Heteroarylcarboxamide compounds

Abstract

The present application provides a compound useful as an effective ingredient of a therapeutic drug composition for a cancer associated with immune cell activation or a cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. The present inventors have researched a compound useful as an effective ingredient of a therapeutic drug composition for a cancer associated with immune cell activation or a cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, and have confirmed that a heteroaryl formamide compound has DGKζ (DGKzeta) inhibitory action, thereby completing the present application. The heteroaryl formamide compound of the present application has DGKζ inhibitory action, and can be used as a therapeutic agent for a cancer associated with immune cell activation or a cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

Description

Technical Field

[0001] This invention relates to heteroarylformamide compounds, which are expected to be useful as pharmaceutical compositions, diacylglycerol kinase ζ (DGKzeta) inhibitors, for example, as therapeutic pharmaceutical compositions for cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly as an active ingredient in therapeutic pharmaceutical compositions for cancers associated with immune cell activation resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. Background Technology

[0002] Cancer immunotherapy has gained attention as the fourth major cancer treatment method after traditional surgical treatment, radiation therapy, and cancer drug therapy (chemotherapy and molecularly targeted drugs). This path was pioneered by anti-cytotoxic T-lymphocyte antigen (CTLA)-4 antibodies (ipilimumab) and anti-PD-1 antibodies (nivolumab and pembrolizumab). CTLA-4 and PD-1 are known as immune checkpoint molecules, acting as "co-stimulatory molecules that can activate inhibitory signals." Currently, the clinical efficacy of anti-PD-1 antibodies against various cancers, including melanoma and non-small cell lung cancer, has been demonstrated, and their indications are continuously expanding. Furthermore, in recent years, antibodies targeting checkpoint molecules other than CTLA-4 and PD-1 have been actively developed worldwide.

[0003] DGK is an enzyme that converts diacylglycerol (DAG) to phosphatidic acid (PA) via phosphorus oxidation. There are 10 subtypes in mammals, broadly classified into 5 classes based on structural characteristics: Type I (α, β, γ), Type II (δ, η, κ), Type III (ε), Type IV (ζ, ι), and Type V (θ). All subtypes possess a highly homologous catalytic domain at the C-terminus and an intramolecular C1 domain homologous to protein kinase C (PKC). The C1 domain is generally considered to be the domain that binds phorbol ester / DAG (Int. J. Mol. Sci. 2013, 14: 6649-6673).

[0004] In T cells, phospholipase Cγ1 (PLCγ1), activated upon 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. Conversely, IP3 releases Ca2+ from the endoplasmic reticulum. 2+Activating the nuclear factor-alpha (NFAT) signaling pathway in activated T cells not only participates in T cell activation but also inducing anergy. T cell anergy refers to an incompletely activated state caused by low co-stimulation (CD28 signaling) during antigen recognition or by inhibition of co-stimulation, resulting in a lack of response even upon re-stimulation.

[0005] DGKα and DGKζ are two major subtypes of T cells. These subtypes regulate the intensity of DAG signaling downstream of antigen stimulation, preventing excessive T cell activation. Moreover, DGKα and DGKζ promote T cell non-responsiveness and play an important role in T cell immune tolerance (JCell Sci. 2013, 126:2176-2186., Crit Rev Immunol. 2013, 33:97-118., Immunol Rev. 2008, 224:249-264.).

[0006] Furthermore, it has been reported that activation of DGKζ-deficient T cells exhibits resistance to PD-1-based inhibitory signals and also 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 been reported that T cells overexpressing PD-1 molecules are extremely fatigued, and anti-PD-1 antibodies become ineffective in this state. Additionally, immunosuppressive factors such as TGF-β are considered one of the mechanisms of resistance to anti-PD-1 therapy (Cancer Treatment Reviews 2017, 52:71-81). It has been reported that NK cell activation based on activation receptor stimulation is negatively regulated by DGKζ, and the proliferation of tumors lacking major histocompatibility gene complex (MHC) type I is inhibited in DGKζKO mice (J Immunol. 2016, 197: 934-941).

[0007] Therefore, in developing DGKζ inhibitors, the anti-tumor effect mediated by immune cell activation, especially T cell activation, is anticipated. The efficacy of anti-PD-1 antibody therapy has also been reported, although it depends on the type of cancer, but is approximately 30% (Front Immunol. 2016, 7:550.), suggesting that DGKζ inhibitors may be effective even in patients resistant to anti-PD-1 antibody therapy.

[0008] Patent document 1 discloses that R59022 and R59499 have DGK inhibitory effects, reduce T cell unresponsiveness, and upregulate immune response.

[0009]

[0010] Patent document 2 discloses compounds represented by the following general formula that have trkA receptor inhibitory effects and are useful for the treatment or prevention of urinary frequency / urgency associated with overactive bladder.

[0011]

[0012] (Please refer to the bulletin for the meaning of the symbols in the formula.)

[0013] However, Patent Document 2 does not specifically disclose the use for cancer treatment or the compound of the present invention containing phenyl groups as essential constituent elements with four consecutive adjacent substituents.

[0014] Patent document 3 discloses compounds represented by the following general formula that are useful as inhibitors of protein kinases such as cyclin-dependent kinases (CDKs) for the treatment or prevention of proliferative diseases.

[0015]

[0016] (Please refer to the bulletin for the meaning of the symbols in the formula.)

[0017] However, Patent Document 3 does not specifically disclose DGK and the compound of the present invention containing phenyl groups as essential constituent elements with four consecutive adjacent substituents.

[0018] The applicant of this application disclosed in Patent Document 4 that compounds represented by the following general formula can be used as DGKζ inhibitors as therapeutic agents for cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

[0019]

[0020] (Please refer to the bulletin for the meaning of the symbols in the formula.)

[0021] However, Patent Document 4 does not specifically disclose the compound of the present invention, and Patent Document 4 is a document published after the priority date of this application.

[0022] Existing technical documents

[0023] Patent documents

[0024] Patent Document 1: US Patent No. 7381401 Specification

[0025] Patent Document 2: International Publication No. WO2007 / 123269

[0026] Patent Document 3: International Publication No. WO2008 / 054702

[0027] Patent Document 4: International Publication No. WO2021 / 132422 Summary of the Invention

[0028] The problem that the invention aims to solve

[0029] A compound is provided that is expected to be useful as a pharmaceutical composition, such as a DGKζ inhibitor, as a therapeutic pharmaceutical composition for cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly as an active ingredient in a therapeutic pharmaceutical composition for cancers associated with immune cell activation resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

[0030] Methods for solving problems

[0031] The inventors conducted in-depth research on compounds useful as active ingredients in therapeutic pharmaceutical compositions for cancers related to immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly for therapeutic pharmaceutical compositions for cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. As a result, it was discovered that heteroarylformamide compounds of formula (I) containing phenyl groups as essential constituent elements, which are generally considered difficult to manufacture, have excellent DGKζ inhibitory activity, thus completing the present invention.

[0032] That is, the present invention relates to compounds of formula (I) or salts thereof, and pharmaceutical compositions comprising compounds of formula (I) or salts thereof and one or more pharmaceutically acceptable excipients.

[0033]

[0034] (in the formula,

[0035] A can be one of the following expressions: (Ai), (A-ii), (A-iii), (A-iv), or (Av).

[0036]

[0037] B is one of the following formulas: (Bi), (B-ii), (B-iii), or (B-iv).

[0038]

[0039] Here, R 1a Halogenated C 1-6 When alkyl, B is (Bi).

[0040] R 1a It is a pyridazinyl or halogenated C 1-6 alkyl,

[0041] R 1b For H or C 1-6 alkyl,

[0042] R 2 C 3-5 cycloalkyl, -O-(C 1-6 Alkyl), halogenated C 1-6 Alkyl, halogen or phenyl,

[0043] R 3 For: i) can be freely selected C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-5 cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C) 1-6 ii) phenyl groups substituted with groups in the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen; 1-6 The C groups substituted in the group consisting of alkyl and halogens 3-8 cycloalkyl; iii) can be 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 pyridyl groups substituted with groups from the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen; or iv) five- to six-membered partially unsaturated heterocycles containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen.

[0044] R 4 For H or F,

[0045] R 5 For H or F,

[0046] R 6 -L2-(CH2)2NR a R b Or piperidinyl,

[0047] L1 is a bond, O, or NH.

[0048] L2 represents a bond, O, or CH2.

[0049] X is CH2 or N-methyl.

[0050] Y is CH or N.

[0051] R a It is H or methyl.

[0052] R b It can be H, methyl, ethyl, cyclopropyl, or -(CH2)2O-CH3.

[0053] m can be 1, 2, or 3.

[0054] It should be noted that, unless otherwise specified, when a symbol in a chemical formula in this specification is used in other chemical formulas, the same symbol has the same meaning.

[0055] Furthermore, this invention relates to a therapeutic pharmaceutical composition 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 one or more pharmaceutically acceptable excipients, particularly a therapeutic pharmaceutical composition for cancers associated with immune cell activation and resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. It should be noted that this 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, particularly a therapeutic agent for cancers associated with immune cell activation and resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, comprising a compound of formula (I) or a salt thereof.

[0056] Furthermore, the present invention relates to: compounds of formula (I) or salts thereof as DGKζ inhibitors; compounds of formula (I) or salts thereof used as DGKζ inhibitors; DGKζ inhibitors containing compounds of formula (I) or salts thereof; the use of compounds of formula (I) or salts thereof in the manufacture of therapeutic pharmaceutical compositions for cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly the use of compounds of formula (I) or salts thereof in the manufacture of therapeutic pharmaceutical compositions for cancers associated with immune cell activation and resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy; the use of compounds of formula (I) or salts thereof for the treatment of cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly the use of compounds of formula (I) or salts thereof in the treatment of cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. Application in the treatment of cancers associated with immune cell activation and resistance to anti-PD-1 antibody / anti-PD-L1 antibody therapy; a compound of formula (I) or a salt thereof for use in the treatment of cancers associated with immune cell activation or 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 the treatment of cancers associated with immune cell activation and resistance to anti-PD-1 antibody / anti-PD-L1 antibody therapy; and a treatment method for cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly a treatment method for cancers associated with immune cell activation and resistance to anti-PD-1 antibody / anti-PD-L1 antibody therapy, including the step of 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 person or other animal in need of the prevention or treatment, and by way of, a person in need of the prevention or treatment.

[0057] Invention Effects

[0058] Compounds of formula (I) or their salts have DGKζ inhibitory activity 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, particularly for cancers associated with immune cell activation resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. Detailed Implementation

[0059] The present invention will be described in detail below.

[0060] In this specification, unless otherwise specified, the following terms shall have the meanings described below. The definitions below are for clarity and not for limitation. When a term is not specifically defined herein, it shall be used in the sense that is generally accepted by those skilled in the art.

[0061] In this instruction manual, "C" 1-6 "Alkyl" refers to a straight or branched chain with 1 to 6 carbon atoms (hereafter simply referred to as C). 1-6 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. As an example, it is C1. 1-3 Alkyl, as a form, is methyl or ethyl, as a form, is methyl, as a form, is ethyl.

[0062] Halogenated C 1-6 "Alkyl" refers to a carbon atom that has been substituted with one or more halogens. 1-6 Alkyl groups. As a form, C groups are substituted with 1 to 5 halogens. 1-6 Alkyl groups, as a form, are C groups substituted with 1 to 5 halogens. 1-3 Alkyl, as a form, is trifluoromethyl, difluoromethyl, difluoroethyl or trifluoroethyl, as a form, is difluoroethyl or trifluoromethyl, as a form, is difluoroethyl, as a form, is trifluoromethyl, as a form, is 2,2-difluoroethyl.

[0063] “C 3-8 "Cycloalkyl" refers to C 3-8 Saturated hydrocarbon cyclic groups can be cross-linked and form spirocyclic rings. 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 mode, it is C 3-5 Cycloalkyl. As a C 3-5 One form of cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl; another form is cyclopropyl; another form is cyclobutyl; and another form is cyclopentyl.

[0064] "Halogen" refers to F, Cl, Br, and I. As a form, it is either F or Cl; as a form, it is F; and as a form, it is Cl.

[0065] "Five- to six-membered partially unsaturated heterocycles" refer to monocyclic heterocycles containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen, with locally unsaturated bonds. Sulfur or nitrogen, as ring atoms, can be oxidized to form oxides or dioxides. Examples include dihydropyridyl, tetrahydropyridyl, dihydrofuranyl, dihydrothiophenyl, dihydropyranyl, thiaranyl, and dihydrothiaranyl. One example is tetrahydropyridyl, another is dihydrofuranyl, and yet another is dihydropyranyl.

[0066] "Can be substituted" means either unsubstituted or "substituted by one or more substituents (e.g., substituents defined below)". The substitution can be at any position where hydrogen is normally present in the group. One way is to say "can be substituted" as "can be substituted by 1 to 5 substituents", and another way is "can be substituted by 1 to 3 substituents". It should be noted that when there are two or more substitutions, these substituents can be the same or different.

[0067] Furthermore, even if the combination is not specifically recorded, one or more methods can be combined with other methods. That is, all methods can be freely combined.

[0068] "Immune cell activation" refers to the reactivation of immune cells, particularly T cells, that have the ability to inhibit cancer cell proliferation or shrink or eliminate cancer cells (hereinafter referred to as anti-tumor activity), and / or the increase in the number of immune cells, particularly activated T cells. One approach is immune cell activation based on the inhibitory effect of DGKζ.

[0069] "Cancers associated with immune cell activation" refer to cancers that exhibit an immune response. One mechanism is the inhibition of cancer cell proliferation or the shrinking or disappearance of cancer cells through immune cell activation. Another mechanism is the inhibition of cancer cell proliferation or the shrinking or disappearance of cancer cells through immune cell activation based on DGKζ inhibition.

[0070] The types of cancers to which this invention can be applied are not particularly limited, but examples include small cell lung cancer, head and neck cancer, kidney cancer, ovarian cancer, non-small cell lung cancer, mismatch repair deficient colorectal cancer, urothelial carcinoma, melanoma, hepatocellular carcinoma, gastric cancer, and bladder cancer.

[0071] "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. This includes, as one way, resistance to anti-PD-1 antibody therapy, and as another way, resistance to anti-PD-L1 antibody therapy. "Resistance" includes primary resistance (where the anti-PD-1 antibody / anti-PD-L1 antibody is initially ineffective) or acquired resistance (where resistance becomes ineffective with continued treatment). In the phrase "resistance to anti-PD-1 antibody / anti-PD-L1 antibody therapy", one method is primary resistance to anti-PD-1 antibody and anti-PD-L1 antibody therapy; another method is acquired resistance to anti-PD-1 antibody and anti-PD-L1 antibody therapy; yet another method is primary resistance to anti-PD-1 antibody therapy; another method is acquired resistance to anti-PD-1 antibody therapy; yet another method is primary resistance to anti-PD-L1 antibody therapy; and yet another method is acquired resistance to anti-PD-L1 antibody therapy.

[0072] "Cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy" refers to cancer that exhibits resistance to anti-PD-1 antibody and / or anti-PD-L1 antibody therapy. This can be categorized as follows: cancer resistant to anti-PD-1 antibody and anti-PD-L1 antibody therapy; cancer resistant to anti-PD-1 antibody therapy; cancer resistant to anti-PD-L1 antibody therapy; cancer with primary resistance to anti-PD-1 antibody and anti-PD-L1 antibody therapy; cancer with acquired resistance to anti-PD-1 antibody and anti-PD-L1 antibody therapy; cancer with primary resistance to anti-PD-1 antibody therapy; cancer with acquired resistance to anti-PD-1 antibody therapy; cancer with primary resistance to anti-PD-L1 antibody therapy; cancer with acquired resistance to anti-PD-L1 antibody therapy.

[0073] The cancers to which this invention can be applied are not particularly limited, but examples include small cell lung cancer, head and neck cancer, kidney cancer, ovarian cancer, non-small cell lung cancer, mismatch repair deficient colorectal cancer, urothelial carcinoma, melanoma, hepatocellular carcinoma, gastric cancer, and bladder cancer that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

[0074] There is no particular limitation on “anti-PD-1 antibody / anti-PD-L1 antibody”, and examples such as antibodies selected from nivolumab, pembrolizumab, atezolizumab, pitilizumab, avelumab, and durvalumab can be listed.

[0075] The following illustrates some ways of using compounds of formula (I) or salts thereof of the present invention.

[0076] (1-1) A is a compound or a salt thereof of the following formula (Ai), (A-ii), (A-iii), (A-iv) or (Av).

[0077]

[0078] (1-2) A is a compound of the following formula (Ai) or (A-ii) or a salt thereof.

[0079]

[0080] (2-1) B is a compound of formula (Bi), (B-ii), (B-iii), or (B-iv) or a salt thereof. Here, R 1a Halogenated C 1-6 When alkyl, B is (Bi).

[0081]

[0082] (2-2) B is a compound of formula (Bia) or (B-ii) or a salt thereof. Here, R 1a Halogenated C 1-6 When alkyl, B is (Bia).

[0083]

[0084] (3-1)R 1a Halogenated C 1-6 When alkyl, B is (Bi) of the compound or its salt.

[0085] (3-2)R 1a Halogenated C 1-6 When alkyl, B is (Bia) of the compound or its salt.

[0086] (3-3)R 1a Halogenated C 1-3 When alkyl, B is (Bia) of the compound or its salt.

[0087] (4)R 1aIt is a pyridazinyl or halogenated C 1-6 Alkyl compounds or their salts. As a way, R 1a It is a pyridazinyl or halogenated C 1-3 Alkyl compounds or their salts. As a way, R 1a It is a compound of pyridazinyl, trifluoromethyl, difluoromethyl, difluoroethyl, or trifluoroethyl, or a salt thereof. As a method, R 1a Compounds of the pyridazinyl or 2,2-difluoroethyl group or their salts. As a method, R 1a Compounds of the pyridazine group or their salts. As a way, R 1a It is a compound of 2,2-difluoroethyl or a salt thereof.

[0088] (5)R 1b For H or C 1-6 Alkyl compounds or their salts. As a way, R 1b For H or C 1-3 Alkyl compounds or their salts. As a way, R 1b Compounds that are H or methyl groups or their salts. As a way, R 1b Compounds of H or their salts. In one manner, R 1b Compounds containing methyl groups or their salts.

[0089] (6)R 2 C 3-5 cycloalkyl, -O-(C 1-6 Alkyl), halogenated C 1-6 Compounds of alkyl, halogen, or phenyl groups or their salts. As a means, R 2 Halogenated C 1-6 Alkyl or halogen compounds or their salts. As a way, R 2 Halogenated C 1-3 Compounds of alkyl, F, Cl, or Br, or their salts. As a means, R... 2 Compounds of CF3, F, or Cl, or their salts. As a way, R 2 For CF3 compounds or their salts. As a way, R 2 For compounds of F or their salts. In one manner, R 2 It is a compound of Cl or its salt.

[0090] (7-1)R 3 For i) can be freely selected C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-5 cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C) 1-6ii) phenyl groups substituted with groups from the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen; 1-6 The C groups substituted in the group consisting of alkyl and halogens 3-8 cycloalkyl; iii) can be 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 A pyridyl group substituted with a group from the group consisting of alkyl, cyano, nitro, methanesulfonyl and halogen; or iv) a compound or a salt thereof containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen in a five- to six-membered partially unsaturated heterocycle.

[0091] (7-2)R 3 For i) can be freely selected C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-5 cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C) 1-6 The phenyl group substituted with a group from the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen, or ii) may be selected from C 1-6 The C groups substituted in the group consisting of alkyl and halogens 3-8 Cycloalkyl compounds or their salts.

[0092] (7-3)R 3 For the free choice C 1-6 The phenyl or C groups substituted in the group consisting of alkyl and halogen are... 3-5 Cycloalkyl compounds or their salts.

[0093] (8)R 4 Compounds of H or F or their salts. In one manner, R 4 Compounds of H or their salts. In one manner, R 4 Compounds of F or their salts.

[0094] (9)R 5 Compounds of H or F or their salts. In one manner, R 5 Compounds of H or their salts. In one manner, R 5 Compounds of F or their salts.

[0095] (10)R 6 -L2-(CH2)2NR a R b Or a piperidinyl compound or its salt. As a way, R 6 -L2-(CH2)2NR a Rb Compounds or salts thereof. As a way, R 6 Compounds containing piperidinyl groups or their salts.

[0096] (11) L1 is a compound of bond, O or NH or a salt thereof. In one manner, L1 is a compound of bond or O or a salt thereof. In one manner, L1 is a compound of bond or a salt thereof. In one manner, L1 is a compound of O or a salt thereof.

[0097] (12) L2 is a compound of O or CH2 or a salt thereof. In one manner, L2 is a compound of O or CH2 or a salt thereof. In another manner, L2 is a compound of O or a salt thereof. In another manner, L2 is a compound of CH2 or a salt thereof.

[0098] (13) X is a CH2 or N-methyl compound or a salt thereof. In one manner, X is a CH2 compound or a salt thereof. In another manner, X is an N-methyl compound or a salt thereof.

[0099] (14) Y is a compound of CH or N or a salt thereof. In one manner, Y is a compound of CH or a salt thereof. In another manner, Y is a compound of N or a salt thereof.

[0100] (15)R a Compounds that are H or methyl groups or their salts. As a way, R a Compounds of H or their salts. In one manner, R a Compounds containing methyl groups or their salts.

[0101] (16)R b It is a compound of H, methyl, ethyl, cyclopropyl, or -(CH2)2O-CH3, or a salt thereof. As a manner, R b Compounds that are H or methyl groups or their salts. As a way, R b Compounds of H or their salts. In one manner, R b Compounds containing methyl groups or their salts.

[0102] (17) A compound or a salt thereof in which m is 1, 2 or 3. Alternatively, a compound or a salt thereof in which m is 1 or 2. Alternatively, a compound or a salt thereof in which m is 1.

[0103] (18) A compound or its salt formed by any two or more combinations of the methods described in (1-1) to (17) above, which do not contradict each other.

[0104] As a combination described above (18), specifically, examples can be listed as follows.

[0105] (19) A is one of the following expressions: (Ai), (A-ii), (A-iii), (A-iv), or (Av).

[0106]

[0107] B is one of the following formulas: (Bi), (B-ii), (B-iii), or (B-iv).

[0108]

[0109] Here, R 1a Halogenated C 1-6 When alkyl, B is (Bi), R 1a It is a pyridazinyl or halogenated C 1-6 Alkyl, R 1b For H or C 1-6 Alkyl, R 2 C 3-5 cycloalkyl, -O-(C 1-6 Alkyl), halogenated C 1-6 Alkyl, halogen or phenyl, R 3 For i) can be freely selected C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-5 cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C) 1-6 phenyl groups substituted with groups in the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen can be selected from C 1-6 The C groups substituted in the group consisting of alkyl and halogens 3-8 cycloalkyl, iii) can be 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 pyridyl groups substituted with groups from the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen, or (iv) five- to six-membered partially unsaturated heterocycles containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, R 4 For H or F, R 5 For H or F, R 6 -L2-(CH2)2NR a R b Or piperidinyl, L1 is a bond, O or NH, L2 is a bond, O or CH2, X is CH2 or N-methyl, Y is CH or N, R a H or methyl, R b Compounds or salts thereof that are H, methyl, ethyl, cyclopropyl or -(CH2)2O-CH3, where m is 1, 2 or 3.

[0110] (20) The compound or a salt thereof according to (19), wherein R 2 Halogenated C 1-6 Alkyl or halogen, R 3 For i) can be freely selected C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-5 cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C) 1-6 The phenyl group substituted with a group from the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen, or ii) may be selected from C 1-6 The C groups substituted in the group consisting of alkyl and halogens 3-8 Cycloalkyl, L1 is a bond or O.

[0111] (21) The compound or a salt thereof according to (20), wherein B is of the following formula (Bia) or (B-ii),

[0112]

[0113] Here, R 1a Halogenated C 1-6 When alkyl, B is (Bia).

[0114] (22) The compound or salt thereof according to (21), wherein A is of the following formula (Ai) or (A-ii).

[0115]

[0116] (23) The compound or its salt according to (22), wherein R 3 For the free choice C 1-6 The phenyl or C groups substituted in the group consisting of alkyl and halogen are... 3-5 cycloalkyl, R b It is H or methyl.

[0117] Examples of specific compounds included in this invention include the following compounds or their salts.

[0118] N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide,

[0119] N-{2-[(3S)-3-(aminomethyl)-4-methylpiperazin-1-yl]-4-(2-chlorophenoxy)-3-(trifluoromethyl)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide,

[0120] N-{2-[(3S)-3-(aminomethyl)-4-methylpiperazin-1-yl]-3-chloro-4-(2-chlorophenoxy)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide,

[0121] N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide,

[0122] N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide,

[0123] N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide,

[0124] N-[4-cyclopentyl-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide,

[0125] N-{2-[(8R,8aS)-8-aminohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3- azole-4-carboxamide, and

[0126] N-[3-chloro-4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide.

[0127] Examples of specific compounds or salts thereof included in this invention include the following compounds or salts thereof.

[0128] N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate,

[0129] N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate,

[0130] N-[4-cyclopentyl-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate,

[0131] N-[3-chloro-4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate, and

[0132] N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate.

[0133] Compounds of formula (I) may exist as tautomers and geometric isomers depending on the type of substituents. In this specification, compounds of formula (I) or their salts are sometimes described as only one type of isomer, but the present invention also includes isomers other than those described herein, as well as isomer isolates or mixtures thereof.

[0134] Furthermore, compounds of formula (I) or their salts sometimes have asymmetric centers or axial asymmetry, and may have enantiomers (optical isomers) based on them. Compounds of formula (I) or their salts comprise any of isolated enantiomers such as (R) bodies, (S) bodies, or mixtures thereof (racemic or non-racemic mixtures). In one manner, the enantiomer is "stereochemically pure." "Stereochemically pure" means a purity that can be recognized by a person skilled in the art as substantially stereochemically pure. Alternatively, the enantiomer is a compound having a stereochemical purity of, for example, 90% ee (enantiomeric excess) or higher, 95% ee or higher, 98% ee or higher, or 99% ee or higher.

[0135] Furthermore, salts of compounds of formula (I) are pharmaceutically acceptable salts of compounds of formula (I), and depending on the type of substituent, sometimes form acid addition salts or salts with bases. Specifically, examples include: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, dibenzoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid; and salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, and various amino acids and amino acid derivatives such as acetylleucine.

[0136] Furthermore, the present invention also includes various hydrates, solvates, and polymorphs of compounds of formula (I) and their salts.

[0137] Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of compounds represented by formula (I). A pharmaceutically acceptable prodrug is a compound having groups that can be decomposed by solvents or converted into amino, hydroxyl, carboxyl, or other groups under physiological conditions. Examples of groups forming prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and "Pharmaceutical Development" (Mitsukawa Shoten, 1990), Vol. 7, Molecular Design, pp. 163-198.

[0138] Furthermore, this invention comprises all pharmaceutically acceptable compounds of formula (I) labeled with one or more radioactive or non-radioactive isotopes, or salts thereof. Examples of suitable isotopes for isotopic labeling of compounds of this invention include hydrogen (…). 2 H and 3 H, etc.), carbon ( 11 C 13 C and 14 C, etc.), nitrogen ( 13 N 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 These isotopes include S, etc.

[0139] The isotopically labeled compounds of this invention can be used in studies such as tissue distribution research of drugs and / or substrates. For example, tritium ( 3 H), carbon-14 ( 14C) Radioactive isotopes can be used for this purpose because they are easy to label and detect.

[0140] Replaced with a heavier isotope, for example, hydrogen replaced by deuterium. 2 H) Sometimes improved metabolic stability can be beneficial to treatment (e.g., prolonged half-life in vivo, reduced required dosage, and reduced drug interactions).

[0141] Replaced with positron-emitting isotopes ( 11 C 18 F, 15 O and 13 (e.g., N) can be used in positron emission tomography (PET) scans to examine substrate receptor occupancy.

[0142] The isotopically labeled compounds of the present invention can generally be manufactured by existing methods known to those skilled in the art, or by using suitable isotopically labeled reagents instead of unlabeled reagents and by the same manufacturing method as in the examples or manufacturing examples.

[0143] Regarding the powder X-ray diffraction patterns described in this specification, in determining crystal identity, the nature of the data, lattice spacing, and overall pattern are important. Diffraction angles and intensities may introduce errors depending on the direction of crystal growth, particle size, and measurement conditions, and therefore should not be interpreted rigidly. In this specification, the diffraction angles (2θ(°)) in the powder X-ray diffraction patterns are interpreted after considering the generally permissible error range in this measurement method; as an example, an error range of ±0.2° can be taken. Furthermore, for example, when measurements are performed in a mixture with excipients, for peaks present near the peaks from the excipients and located on the slope of the baseline, the apparent peak may shift within a range of ±0.3°.

[0144] (Manufacturing method)

[0145] Compounds of formula (I) and their salts can be manufactured using various known synthetic methods based on their basic structure or the types of substituents. In this case, depending on the type of functional group, it is sometimes technically effective to pre-replace the functional group with a suitable protecting group (a group that can be easily converted to the functional group) during the stage from the starting material to the intermediate. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis" (4th edition, 2006) by Wuts (PGMWuts) and Greene (TWGreene), which can be appropriately selected based on their reaction conditions. In such methods, after introducing the protecting group and reacting, the protecting group is removed as needed, thereby obtaining the desired compound.

[0146] Furthermore, the prodrug of the compound of formula (I) can be manufactured in the same manner as the protecting group described above, either by introducing a specific group during the process from the starting material to the intermediate, or by further reacting the obtained compound of formula (I). The reaction can be carried out using methods known to those skilled in the art, such as conventional esterification, amidation, and dehydration.

[0147] The following describes representative methods for manufacturing compounds of formula (I). Each manufacturing method may also be described with reference to the appended references. It should be noted that the manufacturing methods of the present invention are not limited to the examples shown below.

[0148] The following abbreviations are sometimes used in this manual.

[0149] DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide, EtOAc = ethyl acetate, EtOH = ethanol, Hex = hexane, MeCN = acetonitrile, MeOH = methanol, THF = tetrahydrofuran, DMI = 1,3-dimethylimidazolin-2-one, NMP = N-methyl-2-pyrrolidone, CH2Cl2 = dichloromethane.

[0150] Boc = tert-butoxycarbonyl, Ph = phenyl, tBu = tert-butyl, Et = ethyl, Me = methyl, Ac = acetyl, Ns = 2-nitrobenzenesulfonyl.

[0151] CDI = 1,1'-carbonylbis(1H-imidazolium), DCC = N,N'-dicyclohexylcarbodiimide, TEA = triethylamine, DIPEA = N,N-diisopropylethylamine, DABCO = 1,4-diazabicyclo[2.2.2]octane, DPPA = diphenyl azidophosphate, HATU = O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, HOBt = 1-hydroxybenzotriazole, KOtBu = potassium tert-butoxide, NaOtBu = sodium tert-butoxide, NMM = N-methylmorpholine, Pd / C = palladium supported carbon, TFA = trifluoroacetic acid, TFAA = trifluoroacetic anhydride, WSC.HCl = N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride.

[0152] 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 dichloride dichloromethane adduct, Pd2(dba)3 = (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one / palladium (3:2).

[0153] Salt water = saturated NaCl aqueous solution, MgSO4 = anhydrous magnesium sulfate, Na2SO4 = anhydrous sodium sulfate, NaHCO3 = sodium bicarbonate, NH4Cl = ammonium chloride, NaBH(OAc)3 = sodium triacetoxyborohydride

[0154]

[0155] (First process)

[0156] This process is a method for obtaining compound (2) by subjecting compound (1) to a reduction reaction.

[0157] This reaction can be carried out using MeOH, EtOH, or 1,4-dioxanone. Compound (1) and a metal are stirred under acidic conditions in a mixed solvent of alkanes and water for 1 hour to 5 days under reflux from room temperature. The acid used can be NH4Cl, AcOH, HCl, etc. The metal used can be Fe, Zn, Sn, etc.

[0158] Alternatively, the reaction can be carried out under a hydrogen atmosphere in a solvent that is inert in the reaction, such as MeOH, EtOH, EtOAc, or a mixture thereof, with stirring for 1 hour to 5 days in the presence of a metal catalyst, from cooling to heating, preferably at room temperature. As the metal catalyst, palladium catalysts such as Pd / C, palladium black, and palladium hydroxide supported on carbon, platinum catalysts such as platinum supported on carbon and platinum oxide, and nickel catalysts such as reduced nickel and Raney nickel can be used.

[0159] (Second process)

[0160] This process is a method for obtaining compound (I) by subjecting compounds (2) and (3) to an amidation reaction followed by appropriate substituent transformation.

[0161] In this amidation reaction, compounds (2) and (3) are used in equal or excess amounts, and their mixture is stirred for 0.1 hours to 5 days in the presence of a condensing agent in a solvent that is inert in the reaction, typically from cooling to heating, preferably -20°C to 60°C. Examples of solvents used herein, without particular limitation, include: aromatic hydrocarbons such as benzene, toluene, or xylene; halogenated hydrocarbons such as CH2Cl2, 1,2-dichloroethane, or chloroform; diethyl ether, THF, 1,4-dichloroethane, etc. Ethers such as alkanes and 1,2-dimethoxyethane; DMF, DMSO, EtOAc, MeCN, or water, and mixtures thereof. Examples of condensing agents include WSC.HCl, DCC, CDI, DPPA, HATU, etc., but are not limited to these. Sometimes additives (e.g., HOBt) are preferred in the reaction. The presence of organic bases such as TEA, DIPEA, NMM, or inorganic bases such as K2CO3, Na2CO3, KOH, etc., can sometimes facilitate the reaction.

[0162] Alternatively, an amidation reaction can 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 acyl halides obtained by reacting with halogenating agents such as POCl3 and SOCl2, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, and active esters obtained by condensation with HOBt. This reaction can be carried out in a solvent that is inert in the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, or ethers, under cooling to reflux, preferably at -20°C to 120°C.

[0163] Following the amidation reaction, appropriate substituent conversions can be performed after introducing and / or removing protecting groups as needed, thereby obtaining the compound of formula (I).

[0164] (Raw Material Synthesis 1)

[0165]

[0166] (in the formula LG) 1 and LG 2 Indicates a leaving group. LG 1 and LG 2 (These can be halogens, etc., and may vary.)

[0167] This manufacturing method is a method for manufacturing raw material compound (1).

[0168] (Third process)

[0169] This process is a method for producing compound (6) from compound (5) through an in-situ substitution reaction.

[0170] This reaction is carried out in an inert solvent or in the absence of solvent, typically with stirring for 0.1 hours to 5 days from cooling to refluxing, preferably at 0°C to 120°C. 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; diethyl ether, THF, and 1,4-dichloroethane. Ethers such as alkanes and 1,2-dimethoxyethane; DMF, DMSO, NMP, EtOAc, MeCN, and mixtures thereof. The presence of organic bases such as TEA, DIPEA, NMM, and DABCO, and inorganic bases such as NaH, K2CO3, Na2CO3, Cs2CO3, and NaOtBu can sometimes facilitate the reaction.

[0171] (Fourth process)

[0172] This process is a method for producing compound (7) by using compound (5) and an organoboron compound via the Suzuki coupling reaction or by using compound (5) and an amine compound via the Buchwald-Hartwig reaction.

[0173] This reaction is carried out in an inert solvent in the presence of a base and a palladium catalyst, typically with stirring for 0.1 hours to 5 days under reflux from room temperature. 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; diethyl ether, THF, and 1,4-dichloroethane. Ethers such as alkanes and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropanol, and butanol; DMF, DMSO, MeCN, DMI, water, and mixtures thereof. Inorganic bases such as NaH, K₂CO₃, Na₂CO₃, Cs₂CO₃, K₃PO₄, and CsF can be listed as bases. Palladium catalysts such as Pd(PPh₃)₄, PdCl₂(PPh₃)₂, Pd(dppf)Cl₂·CH₂Cl₂, and Pd₂(dba)₃ can be used. The presence of ligands such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (SPhos) sometimes facilitates the reaction. Additionally, heating the reaction mixture by microwave irradiation sometimes promotes the reaction. For example, the following literature can be consulted as references for this reaction.

[0174] J.Am.Chem.Soc.127,4685-4696,2005

[0175] Angew.Chem.,Int.Ed.Engl.34,1348-1350,1995

[0176] Alternatively, compound (7) can be produced by an in-situ substitution reaction from compound (5) and an amine compound. The reaction conditions in this case are the same as in the third step.

[0177] (Fifth process)

[0178] This process is a method for producing compound (1) from compound (6) and an amine compound through an in-situ substitution reaction.

[0179] The reaction conditions are the same as those in the third step.

[0180] (Sixth process)

[0181] This process is a method for producing compound (1) from compound (7) by in-situ substitution reaction or a method for producing compound (1) by using compound (7) and organoboron compound via Suzuki coupling reaction.

[0182] The reaction conditions for the in-situ substitution reaction are the same as those for the third step. Additionally, the reaction conditions for the Suzuki coupling reaction are the same as those for the fourth step.

[0183] (Raw Material Synthesis 2)

[0184]

[0185] (In the formula, P1 represents H or a protecting group, and P2 represents a protecting group.)

[0186] This manufacturing method is a method for manufacturing a raw material compound (7-b) as one of the methods described in (raw material synthesis 1).

[0187] (Seventh step)

[0188] This process is a method for producing compound (7-b) by oxidizing compound (7-a) and then reacting it with compound (8) via a reductive amination reaction.

[0189] The oxidation reaction of compound (7-a) is carried out by using compound (7-a) and a specified oxidant in equal or excess amounts in a solvent that is inert in the reaction, under stirring typically from ice cooling to reflux for 0.1 hours to 5 days. The specified oxidant is not particularly limited, but examples include Dess-Martin periodinane. Examples of solvents used herein are also not particularly limited, but examples include CH₂Cl₂, 1,2-dichloroethane, chloroform, carbon tetrachloride, and other halogenated hydrocarbons.

[0190] In the reductive amination reaction, the aldehyde and compound (8) obtained by the aforementioned oxidation reaction are used in equal or excess amounts, and the mixture is stirred in the presence of a reducing agent in a solvent that is inert in the reaction, typically for 0.1 hours to 5 days, from -45°C to reflux. Examples of solvents used herein, without particular limitation, include: alcohols such as MeOH and EtOH; diethyl ether, THF, 1,4-diethyl ether, etc. Ethers such as alkanes and dimethoxyethane, and mixtures thereof. Examples of reducing agents include sodium cyanoborohydride, sodium triacetoxyborohydride, and sodium borohydride. Sometimes, the reaction is preferably carried out in the presence of dehydrating agents such as molecular sieves or acids such as acetic acid, hydrochloric acid, or isopropoxytitanium(IV) complexes.

[0191] (Raw Material Synthesis 3)

[0192]

[0193] (In the formula, P1 represents H or a protecting group, and P2 represents a protecting group.)

[0194] This manufacturing method is a method for manufacturing a raw material compound (1-d) as one of the methods described in (raw material synthesis 1).

[0195] (Eighth process)

[0196] This process is a method for producing compound (9) by introducing a leaving group into compound (1-c) and then reacting it with Gabriel amine.

[0197] In this reaction, an equal or excessive amount of the compound (1-c) obtained by reacting a halosulfonyl compound such as MsCl or TsCl, or an anhydride such as methanesulfonic anhydride or p-toluenesulfonic anhydride, in an inert solvent in the presence of a base, and potassium phthalimide are used. The mixture is stirred in an inert solvent in the presence of a base, from ice cooling to reflux, preferably from 0°C to 120°C, typically for 0.1 hours to 5 days. Examples of solvents are not particularly limited, but include aromatic hydrocarbons such as toluene, 1,4-di(2 ... Alkane and other ethers; halogenated hydrocarbons such as CH2Cl2; DMF, DMSO, EtOAc, MeCN, and mixtures thereof. Examples of bases include organic bases such as TEA, DIPEA, or NMM, or inorganic bases such as K2CO3, Na2CO3, or KOH.

[0198] Following the above reaction, compound (9) can be obtained by deprotection of phthalimide with hydrazine in a solvent that is inert in the reaction.

[0199] For reference in this reaction, see, for example, the following literature.

[0200] Angew.Chem.,Int.Ed.Engl.7,919-930,1968

[0201] (Ninth process)

[0202] This process is a method for producing compound (1-d) by introducing a protecting group into compound (9).

[0203] Protecting groups used in this reaction can be listed as, for example, those described in "Greene's Protective Groups in Organic Synthesis (4th Edition, 2006)" by Wuts (PGMWuts) and Greene (TWGreene), and can be appropriately selected according to their reaction conditions.

[0204] (Raw Material Synthesis 4)

[0205]

[0206] (In the formula, P1 represents H or a protecting group, and P2 represents a protecting group.)

[0207] This manufacturing method is a method for manufacturing compound (1-b) as one of the compounds (1) described in the aforementioned (raw material synthesis 1).

[0208] (Tenth step)

[0209] This process is a method for producing compound (10) by deprotection of the phthalimide group after photo-extending reaction of compound (1-a) with phthalimide.

[0210] The photoelectrophoretic reaction of compound (1-a) involves using equal or excess amounts of compound (1-a) and phthalimide, mixing them in a solvent that is inert in the reaction, in the presence of known diazocarboxylic esters or diazocarboxamides and known phosphines, and stirring typically for 0.1 hours to 5 days under conditions ranging from cooling to reflux, preferably from 0°C to 150°C. Examples of solvents used herein, without particular limitation, include aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMSO, EtOAc, MeCN, and mixtures thereof.

[0211] Following the above reaction, compound (10) can be obtained by deprotection of phthalimide with hydrazine in an inert solvent during the reaction.

[0212] For reference regarding the aforementioned photoelongation reaction, see, for example, Synthesis (1981), 1.

[0213] (Eleventh process)

[0214] This process is a method for producing compound (1-b) by introducing a protecting group into compound (10).

[0215] The reaction conditions are the same as those in the ninth step.

[0216] The compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates, or polymorphs. Salts of the compounds of formula (I) can also be prepared by conventional salt-forming reactions.

[0217] Separation and purification can be carried out using common chemical operations such as extraction, fractional crystallization, and various chromatographic methods.

[0218] Various isomers can be produced by selecting appropriate starting material compounds, or they can be separated by utilizing the differences in physicochemical properties between the isomers. For example, optical isomers can be obtained by conventional optical resolution methods for racemates (e.g., stepwise crystallization by introducing diastereomeric salts of optically active bases or acids, chromatography using chiral columns, etc.), or they can be produced from appropriate optically active starting material compounds.

[0219] The pharmacological activity of compounds of formula (I) can be confirmed by the following tests or known modified tests. It should be noted that in this specification, the amount of the test compound is expressed as the weight of the free body. Furthermore, when using commercially available reagents, kits, etc., the tests can be performed according to the instructions for use.

[0220] Evaluation of the inhibitory effect of DGKζ in Experiment 1

[0221] Using ADP-Glo TM The following method was used to investigate the inhibitory effect of the test compound on human recombinant DGKζ (Carna Bio, 12-410-20N) using the Kinase Assay (Promega).

[0222] Add 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)) to a 384-well plate (Greiner Bio-one). Similarly, add 3 μL of the test compound diluted in Assay buffer to achieve the target final concentration. After standing at room temperature for 15 minutes, add 3 μL of substrate (150 μM 1-oleoyl-2-acetyl-sn-propanetriol (SIGMA-ALDRICH), 480 μM phosphatidylserine (Avanti), 150 μM UltraPure-ATP (ADP-Glo ​​included)) dissolved in Lipid dilution buffer (40 mM Tris-HCl pH 7.5, 0.1 mg / mL BSA, 1 mM DTT) and let stand at room temperature for 30 minutes to allow the reaction to proceed. Then, 3 μL of ADP-Glo ​​Reagent was added, and the mixture was allowed to stand at room temperature for 40 minutes to stop the enzyme reaction. Next, 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 without DGKζ enzyme was set as 100% inhibition. The 50% inhibition concentration (IC50) was calculated using a sigmoid-Emax model nonlinear regression analysis. 50 The results for several compounds of formula (I) are shown in Table 1. It should be noted that in the table, Ex represents the example number described later.

[0223] [Table 1]

[0224]

[0225] Evaluation of the role of IL-2 production in the human T-cell leukemia cell line Jurkat E6.1 (Example 2)

[0226] The effects of the tested compounds on IL-2 production induced by T-cell receptor (TCR) stimulation (anti-CD3 / anti-CD28) in Jurkat E6.1 cells (ECACC, 88042803) were evaluated.

[0227] In a 96-well plate (Iwaki), 50 μL / well of 5 μg / mL anti-CD3 antibody (eBioscience, OKT3 clone) diluted with phosphate-buffered saline (PBS) was added, and the plate was incubated at 4°C for at least 12 hours to prepare the plate coated with anti-CD3 antibody. For the experiment, the plate was washed once with 200 μL of PBS, and then 10 μL / well of 10 μg / mL anti-CD28 antibody (eBioscience, 28.2 clone) diluted with RPMI 1640 medium (Sigma-Aldrich) containing 10% fetal bovine serum (Hyclone) was added to prepare the culture plate for TCR stimulation.

[0228] Next, to achieve the target final concentration, the test compound was mixed with Jurkat E6.1 cells at a concentration of 1 × 10⁻⁶ cells per well. 5 Seeding was performed at 90 μL / well using a 1 × 10⁻⁶ cell-to-well method (i.e., ultimately seeded at 1 × 10⁻⁶ cells per well). 5 (Culturing 100 μL / well of cells). Cell culture conditions were performed using RPMI 1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2.

[0229] After 24 hours, the culture supernatant was recovered, and IL-2 was quantified using the AlphaLISA Human IL-2 Immunoassay Kit (PerkinElmer). IL-2 measurements were performed using EnVision 2104-0010 and EnVision 2104-0020 kits (PerkinElmer) under standard Alpha Screen conditions (fluorescence intensity measured at 570 nm with an excitation wavelength of 680 nm). The IL-2 quantification value for the solvent-treated control was set to 1. The concentration of the test compound (EC50) required to increase the IL-2 quantification value of the treated sample to 10 times that of the control was calculated using a Sigmoid-Emax model nonlinear regression analysis. 10fold The results for several compounds tested using formula (I) are shown in Table 2. It should be noted that in the table, Ex represents the example number described later.

[0230] [Table 2]

[0231] Ex <![CDATA[EC 10fold (nM)]]> 1 110 13 340 20 36 29 40 45 8.1 47 72 48 35 80 460 86 24 122 110 123 26 124 410 125 56 126 31

[0232] Example 3: Evaluation of antitumor activity in a syngeneic mouse model bearing mouse melanoma cell line B16-F1

[0233] B16-F1 cells (ATCC, CRL-6323) were prepared by suspending them in PBS to form 2.0 × 10⁻⁶ cells. 6A cell suspension of 10 cells / mL was subcutaneously implanted in 50 μL of the solution into 5-week-old female mice (C57BL / 6J, Charles River Pharmaceuticals, Japan). Five days after implantation, the mice were divided into groups with approximately equal tumor volumes, and administration of the test compound began. The experiment was conducted with 10 mice in each of the solvent group and the test compound administration group. The solvent group received 0.5% methylcellulose (Shin-Etsu Chemical Co., Ltd.) orally, while the test compound administration group received the test compound orally in 0.5% methylcellulose. Administration was performed once daily for 10 days, with tumor diameter and body weight measured twice weekly. Tumor volume was calculated using the following formula.

[0234] Tumor volume (mm) 3 [[Tumor's long diameter (mm)] × [Tumor's short diameter (mm)]] 2 ×0.5

[0235] The tumor proliferation inhibition rate (%) of the test compound was calculated by setting the tumor volume of the solvent group before the start of administration to 100% inhibition and the tumor volume of the solvent group on the second day after the final administration to 0% inhibition. The results for several test compounds of formula (I) are shown in Table 3. It should be noted that in the table, Ex represents the example number described later.

[0236] [Table 3]

[0237] Ex Single dose (mg / kg) Anti-tumor effect 1 0.03 35% inhibition 13 0.3 36% inhibition 20 0.3 33% inhibition 29 0.3 41% inhibition 45 0.03 30% inhibition 47 0.3 42% inhibition 48 0.3 40% inhibition 80 0.3 31% inhibition 86 0.3 31% inhibition

[0238] Based on the results of the above experiments, the DGKζ inhibitory effect of several compounds of formula (I) was confirmed (Experimental Example 1). Furthermore, regarding the compounds of formula (I), the production of IL-2 in human T-cell leukemia cell lines was confirmed (Experimental Example 2). In addition, regarding the compounds of formula (I), antitumor activity in mouse models was confirmed (Experimental Example 3). In particular, it is known that the B16-F1 cells used in Experimental Example 3 are cells that generally do not show efficacy against anti-PD-1 antibodies / anti-PD-L1 antibodies; however, it was confirmed that even in mouse models bearing tumors with these cells, the compounds of formula (I) exhibited antitumor activity. Therefore, the compounds of formula (I) can be used for the treatment of cancers related to immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, especially immune cell activation-related cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

[0239] Pharmaceutical compositions containing one or more of the compounds of formula (I) or their salts as active ingredients can be prepared by commonly used methods using excipients, pharmaceutical excipients or pharmaceutical carriers, etc., commonly used in the art.

[0240] Administration can be performed by any of the following methods: oral administration via tablets, pills, capsules, granules, powders, liquids, etc.; or non-oral administration via intra-articular, intravenous, or intramuscular means such as injections, suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, inhalants, etc.

[0241] As a solid composition for oral administration, tablets, powders, granules, etc., can be used. In such a solid composition, one or more active ingredients are mixed with at least one inactive excipient. The composition may contain inert additives, such as lubricants, disintegrants, stabilizers, and solubilizers, according to conventional methods. Tablets, powders, granules, or pills may be coated with a wax, sugar coating, or a gastrointestinal or enteric-soluble film as needed.

[0242] Liquid compositions intended for oral administration contain pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups, or elixirs, and contain commonly used inert diluents such as purified water or ethanol. In addition to inert diluents, the liquid composition may also contain solubilizers, humectants, suspending agents, sweeteners, flavorings, fragrances, and preservatives.

[0243] Injectable formulations intended for non-oral 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 isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizers. They are sterilized, for example, by filtration through a bacterial trap, by combining with a bactericide, or by irradiation. Alternatively, they can be formulated as sterile solid compositions and dissolved or suspended in sterile water or sterile injectable solvents before use.

[0244] As external agents, they include ointments, plasters, creams, gels, mud dressings, sprays, lotions, eye drops, and eye ointments. They contain commonly used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions, etc.

[0245] Inhalers or nasal inhalers, or other mucosal preparations, can be made from solid, liquid, or semi-solid substances and can be manufactured using conventionally known methods. For example, known excipients, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc., can be appropriately added. Administration can be performed using suitable inhalation or blowing devices. For example, known devices or nebulizers, such as metered-dose inhalers, can be used to administer the compound alone or as a mixture of formulations, in powder form, or in combination with a pharmaceutically acceptable carrier, in the form of a solution or suspension. Dry powder inhalers, etc., can be single- or multiple-dose inhalers that utilize dry powder or powder-containing capsules. Alternatively, they can be administered via pressurized aerosol sprays using suitable propellants, such as chlorofluorocarbons or carbon dioxide.

[0246] When administered orally, the daily dose is typically approximately 0.001–100 mg / kg, preferably 0.1–30 mg / kg, and more preferably 0.1–10 mg / kg per unit body weight, administered once or divided into 2–4 doses. When administered intravenously, the daily dose is typically approximately 0.0001–10 mg / kg per unit body weight, administered once daily or divided into multiple doses. Additionally, as a mucosal agent, the dose is typically approximately 0.001–100 mg / kg per unit body weight, administered once daily or divided into multiple doses. The dosage should be appropriately determined based on individual circumstances, taking into account symptoms, age, and sex.

[0247] Although they may vary depending on the route of administration, dosage form, site of administration, type of excipient or additive, the pharmaceutical compositions of the present invention contain 0.01 to 100% by weight, or in one manner 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof as active ingredients.

[0248] The compound of formula (I) can be used in combination with various therapeutic or preventative agents for diseases for which the compound of formula (I) is believed to be effective. This combination may be administered simultaneously, or additionally, continuously, or at desired intervals. Simultaneously administered formulations may be combination agents or separately formulated.

[0249] Example

[0250] The following describes in further detail the method for manufacturing compounds of formula (I) based on examples. It should be noted that the present invention is not limited to the compounds described in the following examples. Furthermore, the method for manufacturing the starting material compounds is shown in the manufacturing examples. Additionally, the method for manufacturing compounds of formula (I) is not limited to the manufacturing methods of the specific examples shown below; compounds of formula (I) can also be manufactured by combinations of these manufacturing methods or by methods obvious to those skilled in the art.

[0251] It should be noted that in this specification, the naming of compounds sometimes uses naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.).

[0252] In addition, for convenience, the concentration in mol / L is expressed as M. For example, 1M sodium hydroxide aqueous solution means a 1 mol / L sodium hydroxide aqueous solution.

[0253] The powder X-ray diffraction results described in this specification were obtained using Empyrean on a Cu tube with a tube current of 40 mA, a tube voltage of 45 kV, a step size of 0.013°, and a wavelength of [missing information]. The diffraction angle range (2θ) was measured under the condition of 2.5 to 40°.

[0254] Manufacturing Example 1

[0255] (2R)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (935 mg) was added to a mixture of 2-bromo-1-chloro-3-fluoro-4-nitrobenzene (1.0 g), TEA (1.2 g), and THF (10 mL), and stirred at room temperature for 16 hours. Water 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 (2R)-4-(2-bromo-3-chloro-6-nitrophenyl)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.8 g) as a solid.

[0256] Manufacturing Example 2

[0257] A mixture of 3.00 g of 2-bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene, 1.00 mL of 2-fluorophenol, 2.88 g of potassium carbonate, and 30 mL of NMP was stirred overnight at 50 °C. After cooling naturally to room temperature, water, EtOAc, and brine were added, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give 3.43 g of 2-bromo-4-(2-fluorophenoxy)-1-nitro-3-(trifluoromethyl)benzene.

[0258] Manufacturing Example 16

[0259] Pd(dppf)Cl2·CH2Cl2 (0.215 g) was added to 2-bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (0.758 g), {2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenoxy]ethyl}carbamate tert-butyl ester (2.844 g), potassium carbonate (0.910 g), and 1,4-dioxane-2-yl)carbamate. The mixture of alkane (20 mL) and water (4 mL) was stirred at 110 °C for 5 hours under an argon atmosphere. After the reaction solution was naturally cooled to room temperature, it was injected into water and extracted with EtOAc. The organic layer was separated, the aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine and dried with Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give 0.502 g of tert-butyl 2-{[3'-fluoro-6'-nitro-2'-(trifluoromethyl)[1,1'-biphenyl]-3-yl]oxy}ethyl)carbamate.

[0260] Manufacturing Example 20

[0261] 10.0 mL of tert-butylchlorodiphenylsilane 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 then injected into water and extracted with EtOAc. The organic layer was separated, the aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine. The organic layers were 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 (1.164 g) as a high-polarity substance.

[0262] Manufacturing Example 21

[0263] A THF (10 mL) solution of (8S,8aR)-8-{[tert-butyldi(phenyl)silyl]oxy}hexahydropyrrolo[1,2-a]pyrazin-1,4-dione (1.164 g) was added to a mixture of lithium aluminum hydride (0.594 g) and THF (40 mL), and stirred under reflux for 17 hours. After the reaction suspension was allowed to cool naturally to room temperature, a mixture of water (0.7 mL) and THF (7.7 mL) and a 4N sodium hydroxide aqueous solution (0.7 mL) were added, followed by the addition of Na₂SO₄, and the mixture was stirred at room temperature for 3 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain (8S,8aS)-octahydropyrrolo[1,2-a]pyrazin-8-ol (0.972 g). This was used directly in the next step without further purification.

[0264] Manufacturing Example 23

[0265] Sodium hydride (60% oil dispersion, 181 mg) was added to a mixture of 2-bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (1.00 g), cyclopentanol (380 μL), and THF (10 mL) under an argon atmosphere and ice cooling, and stirred at room temperature for 3 hours. Water was added under ice cooling, and the mixture was extracted with EtOAc, washed with brine, and dried over MgSO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give 2-bromo-4-(cyclopentoxy)-1-nitro-3-(trifluoromethyl)benzene (935 mg).

[0266] Manufacturing Example 33

[0267] NaBH(OAc)3 (8.74 g) was added to a mixture of [(2S)-4-benzylpiperazin-2-yl]methanol dihydrochloride (5.76 g), 37% formaldehyde aqueous solution (3.35 mL), sodium acetate (3.38 g), and THF (60 mL) under ice-cooling conditions, and stirred at room temperature for 6 hours. A saturated NaHCO3 aqueous solution was added until foaming disappeared, and the mixture was extracted with EtOAc. A 5M sodium hydroxide aqueous solution was added to the aqueous layer, and the mixture was extracted twice with diethyl ether. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give [(2S)-4-benzyl-1-methylpiperazin-2-yl]methanol (4.48 g).

[0268] Manufacturing Example 34

[0269] A solution of [(2R)-4-benzyl-1-methylpiperazin-2-yl]methanol (5.27 g), TEA (6.7 mL), and THF (100 mL) was cooled in an ice-MeOH bath, and methanesulfonyl chloride (1.96 mL) was slowly added. The mixture was stirred for 1 hour under ice cooling, followed by the addition of 40% methylamine aqueous solution (40 mL), and then stirred at 70 °C for 3 hours. After natural cooling, the reaction solution was concentrated under reduced pressure. Water and CH2Cl2 were added to the residue, and the aqueous layer was separated. The aqueous layer was extracted twice with CH2Cl2, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure.

[0270] The resulting oil (4.95 g) was dissolved in CH2Cl2 (100 mL), and di-tert-butyl dicarbonate (11 g) was added under ice cooling. The mixture was stirred at room temperature for 2 hours. CH2Cl2 and water were added to the reaction mixture, and the aqueous layer was separated. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ammonia / MeOH / chloroform) to give {[(2R)-4-benzyl-1-methylpiperazin-2-yl]methyl}(methyl)carbamate tert-butyl ester (5.92 g).

[0271] Manufacturing Example 36

[0272] Activated carbon (500 mg) was added to a solution of {[(2R)-4-benzyl-1-methylpiperazin-2-yl]methyl}(methyl)carbamate tert-butyl ester (4.92 g) and EtOH (100 mL), and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. 10% Pd / C (containing water, 510 mg) was added to the resulting oily solution of EtOH (100 mL) under a nitrogen atmosphere. The reaction was stirred at room temperature under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give methyl{[(2R)-1-methylpiperazin-2-yl]methyl}carbamate tert-butyl ester (3.43 g).

[0273] Manufacturing Example 38

[0274] Add Pd(dppf)Cl2·CH2Cl2 (142 mg) to 1-bromo-3-fluoro-4-nitro-2-(trifluoromethyl)benzene (500 mg), 2-fluorophenylboronic acid (316 mg), cesium carbonate (1.13 g), and 1,4-dioxane. The mixture of alkyl (6 mL) and water (1.7 mL) was stirred at 120 °C for 30 minutes under microwave irradiation. After natural cooling, it was diluted with EtOAc, filtered through diatomaceous earth, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give 2',3-difluoro-4-nitro-2-(trifluoromethyl)-1,1'-biphenyl (403 mg).

[0275] Manufacturing Example 39

[0276] tert-butyl methyl{[(2R)-1-methylpiperazin-2-yl]methyl}carbamate (735 mg), 2-bromo-4-(2-fluorophenoxy)-1-nitro-3-(trifluoromethyl)benzene (1.15 g), potassium carbonate (627 mg), and 1,4-dimethylbenzene. The mixture of alkyl (5.75 mL) was stirred at 110 °C for 24 hours. After natural cooling, the reaction mixture was diluted with EtOAc. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give ({(2R)-4-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate tert-butyl ester (1.31 g).

[0277] Manufacturing Example 60

[0278] Under ice-cooled conditions, tert-butyl (2R)-2-(hydroxymethyl)piperazine-1-carboxylate (1.55 g) and TEA (1.10 mL) were added sequentially to a THF (21 mL) solution of 1-bromo-3-fluoro-4-nitro-2-(trifluoromethyl)benzene (2.07 g). The reaction mixture was stirred under ice-cooled conditions for 1 hour, and then stirred at room temperature for 64 hours. EtOAc and water were added to the reaction mixture, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl (2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-(hydroxymethyl)piperazine-1-carboxylate (2.27 g) as a solid.

[0279] Manufacturing Example 75

[0280] Under ice cooling, 2.98 g of Dysmart reagent was added to a CH2Cl2 solution (2.27 g) of (2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (2.27 g) and stirred at room temperature for 3 hours. Under ice cooling, 10% aqueous sodium sulfite and saturated NaHCO3 aqueous solution were added and stirred at room temperature for 30 minutes. The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4. The solution was concentrated under reduced pressure to give (2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-formylpiperazine-1-carboxylate tert-butyl ester (2.20 g) as a solid.

[0281] Manufacturing Example 91

[0282] To a THF (29 mL) solution of (1S,2R,5S)-5-methyl-2-(propane-2-yl)cyclohexyl ester (2.6 g) of (3S)-3-fluoro-2-oxopiridine-3-carboxylic acid, a borane-THF complex (0.91 M THF solution, 29 mL) was added under an argon atmosphere, and the mixture was stirred overnight at 70 °C. After naturally cooling to room temperature, MeOH (30 mL) and 2 M hydrochloric acid (30 mL) were added, and the mixture was stirred at 60 °C for 1 hour. The mixture was concentrated under reduced pressure by azeotropic distillation with toluene. To a NMP (52 mL) solution of the resulting residue, 2.3 g of 2-bromo-4-(2-fluorophenoxy)-1-nitro-3-(trifluoromethyl)benzene and 3 g of potassium carbonate were added, and the mixture was stirred overnight at 120 °C. 2-Bromo-4-(2-fluorophenoxy)-1-nitro-3-(trifluoromethyl)benzene (730 mg) was added, and the mixture was stirred overnight at 120 °C. The mixture was diluted with EtOAc, washed with water and brine, and dried over MgSO4. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give {(3S)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methanol (1.9 g).

[0283] Manufacturing Example 92

[0284] NaBH(OAc)3 (1.93 g) was added to a mixture of (2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-formylpiperazin-1-carboxylic acid tert-butyl ester (2.20 g), 2M methylamine / THF solution (4.56 mL), acetic acid (522 μL), and CH2Cl2 (22 mL), and stirred at room temperature for 16 hours. A saturated aqueous solution of NaHCO3 was added, and the mixture was stirred at room temperature for 1 hour. The aqueous layer was separated, extracted with CH2Cl2, and the combined organic layers were washed with brine. The mixture was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc + chloroform / MeOH) to give (2S)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-[(methylamino)methyl]piperazin-1-carboxylic acid tert-butyl ester (1.91 g).

[0285] Manufacturing Example 108

[0286] Under ice-cooled conditions, TFAA (1.08 mL) was slowly added to a mixture of (2S)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-[(methylamino)methyl]piperazine-1-carboxylic acid tert-butyl ester (1.91 g), DIPEA (1.97 mL), and CH2Cl2 (19.1 mL), and stirred at room temperature for 2 hours. A saturated aqueous solution of NH4Cl was added, and the mixture was extracted with CH2Cl2 using an ISOLUTE (registered trademark) phase separator and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give (2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-{[methyl(trifluoroacetyl)amino]methyl}piperazine-1-carboxylic acid tert-butyl ester (1.42 g) as a solid.

[0287] Manufacturing Example 123

[0288] To a mixture of (2R)-4-[2-chloro-3-(2-fluorophenoxy)-6-nitrophenyl]-2-formylpiperazine-1-carboxylic acid tert-butyl ester (859 mg), 2M methylamine / THF solution (1.8 mL), CH2Cl2 (9 mL), and acetic acid (206 μL), NaBH(OAc)3 (760 mg) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2 using an ISOLUTE (registered trademark) phase separator, and concentrated under reduced pressure. CH2Cl2 (9 mL) and DIPEA (920 μL) were added to the residue, and TFAA (506 μL) was added under ice-cooling conditions, and the mixture was stirred at room temperature for 1 hour. DIPEA (230 μL) and TFAA (126 μL) were added under ice-cooling conditions, and the mixture was stirred at room temperature for 30 minutes. Add saturated NH4Cl aqueous solution, extract with dichloromethane using an ISOLUTE (registered trademark) phase separator, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (Hex / EtOAc) and silica gel column chromatography (Hex / chloroform→Hex / EtOAc) to give (2R)-4-[2-chloro-3-(2-fluorophenoxy)-6-nitrophenyl]-2-{[methyl(trifluoroacetyl)amino]methyl}piperazine-1-carboxylic acid tert-butyl ester (606 mg) in solid form.

[0289] Manufacturing Example 125

[0290] An aqueous solution of potassium phosphate (0.7 g) dissolved in water (2 mL) was added to a mixture of (2R)-4-[2-bromo-3-(2-fluorophenoxy)-6-nitrophenyl]-2-{[methyl(trifluoroacetyl)amino]methyl}piperazine-1-carboxylic acid tert-butyl ester (0.70 g), tricyclohexylphosphine (96 mg), cyclopropylboronic acid (0.28 g), and toluene (20 mL). After purging the system with argon, palladium acetate (49 mg) was added, and the mixture was stirred at 110 °C for 8 hours. After naturally cooling to room temperature, the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain (2R)-4-[2-cyclopropyl-3-(2-fluorophenoxy)-6-nitrophenyl]-2-{[methyl(trifluoroacetyl)amino]methyl}piperazine-1-carboxylic acid tert-butyl ester (0.42 g).

[0291] Manufacturing Example 127

[0292] Under ice cooling, 4M HCl / 1,4-dimethylbenzene ether was added to a CH2Cl2 (15 mL) solution of (2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (3.33 g). The alkane solution (15 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give {(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperazin-2-yl}methanol-hydrochloride (3.1 g).

[0293] Manufacturing Example 144

[0294] Sodium acetate (770 mg) was added to a mixture of {(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperazin-2-yl}methanol-hydrochloride (2.93 g) and THF (80 mL) under ice cooling, and the mixture was stirred for 10 minutes at room temperature. 1H-benzotriazole-1-methanol (1.4 g) was added, and the mixture was stirred for 10 minutes at room temperature. NaBH(OAc)3 (2 g) was added, and the mixture was stirred for 12 hours at room temperature. The reaction mixture was cooled in an ice bath, and a saturated aqueous solution of NaHCO3 was added. The mixture was diluted with water and EtOAc to separate into two layers. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (Hex / chloroform / EtOAc→chloroform / MeOH) to obtain {(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methanol (2.65 g).

[0295] Manufacturing Example 150

[0296] To a mixture of (2R)-4-[2-chloro-3-(2-fluorophenoxy)-6-nitrophenyl]-2-{[methyl(trifluoroacetyl)amino]methyl}piperazine-1-carboxylic acid tert-butyl ester (603 mg) and CH2Cl2 (6 mL), 4 M HCl / 1,4-diphenyl ether was added under ice cooling. An alkane solution (4 mL) was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure. THF (12 mL) was added to the residue, followed by 1H-benzotriazole-1-methanol (230 mg), sodium acetate (130 mg), and NaBH(OAc)3 (330 mg). The mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with a mixed solvent (chloroform / MeOH). 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 / MeOH). The resulting substance was then purified by silica gel column chromatography (chloroform / EtOAc) to give N-({(2R)-4-[2-chloro-3-(2-fluorophenoxy)-6-nitrophenyl]-1-methylpiperazin-2-yl}methyl)-2,2,2-trifluoro-N-methylacetamide (415 mg) in solid form.

[0297] Manufacturing Example 158

[0298] Under ice cooling, methanesulfonic anhydride (1.74 g) was added to a solution of {(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methanol (2.65 g) and DIPEA (2.4 mL) in CH2Cl2 (60 mL), and the mixture was stirred for 1 hour under the same conditions. Then, methanesulfonic anhydride (440 mg) was added, and the mixture was stirred for 1 hour under the same conditions. The reaction mixture was diluted with chloroform and water, and the aqueous layer was separated. The aqueous layer was extracted with chloroform, and the combined organic layers were dried over Na2SO4. The mixture was concentrated under reduced pressure to give methyl methanesulfonate {(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl} (3.18 g).

[0299] Manufacturing Example 164

[0300] Potassium phthalimide (1.7 g) was added to a mixture of methanesulfonic acid {(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl ester (3.18 g) and NMP (60 mL), and stirred at 50 °C for 12 hours. A saturated aqueous solution of NH4Cl, EtOAc, and water were added under ice bath conditions, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give 2-({(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione (1.8 g).

[0301] Manufacturing Example 171

[0302] Under ice cooling, methanesulfonic anhydride (920 mg) and DIPEA (1.1 mL) were added to a CH2Cl2 (38 mL) solution of {(3S)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methanol (1.9 g), and the mixture was stirred for 1 hour. Water was added, and the mixture was extracted with chloroform using an ISOLUTE (registered trademark) phase separator and concentrated under reduced pressure. Potassium phthalimide (1.2 g) was added to a NMP (19 mL) solution of the resulting residue, and the mixture was stirred overnight at 60 °C. The mixture was heated to 120 °C and stirred for 2 hours. Potassium phthalimide (800 mg) was added, and the mixture was stirred at 100 °C for 7 days. Water and brine were added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (Hex / EtOAc) to give 2-({(3S)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)-1H-isoindole-1,3(2H)-dione (1.2 g) in solid form.

[0303] Manufacturing Example 173

[0304] Diisopropyl azodicarbonate (0.6 mL) was added to a mixed solution of (8S,8aR)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-ol (0.886 g), THF (13.5 mL), benzoic acid (0.245 g), and triphenylphosphine (0.792 g) under an argon atmosphere and ice cooling, and stirred at room temperature for 6.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give a mixture (1.648 g) mainly containing (8R,8aR)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-ylbenzoate.

[0305] Manufacturing Example 174

[0306] Potassium carbonate (1.396 g) was added to a mixed solution containing mainly (8R,8aR)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-ylbenzoate (1.648 g) and MeOH (20 mL), and stirred at room temperature for 6 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give (8R,8aR)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-ol (0.631 g) as a solid.

[0307] Manufacturing Example 175

[0308] Diisopropyl azodicarbonate (0.62 mL) was added to a mixed solution of (8S,8aS)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-ol (0.922 g), THF (15 mL), phthalimide (0.322 g), and triphenylphosphine (0.824 g) under an argon atmosphere and ice cooling, and stirred at room temperature for 2.5 hours. The reaction mixture was then injected into water and extracted with EtOAc. The organic layer was separated, the aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine. The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give a mixture (1.480 g) mainly containing 2-{(8R,8aS)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-yl}-1H-isoindole-1,3(2H)-dione.

[0309] Manufacturing Example 179

[0310] HATU (0.96 g) was added to a mixture of 1-{(3S)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methylamine (0.70 g), methoxyacetic acid (0.18 g), DIPEA (0.62 mL), and DMF (10 mL), and stirred at room temperature for 16 hours. Water 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 N-({(3S)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)-2-methoxyacetamide (0.70 g).

[0311] Manufacturing Example 180

[0312] Under ice cooling, the borane THF complex (1M THF solution, 3 mL) was slowly added to a mixture of N-({(3S)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)-2-methoxyacetamide (0.50 g) and THF (10 mL), and stirred at room temperature for 2 hours. The reaction was stopped by adding methanol, and the mixture was concentrated under reduced pressure to give N-({(3S)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)-2-methoxyethane-1-amine (0.30 g). This was used directly in subsequent reactions without further purification.

[0313] Manufacturing Example 181

[0314] A mixture of 1.2 g of 2-({(3S)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)-1H-isoindole-1,3(2H)-dione (1.2 mL) and MeOH was added to a solution of hydrazine monohydrate (520 μL), and the mixture was stirred at 60 °C for 1 hour. Water was added, and the mixture was extracted with chloroform using an ISOLUTE (registered trademark) phase separator and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / MeOH) to give 270 mg of 1-{(3R)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methylamine.

[0315] Manufacturing Example 186

[0316] To a DMF (2.7 mL) solution of 1-{(3R)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methylamine (270 mg), 270 mg of ditert-butyl dicarbonate and 210 μL of DIPEA were added, and the mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl ({(3R)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (310 mg).

[0317] Manufacturing Example 193

[0318] Hydrazine monohydrate (0.8 mL) was added to a mixture of 2-({(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione (1.8 g) and MeOH (20 mL), and stirred at 60 °C for 2 hours. After naturally cooling to room temperature, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Di-tert-butyl dicarbonate (2 g) was added to a mixture of the residue, DMF (40 mL), and DIPEA (1.6 mL), and stirred at room temperature for 3 hours. Water and EtOAc were added, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl carbamate ({(2S)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)carbamate (1.60 g).

[0319] Manufacturing Example 201

[0320] NaBH(OAc)3 (762 mg) was added to a mixture of N-({(2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]piperazin-2-yl}methyl)-2,2,2-trifluoro-N-methylacetamide hydrochloride (1.27 g), sodium acetate (295 mg), 1H-benzotriazole-1-methanol (536 mg), and THF (25.4 mL), and stirred at room temperature for 16 hours. A saturated aqueous solution of NaHCO3 was added, and the mixture was stirred at room temperature for 10 minutes. EtOAc and water were added, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine. The mixture was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain N-({(2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)-2,2,2-trifluoro-N-methylacetamide (1.40 g) in solid form.

[0321] Manufacturing Example 210

[0322] Potassium carbonate (700 mg) was added to a mixture of N-({(2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)-2,2,2-trifluoro-N-methylacetamide (1.0 g), MeOH (10 mL), and water (3.4 mL), and stirred at 50 °C for 2 hours. After natural cooling at room temperature, a saturated aqueous solution of NH4Cl was added, and the mixture was stirred for 5 minutes. Chloroform and water were added, and extraction was performed using an ISOLUTE (registered trademark) phase separator. The mixture was dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in THF (10 mL), and di-tert-butyl dicarbonate (530 mg) and TEA (420 μL) were added, and the mixture was stirred at room temperature for 16 hours. EtOAc and water were added, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine. The mixture was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain ({(2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate tert-butyl ester (720 mg).

[0323] Manufacturing Example 211

[0324] Pd(PPh3) 4( 110 mg) was added to ({(2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate tert-butyl ester (490 mg), 1-cyclopentenylboronic acid (130 mg), potassium carbonate (260 mg), 1,4-di The mixture of alkane (10 mL) and water (1 mL) was stirred at 120 °C for 2 hours under microwave irradiation. After naturally cooling to room temperature, EtOAc and water were added, and the mixture was stirred for 5 minutes. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with water and brine and dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give ({(2R)-4-[3-(cyclopent-1-en-1-yl)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate tert-butyl ester (420 mg).

[0325] Manufacturing Example 214

[0326] Add 15 mL of TFA to 4-[3-(cyclobutyloxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-( The mixture of alkyl-2-yl)-1H-pyrazole (2.594 g) and CH2Cl2 (30 mL) was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted twice with CH2Cl2 by adding saturated NaHCO3 aqueous solution. The combined organic layers were dried over Na2SO4. The solution was concentrated under reduced pressure and purified by silica gel column chromatography (Hex / EtOAc) to give 4-[3-(cyclobutyloxy)-6-nitro-2-(trifluoromethyl)phenyl]-1H-pyrazole (1.907 g) as a solid.

[0327] Manufacturing Example 215

[0328] Cesium carbonate (1.254 g) was added to a mixed solution of 4-[3-(cyclobutyloxy)-6-nitro-2-(trifluoromethyl)phenyl]-1H-pyrazole (0.840 g), (3-bromopropyl)carbamate tert-butyl ester (0.732 g), and DMF (14 mL), and stirred at room temperature for 3 hours. The reaction mixture was injected into water and extracted twice with EtOAc. The combined organic layers were washed with water and brine and dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give (3-{4-[3-(cyclobutyloxy)-6-nitro-2-(trifluoromethyl)phenyl]-1H-pyrazole-1-yl}propyl)carbamate tert-butyl ester (0.831 g) as a solid.

[0329] Manufacturing Example 216

[0330] Under an argon atmosphere and under ice cooling, sodium hydride (55% oil dispersion, 0.019 g) was added to a mixed solution of {(8R,8aS)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-yl}carbamate tert-butyl ester (0.200 g) and DMF (2.5 mL), and stirred for 40 minutes under ice cooling. Methyl iodine (35 μL) was then added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was then injected into water, extracted with EtOAc, and the organic layer was washed with water and brine and dried over Na₂SO₄. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl (0.131 g) of {(8R,8aS)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-yl}(methyl)carbamate.

[0331] Manufacturing Example 222

[0332] Cesium carbonate (1.78 g) was added to a MeCN (20 mL) solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (841 mg), and the mixture was stirred at room temperature for 10 minutes. Then, 3,4,6-trichloropyridazine (1 g) was added, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with EtOAc and filtered through diatomaceous earth to remove insoluble matter. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / Hex / chloroform) to give ethyl 1-(3,6-dichloropyridazine-4-yl)-5-methyl-1H-pyrazole-3-carboxylate (1.37 g) as a solid.

[0333] Manufacturing Example 225

[0334] To a THF / EtOH (1 / 1, 30 mL) solution of 1-(3,6-dichloropyridazin-4-yl)-5-methyl-1H-pyrazole-3-carboxylate (1.37 g), TEA (1.3 mL) and a palladium-activated carbon ethylenediamine complex (3.5-6.5% Pd, 137 mg) were added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. Insoluble matter was removed by diatomaceous earth filtration, and the filtrate was concentrated under reduced pressure to obtain a solid. The solid was separated by dilution with chloroform and water. The aqueous layer was extracted with chloroform, and the combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / chloroform) to give 5-methyl-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxylate (521 mg) as a solid.

[0335] Manufacturing Example 228

[0336] Under ice-cooling conditions, 10 mL of 1 M sodium hydroxide aqueous solution was added to a mixture of ethyl 5-methyl-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxylate (521 mg) and THF / EtOH (1 / 1, 30 mL), and the reaction mixture was stirred at room temperature for 4 hours. Under ice-cooling conditions, 10 mL of 1 M hydrochloric acid was added, followed by concentration under reduced pressure. The resulting residue was diluted with water, the precipitated solid was filtered off, and dried under reduced pressure to give 395 mg of 5-methyl-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxylic acid in solid form.

[0337] Manufacturing Example 231

[0338] Methyl iodine (124 μL) was added to a mixture of N-cyclopropyl-2,2,2-trifluoro-N-({(2R)-4-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperazin-2-yl}methyl)acetamide hydrochloride (390 mg), DIPEA (342 μL), and DMF (4 mL), and stirred at room temperature for 16 hours. EtOAc and water were added, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine and dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give N-cyclopropyl-2,2,2-trifluoro-N-({(2R)-4-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)acetamide (143 mg).

[0339] Manufacturing Example 232

[0340] To ({(2R)-4-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate tert-butyl ester (3.41 g) 1,4-di A solution of NH4Cl (3.36 g) in 25 mL of water was added to an alkyl (50 mL) solution, followed by the addition of zinc powder (4.11 g) under ice-cooling conditions. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc and water and filtered through diatomaceous earth. The filtrate was separated, the aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4. The solution was concentrated under reduced pressure to give ({(2R)-4-[6-amino-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate tert-butyl ester (3.32 g).

[0341] Manufacturing Example 293

[0342] Add zinc powder (550 mg) to ({(2R)-4-[3-(cyclopent-1-en-1-yl)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate tert-butyl ester (420 mg), NH4Cl (450 mg), and 1,4-di The mixture of alkane (4.2 mL) and water (1.7 mL) was stirred at room temperature for 1 hour. The solution was diluted with chloroform, and the aqueous layer was separated using an ISOLUTE (registered trademark) phase separator. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was dissolved in MeOH (8.4 mL), and 10% Pd / C (50% water content, 180 mg) was added. The mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere (3 atm). After removing insoluble matter through diatomaceous earth filtration, the solution was concentrated under reduced pressure. The residue was dissolved in MeOH (8.4 mL), and 10% Pd / C (50% water content, 60 mg) was added. The mixture was stirred at room temperature for 48 hours under a hydrogen atmosphere (3 atm). After removing insoluble matter through diatomaceous earth filtration, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / MeOH) to obtain ({(2R)-4-[6-amino-3-cyclopentyl-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate tert-butyl ester (320 mg) in solid form.

[0343] Manufacturing Example 294

[0344] HATU (3.58 g) was added to a mixture of ({(2R)-4-[6-amino-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate tert-butyl ester (3.22 g), 1-(pyridazin-4-yl)-1H-pyrazole-3-carboxylic acid (1.43 g), DIPEA (3.3 mL), and DMF (50 mL). The reaction mixture was stirred at 50 °C for 12 hours. After cooling naturally to room temperature, chloroform and water were added to the reaction mixture, and the aqueous layer was separated. The aqueous layer was extracted with chloroform, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / MeOH) to obtain tert-butyl ({(2R)-4-[3-(2-fluorophenoxy)-6-{[1-(pyridazin-4-yl)-1H-pyrazole-3-carbonyl]amino}-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (4.35 g).

[0345] Manufacturing Example 403

[0346] An aqueous solution of potassium carbonate (0.24 g) dissolved in water (2 mL) was added to a mixture of N-{3-chloro-2-[(3R)-3-({[(3,4-dimethoxyphenyl)methyl](trifluoroacetyl)amino}methyl)-4-methylpiperazin-1-yl]-4-(2-fluorophenoxy)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide (0.27 g) and MeOH (10 mL), and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, diluted with EtOAc, and washed three times with water. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to obtain N-{3-chloro-2-[(3S)-3-({[(3,4-dimethoxyphenyl)methyl]amino}methyl)-4-methylpiperazin-1-yl]-4-(2-fluorophenoxy)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide (0.16 g) in solid form.

[0347] Manufacturing Example 404

[0348] Add TFA (1 mL) to (2R)-2-{[methyl(trifluoroacetyl)amino]methyl}-4-[3-phenoxy-6-{[2-(pyridazin-4-yl)-1,3- The mixture of 0.414 g of tert-butyl piperazine-1-carboxylate and 2 mL of CH2Cl2 was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with CH2Cl2 by adding saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to give N-{2-[(3R)-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3- Azoxyl-4-carboxamide (0.333g).

[0349] Manufacturing Example 405

[0350] Add NaBH(OAc)3 (0.156 g) to N-{2-[(3R)-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3- A mixture of 0.318 g of azole-4-carboxamide, 5 mL of CH2Cl2, and 0.2 mL of 37% formaldehyde aqueous solution was stirred at room temperature for 2 hours. The reaction mixture was then injected into a saturated NaHCO3 aqueous solution and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / MeOH) to give N-{2-[(3R)-4-methyl-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3- Azoxyl-4-carboxamide (0.287g).

[0351] The compounds shown in Table 4 below are manufactured by operating in the same manner as the manufacturing methods of the manufacturing examples described above. Furthermore, the structures of the compounds of each manufacturing example are shown in Table 4 below, and the manufacturing methods and physicochemical data of the compounds of each manufacturing example are shown in Table 5. They can be easily manufactured using the manufacturing methods of the manufacturing examples described above, as well as methods obvious to those skilled in the art, or variations thereof.

[0352] Example 1

[0353] TFA (330 μL) was added to a mixture of ({(3S)-1-[6-{[1-(2,2-difluoroethyl)-1H-pyrazole-3-carbonyl]amino}-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)tert-butyl carbamate (275 mg) and CH2Cl2 (3 mL), and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was separated by adding a mixed solvent (chloroform / MeOH) and a saturated aqueous solution of NaHCO3. The organic layer was dried over Na2SO4. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform / MeOH / ammonia). The resulting substance was dissolved in EtOAc (3 mL), and 4 M HCl / EtOAc solution (500 μL) was added. The mixture was stirred at room temperature for 10 minutes. The residue was concentrated under reduced pressure, solidified and washed with isopropyl ether, and then dried under reduced pressure to obtain N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide hydrochloride (210 mg) in solid form.

[0354] Example 22

[0355] Add potassium carbonate (78 mg) to N-[4-(2-fluorophenoxy)-2-[(3R)-4-methyl-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3- A mixture of 190 mg azole-4-carboxamide, 630 μL water, and 2 mL MeOH was stirred at room temperature for 2 hours. Water, a saturated aqueous NH4Cl solution, and chloroform were added to separate the aqueous layer. The aqueous layer was extracted with a mixed solvent (chloroform / MeOH), and the combined organic layers were dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / MeOH / ammonia). The resulting substance was dissolved in 2 mL EtOAc, and 350 μL of 4 M HCl / EtOAc solution was added. The mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, and the residue was washed with ether and dried under reduced pressure to give N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3- Azole-4-carboxamide trihydrochloride (131 mg).

[0356] Example 29

[0357] Under ice cooling, 10 mL of TFA was added to a mixture of 4.3 g of ({(2R)-4-[3-(2-fluorophenoxy)-6-{[1-(pyridazin-4-yl)-1H-pyrazole-3-carbonyl]amino}-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate tert-butyl ester (4.3 g) and CH2Cl2 (40 mL), and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was treated with water, chloroform, and NaHCO3 to make it alkaline. The mixture was separated using a separatory funnel, and the aqueous layer was extracted with chloroform. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / MeOH / ammonia). The resulting amorphous material was washed with EtOAc / Hex to obtain N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (2.62 g) in solid form.

[0358] Example 86

[0359] Potassium carbonate (68 mg) was added to a mixture of N-{3-chloro-4-(2-fluorophenoxy)-2-[(3R)-4-methyl-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (159 mg), MeOH (1.5 mL), and water (0.5 mL). The mixture was stirred at 50 °C for 2 hours. After natural cooling, a saturated aqueous solution of NH4Cl was added, and the mixture was extracted with a mixed solvent (chloroform / MeOH). The organic layer was dried over MgSO4. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform / MeOH / ammonia) to obtain N-[3-chloro-4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (106 mg) in solid form.

[0360] Example 109

[0361] HATU (17.1 mg) and DMF (100 μL) were added to a mixture of ({(3S)-1-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate tert-butyl ester (14.0 mg), 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid (7.3 mg), DIPEA (20.5 μL), and DMF (600 μL), and stirred overnight at 50 °C. After natural cooling, chloroform and water were added, the organic layer was separated, concentrated under reduced pressure, and the residue was purified by LC-MS (formic acid water / MeOH). The obtained substance was dissolved in CH2Cl2 (250 μL), and 4M HCl / 1,4-di(2,3-dihydroxyethyl)-2-dihydroxyethyl ester ( ... The alkane solution (250 μL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and a mixed solvent (chloroform / MeOH) and a saturated aqueous solution of NaHCO3 were added to the residue. The organic layer was separated and concentrated under reduced pressure to give N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide (6.9 mg).

[0362] Example 112

[0363] Trifluoromethanesulfonic acid (1 mL) was added to a mixture of N-{3-chloro-2-[(3S)-3-({[(3,4-dimethoxyphenyl)methyl]amino}methyl)-4-methylpiperazin-1-yl]-4-(2-fluorophenoxy)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide (0.15 g) and TFA (1 mL). The mixture was stirred at room temperature for 16 hours and then at 60 °C for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give N-{2-[(3S)-3-(aminomethyl)-4-methylpiperazin-1-yl]-3-chloro-4-(2-fluorophenoxy)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide (31 mg) in solid form.

[0364] Example 113

[0365] Add NaBH(OAc)3 (0.064 g) to N-[4-(cyclobutyloxy)-2-{2-[2-(methylamino)ethoxy]pyridin-4-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3- A mixture of 0.110 g of azole-4-carboxamide, 2 mL of CH2Cl2, and 81 μ L of 37% formaldehyde aqueous solution was stirred at room temperature for 15 hours. The reaction mixture was then injected into a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2. The organic layer was separated, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to give N-[4-(cyclobutyloxy)-2-{2-[2-(dimethylamino)ethoxy]pyridin-4-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3- Azoxyl-4-carboxamide (0.098g).

[0366] Example 122

[0367] N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (5 g) was dissolved in EtOH (50 mL) at 80 °C. Succinic acid (1.06 g) and water (2.5 mL) were added, and the mixture was stirred at room temperature for 48 hours. The precipitate was filtered off and dried under reduced pressure to obtain a solid (5.50 g). A mixture of the obtained solid (5.45 g), EtOH (40 mL), and water (4 mL) was stirred at 70 °C to form a solution, and then stirred at room temperature for 24 hours. The precipitate was filtered and dried at 40°C under reduced pressure for 2 days to obtain N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate (4.36 g) in crystalline form.

[0368] Example 123

[0369] Succinic acid (34 mg) was added to a mixture of N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (150 mg) and EtOH (2 mL) at 70 °C, followed by the addition of water (100 μL). The mixture was stirred at room temperature for 24 hours. The mixture was then concentrated under reduced pressure. MeCN (10 mL) was added to the residue, and the mixture was stirred at room temperature for 24 hours. The precipitate was filtered off and dried under reduced pressure to obtain N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate (165 mg) in crystalline form.

[0370] Example 126

[0371] Succinic acid (22 mg) was added to a mixture of N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (100 mg) and EtOH (1 mL) at 70 °C, and water (50 μL) was added. The mixture was stirred at room temperature for 2 days. The precipitated solid was filtered off and dried under reduced pressure to obtain N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate (77 mg) in crystalline form.

[0372] The compounds shown in Table 6 below were manufactured using the same methods as those used in the embodiments described above. Furthermore, the structures of the compounds of each embodiment are shown in Table 6 below, and the manufacturing methods and physicochemical data of the compounds of each embodiment are shown in Table 7 below. They can be readily manufactured using the manufacturing methods of the embodiments described above, as well as methods obvious to those skilled in the art, or variations thereof.

[0373] Additionally, the following abbreviations are sometimes used in the tables described below.

[0374] PEx: Manufacturing Example Number, Ex: Example Number, PSyn: Manufacturing Method of the Manufacturing Example Compound (The number in the PSyn column indicates that the compound was manufactured using the same method as the compound whose manufacturing example number is used. For example, a compound with PSyn column 1 indicates that it was manufactured using the same method as the compound in Manufacturing Example 1), Syn: Manufacturing Method of the Example Compound (The number in the Syn column indicates that the compound was manufactured using the same method as the compound whose example number is used. For example, a compound with Syn column 1 indicates that it was manufactured using the same method as the compound in 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 ESI, unless otherwise specified [MH]). - NMR DMSO-d6 (400MHz) or NMR DMSO-d6 (500MHz): DMSO-d6 1 The δ value (ppm) of the signal in H-NMR, NMR DMSO-d6 (400MHz, 80℃): the δ value of the signal in DMSO-d6 under heating at 80℃. 1The δ value (ppm) of the signal in H-NMR, NMR CDCl3 (400MHz), or NMR CDCl3 (500MHz): CDCl3 1 In H-NMR, the signal values ​​are: δ (ppm), s: singlet (spectrum), d: doublet (spectrum), t: triplet (spectrum), m: multiplet (spectrum), br: broad peak (spectrum), and dd: double doublet (spectrum).

[0375] Unless otherwise specified, a compound represents an optical isomer having the absolute stereoconfiguration described in its chemical structural formula. In the structural formula, HCl indicates that the compound is a monohydrochloride, 2HCl indicates that the compound is a dihydrochloride, and 3HCl indicates that the compound is a trihydrochloride.

[0376] [Table 4-1]

[0377]

[0378] [Table 4-2]

[0379]

[0380] [Table 4-3]

[0381]

[0382] [Table 4-4]

[0383]

[0384] [Table 4-5]

[0385]

[0386] [Table 4-6]

[0387]

[0388] [Table 4-7]

[0389]

[0390] [Table 4-8]

[0391]

[0392] [Table 4-9]

[0393]

[0394] [Table 4-10]

[0395]

[0396] [Table 4-11]

[0397]

[0398] [Table 4-12]

[0399]

[0400] [Table 4-13]

[0401]

[0402] [Table 4-14]

[0403]

[0404] [Table 4-15]

[0405]

[0406] [Table 4-16]

[0407]

[0408] [Table 4-17]

[0409]

[0410] [Table 4-18]

[0411]

[0412] [Table 4-19]

[0413]

[0414] [Table 4-20]

[0415]

[0416] [Table 4-21]

[0417]

[0418] [Table 4-22]

[0419]

[0420] [Table 4-23]

[0421]

[0422] [Table 4-24]

[0423]

[0424] [Table 4-25]

[0425]

[0426] [Table 4-26]

[0427]

[0428] [Table 4-27]

[0429]

[0430] [Table 4-28]

[0431]

[0432] [Table 4-29]

[0433]

[0434] [Table 4-30]

[0435]

[0436] [Table 4-31]

[0437]

[0438] [Table 4-32]

[0439]

[0440] [Table 4-33]

[0441]

[0442] [Table 4-34]

[0443]

[0444] [Table 4-35]

[0445]

[0446] [Table 4-36]

[0447]

[0448] [Table 4-37]

[0449]

[0450] [Table 4-38]

[0451]

[0452] [Table 4-39]

[0453]

[0454] [Table 4-40]

[0455]

[0456] [Table 4-41]

[0457]

[0458] [Table 4-42]

[0459]

[0460] [Table 4-43]

[0461]

[0462] [Table 4-44]

[0463]

[0464] [Table 4-45]

[0465]

[0466] [Table 4-46]

[0467]

[0468] [Table 4-47]

[0469]

[0470] [Table 4-48]

[0471]

[0472] [Table 4-49]

[0473]

[0474] [Table 4-50]

[0475]

[0476] [Table 4-51]

[0477]

[0478] [Table 5-1]

[0479]

[0480] [Table 5-2]

[0481]

[0482] [Table 5-3]

[0483]

[0484] [Table 5-4]

[0485]

[0486] [Table 5-5]

[0487]

[0488] [Table 5-6]

[0489]

[0490] [Table 5-7]

[0491]

[0492] [Table 5-8]

[0493]

[0494] [Table 5-9]

[0495]

[0496] [Table 5-10]

[0497]

[0498] [Table 5-11]

[0499]

[0500] [Table 5-12]

[0501]

[0502] [Table 5-13]

[0503] PEx PSyn DAT 295 294 ESI+: 639.3 296 294 ESI+: 646.5 297 294 ESI+: 610.4 298 294 ESI+: 616.4 299 294 ESI+: 588.5 300 294 ESI+: 660.4 301 294 ESI+: 671.4 302 294 ESI+: 592.5 303 294 ESI+: 658.3 304 294 ESI+: 664.4 305 294 ESI+: 642.3 306 294 ESI+: 680.3, 682.3 307 294 ESI+: 682.4 308 294 ESI+: 672.2 309 294 ESI+: 656.3 310 294 ESI+: 667.4 311 294 ESI+: 683.3, 685.2 312 294 ESI+: 697.2, 699.2 313 294 ESI+: 674.4 314 294 ESI+: 627.4 315 294 ESI+: 707.4 316 294 ESI+: 696.5 317 294 ESI+: 704.4 318 294 ESI+: 691.4 319 294 ESI+: 692.5 320 294 ESI+: 631.4 321 294 ESI+: 686.3 322 294 ESI+: 617.4 323 294 ESI+: 695.3 324 294 ESI+: 671.4 325 294 ESI+: 657.4 326 294 ESI+: 664.3, 666.3 327 294 ESI+: 649.3, 651.2 328 294 ESI+: 663.3, 665.3 329 294 ESI+: 692.4

[0504] [Table 5-14]

[0505] PEx PSyn DAT 330 294 ESI+: 645.5 331 294 ESI+: 646.5 332 294 ESI+: 663.4 333 294 ESI+: 662.4 334 294 ESI+: 697.3, 699.3 335 294 ESI+: 655.4 336 294 ESI+: 674.4 337 294 ESI+: 687.3, 689.3 338 294 ESI+: 673.3, 675.3 339 294 ESI+: 685.5 340 294 ESI+: 699.3 341 294 ESI+: 698.2, 700.2 342 294 ESI+: 643.4 343 294 ESI+: 629.4 344 294 ESI+: 644.4 345 294 ESI+: 657.4 346 294 ESI+: 631.4 347 294 ESI+: 700.3, 702.3 348 294 ESI+: 684.3 349 294 ESI+: 617.4 350 294 ESI+: 647.3, 649.2 351 294 ESI+: 633.2, 635.2 352 294 ESI+: 648.2, 650.2 353 294 ESI+: 671.4 354 294 ESI+: 672.4 355 294 ESI+: 675.4 356 294 ESI+: 657.4 357 294 ESI+: 671.4 358 294 ESI+: 672.4 359 294 ESI+: 653.4, 655.3 360 294 ESI+: 639.3, 641.4 361 294 ESI+: 654.3, 656.3 362 294 ESI+: 684.4 363 294 ESI+: 641.4 364 294 ESI+: 642.4

[0506] [Table 5-15]

[0507] PEx PSyn DAT 365 294 ESI+: 681.4 366 294 ESI+: 682.3 367 294 ESI+: 657.4 368 294 ESI+: 674.4 369 294 ESI+: 669.5 370 294 ESI+: 670.5 371 294 ESI+: 654.0 372 294 ESI+: 653.1 373 294 ESI+: 639.3 374 294 ESI+: 769.0 375 294 ESI+: 652.2 376 294 ESI+: 610.1 377 294 ESI+: 712.7 378 294 ESI+: 648.4 379 294 ESI+: 662.3 380 294 ESI+: 663.2 381 294 ESI+: 649.4 382 294 ESI+: 677.5 383 294 ESI+: 663.3 384 294 ESI+: 676.4 385 294 ESI+: 639.5 386 294 ESI+: 650.3 387 294 ESI+: 627.4 388 294 ESI+: 666.3 389 294 ESI+: 680.3 390 294 ESI+: 772.4 391 294 ESI+: 683.2 392 294 ESI+: 697.4 393 294 ESI+: 640.4 394 294 ESI+: 684.4 395 294 ESI+: 630.4 396 294 ESI+: 629.3 397 294 ESI+: 632.3 398 294 ESI+: 617.4 399 294 ESI+: 698.6

[0508] [Table 5-16]

[0509] PEX PSyn DAT 400 294 ESI+: 631.6 401 294 ESI+: 683.5 402 294 ESI+: 697.5 403 403 ESI+: 673.1 404 404 ESI+: 650.3 405 405 ESI+: 664.3

[0510] [Table 6-1]

[0511]

[0512] [Table 6-2]

[0513]

[0514] [Table 6-3]

[0515]

[0516] [Table 6-4]

[0517]

[0518] [Table 6-5]

[0519]

[0520] [Table 6-6]

[0521]

[0522] [Table 6-7]

[0523]

[0524] [Table 6-8]

[0525]

[0526] [Table 6-9]

[0527]

[0528] [Table 6-10]

[0529]

[0530] [Table 6-11]

[0531]

[0532] [Table 6-12]

[0533]

[0534] [Table 6-13]

[0535]

[0536] [Table 6-14]

[0537]

[0538] [Table 6-15]

[0539]

[0540] [Table 6-16]

[0541]

[0542] [Table 7-1]

[0543]

[0544] [Table 7-2]

[0545]

[0546] [Table 7-3]

[0547]

[0548] [Table 7-4]

[0549]

[0550] [Table 7-5]

[0551] Ex Syn DAT 88 86 ESI+: 531.4 89 86 ESI+: 611.4 90 86 ESI+: 535.4 91 29 ESI+: 586.2, 588.2 92 86 ESI+: 599.4 93 86 ESI+: 568.3, 570.3 94 86 ESI+: 567.3, 569.2 95 86 ESI+: 601.4, 603.4 96 86 ESI+: 603.3 97 86 ESI+: 602.2, 604.2 98 86 ESI+: 552.3 99 86 ESI+: 545.3 100 86 ESI+: 546.4 101 86 ESI+: 585.4 102 86 ESI+: 586.4 103 86 ESI+: 558.0 104 86 ESI+: 557.1 105 86 ESI+: 568.2 106 86 ESI+: 536.3 107 86 ESI+: 521.4 108 86 ESI+: 535.4 109 109 ESI+: 542.5 110 109 ESI+: 569.5 111 109 ESI+: 593.5 112 112 ESI+: 523.0 113 113 ESI+: 569.3 114 113 ESI+: 554.2 115 113 ESI+: 594.3 116 113 ESI+: 582.4 117 113 ESI+: 568.2 118 113 ESI+: 611.4 119 113 ESI+: 558.4 120 113 ESI+: 612.4 121 113 ESI+: 557.3

[0552] [Table 7-6]

[0553]

[0554] [Table 7-7]

[0555]

[0556] Industrial availability

[0557] The compounds of the present invention or their salts are useful as DGKζ inhibitors and can be used as active ingredients in pharmaceutical compositions, such as therapeutic pharmaceutical compositions for cancers associated with immune cell activation or cancers resistant to PD-1 antibody / anti-PD-L1 antibody therapy.

Claims

1. A compound of formula (I) or a salt thereof, In the formula, A is either (Ai) or (A-ii) as shown below. B is either (Bia) or (B-ii) as shown below. Here, R 1a Halogenated C 1-6 When alkyl, B is (Bia). R 1a It is a pyridazinyl or halogenated C 1-6 alkyl, R 1b For H or C 1-6 alkyl, R 2 Halogenated C 1-6 Alkyl or halogen, R 3 For: i) Optionally selected free C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-5 cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenated C) 1-6 ii) phenyl groups substituted with groups from the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen; ii) optionally selected from C 1-6 The C groups substituted in the group consisting of alkyl and halogens 3-8 cycloalkyl, R 4 For H or F, R 5 For H or F, L1 is either a bond or an 0. X is CH2 or N-methyl. R a It is H or methyl. R b It can be H, methyl, ethyl, cyclopropyl or -(CH2)2O-CH3.

2. The compound or a salt thereof according to claim 1, wherein, R 3 C is the only option to be chosen. 1-6 The phenyl or C groups substituted in the group consisting of alkyl and halogen are... 3-5 cycloalkyl, R b It is H or methyl.

3. The compound or a salt thereof according to claim 1, wherein, The compound or its salt is selected from N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide, N-{2-[(3S)-3-(aminomethyl)-4-methylpiperazin-1-yl]-4-(2-chlorophenoxy)-3-(trifluoromethyl)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide, N-{2-[(3S)-3-(aminomethyl)-4-methylpiperazin-1-yl]-3-chloro-4-(2-chlorophenoxy)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide, N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide, N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide, N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide, N-[4-cyclopentyl-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide, N-{2-[(8R,8aS)-8-aminohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3- azole-4-carboxamide and The group consists of N-[3-chloro-4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}phenyl]-1-(pyrazin-4-yl)-1H-pyrazole-3-carboxamide.

4. The compound or a salt thereof according to claim 1, wherein, The compound or its salt is selected from N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate, N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate, N-[4-cyclopentyl-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate, N-[3-chloro-4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate and The group consists of N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate.

5. A pharmaceutical composition comprising the compound of claim 1 or a salt thereof and one or more pharmaceutically acceptable excipients.

6. The pharmaceutical composition according to claim 5, wherein it is a therapeutic pharmaceutical composition for cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

7. Use of the compound of claim 1 or a salt thereof in the manufacture of a therapeutic pharmaceutical composition for cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

8. A DGKζ inhibitor comprising a compound of formula (I) according to claim 1 or a salt thereof.

9. The compound or a salt thereof according to claim 3, wherein, The compound or its salt is N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide.

10. The compound or a salt thereof according to claim 9, wherein, The compound or its salt is N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate.

11. The compound or a salt thereof according to claim 3, wherein, The compound or its salt is N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide.

12. The compound or a salt thereof according to claim 11, wherein, The compound or its salt is N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate.

13. The compound or a salt thereof according to claim 3, wherein, The compound or its salt is N-[4-cyclopentyl-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide.

14. The compound or a salt thereof according to claim 13, wherein, The compound or its salt is N-[4-cyclopentyl-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate.

15. The compound or a salt thereof according to claim 3, wherein, The compound or its salt is N-[3-chloro-4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide.

16. The compound or a salt thereof according to claim 15, wherein, The compound or its salt is N-[3-chloro-4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}phenyl]-1-(pyrazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate.

17. The compound or a salt thereof according to claim 3, wherein, The compound or its salt is N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide.

18. The compound or a salt thereof according to claim 17, wherein, The compound or its salt is N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monosuccinate.

19. The compound or a salt thereof according to claim 10, wherein the compound is a crystal having a powder X-ray diffraction pattern comprising the following diffraction angles 2θ: 8.4°, 9.9°, 10.5°, 11.2°, 11.4°, 14.7°, 16.3°, 19.2°, 22.2°, 24.0°.

20. The compound or a salt thereof according to claim 12, wherein the compound is a crystal having a powder X-ray diffraction pattern comprising the following diffraction angles 2θ: 8.4°, 9.9°, 10.5°, 11.2°, 11.4°, 14.7°, 16.3°, 19.2°, 22.2°, 24.0°.

21. The compound or a salt thereof according to claim 14, wherein the compound is a crystal having a powder X-ray diffraction pattern comprising the following diffraction angles 2θ: 7.7°, 8.1°, 11.6°, 12.8°, 20.3°, 20.7°, 22.3°.

22. The compound or a salt thereof according to claim 16, wherein the compound is a crystal having a powder X-ray diffraction pattern comprising the following diffraction angles 2θ: 7.0°, 10.5°, 12.1°, 14.4°, 14.6°, 17.8°, 19.3°, 19.9°, 20.2°, 21.2°.

23. The compound or a salt thereof according to claim 18, wherein the compound is a crystal having a powder X-ray diffraction pattern comprising the following diffraction angles 2θ: 9.4°, 10.7°, 12.3°, 13.2°, 14.0°, 16.8°, 20.7°, 21.1°, 23.0°, 23.5°.

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