Heteroaryl carboxamide compound

Abstract

A compound useful as an active ingredient of a pharmaceutical composition for treatment of cancer related to activation of immune cells or cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy is provided. The present inventors have conducted studies on a compound useful as an active ingredient of a pharmaceutical composition for treatment of cancer related to activation of immune cells or cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, and confirmed that a heteroaryl carboxamide compound has DGK (DGKzeta) inhibitory effect, leading to completion of the present invention. The heteroaryl carboxamide compound of the present invention has DGK inhibitory effect, and can be used as a therapeutic agent for treatment of cancer related to activation of immune cells or cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

Description

Heteroaryl Carboxamide Compounds

[0001] The present invention relates to pharmaceutical compositions, including heteroarylcarboxamide compounds that are useful as diacylglycerol kinase zeta (DGKzeta) inhibitors, and are expected to be useful as active ingredients in pharmaceutical compositions for treating, for example, cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly cancers associated with immune cell activation that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

[0002] Cancer immunotherapy is gaining attention as the fourth pillar of cancer treatment, following traditional surgical treatment, radiation therapy, and cancer chemotherapy (chemotherapy and molecular-targeted drugs). Its development was paved by the anti-cytotoxic T-lymphocyte antigen (CTLA)-4 antibody (ipilimumab) and anti-PD-1 antibody (nivolumab, pembrolizumab). CTLA-4 and PD-1 are called immune checkpoint molecules and function as "co-stimulatory molecules that can transmit inhibitory signals." Anti-PD-1 antibodies have now proven clinically effective in many cancers, including melanoma and non-small cell lung cancer, and their indications are expanding. In recent years, the development of antibodies targeting checkpoint molecules other than CTLA-4 and PD-1 has been intensified worldwide. DGK is an enzyme that phosphorylates diacylglycerol (DAG) to convert it to phosphatidic acid (PA). Mammals have 10 isoforms, which can be broadly classified into five types based on structural characteristics. There are three isoforms: type I (α, β, γ), type II (δ, η, κ), type III (ε), type IV (ζ, ι), and type V (θ). All isoforms have a highly homologous catalytic domain at the C-terminus and a C1 domain with intramolecular homology to protein kinase C (PKC). The C1 domain is thought to be the domain where phorbol esters / DAG bind (Int. J. Mol. Sci. 2013, 14: 6649-6673). In T cells, phospholipase Cγ1 (PLCγ1) activated by antigen stimulation generates DAG and inositol triphosphate (IP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). The generated DAG activates multiple downstream signals, including the RAS, NF-κB, and AKT pathways, leading to T cell activation. Meanwhile, IP3 transports Ca from the endoplasmic reticulum. 2+DGKα and DGKζ are two major isoforms in T cells. These are involved in promoting T cell anergy and T cell tolerance by activating nuclear factor of activated T cells (NFAT) signaling through the release of DGKα. T cell anergy is an incompletely activated state resulting from a decrease or inhibition of costimulatory activity (CD28 signaling) during antigen recognition, leading to unresponsiveness to restimulation. DGKα and DGKζ are two major isoforms in T cells. Each isoform regulates the strength of DAG signaling downstream of antigen stimulation, preventing excessive T cell activation. Furthermore, DGKα and DGKζ promote T cell anergy and play an important role in T cell tolerance (J Cell Sci. 2013, 126:2176-2186; Crit Rev Immunol. 2013, 33:97-118; Immunol Rev. 2008, 224:249-264). Furthermore, it has been reported that activated DGKζ-deficient T cells are resistant to PD-1 inhibitory signals and also to PD-1-independent immunosuppressive factors such as transforming growth factor (TGF)-β, adenosine, and PGE2 (Cancer Res. 2017, 77:5676-5686., Front Cell Dev Biol. 2016, 4:108.). It has been reported that T cells overexpressing PD-1 are severely exhausted, and in this state, anti-PD-1 antibodies are ineffective. Furthermore, immunosuppressive factors such as TGF-β are thought to be one of the mechanisms of resistance to anti-PD-1 therapy (Cancer Treatment Reviews 2017, 52: 71-81). DGKζ negatively regulates NK cell activation mediated by activating receptors, and it has been reported that the growth of major histocompatibility complex (MHC) class I-deficient tumors is suppressed in DGKζ-KO mice (J Immunol. 2016, 197:934-941). Therefore, the development of DGKζ inhibitors is expected to have antitumor effects via immune cell activation, particularly T cell activation.Furthermore, it has been reported that the response rate of anti-PD-1 antibody therapy is approximately 30%, depending on the type of cancer (Front Immunol. 2016, 7:550.), and DGKζ inhibitors are expected to be useful for such patients who are resistant to anti-PD-1 antibody therapy.

[0003] Patent Document 1 discloses that R59022 and R59499 have DGK inhibitory activity, alleviate T cell anergy, and upregulate immune responses.

[0004] Patent Document 2 discloses that a compound represented by the following general formula has a trkA receptor inhibitory effect and is useful for treating or preventing frequent urination, urgency, and the like associated with overactive bladder. (For the meaning of the symbols in the formula, see the publication.) However, Patent Document 2 does not specifically disclose the use in the treatment of cancer, or the compound of the present invention consisting of a phenyl group having four adjacent consecutive substituents as essential components.

[0005] Patent Document 3 discloses that compounds represented by the following general formula are useful as inhibitors of protein kinases such as cyclin-dependent kinases (CDKs) for treating or preventing proliferative diseases and the like. (For the meaning of the symbols in the formula, see the publication.) However, Patent Document 3 does not specifically disclose DGK or the compound of the present invention consisting of a phenyl group having four adjacent consecutive substituents as essential components.

[0006] In Patent Document 4, the applicant of the present application discloses that a compound represented by the following general formula can be used as a DGKζ inhibitor for the treatment of cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. (For the meaning of the symbols in the formula, see the publication.) However, Patent Document 4 does not specifically disclose the compound of the present invention, and Patent Document 4 was published after the priority date of the present application.

[0007] U.S. Patent No. 7,381,401 International Publication No. WO2007 / 123269 International Publication No. WO2008 / 054702 International Publication No. WO2021 / 132422

[0008] Provided is a compound that is useful as a pharmaceutical composition, for example, a DGKζ inhibitor, and is expected to be useful as an active ingredient in a pharmaceutical composition for treating cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly cancers associated with immune cell activation that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

[0009]

[0003] The present inventors have conducted extensive research into compounds useful as active ingredients in pharmaceutical compositions for treating cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly cancers associated with immune cell activation that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. As a result, they discovered that heteroarylcarboxamide compounds of formula (I), which consist of a phenyl group essential for four adjacent substituents, which are generally difficult to prepare, have excellent DGKζ inhibitory activity, leading to the completion of the present invention. Specifically, the present invention relates to a compound of formula (I) or a salt thereof, and to pharmaceutical compositions containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients. (wherein A is represented by the following formula (Ai), (A-ii), (A-iii), (A-iv), or (Av), B is represented by the following formula (Bi), (B-ii), (B-iii), or (B-iv): where R 1a Halogeno C 1-6 When alkyl, B is (Bi), and R 1a is pyridazinyl or halogeno C 1-6 is alkyl, and R 1b is H or C 1-6 is alkyl, and R 2 is C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), halogeno C 1-6 alkyl, halogen, or phenyl; R3 i) C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenoC 1-6 ii) phenyl optionally substituted with a group selected from the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen; 1-6 C optionally substituted with a group selected from the group consisting of alkyl and halogen 3-8 cycloalkyl, iii) C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenoC 1-6 iv) a 5- to 6-membered partially unsaturated heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, wherein R 4 is H or F, R 5 is H or F, R 6 is -L2-(CH2)2NR a R b or piperidinyl, L1 is a bond, O or NH, L2 is a bond, O or CH2, X is CH2 or N-methyl, Y is CH or N, R a is H or methyl, R b is H, methyl, ethyl, cyclopropyl, or —(CH2)2O—CH3, and m is 1, 2, or 3.

[0010] Unless otherwise specified, when a symbol in a chemical formula in this specification is used in other chemical formulas, the same symbol has the same meaning.

[0011] The present invention also relates to a pharmaceutical composition for treating cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, comprising a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients, particularly a pharmaceutical composition for treating cancers associated with immune cell activation that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy. This pharmaceutical composition also encompasses therapeutic agents for cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly therapeutic agents for cancers associated with immune cell activation that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, comprising a compound of formula (I) or a salt thereof. The present invention also relates to a compound of formula (I) or a salt thereof which is a DGKζ inhibitor; a compound of formula (I) or a salt thereof for use as a DGKζ inhibitor; a DGKζ inhibitor containing a compound of formula (I) or a salt thereof; use of a compound of formula (I) or a salt thereof for producing a pharmaceutical composition for treating cancer associated with immune cell activation or cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly use of a compound of formula (I) or a salt thereof for producing a pharmaceutical composition for treating cancer associated with immune cell activation which is resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy; use of a compound of formula (I) or a salt thereof for treating cancer associated with immune cell activation or cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly .... The present invention relates to use of a compound of formula (I) or a salt thereof for treating a cancer associated with immune cell activation that is resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy; a compound of formula (I) or a salt thereof for use in treating a cancer associated with immune cell activation or a cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly a compound of formula (I) or a salt thereof for use in treating a cancer associated with immune cell activation that is resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy; and a method for treating a cancer associated with immune cell activation or a cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, which comprises administering to a subject an effective amount of a compound of formula (I) or a salt thereof, particularly a method for treating a cancer associated with immune cell activation that is resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.The "subject" refers to a human or other animal in need of the prevention or treatment, and in one embodiment, the subject is a human in need of the prevention or treatment.

[0012] The compound of formula (I) or a salt thereof has a DGKζ inhibitory activity and can be used as a therapeutic agent for cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, in particular, as a therapeutic agent for cancers associated with immune cell activation that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

[0013] The present invention will be described in detail below. In this specification, the following terms have the meanings indicated below unless otherwise specified. The following definitions are intended to clarify, but not limit, the defined terms. If a term is not specifically defined herein, it is used in the sense generally accepted by those skilled in the art.

[0014] As used herein, "C 1-6 "Alkyl" means a straight or branched alkyl group having 1 to 6 carbon atoms (hereinafter referred to as C 1-6 Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. 1-3 It is alkyl, and in one embodiment, it is methyl or ethyl, and in one embodiment, it is methyl, and in one embodiment, it is ethyl.

[0015] "Halogeno C 1-6 "Alkyl" means a C substituted with one or more halogens. 1-6 In one embodiment, C substituted with 1 to 5 halogen atoms is alkyl. 1-6 alkyl, and in one embodiment, C substituted with 1 to 5 halogens. 1-3In one embodiment, it is alkyl, and in another embodiment, it is trifluoromethyl, difluoromethyl, difluoroethyl, or trifluoroethyl. In another embodiment, it is difluoroethyl or trifluoromethyl. In another embodiment, it is difluoroethyl. In another embodiment, it is trifluoromethyl. In another embodiment, it is 2,2-difluoroethyl.

[0016] "C 3-8 "Cycloalkyl" means C 3-8 It is a saturated hydrocarbon ring group of the formula (I), which may have a bridge or may form a spiro ring. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2,2,1]heptyl, bicyclo[3,1,0]hexyl, bicyclo[3,1,1]heptyl, spiro[2,5]octyl, etc. In one embodiment, C 3-5 It is a cycloalkyl. 3-5 Certain embodiments of cycloalkyl include cyclopropyl, cyclobutyl, or cyclopentyl, and certain embodiments include cyclopropyl, cyclobutyl, and cyclopentyl.

[0017] "Halogen" refers to F, Cl, Br, or I, and in one embodiment, F or Cl, in one embodiment, F, and in one embodiment, Cl.

[0018] A "5- to 6-membered partially unsaturated heterocycle" is a 5- to 6-membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen and having an unsaturated bond in a portion thereof. The sulfur or nitrogen ring atom may be oxidized to form an oxide or dioxide. Examples include dihydropyridyl, tetrahydropyridyl, dihydrofuranyl, dihydrothienyl, dihydropyranyl, thiopyranyl, and dihydrothiopyranyl. In one embodiment, it is tetrahydropyridyl, in another embodiment, it is dihydrofuranyl, and in another embodiment, it is dihydropyranyl.

[0019] "Optionally substituted" means unsubstituted or "substituted with one or more substituents (for example, the substituents defined below)." Substitution may occur at any position in the group where a hydrogen atom would normally be present. In one embodiment, "optionally substituted" means "optionally substituted with 1 to 5 substituents," and in another embodiment, "optionally substituted with 1 to 3 substituents." In the case of multiple substitutions, the substituents may be the same or different. Furthermore, even if a combination is not specifically described, one or more embodiments can be combined with other embodiments. In other words, all embodiments can be freely combined.

[0020] "Immune cell activation" refers to reactivating immune cells, particularly T cells, that have the ability to suppress the proliferation of, or reduce or eliminate cancer cells (hereinafter referred to as antitumor activity), and / or increasing the number of immune cells, particularly activated T cells. In one embodiment, this is immune cell activation based on DGKζ inhibition.

[0021] "Cancer associated with immune cell activation" refers to a cancer that exhibits immunoresponsiveness, and in some embodiments, refers to a cancer in which cancer cell proliferation is suppressed or cancer cells are reduced or eliminated by immune cell activation. In some embodiments, refers to a cancer in which cancer cell proliferation is suppressed or cancer cells are reduced or eliminated by immune cell activation due to DGKζ inhibitory activity. In some embodiments, refers to a cancer in which cancer cell proliferation is suppressed or cancer cells are reduced or eliminated by immune cell activation due to DGKζ inhibitory activity. In some embodiments, refers to a cancer in which cancer cell proliferation is suppressed or cancer cells are reduced or eliminated by immune cell activation due to DGKζ inhibitory activity. Cancers to which the present invention can be applied include, but are not limited to, small cell lung cancer, head and neck cancer, renal cancer, ovarian cancer, non-small cell lung cancer, mismatch repair-deficient colorectal cancer, urothelial cancer, melanoma, hepatocellular carcinoma, gastric cancer, and bladder cancer.

[0022] "Resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy" means having resistance to anti-PD-1 antibody and / or anti-PD-L1 antibody therapy. In one embodiment, it means having resistance to anti-PD-1 antibody and anti-PD-L1 antibody therapy, in another embodiment, having resistance to anti-PD-1 antibody therapy, and in another embodiment, having resistance to anti-PD-L1 antibody therapy. "Resistance" includes primary resistance, in which anti-PD-1 antibody / anti-PD-L1 antibody is not effective from the start, and acquired resistance, in which the antibody becomes less effective as treatment continues. In "having resistance to anti-PD-1 antibody / anti-PD-L1 antibody therapy," one embodiment refers to having natural resistance to anti-PD-1 antibody and anti-PD-L1 antibody therapy, one embodiment refers to having acquired resistance to anti-PD-1 antibody and anti-PD-L1 antibody therapy, one embodiment refers to having natural resistance to anti-PD-1 antibody therapy, one embodiment refers to having acquired resistance to anti-PD-1 antibody therapy, one embodiment refers to having natural resistance to anti-PD-L1 antibody therapy, and one embodiment refers to having acquired resistance to anti-PD-L1 antibody therapy.

[0023] "Cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy" means cancer resistant to anti-PD-1 antibody and / or anti-PD-L1 antibody therapy. In one embodiment, the cancer is resistant to anti-PD-1 antibody and anti-PD-L1 antibody therapy, in another embodiment, cancer resistant to anti-PD-1 antibody therapy, in another embodiment, cancer resistant to anti-PD-L1 antibody therapy, in another embodiment, cancer with natural resistance to anti-PD-1 antibody and anti-PD-L1 antibody therapy, in another embodiment, cancer with acquired resistance to anti-PD-1 antibody and anti-PD-L1 antibody therapy, in another embodiment, cancer with natural resistance to anti-PD-1 antibody therapy, in another embodiment, cancer with acquired resistance to anti-PD-1 antibody therapy, in another embodiment, cancer with natural resistance to anti-PD-L1 antibody therapy, and in another embodiment, cancer with acquired resistance to anti-PD-L1 antibody therapy. The cancer to which the present invention can be applied is not particularly limited, and examples include cancers that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, such as small cell lung cancer, head and neck cancer, renal cancer, ovarian cancer, non-small cell lung cancer, mismatch repair deficient colorectal cancer, urothelial cancer, melanoma, hepatocellular carcinoma, gastric cancer, and bladder cancer.

[0024] The "anti-PD-1 antibody / anti-PD-L1 antibody" is not particularly limited, but examples include antibodies selected from nivolumab, pembrolizumab, atezolizumab, pidilizumab, avelumab, and durvalumab.

[0025] Certain embodiments of the compound of formula (I) or a salt thereof of the present invention are shown below: (1-1) A compound or a salt thereof, wherein A is represented by the following formula (Ai), (A-ii), (A-iii), (A-iv), or (Av). (1-2) A compound or a salt thereof, wherein A is the following formula (Ai) or (A-ii): (2-1) A compound or a salt thereof, wherein B is represented by the following formula (Bi), (B-ii), (B-iii), or (B-iv), wherein R 1aHalogeno C 1-6 When alkyl, B is (Bi). (2-2) A compound or a salt thereof, wherein B is represented by the following formula (Bia) or (B-ii): 1a Halogeno C 1-6 When alkyl, B is (Bia). (3-1) R 1a Halogeno C 1-6 When R is alkyl, B is (Bi), or a salt thereof. (3-2) R 1a Halogeno C 1-6 When R is alkyl, B is (Bia), or a salt thereof. (3-3) R 1a Halogeno C 1-3 When R is alkyl, B is (Bia), or a salt thereof. 1a pyridazinyl or halogeno C 1-6 In one embodiment, R 1a pyridazinyl or halogeno C 1-3 In one embodiment, R 1a In one embodiment, the compound or salt thereof is a compound in which R 1a In one embodiment, the compound or salt thereof is a compound in which R 1a In one embodiment, R is pyridazinyl or a salt thereof. 1a (5) A compound or a salt thereof, wherein R is 2,2-difluoroethyl. 1b But H or C 1-6 In one embodiment, R 1b But H or C 1-3 In one embodiment, R 1b is H or methyl. In one embodiment, R 1b is H. In one embodiment, R 1b is methyl or a salt thereof. 2 But C 3-5 Cycloalkyl, -O-(C1-6 Alkyl), halogeno C 1-6 In one embodiment, R is a compound or a salt thereof, wherein R is an alkyl, halogen, or phenyl. 2 But, Halogeno C 1-6 In one embodiment, R is a compound or a salt thereof, 2 But, Halogeno C 1-3 In one embodiment, R is a compound or a salt thereof, wherein R is an alkyl, F, Cl, or Br. 2 is CF3, F, or Cl, or a salt thereof. 2 In one embodiment, the compound or salt thereof is 2 In one embodiment, the compound or salt thereof is 2 (7-1) R is a compound or a salt thereof 3 However, i) C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenoC 1-6 ii) phenyl optionally substituted with a group selected from the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen; 1-6 C optionally substituted with a group selected from the group consisting of alkyl and halogen 3-8 cycloalkyl, iii) C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenoC 1-6 (7-2) R is a compound or a salt thereof, which is a 5- or 6-membered partially unsaturated heterocycle containing 1 to 4 heteroatoms selected from the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen, or iv) a compound or a salt thereof, which is a 5- or 6-membered partially unsaturated heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen. 3 However, i) C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenoC 1-6phenyl optionally substituted with a group selected from the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen; or ii) C 1-6 C optionally substituted with a group selected from the group consisting of alkyl and halogen 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 3 But C 1-6 Phenyl optionally substituted with a group selected from the group consisting of alkyl and halogen, or C 3-5 (8) R is a compound or a salt thereof. 4 is H or F, or a salt thereof. 4 is H, or a salt thereof. 4 (9) A compound or a salt thereof wherein R is F. 5 is H or F, or a salt thereof. 5 is H, or a salt thereof. 5 (10) A compound or a salt thereof, wherein R 6 But -L2-(CH2)2NR a R b or piperidinyl, or a salt thereof. 6 But -L2-(CH2)2NR a R b In one embodiment, a compound or a salt thereof, 6is piperidinyl, or a salt thereof. (11) A compound or a salt thereof wherein L1 is a bond, O, or NH. In one embodiment, a compound or a salt thereof wherein L1 is a bond or O. In one embodiment, a compound or a salt thereof wherein L1 is a bond. In one embodiment, a compound or a salt thereof wherein L1 is O. (12) A compound or a salt thereof wherein L2 is a bond, O, or CH2. In one embodiment, a compound or a salt thereof wherein L2 is O or CH2. In one embodiment, a compound or a salt thereof wherein L2 is O. In one embodiment, a compound or a salt thereof wherein L2 is CH2. (13) A compound or a salt thereof wherein X is CH2 or N-methyl. In one embodiment, a compound or a salt thereof wherein X is CH2. In one embodiment, a compound or a salt thereof wherein X is N-methyl. (14) A compound or a salt thereof wherein Y is CH or N. In one embodiment, a compound or a salt thereof wherein Y is CH. In one embodiment, a compound or a salt thereof wherein Y is N. (15) R a is H or methyl, or a salt thereof. a is H, or a salt thereof. a (16) A compound or a salt thereof, wherein R is methyl. b is H, methyl, ethyl, cyclopropyl, or —(CH 2 ) 2 O—CH 3 , or a salt thereof. b is H or methyl. b In one embodiment, a compound or a salt thereof, wherein R b is methyl. (17) A compound or a salt thereof wherein m is 1, 2, or 3. In one embodiment, a compound or a salt thereof wherein m is 1 or 2. In one embodiment, a compound or a salt thereof wherein m is 1. (18) A compound or a salt thereof which is a combination of any two or more of the embodiments described above in (1-1) to (17) that are not contradictory.

[0026] Specific examples of the combination described in (18) above include the following: (19) A is represented by the following formula (Ai), (A-ii), (A-iii), (A-iv), or (Av): B is represented by the following formula (Bi), (B-ii), (B-iii), or (B-iv): where R 1a Halogeno C 1-6 When alkyl, B is (Bi) and R 1a pyridazinyl or halogeno C 1-6 alkyl, and R 1b But H or C 1-6 alkyl, and R 2 But C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), halogeno C 1-6 alkyl, halogen, or phenyl; R 3 However, i) C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenoC 1-6 ii) phenyl optionally substituted with a group selected from the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen; 1-6 C optionally substituted with a group selected from the group consisting of alkyl and halogen 3-8 cycloalkyl, iii) C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenoC 1-6 iv) a 5- to 6-membered partially unsaturated heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, wherein R 4 is H or F, and R 5 is H or F, and R 6 But -L2-(CH2)2NR a R b or piperidinyl, L1 is a bond, O or NH, L2 is a bond, O or CH2, X is CH2 or N-methyl, Y is CH or N, and R ais H or methyl, and R b (20) A compound or a salt thereof, wherein R is H, methyl, ethyl, cyclopropyl, or —(CH)O—CH, and m is 1, 2, or 3. 2 But, Halogeno C 1-6 alkyl or halogen, R 3 However, i) C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-5 Cycloalkyl, -O-(C 1-6 Alkyl), -O-(halogenoC 1-6 phenyl optionally substituted with a group selected from the group consisting of alkyl, cyano, nitro, methanesulfonyl, and halogen; or ii) C 1-6 C optionally substituted with a group selected from the group consisting of alkyl and halogen 3-8 The compound or salt thereof according to (19), wherein B is cycloalkyl and L1 is a bond or O. (21) B is represented by the following formula (Bia) or (B-ii), where R 1a Halogeno C 1-6 (22) The compound or salt thereof according to (21), wherein A is the following formula (Ai) or (A-ii): (23) R 3 But C 1-6 Phenyl optionally substituted with a group selected from the group consisting of alkyl and halogen, or C 3-5 is cycloalkyl, and R b is H or methyl, or a salt thereof according to (22).

[0027] Examples of specific compounds encompassed by the present invention include the following compounds or salts thereof: N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide, N-{2-[(3S)-3-(aminomethyl)-4-methylpiperazin-1-yl]-4-(2-chlorophenoxy)-3-(trifluoromethyl)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide, N-{2-[(3S)-3-(aminomethyl)-4-methylpiperazin-1-yl]-3-chloro-4-(2-chlorophenoxy)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide, N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide, N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide, N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide, N-[4-cyclopentyl-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide, N-{2-[(8R,8aS)-8-aminohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-Oxaazole-4-carboxamide, and N-[3-chloro-4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide.

[0028] Examples of specific compounds or salts thereof encompassed by the present invention include the following compounds or salts thereof: N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monobutanedioic acid salt, N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monobutanedioic acid salt, N-[4-cyclopentyl-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monobutanedioic acid salt, N-[3-chloro-4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monobutanedioic acid salt, and N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monobutanedioic acid salt.

[0029] Compounds of formula (I) may exist as tautomers or geometric isomers depending on the type of substituents. Although compounds of formula (I) or salts thereof may be described herein in only one isomeric form, the present invention encompasses other isomers, including isolated isomers and mixtures thereof. Furthermore, compounds of formula (I) or salts thereof may have asymmetric centers or axial asymmetry, which may result in the existence of enantiomers (optical isomers). Compounds of formula (I) or salts thereof encompass both isolated individual enantiomers, such as the (R) form and the (S) form, and mixtures thereof (including racemic and non-racemic mixtures). In one embodiment, an enantiomer is "stereochemically pure." "Stereochemically pure" refers to a purity that can be recognized by those skilled in the art as being substantially stereochemically pure. In another embodiment, an enantiomer is a compound having a stereochemical purity of, for example, 90% ee (enantiomeric excess) or greater, 95% ee or greater, 98% ee or greater, or 99% ee or greater.

[0030] Furthermore, the salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. Specific examples 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, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid, inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, and various amino acids and amino acid derivatives such as acetylleucine.

[0031] Furthermore, the present invention also encompasses various hydrates and solvates of the compound of formula (I) and its salts, as well as crystalline polymorphic substances thereof.

[0032] Furthermore, the present invention also encompasses pharmaceutically acceptable prodrugs of the compounds represented by formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and "Drug Development" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design, 163-198.

[0033] The present invention also encompasses all compounds of formula (I) or salts thereof that are labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Suitable examples of isotopes used to isotopic label the compounds of the present invention include hydrogen ( 2 H and 3 H, etc.), carbon ( 11 C. 13 C and 14 C, etc.), nitrogen ( 13 N and 15 N, etc.), oxygen ( 15 O, 17 O and 18 O etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I etc.), phosphorus ( 32 P, etc.), sulfur ( 35 Isotopes of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 3 H), carbon 14 ( 14 Radioactive isotopes such as C may be used for this purpose due to their ease of labeling and detection. Substitution of heavier isotopes, e.g., deuterium for hydrogen ( 2 Substitution with positron-emitting isotopes (H) may be therapeutically advantageous due to increased metabolic stability (e.g., increased in vivo half-life, reduced dosage requirements, and fewer drug interactions). 11 C, 18 F, 15 O and 13Substitution with an isotopically labeled N or the like can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by conventional methods known to those skilled in the art, or by methods similar to those described in the Examples or Preparations, using appropriate isotopically labeled reagents in place of unlabeled reagents.

[0034] The powder X-ray diffraction patterns described herein should not be interpreted strictly because, due to the nature of the data, the crystal lattice spacing and overall pattern are important for determining the identity of the crystals, and the diffraction angle and diffraction intensity may have some error depending on the direction of crystal growth, particle size, and measurement conditions. In this specification, the diffraction angle (2θ (°)) in the powder X-ray diffraction pattern is interpreted taking into account the error range normally allowed for in the measurement method, and in some embodiments, an error range of ±0.2° may be used. Furthermore, for example, when measured in a mixture with an excipient, a peak that is located near a peak derived from the excipient and on the baseline slope may appear to shift by ±0.3°.

[0035] (Production Method) The compound of formula (I) and its salts can be produced by various known synthetic methods, taking advantage of characteristics based on their basic structure or the type of substituents. In this case, depending on the type of functional group, it may be effective from a manufacturing technology perspective to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage from raw materials to intermediates. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis" (4th ed., 2006) by P.G.M. Wuts and T.W. Greene, and the like. These protecting groups can be appropriately selected and used depending on the reaction conditions. In such a method, the desired compound can be obtained by introducing the protecting group, conducting the reaction, and then removing the protecting group as necessary. Furthermore, prodrugs of the compound of formula (I) can be produced by introducing a specific group at the stage from raw materials to intermediates, or by further reacting the resulting compound of formula (I), similar to the above-mentioned protecting groups. The reaction can be carried out by applying conventional methods known to those skilled in the art, such as esterification, amidation, and dehydration. Representative methods for producing the compound of formula (I) are described below. Each method can be performed by referring to the references attached to the description. However, the production method of the present invention is not limited to the examples shown below.

[0036] The following abbreviations may be used herein: 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, CHCl = dichloromethane, Boc = tert-butoxycarbonyl, Ph = phenyl, tBu = tert-butyl, Et = ethyl, Me = methyl, Ac = acetyl, Ns = 2-nitrobenzenesulfonyl. CDI = 1,1'-carbonylbis(1H-imidazole), DCC = N,N'-dicyclohexylcarbodiimide, TEA = triethylamine, DIPEA = N,N-diisopropylethylamine, DABCO = 1,4-diazabicyclo[2.2.2]octane, DPPA = diphenylphosphoryl azide, HATU = O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HOBt = 1-hydroxybenzotriazole, KOtBu = potassium tert-butoxide, NaOtBu = sodium tert-butoxide, NMM = N-methylmorpholine, Pd / C = palladium on carbon, TFA = trifluoroacetic acid, TFAA = trifluoroacetic anhydride, WSC.HCl = 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 = (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium (3:2), brine = saturated aqueous NaCl solution, MgSO4 = anhydrous magnesium sulfate, Na2SO4 = anhydrous sodium sulfate, NaHCO3 = sodium bicarbonate, NH4Cl = ammonium chloride, NaBH(OAc)3 = sodium triacetoxyborohydride.

[0037]

[0038] (Step 1) This step involves subjecting compound (1) to a reduction reaction to obtain compound (2). This reaction can be carried out by stirring compound (1) and a metal under acidic conditions in a mixed solvent of MeOH, EtOH, or 1,4-dioxane with water at room temperature or under reflux for 1 hour to 5 days. Examples of acids that can be used include NHCl, AcOH, and HCl. Examples of metals that can be used include Fe, Zn, and Sn. This reaction can also be carried out by stirring compound (1) in a reaction-inert solvent such as MeOH, EtOH, or EtOAc, or a mixed solvent thereof, in the presence of a metal catalyst under cooling to heating, preferably at room temperature, for 1 hour to 5 days. Examples of metal catalysts that can be used include palladium catalysts such as Pd / C, palladium black, and palladium hydroxide on carbon; platinum catalysts such as platinum on carbon or platinum oxide; and nickel catalysts such as reduced nickel and Raney nickel.

[0039] (Step 2) This step involves amidation of compound (2) and compound (3), followed by appropriate conversion of the substituents to obtain a compound of formula (I). This amidation reaction involves using equal amounts of compound (2) and compound (3), or an excess of either compound, and stirring the mixture in the presence of a condensing agent in a reaction-inert solvent under cooling to heating, preferably at temperatures between -20°C and 60°C, typically for 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as CHCl, 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 condensing agents include, but are not limited to, WSC.HCl, DCC, CDI, DPPA, and HATU. The use of an additive (e.g., HOBt) may be preferable for the reaction. Carrying out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as K2CO3, Na2CO3, or KOH, may be advantageous for smooth reaction progression. Alternatively, an amidation reaction can be used in which compound (3) is converted into a reactive derivative and then reacted with compound (2). Examples of reactive derivatives of compound (3) include acid halides obtained by reaction with a halogenating agent such as POCl3 or SOCl2, mixed acid anhydrides obtained by reaction with isobutyl chloroformate, and activated esters obtained by condensation with HOBt. This reaction can be carried out in a reaction-inert solvent such as halogenated hydrocarbons, aromatic hydrocarbons, or ethers, under cooling to reflux, preferably at temperatures between -20°C and 120°C. After the amidation reaction, a protecting group can be introduced and / or removed as necessary, followed by appropriate conversion of the substituents to obtain a compound of formula (I).

[0040] (Raw material synthesis 1) (LG in the formula 1 and L.G. 2 indicates a leaving group. LG 1 and L.G. 2are halogens, etc., and may be different from each other.)

[0041] This production method is a method for producing starting compound (1). (Step 3) This step is a method for producing compound (6) from compound (5) via an ipso substitution reaction. This reaction is carried out in a reaction-inert solvent or without a solvent, under cooling to reflux, preferably at 0°C to 120°C, and is typically stirred for 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, halogenated hydrocarbons such as CHCl, 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. Performing the reaction in the presence of an organic base such as TEA, DIPEA, NMM, or DABCO, or an inorganic base such as NaH, KCO, NaCO, CsCO, or NaOtBu may be advantageous for smooth reaction progression.

[0042] (Step 4) This step involves the Suzuki coupling reaction of compound (5) with an organoboron compound to produce compound (7), or the Buchwald-Hartwig reaction of compound (5) with an amine compound to produce compound (7). This reaction is carried out in a reaction-inert solvent in the presence of a base and a palladium catalyst, at room temperature or under reflux, typically with stirring for 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, halogenated hydrocarbons such as CHCl, 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 MeOH, EtOH, isopropyl alcohol, and butanol; DMF, DMSO, MeCN, DMI; water; and mixtures thereof. Examples of bases include inorganic bases such as NaH, K2CO3, Na2CO3, Cs2CO3, K3PO4, and CsF. Examples of palladium catalysts include Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2.CH2Cl2, and Pd2(dba)3. Carrying out the reaction in the presence of a ligand such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (SPhos) can be advantageous for smooth reaction. Heating the reaction mixture by microwave irradiation can also be advantageous for smooth reaction. For references regarding this reaction, see, for example, the following: J. Am. Chem. Soc. 127, 4685-4696, 2005 Angew. Chem., Int. Ed. Engl. 34, 1348-1350, 1995 Compound (7) can also be produced from compound (5) and an amine compound by an ipso substitution reaction. In this case, the reaction conditions are the same as those in the third step.

[0043] (Step 5) This step is a method for producing compound (1) from compound (6) and an amine compound by ipso substitution reaction. The reaction conditions are the same as those in Step 3.

[0044] (Step 6) This step is a method for producing compound (1) from compound (7) by an Ipso substitution reaction, or a method for producing compound (1) by a Suzuki coupling reaction using compound (7) and an organoboron compound. The reaction conditions for the Ipso substitution reaction are the same as those for Step 3. The reaction conditions for the Suzuki coupling reaction are the same as those for Step 4.

[0045] (Raw material synthesis 2) (In the formula, P1 represents H or a protecting group, and P2 represents a protecting group.)

[0046] This production method is a method for producing starting compound (7-b), which is one embodiment of compound (7) described in (Starting Material Synthesis 1) above. (Seventh Step) This step involves oxidizing compound (7-a) and then subjecting it to reductive amination with compound (8) to produce compound (7-b). The oxidation reaction of compound (7-a) is carried out by using an equivalent or excess amount of compound (7-a) and a predetermined oxidizing agent in a reaction-inert solvent, stirring under ice-cooling or reflux, typically for 0.1 hours to 5 days. Examples of the predetermined oxidizing agent include, but are not limited to, Dess-Martin periodinane. Examples of solvents used here include, but are not limited to, halogenated hydrocarbons such as CHCl, 1,2-dichloroethane, chloroform, and carbon tetrachloride. The reductive amination reaction involves using an equivalent amount of the aldehyde obtained by the oxidation reaction described above and compound (8), or an excess amount of either, and stirring the mixture in the presence of a reducing agent in a reaction-inert solvent at a temperature ranging from −45°C to reflux for typically 0.1 hours to 5 days. Examples of the solvent used include, but are not limited to, alcohols such as MeOH and EtOH, ethers such as diethyl ether, THF, 1,4-dioxane, and dimethoxyethane, and mixtures thereof. Examples of the reducing agent include sodium cyanoborohydride, sodium triacetoxyborohydride, and sodium borohydride. It may be preferable to carry out the reaction in the presence of a dehydrating agent such as molecular sieves or an acid such as acetic acid, hydrochloric acid, or titanium(IV) isopropoxide complex.

[0047] (Raw material synthesis 3) (In the formula, P1 represents H or a protecting group, and P2 represents a protecting group.)

[0048] This production method is a method for producing starting compound (1-d), which is one embodiment of compound (1) described in the above (Starting Material Synthesis 1). (Step Eight) This step involves introducing a leaving group into compound (1-c) and then subjecting it to a Gabriel amine reaction to produce compound (9). In this reaction, compound (1-c) is reacted with a halogenated sulfonyl compound such as MsCl or TsCl, or an acid anhydride such as methanesulfonic anhydride or p-toluenesulfonic anhydride, in a reaction-inert solvent in the presence of a base, to produce a compound, and potassium phthalimide, either in equal amounts or in excess of one of the two. This mixture is stirred in a reaction-inert solvent in the presence of a base under ice-cooling or reflux, preferably at 0°C to 120°C, typically for 0.1 hours to 5 days. Examples of solvents include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as 1,4-dioxane, halogenated hydrocarbons such as CHCl, DMF, DMSO, EtOAc, MeCN, and mixtures thereof. Examples of the base include organic bases such as TEA, DIPEA, or NMM, and inorganic bases such as K2CO3, Na2CO3, or KOH. After the reaction, compound (9) can be obtained by deprotecting the phthalimide with hydrazine in a solvent inert to the reaction. The following literature is a reference for this reaction: Angew. Chem., Int. Ed. Engl. 7, 919-930, 1968

[0049] (Step 9) This step is a method for producing compound (1-d) by introducing a protecting group into compound (9). Examples of the protecting group used in this reaction include those described in "Greene's Protective Groups in Organic Synthesis" (4th ed., 2006) by PGM Wuts and TW Greene, and can be appropriately selected and used depending on the reaction conditions.

[0050] (Raw material synthesis 4) (In the formula, P1 represents H or a protecting group, and P2 represents a protecting group.)

[0051] This production method is a method for producing compound (1-b), which is one embodiment of compound (1) described above in (Starting Material Synthesis 1).

[0052] (Step 10) This step involves the Mitsunobu reaction of compound (1-a) with phthalimide, followed by deprotection of the phthalimide group to produce compound (10). The Mitsunobu reaction of compound (1-a) involves using equal amounts of compound (1-a) and phthalimide, or an excess of either, and stirring the mixture in the presence of known diazocarboxylic acid esters or diazocarboxylic acid amides and known phosphines in a reaction-inert solvent, under cooling to reflux, preferably at 0°C to 150°C, for typically 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMSO, EtOAc, MeCN, and mixtures thereof. After the reaction, compound (10) can be obtained by deprotecting the phthalimide with hydrazine in a reaction-inert solvent. For references on the Mitsunobu reaction, see, for example, the following: Synthesis (1981), 1

[0053] (Step 11) This step is a method for producing compound (1-b) by introducing a protecting group from compound (10). The reaction conditions are the same as in Step 9.

[0054] The compound of formula (I) is isolated and purified as a free compound, its salt, hydrate, solvate, or crystalline polymorph. A salt of the compound of formula (I) can also be produced by a conventional salt formation reaction. Isolation and purification are carried out using conventional chemical procedures such as extraction, fractional crystallization, and various types of chromatography. Various isomers can be produced by selecting appropriate starting compounds, or can be separated by utilizing differences in physicochemical properties between isomers. For example, optical isomers can be obtained by common optical resolution methods for racemates (e.g., fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.), or can also be produced from appropriate optically active starting compounds.

[0055] The pharmacological activity of the compound of formula (I) can be confirmed by the following test or a known modified test. In this specification, the dose of the test compound is expressed in terms of the weight of the free form. When using commercially available reagents or kits, the test can be carried out according to the instructions provided with the commercially available products.

[0056] Test Example 1 Evaluation of DGKζ Inhibitory Effect The inhibitory effect of the test compound on human recombinant DGKζ (Carna Bio, 12-410-20N) was evaluated using ADP-Glo TMThe following method was used for detection using a Kinase Assay (Promega): 3 μL of DGKζ enzyme (90 ng / mL) dissolved in Assay buffer (40 mM Tris-HCl pH 7.5, 10 mM MgCl2, 1 mM dithiothreitol (DTT), 0.1 mg / mL bovine serum albumin (BSA)) was added to a 384-well plate (Greiner Bio-one), and 3 μL of a test compound diluted in Assay buffer to the desired final concentration was added. After incubation at room temperature for 15 minutes, 3 μL of substrate (150 μM 1-oleoyl-2-acetyl-sn-glycerol (Sigma-Aldrich), 480 μM Phosphatidylserine (Avanti), 150 μM UltraPure-ATP (ADP-Glo)) dissolved in lipid dilution buffer (40 mM Tris-HCl pH 7.5, 0.1 mg / mL BSA, 1 mM DTT) was added and incubated at room temperature for 30 minutes. The enzyme reaction was then stopped by adding 3 μL of ADP-Glo ​​Reagent and incubating at room temperature for 40 minutes. Six μL of Kinase Detection Reagent was then added and incubated at room temperature for 30 minutes. Luminescence was then measured using an ARVO X3 (PerkinElmer). The signal value in the solvent treatment was defined as 0% inhibition, and the signal value in the absence of DGKζ enzyme was defined as 100% inhibition. The 50% inhibitory concentration (IC 50 ) was calculated by Sigmoid-Emax model nonlinear regression analysis. The results for several test compounds of formula (I) are shown in Table 1. In the table, Ex represents the Example number described below.

[0057]

[0058] Test Example 2: Evaluation of IL-2 production in the human T-cell leukemia cell line Jurkat E6.1 The effect of a test compound on IL-2 production induced by T cell receptor (TCR) stimulation (anti-CD3 / anti-CD28) in Jurkat E6.1 cells (ECACC, 88042803) was evaluated. A 5 μg / mL anti-CD3 antibody (eBioscience, OKT3 clone) diluted with phosphate-buffered saline (PBS) was added to a 96-well plate (Iwaki) at 50 μL / well and allowed to stand at 4°C for at least 12 hours to prepare a pre-coated anti-CD3 antibody plate. Before use in the experiment, the plates were washed once with 200 μL of PBS, and then 10 μL / well of anti-CD28 antibody (eBioscience, 28.2 clone) diluted to a concentration of 10 μg / mL in culture medium (RPMI1640 medium (Sigma-Aldrich) containing 10% fetal bovine serum (Hyclone)) was added. The plate was then used as a culture plate for TCR stimulation assay. Subsequently, the test compound and Jurkat E6.1 cells were mixed to the desired final concentration, and 1x10 cells were cultured per well. 5 Cells were seeded at 90 μL / well (i.e., 1 × 10 5 Cells were cultured at 100 μL / well. Cell culture conditions were RPMI1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2. After 24 hours, the culture supernatant was collected and IL-2 was quantified using the AlphaLISA human IL2 Immunoassay Research kit (PerkinElmer). IL-2 was measured using EnVision 2104-0010 and EnVision 2104-0020 (PerkinElmer) under standard AlphaScreen settings (fluorescence intensity at 570 nm with an excitation wavelength of 680 nm). The IL-2 quantification value of the vehicle-treated control was set to 1, and the test compound concentration at which the IL-2 quantification value of the test compound-treated sample increased 10-fold compared to the control (EC 10fold) was calculated by inverse estimation using Sigmoid-Emax model nonlinear regression analysis. The results for several test compounds of formula (I) are shown in Table 2. In the table, Ex represents the example number described below.

[0059]

[0060] Test Example 3: Evaluation of antitumor activity in a syngeneic mouse model bearing mouse melanoma cell line B16-F1. B16-F1 cells (ATCC, CRL-6323) were suspended in PBS and 2.0 x 10 6 Cell suspensions prepared at 100 cells / mL were inoculated subcutaneously into 5-week-old female mice (C57BL / 6J, Charles River Japan) in a volume of 50 μL. Five days after inoculation, the mice were divided into groups so that tumor volumes were roughly equivalent between groups, and administration of the test compound began. The test was conducted with 10 mice in each of the vehicle and test compound groups. 0.5% methylcellulose (Shin-Etsu Chemical Co., Ltd.) was orally administered to the vehicle group, and a mixture of 0.5% methylcellulose and the test compound was orally administered to the test compound group. Administration was performed once daily for 10 days, and tumor diameter and body weight were measured twice a week. The following formula was used to calculate tumor volume: [tumor volume (mm 3 )] = [Tumor long diameter (mm)] x [Tumor short diameter (mm)] 2 The tumor growth inhibition rate (%) by the test compound was calculated by setting the tumor volume in the vehicle group immediately before the start of administration as 100% inhibition and the tumor volume in the vehicle group on the day after the final administration as 0% inhibition. The results for several test compounds of formula (I) are shown in Table 3. In the table, Ex indicates the example number described below.

[0061]

[0062] As a result of the above tests, several compounds of formula (I) were confirmed to have DGKζ inhibitory activity (Test Example 1). Furthermore, several compounds of formula (I) were confirmed to induce IL-2 production in human T-cell leukemia cell lines (Test Example 2). Furthermore, several compounds of formula (I) were confirmed to have antitumor activity in a mouse model (Test Example 3). In particular, the B16-F1 cells used in Test Example 3 are cells against which anti-PD-1 antibodies / anti-PD-L1 antibodies are generally known to be ineffective. Even in a mouse model bearing these cells, several compounds of formula (I) were confirmed to exhibit antitumor activity. Therefore, the compounds of formula (I) can be used for the treatment of cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, particularly cancers associated with immune cell activation that are resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

[0063] Pharmaceutical compositions containing one or more compounds of formula (I) or salts thereof as an active ingredient can be prepared by a commonly used method using excipients commonly used in the art, i.e., pharmaceutical excipients, pharmaceutical carriers, etc. Administration may be in the form of oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using intra-articular, intravenous, intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, etc.

[0064] Solid compositions for oral administration include tablets, powders, granules, etc. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The compositions may contain inert additives, such as lubricants, disintegrants, stabilizers, and solubilizers, according to conventional methods. Tablets, powders, granules, or pills may be coated with wax, sugar coating, or a film of a gastric or enteric substance, as needed. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents, such as purified water or ethanol. In addition to the inert diluent, the liquid compositions may contain adjuvants such as solubilizers, wetting agents, and suspending agents, as well as sweeteners, flavors, fragrances, and preservatives.

[0065] Injectable preparations for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include alcohols such as ethanol. Such compositions may further contain an isotonic agent, an antiseptic, a wetting agent, an emulsifier, a dispersant, a stabilizer, or a solubilizing agent. These are sterilized, for example, by filtration through a bacteria-retaining filter, addition of a sterilizing agent, or irradiation. Alternatively, sterile solid compositions can be prepared and dissolved or suspended in sterile water or a sterile injectable solvent before use.

[0066] External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments, etc. They contain commonly used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions, etc.

[0067] Transmucosal agents such as inhalants and nasal agents may be in solid, liquid, or semisolid form and may be prepared according to conventional methods. For example, known excipients, as well as pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc., may be added as appropriate. Administration can be performed using a suitable inhalation or insufflation device. For example, known devices such as metered-dose inhalers or nebulizers can be used to administer the compound alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. Dry powder inhalers and the like may be for single or multiple doses, and can utilize dry powders or powder-containing capsules. Alternatively, the compound may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as a chlorofluoroalkane or carbon dioxide.

[0068] For oral administration, the daily dosage is typically approximately 0.001 to 100 mg / kg of body weight, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg, administered in a single dose or in two to four divided doses. For intravenous administration, the daily dosage is typically approximately 0.0001 to 10 mg / kg of body weight, administered once or multiple times daily. For transmucosal administration, the daily dosage is approximately 0.001 to 100 mg / kg of body weight, administered once or multiple times daily. The dosage is determined appropriately for each individual case, taking into account symptoms, age, sex, and other factors.

[0069] Although it varies depending on the route of administration, dosage form, administration site, and types of excipients and additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in one embodiment, 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof as active ingredients.

[0070] The compound of formula (I) can be used in combination with various therapeutic or preventive agents for diseases for which the compound of formula (I) is considered to be effective. The combination may be administered simultaneously, or separately, consecutively, or at a desired time interval. The simultaneous administration preparation may be a combined preparation or may be formulated separately.

[0071] The production method of the compound of formula (I) will be explained in more detail below based on examples. Note that the present invention is not limited to the compounds described in the following examples. In addition, production methods of the starting compounds are shown in the production examples. In addition, the production method of the compound of formula (I) is not limited to the production methods of the specific examples shown below, and the compound of formula (I) can also be produced by a combination of these production methods or by methods that are obvious to those skilled in the art.

[0072] In this specification, naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used to name compounds.

[0073] For convenience, the concentration in mol / l is expressed as M. For example, a 1M aqueous solution of sodium hydroxide means a 1 mol / l aqueous solution of sodium hydroxide.

[0074] The powder X-ray diffraction results described herein were measured using an Empyrean tube under the following conditions: a Cu tube, a tube current of 40 mA, a tube voltage of 45 kV, a step width of 0.013°, a wavelength of 1.5418 Å, and a diffraction angle range (2θ) of 2.5 to 40°.

[0075] Preparation Example 1: (2R)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (935 mg) was added to a mixture of 2-bromo-1-chloro-3-fluoro-4-nitrobenzene (1.0 g), TEA (1.2 g), and THF (10 mL) and stirred at room temperature for 16 hours. Water was added, and the mixture was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hex / EtOAc) to give tert-butyl (2R)-4-(2-bromo-3-chloro-6-nitrophenyl)-2-(hydroxymethyl)piperazine-1-carboxylate (1.8 g) as a solid.

[0076] Preparation Example 2 A mixture of 2-bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (3.00 g), 2-fluorophenol (1.00 mL), potassium carbonate (2.88 g), and NMP (30 mL) was stirred at 50°C overnight. After cooling to room temperature, water, EtOAc, and brine were added, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Hex / EtOAc) to give 2-bromo-4-(2-fluorophenoxy)-1-nitro-3-(trifluoromethyl)benzene (3.43 g).

[0077] Preparation Example 16: Pd(dppf)Cl2·CHCl2 (0.215 g) was added to a mixture of 2-bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (0.758 g), tert-butyl {2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl}carbamate (2.844 g), potassium carbonate (0.910 g), 1,4-dioxane (20 mL), and water (4 mL), and the mixture was stirred at 110 °C for 5 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, the aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl (2-{[3'-fluoro-6'-nitro-2'-(trifluoromethyl)[1,1'-biphenyl]-3-yl]oxy}ethyl)carbamate (0.502 g).

[0078] Preparation Example 20: tert-Butylchlorodiphenylsilane (10.0 mL) was added to a mixture of (8S)-8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-1,4-dione (3.250 g), DMF (48 mL), and imidazole (3.972 g), and the mixture was stirred at room temperature for 23 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / MeOH) to give (8S,8aS)-8-{[tert-butyldi(phenyl)silyl]oxy}hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (1.786 g) as a less polar substance and (8S,8aR)-8-{[tert-butyldi(phenyl)silyl]oxy}hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (1.164 g) as a more polar substance.

[0079] Preparation Example 21: A solution of (8S,8aR)-8-{[tert-butyldi(phenyl)silyl]oxy}hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (1.164 g) in THF (10 mL) was added to a mixture of lithium aluminum hydride (0.594 g) and THF (40 mL) and stirred under reflux for 17 hours. After cooling to room temperature, a mixture of water (0.7 mL) and THF (7.7 mL) and 4N aqueous sodium hydroxide (0.7 mL) were added, followed by addition of Na2SO4 and stirring at room temperature for 3 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give (8S,8aS)-octahydropyrrolo[1,2-a]pyrazin-8-ol (0.972 g). This was used in the next step without further purification.

[0080] Preparation Example 23: Under an argon atmosphere and ice-cooling, sodium hydride (60% oil dispersion, 181 mg) was added to a mixture of 2-bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (1.00 g), cyclopentanol (380 μL), and THF (10 mL), and the mixture was stirred at room temperature for 3 hours. Water was added under ice-cooling, and the mixture was extracted with EtOAc, washed with brine, and dried over MgSO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Hex / EtOAc) to give 2-bromo-4-(cyclopentyloxy)-1-nitro-3-(trifluoromethyl)benzene (935 mg).

[0081] Preparation Example 33: Under ice cooling, NaBH(OAc) (8.74 g) was added to a mixture of [(2S)-4-benzylpiperazin-2-yl]methanol dihydrochloride (5.76 g), 37% aqueous formaldehyde (3.35 mL), sodium acetate (3.38 g), and THF (60 mL), and the mixture was stirred at room temperature for 6 hours. Saturated aqueous NaHCO was added until bubbling ceased, and the mixture was extracted with EtOAc. 5M aqueous sodium hydroxide was added to the aqueous layer, and the mixture was extracted twice with diethyl ether. The combined organic layers were dried over NaSO and concentrated under reduced pressure to give [(2S)-4-benzyl-1-methylpiperazin-2-yl]methanol (4.48 g).

[0082] Preparation Example 34: A solution of [(2R)-4-benzyl-1-methylpiperazin-2-yl]methanol (5.27 g), TEA (6.7 mL), and THF (100 mL) was cooled in an ice-MeOH bath, followed by the slow addition of methanesulfonyl chloride (1.96 mL). The mixture was stirred for 1 hour under ice-cooling, and then 40% aqueous methylamine (40 mL) was added, followed by stirring at 70°C for 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and water and CHCl were added to the residue, and the aqueous layer was separated. The aqueous layer was extracted twice with CHCl, and the combined organic layers were dried over NaSO and concentrated under reduced pressure. The resulting oil (4.95 g) was dissolved in CHCl (100 mL), and di-tert-butyl dicarbonate (11 g) was added under ice-cooling. The mixture was stirred at room temperature for 2 hours. CHCl and water were added to the reaction mixture, and the aqueous layer was separated. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (aqueous ammonia / MeOH / chloroform) to give tert-butyl {[(2R)-4-benzyl-1-methylpiperazin-2-yl]methyl}(methyl)carbamate (5.92 g).

[0083] Production Example 36: To a solution of tert-butyl {[(2R)-4-benzyl-1-methylpiperazin-2-yl]methyl}(methyl)carbamate (4.92 g) and EtOH (100 mL), activated carbon (500 mg) was added and stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a solution of the resulting oil and EtOH (100 mL), 10% Pd / C (aqueous, 510 mg) was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give tert-butyl methyl{[(2R)-1-methylpiperazin-2-yl]methyl}carbamate (3.43 g).

[0084] Preparation Example 38: Pd(dppf)Cl.CHCl (142 mg) was added to a mixture of 1-bromo-3-fluoro-4-nitro-2-(trifluoromethyl)benzene (500 mg), 2-fluorophenylboronic acid (316 mg), cesium carbonate (1.13 g), 1,4-dioxane (6 mL), and water (1.7 mL), followed by stirring at 120°C for 30 minutes under microwave irradiation. After cooling, the mixture was diluted with EtOAc, filtered through Celite, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hex / EtOAc) to give 2',3-difluoro-4-nitro-2-(trifluoromethyl)-1,1'-biphenyl (403 mg).

[0085] Preparation Example 39: A mixture of tert-butyl methyl{[(2R)-1-methylpiperazin-2-yl]methyl}carbamate (735 mg), 2-bromo-4-(2-fluorophenoxy)-1-nitro-3-(trifluoromethyl)benzene (1.15 g), potassium carbonate (627 mg), and 1,4-dioxane (5.75 mL) was stirred at 110°C for 24 hours. After cooling, the reaction mixture was diluted with EtOAc. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl ({(2R)-4-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (1.31 g).

[0086] Preparation Example 60: To a solution of 1-bromo-3-fluoro-4-nitro-2-(trifluoromethyl)benzene (2.07 g) in THF (21 mL) was added tert-butyl (2R)-2-(hydroxymethyl)piperazine-1-carboxylate (1.55 g) and TEA (1.10 mL) sequentially under ice cooling. The reaction mixture was stirred for 1 hour under ice cooling and then at room temperature for 64 hours. EtOAc and water were added to the reaction mixture, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl (2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-(hydroxymethyl)piperazine-1-carboxylate (2.27 g) as a solid.

[0087] Preparation Example 75: To a solution of tert-butyl (2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-(hydroxymethyl)piperazine-1-carboxylate (2.27 g) in CHCl (15.6 mL) was added Dess-Martin reagent (2.98 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Under ice-cooling, 10% aqueous sodium sulfite and saturated aqueous NaHCO were added, and the mixture was stirred at room temperature for 30 minutes. The aqueous layer was separated and extracted with CHCl. ​​The combined organic layers were washed with brine and dried over NaSO. Concentration under reduced pressure gave tert-butyl (2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-formylpiperazine-1-carboxylate (2.20 g) as a solid.

[0088] Production Example 91: To a solution of (1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl (3S)-3-fluoro-2-oxopiperidine-3-carboxylate (2.6 g) in THF (29 mL), borane-THF complex (0.91 M THF solution, 29 mL) was added under an argon atmosphere, and the mixture was stirred overnight at 70 °C. After cooling to room temperature, MeOH (30 mL) and 2 M hydrochloric acid (30 mL) were added, and the mixture was stirred at 60 °C for 1 hour. The mixture was concentrated under reduced pressure by azeotropy with toluene. To a solution of the resulting residue in NMP (52 mL), 2-bromo-4-(2-fluorophenoxy)-1-nitro-3-(trifluoromethyl)benzene (2.3 g) and potassium carbonate (3 g) were added, and the mixture was stirred overnight at 120 °C. 2-Bromo-4-(2-fluorophenoxy)-1-nitro-3-(trifluoromethyl)benzene (730 mg) was added and stirred at 120 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, and then dried over MgSO. The solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (Hex / EtOAc) to give {(3S)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methanol (1.9 g).

[0089] Preparation Example 92: NaBH(OAc)3 (1.93 g) was added to a mixture of tert-butyl (2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-formylpiperazine-1-carboxylate (2.20 g), 2 M methylamine / THF solution (4.56 mL), acetic acid (522 μL), and CHCl2 (22 mL), and the mixture was stirred at room temperature for 16 hours. Saturated aqueous NaHCO3 was added, and the mixture was stirred at room temperature for 1 hour. The aqueous layer was separated, extracted with CHCl2, and the combined organic layers were washed with brine. The mixture was dried over NaSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hex / EtOAc + chloroform / MeOH) to give tert-butyl (2S)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-[(methylamino)methyl]piperazine-1-carboxylate (1.91 g).

[0090] Preparation Example 108: Under ice cooling, TFAA (1.08 mL) was slowly added to a mixture of tert-butyl (2S)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-[(methylamino)methyl]piperazine-1-carboxylate (1.91 g), DIPEA (1.97 mL), and CHCl (19.1 mL), followed by stirring at room temperature for 2 hours. Saturated aqueous NHCl was added, and the mixture was extracted with CHCl using an ISOLUTE® Phase Separator and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hex / EtOAc) to give tert-butyl (2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-2-{[methyl(trifluoroacetyl)amino]methyl}piperazine-1-carboxylate (1.42 g) as a solid.

[0091] Preparation Example 123: To a mixture of tert-butyl (2R)-4-[2-chloro-3-(2-fluorophenoxy)-6-nitrophenyl]-2-formylpiperazine-1-carboxylate (859 mg), 2M methylamine / THF solution (1.8 mL), CHCl (9 mL), and acetic acid (206 μL), NaBH(OAc) (760 mg) was added and stirred at room temperature for 2 hours. Saturated aqueous NaHCO was added, and the mixture was extracted with CHCl using an ISOLUTE® phase separator and concentrated under reduced pressure. CHCl (9 mL) and DIPEA (920 μL) were added to the residue, and TFAA (506 μL) was added under ice cooling. The mixture was stirred at room temperature for 1 hour. DIPEA (230 μL) and TFAA (126 μL) were added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous NH4Cl was added, and the mixture was extracted with dichloromethane using an ISOLUTE (registered trademark) phase separator and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / Et0Ac) and silica gel column chromatography (Hex / chloroform → Hex / Et0Ac) to give tert-butyl (2R)-4-[2-chloro-3-(2-fluorophenoxy)-6-nitrophenyl]-2-{[methyl(trifluoroacetyl)amino]methyl}piperazine-1-carboxylate (606 mg) as a solid.

[0092] Preparation Example 125: A solution of potassium phosphate (0.7 g) in water (2 mL) was added to a mixture of tert-butyl (2R)-4-[2-bromo-3-(2-fluorophenoxy)-6-nitrophenyl]-2-{[methyl(trifluoroacetyl)amino]methyl}piperazine-1-carboxylate (0.70 g), tricyclohexylphosphine (96 mg), cyclopropylboronic acid (0.28 g), and toluene (20 mL). After purging the system with argon, palladium acetate (49 mg) was added and stirred at 110°C for 8 hours. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hex / Et0Ac) to give tert-butyl (2R)-4-[2-cyclopropyl-3-(2-fluorophenoxy)-6-nitrophenyl]-2-{[methyl(trifluoroacetyl)amino]methyl}piperazine-1-carboxylate (0.42 g).

[0093] Preparation Example 127: To a solution of tert-butyl (2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-2-(hydroxymethyl)piperazine-1-carboxylate (3.33 g) in CHCl (15 mL) was added 4 M HCl / 1,4-dioxane solution (15 mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give {(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperazin-2-yl}methanol monohydrochloride (3.1 g).

[0094] Preparation Example 144: To a mixture of {(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperazin-2-yl}methanol monohydrochloride (2.93 g) and THF (80 mL) was added sodium acetate (770 mg) under ice cooling and stirred at room temperature for 10 minutes. 1H-Benzotriazole-1-methanol (1.4 g) was added and stirred at room temperature for 10 minutes. NaBH(OAc)3 (2 g) was added and stirred at room temperature for 12 hours. After cooling the reaction mixture in an ice bath, saturated aqueous NaHCO3 was added, diluted with water and EtOAc, and the two layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4. The residue was purified by silica gel column chromatography (Hex / chloroform / EtOAc → chloroform / MeOH) to give {(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methanol (2.65 g).

[0095] Preparation Example 150: To a mixture of tert-butyl (2R)-4-[2-chloro-3-(2-fluorophenoxy)-6-nitrophenyl]-2-{[methyl(trifluoroacetyl)amino]methyl}piperazine-1-carboxylate (603 mg) and CHCl (6 mL), 4M HCl / 1,4-dioxane solution (4 mL) was added under ice cooling and stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure. THF (12 mL) was added to the residue, and 1H-benzotriazole-1-methanol (230 mg), sodium acetate (130 mg), and NaBH(OAc) (330 mg) were added, followed by stirring at room temperature for 1 hour. Saturated aqueous NaHCO was added, and the mixture was extracted with a mixed solvent (chloroform / MeOH). The organic layer was dried over MgSO. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / MeOH), and the resulting substance was purified by silica gel column chromatography (chloroform / EtOAc) to give N-({(2R)-4-[2-chloro-3-(2-fluorophenoxy)-6-nitrophenyl]-1-methylpiperazin-2-yl}methyl)-2,2,2-trifluoro-N-methylacetamide (415 mg) as a solid.

[0096] Preparation Example 158: To a solution of {(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methanol (2.65 g) and DIPEA (2.4 mL) in CHCl (60 mL) was added methanesulfonic anhydride (1.74 g) under ice-cooling and stirred for 1 hour under the same conditions. Methanesulfonic anhydride (440 mg) was added and stirred for 1 hour under the same conditions. The reaction mixture was diluted with chloroform and water, and the aqueous layer was separated. The aqueous layer was extracted with chloroform, and the combined organic layers were dried over NaSO. Concentration under reduced pressure gave {(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl methanesulfonate (3.18 g).

[0097] Preparation Example 164: Potassium phthalimide (1.7 g) was added to a mixture of {(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl methanesulfonate (3.18 g) and NMP (60 mL), followed by stirring at 50°C for 12 hours. Saturated aqueous NH4Cl, EtOAc, and water were added in an ice bath, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4. After concentration under reduced pressure, the residue was purified by silica gel chromatography (Hex / EtOAc) to give 2-({(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione (1.8 g).

[0098] Preparation Example 171: To a solution of {(3S)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methanol (1.9 g) in CHCl (38 mL) was added methanesulfonic anhydride (920 mg) and DIPEA (1.1 mL) under ice cooling, and the mixture was stirred for 1 hour. Water was added, and the mixture was extracted with chloroform using an ISOLUTE® phase separator and concentrated under reduced pressure. Potassium phthalimide (1.2 g) was added to a solution of the resulting residue in NMP (19 mL), and the mixture was stirred overnight at 60°C. The mixture was heated to 120°C and stirred for 2 hours. Potassium phthalimide (800 mg) was added, and the mixture was stirred at 100°C for 7 days. Water and brine were added, and the mixture was extracted with EtOAc. The organic layer was dried over NaSO. The residue was purified by silica gel column chromatography (Hex / Et0Ac) to give 2-({(3S)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)-1H-isoindole-1,3(2H)-dione (1.2 g) as a solid.

[0099] Preparation Example 173: Under an argon atmosphere and ice cooling, diisopropyl azodicarboxylate (0.6 mL) was added to a mixture of (8S,8aR)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-ol (0.886 g), THF (13.5 mL), benzoic acid (0.245 g), and triphenylphosphine (0.792 g), and the mixture was stirred at room temperature for 6.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give a mixture (1.648 g) mainly containing (8R,8aR)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-yl benzoate.

[0100] Preparation Example 174: Potassium carbonate (1.396 g) was added to a mixture (1.648 g) containing mainly (8R,8aR)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-yl benzoate and MeOH (20 mL), followed by stirring at room temperature for 6 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Water was added to the residue, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give (8R,8aR)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-ol (0.631 g) as a solid.

[0101] Preparation Example 175: Under an argon atmosphere and ice cooling, diisopropyl azodicarboxylate (0.62 mL) was added to a mixture of (8S,8aS)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-ol (0.922 g), THF (15 mL), phthalimide (0.322 g), and triphenylphosphine (0.824 g), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, the aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to give a mixture (1.480 g) containing mainly 2-{(8R,8aS)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-yl}-1H-isoindole-1,3(2H)-dione.

[0102] Preparation Example 179: HATU (0.96 g) was added to a mixture of 1-{(3S)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methanamine (0.70 g), methoxyacetic acid (0.18 g), DIPEA (0.62 mL), and DMF (10 mL), and the mixture was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hex / EtOAc) to give N-({(3S)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)-2-methoxyacetamide (0.70 g).

[0103] Production Example 180: Under ice cooling, borane THF complex (1 M THF solution, 3 mL) was slowly added to a mixture of N-({(3S)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)-2-methoxyacetamide (0.50 g) and THF (10 mL), followed by stirring at room temperature for 2 hours. The reaction was quenched with methanol and concentrated under reduced pressure to give N-({(3S)-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)-2-methoxyethan-1-amine (0.30 g). This was used in the next reaction without further purification.

[0104] Production Example 181: To a mixture of 2-({(3S)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)-1H-isoindole-1,3(2H)-dione (1.2 g) and MeOH (12 mL), hydrazine monohydrate (520 μL) was added and stirred at 60° C. for 1 hour. Water was added, and the mixture was extracted with chloroform using an ISOLUTE (registered trademark) phase separator and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / MeOH) to give 1-{(3R)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methanamine (270 mg).

[0105] Preparation Example 186: To a solution of 1-{(3R)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methanamine (270 mg) in DMF (2.7 mL), di-tert-butyl dicarbonate (270 mg) and DIPEA (210 μL) were added and stirred at room temperature for 1 hour. Water was added, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl ({(3R)-3-fluoro-1-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (310 mg).

[0106] Preparation Example 193: Hydrazine monohydrate (0.8 mL) was added to a mixture of 2-({(2R)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione (1.8 g) and MeOH (20 mL), followed by stirring at 60° C. for 2 hours. After allowing to cool to room temperature, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, DMF (40 mL), and DIPEA (1.6 mL), di-tert-butyl dicarbonate (2 g) was added, followed by stirring at room temperature for 3 hours. Water and EtOAc were added, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over NaSO. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Hex / Et0Ac) to give tert-butyl ({(2S)-4-[3-(2-chlorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)carbamate (1.60 g).

[0107] Preparation Example 201: NaBH(OAc)3 (762 mg) was added to a mixture of N-({(2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]piperazin-2-yl}methyl)-2,2,2-trifluoro-N-methylacetamide monohydrochloride (1.27 g), sodium acetate (295 mg), 1H-benzotriazole-1-methanol (536 mg), and THF (25.4 mL), followed by stirring at room temperature for 16 hours. Saturated aqueous NaHCO3 was added, followed by stirring at room temperature for 10 minutes. EtOAc and water were added, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine. The mixture was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hex / Et0Ac) to give N-({(2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)-2,2,2-trifluoro-N-methylacetamide (1.40 g) as a solid.

[0108] Preparation Example 210: Potassium carbonate (700 mg) was added to a mixture of N-({(2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)-2,2,2-trifluoro-N-methylacetamide (1.0 g), MeOH (10 mL), and water (3.4 mL), and the mixture was stirred at 50° C. for 2 hours. After cooling to room temperature, saturated aqueous NH4Cl was added, and the mixture was stirred for 5 minutes. Chloroform and water were added, and the mixture was extracted using an ISOLUTE (registered trademark) phase separator. The mixture was dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in THF (10 mL), and di-tert-butyl dicarbonate (530 mg) and TEA (420 μL) were added, followed by stirring at room temperature for 16 hours. EtOAc and water were added, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine. After drying over NaSO and concentrating under reduced pressure, the residue was purified by silica gel chromatography (Hex / Et0Ac) to give tert-butyl ({(2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (720 mg).

[0109] Production example 211 Pd(PPh3) 4 (110 mg) was added to a mixture of tert-butyl ({(2R)-4-[3-bromo-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (490 mg), 1-cyclopentenylboronic acid (130 mg), potassium carbonate (260 mg), 1,4-dioxane (10 mL), and water (1 mL), and the mixture was stirred at 120°C for 2 hours under microwave irradiation. After cooling to room temperature, EtOAc and water were added, and the mixture was stirred for 5 minutes. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with water and brine and dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Hex / Et0Ac) to give tert-butyl ({(2R)-4-[3-(cyclopent-1-en-1-yl)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (420 mg).

[0110] Preparation Example 214: TFA (15 mL) was added to a mixture of 4-[3-(cyclobutyloxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-(oxan-2-yl)-1H-pyrazole (2.594 g) and CHCl (30 mL), followed by stirring at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and saturated aqueous NaHCO was added to the residue, followed by extraction twice with CHCl. ​​The combined organic layers were dried over NaSO. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (Hex / EtOAc) to give 4-[3-(cyclobutyloxy)-6-nitro-2-(trifluoromethyl)phenyl]-1H-pyrazole (1.907 g) as a solid.

[0111] Preparation Example 215: Cesium carbonate (1.254 g) was added to a mixture of 4-[3-(cyclobutyloxy)-6-nitro-2-(trifluoromethyl)phenyl]-1H-pyrazole (0.840 g), tert-butyl (3-bromopropyl)carbamate (0.732 g), and DMF (14 mL), followed by stirring at room temperature for 3 hours. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with water and brine and dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / EtOAc) to give tert-butyl (3-{4-[3-(cyclobutyloxy)-6-nitro-2-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}propyl)carbamate (0.831 g) as a solid.

[0112] Preparation Example 216: Under an argon atmosphere and ice-cooling, sodium hydride (55% oil dispersion, 0.019 g) was added to a mixture of tert-butyl {(8R,8aS)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-yl}carbamate (0.200 g) and DMF (2.5 mL), and the mixture was stirred for 40 minutes under ice-cooling. Methyl iodide (35 μL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine and dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex / Et0Ac) to give tert-butyl {(8R,8aS)-2-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]octahydropyrrolo[1,2-a]pyrazin-8-yl}(methyl)carbamate (0.131 g).

[0113] Preparation Example 222: Cesium carbonate (1.78 g) was added to a solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (841 mg) in MeCN (20 mL) and the mixture was stirred at room temperature for 10 minutes. 3,4,6-Trichloropyridazine (1 g) was added and the mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with EtOAc and filtered through Celite to remove insoluble material. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / Hex / chloroform) to give ethyl 1-(3,6-dichloropyridazin-4-yl)-5-methyl-1H-pyrazole-3-carboxylate (1.37 g) as a solid.

[0114] Preparation Example 225: To a solution of ethyl 1-(3,6-dichloropyridazin-4-yl)-5-methyl-1H-pyrazole-3-carboxylate (1.37 g) in THF / EtOH (1 / 1, 30 mL), TEA (1.3 mL) and palladium-activated carbon ethylenediamine complex (3.5-6.5% Pd, 137 mg) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. Insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to give a solid. This was diluted with chloroform and water, and the two layers were separated. The aqueous layer was extracted with chloroform, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / chloroform) to give ethyl 5-methyl-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxylate (521 mg) as a solid.

[0115] Preparation Example 228: To a mixture of ethyl 5-methyl-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxylate (521 mg) and THF / EtOH (1 / 1, 30 mL) was added 1 M aqueous sodium hydroxide (10 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 4 hours. 1 M hydrochloric acid (10 mL) was added under ice-cooling, and the mixture was concentrated under reduced pressure. The resulting residue was diluted with water, and the precipitated solid was collected by filtration and dried under reduced pressure to give 5-methyl-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxylic acid (395 mg) as a solid.

[0116] Preparation Example 231: Methyl iodide (124 μL) was added to a mixture of N-cyclopropyl-2,2,2-trifluoro-N-({(2R)-4-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]piperazin-2-yl}methyl)acetamide monohydrochloride (390 mg), DIPEA (342 μL), and DMF (4 mL), followed by stirring at room temperature for 16 hours. EtOAc and water were added, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine and dried over Na2SO4. The residue was purified by silica gel chromatography (Hex / Et0Ac) to give N-cyclopropyl-2,2,2-trifluoro-N-({(2R)-4-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)acetamide (143 mg).

[0117] Production Example 232: To a solution of tert-butyl ({(2R)-4-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (3.41 g) in 1,4-dioxane (50 mL) was added a solution of NH4Cl (3.36 g) in water (25 mL), and then zinc powder (4.11 g) was added under ice cooling and stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc and water and then filtered through Celite. The filtrate was separated, the aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4. Concentration under reduced pressure gave tert-butyl ({(2R)-4-[6-amino-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (3.32 g).

[0118] Preparation Example 293: Zinc powder (550 mg) was added to a mixture of tert-butyl ({(2R)-4-[3-(cyclopent-1-en-1-yl)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (420 mg), NH4Cl (450 mg), 1,4-dioxane (4.2 mL), and water (1.7 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with chloroform, and the aqueous layer was separated using an ISOLUTE (registered trademark) phase separator. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in MeOH (8.4 mL), and 10% Pd / C (50% water content, 180 mg) was added. The mixture was stirred under a hydrogen atmosphere (3 atm) at room temperature for 8 hours. Insoluble matter was removed by filtration through Celite, and the mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (8.4 mL), and 10% Pd / C (50% aqueous, 360 mg) was added. The mixture was stirred under a hydrogen atmosphere (3 atm) at room temperature for 48 hours. Insoluble matter was removed by filtration through Celite, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform / MeOH) to give tert-butyl ({(2R)-4-[6-amino-3-cyclopentyl-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (320 mg) as a solid.

[0119] Production Example 294: To a mixture of tert-butyl ({(2R)-4-[6-amino-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (3.22 g), 1-(pyridazin-4-yl)-1H-pyrazole-3-carboxylic acid (1.43 g), DIPEA (3.3 mL), and DMF (50 mL) was added HATU (3.58 g). The reaction mixture was stirred at 50° C. for 12 hours. After cooling to room temperature, chloroform and water were added to the reaction mixture, and the aqueous layer was separated. The aqueous layer was extracted with chloroform, and the combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / MeOH) to give ({(2R)-4-[3-(2-fluorophenoxy)-6-{[1-(pyridazin-4-yl)-1H-pyrazole-3-carbonyl]amino}-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl) tert-butyl carbamate (4.35 g).

[0120] Preparation Example 403: A solution of potassium carbonate (0.24 g) in water (2 mL) was added to a mixture of N-{3-chloro-2-[(3R)-3-({[(3,4-dimethoxyphenyl)methyl](trifluoroacetyl)amino}methyl)-4-methylpiperazin-1-yl]-4-(2-fluorophenoxy)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide (0.27 g) and MeOH (10 mL), followed by stirring at room temperature for 16 hours. The mixture was concentrated under reduced pressure, diluted with EtOAc, and washed three times with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCl / MeOH) to give N-{3-chloro-2-[(3S)-3-({[(3,4-dimethoxyphenyl)methyl]amino}methyl)-4-methylpiperazin-1-yl]-4-(2-fluorophenoxy)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide (0.16 g) as a solid.

[0121] Preparation Example 404: TFA (1 mL) was added to a mixture of tert-butyl (2R)-2-{[methyl(trifluoroacetyl)amino]methyl}-4-[3-phenoxy-6-{[2-(pyridazin-4-yl)-1,3-oxazole-4-carbonyl]amino}-2-(trifluoromethyl)phenyl]piperazine-1-carboxylate (0.414 g) and CHCl (2 mL), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and saturated aqueous NaHCO was added to the residue, followed by extraction with CHCl. ​​The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl / MeOH) to give N-{2-[(3R)-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-oxaazole-4-carboxamide (0.333 g).

[0122] Preparation Example 405: NaBH(OAc)3 (0.156 g) was added to a mixture of N-{2-[(3R)-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-oxaazole-4-carboxamide (0.318 g), CHCl2 (5 mL), and 37% aqueous formaldehyde (0.2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted with CHCl2. The organic layer was dried over NaSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / MeOH) to give N-{2-[(3R)-4-methyl-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,3-oxaazole-4-carboxamide (0.287 g).

[0123] The compounds shown in Table 4 below were produced in the same manner as in the production examples shown above. The structure of each example compound is shown in Table 4 below, and the production method and physicochemical data of each example compound are shown in Table 5. These compounds can be easily produced by using the production methods in the above examples, methods obvious to those skilled in the art, or modifications thereof.

[0124] Example 1: TFA (330 μL) was added to a mixture of tert-butyl ({(3S)-1-[6-{[1-(2,2-difluoroethyl)-1H-pyrazole-3-carbonyl]amino}-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (275 mg) and CHCl (3 mL), followed by stirring at room temperature for 16 hours. After concentration under reduced pressure, a mixed solvent (chloroform / MeOH) and saturated aqueous NaHCO were added to the residue, and the organic layer was separated and dried over NaSO. After concentration under reduced pressure, the residue was purified by silica gel chromatography (chloroform / MeOH / aqueous ammonia). The resulting material was dissolved in EtOAc (3 mL), and 4M HCl / EtOAc solution (500 μL) was added, followed by stirring at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, and the residue was solidified and washed with isopropyl ether. The residue was then dried under reduced pressure to give N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide monohydrochloride (210 mg) as a solid.

[0125] Example 22: Potassium carbonate (78 mg) was added to a mixture of N-[4-(2-fluorophenoxy)-2-[(3R)-4-methyl-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-oxaazole-4-carboxamide (190 mg), water (630 μL), and MeOH (2 mL), and the mixture was stirred at room temperature for 2 hours. Water, saturated aqueous NH4Cl, and chloroform were added, and the aqueous layer was separated. The aqueous layer was extracted with a mixed solvent (chloroform / MeOH), and the combined organic layers were dried over Na2SO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform / MeOH / aqueous ammonia). The resulting material was dissolved in EtOAc (2 mL), and 4M HCl / EtOAc solution (350 μL) was added. The mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether and dried under reduced pressure to give N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-oxaazole-4-carboxamide trihydrochloride (131 mg) as a solid.

[0126] Example 29: Under ice cooling, TFA (10 mL) was added to a mixture of tert-butyl ({(2R)-4-[3-(2-fluorophenoxy)-6-{[1-(pyridazin-4-yl)-1H-pyrazole-3-carbonyl]amino}-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (4.3 g) and CHCl (40 mL), followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was made basic by adding water, chloroform, and NaHCO. The mixture was separated using a separatory funnel, and the aqueous layer was extracted with chloroform. The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / MeOH / aqueous ammonia). The resulting amorphous solid was washed with EtOAc / Hex to give N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (2.62 g) as a solid.

[0127] Example 86: Potassium carbonate (68 mg) was added to a mixture of N-{3-chloro-4-(2-fluorophenoxy)-2-[(3R)-4-methyl-3-{[methyl(trifluoroacetyl)amino]methyl}piperazin-1-yl]phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (159 mg), MeOH (1.5 mL), and water (0.5 mL), followed by stirring for 2 hours at 50° C. After cooling, saturated aqueous NH4Cl was added, followed by extraction with a mixed solvent (chloroform / MeOH), and the organic layer was dried over MgSO4. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform / MeOH / aqueous ammonia) to give N-[3-chloro-4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (106 mg) as a solid.

[0128] Example 109: HATU (17.1 mg) and DMF (100 μL) were added to a mixture of tert-butyl ({(3S)-1-[6-amino-3-phenoxy-2-(trifluoromethyl)phenyl]piperidin-3-yl}methyl)carbamate (14.0 mg), 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid (7.3 mg), DIPEA (20.5 μL), and DMF (600 μL), followed by stirring at 50° C. overnight. After cooling, chloroform and water were added, the organic layer was separated, concentrated under reduced pressure, and the residue was purified by LC-MS (formic acid water / MeOH). The resulting substance was dissolved in CHCl (250 μL), and 4M HCl / 1,4-dioxane solution (250 μL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and a mixed solvent (chloroform / MeOH) and saturated aqueous NaHCO3 solution were added to the residue. The organic layer was separated and concentrated under reduced pressure to give N-{2-[(3S)-3-(aminomethyl)piperidin-1-yl]-4-phenoxy-3-(trifluoromethyl)phenyl}-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide (6.9 mg).

[0129] Example 112 Trifluoromethanesulfonic acid (1 mL) was added to a mixture of N-{3-chloro-2-[(3S)-3-({[(3,4-dimethoxyphenyl)methyl]amino}methyl)-4-methylpiperazin-1-yl]-4-(2-fluorophenoxy)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide (0.15 g) and TFA (1 mL), and the mixture was stirred at room temperature for 16 hours and at 60 ° C. for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give N-{2-[(3S)-3-(aminomethyl)-4-methylpiperazin-1-yl]-3-chloro-4-(2-fluorophenoxy)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide (31 mg) as a solid.

[0130] Example 113: NaBH(OAc) (0.064 g) was added to a mixture of N-[4-(cyclobutyloxy)-2-{2-[2-(methylamino)ethoxy]pyridin-4-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-oxaazole-4-carboxamide (0.110 g), CHCl (2 mL), and 37% aqueous formaldehyde (81 μL), followed by stirring at room temperature for 15 hours. The reaction mixture was poured into saturated aqueous NaHCO and extracted with CHCl. ​​The organic layer was separated, the aqueous layer extracted with CHCl, and the combined organic layers were dried over NaSO. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl / MeOH) to give N-[4-(cyclobutyloxy)-2-{2-[2-(dimethylamino)ethoxy]pyridin-4-yl}-3-(trifluoromethyl)phenyl]-2-(pyridazin-4-yl)-1,3-oxaazole-4-carboxamide (0.098 g) as a solid.

[0131] Example 122: N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (5 g) was dissolved in EtOH (50 mL) at 80°C, and succinic acid (1.06 g) and water (2.5 mL) were added thereto and stirred at room temperature for 48 hours. The precipitate was collected by filtration and dried under reduced pressure to obtain a solid (5.50 g). A mixture of the obtained solid (5.45 g), EtOH (40 mL), and water (4 mL) was stirred at 70°C to form a solution, followed by stirring at room temperature for 24 hours. The precipitate was collected by filtration and dried under reduced pressure at 40°C for 2 days to give N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxyamide monobutanedioic acid salt (4.36 g) as crystals.

[0132] Example 123: Succinic acid (34 mg) was added to a mixture of N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (150 mg) and EtOH (2 mL) at 70°C, and water (100 μL) was added, followed by stirring at room temperature for 24 hours. The mixture was concentrated under reduced pressure. MeCN (10 mL) was added to the residue, and the mixture was stirred at room temperature for 24 hours. The precipitate was collected by filtration and dried under reduced pressure to give N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxyamide monobutanedioic acid salt (165 mg) as crystals.

[0133] Example 126: At 70 ° C., succinic acid (22 mg) was added to a mixture of N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (100 mg) and EtOH (1 mL), and water (50 μL) was added. The mixture was stirred at room temperature for 2 days. The precipitated solid was collected by filtration and dried under reduced pressure to give N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monobutanedioic acid salt (77 mg) as crystals.

[0134] The compounds shown in Table 6 below were produced in the same manner as the production methods of the above-mentioned Examples. The structures of the Example compounds are shown in Table 6 below, and the production methods and physicochemical data of the Example compounds are shown in Table 7 below. These compounds can be easily produced by using the production methods of the above-mentioned Examples, methods obvious to those skilled in the art, or modifications thereof.

[0135] In the tables below, the following abbreviations may be used: PEx: Production Example number; Ex: Example number; PSyn: Production method for the Production Example compound (the number in the PSyn column indicates that the compound was produced using the corresponding raw materials by the same method as the compound with that number as the Production Example number. For example, a compound with 1 in the PSyn column means that it was produced by the same method as the compound of Production Example 1); Syn: Production method for the Example compound (the number in the Syn column indicates that the compound was produced using the corresponding raw materials by the same method as the compound with that number as the Example number. For example, a compound with 1 in the Syn column means that it was produced by the same method as the compound of Example 1); Str: Chemical structure; DAT: Physicochemical data; ESI+: m / z value in mass spectrometry (ionization method ESI, [M+H] unless otherwise specified). + , or [M+Na] + ), ESI-: m / z value in mass spectrometry (ionization method ESI, unless otherwise specified [M−H] - ), NMR DMSO-d6 (400 MHz), or NMR DMSO-d6 (500 MHz): 1 H-NMR signal δ value (ppm), NMR DMSO-d6 (400 MHz, 80°C): in DMSO-d6 under heating at 80°C 1 δ value (ppm) of the signal in H-NMR, NMR CDCl3 (400 MHz), or NMR CDCl3 (500 MHz): in CDCl3 1 δ value (ppm) of the signal in H-NMR, s: singlet (spectrum), d: doublet (spectrum), t: triplet (spectrum), m: multiplet (spectrum), br: broad line (spectrum), dd: double doublet (spectrum).

[0136] Unless otherwise specified, compounds are optical isomers with the absolute configuration shown in the chemical structure. HCl in the structure indicates that the compound is a monohydrochloride, 2HCl indicates that the compound is a dihydrochloride, and 3HCl indicates that the compound is a trihydrochloride.

[0137]

[0138]

[0139]

[0140]

[0141] The compound of the present invention or a salt thereof is useful as a DGKζ inhibitor and may be used as an active ingredient in pharmaceutical compositions, for example, pharmaceutical compositions for treating cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

Claims

1. A compound of formula (I) or a salt thereof wherein R 1a is halogeno C 1-6 alkyl, B is (B-i), and R 1a is pyridazinyl, or halogeno C 1-6 alkyl, and R 1b is H or C 1-6 alkyl, and R 2 is C 3-5 cycloalkyl, -O-(C 1-6 alkyl), halogeno C 1-6 alkyl, halogen, or phenyl, and R 3 is i) phenyl optionally substituted with a group selected from the group consisting of C 1-6 alkyl, halogeno C 1-6 alkyl, C 3-5 cycloalkyl, -O-(C 1-6 alkyl), -O-(halogeno C 1-6 alkyl), cyano, nitro, methanesulfonyl, and halogen, ii) C 1-6 cycloalkyl optionally substituted with a group selected from the group consisting of C 3-8 alkyl and halogen, iii) pyridyl optionally substituted with a group selected from the group consisting of C 1-6 alkyl, halogeno C 1-6 alkyl, C 3-5 cycloalkyl, -O-(C 1-6 alkyl), -O-(halogeno C 1-6 alkyl), cyano, nitro, methanesulfonyl, and halogen, or iv) a 5- to 6-membered partially unsaturated heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and R 4 is H or F, and R 5 is H or F, and R 6 is -L 2 -(CH 2 ) 2 NR a R b or piperidinyl, and L 1 is a bond, O, or NH, and L 2 is a bond, O, or CH 2 and X is CH 2 or N-methyl, Y is CH or N, R a is H or methyl, R b is H, methyl, ethyl, cyclopropyl, or -(CH 2 ) 2 O-CH 3 and m is 1, 2, or 3).

2. R 2 is a halogeno C 1-6 alkyl, or a halogen, and R 3 is i) phenyl optionally substituted with a group selected from the group consisting of C 1-6 alkyl, halogeno C 1-6 alkyl, C 3-5 cycloalkyl, -O-(C 1-6 alkyl), -O-(halogeno C 1-6 alkyl), cyano, nitro, methanesulfonyl, and halogen, or ii) C 1-6 alkyl, and C 3-8 cycloalkyl optionally substituted with a group selected from the group consisting of alkyl and halogen, and L 1 is a bond or O, the compound or a salt thereof according to claim 1.

3. B is represented by the following formula (B-i-a) or (B-ii): Here, R 1a is halogenated C 1-6 alkyl, and B is (B-i-a). The compound or a salt thereof according to claim 2 4. The compound or a salt thereof according to claim 3, wherein A is represented by the following formula (A-i) or (A-ii).

5. R 3 is phenyl optionally substituted with a group selected from the group consisting of C 1-6 alkyl, and halogen, or C 3-5 cycloalkyl, and R b is H, or methyl, the compound or a salt thereof according to claim 4.

6. N-{2-[(3S)-3-(Aminomethyl)piperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide, N-{2-[(3S)-3-(aminomethyl)-4-methylpiperazin-1-yl]-4-(2-chlorophenoxy)-3-(trifluoromethyl)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide, N-{2-[(3S)-3-(aminomethyl)-4-methylpiperazin-1-yl]-3-chloro-4-(2-chlorophenoxy)phenyl}-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide, N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide, N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide, N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide, N-[4-cyclopentyl-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide, N-{2-[(8R,8aS)-8-aminohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-2-(pyridazin-4-yl)-1,The compound or a salt thereof according to claim 1, which is selected from the group consisting of 3-oxazole-4-carboxamide and N-[3-chloro-4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide., 7. The compound or a salt thereof according to claim 1, which is selected from the group consisting of N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monobutanedioate, N-[4-(2-fluorophenoxy)-2-{(3R)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monobutanedioate, N-[4-cyclopentyl-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monobutanedioate, N-[3-chloro-4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monobutanedioate, and N-{2-[(3R)-3-(aminomethyl)-3-fluoropiperidin-1-yl]-4-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl}-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide monobutanedioate.

8. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and one or more pharmaceutically acceptable excipients.

9. The pharmaceutical composition according to claim 8, which is a pharmaceutical composition for the treatment of cancer associated with immune cell activation or cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

10. Use of the compound or a salt thereof according to claim 1 for the manufacture of a pharmaceutical composition for the treatment of cancer associated with immune cell activation or cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

11. The compound or a salt thereof according to claim 1 for use in the treatment of cancer associated with immune cell activation or cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

12. Use of the compound or a salt thereof according to claim 1 for the treatment of cancer associated with immune cell activation or cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy.

13. A DGKζ inhibitor containing the compound of formula (I) or a salt thereof.

14. A method for treating cancer associated with immune cell activation, or cancer resistant to anti-PD-1 antibody / anti-PD-L1 antibody therapy, which comprises administering to a subject an effective amount of the compound of claim 1 or a salt thereof.