022] Patent Document 2: International Publication No. WO2007 / 123269

[0023] Patent Document 3: International Publication No. WO2008 / 054702 Summary of the Invention

[0024] Problems to be solved by the invention

[0025] Provided are compounds that are expected to be useful as pharmaceutical compositions, for example, DGKζ inhibitors, and compounds that are useful as active ingredients in pharmaceutical compositions for treating cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy and associated with immune cell activation.

[0026] Methods used to solve problems

[0027] The present inventors have conducted intensive research on compounds useful as active ingredients in pharmaceutical compositions for treating cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly in pharmaceutical compositions for treating cancers associated with immune cell activation that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. As a result, they discovered that pyridazinylthiazolecarboxamide compounds of formula (I) containing a phenyl group having four consecutive adjacent substituents as essential components, which are generally difficult to produce, have excellent DGKζ inhibitory activity, leading to the completion of the present invention.

[0028] That is, the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing the compound of formula (I) or a salt thereof, and one or more pharmaceutically acceptable excipients.

[0029]

[0030] (Where,

[0031] R 1 is the following formula (i), (ii), (iii), (iv) or (v),

[0032]

[0033] R 2 C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 alkyl), methylsulfonyl, halo C 1-6 Alkyl or halogen,

[0034] R 3 i) is selected by C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C1-6 Alkyl), -O-(halogenated C 1-6 alkyl), cyano, nitro, methanesulfonyl and halogen substituted or unsubstituted phenyl; ii) is selected from the group consisting of C 1-6 Alkyl and halogen substituted or unsubstituted C 3-8 Cycloalkyl; iii) is selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C 1-6 alkyl), cyano, nitro, methanesulfonyl and halogen substituted or unsubstituted pyridyl; iv) is selected from C 1-6 substituted or unsubstituted pyrazolyl group selected from the group consisting of alkyl and halogen; or v) C 1-6 Alkyl-substituted or unsubstituted pyrrolidinyl,

[0035] R 4 is H or F,

[0036] L is a bond, CO, SO2, O or NH,

[0037] X is CH2, O or N-methyl,

[0038] Y is CH2 or O,

[0039] R a is H or methyl,

[0040] R b is H, methyl, ethyl or -(CH2)2O-CH3,

[0041] R c is H, methyl or oxetane,

[0042] R d is H, methyl, -(CH2)2OH, -(CH2)2O-CH3 or oxetane,

[0043] m is 1 or 2,

[0044] n is 1 or 2.)

[0045] It should be noted that, unless otherwise specified, when a symbol in a chemical formula in the present specification is used in another chemical formula, the same symbol has the same meaning.

[0046] In addition, the present invention relates to a pharmaceutical composition for treating cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, comprising a compound of formula (I) or a salt thereof, and in particular, a pharmaceutical composition for treating cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. It should be noted that the pharmaceutical composition comprises a therapeutic agent for cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, comprising a compound of formula (I) or a salt thereof, and in particular, a therapeutic agent for cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

[0047] The present invention also relates to a compound of formula (I) or a salt thereof as a DGKζ inhibitor, a compound of formula (I) or a salt thereof for use as a DGKζ inhibitor, a DGKζ inhibitor containing a compound of formula (I) or a salt thereof, and the use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for treating cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, in particular, the use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for treating cancers associated with immune cell activation that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, and the use of a compound of formula (I) or a salt thereof in the treatment of cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, in particular, a compound of formula (I) or a salt thereof. Use in treating cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy and associated with immune cell activation, a compound of formula (I) or a salt thereof for use in treating cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly a compound of formula (I) or a salt thereof for use in treating cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy and associated with immune cell activation, and a method for treating cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy and associated with immune cell activation, particularly a method for treating cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy and associated with immune cell activation, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a subject. It should be noted that "subject" refers to a human or other animal in need of prevention or treatment, and in one embodiment, refers to a human in need of prevention or treatment.

[0048] Effects of the Invention

[0049] The compound of formula (I) or a salt thereof has a DGKζ inhibitory effect and can be used as a therapeutic agent for cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly for cancers associated with immune cell activation that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. DETAILED DESCRIPTION

[0050] Hereinafter, the present invention will be described in detail.

[0051] In this specification, unless otherwise specified, the following terms have the meanings indicated below. The following definitions are provided to clarify the defined terms and are not intended to limit them. In the absence of a specific definition for a term used herein, the term is used with the meaning generally accepted by those skilled in the art.

[0052] In this manual, “C 1-6 "Alkyl" refers to a linear or branched chain with 1 to 6 carbon atoms (hereinafter referred to as C 1-6 ) alkyl. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. As one embodiment, C 1-3 Alkyl; as one embodiment, methyl or ethyl; as one embodiment, methyl; as one embodiment, ethyl.

[0053] "Halogenated C 1-6 "Alkyl" refers to a C 1-6 Alkyl. In one embodiment, C 1-6 Alkyl; as one embodiment, a halogenated C substituted with 1 to 5 halogens 1-3 Alkyl; in one embodiment, difluoromethyl or trifluoromethyl; in one embodiment, trifluoromethyl.

[0054] “C 3-8 "Cycloalkyl" refers to C 3-8 The saturated hydrocarbon ring group may be cross-linked or spiro-cyclic. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2,2,1]heptyl, bicyclo[3,1,0]hexyl, bicyclo[3,1,1]heptyl, spiro[2,5]octyl, etc. As one embodiment, C 3-5 Cycloalkyl. As C 3-5 One embodiment of the cycloalkyl group is cyclopropyl, cyclobutyl or cyclopentyl; another embodiment is cyclopropyl; another embodiment is cyclobutyl; another embodiment is cyclopentyl.

[0055] "Halogen" refers to F, Cl, Br, I, and in one embodiment, F or Cl; in another embodiment, F; in another embodiment, Cl.

[0056] “Substituted or unsubstituted by…” means unsubstituted or “substituted by one or more substituents (for example, substituents defined below)”. Substitution may be at any position as long as it is at a position where hydrogen is normally present in the group. In one embodiment, “substituted or unsubstituted by…” means “substituted or unsubstituted by 1 to 5 substituents”, and in another embodiment, it means “substituted or unsubstituted by 1 to 3 substituents”. It should be noted that in the case of multiple substitutions, their substituents may be the same or different.

[0057] Furthermore, even if no combination is specifically described, one or two or more aspects may be combined into other aspects. In other words, all aspects can be freely combined.

[0058] "Immune cell activation" refers to the reactivation of immune cells, particularly T cells, that have the ability to inhibit cancer cell proliferation or cause cancer cell shrinkage or elimination (hereinafter referred to as anti-tumor activity); and / or the increase in the number of immune cells, particularly activated T cells. One embodiment includes immune cell activation based on DGKζ inhibition.

[0059] "Cancer associated with immune cell activation" refers to cancer that exhibits immune responsiveness. In one embodiment, this refers to cancer in which cancer cell proliferation is suppressed, or cancer cells are reduced or eliminated, due to immune cell activation. In another embodiment, this refers to cancer in which cancer cell proliferation is suppressed, or cancer cells are reduced or eliminated, due to immune cell activation. In another embodiment, this refers to cancer in which cancer cell proliferation is suppressed, or cancer cells are reduced or eliminated, due to immune cell activation through DGKζ inhibition. In another embodiment, this refers to cancer in which cancer cell proliferation is suppressed, or cancer cells are reduced or eliminated, due to immune cell activation through DGKζ inhibition.

[0060] Cancers to which the present invention is applicable are not particularly limited, and examples thereof include small cell lung cancer, head and neck cancer, renal cancer, ovarian cancer, non-small cell lung cancer, mismatch repair-deficient colorectal cancer, urothelial carcinoma, melanoma, hepatocellular carcinoma, gastric cancer, and bladder cancer.

[0061] "Resistance to anti-PD-1 antibody / anti-PD-L1 antibody therapy" refers to resistance to anti-PD-1 antibody and / or anti-PD-L1 antibody therapy. In one embodiment, it refers to resistance to both anti-PD-1 and anti-PD-L1 antibody therapy; in another embodiment, it refers to resistance to anti-PD-1 antibody therapy; in another embodiment, it refers to resistance to anti-PD-L1 antibody therapy. Specifically, it refers to the initial ineffectiveness of immunotherapy based on anti-PD-1 and / or anti-PD-L1 antibodies (primary resistance) or the development of treatment resistance (acquired resistance) midway through treatment, leading to renewed cancer cell proliferation.

[0062] "Cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy" refers to cancer resistant to anti-PD-1 antibody and / or anti-PD-L1 antibody therapy. In one embodiment, this refers to cancer resistant to anti-PD-1 and anti-PD-L1 antibody therapy; in another embodiment, this refers to cancer resistant to anti-PD-1 antibody therapy; in another embodiment, this refers to cancer resistant to anti-PD-L1 antibody therapy; in another embodiment, this refers to cancer in which immunotherapy based on anti-PD-1 and / or anti-PD-L1 antibodies is ineffective from the beginning of treatment (primary resistance) or develops resistance to treatment midway (acquired resistance), leading to recurrence of cancer cells.

[0063] Cancers to which the present invention can be applied are not particularly limited, and examples thereof include small cell lung cancer, head and neck cancer, renal cancer, ovarian cancer, non-small cell lung cancer, mismatch repair-deficient colorectal cancer, urothelial carcinoma, melanoma, hepatocellular carcinoma, gastric cancer, and bladder cancer, which are cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

[0064] The “anti-PD-1 antibody / anti-PD-L1 antibody” is not particularly limited, and examples thereof include antibodies selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, pidilizumab, avelumab, and durvalumab.

[0065] One embodiment of the compound of formula (I) or a salt thereof of the present invention is shown below.

[0066] (1-1)R 1 It is a compound of the following formula (i), (ii), (iii), (iv) or (v) or a salt thereof.

[0067]

[0068] (1-2)R 1 It is a compound of the following formula (ia), (ii-a), (iii-a) or (v) or a salt thereof.

[0069]

[0070] (1-3)R 1 It is a compound of the following formula (i), (ii), (iii) or (iv) or a salt thereof.

[0071]

[0072] (1-4)R 1 It is a compound represented by the following formula (ia), (ii-a) or (iii-a) or a salt thereof.

[0073]

[0074] (2)R 2 C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 alkyl), methylsulfonyl, halo C 1-6 An alkyl or halogen compound or a salt thereof. In one embodiment, R 2 Halogenated C 1-6 An alkyl or halogen compound or a salt thereof. In one embodiment, R 2 Halogenated C 1-3 A compound or a salt thereof of an alkyl group, F, Cl or Br. In one embodiment, R 2 is a compound or a salt thereof of CF3, F or Cl. In one embodiment, R 2 A compound or a salt thereof of CF3. 2 A compound or a salt thereof wherein R 2 is a compound of Cl or a salt thereof.

[0075] (3-1) A compound or a salt thereof, wherein R 3 i) is selected by C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C 1-6 alkyl), cyano, nitro, methanesulfonyl and halogen substituted or unsubstituted phenyl; ii) is selected from the group consisting of C 1-6 Alkyl and halogen substituted or unsubstituted C 3-8 Cycloalkyl; iii) is selected from C 1-6Alkyl, halogenated C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C 1-6 alkyl), cyano, nitro, methanesulfonyl and halogen substituted or unsubstituted pyridyl; iv) is selected from C 1-6 substituted or unsubstituted pyrazolyl group selected from the group consisting of alkyl and halogen; or v) C 1-6 Alkyl-substituted or unsubstituted pyrrolidinyl.

[0076] (3-2) A compound or a salt thereof, wherein R 3 i) is selected by C 1-6 phenyl substituted or unsubstituted by a group selected from the group consisting of alkyl, cyano, nitro and halogen; ii) C 3-8 cycloalkyl; iii) pyridyl; iv) C 1-6 alkyl-substituted or unsubstituted pyrazolyl; or v) pyrrolidinyl.

[0077] (3-3) A compound or a salt thereof, wherein R 3 i) is selected by C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C 1-6 alkyl), cyano, nitro, methanesulfonyl and halogen substituted or unsubstituted phenyl; or ii) is selected from the group consisting of C 1-6 Alkyl and halogen substituted or unsubstituted C 3-8 Cycloalkyl.

[0078] (3-4) A compound or a salt thereof, wherein R 3 To be selected by C 1-6 A substituted or unsubstituted phenyl or C 3-5 Cycloalkyl.

[0079] (4)R 4 is a compound or a salt thereof in which R 4 A compound or a salt thereof in which R 4 is a compound of F or a salt thereof.

[0080] (5) A compound or a salt thereof in which L is a bond, CO, SO2, O, or NH. In one embodiment, a compound or a salt thereof in which L is a bond, O, or NH. In one embodiment, a compound or a salt thereof in which L is O or NH. In one embodiment, a compound or a salt thereof in which L is O. In one embodiment, a compound or a salt thereof in which L is NH.

[0081] (6) A compound or a salt thereof in which X is CH2, O or N-methyl. In one embodiment, X is a compound or a salt thereof in which X is CH2 or N-methyl. In one embodiment, X is a compound or a salt thereof in which X is CH2. In one embodiment, X is a compound or a salt thereof in which X is N-methyl.

[0082] (7) A compound or a salt thereof, wherein Y is CH2 or O. In one embodiment, a compound or a salt thereof, wherein Y is CH2. In one embodiment, a compound or a salt thereof, wherein Y is O.

[0083] (8)R a is a compound or a salt thereof in which R a A compound or a salt thereof in which R a A compound or a salt thereof in which is methyl.

[0084] (9)R b is a compound or a salt thereof which is H, methyl, ethyl or -(CH2)2O-CH3. b is a compound or a salt thereof in which R b A compound or a salt thereof in which R b A compound or a salt thereof in which is methyl.

[0085] (10)R c is a compound or a salt thereof in which R is H, methyl or oxetane. c is a compound or a salt thereof in which R c A compound or a salt thereof in which R c A compound or a salt thereof in which is methyl.

[0086] (11)R d A compound or a salt thereof is H, methyl, -(CH2)2OH, -(CH2)2O-CH3 or an oxetane group. In one embodiment, R d A compound or a salt thereof which is -(CH2)2OH or -(CH2)2O-CH3. d A compound or a salt thereof which is -(CH2)2OH. d A compound or a salt thereof which is -(CH2)2O-CH3.

[0087] (12) The compound or salt thereof, wherein m is 1 or 2. In one embodiment, the compound or salt thereof, wherein m is 1. In one embodiment, the compound or salt thereof, wherein m is 2.

[0088] (13) The compound or salt thereof, wherein n is 1 or 2. In one embodiment, the compound or salt thereof, wherein n is 1. In one embodiment, the compound or salt thereof, wherein n is 2.

[0089] (14) A compound or a salt thereof, which is a combination of any two or more of the above-mentioned embodiments (1-1) to (13) that are not inconsistent with each other.

[0090] Specific examples of the combination described in (14) include the following.

[0091] (15) A compound or a salt thereof, wherein R 1 is the following formula (i), (ii), (iii), (iv) or (v),

[0092]

[0093] R 2 C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 alkyl), methylsulfonyl, halo C 1-6 Alkyl or halogen, R 3 i) is selected by C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C 1-6 alkyl), cyano, nitro, methanesulfonyl and halogen substituted or unsubstituted phenyl; ii) is selected from the group consisting of C 1-6 Alkyl and halogen substituted or unsubstituted C 3-8 Cycloalkyl; iii) is selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C 1-6 alkyl), cyano, nitro, methanesulfonyl and halogen substituted or unsubstituted pyridyl; iv) is selected from C 1-6 substituted or unsubstituted pyrazolyl group selected from the group consisting of alkyl and halogen; or v) C 1-6 Alkyl-substituted or unsubstituted pyrrolidinyl, R 4 is H or F, L is a bond, CO, SO2, O or NH, X is CH2, O or N-methyl, Y is CH2 or O, R a is H or methyl, R b is H, methyl, ethyl or -(CH2)2O-CH3, R c is H, methyl or oxetane, Rd is H, methyl, -(CH2)2OH, -(CH2)2O-CH3 or oxetanyl, m is 1 or 2, and n is 1 or 2.

[0094] (16) The compound or salt thereof according to (15), wherein R 2 Halogenated C 1-6 Alkyl or halogen, L is a bond, O or NH, X is CH2 or N-methyl, R c is H or methyl, and m is 1.

[0095] (17) The compound or salt thereof according to (16), wherein R 1 It is the following formula (ia), (ii-a), (iii-a) or (v).

[0096]

[0097] (18) The compound or salt thereof according to (17), wherein R 3 To be selected by C 1-6 A substituted or unsubstituted phenyl or C 3-5 Cycloalkyl.

[0098] (19) The compound or salt thereof according to (18), wherein R 2 CF3, R 4 H, R b is H or methyl, R c For H.

[0099] Specific examples of the combination described in (14) include the following.

[0100] (20) A compound or a salt thereof, wherein R 1 is the following formula (i), (ii), (iii) or (iv),

[0101]

[0102] R 2 Halogenated C 1-6 Alkyl or halogen, R 3 i) is selected by C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C 1-6 alkyl), cyano, nitro, methanesulfonyl and halogen substituted or unsubstituted phenyl; ii) is selected from the group consisting of C 1-6 Alkyl and halogen substituted or unsubstituted C3-8 Cycloalkyl; iii) is selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C 1-6 alkyl), cyano, nitro, methanesulfonyl and halogen substituted or unsubstituted pyridyl; iv) is selected from C 1-6 substituted or unsubstituted pyrazolyl group selected from the group consisting of alkyl and halogen; or v) C 1-6 Alkyl-substituted or unsubstituted pyrrolidinyl, R 4 is H or F, L is a bond, O or NH, X is CH2, O or N-methyl, Y is CH2 or O, R a is H or methyl, R b is H, methyl, ethyl or -(CH2)2O-CH3, R c is H, methyl or oxetane, R d is H, methyl, -(CH2)2OH, -(CH2)2O-CH3 or oxetanyl, m is 1 or 2, and n is 1 or 2.

[0103] (21) The compound or salt thereof according to (20), wherein R 1 is the following formula (i), (ii), (iii) or (iv),

[0104]

[0105] R 2 Halogenated C 1-6 Alkyl or halogen, R 3 i) is selected by C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C 1-6 alkyl), cyano, nitro, methanesulfonyl and halogen substituted or unsubstituted phenyl; ii) is selected from the group consisting of C 1-6 Alkyl and halogen substituted or unsubstituted C 3-8 Cycloalkyl; iii) is selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C 1-6 alkyl), cyano, nitro, methanesulfonyl and halogen substituted or unsubstituted pyridyl; iv) is selected from C 1-6substituted or unsubstituted pyrazolyl group selected from the group consisting of alkyl and halogen; or v) C 1-6 Alkyl-substituted or unsubstituted pyrrolidinyl, R 4 is H or F, L is O or NH, X is CH2 or N-methyl, Y is CH2 or O, R a H, R b is H, methyl, ethyl or -(CH2)2O-methyl, R c is H or methyl, R d is H, methyl, -(CH2)2OH, -(CH2)2O-CH3 or oxetanyl, m is 1, and n is 1 or 2.

[0106] (22) The compound or salt thereof according to (21), wherein R 1 It is the following formula (ia), (ii-a) or (iii-a).

[0107]

[0108] (23) The compound or salt thereof according to (22), wherein R 3 To be selected by C 1-6 A substituted or unsubstituted phenyl or C 3-5 Cycloalkyl.

[0109] (24) The compound or salt thereof according to (23), wherein R 2 CF3, R 4 H, R b is H or methyl, R c For H.

[0110] As specific examples of the compounds included in the present invention, the following compounds or salts thereof can be mentioned.

[0111] N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide,

[0112] N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(3-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide,

[0113] N-{2-[9-(2-methoxyethyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide,

[0114] N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide,

[0115] N-[4-(2-fluorophenoxy)-2-{(3S)-3-[(methylamino)methyl]piperidin-1-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide,

[0116] N-{2-[(2R)-2-(aminomethyl)pyrrolidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide,

[0117] N-{2-[(8R,8aS)-8-aminohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide, and

[0118] N-{2-[(8R,8aS)-8-(dimethylamino)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide.

[0119] As specific examples of the compounds included in the present invention, the following compounds or salts thereof can be mentioned.

[0120] N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide,

[0121] N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(3-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide,

[0122] N-{2-[9-(2-methoxyethyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide,

[0123] N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide,

[0124] N-[4-(2-fluorophenoxy)-2-{(3S)-3-[(methylamino)methyl]piperidin-1-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide, and

[0125] N-{2-[(2R)-2-(Aminomethyl)pyrrolidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide.

[0126] As specific examples of the compound or its salt included in the present invention, the following compounds or their salts can be mentioned.

[0127] N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide mono[(2E)-2-butenedioic acid] salt,

[0128] N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(3-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide mono[(2E)-2-butenedioic acid] salt,

[0129] N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide mono[(2E)-2-butenedioic acid] salt,

[0130] N-[4-(2-fluorophenoxy)-2-{(3S)-3-[(methylamino)methyl]piperidin-1-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide mono[(2E)-2-butenedioic acid] salt, and N-{2-[(2R)-2-(aminomethyl)pyrrolidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide mono[(2E)-2-butenedioic acid] salt.

[0131] In the compound of formula (I), tautomers and geometric isomers may exist depending on the type of substituents. In this specification, the compound of formula (I) or its salt is sometimes described as only one form of isomer, but the present invention also includes other isomers, and also includes isomer isolates or mixtures thereof.

[0132] In addition, the compound of formula (I) or its salt sometimes has an asymmetric center or axial asymmetry, and there will be enantiomers (optical isomers) based on this. The compound of formula (I) or its salt also includes any of the enantiomers such as the (R) body and the (S) body separated, and their mixtures (including racemic mixtures or non-racemic mixtures). In one embodiment, the enantiomer is "stereochemically pure". "Stereochemically pure" refers to the purity to the extent that a person skilled in the art can substantially identify it as stereochemically pure. As another embodiment, the enantiomer is, for example, a compound having a stereochemical purity of 90% ee (enantiomeric excess) or more, 95% ee or more, 98% ee or more, or 99% ee or more.

[0133] In addition, the salt of the compound of formula (I) refers to a pharmaceutically acceptable salt of the compound of formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. Specifically, examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid ((2E)-2-butenedioic acid), maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid; inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; and various amino acids and amino acid derivatives such as acetylleucine.

[0134] In addition, the present invention also includes various hydrates, solvates and polymorphs of the compound of formula (I) and its salts.

[0135] In addition, the present invention also includes pharmaceutically acceptable prodrugs of the compounds represented by formula (I). Pharmaceutically acceptable prodrugs are compounds having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of prodrug-forming groups include those described in Prog. Med., 5, 2157-2161 (1985) and in "Development of Pharmaceuticals" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design, 163-198.

[0136] In addition, the present invention includes all pharmaceutically acceptable compounds of formula (I) or salts thereof that are labeled with one or more radioactive or non-radioactive isotopes. Examples of isotope-labeled isotopes suitable for use in the compounds of the present invention include hydrogen ( 2 H and 3 H, etc.), carbon ( 11 C. 13 C and 14 C, etc.), nitrogen ( 13N and 15 N, etc.), oxygen ( 15 O. 17 O and 18 O, etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I, etc.), phosphorus ( 32 P, etc.), sulfur ( 35 S, etc.)

[0137] The compounds of the present invention labeled with isotopes can be used for studies such as tissue distribution of drugs and / or substrates. For example, tritium ( 3 H), carbon 14 ( 14 C) and other radioactive isotopes can be used for this purpose.

[0138] Substitution of hydrogen to a heavier isotope, such as deuterium ( 2 H) substitution may sometimes be therapeutically advantageous due to improved metabolic stability (e.g., increased in vivo half-life, reduced dosage requirements, reduced drug interactions).

[0139] To test substrate receptor occupancy, positron emitting isotopes ( 11 C. 18 F. 15 O and 13 N, etc.) can be used in positron emission tomography (PET) experiments.

[0140] The isotope-labeled compounds of the present invention can generally be produced by conventional methods known to those skilled in the art, or by the same production methods as in the Examples or Production Examples using appropriate isotope-labeled reagents instead of unlabeled reagents.

[0141] About the powder X-ray diffraction pattern described in this specification, in the identification of the identity of crystallization, the nature of the data, lattice spacing, overall pattern are very important, and the diffraction angle and diffraction intensity may produce some errors according to the direction of crystal growth, the size of the particles, and the measurement conditions, and therefore should not be strictly interpreted. In this specification, the diffraction angle (2θ (°)) in the powder X-ray diffraction pattern is interpreted after considering the error range generally allowed in the determination method, and as a way, an error range of ± 0.2° can be taken. In addition, for example, when measuring in the state of a mixture with an excipient, for a peak present near the peak from the excipient and in the slope of the baseline, the apparent peak is likely to shift within the range of ± 0.3°.

[0142] (Manufacturing Method)

[0143] The compound of formula (I) and salt thereof can utilize the feature based on the kind of its basic structure or substituent, and various known synthetic methods are applied to manufacture.At this moment, according to the kind of functional group, sometimes in advance, the functional group is replaced with suitable protecting group (can be easily converted into the group of this functional group) in the stage from raw material to intermediate and is effective in manufacturing technology.As such protecting group, for example, can enumerate the protecting group etc. recorded in Wuts (PGM Wuts) and Greene (TW Greene) write, " Greene's Protective Groups in Organic Synthesis (the 4th edition, 2006) ", can suitably select to use according to their reaction conditions.In such method, after importing this protecting group and reacting, remove protecting group as required, thus can obtain desired compound.

[0144] In addition, the prodrug of the compound of formula (I) can be prepared by introducing a specific group at the stage from the raw material to the intermediate or further reacting the obtained compound of formula (I) in the same manner as the above-mentioned protecting group. The reaction can be carried out by applying methods well known to those skilled in the art such as conventional esterification, amidation, and dehydration.

[0145] Representative methods for producing compounds of formula (I) are described below. Each method can also be performed with reference to the references appended to this description. It should be noted that the production method of the present invention is not limited to the examples shown below.

[0146] In this specification, the following abbreviations are sometimes used.

[0147] DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide, EtOAc = ethyl acetate, EtOH = ethanol, Hex = hexane, MeCN = acetonitrile, MeOH = methanol, THF = tetrahydrofuran, DMI = 1,3-dimethyl-2-imidazolidinone, NMP = N-methyl-2-pyrrolidone, CH2Cl2 = dichloromethane.

[0148] Boc = tert-butoxycarbonyl, Ph = phenyl, tBu = tert-butyl, Et = ethyl, Me = methyl, Ac = acetyl, Ns = 2-nitrobenzenesulfonyl.

[0149] CDI = 1,1'-carbonylbis(1H-imidazole), DCC = N,N'-dicyclohexylcarbodiimide, TEA = triethylamine, DIPEA = N,N-diisopropylethylamine, DABCO = 1,4-diazabicyclo[2.2.2]octane, DPPA = diphenylphosphorylazide, HATU = O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HOBt = 1-hydroxybenzotriazole, KOtBu = potassium tert-butoxide, NaOtBu = sodium tert-butoxide, NMO = N-methylmorpholine, Pd / C = palladium on carbon, TFA = trifluoroacetic acid, TFAA = trifluoroacetic anhydride, WSC.HCl = N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride.

[0150] Pd(PPh3)4=tetrakis(triphenylphosphine)palladium, PdCl2(PPh3)2=bis(triphenylphosphine)palladium(II) dichloride, Pd(dppf)Cl2·CH2Cl2=[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, Pd2(dba)3=(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one / palladium (3:2).

[0151] brine = saturated aqueous NaCl solution, MgSO4 = anhydrous magnesium sulfate, Na2SO4 = anhydrous sodium sulfate, NaHCO3 = sodium bicarbonate, NH4Cl = ammonium chloride, NaBH(OAc)3 = sodium triacetoxyborohydride.

[0152]

[0153] (Where R 1a Represents R 1 or R 1 Protective group adducts.

[0154] (First process)

[0155] This step is a method of obtaining compound (2) by subjecting compound (1) to a reduction reaction.

[0156] The reaction can be carried out by stirring compound (1) and a metal in a mixed solvent of methanol, ethanol, 1,4-dioxane, or water under acidic conditions from room temperature to reflux for 1 hour to 5 days. Examples of the acid include NH4Cl, AcOH, and HCl. Examples of the metal include Fe, Zn, and Sn.

[0157] Alternatively, the reaction can be carried out by stirring compound (1) in the presence of a metal catalyst in a hydrogen atmosphere in a solvent inert to the reaction such as MeOH, EtOH, EtOAc, or a mixed solvent thereof, from cooling to heating, preferably at room temperature for 1 hour to 5 days. Examples of the metal catalyst include palladium catalysts such as Pd / C, palladium black, and palladium hydroxide-supported carbon, platinum catalysts such as platinum-supported carbon and platinum oxide, and nickel catalysts such as reduced nickel and Raney nickel.

[0158] (Second process)

[0159] This step is a method of obtaining a compound of formula (I) by subjecting compound (2) and compound (3) to an amidation reaction and then converting appropriate substituents.

[0160] In this amidation reaction, compound (2) and compound (3) are used in equal amounts or in excess of one of them, and their mixture is stirred in a solvent inert to the reaction in the presence of a condensing agent, from cooling to heating, preferably at -20°C to 60°C, for usually 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as CH2Cl2, 1,2-dichloroethane, and chloroform, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane, DMF, DMSO, EtOAc, MeCN, or water, and mixtures thereof. Examples of condensing agents include, but are not limited to, WSC.HCl, DCC, CDI, DPPA, POCl3, and HATU. In some cases, it is preferable to use an additive (e.g., HOBt) in the reaction. Conducting the reaction in the presence of an organic base such as TEA, DIPEA, or NMO, or an inorganic base such as K 2 CO 3 , Na 2 CO 3 , or KOH may sometimes facilitate the smooth progress of the reaction.

[0161] Alternatively, an amidation reaction may be used in which compound (3) is converted into a reactive derivative and then reacted with compound (2). Examples of reactive derivatives of compound (3) include acid halides obtained by reaction with a halogenating agent such as POCl3 or SOCl2, mixed acid anhydrides obtained by reaction with isobutyl chloroformate, and active esters obtained by condensation with HOBt. This reaction can be carried out in a solvent inert to the reaction, such as a halogenated hydrocarbon, aromatic hydrocarbon, or ether, under cooling or heating under reflux, preferably at -20°C to 120°C.

[0162] After the amidation reaction, the protective group is introduced and / or removed as needed, and then the appropriate substituent is converted to obtain a compound of formula (I). 1a R 1In the case of an adduct containing a protecting group, the protecting group can be removed under appropriate reaction conditions to obtain a compound of formula (I).

[0163] (Raw material synthesis)

[0164]

[0165] (LG 1 and LG 2 Indicates a leaving group. LG 1 and LG 2 is halogen, etc., and is different for each.)

[0166] This production method is a method for producing the starting compound (1).

[0167] (Third Process)

[0168] This step is a method for producing compound (6) from compound (5) by autosubstitution reaction.

[0169] This reaction is carried out in a reaction-inert solvent or in the absence of a solvent, with stirring from cooling to heating under reflux, preferably at 0°C to 120°C, for typically 0.1 hour to 5 days. Examples of solvents used herein are not particularly limited and include halogenated hydrocarbons such as CH2Cl2, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; DMF, DMSO, NMP, EtOAc, MeCN, and mixtures thereof. It may be beneficial to conduct the reaction in the presence of an organic base such as TEA, DIPEA, NMO, or DABCO; or an inorganic base such as NaH, K2CO3, Na2CO3, Cs2CO3, or NaOtBu to facilitate the reaction.

[0170] (Fourth Process)

[0171] This step is a method for producing compound (7) by Suzuki coupling reaction using compound (5) and an organoboron compound, or a method for producing compound (7) by Buchwald-Hartwig reaction using compound (5) and an amine compound.

[0172] This reaction is carried out in a reaction-inert solvent in the presence of a base and a palladium catalyst, typically with stirring from room temperature to reflux for 0.1 hours to 5 days. Examples of solvents used here are not particularly limited, but include: CH2Cl2, halogenated hydrocarbons such as 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, isopropanol, and butanol; DMF, DMSO, MeCN, DMI; water; and mixtures thereof. Examples of bases include inorganic bases such as NaH, K2CO3, Na2CO3, Cs2CO3, K3PO4, and CsF. Examples of palladium catalysts include Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2·CH2Cl2, and Pd2(dba)3. Performing the reaction in the presence of a ligand such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (SPhos) can sometimes facilitate the reaction. Furthermore, heating the reaction mixture by microwave irradiation can sometimes facilitate the reaction. For example, the following references can be used as references for this reaction.

[0173] J.Am.Chem.Soc.127,4685-4696,2005

[0174] Angew.Chem.,Int.Ed.Engl.34,1348-1350,1995

[0175] This step is also a method for producing compound (7) from compound (5) by autosubstitution reaction. The reaction conditions are the same as those in the third step.

[0176] (Fifth and Sixth Processes)

[0177] This step is a method for producing compound (1) from compound (6) or compound (7) by autosubstitution reaction.

[0178] The reaction conditions are the same as those in the third step.

[0179] It should be noted that, as another method for producing compound (1), the R 2 Replaced with a leaving group such as halogen (hereinafter, the leaving group such as halogen is referred to as LG 3 LG 3 With LG 1 and LG 2 Different. ) of the compound (5a) as a raw material, in the same manner as in the fourth step, the compound (7) is prepared by adding R 2 Replaced with LG 3Then, in the same manner as in the sixth step, the compound (1) is prepared by 2 Replaced with LG 3 The compound (1a) is prepared, and the compound (1) is produced in the same manner as in the fourth step.

[0180] The compound of formula (I) is isolated and purified as a free compound, a salt, a hydrate, a solvate or a polycrystalline substance thereof. A salt of the compound of formula (I) can also be produced by a salt-forming reaction according to a conventional method.

[0181] Isolation and purification can be carried out by applying common chemical operations such as extraction, fractional crystallization, and various chromatography methods.

[0182] Various isomers can be produced by selecting appropriate starting compounds, or can be separated by utilizing the differences in physicochemical properties between isomers. For example, optical isomers can be obtained by conventional optical resolution methods of racemates (e.g., fractional crystallization of diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.), or can be produced from appropriate optically active starting compounds.

[0183] The pharmacological activity of the compound of formula (I) can be confirmed by the following test or known modified test. It should be noted that, in this specification, the amount of the test compound is expressed by weight converted into the free form. In addition, when using commercially available reagents or test kits, it can be implemented according to the instructions of the commercial product.

[0184] Test Example 1 Evaluation of DGKζ Inhibitory Effect

[0185] Using ADP-Glo TM The following method was used to examine the inhibitory effect of the test compound on human recombinant DGKζ (Carna Bio, 12-410-20N) using Kinase Assay (Promega).

[0186] To a 384-well plate (Greiner Bio-one), 3 μL of DGKζ enzyme (90 ng / mL) dissolved in assay buffer (40 mM Tris-HCl pH 7.5, 10 mM MgCl2, 1 mM dithiothreitol (DTT), 0.1 mg / mL bovine serum albumin (BSA)) was added. Similarly, 3 μL of the test compound diluted in assay buffer was added to achieve the target final concentration. After standing at room temperature for 15 minutes, 3 μL of substrate (150 μM 1-oleoyl-2-acetyl-sn-glycerol (Sigma-Aldrich), 480 μM phosphatidylserine (Avanti), 150 μM UltraPure-ATP (ADP-Glo)) dissolved in Lipid dilution buffer (40 mM Tris-HCl pH 7.5, 0.1 mg / mL BSA, 1 mM DTT) was added and allowed to react at room temperature for 30 minutes. Then, 3 μL of ADP-Glo ​​Reagent was added and the reaction was stopped by standing at room temperature for 40 minutes. Furthermore, 6 μL of kinase detection reagent was added, and after standing at room temperature for 30 minutes, luminescence was measured using ARVOX3 (PerkinElmer). The signal value in the solvent treatment was set as 0% inhibition, and the signal value in the absence of DGKζ enzyme was set as 100% inhibition. The 50% inhibition concentration (IC) was calculated by Sigmoid-Emax model nonlinear regression analysis. 50 ). The results of several test compounds of formula (I) are shown in Table 1. It should be noted that in the table, Ex represents the example number described below. In addition, in the table, compound C (cpd.C) represents the test compound of Example 199 described in International Publication No. WO2008 / 054702.

[0187] [Table 1]

[0188]

[0189] Experimental Example 2 Evaluation of IL-2 Production in Human T-Cell Leukemia Cell Line Jurkat E6.1

[0190] The effects of test compounds on IL-2 production induced by T cell receptor (TCR) stimulation (anti-CD3 / anti-CD28) were evaluated in Jurkat E6.1 cells (ECACC, 88042803).

[0191] A 5 μg / mL anti-CD3 antibody (eBioscience, OKT3 clone) diluted with phosphate-buffered saline (PBS) was added to a 96-well plate (Iwaki) at 50 μL / well and allowed to stand at 4°C for at least 12 hours. A plate coated with anti-CD3 antibody was prepared in advance. When used in the experiment, the plate was washed once with 200 μL of PBS, and then an anti-CD28 antibody (eBioscience, 28.2 clone) diluted to a concentration of 10 μg / mL in a culture medium (RPMI1640 medium (Sigma-Aldrich) containing 10% fetal bovine serum (Hyclone)) was added at 10 μL / well. This plate was used as a culture plate for TCR stimulation and assayed.

[0192] Next, the test compound and Jurkat E6.1 cells were mixed to achieve the target final concentration, with 1×10 5 Cells were seeded in 90 μL / well (i.e., 1×10 5 Cells were cultured at 100 μL / well. Cell culture was performed using RPMI1640 medium containing 10% fetal bovine serum in the presence of 5% CO 2 at 37°C.

[0193] After 24 hours, the culture supernatant was recovered and IL-2 was quantified using the AlphaLISA Human IL2 Immunoassay Kit (PerkinElmer). In the IL-2 assay, EnVision 2104-0010 and EnVision 2104-0020 (PerkinElmer) were used to measure the fluorescence intensity at 570 nm under the standard setting conditions of Alpha Screen (with an excitation wavelength of 680 nm). The IL-2 quantitative value of the solvent-treated control was set to 1, and the Sigmoid-Emax model nonlinear regression analysis was used to calculate the test compound concentration (EC) when the IL-2 quantitative value of the test compound-treated sample increased 10 times that of the control. 10fold The results of several test compounds of formula (I) are shown in Table 2. It should be noted that in the table, Ex represents the example number described below.

[0194] [Table 2]

[0195]

[0196] Experimental Example 3 Evaluation of Antitumor Effects in Syngeneic Mouse Models Bearing Mouse Colorectal Cancer Cell Line MC38

[0197] MC38 cells (obtained from National Cancer Institute) were suspended in PBS and prepared into 4.0×10 6 A cell suspension of 10 cells / mL was implanted subcutaneously into 6-week-old female mice (C57BL / 6J, Charles River, Japan) in a volume of 50 μL. Four days after implantation, the groups were divided into groups with roughly the same tumor volume between the groups, and the administration of the test compound was started. The experiment was carried out with 10 mice each in the solvent group and the test compound administration group. For the solvent group, 0.5% methylcellulose (Shin-Etsu Chemical Co., Ltd.) was administered orally, and for the test compound administration group, the test compound was mixed in 0.5% methylcellulose for oral administration. Administration was carried out twice a day from the 1st to the 10th day and once on the 11th day, and tumor diameter and body weight were measured twice every 1 week. Tumor volume was calculated using the following formula.

[0198] [Tumor volume (mm 3 )] = [long diameter of tumor (mm)] × [short diameter of tumor (mm)] 2 ×0.5

[0199] The tumor growth inhibition rate (%) based on the test compound was calculated by setting the tumor volume of the test compound-administered group immediately before dosing to 100% inhibition and the tumor volume of the vehicle-administered group on the day dosing ended to 0% inhibition. The results for several test compounds of formula (I) are shown in Table 3. In the table, "Ex" represents the Example number described below.

[0200] [Table 3]

[0201] Ex Single dose (mg / kg) Anti-tumor effects 9 5 64% inhibition 10 4.7 60% inhibition 11 5 63% inhibition 33 5 36% inhibition 34 5 55% inhibition

[0202] Experimental Example 4 Evaluation of Antitumor Effects in Syngeneic Mouse Models Bearing Mouse Melanoma Cell Line B16-F1

[0203] B16-F1 cells (ATCC, CRL-6323) were suspended in PBS and prepared into 2.0×10 6 cells / mL or 1.0×10 7A cell suspension of 5 cells / mL was implanted subcutaneously into 5-week-old female mice (C57BL / 6J, Charles River, Japan) in a volume of 50 μL. Five days after implantation, the mice were divided into groups with roughly the same tumor volume between the groups, and the administration of the test compound was started. The experiment was carried out with 10 mice each in the solvent group and the test compound administration group. For the solvent group, 0.5% methylcellulose (Shin-Etsu Chemical Co., Ltd.) was administered orally, and for the test compound administration group, the test compound was mixed in 0.5% methylcellulose and administered orally. Administration was carried out according to the dosing regimen described in Table 4, and tumor diameter and body weight were measured twice every week. Tumor volume was calculated using the following formula.

[0204] [Tumor volume (mm 3 )] = [long diameter of tumor (mm)] × [short diameter of tumor (mm)] 2 ×0.5

[0205] The tumor growth inhibition rate (%) based on the test compound was calculated by setting the tumor volume of the test compound-administered group immediately before dosing to 100% inhibition and the tumor volume of the vehicle-administered group on the second day of final dosing to 0% inhibition. The results for several test compounds of formula (I) are shown in Table 4. In the table, "Ex" represents the Example number described below.

[0206] [Table 4]

[0207]

[0208] According to the results of the above test, the DGKζ inhibitory effect of several compounds of formula (I) was confirmed (Test Example 1). In addition, for several compounds of formula (I), IL-2 production in human T-cell leukemia cell lines was confirmed (Test Example 2). In addition, for several compounds of formula (I), anti-tumor effects in mouse models were confirmed (Test Examples 3 and 4). In particular, the B16-F1 cells used in Test Example 4 are cells in which anti-PD-1 antibodies / anti-PD-L1 antibodies generally do not show efficacy. Even in a mouse model bearing tumors with these cells, several compounds of formula (I) were confirmed to show anti-tumor effects. Therefore, the compound of formula (I) can be used in the treatment of cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, especially cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, etc.

[0209] Pharmaceutical compositions containing one or more compounds of formula (I) or salts thereof as active ingredients can be prepared using excipients commonly used in the art, ie, pharmaceutical excipients or pharmaceutical carriers, by commonly used methods.

[0210] Administration can be in any form, such as oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, etc., into the article, vein, or muscle.

[0211] Solid compositions for oral administration include tablets, powders, granules, and the like. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The compositions may contain inert additives such as lubricants, disintegrants, stabilizers, and dissolution aids according to conventional methods. Tablets, powders, granules, or pills may be coated with wax, sugar coating, or a film of a gastric-soluble or enteric-soluble substance, as needed.

[0212] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs, and commonly used inert diluents, such as purified water or ethanol. In addition to the inert diluent, the liquid composition may also contain adjuvants such as solubilizers, wetting agents, and suspending agents, as well as sweeteners, flavoring agents, fragrances, and preservatives.

[0213] Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include, for example, alcohols such as ethanol. Such compositions may also contain isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubility aids. These compositions may be sterilized, for example, by filtration through a bacteria-retaining filter, addition of a bactericide, or irradiation. Alternatively, these compositions may be prepared as sterile solid compositions and dissolved or suspended in sterile water or a sterile solvent for injection prior to use.

[0214] External preparations include ointments, plasters, creams, gels, poultices, sprays, lotions, eye drops, eye ointments, etc. They contain commonly used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions, etc.

[0215] Inhalants or transmucosal preparations such as nasal preparations can use solid, liquid or semisolid substances and can be manufactured according to conventional methods. For example, known excipients, pH regulators, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. can be appropriately added. Administration can be performed using a suitable device for inhalation or blowing. For example, a known device such as a metered dose inhalation device or a nebulizer can be used to administer the compound alone or as a powder of a prescribed mixture, or in combination with a pharmaceutically acceptable carrier in the form of a solution or suspension. Dry powder inhalers, etc. can be inhalers for single or multiple administration, and can utilize dry powder or powder-containing capsules. Alternatively, the form can be a pressurized aerosol spray using a suitable propellant, such as a suitable gas such as a chlorofluoroalkane or carbon dioxide.

[0216] Generally, for oral administration, the daily dosage is approximately 0.001 to 100 mg / kg per unit body weight, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg, administered once or divided into two to four doses. For intravenous administration, the daily dosage is approximately 0.0001 to 10 mg / kg per unit body weight, administered once a day or divided into multiple doses. For transmucosal administration, the dosage is approximately 0.001 to 100 mg / kg per unit body weight, administered once a day or divided into multiple doses. The dosage should be determined appropriately for each individual case, taking into account symptoms, age, gender, and other factors.

[0217] Although varying depending on the administration route, dosage form, administration site, and types of excipients or additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in one embodiment, 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof as active ingredients.

[0218] The compound of formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of formula (I) is believed to be effective. The combination can be administered simultaneously, or continuously, or at desired intervals. The formulations for simultaneous administration can be a combination of agents or can be formulated separately.

[0219] Example

[0220] Hereinafter, based on embodiment, the manufacture method of the compound of formula (I) is described in further detail.It should be noted that the present invention is not limited to the compound described in the following embodiment.In addition, the manufacture method of raw material compound is shown in the manufacture example.In addition, the manufacture method of the compound of formula (I) is not limited only to the manufacture method of the specific embodiment shown below, and the compound of formula (I) can also be manufactured by the combination of these manufacture methods or the method obvious to those skilled in the art.

[0221] In addition, in this specification, naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used to name compounds.

[0222] For convenience, the concentration mol / l is expressed as M. For example, a 1M sodium hydroxide aqueous solution means a 1 mol / l sodium hydroxide aqueous solution.

[0223] The powder X-ray diffraction results described in this specification were obtained using Empyrean with a tube bulb: Cu, tube current: 40 mA, tube voltage: 45 kV, step size: 0.013°, wavelength: The diffraction angle range (2θ) was measured at 2.5 to 40°.

[0224] Production Example 1

[0225] K2CO3 (14.4 g) was added to a mixture of 2-bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (15 g), phenol (4.91 g) and NMP (150 mL) and stirred at 50 ° C for 16 hours. After the reaction solution was cooled to room temperature, EtOAc and water were added to separate the aqueous layer. The aqueous layer was extracted with EtOAc, and the combined organic layer was washed with water and brine and dried over MgSO4. Concentrated under reduced pressure, the residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain 2-bromo-1-nitro-4-phenoxy-3-(trifluoromethyl)benzene (18.4 g).

[0226] Production Example 13

[0227] To a mixture of 2-chloro-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (4.3 g), 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.5 g), Pd(dppf)Cl2·CH2Cl2 (590 mg), and K2CO3 (4 g) were added 1,4-dioxane (45 mL) and water (9 mL), and the mixture was stirred at 100°C for 20 hours under an argon atmosphere. After cooling to room temperature, water and EtOAc were added, the mixture was filtered through Celite, and then extracted with EtOAc. The organic layer was dried over MgSO4. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl 4-[3-fluoro-6-nitro-2-(trifluoromethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (4.65 g).

[0228] Production Example 16

[0229] Under a nitrogen atmosphere, PdCl2(PPh3)2 (487 mg) was added to a mixture of 2-bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (2 g), tert-butyl {[(3R)-piperidin-3-yl]methyl}carbamate (1.63 g), K2CO3 (2.87 g), and 1,4-dioxane (20 mL), and stirred at 100°C for 3 hours. The reaction solution was allowed to cool to room temperature, then water was added, extracted with EtOAc, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl ({(3S)-1-[3-fluoro-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (1.70 g) as a solid.

[0230] Production Example 17

[0231] Under ice-cooling, sodium hydride (60% oil dispersion, 570 mg) was added to a mixture of tert-butyl 4-[3-fluoro-6-nitro-2-(trifluoromethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (4.6 g), phenol (1.3 g), and NMP (23 mL). The mixture was stirred under ice-cooling for 1 hour under an argon atmosphere. Water was added under ice-cooling, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl 4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (5.18 g).

[0232] Production Example 21

[0233] Under ice-cooling, tert-butyl ({(3S)-1-[3-fluoro-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (300mg) was added to a mixture of cyclopropyl alcohol (0.10mL), NaOtBu (205mg) and DMF (6mL) and stirred at room temperature for 1 hour. The reaction was quenched with water, extracted with EtOAc, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl ({(3S)-1-[3-(cyclopropyloxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (250mg) as a solid.

[0234] Production Example 30

[0235] A 4M HCl / 1,4-dioxane solution (30 mL) was added to a mixture of tert-butyl (3S)-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]piperidine-1-carboxylate (8.106 g) and ethanol (60 mL), and the mixture was stirred at room temperature for 11 hours. The mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol and diethyl ether. The precipitated solid was filtered and washed with diethyl ether. The filtered solid was dried under reduced pressure to obtain 2-{[(3R)-piperidin-3-yl]methyl}-1H-isoindole-1,3(2H)-dione monohydrochloride (5.695 g) as a solid.

[0236] Production Example 31

[0237] To a mixture of [(3S)-1-(tert-butoxycarbonyl)piperidin-3-yl]acetic acid (2.9 g) and NH4Cl (960 mg) were added CH2Cl2 (24 mL), water (12 mL), WSC.HCl (2.5 g), TEA (5.8 mL), and HOBt (1.8 g), followed by stirring at room temperature overnight. 1 M hydrochloric acid was added to the reaction solution to adjust the pH to 2-3, followed by extraction using an ISOLUTE (registered trademark) phase separator. The separated organic layer was washed with a saturated aqueous NaHCO3 solution and concentrated under reduced pressure to obtain tert-butyl (3S)-3-(2-amino-2-oxoethyl)piperidine-1-carboxylate (2.7 g).

[0238] Production Example 32

[0239] Under ice-cold, lithium aluminum hydride (130 mg) was added to a mixture of (3S)-3-(2-amino-2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (335 mg) and THF (7 mL), and the mixture was stirred at room temperature overnight. Under ice-cold, water (130 μL), 1M sodium hydroxide aqueous solution (130 μL), water (390 μL) were added, and the mixture was diluted with 10% methanol / CH2Cl2, and stirred at room temperature for 1 hour. Celite was filtered and the filtrate was concentrated under reduced pressure. After CH2Cl2 (4 mL) and DIPEA (360 μL) were added to the residue at room temperature, TFAA (240 μL) was added under ice-cold, and the mixture was stirred at room temperature overnight. Saturated NH4Cl aqueous solution was added, extracted using ISOLUTE (registered trademark) phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl (3S)-3-[2-(2,2,2-trifluoroacetamido)ethyl]piperidine-1-carboxylate (139 mg).

[0240] Production Example 33

[0241] A 4M HCl / 1,4-dioxane solution (1 mL) was added to a mixture of tert-butyl (3S)-3-[2-(2,2,2-trifluoroacetamido)ethyl]piperidine-1-carboxylate (137 mg) and diethyl ether (1 mL) at room temperature, and the mixture was stirred overnight. The mixture was concentrated under reduced pressure to obtain 2,2,2-trifluoro-N-{2-[(3S)-piperidin-3-yl]ethyl}acetamide monohydrochloride (117 mg).

[0242] Production Example 34

[0243] To a mixture of 2-bromo-1-nitro-4-phenoxy-3-(trifluoromethyl)benzene (4.15 g) and 1,4-dioxane (60 mL) were added DIPEA (3 mL) and tert-butyl {[(3R)-piperidin-3-yl]methyl}carbamate (3 g), and the mixture was stirred at 100°C overnight. After cooling, water was added, and extraction was performed with EtOAc. After drying over MgSO4, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl ({(3S)-1-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (4.87 g).

[0244] Production Example 60

[0245] Under an argon atmosphere, sodium hydride (60% oil dispersion, 410 mg) was added four times to a mixture of ({(3S)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamic acid tert-butyl ester (3.5 g), iodomethane (860 μL) and DMF (35 mL) under ice-cooling and stirred at room temperature for 3 hours. Under ice-cooling, the reaction was quenched with water. EtOAc was used for extraction. The organic layer was washed with water and brine and dried with MgSO4. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain ({(3R)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)(methyl)carbamic acid tert-butyl ester (3.44 g) as a solid.

[0246] Production Example 68

[0247] Under ice cooling, Dess-Martin reagent (120 mg) was added to a mixture of (2R)-2-(hydroxymethyl)-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (110 mg) and CH2Cl2 (2 mL), and the mixture was stirred at room temperature for 1 hour. Dess-Martin reagent (120 mg) was further added, and the mixture was stirred at room temperature for 30 minutes. 10% aqueous sodium sulfite solution and saturated NaHCO3 aqueous solution were added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted using an ISOLUTE (registered trademark) phase separator and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain (2R)-2-formyl-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (86 mg).

[0248] Production Example 69

[0249] To a mixture of (2R)-2-formyl-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (84 mg) and CH2Cl2 (1 mL) were added 2M methylamine / THF solution (170 μL), acetic acid (20 μL), and NaBH(OAc)3 (75 mg), followed by stirring at room temperature for 2 hours. A saturated aqueous NaHCO3 solution was added to the reaction solution, and extraction was performed using an ISOLUTE (registered trademark) phase separator. The mixture was concentrated under reduced pressure to obtain (2S)-2-[(methylamino)methyl]-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (93 mg).

[0250] Production Example 70

[0251] Under ice-cooling, DIPEA (50 μL) and TFAA (35 μL) were added to a mixture of (2S)-2-[(methylamino)methyl]-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (93 mg) and CH2Cl2 (1 mL), and the mixture was stirred at room temperature for 1 hour. DIPEA (50 μL) and TFAA (35 μL) were added to the reaction solution under ice-cooling and stirred at room temperature for 15 minutes. Saturated NH4Cl aqueous solution was added to the reaction solution, extracted using ISOLUTE (registered trademark) phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain (2R)-2-{[methyl(trifluoroacetyl)amino]methyl}-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (81 mg).

[0252] Production Example 71

[0253] To a mixture of (2R)-2-formyl-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (1.04 g) and CH2Cl2 (10 mL) were added O-benzylhydroxylamine (320 μL), acetic acid (180 μL), NaBH(OAc)3 (670 mg), and the mixture was stirred at room temperature overnight. Sodium cyanoborohydride (200 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (200 mg) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Methanol (3 mL) was added and stirred overnight. Saturated NaHCO3 aqueous solution was added, the mixture was stirred at room temperature for 1 hour, extracted using an ISOLUTE (registered trademark) phase separator, and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL), DIPEA (720 μL) was added, and TFAA (450 μL) was added under ice-cold conditions, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous NH4Cl solution was added, extracted using an ISOLUTE (registered trademark) phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain (2R)-2-{[(benzyloxy)amino]methyl}-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (426 mg).

[0254] Production Example 72

[0255] Under ice cooling, pyridine (310 μL) and acetic anhydride (360 μL) were added to a mixture of {(2R)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]pyrrolidin-2-yl}methanol (510 mg) and CH2Cl2 (5 mL), and the mixture was stirred at room temperature overnight. Saturated NH4Cl aqueous solution was added, extracted using an ISOLUTE (registered trademark) phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain {(2R)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]pyrrolidin-2-yl}methyl acetate (170 mg).

[0256] Production Example 73

[0257] Hydrazine monohydrate (110 μL) was added to a mixture of 2-{[(3R)-1-(2,4-difluoro-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methyl}-1H-isoindole-1,3(2H)-dione (0.376 g) and MeOH (5 mL), and the mixture was stirred under reflux for 3 hours. After cooling to room temperature, the mixture was poured into a 5% aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was separated, the aqueous layer was extracted with chloroform, and the combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to obtain 1-[(3S)-1-(2,4-difluoro-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methylamine (0.266 g).

[0258] Production Example 75

[0259] Di-tert-butyl dicarbonate (202 μL) was added to a mixture of 1-[(3S)-1-(2,4-difluoro-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methylamine (0.266 g), CH2Cl2 (5 mL), and TEA (153 μL), and stirred at room temperature for 63 hours. The reaction solution was poured into water and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl {[(3S)-1-(2,4-difluoro-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methyl}carbamate (0.294 g).

[0260] Production Example 77

[0261] Zinc powder (6.4 g) and NH4Cl (5.24 g) were added to a mixture of tert-butyl ({(3S)-1-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (4.85 g), 1,4-dioxane (150 mL) and water (30 mL) under ice cooling. After stirring at room temperature for 3 hours, the insoluble matter was filtered using celite. The obtained filtrate was concentrated under reduced pressure, and a saturated aqueous NaHCO3 solution was added to the residue, and extraction was performed using chloroform. After drying over MgSO4, the mixture was concentrated under reduced pressure to obtain tert-butyl ({(3S)-1-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (4.56 g).

[0262] Production Example 122

[0263] Under a nitrogen atmosphere, to a mixture of tert-butyl (2R)-2-{[(benzyloxy)amino]methyl}-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-1-carboxylate (424 mg), EtOAc (2 mL), and ethanol (2 mL) was added 10% aqueous palladium hydroxide on carbon (100 mg), replaced with hydrogen, and stirred at room temperature for 2 hours. After nitrogen replacement, the mixture was diluted with EtOAc and filtered through Celite. The filtrate was concentrated under reduced pressure to give tert-butyl (2S)-2-(aminomethyl)-4-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-1-carboxylate (347 mg).

[0264] Production Example 123

[0265] Ethyl trifluoroacetate (110 μL) was added to a mixture of tert-butyl (2S)-2-(aminomethyl)-4-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-1-carboxylate (345 mg) and methanol (2 mL), and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to obtain tert-butyl (2S)-4-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]-2-[(2,2,2-trifluoroacetamido)methyl]piperazine-1-carboxylate (380 mg).

[0266] Production Example 124

[0267] To a mixture of tert-butyl ({(3S)-1-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (4.56 g) and DMF (50 mL) were added 2-(pyridazin-4-yl)-1,3-thiazole-4-carboxylic acid (2.23 g), DIPEA (3 mL), and HATU (4.5 g), and the mixture was stirred at 50°C overnight. The reaction mixture was allowed to cool to room temperature, and then water was added to the reaction mixture under ice-cooling, and the precipitated solid was filtered. The resulting solid was dissolved in chloroform, water was added, and extraction with chloroform was performed. After drying over MgSO4, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl {[(3S)-1-{3-phenoxy-6-[2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide]-2-(trifluoromethyl)phenyl}piperidin-3-yl]methyl}carbamate (5.85 g) as a solid.

[0268] Production Example 172

[0269] To a mixture of {(2R)-1-[3-(2-fluorophenoxy)-6-{[2-(pyridazin-4-yl)-1,3-thiazole-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]pyrrolidin-2-yl}methyl acetate (194 mg) and methanol (1 mL) were added water (0.1 mL) and KCO (135 mg), followed by stirring at room temperature overnight. The reaction solution was diluted with EtOAc, filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain N-[4-(2-fluorophenoxy)-2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (200 mg).

[0270] Production Example 173

[0271] Under ice cooling, Dess-Martin reagent (220 mg) was added to a mixture of N-[4-(2-fluorophenoxy)-2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazine-4-yl)-1,3-thiazole-4-carboxamide (198 mg) and CH2Cl2 (2 mL), and the mixture was stirred at room temperature for 1 hour. 10% aqueous sodium sulfite solution and saturated NaHCO3 aqueous solution were added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Extraction was performed using an ISOLUTE (registered trademark) phase separator, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain N-[4-(2-fluorophenoxy)-2-[(2R)-2-formylpyrrolidin-1-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazine-4-yl)-1,3-thiazole-4-carboxamide (112 mg).

[0272] Production Example 174

[0273] Under ice cooling, trifluoromethanesulfonic anhydride (52 μL) was added to a mixture of tert-butyl ({(3S)-1-[3-hydroxy-6-{[2-(pyridazin-4-yl)-1,3-thiazole-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (0.075 g), CHCl (4.5 mL), and pyridine (50 μL), and the mixture was stirred at room temperature for 8 hours. The reaction solution was poured into water and extracted with CHCl. ​​The organic layer was washed with 10% hydrochloric acid, water, and brine, dried over NaSO, and concentrated under reduced pressure. Trifluoromethanesulfonic anhydride (64 μL) was added to a mixture of the residue and pyridine (2.6 mL) under ice cooling, and the mixture was stirred at room temperature for 13 hours. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with 10% hydrochloric acid, water and brine, dried over Na2SO4, and concentrated under reduced pressure to obtain 3-[(3S)-3-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl]-4-{[2-(pyridazine-4-yl)-1,3-thiazole-4-carbonyl]amino}-2-(trifluoromethyl)phenyl trifluoromethanesulfonate (0.103 g).

[0274] Production Example 175

[0275] Under an argon atmosphere, a mixture of 3-[(3S)-3-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl]-4-{[2-(pyridazin-4-yl)-1,3-thiazole-4-carbonyl]amino}-2-(trifluoromethyl)phenyl trifluoromethanesulfonate (0.103 g) and THF (2.5 mL) was added to a mixture of KCO (0.030 g), phenylboronic acid (0.027 g), and Pd(PPh) (0.017 g). Water (0.5 mL) was then added, and the mixture was stirred at 110-130°C for 8 hours. The reaction mixture was allowed to cool to room temperature, poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl ({(3S)-1-[4-{[2-(pyridazin-4-yl)-1,3-thiazole-4-carbonyl]amino}-2-(trifluoromethyl)[1,1'-biphenyl]-3-yl]piperidin-3-yl}methyl)carbamate (0.067 g).

[0276] Production Example 176

[0277] A 4M HCl / 1,4-dioxane solution (10 mL) was added to a mixture of tert-butyl 4-[3-phenoxy-6-{[2-(pyridazin-4-yl)-1,3-thiazole-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (2.4 g) and methanol (24 mL), and the mixture was stirred at room temperature for 19 hours. The mixture was concentrated under reduced pressure, and a saturated aqueous NaHCO3 solution was added to the residue. The mixture was extracted with a mixed solvent (chloroform / methanol), and the organic layer was dried over MgSO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain N-[4-phenoxy-2-(1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (1.57 g) as a solid.

[0278] Production Example 182

[0279] Under ice cooling, DIPEA (30 μL) and 2-nitrobenzenesulfonyl chloride (30 mg) were added to a mixture of N-{2-[(3R)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazine-4-yl)-1,3-thiazole-4-carboxamide (63 mg) and CH2Cl2 (1 mL), and the mixture was stirred for 1 hour under ice cooling. Saturated aqueous NH4Cl solution was added, extracted using an ISOLUTE (registered trademark) phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain N-{2-[(3S)-3-{[(2-nitrobenzene-1-sulfonyl)amino]methyl}piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazine-4-yl)-1,3-thiazole-4-carboxamide (94 mg).

[0280] Production Example 185

[0281] To a mixture of N-{2-[(3S)-3-{[(2-nitrobenzene-1-sulfonyl)amino]methyl}piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (90 mg) and MeCN (1 mL) was added iodomethane (25 μL) and cesium carbonate (45 mg), followed by stirring at room temperature for 30 minutes. EtOAc was added, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain N-{2-[(3S)-3-{[methyl(2-nitrobenzene-1-sulfonyl)amino]methyl}piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (83 mg).

[0282] Production Example 190

[0283] To a mixture of N-{2-[(3R)-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (40 mg) and CH2Cl2 (1 mL) were added 35% aqueous formaldehyde solution (10 μL), acetic acid (5 μL), and NaBH(OAc)3 (20 mg), followed by stirring at room temperature overnight. Saturated aqueous NaHCO3 solution was added to the reaction mixture, stirred for 10 minutes, extracted using an ISOLUTE (registered trademark) phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc amino silica gel) to obtain N-{2-[(3R)-4-methyl-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (36 mg).

[0284] Production Example 192

[0285] Thiophenol (0.38 g) was added to a mixture of sodium hydride (60% oil dispersion, 0.208 mg) and THF (5 mL) at -78°C, and the mixture was stirred at -78°C for 15 minutes. 2-Bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (1.00 g) was added, and the mixture was stirred at -78°C for 15 minutes. A saturated aqueous solution of NH4Cl was added, and the mixture was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give 2-bromo-1-nitro-4-(phenylthio)-3-(trifluoromethyl)benzene (0.50 g).

[0286] Production Example 193

[0287] Under ice cooling and argon atmosphere, potassium nitrate (0.84 g) was added to a mixture of 1,3-difluoro-2-(methylsulfonyl)benzene (1.60 g) and concentrated sulfuric acid (12 mL) and stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and the precipitated solid was filtered. The obtained solid was dissolved in EtOAc, washed with a saturated aqueous solution of NaHCO3, and dried with Na2SO4. Concentrated under reduced pressure, 1,3-difluoro-2-(methylsulfonyl)-4-nitrobenzene (1.80 g) was obtained as a solid.

[0288] Production Example 194

[0289] Under ice cooling, 30% hydrogen peroxide (5 mL) was added dropwise to a mixture of 4-amino-3-fluoro-2-(trifluoromethyl)benzoic acid (1.30 g) and THF (15 mL), and the mixture was stirred at room temperature for 5 minutes and at 80° C. for 2 hours. After cooling naturally to room temperature, the reaction mixture was poured into ice water and extracted twice with EtOAc. The combined organic layer was washed with water and dried over Na2SO4. The mixture was concentrated under reduced pressure to obtain 3-fluoro-4-nitro-2-(trifluoromethyl)benzoic acid (1.20 g) as a solid.

[0290] Production Example 195

[0291] Under ice-cold, oxalyl chloride (2.03mL) is added dropwise to a mixture of 3-fluoro-4-nitro-2-(trifluoromethyl) benzoic acid (1.20g) and CH2Cl2 (30mL), followed by addition of a catalytic amount of DMF. Under ice-cold, the reaction mixture is stirred for 1 hour and then concentrated under reduced pressure. The residue is dissolved in benzene (15mL), and under ice-cold, aluminum chloride (1.26g) is added over 5 minutes and stirred at room temperature for 1 hour. The reaction mixture is injected onto ice and extracted three times with EtOAc. After the combined organic layer is dried using Na2SO4, it is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (Hex / EtOAc) to obtain [3-fluoro-4-nitro-2-(trifluoromethyl) phenyl] (phenyl) ketone (0.80g) as a solid.

[0292] Production Example 196

[0293] Tert-butylchlorodiphenylsilane (10.0 mL) was added to a mixed solution of (8S)-8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-1,4-dione (3.250 g), DMF (48 mL), and imidazole (3.972 g), and stirred at room temperature for 23 hours. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / MeOH) to obtain (8S,8aS)-8-{[tert-butyldi(phenyl)silyl]oxy}hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (1.786 g) as a low-polarity substance and (8S,8aR)-8-{[tert-butyldi(phenyl)silyl]oxy}hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (g) as a high-polarity substance.

[0294] Production Example 197

[0295] A solution of (8S,8aR)-8-{[tert-butyldi(phenyl)silyl]oxy}hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (1.164 g) in THF (10 mL) was added to a mixture of lithium aluminum hydride (0.594 g) and THF (40 mL), and the mixture was stirred under reflux for 17 hours. The reaction suspension was allowed to cool to room temperature, and then a mixture of water (0.7 mL) and THF (7.7 mL) and 4N aqueous sodium hydroxide solution (0.7 mL) were added. NaSO was then added, and the mixture was stirred at room temperature for 3 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain (8S,8aS)-octahydropyrrolo[1,2-a]pyrazin-8-ol (0.972 g).

[0296] Production Example 216

[0297] Under an argon atmosphere, diisopropyl azodicarboxylate (262 μL) was added to a mixed solution of (8S,8aS)-2-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-ol (0.375 g), THF (6 mL), benzoic acid (0.119 g), and triphenylphosphine (0.349 g) under ice-cooling. The mixture was gradually warmed to room temperature and stirred for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain (8R,8aS)-2-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-yl benzoate (0.518 g).

[0298] Production Example 220

[0299] Under an argon atmosphere, palladium acetate (24 mg) was added to a mixture of tert-butyl {[(3S)-1-(2-bromo-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methyl}carbamate (550 mg), cyclopropylboronic acid (112 mg), tricyclohexylphosphine (30 mg), toluene (9 mL) and water (1 mL), and stirred at 110 ° C for 4 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl {[(3S)-1-(2-cyclopropyl-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methyl}carbamate (280 mg).

[0300] Production Example 221

[0301] Under an argon atmosphere, diisopropyl azodicarboxylate (0.13 mL) was added to a mixed solution of (8S,8aS)-2-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-ol (0.233 g), THF (4 mL), phthalimide (0.090 g), and triphenylphosphine (0.173 g) under ice-cooling. The mixture was gradually warmed to room temperature and stirred for 15 hours. Triphenylphosphine (0.173 g) and diisopropyl azodicarboxylate (0.13 mL) were added to the reaction mixture under ice-cooling, and the mixture was gradually warmed to room temperature and stirred for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain 2-{(8R,8aS)-2-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-yl}-1H-isoindole-1,3(2H)-dione (0.214 g).

[0302] Production Example 271

[0303] Under ice cooling, m-chloroperbenzoic acid (40% water content, 385 mg) was added to a mixture of tert-butyl {[(3S)-1-{6-[(2-bromo-1,3-thiazole-4-carbonyl)amino]-3-(phenylthio)-2-(trifluoromethyl)phenyl}piperidin-3-yl]methyl}carbamate (300 mg) and CHCl (5 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated aqueous sodium thiosulfate and extracted twice with CHCl. ​​The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl ({(3S)-1-[3-(benzenesulfonyl)-6-[(2-bromo-1,3-thiazole-4-carbonyl)amino]-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (200 mg).

[0304] Production Example 272

[0305] Under an argon atmosphere, Pd(PPh3)4 (33 mg) was added to a mixture of tert-butyl ({(3S)-1-[3-(benzenesulfonyl)-6-[(2-bromo-1,3-thiazole-4-carbonyl)amino]-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (200 mg), 4-(tributylstannyl)pyridazine (115 mg), and toluene (10 mL), and stirred at 100°C for 24 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl ({(3S)-1-[3-(benzenesulfonyl)-6-{[2-(pyridazin-4-yl)-1,3-thiazole-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (100 mg).

[0306] The compounds shown in Tables 5-1 to 5-35 described below were produced in the same manner as in the production examples described above. The structures of the compounds in each production example are shown in Tables 5-1 to 5-35 described below, and the production methods and physicochemical data of the compounds in each production example are shown in Tables 6-1 to 6-12. These compounds can be easily produced by using the production methods described in the production examples above, methods readily apparent to those skilled in the art, or variations thereof.

[0307] Example 1

[0308] To a mixture of N-[2-(1-oxa-4,9-diazaspiro[5.5]undecane-4-yl)-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (93 mg) and CH2Cl2 (1 mL) were added 35% aqueous formaldehyde solution (50 μL), acetic acid (40 μL), and NaBH(OAc)3 (100 mg), followed by stirring at room temperature for 1 hour. Saturated aqueous NaHCO3 solution was added to the reaction solution, stirred for 10 minutes, extracted using an ISOLUTE (registered trademark) phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol). The obtained oil was solidified with MeCN, filtered, and dried under reduced pressure to obtain N-[2-(9-methyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (72 mg) as a solid.

[0309] Example 6

[0310] To a mixture of N-{2-[(3R)-4-methyl-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (35 mg) and methanol (0.5 mL) was added KCO (15 mg) and water (0.1 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with EtOAc, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol / ammonia water). The obtained crude product was solidified with diethyl ether, and the generated solid was filtered and dried at 50°C under reduced pressure to obtain N-[2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (17 mg) as a solid.

[0311] Example 9

[0312] Under ice cooling, TFA (7 mL) was added to a mixture of tert-butyl {[(3S)-1-{3-phenoxy-6-[2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide]-2-(trifluoromethyl)phenyl}piperidin-3-yl]methyl}carbamate (5.83 g) and CH2Cl2 (60 mL), and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, diluted with CH2Cl2, and then neutralized with saturated aqueous NaHCO3 solution under ice cooling. After extraction with chloroform, the mixture was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol / ammonia water). The obtained solid was washed with diethyl ether to obtain N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (3.52 g) as a solid.

[0313] Example 49

[0314] To a mixture of N-{2-[(3R)-3-{[methyl(2-nitrobenzene-1-sulfonyl)amino]methyl}piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (202 mg) and DMF (1 mL) was added thioglycolic acid (60 μL) and lithium hydroxide monohydrate (60 mg), and the mixture was stirred at 70 ° C for 15 minutes. After natural cooling, CH2Cl2 and saturated NaHCO3 aqueous solution were added to the reaction solution and stirred, extracted using an ISOLUTE (registered trademark) phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / chloroform). The obtained oil was solidified with MeCN, filtered, and dried under reduced pressure to obtain N-[2-{(3S)-3-[(methylamino)methyl]piperidin-1-yl}-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (29 mg) as a solid.

[0315] Example 54

[0316] To a mixture of N-{2-[(3R)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (83 mg) and CH2Cl2 (1 mL) were added 35% aqueous formaldehyde solution (50 μL), acetic acid (35 μL), and NaBH(OAc)3 (100 mg), followed by stirring at room temperature for 1 hour. Saturated aqueous NaHCO3 solution was added, stirred at room temperature for 10 minutes, extracted using an ISOLUTE (registered trademark) phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), and the resulting substance was dissolved in EtOAc, followed by addition of 4M HCl / EtOAc solution (120 μL). The precipitated solid was filtered and dried at 50° C. under reduced pressure to obtain N-[2-{(3R)-3-[(dimethylamino)methyl]piperidin-1-yl}-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide dihydrochloride (71 mg) as a solid.

[0317] Example 59

[0318] To a mixture of N-[2-(1-oxa-4,9-diazaspiro[5.5]undec-4-yl)-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (100 mg) and MeCN (1 mL) were added DIPEA (35 μL) and 1-bromo-2-methoxyethane (20 μL), and the mixture was stirred at 100°C for 1 hour under microwave irradiation. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), diluted with EtOAc, and a 4M HCl / 1,4-dioxane solution (130 μL) was added at room temperature, followed by stirring at room temperature for 10 minutes. The precipitated solid was filtered and dried under reduced pressure to obtain N-{2-[9-(2-methoxyethyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide dihydrochloride (67 mg) as a solid.

[0319] Example 62

[0320] At room temperature, 3-oxetanone (60 mg), acetic acid (45 μL), and NaBH (OAc) 3 (160 mg) were added to a mixture of N- [2- (1-oxa-4,9-diazaspiro [5.5] undecane-4-yl) -4-phenoxy-3- (trifluoromethyl) phenyl] -2- (pyridazine-4-yl) -1,3-thiazole-4-carboxamide (150 mg) and CH 2 Cl 2 (1 mL), and the mixture was stirred overnight. Saturated aqueous NaHCO 3 solution was added, stirred at room temperature for 30 minutes, extracted using an ISOLUTE (registered trademark) phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily substance. The reaction mixture was solidified using EtOAc, Hex, and diisopropyl ether, filtered, and then dried under reduced pressure to obtain N-{2-[9-(oxetane-3-yl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (99 mg) as a solid.

[0321] Example 63

[0322] To a mixture of N-[4-(2-fluorophenoxy)-2-[(2R)-2-formylpyrrolidin-1-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazine-4-yl)-1,3-thiazole-4-carboxamide (60 mg) and CH2Cl2 (0.5 mL) was added 3-oxetane (25 mg), acetic acid (20 μL), and NaBH(OAc)3 (70 mg), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of NaHCO3 was added, and the mixture was stirred at room temperature for 30 minutes. Extraction was performed using an ISOLUTE (registered trademark) phase separator, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily substance. Diethyl ether was added to the obtained oil, and the mixture was concentrated under reduced pressure to obtain N-[4-(2-fluorophenoxy)-2-[(2R)-2-{[(oxetan-3-yl)amino]methyl}pyrrolidin-1-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (20 mg) as a solid.

[0323] Example 64

[0324] A mixture of 2-bromo-1-nitro-4-phenoxy-3-(trifluoromethyl)benzene (10.9 mg), tert-butylmethyl[(piperidin-3-yl)methyl]carbamate (20.7 mg), DIPEA (20 μL), and NMP (250 μL) was stirred at 120°C overnight. After cooling, PS-Isocyanate (150 mg) and chloroform (1 mL) were added to the reaction solution and stirred overnight. The insoluble matter was then filtered and the filtrate was concentrated under reduced pressure. Ethanol (0.8 mL), water (0.2 mL), NH4Cl (0.8 mg), and reduced iron (10 mg) were added to the resulting residue and stirred at 80°C overnight. After cooling naturally, water and chloroform were added to the reaction solution to perform a liquid separation operation, and the resulting organic layer was concentrated under reduced pressure. To the resulting residue were added 2-(pyridazin-4-yl)-1,3-thiazole-4-carboxylic acid (6.2 mg), DIPEA (10 μL), and DMF (185 μL), followed by a solution of HATU (13.3 mg) in DMF (200 μL), and the mixture was stirred overnight at room temperature. The product was fractionated and purified using HPLC (column: SunFire (registered trademark) MeOH / 0.1% HCOOH-H2O). TFA (500 μL) was added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous NaHCO3 solution and chloroform were added, and a liquid separation operation was performed. The obtained organic layer was concentrated under reduced pressure to obtain N-[2-{3-[(methylamino)methyl]piperidin-1-yl}-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazine-4-yl)-1,3-thiazole-4-carboxamide (3.8 mg).

[0325] Example 78

[0326] Hydrazine monohydrate (19.8 μL) was added to a mixture of N-{2-[(8R,8aS)-8-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (0.097 g) and MeOH (1.4 mL). The mixture was stirred under reflux for 6 hours. The reaction mixture was allowed to cool to room temperature, poured into a 5% aqueous sodium hydroxide solution, and extracted with CHCl. ​​The organic layer was separated, the aqueous layer was extracted with CHCl, and the combined organic layers were dried over MgSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to obtain N-{2-[(8R,8aS)-8-aminohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (0.047 g).

[0327] Example 83

[0328] EtOAc and saturated aqueous NaHCO3 solution were added to N-[4-(2-fluorophenoxy)-2-{(3S)-3-[(methylamino)methyl]piperidin-1-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide monohydrochloride (200 mg), and after temporary stirring, the aqueous layer was separated. The aqueous layer was extracted with a mixed solvent (EtOAc / MeOH), and the combined organic layer was washed with water and brine and dried with Na2SO4. Concentrated under reduced pressure. 2-Propanol (4 mL) was added to the residue and temporarily stirred at 80°C. Fumaric acid (40 mg) and water (200 μL) were added thereto and stirred at room temperature for 24 hours. The precipitate was filtered and then dried under reduced pressure to obtain N-[4-(2-fluorophenoxy)-2-{(3S)-3-[(methylamino)methyl]piperidin-1-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide mono[(2E)-2-butenedioic acid] salt (141 mg) as crystals.

[0329] Example 84

[0330] Ethanol (2 mL) was added to N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide (100 mg), and the mixture was stirred at 75°C to dissolve the mixture. Fumaric acid (23 mg) and water (400 μL) were added, and the mixture was stirred at room temperature overnight. The precipitate was filtered and dried under reduced pressure to obtain N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide mono[(2E)-2-butenedioic acid] salt (73 mg) as crystals.

[0331] The compounds shown in Tables 7-1 to 7-11 below were produced in the same manner as in the above-described examples. The structures of the compounds of the examples are shown in Tables 7-1 to 7-11 below, and the production methods and physicochemical data of the compounds of the examples are shown in Tables 8-1 to 8-5 below. These compounds can be easily produced by using the production methods of the above-described examples and methods obvious to those skilled in the art, or variations thereof.

[0332] In addition, the structures and physicochemical data of the reference example compounds are shown in the following Table 9. These compounds can be easily produced by using the production methods of the above-mentioned Production Examples or Examples, methods obvious to those skilled in the art, or modifications thereof.

[0333] In addition, in the following tables, the following abbreviations may be used.

[0334] PEx: Production Example number, Ex: Example number, PSyn: Production method of the production example compound (the number in the PSyn column indicates that the compound was produced by the same method as the compound with the number as the production example number using the corresponding raw materials. For example, the compound with a 1 in the PSyn column indicates that it was produced by the same method as the compound of Production Example 1), Syn: Production method of the example compound (the number in the Syn column indicates that the compound was produced by the same method as the compound with the number as the example number using the corresponding raw materials. For example, the compound with a 1 in the Syn column indicates that it was produced by the same method as the compound of Example 1), Str: Chemical structural formula, DAT: Physicochemical data, ESI+: m / z value in mass spectrometry analysis (ionization method ESI, unless otherwise specified [M+H] + or[M+Na] + ), ESI-: m / z value in mass spectrometry (ionization method ESI, unless otherwise specified [MH] -), NMR DMSO-d6 (400 MHz), or NMR DMSO-d6 (500 MHz): 1 δ value (ppm) of the signal in H-NMR, NMR CDCl3 (400 MHz), or NMR CDCl3 (500 MHz): 1 δ value (ppm) of a signal in H-NMR, s: singlet (spectrum), d: doublet (spectrum), t: triplet (spectrum), m: multiplet (spectrum), br: broad peak (spectrum), dd: doublet (spectrum).

[0335] Unless otherwise specified, a compound represents an optical isomer having the absolute stereo configuration described in the chemical formula. HCl in the formula represents the monohydrochloride salt, 2HCl represents the dihydrochloride salt, and 3HCl represents the trihydrochloride salt.

[0336] [Table 5-1]

[0337]

[0338] [Table 5-2]

[0339]

[0340] [Table 5-3]

[0341]

[0342] [Table 5-4]

[0343]

[0344] [Table 5-5]

[0345]

[0346] [Table 5-6]

[0347]

[0348] [Table 5-7]

[0349]

[0350] [Table 5-8]

[0351]

[0352] [Table 5-9]

[0353]

[0354] [Table 5-10]

[0355]

[0356] [Table 5-11]

[0357]

[0358] [Table 5-12]

[0359]

[0360] [Table 5-13]

[0361]

[0362] [Table 5-14]

[0363]

[0364] [Table 5-15]

[0365]

[0366] [Table 5-16]

[0367]

[0368] [Table 5-17]

[0369]

[0370] [Table 5-18]

[0371]

[0372] [Table 5-19]

[0373]

[0374] [Table 5-20]

[0375]

[0376] [Table 5-21]

[0377]

[0378] [Table 5-22]

[0379]

[0380] [Table 5-23]

[0381]

[0382] [Table 5-24]

[0383]

[0384] [Table 5-25]

[0385]

[0386] [Table 5-26]

[0387]

[0388] [Table 5-27]

[0389]

[0390] [Table 5-28]

[0391]

[0392] [Table 5-29]

[0393]

[0394] [Table 5-30]

[0395]

[0396] [Table 5-31]

[0397]

[0398] [Table 5-32]

[0399]

[0400] [Table 5-33]

[0401]

[0402] [Table 5-34]

[0403]

[0404] [Table 5-35]

[0405]

[0406] [Table 6-1]

[0407]

[0408] [Table 6-2]

[0409]

[0410] [Table 6-3]

[0411]

[0412] [Table 6-4]

[0413]

[0414] [Table 6-5]

[0415]

[0416] [Table 6-6]

[0417]

[0418] [Table 6-7]

[0419]

[0420] [Table 6-8]

[0421]

[0422] [Table 6-9]

[0423]

[0424] [Table 6-10]

[0425]

[0426] [Table 6-11]

[0427]

[0428] [Table 6-12]

[0429]

[0430] [Table 7-1]

[0431]

[0432] [Table 7-2]

[0433]

[0434] [Table 7-3]

[0435]

[0436] [Table 7-4]

[0437]

[0438] [Table 7-5]

[0439]

[0440] [Table 7-6]

[0441]

[0442] [Table 7-7]

[0443]

[0444] [Table 7-8]

[0445]

[0446] [Table 7-9]

[0447]

[0448] [Table 7-10]

[0449]

[0450] [Table 7-11]

[0451]

[0452] [Table 8-1]

[0453]

[0454] [Table 8-2]

[0455]

[0456] [Table 8-3]

[0457]

[0458] [Table 8-4]

[0459]

[0460] [Table 8-5]

[0461]

[0462] [Table 9]

[0463]

[0464] Industrial applicability

[0465] The compound of the present invention or a salt thereof is useful as a DGKζ inhibitor and can be used as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

Claims

1. A compound selected from the group consisting of N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide, N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(3-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide, N-{2-[9-(2-methoxyethyl)-1-oxa-4,9- Diazaspiro[5.5]undec-4-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide, N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide, N-[4-(2-fluorophenoxy)-2-{(3S)-3-[(methylamino)methyl]piperidin-1-yl}- 3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide, N-{2-[(2R)-2-(aminomethyl)pyrrolidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide, N-{2-[(8R,8aS)-8-aminohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide Use of a compound selected from the group consisting of )-1,3-thiazole-4-carboxamide and N-{2-[(8R,8aS)-8-(dimethylamino)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide or a salt thereof in the manufacture of a pharmaceutical composition for treating cancer associated with immune cell activation or cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, wherein: The cancer is selected from the group consisting of leukemia, mismatch repair deficient colorectal cancer and melanoma.

2. A compound selected from the group consisting of N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide mono[(2E)-2-butenedioic acid] salt, N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(3-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide mono[(2E)-2-butenedioic acid] salt, N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide mono[(2E)-2-butenedioic acid] salt, N-[4-( Use of a compound or a salt thereof selected from the group consisting of N-{2-[(2R)-2-(aminomethyl)pyrrolidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4-carboxamide mono[(2E)-2-butenedioic acid] salt in the manufacture of a pharmaceutical composition for treating cancer associated with immune cell activation or cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, wherein the cancer is selected from the group consisting of leukemia, mismatch repair-deficient colorectal cancer and melanoma.

3. The use according to claim 1 or 2, wherein: The cancer is leukemia.

4. The use according to claim 1 or 2, wherein: The cancer is mismatch repair deficient colorectal cancer.

5. The use according to claim 1 or 2, wherein: The cancer is melanoma.

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