PYRIDAZYNYL-THIAZOLECARBOXAMIDE COMPOUND

Abstract

A compound useful as an active ingredient in a pharmaceutical composition for the treatment of cancer related to the activation of immune cells or cancer resistant to treatment with anti-PD-1 / anti-PD-L1 antibodies is provided. The inventors hereof have conducted studies on a compound useful as an active ingredient in a pharmaceutical composition for the treatment of cancer related to the activation of immune cells or cancer resistant to treatment with anti-PD-1 / anti-PD-L1 antibodies and discovered that a pyridazinyl-thiazolcarboxamide compound has an inhibitory effect on DGKβ (DGKzeta), leading to the achievement of the present invention.The pyridazinyl-thiazolcarboxamide compound of the present invention has an inhibitory effect on DGK and can be used as a therapeutic agent for the treatment of cancer related to the activation of immune cells or cancer that offers resistance to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies.

Description

PYRIDAZYNYL-THIAZOLECARBOXAMIDE COMPOUND Field of technology The present invention relates to a pyridazinyl-thiazolcarboxamide compound that is useful as a pharmaceutical composition, for example, a diacylglycerol kinase ξ (DGKzeta) inhibitor, and is expected to be useful as an active ingredient of, for example, a pharmaceutical composition for the treatment of cancer related to the activation of immune cells or cancer resistant to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies, in particular a pharmaceutical composition for the treatment of cancer related to the activation of immune cells, which offers resistance to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies. Background of the technique Cancer immunotherapy has gained attention as the fourth major cancer treatment approach, following conventional surgery, radiation therapy, and anticancer drugs (chemotherapy and drugs designed to target specific molecular targets). An anti-CTLA-4 (cytotoxic T-cell-associated antigen-4) antibody (ipilimumab) and an anti-PD-1 antibody (nivolumab or pembrolizumab) paved the way for cancer immunotherapy. CTLA-4 and PD-1 are known as checkpoint molecules and function as inhibitory checkpoint molecules. Currently, the anti-PD-1 antibody has demonstrated efficacy in clinical practice against many cancers, including melanoma and non-small cell lung cancer, and its use is expanding.In recent years, the development of antibodies that selectively target checkpoint molecules other than CTLA-4 and PD-1 has gained momentum worldwide. DGK is an enzyme that converts diacylglycerol (DAG) to phosphatidic acid (PA) through phosphorylation. In mammals, DGK has ten isoforms, broadly classified into five types based on their structural characteristics. These five isoform types are type I (α, β, γ), type II (δ, η, κ), type III (ε), type IV (ξ, ε), and type V (Θ). All isoforms share a highly homologous catalytic domain in their C-terminal region and a C1 domain, homologous to protein kinase C (PKC), within the molecule. The C1 domain is considered to be a domain to which phorbol / DAG esters bind (Int. J. Mol. Sci. 2013, 14: 6649-6673). In T cells, antigenic-activated phospholipase Cy1 (PCLyl) produces diglyceride (DAG) and inositol triphosphate (IP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). The DAG produced activates a plurality of downstream signaling pathways, including the RAS, NF-κB, and AKT pathways, leading to T cell activation. Furthermore, IP3 activates nuclear factor-activated T cell (NFAT) signaling by releasing Ca2+ from the endoplasmic reticulum and is involved not only in T cell activation but also in the induction of anergy. T cell anergy constitutes a state of incomplete activation caused by the depression of the costimulatory signal (CD28 signal) or the inhibition of the costimulatory signal during antigen recognition, and in this state, no response occurs, not even by restimulation. DGK a and DGK ξ are two major isoforms in T cells and each of them adjusts the intensity of the DAG sequence signal down of antigenic stimulation to prevent over-activation of T cells. In addition, DGK a and DGK ξ promote T cell anergy and play an important role in T cell immune tolerance (J Cell Sci. 2013, 126:2176-2186., CritRev Immunol. 2013, 33: 97-118., Immunol rev. 2008, 224:249-264). Furthermore, activation of T cells lacking DGKξ has been reported to produce resistance to PD-1 inhibitory signals and resistance to transforming growth factor (TGF-β) and PD-1-independent immunosuppressive factors such as adenosine and PGE2 (Cancer Res. 2017, 77: 5676-5686; Front Cell Dev Biol. 2016, 4:108). T cells with overexpressed PD-1 molecules have been reported to be extremely exhausted, and in this state, anti-PD-1 antibodies are ineffective. Immunosuppressive factors such as TGF-β are considered one of the mechanisms of resistance to anti-PD-1 antibody treatment (Cancer Treatment Reviews 2017, 52: 71-81).It has been reported that in NK cells, DGKξ negatively controls NK cell activation by stimulating the activated receptor, and that in mice with deactivated genes that feature DGKξ enzymes, tumor proliferation due to major histocompatibility complex (MHC) class I deficiency is suppressed (J Immunol. 2016, 197: 934-941). Therefore, the production of a DGKξ inhibitor is expected to have an antineoplastic effect through the activation of immune cells, particularly T cells. Furthermore, the remission rate following anti-PD-1 antibody treatment has been reported to vary depending on the cancer type, but generally approaches 30% (Front Immunol. 2016, 7: 550), and the DGKξ inhibitor is also expected to be useful in patients resistant to anti-PD-1 antibody treatment. Patent Document 1 discloses that R59022 and R59499 have an inhibitory effect on DGK, relieve T cell anergy, and upregulate the immune response. [Chemical formula 11 caa / ηη / ζζηζ / Ε / γίΛΐ (R59022) (R59499) Patent Document 2 discloses that the compound of the following formula has an inhibitory effect on the trkA receptor and is useful for the treatment or prevention of frequent urination and bladder tenesmus associated with overactive bladder, etc. [Chemical formula 21 paa / ηη / ζζηζ / Ε / γίΛΐ (See publication for the meanings of the symbols in the formula). In Patent Document 2, however, there is no specific disclosure regarding use in a cancer treatment, and the compound of the present invention, comprising a phenyl group with a sequence of four adjacent substituents, is an indispensable component. Patent Document 3 discloses that the compound of the following formula is useful for the treatment or prevention of proliferative disorders, etc., as a protein kinase inhibitor against a cyclin-dependent kinase (CDK), etc. Patent Document 3 also discloses the compound of Example 199 (hereinafter referred to as Compound C). [Chemical formula 3-11 [Chemical formula 3-21 Example 199 (See publication for the meanings of the symbols in the formula). In Patent Document 3, however, there is no specific disclosure about DGK and the compound of the present invention, comprising a phenyl group with a sequence of four adjacent substituents, is an indispensable component. Related technical document Patent Document Patent Document 1: U.S. Patent No. 7,381,401 Patent Document 2: International Publication No. WO 02007 / 123269 Patent Document 3: International Publication No. WO 02008 / 054702 paa / nn / zznz / E / YiAi Brief description of the invention Technical Problem A compound is indicated that is useful as a pharmaceutical composition, for example, a DGKξ inhibitor, and is expected to be useful as an active ingredient of a pharmaceutical composition for the treatment of cancer related to the activation of immune cells or cancer resistant to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies, in particular a pharmaceutical composition for the treatment of cancer related to the activation of immune cells, which offers resistance to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies. Solution to the Problem The inventors hereof have conducted extensive research on a compound useful as an active ingredient in a pharmaceutical composition for the treatment of cancer related to immune cell activation or cancer resistant to treatment with anti-PD-1 / anti-PD-L1 antibodies, in particular a pharmaceutical composition for the treatment of cancer related to immune cell activation that exhibits resistance to treatment with anti-PD-1 / anti-PD-L1 antibodies. As a result, the inventors hereof have discovered that a pyridazinyl-thiazolcarboxamide compound of formula (1) has an excellent inhibitory effect on DGKξ, leading to the realization of the present invention. As an essential component, the pyridazinyl-thiazolcarboxamide compound of formula (1) comprises a phenyl group having a sequence of four adjacent substituents, which is generally considered difficult to synthesize. That is, the present invention relates to a compound of formula (I) or a salt thereof, and to a pharmaceutical composition containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients: [Chemical formula 41 (1) where R1 is a group of formula (I), (II), (III) (IV) or (V): [Chemical formula 51 pair / ηη / ζζηζ / Ε / γίΛΐ R2 is a C1-6 alkyl, a C3-5 cycloalkyl, an -O-(C1-6 alkyl), methanesulfonyl, a Cv6 halogen-alkyl or a halogen, R3 is I) a phenyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a C1-6 halogen alkyl, a C3-5 cycloalkyl, an -O-(alkyl Oi-e), an -O-(halogen alkyl Ci-e), cyano, nitro, methanesulfonyl and a halogen, II) a C3-8 cycloalkyl optionally substituted with a group selected from the group consisting of an alkyl Ci-e and a halogen, III) a pyridyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a C1-6 halogen alkyl, a C3-5 cycloalkyl, an -O-(alkyl Ci-b), an -O-(halogen alkyl Ci-e), cyano, nitro, methanesulfonyl and a halogen, IV) a pyrazolyl optionally substituted with a group selected from of the group consisting of an alkyl (Ley a halogen, or V) a pyrrolidinyl optionally substituted with a C1-6 alkyl, R4es H or F, L is a bond, CO, SO2, O or NH, X is CH2, O or N-methyl, Yes CH2u O, Raes H or methyl, Rbes H, methyl, ethyl or -(CHLLO-CHs, Rces H, methyl or oxetanyl, Rdes H, methyl, -(CH2)2OH, -(CH2)2O-CH3 or oxetanyl, m is 1 or 2, and n is 1 or 2. When the symbols of one chemical formula are used in other chemical formulas in this description, the same symbols have the same meanings, unless otherwise specified. Furthermore, the present invention relates to a pharmaceutical composition for the treatment of cancer related to the activation of immune cells or cancer resistant to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies, containing a compound of formula (I) or a salt thereof, in particular a pharmaceutical composition for the treatment of cancer related to the activation of immune cells, which offers resistance to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies.Note that the pharmaceutical composition includes a therapeutic agent for the treatment of cancer related to the activation of immune cells or cancer resistant to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies, containing a compound of formula (I) or a salt thereof, in particular a therapeutic agent for the treatment of cancer related to the activation of immune cells, which offers resistance to treatment with anti-PD1 antibodies / anti-PD-L1 antibodies. Furthermore, the present invention relates to a compound of formula (I) or a salt thereof that is a DGKξ inhibitor; a compound of formula (I) or a salt thereof that is used as a DGKξ inhibitor; a DGKξ inhibitor comprising a compound of formula (I) or a salt thereof; the use of a compound of formula (I) or a salt thereof for the preparation of a pharmaceutical composition for the treatment of cancer related to immune cell activation or cancer resistant to treatment with anti-PD-1 / anti-PD-L1 antibodies, in particular for the treatment of cancer related to immune cell activation that is resistant to treatment with anti-PD-1 / anti-PD-L1 antibodies; the use of a compound of formula (I) or a salt thereof for the treatment of cancer related to immune cell activation or cancer resistant to treatment with anti-PD-1 / anti-PD-L1 antibodies.in particular for the treatment of cancer related to the activation of immune cells, which is resistant to treatment with anti-PD-1 / anti-PD-L1 antibodies; a compound of formula (I) or a salt thereof used for the treatment of cancer related to the activation of immune cells or cancer resistant to treatment with anti-PD-1 / anti-PD-L1 antibodies, in particular for the treatment of cancer related to the activation of immune cells, which is resistant to treatment with anti-PD-1 / anti-PD-L1 antibodies, and a method for the treatment of cancer related to the activation of immune cells or cancer resistant to treatment with anti-PD-1 / anti-PD-L1 antibodies, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a subject,In particular, a method for treating cancer related to the activation of immune cells, which confers resistance to treatment with anti-PD-1 / anti-PD-L1 antibodies. The subject is a human being or other animal requiring cancer treatment or prevention. In one modality, the subject is a human requiring cancer treatment or prevention. Beneficial Effects of the Invention A compound of formula (I) or a salt thereof has an inhibitory effect on DGKξ and can be used as a therapeutic agent for the treatment of cancer related to the activation of immune cells or cancer resistant to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies, in particular a therapeutic agent for the treatment of cancer related to the activation of immune cells, which offers resistance to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies. Description of the Modalities From here on, the present invention will be described in detail. In this description, the following expressions have the following meanings, unless otherwise specified. The following definitions are intended to clarify the expressions defined in caa / ηη / ζζηζ / E / γίΛΐ rather than to limit the meaning of the expressions. If an expression used herein is not specifically defined, it is used with a meaning commonly accepted by those skilled in the art. In this description, alkyl Ci represents a linear or branched alkyl having from 1 to 6 carbon atoms (hereafter abbreviated as Ci e). Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. In one embodiment, alkyl Ci6 is a Ci 3 alkyl. In one embodiment, alkyl C1 e is methyl or ethyl. In one embodiment, alkyl Ci e is methyl. In one embodiment, alkyl Ci e is ethyl. C1-6 halogen alkyl represents a C1-6 alkyl substituted with one or more halogens. In one embodiment, C1-6 halogen alkyl represents a C1-6 alkyl substituted with one to five halogens. In one embodiment, C1-6 halogen alkyl represents a C13 alkyl substituted with one to five halogens. In one embodiment, C1-6 halogen alkyl is difluoromethyl or trifluoromethyl. In one embodiment, C1-6 halogen alkyl is trifluoromethyl. A C3-8 cycloalkyl group is a saturated C3-8 hydrocarbon ring group and can be crosslinked or form a spiro ring. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2,2,1]heptyl, bicyclo[3,1,1]hexyl, bicyclo[3,1,1]heptyl, and spiro[2,5]octyl. In one embodiment, a C3-8 cycloalkyl group is a C3-5 cycloalkyl group. In one embodiment, a C3-5 cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl. In one embodiment, a C3-5 cycloalkyl group is cyclopropyl. In one embodiment, a C3-5 cycloalkyl group is cyclobutyl. In one embodiment, a C3-5 cycloalkyl group is cyclopentyl. The halogen is F, OI, Br, or I. In one form, the halogen is F or OI. In one form, the halogen is OI. The expression "optionally substituted" means unsubstituted or substituted with one or more substituents (e.g., substituents as defined below). Substitution can occur at any position, provided there is a hydrogen atom normally present in that position. In one embodiment, the expression "optionally substituted with" means optionally substituted with one to five substituents. In another embodiment, the expression "optionally substituted with" means optionally substituted with one to three substituents. When there is a plurality of substituents, these may be the same substituents or different substituents. One or more modalities can be combined with another modality even if a specific combination is not described. In other words, all modalities can be combined freely. The expression "immune cell activation" means that immune cells capable of suppressing cancer cell proliferation or reducing or eliminating cancer cells (hereafter referred to as antineoplastic activity), particularly T cells, are reactivated, and / or that the number of immune cells, particularly activated T cells, has increased. In one modality, the expression "immune cell activation" means the activation of immune cells based on the inhibitory effect on DGKξ. Immune-activated cancer is a cancer that has the capacity for an immune response. In one modality, immune-activated cancer is a cancer in which the proliferation of cancer cells is suppressed or in which cancer cells are reduced or eliminated through the activation of immune cells. In one modality, immune-activated cancer is a cancer in which the proliferation of cancer cells is suppressed through the activation of immune cells. In one modality, immune-activated cancer is a cancer in which the proliferation of cancer cells is reduced or eliminated through the activation of immune cells.In one modality, immune cell activation-related cancer is a cancer in which the proliferation of cancer cells is suppressed or in which cancer cells are reduced or eliminated through the activation of immune cells based on the inhibitory effect on DGKξ. In one modality, immune cell activation-related cancer is a cancer in which the proliferation of cancer cells is suppressed through the activation of immune cells based on the inhibitory effect on DGKξ. In one modality, immune cell activation-related cancer is a cancer in which the proliferation of cancer cells is reduced or eliminated through the activation of immune cells based on the inhibitory effect on DGKξ. Examples of cancers to which the invention in question may be applied include, but are not limited to, small cell lung cancer, head and neck cancer, kidney cancer, ovarian cancer, non-small cell lung cancer, intestinal cancer with alteration of the reparative pathway, urothelial cancer, melanoma, hepatocellular carcinoma, stomach cancer, and bladder cancer. The expression "resistant to anti-PD-1 antibodies / anti-PD-L1 antibodies" means resistant to treatment with anti-PD-1 antibodies and / or treatment with anti-PD-L1 antibodies. In one modality, the expression "resistant to anti-PD-1 antibodies / anti-PD-L1 antibodies" means resistant to treatment with both anti-PD-1 antibodies and anti-PD-L1 antibodies. In one modality, the expression "resistant to anti-PD-1 antibodies / anti-PD-L1 antibodies" means resistant to treatment with anti-PD-1 antibodies. In one modality, the expression "resistant to anti-PD-1 antibodies / anti-PD-L1 antibodies" means resistant to treatment with anti-PD-L1 antibodies.In particular, resistant expression to anti-PD-1 / anti-PD-L1 antibody treatment means that immunotherapy with an anti-PD-1 antibody and / or an anti-PD-L1 antibody becomes ineffective shortly after the start of treatment (primary resistance) or acquires resistance to treatment from the middle of treatment onwards (acquired resistance), so that the cancer cells proliferate again. The expression "cancer resistant to anti-PD-1 antibodies / anti-PD-L1 antibodies" means cancer resistant to treatment with anti-PD-1 antibodies and / or treatment with anti-PD-L1 antibodies. In one modality, the expression "cancer resistant to anti-PD-1 antibodies / anti-PD-L1 antibodies" means cancer resistant to both anti-PD-1 antibody treatment and anti-PD-L1 antibody treatment. In one modality, the expression "cancer resistant to anti-PD-1 antibodies / anti-PD-L1 antibodies" means cancer resistant to treatment with anti-PD-1 antibodies. In one modality, the expression "cancer resistant to anti-PD-1 antibodies / anti-PD-L1 antibodies" means cancer resistant to treatment with anti-PD-L1 antibodies.In particular, the expression cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody treatment means a cancer for which immunotherapy with an anti-PD1 antibody and / or an anti-PD-L1 antibody becomes ineffective shortly after the start of treatment (primary resistance) or which acquires resistance to treatment from the middle of treatment onwards (acquired resistance), so that the cancer cells proliferate again. Examples of cancers to which the invention in question may be applied include cancers resistant to treatment with anti-PD-1 / anti-PD-L1 antibodies, including, but not limited to, small cell lung cancer, head and neck cancer, kidney cancer, ovarian cancer, non-small cell lung cancer, intestinal cancer with impaired repair pathway, urothelial cancer, melanoma, hepatocellular carcinoma, stomach cancer, and bladder cancer. Examples of anti-PD-1 antibodies / anti-PD-L1 antibodies include, but are not limited to, an antibody selected from nivolumab, pembrolizumab, atezolizumab, pidilizumab, avelumab, and durvalumab. The following will show a modality of the compound of formula (I) or of a salt thereof of the present invention: (1-1) A compound or a salt of the same in which R1 is a group of the following formula (I), (II), (III) (IV) or (V): Chemical formula 61 caa / nn / zznz / E / YiAi (1-2) A compound or a salt of the same in which R1 is a group of the following formula (la), (IIa), (Hl-a) or (Va): [Chemical formula 71 (1-3) A compound or a salt of the same in which R1 is a group of the following formula (I), (II), (III) or (IV): [Chemical formula 81 paa / ηη / ζζηζ / Ε / γίΛΐ (1-4) A compound or a salt of the same in which R1 is a group of the following formula (la), (II- a) or (III-a): [Chemical formula 91 (ia) (ii-a) (ii-a) (2) A compound or a salt thereof wherein R2 is an O 6 alkyl, a C35 cycloalkyl, a -O(Cie alkyl), methanesulfonyl, a C1-6O halogen-alkyl, or a halogen; in one embodiment, a compound or a salt thereof wherein R2 is a Ci-βθ halogen-alkyl, or a halogen; in one embodiment, a compound or a salt thereof wherein R2 is a C1-3 halogen-alkyl, F, OI, or Br; in one embodiment, a compound or a salt thereof wherein R2 is CF3, F, or Cl; in one embodiment, a compound or a salt thereof wherein R2 is CF3; in one embodiment, a compound or a salt thereof wherein R2 is F; or in one embodiment, a compound or a salt thereof wherein R2 is Cl; (3-1) A compound or a salt thereof wherein R3 is I) a phenyl optionally substituted with a group selected from the group consisting of a C1e alkyl, a C1s halogen alkyl, a C3-5 cycloalkyl, an -O-(C1e alkyl), an -O-(C1e halogen alkyl), cyano, nitro, methanesulfonyl and a halogen, II) a C3-8 cycloalkyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl and a halogen, III) a pyridyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a C1-6 halogen alkyl, a C3-5 cycloalkyl, an -O-(C1e alkyl), an -O-(C1e halogen alkyl), cyano, nitro, methanesulfonyl and a halogen, IV) a optionally substituted pyrazolyl group selected from the group consisting of an alkyl Ciey and a halogen, or V) a pyrrolidinyl group optionally substituted with an alkyl Cie; (3-2) A compound or a salt thereof wherein R3 is I) a phenyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, cyano, nitro and a halogen, II) a C3-8 cycloalkyl, III) a pyridyl, IV) a pyrazolyl optionally substituted with a C1-6 alkyl or (V) a pyrrolidinyl; (3-3) A compound or a salt thereof wherein R3 is I) a phenyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a C1-b halogen alkyl, a C3-5 cycloalkyl, an -O-(C1-e alkyl), an -O-(C1-6 halogen alkyl), cyano, nitro, methanesulfonyl and a halogen, or II) a C3-8 cycloalkyl optionally substituted with a group selected from the group consisting of a C1-e alkyl and a halogen; (3-4) A compound or a salt thereof wherein R3 is a phenyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl and a halogen, or a C3-5 cycloalkyl; (4) A compound or a salt thereof wherein R4 is H or F; in one embodiment, a compound or a salt thereof wherein R4 is H, or in one embodiment, a compound or a salt thereof wherein R4 is F; (5) A compound or a salt thereof in which L is a bond, CO, SO2, O or NH; in one embodiment, a compound or a salt thereof in which L is a bond, O or NH; in one embodiment, a compound or a salt thereof in which L is O or NH; in one embodiment, a compound or a salt thereof in which L is O, or in one embodiment, a compound or a salt thereof in which L is NH; (6) A compound or a salt thereof wherein X is CH2, O or N-methyl; in one embodiment, a compound or a salt thereof wherein X is CH2 or N-methyl; in one embodiment, a compound or a salt thereof wherein X is CH2, or in one embodiment, a compound or a salt thereof wherein X is N-methyl; (7) A compound or a salt thereof wherein Y is CH2u O; in one embodiment, a compound or a salt thereof wherein Y is CH2, or in one embodiment, a compound or a salt thereof wherein Y is O; (8) A compound or a salt of the same in which Raes is H or methyl; in one embodiment, a compound or a salt of the same in which Raes is H, or in one embodiment, a compound or a salt of the same in which Raes is methyl; (9) A compound or salt thereof in which Rbes H, methyl, ethyl or -(CH2)2O-CH3; in one embodiment, a compound or salt thereof in which Rbes H or methyl; in one embodiment, a compound or salt thereof in which Rbes H, or in one embodiment, a compound or salt thereof in which Rbes methyl; (10) A compound or a salt thereof in which Rces H, methyl, ethyl or oxethanyl; in one embodiment, a compound or a salt thereof in which Rces H or methyl; in one embodiment, a compound or a salt thereof in which Rces H, or in one embodiment, a compound or a salt thereof in which Rces methyl; (11) A compound or a salt thereof in which Rdes H, methyl, -(CH2)2OH, -(CH2)2O-CH3 or oxethanyl; in one embodiment, a compound or a salt thereof in which Rdes -(CH2)2OH or -(CH2)2OCH3; in one embodiment, a compound or a salt thereof in which Rdes -(CH2)2OH, or in one embodiment, a compound or a salt thereof in which Rdes -(CH2)2O-CH3; (12) A compound or a salt of the same in which m is 1 or 2; in one mode, a compound or a salt of the same in which m is 1, or in one mode, a compound or a salt of the same in which m is 2; (13) A compound or a salt of the same in which, n is 1 or 2; in one mode, a compound or a salt of the same in which, n is 1, or in one mode, a compound or a salt of the same in which, n is γαα i nn / zznz / E / YiAi 2, or (14) A compound or a salt of the same that is an arbitrary combination of two or more of the modalities (1-1) to (13) that does not cause a contradiction. Specific examples of the combination described in (14) include the following modalities: (15) A compound or a salt of the same in which R1 is a group of the following formula (I), (II), (III), (IV) or (V): [Chemical formula 101] where R2 is a C1-6 alkyl, a C3-5 cycloalkyl, an -O-(C1-6 alkyl), methanesulfonyl, a C1-6 halo-alkyl or a halogen; R3 is I) a phenyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a C1-6 halogen alkyl, a C3-5 cycloalkyl, an -O(Ci-e alkyl), an -O-(Ci-e halogen alkyl), cyano, nitro, methanesulfonyl and a halogen, II) a Cs-s cycloalkyl optionally substituted with a group selected from the group consisting of a Cis alkyl and a halogen, III) a pyridyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a C1-6 halogen alkyl, a C3-5 cycloalkyl, an -O-(Ci-e alkyl), an -O-(Ci-e halogen alkyl C1-6), cyano, nitro, methanesulfonyl and a halogen, IV) a pyrazolyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl and a halogen, or V) a pyrrolidinyl optionally substituted with a C1-e alkyl; R4 is H or F; L is a bond, CO, SO2, O or NH; X is CH2, O or N-methyl; Y is CH2U O; Ra is H or methyl; Rbes H, methyl, ethyl or -(CH2)2O-CH3; Rces H, methyl or oxetanyl; Rdes H, methyl, -(CH2)2OH, -(CH2)2O-CH3 or oxetanyl; m is 1 or 2; n is 1 or 2; (16) The compound or salt of the same described in (15) wherein R2 is a halogen-alkyl; Ci-eo is a halogen; L is a bond, O or NH; X is CH2 or N-methyl; Rces is H or methyl; m is 1; (17) The compound or salt of the same described in (16) wherein R1 is a group of the following formula (la), (ll-a), (lll-a) or (Va): [Chemical formula 111 (18) The compound or salt thereof described in (17) wherein R3 is a phenyl optionally substituted with a group selected from the group consisting of a C1 alkyl and a halogen, or a C3-5 cycloalkyl; (19) The compound or salt of the same described in (18) wherein R2 is CF3, R4 is H, R3 is H or methyl and R4 is H. Specific examples of the combination described in (14) include the following modalities: (20) A compound or a salt of the same in which R1 is a group of the following formula (I), (II), (III) or (IV): (Chemical formula 121 paa / ηη / ζζηζ / Ε / γίΛΐ where R2 is a halogen-alkyl Ci-e or a halogen; R3 is I) a phenyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a C1-6 halogen alkyl, a C3-5 cycloalkyl, an -O-(Ci-β alkyl), an -O-(Ci-s halogen alkyl), cyano, nitro, methanesulfonyl, and a halogen, II) a C38 cycloalkyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl and a halogen, III) a pyridyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a C1-6 halogen alkyl, a C3-5 cycloalkyl, an -O-(Ci-e alkyl), an -O-(C1-6 halogen alkyl), cyano, nitro, methanesulfonyl, and a halogen, IV) a pyrazolyl optionally substituted with a group selected from the group consisting of an alkyl Ciey and a halogen, or V) a pyrrolidinyl optionally substituted with an alkyl Ci-θ; R4 is H or F; L is a bond, O or NH; X is CH2, O or N-methyl; Y is CH2 or O;Raes H or methyl; Rbes H, methyl, ethyl or -(CH2)2O-CH3; Rces H, methyl or oxetanyl; Rdes H, methyl, -(CH2)2OH, -(CH2)2O-CH3 or oxetanyl; m is 1 or 2 and n is 1 or 2; (21) A compound or salt thereof described according to (20), wherein R1 is a group of formula (I), (II), (III) or (IV): [Chemical formula 131 H R2 is a halogen-alkyl Ci-eo is a halogen; R3 is I) a phenyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a C1-6 halogen alkyl, a C3-5 cycloalkyl, an -O-(C1-6 alkyl), an -O-(C1-e halogen alkyl), cyano, nitro, methanesulfonyl, and a halogen, II) a C3-8 cycloalkyl optionally substituted with a group selected from the group consisting of a C1-e alkyl and a halogen, III) a pyridyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a C1-6 halogen alkyl, a C3-5 cycloalkyl, an -O-(C1-6 alkyl), an -O-(C1-6 halogen alkyl), cyano, nitro, methanesulfonyl, and a halogen, IV) a pyrazolyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl and a halogen, or V) a pyrrolidinyl optionally substituted with an alkyl Oí e; R4 is H or F; L is O or NH; X is CH2O N-methyl; Y is CH2 or O; Ra is H;Rbes H, methyl, ethyl or -(CH2)2O-methyl; Rces H or methyl; Rdes H, methyl, -(ΟΗς^ΟΗ, -(0Η2)2Ο-0Η3u oxetanyl; m is 1 and n is 1 or 2; (22) The compound or salt thereof described in (21) wherein R1 is a group of the following formula (la), (ll-a) or (lll-a): [Chemical formula 141 (ia) (ll-a) (lll-a) caa / ηη / ζζηζ / E / γίΛΐ (23) The compound or salt thereof described in (22) wherein R3 is a phenyl optionally substituted with a group selected from the group consisting of a C3 alkyl and a halogen, or a C35 cycloalkyl; (24) The compound or salt thereof described in (23) wherein R2 is CF3, R4 is H, R3 is H or methyl and R4 is H. Examples of the specific compounds covered by the present invention include the following compounds or salts thereof: N-{2-[(3S)-3-(am¡nomethyl)p¡per¡din-1-¡l]-4-phenoxy¡-3-(trifluoromethyl)phen¡l}-2-(pyr¡daz¡n-4-¡l)-1,3-thiazol-4carboxamide; N-{2-[(3S)-3-(am¡nomet¡l)piper¡d¡n-1-yl]-4-(3-fluorophenox¡)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)1,3-thiazol-4-carboxamida; N-{2-[9-(2-methoxyethyl)-1-oxa-4,9-diazaespiro[5.5]undecan-4-yl]-4-fenoxy-3-(trifluoromethyl)phenol}-2(pyridazin-4-yl)-1,3-thiazol-4-carboxamida; N-{2-[(3S)-3-(aminomethyl)p¡peridin-1 -yl]-4-(2-fluorophenoxy)-3-(tr¡fluoromet¡l)phenyl}-2-(pyridazin-4-yl)1,3-thiazol-4-carboxamide; N-[4-(2-fluorophenoxy)-2-{(3S)-3-[(methylamino)methyl]piperidin-1 -iI}-3-(trifluoromethyl)phenyl]-2-(pyridazin4-11)-1,3-thiazol-4-carboxamida; N-{2-[(2R)-2-(aminomethyl)p¡rrol¡d¡n-1 -yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4carboxamide; N-{2-[(8R,8aS)-8-aminohexahidropyrrolo[1,2-a]pyrazin-2(1 H)-yl]-4-fenoxy-3-(trifluoromethyl)phenyl}-2(pyridazin-4-yl)-1,3-thiazol-4-carboxamida y N-{2-[(8R,8aS)-8-(dimethylamino)hexahydropyrrolo[1,2-a]pyrazin-2(1 H)-yl]-4-phenoxy-3(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide. Examples of the specific compounds covered by the present invention include the following compounds or salts thereof: N-{2-[(3S)-3-(aminomethyl)piperidín-1-¡l]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridaz¡n-4-¡l)-1,3-thiazole-4carboxamide; N-{2-[(3S)-3-(aminomethyl)p¡per¡din-1-yl]-4-(3-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)1,3-thiazol-4-carboxamide; N-{2-[9-(2-methoxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2(pyridazin-4-yl)-1,3-thiazol-4-carboxamide; N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)1,3-thiazol-4-carboxamide; and N-{2-[(2R)-2-(aminomethyl)pyrrolidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazole-4carboxamide. Examples of the specific compounds covered by the present invention include the following compounds or salts thereof: N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide mono[(2E)-but-2-enedioate]; N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(3-f luorophenoxy)-3(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide mono[(2E)-but-2-enedioate]; N-{2-[(3S)-3-(aminomethyl)p¡per¡din-1-yl]-4-(2-fluorophenoxy¡)-3(trifluoromethyl)phenyl}-2-(pyr¡daz¡n-4-¡l)-1,3-thiazol-4-carboxamide mono[(2E)-but-2-enedioate]; and N-{2-[(2R)-2-(aminomethyl)pyrrolidin-1-yl]-4-phenoxy-3(trifluoromethyl)phenyl}-2-(pyridazin-4-l)-1,3-thiazole-4-carboxamide mono[(2E)-but-2-enedioate]. The compound of formula (I) may have tautomers and geometric isomers depending on the type of substituent. In the present description, the compound of formula (I) or its salt may be described in a single isomeric form, but the present invention encompasses other isomers, isolated forms of isomers, or mixtures thereof. The compound of formula (I) or a salt thereof may have an asymmetric center or axial chirality, depending on which enantiomers (optical isomers) are present. The compound of formula (I) or a salt thereof encompasses all isolated individual enantiomers, such as the (R) and (S) configurations, and mixtures thereof (including racemic or non-racemic mixtures). In one embodiment, the enantiomer is stereochemically pure. The term stereochemically pure refers to a degree of purity at which those skilled in the art can recognize the enantiomer as substantially and stereochemically pure. In another embodiment, the enantiomer is a compound having a stereochemical purity of, for example, 90% ee (enantiomeric excess) or more, 95% ee or more, 98% ee or more, or 99% ee or more. γαα / nn / zznz / E / YiAi The salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and a salt can be formed by the addition of an acid or a base depending on the type of substituent.Specific examples of these include acid addition salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid ((2E)-but-2-enedioic acid), maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluyltartaric 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, various amino acids, such as acetyl-leucine, and amino acid derivatives. Furthermore, the present invention covers various hydrates, solvates and crystalline polymorphism substances of compounds of formula (I) and salts thereof. Furthermore, the present invention encompasses pharmaceutically acceptable prodrugs of the compounds of formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of the group forming the prodrug include groups as described in Prog. Med., 5, 2157-2161 (1985) and in Pharmaceutical research and development (Hirokawa Shoten Co., 1990), Vol. 7, Molecular Design, 163-198. The present invention covers all compounds of formula (I) labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes, or salts thereof. Examples of preferred isotopes used for isotopic labeling of the compound of the present invention include isotopes of hydrogen (e.g., 2H and 3H), carbon (e.g., 11C, 13C, and 14C), nitrogen (e.g., 13N and 15N), oxygen (e.g., 15O, 17O, and 18O), fluorine (e.g., 18F), chlorine (e.g., 36Cl), iodine (e.g., 123I and 125I), phosphorus (e.g., 32P), and sulfur (e.g., 35S). The isotopically labeled compound of the invention in this application can be used in studies on the histological distributions of drugs and / or substrates. For example, radioactive isotopes such as tritium (3H) and carbon-14 (14C) can be used for this purpose due to their ease of labeling and convenience of detection. Replacement with a heavier isotope, for example, replacement of hydrogen with deuterium (2H), can be therapeutically beneficial because it improves metabolic stability (e.g., increased in vivo half-life, decreased required dose, or decline in drug interaction). Replacement with positron-emitting isotopes (e.g., 11C, 18F, 15O and 13N) can be applied in positron emission tomography (PET) tests to examine the substrate acceptor occupancy rate. The isotopically labeled compound of the present invention can, in general, be prepared by a conventional method known to those skilled in the art, or by the same production method described in the Examples or in the Production Examples using appropriate isotopically labeled reagents instead of unlabeled reagents. pair / nn / zznz / E / YiAi In the powder X-ray diffraction described in the relevant document, the distance to the crystal lattice and the overall pattern are important for crystal identification, taking into account the characteristics of the data. The diffraction angle and intensity can vary slightly depending on the crystal growth direction, particle size, and measurement conditions, and should not be interpreted rigidly. As used herein, the diffraction angle (20) in the powder X-ray diffraction pattern is interpreted with a generally acceptable margin of error in the measurement, for example, a margin of error of ±0.2°. Furthermore, for example, a peak close to an excipient-derived peak and on a sloping baseline of the peak may be visually shifted by ±0.3° if the powder X-ray measurement is performed in the state of an excipient mixture. (Preparation method) The compound of formula (I) and a salt thereof can be prepared by applying various known synthetic methods, taking advantage of the characteristics of the basic structure or the type of substituent of the compound. Depending on the type of functional group, replacing the functional group with an appropriate protecting group (a group that can be readily converted into the functional group) during the formation of an intermediate from a starting material can be an effective production technique. Examples of protecting groups include those described in PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis (Vol. 4, 2006), and depending on the reaction conditions, an appropriate protecting group can be selected and used. In this method, such a protecting group is introduced, a reaction is carried out, and the protecting group is removed, if necessary, to obtain the desired compound. The prodrug for the compound of formula (I) can be prepared by introducing a specific group during the formation of an intermediate product from a raw material, as in the case of the protecting group described above, or by means of a further reaction using the resulting compound of formula (I). The reaction can be carried out using a method known to those skilled in the art, such as common esterification, amidation, or dehydration methods. From here on, a typical method for preparing the compound of formula (I) will be described. Each production method can be carried out by referring to the references cited in the description. The production method according to the present invention is not limited to the example shown below. The following abbreviations may be used in this description. DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide, EtOAc = ethyl acetate, EtOH = ethanol, Hex = hexane, MeCN = acetonitrile, MeOH = methanol, THF = tetrahydrofuran, DMI = 1,3-dimethylimidazolidin-2-one, NMP = N-methyl-2-pyrrolidone, CH2Cl2 = dichloromethane. Boc = tert-butoxycarbonyl, Ph = phenyl, tBu = tert-butyl, Et = ethyl, Me = methyl, Ac = acetyl, Ns = 2nitrobenzenesulfonyl. GDI = 1 ,T-carbonylbis(1 H-imidazole), DCC = Ν,Ν'-dicyclohexylcarbodiimide, TEA = triethylamine, DIPEA = Ν,Ν-diisopropylethylamine, DABCO = 1,4-dlazabicyclo[2.2.2]octane, DPPA = diphenylphosphorylazide, crr i nn / zznz / E / YiAi HATU = hexafluorofosfato de 0-(7-azabenzotriazol-1-il)-N,N,N',N'-tetramet¡luronio, HOBt = 1hidroxibenzotriazol, KOtBu = tert-butóxido de potasio, NaOtBu = tert-butóxido de sodio, NMO = Nmetilmorfolina, Pd / C = paladio sobre carbono, TFA = ácido trifluoroacetico, TFAA = anhídrido trifluoroacetico, WSC.HCI = hidrocloruro de N-[3-(d¡met¡llamino)prop¡l]-N'-et¡lcarbod¡¡m¡da. Pd(PPhs)4= tetrakis(trifen¡lfosfano)palad¡o, PdCÍ2(PPh3)2= bis(tr¡fen¡lfosfano)palad¡o(lI) dichloride, Pd(dppf)CÍ2 CH2Cl2= dichloride adduct [1,1'-bis(diphenylphosphano)ferroceno]palad¡o (II) and dichloromethane, Pd2(dba)s = (1 E,4E)-1,5-diphenylpenta-1,4-dien-3-ona / paladium (3:2). salt = watery solution saturated with NaCl, MgSO4 = anhydrous magnesium sulphate, Na2SO4 = anhydrous sodium sulphate, NaHCOs = sodium hydrogen carbonate, NH4CI = ammonium chloride, NaBH(OAc)3 = sodium triacetoxiborohydride. [Fórmula química 151 prr i ​​nn / zznz / E / YiAi (where R1arepresents R1o a protecting group or adduct of R1) (First step) This step is a method in which compound (1) is subjected to a reduction reaction to obtain compound (2). This reaction can be carried out by stirring compound (1) and a metal at room temperature or under reflux heating in acidic conditions in a mixture of solvents such as methanol, ethanol, 1,4-dioxane, or similar solvents and water for a period ranging from 1 hour to 5 days. The acids used are NH4Cl, AcOH, HCl, or similar solvents. The metals used are Fe, Zn, Sn, or similar solvents. Furthermore, this reaction can be carried out by stirring compound (1) in the presence of a metallic catalyst under heating or cooling conditions, preferably at room temperature, in a solvent that is inactive with respect to the reaction, such as MeOH, EtOH, or EtOAc, and a mixture of these solvents, in a hydrogen atmosphere, for a period ranging from 1 hour to 5 days. Metallic catalysts used include palladium catalysts, such as Pd / C, palladium black, and palladium hydroxide on carbon; platinum catalysts, such as platinum on carbon and platinum oxide; nickel catalysts, such as reduced nickel and Raney nickel; and similar catalysts. (Second step) This step is a method in which compound (2) and compound (3) are subjected to an amidation reaction and then the substituents are appropriately modified to obtain the compound of formula (I). In the amidation reaction, compound (2) and compound (3) are used in such a way that the amounts of the compounds are equivalent to each other, or the amount of one of the compounds is in excess, and a mixture of the compounds is stirred in the presence of a condensing agent under heating or cooling conditions, preferably between -20 °C and -60 °C, in a solvent that is inactive with respect to the reaction, generally for a period that can vary from 0.1 hour to 5 days. There is no particular limitation with respect to the solvent used in this step; examples include aromatic hydrocarbons, such as benzene, toluene, and xylene; halogenated hydrocarbons, such as CH₂Cl₂, 1,2-dichloroethane, and chloroform; ethers, such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; DMF, DMSO, EtOAc, MeCN, water, and mixtures thereof. Examples of condensation agents include, but are not limited to, WSC, HCI, DCC, CDI, DPPA, POChy HATU.The use of an additive (e.g., HOBt) may be favorable to the reaction. It may be beneficial to carry out the reaction in the presence of an organic base, such as TEA, DIPEA, or NMO, or an inorganic base, such as K₂CO₃, Na₂CO₃, or KOH, to make the reaction proceed smoothly. In addition, an amidation reaction can be used in which compound (3) is converted into a reactive derivative, which is then reacted with compound (2). Examples of reactive derivatives of compound (3) include acid halides obtained by reacting the compound with a halogenating agent such as POCl₂SOCl₂, mixed acid anhydrides obtained by reacting the compound with isobutyl chloroformate or similar agents, and active esters obtained by condensation of the compound with HOB₄ or similar agents. This reaction can be carried out under cooling or reflux conditions, preferably between -20 °C and 120 °C, in a reaction-inactive solvent such as a halogenated hydrocarbon, an aromatic hydrocarbon, or an ether. Following the amidation reaction, a protecting group is introduced and / or removed if necessary, and the substituents are modified appropriately to obtain the compound of formula (I). For example, if R1a of compound (3) is an adduct of a protecting group from R1, the protecting group can be removed under appropriate reaction conditions to obtain the compound of formula (I). (Synthesis of raw materials) [Chemical formula 16] CRR ! ηη / 77ηZ / E / YILI (where LG1 and LG2 each represent a leaving group. LG1 and LG2, which are different from each other, can be halogens, etc.). This production method is a method for preparing the compound (1) that will serve as raw material. (Third step) This step is a method in which compound (6) is prepared from compound (5) through an ipso position substitution reaction. In this reaction, the compound is stirred under cooling or reflux conditions, preferably between 0 °C and 120 °C, in a solvent that is inactive with respect to the reaction or in a solvent-free medium, generally for a period ranging from 0.1 hours to 5 days. There is no particular limitation regarding the solvent used in this step; examples include halogenated hydrocarbons, such as CH₂Cl₂, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons, such as benzene, toluene, and xylene; ethers, such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; DMF, DMSO, NMP, EtOAc, MeCN, water, and mixtures thereof. It may be beneficial to carry out the reaction in the presence of an organic base, such as TEA, DIPEA, NMO, or DABCO, or an inorganic base, such as NaH, K2CO3, Na2CO3, CS2CO3O, or NaOtBu, to make the reaction proceed smoothly. (Step Four) This step is a method in which compound (7) is prepared by a Suzuki coupling reaction using compound (5) and an organoboron compound, or a method in which compound (7) is prepared by a Buchwald-Hartwig reaction using compound (5) and an amine compound. In this reaction, the compound is stirred at room temperature or under reflux by heating in the presence of a base and a palladium catalyst, in a solvent that is inactive with respect to the reaction, typically for a period ranging from 0.1 hours to 5 days. There is no particular limitation regarding the solvent used in this step; examples include halogenated hydrocarbons, such as CH₂Cl₂, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons, such as benzene, toluene, and xylene; ethers, such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols, such as methanol, ethanol, isopropyl alcohol, and butanol; DMF, DMSO, MeCN, DMI, water, and mixtures thereof. Examples of bases include inorganic bases such as NaH, K2CO3, Na2COs, CS2CO3, KsPO4, and CsF. Examples of palladium catalysts include Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2CH2Cl2, and Pd2(dba)s.It may be beneficial to carry out the reaction in the presence of a ligand such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphane (SPhos) to make the reaction proceed smoothly. Heating the reaction mixture by microwave irradiation may also be beneficial to make the reaction proceed smoothly. The following sources can be consulted for references on this reaction: J. Am. Chem. Soc. 127, 4685-4696, 2005 Angew. Chem., Int. Ed. Engl. 34, 1384-1350, 1995 Furthermore, this step is a method in which compound (7) is prepared from compound (5) by an ipso-position substitution reaction. The reaction conditions are the same as in the third step. (Fifth and sixth steps) This step is a method in which compound (1) is prepared from compound (6) or compound (7) by means of a substitution reaction at the ipso position. The reaction conditions are the same as in the third step. In an alternative method for preparing compound (1), compound (5a) can be used as a starting material, wherein R2 of compound (5) is substituted with a leaving group such as a halogen (the leaving group such as a halogen is referred to as LG3, which differs from LG1 and LG2). Compound (7a), wherein R2 of compound (7) is substituted with LG3, is prepared from compound (5a) as in step four. Then, compound (1a), wherein R2 of compound (1) is substituted with LG3, is prepared as in step six, and compound (1) is prepared as in step four. The compound of formula (I) is isolated as a free compound or as a salt, hydrate, solvate, or polymorphic crystalline substance thereof, and is purified. The salt of the compound of formula (I) can be prepared by subjecting the compound to a conventional salt-forming reaction. Isolation and purification are carried out using normal chemical operations, such as extraction, fractional crystallization, and various types of chromatography. Various types of isomers can be prepared by selecting a suitable compound as a raw material, or they can be separated by exploiting differences in the physicochemical properties of the isomers. For example, optical isomers can be obtained by a general method of optical resolution of racemates (e.g., fractional crystallization to obtain a diastereomer salt with an optically active base or acid, or chromatography using a chiral column), or they can be prepared from an optically active compound suitable as a raw material. The pharmacological activity of the compound of formula (I) can be confirmed by the following assay or by a known enhancement assay. In this description, the dosage of a test compound is given based on its weight in free form. When a commercially available reagent, kit, or similar item is used, the assay may be performed according to the instructions for the commercially available product. Example trial 1: Evaluation of the inhibitory effect of DGK ξ The inhibitory effect of a test compound on recombinant human-derived DGKξ (Cama Biosciences, Inc., 12-410-20N) was examined using the following method in which detection is performed with an ADP-Glo™ kinase assay (Promega Corporation). In a 384-well plate (Greiner Bio-One Co., Ltd.), 3 pL of a DGKξ enzyme dissolved in buffer (Tris-HCl, 40 mM, pH = 7.5; MgCk, 10 mM; dithiothreitol (DTT), 1 mM; and bovine serum albumin (BSA), 0.1 mg / mL) (90 ng / mL) were added; then 3 pL of the test compound diluted with the same buffer were added to obtain a final intended concentration. The mixture was allowed to stand at room temperature for 15 minutes. Then, 3 pL of a substrate (1-oleoyl-2-acetyl-singleglycerol [Sigma-Aldrich Co. LLC.], 150 pM, phosphatidylserine [Avanti Polar Lipids, Inc.], 480 pM, and UltraPureATP, 150 pM [which comes with ADP-Glo]) were added, and the mixture was allowed to stand at room temperature for 30 minutes to react. Following this, 3 pL of an ADP-Glo ​​reagent were added, and the mixture was allowed to stand at room temperature for 40 minutes to stop the enzymatic reaction.In addition, 6 pL of a kinase detection reagent were added, the mixture was allowed to stand at room temperature for 30 minutes, and the luminescence was measured using an ARVO X3 instrument (PerkinElmer, Inc.). The semimaximal inhibitory concentration (ICso) was calculated using the Sigmoid-Emax model of nonlinear regression analysis, in which the signal value in the solvent treatment was set as 0% inhibition and the signal value without the addition of the DGKξ enzyme was set as 100% inhibition. Table 1 shows the results for some test compounds of formula (I). In the table, Ex represents the number of each example described below. Also in the table, compound C (cpd. C) represents the test compound of Example 199 described in International Publication WO 2008 / 054702. γαα / ηη / ζζηζ / Ε / γίΛΐ [Table 11 Ex IC50 (nM) Ex IC50 (nM) Ex IC50 (nM) Ex IC50 (nM) 1 3 23 10 45 24 67 12 2 53 24 11 46 40 68 5 3 20 25 42 47 147 69 13 4 50 26 46 48 8 70 7 5 48 27 90 49 10 71 44 6 3 28 42 50 23 72 18 7 110 29 426 51 16 73 0.7 8 9 30 39 52 23 74 41 9 8 31 23 53 27 75 6 10 8 32 31 54 17 76 6 11 19 33 5 55 99 77 2 12 17 34 12 56 29 78 5 13 13 35 2 57 240 79 47 14 13 36 13 58 144 80 0.7 15 7 37 26 59 2 81 152 16 41 38 3 60 3 82 3 17 13 39 7 61 3 83 5 18 19 40 50 62 10 84 6 19 15 41 11 63 429 85 15 20 44 42 23 64 30 86 3 21 6 43 36 65 12 87 20 22 5 44 19 66 32 cpd. C >2000 Example assay 2: Evaluation of !L-2 production in the Jurkat E6.1 cell line of human T-cell leukemia. The effect of the test compound on IL-2 production was evaluated by stimulation of the T cell receptor (TCR) (antl-CD3 / anti-CD28) in Jurkat E6.1 cells (ECACC, 88042803). pg / mL of anti-CD3 antibody (eBioscience, Inc., clone OKT3) diluted with phosphate-buffered saline (PBS) was added to a 96-well plate (Iwaki & Co., Ltd.) at a rate of 50 pL / well and allowed to stand at 4 °C for 12 hours or more to provide a pre-coated plate with anti-CD3 antibody. When the plate was used in experiments, it was washed once with 200 pL of PBS; An anti-CD28 antibody (eBioscience, Inc., clone 28.2) diluted to a concentration of 10 pg / mL was then added to a culture medium (RPMI1640 [Sigma-Aldrich Co. LLC.] containing 10% fetal bovine serum [Hyclone Laboratories, Inc.]) at a rate of 10 pL / well, and the plate was used for the assay as a TCR stimulation culture plate. Subsequently, the test compound was mixed with Jurkat E6.1 cells to achieve the intended final concentration, and the mixture was implanted at a rate of 90 pL / well, resulting in a cell density of 1 x 10⁵ cells per well (i.e., the final culture was performed at a density of 1 x 10⁵ cells / 100 pL / well). For cell culture, the culture was performed at 37 °C in the presence of 5% CO₂ using RPMI1640 culture medium containing 10% fetal bovine serum. After 24 hours, the culture supernatant was collected and a quantitative determination of IL-2 was performed using an AlphaLISA human IL-2 immunoassay research kit (PerkinElmer, Inc.). IL-2 determination was performed under standard AlphaScreen environment conditions (fluorescence intensity at 570 nm was measured with an excitation wavelength of 680 nm) using EnVision 2104-0010 and EnVision 2104-0020 instruments (PerkinElmer, Inc.). The quantitative IL-2 value for the solvent treatment control was set at 1, and the concentration of the test compound at which the quantitative IL-2 value of the test compound treatment sample increased to 10 times the quantitative IL-2 value of the control (ECiofoid) was calculated by inverse estimation using the Sigmoid-Emax model of nonlinear regression analysis. Table 2 shows the results for some test compounds of formula (I).In the table, Ex represents the number of each example described below. γαα / ηη / ζζηζ / Ε / γίΛΐ [Table 2] Ex ECiofoid (nM) 9 18 10 173 11 32 33 9 34 30 59 36 78 27 80 5 Example trial 3: Evaluation of the antineoplastic effect in a syngeneic mouse model carrying the MC38 cell line of colon adenocarcinoma in mice A liquid cell suspension, prepared by suspending MC38 cells (supplied by the U.S. National Cancer Institute) in PBS at a density of 4.0 x 10⁶ cells / mL, was inoculated into 6-week-old rats (C57BL / 6J, from Charles River Laboratories Japan, Inc.) in a volume of 50 pL. Four days post-inoculation, the rats were pooled so that there were no substantial differences in tumor volume between groups, and administration of the test compound was initiated. The assay was conducted with a solvent group and a test compound administration group, each containing 10 rats. The solvent group received 0.5% methylcellulose (Shin-Etsu Chemical Co., Ltd.) orally, and the test compound administration group received 0.5% methylcellulose mixed with the test compound orally.The medication was administered twice daily from day 1 to day 10 and once daily from day 11 onward. Tumor diameter and body weight were measured twice weekly. The following expression was used to calculate tumor volume. [tumor volume (mm3)] = [largest diameter of tumor (mm)] x [smallest diameter of tumor (mm)]2x 0.5 The relative inhibition of tumor growth (%) of the test compound was calculated, where the tumor volume of the test compound administration group immediately before the start of administration was set at 100% and the tumor volume of the solvent group on the last day of administration was set at 0% inhibition. Table 3 shows the results for some test compounds of formula (I). In the table, Ex represents the number of each example described below. prr ¡ ηη / ζζηζ / Ε / γίΛΐ [Table 31 Ex Dose (mg / kg) Antineoplastic effect 9 5 64% inhibition 10 4.7 60% inhibition 11 5 63% inhibition 33 5 36% inhibition 34 5 55% inhibition Example trial 4: Evaluation of the antineoplastic effect in a syngeneic mouse model carrying the B16-F1 cell lineage of melanoma in mice A liquid cell suspension, prepared by suspending B16-F1 cells (ATCC, CRL-6323) in PBS at a concentration of 2.0 x 10⁶ cells / mL or 1.0 x 10⁷ cells / mL, was inoculated into 5-week-old rats (C57BL / 6J, from Charles River Laboratories Japan, Inc.) in a volume of 50 pL. Five days post-inoculation, the rats were pooled so that there were no substantial differences in tumor volume between groups, and administration of the test compound was initiated. The assay was conducted with a solvent group and a test compound administration group, each containing 10 rats. The solvent group received 0.5% methylcellulose orally, and the test compound administration group received 0.5% methylcellulose mixed with the test compound orally. The administration was carried out according to the dosage regimen described in Table 4. The tumor diameter and body weight were measured twice a week.The following expression was used to calculate the tumor volume. [tumor volume (mm3)] = [largest diameter of tumor (mm)] x [smallest diameter of tumor (mm)]2x 0.5 The relative inhibition of tumor growth (%) of the test compound was calculated, where the tumor volume of the test compound administration group immediately before the start of administration was set at 100% and the tumor volume of the solvent group on the day after the last administration was set at 0% inhibition. Table 4 shows the results for some test compounds of formula (I). In the table, Ex represents the number of each example described below. γαα / ηη / ζζηζ / Ε / γίΛΐ [Table 41 Ex Dose (mg / kg) Administration Frequency Administration Duration (days) Number of cells for inoculation (number of cells) Antineoplastic effect 9 0.5 2 / day 10 5 x 10⁵ 36% inhibition 10 0.1 1 / day 8 1 x 10⁵ 42% inhibition 34 1.5 2 / day 10 5 x 10⁵ 48% inhibition 59 0.1 1 / day 8 1 x 10⁵ 46% inhibition 78 0.3 1 / day 10 1 x 10⁵ 30% inhibition 80 0.03 1 / day 10 1 x 10⁵ 30% inhibition The results of the previous assay demonstrated that some compounds of formula (I) had an inhibitory effect on DGKξ (Example Test 1). It was also confirmed that some compounds of formula (I) had the ability to produce IL-2 in the human T-cell leukemia cell line (Example Test 2). Furthermore, it was confirmed that some compounds of formula (I) had an antineoplastic effect in the murine model (Examples Test 3 and 4). In particular, it was confirmed that some compounds of formula (I) exhibited an antineoplastic effect in B16-F1 cell-bearing mice used in Example Test 4, even though it is generally known that anti-PD1 / anti-PD-L1 antibodies do not show pharmacological efficacy in B16-F1 cells. Therefore, the compound of formula (I) can be used for treatment, etc., of a cancer related to the activation of immune cells or a cancer resistant to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies, in particular a cancer related to the activation of immune cells, which offers resistance to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies, etc. A pharmaceutical composition containing one or more of the compounds of formula (I) or salts thereof as active ingredients may be prepared by a commonly used method with an excipient commonly used in the art, i.e., a pharmaceutical excipient, a pharmaceutical vehicle, or the like. Administration may be oral administration with tablets, pills, capsules, granules, powders, solutions or similar; or parenteral administration with injectable preparations for intra-articular injection, intravenous injection, intramuscular injection or similar; suppositories; eye drops; eye ointments; transdermal solutions; ointments; transdermal patches; transmucosal solutions, transmucosal patches, inhalation or similar. As a solid oral dosage form, a tablet, powder, granule, or similar product is used. In such a solid dosage form, one or more active ingredients are mixed with at least one inactive excipient. The composition may conventionally contain inactive additives, such as a lubricant, a disintegrant, a stabilizer, and a solubilizer. The tablet, powder, granule, or pill may be coated with a wax, a sugar coating, or a film of a substance soluble in the stomach or intestine. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs and contain a commonly used inactive diluent, such as purified water or ethanol. Such a liquid composition may contain adjuvants, such as a solubilizer, a wetting agent, a sweetener, a flavoring, a fragrance, and a preservative, in addition to the inactive diluent. The injectable preparation for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension, or emulsion. Examples of aqueous solvents include distilled water for injection and physiological saline solutions. Examples of non-aqueous solvents include alcohols such as ethanol. Such a composition may also contain a tonic, preservative, wetting agent, emulsifier, dispersant, stabilizer, or solubilizer. The composition is sterilized, for example, by filtration involving passage through a bacterial retention filter, the addition of a bactericide, or irradiation. Alternatively, a sterile solid composition may be prepared and dissolved or suspended in water or a sterile solvent for injection prior to use. External preparations include ointments, plasters, creams, gelatin preparations, poultices, sprays, lotions, drops, and ophthalmic ointments. External preparations may contain an ointment base, a lotion base, an aqueous or non-aqueous solution, a suspension, an emulsion, or similar substances, all of which are commonly used. A transmucosal preparation, such as an inhalation or nasal preparation, is liquid, solid, or semisolid and may be prepared according to a known conventional method. For example, a known excipient, pH regulator, preservative, surfactant, lubricant, stabilizer, thickener, and the like may be added to the transmucosal preparation, as appropriate. An appropriate inhalation or insufflation device may be used for administration. For example, using a known device, such as a metered-dose inhaler or spray, the compound may be administered alone, as a powder from a prescribed mixture, or as a liquid solution or suspension obtained by combining the compound with a pharmaceutically acceptable vehicle.The dry powder inhaler or similar device may be for single-dose or multi-dose administration, allowing the use of dry powder or a capsule containing powder, or it may be in the form of an aerosol using an appropriate ejection agent, for example, a suitable gas such as a chlorofluoroalkane or carbon dioxide. prr / nn / zznz / E / YiAi In general, for oral administration, the appropriate daily dose based on body weight is approximately 0.001 mg / kg to 100 mg / kg, preferably 0.1 mg / kg to 30 mg / kg, more preferably 0.1 mg / kg to 10 mg / kg, in a single dose or 2 to 4 divided doses. For intravenous administration, the appropriate daily dose based on body weight is approximately 0.0001 mg / kg to 10 mg / kg in a single dose or two or more divided doses. For transmucosal administration, the appropriate daily dose based on body weight is approximately 0.001 mg / kg to 100 mg / kg in a single dose or two or more divided doses. The dose is correctly determined taking into account the symptom, age, sex, and similar considerations. Depending on the route of administration, the pharmaceutical form, the site of administration, and the types of excipients and additives, the pharmaceutical composition according to the present invention contains one or more compounds of formula (I) or salts thereof as active ingredients in an amount of 0.01% by weight to 100% by weight, or from 0.01% by weight to 50% by weight in one modality. The compound of formula (I) may be used in combination with various therapeutic or prophylactic agents for diseases against which the compound of formula (I) may be effective. Combined use may be by simultaneous, separate, or sequential administration, or by administration at a desired interval. Preparations for simultaneous administration may be in the form of a combination preparation or may be separately formulated preparations. Examples From this point forward, the method for preparing the compound of formula (I) will be described in more detail by means of Examples. The present invention is not limited to the compounds described in the Examples. Methods for preparing compounds for use as raw materials will be demonstrated in the production examples. The method for preparing the compound of formula (I) is not limited to the specific methods in the Examples cited below, and the compound of formula (I) may also be prepared by a combination of these production methods or by methods obvious to those skilled in the art. In this description, software for generating names, such as ACD / Name (registered trademark) (Advanced Chemistry Development, Inc.) may be used to name a compound. For convenience, “mol / L” as a unit of concentration is represented by “M”. For example, a 1 M aqueous solution of sodium hydroxide means an aqueous solution of sodium hydroxide at 1 mol / L. In the present description, the results of the powder X-ray diffraction test were determined using an Empyrean instrument under the following conditions: tube: Cu; tube current: 40 mA; tube voltage: 45 kV; step amplitude: 0.013°; wavelength: 1.5418 A; diffraction angle measurement range (2Θ): 2.5 - 40°. Preparation example 1 To a mixture of 2-bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (15 g), phenol (4.91 g), and NMP caa / nn / zznz / E / YiAi (150 mL), K₂CO₃ (14.4 g) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled to room temperature; then EtOAc and water were added, and the aqueous layer separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried with MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain 2-bromo-1-nitro-4-phenoxy-3-(trifluoromethyl)benzene (18.4 g). Preparation example 13 To a mixture of 2-chloro-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (4.3 g), 1-(tert-butoxycarbonyl)1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-1)pyridine (4.5 g), Pd(dppf)Cl2CH2Cl2 (590 mg), and K2CO3 (4 g), 1,4-dioxane (45 mL) and water (9 mL) were added. The reaction mixture was stirred in an argon atmosphere at 100 °C for 20 hours. The reaction mixture was cooled to room temperature; then EtOAc and water were added, and the resulting mixture was filtered through Celite and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl 4-[3-fluoro-6-nitro-2-(trifluoromethyl)phenyl]-3,6-dihydropyridin-1 (2H)carboxylate (4.65 g). Preparation example 16 Under a nitrogen atmosphere, PdCl2(PPh3)2 (487 mg) was added to a mixture of 2-bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (2 g), {[(3R)-piperidin-3-1]methyl}carbamate (1.63 g), K2OO3 (2.87 g), and 1,4-dioxane (20 mL). The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature; water was then added, the resulting mixture was extracted with EtOAc, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl ({(3S)-1 -[3-fluoro-6-nitro-2-(trifluoromethyl)phenyl]p¡per¡n-3yl}methyl)carbamate (1.70 g) as a solid. Preparation example 17 A mixture of 4.6 g tert-butyl 4-[3-fluoro-6-nitro-2-(trifluoromethyl)phenyl]-3,6-dihydropyridin-1(2H)-carboxylate (4.6 g), phenol (1.3 g), and NMP (23 mL) was mixed with sodium hydride (60% oil dispersion, 570 mg) under ice-cooled conditions. The resulting mixture was stirred under ice-cooled conditions and then in an argon atmosphere for 1 hour. Under ice-cooled conditions, water was added, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl 4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]-3,6-dihydropyridine-1 (2H)-carboxylate (5.18 g). Example of preparation 21 Under ice-cooled conditions, tert-butyl (300 mg) tert-butyl (3S)-1-[3-fluoro-6-nitro-2-(tnfluoromethyl)phenyl]pyridine-3-methyl)carbamate was added to a mixture of cyclopropanol (0.10 mL), NaO₂ (205 mg), and DMF (6 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with water, the mixture was extracted with EtOAc, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain (3S)-1 paa / ηη / ζζηζ / E / γίΛΐ [3-(cyclopropyloxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)tert-butyl carbamate (250 mg) as a solid. Example of preparation 30 A mixture of 30 mL of 4 M HCl / 1,4-dioxyethanol was added to a mixture of 3S)-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]piperidin-1-carboxylate (8.106 g) and ethanol (60 mL). The reaction mixture was stirred at room temperature for 11 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized with ethanol and diethyl ether. The crystallized solid was extracted by filtration and washed with diethyl ether. The solid obtained by filtration was dried under reduced pressure to obtain 2-{[(3R)-piperidin-3-yl]methyl}-1H-isoindol-1,3(2H)-dione monohydrochloride (5.695 g) as a solid. Preparation example 31 To a mixture of [(3S)-1-(tert-butoxycarbonyl)piperidin-3-yl]acetic acid (2.9 g) and NH4Cl (960 mg) were added CH2Cl2 (24 mL), water (12 mL), WSC.HCl (2.5 g), TEA (5.8 mL), and HOBt (1.8 g). The reagent mixture was stirred overnight at room temperature. 1 M hydrochloric acid was added to the reagent mixture until a pH of 2 to 3 was reached; the mixture was then extracted using an ISOLUTE phase separator (registered trademark). The separated organic layer was washed with saturated aqueous NaHCO3 solution and concentrated under reduced pressure to obtain tert-butyl (3S)-3-(2-amino-2-oxoethyl)piperidin-1-carboxylate (2.7 g). Example preparation 32 To a mixture of (3S)-3-(2-amino-2-oxoethyl)piperidin-1-tert-butyl carboxylate (335 mg) and THF (7 mL) lithium aluminum hydride (130 mg) was added under ice-cold conditions. The reaction mixture was stirred overnight at room temperature. Under ice-cold conditions, water (130 mL), 1 M aqueous sodium hydroxide solution (130 mL), and water (390 mL) were added; the resulting mixture was then diluted with 10% methanol in CH₂Cl₂ and stirred at room temperature for 1 hour. After the insoluble material was removed by filtration through Celite, the filtrate was concentrated under reduced pressure. CH₂Cl₂ (4 mL) and DIPEA (360 mL) were added to the residue at room temperature; then TFAA (240 mL) was added under ice-cold conditions. The reaction mixture was stirred overnight at room temperature. Saturated aqueous NH4Cl solution was added.The resulting mixture was extracted using an ISOLUTE phase separator (registered trademark) and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl (3S)-3-[2-(2,2,2-trifluoroacetamide)ethyl]piperidin-1-carboxylate (139 mg). Preparation example 33 A mixture of (3S)-3-[2-(2,2,2-trifluoroacetamide)ethyl]pyridinium-1-carboxylate (137 mg) and ethyl ether (1 mL) was mixed with 4 M HCl / 1,4-dioxane solution (1 mL) at room temperature. The reagent mixture was stirred overnight. The reagent mixture was concentrated under reduced pressure to obtain 2,2,2-trifluoro-N-{2-[(3S)-pyridinium-3-ethyl]acetamide monohydrochloride (117 mg). Preparation example 34 To a mixture of 2-bromo-1-nitro-4-phenoxy-3-(trifluoromethyl)benzene (4.15 g) and 1,4-dioxane (60 mL) were added DIPEA (3 mL) and {[(3R)-piperidin-3-yl]methyl}carbamate (3 g). The reagent mixture was stirred overnight at 100 °C. The reagent mixture was cooled to room temperature; then water was added and the resulting mixture was extracted with EtOAc. The extract was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain ({(3S)-1-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-methyl)carbamate of tert-butyl (4.87 g). Example of preparation 60 Under an argon atmosphere, a mixture of tert-butyl (3{(3S)-1-[3-(2-fluorophenoxy)-6-nitro-2(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (3.5 g), iodomethane (860 mL), and DMF (35 mL) was reacted with sodium hydride (60% oil dispersion, 410 mg) in four parts under ice-cooled conditions. The reaction mixture was stirred at room temperature for 3 hours. Under ice-cooled conditions, the reaction was quelled with water. The mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain ({(3R)-1 -[3-(2fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)(methyl)carbamate tert-butyl (3.44 g) as a solid. Example of preparation 68 Dess-Martin reagent (120 mg) was added to a mixture of (2R)-2-(hydroxymethyl)-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]perazin-1-butyl carboxylate (110 mg) and CH2Cl2 (2 mL) under ice-cooled conditions. The reagent mixture was stirred at room temperature for 1 hour. An additional 120 mg of Dess-Martin reagent was added, and the resulting mixture was stirred at room temperature for 30 minutes. A 10% aqueous sodium sulfite solution and a saturated aqueous NaHCO3 solution were added to the reagent mixture under ice-cooled conditions. The resulting mixture was stirred at room temperature for 30 minutes and extracted using an ISOLUTE phase separator (registered trademark). The extract was concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl (2R)-2-formyl-4[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazin-1-carboxylate (86 mg). Preparation example 69 A solution of 2 M / THF methylamine solution (170 pL), acetic acid (20 pL), and NaBH(OAc)3 (75 mg) was added to a solution of (2R)-2-formyl-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazin-1-tert-butyl carboxylate (84 mg) in CH2&2 (1 mL). The reagent mixture was stirred at room temperature for 2 hours. Saturated aqueous NaHCO3 solution was then added to the reagent mixture. The resulting mixture was extracted using an ISOLUTE phase separator (registered trademark) and the extract was concentrated under reduced pressure to obtain (2S)-2-[(methylamino)methyl]-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazin-1-tert-butyl carboxylate (93 mg). Example of preparation 70 To a mixture of tert-butyl (2S)-2-[(methylamino)methyl]-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]perazin-1-carboxylate (93 mg) and CH2Cl2 (1 mL) DIPEA (50 pL) and TFAA (35 pL) were added under ice-cooled conditions. The reagent mixture was stirred at room temperature for 1 hour. Saturated aqueous NH4Cl solution was then added to the reagent mixture. The resulting mixture was extracted using an ISOLUTE phase separator (registered trademark) and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain tert-butyl (2R)-2-{[methyl(trifluoroacetyl)amino]methyl}-4-[6-nitro-3-phenoxy-2(trifluoromethyl)phenyl]perazin-1-carboxylate (81 mg). Preparation example 71 To a mixture of tert-butyl (2R)-2-formyl-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazin-1-carboxylate (1.04 g) and CELCb^0 mL, o-benzylhydroxylamine (320 mL), acetic acid (180 mL), and NaBH(OAc)s (670 mg) were added. The resulting mixture was stirred overnight at room temperature. Sodium cyanoborohydride (200 mg) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (200 mg) was added again, and the resulting mixture was stirred overnight at room temperature. Methanol (3 mL) was added, and the resulting mixture was stirred overnight. Saturated aqueous NaHCO3 solution was added. The resulting mixture was stirred at room temperature for 1 hour, extracted using an ISOLUTE phase separator (registered trademark), and the extract was concentrated under reduced pressure.The residue was dissolved in CELCLUO mL and DIPEA (720 pL) was added; then TFAA (450 pL) was added under ice-cooled conditions. The reagent mixture was stirred at room temperature for 30 minutes. Saturated aqueous NH4Cl solution was added. The resulting mixture was extracted using an ISOLUTE phase separator (registered trademark) and the extract was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Hex / EtOAc) to obtain tert-butyl (2R)-2-{[(benzyloxy)amino]methyl}-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]perazin-1-carboxylate (426 mg). Example of preparation 72 To a mixture of {(2R)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phen]pyrrolidine-2-1}methanol (510 mg) and CH2Cl2 (5 mL) pyridine (310 pL) and acetic anhydride (360 pg) were added under ice-cooled conditions. The resulting mixture was stirred overnight at room temperature. Saturated aqueous NH4Cl solution was added. The resulting mixture was extracted using an ISOLUTE phase separator (registered trademark) and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain {(2R)-1-[3-(2fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]pyrrolidine-2-yl}methyl acetate (170 mg). Preparation example 73 Hydrazine monohydrate (110 mL) was added to a mixture of 2-{[(3R)-1-(2,4-difluoro-6-nitro-3-phenoxyphenyl)piperidin-3-1]methyl}-1H-isoindole-1,3(2H)-dione (0.376 g) and MeOH (5 mL). The reaction mixture was stirred under reflux for 3 hours. The reaction mixture was cooled to room temperature; then poured into 5% aqueous sodium hydroxide solution, and the resulting mixture was extracted with chloroform. The organic layer was separated, the aqueous layer was extracted with chloroform, and the combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to obtain 1-[(3S)-1-(2,4-difluoro-6-nitro-3-phenoxyphenyl)piperidin-3-1]methanamine (0.266 g). paa / ηη / ζζηζ / Ε / γίΛΐ Example of preparation 75 To a mixture of 1-[(3S)-1-(2,4-difluoro-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methanamine (0.266 g), CH2Cl2 (5 mL), and TEA (153 pL), di-tert-butyl dicarbonate (202 pL) was added. The reaction mixture was stirred at room temperature for 63 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain {[(3S)-1-(2,4-difluoro-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methyl}carbamate (0.294 g). Preparation example 77 To a mixture of ({(3S)-1-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-1}methyl)carbamate tert-butyl (4.85 g), 1,4-dioxane (150 mL), and water (30 mL) were added zinc powder (6.4 g) and NH4Cl (5.24 g) under ice-cooled conditions. The reaction mixture was stirred at room temperature for 3 hours; then, the insoluble substances were separated by filtration through Celite. The resulting filtrate was concentrated under reduced pressure; saturated aqueous NaHCO3 solution was then added to the residue, and the resulting mixture was extracted with chloroform. The extract was dried over MgSO4 and then concentrated under reduced pressure to obtain tert-butyl ({(3S)-1-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (4.56 g). Example of preparation 122 To a mixture of tert-butyl (2R)-2-{[(benzyloxy)amino]methyl}-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazin-1-carboxylate (424 mg), EtOAc (2 mL), and ethanol (2 mL), palladium hydroxide on 10% hydrated carbon (100 mg) was added in a nitrogen atmosphere, which was then replaced by a hydrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. After replacement with a nitrogen atmosphere, the reactive mixture was diluted with EtOAc, filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain tert-butyl (2S)-2-(aminomethyl)-4-[6-amino-3-phenoxy-2(trifluoromethyl)phenyl]perazin-1-carboxylate (347 mg). Example of preparation 123 To a mixture of tert-butyl (2S)-2-(aminomethyl)-4-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]piperazin-1-carboxylate (345 mg) and methanol (2 mL) ethyl trifluoroacetate (110 mL) was added. The reagent mixture was stirred overnight at room temperature. The reagent mixture was concentrated under reduced pressure to obtain tert-butyl (2S)-4-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]-2-[(2,2,2-trifluoroacetamide)methyl]piperazin-1-carboxylate (380 mg). Example of preparation 124 To a mixture of {(3S)-1-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-methyl)carbamate tert-butyl (4.56 g) and DMF (50 mL) were added 2-(pyridazin-4-yl)-1,3-thiazol-4-carboxylic acid (2.23 g), DIPEA (3 mL), and HATU (4.5 g). The resulting mixture was stirred overnight at 50 °C. The reaction mixture was cooled to room temperature; then water was added under ice-cooling conditions, and the solid precipitate was extracted by filtration. The resulting solid was dissolved in chloroform, water was added, and the resulting mixture was extracted with chloroform. The extract was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography caa i ηη / ζζηζ / E / γίΛΐ (Hex / EtOAc) to obtain {[(3S)-1-{3-phenoxy-6-[2-(pyridazin-4-1l)-1,3-thiazol-4-carboxamide]-2(trifluoromethyl)phenyl}piperidin-3-1l]methyl}carbamate of tert-butyl (5.85 g) as a solid. Preparation example 172 To a mixture of {(2R)-1-[3-(2-fluorophenoxy)-6-{[2-(pyridazin-4-yl)-1,3-thiazol-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]pyrrolididin-2-yl}methyl acetate (194 mg) and methanol (1 mL) were added water (0.1 mL) and K2CO3 (135 mg). The reagent mixture was stirred overnight at room temperature. The reagent mixture was diluted with EtOAc, filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain N-[4-(2-fluorophenoxy)-2-[(2R)-2-(hydroxymethyl)pyrrolididin-1-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (200 mg). Preparation example 173 Dess-Martin reagent (220 mg) was added to a mixture of N-[4-(2-fluorophenoxy)-2-[(2R)-2-(hydroxymethyl)pyrrolidine-1-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (198 mg) and CH₂Cl₂ (2 mL) under ice-cooled conditions. The reagent mixture was stirred at room temperature for 1 hour. A 10% aqueous sodium sulfite solution and a saturated aqueous NaHCO₃ solution were then added to the reagent mixture under ice-cooled conditions. The resulting mixture was stirred at room temperature for 30 minutes. The reagent mixture was extracted using an ISOLUTE phase separator (registered trademark), and the extract was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform / methanol) to obtain N-[4-(2-fluorophenoxy)-2-[(2R)-2-formylpyrrolidin-1-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (112 mg). Preparation example 174 A mixture of ({(3S)-1-[3-hydroxy-6-{[2-(pyridazin-4-1)-1,3-thazol-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]pyridine-3-1}methyl)carbamate of tert-butyl (0.075 g), CH2Cl2 (4.5 mL), and pyridine (50 pL) was treated with trifluoromethanesulfonic anhydride (52 pL) under ice-cooled conditions. The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with CH2Cl2. The organic layer was washed with 10% hydrochloric acid, water, and brine, then dried over NapSCL and concentrated under reduced pressure. Trifluoromethanesulfonic anhydride (64 pL) was added to a mixture of the residue and pyridine (2.6 mL) under ice-cooled conditions. The reaction mixture was stirred at room temperature for 13 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with EtOAc.The organic layer was washed with 10% hydrochloric acid, water and brine, then dried over Na2SO4 and concentrated under reduced pressure to obtain 3-[(3S)-3-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl]-4-{[2-(pyridazin-4-yl)1,3-thiazol-4-carbonyl]amino}-2-(trifluoromethyl)phenyl trifluoromethanesulfonate (0.103 g). Example of preparation 175 Under an argon atmosphere, a mixture of K2CO3 (0.030 g), phenylboronic acid (0.027 g), and Pd(PPha)4 (0.017 g) was mixed with a mixture of 3-[(3S)-3-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl]-4-{[2-(pyridazin-4-yl)-1,3-thiazol-4-carbonyl]amino}-2(trifluoromethyl)phenyl trifluoromethanesulfonate (0.103 g) and THF (2.5 mL); then, water (0.5 mL) was added. The reagent mixture was stirred between 110 °C and 130 °C for 8 hours. The reagent mixture was cooled to room temperature; then it was poured into water, and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl ({(3S)-1-[4-{[2-(pyridazin-4-yl)-1,3-thiazol-4-carbonyl]amino}-2-(trifluoromethyl)[1,1'-biphenyl]-3-yl]piperidin-3-yl}methyl)carbamate (0.067 g). Example of preparation 176 A mixture of 4 M HCl / 1,4-dioxane solution (10 mL) was added to a mixture of 4-[3-phenoxy-6-{[2-(pyridazin-4-yl)-1,3-thiazol-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]3,6-dihydropyridin-1(2H)-carboxylate (2.4 g) and methanol (24 mL). The reagent mixture was stirred at room temperature for 19 hours. The reagent mixture was concentrated under reduced pressure; saturated aqueous NaHCO3 solution was added to the residue, and the resulting mixture was extracted with a solvent mixture (chloroform / methanol). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain N-[4-phenoxy-2-(1,2,3,6-tetrahydropyridin-4-11)-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-11)-1,3-thiazol-4-carboxamide (1.57 g) as a solid. Example of preparation 182 A mixture of N-{2-[(3R)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin4-11)-1,3-thiazol-4-carboxamide (63 mg) and CH2CI2 (1 mL) was mixed with DIPEA (30 pL) and 2-nitrobenzenesulfonyl chloride (30 mg) under ice-cold conditions. The reaction mixture was stirred for 1 hour under ice-cold conditions. Saturated aqueous NH4Cl solution was added. The resulting mixture was extracted using an ISOLUTE phase separator (registered trademark) and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain N-{2-[(3S)-3-{[(2-nitrobenzene-1 -su Ifoni I) am i no] metí I} piperidi n -1 -yl]-4phenoxy-3-(trifluoromethyl)phen¡l}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (94 mg). Example of preparation 185 To a mixture of N-{2-[(3S)-3-{[(2-nitrobenzene-1-sulfonyl)amino]methyl}pyridine-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (90 mg) and MeCN (1 mL) methyl iodide (25 mL) and cesium carbonate (45 mg) were added at room temperature. The reagent mixture was stirred at room temperature for 30 minutes. EtOAc was added, the resulting mixture was filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain N-{2-[(3S)-3-{[methyl(2-nitrobenzene-1sulfonyl)amino]methyl}piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (83 mg). Example of preparation 190 A mixture of N-{2-[(3R)-3-{[methyl(trifluoroacetylamino]methyl}piperazin-1-yl]-4-phenoxy-3(trifluoromethyl)phenyl}-2-(pyridazi-4-1L)-1,3-thiazol-4-carboxamide (40 mg) and CH2Cl2 (1 mL) was mixed with 35% aqueous formaldehyde solution (10 mL), acetic acid (5 mL), and NaBH(OAc)3 (20 mg). The reaction mixture was stirred overnight at room temperature. Saturated aqueous NaHCO3 solution was then added to the reaction mixture. The resulting mixture was stirred for 10 minutes, extracted using an ISOLUTE phase separator (registered trademark), and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc with aminosilica gel) to obtain N-{2-[(3R)-4-methyl-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (36 mg). Example of preparation 192 To a mixture of sodium hydride (60% oil dispersion, 0.208 mg) and THF (5 mL), thiophenol (0.38 g) was added at -78 °C. The reaction mixture was stirred at -78 °C for 15 minutes. 2-bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (1.00 g) was added, and the reaction mixture was stirred at -78 °C for 15 minutes. A saturated aqueous solution of NH4Cl was added, and the resulting mixture was extracted three times with EtOAc. The combined organic layer was dried over NaaSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to yield 2-bromo-1-nitro-4-(phenylsulfanyl)-3-(trifluoromethyl)benzene (0.50 g). Example of preparation 193 Under an argon atmosphere, potassium nitrate (0.84 g) was added to a mixture of 1,3-difluoro-2-(methanesulfonyl)benzene (1.60 g) and concentrated sulfuric acid (12 mL) under ice-cooled conditions. The reaction mixture was stirred at room temperature for 2 hours. The mixture was then poured into ice-cold water, and the resulting solid precipitate was extracted by filtration. The solid was dissolved in EtOAc, washed with saturated aqueous NaHCO3 solution, and dried over Na2SO4. The residue was concentrated under reduced pressure to obtain 1,3-difluoro-2-(methanesulfonyl)-4-nitrobenzene (1.80 g) as a solid. Example of preparation 194 A mixture of 4-amino-3-fluoro-2-(trifluoromethyl) benzoate (1.30 g) and THF (15 mL) was added dropwise to 30% hydrogen peroxide solution (5 mL) under ice-cooled conditions. The reaction mixture was stirred at room temperature for 5 minutes and then at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, then poured into ice water, and the resulting mixture was extracted twice with EtOAc. The combined organic layers were washed with water and dried over Na₂SO₄. The residue was concentrated under reduced pressure to obtain 3-fluoro-4-nitro-2-(trifluoromethyl) benzoate (1.20 g) as a solid. Example of preparation 195 To a mixture of 3-fluoro-4-nitro-2-(trifluoromethyl)benzoic acid (1.20 g) and CH₂Cl₂ (30 mL), oxalyl chloride (2.03 mL) was added dropwise under ice-cooled conditions, and a catalytic amount of DMF was added. The reaction mixture was stirred for 1 hour under ice-cooled conditions and then concentrated under reduced pressure. The residue was dissolved in benzene (15 mL), aluminum chloride (1.26 g) was added for at least 5 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured onto ice and extracted three times with EtOAc. The combined organic layers were dried over Na₂SO₄ and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain [3-fluoro-4-nitro-2(trifluoromethyl)phenyl](phenyl)methanone (0.80 g) as a solid. Example of preparation 196 A mixture of (8S)-8-hydroxyhexahydropyrrolo[1,2-a]pyrazin-1,4-dione (3.250 g), DMF (48 mL), and imidazole (3.972 g) was mixed with tert-butylchlorodiphenylsilane (10.0 mL). The reagent mixture was stirred at room temperature for 23 hours. The reagent mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over NaaSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / MeOH) to obtain (8S,8aS)-8-{[ferf-butyldi(phenyl)sil¡l]oxy}hexah¡dropyrrolo[1,2-a]pyrazin-1,4-dione (1.786 g) as a less polar substance and (8S,8aR)-8-{[tert-butyldi(phenyl)sil¡l]oxy¡}hexah¡dropyrrolo[1,2-a]pyrazin-1,4-dione (1.164 g) as a more polar substance. Example of preparation 197 A mixture of lithium aluminum hydride (0.594 g) and THF (40 mL) was mixed with a solution of (8S,8aR)-8-{[tert-butyldi(phenyl)sil]oxy}hexahydropyrrolo[1,2-a]pyrazin-1,4-dione (1.164 g) in THF (10 mL). The reaction mixture was stirred under reflux by heating for 17 hours. The reaction suspension was cooled to room temperature, and a mixture of water (0.7 mL) and THF (7.7 mL) and 4 N aqueous sodium hydroxide (0.7 mL) was added. Na₂SO₄ was added to the resulting mixture, which was stirred at room temperature for 3 hours and filtered through Celite. The filtrate was concentrated under reduced pressure to obtain (8S,8aS)-octahydropyrrolo[1,2-a]pyrazin-8-ol (0.972 g). Example of preparation 216 Under an argon atmosphere, a mixture of (8S,8aS)-2-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-ol (0.375 g), THF (6 mL), benzoic acid (0.119 g), and triphenylphosphane (0.349 g) was treated with diisopropyl azodicarboxylate (262 mL) under ice-cooled conditions. The reaction mixture was allowed to slowly reach room temperature and was stirred for 15 hours. The reactive mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain (8R,8aS)-2-[6-nitro-3-phenoxy-2(trifluoromethyl)phenyl]octahydropyrrolo[ 1,2-a]pyrazin-8-1-benzoic acid (0.518 g). Example of preparation 220 Under an argon atmosphere, palladium acetate (24 mg) was added to a mixture of {[(3S)-1-(2-bromo-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methyl}carbamate (550 mg), cyclopropylboronic acid (112 mg), tricyclohexylphosphane (30 mg), toluene (9 mL), and water (1 mL). The reagent mixture was stirred at 110 °C for 4 hours with microwave irradiation. The reagent mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain {[(3S)-1-(2-cyclopropyl-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methyl}carbamate (280 mg). Example of preparation 221 Under an argon atmosphere, a mixture of (8S,8aS)-2-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-ol (0.233 g), THF (4 mL), phthalimide (0.090 g), and triphenylphosphane (0.173 g) was mixed with diisopropyl azodicarboxylate (0.13 mL) under ice-cooled conditions. The reaction mixture was allowed to cool slowly to room temperature and stirred for 15 hours. Triphenylphosphane (0.173 g) and diisopropyl azodicarboxylate (0.13 mL) were added to the reaction mixture under ice-cooled conditions. The reaction mixture was then allowed to cool slowly to room temperature and stirred for 8 hours. The reactive mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Hex / EtOAc) caa / ηη / ζζηζ / E / γίΛΐ to obtain 2-{(8R,8aS)-2-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-yl}-1 Hisoindol-1,3(2H)-dione (0.214 g). Example of preparation 271 To a mixture of {[(3S)-1-{6-[(2-bromo-1,3-thiazol-4-carbonyl)amino]-3-(phenylsulfanyl)-2-(trifluoromethyl)phenyl}piperidin-3-yl]methyl}carbamate tert-butyl (300 mg) and CH2Cl2 (5 mL) m-Chloroperbenzoic acid (water content: 40%, 385 mg) was added under ice-cooled conditions. The reaction mixture was stirred at room temperature for 12 hours. The reaction was deactivated with a saturated aqueous solution of sodium thiosulfate and extracted twice with CH2Cl2. The combined organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain ({(3S)-1-[3-(benzenesulfonyl)-6-[(2-bromo-1,3-thiazol-4-carbonyl)amino]-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)feri-butyl carbamate (200 mg). Example of preparation 272 In an argon atmosphere, Pd(PPh3)4 (33 mg) was added to a mixture of {(3S)-1-[3-(benzenesulfonyl)-6-[(2-bromo-1,3-thiazol-4-carbonyl)amino]-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (200 mg), 4-(tributylstannyl)pyridazine (115 mg), and toluene (10 mL). The reagent mixture was stirred at 100 °C for 24 hours. The reagent mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain ({(3S)-1-[3-(benzenesulfonyl)-6-{[2-(pyridazin-4-yl)-1,3-thiazol-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl) tert-butyl carbamate (100 mg). The compounds shown in Tables 5-1 through 5-35 below were prepared in the same manner as in the production methods of the Production Examples described above. Tables 5-1 through 5-35 below show the structures of the compounds from the Production Examples, and Tables 6-1 through 6-12 show the preparation methods and physicochemical data for these compounds. These compounds can be readily prepared using the production methods of the Production Examples above, which are obvious to those skilled in the art, or by methods modified from them. Example 1 A mixture of N-[2-(1-oxa-4,9-diazaspiro[5,5]undecan-4-yl)-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (93 mg) and CH2Cl2 (1 mL) was mixed with 35% aqueous formamide solution (50 mL), acetic acid (40 mL), and NaBH(OAc)3 (100 mg). The reagent mixture was stirred at room temperature for 1 hour. Saturated aqueous NaHCO3 solution was then added to the reagent mixture. The resulting mixture was stirred for 10 minutes, extracted using an ISOLUTE phase separator (registered trademark), and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily substance. The oily substance was solidified with MeCN, extracted by filtration, and dried under reduced pressure to obtain N-[2-(9-methyl-1-oxa-4,9-diazaespiro[5.5]undecan-4-1)-4-phenoxy-3-(trifluoromethyl)phen]-2prr i ​​nn / zznz / E / YiAi (pyridazin-4-1)-1,3-thiazol-4-carboxamide (72 mg) as a solid. Example 6 To a mixture of N-{2-[(3R)-4-methyl-3-{[methyl(tnfluoroacetyl)amino]methyl}pyrazin-1-1]-4-phenoxy-3(trifluoromethyl)phenyl}-2-(pyridazin-4-1)-1,3-thiazol-4-carboxamide (35 mg) and methanol (0.5 mL) were added K₂CO₃ (15 mg) and water (0.1 mL). The reagent mixture was stirred at room temperature for 1.5 hours. The reagent mixture was diluted with EtOAc, filtered through Celite, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol / aqueous ammonia). The resulting crude product was solidified with ethyl ether and the resulting solid substance was extracted by filtration and dried at 50 °C under reduced pressure to obtain N-[2-{(3S)-4-methyl-3[(methylamino)methyl]pyrazin-1-yl}-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (17 mg) as a solid. Example 9 To a mixture of {[(3S)-1,3-phenoxy-6-[2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide]-2-(trifluoromethyl)phenyl}piperidin-3-yl]methyl}carbamate (5.83 g) and CH₂Cl₂ (60 mL) TFA (7 mL) was added under ice-cooled conditions. The reagent mixture was stirred overnight at room temperature. The reagent mixture was concentrated under reduced pressure, diluted with CFLCl, and then neutralized by adding a saturated aqueous solution of NaHCO₃ under ice-cooled conditions. The resulting mixture was extracted with chloroform, and the extract was dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol / aqueous ammonia). The resulting solid substance was washed with ethyl ether to obtain N-{2-[(3S)-3-(aminomethyl)pyridine-1-1l]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-1l)-1,3-thiazol-4-carboxamide (3.52 g) as a solid. Example 49 Thioglycolic acid (60 μL) and lithium hydroxide monohydrate (60 mg) were added to a mixture of N-{2-[(3R)-3-{[methyl(2-nitrobenzen-1-sulfonyl)am i no] methyl 1Jpiperidin-1-yl]-4-phenoxy-3(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (202 mg) and DMF (1 mL). The reagent mixture was stirred at 70 °C for 15 minutes. The reagent mixture was cooled to room temperature; then, CH2Cl2 and saturated aqueous NaHCO3 solution were added. The resulting mixture was stirred and extracted using an ISOLUTE phase separator (registered trademark), and the extract was concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc / chloroform) to obtain an oily substance. The oily substance was solidified with MeCN, extracted by filtration, and then dried under reduced pressure to obtain N-[2-{(3S)-3-[(methylamino)methyl]pyridine-1-yl}-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (29 mg) as a solid. paa / nn / zz / E / yLi Example 54 A mixture of N-{2-[(3R)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin4-11)-1,3-tlazol-4-carboxamide (83 mg) and CH2Cl2 (1 mL) was mixed with 35% aqueous formaldehyde solution (50 mL), acetic acid (35 mL), and NaBH(OAc)s (100 mg). The reaction mixture was stirred at room temperature for 1 hour. Saturated aqueous NaHCO3 solution was then added. The resulting mixture was stirred at room temperature for 10 minutes, extracted using an ISOLUTE phase separator (registered trademark), and the extract was concentrated under reduced pressure.The resulting residue was purified by silica gel chromatography (chloroform / methanol), the resulting substance was dissolved in EtOAc, then a 4 M HCl / EtOAc solution (120 pL) was added and the precipitated solid substance was extracted by filtration and dried at 50 °C under reduced pressure to obtain N-[2-{(3R)-3[(dimethylamino)methyl]piperidin-1 -yl}-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide dihydrochloride (71 mg) as a solid. Example 59 To a mixture of N-[2-(1-oxa-4,9-diazaspiro[5,5]undecan-4-yl)-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (100 mg) and MeCN (1 mL) were added DIPEA (35 pL) and 1-bromo-2-methoxyethane (20 pL). The reagent mixture was stirred at 100°C for 1 hour under microwave irradiation. The reagent mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and diluted with EtOAc. 4 M HCl / 1,4-dloxane solution (130 pL) was added at room temperature, and the resulting mixture was stirred at room temperature for 10 minutes. The precipitated solid was extracted by filtration and dried under reduced pressure to obtain N-{2-[9-(2-methoxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-4phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide dihydrochloride (67 mg) as a solid. Example 62 To a mixture of N-[2-(1-oxa-4,9-diazaspiro[5,5]undecan-4-1)-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-1)-1,3-thiazol-4-carboxamide (150 mg) and CH2Cl2 (1 mL) were added 3-oxethanone (60 mg), acetic acid (45 mL), and NaBH(OAc)3 (160 mg) at room temperature. The reaction mixture was stirred overnight. Saturated aqueous NaHCO3 solution was added. The resulting mixture was stirred at room temperature for 30 minutes, extracted using an ISOLUTE phase separator (registered trademark), and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain an oily substance. The oily substance was solidified with EtOAc, Hex and diisopropyl ether, extracted by filtration and then dried under reduced pressure to obtain N-{2-[9-(oxetan-3-1l)-1-oxa-4,9-diazaespiro[5.5]undecan-4-1l]-4-phenoxy-3-(trifluoromethyl)phenyl}-2(pyridazin-4-1l)-1,3-thiazol-4-carboxamide (99 mg) as a solid. Example 63 A mixture of N-[4-(2-fluorophenoxy)-2-[(2R)-2-formylpyrrolidine-1-11]-3-(trifluoromethyl)phenyl]-2-caa / nn / zznz / E / YiAi (pyridazin-4-yl)-1,3-thiazol-4-carboxamide (60 mg) and CH2CI2 (0.5 mL) was mixed with 3-oxethanamine (25 mg), acetic acid (20 mL), and NaBH(OAc)3 (70 mg). The reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous NaHCO3 solution was added. The resulting mixture was stirred at room temperature for 30 minutes, extracted using an ISOLUTE phase separator (registered trademark), and the extract was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform / methanol) to obtain an oily substance. Ethyl ether was added to the resulting oily substance and the resulting mixture was concentrated under reduced pressure to obtain N-[4-(2-fluorophenoxy)-2-[(2R)-2-{[(oxetan-3-1l)amino]methyl}pyrrolidine-1-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-1l)-1,3-thiazol-4-carboxamide (20 mg) as a solid. Example 64 A mixture of 2-bromo-1-nitro-4-phenoxy-3-(trifluoromethyl)benzene (10.9 mg), tert-butyl methyl[(piperidin-3-yl)methyl]carbamate (20.7 mg), DIPEA (20 µL), and NMP (250 µL) was stirred overnight at 120 °C. The reagent mixture was cooled, PS-isosocyanate (150 mg) and chloroform (1 mL) were added, and the reagent mixture was stirred overnight. Insoluble substances were then separated by filtration, and the filtrate was concentrated under reduced pressure. Ethanol (0.8 mL), water (0.2 mL), NH₄Cl (0.8 mg), and reduced iron (10 mg) were added to the resulting residue. The reagent mixture was stirred overnight at 80 °C. The reactive mixture was cooled to room temperature, water and chloroform were added, a liquid separation process was carried out, and the resulting organic layer was concentrated under reduced pressure. 2-(pyridazin-4-yl)-1,3-thiazol-4-carboxylic acid (6.2 mg), DIPEA (10 pL), and DMF (185 pL) were added to the resulting residue; then, a HATU solution (13) was added.3 mg) in DMF (200 pL) and the reagent mixture was stirred overnight at room temperature. Separation and purification were performed by HPLC (column: SunFire (registered trademark) (MeOH / 0.1% HCOOH-H2O). TFA (500 pL) was added to the resulting residue and the mixture was stirred for 1 hour. The reagent mixture was concentrated under reduced pressure, chloroform and a saturated aqueous solution of NaHCO3 were added, a liquid separation process was carried out, and the resulting organic layer was concentrated under reduced pressure to obtain N-[2-{3[(methylamine)methyl]pipendin-1-yl}-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (3.8 mg). Example 78 Hydrazine monohydrate (19.8 mL) was added to a mixture of N-{2-[(8R,8aS)-8-(1,3-dioxo-1,3-dihydro-2H-isondol-2-yl)hexahydropyrrolo[1,2a]pyrazin-2(1 H)-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (0.097 g) and MeOH (1.4 mL). The reagent mixture was stirred under reflux for 6 hours. The reagent mixture was cooled to room temperature; then poured into 5% aqueous sodium hydroxide solution and the resulting mixture was extracted with CH2Cl2. The organic layer was separated, the aqueous layer was extracted with CH2Cl2, and the combined organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to obtain N-{2-[(8R,8aS)-8-aminohexahydropyrrolo[l,2-a]pyrazin-2(1H)-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}γαα / ηη / ζζηζ / E / γίΛΐ 2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (0.047 g). Example 83 To a monohydrochloride salt of N-[4-(2-fluorophenoxy)-2-{(3S)-3-[(methylamino)methyl]pyridine-1-II}3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (200 mg) EtOAc and a saturated aqueous solution of NaHCO3 were added. The reaction mixture was stirred briefly. The aqueous layer was separated and extracted with solvents combining EtOAc and MeOH, and the combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. 2 mL of propanol was added to the residue, and the mixture was stirred briefly at 80 °C. Fumaric acid (40 mg) and water (200 pL) were added to the mixture and stirred at room temperature for 24 hours. The precipitate was extracted by filtration and dried under reduced pressure to obtain N-[4-(2-fluorophenoxy)-2-{(3S)-3[(methylamino)methyl]piperidin-1-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-1L)-1,3-thiazol-4-carboxamide mono[(2E)-but-2-enedioate] (141 mg) as a crystal. Example 84 N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (100 mg) was mixed with ethanol (2 mL) and shaken at 75 °C to obtain a solution. Fumaric acid (23 mg) and water (400 mL) were added to the solution and it was shaken overnight at room temperature. The precipitate was extracted by filtration and dried under reduced pressure to obtain mono[(2E)-but2-enedioate] of N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethylphenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide (73 mg) as a crystal. The compounds shown in Tables 7-1 to 7-11 below were prepared in the same manner as in the methods of the Examples described above. Tables 7-1 to 7-11 below show the structures of the compounds in each Example, and Tables 8-1 to 8-5 show the methods of preparation for the compounds in each Example and the physicochemical data. These compounds can be readily prepared by the methods of the preceding Examples, which are obvious to those skilled in the art, or by methods modified from them. Table 9 below shows the structure and physicochemical data of the compound in the Reference Example. The compound can be readily prepared by the preparation methods in the preceding Examples or Preparation Examples, which are obvious to those skilled in the art, or by methods modified from these. In the tables below, the following abbreviations may be used. PEx: Preparation Example Number Ex: Example Number PSyn: Preparation method of the compound in the Preparation Example (the number in the PSyn field indicates that the compound in question was prepared using the same method as for a compound in the Preparation Example whose number is identical to that in the PSyn field and using the corresponding raw materials; for example, the compound in a PSyn field whose number is 1 was prepared using the same method as for the compound in Preparation Example 1). Syn: Preparation method of the compound in the Example (the number in the Syn field indicates that the compound in question was prepared using the same method as for a compound in the Example whose number is identical to that in the Syn field and using the corresponding raw materials; for example, the compound in a Syn field whose number is 1 was prepared using the same method as for compound 1 in Example). Str: Structural chemical formula DAT: Physicochemical data ESI+: m / z value in mass analysis (ESI by ionization method, [M+H]+ or [M+Na]+ unless otherwise specified) ESI+: m / z value in mass analysis (ESI by ionization method, [M+H] unless otherwise specified) NMR DMSO-d6 (400 MHz) or NMR DMSO-d6 (500 MHz): δ signal value (ppm) in 1H-NMR in DMSO-d6 NMR CDCh (400 MHz) or NMR CDCb (500 MHz): δ signal value (ppm) in 1H-NMR in CDCI3 s: Single line (spectrum) d: Double line (spectrum) t: Triple line (spectrum) m: Multiple line (spectrum) br: Broad line (spectrum) dd: Double double line (spectrum) Unless otherwise specified, the compound is an optical isomer that has an absolute steric conformation described by a structural chemical formula. In the structural formula, HCl indicates that the compound in question is a monohydrochloride, 2HCl indicates that the compound in question is a dihydrochloride, and 3HCl indicates that the compound in question is a trihydrochloride. par i nn / zznz / E / YiAi [Table 5-1] ΡΕχ Str PEx Str 1 Br f3c. Λ no, ' Ό 0-- --7--- 0 5 Br F,C 1 NO, i :r o- CL 2 Br F3C. ,1 no2 Il IT 0 F... 1 1 II's. -'y' 6 Br F..C. ...... Noy ​​' i go o Cl 3 Br oc · no? (JO ---·- I 7 Br F3C । NO2 TTG ' ·: NC, Λ IJ 4 Br F-¡C 1 N0? 'OIJ íl f F 8 Br F3C .Λ NO, ' FT O-' gaa / nn / zz / E / yLi [Table 5-2] PEx Str PEx Str 9 Br F3C NO·: -N ' - i I 13 Boc N. u F2C NOp F^^X 10 Cl F. Λ no2 Ι 0 F. Λ IJ 14 Boc n. no· F \:í:> 11 Cl eA / NO2 JL FM 15 Boc IN FXXNO2 Ύ Ύ F 12 Cl F3C.1nO2 0^^ 16 . Boc IIH ^-N-^ f3c NO2 Y Y gaa / nn / zz / E / yLi [Table 5-3] PEx Str PEx Str 17 Boc IN F3G / l / NO2 21 _ Boc II h F3C.A ,NO2 1J Γ 18 Boc N f3c^A.no2 Γ 22 . / Boc 1 1 h F3C^A.NO2 JJ Γ 19 F'^ Ι ¿oc 23 .. Boc LJH F3CxJX / NO2 TJ y 20 Boc NF / LnO2 u 24 ~ Boc 1 JH F3C.A^O2 ^JN Me [Table 5-4] PEx Str PEx Str 25 „ Boc II η F3C\ÁNO2 Me 29 .. Boc LJH f3c^L,m°2 XX fXXf XX F 26 .. Boc II π F3C^1,NO2 JJ cb 30 HCI COb 27 .. Boc LJH F3C^L / NO2 X / Me.JL 31 - NH2 ry Ψ 0 ¿oc 28 Boc LJH F3C1ÁNO2 XX XX 32 Boc o A „cWJ H gaa / nn / zz / E / yLi [Table 5-5] PEx Str PEx Str 33 HCI JUÓ H 37 Boc • ' •^ ' N ' . JHN' A, F 34 0 0, ri f3c-' γ' no, NS í ') Boc ' ' 38 crV FgC' y NOj N. r1 NH Boc 35 F;íC 7'NO;; N ,NH Box 39 01 . ' V 0.^ FyC''^'^ N NH Boc' 36 I . ,,-ογ V 0 £ 1 FoC ύ NO2 K h 1' 1 N 1 J Boc' 40 NC'^J O.. . C 'y N O2 N. Boc' crr and ηη / ζζηζ / Ε / γίΛΐ [Table 5–6] PEx Str PEx Str 41 ij 0.., .. F;C ·· ' NO? ,N. hr Ί Μ ± J Boc 45 1! J FgC^F^^ 0 42 / ' I . ...N. ,. RjC^NO;; X. N 1 J Boc - 46 ,.-·'--. [ 0 . : i f2c ··<···· 'NO2 ,.N... HM ] Bcc 43 0 r ί F '· ' NO, _ N Boc..„N ·.. b H 47 0 J 1 .N. Boc y^No, N. 0 44 OF cyL Ύ 2 Ρ-Ο2 w-^ε H Π y-no, N, [Table 5–7] PEx Str PEx Str 49 O r ii FaC ! NO; YES. JJN ¿oc 53 Π F - -y O r ί F,C vn N Boc... m / ··' < \ -NH ; 50 O O. r ϊ F3 C x · XNQ> ,N.. N BocJ 54 Q FgCr^^NC^ boAQ 51 0 o. T 1 F3C NO- ,n 0 < ' FoC '' W' H 55 Q F3C^^NO2 βοΑΛΡ 52 0 -.C ' ·· “ NO- H N.„ N.......< ) Boc ' ' 56 Q Ji 1 f3c^y^no2 A Boc. _ 1 JH [Tabla 5-8] PEx Str PEx Str 57 c4 J! 1 f^y^no2 Boc Me 61 CIA'^ O · f:.c γ yo N Λ] N. Boc'' Me 58 Ν=λ Me ¿ ... r ί F_.C' - NO. N. H í Ί Bcc < ' 62 ~T FjC'· 'y'- NO2 v· ·κ· Me 59 -7 0 ... = .C ' NOZ. ' N. HO 63 F V 0 ..V-.. F3c-''<:y^ N Boc Me 60 0 Γ 1 F,C NO:, K r J Boc' Me 64 T F.CJ · ' NO Me J N Boc 1,1 y [Tabla 5-9] PEx Str PEx Str 65 0 . -?C ' - ' NO? „ A B0C'-N ) Me ' ' 69 ¿. ... , Fr.,C NO·,. Me -Y HNS 1 J Ν' ¿oc 66 Q I J F3C^Y'''NO2 ó A Boc Me 70 f.....I i ... r ¡i F3C·' '· -NO2 Me i II i 0 Boc 67 Q f3c^y?j^no2 .N. Boc^ Me 71 Q X1 F3C^^n°2 Boc 68 O r 0 '--.Ο Ι\Ογ . ,Ν. ohc^'Nx Boc 72 F-ψ o . <> . . . F:?1C ’ '' NO;. , κ AcO [Tabla 5-10] PEx Str PEx Str 73 a 1 Y f^y^no2 N h2n^YJ 77 OI 0 ? P3O·'··';^ N. H i I Boc 74 1 Y P3(Tj^NO2 N h2n^Y^J 78 1Π 0... . . f3c^-A-nh2 ,.N, Boc Me 75 o F ¿.YTYF / y^NO2 H II x JL J Boc 79 F. . .· r ii Y o.^ ^...,^ F3C h2 N. NJJ Boc - 76 0^ TY f3c / ^^no2 N H II AL J Boc 80 ci^V 0 r I1 F:C NH2 M. ,NH Boc' [Table 5-11] PEx Str PEx Str 81 CL r ii í r τι = .c nh, N. JNH Boc' 85 1' 1 o. .. .. 11 F ' :|· N-? η N. 3oc--N Τ' H ' 82 Π NC · 0 L Ί γ NH^ N. N í 1 Boc < - 86 .. 1 T 0,. F3C-' 'y -'NH2 r M o Boc 83 N.-, j Τ'' O. F^C'^^ NH í 1 Boc' ' 87 r ργ / F3C·'^ ,,.N.... A'J NH Boc' 84 Γ—] k Ñ. .... r ί 50 nh2 N, H ί Ί A Jx J Boc ' 88 O. T o.. F;iC- Boc.. N ··· H ΤΙ γ-ΙΜΗ? 1X1. gaa / nn / zz / E / yLi [Table 5-12] PEx Str PEx Str 5 10 89 Boc ,,N.^ I 3C. 1 NH? 1Ύ O' □ 93 Γ H cr Y 0. . 1 F:C NH; N N. Boc ' Me 15 20 90 [> oo >—< / —\ ó, y---' Z—03 \\ f / v. / O <. '-------- r> ZI 94 O i 0.^ f3c-· Me f L j NH_ ,.N.. 25 91 X ri -,c NH,. N. H í I N. ,Λ J Boc 95 X X. F3CMe f3c. n, iT 0 X -γ '~nh2 N u ¿oc 30 35 92 0. Π T ¡1 F · NH? 'N'' ¿oc 96 Ci XF:!C...... r' ON Boc' u. Y nh2 prr ; nn / zz / E / yLi [Table 5-13] PEx Str PEx Str 97 N=, Me-X 0 · T' Il N η ί Ι N J. J Bos' 101 Y ¥ T F3C^Y^NH2 N η Γ Ί Boc 98 O T o .. FjcTyT.^^ A o ii Γ h ..C XI ο H 102 F3C^^^NH2 N H II M ) Boc 99 'X Vi FC j ' ΝΗ; H .·„ N N . .....\ ' / Boc 3 ; 103 9 f3c^y^nh2 / N\ H II Boc 100 Y ο FC ' , N H2 Me N .....( ') Boc 1 ' 104 Me^ N-N ¥ F3C^xf^NH2 N H II Λ J Boc gaa / nn / zz / E / yLi [Table 5-14] PEx Str PEx Str 105 Me jj JL f3c^^nh2 N Η || Boc 109 T FV 0 ... ' . F:¡C NFQ N Boc.._y^.Z z Me 106 F . > 0... < F3C h2 ~ ... A AcO \__ / 110 Me^Ql JÍ JL F3C^Y^NH2 / N\ Η II Boc 107 Q JÍ J f3c^^nh2 _N. Η II .NJ Boc 111 F-^y^F JÍ JL f3c / y^nh2 _N. Η II Boc 108 FV 0 F3C ' NH : N. H 112 F Ll F^Y^F JÍ JL f3c^y^nh2 N Η || Boc crr and ηη / ζζηζ / Ε / γίΛΐ [Table 5–15] PEx Str PEx Str 113 v Ϊ IJI F^Y^NH2 Boc 117 0 0.^. JÍ 2 f3c^y^nh2 BoAQ 114 Ο^Λ JÍ J F'xy^NH2 N. Η II Boc ~ 118 HO^ / x JÍ JI Ε3( / γΑΗ2 _N. Η II Boc 115 Q JÍ bay^I f3c f3c^y^nh2 Μθ A Boc / NFF 116 Q 1 JI f3c^y^nh2 Μθ Αη Βοο-%'Ά 120 Q JÍ JI F3C^Y^NH2 A Boc I ) H . [Table 5–16] PEx Str PEx Str 121 Y. f^y^nh2 Me i 1 1 M JL J Boc 125 .Π F' Ύ ° I 0 FO .......-N — N ' / H n I * Me LS =' NJJ Boc 122 ¿Y = .G ' NH, .K. ¿oc 126 F.. ζ Ϊ 0 L - NN f3c YY 'n H Í.s' \_ / HI N. J Boc '· 123 T o. I 1 F,C γ NH; .N. H í 1 0 N ' y N ÍFJ OC 127 ci-ψ or Tí i ? .YK| ahyhrj .N. J Boc 124 Aq 0 FC ' N Ί í 3 ¿ H (y..... > H ' ] N. J Boc 128 CD O q O _ OO / / Zv ,> \ / \\ Yo ώ ¿z. Cl Z. for / ηη / ζζηζ / Ε / γίΛΐ [Table 5–17] ΡΕχ Str PEx Str 129 Π nc -y yo 3 A Η íy..... XH ' ' N ,, Boc' 133 i: C 1.1. IJ M .----N F3C' IXWNNH i S \- / Γ . 1 Ό Boc' 130 N_-, LTV> or 1·-. LUN ,—N - τ Ti vw / XH LS Η Γ ' Boc' < 134 Π F'V o..s F3C' H ..NJ Boc 1 Ί ? 'Vn-Av^ n HU—OU 131 (X 0 ....... OV i Boc < 135 '' ' \ TF;1C' BocN H ΐ i. T yy ° ( 132 1 0 - cijiXn í H LSM_1 Boc.....W ) H '—fc ... V yo F 136 γαα / ηη / ζζηζ / Ε / γίΛΐ [Table 5–18] PEx Str PEx Str 137 i 0 f3c : u • NH Π -N-' Boc _-N tA ,· NN 141 Boc... O O.._ F3C' -N ' Me Y' A, Il l N ' H .N ÍA NY 138 Boc Y ¡ i. T Ί y H Ί Ί N--vY-- v1 1 -NA Ai T 142 f3A Ί o I O. F:1C Me A ] Al LNHA Boc - A —í ls í 1 139 Y O. F Ό ? x tr _N Í-A —N ñ 143 o YF:iC' il ° N ' H .N LA —NN ¿oc Boc'' Γ A..--- - J 140 Cl Boc'' £1 T o , F,C ' \ Me AH MJ Ao el ^N. 144 Me- Boc'' N=·, N. X Ϊ O., F3C·'·' H N'^ Γ í '''Ν' H .N lí >4 --s ·. N par i nn / zzh / E / yLi [Table 5-19] PEx Str PEx Str 145 T' °y> 0 2 N' 3 AH Ls..... 0 / j Ll Γ FC NH 149 H \ | Boc 146 IO F3C T ü Y %—í Ñ H N ' -S \— / N·-- / ' / Boc' 150 ς\ F3C^nX¿^, H II Boc 147 T ° · o FC ΧΑνΛ.......N ,. N «inh N . 'i ) Boc 151 Mq^ H II M ) Boc 148 YH || Boc 152 Me^ N? H II Boc [Table 5-20] PEx Str PEx Str 153 0 I-. L. UNN %.....τ yw n .... x H Js' AcO......\ ? ___________f 157 Me^q^ H II Boc 154 9 H 11 .NA ) Boc 158 1Π H II Boc 155 T L. 1 JN ,v^- C3C i N / / n _ .. N Bcc -N .....9 9 H '—! 159 ''T' F°xv.......κ 3 A LsK-Á ° NN j ¿F3 ¿OC 156 Y' 1 ° LI u N y... 1 HL / -W n N, 3oc -N ) Me 160 F jCI F^A^FH [| JA-Y f Boc par / nn / zz / E / yLi [Table 5-21] РЭх Str 161 Boc 162 ?и H II _N. ) Бос 163 9. ¿ / Ахо· БооЛ'0 164 9„ Ай99х> Boc^N^ ХГ PEX Str 165 9. «Alchi BooLO 166 H II Boc 167 ^Lx- Boc / N^^O^ 168 9. ' / i / 9x5 Boc. _ 1 J H gaa / nn / zz / E / yLi [Table 5-22] gaa / nn / zz / E / yLi [Table 5-23] PEx Str PEx Str 177 YF°IX?.......N 3 IH HjW-f [......1 -νη 181 I η H 178 o · I1 1 ϊ NNFT Η ΥΥ Y 'N 'NH 182 Ó ¿ ..... F cAó......' 3 Λ η Η ' Ί Μ ...-. J Ns --ν' 179 'T ° : · 0 f3c^ X ......y Me A-- H ^S' FC NJ y < N l ii OM 183 Ο Τ' F Ο-Χ-Χ Α „Ν 4 Ν F3C - Μ I 'I—ó Ν Ν Η ' <s' \=Τ Η Γ Ί ,Ν„ J Ns ' 180 O T Yi ° f cΥχγγ-Ν· 7 n' 3 Λ Η ....... H í 1 0.. -N- JU Íf:! h 184 Γ ] Τ °ΎΧ 0 I. IJ Μ ,— Ν Λ Η S Η (' Ί .nJ... J Ns '< gaa / nn / zz / E / yLi [Table 5-24] ΡΕχ Str ΡΕχ Str 185 Π τ ° Γ 0 F cWU -Ν b Ν' F3C Γ Ν -γ, 'Ν Me A- ~S ,; ,1 .. Ns' 189 'Τ Μ ο F c-XJ'V^ rHi ,. 3 ώ η MeO-' 'η r- --, 'b N. XJ Ns·- — 186 71 τ FC ' 1 Ν 0 -Ν % Ν' F3C ν Η V Ν Me <Ν'>, -S =' Ñ 1 J Ns * 190 Π Ί 0 P r^· 7K|A .ν <-N f3c ϊ ü Τ N Me vN- H --S F3c N. ^.J γ 'Ν' I i 0 Me 187 F. ,-, ΤΊ Τ ο _ η. ° Ν F3c- Ύ ..... Me ,-¾ Η íLS ,Ν. Ns ' 191 0 0, ,L. 1 un . n 'Ñ NH ILS' \= / H í I 0 N. JJ GF3 Me 188 F, .· Τ i τ ο L· 1 11 N ,—Ν WΝ >Λ / 1 -Ñ Et Η L'-S —' 4 J. J Ns' ' ' gaa i nn / zzhiz / E / yLi [Table 5-25] PEx Str PEx Str 192 Q F3C'^Y^'NO2 Br 196-1 H °VN Me I*1® I ί MeX^^'-C^O xb 193 °\ jC X >S^V^NO2 o^l T Me F 196-2 HO^N Me Mθ ρ<,ζ£ MθΛ / Vσχ 194 0 HoAA F3CY^NO2 F 197 H / N\ ΗΟλ,,,^^τ 195 0 0 jfX F3C^Y^NO2 F 198 H Λ crr i nn / zz / E / yLi [Table 5-26] PEx Str PEx Str 199 Q yXX lí 203 Y I1 F3C^y^NO2 N BocHN^XX 200 Y Ι 1 Me^y^-NO2 Cl 204 CL^ Bry^NO2 N BocHN^l^ 201 Y 0.^ M6^y^no2 Cl 205 F^^ MeOy^NC^ N BocHN^Jx^J 202 Y 1 1 P3O^^NO2 Br 206 Y ex JL X / Sz>^'NO2 o^l N Me<> BocHNy^^ gaa / nn / zz / E / yLi [Table 5-27] PEx Str PEx Str 207 0 0 jlX F3C^Y^NO2 N BocHN^J^J 211 Y 0^^ JÍ 2 Me^f^NO2 N BocHN^J^^ 208 Q JÍ 1 f3c^y^no2 HO / m , / V 212 Y JÍ 1 F3C^Y^NO2 / N\ HO / / „ 209 Q jí1 F3C^^NO2 / N\ HO / „ 213 9 Ι 1 Me^Y^NO2 N H0^ψ Boc 210 Y 0.^ I 1 Mth^γNO2 N BocHN^J^J 214 Y 0^^ JÍ JI Br^^NO2 N BocHN^J^^ gaa / nn / zz / E / yLi [Table 5-28] for i ηη / ζζηζ / Ε / γίΛΐ [Table 5-29] PEx Str 223 Q f3c^y^no2 0 224 Q JÍ1 F3C^Y^NO2 0 N CÚ.....A 0 225 Y F3C^Y^NO2 cgLO 0 226 Y JÍ 1 Me^^NO2 A OHC^y Boc PEx Str 227 Y Me^YNO2 MAÁp Boc 228 Y JÍ 1 Me^y^NO2 Me ,N FsC^N^ÁJ θ Boc 229 Y f3c^y^no2 / N\ 230 Y JÍ 1 f3c^y^no2 / N\ H2N / „ to ηη / ζζηζ / Ε / γίΛΐ [Table 5-30] PEx Str PEx Str 231 Q JI F3C^A'NO2 Λ h2N / / „,An> 235 YI JI F3C^^NO2 A BocHN^An^ 232 Y JI JI F3c^n°2 Han^Qr 236 AND JOHN JI / THE F^-jA / N Boc 237 Q THE F3c^-jA Boc \__ / 234 0 0^ / x THE F3cA^n°2 / N\ BocHN / ^.^ / ^A 238 AND THE F3c^^no2 / AS Boc \__ for i ηη / ζζηζ / Ε / γίΛΐ [Table 5-31] ΡΕχ Str PEx Str 239 QT 1 Me^YNO2 Me ,N f3c_Ñ-^nJ OH 243 9 J! 1 MeO^Y^NH2 N BocHN^XJ 240 Q 1 1 Me^yN02 Me ,N f3cvn^nJ θ Me 244 QQ^XX 3s^^nh2 θ^Τ N Me^ % BocHN^J^J 241 Q s. 11 F3C^Y^NH2 N BocHN^l^ 245 0 ° jlX f3c^^nh2 N BocHN^J^^ 242 9 XX BocHN^C^ 246 Q Ji J F3C^|^NH2 0 N 0 [Table 5-32] PEx Str PEx Str 247 Q F3C^Y^NH2 O 251 YXX f3c^^nh2 BocHN / / ,,.^^ 248 Y Me^Y^NH2 N BocHN^XX 252 YX 1 f3c^ynh2 & BocHN / λ,, / ^ν^ 249 Q 0. IX Mth^γ NH2 N BocHN^XX 253 YXX F3C^Y^NH2 / N\ BocH 250 YXX f3c^y^nh2 Boc \—' 254 YX 1 f3c^vnh2 ^N\ Boc \—1 par / nn / zz / E / yLi [Table 5-33] PEx Str PEx Str 255 9 jf J Me^Y^NH2 Me ,N f3cvn^ÁnJ θ Me 259 Yahi BocHN^YY 256 9 BocHN^Cj 260 0 BocHN^XJ 257 Material> BocHN^YY 261 9. 258 BocHN^CJ 262 9. gaa / nn / zz / E / yLi [Table 5-34] PEx Str PEx Str 263 X BocHN^jCj 267 BocHN / / z„Xn^ 264 9. BocHN^Cj 268 Y BocH 265 9. „ Boc \—1 269 Lán^ Boc \__1 266 BocHN^.^^Fr 270 9. Fs'trO F3Cvn^ÁnJ θ Me prr ; nn / zz / E / yLi [Table 5-35] caa i nn / zz / E / yLi [Table 6-1] PEx PSyn DAT 1 1 NMR DMSO-d6 (500 MHz): 7.16-7.21 (3H. m). 7.26-7.32 (1H. m). 7.45-7.51 (2H. m). 8.15-8.20 (1H. m) 2 1 ESI+: 402.3 3 1 NMR CDCI3 (500 MHz): 6.73-6.85 (2H. m). 6.92-7.00 (1H. m). 7.01 -7.05 (1H. m). 7.37-7.44 (1H. m). 7.69-7.73 (1H. m) 4 1 NMR CDCI3 (500 MHz): 6.90-6.94 (1H. m). 7.01 -7.06 (2H. m). 7.10-7.16 (2H. m). 7.65-7.69 (1H. m) 5 1 NMR DMSO-d6 (500 MHz): 7.04-7.08 (1H. m). 7.36-7.40 (2H. m). 7.46-7.50 (1H. m). 7.68-7.71 (1 H. m). 8.15-8.18 (1H. m) 6 1 NMR DMSO-d6 (500 MHz): 7.15-7.19 (1H. m). 7.32-7.36 (2H. m). 7.37-7.39 (1H. m). 7.49 (1H. t). 8.19-8.23 (1 H. m) 7 1 ESI+: 387.1 8 1 ESI+: 365.1 9 1 ESI+: 341.2 10 1 NMR DMSO-d6 (500 MHz): 7.08-7.14 (1H. m). 7.30-7.53 (4H. m). 8.01 (1H. dd) 11 1 NMR CDCI3 (400 MHz): 6.98 (2H. d). 7.15 - 7.19 (1H. m). 7.33-7.39 (2H. m). 7.74 (1H. dd) 12 1 NMR CDCI3 (400 MHz): 5.28 (2H. s). 7.05 (1H. d). 7.34 - 7.44 (5H. m). 7.85 (1H.d) 13 13 ESI+: 413.1 14 13 ESI+: 363.3 15 13 NMR CDCI3 (400 MHz): 1.50 (9H. s). 2.38 (2H. br s). 3.68 (2H. br s). 4.03 (2H. br s). 5.61 (1H. br s). 7.66 - 7.71 (1H. m). 16 16 ESI+: 422.3 17 17 ESI+: 487.2 18 17 ESI+: 451.2 19 17 ESI+: 415.3 20 17 NMR CDCI3 (400 MHz): 0.69 - 0.74 (2H. m). 0.89 - 0.93 (2H. m). 1.50 (9H. s). 2.38 (2H. br s). 3.68 (2H. br s). 4.01 (2H. br s). 4.34 - 4.39 (1H. m). 5.55 -5.58 (1H. m). 7.61 (1H. d) γαα / ηη / ζζηζ / Ε / γίΛΐ [Tabla 6-21 PEx PSyn DAT 21 21 ESI+: 460.5 22 21 ESI+: 474.7 23 21 ESI+: 488.2 24 21 ESI+: 500.2 25 21 ESI+: 400.1 26 21 ESI+: 495.3 27 21 ESI+: 510.3 28 21 ESI+: 532.2 29 21 ESI+: 550.2 30 30 NMR CDCl3 (400 MHz): 1.33 - 1.44 (1 H. m). 1.68 - 1.79 (1H. m). 1.91 - 1.99 (2H. m). 2.21 - 2.27 (1 H. m). 2.77 - 2.83 (1 H. m). 2.88 - 2.94 (1H. m). 3.30 3.38 (2H. m). 3.61 - 3.71 (2H. m). 7.81 - 7.89 (4H. m) 31 31 ESI+: 265.4 32 32 ESI+: 347.4 33 33 ESI+: 225.4 34 34 ESI+: 496.2 35 34 ESI+: 536.4 36 34 ESI+: 536.4 37 34 ESI+: 536.4 38 34 ESI+: 530.2 39 34 ESI+: 552.3. 554.3 40 34 ESI+: 543.4 41 34 ESI+: 497.3 42 34 ESI+: 495.4 43 34 ESI+: 450.4 44 34 ESI+: 494.2 45 34 NMR CDCl3 (400 MHz): 1.19 - 1.22 (1H. m). 1.68 - 1.85 (3H. m). 2.18 (1 H. br s). 2.79 - 2.84 (1 H. m). 3.02 - 3.09 (3H. m). 3.50 - 3.61 (2H. m). 5.18 (2H. s). 6.80 (1H. d). 7.31 - 7.42 (5H. m). 7.64 (1H. d). 7.69 - 7.72 (2H. m). 7.81 - 7.85 (2H. m) 46 34 ESI+: 496.4 47 34 ESI+: 560.4 48 34 ESI+: 482.2 crr i nn / zznz / E / YiAi [Table 6-3] PEx PSyn DAT 49 34 ESI+: 520.3 50 34 ESI+: 558.4 51 34 ESI+: 506.3 52 34 ESI+: 518.4 53 34 ESI+: 522.2 54 34 NMR CDCI3 (400 MHz): 1.46 (9 Hz). 2.89 - 3.13 (4 Hz). 3.28 - 3.33 (2 Hz). 3.71 - 3.88 (3 Hz). 4.88 (1 Hz br s). 6.73 (1 Hz d). 7.04 - 7.06 (2 Hz). 7.22 - 7.24 (1 Hz). 7.40 - 7.44 (2 Hz). 7.63 (1H.d) 55 34 NMRCDCI3 (400 MHz): 1.46 (9H.s). 2.90 (1H.d). 2.96 - 3.14 (3H.m). 3.27-3.34(2H.m). 3.71 - 3.81 (2H.m). 3.87 (1H.dd). 4.88 (1 H. br s). 6.73 (1H.d). 7.04 7.06 (2H.m). 7.22 - 7.26 (1 H.m). 7.40 - 7.44 (2H.m). 7.63 (1H.d) 56 34 ESI+: 534.4 57 34 NMR CDCI3 (400 MHz): 1.14 -1.20 (1H.m). 1.42 (9H.s). 1.57 - 1.75 (3H.m). 1.99 - 2.02 (1 H.m). 2.71 - 2.83 (5H.m). 3.03 - 3.13 (4H.m). 6.96 (2H.d). 7.10 - 7.14 (1 H.m). 7.31 - 7.35 (2H.m). 7.39 (1H.dd) 58 1+34 ESI+: 500.3 59 1+34 ESI+:401.3 60 60 ESI+: 550.4 61 60 ESI+: 566.4 62 60 ESI+: 518.4 63 60 ESI+: 550.4 64 60 ESI+: 532.4 65 60 ESI+: 514.2 66 60 NMR CDCI3 (400 MHz): 1.46 (9H.s). 2.89 - 3.10 (7H.m). 3.29 - 3.43 (2H. m). 3.75 - 3.88 (3H. m). 6.73 (1H. d). 7.05 (2H. d). 7.22 - 7.26 (1H. m). 7.40 - 7.44 (2H. m). 7.63 (1H. d) 67 60 NMR CDCI3 (400 MHz): 1.46 (9H. s). 2.89 - 3.11 (7H. m). 3.28 - 3.44 (2H. m). 3.74 - 3.99 (3H. m). 6.73 (1H. d). 7.05 (2H. d). 7.23 - 7.26 (1H. m). 7.40 - 7.44 (2H. m). 7.63 (1H.d) 68 68 ESI-: 494.3. [Tabla 6-4] PEx PSyn DAT 69 69 ESI+: 511.4 70 70 ESI+: 629.4 71 71 ESI+: 603.4 72 72 ESI+: 443.2 73 73 NMR CDCI3 (400 MHz): 1.08-1.18 (2H. m). 1.62 - 1.87 (3H. m). 2.54 - 2.64 (2H. m). 2.72 - 2.78 (1H. m). 2.97 - 3.09 (2H. m). 3.19 - 3.29 (1H. m). 6.84 6.97 (2H. m). 7.08-7.14 (1H. m). 7.31 - 7.40 (3H. m) 74 73 NMR CDCI3 (400 MHz): 1.03-1.06 (1H. m). 1.65 - 1.88 (4H. m). 2.58 - 2.69 (3H. m). 2.95 - 3.19 (3H. m). 5.21 (2H. s). 6.82 (1H. d). 7.32 - 7.41 (5H. m). 7.66 (1H. d) 75 75 NMR CDCI3 (400 MHz): 1.14 - 1.28 (2H. m). 1.42 - 1.43 (9H. m). 1.59 - 1.88 (3H. m). 2.74 - 3.24 (6H. m). 4.45 - 4.56 (1H. m). 6.83 - 6.98 (2H. m). 7.08 7.15 (1H. m). 7.31-7.40 (3H. m) 76 75 NMR CDCI3 (400 MHz): 1.08-1.10 (1H. m). 1.43 (9H. s). 1.65-1.88 (4H. m). 2.65-2.71 (1H. m). 2.90-3.11 (5H. m). 4.53 (1H. br s). 5.21 (2H. s). 6.83 (1H. d). 7.32-7.41 (5H. m). 7.66 (1H. d) 77 77 ESI+: 466.3 78 77 ESI+: 498.4 79 77 ESI+: 484.4 80 77 ESI+: 500.2 502.2 81 77 ESI+: 500.4. 502.3 82 77 ESI+: 491.4 83 77 ESI+: 467.4 84 77 ESI+: 443.4 85 77 ESI+: 420.5 86 77 ESI+: 530.3 87 77 ESI+: 484.5 88 77 ESI+: 452.3 89 77 ESI+: 457.2 90 77 ESI+: 421.4 91 77 ESI+: 466.4 92 77 ESI+: 385.4. crr i ηη / ζζηζ / Ε / γίΛΐ [Table 6-51 PEx PSyn DAT 93 77 ESI+: 514.4. 516.4 94 77 ESI+: 466.4 95 77 ESI+: 577.4 96 77 ESI+: 528.4 97 77 ESI+: 470.4 98 77 ESI+: 476.4 99 77 ESI+: 466.4 100 77 ESI+: 480.4 101 77 ESI+: 430.3 102 77 ESI+: 444.1 103 77 ESI+: 458.3 104 77 ESI+: 470.3 105 77 ESI+: 470.3 106 77 ESI+: 413.2 107 77 ESI+: 464.2 108 77 ESI+: 470.3 109 77 ESI+: 484.4 110 77 ESI+: 423.9 111 77 ESI+: 502.2 112 77 ESI+: 520.3 113 77 NMR CDCI3 (400 MHz): 0.53 - 0.58 (2H. m). 0.85 - 0.90 (2H. m). 1.50 (9H. s). 2.31 (2H. br s). 3.63 (2H. t). 3.76 (2H. br s). 4.00 - 4.06 (1H. m). 4.06 (2H. br s). 5.76 (1H. br s). 6.24 (1H. dd) 114 77 NMR CDCI3 (400 MHz): 0.96 - 1.04 (1H. m). 1.43 (9H. s). 1.43- 1.82 (4H. m). 2.69 - 2.74 (1H. m). 2.93 - 3.03 (5H. m). 4.31 (2H. br s). 4.57 (1H. br s). 6.33 (1H. dd). 6.92 (2H. d). 7.02 (1H. t). 7.28 (2H. t) 115 77 NMR CDCI3 (400 MHz): 1.43 (9H. s). 2.67 - 2.98 (2H. m). 3.11 - 3.26 (3H. m). 3.52 - 3.96 (4H. m). 6.72 - 6.84 (3H. m). 6.95 - 7.04 (2H. m). 7.24 - 7.30 (2H. m) 116 77 NMR CDCI3 (400 MHz): 1.44 (9H. s). 2.75 (1 H. d). 2.83 (1H. d). 2.94 (3H. s). 3.04 - 3.16 (1H. m). 3.28 - 3.49 (2H. m). 3.70 - 4.00 (4H. m). 4.23 (2H. br s). 6.74 - 6.85 (2H. m). 6.90 (2H. d). 7.00 - 7.05 (1H. m). 7.26 - 7.30 (2H. m) γαα / ηη / ζζηζ / Ε / γίΛΐ [Tabla 6-61 PEx PSyn DAT 117 77 NMR CDCI3 (400 MHz): 1.46 (9 Hz). 2.69 - 3.00 (2 Hz). 3.15-3.28 (3 Hz). 3.48 - 3.98 (4 Hz). 6.74 - 6.79 (2 Hz). 6.84 - 6.86 (1 Hz). 6.97 - 7.06 (2 Hz). 7.26 - 7.32 (2 Hz) 118 77 ESI+: 390.3 119 77 NMR CDCI3 (400 MHz): 1.44 (9 Hz). 2.75 (1 Hz). 2.84 (1 Hz). 2.94 (3 Hz). 3.02 - 3.17 (1 H.m). 3.28 - 3.46 (2H.m). 3.67 - 3.99 (4H.m). 4.23 (2H.br s). 6.74 - 6.84 (2H.m). 6.90 (2H.d). 7.00 - 7.06 (1H.m). 7.28 - 7.30 (2H.m) 120 77 NMR CDCI3 (400MHz): 1.45 (9H.s). 1.64 - 1.69 (2H.m). 2.73 - 2.89 (2H.m). 2.96 - 3.17 (1 H.m). 3.19 - 3.48 (3H.m). 3.63 - 4.00 (4H.m). 4.22 (1 H.br s). 4.90 (1 H.br s). 6.73 - 6.85 (2H.m). 6.88 - 6.94 (2H.m). 6.99 - 7.05 (1H.m). 7.28 - 7.33 (2H.m) 121 77 ESI+: 448.3 122 122 ESI+: 467.4 123 123 ESI+: 563.2 124 124 ESI+: 655.3 125 124 ESI+: 687.4 126 124 ESI+: 695.4 127 124 ESI+: 689.4 128 124 ESI+: 711.4. ESI+: 697 132 124 ESI+: 6975 134 124 ESI+: 673.4 135 124 ESI+: 641.3 136 124 ESI+: 624.2 137 124 ESI+: 588.2. 138 124 ESI+: 655.4 139 124 ESI+: 574.4 140 124 ESI+: 703.4 141 124 ESI+: 655.4 prr / nn / zz / E / yLi5[Table 6-7] PEx PSyn DAT 142 124 ESI+: 788.4 143 124 ESI+: 717.4 144 124 ESI+: 659.4 145 124 ESI+: 665.3 146 124 ESI+: 677.4 147 124 ESI+: 669.4 148 124 ESI+: 619.3 149 124 ESI+: 633.3 150 124 ESI+: 647.3 151 124 ESI+: 659.3 152 124 ESI+: 659.5 153 124 ESI+: 602.3 154 124 ESI+: 654.2 155 124 ESI+: 659.3 156 124 ESI+: 673.3 157 124 ESI+: 669.3 158 124 ESI-: 689.2 159 124 ESI+: 752.3 160 124 ESI-: 707.1 161 124 ESI+: 578.3 162 124 ESI+: 623.3 163 124 ESI+: 679.3 164 124 ESI+: 693.3 165 124 ESI+: 679.3 166 124 ESI+: 601.1 167 124 ESI+: 693.2 168 124 ESI+: 693.2 169 124 NMR CDCl3 (400 MHz): 1.18 - 1.31 (1H.m). 1.31 (9H. br s). 1.96 - 2.31 (4H. m). 2.75 (3H. s). 2.93 - 3.30 (6H. m). 6.95 (2H. d). 7.07 (1H. t). 7.31 (2H. t). 7.90 - 7.98 (1H. m). 8.37 - 8.40 (1H. m). 8.47 (1H. s). 9.40 (1H. br s). 9.80 9.85 (1H. m). 10.88 (1H. br s) 170 77+124 ESI+: 673.4 171 77+124 ESI+: 687.4 172 172 ESI+: 560.2 [Table 6-8] PEx PSyn DAT 173 173 ESI+: 558.2 174 174 ESI+: 732.9 175 175 ESI+: 661.3 176 176 ESI+: 524.2 177 176 ESI+: 488.1 178 176 ESI+: 452.3 179 176 ESI+: 666.4 180 176 ESI+: 652.3 181 176 ESI+: 456.2 182 182 ESI+: 740.3 183 182 ESI+: 740.3 184 182 ESI+: 758.1 185 185 ESI+: 754.3 186 185 ESI+: 754.4 187 185 ESI+: 772.4 188 185 ESI+: 786.3 189 185 ESI+: 816.4 190 190 ESI+: 680.3 191 190 ESI+: 666.4 prr / ηη / ζζηζ / Ε / γίΛΐ [Table 6-91 PEx PSyn DAT 192 192 NMR DMSO-d6 (400 MHz): 7.00 (1H. d). 7.57-7.64 (5H. m). 7.97 (1 H. d) 193 193 NMR DMSO-d6 (400 MHz): 3.52 (3H. s). 7.61 (1H. t). 8.55-8.61 (1 H. m) 194 194 ESI+: 275.3 195 195 NMR DMSO-d6 (400 MHz): 7.60 (2H. t). 7.67 (1H. d). 7.75-7.81 (3H. m). 8.58 (1H.t) 196-1 196 NMR CDCI3 (400 MHz): 1.09 (9H. s). 1.61-1.70 (1H. m). 1.75-1.84 (1H. m). 3.47-3.54 (1H. m). 3.69-3.80 (2H. m). 4.01-4.07 (2H. m). 4.84-4.87 (1H. m). 6.00-6.01 (1H. m). 7.37-7.46 (6H. m). 7.67-7.74 (4H. m) 196-2 196 NMR CDCI3 (400 MHz): 1.00 (9H. s). 1.60-1.69 (2H. m). 3.37-3.43 (1H. m). 3.95-4.20 (4H. m). 4.81 (1H. br s). 6.43 (1H. br s). 7.37-7.46 (6H. m). 7.647.76 (4H. m) 197 197 ESI+: 143.1 198 197 ESI+: 143.1 199 1 NMR CDCI3 (400 MHz): 3.46 (3H. s). 6.75 (1H. dd). 7.16 (2H. d). 7.36 (1H. t). 7.51 (2H. t). 8.18 (1H.t) 200 1 NMR CDCI3 (400 MHz): 0.80-0.91 (4H. m). 2.29 (3H. s). 3.80-3.84 (1 H. m). 7.20 (1H. d). 7.79 (1H. d) 201 1 NMR CDCI3 (400 MHz): 2.47 (3H. s). 6.73 (1H. d). 7.00-7.02 (2H. m). 7.207.24 (1 H. m). 7.39-7.43 (2H. m). 7.65 (1H. d) 202 1 NMR CDCl3 (400 MHz): 0.83-0.97 (4H. m). 3.87-3.92 (1H. m). 7.48 (1H. d). 7.79 (1H.d) 203 34 ESI+: 535.1 204 34 ESI+: 449.9 205 34 ESI+: 384.1 206 34 ESI+: 506.3 207 34 ESI+: 530.0 208 34 ESI+: 424.2 209 34 ESI+: 424.3 210 34 ESI+: 406.3. 211 34 ESI+: 442.4 212 34 ESI+: 388.2 γαα / nn / zznz / E / YiAi [Table 6-101] PEx PSyn DAT 213 34 NMR CDCI3 (400 MHz): 1.49 (9H. s). 2.33 (3H. s). 2.88-3.44 (5H. m). 3.804.32 (4H. m). 6.61 (1 H. d). 6.99 (2H. d). 7.14-7.22 (1H. m). 7.31-7.52 (3H. m) 214 1 ESI+: 508.2 215 1 ESI+: 458.6 216 216 NMR CDCI3 (400 MHz): 1.79-1.84 (1H. m). 2.47-2.57 (4H. m). 2.96-2.99 (1H. m). 3.07-3.18 (3H. m). 3.32-3.39 (2H. m). 5.04-5.09 (1H. m). 6.70 (1H. d). 7.04 (2H. d). 7.23 (1H. t). 7.39-7.46 (4H. m). 7.54-7.58 (1H. m). 7.60 (1H. d). 8.03 (2H. d) 217 216 NMR CDCI3 (400 MHz): 1.98-2.05 (1H. m). 2.17-2.26 (1H. m). 2.39-2.50 (3H. m). 3.06-3.14 (2H. m). 3.23-3.34 (2H. m). 3.39-3.44 (2H. m). 5.45-5.49 (1H. m). 6.71 (1H. d). 7.04 (2H. d). 7.23 (1 H. t). 7.39-7.46 (4H. m). 7.547.59 (2H. m). 8.06 (2H. d) 218 34 ESI+: 424.3 219 34 NMR CDCI3 (400 MHz): 1.70-1.78 (1H. m). 2.05-2.26 (3H. m). 2.32-2.37 (1H. m). 3.00-3.04 (2H. m). 3.19-3.23 (2H. m). 3.29-3.35 (2H. m). 4.16-4.19 (1H. m). 6.71 (1H. d). 7.05 (2H. d). 7.23 (1 H. t). 7.39-7.44 (2H. m). 7.60 (1H. d) 220 220 ESI+: 468.1 221 221 ESI+: 553.3 222 221 ESI+: 553.2 223 221 ESI+: 553.2 224 221 ESI+: 553.3 225 221 ESI+: 517.3 226 68 NMR CDCI3 (400 MHz): 1.48-1.51(9H.m). 2.27 (3H.s). 2.93-3.16(1H.m). 3.18-3.63(4H.m). 3.85-4.13(1H.m). 4.68-4.90(1H.m). 6.61 (1H.d). 6.957.04 (2H.m). 7.15-7.22(1H.m). 7.32-7.43(2H.m). 7.48 (1H.d). 9.68-9.70 (1H.m) 227 69 NMR CDCI3 (400MHz): 1.45-1.48 (9H.m). 2.25 (3H.s). 2.32 (3H.s). 2.71 3.65 (7H.m). 3.80-4.75(2H.m). 6.53-6.66(1H.m). 6.91-7.04(2H.m). 7.137.21 (1H.m). 7.32-7.49(3H.m). [Tabla 6-111 PEx PSyn DAT 228 70 ESI+: 575.5 229 73 ESI+: 423.3 230 73 ESI+: 423.2 231 73 ESI+: 423.3 232 73 ESI+: 387.3 233 75 ESI+: 523.4 234 75 ESI+: 523.3 235 75 ESI+: 523.4 236 75 ESI+: 487.3 237 60 ESI+: 537.3 238 60 ESI+: 501.4 239 30 NMR CDCl3 (400 MHz): 2.30-2.31 (3H.m). 2.74-3.51 (12H. m). 6.59 (1H. d). 6.95-7.03 (2H. m). 7.14-7.22 (1H. m). 7.34-7.52 (3H. m) 240 190 NMR CDCl3 (400 MHz): 2.29-2.30 (3H. m). 2.41-2.57 (4H. m). 2.61-2.74 (1H. m). 2.82-3.34 (9H. m). 3.67-4.05 (1H. m). 6.59 (1H. d). 6.97-7.03 (2H. m). 7.157.21 (1H. m). 7.35-7.46 (3H. m) 241 77 ESI+: 504.5 242 77 ESI+: 438.1 243 77 ESI+: 428.9 244 77 - 245 77 ESI+: 477.5 246 77 ESI+: 523.3 247 77 ESI+: 523.3 248 77 ESI+: 376.4 249 77 ESI+: 412.3 250 77 ESI+: 507.4 251 77 ESI+: 493.4 252 77 ESI+: 493.4 253 77 ESI+: 457.4 254 77 ESI+: 471.4 prr i ​​ηη / ζζηζ / Ε / γίΛΐ [Table 6-121] PEx PSyn DAT 255 77 NMR CDCI3 (400 MHz): 2.18 (3H.s). 2.40-2.66(5H.m). 2.84-3.03(3H.m). 3.18 (3H.s). 3.28-3.34(1H.m). 3.39-3.82(2H.m). 3.88-4.01(1H.m). 6.59 (1H.d). 6.70 (1H.d). 6.83 (2H.d). 6.94-7.01(1H.m). 7.22-7.34 (2H.m) 256 124 ESI+: 695.1 257 124 ESI+: 627.2 258 124 ESI+: 615.2 259 124 ESI+: 665.1 260 124 ESI+: 667.1 261 124 ESI+: 712.3 262 124 ESI+: 712.5 263 124 ESI+: 565.4 264 124 ESI+: 601.5 265 124 ESI+: 696.3 266 124 ESI+: 682.4 267 124 ESI+: 682.4 268 124 ESI+: 646.5 269 124 ESI+: 660.5 270 124 NMR CDCI3 (400 MHz): 2.32 (3H.s). 2.59-3.89(14H.m). 3.96-4.18(1H.m). 6.88-6.96(3H.m). 7.03-7.10 (1H.m). 7.28-7.37(2H.m). 7.97 (1H.dd). 8.43 (1H.d). 8.45 (1H.s). 9.42-9.48(1H.m). 9.88-9.95(1H.m). 10.53 (1H.brs) 271 271 ESI+: 725.3 272 272 ESI+: 725.2 [Tabla 7-2] γαα i ηη / ζζηζ / Ε / γίΛΐ [Tabla 7-3] γαα / ηη / ζζηζ / Ε / γίΛΐ [Tabla 7-5] And Str 33 jO 34 35 f3c-^X^ ¿X 36 jO crV 2HCI f3c^Q^^ n ¥s / \= / ΜθΗνΧΧ Ex Str 37 2HCI ¿Xw MeHlT 38 qX \ ™ b T z 39 9 f3c-^X^n^^ . HH / —\ \= / H2lK^\T 40 θ'ι^^ γαα / ηη / ζζηζ / Ε / γίΛΐ [Table 7–7] Ex Str 49 -Yytw ΜβΗΝ^^ 50 2HCI YYw 51 XJ MeHNx^X^ 52 Κ / \. 2HCI EtHNX^\J Ex Str 53 VJY 2HCI XySryO H í ] 54 2HCI Μθ2^'Ό 55 2HCI F3^r\y^ Me2N\^É_. J 56 Dog [Table 7–9] Ex Str Ex Str 65 Q JjJj JL.n / AY Me í ArV-O / N\ \= / MeHNx 1 J Me 69 9 ^λλΙ n / =^ Me <0 JH IV-VA *Ά θ H2N\Z\Z 66 Z £ bb IZ ω / Az\ \\ z 60 a- z CM T 67 A > CM x 71 Y JJí^J zHY i HU / \ ZN\ \= / H2N\Z\Z 68 Y JÍ ZL JLjm / ΗΛ ihv / —\ 72 JíJjL jt JM zK Me^V^N^X7.N.\\ i H2N^U\Z [Table 7–10] Ex Str Ex Str 73 77 Y F3C5y\v<> MeHN^ / ^P 74 99 η2ν / / λ.0τ 78 y γΥΥν^ H2Nfc^2jr 75 9. H2%, / y 79 y .^ / yo ητ^ 9. XAvo Me2N^ γαα / ηη / ζζηζ / Ε / γίΛΐ gaa / nn / zz / E / yLi [Table 8-1] Ex Syn DAT 1 1 ESI+: 611.4 2 1 ESI+: 604.2 3 1 ESI+: 568.1 4 1 ESI+: 532.3 5 1 ESI+: 536.2 6 6 ESI+: 584.2 7 6 ESI+: 569.4 8 6 ESI+: 570.4 9 9 ESI+: 555.3 NMR DMSO-d6 (500 MHz): 1.03-1.24 (1H. m). 1.69-1.89 (1H. m). 1.96-2.16 (3H. m). 2.37-2.59 (2H. m). 2.72 (1H. t). 2.92-3.07 (2H. m). 3.12-3.22 (1H. m). 6.937.44 (6H. m). 8.19-8.86 (3H. m). 9.47-10.63 (3H. m) 10 9 ESI+: 587.4 NMR DMSO-d6 (500 MHz): 1.09-1.29 (1H. m). 1.61-2.12 (3H. m). 2.37-2.47 (4H. m). 2.65-2.90 (3H. m). 2.99-3.04 (2H. m). 3.22-3.30 (1H. m). 6.98-7.45 (5H. m). 8.16-8.91 (5H. m). 9.52-10.50 (3H. m) 11 9 ESI+: 573.4 NMR DMSO-d6 (500 MHz): 1.02-1.16 (1H. m). 1.70-2.16 (4H. m). 2.34-2.76 (3H. m). 2.94-3.06 (2H. m). 3.11-3.20 (1H. m). 6.74-7.46 (5H. m). 8.19-8.90 (3H. m). 9.46-10.70 (3H. m) 12 9 ESI+: 597.3 13 9 ESI+: 519.3 14 9 ESI+: 533.4 15 9 ESI+: 547.4 16 9 ESI+: 559.3 17 9 ESI+: 559.3 18 9 ESI+: 554.2 19 9 ESI+: 559.2 20 9 ESI+: 573.3 21 9 ESI+: 569.4 22 9 ESI+: 591.3 23 9 ESI+: 609.4 [Table 8-2] Ex Syn DAT 24 9 ESI+: 523.4 25 9 ESI+: 557.4 26 9 ESI+: 571.4 27 9 ESI+: 557.4 par i ηη / ζζηζ / Ε / γίΛΐ 28 9 ESI+: 539.4 29 9 ESI+: 571.2 30 9 ESI+: 571.2 31 9 ESI+: 537.2 32 9 ESI+: 555.3 33 9 ESI+: 573.4 NMR DMSO-d6 (500 MHz): 1.02-1.20 (1H. m). 1.71-1.88 (1H. m). 1.96-2.17 (3H. m). 2.36-2.65 (2H. m). 2.73 (1H. t). 2.93-3.08 (2H. m). 3.12-3.19 (1H. m). 6.957.45 (5H. m). 8.18-8.84 (3H. m). 9.43-10.61 (3H. m) 34 9 ESI+: 541.2 NMR DMSO-d6 (500 MHz): 1.96-2.17 (4H. m). 2.43-2.60 (2H. m). 3.04 (1H. s). 3.42-3.52 (2H. m). 7.00-7.04 (2H. m). 7.06 (1H. d). 7.12-7.19 (1H. m). 7.37-7.44 (2H. m). 8.18-8.24 (1H. m). 8.56-8.64 (1H. m). 8.79 (1H. s). 9.47-9.50 (1H. m). 9.81-9.84 (1H. m) 35 9 ESI+: 589.3. 591.4 36 9 ESI+: 603.4. 605.3 37 9 ESI+: 555.4 38 9 ESI+: 580.2 39 9 ESI+: 556.2 40 9 ESI+: 589.2. 591.2 41 9 ESI+: 573.3 42 9 ESI+: 595.4 43 9 ESI+: 587.3 44 9 ESI+: 559.4 45 9 ESI+: 555.4 46 9 ESI+: 569.4 47 9 ESI+: 532.4 48 9 ESI+: 509.2 gaa / nn / zz / E / yLi [Table 8-3] Ex Syn DAT 49 49 ESI+: 569.3 50 49 ESI+: 569.3 51 49 ESI+: 587.2 52 49 ESI+: 601.2 53 49 ESI+: 631.2 54 54 ESI+: 583.4 55 54 ESI+: 583.3 56 54 ESI+: 585.4 57 54 ESI+: 551.3 58 54 ESI+: 599.4 59 59 ESI+: 655.4 NMR DMSO-d6 (500 MHz): 1.69-1.92 (2H.m). 1.99-2.22 (1H.m). 2.30-2.41 (1H.m). 2.83-3.41 (13H.m). 3.55-3.99 (4H.m). 6.97-7.03 (2H.m). 7.06-7.12 (1H. m). 7.14-7.20 (1H. m). 7.38-7.46 (2H.m). 8.24 (1H. d). 8.29-8.34 (1H.m). 8.82-8.83 (1H.m). 9.47-9.52 (1H.m). 9.90-9.96 (1H.m). 10.03-10.13 (2H. m) 60 59 ESI+: 641.4 61 59 ESI+: 653.4 62 62 ESI+: 653.4 63 63 ESI+: 615.2 64 64 ESI+: 569.3 prr ; nn / zz / E / yLi [Table 8-41] Ex Syn DAT 65 6 ESI+: 530.3 66 9 ESI+: 603.3 67 9 ESI+: 527.3 68 9 ESI+: 517.3 69 9 ESI+: 565.2 70 9 ESI+: 567.0 71 9 ESI+: 465.2 72 9 ESI+: 501.3 73 9 ESI+: 596.5 74 9 ESI+: 582.4 75 9 ESI+: 582.3 76 9 ESI+: 546.4 77 9 ESI+: 560.3 78 78 ESI+: 582.3 NMR DMSO-d6 (400 MHz): 1.25-1.34 (1H. m). 1.75-2.49 (6H. m). 2.87-3.58 (7H. m). 6.91-7.16 (4H. m). 7.36-7.41 (2H. m). 8.30-8.40 (1H. m). 8.51-8.74 (1H. m). 8.82 (1H. s). 9.41-9.50 (1H. m). 9.94-9.96 (1H. m). 10.13-10.40 (1H. m) 79 78 ESI+: 582.3 80 54 ESI+: 610.4 NMR DMSO-d6 (400 MHz): 1.56-1.77 (2H. m). 1.96-2.35 (8H. m). 2.50-2.67 (2H. m). 2.89-3.63 (6H. m). 6.94-7.18 (4H. m). 7.37-7.43 (2H. m). 8.29-8.40 (1H. m). 8.50-8.69 (1 H. m). 8.83-8.84 (1H. m). 9.43-9.49 (1H. m). 9.95-9.96 (1H. m). 10.15-10.39 (1H. m) 81 54 ESI+: 610.3 82 54 ESI+: 574.4 83 83 ESI+: 587.3 NMR DMSO-d6 (500 MHz): 1.11-1.26 (1H. m). 1.54-2.12 (3H. m). 2.25-2.45 (4H. m). 2.55-2.84 (3H. m). 2.93-3.30 (3H. m). 6.30 (2H. s). 6.95-7.46 (5H. m). 8.15- 100 8.85(3H.m). 9.48-10.54 (3H.m) 2Θ(°)=7.2. 8.8. 10.4. 10.7. 14.4. 15.1.20.0. 21.7. 24.0. 26.7 [Tabla 8-51 5 Ex Syn DAT 84 84 ESI+: 555.4 NMR DMSO-d6 (500 MHz): 1.09-1.27 (1H. m). 1.54-2.38 (4H. m). 2.61-2.86 (3H. m). 2.93-3.30 (3H. m). 6.34 (2H. s). 6.94-7.44 (6H. m). 8.18-8.85 (3H. m). 9.4710.60 (3H. m) 20(°)=5.4. 9.2. 10.4. 12.0. 14.1. 14.9. 16.4. 21.2. 23.7. 26.3 10 85 84 ESI+: 573.3 NMR DMSO-d6 (500 MHz): 1.13-1.28 (1H. m). 1.55-2.40 (4H. m). 2.61-2.88 (3H. m). 2.93-3.33 (3H. m). 6.33 (2H. s). 6.75-7.46 (5H. m). 8.17-8.89 (3H. m). 9.4810.63 (3H. m) 20(°)=9.3. 9.6. 10.4. 12.0. 13.9. 14.2. 15.2. 16.4. 22.4. 23.8 15 86 84 ESI+: 573.3 NMR DMSO-d6 (500 MHz): 1.09-1.29 (1H. m). 1.53-2.41 (4H. m). 2.61-2.86 (3H. m). 2.93-3.30 (3H. m). 6.33 (2H. s). 6.95-7.46 (5H. m). 8.16-8.87 (3H. m). 9.4610.60 (3H. m) 26(°)=9.3. 10.4. 12.1. 14.2. 14.9. 16.5. 18.0. 18.9. 23.9. 26.6 20 87 84 ESI+: 541.3 NMR DMSO-d6 (500 MHz): 1.92-2.30 (4H. m). 2.60-2.72 (2H. m). 3.05 (1H. br s). 3.47 (1H. br s). 3.62 (1H. br s). 6.41 (2H. s). 7.01 -7.05 (2H. m). 7.06-7.14 (1H. m). 7.15-7.20 (1H. m). 7.39-7.45 (2H. m). 8.18-8.25 (1H. m). 8.67-8.80 (1H. m). 8.81 (1 H. s). 9.45-9.54 (1H. m). 9.78-9.86 (1 H. m) 20(°)=6.2. 6.6. 11.0. 13.3. 15.9. 16.6. 17.9. 19.7. 20.3. 25.4. Industrial Application The compound of the present invention or a salt thereof are useful as an inhibitor of DGKξ and can be used as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for the treatment of a cancer related to the activation of immune cells or a cancer that offers resistance to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies.

Claims

CLAIMS 1. A compound of formula (I): [Chemical formula 1] γαα / nn / zznz / E / YiAi (I) or a salt thereof, wherein: R1 is a group of formula (I), (II), (III), (IV) or (V): [Chemical formula 2] R2 is a C1-6 alkyl, a C3-5 cycloalkyl, an -O-(C1-6 alkyl), methanesulfonyl, a C1-6 halogen alkyl or a halogen, R3 is I) a phenyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a C1-6 halogen alkyl, a C3-5 cycloalkyl, an -O-(C1-e alkyl), an -O-(C1-e halogen alkyl), cyano, nitro, methanesulfonyl and a halogen, II) a optionally substituted C3 s cycloalkyl with a group selected from the group consisting of a Ci-e alkyl and a halogen, III) a pyridyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a C1-6 halogen-alkyl, a C3-5 cycloalkyl, an -O-(Ci-s alkyl), an -O-(Ci-e halogen-alkyl), cyano, nitro, methanesulfonyl and a halogen,IV) a pyrazolyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl and a halogen, or V) a pyrrolidinyl optionally substituted with a C1-6 alkyl, R4 is H or F, L is a bond, CO, SO2, O or NH, X is CH2, O or N-methyl, Y or CH2O, Ra is H or methyl, Rb is H, methyl, ethyl or -(CH2)2O-CH3, Rc is H, methyl or oxetanyl, Rd is H, methyl, -(CH2)2OH, -(CH2)2O-CH3 or oxetanyl, m is 1 or 2, and n is 1 or 2.

2. A compound or salt thereof according to claim 1, wherein R2 is a C1-6O halogen-alkyl; L is a bond, O or NH; X is CH2 or N-methyl; Rc is H or methyl; m is 1.

3. A compound or a salt thereof according to claim 2, wherein R1 is a group of formula (a), (ll-a), (lll-a) or (v): [Chemical formula 3] (a) (a) (ll-a) (v) 4. A compound or a salt thereof according to claim 3, wherein R3 is a phenyl optionally substituted with a group selected from the group consisting of a C3-y alkyl and a halogen, or a C3-5 cycloalkyl.

5. A compound or salt thereof according to claim 4, wherein R2 is CF3, R4 is H, Rb is H or methyl and Rc is H.

6. A compound or salt of the same note with the indication 1, where the compound is selected from the group that consists of: N-{2-[(3S)-3-(am¡nomethyl)p¡peridin-1 -yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4carboxamida; N-{2-[(3S)-3-(am¡nomet¡l)p¡pend¡n-1-¡l]-4-(3-fluorophenox¡)-3-(tr¡fluoromet¡l)fen¡l}-2-(pir¡daz¡n-4-¡l)1,3-thiazol-4-carboxamida; N-{2-[9-(2-methoxyethyl)-1 -oxa-4,9-diazaespiro[5.5]undecan-4-¡l]-4-phenox¡-3-(tri¡fluoromethyl)phen¡l}-2(pihadaz¡n-4-¡l)-1,3-thiazol-4-carboxamide; N-{2-[(3S)-3-(aminomethyl)p¡perdin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridaz¡n-4-¡l)1,3-thiazol-4-carboxamide; N-[4-(2-fluorophenoxy)-2-{(3S)-3-[(methylamino)methyl]piperidine-1 -yl}-3-(trifluoromethyl)phenyl]-2-(pyridaz¡n4-yl)-1,3-thiazol-4-carboxamide; N-{2-[(2R)-2-(aminomethyl)pyrrolid¡n-1 -yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4carboxamide; N-{2-[(8R,8aS)-8-aminohexahydro¡rrolo[1,2-a]pyrazin-2(1 H)-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2(pyridazin-4-yl)-1,3-thiazol-4-carboxamida y N-{2-[(8R,8aS)-8-(dimet¡lam¡no)hexah¡drop¡rrolo[1,2-a]pyrazin-2(1 H)-yl]-4-phenoxy-3(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide.

7. A compound or a salt of the same type of salt with the indication 1, where the compound or the salt of the same is selected from the group that consists of: mono[(2E)-but-2-enedioate] of N-{2-[(3S)-3-(aminomet¡l)piper¡d¡n-1 -il]-4-fenoxi-3 103 (trifluoromethyl)phenyl}-2-(pyridazn-4-yl)-1,3-thiazol-4-carboxamida; mono[(2E)-but-2-enedioate] de N-{2-[(3S)-3-(am¡nometil)p¡per¡d¡n-1 - yl]-4-(3-fluorophenoxy)-3(trifluorometil)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide; mono[(2E)-but-2-enedioate] de N-{2-[(3S)-3-(aminometil)p¡per¡d¡n-1 -yl]-4-(2-fluorophenox¡)-3(trifluorometil)phenyl}-2-(pyridazin-4-yl)-1,3-thiazol-4-carboxamide; mono[(2E)-but-2-enedioato] de N-[4-(2-fluorofenoxy)-2-{(3S)-3-[(methylamino)metil]piperidin-1 -yl}-3(trifluorometil)fenil]-2-(piridazin-4-yl)-1,3-thiazol-4-carboxamida y mono[(2E)-but-2-enedioato] de N-{2-[(2R)-2-(aminometil)pirrol¡din-1 -yl]-4-fenox i-3(trifluoromet¡l)fen¡l}-2-(p¡r¡daz¡n-4-¡l)-1,3-thiazol-4-carboxamida.

8. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1.

9. The pharmaceutical composition according to claim 8, which serves for the treatment of cancer related to the activation of immune cells or cancer that offers resistance to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies.

10. The use of the compound or a salt thereof according to claim 1, for the preparation of a pharmaceutical composition for the treatment of cancer related to the activation of immune cells or cancer that offers resistance to treatment with anti-PD1 antibodies / anti-PD-L1 antibodies.

11. The compound or a salt thereof according to claim 1, for use in the treatment of cancer related to the activation of immune cells or cancer that offers resistance to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies.

12. The use of a compound or a salt thereof according to claim 1, for the treatment of cancer related to the activation of immune cells or cancer that offers resistance to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies.

13. A DGKξ inhibitor comprising a compound of formula (I) or a salt thereof.

14. A method for treating cancer related to the activation of immune cells or cancer that offers resistance to treatment with anti-PD-1 antibodies / anti-PD-L1 antibodies, comprising administering an effective amount of the compound or a salt thereof according to claim 1 to a subject.