Pharmaceutical composition comprising pyridazinyl-thiazolecarboxamide compound

Abstract

A compound useful as an active ingredient of a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) is provided. In an embodiment, a compound useful as an active ingredient of a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD- LI antibody therapy is provided. In addition, a pharmaceutical composition, comprising administering an effective amount of a compound, for example, a DGK ξ inhibitor, to the subject in combination with a combination therapy for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) and / or non-small cell lung cancer is provide. The present inventors have conducted studies on a compound useful as an active ingredient of a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer), in an embodiment, for treatment of colorectal cancer (except for mismatch repair- deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD- LI antibody therapy, and found that a pyridazinyl-thiazolecarboxamide compound has DGK ξ (DGKzeta) inhibitory effect, leading to completion of the present invention. The pyridazinyl-thiazolecarboxamide compound of the present invention has DGK ξ inhibitory effect, and can be used as a therapeutic agent for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer), in an embodiment, for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy. In addition, the pharmaceutical composition, comprising administering an effective amount of the pyridazinyl-thiazolecarboxamide compound of the present invention or a salt thereof to the subject in combination with a combination therapy can be used as a therapeutic agent for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) and / or non-small cell lung cancer.

Description

DESCRIPTIONTitle of Invention: PHARMACEUTICAL COMPOSITION COMPRISING PYRIDAZINYL-THIAZOLECARBOXAMIDE COMPOUNDTechnical Field

[0001] The present invention relates to a pyridazinyl-thiazolecarboxamide compound which is useful as a pharmaceutical composition, for example, a diacylglycerol kinase (DGKzeta) inhibitor, and is expected to be useful as an active ingredient of, for example, a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repairdeficient bowel cancer). In an embodiment, the present invention relates to a pyridazinyl-thiazolecarboxamide compound which is useful as a pharmaceutical composition, for example, a diacylglycerol kinase (DGKzeta) inhibitor, and is expected to be useful as an active ingredient of, for example, a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy, particularly a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy.

[0002] In addition, the present invention relates to a pharmaceutical composition, comprising a pyridazinyl-thiazolecarboxamide compound, for example, diacylglycerol kinase § (DGKzeta) inhibitor as an active ingredient, in combination with a combination therapy for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) and / or non-small cell lung cancer.Background Art

[0003] Cancer immunotherapy has drawn attention as the fourth mainstay cancer treatment method following conventional surgical treatment, radiation therapy and cancer drug therapy (chemotherapy and molecular targeted drugs). It is an anti-cytotoxic T-lymphocyte antigen(CTLA)-4 antibody (ipilimumab) and an anti-PD-1 antibody (nivolumab or pembrolizumab) that have paved the way for the cancer immunotherapy. CTLA-4 and PD-1 are called immune checkpoint molecules, and function as "inhibitory checkpoint molecules".Currently, the anti-PD-1 antibody is proven to be effective in clinical practice against many cancers including melanoma and non-small cell lung cancer, and application of the anti-PD-1 antibody is expanding. In recent years, development of antibodies targeting checkpoint molecules other than CTLA-4 and PD-1 has become active throughout the world.DGK is an enzyme which converts diacylglycerol (DAG) into phosphatidic acid (PA) by phosphorylation. In mammals, DGK has ten isoforms, which are classified broadly into five types according to structural characteristics. These five types of isoforms are type I (a, p, y), type II (8, r|, K), type III (s), type IV (, i) and type V (0). All the isoforms have a catalytic domain, which is highly homologous among them, in the C-terminal portion, and a Cl domain, which has a homology with protein kinase C (PKC), in the molecule. The Cl domain is considered to be a domain to which phorbol ester / DAG binds (Int. J. Mol. Sci.2013, 14: 6649-6673).In T cells, phospholipase Cyl (PLCyl) activated by antigenic stimulation produces DAG and inositol triphosphate (IP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). The produced DAG activates a plurality of downstream signals including RAS, NF-KB and AKT pathways, leading to activation of T cells. On the other hand, IP3 activates nuclear factor of activated T cells (NF AT) signals via discharge of Ca2+from the endoplasmic reticulum, and is involved in not only activation of T cells but also induction of anergy. The anergy of T cells is an incomplete activated state caused by depression of costimulatory (CD28 signal) or inhibition of costimulatory during antigen recognition, and in this state, no response is produced even by restimulation.DGK a and DGK are two main isoforms in T cells, and each of these isoforms adjusts the intensity of the DAG signal down stream of antigenic stimulation to prevent excessive activation of T cells. Further, DGK a and DGK 5, promote anergy of T cells, and play an important role in immune tolerance of T cells (J Cell Sci. 2013, 126:2176-2186., CritRev Immunol. 2013, 33: 97-118., Immunol rev. 2008, 224: 249-264).Further, activation of T cells lacking DGK has been reported to produce resistance to inhibitory signals from PD-1, and resistance to a transforming growth factor (TGF)- and PD-1 independent immunosuppressive factors such as Adenosine and PGE2 (Cancer Res. 2017, 77: 5676-5686., Front Cell Dev Biol. 2016, 4: 108.). It has been reported that T cells having overexpressed PD-1 molecules are extremely exhausted, and that in this state, the anti-PD-1 antibody has no effect. Immunosuppressive factors such as TGF-P are considered to be one of resistance mechanisms of anti-PD-1 therapy (Cancer treatment Reviews 2017, 52: 71-81). It has been reported that in NK cells, DGK negatively controls activation of NK cells by activated receptor stimulation, and that in DGK 5, KO mice, growth of a major histocompatibility complex (MHC) class I-deficient tumor is suppressed (J Immunol. 2016, 197: 934-941).Therefore, a DGK inhibitor to be produced is expected to have antitumor effect through activation of immune cells, particularly activation of T cells. Further, it has been reported that the response rate of anti-PD-1 antibody therapy varies depending on a type of cancer, but is approximately 30% in general, (Front Immunol. 2016, 7: 550), and the DGK inhibitor is also expected to be useful for patients with resistance to anti-PD-1 antibody therapy.

[0004] The genome contains repeated sequences of short base sequences called microsatellites. During DNA replication, errors can occur in microsatellites, but these errors are usually repaired by mismatch repair (MMR) proteins. It is known that in cancer, abnormalities in MMR proteins impair MMR function, resulting in failure to repair microsatellite errors that occur during DNA replication, resulting in microsatellites showing an unusual number of repeats. Colon cancer is broadly classified into microsatellite instability-high (MSI-H) colon cancer, in which changes in the number of repeats of microsatellites occur frequently, and microsatellite stable (MSS) colon cancer, in which changes in the number of repeats of microsatellites occur infrequently or not at all. Anti-PD-1 antibodies are used as one of the standard treatments for MSI-H colon cancer. On the otherhand, clinical trials have not shown any significant therapeutic effect of anti-PD-1 antibodies against MSS colorectal cancer, and they are not currently approved as a treatment (Front Oncol. 2019, 9: 396.).

[0005] Patent Document 1 discloses that R59022 and R59499 have DGK inhibitory effect, alleviate anergy of T cells, and upregulate the immune response.[Chemical Formula 1](R59022)

[0006] Patent Document 2 discloses that the compound of the following formula has trkA receptor inhibitory effect, and is useful for treatment or prevention of frequent urination and urge to urinate associated with the hyperactive bladder, etc.[Chemical Formula 2](See the publication for the meanings of the symbols in the formula)In Patent Document 2, however, there is no specific disclosure of the use in a treatment of cancer and the compound of the present invention comprising a phenyl group having a sequence of four adjacent substituents as an indispensable constituent feature.Patent Document 3 discloses that the compound of the following formula is useful for 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 3-1](B)[Chemical Formula 3-2]Example 199(See the publication for the meanings of the symbols in the formula)In Patent Document 3, however, there is no specific disclosure of DGK and the compound of the present invention comprising a phenyl group having a sequence of four adjacent substituents as an indispensable constituent feature.Citation ListPatent Document

[0007] Patent Document 1: U. S. Patent No. 7,381,401Patent Document 2: WO 2007 / 123269Patent Document 3: WO 2008 / 054702Patent Document 4: WO 2021 / 132422Patent Document 5: WO 2022 / 114164Patent Document 6: JP2009-524677Patent Document 7: JP2014-221840Patent Document 8: W02020 / 006018Patent Document 9: JP2020-532561Patent Document 10: JP2008-528520Summary of InventionTechnical Problem

[0008] A compound which is useful as a pharmaceutical composition, for example, a DGK S, inhibitor, and is expected to be useful as an active ingredient of a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) is provide. In an embodiment, a compound which is useful as a pharmaceutical composition, for example, a DGK inhibitor, and is expected to be useful as an active ingredient of a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy, particularly a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy is provide.

[0009] In addition, a pharmaceutical composition, comprising administering an effective amount of a compound, for example, a DGK 5, inhibitor, to the subject in combination with a combination therapy for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) and / or non-small cell lung cancer is provide.Solution to Problem

[0010] The present inventors have extensively conducted studies on a compound useful as an active ingredient of a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer), in an embodiment, for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy, particularly a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy. As a result, the present inventors have found that apyridazinyl-thiazolecarboxamide compound of formula (1) has excellent DGK inhibitory effect and is useful for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer), leading to completion of the present invention. The pyridazinyl-thiazolecarboxamide compound of formula (1) comprises a phenyl group having a sequence of four adjacent substituents, which is generally considered difficult of be synthesized, as an indispensable constituent feature.That is, the present invention relates to a compound of formula (I) or a salt thereof, which has excellent DGK inhibitory effect and is useful for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer), and a pharmaceutical composition containing a compound of formula (I) or a salt thereof, and one or more pharmaceutically acceptable excipients, which has excellent DGK inhibitory effect and is useful for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer):[Chemical Formula 4]R4(I)whereinR1is a group of formula (i), (ii), (iii) (iv) or (v):[Chemical Formula 5]R2is a Ci-6 alkyl, a C3-5 cycloalkyl, an -O-(Ci-6 alkyl), methanesulphonyl, a halogeno-Ci-6 alkyl or a halogen,R3is i) a phenyl optionally substituted with a group selected from the groupconsisting of a Ci-6 alkyl, a halogeno-Ci-6 alkyl, a C3-5 cycloalkyl, an -O-(Ci-6 alkyl), an -O-(halogeno-Ci-6 alkyl), cyano, nitro, methanesulphonyl 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 halogeno-Ci-6 alkyl, a C3-5 cycloalkyl, an -O-(Ci-6 alkyl), an -O-(halogeno-C1-6 alkyl), cyano, nitro, methanesulphonyl and a halogen, iv) a pyrazolyl optionally substituted with a group selected from the group consisting of a Ci-6 alkyl and a halogen, or v) a pyrrolidinyl optionally substituted with a C1-6 alkyl,R4is H or F,L is a bond, CO, SO2, O or NH,X is CH2, O or N-methyl,Y is CH2or O,Rais H or methyl,Rbis H, methyl, ethyl or -(CH2)2O-CH3,Rcis H, methyl or oxetanyl,Rdis H, methyl, -(CH2)2OH, -(CH2)2O-CH3or oxetanyl,m is 1 or 2, andn is 1 or 2.

[0011] When symbols in a chemical formula are used in other chemical formulae in the present description, the same symbols have the same meanings unless otherwise specified.

[0012] In addition, the present invention relates to a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer), containing a compound of formula (I) or a salt thereof. Note that, the pharmaceutical composition includes a therapeutic agent for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer), containing a compound of formula (I) or a salt thereof.In addition, the present invention relates to use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treatment of colorectalcancer (except for mismatch repair-deficient bowel cancer); use of a compound of formula (I) or a salt thereof for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer); a compound of formula (I) or a salt thereof which is used for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer); and a method for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer), comprising administering an effective amount of a compound of formula (I) or a salt thereof to a subject. The "subject" is a human or another animal in need of prevention or treatment of the cancer. In an embodiment, the "subject" is a human in need of prevention or treatment of the cancer.

[0013] In addition, the present invention relates to a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy, containing a compound of formula (I) or a salt thereof, particularly a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy. Note that, the pharmaceutical composition includes a therapeutic agent for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy, containing a compound of formula (I) or a salt thereof, particularly a therapeutic agent for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy.In addition, the present invention relates to use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy, particularly for treatment ofcolorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy; use of a compound of formula (I) or a salt thereof for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy, particularly for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy; a compound of formula (I) or a salt thereof which is used for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy, particularly for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy; and a method for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a subject, particularly a method for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD- 1 antibody / anti-PD-Ll antibody therapy. The "subject" is a human or another animal in need of prevention or treatment of the cancer. In an embodiment, the "subject" is a human in need of prevention or treatment of the cancer.

[0014] In addition, the present inventors have extensively conducted studies on a pharmaceutical composition, comprising administering an effective amount of a compound of formula (I) or a salt thereof to the subject in combination with a combination therapy. As a result, the present inventors have found that a pharmaceutical composition, comprising administering an effective amount of a compound of formula (I) or a salt thereof to thesubject in combination with a combination therapy is useful for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) and / or non-small cell lung cancer, leading to completion of the present invention.In addition, the present inventors have found that a method for treatment of colorectal cancer (except for mismatch repair deficient bowel cancer) and / or non-small cell lung cancer, which comprises administering an effective amount of the pharmaceutical composition, comprising the compound of formula (I) or a salt thereof, to the subject in combination with a combination therapy. In an embodiment, the present inventors have found that a method for treatment of colorectal cancer (except for mismatch repair deficient bowel cancer), which comprises administering an effective amount of the pharmaceutical composition, comprising the compound of formula (I) or a salt thereof, to a subject in combination with a combination therapy selected from the group consisting of i) TAS- 102 and bevacizumab, ii) mFOLFOX6 chemotherapy regimen and bevacizumab, and iii) FOLFIRI chemotherapy regimen and bevacizumab. In an embodiment, the present inventors have found that a method for treatment of non-small cell lung cancer, which comprises administering an effective amount of the pharmaceutical composition, comprising the compound of formula (I) or a salt thereof, to a subject in combination with a combination therapy selected from the group consisting of i) docetaxel, ii) docetaxel and ramucirumab, and iii) pembrolizumab, carboplatin, and pemetrexed.Brief Description of Drawings

[0015] [Fig. 1] Figure 1 is a view showing the time course of tumor volume in the control group, the test compound (3 mg / kg) administration group, the standard colorectal cancer treatment group TAS-102 (100 mg / kg) and anti-VEGF-A antibody (5 mg / kg) administration group, and the combination group in a syngeneic mouse model bearing the mouse colon cancer cell line CT26. WT. The vertical axis indicates tumor volume, and the horizontal axis indicates the number of days after the first administration.[Fig. 2] Figure 2 is a view showing a scatter plot of tumor volume and standard error for each individual on the day after the final administration of the control group, the test compound (3 mg / kg) administration group, the group administered TAS-102 (100 mg / kg) and anti-VEGF-A antibody (5 mg / kg) as standard treatments for colon cancer, and the combined group in a syngeneic mouse model bearing the mouse colon cancer cell line CT26. WT. The vertical axis shows tumor volume, and the horizontal axis shows each administration group. ** indicates a significant change in tumor volume between the two groups by Student's t-test (**: P < 0.01). Advantageous Effects of Invention

[0016] A compound of formula (I) or a salt thereof has a DGK inhibitory effect, and can be used as a therapeutic agent for treatment of colorectal cancer (except for mismatch repairdeficient bowel cancer). In an embodiment, a compound of formula (I) or a salt thereof has a DGK S, inhibitory effect, and can be used as a therapeutic agent for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy, particularly a therapeutic agent for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy.

[0017] A pharmaceutical composition, comprising administering an effective amount of a compound of formula (I) or a salt thereof to the subject in combination with a combination therapy can be used as a therapeutic agent for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) and / or non-small cell lung cancer.Description of Embodiments

[0018] Hereinafter, the present invention will be described in detail.In the present description, the following terms have the following meanings unless otherwise specified. The following definitions are intended to clarify the defined terms rather than limiting the terms. If a term used herein is not specifically defined, such a term is used with a meaning which is commonly accepted by those skilled in the art.

[0019] In the present description, the " Ci-6 alkyl" is a linear or branched alkyl having 1 to 6 carbon atoms (hereinafter, abbreviated as C1-6). Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. In an embodiment, the " Ci-6 alkyl" is a C1-3 alkyl. In an embodiment, the " C1-6 alkyl" is methyl or ethyl. In an embodiment, the " C1-6 alkyl" is methyl. In an embodiment, the " C1-6 alkyl" is ethyl.

[0020] The "halogeno-Ci-6 alkyl" is a C1-6alkyl substituted with one or more halogens. In an embodiment, the "halogeno-Ci-6 alkyl" is a Ci-6 alkyl substituted with one to five halogens. In an embodiment, the "halogeno-Ci-6 alkyl" is a halogeno-C1-3alkyl substituted with one to five halogens. In an embodiment, the "halogeno-Ci-6 alkyl" is difluoromethyl or trifluoromethyl. In an embodiment, the "halogeno-Ci-6 alkyl" is trifluoromethyl.

[0021] The " C3-8 cycloalkyl" is a saturated hydrocarbon ring group of C3-8, and may be crosslinked, or may form a spiro-ring. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2,2,l]heptyl, bicyclo[3,10]hexyl, bicyclo [3, l,l]heptyl and spiro[2,5]octyl. In an embodiment, the " C3-8 cycloalkyl" is a " C3- 5 cycloalkyl". In an embodiment, the " C3-5 cycloalkyl" is cyclopropyl, cyclobutyl or cyclopentyl. In an embodiment, the " C3-5 cycloalkyl" is cyclopropyl. In an embodiment, the " C3-5 cycloalkyl" is cyclobutyl. In an embodiment, the " C3-5 cycloalkyl" is cyclopentyl.

[0022] The "halogen" is F, Cl, Br or I. In an embodiment, the "halogen" is F or Cl. In an embodiment, the "halogen" is Cl.

[0023] The term "optionally substituted" means being unsubstituted, or being "substituted with one or more substituents (e.g. substituents as defined below)". The substituent may occur at any position as long as hydrogen is normally present at the position. In an embodiment, the term "optionally substituted" means being "optionally substituted with one to five substituents". In another embodiment, the term "optionally substituted" means being "optionally substituted with one to three substituents". When there are a plurality of substituents, these substituents may be the same or different.One or more embodiments can be combined with another embodiment even thougha specific combination is not described. That is, all embodiments can be freely combined.

[0024] The "activation of immune cells" means that immune cells having the capability of suppressing growth of cancer cells or shrinking or eliminating cancer cells (hereinafter, referred to as antitumor activity), particularly T cells are reactivated, and / or that the number of immune cells, particularly activated T cells is increased. In an embodiment, the term "activation of immune cells" means activation of immune cells based on DGK ζ inhibitory effect.

[0025] The "cancer related to activation of immune cells" is a cancer having immune responsiveness. In an embodiment, the "cancer related to activation of immune cells" is a cancer in which growth of cancer cells is suppressed or cancer cells are shrunk or eliminated by activation of immune cells. In an embodiment, the "cancer related to activation of immune cells" is a cancer in which growth of cancer cells is suppressed by activation of immune cells. In an embodiment, the "cancer related to activation of immune cells" is a cancer in which growth of cancer cells are shrunk or eliminated by activation of immune cells. In an embodiment, the "cancer related to activation of immune cells" is a cancer in which growth of cancer cells is suppressed or cancer cells are shrunk or eliminated by activation of immune cells based on DGK S, inhibitory effect. In an embodiment, the "cancer related to activation of immune cells" is a cancer in which growth of cancer cells is suppressed by activation of immune cells based on DGK t, inhibitory effect. In an embodiment, the "cancer related to activation of immune cells" is a cancer in which growth of cancer cells are shrunk or eliminated by activation of immune cells based on DGK inhibitory effect.Examples of cancers to which the subject invention can be applied include, but are not limited to small cell lung cancer, head and neck cancer, kidney cancer, ovary cancer, nonsmall cell lung cancer, mismatch repair-deficient bowel cancer, urothelial cancer, melanoma, hepatocyte cancer, stomach cancer and bladder cancer.

[0026] Examples of cancers to which the subject invention can be applied include, but are not limited to colorectal cancer (except for mismatch repair-deficient bowel cancer). In anembodiment, the term " colorectal cancer (except for mismatch repair-deficient bowel cancer)” means colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells. In an embodiment, the term " colorectal cancer (except for mismatch repair-deficient bowel cancer)” or “colorectal cancer (except for mismatch repairdeficient bowel cancer) related to activation of immune cells” means Microsatellite stable (MSS) colorectal cancer.

[0027] The term "resistant to anti-PD-1 antibody / anti-PD-Ll antibody therapy" means "resistant to an anti-PD-1 antibody therapy and / or an anti-PD-Ll antibody therapy". In an embodiment, the term "resistant to anti-PD-1 antibody / anti-PD-Ll antibody therapy" means "resistant to an anti-PD-1 antibody therapy and an anti-PD-Ll antibody therapy". In an embodiment, the term "resistant to anti-PD-1 antibody / anti-PD-Ll antibody therapy" means "resistant to an anti-PD-1 antibody therapy". In an embodiment, the term "resistant to anti-PD-1 antibody I anti-PD-Ll antibody therapy" means "resistant to an anti-PD-Ll antibody therapy". In particular, the term "resistant to anti-PD-1 antibody / anti-PD-Ll antibody therapy" means that immunotherapy with an anti-PD-1 antibody and / or an anti-PD-Ll antibody becomes ineffective soon after the start of treatment (primary resistance), or acquires resistance to treatment from the middle of the treatment (acquired resistance), so that cancer cells grow again.

[0028] The "cancer resistant to anti-PD-1 antibody / anti-PD-Ll antibody therapy" means a cancer resistant to an anti-PD-1 antibody therapy and / or an anti-PD-Ll antibody therapy. In an embodiment, the "cancer resistant to anti-PD-1 antibody / anti-PD-Ll antibody therapy" means a cancer resistant to an anti-PD-1 antibody therapy and an anti-PD-Ll antibody therapy. In an embodiment, the "cancer resistant to anti-PD-1 antibody / anti-PD-Ll antibody therapy" means a cancer resistant to an anti-PD-1 antibody therapy. In an embodiment, the "cancer resistant to anti-PD-1 antibody / anti-PD-Ll antibody therapy" means a cancer resistant to an anti-PD-Ll antibody therapy. In particular, the "cancer resistant to anti-PD-1 antibody / anti-PD-Ll antibody therapy" means a cancer in which immunotherapy with an anti-PD-1 antibody and / or an anti-PD-Ll antibody becomesineffective soon after the start of treatment (primary resistance), or acquires resistance to treatment from the middle of the treatment (acquired resistance), so that cancer cells grow again.Examples of cancers to which the subject invention can be applied include cancers resistant to anti-PD-1 antibody / anti-PD-Ll antibody therapy, which include, but are not limited to, small cell lung cancer, head and neck cancer, kidney cancer, ovary cancer, nonsmall cell lung cancer, mismatch repair-deficient bowel cancer, urothelial cancer, melanoma, hepatocyte cancer, stomach cancer and bladder cancer.

[0029] Examples of cancers to which the subject invention can be applied include, but are not limited to colorectal cancer (except for mismatch repair-deficient bowel cancer). In an embodiment, the term " colorectal cancer (except for mismatch repair-deficient bowel cancer)” means colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy. In an embodiment, the term " colorectal cancer (except for mismatch repair-deficient bowel cancer)” or “colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD- 1 antibody / anti-PD-Ll antibody therapy" means Microsatellite stable (MSS) colorectal cancer.

[0030] Examples of cancers to which the subject invention can be applied include, but are not limited to colorectal cancer (except for mismatch repair-deficient bowel cancer). In an embodiment, the term " colorectal cancer (except for mismatch repair-deficient bowel cancer)” means colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy. In an embodiment, the term " colorectal cancer (except for mismatch repair-deficient bowel cancer)” or “colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD- 1 antibody / anti-PD-Ll antibody therapy" means Microsatellite stable (MSS) colorectal cancer.

[0031] Examples of "anti-PD-1 antibody / anti-PD-Ll antibody" include, but are not limitedto, an antibody selected from Nivolumab, Pembrolizumab, Atezolizumab, Pidilizumab, Avelumab and Durvalumab.

[0032] An embodiment of the compound of formula (I) or a salt thereof of the present invention will be shown below:(1-1) A compound or a salt thereof in which R1is a group of the following formula (i), (ii), (iii) (iv) or (v):[Chemical Formula 6]H(1-2) A compound or a salt thereof in which R1is a group of the following formula (i-a), (ii-a), (iii-a) or (v):[Chemical Formula 7](1-3) A compound or a salt thereof in which R1is a group of the following formula (i), (ii), (iii) or (iv):[Chemical Formula 8](1-4) A compound or a salt thereof in which R1is a group of the following formula (i-a), (ii-a) or (iii-a):[Chemical Formula 9](i-a) (ii-a) (iii-a)(2) A compound or a salt thereof in which R2is a Ci-6 alkyl, a C3-5 cycloalkyl, an -O-(C1-6 alkyl), methanesulphonyl, a halogeno-Ci-6 alkyl or a halogen; in an embodiment, a compound or a salt thereof in which R2is a halogeno-Ci-6 alkyl or a halogen; in an embodiment, a compound or a salt thereof in which R2is a halogeno-Ci-3 alkyl, F, Cl or Br; in an embodiment, a compound or a salt thereof in which R2is CF3, F or Cl; in an embodiment, a compound or a salt thereof in which R2is CF3; in an embodiment, a compound or a salt thereof in which R2is F; or in an embodiment, a compound or a salt thereof in which R2is Cl;(3-1) A compound or a salt thereof in which R3is i) a phenyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a halogeno-Ci-6 alkyl, a C3-5 cycloalkyl, an -O-(C 1-6 alkyl), an -O-(halogeno-C 1-6 alkyl), cyano, nitro, methanesulphonyl 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 halogeno-Ci-6 alkyl, a C3- 5 cycloalkyl, an -O-(Ci-6 alkyl), an -O-(halogeno-Ci-6 alkyl), cyano, nitro, methanesulphonyl and a halogen, iv) a pyrazolyl optionally substituted with a group selected from the group consisting of a Ci-6 alkyl and a halogen, or v) a pyrrolidinyl optionally substituted with a Ci- 6 alkyl;(3-2) A compound or a salt thereof in which R3is 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 in which R3is i) a phenyl optionally substituted with a group selected from the group consisting of a Ci-6 alkyl, a halogeno-Ci-6 alkyl, a C3. 5 cycloalkyl, an -O-(Ci-6 alkyl), an -O-(halogeno-Ci-6 alkyl), cyano, nitro, methanesulphonyl and a halogen, or ii) a C3-8 cycloalkyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl and a halogen;(3-4) A compound or a salt thereof in which R3is a phenyl optionally substituted with a group selected from the group consisting of a Ci-6 alkyl and a halogen, or a C3-5 cycloalkyl;(4) A compound or a salt thereof in which R4is H or F; in an embodiment, a compound or a salt thereof in which R4is H; or in an embodiment, a compound or a salt thereof in which R4is F;(5) A compound or a salt thereof in which L is a bond, CO, SO2, O or NH; in an embodiment, a compound or a salt thereof in which L is a bond, O or NH; in an embodiment, a compound or a salt thereof in which L is O or NH; in an embodiment, a compound or a salt thereof in which L is O; or in an embodiment, a compound or a salt thereof in which L is NH;(6) A compound or a salt thereof in which X is CH2, O or N-methyl; in an embodiment, a compound or a salt thereof in which X is CH2 or N-methyl; in an embodiment, a compound or a salt thereof in which X is CH2; or in an embodiment, a compound or a salt thereof in which X is N-methyl;(7) A compound or a salt thereof in which Y is CH2 or O; in an embodiment, a compound or a salt thereof in which Y is CH2; or in an embodiment, a compound or a salt thereof in which Y is O;(8) A compound or a salt thereof in which Rais H or methyl; in an embodiment, a compound or a salt thereof in which Rais H; or in an embodiment, a compound or a salt thereof in which Rais methyl;(9) A compound or a salt thereof in which Rbis H, methyl, ethyl or -(CH2)2O-CH3; in an embodiment, a compound or a salt thereof in which Rbis H or methyl; in an embodiment, a compound or a salt thereof in which Rbis H; or in an embodiment, acompound or a salt thereof in which Rbis methyl;(10) A compound or a salt thereof in which Rcis H, methyl or oxetanyl; in an embodiment, a compound or a salt thereof in which Rcis H or methyl; in an embodiment, a compound or a salt thereof in which Rcis H; or in an embodiment, a compound or a salt thereof in which Rcis methyl;(11) A compound or a salt thereof in which Rdis H, methyl, -(CH2)2OH, -(CH2)2O-CH3 or oxetanyl; in an embodiment, a compound or a salt thereof in which Rdis -(CH2)2OH or -(CH2)2O-CH3; in an embodiment, a compound or a salt thereof in which Rdis -(CH2)2OH; or in an embodiment, a compound or a salt thereof in which Rdis -(CH2)2O-CH3;(12) A compound or a salt thereof in which m is 1 or 2; in an embodiment, a compound or a salt thereof in which m is 1; or in an embodiment, a compound or a salt thereof in which m is 2;(13) A compound or a salt thereof in which n is 1 or 2; in an embodiment, a compound or a salt thereof in which n is 1; or in an embodiment, a compound or a salt thereof in which n is 2; or(14) A compound or a salt thereof that is a combination of arbitrary two or more of embodiments (1-1) to (13), which does not cause a contradiction.

[0033] Specific examples of the combination described in (14) include the following embodiments:(15) A compound or a salt thereof in which R1is a group of the following formula (i), (ii), (iii) (iv) or (v):[Chemical Formula 10]whrein R2is a C1-6 alkyl, a C3-5 cycloalkyl, an -O-(Ci-6 alkyl), methanesulphonyl, a halogeno-Ci-6 alkyl or a halogen; R3is i) a phenyl optionally substituted with a group selected from the group consisting of a Ci-6 alkyl, a halogeno-Ci-6 alkyl, a C3-5 cycloalkyl, an -O-(Ci-6 alkyl), an -O-(halogeno-Ci-6 alkyl), cyano, nitro, methanesulphonyl 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 halogeno-Ci-6 alkyl, a C3-5 cycloalkyl, an -O-(Ci-6 alkyl), an -O-(halogeno-C1-6 alkyl), cyano, nitro, methanesulphonyl 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; R4is H or F; L is a bond, CO, SO2, O or NH; X is CH2, O or N-methyl; Y is CH2 or O; Rais H or methyl; Rbis H, methyl, ethyl or -(CH2)2O-CH3; Rcis H, methyl or oxetanyl; Rdis H, methyl, -(CH₂)₂OH, -(CH₂)₂O-CH₃ or oxetanyl; m is 1 or 2; n is 1 or 2;(16) The compound or the salt thereof described in (15) in which R2is a halogeno-C1-6 alkyl or a halogen; L is a bond, O or NH; X is CH2 or N-methyl; Rcis H or methyl; m is 1;(17) The compound or the salt thereof described in (16) in which R1is a group of the following formula (i-a), (ii-a), (iii-a) or (v):(18) The compound or the salt thereof described in (17) in which R3is a phenyl optionally substituted with a group selected from the group consisting of a 1-6 alkyl and a halogen, or a C3-5 cycloalkyl;(19) The compound or the salt thereof described in (18) in which R2is CF3, R4is H, Rbis H or methyl and Rcis H.

[0034] Specific examples of the combination described in (14) include the followingembodiments:(20) A compound or a salt thereof in which R1is a group of the following formula (i), (ii), (iii) or (iv):[Chemical Formula 12]whrein R2is a halogeno-Ci-6 alkyl or a halogen; R3is i) a phenyl optionally substituted with a group selected from the group consisting of a Ci-6 alkyl, a halogeno-Ci-6 alkyl, a C3- 5 cycloalkyl, an -O-(Ci-6 alkyl), an -O-(halogeno-Ci-6 alkyl), cyano, nitro, methanesulphonyl 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 halogeno-Ci-6 alkyl, a C3- 5 cycloalkyl, an -O-(C 1-6 alkyl), an -O-(halogeno-Ci-6 alkyl), cyano, nitro, methanesulphonyl 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 Ci- 6 alkyl; R4is H or F; L is a bond, O or NH; X is CH2, O or N-methyl; Y is CH2 or O; Rais H or methyl; Rbis H, methyl, ethyl or -(CH₂)₂O-CH₃; Rcis H, methyl or oxetanyl; Rdis H, methyl, -(CH₂)₂OH, -(CH₂)₂O-CH₃ or oxetanyl; m is 1 or 2; and n is 1 or 2;(21) A compound or the salt thereof described in according to (20), in which R1is a group of formula (i), (ii), (iii) or (iv):[Chemical Formula 13]R2is a halogeno-Ci-6 alkyl or a halogen; R3is i) a phenyl optionally substituted with a group selected from the group consisting of a Ci-6 alkyl, a halogeno-Ci-6 alkyl, a C3-5 cycloalkyl, an -O-(Ci-6 alkyl), an -O-(halogeno-Ci-6 alkyl), cyano, nitro, methanesulphonyl 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 halogeno-Ci-6 alkyl, a C3-5 cycloalkyl, an -O-(Ci-6 alkyl), an -O-(halogeno-C 1-6 alkyl), cyano, nitro, methanesulphonyl and a halogen, iv) apyrazolyl 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; R4is H or F; L is O or NH; X is CH2 or N-methyl; Y is CH2 or O; Rais H; Rbis H, methyl, ethyl or -(CH2)2O-methyl; Rcis H or methyl; Rdis H, methyl, -(CH₂)₂OH, -(CH₂)₂O-CH₃ or oxetanyl; m is 1; and n is 1 or 2;(22) The compound or the salt thereof described in (21) in which R1is a group of formula (i-a), (ii-a) or (iii-a):[Chemical Formula 14](iii-a)(23) The compound or the salt thereof described in (22) in which R3is 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;(24) The compound or the salt thereof described in (23) in which R2is CF3, R4is H, Rbis H or methyl and Rcis H.

[0035] Examples of specific compounds encompassed by the present invention include the following compounds or salts thereof:N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide;N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-(3-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)- 1,3-thiazole-4-carboxamide;N- {2-[9-(2 -methoxy ethyl)- 1 -oxa-4,9-diazaspiro [5.5]undecan-4-yl] -4-phenoxy-3 -(trifluoromethyl)phenyl} -2-(pyridazin-4-yl)- 1,3-thiazole-4-carboxamide;N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)- 1,3-thiazole-4-carboxamide;N-[4-(2-fhiorophenoxy)-2-{(3S)-3-[(methylamino)methyl]piperidin-l-yl}-3-(trifhioromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide;N-{2-[(2R)-2-(aminomethyl)pyrrolidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-y 1)- 1, 3 -thiazo le-4-carboxamide;N-{2-[(8R,8aS)-8-aminohexahydropyrrolo[l,2-a]pyrazine-2(lH)-yI]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide; andN-{2-[(8R,8aS)-8-(dimethylamino)hexahydropyrrolo[l,2-a]pyrazine-2(lH)-yl]-4-phenoxy-3-(trifhioromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide.

[0036] Examples of specific compounds encompassed by the present invention include the following compounds or salts thereof:N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide;N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-(3-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)- 1,3-thiazole-4-carboxamide;N-{2-[9-(2-methoxyethyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide;N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide;N-[4-(2-fluorophenoxy)-2-{ (3 S)-3 - [(methylamino)methyl]piperidin- 1 -yl } -3 -(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide; andN-{2-[(2R)-2-(aminomethyl)pyrrolidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)- 1,3-thiazole-4-carboxamide.

[0037] Examples of specific compounds encompassed by the present invention include the following compounds or salts thereof:N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide mono[(2E)-but-2-enedioate];N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-(3-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide mono[(2E)-but-2-enedioate];N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide mono[(2E)-but-2-enedioate];N-[4-(2-fluorophenoxy)-2-{(3S)-3-[(methylamino)methyI]piperidin-l-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide mono[(2E)-but-2-enedioate]; andN-{2-[(2R)-2-(aminomethyl)pyrrolidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide mono[(2E)-but-2-enedioate],

[0038] The compound of formula (I) can have tautomers and geometric isomers depending on the type of a substituent. In the present description, the compound of formula (I) or a salt thereof may be described in only one isomer 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, based on which enantiomers (optical isomers) can be present. The compound of formula (I) or a salt thereof encompass all of isolated individual enantiomers such as (R) and (S) configurations and mixtures thereof (including racemic mixtures or non-racemic mixtures). In an embodiment, the enantiomer is "stereochemically pure". Theterm "stereochemically pure" refers to a purity with which those skilled in the art can recognize the enantiomer as being substantially 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.

[0039] The salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and an acid addition salt or a salt with a base may be formed depending on the type of a substituent. Specific examples thereof 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, ditoluoyltartaric 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 acetylleucine, and amino acid derivatives.

[0040] Further, the present invention encompasses various hydrates, solvates and substances of crystalline polymorphism of the compounds of formula (I) and salts thereof.Furthermore, the present invention encompasses pharmaceutically acceptable prodrugs of the compounds of formula (I). The pharmaceutically acceptable prodrug is a compound having a group which 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 that forms the prodrug include groups as described in Prog. Med., 5, 2157-2161 (1985) and " Pharmaceutical research and development" (Hirokawa Shoten Co., 1990), Vol. 7, Molecular Design, 163-198.

[0041] The present invention encompasses all of compounds of formula (I) which are labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes, or salts thereof. Examples of preferred isotopes used for isotope labels for the compound of the present invention include isotopes of hydrogen (e.g.2H and3H), carbon(e.g.11C,13C and14C), nitrogen (e.g.13N and15N), oxygen (e.g.150,17O and18O), fluorine (e.g.18F), chlorine (e.g.36C1), iodine (e.g.123I and125I), phosphorus (e.g.32P) and sulfur (e.g.35S).The isotopically labeled compound of the invention of the present application can be used for studies on 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 from the viewpoint of ease of labeling and convenience of detection.Replacement by a heavier isotope, for example replacement of hydrogen by deuterium (2H) may be therapeutically advantageous because metabolic stability is improved (e.g. increased in vivo half-life, decreased necessary dose or declined drug interaction).Replacement by positron-emitting isotopes (e.g.11C,18F,15O and13N) can be applied in positron emission tomography (PET) tests for examining the substrate acceptor occupancy rate.The isotopically labeled compound of the present invention can be generally prepared by a conventional method known to those skilled in the art, or by the same production method as in Examples or Production Examples using appropriate isotopically labeled reagents instead of non-labeled reagents.

[0042] In powder X-ray diffraction described in the subject specification, the crystal lattice distance and the entire pattern are important for the identification of crystals in view of the characteristics of the data. A diffraction angle and intensity may slightly vary depending on the direction of crystal growth, the particle size, and the measuring conditions, and should not be interpreted strictly. As used herein, the diffraction angle (20) in the powder X-ray diffraction pattern is interpreted with a margin of error generally acceptable in the measurement, for example, a margin of error of ±0.2°. Moreover, for example, a peak which is nearby a peak derived from excipients and on a tilted baseline of the peak can visually shift by ±0.3° in the case that powder X-ray measurement is performed in the state of a mixture with excipients.

[0043] (Preparing Method)The compound of formula (I) and a salt thereof can be prepared by applying various known synthesis methods by making use of characteristics based on the basic structure or the type of a substituent of the compound. Here, depending on the type of a functional group, replacement of the functional group by an appropriate protective group (group easily convertible into the functional group) during formation of an intermediate from a raw material may be effective as a production technique. Examples of the protective group include protective groups as described in P. G. M. Wuts and T. W. Greene, " Greene's Protective Groups in Organic Synthesis (Vol. 4, 2006)", and according to the reaction conditions, an appropriate protective group may be selected and used. In this method, such a protective group is introduced, and a reaction is carried out, followed by removing the protective group if necessary to obtain a desired compound.The prodrug for the compound of formula (I) can be prepared by introducing a specific group during formation of an intermediate from a raw material as in the case of the above-described protective group, or by further carrying out a reaction using the resulting compound of formula (I). The reaction can be carried out by applying a method known to those skilled in the art, such as common esterification, amidation or dehydration.Hereinafter, 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.

[0044] In the present description, the following abbreviations may be used.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, CH2CI2 = dichloromethane.Boc = tert-butoxycarbonyl, Ph = phenyl, tBu = tert-butyl, Et = ethyl, Me = methyl, Ac = acetyl, Ns = 2-nitrobenzenesulfonyl.CDI = l,l'-carbonylbis(lH-imidazole), DCC = N, N'-dicyclohexylcarbodiimide,TEA = triethylamine, DIPEA = N, N-diisopropylethylamine, DABCO = 1,4-diazabicyclo[2.2.2]octane, DPPA = diphenylphosphoryl azide, HATU = O-(7-azabenzotriazol-l-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate, HOBt = 1-hydroxybenzotriazole, KOtBu = potassium tert-butoxide, NaOtBu = sodium tert-butoxide, NMO = N-methylmorpholine, Pd / C = palladium-carrying carbon, TFA = trifluoroacetic acid, TFAA = trifluoroacetic anhydride, WSC. HC1 =N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride.Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium, PdCl2(PPh3)2= bis(triphenylphosphine)palladium (II) dichloride, Pd(dppf)Cl2·CH2Cl2= [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane adduct, Pd2(dba)3 = (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one / palladium (3:2).brine = saturated NaCl aqueous solution, MgSO4= anhydrous magnesium sulfate, Na2SC>4 = anhydrous sodium sulfate, NaHCCh = sodium hydrogencarbonate, NH4CI = ammonium chloride, NaBH(0Ac)3 = sodium triacetoxyborohydride.

[0045] [Chemical Formula 15]o(wherein Rlarepresents R1or a protecting group-adduct of R1)

[0046] (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 by heating under acidic conditions in a mixed solvent of methanol, ethanol, 1,4-dioxane or the like and water for 1 hour to 5 days. As the acid, NH4CI, AcOH, HC1 or the like is used. As the metal, Fe, Zn, Sn or the like is used.In addition, this reaction can be carried out by stirring compound (1) in the presence of a metal catalyst under cooling or heating, preferably at room temperature, in a solvent inactive to the reaction, such as MeOH, EtOH or EtOAc, and a mixed solvent thereof, in a hydrogen atmosphere for 1 hour to 5 days. As the metal catalyst, palladium catalysts such as Pd / C, palladium black and palladium hydroxide-carrying carbon, platinum catalysts such as platinum-carrying carbon and platinum oxide, nickel catalysts such as reduced nickel and Raney nickel, and the like are used.

[0047] (Second Step)This step is a method in which compound (2) and compound (3) are subjected to an amidation reaction, and substituents are then appropriately converted to obtain the compound of formula (I).In the amidation reaction, compound (2) and compound (3) are used in such a manner that the amounts of the compounds are equal to each other, or the amount of one of the compounds is excessive, and a mixture of the compounds is stirred in the presence of a condensing agent under cooling or heating, preferably at -20°C to 60°C, in a solvent inactive to the reaction, typically for 0.1 hours to 5 days. The solvent used here is not particularly limited, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as CH2CI2, 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 the condensing agent include, but are not limited to, WSC. HC1, DCC, CDI, DPPA, POCI3 and HATU. Use of an additive (e.g. HOBt) may be favorable to the reaction. It may be advantageous 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 for causing the reaction to smoothly proceed.In addition, an amidation reaction can be used in which compound (3) is converted into a reactive derivative, and then reacted with compound (2). Examples of the reactive derivative of compound (3) include acid halides obtained by reaction of the compound with a halogenating agent such as POCI3 or S0CI2, mixed acid anhydrides obtained by reaction ofthe compound with isobutyl chloroformate or the like, and active esters obtained by condensing the compound with HOBt or the like. This reaction can be carried out under cooling or under reflux by heating, preferably at -20°C to 120°C, in a solvent inactive to the reaction, such as a halogenated hydrocarbon, an aromatic hydrocarbon or an ether.After the amidation reaction, a protective group is introduced and / or removed if necessary, and substituents are appropriately converted to obtain the compound of formula (I). For example, if Rlaof compound (3) is a protecting group-adduct of R1, the protective group can be removed under appropriate reaction conditions to obtain the compound of formula (I).

[0048] (Synthesis of Raw Material)[Chemical Formula 16](7)(wherein LG1and LG2each represent a leaving group. LG1and LG2are different from each other, which may be halogens etc.)

[0049] This production method is a method for preparing raw material compound (1). (Third Step)This step is a method in which compound (6) is prepared from compound (5) through an ipso-substitution reaction.In this reaction, the compound is stirred under cooling or under reflux by heating, preferably at 0°C to 120°C, in a solvent inactive to the reaction or under a solvent-free condition, typically for 0.1 hours to 5 days. The solvent used here is not particularly limited, and examples thereof include halogenated hydrocarbons such as CH2CI2, 1,2-dichloroethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene,ethers such as diethyl ether, THF, 1,4-dioxane and 1,2-dimethoxyethane, DMF, DMSO, NMP, EtOAc, MeCN, and mixtures thereof. It may be advantageous 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, Na2CC>3, CS2CO3 or NaOtBu for causing the reaction to smoothly proceed.

[0050] (Fourth Step)This step is a method in which compound (7) is prepared through a Suzuki coupling reaction using compound (5) and an organoboron compound, or a method in which compound (7) is prepared through 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 inactive to the reaction typically for 0.1 hours to 5 days. The solvent used here is not particularly limited, and examples thereof 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 the base include inorganic bases such as NaH, K2CO3, Na2CO3, CS2CO3, K3PO4 and CsF. Examples of the palladium catalyst include Pd(PPh3)4, PdC12(PPh3)2, Pd(dppf)Cl2·CH2Cl2and Pd2(dba)3. It may be advantageous to carry out the reaction in the presence of a ligand such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (SPhos) for causing the reaction to smoothly proceed. It may be advantageous to heat the reaction mixture by microwave irradiation for causing the reaction to smoothly proceed. As references for this reaction, for example, it is possible to refer to the following.J. Am. Chem. Soc. 127, 4685-4696, 2005Angew. Chem., Int. Ed. Engl. 34, 1384-1350, 1995In addition, this step is a method in which compound (7) is prepared from compound (5) through an ipso-substitution reaction. The reaction conditions are the same as in thethird step.

[0051] (Fifth and Sixth Steps)This step is a method in which compound (1) is prepared from compound (6) or (7) through an ipso-substitution reaction.The reaction conditions are the same as in the third step.

[0052] In an alternative method for preparing compound (1), compound (5a) in which R2of compound (5) is substituted with a leaving group such as halogens, can be used as a raw material (the leaving group such as halogens is referred to as LG3, which differs from LG1and LG2). Compound (7a) in which R2of compound (7) is substituted with LG3, is prepared from compound (5a), as in the fourth step. Then, compound (la) in which R2of compound (1) is substituted with LG3, is prepared as in the sixth step, and compound (1) is prepared as in the fourth step.

[0053] The compound of formula (I) is isolated as a free compound, or a salt, a hydrate, a solvate or a crystal-polymorphic substance thereof, and purified. The salt of the compound of formula (I) can be prepared by subjecting the compound to a conventional salt formation reaction.The isolation and purification is performed by applying normal chemical operations such as extraction, fractional crystallization and various kinds of chromatography.Various isomers can be prepared by selection of an appropriate raw material compound, or separated by making use of a difference in physicochemical properties between isomers. For example, optical isomers can be obtained by a general method for optically resolving racemates (e.g. fractional crystallization to derive a diastereomer salt with an optically active base or acid, or chromatography using a chiral column), or prepared from an appropriate optically active raw material compound.

[0054] The pharmacological activity of the compound of formula (I) can be confirmed through the following test, or a known improvement test. In the present description, the dose of a test compound is shown in terms of a weight in a free form. When a commercially available reagent, kit or the like is used, the test can be conducted in accordance with theinstructions of the commercially available product.

[0055] Test Example 1: Evaluation of DGK Inhibitory EffectThe inhibitory effect of a test compound on human recombinant DGK ζ (Carna Biosciences, Inc., 12-410-20N) was examined by the following method in which detection is performed with ADP-Glo ™ Kinase Assay (Promega Corporation).To a 384-well plate (Greiner Bio-One Co., Ltd.), 3 µL of a DGK ζ enzyme dissolved in an assay buffer (40 mM Tris-HCl pH 7.5, 10 mM MgCl2, 1 mM dithiothreitol (DTT) and 0.1 mg / mL bovine serum albumin (BSA)) (90 ng / mL) was added, and 3 pL of the test compound diluted with the same assay buffer was added so that an intended final concentration was obtained. The mixture was left standing at room temperature for 15 minutes, 3 pL of a substrate (150 pM l-oleoyl-2-acetyl-sn-glycerol (Sigma-Aldrich Co. LLC.), 480 pM phosphatidyl serine (Avanti Polar Lipids, Inc.) and 150 pM UltraPure-ATP (attached to ADP-Glo)) was then added, and the mixture was left standing at room temperature for 30 minutes to react. Thereafter, 3 pL of an ADP-Glo Reagent was added, and the mixture was left standing at room temperature for 40 minutes to stop the enzyme reaction. Further, 6 pL of a Kinase-Detection Reagent was added, the mixture was left standing at room temperature for 30 minutes, and the luminescence was then measured using ARVO X3 (PerkinElmer, Inc.). The half maximal inhibitory concentration (IC50) was calculated by Sigmoid-Emax model non-linear regression analysis, where the signal value in solvent treatment was set to 0% inhibition and the signal value without addition of the DGK enzyme was set to 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 the Example 199 described in the international publication WO 2008 / 054702.

[0056] [Table 1]IC50(nM) Ex IC50(nM) Ex IC50(nM) Ex IC50(nM)(nM) (nM) (nM) (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 2022 5 44 19 66 32 cpd. C >2000

[0057] Test Example 2: Evaluation of IL-2 Production in human T Cell Leukemia Cell Line Jurkat E6.1The effect of the test compound on the IL-2 production by T cell receptor (TCR) stimulation (anti-CD3 / anti-CD28) in Jurkat E6.1 cells (ECACC, 88042803) was evaluated.A 5 pg / mL anti-CD3 antibody (eBioscience, Inc., OKT3 clone) diluted with phosphate buffer saline (PBS) was added to a 96-well plate (Iwaki & Co., Ltd.) at50 pL / well, and left standing at 4°C for 12 hours or more to provide an anti-CD3 antibody- coated plate in advance. When the plate was used for experiments, the plate was washed with 200 pL of PBS once, an anti-CD28 antibody (eBioscience, Inc., 28.2 clone) diluted to aconcentration of 10 pg / mL with a culture medium (RPMI1640 (Sigma-Aldrich Co. LLC.) containing 10% fetal bovine serum (Hyclone Laboratories, Inc.)) was then added at10 pL / well, and the plate was used for assay as a culture plate for TCR stimulation.Subsequently, the test compound was mixed with Jurkat E6.1 cells in such a manner that an intended final concentration was obtained, and the mixture was plated at 90 pL / well so that the number of cells per well was 1 x 105(that is, finally the culture was performed at 1 x 105cells / 100 pL / well). For culture cell conditions, the culture was performed at 37°C in the presence of 5% CO2using RPMI1640 medium containing 10% fatal bovine serum.After 24 hours, the culture supernatant was collected, and IL-2 was quantitatively determined using AlphaLISA human IL2 Immunoassay Research Kit (PerkinElmer, Inc.). The IL-2 measurement was performed under Alpha Screen standard setting conditions (the fluorescence intensity at 570 nm was measured with an excitation wavelength of 680 nm) using EnVision 2104-0010 and EnVision 2104-0020 (PerkinElmer, Inc.). The IL- 2 quantitative value of the solvent treatment control was set to 1, and the test compound concentration at which the IL-2 quantitative value of the test compound treatment sample increased to 10 times the IL-2 quantitative value of the control (EC10fold) was calculated by inverse estimation with the aid of Sigmoid-Emax model non-linear 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.

[0058] [Table 2]EC10foldEx(nM)9 1810 17311 3233 934 3059 3678 2780 5

[0059] Test Example 3: Evaluation of Antitumor Effect in Syngeneic Mouse Model Bearing Mouse Colon Adenocarcinoma Cell Line MC38A cell suspension liquid prepared by suspending MC38 cells (supplied from National Cancer Institute) in PBS at 4.0 x 106cells / mL was subcutaneously inoculated into 6-week-old female mice (C57BL / 6J from Charles River Laboratories Japan, Inc.) in a volume of 50 µL. 4 days after the inoculation, the mice were grouped in such a manner that there was substantially no difference in tumor volume between groups, and administration of the test compound was started. The test was conducted with a solvent group and a test compound administration group each having 10 mice. 0.5% methylcellulose (Shin-Etsu Chemical Co., Ltd.) was orally administered to the solvent group, and 0.5% methylcellulose mixed with the test compound was orally administered to the test compound administration group. The administration was performed twice a day from day 1 to day 10 and once a day on day 11, and the tumor diameter and the body weight were measured twice a week. The following expression was used for calculation of the tumor volume.[Tumor volume (mm3)] = [tumor major diameter (mm)] x [tumor minor diameter (mm)]2x 0.5The relative tumor growth inhibition (%) of the test compound was calculated, where the tumor volume of the test compound administration group immediately before the start of administration was set to 100% inhibition, and the tumor volume of the solvent group on the last day of administration was set to 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.

[0060] [Table 3]Ex Dose (mg / kg) Antitumor effect9 5 64% Inhibition10 4.7 60% Inhibition11 5 63% Inhibition33 5 36% Inhibition34 5 55% Inhibition

[0061] Test Example 4: Evaluation of Antitumor Effect in Syngeneic Mouse ModelBearing Mouse Melanoma Cell Line B16-F1A cell suspension liquid prepared by suspending B16-F1 cells (ATCC, CRL-6323) in PBS at 2.0 x 106cells / mL or 1.0 x 107cells / mL was subcutaneously inoculated into 5-week-old female mice (C57BL / 6J from Charles River Laboratories Japan, Inc.) in a volume of 50 pL. 5 days after the inoculation, the mice were grouped in such a manner that there was substantially no difference in tumor volume between groups, and administration of the test compound was started. The test was conducted with a solvent group and a test compound administration group each having 10 mice. 0.5% methylcellulose was orally administered to the solvent group, and 0.5% methylcellulose mixed with the test compound was orally administered to the test compound administration group. The administration was performed according to the regimen described in Table 4, and the tumor diameter and the body weight were measured twice a week. The following expression was used for calculation of the tumor volume.[Tumor volume (mm3)] = [tumor major diameter (mm)] x [tumor minor diameter (mm)]2x 0.5The relative tumor growth inhibition (%) of the test compound was calculated, where the tumor volume of the test compound administration group immediately before the start of administration was set to 100% inhibition, and the tumor volume of the solvent group on the day after the last administration was set to 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.

[0062] [Table 4]Ex Dose Frequency of Duration of Number of Antitumor (mg / kg) administration administration cells for inoculation effect (day) (cell number)9 0.5 2 / day 10 5xl0536% Inhibition 10 0.1 1 / day 8 IxlO542% Inhibition 34 1.5 2 / day 10 5xl0548% Inhibition 59 0.1 1 / day 8 IxlO546% Inhibition 78 0.3 1 / day 10 IxlO530% Inhibition80 0.03 1 / day 10 IxlO530% Inhibition

[0063] The results of the above test showed that some compounds of formula (I) had DGK ζ inhibitory effect (Test Example 1). It was also confirmed that some compounds of formula (I) had the capacity to produce IL-2 in human T cell leukemia cell line (Test Example 2). Further, it was confirmed that some compounds of formula (I) had an antitumor effect in the mouse model (Test Examples 3 and 4). In particular, it was confirmed that some compounds of formula (I) showed an antitumor effect in the mice bearing B16-F1 cells, which were used in the Test Example 4, although it is generally known that anti-PD-1 antibody / anti-PD-Ll antibody does not show a pharmacological efficacy in B16-F1 cells. Therefore, the compound of formula (I) can be used for treatment of cancer related to activation of immune cells or a cancer having resistance to anti-PD- 1 antibody / anti-PD-Ll antibody therapy etc., particularly cancer related to activation of immune cells, which has resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy, etc.

[0064] Test Example 5: Evaluation of Antitumor Effect in Syngeneic Mouse Model Bearing a murine colorectal cancer cell line CT26. WTCT26. WT cells (purchased from American Type Culture Collection) were suspended in PBS and cell suspensions prepared in 4.0x107 cell / mL were planted subcutaneously in 5-week-old female mice (BALB / cAnNCrlCrlj, Charles River, Japan) at a volume of 50pL. Five days after planting, the animals were divided into groups so that the tumor volume between the groups was almost equal, and the administration of the test compound was started. The test was conducted in 10 animals each in the vehicle group and the test compound-treated group, and the test compound was orally administered in a mixture of 0.5% methylcellulose (Shin-Etsu Chemical Co., Ltd.) in the vehicle group and 0.5% methylcellulose in the test compound-treated group. The treatment was given once daily for 14 days from the first day. All individuals also received intraperitoneal PBS and saline, and tumor diameter and body weight were measured twice a week. The following equation was used to calculate tumor volume:[Tumor volume (mm3)] = [tumor major diameter (mm)] x [tumor minor diameter (mm)]2x 0.5.The percentage inhibition of tumor growth by the test compound is shown on xx of the table. The percentage inhibition of tumor growth was calculated as 100% inhibition of the tumor volume in the test compound treatment group immediately before the start of administration and 0% inhibition of the tumor volume in the vehicle group on the day of completion of administration. Table 5 shows the results for some test compounds of formula (I). In the table, Ex represents the number of each Example described below.

[0065] [Table 5]Ex Dose (mg / kg) Antitumor effect9 3 44% inhibition

[0066] Test Example 6: Evaluation of the anti-tumor effect combined with standard colorectal cancer drugs in syngeneic mouse model bearing the mouse colorectal cancer cell line CT26. WTA cell suspension liquid prepared by suspending CT26. WT cells (ATCC, CRL-2638) in PBS at 1.0×107cells / mL was subcutaneously inoculated into 6-week-old female mice (BALB / cJ, The Jackson Laboratory Japan, Inc., Japan) in a volume of 100 pL. Five days after the inoculation, the mice were allocated with similar mean tumor volumes among groups, and administration of the test compound and standard colorectal cancer drugs was started. The test was conducted with a control group, a test compound administration group, a standard colorectal cancer drugs administration group and a combination group of 10 mice each. TAS- 102 (Angene, AG00FFPP) and anti-VEGF-A antibody (BioXCell, BE0399, anti-mVEGF-A Ab) were used as standard colorectal cancer drugs. The control group was administered with 0.5% methylcellulose (Shin-Etsu Chemical Co., Ltd.) and 0.5% hydroxymethylcellulose (SIGMA-ALDRICH) orally, and PBS intraperitoneally. The test compound administration group was administered with 0.5% methylcellulose mixed with the test compound (3 mg / kg) and 0.5% hydroxymethylcellulose orally, and PBS intraperitoneally. The standard colorectal cancer drugs administration group was administered with 0.5% methylcellulose and 0.5% hydroxymethylcellulose mixed with TAS-102 (100 mg / kg) orally, and anti-VEGF-A antibody (5 mg / kg) intraperitoneally. The combination group was administered with 0.5%methylcellulose mixed with the test compound (3 mg / kg) and 0.5% hydroxymethylcellulose mixed with TAS-102 (100 mg / kg) orally, and anti-VEGF-A antibody (5 mg / kg) intraperitoneally. The test compound and TAS-102 were administered once daily for 14 days, and the anti-VEGF-A antibody was administered twice weekly. The tumor diameter and the body weight were measured twice weekly. The following equation was used to calculate the tumor volume:[Tumor volume (mm3)] = [tumor major diameter (mm)] x [tumor minor diameter (mm)]2x 0.5The relative tumor growth inhibition (%) of each group is calculated, where the tumor volume of the control group immediately before the start of administration is set to 100% inhibition, and the tumor volume of the control group on the day after the last administration is set to 0% inhibition.

[0067] The results of the above tests are shown in Figures 1 and 2. The test compound was confirmed to have an antitumor effect in a mouse model (Test Example 5). Furthermore, the group administered the test compound in combination with the standard colorectal cancer drugs showed a stronger tumor growth inhibitory effect than the group administered the test compound or the group administered the standard colorectal cancer drugs (Test Example 6).

[0068] The compound of formula (I) can be used for treatment for colorectal cancer (except for mismatch repair-deficient bowel cancer) etc. In an embodiment, the compound of formula (I) can be used for treatment of colorectal cancer (except for mismatch repairdeficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-L1 antibody therapy etc., particularly colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells, which has resistance to anti-PD- 1 antibody / anti-PD-Ll antibody therapy, etc.

[0069] A pharmaceutical composition containing one or more of the compounds of formula (I) or salts thereof as active ingredients can be prepared by a commonly used method with an excipient commonly used in the art, i.e. an excipient for pharmaceutical use, a carrier forpharmaceutical use, or the like.The administration may be either oral administration with tablets, pills, capsules, granules, powders, solutions or the like, or parenteral administration with injection preparations for intraarticular injection, intravenous injection, intramuscular injection or the like, suppositories, eye-drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalations or the like.

[0070] As a solid composition for oral administration, a tablet, a powder, a granule or the like is used. In such a solid composition, one or more active ingredients are mixed with at least one inactive excipient. The composition may conventionally contain inactive additives, for example a lubricant, a disintegrant, a stabilizer and a solubilizing agent. The tablet, powder, granule or pill may be coated with a wax, a sugarcoating or a stomach-soluble or enteric substance film.Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, and contain a commonly used inactive diluents, for example purified water or ethanol. Such a liquid composition may contain adjuvants such as a solubilizer, a wetting agent and a suspension, a sweetening agent, a flavor, a fragrance and a preservative in addition to the inactive diluent.

[0071] The injection preparation for parenteral administration contains a sterile aqueous or nonaqueous solution, a suspension or an emulsion. Examples of the aqueous solvent include distilled water for injection of physiological saline solutions. Examples of the nonaqueous solvent include alcohols such as ethanol. Such a composition may further contain a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer or a solubilizing agent. The composition is sterilized by, for example, filtration involving passage through a bacteria retention filter, addition of a bactericide or irradiation. In addition, a sterile solid composition can be prepared, and dissolved or suspended in sterile water or a sterile solvent for injection before use.

[0072] The external preparation encompasses ointments, plasters, creams, gelatinous preparations, cataplasms, sprays, lotions, eye-drops, and eye ointments. The externalpreparation contains a commonly used ointment base, lotion base, aqueous or nonaqueous solution, suspension, emulsion or the like.

[0073] The transmucosal preparation such as an inhalation or a nasal preparation is solid, liquid or semisolid, and can be prepared in accordance with a known conventional method. For example, a known excipient, and a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer, a thickener and the like may be added to the transmucosal preparation, as appropriate. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered administration / inhalation device, or a sprayer, the compound can be administered alone, as powder of a prescribed mixture, or a solution or suspension liquid obtained by combining the compound with a pharmaceutically acceptable carrier. The dry powder inhaler or the like may be one for single-dose administration or multi-dose administration, and enables use of dry powder or a dry powder-containing capsule, or may be in the form of a press aerosol spray using an appropriate ejection agent, for example a suitable gas such as a chlorofluoroalkane or carbon dioxide.

[0074] Normally, in the case of oral administration, the appropriate daily dose per body weight is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg, in a single dose or 2 to 4 divided doses. In the case of intravenous administration, the appropriate daily dose per body weight is about 0.0001 to 10 mg / kg in a single dose or two or more divided doses. In the case of transmucosal administration, the daily dose per body weight is about 0.001 to 100 mg / kg in a single dose or two or more divided doses. The dose is appropriately determined with consideration given to a symptom, an age, a sex and the like.

[0075] In an embodiment, the compound of formula (I) or a salt thereof is administered orally at a dose of 10 mg to 200 mg once daily. In an embodiment, the compound of formula (I) or a salt thereof is administered orally at a dose of 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, or 200 mg once daily. In an embodiment, the compound of formula (I) or a salt thereof is administered orally at a dose of 25 mg to 100 mg twice daily. In anembodiment, the compound of formula (I) or a salt thereof is administered orally at a dose of 25 mg, 35 mg, 50 mg, 75 mg, or 100 mg twice daily. The dose is appropriately determined with consideration given to a symptom, an age, a sex and the like.

[0076] The administration condition of formula (I) or a salt thereof will be explored at dosing with or without food.

[0077] Depending on an administration route, a dosage form, an administration site, and 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 to 100 wt%, or 0.01 to 50 wt% in an embodiment.

[0078] The compound of formula (I) can be used in combination with various therapeutic agents or prophylactic agents for diseases against which the compound of formula (I) may be effective. The combined use may be simultaneous administration, separate and sequential administration, or administration at a desired time interval. Preparations for simultaneous administration may be in the form of a combination preparation, or may be separately formulated preparations.

[0079] In an embodiment, the compound of formula (I) or a salt thereof is administered to the subject in combination with a combination therapy selected from the group consisting of i) TAS-102 and bevacizumab, ii) mFOLFOX6 chemotherapy regimen and bevacizumab, and iii) FOLFIRI chemotherapy regimen and bevacizumab. In an embodiment, the compound of formula (I) or a salt thereof is administered to the subject in combination with a combination therapy, which comprises TAS-102 and bevacizumab. In an embodiment, the compound of formula (I) or a salt thereof is administered to the subject in combination with a combination therapy, which comprises mFOLFOX6 chemotherapy regimen and bevacizumab. In an embodiment, the compound of formula (I) or a salt thereof is administered to the subject in combination with a combination therapy, which comprises FOLFIRI chemotherapy regimen and bevacizumab.

[0080] (TAS-102 (Trifluridine + Tipiracil))TAS- 102 is administered to the subject at a dose of 35 mg / m2up to a maximum dose of 80 mg per dose (based on the trifluridine component) per OS (PO) twice daily.

[0081] (Bevacizumab)Bevacizumab is administered to the subject at a dose of 5 mg / kg intravenous injection (IV).When given in combination with TAS- 102, bevacizumab is administered after TAS-102.When given in combination with mFOLFOX6, bevacizumab is administered before mFOLFOX6.When given in combination with FOLFIRI, bevacizumab is administered before FOLFIRI.

[0082] (mFOLFOX6 chemotherapy regimen)mFOLFOX6 is the combination of oxaliplatin, 5-FU and leucovorin: Oxaliplatin 85 mg / m2IV on day 1, Leucovorin 400 mg / m2IV on day 1, and 5-FU 400 mg / m2IV bolus on day 1, followed by 1200 mg / m2 / day x 2 days (total 2400 mg / m2over 46-48 hours) IV continuous infusion. Oxaliplatin may be given either over 2 hours or may be infused over a shorter time at a rate of 1 mg / m2 / min. Repeat every 2 weeks.

[0083] (FOLFIRI chemotherapy regimen)FOLFIRI is the combination of irinotecan, 5-FU and leuvovorin: Irinotecan 180 mg / m2IV over 30-90 minutes on day 1, Leucovorin 400 mg / m2IV infusion to match duration of irinotecan infusion on day 1, and 5-FU 400 mg / m2IV bolus on day 1, followed by 1200 mg / m2 / day x 2 days (total 2400 mg / m2over 46–48 hours) continuous infusion. Repeat every 2 weeks.

[0084] A pharmaceutical composition comprising the compound of formula (I) or a salt thereof is administered to the subject in combination with a combination therapy selected from the group consisting of i) TAS-102 and bevacizumab, ii) mFOLFOX6 chemotherapy regimen and bevacizumab, and iii) FOLFIRI chemotherapy regimen and bevacizumab for treatment of colorectal cancer (except for mismatch repair deficient bowel cancer).

[0085] In an embodiment, the compound of formula (I) or a salt thereof is administered to the subject in combination with a combination therapy selected from the group consisting of i) docetaxel, ii) docetaxel and ramucirumab, and iii) pembrolizumab, carboplatin, and pemetrexed. In an embodiment, the compound of formula (I) or a salt thereof is administered to the subject in combination with a combination therapy, which comprises docetaxel. In an embodiment, the compound of formula (I) or a salt thereof is administered to the subject in combination with a combination therapy, which comprises docetaxel and ramucirumab. In an embodiment, the compound of formula (I) or a salt thereof is administered to the subject in combination with a combination therapy, which comprises pembrolizumab, carboplatin, and pemetrexed.

[0086] (Docetaxel)Docetaxel is administered to the subject at a dose of at 75 mg / m2intravenous injection (IV) over 1 hour every 3 weeks.

[0087] (Ramucirumab (CYRAMZA®))Ramucirumab is administered to the subject at 10 mg / kg intravenous injection (IV) every 3 weeks. When given in combination with docetaxel, ramucirumab is administered prior to docetaxel infusion.

[0088] (Pembrolizumab)Pembrolizumab is administered to the subject at the approved dose of 400 mg every6 weeks or 200 mg every 3 weeks using a 30 minute intravenous infusion. In an embodiment, Pembrolizumab is administered to the subject at the approved dose of 200 mg every 3 weeks using a 30 minute intravenous infusion.

[0089] (Carboplatin)Carboplatin is administered at the approved dose of AUC 5 or AUC 6 intravenous injection (IV) every 3 weeks. When given in combination with pemetrexed, carboplatin is administered prior to administration of pemetrexed.

[0090] (Pemetrexed)Pemetrexed is administered at the approved dose of 500 mg / m2intravenous injection (IV) infusion over 10 minutes every 3 weeks. When given in combination with pembrolizumab and carboplatin or cisplatin, pemetrexed is administered after pembrolizumab and prior to carboplatin or cisplatin every 3 weeks for 4 cycles

[0091] A pharmaceutical composition comprising the compound of formula (I) or a salt thereof is administered to the subject in combination with a combination therapy selected from the group consisting of i) docetaxel, ii) docetaxel and ramucirumab, and iii) pembrolizumab, carboplatin, and pemetrexed for treatment of non-small cell lung cancer.Examples

[0092] Hereinafter, the method for preparing the compound of formula (I) will be described in more detail by way of Examples. The present invention is not limited to the compounds described in Examples. Methods for preparing raw material compounds will be shown in production examples. The method for preparing the compound of formula (I) is not limited to the specific methods of Examples shown below, and the compound of formula (I) can be also prepared by a combination of these production methods, or methods obvious to those skilled in the art.

[0093] In the present description, naming software such as ACD / Name (registered trademark)(Advanced Chemistry Development, Inc.) may be used for naming a compound.

[0094] For convenience, mol / 1 as a unit of concentration is represented by M. For example, the 1 M sodium hydroxide aqueous solution means a sodium hydroxide aqueous solution at 1 mol / 1.

[0095] In the present description, results of powder X-ray diffraction were measured using Empyrean under the following conditions:tube: Cu; tube current: 40 mA; tube voltage: 45 kV; step width: 0.013°; wave length:1.5418A; measurement range of diffraction angle (20): 2.5-40°.

[0096] Preparation Example 1To a mixture of 2-bromo-4-fluoro-l-nitro-3-(trifluoromethyl)benzene (15 g), phenol (4.91 g) and NMP (150 mL) was added K2CO3(14.4 g), and the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature, EtOAc and water were then added, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried with MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give 2-bromo-l-nitro-4-phenoxy-3-(trifluoromethyl)benzene (18.4 g).

[0097] Preparation Example 13To a mixture of 2-chloro-4-fluoro-l-nitro-3-(trifluoromethyl)benzene (4.3 g), 1-(tert-butoxycarbonyl)-l,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (4.5 g), Pd(dppf)Cl2·CH2Cl2(590 mg) and K2CO3(4 g) were added 1,4-dioxane (45 mL) and water (9 mL), and the reaction mixture was stirred under an argon atmosphere at 100°C for 20 hours. The reaction mixture was cooled to room temperature, water and EtOAc were then added, and the resulting mixture was filtered through celite, and then 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 give tert-butyl 4-[3-fluoro-6-nitro-2-(trifluoromethyl)phenyl]-3,6-dihydropyridine- l(2H)-carboxy late (4.65 g).

[0098] Preparation Example 16Under a nitrogen atmosphere, to a mixture of 2-bromo-4-fluoro-l-nitro-3-(trifluoromethyl)benzene (2 g), tert-butyl {[(3R)-piperidin-3-yl]methyl}carbamate (1.63 g), K2CO3(2.87 g) and 1,4-dioxane (20 mL) was added PdCl2(PPh3)2(487 mg), and 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 give tert-butyl ({(3S)-l-[3-fluoro-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (1.70 g) as a solid.

[0099] Preparation Example 17To a mixture of tert-butyl 4-[3-fluoro-6-nitro-2-(trifluoromethyl)phenyl]-3,6-dihydropyridine-l(2H)-carboxylate (4.6 g), phenol (1.3 g) and NMP (23 mL) was added sodium hydride (60% oil dispersion, 570 mg) under ice cooling, and the resulting mixture was stirred under ice cooling under an argon atmosphere for 1 hour. Under ice cooling, 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 give tert-butyl 4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]-3,6-dihydropyridine- 1 (2H)-carboxylate (5.18 g).

[0100] Preparation Example 21Under ice cooling, to a mixture of cyclopropanol (0.10 mL), NaOtBu (205 mg) and DMF (6 mL) was added tert-butyl ({(3S)-l-[3-fluoro-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (300 mg), and 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 give tert-butyl ({(3S)-l-[3-(cyclopropyloxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (250 mg) as a solid.

[0101] Preparation Example 30To a mixture of tert-butyl (3S)-3-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]piperidine-l -carboxylate (8.106 g) and ethanol (60 mL) was added 4 M HCl / 1,4-dioxane solution (30 mL), and the reaction mixture was stirred at room temperature for 11 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol and diethyl ether. The crystallized solid substance was taken by filtration, and washed with diethyl ether. The solid substance taken by filtration was dried under reduced pressure to give 2-{[(3R)-piperidin-3-yl]methyl}-lH-isoindolel,3(2H)-dione monohydrochloride (5.695 g) as a solid.

[0102] Preparation Example 31To a mixture of [(3S)-l-(tert-butoxycarbonyl)piperidin-3-yl]acetic acid (2.9 g) and NH4Cl (960 mg) were added CH2Cl2(24 mL), water (12 mL), WSC. HC1 (2.5 g), TEA (5.8 mL) and HOBt (1.8 g), and the reaction mixture was stirred overnight at room temperature. 1 M hydrochloric acid was added to the reaction mixture to a pH of 2 to 3, and the mixture was then extracted using ISOLUTE (registered trademark) Phase Separator. The separated organic layer was washed with saturated NaHCO3aqueous solution, and concentrated under reduced pressure to give tert-butyl (3S)-3-(2-amino-2-oxoethyl)piperidine-l -carboxylate (2.7 g).

[0103] Preparation Example 32To a mixture of tert-butyl (3S)-3-(2-amino-2-oxoethyl)piperidine-l -carboxylate (335 mg) and THF (7 mL) was added Lithium aluminum hydride (130 mg) under ice cooling, and the reaction mixture was stirred overnight at room temperature. Under ice cooling, water (130 pL), a 1 M sodium hydroxide aqueous solution (130 pL) and water (390 pL) were added, and the resulting mixture was then diluted with 10% methanol / CH2Ch, and stirred at room temperature for 1 hour. After an insoluble material was separated by filtration through celite, and the filtrate was concentrated under reduced pressure. CH2Cl2(4 mL) and DIPEA (360 pL) were added to the residue at room temperature, TFAA (240 pL) was then added under ice cooling, and the reaction mixture was stirred overnight at roomtemperature. A saturated NH4CI aqueous solution was added, the resulting mixture was extracted using ISOLUTE (registered trademark) Phase Separator, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl (3S)-3-[2-(2,2,2-trifluoroacetamide)ethyl]piperidine-l -carboxylate (139 mg).

[0104] Preparation Example 33To a mixture of tert-butyl (3S)-3-[2-(2,2,2-trifluoroacetamide)ethyl]piperidine-l-carboxylate (137 mg) and diethyl ether (1 mL) was added 4 M HCl / l,4-dioxane solution (1 mL) at room temperature, and the reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to give 2,2,2-trifluoro-N-{2-[(3S)-piperidin-3-yl]ethyl}acetamide monohydrochloride (117 mg).

[0105] Preparation Example 34To a mixture of 2-bromo-l-nitro-4-phenoxy-3-(trifluoromethyl)benzene (4.15 g) and 1,4-dioxane (60 mL) were added DIPEA (3 mL) and tert-butyl {[(3R)-piperidin-3-yl]methyl} carbamate (3 g), and the reaction mixture was stirred overnight at 100°C. The reaction mixture was cooled to room temperature, water was then added, and the resulting mixture was extracted with EtOAc. The extract was dried over MgSO4, and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl ({(3S)-l-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (4.87 g).

[0106] Preparation Example 60Under an argon atmosphere, to a mixture of tert-butyl (3{(3S)-l-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (3.5 g), iodomethane (860 p. L) and DMF (35 mL) was added sodium hydride (60% oil dispersion, 410 mg) in four parts under ice cooling, and the reaction mixture was stirred at room temperature for 3 hours. Under ice cooling, the reaction was quenched 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 bysilica gel column chromatography (Hex / EtOAc) to give tert-butyl ({(3R)-l-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)(methyl)carbamate (3.44 g) as a solid.

[0107] Preparation Example 68To a mixture of tert-butyl (2R)-2-(hydroxymethyl)-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-l -carboxylate (110 mg) and CH2CI2 (2 mL) was added A Dess-Martin reagent (120 mg) under ice cooling, and the reaction mixture was stirred at room temperature for 1 hour. The Dess-Martin reagent (120 mg) was further added, and the resulting mixture was stirred at room temperature for 30 minutes. A 10% sodium sulfite aqueous solution and a saturated NaHCO3 aqueous solution were added to the reaction mixture under ice cooling, and the resulting mixture was stirred at room temperature for 30 minutes, and extracted using ISOLUTE (registered trademark) Phase Separator. The extract was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl (2R)-2-formyl-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-l -carboxylate (86 mg).

[0108] Preparation Example 69To a solution of tert-butyl (2R)-2-formyl-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-l -carboxylate (84 mg) in CH2CI2 (1 mL) were added 2 M methylamine / THF solution (170 pL), acetic acid (20 pL) and NaBH(OAc)3 (75 mg), and the reaction mixture was stirred at room temperature for 2 hours. A saturated NaHCO3 aqueous solution was added to the reaction mixture, the resulting mixture was extracted using ISOLUTE (registered trademark) Phase Separator, and the extract was concentrated under reduced pressure to give tert-butyl (2S)-2-[(methylamino)methyl]-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-l -carboxylate (93 mg).

[0109] Preparation Example 70To a mixture of tert-butyl (2S)-2-[(methylamino)methyl]-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-l -carboxylate (93 mg) and CH2CI2 (1 mL) were added DIPEA (50 pL) and TFAA (35 pL) under ice cooling, and the reaction mixture was stirred atroom temperature for 1 hour. DIPEA (50 pL) and TFAA (35 pL) were added to the reaction mixture, and the resulting mixture was stirred at room temperature for 15 minutes. A saturated NH4CI aqueous solution was added to the reaction liquid, the resulting mixture was extracted using ISOLUTE (registered trademark) Phase Separator, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give tert-butyl (2R)-2-{[methyl(trifluoroacetyl)amino]methyl}-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-l -carboxylate (81 mg).

[0110] Preparation Example 71To a mixture of tert-butyl (2R)-2-formyl-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-l -carboxylate (1.04 g) and CH2CI2 (10 mL) were added O-benzylhydroxylamine (320 pL), acetic acid (180 pL) and NaBH(OAc)3 (670 mg), and 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 thereto, and the resulting mixture was stirred overnight at room temperature. Methanol (3 mL) was added, and the resulting mixture was stirred overnight. A saturated NaHCO3 aqueous solution was added, the resulting mixture was stirred at room temperature for 1 hour, and extracted using ISOLUTE (registered trademark) Phase Separator, and the extract was concentrated under reduced pressure. The residue was dissolved in CH2CI2 (10 mL), DIPEA (720 pL) was added, TFAA (450 pL) was then added under ice cooling, and the reaction mixture was stirred at room temperature for 30 minutes. A saturated NH4CI aqueous solution was added, the resulting mixture was extracted using ISOLUTE (registered trademark) Phase Separator, and the extract was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hex / EtOAc) to give tert-butyl (2R)-2-{[(benzyloxy)amino]methyl}-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine- 1 -carboxylate (426 mg).

[0111] Preparation Example 72To a mixture of {(2R)-l-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]pyrrolidin-2-yl}methanol (510 mg) and CH2CI2 (5 mL) were added Pyridine (310 pL) and acetic anhydride (360 μg) under ice cooling, and the resulting mixture was stirred overnight at room temperature. A saturated NH4CI aqueous solution was added, the resulting mixture was extracted using ISOLUTE (registered trademark) Phase Separator, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give {(2R)-l-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]pyrrolidin-2-yl}methyl acetate (170 mg).

[0112] Preparation Example 73To a mixture of 2-{[(3R)-l-(2,4-difluoro-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methyl}-lH-isoindol-l,3(2H)-dione (0.376 g) and MeOH (5 mL) was added hydrazine monohydrate (110 pL), and the reaction mixture was stirred at reflux for 3 hours. The reaction mixture was cooled to room temperature, then poured into a 5% sodium hydroxide aqueous 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 Na2SC>4, and concentrated under reduced pressure to give 1-[(3S)-l-(2,4-difluoro-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methaneamine (0.266 g).

[0113] Preparation Example 75To a mixture of l-[(3S)-l-(2,4-difluoro-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methaneamine (0.266 g), CH2Cl2 (5 mL) and TEA (153 pL) was added di-tert-butyl dicarbonate (202 pL), and 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 CH2CI2. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl { [(3 S)- 1 -(2,4-difluoro-6-nitro-3 -phenoxypheny l)piperidin-3 -yl]methyl} carbamate (0.294 g).

[0114] Preparation Example 77To a mixture of tert-butyl ({(3S)-l-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (4.85 g), 1,4-dioxane (150 mL) andwater (30 mL) were added zinc powder (6.4 g) and NH4CI (5.24 g) under ice cooling. The reaction mixture was stirred at room temperature for 3 hours, and insoluble substances were then separated by filtration through celite. The resulting filtrate was concentrated under reduced pressure, a saturated NaHCO3 aqueous 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 give tert-butyl ({(3S)-l-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (4.56 g).

[0115] Preparation Example 122To a mixture of tert-butyl (2R)-2-{[(benzyloxy)amino]methyl}-4-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-l -carboxylate (424 mg), EtOAc (2 mL) and ethanol (2 mL) was added Hydrous 10% palladium hydroxide-carrying carbon (100 mg) under a nitrogen atmosphere, which was then replaced by a hydrogen atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. After replacement by a nitrogen atmosphere, the reaction mixture was then diluted with EtOAc, and filtered through celite, and the filtrate was concentrated under reduced pressure to give tert-butyl (2S)-2-(aminomethyl)-4-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-l -carboxylate (347 mg).

[0116] Preparation Example 123To a mixture of tert-butyl (2S)-2-(aminomethyl)-4-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]piperazine-l -carboxylate (345 mg) and methanol (2 mL) was added Ethyl trifluoroacetate (110 pL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give tertbutyl (2S)-4-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]-2-[(2,2,2-trifluoroacetamide)methyl]piperazine-l -carboxylate (380 mg).

[0117] Preparation Example 124To a mixture of tert-butyl ({(3S)-l-[6-amino-3-phenoxy-2- (trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (4.56 g) and DMF (50 mL) were added 2-(Pyridazin-4-yl)-l,3-thiazole-4-carboxylic acid (2.23 g), DIPEA (3 mL) and HATU(4.5 g), and the resulting mixture was stirred overnight at 50°C. The reaction mixture was cooled to room temperature, water was then added to the reaction mixture under ice cooling, and the precipitated solid substance was taken by filtration. The resulting solid substance 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, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl { [(3 S)- 1 - { 3-phenoxy-6- [2-(pyridazin-4-yl)- 1,3 -thiazole-4-carboxamide]-2-(trifluoromethyl)phenyl}piperidin-3-yl]methyl}carbamate (5.85 g) as a solid.

[0118] Preparation Example 172To a mixture of {(2R)-l-[3-(2-fluorophenoxy)-6-{[2-(pyridazin-4-yl)-l,3-thiazole-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]pyrrolidin-2-yl}methyl acetate (194 mg) and methanol (1 mL) were water (0.1 mL) and K2CO3 (135 mg), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc, and then filtered through celite, and the filtrate was concentrated under reduced pressure to give N-[4-(2-fluorophenox)-2-[(2R)-2-(hydroxymethyl)pyrrolidin-l-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (200 mg).

[0119] Preparation Example 173To a mixture of N-[4-(2-fluorophenoxy)-2-[(2R)-2-(hydroxymethyl)pyrrolidin-l-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (198 mg) and CH2CI2 (2 mL) was added Dess-Martin reagent (220 mg) under ice cooling, and the reaction mixture was stirred at room temperature for 1 hour. Under ice cooling, 10% sodium sulfite aqueous solution and a saturated NaHCCh aqueous solution were added, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted using ISOLUTE (registered trademark) Phase Separator, and the extract was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform / methanol) to give N-[4-(2-fluorophenoxy)-2-[(2R)-2-formylpyrrolidin-l-yl]-3- (trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (112 mg).

[0120] Preparation Example 174To a mixture of tert-butyl ({(3S)-l-[3-hydroxy-6-{[2-(pyridazin-4-yl)-l,3-thiazole-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (0.075 g), CH2CI2 (4.5 mL) and pyridine (50 pL) was added Trifluoromethanesulfonic anhydride (52 pL) under ice cooling, and 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 CH2CI2. The organic layer was washed with 10% hydrochloric acid, water and brine, then dried over Na₂SO₄, and concentrated under reduced pressure. To a mixture of the residue and pyridine (2.6 mL) was added Trifluoromethanesulfonic anhydride (64 pL) under ice cooling, and 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 give 3-[(3S)-3-{[(tert-butoxycarbonyl)amino]methyl}piperidin-l-yl]-4-{[2-(pyridazin-4-yl)-l,3-thiazole-4-carbonyl]amino)-2-(trifluoromethyl)phenyl trifluoromethanesulfonate (0.103 g).

[0121] Preparation Example 175Under an argon atmosphere, to a mixture of K2CO3 (0.030 g), phenylboronic acid (0.027 g) and Pd (PPhs)4 (0.017 g) was added a mixture of 3-[(3 S)-3- { [(tert-butoxycarbonyl)amino]methyl}piperidin-l-yl]-4-{[2-(pyridazin-4-yl)-l,3-thiazole-4-carbonyl]amino}-2-(trifluoromethyl)phenyl trifluoromethanesulfonate (0.103 g) and THF (2.5 mL), water (0.5 mL) was then added, and the reaction mixture was stirred at 110 to 130°C for 8 hours. The reaction mixture was cooled to room temperature, and then 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 give tert-butyl ({(3 S)- 1 -[4-{ [2-(pyridazin-4-yl)- 1,3-thiazole-4-carbonyl]amino } -2-(trifluoromethyl)[ 1, 1 '-biphenyl]-3-yl]piperidin-3-yl}methyl)carbamate (0.067 g).

[0122] Preparation Example 176To a mixture of tert-butyl 4-[3-phenoxy-6-{[2-(pyridazin-4-yl)-l,3-thiazole-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]-3,6-dihydropyridine-l(2H)-carboxylate (2.4 g) and methanol (24 mL) was added 4 M HCl / l,4-dioxane solution (10 mL), and the reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, a saturated NaHCOs aqueous solution was added to the residue, and the resulting mixture was extracted with a mixed solvent (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 give N-[4-phenoxy-2-(l,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (1.57 g) as a solid.

[0123] Preparation Example 182To a mixture of N-{2-[(3R)-3-(aminomethyl)piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (63 mg) and CH2CI2 (1 mL) were added DIPEA (30 pL) and 2-nitrobenzenesulfonyl chloride (30 mg) under ice cooling, and the reaction mixture was stirred for 1 hour under ice cooling. A saturated NH4CI aqueous solution was added, the resulting mixture was extracted using ISOLUTE (registered trademark) Phase Separator, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give N-{2-[(3S)-3-{[(2-nitrobenzene-l-sulfonyl)amino]methyl}piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (94 mg).

[0124] Preparation example 185To a mixture of N-{2-[(3S)-3-{[(2-nitrobenzene-l-sulfonyl)amino]methyl}piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (90 mg) and MeCN (1 mL) were added Methyl iodide (25 pL) and cesium carbonate (45 mg) at room temperature, and the reaction mixture was stirred at room temperature for 30 minutes. EtOAc was added, the resulting mixture was filtered through celite, and the filtrate was then concentrated under reduced pressure to give N-{2-[(3S)-3-{[methyl(2-nitrobenzene-l-sulfonyl)amino]methyl}piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (83 mg).

[0125] Preparation Example 190To a mixture of N-{2-[(3R)-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (40 mg) and CH2CI2 (1 mL) were added 35% formaldehyde aqueous solution (10 pL), acetic acid (5 pL) and NaBH(OAc)3 (20 mg), and the reaction mixture was stirred overnight at room temperature. A saturated NaHCCh aqueous solution was added to the reaction mixture, the resulting mixture was stirred for 10 minutes, and extracted using ISOLUTE (registered trademark) Phase Separator, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc aminosilica gel) to give N-{2-[(3R)-4-methyl-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (36 mg).

[0126] Preparation Example 192To a mixture of sodium hydride (60% oil dispersion, 0.208 mg) and THF (5 mL), was added thiophenol (0.38 g) at -78°C, and the reaction mixture was stirred at -78°C for 15 minutes. 2-bromo-4-fluoro-l-nitro-3-(trifluoromethyl)benzene (1.00 g) was added, and the reaction mixture was stirred at -78°C for 15 minutes. A saturated NH4CI aqueous solution was added, the resulting mixture was extracted three times with EtOAc. The combined organic layer was dried over Na2SC>4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give 2-bromo-l-nitro-4-(phenylsulfanyl)-3-(trifluoromethyl)benzene (0.50 g).

[0127] Preparation Example 193Under an argon atmosphere, to a mixture of l,3-difluoro-2-(methanesulphonyl)benzene (1.60 g) and concentrated sulfuric acid (12 mL) was added potassium nitrate (0.84 g) under ice cooling, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and the precipitated solid was taken by filtration. The obtained solid was dissolved in EtOAc, washed with a saturated NaHCOs aqueous solution, and dried over Na₂SO₄. The residuewas concentrated under reduced pressure to give l,3-difluoro-2-(methanesulphonyl)-4-nitrobenzene (1.80 g) as a solid.

[0128] Preparation Example 194To a mixture of 4-amino-3-fluoro-2-(trifluoromethyl) benzoate (1.30 g) and THF (15 mL) was added dropwise 30% hydrogen peroxide solution (5 mL) under ice cooling, and the reaction mixture was stirred at room temperature for 5 minutes and 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 give 3-fluoro-4-nitro-2-(trifluoromethyl) benzoate (1.20 g) as a solid.

[0129] Preparation Example 195To a mixture of 3-fluoro-4-nitro-2-(trifluoromethyl) benzoic acid (1.20 g) and CH2CI2 (30 mL) was added dropwise oxalyl chloride (2.03 mL) under ice cooling, and a catalytic amount of DMF was added. The reaction mixture was stirred for 1 hour under ice cooling, and then concentrated under reduced pressure. The residue was dissolved in benzene (15 mL), and aluminum chloride (1.26 g) was added for at least 5 minutes and stirred at room temperature for 1 hour. The reaction mixture was poured on an 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 give [3-fluoro-4-nitro-2-(trifluoromethyl)phenyl](phenyl)methanone (0.80 g) as a solid.

[0130] Preparation Example 196To a mixture of (8S)-8-hydroxyhexahydropyrrolo[l,2-a]pyrazine-l, 4-dione (3.250 g), DMF (48 mL) and imidazole (3.972 g) was added tert-butyl chlorodiphenyl silane (10.0 mL), and the reaction mixture was stirred at room temperature for 23 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na₂SO₄, and then, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / MeOH) to give (8S,8aS)-8-{[tert-butyldi(phenyl)silyl]oxy}hexahydropyrrolo[l,2-a]pyrazine-l, 4-dione (1.786 g) as a less polar substance and (8S,8aR)-8-{[tert-butyldi(phenyl)silyl]oxy}hexahydropyrrolo[l,2-a]pyrazine- 1,4-dione (1.164 g) as a more polar substance.

[0131] Preparation Example 197To a mixture of lithium aluminum hydride (0.594 g) and THF (40 mL) was added THF (10 mL) solution of (8S,8aR)-8-{[tert-butyldi(phenyl)silyl]oxy}hexahydropyrrolo[l,2-a]pyrazine- 1,4-dione (1.164 g), and the reaction mixture was stirred at 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 4N aqueous sodium hydroxide (0.7 mL) were added. To the resulting mixture was added Na₂SO₄ and the mixture was stirred at room temperature for 3 hours, and filtered through celite. The filtrate was concentrated under reduced pressure to give (8S,8aS)-octahydropyrrolo[l,2-a]pyrazine-8-ol (0.972 g).

[0132] Preparation Example 216Under an argon atmosphere, to a mixture of (8S,8aS)-2-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]octahydropyrrolo[l,2-a]pyrazine-8-ol (0.375 g), THF (6 mL), benzoic acid (0.119 g) and triphenylphosphine (0.349 g) was added diisopropyl azodicarboxylate (262 pL) under ice cooling. The reaction mixture was allowed to slowly warm to room temperature and was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give benzoic acid (8R,8aS)-2-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]octahydropyrrolo[l,2-a]pyrazine-8-yl (0.518 g).

[0133] Preparation Example 220Under an argon atmosphere, to a mixture of tert-butyl {[(3S)-l-(2-bromo-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methyl}carbamate (550 mg), cyclopropyl boronic acid (112 mg), tricyclohexylphosphine (30 mg), toluene (9 mL) and water (1 mL) was added palladium acetate (24 mg), and the reaction mixture was stirred at 110°C for 4 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl {[(3S)-1-(2-cyclopropyl-6-nitro-3-phenoxyphenyl)piperidin-3-yl]methyl} carbamate (280 mg).

[0134] Preparation Example 221Under an argon atmosphere, to a mixture of (8S,8aS)-2-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]octahydropyrrolo[l,2-a]pyrazine-8-ol (0.233 g), THF (4 mL), phthalimide (0.090 g) and triphenylphosphine (0.173 g) was added diisopropyl azodicarboxylate (0.13 mL) under ice cooling, and the reaction mixture was allowed to slowly warm to room temperature and stirred for 15 hours. Triphenylphosphine (0.173 g) and diisopropyl azodicarboxylate (0.13 mL) were added to the reaction mixture under ice cooling, and then allowed to slowly warm to room temperature and stirred for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give 2-{(8R,8aS)-2-[6-nitro-3-phenoxy-2-(trifluoromethyl)phenyl]octahydropyrrolo[ 1,2-a]pyrazine-8-yl } - 1 H-isoindole- 1,3(2H)-dione (0.214 g).

[0135] Preparation Example 271To a mixture of tert-butyl {[(3S)-l-{6-[(2-bromo-l,3-thiazole-4-carbonyl)amino]-3-(phenylsulfanyl)-2-(trifluoromethyl)phenyl}piperidin-3-yl]methyl}carbamate (300 mg) and CH₂Cl₂ (5 mL) was added m-chloroperbenzoic acid (water content: 40%, 385 mg) under ice cooling, and the reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched with a saturated aqueous solution of sodium thiosulfate and was 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 give tert-butyl ({(3S)-l-[3-(benzene sulfonyl)-6-[(2-bromo- l,3-thiazole-4-carbonyl)amino]-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (200 mg).

[0136] Preparation Example 272Under an argon atmosphere, to a mixture of tert-butyl ({ (3 S)- 1 -[3- (benzenesulfonyl)-6-[(2-bromo-l,3-thiazole-4-carbonyl)amino]-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (200 mg), 4-(tributylstannyl)pyridazine (115 mg) and toluene (10 mL) was added Pd(PPh3)4 (33 mg), and the reaction mixture was stirred at 100°C for 24 hours. The reaction mixture was cooled to room temperature, and then, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl ({(3S)-l-[3-(benzenesulfonyl)-6-{[2-(pyridazine-4-yl)-l,3-thiazole-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (100 mg).

[0137] The compounds shown in Tables 5-1 to 5-35 below were prepared in the same manner as in the production methods of Production Examples described above. Tables 5-1 to 5-35 below show the structures of the compounds of Production Examples, and Tables 6-1 to 6-12 show the methods for preparing the compounds of Production Examples and physiochemical data. These compounds can be easily prepared by using the production methods of Production Examples above, methods obvious to those skilled in the art, or modified methods thereof.

[0138] Example 1To a mixture ofN-[2-(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (93 mg) and CH2CI2 (1 mL) were added 35% formamide aqueous solution (50 pL), acetic acid (40 pL) and NaBH(OAc)₃ (100 mg), and the reaction mixture was stirred at room temperature for 1 hour. A saturated NaHCO3 aqueous solution was added to the reaction mixture, the resulting mixture was stirred for 10 minutes, and extracted using ISOLUTE (registered trademark) Phase Separator, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give an oily substance. The oily substance was solidified with MeCN, taken by filtration, and then dried under reduced pressure to give N-[2-(9-methyl-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (72 mg) as a solid.

[0139] Example 6To a mixture of N-{2-[(3R)-4-methyl-3-{ [methyl(trifluoroacetyl)amino]methyl}piperazin- 1 -yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (35 mg) and methanol (0.5 mL) were added K2CO3 (15 mg) and water (0.1 mL), and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with EtOAc, and 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 diethyl ether, and the resulting solid substance was taken by filtration, and dried at 50°C under reduced pressure to give N-[2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-l-yl}-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (17 mg) as a solid.

[0140] Example 9To a mixture of tert-butyl {[(3S)-l-3-phenoxy-6-[2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide]-2-(trifluoromethyl)phenyl}piperidin-3-yl]methyl}carbamate (5.83 g) and CH2CI2 (60 mL) was added TFA (7 mL) under ice cooling, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with CH2CI2, and then neutralized by addition of a saturated NaHCO3 aqueous solution under ice cooling. The resulting mixture was extracted with chloroform, and the extract was then 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 diethyl ether to give N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-phenoxy-3- (trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (3.52 g) as a solid.

[0141] Example 49To a mixture of N-{2-[(3R)-3-{[methyl(2-nitrobenzene-l-sulfonyl)amino]methyl}piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (202 mg) and DMF (1 mL) were thioglycolic acid (60 pL) and lithium hydroxide monohydrate (60 mg), and the reaction mixture was stirred at 70°C for15 minutes. The reaction mixture was cooled to room temperature, CH2CI2 and a saturated NaHCOs aqueous solution were then added to the reaction mixture, the resulting mixture was stirred, and extracted using ISOLUTE (registered trademark) Phase Separator, and the extract was concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc / chloroform) to give an oily substance. The oily substance was solidified with MeCN, taken by filtration, and then dried under reduced pressure to give N-[2- { (3 S)-3- [(methylamino)methy l]piperidin- 1 -yl } -4-phenoxy-3 -(trifluoromethyl)pheny l]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (29 mg) as a solid.

[0142] Example 54To a mixture of N-{2-[(3R)-3-(aminomethyl)piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (83 mg) and CH2CI2 (1 mL) were added 35% formaldehyde aqueous solution (50 pL), acetic acid (35 pL) and NaBH(OAc)3 (100 mg), and the reaction mixture was stirred at room temperature for 1 hour. A saturated NaHCO3 aqueous solution was added, the resulting mixture was stirred at room temperature for 10 minutes, and extracted using ISOLUTE (registered trademark) Phase separator, and the extract was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform / methanol), the resulting substance was dissolved in EtOAc, a 4 M HCl / EtOAc solution (120 pL) was then added, and the precipitated solid substance was taken by filtration, and dried at 50°C under reduced pressure to give N-[2- { (3R)-3 -[(dimethy lamino)methyl]piperidin- 1 -yl } -4-phenoxy-3 -(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide dihydrochloride (71 mg) as a solid.

[0143] Example 59To a mixture of N-[2-(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-phenoxy-3- (trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (100 mg) and MeCN (1 mL) were added DIPEA (35 pL) and l-bromo-2-methoxyethane (20 pL), and the reaction mixture was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (chloroform / methanol), and diluted with EtOAc, 4 M HCl / l,4-dioxane solution (130 pL) was added at room temperature, and the resulting mixture was stirred at room temperature for 10 minutes. The precipitated solid was taken by filtration, and dried under reduced pressure to give N-{2-[9-(2-methoxyethyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide dihydrochloride (67 mg) as a solid.

[0144] Example 62To a mixture of N-[2-(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (150 mg) and CH2CI2 (1 mL) were added 3-oxetanone (60 mg), acetic acid (45 pL) and NaBH(OAc)3 (160 mg) at room temperature, and the reaction mixture was stirred overnight. A saturated NaHCCh aqueous solution was added, the resulting mixture was stirred at room temperature for 30 minutes, and extracted using ISOLUTE (registered trademark) Phase separator, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give an oily substance. The oily substance was solidified with EtOAc, Hex and diisopropyl ether, taken by filtration, and then dried under reduced pressure to give N-{2-[9-(oxetan-3-yl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (99 mg) as a solid.

[0145] Example 63To a mixture of N-[4-(2-fluorophenoxy)-2-[(2R)-2-formylpyrrolidin-l-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (60 mg) and CH2Ch(0.5 mL) were added 3-oxetanamine (25 mg), acetic acid (20 pL) and NaBH(OAc)3 (70 mg), and the reaction mixture was stirred at room temperature for 2 hours. A saturated NaHCOs aqueous solution was added, the resulting mixture was stirred at room temperature for 30 minutes, and extracted using ISOLUTE (registered trademark) Phase separator, and the extract was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (chloroform / methanol) to give an oily substance. Diethyl ether was added to the resulting oily substance, and the resulting mixture was concentrated under reduced pressure to give N-[4-(2-fluorophenoxy)-2-[(2R)-2-{[(oxetan-3-yl)amino]methyl}pyrrolidin-l-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (20 mg) as a solid.

[0146] Example 64A mixture of 2-bromo-l-nitro-4-phenoxy-3-(trifluoromethyl)benzene (10.9 mg), tert-butyl, methyl[(piperidin-3-yl)methyl]carbamate (20.7 mg), DIPEA (20 pL) and NMP (250 pL) was stirred overnight at 120°C. The reaction mixture was cooled, PS-Isocyanate (150 mg) and chloroform (1 mL) were then added thereto, and the reaction mixture was stirred overnight. Thereafter, insoluble substances were separated by filtration, and the filtrate was concentrated under reduced pressure. To the resulting residue were added ethanol (0.8 mL), water (0.2 mL), NH4CI (0.8 mg) and reduced iron (10 mg). The reaction mixture was stirred overnight at 80°C. The reaction mixture was cooled to room temperature, water and chloroform were added thereto, a liquid separation process was carried out, and the resulting organic layer was concentrated under reduced pressure. To the resulting residue were added 2-(Pyridazin-4-yl)-l,3-thiazole-4-carboxylic acid (6.2 mg), DIPEA (10 pL) and DMF (185 pL), a solution of HATU (13.3 mg) in DMF (200 pL) was then added, and the reaction mixture was stirred overnight at room temperature. Separation and purification was performed with HPLC (column: SunFire (registered trademark) (MeOH / 0.1% HCOOH-H2O), TFA (500 pL) was added to the resulting residue, and the resulting mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, a saturated NaHCO3 aqueous solution and chloroform were added, a liquid separation process was carried out, and the resulting organic layer was concentrated under reduced pressure to give N-[2-{3-[(methylamino)methyl]piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (3.8 mg).

[0147] Example 78To a mixture of N-{2-[(8R,8aS)-8-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-y l)hexahydropyrrolo [ 1,2-a]pyrazine-2( 1 H)-yl] -4-phenoxy-3 -(trifluoromethyl)phenyl } -2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (0.097 g) and MeOH (1.4 mL) was added hydrazine monohydrate (19.8 pL), and the reaction mixture was stirred at reflux for 6 hours. The reaction mixture was cooled to room temperature, then poured into a 5% sodium hydroxide aqueous solution, and the resulting mixture was extracted with CH2CI2. The organic layer was separated, the aqueous layer was extracted with CH2CI2, 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 to give N-{2-[(8R,8aS)-8-aminohexahydropyrrolo[l,2-a]pyrazine-2(lH)-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (0.047 g).

[0148] Example 83T o N-[4-(2-fluorophenoxy)-2- { (3 S)-3 - [(methylamino)methyl]piperidin- 1 -y 1 } -3 -(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide monohydrochloride salt (200 mg) was added EtOAc and a saturated NaHCCE aqueous solution, and the reaction mixture was stirred for a while. The aqueous layer was separated, the aqueous layer was 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. The residue was added with 2-propanol (4 mL) and stirred for a while at 80°C. To the mixture were added fumaric acid (40 mg) and water (200 pL) and stirred at room temperature for 24 hours. The precipitate was taken by filtration, and dried under reduced pressure to give N-[4-(2-fluorophenoxy)-2- { (3 S)-3 -[(methylamino)methyl]piperidin- 1 -yl } -3 -(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide mono[(2E)-but-2-enedioate] (141 mg) as a crystal.

[0149] Example 84To N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide (100 mg) was added ethanol (2 mL) and stirred at 75°C to obtain a solution. To the solution, fumaric acid (23 mg) and water (400 μL) were added and stirred overnight at room temperature. Theprecipitate was taken by filtration, and dried under reduced pressure to give N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide mono[(2E)-but-2-enedioate] (73 mg) as a crystal.

[0150] The compounds shown in Tables 7-1 to 7-11 below were prepared in the same manner as in the preparation methods of Examples described above. Tables 7-1 to 7- 11 below show the structures of the compounds of each Example, and Tables 8-1 to 8-5 show the methods for preparing the compounds of each Example and physiochemical data. These compounds can be easily prepared by using the preparation methods of Examples above, methods obvious to those skilled in the art, or modified methods thereof.

[0151] Table 9 below shows the structure and the physiochemical data of the compound of Reference Example. The compound can be easily prepared by using the preparation methods of Examples above or Preparation Examples, methods obvious to those skilled in the art, or modified methods thereof.

[0152] In the tables below, the following abbreviations may be used.PEx: Number of Preparation ExampleEx: Number of ExamplePSyn: Method for preparing compound of Preparation Example (the number of the PSyn field indicates that the compound concerned was prepared using the same method as that for a compound of Preparation Example whose number is identical to that of the PSyn field, and using corresponding raw materials; for example, the compound of a PSyn field whose number is 1 was prepared using the same method as that for the compound of Preparation Example 1)Syn: Method for preparing compound of Example (the number of the Syn field indicates that the compound concerned was prepared using the same method as that for a compound of Example whose number is identical to that of the Syn field, and using corresponding raw materials; and for example, the compound of a Syn field whose number is 1 was prepared using the same method as that for the compound of Example 1)Str: Chemical structural formulaDAT: Physiochemical dataESI+: m / z value in mass analysis (ionization method ESI, [M+H]+or [M+Na]+unless otherwise specified)ESI-: m / z value in mass analysis (ionization method ESI, [M-H]’ unless otherwise specified) NMR DMSO-d6 (400 MHz) or NMR DMSO-d6 (500 MHz): δ value of signal (ppm) in ¹H-NMR in DMSO-d6NMR CDCl₃ (400 MHz) or NMR CDCl₃ (500 MHz): δ value of signal (ppm) in ¹H-NMR in CDCl₃s: Single line (spectrum)d: Double line (spectrum)t: Triple line (spectrum)m: Multiple line (spectrum)br: Broad line (spectrum)dd: Double double line (spectrum)

[0153] Unless otherwise specified, the compound is an optical isomer having an absolute steric conformation described in a chemical structural formula. In the structural formula, HC1 indicates that the compound concerned is a monohydrochloride, 2HC1 indicates that the compound concerned is a dihydrochloride, and 3HC1 indicates that the compound concerned is a trihydrochloride.Table 5-1]PEx Str PEx StrBrF3C 1 N0?°ow^><=1 / A CD m— 5\ # -’x _o N>Br BrF3CXAT, O2 FgCx>^^^xx_. N O2 J J Jj J 2 6F\ JL OZ 71 r=.l ~n J r— o T / \ G> JV / / A CD—# “l_ Br z OF C^ o XJ 3 ^J N° M2 3 7OA^NC*x^BrF3C, 1 NO24 8Table 5-2]PEx Str PEx Stro.. \ > — — X\ / / V\ O / )\ / Z CQ~~ ~ 'BrF3CX^L / NO? o LCOU- 9 jf J 13CI BocI'll10 14F^ -XF\ Jk / N02 XJBocNFXXN°211 oXJ15F^k^NO2 6FF. J3oc F3C Jf NO2I J HT j12 16F3C'VA^-NO2Table 5-3]PEx Str PEx StrBoc_ Boc N I J H17F3C^ U\ / NO2 21 F3C J. NO2jf J J Jy IBocN l C'o(J — — / 18 F3CxX \ o \ h. NO222n^^ OU- ^ ° °~ \r> 2O N> Boc I JHCD OO19 23F3C^^NO2rBoc Boc N L JH^NKF3CX A^NO2 20 24 / K N-NXfMeo Table >4] _ o tn PEx Str PEx Str<y b AZCDZ u_ — / ~n / =V o o i- 25 29b 'qPP IZ r- IZ iCD co o o o ooo oCQ o HCItn026 y <?xb o" 30TbbH^ b“ m C v o o—( Oz / \ o > z— ' < o —LL \= / J_ T \ / iT W COz xLLtv 27 31Boc 28 32 o r i 3HTable 5-5] o o PEx Str PEx Str CD o z o z ZI C J\ C 4\ZX / zxy D ~Q; Q2 W / \_- HCI Zv CoU_ - \ / \ V / \ ( IZ U- / « ' —X°\ / HI ZT1\ / 7— z o - Z o O CQV / O O tu O““I33 1 O _ 37 ll_ CDx fx A13HXX^ (z\ \ / / .P roz34 X 1 38F3C' / XyXTMO2OO N.o o 4 / Vz *-- CD Oo£ N \ W O1 J ° ) Tl - <xBo§ <c ~ #X> O o Z---TA \ / \ / i= _ _j? 35 3936 40Table 5-6] 0 PEx Str PEx Str z zQClz- CD CD O OO j I v c y°°~^ ~P T Z LU - ' ' \ \ 1 Z ZI71— •,, \041 Z^ 00 -fl- 45 0 0co co F3C^S^NO2 C P# Z— - z0 w 0°n42 F„C-XS / LXNO?46NH f ]M J BO< A43 47Q,cpk44248F'XP^NOFJC^Y^-NOJ BOC^'- AJ.) 1 _ I 0Table 5-7] O PEx Str PEx Str z ^> o < X— Xlx / oo49 53 co Xl, N Boc^ / fa-^-QiQo z'50 X I z54y / XDK / \ o=”\\ / ) z z co — — F3cX^NO2Q s,°- ZI U- - ' 'OK u_ V# — ' Xz 'o=° N J / N XX oxBot;B co IocUL51 55Q52 56F3C-^y^N Og F3C^Y^NO2 H,, NB0CZBOC^NX\\'''V^O^HTable 5-8]PEx Str PEx Stro° 203o -n V q oD <\ \ ) ~n — \ \ / ZIw / 71 Z V\^,.,.Px> J J5 J o o z 2^<-- 7 F OA \ / o" / \ / ^^NO261\ 2 / s / * / y. / / o < z' 7- zP rBoe"" "" Me £58 62 k 1F3C" X / KNO2, AB ro oo CD Ocr - O-N7(Jq ~n — >K\ / « / v< IVle / 3wOo O O zv n y-<-—-A \ / / / \> hx 7sx—— \( ® ~Z\ 7—- ZP p 59 63F3C"\AlO2 / I,lh. / N X.HO VJ60 643TAI F C" XX™O2MeTable 5-9] o CM PEx Str PEx Str / z= / O O / / Z 4 ZCD—“~ / \ r\ o=~ z 4 z A co——co o o°y S aTCO o < ^: Z IL-’ --1”~JI 2 S Z u_o—x f=o X65 \ O 04 ro- 69 coUL^ [z—P rCMoz66 J (___ __ / \ / \ o 704 Az z co-—.0X ULV' 43 P>^° XrO ABoc^ '" Me J1 / r\HJ <ny ZZA^z o^-- \ / \ / o _ ' ' ' ) o — — -Z. OJ 1 N> 67 F3C^j^NO271rOBoc Me68 72F3C^^NO2 / I, II i, / K X,Ac0V_7Table 5-10]PEx Str PEx Str i \ ) \ I r L= wOz^} / O oz *--ou_ <o X.O CO73 7774 78F3C^^NO2N oS’ T o) m — \O ZI -n — > >° °~\ / / X n>\ C / z—I Xj i K> 75 79F3C^J^NH2A M J. J BocTable 5-11] M C T PEx Str PEx StrCDZ oW W°“° 9\ZI T1 / ; \ 0 \81 Z# O 0- 85 0o c53lHz\yzIxz82 864 4\ / zCD4o o V 0T 0 / o u- ° 9 / 0 -no > XZ OX— A CD A^ / O 0Z 4M--^ 0 -n- V \ / x=_.^Z- / z rC?jl X N> X NJ 83 Yji 87F3Cz ''yxT] H2.rX1Q]84 F3C^^NH288A F3C^X'SMH2H r ]. N J. N Boer Boc-^V'X / |_| V— / Table 5-13]PEx Str PEx Str-n w MJJO V IZ T1 - v,97 AA Q 1 J 101F3C^0^N H2F3C^Y ^NH2N _N.H ^ f VZH’ / l H I I N J. JBoc" z BocIbJ98 102 F3C^^XNH2_N. coo H | | JBoc °\ZI -n!r!<.z IEro 99 103?«F3CXLV^NH2F3C^^NH2ZN^ / »-Q H | | / N. -L J Boc Boc100 104F3C-^V^NH2Me3JBocM CN C Table 5-14] T X PEx Str PEx Str z Me _ LL \b co<x yo Y o- b Q \ 2 XZ U? M>°\> X u- 5 0 c o o r10 1 9 cooF3C^^N H2H | |A J. JBooX)106 1103F3C^^NH F C^Y^N H22, co _N. / hu.x A x. o H | | Acer ° " X\ AAJ Boxbz:cx / / y O O A -n——z 9 X HN_. NJ 107 111F3C^X^N H2N H I IBox108 112F3C^O^NH2NBoc-^N / / fo<^Table 5-15] T PEx Str PEx Str Zy o un IZ LT 9 Xoo113 117 CD F3(T X\IH2 / N I BOC Boc Cr114 118XZM—ooCD90. ^115 119FSC^Y^NHZ F3C^^NH2 / N MeBOCX'Q Boc / Nx^cr99116 120 1 JL F3cr ^SJ H2 F3C^i^NH2 Me / kBoX^'' XTB0CX'N / X^'V'^O'^HTable 5-16]PEx Str PEx StrJ F^C-^121 ]T J 125F^j^NH2Me1 I 1 / NKJ\ J BocxBocz z X Xr / O— yy 2122 / \ / \ o — 126CD ■ p3cAy N ^\>_yjN. JT M H r "i / £ Vj cyo- N. J. JBocXozci-^y^123 127F3C'VLH\V£> H r ''isBoc"(^JjCIX^^124 128NM'Ls / \ — / H fN. J. J H f 'lN. JI JBoc Bor "[Table 5-17]PEx Str PEx Str129 133Boe xP9 "130 134 co\ o= -T| o ZI Q ° " H o O\xH I I ) ZI n — <\ / / _N. J. Ju / £# „ O OBoc ) A- z 00 a> ——\ o V V Vx' Q—IZ( IZ U- ' —\> o IZ Z O ^o=tn^ 131F399\V<; N 135 62”'Z H ( JSK J. J K ^-~s \= / Boc BOC-N^'OHF132 136BOC-H / / '"<S S—7HTable 5-18]PEx Str PEx StrY137 FSC'^ N'YV-^A 1410 io^c ^le138 142Me Y~x| / H fFsC^^JBocX FAnAI-\-N ^N139 °Vx / 143. A. JiLc Boer 'N=,Me-X^140 144NMU-s7Vx / H I I M J. JBoc BocTable 5-19]PEx Str PEx Str145 149H I I AA JBoerV. 0146 s\ o= 150 CD CD o OZI ° °s S\\ZIFJI Z.H3°VHK ° o A | | \> O O O J A\~ J. JO°- Boer( o= ^5^ C OH> ZIZ IZ IX. cO o^^o0=" £f c 147 151 & u=MeBoeV— 7148F152H’c^ I VI tH>Boer AA / 1Table 5-20]PEx Str PEx StrMe-^153 157XF’O MCJX^ (W Ac kJ Boer. )PFJ^XF154HX0158F=c5Vt>^> H | |M J. > J\L J Boc Boc^T?o0'yX o155 159J s k O"F3CXJ H BOC^NHZ*'Y > •.. wCF3 ^ocFk lFXz^F156F*^ \VCN160BOC^N / ^£^ HFSCV I I«\W Me X k. JBoc^Table 5-21]PEx Str PEx StrCD O O\ ZI9.161 165IZJ>o=W. JWBoc6162 166F=°b «\y<>H I I K JBoer9. 9163 167MF=eCT | / NxH ^-WS \= / BOCXQ Boc^^O^9..164 168Boer 1 J Boc^'"^ HTable 5-22]PEx Str PEx StrF'Xpl169 J 173Me JK \= / OHC / ;^~~S \— / BocFsC^O170 174F3C^NA^_0H r iH f " TJI J. J BoaBoerF0171 175H (M© < *''sV~'*S '■ — 'Boc AA>BocFAXJ°172 176F c^V^ HNX\r I \ 7 — T (Fz’I NIL-S \== / HOZ. O SKHZS>= Table f >-23]PEx Str PEx Str^> O < n—zxIZ177 181 \ / \ ^■I: u~~ —^o==_ / C^O U- CZZ^0H,2L~) 17y (> / 178 182^ O=ZIHf lNS / N'X\'''0 O«° °~“y°~oC^l179 183MFSeCV x-N\'H\V< \=3 / JYrWF3CX^X^JX^J H [ ]JI JNsF?180 184FsC-'''^N ‘--s \=y H Q K Jx JNsxTable 5-25]PEx Str PEx StroX196- 1921F3CX^^NO2BrH0<^N'> Ck jC jl 196- Me MeO / „. Z' N J'O 193 ^'^Y^'NOO 2 MeXsjZ O on JMe Fn nG'p? oZI0 H Hcr^yn / N\ 194 197F3C'xy^NO2FHO / / / ,'O4^0195 1980F3C- J^LYX^N°2FTable 5-26]PEx Str PEx StrYQ199 203 1 1oXL l^S^V^NO2F3C'^^NO2NBocHN^XJCl\^Y1 J Br'^^NO 200 2042X 1 N MexY^NO2Cl BocHN^J^XMeO2 1 0xix^NO 0 2 52N1 JMe' y TIty BocHN^XXJ ClY0202 206 0. X I F3C'^f^NO2 oY r ° Br2Me< S BocHNXx<rXJTable 5-27]PEx Str PEx Str0207 211F3C- J^OY^L 1NO2Me^^NO2N NBocHN^lJ BocHN^l^JQ Y208 1 J FF3C-^Y^NO2 2123C^f^NO2 / H AN\ O / / Z,H0 / / ,„^N^Q209 I 1F3Cx^f^xNO2213 Me'^ y^NOzHO-A A- ^ocY210 Me^ 1Y 1^NOz 214Br^ JA N Y^N°2NBocHN^J^JBocHN^^J^JTable 5-28]PEx Str PEx Str Q Q 0.215219NBocHN^J^J HO^216 F3C^^^NO2220v<N"> 0217 F3C^Y^NO2221 F3C / ^f^xNO20 0^9Q 9218 I JF3C'x^k ''NO2222 F3C / i^LxNO2 / N>c> L9Table 5-29]PEx Str PEx Str223 F3C'^Y^NO2227 Me^Y^NO2_ o M KMArQBocJJ224 F3CX'^ 1'H\IO2228 MexJ^f 1xNO2Me. N Q^N.F3C^N^LNJ 0 E-JocY O. ^F3CXIH^ 2N°2225 229 F3C- T'^f 1?'SlO2 / N\ C YYH2N^ / SrQ226 Me^ y^NC^ 230 F3C-X\^NO2A OHC^N^ H2N»„. A^BocTable 5-30]PEx Str PEx Str231 F3C / ^^'NO2235 F3CxJ^lf 1^NO2H2N / / ,,. / Sr BOCHN / / ,„Z-. N'>Y Y232 F3C'^ J!X1 1N^KNO\2236 F3C^^ 1NO / 2Y) H2N^y BOCHNM^ / > T233 F3C / Y^NO2237 F3C^^NO2BOCHN^Z-N> <N^] Boc \_JQ Y234 J! 1 238 F3C / Lxf^NO2F3C^Y^NO2Me \ J Boc \ _ JTable 5-31]PEx Str PEx StrQ 0^239 MexXx^NO2243Me, N MeCr 1'x^ JNH2NF3CVN^XNJBocHN^XJ0HQ 0^240 Mex^x^NO2244 o.Me, N T I F30A CVN^XNJ Mer A^BocHN^^XX° l\^le0241 245F3CxJxy; Jx'NH20N FsCrXN^NH;, BocHN^XJ BocHN^X^J0242 246V7 F3C' X^X 1^NH2v / T^XKN H2BocHN^XX cv<?Table 5-32]PEx Str PEx StrQ0^ Q°'YX^ 247 F3C-^Y^N H2251 F3C-X^^N H2BOCHN / / Z„^AN^Y °-Y^248 Me / Y^N H2252F3C'xixf:^N H2 NBocHN^l^J BOCHN / ,,,, / SJ>Q Y249 253 F3C'^Y^N H2Mex\^N H2l\LBOCHNM^ fSNK) BocHN^L^JY250 F3C-^Y^N H2254 F3C-^Y^N H2>k Me / N> Me ' >\ J \ ’ J N^^hr Boc \ — 1 Boc \ 1Table 5-33]PEx Str PEx Strjf 1255 Me / y^N H2259Me JMFSCYMJ BocHN^l^J0MeQ]256 260BocHN^Cj BOCHN^L^Jo2579n. ° 261Q^y BocHN^Jx^J258 262Meo^ i\x >’ - BocHN^CjTable 5-34]PEx Str PEx StrY263 267'■°Y^sYx!" BocHN^^CJ] BocHN / ,„,Y264 268F3CV ALH > BOCHNM^AN-YBocHNx^OY265 F3c-Q-N'1Y-N<^N 269Me ^Nx. W \= / \?JhK / ~''hrBoc \ _ / Boc \ — 1266 270BocHN / / ,,,^ / ^ / F3CY%XNJo I^ieTable 5-35]PEx Str PEx Str271 2725^ \. VBrBocHN^CJJ BOCHN^I^[Table 6-1]PEx PSyn DATNMR DMSO-d6 (500 MHz): 7.16-7.21 (3H, m), 7.26-7.32 1 1 (1H, m), 7.45-7.51 (2H, m), 8.15-8.20 (1H, m)2 1 ESI+: 402.3NMR CDCl3 (500 MHz): 6.73-6.85 (2H, m), 6.92-7.00 3 1 (1H, m), 7.01-7.05 (1H, m), 7.37-7.44 (1H, m), 7.69-7.73(1H, m)NMR CDCl3 (500 MHz): 6.90-6.94 (1H, m), 7.01-7.06 4 1(2H, m), 7.10-7.16 (2H, m), 7.65-7.69 (1 H, m)NMR DMSO-d6 (500 MHz): 7.04-7.08 (1H, m), 7.36-7.40 5 1 (2H, m), 7.46-7.50 (1H, m), 7.68-7.71 (1H, m), 8.15-8.18(1H, m)NMR DMSO-d6 (500 MHz): 7.15-7.19 (1H, m), 7.32-7.36 6 1(2H, m), 7.37-7.39 (1H, m), 7.49 (1H, t), 8.19-8.23 (1H, m) 7 1 ESI+: 387.18 1 ESI+: 365.19 1 ESI+: 341.2NMR DMSO-d6 (500 MHz): 7.08-7.14 (1H, m), 7.30-7.53 10 1(4H, m), 8.01 (1H, dd)NMR CDCl3 (400 MHz): 6.98 (2H, d), 7.15 - 7.19 (1H, m), 11 17.33 - 7.39 (2H, m), 7.74 (1H, dd)NMR CDCl3 (400 MHz): 5.28 (2H, s), 7.05 (1H, d), 7.34 - 12 17.44 (5H, m), 7.85 (1H, d)13 13 ESI+: 413.114 13 ESI+: 363.3NMR CDCl3 (400 MHz): 1.50 (9H, s), 2.38 (2H, br s), 3.68 15 13 (2H, br s), 4.03 (2H, br s), 5.61 (1 H, br s), 7.66 - 7.71 (1 H, m)16 16 ESI+: 422.317 17 ESI+: 487.218 17 ESI+: 451.219 17 ESI+: 415.3NMR CDCl3 (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 20 17(2H, br s), 4.34 - 4.39 (1 H, m), 5.55 -5.58 (1 H, m), 7.61(1 H, d)[Table 6-2]PEx PSyn DAT21 21 ESI+: 460.522 21 ESI+: 474.723 21 ESI+: 488.224 21 ESI+: 500.225 21 ESI+: 400.126 21 ESI+: 495.327 21 ESI+: 510.328 21 ESI+: 532.229 21 ESI+: 550.2NMR CDCl3(400 MHz): 1.33 - 1.44 (1 H, m), 1.68 - 1.79 (1 H, m), 1.91 - 1.99 (2H, m), 2.21 - 2.27 (1 H, m), 2.77 - 30 302.83 (1 H, m), 2.88 - 2.94 (1 H, m), 3.30 - 3.38 (2H, m), 3.61 - 3.71 (2H, m), 7.81 - 7.89 (4H, m)31 31 ESI+: 265.432 32 ESI+: 347.433 33 ESI+: 225.434 34 ESI+: 496.235 34 ESI+: 536.436 34 ESI+: 536.437 34 ESI+: 536.438 34 ESI+: 530.239 34 ESI+: 552.3, 554.340 34 ESI+: 543.441 34 ESI+: 497.342 34 ESI+: 495.443 34 ESI+: 450.444 34 ESI+: 494.2NMR 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 45 34 (3H, m), 3.50 - 3.61 (2H, m), 5.18 (2H, s), 6.80 (1 H, 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+: 496.447 34 ESI+: 560.448 34 ESI+: 482.2[Table 6-3]PEx PSyn DAT49 34 ESI+: 520.350 34 ESI+: 558.451 34 ESI+: 506.352 34 ESI+: 518.453 34 ESI+: 522.2NMR CDCl3(400 MHz): 1.46 (9H, s), 2.89 - 3.13 (4H, m), 3.28 - 3.33 (2H, m), 3.71 - 3.88 (3H, m), 4.88 (1 H, br s), 54 346.73 (1 H, d), 7.04 - 7.06 (2H, m), 7.22 - 7.24 (1 H, m), 7.40 - 7.44 (2H, m), 7.63 (1H, d)NMR CDCl3(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), 55 34 3.87 (1 H, dd), 4.88 (1 H, br s), 6.73 (1 H, d), 7.04 - 7.06 (2H, m), 7.22 - 7.26 (1H, m), 7.40 - 7.44 (2H, m), 7.63 (1H, d)56 34 ESI+: 534.4NMR CDCl3(400 MHz): 1.14 - 1.20 (1 H, m), 1.42 (9H, s), 1.57 - 1.75 (3H, m), 1.99 - 2.02 (1 H, m), 2.71 - 2.83 (5H, 57 34m), 3.03 - 3.13 (4H, m), 6.96 (2H, d), 7.10 - 7.14 (1H, m), 7.31 - 7.35 (2H, m), 7.39 (1H, dd)58 1+34 ESI+: 500.359 1+34 ESI+: 401.360 60 ESI+: 550.461 60 ESI+: 566.462 60 ESI+: 518.463 60 ESI+: 550.464 60 ESI+: 532.465 60 ESI+: 514.2NMR CDCl3(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 (1 H, d), 7.05 66 60(2H, d), 7.22 - 7.26 (1 H, m), 7.40 - 7.44 (2H, m), 7.63 (1 H, d)NMR CDCl3(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 67 60(2H, d), 7.23 - 7.26 (1 H, m), 7.40 - 7.44 (2H, m), 7.63 (1 H, d)68 68 ESI-: 494.3[Table 6-4]PEx PSyn DAT69 69 ESI+: 511.470 70 ESI+: 629.471 71 ESI+: 603.472 72 ESI+: 443.2NMR CDCl3(400 MHz): 1.08 - 1.18 (2H, m), 1.62 - 1.87 (3H, m), 2.54 - 2.64 (2H, m), 2.72 - 2.78 (1 H, m), 2.97 - 73 733.09 (2H, m), 3.19 - 3.29 (1 H, m), 6.84 - 6.97 (2H, m), 7.08 - 7.14 (1H, m), 7.31 - 7.40 (3H, m)NMR CDCl3(400 MHz): 1.03 - 1.06 (1 H, m), 1.65 - 1.88 74 73 (4H, m), 2.58 - 2.69 (3H, m), 2.95 - 3.19 (3H, m), 5.21 (2H, s), 6.82 (1 H, d), 7.32 - 7.41 (5H, m), 7.66 (1 H, d) NMR CDCl3(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 - 75 754.56 (1H, m), 6.83 - 6.98 (2H, m), 7.08 - 7.15 (1H, m), 7.31 - 7.40 (3H, m)NMR CDCl3(400 MHz): 1.08 - 1.10 (1H, m), 1.43 (9H, s), 1.65 - 1.88 (4H, m), 2.65 - 2.71 (1 H, m), 2.90 - 3.11 (5H, 76 75m), 4.53 (1 H, br s), 5.21 (2H, s), 6.83 (1 H, d), 7.32 - 7.41 (5H, m), 7.66 (1H, d)77 77 ESI+: 466.378 77 ESI+: 498.479 77 ESI+: 484.480 77 ESI+: 500.2, 502.281 77 ESI+: 500.4, 502.382 77 ESI+: 491.483 77 ESI+: 467.484 77 ESI+: 443.485 77 ESI+: 420.586 77 ESI+: 530.387 77 ESI+: 484.588 77 ESI+: 452.389 77 ESI+: 457.290 77 ESI+: 421.491 77 ESI+: 466.492 77 ESI+: 385.4[Table 6-5]PEx PSyn DAT93 77 ESI+: 514.4, 516.494 77 ESI+: 466.495 77 ESI+: 577.496 77 ESI+: 528.497 77 ESI+: 470.498 77 ESI+: 476.499 77 ESI+: 466.4100 77 ESI+: 480.4101 77 ESI+: 430.3102 77 ESI+: 444.1103 77 ESI+: 458.3104 77 ESI+: 470.3105 77 ESI+: 470.3106 77 ESI+: 413.2107 77 ESI+: 464.2108 77 ESI+: 470.3109 77 ESI+: 484.4110 77 ESI+: 423.9111 77 ESI+: 502.2112 77 ESI+: 520.3NMR CDCl3(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), 3.76 113 77(2H, br s), 4.00 - 4.06 (1 H, m), 4.06 (2H, br s), 5.76 (1 H, brs), 6.24 (1H, dd)NMR CDCl3(400 MHz): 0.96 - 1.04 (1H, m), 1.43 (9H, s), 1.43 - 1.82 (4H, m), 2.69 - 2.74 (1 H, m), 2.93 - 3.03 (5H, 114 77m), 4.31 (2H, br s), 4.57 (1 H, br s), 6.33 (1 H, dd), 6.92 (2H, d), 7.02 (1H, t), 7.28 (2H, t)NMR CDCl3(400 MHz): 1.43 (9H, s), 2.67 - 2.98 (2H, m), 115 77 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)NMR CDCl3(400 MHz): 1.44 (9H, s), 2.75 (1H, d), 2.83 (1 H, d), 2.94 (3H, s), 3.04 - 3.16 (1 H, m), 3.28 - 3.49 (2H, 116 77m), 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)[Table 6-6]PEx PSyn DATNMR CDCI3(400 MHz): 1.46 (9H, s), 2.69 - 3.00 (2H, m), 3.15 - 3.28 (3H, m), 3.48 - 3.98 (4H, m), 6.74 - 6.79 (2H, 117 77m), 6.84 - 6.86 (1H, m), 6.97 - 7.06 (2H, m), 7.26 - 7.32 (2H, m)118 77 ESI+: 390.3NMR CDCI3(400 MHz): 1.44 (9H, s), 2.75 (1H, d), 2.84 (1 H, d), 2.94 (3H, s), 3.02 - 3.17 (1 H, m), 3.28 - 3.46 (2H, 119 77m), 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) NMR CDCI3(400 MHz): 1.45 (9H, s), 1.64 - 1.69 (2H, m), 2.73 - 2.89 (2H, m), 2.96 - 3.17 (1H, m), 3.19 - 3.48 (3H, 120 77 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+: 448.3122 122 ESI+: 467.4123 123 ESI+: 563.2124 124 ESI+: 655.3125 124 ESI+: 687.4126 124 ESI+: 695.4127 124 ESI+: 689.4128 124 ESI+: 711.4, 713.4129 124 ESI+: 702.4130 124 ESI+: 678.4131 124 ESI+: 632.4132 124 ESI+: 609.2133 124 ESI+: 697.5134 124 ESI+:673.4135 124 ESI+: 641.3136 124 ESI+: 624.2137 124 ESI+: 588.2138 124 ESI+: 655.4139 124 ESI+: 574.4140 124 ESI+: 703.4141 124 ESI+: 655.4[Table 6-7]PEx PSyn DAT142 124 ESI+: 788.4143 124 ESI+: 717.4144 124 ESI+: 659.4145 124 ESI+: 665.3146 124 ESI+: 677.4147 124 ESI+: 669.4148 124 ESI+: 619.3149 124 ESI+: 633.3150 124 ESI+: 647.3151 124 ESI+: 659.3152 124 ESI+: 659.5153 124 ESI+: 602.3154 124 ESI+: 654.2155 124 ESI+: 659.3156 124 ESI+: 673.3157 124 ESI+: 669.3158 124 ESI-: 689.2159 124 ESI+: 752.3160 124 ESI-: 707.1161 124 ESI+: 578.3162 124 ESI+: 623.3163 124 ESI+: 679.3164 124 ESI+: 693.3165 124 ESI+: 679.3166 124 ESI+: 601.1167 124 ESI+: 693.2168 124 ESI+: 693.2NMR CDCI3(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), 169 124 6.95 (2H, d), 7.07 (1 H, t), 7.31 (2H, t), 7.90 - 7.98 (1 H, m),8.37 - 8.40 (1 H, m), 8.47 (1 H, s), 9.40 (1 H, br s), 9.80 - 9.85 (1H, m), 10.88 (1H, br s)170 77+124 ESI+:673.4171 77+124 ESI+:687.4172 172 ESI+:560.2[Table 6-8]PEx PSyn DAT 173 173 ESI+: 558.2174 174 ESI+: 732.9175 175 ESI+: 661.3176 176 ESI+: 524.2177 176 ESI+: 488.1178 176 ESI+: 452.3179 176 ESI+: 666.4180 176 ESI+: 652.3181 176 ESI+: 456.2182 182 ESI+: 740.3183 182 ESI+: 740.3184 182 ESI+: 758.1185 185 ESI+: 754.3186 185 ESI+: 754.4187 185 ESI+: 772.4188 185 ESI+: 786.3189 185 ESI+: 816.4190 190 ESI+: 680.3191 190 ESI+: 666.4[Table 6-9]PEx PSyn DATNMR DMSO-d6 (400 MHz): 7.00 (1H, d), 7.57-7.64 (5H, 192 192m), 7.97 (1H, d)193 NMR DMSO-d6 (400 MHz): 3.52 (3H, s), 7.61 (1 H, t), 1938.55-8.61 (1H, m)194 194 ESI+: 275.3195 NMR DMSO-d6 (400 MHz): 7.60 (2H, t), 7.67 (1H, d), 1957.75-7.81 (3H, m), 8.58 (1H, t)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), 196-1 1964.01-4.07 (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)NMR CDCI3 (400 MHz): 1.00 (9H, s), 1.60-1.69 (2H, m), 196-2 196 3.37-3.43 (1H, m), 3.95-4.20 (4H, m), 4.81 (1H, brs), 6.43(1H, brs), 7.37-7.46 (6H, m), 7.64-7.76 (4H, m)197 197 ESI+: 143.1198 197 ESI+: 143.1NMR CDCI3 (400 MHz): 3.46 (3H, s), 6.75 (1H, dd), 7.16 199 1(2H, d), 7.36 (1H, t), 7.51 (2H, t), 8.18 (1H, t)NMR CDCI3 (400 MHz): 0.80-0.91 (4H, m), 2.29 (3H, s), 200 13.80-3.84 (1H, m), 7.20 (1H, d), 7.79 (1H, d)NMR CDCI3 (400 MHz): 2.47 (3H, s), 6.73 (1H, d), 7.00- 201 1 7.02 (2H, m), 7.20-7.24 (1H, m), 7.39-7.43 (2H, m), 7.65(1H, d)NMR CDCI3 (400 MHz): 0.83-0.97 (4H, m), 3.87-3.92 202 1(1H, m), 7.48 (1H, d), 7.79 (1H, d)203 34 ESI+: 535.1204 34 ESI+: 449.9205 34 ESI+: 384.1206 34 ESI+: 506.3207 34 ESI+: 530.0208 34 ESI+: 424.2209 34 ESI+: 424.3210 34 ESI+: 406.3211 34 ESI+: 442.4212 34 ESI+: 388.2[Table 6-10]PEx PSyn DATNMR CDCI3 (400 MHz): 1.49 (9H, s), 2.33 (3H, s), 2.88- 213 34 3.44 (5H, m), 3.80-4.32 (4H, m), 6.61 (1H, d), 6.99 (2H, d), 7.14-7.22 (1H, m), 7.31-7.52 (3H, m)214 1 ESI+: 508.2215 1 ESI+: 458.6NMR 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), 3.32-3.39 216 216 (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)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), 3.23-3.34 217 216 (2H, m), 3.39-3.44 (2H, m), 5.45-5.49 (1H, m), 6.71 (1H, d), 7.04 (2H, d), 7.23 (1H, t), 7.39-7.46 (4H, m), 7.54-7.59 (2H, m), 8.06 (2H, d)218 34 ESI+: 424.3NMR 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), 3.19-3.23 219 34 (2H, m), 3.29-3.35 (2H, m), 4.16-4.19 (1H, m), 6.71 (1H, d), 7.05 (2H, d), 7.23 (1H, t), 7.39-7.44 (2H, m), 7.60 (1H, d)220 220 ESI+: 468.1221 221 ESI+: 553.3222 221 ESI+: 553.2223 221 ESI+: 553.2224 221 ESI+: 553.3225 221 ESI+: 517.3NMR 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), 226 68 4.68-4.90 (1H, m), 6.61 (1H, d), 6.95-7.04 (2H, m), 7.15- 7.22 (1H, m), 7.32-7.43 (2H, m), 7.48 (1H, d), 9.68-9.70 (1H, m)NMR CDCI3 (400 MHz): 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- 227 696.66 (1H, m), 6.91-7.04 (2H, m), 7.13-7.21 (1H, m), 7.32-7.49 (3H, m)[Table 6-11]PEx PSyn DAT228 70 ESI+: 575.5229 73 ESI+: 423.3230 73 ESI+: 423.2231 73 ESI+: 423.3232 73 ESI+: 387.3233 75 ESI+: 523.4234 75 ESI+: 523.3235 75 ESI+: 523.4236 75 ESI+: 487.3237 60 ESI+: 537.3238 60 ESI+: 501.4NMR CDCI3 (400 MHz): 2.30-2.31 (3H, m), 2.74-3.51 239 30 (12H, m), 6.59 (1H, d), 6.95-7.03 (2H, m), 7.14-7.22 (1H, m), 7.34-7.52 (3H, m)NMR CDCI3 (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), 3.67-4.05 240 190(1H, m), 6.59 (1 H, d), 6.97-7.03 (2H, m), 7.15-7.21 (1H, m), 7.35-7.46 (3H, m)241 77 ESI+: 504.5242 77 ESI+: 438.1243 77 ESI+: 428.9244 77 - 245 77 ESI+: 477.5246 77 ESI+: 523.3247 77 ESI+: 523.3248 77 ESI+: 376.4249 77 ESI+: 412.3250 77 ESI+: 507.4251 77 ESI+: 493.4252 77 ESI+: 493.4253 77 ESI+: 457.4254 77 ESI+: 471.4[Table 6-12]PEx PSyn DATNMR 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- 255 773.82 (2H, m), 3.88-4.01 (1 H, m), 6.59 (1H, d), 6.70 (1H, d), 6.83 (2H, d), 6.94-7.01 (1 H, m), 7.22-7.34 (2H, m) 256 124 ESI+: 695.1257 124 ESI+: 627.2258 124 ESI+: 615.2259 124 ESI+: 665.1260 124 ESI+: 667.1261 124 ESI+: 712.3262 124 ESI+: 712.5263 124 ESI+: 565.4264 124 ESI+: 601.5265 124 ESI+: 696.3266 124 ESI+: 682.4267 124 ESI+: 682.4268 124 ESI+: 646.5269 124 ESI+: 660.5NMR 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), 270 1247.28-7.37 (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+: 725.3272 272 ESI+: 725.2Table M] _Ex Str Ex StrY 1f1 JO. JL 5 V A w ty G / 0^Hf2 6 / Q 5c\ ZY3 •r 7AM / AwF’cVAy-0HA H2IST4 A Aw 8r*YAw 'A H2N^ I )MeHTable 7-2]Ex Str Ex Str / _ CM \ oV T XY2HC, 9 13j > I o O ▼ —yr Y y M rW -HzNx< C^H2NX^J\^FzXp HCI 2HCI 10 14>'<i z '■"s' \= / "cVAwH2N^ZZyU_ TZy J V LL? o n o 4—11 15Meo Y 2HCI 12 F3C / \H16- - Ly O N1HN _ / Table 7^J _Ex Str Ex Str“VX)YMe2HCI 17 21F3C^ Y^Y H'Z^VYY \^= / H2NX^J\YCj / 1 3HCI p / ^Y^FJ 2HCI 18 22YY \= / HzNx^X^FpJ^U^F 2HCI 19 23Y Y wH2r / \_yH2NXY\YJO20 24MeHNz\ / HzNx<k^[Table 7-4]Ex Str Ex Str25 9, 291Hu '—-s z — \ \= / / * F3cr jQ 1HA [I n \ z _ — / \ / % / -^0 '26 30 FgC-^^ 1^ H 17 - (' I1MeHN^0 H2N-^'" 0X / 927FsC31 ^MeHNrAx) \Z\z28 32[Table 7-5]Ex Str Ex Str p t2HCI 33 37cA F Xl iN / o1 / 3C / ^,«„ / Y%YYu~sW \= / > MeHNz\ / p tNCX^^34 38ZIF’c''^ l-W \ _ / UL Xc< XVJI35 39H2NxZ\zcr JO^ 2HCI36 40FICVAW[Table 7-6]Ex Str Ex Str7 / ~ \ J1 / 41 45 9FSCV AM >2HCI 42 46M. HN^ / *-0 ’LZA= / 43 47f»XVxy£}<H2NX^\^N=\Me-'t\z^ F44 48FaC^'^V'' ™IH|l 7 — \ Z1HIZ-6H2NXU\XJ[Table 7-7]Ex Str Ex StrX 2HCI 49 XX 1 -< 53N lUs7\= / MeCr ^^ / 0l^jl 2HCI 2HCI50 54AX SZ\= / '•V A wFx^pl 2HCI 51 55Fsc^ \yoF>c^ \x >FX x\M 2HCI9.52 56X X w "Et NC^ ALM3 H 1 JNMe2%A^[Table 7-8]Ex Str Ex Str2HCI 57 6158 62Me2N / x^''- V2HCI59 63-? AwF^ tr\yo ^ -oo9.60F’c^X\yo 64p3C / / 'H^=\---\ Cx w Hcr ^ NHMe[Table 7-9]Ex Str Ex Str65 69HeV A yo YYA yy> M. HN^Q SS's H2N^l^xJl\!le66 70H2NX<^\XJY67 71vV AryOHe^ \yoH2N^X^J68 72H2N^C^H2N^AXXJ[Table 7-10]Ex Str Ex Str Y73 77MeHNih^y^ MeHN^Z^N^Qj74 78F3C5 T\V-0w% y4H2N / / ^^r H2N^2yQi75 79FjcQ \y^ H2N / / „ H2N>z^>rY76F=C^ \V£> 80H2NM^SJ^Me? N^ \^j[Table 8-1]Ex Syn DAT1 1 ESI+: 611.42 1 ESI+: 604.23 1 ESI+: 568.14 1 ESI+: 532.35 1 ESI+: 536.26 6 ESI+: 584.27 6 ESI+: 569.48 6 ESI+: 570.4ESI+: 555.3NMR DMSO-d6(500 MHz): 1.03-1.24 (1H, m), 1.69-1.89 9 9 (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), 6.93-7.44 (6H, m), 8.19-8.86 (3H, m), 9.47-10.63 (3H, m)ESI+: 587.4NMR DMSO-d6(500 MHz): 1.09-1.29 (1H, m), 1.61-2.12 10 9 (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)ESI+: 573.4NMR DMSO-d6(500 MHz): 1.02-1.16 (1 H, m), 1.70-2.16 11 9 (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+: 597.313 9 ESI+: 519.314 9 ESI+: 533.415 9 ESI+: 547.416 9 ESI+: 559.317 9 ESI+: 559.318 9 ESI+: 554.219 9 ESI+: 559.220 9 ESI+: 573.321 9 ESI+: 569.422 9 ESI+: 591.323 9 ESI+: 609.4[Table 8-2]Ex Syn DAT24 9 ESI+: 523.425 9 ESI+: 557.426 9 ESI+: 571.427 9 ESI+: 557.428 9 ESI+: 539.429 9 ESI+: 571.230 9 ESI+: 571.231 9 ESI+:537.232 9 ESI+:555.3ESI+: 573.4NMR DMSO-d6(500 MHz): 1.02-1.20 (1H, m), 1.71-1.88 33 9 (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), 6.95-7.45 (5H, m), 8.18-8.84 (3H, m), 9.43-10.61 (3H, m)ESI+: 541.2NMR DMSO-d6(500 MHz): 1.96-2.17 (4H, m), 2.43-2.60 (2H, m), 3.04 (1 H, s), 3.42-3.52 (2H, m), 7.00-7.04 (2H, 34 9m), 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, 591.436 9 ESI+ 603.4, 605.337 9 ESI+ 555.438 9 ESI+ 580.239 9 ESI+ 556.240 9 ESI+ 589.2, 591.241 9 ESI+ 573.342 9 ESI+ 595.443 9 ESI+ 587.344 9 ESI+ 559.445 9 ESI+ 555.446 9 ESI+ 569.447 9 ESI+ 532.448 9 ESI+ 509.2[Table 8-3]Ex Syn DAT49 49 ESI+: 569.350 49 ESI+: 569.351 49 ESI+: 587.252 49 ESI+: 601.253 49 ESI+: 631.254 54 ESI+: 583.455 54 ESI+: 583.356 54 ESI+: 585.457 54 ESI+: 551.358 54 ESI+: 599.4ESI+: 655.4NMR 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 59 59 (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+: 641.461 59 ESI+: 653.462 62 ESI+: 653.463 63 ESI+: 615.264 64 ESI+: 569.3[Table 8-4]Ex Syn DAT65 6 ESI+: 530.366 9 ESI+: 603.367 9 ESI+: 527.368 9 ESI+: 517.369 9 ESI+: 565.270 9 ESI+: 567.071 9 ESI+: 465.272 9 ESI+: 501.373 9 ESI+: 596.574 9 ESI+: 582.475 9 ESI+: 582.376 9 ESI+: 546.477 9 ESI+: 560.3ESI+: 582.3NMR 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 78 78(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+: 582.3ESI+: 610.4NMR 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 80 54(4H, m), 7.37-7.43 (2H, m), 8.29-8.40 (1H, m), 8.50-8.69 (1H, 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+: 610.382 54 ESI+: 574.4ESI+: 587.3NMR 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 83 83 (3H, m), 6.30 (2H, s), 6.95-7.46 (5H, m), 8.15-8.85 (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[Table 8-5]Ex Syn DATESI+: 555.4NMR 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, 84 84 s), 6.94-7.44 (6H, m), 8.18-8.85 (3H, m), 9.47-10.60 (3H, m)2θ(°)=5.4, 9.2, 10.4, 12.0, 14.1, 14.9, 16.4, 21.2, 23.7, 26.3ESI+: 573.3NMR 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, 85 84 s), 6.75-7.46 (5H, m), 8.17-8.89 (3H, m), 9.48-10.63 (3H, m)2θ(°)=9.3, 9.6, 10.4, 12.0, 13.9, 14.2, 15.2, 16.4, 22.4, 23.8ESI+: 573.3NMR DMSO-d6(500 MHz): 1.09-1.29 (1 H, m), 1.53-2.41 (4H, m), 2.61-2.86 (3H, m), 2.93-3.30 (3H, m), 6.33 (2H, 86 84 s), 6.95-7.46 (5H, m), 8.16-8.87 (3H, m), 9.46-10.60 (3H, m)2θ(°)=9.3, 10.4, 12.1, 14.2, 14.9, 16.5, 18.0, 18.9, 23.9, 26.6ESI+: 541.3NMR DMSO-d6(500 MHz): 1.92-2.30 (4H, m), 2.60-2.72 (2H, m), 3.05 (1 H, br s), 3.47 (1 H, br s), 3.62 (1 H, br s), 6.41 (2H, s), 7.01-7.05 (2H, m), 7.06-7.14 (1H, m), 7.15- 87 84 7.20 (1H, m), 7.39-7.45 (2H, m), 8.18-8.25 (1H, m), 8.67- 8.80 (1H, m), 8.81 (1H, s), 9.45-9.54 (1H, m), 9.78-9.86 (1H, m)2θ(°)=6.2, 6.6, 11.0, 13.3, 15.9, 16.6, 17.9, 19.7, 20.3,25.4[Table 9]Reference Example Str DAT91oN IL / \ / ESI+: 607.4HIndustrial Applicability

[0154] The compound of the present invention or a salt thereof is useful as a DGK inhibitor, and can be used as an active ingredient of a pharmaceutical composition, for example a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer), in an embodiment, for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy. In addition, the pharmaceutical composition, comprising administering an effective amount of the compound of the present invention or a salt thereof to the subject in combination with a combination therapy can be used as a therapeutic agent for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer) and / or non-small cell lung cancer.

Claims

CLAIMS

1. A compound of formula (I):[Chemical Formula 1](I)or a salt thereof, for use in the treatment of colorectal cancer (except for mismatch repairdeficient bowel cancer), whereinR1is a group of formula (i), (ii), (iii) (iv) or (v):[Chemical Formula 2]R2is a Ci-6 alkyl, a C3-5 cycloalkyl, an -O-(Ci-6 alkyl), methanesulphonyl, a halogeno-Ci-6 alkyl or a halogen,R3is i) a phenyl optionally substituted with a group selected from the group consisting of a C1-6 alkyl, a halogeno-Ci-6 alkyl, a C3-5 cycloalkyl, an -O-(Ci-6 alkyl), an -O-(halogeno-Ci-6 alkyl), cyano, nitro, methanesulphonyl 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 halogeno-Ci-6 alkyl, a C3-5 cycloalkyl, an -O-(Ci-6 alkyl), an -O-(halogeno-C1-6 alkyl), cyano, nitro, methanesulphonyl 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,R4is H or F,L is a bond, CO, SO2, O or NH,X is CH2, O orN-methyl,Y is CH2or O,Rais H or methyl,Rbis H, methyl, ethyl or-(CH2)2O-CH3,Rcis H, methyl or oxetanyl,Rdis H, methyl, -(CH2)2OH, -(CH2)2O-CH3or oxetanyl,m is 1 or 2, andn is 1 or 2.

2. A compound or a salt thereof according to claim 1, wherein R2is a halogeno-Ci-6 alkyl or a halogen, L is a bond, O or NH, X is CH2or N-methyl, Rcis H or methyl, m is 1.

3. A compound or a salt thereof according to claim 2, wherein R1is a group of formula (i-a), (ii-a), (iii-a) or (v):[Chemical Formula 3]

4. A compound or a salt thereof according to claim 3, wherein R3is a phenyl optionally substituted with a group selected from the group consisting of a Ci-6 alkyl and a halogen; or a C3-s cycloalkyl.

5. A compound or a salt thereof according to claim 4, wherein R2is CF3, R4is H, Rbis H or methyl, and Rcis H.

6. A compound or a salt thereof according to claim 1, wherein the compound is selected from the group consisting of:N- { 2-[(3 S)-3 -(aminomethyl)piperidin- 1 -yl]-4-phenoxy-3 -(trifluoro methyl)phenyl } -2-(pyridazin-4-yl)- 1,3 -thiazole-4-carboxamide;N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-(3-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide;N-{2-[9-(2-methoxyethyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide;N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide;N-[4-(2-fluorophenoxy)-2- { (3 S)-3 -[(methylamino)methy l]pip er id i n- 1 -yl } -3 -(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide;N-{2-[(2R)-2-(aminomethyl)pyrrolidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-y 1)- 1,3 -thiazole-4-carboxamide;N-{2-[(8R,8aS)-8-aminohexahydropyrrolo[l,2-a]pyrazine-2(lH)-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide; andN-{2-[(8R,8aS)-8-(dimethylamino)hexahydropyrrolo[l,2-a]pyrazine-2(lH)-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide.

7. A compound or a salt thereof according to claim 1, wherein the compound or a salt thereof is selected from the group consisting of:N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide mono[(2E)-but-2-enedioate];N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-(3-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide mono[(2E)-but-2-enedioate];N-{2-[(3S)-3-(aminomethyl)piperidin-l-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-y 1)- 1,3 -thiazole-4-carboxamide mono [(2E)-but-2-enedioate];N-[4-(2-fluorophenoxy)-2- { (3 S)-3 -[(methylamino)methyl]piperidin- 1 -y 1 } -3 - (trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-l,3-thiazole-4-carboxamide mono[(2E)-but-2-enedioate]; andN-{2-[(2R)-2-(aminomethyl)pyrrolidin-l-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2- (pyridazin-4-yl)-l,3-thiazole-4-carboxamide mono[(2E)-but-2-enedioate].

8. A pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer), comprising the compound or a salt thereof according to claim 1.

9. The pharmaceutical composition according to claim 8, where colorectal cancer (except for mismatch repair-deficient bowel cancer) is colorectal cancer (except for mismatch repair-deficient bowel cancer) related to activation of immune cells or colorectal cancer (except for mismatch repair-deficient bowel cancer) having resistance to anti-PD-1 antibody / anti-PD-Ll antibody therapy.

10. The pharmaceutical composition according to claim 8 or 9, wherein colorectal cancer (except for mismatch repair-deficient bowel cancer) is microsatellite stable (MSS) colorectal cancer.

11. The pharmaceutical composition according to any one of claims 8 to 10, wherein the compound or a salt thereof according to claim 1 is administered orally at a dose of 10 mg to 200 mg once daily.

12. The pharmaceutical composition according to any one of claims 8 to 10, wherein the compound or a salt thereof according to claim 1 is administered orally at a dose of 25 mg to 100 mg twice daily.

13. The pharmaceutical composition according to any one of Claims 8 to 12, wherein the pharmaceutical composition is administered to the subject in combination with a combination therapy selected from the group consisting of i) TAS- 102 and bevacizumab, ii) mFOLFOX6 chemotherapy regimen and bevacizumab, and iii) FOLFIRI chemotherapy regimen and bevacizumab.

14. The pharmaceutical composition according to Claim 13, wherein the said combination therapy comprises TAS-102 and bevacizumab.

15. The pharmaceutical composition according to Claim 13, wherein the said combination therapy comprises mFOLFOX6 chemotherapy regimen and bevacizumab.

16. The pharmaceutical composition according to Claim 15, wherein mFOLFOX6 chemotherapy regimen comprises oxaliplatin, leucovorin and fluorouracil (5-FU).

17. The pharmaceutical composition according to Claim 13, wherein the said combination therapy comprises FOLFIRI chemotherapy regimen and bevacizumab.

18. The pharmaceutical composition according to Claim 17, wherein FOLFIRI chemotherapy regimen comprises irinotecan, leucovorin and fluorouracil (5-FU).

19. Use of the compound or a salt thereof according to claim 1, for the manufacture of a pharmaceutical composition for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer).

20. The compound or a salt thereof according to claim 1, for use in treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer).

21. Use of the compound or a salt thereof according to claim 1, for treatment of colorectal cancer (except for mismatch repair-deficient bowel cancer).

22. A method for treatment of colorectal cancer (except for mismatch repairdeficient bowel cancer), which comprises administering an effective amount of the compound or a salt thereof according to claim 1 to a subject.

23. A method for treatment of colorectal cancer (except for mismatch repair deficient bowel cancer), which comprises administering an effective amount of the pharmaceutical composition according to any one of Claims 8 to 12 to a subject in combination with a combination therapy selected from the group consisting of i) TAS- 102 and bevacizumab, ii) mFOLFOX6 chemotherapy regimen and bevacizumab, and iii) FOLFIRI chemotherapy regimen and bevacizumab.

24. A pharmaceutical composition for treatment of non-small cell lung cancer, comprising the compound or a salt thereof according to claim 1, wherein the pharmaceutical composition is administered to the subject in combination with a combination therapy selected from the group consisting of i) docetaxel, ii) docetaxel and ramucirumab, and iii) pembrolizumab, carboplatin, and pemetrexed.

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