BR112017026994B1 - COMPOUND, AND, PHARMACEUTICAL COMPOSITION. - Google Patents

Abstract

COMPOUND, AND, PHARMACEUTICAL COMPOSITION. The present invention provides a compound represented by general formula (Ia) or a pharmacologically acceptable salt thereof. In the general formula (Ia), two R moieties each independently represent a C1-3 alkyl group or the like; and R1, R2 and R3 each independently represent an optionally substituted linear or branched C1-4 alkyl group.

Description

TECHNICAL FIELD

[001] The present invention relates to a substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof that has excellent CDK7 inhibitory activity and is useful as a medicament (e.g., a medicament for the treatment or prevention cancer, an inflammatory disease, an allergic disease or a chronic respiratory disease).

PREVIOUS TECHNIQUE

[002] CDKs (Cyclin-Dependent Kinases) are cell growth control factors that are involved in entry into DNA synthesis (S phase) of the cell cycle and into a mitotic phase (M phase), etc. ., and many types of CDKs are known. Also, CDK activation is controlled in multiple stages through phosphorylation or dephosphorylation of the threonine residue of the active loop (T-loop) in its three-dimensional structure. When the specific threonine residue of CDK is phosphorylated, it forms a complex with a specific cyclin and is activated. This complex, which is important for cell cycle control, includes CDK1, CDK2/cyclin A, CDK1/cyclins B1 to B3 and CDK2, CDK4, CDK5, CDK6/cyclin D1 to D3, and CDK2/cyclin E, which are, respectively, involved in specific periods of the cell cycle. CDK7 forms a CDK-activating kinase (CAK) together with cyclin H and MAT1 in metazoans and participates in the phosphorylation of CDKs (e.g., CDK1, CDK2, CDK4, and CDK6) required for cell cycle progression (see Non-Patent Literature 1).

[003] Excessive cell growth due to abnormal activation of CDKs is a common feature in many cancers, and it is known that this is associated with a loss of checkpoint functions involved in cell cycle control of cancer cells (see Non-Patent Literature 2). Also, it is known that CDKs have functions other than cell cycle control, and it is known that CDK7 favors the binding of RNA polymerase II (RNAPII) to DNA and its elongation to positively control transcription through the phosphorylation of serine in the COOH domain -terminal of RNAPII (see Non-Patent Literature 3).

[004] CDK7 inhibitors show effects in cell growth tests of various cancer cells and cancer-bearing mouse models, and inhibition is predicted to be useful as anticancer agents (see Non-Patent Literatures 4 and 5) .

[005] Additionally, it has been reported that in mouse models showing collagen-induced rheumatism, improvement in clinical scores or tissue damage, decrease in levels of inflammation-induced cytokines such as IL-6, IL-1β, and IL- 17, and anti-CII-IgG2a, and decrease in the proportion of Th17 cells are achieved by inhibition of CDK7 (see Non-Patent Literature 6).

[006] It is further predicted that CDK7 inhibitors, which play an important role in cell cycle progression, also have effects on the suppression of infection by viruses such as HIV, EBV, and HCV, and cardiomegaly (see Literature of Non-Patent 7 and 8). Examples of diseases for which CDK7 inhibitors appear to be useful, in addition to those described above, include autoimmune diseases typified by pisoriasis and multiple sclerosis; neurodegenerative diseases such as Alzheimer's disease, etc.; allergic diseases typified by atopic dermatitis; etc.; chronic respiratory diseases typified by obstructive pulmonary disease (COPD, Chronic Obstructive Pulmonary Disease), etc.; and fibrosis typified by idiopathic pulmonary fibrosis, etc. (see Non-Patent Literatures 9 to 11 and Non-Patent Literatures 16 to 18).

[007] Although the development of many CDK inhibitors is currently underway, there are not many compounds that have an excellent CDK7 inhibitory effect (see Non-Patent Literature 15). LIST OF CITATIONS Patent Literature Patent Literature 1: WO 2002/012242 Patent Literature 2: WO 2004/056827 Patent Literature 3: WO 2004/080457 Patent Literature 4: WO 2007/068637 Patent Literature 5: WO 200 7/ 072153 Patent Literature 6: WO 2007/099171 Patent Literature 7: WO 2008/043745 Patent Literature 8: WO 2008/125945 Patent Literature 9: WO 2011/044264 Patent Literature 10: WO 2008/151304 Patent Literature 11 : WO 2013/128028 Patent Literature 12: WO 2013/128029 Patent Literature 13: WO 2014/063068 Patent Literature 14: WO 2015/058126 Patent Literature 15: WO 2015/058140 Patent Literature 16: 2015/058163 Patent Literature 17: WO 2015/124941 Patent Literature 18: WO 2015/154022 Patent Literature 19: WO 2015/154038 Patent Literature 20: WO 2015/154039 Non-Patent Literatures Non-Patent Literature 1: Journal of Cell Science 2005, 118 (20), 5171-5180 Non-Patent Literature 2: Nature Reviews Cancer 2009, 9, 153-166 Non-Patent Literature 3: Biochim. Biophys. Acta 2004, 1677, 64-73 Non-Patent Literature 4: Nature 2014, 511, 616-620 Non-Patent Literature 5: Cancer Res. 2009, 69, 6208-6215 Non-Patent Literature 6: Clin. Exp. Med. 2015, 15, 269-275 Non-Patent Literature 7: Curr. HIV Res. 2003, 1 (2), 131-152 Non-Patent Literature 8: Mol. Cell. Biol. 1998, 18 (11), 6729-6736 Non-Patent Literature 9: Br. J. Dermatol. 2000, 143 (5), 950-956 Non-Patent Literature 10: Biochem. Biophys. Res. Commun 2013, 435 (3), 378-384 Non-Patent Literature 11: Neurobiol. Aging 2000, 6, 807-813 Non-Patent Literature 12: Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739 Non-Patent Literature 13: Bioorganic & Medicinal Chemistry 2010, 18 (5), 1844-1853 Literature of Non-Patent Literature 14: ChemMedChem 2007, 2, 841-852 Non-Patent Literature 15: Current Drug Targets, 2010, 11, 291-302 Non-Patent Literature 16: Clinical & Experimental Allergy, 2011, 41, 673-687 Non-Patent Literature Patent 17: Cell Death and Differentiation, 2012, 19, 1950-1961 Non-Patent Literature 18: Am. J. Physiol. Lung Cell Mol., 2004, 286, 727-733

SUMMARY OF THE INVENTION Technical problem

[008] The present inventors have conducted studies on new substituted dihydropyrrolopyrazole compounds with the aim of developing excellent CDK7 inhibitors and have completed the present invention by the discovery that a new substituted dihydropyrrolopyrazole compound having a specific structure or salt Pharmacologically acceptable thereof has excellent CDK7 inhibitory activity and is useful as a medicine (e.g., a medicine for the treatment or prevention of cancers, inflammatory diseases, allergic diseases or chronic diseases).

[009] Patent Literatures 1 to 9 and Non-Patent Literatures 12 to 14 describe a compound having a 6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole skeleton, but not disclose the compound according to the present invention or the pharmacologically acceptable salt thereof.

[0010] As compounds that inhibit CDK7, pyrazolopyrimidine derivatives are described in Patent Literature 10, pyrazolotriazine derivatives are described in Patent Literature 11 and 12, phenyl derivatives are described in Patent Literature 13 and Non-Patent Literature 4 , and heterocyclic compounds are described in Patent Literatures 14 to 20; however, a compound having a 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton is not described.

Solution of the problem

[0011] The present invention provides a new substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof that has excellent CDK7 inhibitory activity; a pharmaceutical composition, preferably a pharmaceutical composition for the treatment or prevention of cancers, benign tumor, angiogenesis, inflammatory diseases (e.g. autoimmune diseases), virus infection (HIV, EBV, HCV, etc.), neurodegenerative diseases (e.g. e.g., Alzheimer's disease), allergic diseases (e.g., atopic dermatitis), chronic diseases (e.g., chronic obstructive pulmonary disease (COPD)), fibrosis (e.g., idiopathic pulmonary fibrosis), diseases of the circulatory system such as cardiomegaly, or impotence, comprising the substituted dihydropyrrolopyrazole compound or the pharmacologically acceptable salt thereof as an active ingredient; use of the substituted dihydropyrrolopyrazole compound or the pharmacologically acceptable salt thereof for the production of a pharmaceutical composition for the treatment or prevention (preferably, the treatment) of diseases (preferably, the diseases described above); a method for treating or preventing (preferably, treating) diseases (preferably, the diseases described above) by administering a pharmaceutically effective amount of the substituted dihydropyrrolopyrazole compound or pharmacologically acceptable salt thereof to a blood animal hot (preferably a human); and a method for producing the substituted dihydropyrrolopyrazole compound or the pharmacologically acceptable salt thereof, or an intermediate thereof.

[0012] Examples of the cancers include urinary bladder cancer, breast cancer, large bowel cancer (e.g., colorectal cancer, e.g., colon adenocarcinoma and colon adenoma), kidney cancer, epidermal cancer, liver cancer, lung cancer (e.g., adenocarcinoma, small cell lung cancer, and non-small cell lung cancer), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, cancer cervical, endometrial cancer, thyroid gland cancer, nose cancer, head and neck cancer, prostate cancer, skin cancer (e.g. squamous cell cancer), tumors of the hematopoietic organ of the lymphatic system (e.g. leukemia , acute lymphatic leukemia, chronic lymphatic leukemia, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), T-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma), hematopoietic organ tumors of the myeloid system (e.g., acute or chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia), follicular thyroid carcinoma, mesenchymal tumors (e.g., fibrosarcoma, Ewing's sarcoma, and rhabdomyosarcoma ), tumors of the central nervous system or peripheral nervous system (e.g., astrocytoma, neuroblastoma, glioma, brain tumor, and schwannoma), melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, and thyroid sarcoma. Kaposi.

[0013] Examples of autoimmune diseases include multiple sclerosis, Guillain-Barré syndrome, myasthenia gravis, chronic atrophic gastritis, autoimmune hepatitis, primary biliary cirrhosis, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis, autoimmune pancreatitis, aortitis syndrome, Goodpasture's disease, rapidly progressive glomerulonephritis, megaloblastic anemia, autoimmune hemolytic anemia, autoimmune neutropenia, idiopathic thrombocytopenic purpura, Graves' disease, Hashimoto's disease, primary hypothyroidism, idiopathic Addison's disease, type 1 diabetes mellitus, circumscribed scleroderma, epidermolysis bullosa acquired, vitiligo vulgaris, autoimmune optic neuropathy, autoimmune inner ear disorder, idiopathic azoospermia, rheumatoid arthritis, systemic lupus erythematosus, drug-induced systemic lupus erythematosus, Sjogren's syndrome, polymyositis, psoriasis, dermatomyositis, scleroderma, vasculitis syndrome, mixed tissue disease conjunctiva, and inflammatory bowel disease. In this context, inflammatory bowel disease (IBD) is a generic name for diseases that cause ulcers or chronic inflammation in the lining of the large intestine or small intestine, and examples include Crohn's disease and ulcerative colitis.

[0014] According to one aspect, the present invention provides the following [1] to [79]: [1] A compound represented by formula (Ia) or a pharmacologically acceptable salt thereof: [Chemical Formula 1] wherein two R moieties are each independently a C1-3 alkyl group or are groups bonded together to form a C2-5 alkylene group; A is an optionally substituted C6-10 aryl group or an optionally substituted heteroaryl group, and Z is a hydrogen atom or an optionally substituted C1-6 alkyl group, or a group represented by ZNA forms a fused bicyclic heterocyclic group upon bonding between A and Z, optionally substituted; and R1, R2 and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.

[0015] [2] A compound represented by formula (I) or a pharmacologically acceptable salt thereof: [Chemical Formula 2] wherein two R moieties are each independently a C1-3 alkyl group or are groups bonded together to form a C2-5 alkylene group; A is an optionally substituted C6-10 aryl group or an optionally substituted heteroaryl group; and R1, R2 and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.

[0016] [3] A compound represented by formula (IIa) or a pharmacologically acceptable salt thereof: [Chemical Formula 3] in which A is an optionally substituted C6-10 aryl group or an optionally substituted heteroaryl group, and Z is a hydrogen atom or an optionally substituted C1-6 alkyl group, or a group represented by ZNA forms a fused bicyclic heterocyclic group upon link between A and Z, optionally substituted; and R1, R2 and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.

[0017] [4] A compound represented by formula (II) or a pharmacologically acceptable salt thereof: [Chemical Formula 4] wherein A is an optionally substituted C6-10 aryl group or an optionally substituted heteroaryl group; and R1, R2 and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.

[0018] [5] A compound represented by formula (IIIa) or a pharmacologically acceptable salt thereof: [Chemical Formula 5] in which A is an optionally substituted C6-10 aryl group or an optionally substituted heteroaryl group, and Z is a hydrogen atom or an optionally substituted C1-6 alkyl group, or a group represented by ZNA forms a fused bicyclic heterocyclic group upon link between A and Z, optionally substituted; and R1, R2 and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.

[0019] [6] A compound represented by formula (III) or a pharmacologically acceptable salt thereof: [Chemical Formula 6] wherein A is an optionally substituted C6-10 aryl group or an optionally substituted heteroaryl group; and R1, R2 and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.

[0020] [7] A compound represented by formula (IVa) or a pharmacologically acceptable salt thereof: [Chemical Formula 7] in which A is an optionally substituted C6-10 aryl group or an optionally substituted heteroaryl group, and Z is a hydrogen atom or an optionally substituted C1-6 alkyl group, or a group represented by ZNA forms a fused bicyclic heterocyclic group upon link between A and Z, optionally substituted; and R1, R2 and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.

[0021] [8] A compound represented by formula (IV) or a pharmacologically acceptable salt thereof: [Chemical Formula 8] wherein A is an optionally substituted C6-10 aryl group or an optionally substituted heteroaryl group; and R1, R2 and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.

[0022] [9] A compound selected from the group of compounds consisting of: 6,6-Dimethyl-N-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide, 6,6-Dimethyl-N-(p-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide, N-(4-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide, N-(4-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5( 1H)-carboxamide, 6,6-Dimethyl-N-(pyridin-3-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide, N-(2-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5( 1H)-carboxamide, 6,6-Dimethyl-N-(o-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide, 6,6-Dimethyl-N-(m-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide, N-([1,1'-biphenyl]-3-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4- c]pyrazol-5(1H)-carboxamide, N-(3-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carboxamide, N-(3-chlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c] pyrazol-5(1H)-carboxamide, N-(2-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide, N-(2-chlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide, N-([1,1'-biphenyl]-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[ 3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-(pyridin-2-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrole [3,4-c]pyrazol-5(1H)-carboxamide, N-(2-ethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[ 3,4-c]pyrazol-5(1H)-carboxamide, N-(2,6-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrole [3,4-c]pyrazol-5(1H)-carboxamide, N-(2,3-difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-di- hydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,3-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-4,6-di -hydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-fluoro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4, 6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-[2-(difluoromethoxy)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]- 4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-ethoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4 ,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-[2-(trifluoromethoxy)phenyl]-3-[1-(trimethylsilyl)cyclobutanecarboxamido] -4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-fluoro-4-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,6-difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl )cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-[2-(tert-butyl)phenyl]-6,6-dimethyl-3-[ 1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-[2-(trifluoromethyl)phenyl]-3 -[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(3-fluoro-2-methylphenyl)-6,6- dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-cyanophenyl)-6,6-dimethyl -3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(4-fluoro-2-methylphenyl)-6, 6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-chloro-6-methylphenyl) -6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-fluoro-3 -methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2- fluoro-5-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N- (5-fluoro-2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide , N-(2,4-difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide, N-(2,5-difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide, N-(2,5-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide, N-(2-chloro-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide, N-(2,4-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide, 3-[1-(Ethyldimethylsilyl)cyclobutanecarboxamido]-N-(2-fluorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide, 6,6-Dimethyl-N-(3-methylisothiazol-4-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-(thiophen-2-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-2,6-dihydropyrrolo[3,4- c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-(thiophen-3-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-2,6-dihydropyrrolo[3,4 -c]pyrazol-5(1H)-carboxamide, N-(2,6-difluoro-4-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]-4,6-dihydropyrrole [3,4-c]pyrazol-5(1H)-carboxamide, N-(2-fluoro-6-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6 -dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-[2-fluoro-6-(trifluoromethyl)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(5-chloro-2-methylphenyl)-6,6-dimethyl-3-[1- (trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,5-dichlorophenyl)-6,6-dimethyl-3-[1 -(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-cyclopropylphenyl)-6,6-dimethyl-3-[1- (trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[1 -(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-(2,4,6-trifluorophenyl)-3 -[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-ethyl-6-methylphenyl)-6,6- dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-bromophenyl)-6,6-dimethyl -3-[1-(trimethylsilyl)cyclobutanocarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-chloro-5-fluorophenyl)-6, 6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(5-chloro-2-fluorophenyl) -6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N- (2,3,6-trifluorophenyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2- chloro-6-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N- [2-(1,1-difluoroethyl)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide, N-(6-chloro-2-fluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4- c]pyrazol-5(1H)-carboxamide, N-(2-fluoro-6-(methoxy-d3)phenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6- dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-[2-chloro-6-(trifluoromethyl)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-fluoro-6-methoxy-3-methylphenyl)-6,6-dimethyl-3 -[1-(trimethylsylyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,6-difluoro-3-methylphenyl)-6 ,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-[2-(difluoromethoxy)-6 -fluorophenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2 -bromo-6-chlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N -(2-chloro-6-fluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide, N-(2-ethyl-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carboxamide, N-(2-bromo-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3, 4-c]pyrazol-5(1H)-carboxamide, N-(2-bromo-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrole [3,4-c]pyrazol-5(1H)-carboxamide, N-(2-chloro-5-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6- dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(6-fluoro-2,3-dihydrobenzofuran-7-yl)-6,6-dimethyl-3-[1- (trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-cyano-6-fluorophenyl)-6,6-dimethyl-3 -[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-chloro-6-cyclopropylphenyl)-6,6- dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-fluoro-3,6-dimethylphenyl) -6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(6-fluorobenzofuran-7 -yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2- chloro-3-fluoro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide, N-[2-(difluoromethoxy)-6-fluorophenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide, N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carboxamide, N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanoamido]-4,6-dihydropyrrolo[ 3,4-c]pyrazol-5(1H)-carboxamide, N-[2-(difluoromethoxy)-6-fluorophenyl]-6,6-dimethyl-3-[2-methyl-2 -(trimethylsilyl)propaneamido]- 4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,6-dichloro-4-fluorophenyl)-6,6-dimethyl-3-[1-( trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-ethyl-6-fluorophenyl)-6,6-dimethyl-3-[ 1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-bromo-6-methylphenyl)-6,6-dimethyl- 3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-chloro-5-methoxyphenyl)-6,6 -dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-ethyl-6-fluorophenyl)- 6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanoamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-bromo -6-methylphenyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propaneamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide , N-(6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propaneamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide, N-(6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4- c]pyrazol-5(1H)-carboxamide N,6,6-trimethyl-N-phenyl-3-[1-(trimethylsilyl)cyclobutanecarboxamide]-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide, N-(6-fluoro-3-methylbenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3 ,4-c]pyrazol-5(1H)-carboxamide, N-(2-chloro-6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4 ,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-[5-(indoline-1-carbonyl)-6,6-dimethyl-1,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide, N-[5-(3,4-dihydro-2H-benzo[b][1,4] oxazine-4-carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide, N-(6 -fluoro-2-methylbenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide, and N-[5-(1H-indol-1-carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl ]-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof. N-(2-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 6,6-Dimethyl-N-(o-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. N-(2-chloro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide or a pharmacologically acceptable salt thereof. N-(5-fluoro-2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide or a pharmacologically acceptable salt thereof. N-(2,5-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. N-(2-chloro-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide or a pharmacologically acceptable salt thereof. N-(2-bromo-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide or a pharmacologically acceptable salt thereof. N-(2-fluoro-3,6-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5( 1H)-carboxamide or a pharmacologically acceptable salt thereof. N-(6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide or a pharmacologically acceptable salt thereof. N-(2-chloro-6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide or a pharmacologically acceptable salt thereof. N-(6-fluoro-2-methylbenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide or a pharmacologically acceptable salt thereof.

[0023] A pharmaceutical composition comprising a compound or a pharmacologically acceptable salt thereof according to any one of [1] to [20].

[0024] The pharmaceutical composition according to [21], in which the pharmaceutical composition is a CDK7 inhibitor.

[0025] The pharmaceutical composition according to [21] or [22], in which the pharmaceutical composition is for the treatment or prevention of a cancer, an inflammatory disease, an allergic disease or a chronic respiratory disease.

[0026] The pharmaceutical composition according to [23], in which the cancer is a blood cancer or a solid cancer.

[0027] The pharmaceutical composition according to [24], in which the blood cancer is multiple myeloma, chronic myelogenous leukemia, blood tumor, hematological malignancy, childhood leukemia, childhood lymphoma, Hodgkin's disease, lymphocytic lymphoma, cutaneous lymphoma, acute leukemia, chronic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, plasma cell neoplasm, lymphoid neoplasm, or AIDS-related cancer.

[0028] The pharmaceutical composition according to [24], in which said solid cancer is bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, non-small cell lung, head and neck cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, uterine cervical cancer, thyroid cancer, prostate cancer, skin cancer including squamous cell carcinoma , fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, glioma and neurilemmoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer or Kaposi's sarcoma.

[0029] The pharmaceutical composition according to [23], in which the inflammatory disease is an autoimmune disease.

[0030] The pharmaceutical composition according to [27], in which the autoimmune disease is rheumatoid arthritis.

[0031] The pharmaceutical composition according to [27], in which the autoimmune disease is psoriasis.

[0032] The pharmaceutical composition according to [27], in which the autoimmune disease is multiple sclerosis.

[0033] The pharmaceutical composition according to [27], in which the autoimmune disease is inflammatory bowel disease.

[0034] The pharmaceutical composition according to [23], in which the chronic respiratory disease is chronic obstructive pulmonary disease.

[0035] The pharmaceutical composition according to [23], in which the allergic disease is atopic dermatitis.

[0036] [34]. The pharmaceutical composition according to any one of [21] to [33], in which the pharmaceutical composition is administered in combination with one or more additional drug(s) selected from the group consisting of anticancer agents, antirheumatic drugs, drugs for the treatment of psoriasis, drugs for the treatment of multiple sclerosis, drugs for the treatment of inflammatory bowel disease, drugs for the treatment of chronic obstructive pulmonary disease and drugs for the treatment of atopic dermatitis.

[0037] The pharmaceutical composition according to any one of [21] to [33], in which the pharmaceutical composition is administered at the same time with or at a different time from a composition comprising, as an active ingredient, one or more drug additional(s) selected from the group consisting of anticancer agents, antirheumatic agents, drugs for the treatment of psoriasis, drugs for the treatment of multiple sclerosis, drugs for the treatment of inflammatory bowel disease, drugs for the treatment of chronic obstructive pulmonary disease and drugs for the treatment of atopic dermatitis.

[0038] The pharmaceutical composition according to any one of [21] to [33], further comprising, as an active ingredient, one or more additional drug(s) selected from the group consisting of anticancer agents , antirheumatic agents, drugs for the treatment of psoriasis, drugs for the treatment of multiple sclerosis, drugs for the treatment of inflammatory bowel disease, drugs for the treatment of chronic obstructive pulmonary disease and drugs for the treatment of atopic dermatitis.

[0039] The pharmaceutical composition according to any one of [34] to [36], in which the additional drug is selected from the group consisting of tyrosine kinase inhibitors, immune system checkpoint inhibitors, DNA alkylating agents, inhibitors of DNA synthesis, platinum-containing drugs, antimetabolites, topoisomerase I inhibitors, topoisomerase II inhibitors, tubulin activator, hormone antagonists, aromatase inhibitors, differentiation inducers, proteasome inhibitors, phospholipid kinase inhibitors, adenosine inhibitors -deaminase, antiangiogenic agents, histone deacetylase (HDAC) inhibitors, BET bromodomain inhibitors, histone demethylase inhibitors, histone methyltransferase inhibitors, matrix metalloprotease inhibitors, farnesyltransferase inhibitors, bisphosphonate preparations, Hsp90 inhibitors, Eg5 kinesin inhibitors, serine-threonine kinase inhibitors, anticytokine agents, immunosuppressants, immunomodulators, active form of external agent analogous to Vitamin D3, S1P1 receptor antagonists, interferon preparations, anticholinergic drugs, leukotriene antagonists, PDE4 inhibitors , PGD2 receptor antagonists, neutrophil elastase inhibitors, antihistamine agents, classical non-steroidal anti-inflammatory drugs, cyclooxygenase inhibitors, nitric oxide-releasing non-steroidal anti-inflammatory drugs, gold preparations, penicillamine, preparations of aminosalicylic acid, antimalarial drugs, pyrimidine synthesis inhibitors, TNF inhibitors, interleukin inhibitors, interleukin receptor antagonists, interleukin drugs, inhibitors of B-cell activation, protein preparations related to co-stimulatory molecules, MAPK inhibitors, gene regulation drugs, cytokine production inhibitors, TNF-α converting enzyme inhibitors, interleukin-1β converting enzyme inhibitors, chemokine antagonists, therapeutic vaccine, gene therapy, antisense compounds, proteasome inhibitors, JAK inhibitors , T-cell inhibitors, inosine monophosphate dehydrogenase (IMPDH) inhibitors, adhesion molecule inhibitors, thalidomine, cathepsin inhibitors, glucose-6-phosphate dehydrogenase inhibitors, dihydroorotate dehydrogenase inhibitors ( DHODH), phospholipase A2 inhibitors, iNOS inhibitors, microtubule stimulants, anti-microtubule agents, MHC class II antagonists, CD4 antagonists, CD23 antagonists, leukotriene B4 receptor antagonists, 5-lipoxygenase inhibitors, inhibitors cathepsin B, westogenesis stimulants, dipeptidyl peptidase inhibitors, collagen agonists, capsaicin creams, sulfa-based drugs, hyaluronic acid derivatives, glucosamine sulfate, amiprilose, CD20 inhibitors, CD52 inhibitors, anti-asthmatic drugs, drugs for the treatment of atopic dermatitis, drugs for the treatment of allergic rhinitis, opioid receptor agonists, immunoglobulins, glatiramer acetate, T-cell receptor vaccine, adhesion molecule inhibitors, muscle relaxants, local anesthetics, local anesthetics, short-acting or long-acting muscarinic receptor antagonists, short-acting or long-acting β-receptor agonists, inhaled steroids, local steroids, drug combinations of β-receptor agonists and inhaled steroids, vitamin derivatives and adrenocortical steroids .

[0040] The pharmaceutical composition according to any one of [34] to [36], in which the additional drug is selected from the group consisting of cisplatin, doxorubicin, Taxotere, Taxol, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone , tamoxifen, 5-fluorouracil, fingolimod, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, gefitinib, erlotinib, panitumumab, afatinib, dasatinib, bosutinib, vandetanib, sunitinib, axitinib, anibe, lenvatinib, lapatinib , Nintendanib, Nilotinibe, Crizotinibe, Ceritinibe, Alectinib, Ibrutinib, Imatinib, Sorafenib, Vemurafenib, Dabrafenib, Trametinib, Palocyclibe, Interferon-2b, Citabirin, Adriamicin, Cytoxan, Genthabin, Uracil Mostard MELPHALANE, CLOORBUIL , pipobroman, triethylenemelamine, triethylenethiophosphoramine, ofatumumab, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, 6-mercaptopurine, 6-thioguanine, regorafenib, ramucirumab, fludarabine phosphate, oxaliplatin, folinate, pentostatin, vinblastine, vincristine, ina, bleomycin , dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drostanolone propionate, testolactone, megestrol acetate, methylprednisolone, testosterone , prednisolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, ansacrine, procarbazine, mitotane, mitoxantrone, Levamisole, Navelbine, anastrozole, letrozole, capecitabine, re loxafin, droloxifene , hexamethylmelamine, bevacizumab, omalizumab, mepolizumab, gemtuzumab ozogamicin, mogamulizumab, pertuzumab, ocrelizumab, alemtuzumab, inotuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, diarsenic trioxide, vinorelbine, porfimer sodium, thiotepa, trastuzumab, letrozole, fulvestrant, exemestane, rituximab , cetuximab, basiliximab, nivolumab, ipilimumab, pembrolizumab, durvalumab, atezolizumab, avelumab, alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen, tiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam, nabumetone, acetaminophen, phenacetin, mida, sulpirin , antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fembufen, pranoprofen, floctafenine, piroxicam, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate , ulinastatin, colchicine, probenecid, sulfimpyrazone, benzbromarone, allopurinol, brentuximab vedotin, sodium gold thiomalate, sodium hyaluronate, atropine, scopolamine, morphine or its salts, pethidine, levorphanol, oxymorphone, celecoxib, etoricoxib, valdecoxib, loxoprofen, auranofin , D-penicillamine, sulfasalazine, mesalazine, olsalazine, balsalazide, chloroquine, leflunomide, tacrolimus, infliximab, etanercept, adalimumab, Certolizumab pegol, golimumab, PASSTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti- -TNF-α, denosumab, anakinra, soluble interleukin-1 receptor antibodies, tocilizumab, anti-interleukin-6 antibodies, interleukin-10, ustekinumab, briakinumab, secukinumab (AIN-457), ixekizumab (LY-2439821), AMG827 , Rituxan, belimumab, abatacept, BMS-582949, inhibitors of molecules involved in signaling transduction, MAPK inhibitors, salicylic acid ointments, urea ointments, iguratimod, tectomilast, belnacasan, HMPL-004, IL-8 antagonists, antagonists CXCR1-CXCR2 duals, reparixin, CCR9 antagonists, denileukin diftitox, CCX025, N-{4-chloro-2-[(1-oxidopyridin-4-yl)carbonyl]phenyl}-4-(propan-2-yloxy) benzene sulfonamide, MCP-1 antagonists, irbesartan, TNF-α vaccines, ISIS-104838, natalizumab, vedolizumab, AJM300, TRK-170, E6007, MX-68, BMS-188667, CKD-461, rimexolone, cyclosporine A, mizoribine, gusperimo, sirolimus, temsirolimus, everolimus, antilymphocyte serum, freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factors, atiprimod dihydrochloride, azathioprine, interferon-α, interferon-β-1b, interferon-β-1a, tofacitinib , baricitinib, carfilzomib, ruxolitinib, dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone-acetonide, fluocinonide, fluocinolone-acetonide, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone propionate, estriol, mycophenolate mofetil, alicaforsen sodium, selectin inhibitors, ELAM-1 inhibitors, VCAM-1 inhibitors, ICAM-1 inhibitors, V-85546, roflumilast, apremilast, VAS203, rheumacon, zanolimumab, DW-1350, zileutone, Tyk2 inhibitors, Synvisc (hylan G-F 20), Orthovisc , atacicept, blisibimod, tizanidine, eperisone, afloqualone, baclofen, diazepam, dantrolene sodium, vitamin D3 derivatives, vitamin D2 derivatives, isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimethoquinol hydrochloride, tulobuterol, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropium bromide, flutropium bromide, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, anlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, Ozgrel hydrochloride, pranlucaste hydrate, seratrodaste, clerthishid, chlorpheniramine maleate, alimemazine tartarate, cleastin fumarate, homoclorclizine hydrochloride, fexofenadine, ketotiphene fumarate, cetirizine hydrochloride, oxatomide, ebstinine Pinastin, loratadine, tramadol, promise , hydroxyzine, homochlorcyclizine, cyproheptadine, mequitazine, emedastine fumarate, pseudoephedrine, bepotastine besylate, levocetirizine, olopatadine hydrochloride, mycophenolate mofetil, daclizumab, galiximab, metformin hydrochloride, visilizumab, aminopterin, Pazopanib hydrochloride, fezakinumab phosphate, of ruxolitinib , ixekizumab, guselkumab, SLx-2119, PRX-167700, lidocaine, tiotropium bromide, salmeterol salmeterol xinafoate, formoterol fumarate, fluticasone propionate, beclomethasone propionate, budesonide, and salmeterol combination drug salmeterol xinafoate and propionate fluticasone.

[0041] The pharmaceutical composition according to any one of [34] to [36], in which the additional drug is 5-fluorouracil.

[0042] The pharmaceutical composition according to any one of [34] to [36], in which the additional drug is oxaliplatin.

[0043] The pharmaceutical composition according to any one of [34] to [36], in which the additional drug is irinotecan.

[0044] A method for treating or preventing a cancer, an inflammatory disease, an allergic disease or a chronic respiratory disease, comprising administering a compound or a pharmacologically acceptable salt thereof according to any one of [1] to [20 ] to an individual who needs it.

[0045] The method according to [42], in which the cancer is a blood cancer or a solid cancer.

[0046] The method according to [43], in which the blood cancer is selected from the group consisting of multiple myeloma, chronic myeloid leukemia, blood tumor, hematological malignancy, childhood leukemia, childhood lymphoma, Hodgkin's disease, lymphocytic lymphoma , cutaneous lymphoma, acute leukemia, chronic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, plasma cell neoplasm, lymphoid neoplasm, and AIDS-related cancer.

[0047] The method according to [43], in which said solid cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, cell lung cancer small cell lung cancer, non-small cell lung cancer, head and neck cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, uterine cervical cancer, thyroid gland cancer, prostate cancer, skin cancer including squamous cell carcinoma, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, glioma and neurilemmoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer and Kaposi's sarcoma.

[0048] The method according to [42], in which the inflammatory disease is an autoimmune disease.

[0049] The method according to [46], in which the autoimmune disease is rheumatoid arthritis.

[0050] The method according to [46], in which the autoimmune disease is psoriasis.

[0051] The method according to [46], in which the autoimmune disease is multiple sclerosis.

[0052] The method according to [46], in which the autoimmune disease is inflammatory bowel disease.

[0053] The method according to [42], in which the chronic respiratory disease is chronic obstructive pulmonary disease.

[0054] The method according to [42], in which the allergic disease is atopic dermatitis.

[0055] The method according to any one of [42] to [52], in which the compound or pharmacologically acceptable salt thereof is administered in combination with one or more selected additional drug(s). of the group consisting of anticancer agents, antirheumatic agents, drugs for the treatment of psoriasis, drugs for the treatment of multiple sclerosis, drugs for the treatment of inflammatory bowel disease, drugs for the treatment of chronic obstructive pulmonary disease and drugs for the treatment of dermatitis atopic.

[0056] The method according to any one of [42] to [52], in which the compound or the pharmacologically acceptable salt thereof is administered at the same time with or at a different time from a composition containing, as an active ingredient , one or more additional drug(s) selected from the group consisting of anticancer agents, antirheumatic agents, drugs for the treatment of psoriasis, drugs for the treatment of multiple sclerosis, drugs for the treatment of inflammatory bowel disease, drugs for the treatment of chronic obstructive pulmonary disease and drugs for the treatment of atopic dermatitis.

[0057] The method according to any one of [42] to [52], in which the administration of the compound or the pharmacologically acceptable salt thereof is the administration of a composition containing, as active ingredients, the compound or the pharmacologically acceptable salt thereof. acceptable thereof and one or more additional drug(s) selected from the group consisting of anticancer agents, antirheumatic agents, drugs for the treatment of psoriasis, drugs for the treatment of multiple sclerosis, drugs for the treatment of intestinal inflammation, drugs for the treatment of chronic obstructive pulmonary disease and drugs for the treatment of atopic dermatitis.

[0058] The method according to any one of [53] to [55], in which the additional drug is selected from the group consisting of tyrosine kinase inhibitors, immune system checkpoint inhibitors, DNA alkylating agents, DNA synthesis, platinum-containing drugs, antimetabolites, topoisomerase I inhibitors, topoisomerase II inhibitors, tubulin activator, hormone antagonists, aromatase inhibitors, differentiation inducers, proteasome inhibitors, phospholipid kinase inhibitors, adenosine inhibitors deaminase, antiangiogenic agents, histone deacetylase (HDAC) inhibitors, BET bromodomain inhibitors, histone demethylase inhibitors, histone methyltransferase inhibitors, matrix metalloprotease inhibitors, farnesyltransferase inhibitors, bisphosphonate preparations, Hsp90 inhibitors, inhibitors of Eg5 kinesin, serine-threonine-kinase inhibitors, anticytokine agents, immunosuppressants, immunomodulators, active form of external agent analogous to Vitamin D3, S1P1 receptor antagonists, interferon preparations, anticholinergic drugs, leukotriene antagonists, PDE4 inhibitors, PGD2 receptor antagonists, neutrophil elastase inhibitors, antihistamine agents, classical non-steroidal anti-inflammatory drugs, cyclooxygenase inhibitors, nitric oxide-releasing non-steroidal anti-inflammatory drugs, gold drugs, penicillamine, acid preparations aminosalicylic, antimalarial drugs, pyrimidine synthesis inhibitors, TNF inhibitors, interleukin inhibitors, interleukin receptor antagonists, interleukin drugs, inhibitors of B-cell activation, preparations of proteins related to costimulatory molecules, MAPK inhibitors, drugs for gene regulation, cytokine production inhibitors, TNF-α converting enzyme inhibitors, interleukin-1β converting enzyme inhibitors, chemokine antagonists, therapeutic vaccine, gene therapy, antisense compounds, proteasome inhibitors, JAK inhibitors, T-cell inhibitors, inosine monophosphate dehydrogenase (IMPDH) inhibitors, adhesion molecule inhibitors, thalidomine, cathepsin inhibitors, glucose-6-phosphate dehydrogenase inhibitors, dihydroorotate dehydrogenase (DHODH) inhibitors ), phospholipase A2 inhibitors, iNOS inhibitors, microtubule stimulants, anti-microtubule agents, MHC class II antagonists, CD4 antagonists, CD23 antagonists, leukotriene B4 receptor antagonists, 5-lipoxygenase inhibitors, cathepsin B, westogenesis stimulants, dipeptidyl peptidase inhibitors, collagen agonists, capsaicin creams, sulfa-based drugs, hyaluronic acid derivatives, glucosamine sulfate, amiprilose, CD20 inhibitors, CD52 inhibitors, anti-asthmatic drugs, pharmaceuticals for the treatment of atopic dermatitis, drugs for the treatment of allergic rhinitis, opioid receptor agonists, immunoglobulins, glatiramer acetate, T-cell receptor vaccine, adhesion molecule inhibitors, muscle relaxants, local anesthetics, local anesthetics, antagonists of short-acting and long-acting muscarinic receptors, short-acting or long-acting β-receptor agonists, inhaled steroids, local steroids, drug combinations of β-receptor agonists and inhaled steroids, vitamin derivatives and adrenocortical steroids.

[0059] The method according to any one of [53] to [55], in which the additional drug is selected from the group consisting of cisplatin, doxorubicin, Taxotere, Taxol, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, fingolimod, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, gefitinib, erlotinib, panitumumab, afatinib, dasatinib, bosutinib, vandetanib, sunitinib, axitinib, , lenvatinib, lapatinib, nintedanib, nilotinib, crizotinib, ceritinib, alectinib, ibrutinib, imatinib, sorafenib, vemurafenib, dabrafenib, trametinib, palbociclib, interferon-alpha-2b, citabine, adriamycin, Cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, ofatumumab, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, 6-mercaptopurine, 6-thioguanine, regorafenib, ramucirumab, fludarabine phosphate, oxaliplatin, folinate, pentostatin, vinblastine, vincristine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drostanolone propionate, testolactone, megestrol acetate, methylprednisolone, sterone, prednisolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, ansacrine, procarbazine, mitotane, mitoxantrone, Levamisole, Navelbine, anastrozole, letrozole, capecitabine relo, xafin, droloxifene, hexamethylmelamine, bevacizumab, omalizumab, mepolizumab, gemtuzumab ozogamicin, mogamulizumab, pertuzumab, ocrelizumab, alemtuzumab, inotuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, diarsenic trioxide, vinorelbine, porfimer sodium, thiotepa, altretamine, trastuzumab, zol, fulvestrant, exemestane, rituximab, cetuximab, basiliximab, nivolumab, ipilimumab, pembrolizumab, durvalumab, atezolizumab, avelumab, alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen, tiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam, nabumetone, acetaminophen, phenacetin, , sulpirin, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fembufen, pranoprofen, floctafenine, piroxicam, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate, ulinastatin, colchicine, probenecid, sulfimpyrazone, benzbromarone, allopurinol, brentuximab vedotin, sodium gold thiomalate, sodium hyaluronate, atropine, scopolamine, morphine or its salts, pethidine, levorphanol, oxymorphone, celecoxib, etoricoxib, valdecoxib, loxoprofen, auranofin, D-penicillamine, sulfasalazine, mesalazine, olsalazine, balsalazide, chloroquine, leflunomide, tacrolimus, infliximab, etanercept, adalimumab, Certolizumab pegol, golimumab, PASSTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti- TNF-α, denosumab, anakinra, soluble interleukin-1 receptor antibodies, tocilizumab, anti-interleukin-6 antibodies, interleukin-10, ustekinumab, briakinumab, secukinumab (AIN-457), ixekizumab (LY-2439821), AMG827, Rituxan, belimumab, abatacept, BMS-582949, inhibitors of molecules involved in signaling transduction, MAPK inhibitors, salicylic acid ointments, urea ointments, iguratimod, tectomilast, belnacasan, HMPL-004, IL-8 antagonists, dual antagonists of CXCR1-CXCR2, reparixin, CCR9 antagonists, denileukin diftitox, CCX025, N-{4-chloro-2-[(1-oxidopyridin-4-yl)carbonyl]phenyl}-4-(propan-2-yloxy)benzene sulfonamide, MCP-1 antagonists, irbesartan, TNF-α vaccines, ISIS-104838, natalizumab, vedolizumab, AJM300, TRK-170, E6007, MX-68, BMS-188667, CKD-461, rimexolone, cyclosporine A, mizoribine , gusperimo, sirolimus, temsirolimus, everolimus, antilymphocyte serum, freeze-dried freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factors, atiprimod dihydrochloride, azathioprine, interferon-α, interferon-β-1b, interferon-β-1a , tofacitinib, baricitinib, carfilzomibe, ruxolitinib, dexamethasone, hexstrol, methimazole, betamethasone, triacinolone-acetonide, fluocynonide, fluorocinolone-acetonid of Mofetila, Alicaforsne Sodium, inhibitors of selectins, ELAM-1 inhibitors, VCAM-1 inhibitors, ICAM-1 inhibitors, V-85546, roflumilast, apremilast, VAS203, rheumacon, zanolimumab, DW-1350, zileutone, Tyk2 inhibitors, Synvisc (hylan G-F 20) , Orthovisc, atacicept, blisibimod, tizanidine, eperisone, afloqualone, baclofen, diazepam, dantrolene sodium, vitamin D3 derivatives, vitamin D2 derivatives, isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimethoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropium bromide, flutropium bromide, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, anlexanox, ibudilast, ketotifen, terfenadine, mequitazine, Azelastine, ozagrel hydrochloride, pranlucaste hydrate, seratrodasta, clerthonynide, chlorpheniramine maleate, alimemazine tartarate, clehtastine fumarate, homoclorclcyclizine, fexofenadine, ketotiphene fumarate, ketirizine hydrochloride, oxatomide, ebastin, ebastin, ebastinine Pinastin, loratadine, tramadol hydrochloride , promethazine, hydroxyzine, homochlorcyclizine, cyproheptadine, mequitazine, emedastine fumarate, pseudoephedrine, bepotastine besylate, levocetirizine, olopatadine hydrochloride, mycophenolate mofetil, daclizumab, galiximab, metformin hydrochloride, visilizumab, aminopterin, Pazopanib hydrochloride, umab, phosphate of ruxolitinib, ixekizumab, guselkumab, SLx-2119, PRX-167700, lidocaine, tiotropium bromide, salmeterol salmeterol xinafoate, formoterol fumarate, fluticasone propionate, beclomethasone propionate, budesonide, and combination drug combination of salmeterol xinafoate and salmeterol fluticasone propionate.

[0060] The method according to any one of [53] to [55], in which the additional drug is 5-fluorouracil.

[0061] The method according to any one of [53] to [55], in which the additional drug is oxaliplatin.

[0062] The method according to any one of [53] to [55], in which the additional drug is irinotecan.

[0063] Use of a compound or a pharmacologically acceptable salt thereof according to any one of [1] to [20] for the production of a pharmaceutical composition that is a CDK7 inhibitor.

[0064] Use of a compound or a pharmacologically acceptable salt thereof according to any one of [1] to [20] for the inhibition of CDK7.

[0065] Use of a compound or a pharmacologically acceptable salt thereof according to any one of [1] to [20] for the treatment or prevention of a cancer, an inflammatory disease, an allergic disease, or a chronic respiratory disease .

[0066] The use according to [63], in which the cancer is a blood cancer or a solid cancer.

[0067] The use according to [64], in which the blood cancer is selected from the group consisting of multiple myeloma, chronic myeloid leukemia, blood tumor, hematological malignancy, childhood leukemia, childhood lymphoma, Hodgkin's disease, lymphocytic lymphoma , cutaneous lymphoma, acute leukemia, chronic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, plasma cell neoplasm, lymphoid neoplasm, and AIDS-related cancer.

[0068] The use according to [64], in which said solid cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, cell lung cancer small cell lung cancer, non-small cell lung cancer, head and neck cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, uterine cervical cancer, thyroid cancer, prostate cancer, skin cancer including squamous cell carcinoma, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, glioma and neurilemmoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer and Kaposi's sarcoma.

[0069] The use according to [63], in which the inflammatory disease is an autoimmune disease.

[0070] The use according to [67], in which the autoimmune disease is rheumatoid arthritis.

[0071] The use according to [67], in which the autoimmune disease is psoriasis.

[0072] The use according to [67], in which the autoimmune disease is multiple sclerosis.

[0073] The use according to [67], in which the autoimmune disease is inflammatory bowel disease.

[0074] The use according to [63], in which the chronic respiratory disease is chronic obstructive pulmonary disease.

[0075] The use according to [63], in which the allergic disease is atopic dermatitis.

[0076] The compound or a pharmacologically acceptable salt thereof according to any one of [1] to [20] for use as an active ingredient in a pharmaceutical composition.

[0077] The compound or a pharmacologically acceptable salt thereof according to [74], wherein the pharmaceutical composition is a pharmaceutical composition for the treatment of a cancer, an inflammatory disease, an allergic disease or a chronic respiratory disease.

[0078] The compound or a pharmacologically acceptable salt thereof according to [75], in which the cancer is a blood cancer or a solid cancer.

[0079] The compound or a pharmacologically acceptable salt thereof according to [75], in which the blood cancer is selected from the group consisting of multiple myeloma, chronic myeloid leukemia, blood tumor, hematological malignancy, childhood leukemia, childhood lymphoma , Hodgkin's disease, lymphocytic lymphoma, cutaneous lymphoma, acute leukemia, chronic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, plasma cell neoplasm, lymphoid neoplasm, and AIDS-related cancer.

[0080] The compound or a pharmacologically acceptable salt thereof according to [75], in which said solid cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, cancer lung cancer, small cell lung cancer, non-small cell lung cancer, head and neck cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, uterine cervical cancer, thyroid cancer, cancer prostate, skin cancer including squamous cell carcinoma, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, glioma and neurilemmoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer and Kaposi's sarcoma.

[0081] The compound or a pharmacologically acceptable salt thereof according to [75], in which the inflammatory disease is an autoimmune disease.

[0082] The compound or a pharmacologically acceptable salt thereof according to [79], in which the autoimmune disease is rheumatoid arthritis.

[0083] The compound or a pharmacologically acceptable salt thereof according to [79], in which the autoimmune disease is psoriasis.

[0084] The compound or a pharmacologically acceptable salt thereof according to [79], in which the autoimmune disease is multiple sclerosis.

[0085] The compound or a pharmacologically acceptable salt thereof according to [79], in which the autoimmune disease is inflammatory bowel disease.

[0086] The compound or a pharmacologically acceptable salt thereof according to [75], in which the chronic respiratory disease is chronic obstructive pulmonary disease.

[0087] The compound or a pharmacologically acceptable salt thereof according to [75], in which the allergic disease is atopic dermatitis.

[0088] Specific examples of the compound represented by general formula (I) of the present invention may include the compounds as shown in Tables 1 to 49 below. In Tables 1 to 49 below, D represents deuterium, Br represents a bromine atom, Cl represents a chlorine atom, F represents a fluorine atom, Me represents a methyl group, Et represents an ethyl group, nPr represents an n- propyl, iPr represents an isopropyl group, cPr represents a cyclopropyl group, tBu represents a tert-butyl group, Ph represents a phenyl group, and MeO represents a methoxy group; -benzofuran-7-yl represents -benzofuran-7-yl; -dihydrobenzofuran-7-yl represents -dihydrobenzofuran-7-yl; pyridin-2-yl represents pyridin-2-yl; pyridin-3-yl represents pyridin-3-yl; -isothiazol-4-yl represents -isothiazol-4-yl; isoxazol-4-yl represents isoxazol-4-yl; thiophen-2-yl represents thiophen-2-yl; -benzofuran-7-yl represents -benzofuran-7-yl. As specific examples, "CF3" represents a trifluoromethyl group, "CHF2O" represents a trifluoromethoxy group, "CD3" represents a group in which three hydrogen atoms constituting the methyl group are replaced by deuterium atoms, "1,1-diF -Et" means a group in which the ethyl group is substituted in position 1 with two fluorine atoms, that is, a 1,1,-difluoroethia group, "2,6-diF-Ph" means a group in which the phenyl is substituted at positions 2 and 6 with fluorine atoms respectively, i.e. a 2,6-difluorophenyl group, "2,4-diCl-6-Me-Ph" means a group in which the phenyl group is substituted at the positions 2 and 4 with chlorine atoms, respectively, and substituted in position 6 with a methyl group, that is, a 2,4-dichloro-6-methylphenyl group, and "CH2CH2CH2CH2" means a 1,4-butylene group formed by binding of two R moieties to each other.

ADVANTAGEOUS EFFECTS OF THE INVENTION

[0089] A substituted dihydropyrrolopyrazole compound represented by general formula (Ia) or a pharmacologically acceptable salt thereof has excellent CDK7 inhibitory activity, high selectivity for a kinase inhibitory effect, excellent safety, and excellent pharmacokinetic properties. Thus, the compound represented by general formula (Ia) or the pharmacologically acceptable salt thereof is useful as a medicine, particularly, a therapeutic drug and/or a prophylactic drug for a cancer, an inflammatory disease, an allergic disease or a chronic respiratory.

DESCRIPTION OF MODALITIES

[0090] An embodiment of the present invention will be described below. In the present specification, each "compound" represented by the general formula (Ia)", etc. is also called "compound (Ia)", etc. for the sake of convenience. Various substituents defined and illustrated below may be arbitrarily selected and combined In the present specification, the "substituted dihydropyrrolopyrazole compound" is also called a "substituted dihydropyrrolopyrazole derivative".

[0091] The embodiment of the present invention is a compound represented by general formula (Ia) or a pharmaceutically acceptable salt thereof. [Chemical Formula 9] In the general formula (Ia),

[0092] two R moieties each independently represent a C1-3 alkyl group or represent groups linked together to form a C2-5 alkylene group;

[0093] A represents an optionally substituted C6-10 aryl group or an optionally substituted heteroaryl group, and Z represents a hydrogen atom or an optionally substituted C1-6 alkyl group, or a group represented by Z-N-A forms a bicyclic heterocyclic group condensed upon the link between A and Z, optionally substituted; It is

[0094] R1, R2 and R3 each independently represent an optionally substituted linear or branched C1-4 alkyl group.

[0095] In the present specification, the term "optionally substituted" means that the group may be unsubstituted or may be additionally substituted with a substituent.

[0096] The substituent means a monovalent group, and its examples include linear or branched C1-6 alkyl groups, C3-6 cycloalkyl groups, linear or branched C2-6 alkenyl groups, C3-6 cycloalkenyl groups, linear C2-6 alkynyl groups or branched, C1-6 alkoxy group, halogen atoms, a hydroxyl group, a cyano group, an oxo group (=O), an amino group, C1-6 alkyl-amino groups, a nitro group, a carboxyl group (-COOH ), a carbamoyl group (-CONH2), N-mono-C1-6-alkyl-carbamoyl groups, N,N-di-C1-6-alkyl-carbamoyl groups (two alkyl groups can be different), C1-6 alkanoyloxyl groups (-OCOR4 ; R4 is a C1-3 alkyl group), C6-10 aryl groups, and heterocyclic groups. The substituent may be additionally substituted with a halogen atom, a hydroxyl group, an amino group, a cyano group, an oxo group (=O), a linear or branched C1-6 alkyl group, a C1-6 alkoxy group, a C6-10 aryl group, a heterocyclic group, or the like. In the case in which the substituent is an amino group or a carboxyl group, the form may be a salt thereof.

[0097] In the case in which the group to which reference is made has two or more substituents, the two substituents may be linked to each other to form a cyclic structure. Examples of the case in which two substituents are attached to each other to form a cyclic structure include a cyclopropyl group, a methylenedioxyl group, and an oxyethylene group. Specifically, in the case in which a methylenedioxyl group is attached to a benzene ring, the substituent becomes a 1,3-benzodioxol group; in the case in which an oxyethylene group is attached to a benzene ring, the substituent becomes a 2,3-dihydrobenzofuranyl group.

[0098] The linear or branched C1-6 alkyl group described in the present specification means a linear or branched alkyl group having from 1 to 6 carbon atoms. Examples of linear or branched C1-6 alkyl groups include C1-6 alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1-ethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 1,1-dimethylbutyl group, a 2-group ,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, and a 2,3-dimethylbutyl group. The substituent is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.

[0099] Examples of a C1-6 alkyl group substituted with a halogen atom include a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a diiodomethyl group, a a trifluoromethyl group, a trichloromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a 2,2-dichloroethyl group, a 2,2,2-trichloroethyl group, a 1-fluoropropyl group, a 2-fluoropropyl group, a 3-fluoropropyl group, a 3,3,3-trifluoropropyl group, a perfluoropropyl group, a 1-fluoromethylethyl group, a 1-difluoromethylethyl group, a 1-trifluoromethylethyl group, a 1-fluoro-1-methylethyl group, a 4-fluorobutyl group, a perfluorobutyl group, a 5-fluoropentyl group, a perfluoropentyl, a 6-fluorohexyl group, a perfluorohexyl group and a perfluorohexyl group.

[00100] A C1-6 alkyl group substituted with an aryl group can be, for example, a C7-11 aralkyl group. The C7-11 aralkyl group means an alkyl group having an aryl group and having a total of 7 to 11 carbon atoms, and examples thereof include a benzyl group, a phenylethyl group, and a naphthylmethyl group.

[00101] The C3-6 cycloalkyl group described in this specification means a cyclic alkyl group having 3 to 6 carbon atoms. Examples of the C3-6 cycloalkyl group include: monocyclic rings such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group; rings condensed as a bicyclo[3.1.0]hexyl group; and spiro rings as a spiro[2.3]hexyl group. The substituent is preferably a cyclopropyl group or a cyclobutyl group.

[00102] The linear or branched C2-6 alkenyl group described in the present specification means a linear or branched alkenyl group having from 2 to 6 carbon atoms. Examples of the linear or branched C2-6 alkenyl group include alkenyl groups such as a vinyl group, a propen-1-yl group, a propen-2-yl group, a 1-butenyl group, a 2-butenyl group, a 3- butenyl, a 1-methyl-1-propenyl group, a 2-methyl-1-propenyl group, a 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 5- pentenyl, a 1-methyl-1-butenyl group, a 2-methyl-1-butenyl group, a 3-methyl-1-butenyl group, a 4-methyl-1-butenyl group, a 1-methyl-2- butenyl, a 2-methyl-2-butenyl group, a 3-methyl-2-butenyl group, a 4-methyl-2-butenyl group, a 1-methyl-3-butenyl group, a 2-methyl-3- butenyl group, a 3-methyl-3-butenyl group, a 4-methyl-3-butenyl group, a 1,2-dimethyl-1-propenyl group, a 1-hexenyl group, a 2-hexenyl group, a 3- hexenyl, a 4-hexenyl group, a 5-hexenyl group, a 6-hexenyl group, and their structural isomers.

[00103] The C3-6 cycloalkenyl group described in this specification means a cycloalkenyl group having 3 to 6 carbon atoms. Examples of the C3-6 cycloalkenyl group include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.

[00104] The C2-6 alkynyl group described in this specification means an alkynyl group having 2 to 6 carbon atoms. Examples of the C2-6 alkynyl group include an ethynyl group, a propargyl group, a butynyl group, a pentynyl group, and a hexinyl group.

[00105] The C1-6 alkoxy group described in the present specification means a group consisting of an oxyl group (-O-) and a linear or branched C1-6 alkyl group or a C3-6 cycloalkyl group linked to the oxyl group. Examples of the C1-6 alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a cyclopropyloxy group, a butoxy group, a cyclobutyloxy group, a pentyloxy group, a cyclopentyloxy group, a hexyloxy group, and a cyclohexyloxy group.

[00106] The C1-6-alkyl-amino group described in the present specification means an amino group substituted with one or two of the aforementioned linear or branched C1-6 alkyl groups or with one or two of the aforementioned C3-6 cycloalkyl groups. Examples of the C1-6 alkylamino group include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a cyclopropylamino group, a butylamino group, a cyclobutylamino group, a pentylamino group, a cyclopentylamino group, a hexylamino group, a cyclohexylamino group, a dimethylamino group, a diethylamino group, an ethyl(methyl)amino group, an isopropyl(methyl)amino group, and a cyclopropyl(methyl)amino group.

[00107] The halogen atom described in this specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[00108] The C6-10 aryl group described in this specification means an aryl group having 6 to 10 carbon atoms. Examples of the C6-10 aryl group include a phenyl group and a naphthyl group.

[00109] The heterocyclic group described in the present specification means a cyclic group having at least one nitrogen atom, one oxygen atom, or one sulfur atom and may be an aromatic heterocyclic group or may be a non-aromatic heterocyclic group. Examples of the aromatic heterocyclic group are a pyridine group, a pyrimidine group, a pyridazine group, a pyrazine group, a triazine group, a pyrrole group, an imidazole group, a pyrazole group, an indole group, an indazole group, a furan group, a benzofuran group, a thiophene group, a benzothiophene group, a thiazole group, an isothiazole group, an oxazole group, an isoxazole group, and an oxadiazole group. Examples of the non-aromatic heterocyclic group include a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, and a thiomorpholinyl group.

[00110] The C2-5 alkylene group formed by the two R moieties linked to each other means a divalent group obtained by the additional removal of a hydrogen atom from a C2-5 alkyl group that corresponds to one having 2 to 5 carbon atoms among the C1-6 alkyl groups described above. Examples of the C2-5 alkylene group include a 1,2-ethylene group, a 1,2-propylene group, a 1,3-propylene group, a 1,2-butylene group, a 1,3-butylene group, a 1,4-butylene group, a 2,3-butylene group, a 1,2-pentylene group, a 1,3-pentylene group, a 1,4-pentylene group, a 1,5-pentylene group, a 2 group, 3-pentylene, and a 2,4-pentylene group.

[00111] The linear or branched C1-4 alkyl group such as R1, R2 or R3 is a linear or branched alkyl group having 1 to 4 carbon atoms and corresponds to one having 1 to 4 carbon atoms among the C1 alkyl groups -6 described above.

[00112] The C1-3 alkyl group such as R4 is an alkyl group having 1 to 3 carbon atoms and corresponds to one having 1 to 3 carbon atoms among the C1-6 alkyl groups described above. Examples of the C1-3 alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group.

[00113] The heteroaryl group such as A corresponds to an aromatic heterocyclic group among the heterocyclic groups described above.

[00114] The compound according to the present embodiment may be a compound represented by any chemical formula of general formula (I), general formula (IIa), general formula (IIIa), or general formula (IVa) or may be a compound represented by any chemical formula of general formula (II), general formula (III), or general formula (IV). [Chemical Formula 10] [Chemical Formula 11] [Chemical Formula 12]

[00115] In the general formula (I), in the general formula (IIa), in the general formula (IIIa), in the general formula (IVa), in the general formula (II), in the general formula (III), and in the general formula ( IV), R1, R2, R3, A, and Z are as defined in general formula (Ia).

[00116] In general formula (Ia) and general formula (I), two R moieties may each independently be a C1-3 alkyl group or may be groups bonded together to form a C2-5 alkylene group .

[00117] In the general formula (I), in the general formula (IIa), in the general formula (IIIa), in the general formula (IVa), in the general formula (II), in the general formula (III), and in the general formula ( IV), R1, R2 and R3 may each independently be an optionally substituted linear or branched C1-4 alkyl group.

[00118] In the general formula (I), in the general formula (IIa), in the general formula (IIIa), in the general formula (IVa), in the general formula (II), in the general formula (III), and in the general formula ( IV), A may be an optionally substituted C6-10 aryl group or an optionally substituted heteroaryl group.

[00119] Compound (Ia) is preferably a compound selected from the following group of compounds: 6,6-dimethyl-N-phenyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3, 4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-1) 6,6-dimethyl-N-(p-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6- dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-25) N-(4-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido ]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-79) N-(4-fluorophenyl)-6,6-dimethyl-3-[1 -(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-7) 6,6-dimethyl-N-(pyridin-3 -yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-1019) N-(2 -fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV- 3) 6,6-dimethyl-N-(o-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-21) 6,6-dimethyl-N-(m-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide (Compound No. IV-23) N-([1,1'-biphenyl]-3-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4 ,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-71) N-(3-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl )cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-5) N-(3-chlorophenyl)-6,6-dimethyl-3 -[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-11) N-(2-methoxyphenyl)-6 ,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanocarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-75) N-( 2-chlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV -9) N-([1,1'-biphenyl]-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4- c]pyrazol-5(1H)-carboxamide (Compound No. IV-69) 6,6-dimethyl-N-(pyridin-2-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6- dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-1007) N-(2-ethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido ]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-27) N-(2,6-dimethylphenyl)-6,6-dimethyl-3- [1-(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-381) N-(2,3-difluorophenyl)- 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-99) N- (2,3-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-375) N-(2-fluoro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c] pyrazol-5(1H)-carboxamide (Compound No. IV-129) N-[2-(difluoromethoxy)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-di -hydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-87) N-(2-ethoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido] -4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-81) 6,6-dimethyl-N-(2-(trifluoromethoxy)phenyl)-3- [1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-93) N-(2-fluoro-4-methylphenyl )-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-125) N-(2,6-difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-105) N-[2-(tert-butyl)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4 -c]pyrazol-5(1H)-carboxamide (Compound No. IV-57) 6,6-dimethyl-N-(2-(trifluoromethyl)phenyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4, 6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-51) N-(3-fluoro-2-methylphenyl)-6,6-dimethyl-3-[1 -(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-357) N-(2-cyanophenyl)-6,6- dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-63) N-(4-fluoro -2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound no. IV-359) N-(2-chloro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide (Compound No. IV-215) N-(2-fluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-di- hydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-123) N-(2-fluoro-5-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-127) N-(5-fluoro-2-methylphenyl)-6,6- dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-361) N-(2,4 -difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV- 101) N-(2,5-difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide (Compound No. IV-103) N-(2,5-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4- c]pyrazol-5(1H)-carboxamide (Compound No. IV-379) N-(2-chloro-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4, 6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-113) N-(2,4-dimethylphenyl)-6,6-dimethyl-3-[1-( trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-377) 3-[1-(ethyldimethylsilyl)cyclobutanecarboxamido]-N-( 2-fluorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-4) 6,6-dimethyl-N- (3-methylisothiazol-4-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV- 1035) 6,6-dimethyl-N-(thiophen-2-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-2,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide (Compound No. IV-1043) 6,6-dimethyl-N-(thiophen-3-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-2,6-dihydropyrrolo[3,4- c]pyrazol-5(1H)-carboxamide (Compound No. IV-1045) N-(2,6-difluoro-4-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]-4 ,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-615) N-(2-fluoro-6-methoxyphenyl)-6,6-dimethyl-3- [1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-161) N-[2-fluoro-6-( trifluoromethyl)phenyl]-6,6-dimethyl-3-[1-(trimethylsylyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound no. IV-153) N-(5-chloro-2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide (Compound No. IV-367) N-(2,5-dichlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[ 3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-197) N-(2-cyclopropylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4, 6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-39) N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[1-( trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-199) 6,6-dimethyl-N-(2,4,6 -trifluorophenyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-599) N-(2 -ethyl-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-389) N-(2-bromophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5( 1H)-carboxamide (Compound No. IV-15) N-(2-chloro-5-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[ 3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-191) N-(5-chloro-2-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido ]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-111) 6,6-dimethyl-N-(2,3,6-trifluorophenyl)- 3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-597) N-(2-chloro-6 -methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV- 247) N-[2-(1,1-difluoroethyl)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide (Compound No. IV-45) N-(6-chloro-2-fluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4 ,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-629) N-[2-fluoro-6-(methoxy-d3)phenyl]-6,6 -dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-177) N-[2- chloro-6-(trifluoromethyl)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxa amide (Compound No. IV-239) N-(2-fluoro-6-methoxy-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsylyl)cyclobutanecarboxamido]-4,6-dihydropyrrole [3,4-c]pyrazol-5(1H)-carbox amide (Compound No. IV-689) N-(2,6-difluoro-3-methylphenyl)-6,6-dimethyl-3-[1-( trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-609) N-[2-(difluoromethoxy)-6-fluorophenyl]- 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-169) N -(2-bromo-6-chlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-207) N-(2-chloro-6-fluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrole [3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-703) N-(2-ethyl-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-137) N-(2-bromo-6-fluorophenyl)-6,6- dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-121) N-(2-bromo -6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound no. IV-299) N-(2-chloro-5-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide (Compound No. IV-213) N-(6-fluoro-2,3-dihydrobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido ]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-997) N-(2-cyano-6-fluorophenyl)-6,6-dimethyl -3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-185) N-(2-chloro- 6-cyclopropylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV -231) N-(2-fluoro-3,6-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide (Compound No. IV-669) N-(6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-di -hydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-1049) N-(2-chloro-3-fluoro-6-methylphenyl)-6,6-dimethyl-3-[ 1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-747) N-[2-(difluoromethoxy)-6 -fluorophenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. III -169) N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. III-199) N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanoamido]-4,6-dihydropyrrole [3,4-c]pyrazol-5(1H)-carboxamide (Compound No. II-199) N-[2-(difluoromethoxy)-6-fluorophenyl]-6,6-dimethyl-3-[2-methyl- 2-(trimethylsilyl)propaneamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carbox amide (Compound No. II-164) N-(2,6-dichloro-4- fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-709 ) N-(2-ethyl-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. III-137) N-(2-bromo-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3 ,4-c]pyrazol-5(1H)-carboxamide (Compound No. III-299) N-(2-chloro-5-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido] -4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-245) N-(2-ethyl-6-fluorophenyl)-6,6-dimethyl-3 -[2-methyl-2-(trimethylsilyl)propanoamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. II-137) N-(2-bromo -6-methylphenyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propaneamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. II-290) N-(6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propaneamido]-4,6-dihydropyrrolo[ 3,4-c]pyrazol-5(1H)-carboxamide (Compound No. II-1049) N-(6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido ]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. III-1049) N,6,6-trimethyl-N-phenyl-3-[1-( trimethylsilyl)cyclobutanecarboxamide]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. I-965) N-(6-fluoro-3-methylbenzofuran-7-yl )-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-1061 ) N-(2-chloro-6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide (Compound No. IV-1063) N-[5-(indoline-1-carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3, 4-c]pyrazol-3-yl]-1 -(trimethylsilyl)cyclobutanecarboxamide (Compound No. I-1000) N-[5-(3,4-dihydro-2H-benzo[b][1,4] oxazine-4-carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. I -1036) N-(6-fluoro-2-methylbenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carboxamide (Compound No. IV-1059) N-[5-(1H-indol-1-carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrh olo[3,4-c]pyrazol-3-yl]-1 -(trimethylsilyl)cyclobutanecarboxamide (Compound No. I-997)

[00120] The compound (Ia) or the pharmacologically acceptable salt thereof may be an individual optical isomer or may be a mixture of a plurality of optical isomers.

[00121] In the case in which geometric isomers or rotational isomers are present in the compound (Ia), these isomers are also included in the present invention. In the case in which tautomers are present in the compound according to the present embodiment, these tautomers are also included in the present invention.

[00122] The "pharmacologically acceptable salt" according to the present embodiment is not particularly limited as long as it is a salt acceptable as a pharmaceutical, and examples thereof include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; salts with organic carboxylic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, lactic acid, and trifluoroacetic acid; salts such as organic sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid; salts with alkali metals such as lithium, sodium, and potassium; salts such as alkaline earth metals such as calcium and magnesium; and quaternary ammonium salts such as ammonia, morpholine, glucosamine, ethylenediamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, diethanolamine, and piperazine.

[00123] Compound (Ia) or the pharmacologically acceptable salt thereof can form a hydrate or a solvate, and each or a mixture thereof is included in the present invention.

[00124] The compound (Ia) may contain an unnatural ratio of an atomic isotope of one or more of the atoms that constitute the compound. Examples of the atomic isotope include deuterium (2H), tritium (3H), carbon-11 11 14 18 35 125 (C), carbon-14 (C), fluorine-18 (F), sulfur-35 (S), and iodine -125 (I). These compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo diagnostic imaging agents. All isotopic variants of compound (Ia) are included in the present invention, regardless of whether they are radioactive.

[00125] The compound (Ia) or the pharmacologically acceptable salt thereof can be used as a pharmaceutical composition, if necessary, by adding a pharmacologically acceptable carrier such as an excipient, a lubricant, a binder, a disintegrant, a coating agent , a stabilizer, a tonicity agent, a buffering agent, a pH adjusting agent, a solubilizing agent, a thickener, a preservative, an antioxidant, a sweetener, a coloring, and/or a flavoring. The pharmaceutical composition may be suitably prepared according to a purpose by a method well known to those skilled in the art.

[00126] In the pharmaceutical composition, the content of compound (Ia) or the pharmacologically acceptable salt thereof can be appropriately adjusted.

[00127] The pharmaceutical composition may be in a dosage form described in the General Rules for Preparations, of the Japanese Pharmacopoeia, 16th edition, for example, a preparation for oral administration such as tablets, capsules, granules or powders, or a preparation for parenteral administration such as injections (e.g. intravenous administration, subcutaneous administration, intramuscular administration, and intraperitoneal administration), eye drops, nasal drops, suppositories, ointments, lotions, creams, gels, sprays, plasters, inhalants or preparations for percutaneous absorption.

[00128] Examples of the excipient include lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, and calcium hydrogen phosphate, and examples of the lubricant include stearic acid, magnesium stearate, and talc. Examples of the binder include starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone, and examples of the disintegrant include carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, and calcium citrate. Examples of the coating agent include hydroxypropylmethylcellulose, macrogol, and silicone resins, and examples of the stabilizer include ethyl p-hydroxybenzoate and benzyl alcohol.

[00129] Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, and mannitol, examples of the buffering agent include boric acid, salts of boric acid, phosphoric acid, salts of phosphoric acid, citric acid , salts of citric acid, acetic acid, salts of acetic acid, ε-aminocaproic acid, and trometamol, and examples of the pH-adjusting agent include hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, sodium hydroxide, potassium, sodium carbonate, and sodium bicarbonate. Examples of the solubilizing agent include polysorbate 80, hydrogenated polyoxyethylenated castor oil 60, macrogol 4000, purified soy lecithin, and polyoxyethylene(160)polyoxypropylene(30)glycol, and examples of the thickener include cellulose polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, poly(alcohol vinyl), and polyvinylpyrrolidone. Examples of the stabilizer include edetic acid and sodium edetate, and examples of the preservative include sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and chlorobutanol.

[00130] Examples of ingredients that may be contained in pharmaceutical compositions for percutaneous administration such as ointments, lotions, creams, gels, and sprays include: absorption promoters such as lauryl alcohol, myristyl alcohol, ethylene glycol-salicylic acid, and pyrrothiodecane; fatty acid esters such as diisopropyl adipate, isopropyl myristate, cetyl lactate, myristyl lactate, isopropyl palmitate, diethyl sebacate, hexyl laurate, and cetyl isooctanoate; aliphatic alcohols such as cetyl alcohol, stearyl alcohol, oleyl alcohol, hexadecyl alcohol, and behenyl alcohol; glycols such as propylene glycol, propylenediol, poly(ethylene glycol) and dipropylene glycol; and surfactants such as sorbitan-fatty acid ester, glycerin-fatty acid ester, polyoxyethylene-sorbitan-fatty acid ester, polyoxyethylene-glycerin-fatty acid ester, poly(ethylene glycol)-fatty acid ester, polyoxyethylene-alkyl ether , polyoxyethylenated castor oil, and hydrogenated polyoxyethylenated castor oil.

[00131] The dose of the compound (Ia) or the pharmacologically acceptable salt thereof can be appropriately varied according to symptoms, age, dosage form, etc. In the case of, for example, oral administration, it can usually be administered in one portion or several divided portions of 0.01 to 2000 mg, preferably 1 to 500 mg per day.

[00132] In relation to ointments, lotions, creams, or gels, a dose having a concentration of 0.0001% (w/v) to 10% (w/v), preferably 0.01% (w/v ) at 5% (w/v) can usually be administered in one portion or in several divided portions.

[00133] Next, a method for producing compound (Ia) or its pharmacologically acceptable salt will be described. The compound or pharmacologically acceptable salt thereof according to the present invention is not limited to the compounds or pharmacologically acceptable salts thereof produced by the production methods described below.

[00134] In the production methods provided below, in the case in which partial structures that inhibit the desired reactions or produce side reactions (for example, a hydroxyl group, an amino group, a carboxyl group, an amide group, a thiol group and the like ) are present in the compounds, the compounds of interest can be obtained by introducing protecting groups into these partial structures, carrying out the desired reactions, and then removing the protecting groups.

[00135] The introduction reaction and the removal reaction of a protecting group can be carried out according to a method routinely used in organic synthetic chemistry (for example, a method described in, for example, "Protective Groups in Organic Synthesis" , 4th ed., T.W. Greene, P.G.M. Wuts, John Wiley & Sons Inc. (2006)).

[00136] Hereinafter, a method for producing compound (Ia) or compound (I) by using compound (1) as a starting material will be described as a method for producing compound (Ia) or compound ( I). A method for producing compound (1) will be described later.<Method of producing compound (Ia)>

[00137] This method is a method for producing compound (Ia) by reacting compound (2) obtained by reacting compound (1) with an acylating agent, with amino compound (3a). In this method, R, R1, R2, R3, A, and Z are as defined in general formula (Ia). The P1 group is a protecting group for the amino group, and X is a leaving group. Although this method is described by presenting the chemical structure of the compound (1) in which the 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton is substituted in position 1 with the P1 group for convenience, the compound (1) may be a compound having a chemical structure corresponding to a tautomer in which the 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton is substituted at position 2 with the P1 group.[Chemical Formula 13]

[00138] The P1 group is not particularly limited as long as it is a substituent known, by those skilled in the art, as a protecting group for the amino group. Examples of the P1 group include: optionally substituted C7-11 aralkyl groups such as a benzyl group, a p-methoxyphenylmethyl group, and an o-nitrophenylmethyl group; optionally substituted C1-6alkylcarbonyl groups such as an acetyl group and a trifluoroacetyl group; arylC6-10-carbonyl groups optionally substituted as a benzoyl group; C1-6-alkoxycarbonyl groups optionally substituted as a methoxycarbonyl group, an ethoxycarbonyl group, a Boc group (tert-butoxycarbonyl group), a Cbz group (benzyloxycarbonyl group), an Fmoc group (fluorenylmethyloxycarbonyl group), and a Teoc group (trimethylsilylethyloxycarbonyl group ); alkenyloxycarbonyl groups such as an Alloc group (allyloxycarbonyl group); alkylsulfonyl groups such as a methanesulfonyl group; and arylC6-10-sulfonyl groups optionally substituted as a p-toluenesulfonyl group.

[00139] Group X is not particularly limited as long as it is a substituent known, by those skilled in the art, as a leaving group. Examples of X include: halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; an imidazolyl group; amino-oxyl groups such as a succinyl-N-oxyl group and a benzotriazolyl-N-oxyl group; C 1-6 alkylcarbonyloxy groups optionally substituted as a pivaloyloxy group; and arylC6-10-carbonyloxy groups optionally substituted as a benzoyloxy group. Alternatively, X may be a hydroxyl group. (Step 1)

[00140] Step 1 is the step of reacting the compound (1) with an acylating agent to obtain the compound (2).

[00141] As the acylating agent, for example, phosgene, diphosgene, triphosgene, carbonyldiimidazole (CDI), N,N'-disuccinimidyl carbonate, or carbonic acid ester can be used.

[00142] The amount of acylating agent used is preferably 0.4 to 3.0 mol, more preferably 0.7 to 1.5 mol, with respect to 1 mol of compound (1).

[00143] The reaction of step 1 can be carried out in a solvent or can be carried out without a solvent. The solvent is not limited as long as the solvent has no influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include dichloromethane, 1,2-dichloroethane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

[00144] In step 1, a base can be added for the purpose of accelerating the reaction. Examples of the base include organic amines such as triethylamine (TEA), diisopropylethylamine (DIPEA), 1,5-diazabicyclo[4.3.0]nonene (DBN), 1,8-diazabicyclo[5.4.0]undecene (DBU), pyridine , and 4-dimethylaminopyridine (DMAP).

[00145] The amount of base added is preferably 1 to 10 mol, more preferably 3 to 6 mol, with respect to 1 mol of compound (1).

[00146] The reaction temperature of step 1 can be appropriately adjusted by those skilled in the art. The reaction temperature is usually -100°C to 0oC, preferably -80°C to -60oC.(Step 2)

[00147] Step 2 is the reaction step of the compound (2) with the amino compound (3a) to obtain the compound (4a).

[00148] The amount of compound (3a) used is preferably 1 to 20 mol, more preferably 2 to 5 mol, with respect to 1 mol of compound (2). Compound (3a) and compound (2) can be dissolved in an organic solvent added to the reaction solution.

[00149] The reaction of step 2 can be carried out in a solvent or can be carried out without a solvent. The solvent is not limited as long as the solvent has no influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include dichloromethane, 1,2-dichloroethane, 1,2-dimethoxyethane, tetrahydrofuran (THF), 1,4-dioxane, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

[00150] In step 2, a base can be added for the purpose of accelerating the reaction. Examples of the base include: organic amines such as triethylamine (TEA), diisopropylethylamine (DIPEA), 1,5-diazabicyclo[4.3.0]nonene (DBN), 1,8-diazabicyclo[5.4.0]undecene (DBU), pyridine, and 4-dimethylaminopyridine (DMAP); and inorganic bases such as potassium carbonate and sodium carbonate.

[00151] The amount of base added is preferably 1 to 20 mol, more preferably 2 to 5 mol, with respect to 1 mol of compound (1).

[00152] The reaction temperature of step 2 can be appropriately adjusted by those skilled in the art. The reaction temperature is usually 0°C to 160oC, preferably 25°C to 120oC.(Step 3)

[00153] Step 3 is the step of removing the P1 group from compound (4a) to produce compound (Ia).

[00154] The reaction conditions of step 3 can be appropriately selected by those skilled in the art according to the type of group P1 used. In the case in which the P1 group is, for example, an optionally substituted C7-11 aralkyl group, the P1 group can be removed by hydrogenolysis or can be removed by the use of protonic acid or Lewis acid. In the case in which the P1 group is an optionally substituted C1-6 alkylcarbonyl group, an optionally substituted C6-10 arylcarbonyl group, or an optionally substituted C6-10 arylsulfonyl group, the P1 group can be removed by the use of protonic acid. or Lewis acid. In the case in which the P1 group is a Boc group, it can be removed by treatment with proton acid or Lewis acid; in the case in which the P1 group is a Cbz group, it can be removed by hydrogenolysis or treatment with a base; and in the case in which the P1 group is a Teoc group, a reagent that forms a fluoride ion such as tetrabutylammonium fluoride can be used. In the case in which the P1 group is a C1-6-alkoxycarbonyl group optionally substituted as a methoxycarbonyl group or an ethoxycarbonyl group, the P1 group can be removed by heating in the presence of an organic amine such as triethylamine (TEA), diisopropylethylamine ( DIPEA), 2-aminoethanol, or N,N-dimethylethane-1,2-diamine, or an inorganic base such as potassium carbonate or sodium carbonate.

[00155] The compound (Ia) obtained by step 3 can be converted into a pharmacologically acceptable salt thereof by a method well known to those skilled in the art. <Method of producing compound (4) 1>

[00156] This method is a method for reacting compound (1) with isocyanate compound (5) to obtain compound (4), and then producing compound (I) according to step 3 described above. Compound (4) corresponds to the general formula (4a) in which the Z group is a hydrogen atom. Step 3 is as mentioned above. This method is a suitable method in case of using isocyanate compound (5). In this method, R, R1, R2, R3, P1 and A are as defined in the above-mentioned method for producing compound (Ia).[Chemical Formula 14] (Step 4)

[00157] Step 4 is the step of reacting compound (1) with isocyanate compound (5) to obtain compound (4).

[00158] The amount of compound (5) used is preferably 1 to 10 mol, more preferably 1 to 3 mol, with respect to 1 mol of compound (1). Compound (5) can be dissolved in an organic solvent added to the reaction solution.

[00159] The reaction of step 4 can be carried out in a solvent or can be carried out without a solvent. The solvent is not limited as long as the solvent has no influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include dichloromethane, 1,2-dichloroethane, 1,2-dimethoxyethane, tetrahydrofuran (THF), 1,4-dioxane, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

[00160] The reaction temperature of step 4 can be appropriately adjusted by those skilled in the art. The reaction temperature is usually -20°C to 100oC, preferably 0°C to 30oC.<Production method of compound (4) 2>

[00161] This method is a method for obtaining the compound (4) by reacting the isocyanate compound (6) obtained by converting the carboxylic acid compound (5) with the compound (1), and then producing the compound (I ) according to step 3 described above. In this method, step 5 and step 6 can be continuously performed without isolating compound (6). In this method, R, R1, R2, R3, P1 and A are as defined in the above-mentioned method for producing compound (Ia).[Chemical Formula 15] (Step 5)

[00162] Step 5 is the step of reacting the compound (5) with diphenylphosphorylazide and a base according to a method described, for example, in Journal of the American Chemical Society, 94 (1972), p. 6203-6205 (Curtius rearrangement) to obtain the isocyanate compound (6).

[00163] The reaction of step 5 can be carried out in a solvent or can be carried out without a solvent. The solvent is not limited as long as the solvent has no influence on the reaction, and examples include: aromatic hydrocarbons such as toluene and xylene; and amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, and 1-methyl-2-pyrrolidone. Toluene is preferred.

[00164] Examples of the base include organic amines such as triethylamine (TEA) and diisopropylethylamine (DIPEA).<Method of production of compound (4) 3>

[00165] This method is a method for obtaining the compound (4) by reacting the isocyanate compound (6) obtained by converting the amide compound (7) with the compound (1), and then producing the compound (I ) according to step 3 described above. In this method, step 7 and step 8 can be continuously performed without isolating the compound (6). This method is a suitable method in case of using amide compound (7). In this method, R, R1, R2, R3, P1 and A are as defined in the above-mentioned method for producing compound (Ia).[Chemical Formula 16] (Step 7)

[00166] Step 7 is the step of reacting the compound (7) with an oxidizing agent according to a method described, for example, in Organic Synthesis, 66 (1988), p. 132-137 (Hofmann rearrangement) to obtain the isocyanate compound (6).

[00167] The reaction of step 7 can be carried out in a solvent or can be carried out without a solvent. The solvent is not limited as long as the solvent has no influence on the reaction, and examples include: aromatic hydrocarbons such as toluene and xylene; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, and 1-methyl-2-pyrrolidone; halogenated aliphatic hydrocarbons such as dichloromethane and 1,2-dichloroethane; halogenated aromatic hydrocarbons such as chlorobenzene and 1,2-dichlorobenzene; and nitriles such as acetonitrile and propionitrile. Toluene is preferred.

[00168] In step 7, a base can be added to the reaction. Examples of the base include: organic amines such as triethylamine (TEA) and diisopropylethylamine (DIPEA); and pyridines such as pyridine, 2,6-lutidine, and 4-picoline. Pyridine is preferred.

[00169] Examples of the oxidizing agent include high valence iodine compounds such as [bis(acetoxy)iodo]benzene, [bis(trifluoroacetoxy)iodo]benzene, and iodosylbenzene, and [bis(trifluoroacetoxy)iodo]benzene is preferred.

[00170] In production methods 1 to 3 for compound (4) described above, compound (4) can be converted into compound (4a) (in which group Z is not a hydrogen atom) by the well-known reaction by those skilled in the art, and the compound (I) can be converted into the compound (Ia) (in which group Z is not a hydrogen atom). For example, in step 4, 6 or 8, the mixture after the reaction can be reacted with an alkylating agent Z-X (in which Z is as defined in general formula (1a), and X is a leaving group). production of compound (1)>

[00171] The compound (1) can be produced, for example, by the method presented below from the compound (8) as a starting material. The compound (8) can be produced, for example, with reference to document WO2007/72153 or by the following steps 11 to 15. [Chemical Formula 17]

[00172] Compound (8) is 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole in which the nitrogen atom in the pyrazole skeleton can be replaced with group P1, and the nitrogen atom in position 5 can be substituted with group P3. The P1 group can replace an acidic proton in the 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton. In this way, the P1 group can be added to position 1 of the 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton or can be added to position 2. Compound (8) and compound (10) will be described by use of the chemical formula in which it is added to position 1 of the 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton, for reasons of convenience.

[00173] In compound (8), P1 has the same meaning as defined in the production method of compound (Ia). The P3 group is not particularly limited as long as it is a substituent known, by those skilled in the art, as a protecting group for the amino group. Examples of the P3 group include: optionally substituted C7-11 aralkyl groups such as a benzyl group, a p-methoxyphenylmethyl group, and an o-nitrophenylmethyl group; optionally substituted C1-6alkylcarbonyl groups such as an acetyl group and a trifluoroacetyl group; arylC6-10-carbonyl groups optionally substituted as a benzoyl group; C1-6-alkoxycarbonyl groups optionally substituted as a methoxycarbonyl group, an ethoxycarbonyl group, a Boc group (tert-butoxycarbonyl group), a Cbz group (benzyloxycarbonyl group), an Fmoc group (fluorenylmethyloxycarbonyl group), and a Teoc group ( trimethylsilylethyloxycarbonyl); alkenyloxycarbonyl groups such as an Alloc group (allyloxycarbonyl group); alkylsulfonyl groups such as a methanesulfonyl group; and arylC6-10-sulfonyl groups optionally substituted as a p-toluenesulfonyl group.

[00174] In formulas (9) and (10), R, R1, R2, and R3 have the same meanings as defined in compound (Ia). Group X is not particularly limited as long as it is a substituent known to those skilled in the art as a leaving group. Examples of X include: halogen atoms; an imidazolyl group; amino-oxyl groups such as a succinyl-N-oxyl group and a benzotriazolyl-N-oxyl group; and acyloxyl groups such as a pivaloyloxyl group and a benzoyloxyl group. Alternatively, X may be a hydroxyl group.

[00175] In the case in which the compound (9) is a carboxylic acid (that is, X is a hydroxyl group), it can be converted into an acid anhydride by a method well known to those skilled in the art and then , reacted with the compound (8), or can be reacted with the compound (8) by using a reagent known, to those skilled in the art, as a condensing agent used in the amide bond formation reaction. (Step 9)

[00176] Step 9 is the reaction step of compound (8) with compound (9) to obtain compound (10).

[00177] The amount of compound (9) used is preferably 1 to 10 mol, more preferably 1 to 3 mol, with respect to 1 mol of compound (8).

[00178] The reaction of step 9 can be carried out in a solvent or can be carried out without a solvent. The solvent is not limited as long as the solvent has no influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include dichloromethane, diethyl ether, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

[00179] In step 9, a base can be added for the purpose of accelerating the reaction. Examples of the base include organic amines such as triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo[4.3.0]nonene (DBN), 1,8-diazabicyclo[5.4.0]undecene (DBU), pyridine, and 4 -dimethylaminopyridine (DMAP).

[00180] The amount of base added is preferably 1 to 20 mol, more preferably 1 to 5 mol, with respect to 1 mol of compound (8).

[00181] The reaction temperature of step 9 can be appropriately adjusted by those skilled in the art. The reaction temperature is usually -40°C to 100oC, preferably -20°C to 20oC.(Step 10)

[00182] Step 10 is the step of carrying out the deprotection reaction of the compound (10) to obtain the compound (1). The P3 group removal reaction may also be carried out by a method well known to those skilled in the art (for example, a method described, for example, in "Protective Groups in Organic Synthesis", 4th ed., T.W. Greene , P.G.M. Wuts, John Wiley & Sons Inc. (2006)).<Compound production method (8)>

[00183] Compound (8) can be produced, for example, by the method presented below from compound (11) as a starting material. In general formulas (13), (14) and (15), P3 is as defined in compound (8).[Chemical Formula 18] (Step 11)

[00184] Step 11 is the step of reacting the compound (11) with acrylonitrile to obtain the compound (12).

[00185] The amount of acrylonitrile used is preferably 1 to 10 mol, more preferably 1 to 3 mol, with respect to 1 mol of the compound (11).

[00186] The reaction of step 11 can be carried out in a solvent or can be carried out without a solvent. The solvent is not limited as long as the solvent has no influence on the reaction, and an aqueous solvent is preferred.

[00187] In step 11, a base can be added for the purpose of accelerating the reaction. Examples of the base include inorganic bases such as potassium hydroxide. The amount of base added is preferably 0.8 to 2 mol, with respect to 1 mol of compound (11).

[00188] The reaction temperature of step 11 can be appropriately adjusted by those skilled in the art. The reaction temperature is usually 0°C to 100°C, preferably 50°C to 90°C. (Step 12)

[00189] Step 12 is the step of protecting the amino group of compound (12) with the P3 group to obtain compound (13). The protective reaction of the amino group with the P3 group can be carried out according to a method well known to those skilled in the art, for example, a method described in "Protective Groups in Organic Synthesis", 4th ed., T.W. Greene, P.G.M. Wuts, John Wiley & Sons Inc. (2006). (Step 13)

[00190] Step 13 is the step of carrying out the cyclization reaction of the compound (13) to obtain the compound (14).

[00191] The reaction of step 13 can be carried out in a solvent or can be carried out without a solvent. The solvent is not limited as long as the solvent has no influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, N,N-dimethylformamide (DMF) and toluene.

[00192] In step 13, a base can be added for the purpose of accelerating the reaction. Examples of the base include sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, n-butyllithium, and potassium tert-butoxide. The amount of base added is preferably 1 to 3 mol with respect to 1 mol of compound (13).

[00193] The reaction temperature of step 13 can be appropriately adjusted by those skilled in the art. The reaction temperature is usually 20°C to 150oC, preferably 50°C to 100oC. (Step 14)

[00194] Step 14 is the step of reacting the compound (14) with hydrazine to obtain the compound (15).

[00195] The reaction of step 14 can be carried out in a solvent or can be carried out without a solvent. The solvent is not limited as long as the solvent has no influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include ethanol, n-propanol, and n-butanol.

[00196] In step 14, an acid can be additionally added for the purpose of accelerating the reaction. Examples of the acid include acetic acid, hydrochloric acid, and sulfuric acid. The amount of acid added is preferably 1 to 10 mol with respect to 1 mol of the compound (14).

[00197] The reaction temperature of step 14 can be appropriately adjusted by those skilled in the art. The reaction temperature is usually 20°C to 150oC, preferably 50°C to 120oC. (Step 15)

[00198] Step 15 is the step of protecting the amino group of compound (15) with the P1 group to obtain compound (8). The protective reaction of the amino group with the P1 group can be carried out according to a method well known to those skilled in the art, for example, a method described in "Protective Groups in Organic Synthesis", 4th ed., T.W. Greene, P.G.M. Wuts, John Wiley & Sons Inc. (2006).

[00199] An alternative embodiment of the present invention is a method for treating or preventing cancer, an inflammatory disease, an allergic disease or a chronic respiratory disease, comprising administering the compound represented by general formula (Ia) or the pharmacologically acceptable salt of the same to an individual who needs it. In this context, the individual in need of the compound represented by general formula (Ia) or the pharmacologically acceptable salt thereof is, for example, a patient having a cancer, an inflammatory disease, an allergic disease or a chronic respiratory disease.

[00200] Examples of cancer include: blood cancers such as multiple myeloma, chronic myeloid leukemia, blood tumor, hematological malignancy, childhood leukemia, childhood lymphoma, Hodgkin's disease, lymphocytic lymphoma, cutaneous lymphoma, acute leukemia, chronic leukemia, lymphoblastic leukemia acute, acute myelogenous leukemia, chronic myelogenous leukemia, plasma cell neoplasm, lymphoid neoplasm, and AIDS-related cancer; and solid cancers such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, head and neck cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, uterine cervical cancer, thyroid gland cancer, prostate cancer, skin cancer including squamous cell cancer, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, glioma and neurilemmoma, melanoma , seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer, and Kaposi's sarcoma.

[00201] Examples of inflammatory disease include autoimmune diseases and more specifically include rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease.

[00202] Examples of chronic respiratory disease include chronic obstructive pulmonary disease (COPD).

[00203] Examples of allergic disease include atopic dermatitis.

[00204] When the compound represented by general formula (Ia) or the pharmacologically acceptable salt thereof is administered, it can be administered in combination with an additional drug. More specifically, a pharmaceutical composition containing the compound represented by general formula (Ia) or the pharmacologically acceptable salt thereof and another composition containing the additional drug can be separately administered and can be administered at the same time or at different times. Alternatively, the pharmaceutical composition containing the compound represented by general formula (Ia) or the pharmacologically acceptable salt thereof may additionally contain the additional drug.

[00205] Additional drug means a drug necessary for the individual, and examples thereof include anticancer agents, antirheumatic agents, drugs for the treatment of psoriasis, drugs for the treatment of multiple sclerosis, drugs for the treatment of inflammatory bowel disease, drugs for the treatment of chronic obstructive pulmonary disease, and drugs for the treatment of atopic dermatitis.

[00206] Examples of the additional drug include tyrosine kinase inhibitors, immune system checkpoint inhibitors, DNA alkylating agents, DNA synthesis inhibitors, platinum-containing drugs, antimetabolites, topoisomerase I inhibitors, topoisomerase II inhibitors, activator of tubulin, hormone antagonists, aromatase inhibitors, differentiation inducers, proteasome inhibitors, phospholipid kinase inhibitors, adenosine deaminase inhibitors, antiangiogenic agents, histone deacetylase (HDAC) inhibitors, BET bromodomain inhibitors, histone inhibitors -demethylase, histone methyltransferase inhibitors, matrix metalloprotease inhibitors, farnesyltransferase inhibitors, bisphosphonate preparations, Hsp90 inhibitors, Eg5 kinesin inhibitors, serine threonine kinase inhibitors, anticytokine agents, immunosuppressants, immunomodulators, active form of external agent analogous to Vitamin D3, S1P1 receptor antagonists, interferon preparations, anticholinergic drugs, leukotriene antagonists, PDE4 inhibitors, PGD2 receptor antagonists, neutrophil elastase inhibitors, antihistamine agents, non-steroidal anti-inflammatory drugs classics (e.g., indomethacin and ibuprofen), cyclooxygenase inhibitors (also including selective COX-1 inhibitors and selective COX-2 inhibitors), nitric oxide-releasing nonsteroidal anti-inflammatory drugs, gold-containing drugs, penicillamine, aminosalicylic acid preparations, antimalarial drugs, pyrimidine synthesis inhibitors, TNF inhibitors, interleukin inhibitors, interleukin receptor antagonists, interleukin drugs, inhibitors of B-cell activation, preparations of proteins related to co-stimulatory molecules, inhibitors of MAPK, gene regulation drugs, cytokine production inhibitors, TNF-α converting enzyme inhibitors, interleukin-1β converting enzyme inhibitors, chemokine antagonists, therapeutic vaccine, gene therapy, antisense compounds, proteasome inhibitors, inhibitors of JAK, T-cell inhibitors, inosine monophosphate dehydrogenase (IMPDH) inhibitors, adhesion molecule inhibitors, thalidomine, cathepsin inhibitors, glucose-6-phosphate dehydrogenase inhibitors, dihydroorotate inhibitors dehydrogenase (DHODH), phospholipase A2 inhibitors, iNOS inhibitors, microtubule stimulants, anti-microtubule agents, MHC class II antagonists, CD4 antagonists, CD23 antagonists, leukotriene B4 receptor antagonists, 5-lipoxygenase inhibitors , cathepsin B inhibitors, westogenesis stimulants, dipeptidyl peptidase inhibitors, collagen agonists, capsaicin creams, sulfa-based drugs, hyaluronic acid derivatives, glucosamine sulfate, amiprilose, CD20 inhibitors, CD52 inhibitors, drugs antiasthmatics, drugs for the treatment of atopic dermatitis, drugs for the treatment of allergic rhinitis, opioid receptor agonists, immunoglobulins, glatiramer acetate, T-cell receptor vaccine, adhesion molecule inhibitors, muscle relaxants, local anesthetics, anesthetics local, short-acting and long-acting muscarinic receptor antagonists (including M1-receptor, M2-receptor, and M3-receptor), β-receptor agonists (including β1-receptor, β2-receptor, β3-receptor, and -β4) short-acting and long-acting, inhaled steroids, local steroids, drug combinations of β-receptor agonists and inhaled steroids, vitamin derivatives, and adrenocortical steroids.

[00207] The additional drug may be, for example, cisplatin, doxorubicin, Taxotere, Taxol, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, fingolimod, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777 , L778,123, BMS 214662, gefitinib, erlotinib, panitumumab, afatinib, dasatinib, bosutinib, vandetanib, sunitinib, axitinib, Pazopanib, lenvatinib, lapatinib, nintedanib, nilotinib, crizotinib, ceritinib, alectinib, ibrutinib, imatinib, so rafenib, vemurafenib, dabrafenib, trametinib, palbociclib, interferon-alpha-2b, citabirin (also called ara-C), adriamycin, Cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, ofatumumab, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, 6-mercaptopurine, 6-thioguanine, regorafenib, ramucirumab, fludarabine phosphate, oxaliplatin, folinate, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, chlorotrianisene, hydroxyprogesterone, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, ansacrine, procarbazine, mitotane, mitoxantrone, Levamisole, Navelbine, anastrozole, letrozole, capecitabine, reloxafin, droloxifene, hexamethylmelamine, bevacizumab, omalizumab, be, gemtuzumab ozogamicin , mogamulizumab, pertuzumab, ocrelizumab, alemtuzumab, inotuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, diarsenic trioxide, vinorelbine, porfimer sodium, thiotepa, altretamine, trastuzumab, letrozole, fulvestrant, exemestane, rituximab, cetuximab, nivolumab, ipilimumab, pembrolizumab, durvalumab, atezolizumab, avelumab, alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen, tiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam, nabumetone, acetaminophen, phenacetin, ethenzamide, sulpirine, antipyrine, migrenin, aspirin, mefenamic acid, acid flufenamic, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fembufen, pranoprofen, floctafenine, piroxicam, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate, ulinastatin, colchicine, probenecid, sulfimpyrazone, benzbromarone, allopurinol, brentuximab vedotin, sodium gold thiomalate, sodium hyaluronate, atropine, scopolamine, morphine or its salts (e.g., morphine hydrochloride), pethidine, levorphanol, oxymorphone, salicylic acid derivatives (e.g., salicylic acid, salicylate sodium, and methyl salicylate), celecoxib, etoricoxib, valdecoxib, loxoprofen, auranofin, D-penicillamine, sulfasalazine, mesalazine, olsalazine, balsalazide, chloroquine, leflunomide, tacrolimus, infliximab, etanercept, adalimumab, Certolizumab pegol, golimumab, PASSTNF- α, soluble TNF-α receptor, TNF-α binding protein, anti-TNF-α antibodies, denosumab, anakinra, soluble interleukin-1 receptor antibodies (e.g., rilonacept and canakinumab), tocilizumab, anti-interleukin antibodies -6 (e.g., tocilizumab), interleukin-10, ustekinumab, briakinumab, secukinumab (AIN-457), ixekizumab (LY-2439821), AMG827, Rituxan, belimumab, abatacept, BMS-582949, molecule inhibitors (e.g., NF-K, NF-KB, IKK-1, IKK-2, and AP-1) involved in signaling transduction (e.g., dimethyl fumarate, dehydroxymethylepoxyquinomycin, DTCM-glutarimide, sesquiterpene-lactone, resveratrol, curcumin, di- indolylmethane noscapine, parthenolide, ixazomib, carfilzomib, delanzomib, marizomib, MLN-4924, IMD-2560, IMD-0354, IMD-1041, BAY-11-7082, BAY-11-7085, MLN120B, BMS-345541, SC-514 , PS-1145 denosumab, vorinostat, romidepsin, SN-50, and T-5224), MAPK inhibitors (e.g., SCI0469, BIRB796, SB203580, VX-702, pamapimod, PH797804, vemurafenib, dabrafenib, trametinib, cobimetinib, CC -359, CC-930, bentamapimod, and reparixin), CCR9 antagonists (e.g., vercirnone sodium), denileukin diftitox, CCX025,N-{4-chloro-2-[(1-oxidopyridin-4-yl)carbonyl]phenyl}-4-(propan-2- ilox i)benzenesulfonamide, MCP-1 antagonists, irbesartan, TNF-α vaccines, ISIS-104838, natalizumab, vedolizumab, AJM300, TRK-170, E6007, MX-68, BMS-188667, CKD-461, rimexolone, cyclosporine A, mizoribine, gusperimo, sirolimus, temsirolimus, everolimus, antilymphocyte serum, freeze-dried freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factors, atiprimod dihydrochloride, azathioprine, interferon-α, interferon-β-1b, interferon- β-1a, tofacitinib, baricitinib, carfilzomibe, ruxolitinib, dexamethasone, hexstrol, methimazole, betamethasone, triacinolone-acetonide, fluocinolone, fluorocinolone, cortisone, hydrocortisone, fluoromethetolone, becclomethason, strioli, striolis mofetyl phenolate, sodium allicaforsne , selectin inhibitors, ELAM-1 inhibitors, VCAM-1 inhibitors, ICAM-1 inhibitors, V-85546, roflumilast, apremilast, VAS203, rheumacon, zanolimumab, DW-1350, zileutone, Tyk2 inhibitors (e.g. compounds or salts thereof described in WO2010/142752), Synvisc (hylan G-F 20), Orthovisc, atacicept, blisibimod, tizanidine, eperisone, afloqualone, baclofen, diazepam, dantrolene sodium, vitamin D3 derivatives (e.g. 5,6-trans -cholecalciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, and calcipotriol), vitamin D2 derivatives (e.g., 5,6-trans-ergocalciferol), isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline, trimethoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropium bromide, flutropium bromide, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, anlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, ciclesonide, chlorpheniramine maleate, alimemazine tartrate, clemastine fumarate, homochlorcyclizine hydrochloride, fexofenadine, ketotifen fumarate, cetirizine hydrochloride, oxatomide, ebastine, and hydrochloride of pinastine, loratadine, tramadol, promethazine, hydroxyzine, homochlorcyclizine, cyproheptadine, mequitazine, emedastine fumarate, pseudoephedrine, bepotastine besylate, levocetirizine, olopatadine hydrochloride, mycophenolate mofetil, daclizumab, galiximab, metformin hydrochloride, visilizumab, aminopterin, hydrate of Pazopanib, Fezakinumab, Ruxolitinib Phosphate, Ixekizumab, Guselkumab, SLx-2119, PRX-167700, Lidocaine, Tiotropium Bromide, Salmeterol Salmeterol Xinafoate, Formoterol Fumarate, Fluticasone Propionate, Beclomethasone Propionate, Budesonide, or a combination of salmeterol xinafoate, salmeterol and fluticasone propionate.

[00208] The additional drug is preferably 5-fluorouracil, oxaliplatin or irinotecan.

EXAMPLES

[00209] Although the present invention is further described below about the compound according to the present embodiment or its pharmaceutically acceptable salt with reference to Examples (Examples 1 to 95), Reference Examples (Reference Examples 1 to 43), and Examples Test Examples (Test Examples 1 to 20), these examples are provided for better understanding of the present invention and are not intended to limit the scope of the present invention.

[00210] In purification by preparative column chromatography, the following devices were used: Apparatus 1: EPCLC-W-Prep 2XY A-Type (manufactured by Yamazen Corp., trade name) Apparatus 2: Purif (commercial brand)-Compact ( manufactured by Moritex Corp., trade name) Apparatus 3: Prominence Preparative System (manufactured by Shimadzu Corp., trade name) The stationary phases used in preparative column chromatography purification are as follows: DIOL silica gel: CHROMATOREX (trade name) DIOL MB 100-40/75 (manufactured by Fuji Silysia Chemical Ltd.) DNH silica gel: CHROMATOREX (trade name) DNH MB 100-40/75 (manufactured by Fuji Silysia Chemical Ltd.) ODS silica gel: XBridge C18 Prep (trade name), particle size: 5 μm, OBD, size: 19 mm X 150 mm (manufactured by Waters Corp.) CSH ODS Silica Gel: OBD, size: 19 mm X 150 mm (manufactured by Waters Corp.) Fluoro-phenyl-silica Gel: : 19 mm DUIS is an ionization mode of a mass spectrum that is a mixed mode of ESI and APCI.

[00211] 1H-NMR is indicated by chemical shift (δ) with tetramethylsilane as an internal standard (0 ppm), and a coupling constant (J value) is indicated per unit Hz, unless otherwise indicated. An abbreviation for the splitting pattern of each peak has the following meaning: s: singlet, d: doublet, t: triplet, q: quartet, br s: broad singlet, and m: multiplet.

[00212] Abbreviations described in the Examples and Reference Examples are commonly used with the meanings generally used in the fields of organic chemistry and pharmacy. Each abbreviation is specifically understood by those skilled in the art as follows. ATP: Adenosine triphosphate Boc: tert-Butyloxycarbonyl Cbz: Benzyloxycarbonyl IQ: Chemical ionization DIPEA: N,N-Diisopropylethylamine DMF: N,N-Dimethylformamide DMSO: Dimethyl sulfoxide DPPA: Diphenylphosphonyl-azide DTT: Dithiothreitol DUIS: Source of dual ionization Et: Ethyl FBS: Fetal bovine serum HEPES: N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid MBP: Myelin basic protein NADPH: Nicotinamide-adenine-dinucleotide-phosphate PBMC: Peripheral blood mononuclear cell PBS: Aqueous solution phosphate buffered sodium chloride TBS: tert-Butyldimethylsilyl TEA: Triethylamine THF: Tetrahydrofuran Tris: Tris-hydroxymethylaminomethane (Example 1) 6,6-Dimethyl-N-phenyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]- 4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide (Compound No. IV-1) [Chemical Formula 19]

[00213] To a solution of 101 mg (0.229 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 3 mL of 1,4-dioxane, 0.116 mL (0.679 mmol) of DIPEA and 0.062 mL (0.68 mmol) of aniline were added at room temperature under an argon atmosphere and reacted at 100°C for 1 hour with stirring. Subsequently, the reaction solution was concentrated under reduced pressure, and 2 mL of methanol and 0.068 mL (1.1 mmol) of 2-aminoethanol were added to the obtained concentration residue and then reacted at room temperature for 1 hour with stirring.

[00214] After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 5 mL of ethyl acetate was added to the concentration residue obtained, followed by washing twice with 5 mL of an aqueous solution of dihydrogen phosphate potassium 5%. The entire organic layer thus obtained was washed with 5 ml of a saturated aqueous solution of sodium bicarbonate and saturated saline, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure.

[00215] The concentration residue obtained was subjected to chromatography in a preparative column (apparatus 1, silica gel, elution solvent: ethyl acetate:methanol = 100:0 ^ 88:12 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by the addition of dichloromethane, and then the solid was deposited by the addition of n-hexane. The obtained solid was collected by filtration and dried under reduced pressure to obtain 77.2 mg of the title compound (yield: 79%) as a white solid.

[00216] Mass spectrum (IQ, m/z): 426 [M+1]+.

[00217] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.86 (br s, total 1H), 9.83 - 9.42 (m, 1H), 8.22 - 7 .91 (m, 1H), 7.56 - 7.47 (m, 2H), 7.26 - 7.16 (m, 2H), 6.96 - 6.88 (m, 1H), 4.64 (br s, 2H), 2.55 - 2.40 (m, 2H), 2.28 - 2.13 (m, 2H), 1.94 - 1.74 (m, 2H), 1.67 ( br s, 6H), 0.09 (s, 9H).(Example 2)

[00218] 6,6-Dimethyl-N-(p-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazol-5 (1 H) -carboxamide (Compound No. IV-25) [Chemical Formula 20]

[00219] To a solution of 121 mg (0.274 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.15 mL (0.86 mmol) of DIPEA and 92.6 mg (0.864 mmol) of p-toluidine were added at room temperature under a nitrogen atmosphere and reacted at 90oC for 1.5 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.15 mL (1.4 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 4 hours with agitation.

[00220] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 70:30 ^ 50:50 ^ 40:60 (V/V)) , and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 93.6 mg of the compound of the title (yield: 78%) as a white solid.

[00221] Mass spectrum (IQ, m/z): 440 [M+1]+.

[00222] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.76 (br s, total 1H), 9.75 - 9.45 (m, 1H), 8.13 - 7 .84 (m, 1H), 7.42 - 7.36 (m, 2H), 7.05 - 6.99 (m, 2H), 4.62 (br s, 2H), 2.54 - 2, 41 (m, 2H), 2.28 - 2.12 (m, 5H), 1.92 - 1.74 (m, 2H), 1.66 (br s, 6H), 0.09 (s, 9H ).(Example 3)

[00223] N-(4-Methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-79) [Chemical Formula 21]

[00224] To a solution of 126 mg (0.286 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.18 mL (1.0 mmol) of DIPEA and 121 mg (0.984 mmol) of 4-methoxyaniline were added at room temperature under a nitrogen atmosphere and reacted at 90oC for 1.5 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.16 mL (1.5 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 14.5 hours with stirring.

[00225] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 70:30 ^ 50:50 ^ 40:60 (V/V)) , and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 106 mg of the title compound (yield: 81%) as a white solid.

[00226] Mass spectrum (IQ, m/z): 456 [M+1]+.

[00227] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.47 - 11.54 (m, 1H), 9.58 (br s, 1H), 7.94 (br s, 1H), 7.43 - 7.34 (m, 2H), 6.85 - 6.76 (m, 2H), 4.59 (s, 2H), 3.70 (s, 3H), 2.54 - 2, 41 (m, 2H), 2.27 - 2.13 (m, 2H), 1.90 - 1.74 (m, 2H), 1.66 (s, 6H), 0.09 (s, 9H) . (Example 4)

[00228] N-(4-Fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-7) [Chemical Formula 22]

[00229] To a solution of 119 mg (0.270 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.15 mL (0.86 mmol) of DIPEA and 0.080 mL (0.83 mmol) of 4-fluoroaniline were added at room temperature under a nitrogen atmosphere and reacted at 90 °C for 2 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.15 mL (1.4 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 2 hours with stirring.

[00230] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 70:30 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 95.9 mg of the compound of the title (yield: 80%) as a white solid.

[00231] Mass spectrum (IQ, m/z): 444 [M+1]+.

[00232] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.76 (br s, total 1H), 9.71 - 9.52 (m, 1H), 8.24 - 8 .05 (m, 1H), 7.57 - 7.45 (m, 2H), 7.11 - 7.00 (m, 2H), 4.71 - 4.52 (m, 2H), 2.55 - 2.40 (m, 2H), 2.28 - 2.12 (m, 2H), 1.92 - 1.74 (m, 2H), 1.73 - 1.57 (m, 6H), 0 .09 (s, 9H).(Example 5)

[00233] 6,6-Dimethyl-N-(pyridin-3-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-1019) [Chemical Formula 23]

[00234] To a solution of 123 mg (0.278 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.15 mL (0.86 mmol) of DIPEA and 79.7 mg (0.847 mmol) of pyridin-3-amine were added at room temperature under a nitrogen atmosphere and reacted at 90 °C for 5 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.15 mL (1.4 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 1.5 hours with stirring.

[00235] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: dichloromethane:methanol = 99:1 ^ 98:2 ^ 97:3 ^ 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 50:50 ^ 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 40:60 (V/V)), and a fraction containing The compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The obtained concentration residue was subjected to extraction three times with ethyl acetate, and subsequently, the entire organic layer was washed with saturated saline, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 34.5 mg of the compound of the title (yield: 29%) as a white solid.

[00236] Mass spectrum (IQ, m/z): 427 [M+1]+.

[00237] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.29 & 11.66 (br s, total 1H), 9.60 (s, 1H), 8.77 - 8.64 (m , 1H), 8.44 - 8.25 (m, 1H), 8.18 - 8.11 (m, 1H), 7.98 - 7.91 (m, 1H), 7.26 (dd, J = 4.6, 8.3 Hz, 1H), 4.74 - 4.57 (m, 2H), 2.57 - 2.41 (m, 2H), 2.28 - 2.13 (m, 2H ), 1.92 - 1.75 (m, 2H), 1.74 - 1.59 (m, 6H), 0.09 (s, 9H).(Example 6)

[00238] N-(2-Fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-3) [Chemical Formula 24]

[00239] To a solution of 118 mg (0.267 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.15 mL (0.86 mmol) of DIPEA and 0.080 mL (0.83 mmol) of 2-fluoroaniline were added at room temperature under a nitrogen atmosphere and reacted at 90 °C for 9 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.15 mL (1.4 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 2.5 hours with stirring.

[00240] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 70:30 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 62.2 mg of the compound of the title (yield: 53%) as a white solid.

[00241] Mass spectrum (IQ, m/z): 444 [M+1]+.

[00242] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.85 (br s, total 1H), 9.80 - 9.50 (m, 1H), 7.91 - 7 .69 (m, 1H), 7.68 - 7.47 (m, 1H), 7.24 - 7.03 (m, 3H), 4.74 - 4.51 (m, 2H), 2.56 - 2.39 (m, 2H), 2.28 - 2.13 (m, 2H), 1.93 - 1.74 (m, 2H), 1.72 - 1.57 (m, 6H), 0 .09 (s, 9H).(Example 7)

[00243] 6,6-Dimethyl-N-(o-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazol-5 (1 H) -carboxamide (Compound No. IV-21) [Chemical Formula 25]

[00244] To a solution of 117 mg (0.265 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.15 mL (0.86 mmol) of DIPEA and 0.090 mL (0.84 mmol) of o-toluidine were added at room temperature under a nitrogen atmosphere and reacted at 90oC for 5 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.15 mL (1.4 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 1.5 hours with stirring.

[00245] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 70:30 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 97.7 mg of the compound of the title (yield: 84%) as a white solid.

[00246] Mass spectrum (IQ, m/z): 440 [M+1]+.

[00247] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.83 (br s, total 1H), 9.73 - 9.49 (m, 1H), 7.76 - 7 .54 (m, 1H), 7.34 - 7.21 (m, 1H), 7.19 - 7.07 (m, 2H), 7.02 (dt, J = 1.2, 7.4 Hz , 1H), 4.71 - 4.52 (m, 2H), 2.54 - 2.40 (m, 2H), 2.27 - 2.12 (m, 5H), 1.93 - 1.73 (m, 2H), 1.72 - 1.54 (m, 6H), 0.09 (s, 9H).(Example 8)

[00248] 6,6-Dimethyl-N-(m-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazol-5 (1 H) -carboxamide (Compound no. IV-23) [Chemical Formula 26]

[00249] To a solution of 105 mg (0.238 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c Ethyl pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.13 mL (0.75 mmol) of DIPEA and 0.080 mL (0.74 mmol) of m-toluidine were added at room temperature under a nitrogen atmosphere and reacted at 90 °C for 2 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.13 mL (1.2 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 1.5 hours with stirring.

[00250] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 70:30 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 90.1 mg of the compound of the title (yield: 86%) as a white solid.

[00251] Mass spectrum (IQ, m/z): 440 [M+1]+.

[00252] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.71 (br s, total 1H), 9.64 - 9.51 (m, 1H), 8.09 - 7 .91 (m, 1H), 7.39 - 7.35 (m, 1H), 7.34 - 7.26 (m, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.77 - 6.71 (m, 1H), 4.70 - 4.52 (m, 2H), 2.54 - 2.42 (m, 2H), 2.29 - 2.13 (m, 5H) ), 1.92 - 1.73 (m, 2H), 1.73 - 1.58 (m, 6H), 0.14 - 0.05 (m, 9H).(Example 9)

[00253] N-([1,1'-Biphenyl]-3-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4- c]pyrazol-5(1H)-carboxamide (Compound No. IV-71) [Chemical Formula 27]

[00254] To a solution of 101 mg (0.230 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.13 mL (0.75 mmol) of DIPEA and 119 mg (0.700 mmol) of [1,1'-biphenyl]-3-amine were added at room temperature under a nitrogen atmosphere and reacted at 90 °C for 4 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.13 mL (1.2 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 1.5 hours with stirring.

[00255] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was suspended in a mixed solvent of ethyl acetate/n-hexane and stirred at room temperature, and then the remaining undissolved solid was collected by filtration, washed with n-hexane, and then dried under pressure. reduced to obtain 92.4 mg of the title compound (yield: 80%) as a white solid.

[00256] Mass spectrum (IQ, m/z): 502 [M+1]+.

[00257] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.71 (br s, total 1H), 9.60 (s, 1H), 8.20 (br s, 1H) , 7.84 (t, J = 1.8 Hz, 1H), 7.66 - 7.54 (m, 3H), 7.51 - 7.43 (m, 2H), 7.39 - 7.28 (m, 2H), 7.25 - 7.19 (m, 1H), 4.67 (br s, 2H), 2.56 - 2.40 (m, 2H), 2.29 - 2.13 ( m, 2H), 1.93 - 1.75 (m, 2H), 1.69 (br s, 6H), 0.10 (s, 9H).(Example 10)

[00258] N-(3-Fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-5) [Chemical Formula 28]

[00259] To a solution of 102 mg (0.231 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.13 mL (0.75 mmol) of DIPEA and 0.070 mL (0.72 mmol) of 3-fluoroaniline were added at room temperature under a nitrogen atmosphere and reacted at 90oC for 3.5 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.13 mL (1.2 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 1.5 hours with stirring.

[00260] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 75:25 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 70.6 mg of the compound of the title (yield: 69%) as a white solid.

[00261] Mass spectrum (IQ, m/z): 444 [M+1]+.

[00262] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.68 (s, total 1H), 9.59 (s, 1H), 8.39 - 8.24 (m, 1H), 7.49 (td, J = 2.2, 12.4 Hz, 1H), 7.38 - 7.31 (m, 1H), 7.28 - 7.19 (m, 1H), 6 .76 - 6.68 (m, 1H), 4.70 - 4.56 (m, 2H), 2.54 - 2.41 (m, 2H), 2.28 - 2.14 (m, 2H) , 1.92 - 1.74 (m, 2H), 1.72 - 1.60 (m, 6H), 0.15 - 0.05 (m, 9H).(Example 11)

[00263] N-(3-Chlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-11) [Chemical Formula 29]

[00264] To a solution of 108 mg (0.245 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.13 mL (0.75 mmol) of DIPEA and 0.080 mL (0.76 mmol) of 3-chloroaniline were added at room temperature under a nitrogen atmosphere and reacted at 90 °C for 4 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.14 mL (1.3 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 13.5 hours with stirring.

[00265] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 75:25 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 93.0 mg of the compound of the title (yield: 82%) as a white solid.

[00266] Mass spectrum (IQ, m/z): 460 [M+1]+.

[00267] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.67 (s, total 1H), 9.64 - 9.55 (m, 1H), 8.38 - 8, 24 (m, 1H), 7.72 (t, J = 2.1 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.24 (t, J = 8.0, 1H) , 6.96 (ddd, J = 0.8, 2.1, 8.0 Hz, 1H), 4.70 - 4.56 (m, 2H), 2.56 - 2.40 (m, 2H) , 2.28 - 2.14 (m, 2H), 1.92 - 1.74 (m, 2H), 1.72 - 1.59 (m, 6H), 0.15 - 0.03 (m, 9H).(Example 12)

[00268] N-(2-Methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-75)[Chemical Formula 30]

[00269] To a solution of 105 mg (0.238 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.13 mL (0.75 mmol) of DIPEA and 0.13 mL (1 .2 mmol) of 2-methoxyaniline were added at room temperature under a nitrogen atmosphere and reacted at 90oC for 3.5 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.13 mL (1.2 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 1.5 hours with stirring.

[00270] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 75:25 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 94.1 mg of the compound of the title (yield: 87%) as a white solid.

[00271] Mass spectrum (IQ, m/z): 456 [M+1]+.

[00272] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.30 & 11.93 (br s, total 1H), 9.85 - 9.52 (m, 1H), 8.05 - 7 .85 (m, 1H), 7.11 (s, 1H), 7.01 (dd, J = 1.4, 8.0 Hz, 1H), 6.99 - 6.92 (m, 1H), 6.88 (dt, J = 1.4, 7.6 Hz, 1H), 4.53 (br s, 2H), 3.84 (s, 3H), 2.57 - 2.40 (m, 2H ), 2.28 - 2.13 (m, 2H), 1.93 - 1.75 (m, 2H), 1.68 (br s, 6H), 0.10 (s, 9H).(Example 13 )

[00273] N-(2-Chlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-9) [Chemical Formula 31]

[00274] To a solution of 106 mg (0.239 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.13 mL (0.75 mmol) of DIPEA and 0.13 mL (1 .2 mmol) of 2-chloroaniline were added at room temperature under a nitrogen atmosphere and reacted at 90oC for 15 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.13 mL (1.2 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 1.5 hours with stirring.

[00275] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 75:25 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain a pale yellow solid.

[00276] The solid obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The obtained concentration residue was subjected to extraction three times with ethyl acetate, and subsequently, the entire organic layer was washed with saturated saline, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 36.5 mg of the compound of the title (yield: 33%) as a white solid.

[00277] Mass spectrum (IQ, m/z): 460 [M+1]+.

[00278] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.29 & 11.86 (br s, total 1H), 9.62 (br s, 1H), 7.85 - 7.52 ( m, 2H), 7.45 (dd, J = 1.4, 8.0 Hz, 1H), 7.32 - 7.23 (m, 1H), 7.15 - 7.05 (m, 1H) , 4.62 (br s, 2H), 2.58 - 2.39 (m, 2H), 2.26 - 2.14 (m, 2H), 1.89 - 1.74 (m, 2H), 1.67 (s, 6H), 0.09 (s, 9H).(Example 14)

[00279] N-([1,1'-Biphenyl]-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4- c]pyrazol-5(1H)-carboxamide (Compound No. IV-69) [Chemical Formula 32]

[00280] To a solution of 150 mg (0.340 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 3 mL of DMF, 0.304 mL (1.70 mmol) of DIPEA and 173 mg (1.02 mmol) of [1. 1'-biphenyl]-2-amine were added at room temperature under an argon atmosphere and reacted at 80oC for 2 hours and at room temperature for 18 hours with stirring. Subsequently, 0.162 mL (1.70 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature for 2 hours with stirring.

[00281] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 75:25 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 53 mg of the title compound (yield: 31%) as a white solid.

[00282] Mass spectrum (IQ, m/z): 502 [M+1]+.

[00283] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.20 & 11.70 (br s, total 1H), 9.54 (s, 1H), 7.67 - 7.37 (m , 6H), 7.35 - 7.15 (m, 4H), 4.43 - 4.20 (m, 2H), 2.57 - 2.39 (m, 2H), 2.26 - 2.11 (m, 2H), 1.92 - 1.72 (m, 2H), 1.49 (s, 6H), 0.08 (s, 9H).(Example 15)

[00284] 6,6-Dimethyl-N-(pyridin-2-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-1007) [Chemical Formula 33]

[00285] To a solution of 129 mg (0.293 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.16 mL (0.92 mmol) of DIPEA and 90.7 mg (0.964 mmol) of pyridin-2-amine were added at room temperature under a nitrogen atmosphere and reacted at 90oC for 10.5 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.16 mL (1.5 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 1.5 hours with stirring.

[00286] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. A mixed solvent of ethyl acetate/m-hexane was added to the obtained concentration residue, and after ultrasonication, the insoluble matter was collected by filtration. The solid thus collected by filtration was washed with n-hexane and then dried under reduced pressure to obtain a pale yellow solid.

[00287] The solid obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 40:60 ^ 80:20 (V/V)) , and a fraction containing the compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The obtained concentration residue was subjected to extraction three times with ethyl acetate, and subsequently, the entire organic layer was washed with saturated saline, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was suspended in a mixed ethyl acetate/n-hexane solvent and stirred at room temperature, and then the remaining undissolved solid was collected by filtration. The solid thus collected by filtration was washed with n-hexane and then dried under reduced pressure to obtain 49.9 mg of the title compound (yield: 40%) as a white solid.

[00288] Mass spectrum (IQ, m/z): 427 [M+1]+.

[00289] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.79 (br s, total 1H), 9.60 (br s, 1H), 8.31 (br s, 1H ), 8.22 (ddd, J = 0.9, 1.9, 4.9, 1H), 7.89 - 7.84 (m, 1H), 7.72 - 7.64 (m, 1H) , 6.97 (ddd, J = 0.9, 4.9, 7.2 Hz, 1H), 4.78 - 4.59 (m, 2H), 2.57 - 2.40 (m, 2H) , 2.28 - 2.13 (m, 2H), 1.92 - 1.75 (m, 2H), 1.69 (br s, 6H), 0.09 (s, 9H).(Example 16)

[00290] N-(2-Ethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazol-5 (1 H) -carboxamide (Compound No. IV-27)[Chemical Formula 34]

[00291] To a solution of 105 mg (0.238 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 and 0.20 mL (1.2 mmol) of DIPEA in 3 mL of 1,4-dioxane, 0.085 mL (0.69 mmol) of 2-ethylaniline were added at room temperature under an argon atmosphere and reacted at 100oC for 2 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.13 mL (1.2 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 1 hour with stirring.

[00292] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with water and saturated saline in that order, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 35:65 ^ 55:45 (V/V)), and a fraction containing the compound of interest was separated into an organic layer and an aqueous layer by the addition of ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 17.6 mg of the title compound (yield: 16 %) as a white solid.

[00293] Mass spectrum (IQ, m/z): 454 [M+1]+.

[00294] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.76 (br s, total 1H), 9.62 - 9.53 (m, 1H), 7.71 - 7 .53 (m, 1H), 7.29 - 7.16 (m, 2H), 7.15 - 7.06 (m, 2H), 4.66 - 4.52 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H), 2.54 - 2.40 (m, 2H), 2.27 - 2.13 (m, 2H), 1.92 - 1.74 (m, 2H ), 1.71 - 1.57 (m, 6H), 1.13 (t, J = 7.6 Hz, 3H), 0.09 (s, 9H).(Example 17)

[00295] N-(2,6-Dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-381)[Chemical Formula 35]

[00296] To a solution of 100 mg (0.227 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 3 mL of 1,4-dioxane, 0.101 mL (0.566 mmol) of DIPEA and 0.042 mL (0.34 mmol) of 2 ,6-dimethylaniline were added at room temperature under an argon atmosphere and reacted at 100oC for 7 hours. Subsequently, the reaction solution was cooled to room temperature and reacted for 20 hours. The resultant was additionally reacted at 150oC for 1 hour in a microwave-heated reaction apparatus. Then, the reaction solution was cooled to room temperature, and 0.053 mL (0.56 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature for 1 hour with stirring.

[00297] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 75:25 ^ 49:51 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: 1,2-dichloroethane:methanol = 98:2 ^ 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 14.7 mg of the title compound (yield: 14 %) as a white solid.

[00298] Mass spectrum (IQ, m/z): 454 [M+1]+.

[00299] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.74 (br s, total 1H), 9.55 (br s, 1H), 7.62 - 7.40 ( m, 1H), 7.08 - 6.97 (m, 3H), 4.68 - 4.48 (m, 2H), 2.58 - 2.39 (m, 2H), 2.27 - 2, 08 (m, 8H), 1.93 - 1.73 (m, 2H), 1.71 - 1.54 (m, 6H), 0.09 (s, 9H).(Example 18)

[00300] N-(2,3-Difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-99) [Chemical Formula 36]

[00301] To a solution of 100 mg (0.227 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.120 mL (0.689 mmol) of DIPEA and 100 mg (0.775 mmol) of 2,3 -difluoroaniline were added at room temperature under an argon atmosphere, reacted at 90oC for 3 hours with stirring, and then reacted at 150oC for 2 hours in a microwave-heated reaction apparatus. Subsequently, 0.120 mL (1.10 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and then reacted at room temperature for 2 hours with stirring.

[00302] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 20:80 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 50:50 (V/V)), and a fraction containing the compound of interest was subjected to extraction with ethyl acetate. The entire organic layer thus obtained was washed with water, dried with anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol, then water was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 13.0 mg of the title compound (yield: 12%) as a white solid.

[00303] Mass spectrum (IQ, m/z): 462 [M+1]+.

[00304] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.74 (br s, total 1H), 9.63 (s, 1H), 8.29 - 7.91 (m , 1H), 7.42 - 7.24 (m, 1H), 7.17 - 7.05 (m, 2H), 4.64 (br s, 2H), 2.59 - 2.39 (m, 2H), 2.27 - 2.12 (m, 2H), 1.92 - 1.73 (m, 2H), 1.65 (s, 6H), 0.09 (s, 9H).(Example 19 )

[00305] N-(2,3-Dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-375) [Chemical Formula 37]

[00306] To a solution of 100 mg (0.227 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c Ethyl pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.120 mL (0.689 mmol) of DIPEA and 82.0 mg (0.677 mmol) of 2 ,3-dimethylaniline were added at room temperature and reacted at 170oC for 1 hour in a microwave-heated reaction apparatus. Subsequently, 0.120 mL (1.10 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and then reacted at room temperature for 16 hours with stirring.

[00307] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 20:80 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, fluoro-phenyl-silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 40:60 (V/V)) , and a fraction containing the compound of interest was subjected to extraction with ethyl acetate. The entire organic layer thus obtained was washed with water, dried with anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol, then water was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 12.3 mg of the title compound (yield: 12%) as a white solid.

[00308] Mass spectrum (IQ, m/z): 454 [M+1]+.

[00309] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.74 (br s, total 1H), 9.64 - 9.51 (m, 1H), 7.80 - 7 .62 (m, 1H), 7.10 - 6.92 (m, 3H), 4.68 - 4.54 (m, 2H), 2.56 - 2.40 (m, 2H), 2.29 - 2.13 (m, 5H), 2.05 (s, 3H), 1.91 - 1.73 (m, 2H), 1.71 - 1.56 (m, 6H), 0.09 (s , 9H).(Example 20)

[00310] N-(2-Fluoro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-129) [Chemical Formula 38]

[00311] To a solution of 133 mg (0.301 mmol [calculation value with purity defined as 100%]) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5 Ethyl ,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.21 mL (1, 2 mmol) of DIPEA and 151 mg (1.21 mmol) of 2-fluoro-6-methylaniline were added at room temperature, reacted at 90oC for 4 hours with stirring, and then reacted at 160oC for 1 hour in a reaction apparatus heated by microwave. Subsequently, the reaction solution was cooled to room temperature, and 0.17 mL (1.6 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 17.5 hours with agitation.

[00312] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure.

[00313] The obtained concentration residue was suspended in a mixed solvent of ethyl acetate/n-hexane and stirred at room temperature, and then, the remaining undissolved solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain a pale yellow solid (approximately 110 mg). The solid obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 50:50 ^ 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The obtained concentration residue was subjected to extraction three times with ethyl acetate, and subsequently, the entire organic layer was washed with saturated saline, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 33.4 mg of the compound of the title (yield: 24% [calculation value with starting material purity set to 100%]) as a white solid.

[00314] Mass spectrum (IQ, m/z): 458 [M+1]+.

[00315] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.69 (s, total 1H), 9.62 - 9.52 (m, 1H), 7.79 - 7, 63 (m, 1H), 7.18 - 7.09 (m, 1H), 7.06 - 6.97 (m, 2H), 4.68 - 4.50 (m, 2H), 2.57 - 2.40 (m, 2H), 2.28 - 2.13 (m, 5H), 1.93 - 1.72 (m, 2H), 1.71 - 1.54 (m, 6H), 0, 17 - 0.03 (m, 9H). (Example 21)

[00316] N-[2-(Difluoromethoxy)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5( 1H)-carboxamide (Compound No. IV-87) [Chemical Formula 39]

[00317] To a solution of 111 mg (0.251 mmol [calculation value with purity defined as 100%]) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5 Ethyl ,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.14 mL (0. 80 mmol) of DIPEA and 0.10 mL (0.80 mmol) of 2-(difluoromethoxy)aniline were added at room temperature under a nitrogen atmosphere and reacted at 100oC for 9.5 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.14 mL (1.3 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 2 hours with stirring.

[00318] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 65:35 ^ 50:50 (V/V)) , and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: dichloromethane:methanol = 100:0 ^ 99:1 ^ 98:2 ^ 97:3 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 62.9 mg of the compound of the title (yield: 51% [calculation value with starting material purity set to 100%]) as a white solid.

[00319] Mass spectrum (IQ, m/z): 492 [M+1]+.

[00320] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.82 (br s, total 1H), 9.62 (br s, 1H), 7.83 - 7.43 ( m, 2H), 7.26 - 6.80 (m, 4H), 4.59 (br s, 2H), 2.57 - 2.40 (m, 2H), 2.26 - 2.13 (m , 2H), 1.91 - 1.74 (m, 2H), 1.66 (s, 6H), 0.09 (s, 9H). (Example 22)

[00321] N-(2-Ethoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-81) [Chemical Formula 40]

[00322] To a solution of 108 mg (0.245 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 3 mL of 1,4-dioxane, 0.215 mL (1.23 mmol) of DIPEA and 0.100 mL (0.765 mmol) of 2 -ethoxyaniline were added at room temperature under an argon atmosphere and reacted at 100oC for 3 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.135 mL (1.24 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature for 1 hour with stirring.

[00323] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 60:40 ^ 80:20 (V/V)), and a fraction containing the compound of interest was separated into an organic layer and an aqueous layer by the addition of ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 52.3 mg of the title compound (yield: 45 %) as a white solid.

[00324] Mass spectrum (IQ, m/z): 470 [M+1]+.

[00325] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.31 & 11.84 (br s, total 1H), 9.65 (br s, 1H), 8.05 - 7.96 ( m, 1H), 7.20 (s, 1H), 7.02 - 6.97 (m, 1H), 6.96 - 6.84 (m, 2H), 4.63 - 4.45 (m, 2H), 4.14 - 4.02 (m, 2H), 2.55- 2.40 (m, 2H), 2.29 - 2.11(m, 2H), 1.94 - 1.59 ( m, 8H), 1.38 (t, J = 7.0 Hz, 3H), 0.08 (s, 9H). (Example 23)

[00326] 6,6-Dimethyl-N-[2-(trifluoromethoxy)phenyl]-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5( 1H)-carboxamide (Compound No. IV-93) [Chemical Formula 41]

[00327] To a solution of 114 mg (0.259 mmol [calculation value with purity defined as 100%]) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5 Ethyl ,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.23 mL (1, 3 mmol) of DIPEA and 0.17 mL (1.3 mmol) of 2-(trifluoromethoxy)aniline were added at room temperature under a nitrogen atmosphere and reacted at 100oC for 18 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.14 mL (1.3 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 1.5 hours with stirring.

[00328] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 65:35 ^ 50:50 (V/V)) , and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: dichloromethane:methanol = 99:1 ^ 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 30.2 mg of the compound of the title (yield: 23% [calculation value with starting material purity set to 100%]) as a white solid.

[00329] Mass spectrum (IQ, m/z): 510 [M+1]+.

[00330] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.74 (br s, total 1H), 9.61 (s, 1H), 7.89 (br s, 1H) , 7.68 - 7.55 (m, 1H), 7.36 - 7.28 (m, 2H), 7.18 (dt, J = 1.6, 7.8 Hz, 1H), 4.60 (br s, 2H), 2.58 - 2.39 (m, 2H), 2.26 - 2.13 (m, 2H), 1.90 - 1.71 (m, 2H), 1.65 ( s, 6H), 0.08 (s, 9H). (Example 24)

[00331] N-(2-Fluoro-4-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-125) [Chemical Formula 42]

[00332] To a solution of 117 mg (0.266 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.23 mL (1.3 mmol) of DIPEA and 0.15 mL (1 .3 mmol) of 2-fluoro-4-methylaniline were added at room temperature under a nitrogen atmosphere and reacted at 100oC for 6.5 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.15 mL (1.4 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and then reacted at room temperature for 1. 5 hours with agitation.

[00333] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 65:35 ^ 50:50 (V/V)) , and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: dichloromethane:methanol = 100:0 ^ 99:1 ^ 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 92.8 mg of the compound of the title (yield: 76%) as a white solid.

[00334] Mass spectrum (IQ, m/z): 458 [M+1]+.

[00335] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.75 (br s, total 1H), 9.60 (br s, 1H), 7.83 - 7.57 ( m, 1H), 7.38 (br s, 1H), 7.03 - 6.96 (m, 1H), 6.94 - 6.88 (m, 1H), 4.60 (br s, 2H) , 2.56 - 2.40 (m, 2H), 2.27 (s, 3H), 2.25 - 2.13 (m, 2H), 1.92 - 1.72 (m, 2H), 1 .64 (br s, 6H), 0.09 (s, 9H). (Example 25)

[00336] N-(2,6-Difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-105) [Chemical Formula 43]

[00337] A solution of 100 mg (0.227 mmol [calculation value with purity defined as 100%]) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5 Ethyl ,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 3 mL of 1,4-dioxane, 0.20 mL (1, 1 mmol) of DIPEA and 0.073 mL (0.68 mmol) of 2,6-difluoroaniline were added at room temperature under an argon atmosphere and reacted at 120oC for 0.5 hour and at 150oC for 2 hours in a reaction apparatus heated by microwave. Subsequently, the reaction solution was cooled to room temperature, and 0.11 mL (1.1 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 1 hour with stirring.

[00338] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: 1,2-dichloroethane:methanol = 99:1 ^ 92:8 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 8.2 mg of the title compound (yield: 8 % [calculation value with starting material purity set to 100%]) as a white solid.

[00339] Mass spectrum (IQ, m/z): 462 [M+1]+.

[00340] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.77 (br s, total 1H), 9.60 (br s, 1H), 7.94 (br s, 1H ), 7.27 (tt, J = 6.3, 8.5 Hz, 1H), 7.13 - 7.04 (m, 2H), 4.60 (br s, 2H), 2.53 - 2 .41 (m, 2H), 2.25 - 2.14 (m, 2H), 1.89 - 1.74 (m, 2H), 1.63 (s, 6H), 0.09 (s, 9H ). (Example 26)

[00341] N-[2-(tert-Butyl)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide (Compound No. IV-57) [Chemical Formula 44]

[00342] To a solution of 154 mg (0.349 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 3 mL of 1,4-dioxane, 0.300 mL (1.72 mmol) of DIPEA and 0.160 mL (1.03 mmol) of 2-(tert-butyl)aniline were added at room temperature under an argon atmosphere, reacted at 100°C for 12 hours with stirring, and then reacted at 150°C for 2 hours in a microwave-heated reaction apparatus. Subsequently, 0.185 mL (1.70 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 2 hours with stirring.

[00343] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 60:40 ^ 80:20 (V/V)), and a fraction containing the compound of interest was separated into an organic layer and an aqueous layer by the addition of ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 31.4 mg of the title compound (yield: 19 %) as a white solid.

[00344] Mass spectrum (IQ, m/z): 482 [M+1]+.

[00345] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.83 (br s, total 1H), 9.66 - 9.49 (m, 1H), 7.53 - 7 .40 (m, 1H), 7.38 - 7.33 (m, 1H), 7.20 - 7.12 (m, 2H), 7.11 - 7.04 (m, 1H), 4.67 - 4.52 (m, 2H), 2.57- 2.39 (m, 2H), 2.27 - 2.12 (m, 2H), 1.93 - 1.72 (m, 2H), 1 .71 - 1.53 (m, 6H), 1.35 (s, 9H), 0.08 (s, 9H). (Example 27)

[00346] 6,6-Dimethyl-N-[2-(trifluoromethyl)phenyl]-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5( 1H)-carboxamide (Compound No. IV-51) [Chemical Formula 45]

[00347] To a solution of 108 mg (0.284 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2(4H )-ethyl carboxylate synthesized in the same way as in Reference Example 3 in 3 mL of 1,4-dioxane, 0.076 mL (0.55 mmol) of 1-isocyanate-2-(trifluoromethyl)benzene was added at room temperature under an argon atmosphere and reacted at room temperature for 1 hour with stirring. Subsequently, 0.150 mL (1.38 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and reacted at room temperature for 1 hour with stirring.

[00348] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 60:40 ^ 80:20 (V/V)), and a fraction containing the compound of interest was separated into an organic layer and an aqueous layer by the addition of ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 71.9 mg of the title compound (yield: 51 %) as a white solid.

[00349] Mass spectrum (IQ, m/z): 494 [M+1]+.

[00350] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.80 (s, total 1H), 9.69 - 9.55 (m, 1H), 7.88 - 7, 51 (m, 4H), 7.40 - 7.33 (m, 1H), 4.66 - 4.49 (m, 2H), 2.56- 2.40 (m, 2H), 2.27 - 2.13 (m, 2H), 1.91 - 1.73 (m, 2H), 1.71 - 1.55 (m, 6H), 0.09 (s, 9H). (Example 28)

[00351] N-(3-Fluoro-2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-357) [Chemical Formula 46]

[00352] To a solution of 120 mg (0.272 mmol [calculation value with purity defined as 100%]) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5 Ethyl ,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.15 mL (0. 86 mmol) of DIPEA and 100 mg (0.799 mmol) of 3-fluoro-2-methylaniline were added at room temperature and reacted at 170oC for 1 hour in a microwave-heated reaction apparatus. Subsequently, 0.15 mL (1.4 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature for 16 hours with stirring.

[00353] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 20:80 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 40:60 (V/V)), and a fraction containing the compound of interest was subjected to extraction by addition of ethyl acetate. The organic layer obtained was washed with water, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol, then water was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 12.4 mg of the title compound (yield: 10% [value of calculation with the purity of the starting material set to 100%]) as a white solid.

[00354] Mass spectrum (IQ, m/z): 458 [M+1]+.

[00355] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.76 (br s, total 1H), 9.66 - 9.54 (m, 1H), 8.02 - 7 .81 (m, 1H), 7.18 - 7.04 (m, 2H), 6.97 - 6.89 (m, 1H), 4.71 - 4.55 (m, 2H), 2.56 - 2.40 (m, 2H), 2.27 - 2.13 (m, 2H), 2.06 (d, J = 1.4 Hz, 3H), 1.91 - 1.73 (m, 2H ), 1.71 - 1.55 (m, 6H), 0.09 (s, 9H). (Example 29)

[00356] N-(2-Cyanophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-63) [Chemical Formula 47]

[00357] To a solution of 160 mg (0.363 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 3 mL of 1,4-dioxane, 0.30 mL (1.7 mmol) of DIPEA and 132 mg (1.12 mmol) of 2-aminobenzonitrile were added at room temperature under an argon atmosphere and reacted at 150oC for 6 hours in a microwave-heated reaction apparatus. Subsequently, 0.200 mL (1.84 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature for 2 hours with stirring.

[00358] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 60:40 ^ 80:20 (V/V)), and a fraction containing the compound of interest was separated into an organic layer and an aqueous layer by the addition of ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 24.5 mg of the title compound (yield: 15 %) as a white solid.

[00359] Mass spectrum (IQ, m/z): 451 [M+1]+.

[00360] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.29 & 11.72 (br s, total 1H), 9.63 (s, 1H), 8.62 - 8.42 (m , 1H), 7.72 (dd, J = 1.3, 7.7 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.55 - 7.44 (m, 1H), 7.28 - 7.20 (m, 1H), 4.72 - 4.59 (m, 2H), 2.56- 2.41 (m, 2H), 2.26 - 2.14 (m, 2H) ), 1.90 - 1.74 (m, 2H), 1.73 - 1.59 (m, 6H), 0.09 (s, 9H). (Example 30)

[00361] N-(4-Fluoro-2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-359) [Chemical Formula 48]

[00362] To a solution of 154 mg (0.349 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c Ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 3 mL of 1,4-dioxane, 0.30 mL (1.7 mmol) of DIPEA and 0.115 mL (1.03 mmol) of 4-fluoro-2-methylaniline were added at room temperature under an argon atmosphere and reacted at 100oC for 5 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.18 mL (1.7 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 0.5 hour with stirring.

[00363] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 50:50 (V/V)), and a fraction containing The compound of interest was separated into an organic layer and an aqueous layer by the addition of ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 76.4 mg of the title compound (yield: 48 %) as a white solid.

[00364] Mass spectrum (IQ, m/z): 458 [M+1]+.

[00365] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.72 (br s, total 1H), 9.61 - 9.54 (m, 1H), 7.79 - 7 .62 (m, 1H), 7.29 - 7.15 (m, 1H), 7.02 (dd, J = 2.9, 9.7 Hz, 1H), 6.93 (dt, J = 2 .9, 8.6 Hz, 1H), 4.68 - 4.50 (m, 2H), 2.56- 2.40 (m, 2H), 2.28 - 2.11 (m, 5H), 1.92 - 1.73 (m, 2H), 1.71 - 1.56 (m, 6H), 0.16 - 0.03 (m, 9H). (Example 31)

[00366] N-(2-Chloro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-215) [Chemical Formula 49]

[00367] To a solution of 200 mg (0.454 mmol [calculation value with purity defined as 100%]) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5 Ethyl ,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 3 mL of 1,4-dioxane, 0.39 mL (2, 3 mmol) of DIPEA and 0.16 mL (1.4 mmol) of 2-chloro-6-methylaniline were added at room temperature under an argon atmosphere, reacted at 120oC for 0.5 hour in a reaction apparatus heated by microwave, and then reacted at 150°C for 2 hours. Subsequently, 0.21 mL (2.3 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature for 2 hours with stirring.

[00368] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 70:30 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: 1,2-dichloroethane:methanol = 99:1 ^ 92:8 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The obtained concentrate was subjected to extraction with ethyl acetate, and subsequently, the entire organic layer was washed with saturated saline solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 23.6 mg of the title compound (yield: 11 % [calculation value with starting material purity set to 100%]) as a white solid.

[00369] Mass spectrum (IQ, m/z): 474 [M+1]+.

[00370] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.73 (br s, total 1H), 9.58 (s, 1H), 7.81 (br s, 1H) , 7.30 (dd, J = 1.3, 7.8 Hz, 1H), 7.23 - 7.11 (m, 2H), 4.61 (br s, 2H), 2.56 - 2, 41 (m, 2H), 2.27 - 2.12 (m, 5H), 1.90 - 1.73 (m, 2H), 1.64 (s, 6H), 0.09 (s, 9H) . (Example 32)

[00371] N-(2-Fluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-123) [Chemical Formula 50]

[00372] To a solution of 120 mg (0.272 mmol [calculation value with purity defined as 100%]) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5 Ethyl ,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.150 mL (0.861 mmol) of DIPEA and 100 mg (0.799 mmol) of 2-fluoro-3-methylaniline were added at room temperature under an argon atmosphere and reacted at 90oC for 11 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.150 mL (1.38 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature for 16 hours with agitation.

[00373] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 20:80 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol, then water was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 42.0 mg of the title compound (yield: 34% [value of calculation with the purity of the starting material set to 100%]) as a white solid.

[00374] Mass spectrum (IQ, m/z): 458 [M+1]+.

[00375] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.76 (br s, total 1H), 9.61 (br s, 1H), 7.88 - 7.57 ( m, 1H), 7.52 - 7.29 (m, 1H), 7.02 - 6.92 (m, 2H), 4.62 (br s, 2H), 2.56 - 2.41 (m , 2H), 2.29 - 2.13 (m, 5H), 1.93 - 1.72 (m, 2H), 1.65 (s, 6H), 0.09 (s, 9H). (Example 33)

[00376] N-(2-Fluoro-5-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-127) [Chemical Formula 51]

[00377] To a solution of 103 mg (0.273 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2(4H )-ethyl carboxylate synthesized in the same manner as in Reference Example 3 in 2 mL of 1,4-dioxane, 0.085 mL (0.65 mmol) of 2-fluoro-5-methylphenyl isocyanate was added at room temperature under a argon atmosphere and reacted at room temperature for 0.5 hour with stirring. Subsequently, 0.140 mL (1.29 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 16 hours with stirring.

[00378] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 40:60 (V/V)), and a fraction containing the compound of interest was subjected to extraction by addition of ethyl acetate. The obtained organic layer was washed with water, dried with anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol, then water was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 63.6 mg of the title compound (yield: 51%) as a white solid.

[00379] Mass spectrum (IQ, m/z): 458 [M+1]+.

[00380] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.79 (br s, total 1H), 9.62 (br s, 1H), 7.74 (br s, 1H ), 7.41 (br s, 1H), 7.04 (dd, J = 8.4, 10.8 Hz, 1H), 6.91 - 6.84 (m, 1H), 4.61 (br s, 2H), 2.56 - 2.40 (m, 2H), 2.30 - 2.14 (m, 5H), 1.93 - 1.72 (m, 2H), 1.65 (s, 6H), 0.09 (s, 9H). (Example 34)

[00381] N-(5-Fluoro-2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-361) [Chemical Formula 52]

[00382] To a solution of 103 mg (0.273 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2(4H )-ethyl carboxylate synthesized in the same manner as in Reference Example 3 in 2 mL of 1,4-dioxane, 0.085 mL (0.66 mmol) of 5-fluoro-2-methylphenyl isocyanate was added at room temperature under a argon atmosphere and reacted at room temperature for 1 hour with stirring. Subsequently, the reaction solution was cooled on ice, and 0.140 mL (1.29 mmol) of N,N-dimethylethane-1,2-diamine was added to it and then reacted at 0oC for 16 hours with stirring.

[00383] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 40:60 (V/V)), and a fraction containing the compound of interest was subjected to extraction by addition of ethyl acetate. The obtained organic layer was washed with water, dried with anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol, then water was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 42.7 mg of the title compound (yield: 34%) as a white solid.

[00384] Mass spectrum (IQ, m/z): 458 [M+1]+.

[00385] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.78 (br s, total 1H), 9.60 (br s, 1H), 7.79 - 7.50 ( m, 1H), 7.38 - 7.11 (m, 2H), 6.83 (dt, J = 2.8, 8.4 Hz, 1H), 4.63 (br s, 2H), 2, 58 - 2.39 (m, 2H), 2.27 - 2.12 (m, 5H), 1.92 - 1.73 (m, 2H), 1.66 (s, 6H), 0.09 ( s, 9H). (Example 35)

[00386] N-(2,4-Difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-101) [Chemical Formula 53]

[00387] To a solution of 103 mg (0.273 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2(4H )-ethyl carboxylate synthesized in the same way as in Reference Example 3 in 3 mL of 1,4-dioxane, 0.050 mL (0.42 mmol) of 2,4-difluoro-1-isocyanate-benzene was added at temperature room under an argon atmosphere and reacted at room temperature for 0.5 hour with stirring. Subsequently, 0.150 mL (1.38 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 1 hour with stirring.

[00388] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution in that order, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 65:35 (V/V)), and a fraction containing The compound of interest was separated into an organic layer and an aqueous layer by the addition of ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 50.2 mg of the title compound (yield: 40 %) as a white solid.

[00389] Mass spectrum (IQ, m/z): 462 [M+1]+.

[00390] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.77 (br s, total 1H), 9.62 (br s, 1H), 7.92 (br s, 1H ), 7.59 - 7.39 (m, 1H), 7.22 (ddd, J = 2.9, 9.1, 10.7 Hz, 1H), 7.03 - 6.96 (m, 1H ), 4.61 (br s, 2H), 2.56 - 2.40 (m, 2H), 2.26 - 2.14 (m, 2H), 1.91 - 1.72 (m, 2H) , 1.64 (s, 6H), 0.09 (s, 9H). (Example 36)

[00391] N-(2,5-Difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-103) [Chemical Formula 54]

[00392] To a solution of 105 mg (0.277 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2(4H )-ethyl carboxylate synthesized in the same manner as in Reference Example 3 in 3 mL of 1,4-dioxane, 0.048 mL (0.41 mmol) of 2,5-difluorophenyl isocyanate was added at room temperature under an atmosphere of argon and reacted at room temperature for 0.5 hour with stirring. Subsequently, 0.150 mL (1.38 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 0.5 hour with stirring.

[00393] An aqueous solution of 5% potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 65:35 (V/V)), and a fraction containing The compound of interest was separated into an organic layer and an aqueous layer by the addition of ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 55.2 mg of the title compound (yield: 43 %) as a white solid.

[00394] Mass spectrum (IQ, m/z): 462 [M+1]+.

[00395] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.29 & 11.80 (br s, total 1H), 9.74 - 9.58 (m, 1H), 8.00 - 7 .75 (m, 1H), 7.68 - 7.47 (m, 1H), 7.24 (ddd, J = 5.2, 9.2, 10.3 Hz, 1H), 6.94 - 6 .84 (m, 1H), 4.71 - 4.58 (m, 2H), 2.57- 2.41 (m, 2H), 2.27 - 2.14 (m, 2H), 1.92 - 1.73 (m, 2H), 1.66 (br s, 6H), 0.09 (s, 9H). (Example 37)

[00396] N-(2,5-Dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-379) [Chemical Formula 55]

[00397] To a solution of 103 mg (0.273 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2(4H )-ethyl carboxylate synthesized in the same manner as in Reference Example 3 in 3 mL of 1,4-dioxane, 0.060 mL (0.43 mmol) of 2,5-dimethylphenyl isocyanate was added at room temperature under an atmosphere of argon and reacted at room temperature for 0.5 hour with stirring. Subsequently, 0.150 mL (1.38 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 1 hour with stirring.

[00398] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution in that order, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 65:35 (V/V)), and an aqueous solution saturated sodium bicarbonate were added to a fraction containing the compound of interest, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with water and saturated saline in that order, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding dichloromethane, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 60.2 mg of the title compound (yield: 49%) as a white solid.

[00399] Mass spectrum (IQ, m/z): 454 [M+1]+.

[00400] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.78 (br s, total 1H), 9.67 - 9.49 (m, 1H), 7.67 - 7 .45 (m, 1H), 7.19 - 7.06 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.83 (dd, J = 1.3, 7 .6 Hz, 1H), 4.67 - 4.50 (m, 2H), 2.57- 2.38 (m, 2H), 2.27 - 2.09 (m, 8H), 1.91 - 1.72 (m, 2H), 1.65 (br s, 6H), 0.09 (s, 9H). (Example 38)

[00401] N-(2-Chloro-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-113) [Chemical Formula 56]

[00402] To a solution of 392 mg (0.890 mmol [calculation value with purity defined as 100%]) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5 Ethyl ,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 2.5 mL of 1,4-dioxane, 0.60 mL ( 3.4 mmol) of DIPEA and 807 mg (5.54 mmol) of 2-chloro-6-fluoroaniline were added at room temperature under a nitrogen atmosphere, reacted at 100°C for 1 hour with stirring, and then reacted at 130°C for 0.5 hour and additionally at 150°C for 2 hours in a microwave-heated reaction apparatus. Subsequently, 0.50 mL (4.6 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature for 1.5 hours with stirring.

[00403] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 65:35 ^ 50:50 (V/V)) , and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: dichloromethane:methanol = 100:0 ^ 99:1 ^ 98:2 ^ 97:3 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain a white solid (approximately 70 mg). The solid obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 50:50 ^ 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The obtained concentration residue was subjected to extraction three times with ethyl acetate, and subsequently, the entire organic layer was washed with saturated saline, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 57.1 mg of the compound of the title (yield: 13% [calculation value with starting material purity set to 100%]) as a white solid.

[00404] Mass spectrum (IQ, m/z): 478 [M+1]+.

[00405] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.69 (br s, total 1H), 9.64 - 9.54 (m, 1H), 8.09 - 7 .89 (m, 1H), 7.38 - 7.19 (m, 3H), 4.69 - 4.52 (m, 2H), 2.56 - 2.39 (m, 2H), 2.28 - 2.13 (m, 2H), 1.93 - 1.73 (m, 2H), 1.70 - 1.54 (m, 6H), 0.15 - 0.04 (m, 9H). (Example 39)

[00406] N-(2,4-Dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-377) [Chemical Formula 57]

[00407] To a solution of 121 mg (0.273 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.23 mL (1.3 mmol) of DIPEA and 0.17 mL (1 .4 mmol) of 2,4-dimethylaniline were added at room temperature under a nitrogen atmosphere and reacted at 100oC for 4 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.15 mL (1.4 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 2 hours with stirring.

[00408] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 65:35 ^ 50:50 ^ 40:60 (V /V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 99.6 mg of the compound of the title (yield: 80%) as a white solid.

[00409] Mass spectrum (IQ, m/z): 454 [M+1]+.

[00410] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.72 (br s, total 1H), 9.56 (s, 1H), 7.67 - 7.45 (m , 1H), 7.19 - 7.05 (m, 1H), 7.00 - 6.95 (m, 1H), 6.94 - 6.87 (m, 1H), 4.67 - 4.50 (m, 2H), 2.56 - 2.39 (m, 2H), 2.28 - 2.10 (m, 8H), 1.93 - 1.72 (m, 2H), 1.71 - 1 .55 (m, 6H), 0.09 (s, 9H). (Example 40)

[00411] 3-[1-(Ethyldimethylsilyl)cyclobutanecarboxamido]-N-(2-fluorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-4) [Chemical Formula 58]

[00412] To a solution of 118 mg (0.301 mmol) of 3-[1-(ethyldimethylsilyl)cyclobutanecarboxamido]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2( 4H)-ethyl carboxylate synthesized in the same manner as in Reference Example 7 in 2 mL of 1,4-dioxane, 0.050 mL (0.44 mmol) of 1-fluoro-2-isocyanatobenzene was added at room temperature under an atmosphere of nitrogen and reacted at room temperature for 50 minutes with stirring. Subsequently, 0.17 mL (1.6 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 1.5 hours with stirring.

[00413] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 65:35 ^ 50:50 (V/V)) , and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 50:50 (V/V)), and a fraction containing The compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The obtained concentrate was subjected to extraction three times with ethyl acetate, and subsequently, the entire organic layer was washed with saturated saline, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 65.1 mg of the compound of the title (yield: 47%) as a white solid.

[00414] Mass spectrum (IQ, m/z): 458 [M+1]+.

[00415] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.76 (br s, total 1H), 9.61 (br s, 1H), 7.92 - 7.48 ( m, 2H), 7.21 - 7.13 (m, 1H), 7.13 - 7.05 (m, 2H), 4.63 (br s, 2H), 2.56 - 2.42 (m , 2H), 2.29 - 2.14 (m, 2H), 1.93 - 1.73 (m, 2H), 1.65 (s, 6H), 0.92 (t, J = 7.9 Hz, 3H), 0.59 (q, J = 7.9 Hz, 2H), 0.08 (s, 6H). (Example 41)

[00416] 6,6-Dimethyl-N-(3-methylisothiazol-4-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-1035) [Chemical Formula 59]

[00417] To a solution of 142 mg (0.323 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.28 mL (1.6 mmol) of DIPEA and 197 mg (1.72 mmol) of 3-methylisothiazol-4-amine were added at room temperature under a nitrogen atmosphere and reacted at 100oC for 2 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.18 mL (1.7 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 1.5 hours with stirring.

[00418] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 70:30 ^ 60:40 ^ 50:50 ^ 40:60 (V /V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: dichloromethane:methanol = 99:1 ^ 98:2 ^ 97:3 ^ 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 102 mg of the title compound (yield: 71%) as a white solid.

[00419] Mass spectrum (IQ, m/z): 447 [M+1]+.

[00420] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.79 (br s, total 1H), 9.73 - 9.54 (m, 1H), 8.70 - 8 .54 (m, 1H), 8.00 - 7.74 (m, 1H), 4.71 - 4.53 (m, 2H), 2.59 - 2.40 (m, 2H), 2.33 (s, 3H), 2.27 - 2.14 (m, 2H), 1.91 - 1.73 (m, 2H), 1.72 - 1.57 (m, 6H), 0.09 (s , 9H). (Example 42)

[00421] 6,6-Dimethyl-N-(thiophen-2-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-1043) [Chemical Formula 60]

[00422] To a solution of 129 mg (0.341 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2(4H )-ethyl carboxylate synthesized in the same manner as in Reference Example 3 in 2 mL of 1,4-dioxane, 0.060 mL (0.59 mmol) of 2-isocyanatothiophene was added at room temperature under an argon atmosphere and reacted at room temperature for 1 hour with stirring. Subsequently, 0.185 mL (1.98 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 1 hour with stirring.

[00423] After completion of the reaction, an aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 56:44 ^ 35:65 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 79:21 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 68.7 mg of the title compound (yield: 47 %) as a white solid.

[00424] Mass spectrum (IQ, m/z): 432 [M+1]+.

[00425] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.63 (br s, total 1H), 9.60 (br s, 1H), 9.48 - 9.28 ( m, 1H), 6.84 - 6.64 (m, 3H), 4.61 (br s, 2H), 2.58 - 2.42 (m, 2H), 2.28 - 2.14 (m , 2H), 1.93 - 1.74 (m, 2H), 1.67 (s, 6H), 0.10 (s, 9H). (Example 43)

[00426] 6,6-Dimethyl-N-(thiophen-3-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-1045) [Chemical Formula 61]

[00427] To a solution of 129 mg (0.341 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2(4H )-ethyl carboxylate synthesized in the same manner as in Reference Example 3 in 2 mL of 1,4-dioxane, 0.060 mL (0.59 mmol) of 3-isocyanatothiophene was added at room temperature under an argon atmosphere and reacted at room temperature for 2 hours with stirring. Subsequently, 0.19 mL (2.0 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 1 hour with stirring.

[00428] After completion of the reaction, an aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 47:53 ^ 35:65 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 59:41 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 48.4 mg of the title compound (yield: 33 %) as a white solid.

[00429] Mass spectrum (IQ, m/z): 432 [M+1]+.

[00430] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.68 (s, total 1H), 9.58 (s, 1H), 8.62 - 8.46 (m, 1H), 7.38 - 7.29 (m, 2H), 7.28 - 7.18 (m, 1H), 4.66 - 4.49 (m, 2H), 2.59 - 2.38 ( m, 2H), 2.28 - 2.13 (m, 2H), 1.93 - 1.73 (m, 2H), 1.72 - 1.57 (m, 6H), 0.09 (s, 9H). (Example 44)

[00431] N-(2,6-Difluoro-4-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol- 5(1H)-carboxamide (Compound No. IV-615) [Chemical Formula 62]

[00432] To a solution of 164 mg (0.372 mmol [calculation value with purity defined as 100%]) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5 Ethyl ,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 1.5 mL of 1,4-dioxane, 0.33 mL ( 1.9 mmol) of DIPEA and 516 mg (3.24 mmol) of 2,6-difluoro-4-methoxyaniline were added at room temperature under a nitrogen atmosphere and reacted at 100oC for 9.5 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.20 mL (1.8 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature. environment for 4 hours with agitation.

[00433] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 75:25 ^ 60:40 ^ 45:55 (V/V)) , and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: 1,2-dichloroethane:methanol = 99:1 ^ 98:2 ^ 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 105 mg of the title compound (yield: 57% [calculation value with starting material purity set to 100%]) as a white solid.

[00434] Mass spectrum (IQ, m/z): 492 [M+1]+.

[00435] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.72 (br s, total 1H), 9.59 (s, 1H), 7.80 - 7.59 (m , 1H), 6.79 - 6.69 (m, 2H), 4.64 - 4.47 (m, 2H), 3.77 (s, 3H), 2.56 - 2.40 (m, 2H ), 2.28 - 2.11 (m, 2H), 1.92 - 1.71 (m, 2H), 1.69 - 1.53 (m, 6H), 0.13 - 0.05 (m , 9H). (Example 45)

[00436] N-(2-Fluoro-6-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-161) [Chemical Formula 63]

[00437] To a solution of 58.5 mg (0.344 mmol) of 2-fluoro-6-methoxybenzoic acid and 0.065 mL (0.37 mmol) of DIPEA in 2 mL of 1,4-dioxane, 0.075 mL (0. 35 mmol) of DPPA was added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled to room temperature, and then a 90 mg (0.24 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrole Ethyl [3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 3 in 2 mL of 1,4-dioxane was added to the reaction solution at room temperature and reacted at room temperature. environment for 1 hour with stirring. Subsequently, 0.125 mL (1.15 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 0.5 hour with stirring.

[00438] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline in that order, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 42.8 mg of the title compound (yield: 38 %) as a white solid.

[00439] Mass spectrum (IQ, m/z): 474 [M+1]+.

[00440] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.76 (br s, total 1H), 9.57 (br s, 1H), 7.46 - 7.27 ( m, 1H), 7.19 (dt, J = 6.5, 8.4 Hz, 1H), 6.88 - 6.83 (m, 1H), 6.82 - 6.75 (m, 1H) , 4.61 - 4.49 (m, 2H), 3.79 (s, 3H), 2.57 - 2.41 (m, 2H), 2.26 - 2.13 (m, 2H), 1 .90 - 1.71 (m, 2H), 1.69 - 1.54 (m, 6H), 0.09 (s, 9H). (Example 46)

[00441] N-[2-Fluoro-6-(trifluoromethyl)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c] pyrazol-5(1H)-carbo xamide (Compound No. IV-153) [Chemical Formula 64]

[00442] To a solution of 84.2 mg (0.405 mmol) of 2-fluoro-6-(trifluoromethyl)benzoic acid and 0.075 mL (0.43 mmol) of DIPEA in 2 mL of 1,4-dioxane, 0.085 mL (0.40 mmol) DPPA was added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled to room temperature, and then a 96 mg (0.25 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrole Ethyl [3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 2 mL of 1,4-dioxane was added to the reaction solution at room temperature and reacted at room temperature for 16 hours with stirring. Subsequently, 0.145 mL (1.33 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 1 hour with stirring.

[00443] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline in that order, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 60:40 ^ 80:20 (V/V)), and the operation of separating a fraction containing the compound of interest into an organic layer and an aqueous layer was carried out by adding ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was washed with saturated saline, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 33.9 mg of the title compound (yield: 26 %) as a white solid.

[00444] Mass spectrum (IQ, m/z): 512 [M+1]+.

[00445] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.78 (br s, total 1H), 9.68 - 9.57 (m, 1H), 8.00 - 7 .82 (m, 1H), 7.62 - 7.49 (m, 3H), 4.66 - 4.50 (m, 2H), 2.56 - 2.41 (m, 2H), 2.27 - 2.14 (m, 2H), 1.92 - 1.72 (m, 2H), 1.67 - 1.51 (m, 6H), 0.09 (s, 9H). (Example 47)

[00446] N-(5-Chloro-2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-367) [Chemical Formula 65]

[00447] To a solution of 150 mg (0.340 mmol [calculation value with purity defined as 100%]) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5 Ethyl ,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.474 mL (2.72 mmol ) of DIPEA and 0.204 mL (1.70 mmol) of 5-chloro-2-methylaniline were added at room temperature under an argon atmosphere, reacted at 100oC for 6 hours with stirring, and subsequently reacted at room temperature for 60 hours. Subsequently, 0.318 mL (3.40 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 1 hour with stirring.

[00448] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: 1,2-dichloroethane:methanol = 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The concentrate obtained was subjected to extraction with ethyl acetate, and the entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 50 mg of the title compound (yield: 31% [ calculation value with the purity of the starting material set to 100%]) as a white solid.

[00449] Mass spectrum (IQ, m/z): 474 [M+1]+.

[00450] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.79 (br s, total 1H), 9.70 - 9.55 (m, 1H), 7.84 - 7 .58 (m, 1H), 7.53 - 7.35 (m, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.06 (dd, J = 2.3, 8 .2 Hz, 1H), 4.73 - 4.52 (m, 2H), 2.58 - 2.39 (m, 2H), 2.29 - 2.11 (m, 5H), 1.93 - 1.73 (m, 2H), 1.72 - 1.56 (m, 6H), 0.09 (s, 9H). (Example 48)

[00451] N-(2,5-Dichlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-197) [Chemical Formula 66]

[00452] To a solution of 344 mg (0.909 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2(4H )-ethyl carboxylate synthesized in the same manner as in Reference Example 3 in 6 mL of 1,4-dioxane, 209 mg (1.11 mmol) of 1,4-dichloro-2-isocyanatobenzene were added at room temperature under a argon atmosphere and reacted at room temperature for 2 hours with stirring.

[00453] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 93:7 ^ 72:28 (V/V)), and a fraction containing 5-[(2,5-dichlorophenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H )-ethyl carboxylate was concentrated under reduced pressure.

[00454] To a solution of the concentration residue obtained in 3 mL of 1,4-dioxane, 0.49 mL (5.3 mmol) of N,N-dimethylethane-1,2-diamine was added and then reacted at temperature environment for 1 hour with stirring.

[00455] After completion of the reaction, an aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 50:50 ^ 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 172 mg of the title compound (yield: 38%) as a white solid.

[00456] Mass spectrum (IQ, m/z): 494 [M+1]+.

[00457] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.31 & 11.84 (br s, total 1H), 9.77 - 9.54 (m, 1H), 8.03 - 7 .81 (m, 1H), 7.81 - 7.56 (m, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.16 (dd, J = 2.5, 8 .6 Hz, 1H), 4.65 (br s, 2H), 2.57 - 2.40 (m, 2H), 2.29 - 2.13 (m, 2H), 1.92 - 1.74 (m, 2H), 1.67 (s, 6H), 0.09 (s, 9H). (Example 49)

[00458] N-(2-Cyclopropylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-39) [Chemical Formula 67]

[00459] To a solution of 257 mg (1.59 mmol) of 2-cyclopropylbenzoic acid in 8 mL of toluene, 0.313 mL (1.80 mmol) of DIPEA and 0.353 mL (1.64 mmol) of DPPA were added to the room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled to room temperature, and then a solution of 400 mg (1.06 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrole Ethyl [3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 2 mL of toluene was added to the reaction solution at 0oC and reacted at 0oC for 1 hour with stirring.

[00460] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 60:40 (V/V)), and a fraction containing5 -[(2-cyclopropylphenyl)carbamoyl]-6,6-dimethyl-3 -[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate Ethyl was concentrated under reduced pressure.

[00461] To a solution of the concentration residue obtained in 5 mL of 1,4-dioxane, 0.494 mL (5.28 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and then reacted at room temperature for 1 hour with stirring.

[00462] After completion of the reaction, a saturated aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 40:60 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 291 mg of the title compound (yield: 59%) as a white solid.

[00463] Mass spectrum (IQ, m/z): 466 [M+1]+.

[00464] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.81 (br s, total 1H), 9.60 (br s, 1H), 7.73 - 7.62 ( m, 1H), 7.55 (br s, 1H), 7.18 - 7.08 (m, 1H), 7.07 - 7.01 (m, 1H), 7.00 - 6.93 (m , 1H), 4.66 (br s, 2H), 2.60 - 2.39 (m, 2H), 2.28 - 2.12 (m, 2H), 2.02 - 1.91 (m, 1H), 1.89 - 1.75 (m, 2H), 1.68 (s, 6H), 0.97 - 0.86 (m, 2H), 0.65 - 0.54 (m, 2H) , 0.09 (s, 9H). (Example 50)

[00465] N-(2,6-Dichlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. IV-199) [Chemical Formula 68]

[00466] To a solution of 500 mg (1.32 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2 Ethyl (4H)-carboxylate synthesized in the same way as in Reference Example 3 in 6 mL of 1,4-dioxane, 260 mg (1.38 mmol) of 1,3-dichloro-2-isocyanatobenzene were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour with stirring. Subsequently, 25.0 mg (0.133 mmol) of 1,3-dichloro-2-isocyanatobenzene was added to the reaction solution and further reacted for 1.5 hours with stirring. Then, the reaction solution was cooled on ice, and 0.580 mL (5.33 mmol) of N,N-dimethylethane-1,2-diamine was added to it and then reacted at room temperature for 16 hours with stirring.

[00467] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DNH silica gel, elution solvent: 1,2-dichloroethane:methanol = 100:0 ^ 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 52:48 (V/V)), and a fraction containing the compound of interest was collected, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with water, dried with anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding aqueous acetonitrile and then the solution was freeze-dried to obtain 136 mg of the title compound (yield: 21%) as a white solid.

[00468] Mass spectrum (IQ, m/z): 494 [M+1]+.

[00469] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.75 (br s, total 1H), 9.60 (s, 1H), 8.22 - 8.01 (m , 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.28 (t, J = 8.1 Hz, 1H), 4.68 - 4.54 (m, 2H), 2 .56 - 2.41 (m, 2H), 2.26 - 2.13 (m, 2H), 1.92 - 1.72 (m, 2H), 1.70 - 1.55 (m, 6H) , 0.09 (s, 9H). (Example 51)

[00470] 6,6-Dimethyl-N-(2,4,6-trifluorophenyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-599) [Chemical Formula 69]

[00471] To a solution of 350 mg (1.99 mmol) of 2,4,6-trifluorobenzoic acid and 0.370 mL (2.12 mmol) of DIPEA in 2 mL of toluene, 0.430 mL (2.00 mmol) of DPPA was added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled to room temperature, and then a 500 mg (1.32 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrole Ethyl [3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 2 mL of toluene was added to the reaction solution at room temperature and reacted at room temperature for 1 hour with agitation. Subsequently, 0.720 mL (6.61 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 2 hours with stirring.

[00472] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution in that order, dried with anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 52:48 (V/V)), and a fraction containing the compound of interest was collected, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with water, dried with anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 236 mg of the title compound (yield: 37%) as a white solid.

[00473] Mass spectrum (IQ, m/z): 480 [M+1]+.

[00474] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.73 (br s, total 1H), 9.61 (s, 1H), 8.00 - 7.81 (m , 1H), 7.26 - 7.13 (m, 2H), 4.59 (br s, 2H), 2.55 - 2.41 (m, 2H), 2.26 - 2.13 (m, 2H), 1.91 - 1.72 (m, 2H), 1.63 (br s, 6H), 0.09 (s, 9H). (Example 52)

[00475] N-(2-Ethyl-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-389) [Chemical Formula 70] Reaction 1.

[00476] To a solution of 79.6 mg (0.210 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2 Ethyl (4H)-carboxylate synthesized in the same way as in Reference Example 3 in 1.5 mL of 1,4-dioxane, 0.040 mL (0.26 mmol) of 1-ethyl-2-isocyanate-3-methylbenzene was added at room temperature under a nitrogen atmosphere and reacted at room temperature for 2 hours with stirring. Subsequently, 0.110 mL (1.01 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 17 hours with stirring. Reaction 2.

[00477] To a solution of 81.3 mg (0.215 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2 Ethyl (4H)-carboxylate synthesized in the same manner as in Reference Example 3 in a mixed solvent of 1.5 mL of 1,4-dioxane and 1.0 mL of THF, 0.040 mL (0.26 mmol) of 1 -ethyl-2-isocyanate-3-methylbenzene was added at 0oC under a nitrogen atmosphere and reacted at 0oC for 2 hours with stirring. Subsequently, 0.110 mL (1.01 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 17 hours with stirring. Reaction 3.

[00478] To a solution of 79.7 mg (0.211 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2 Ethyl (4H)-carboxylate synthesized in the same way as in Reference Example 3 in 1.5 mL of dichloromethane, 0.040 mL (0.26 mmol) of 1-ethyl-2-isocyanate-3-methylbenzene was added at room temperature under a nitrogen atmosphere and reacted at room temperature for 2 hours with stirring. Subsequently, 0.110 mL (1.01 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 17 hours with stirring. Reaction 4.

[00479] To a solution of 79.7 mg (0.211 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2 Ethyl (4H)-carboxylate synthesized in the same way as in Reference Example 3 in 1.5 mL of dichloromethane, 0.040 mL (0.26 mmol) of 1-ethyl-2-isocyanate-3-methylbenzene was added at 0oC under a nitrogen atmosphere and reacted at 0oC for 2 hours with stirring. Subsequently, 0.110 mL (1.01 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 17 hours with stirring. Reaction 5.

[00480] To a solution of 80.2 mg (0.212 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2 Ethyl (4H)-carboxylate synthesized in the same way as in Reference Example 3 in 1.5 mL of dichloromethane, 0.080 mL (0.46 mmol) of DIPEA and 0.040 mL (0.26 mmol) of 1-ethyl-2 -isocyanate-3-methylbenzene were added in this order at 0oC under a nitrogen atmosphere and reacted at 0oC for 2 hours with stirring. Subsequently, 0.110 mL (1.01 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 17 hours with stirring. Reaction 6.

[00481] To a solution of 79.7 mg (0.211 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazol-2 Ethyl (4H)-carboxylate synthesized in the same way as in Reference Example 3 in 1.5 mL of pyridine, 0.040 mL (0.26 mmol) of 1-ethyl-2-isocyanate-3-methylbenzene was added at 0oC under a nitrogen atmosphere and reacted at 0oC for 2 hours with stirring. Subsequently, 0.110 mL (1.01 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 17 hours with stirring.

[00482] After completion of the reaction, ethyl acetate was added to the reaction solution of reaction 3, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: 1,2-dichloroethane:methanol = 98:2 ^ 97:3 ^ 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 78.6 mg of a white foam.

[00483] Also, the reaction solutions from reactions 1, 2, 4, 5, and 6 were combined, and then, the same purification operation, as above, was carried out to obtain 440 mg of a white foam.

[00484] These two products thus obtained were combined, dissolved in aqueous acetonitrile, and the solution was freeze-dried to obtain 429 mg of the title compound (yield: 72%) as a white solid.

[00485] Mass spectrum (IQ, m/z): 468 [M+1]+.

[00486] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.74 (br s, total 1H), 9.56 (s, 1H), 7.51 (br s, 1H) , 7.11 - 7.00 (m, 3H), 4.59 (br s, 2H), 2.57 (q, J = 7.5 Hz, 2H), 2.53 - 2.41 (m, 2H), 2.26 - 2.12 (m, 5H), 1.88 - 1.73 (m, 2H), 1.63 (s, 6H), 1.11 (t, J = 7.5 Hz , 3H), 0.09 (s, 9H). (Example 53)

[00487] N-(2-Bromophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)- carboxamide (Compound No. IV-15) [Chemical Formula 71]

[00488] To a solution of 152 mg (0.345 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 and 0.300 mL (1.72 mmol) of DIPEA in 3 mL of 1,4-dioxane, 182 mg (1.06 mmol) of 2-bromoaniline were added at room temperature under an argon atmosphere and reacted at 100oC for 30 hours with stirring. The reaction solution was cooled to room temperature, and then 0.185 mL (1.70 mmol) of N,N-dimethylethane-1,2-diamine was added to the room temperature reaction solution and reacted at room temperature for 0 .5 hours with stirring.

[00489] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution in that order, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 50:50), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 65:35 (V/V)), and the Separation of a fraction containing the compound of interest into an organic layer and an aqueous layer was carried out by adding ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure. The solid obtained was dissolved in aqueous acetonitrile and the solution was freeze-dried. The solid obtained was subjected again to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 50:50), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 20.5 mg of the title compound (yield: 12%) as a white solid.

[00490] Mass spectrum (IQ, m/z): 504 [M+1]+.

[00491] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.30 & 11.89 (br s, total 1H), 9.74 - 9.57 (m, 1H), 7.79 - 7 .54 (m, 3H), 7.36 - 7.29 (m, 1H), 7.08 - 7.00 (m, 1H), 4.69 - 4.55 (m, 2H), 2.58 - 2.40 (m, 2H), 2.28 - 2.14 (m, 2H), 1.91 - 1.74 (m, 2H), 1.73 - 1.57 (m, 6H), 0 .15 - 0.04 (m, 9H). (Example 54)

[00492] N-(5-Chloro-2-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-111) [Chemical Formula 72]

[00493] To a solution of 346 mg (1.98 mmol) of 5-chloro-2-fluorobenzoic acid in 10 mL of 1,4-dioxane, 0.391 mL (2.25 mmol) of DIPEA and 0.441 mL (2. 05 mmol) of DPPA were added in this order at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100°C for 1 hour with stirring. The reaction solution was cooled to room temperature, and then a 500 mg (1.32 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrole Ethyl [3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 1 mL of 1,4-dioxane was added to the reaction solution at room temperature and reacted at room temperature for 2 hours with stirring.

[00494] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 95:5 ^ 75:25 (V/V)), and a fraction containing 5-[(5-chloro-2-fluorophenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2 Ethyl (4H)-carboxylate was concentrated under reduced pressure.

[00495] To a solution of the concentration residue obtained in 5 mL of 1,4-dioxane, 0.617 mL (6.60 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and then reacted at room temperature for 1 hour with stirring.

[00496] After completion of the reaction, an aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 55:45 ^ 45:55 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The concentrate obtained was subjected to extraction with ethyl acetate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 141 mg of the title compound (yield: 22%) as a white solid.

[00497] Mass spectrum (IQ, m/z): 478 [M+1]+.

[00498] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.29 & 11.77 (br s, total 1H), 9.72 - 9.58 (m, 1H), 8.05 - 7 .84 (m, 1H), 7.84 - 7.67 (m, 1H), 7.30 - 7.19 (m, 1H), 7.17 - 7.08 (m, 1H), 4.71 - 4.55 (m, 2H), 2.57 - 2.40 (m, 2H), 2.28 - 2.13 (m, 2H), 1.92 - 1.74 (m, 2H), 1 .73 - 1.59 (m, 6H), 0.14 - 0.04 (m, 9H). (Example 55)

[00499] N-(2-Chloro-5-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-191) [Chemical Formula 73]

[00500] To a solution of 346 mg (1.98 mmol) of 2-chloro-5-fluorobenzoic acid in 5 mL of 1,4-dioxane, 0.391 mL (2.25 mmol) of DIPEA and 0.441 mL (2, 05 mmol) of DPPA were added in this order at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled to room temperature, and then a 500 mg (1.32 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrole Ethyl [3,4-c]pyrazol-2(4H)-carboxylate in 1 mL of 1,4-dioxane synthesized in the same manner as in Reference Example 3 was added to the reaction solution at room temperature and reacted at room temperature for 2 hours with stirring.

[00501] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 95:5 ^ 75:25 (V/V)), and a fraction containing 5-[(2-chloro-5-fluorophenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2 Ethyl (4H)-carboxylate was concentrated under reduced pressure.

[00502] To a solution of the residue of the concentration obtained in 5 mL of 1,4-dioxane, 0.62 mL (6.6 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and then reacted at room temperature for 1 hour with stirring.

[00503] After completion of the reaction, an aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 55:45 ^ 45:55 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The concentrate obtained was subjected to extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 163 mg of the title compound (yield: 26%) as a white solid.

[00504] Mass spectrum (IQ, m/z): 478 [M+1]+.

[00505] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.32 & 11.87 (br s, total 1H), 9.75 - 9.58 (m, 1H), 7.86 - 7 .54 (m, 2H), 7.50 (dd, J = 5.9, 8.9 Hz, 1H), 7.00 - 6.91 (m, 1H), 4.73 - 4.54 (m , 2H), 2.57 - 2.39 (m, 2H), 2.29 - 2.12 (m, 2H), 1.93 - 1.75 (m, 2H), 1.74 - 1.57 (m, 6H), 0.15 - 0.03 (m, 9H). (Example 56)

[00506] 6,6-Dimethyl-N-(2,3,6-trifluorophenyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-597) [Chemical Formula 74]

[00507] To a suspension of 356 mg (2.02 mmol) of 2,3,6-trifluorobenzoic acid in 4.0 mL of toluene, 0.380 mL (2.73 mmol) of triethylamine and 0.430 mL (2.00 mmol) ) of DPPA were added in this order at room temperature under an argon atmosphere and reacted at 100oC for 1 hour with stirring. The reaction solution was cooled to room temperature, then added to a solution of 509 mg (1.35 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrole Ethyl [3, 4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 4.0 mL of toluene at 0oC, and reacted at 0oC for 1.5 hours with stirring. Subsequently, 0.730 mL (6.71 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 2 hours with stirring.

[00508] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, n-hexane:ethyl acetate = 80:20 ^ 70:30 ^ 60:40 ^ 50:50), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: 1,2-dichloroethane:methanol = 98:2 ^ 97:3 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The deposited solid was collected by filtration, washed with water, and then dried under reduced pressure. Subsequently, the obtained solid was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 44.6 mg of the title compound (yield: 7%) as a white solid.

[00509] Mass spectrum (IQ, m/z): 480 [M+1]+.

[00510] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.71 (br s, total 1H), 9.61 (s, 1H), 8.18 (br s, 1H) , 7.41 - 7.29 (m, 1H), 7.18 - 7.10 (m, 1H), 4.62 (br s, 2H), 2.58 - 2.40 (m, 2H), 2.28 - 2.12 (m, 2H), 1.93 - 1.72 (m, 2H), 1.63 (br s, 6H), 0.09 (s, 9H). (Example 57)

[00511] N-(2-Chloro-6-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-247) [Chemical Formula 75]

[00512] To a solution of 370 mg (1.98 mmol) of 2-chloro-6-methoxybenzoic acid in 10 mL of 1,4-dioxane, 0.391 mL (2.25 mmol) of DIPEA and 0.427 mL (1. 98 mmol) of DPPA were added in this order at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled to room temperature, and then a 500 mg (1.32 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrole Ethyl [3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 1 mL of 1,4-dioxane was added to the reaction solution at room temperature and reacted at room temperature for 2 hours with stirring.

[00513] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 72:28 ^ 30:70 (V/V)), and a fraction containing 5-[(2-chloro-6-methoxyphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2 Ethyl (4H)-carboxylate was concentrated under reduced pressure.

[00514] To a solution of the concentration residue obtained in 3 mL of 1,4-dioxane, 0.617 mL (6.60 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and then reacted at room temperature for 15 hours with stirring.

[00515] After completion of the reaction, an aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 70:30 ^ 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The concentrate obtained was subjected to extraction with ethyl acetate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 172 mg of the title compound (yield: 27%) as a white solid.

[00516] Mass spectrum (IQ, m/z): 490 [M+1]+.

[00517] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.75 (br s, total 1H), 9.55 (br s, 1H), 7.64 - 7.43 ( m, 1H), 7.20 (t, J = 8.3 Hz, 1H), 7.08 - 6.95 (m, 2H), 4.66 - 4.47 (m, 2H), 3.78 (s, 3H), 2.56 - 2.39 (m, 2H), 2.28 - 2.11 (m, 2H), 1.93 - 1.72 (m, 2H), 1.71 - 1 .52 (m, 6H), 0.09 (s, 9H). (Example 58)

[00518] N-[2-(1,1-Difluoroethyl)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c] pyrazole-5(1H)-carboxamide (Compound No. IV-45) [Chemical Formula 76]

[00519] To a suspension of 334 mg (1.79 mmol) of 2-(1,1-difluoroethyl)benzoic acid in 4.0 mL of toluene, 0.410 mL (2.35 mmol) of DIPEA and 0.390 mL (1 .81 mmol) of DPPA were added in this order at room temperature under a nitrogen atmosphere and reacted at room temperature for 50 minutes and subsequently at 100oC for 75 minutes with stirring. The reaction solution was cooled to room temperature and then diluted with 2.0 mL of dichloromethane, and subsequently, this solution was added to a solution of 462 mg (1.22 mmol) of 6,6-dimethyl-3-[ Ethyl 1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 3 in 4.0 mL of dichloromethane at 0oC and reacted at 0oC for 2 hours with stirring.

[00520] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction three times with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 70:30 ^ 50:50 ^ 40:60 ^ 30: 70 (V/V)), and a fraction containing 5-{[2-(1,1-difluoroethyl)phenyl]carbamoyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5, Ethyl 6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate was concentrated under reduced pressure.

[00521] To a solution of 334 mg (0.594 mmol) of 5-{[2-(1,1-difluoroethyl)phenyl]carbamoyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]- Ethyl 5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate obtained in a mixed solvent of 3.0 mL of THF and 0.50 mL of ethanol, 0.330 mL (3.03 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under a nitrogen atmosphere and then reacted at room temperature for 1.5 hours with stirring.

[00522] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction three times with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 65:35 ^ 50:50 (V/V)) , and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 246 mg of the title compound (yield: 41%) as a white solid.

[00523] Mass spectrum (IQ, m/z): 490 [M+1]+.

[00524] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.29 & 11.86 (br s, total 1H), 9.60 (br s, 1H), 7.77 - 7.63 ( m, 1H), 7.54 - 7.35 (m, 3H), 7.27 - 7.17 (m, 1H), 4.54 (br s, 2H), 2.57 - 2.39 (m , 2H), 2.29 - 2.12 (m, 2H), 1.99 (t, J = 19.4 Hz, 3H), 1.90 - 1.74 (m, 2H), 1.66 ( br s, 6H), 0.09 (s, 9H). (Example 59)

[00525] N-(6-Chloro-2-fluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carboxamide (Compound No. IV-629) [Chemical Formula 77]

[00526] To a suspension of 349 mg (1.85 mmol) of 6-chloro-2-fluoro-3-methylbenzoic acid in 4.0 mL of toluene, 0.430 mL (2.47 mmol) of DIPEA and 0.400 mL ( 1.86 mmol) of DPPA were added in this order at room temperature under a nitrogen atmosphere and reacted at room temperature for 45 minutes and subsequently at 90oC for 1.5 hours with stirring. The reaction solution was cooled to room temperature and then diluted with 2.0 mL of dichloromethane, and subsequently, this solution was added dropwise to a solution of 443 mg (1.17 mmol) of 6,6-dimethyl-3 Ethyl -[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 3 in 4.0 mL of dichloromethane at 0oC and reacted at 0oC for 1.5 hours with stirring.

[00527] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction three times with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 70:30 ^ 60:40 ^ 50:50 ^ 40: 60 (V/V)), and a fraction containing 5-[(6-chloro-2-fluoro-3-methylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5 Ethyl ,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate was concentrated under reduced pressure.

[00528] To a solution of 401 mg (0.711 mmol) of 5-[(6-chloro-2-fluoro-3-methylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido] Ethyl -5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate obtained in 3.0 mL of THF, 0.400 mL (3.68 mmol) of N,N-dimethylethane-1 ,2-diamine was added at room temperature under a nitrogen atmosphere and then reacted at room temperature for 1.5 hours with stirring.

[00529] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction three times with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 65:35 ^ 50:50 ^ 40:60 (V /V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 285 mg of the title compound (yield: 50%) as a white solid.

[00530] Mass spectrum (IQ, m/z): 492 [M+1]+.

[00531] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.69 (br s, total 1H), 9.61 - 9.53 (m, 1H), 8.03 - 7 .83 (m, 1H), 7.26 - 7.12 (m, 2H), 4.68 - 4.50 (m, 2H), 2.57 - 2.39 (m, 2H), 2.28 - 2.13 (m, 5H), 1.93 - 1.72 (m, 2H), 1.70 - 1.54 (m, 6H), 0.17 - 0.03 (m, 9H). (Example 60)

[00532] N-[2-Fluoro-6-(methoxy-d3)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carboxamide (Compound No. IV-177) [Chemical Formula 78]

[00533] To a solution of 300 mg (0.680 mmol [calculation value with purity defined as 100%]) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5 Ethyl ,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 5 mL of 1,4-dioxane, 0.592 mL (3.40 mmol ) of DIPEA and 294 mg (2.04 mmol) of 2-fluoro-6-(methoxy-d3)aniline synthesized in the same manner as in Reference Example 9 were added at room temperature under an argon atmosphere and reacted at room temperature for 66 hours and subsequently at 100oC for 20 hours with stirring.

[00534] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 95:5 ^ 30:70 (V/V)), and a fraction containing 5-{[2-fluoro-6-(methoxy-d3)phenyl]carbamoyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4- Ethyl c]pyrazol-2(4H)-carboxylate was concentrated under reduced pressure.

[00535] To a solution of the concentration residue obtained in 3 mL of 1,4-dioxane, 0.318 mL (3.40 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and then reacted at room temperature for 1 hour with stirring.

[00536] After completion of the reaction, a saturated aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 65:35 ^ 40:60 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 77.8 mg of the title compound (yield: 24% [calculation value with the purity of the starting material set to 100%]) as a white solid.

[00537] Mass spectrum (IQ, m/z): 477 [M+1]+.

[00538] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.73 (br s, total 1H), 9.56 (s, 1H), 7.46 - 7.25 (m , 1H), 7.18 (dt, J = 6.5, 8.4 Hz, 1H), 6.88 - 6.82 (m, 1H), 6.82 - 6.74 (m, 1H), 4.65 - 4.45 (m, 2H), 2.56 - 2.39 (m, 2H), 2.28 - 2.11 (m, 2H), 1.92 - 1.72 (m, 2H) ), 1.70 - 1.53 (m, 6H), 0.09 (s, 9H). (Example 61)

[00539] N-[2-Chloro-6-(trifluoromethyl)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c] pyrazol-5(1H)-carboxamide (Compound No. IV-239) [Chemical Formula 79]

[00540] To a solution of 389 mg (1.73 mmol) of 2-chloro-6-(trifluoromethyl)benzoic acid and 0.32 mL (1.8 mmol) of DIPEA in 2 mL of toluene, 0.37 mL (1.7 mmol) DPPA was added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled to room temperature, and then a solution of 450 mg (1.19 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrole Ethyl [3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 3 in 2 mL of toluene was added to the reaction solution at room temperature and reacted at room temperature for 12 hours with agitation. Subsequently, 0.82 mL (7.5 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted at room temperature for 2 hours with stirring.

[00541] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution in that order, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, n-hexane:ethyl acetate = 80:20 ^ 30:70), and a fraction containing the compound of interest was concentrated under pressure reduced. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous dipotassium bisphosphate solution = 55:45 (V/V)), and a fraction containing The compound of interest was separated into an organic layer and an aqueous layer by the addition of ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The obtained organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 29.5 mg of the title compound (yield: 5%) as a white solid.

[00542] Mass spectrum (DUIS, m/z): 528 [M+1]+.

[00543] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.72 (br s, total 1H), 9.58 (s, 1H), 8.16 - 7.98 (m , 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.73 - 7.68 (m, 1H), 7.50 (t, J = 8.0 Hz, 1H), 4 .78 - 4.38 (m, 2H), 2.55- 2.41 (m, 2H), 2.27 - 2.12 (m, 2H), 1.91 - 1.72 (m, 2H) , 1.70 - 1.52 (m, 6H), 0.15 - 0.03 (m, 9H). (Example 62)

[00544] N-(2-Fluoro-6-methoxy-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carbo xamide (Compound No. IV-689) [Chemical Formula 80]

[00545] To a solution of 276 mg (1.50 mmol) of 2-fluoro-6-methoxy-3-methylbenzoic acid synthesized in the same manner as in Reference Example 11 in 2 mL of dehydrated toluene, 0.350 mL (2, 00 mmol) of DIPEA and 0.320 mL (1.49 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a solution of 475 mg (1.25 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4 Ethyl -c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 2 ml of dehydrated toluene was added thereto at room temperature and reacted at room temperature for 1 hour with stirring.

[00546] After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing 5-[(2-fluoro-6-methoxy-3-methylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4- Ethyl c]pyrazol-2(4H)-carboxylate was concentrated under reduced pressure and dried under reduced pressure.

[00547] To a solution of the concentration residue obtained in 2 mL of dehydrated dichloromethane, 0.400 mL (3.67 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an argon atmosphere and reacted at room temperature for 1 hour with stirring.

[00548] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with dichloromethane. The organic layer obtained was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in that order, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 466 mg of the title compound (yield: 76%) as a white solid.

[00549] Mass spectrum (IQ, m/z): 488 [M+1]+.

[00550] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.23 & 11.75 (br s, total 1H), 9.56 (s, 1H), 7.33 (br s, 1H) , 7.08 - 7.01 (m, 1H), 6.78 - 6.71 (m, 1H), 4.55 (br s, 2H), 3.75 (s, 3H), 2.55 - 2.41 (m, 2H), 2.24 - 2.13 (m, 5H), 1.88 - 1.75 (m, 2H), 1.62 (s, 6H), 0.09 (s, 9H). (Example 63)

[00551] N-(2,6-Difluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide (Compound No. IV-609) [Chemical Formula 81]

[00552] To a solution of 341 mg (1.98 mmol) of 2,6-difluoro-3-methylbenzoic acid [purchased from Aurum Pharmatech LLC] in 8 mL of toluene, 0.391 mL (2.24 mmol) of DIPEA and 0.44 mL (2.0 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a 500 mg (1.32 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4 Ethyl -c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 2 ml of toluene was added thereto at room temperature and reacted at room temperature for 2 hours with stirring.

[00553] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 70:30 (v/v)), and a fraction containing 5-[(2,6-difluoro-3-methylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole Ethyl -2(4H)-carboxylate was concentrated under reduced pressure.

[00554] To a solution of the concentration residue obtained in 5 mL of 1,4-dioxane, 0.617 mL (6.60 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 1 hour with stirring.

[00555] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 40:60 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 409 mg of the title compound (yield: 65%) as a white solid.

[00556] Mass spectrum (IQ, m/z): 476 [M+1]+.

[00557] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.70 (br s, total 1H), 9.58 (s, 1H), 7.99 - 7.75 (m , 1H), 7.20 - 7.07 (m, 1H), 7.03 - 6.92 (m, 1H), 4.68 - 4.49 (m, 2H), 2.56 - 2.40 (m, 2H), 2.27 - 2.13 (m, 5H), 1.92 - 1.74 (m, 2H), 1.70 - 1.55 (m, 6H), 0.09 (s , 9H). (Example 64)

[00558] N-[2-(Difluoromethoxy)-6-fluorophenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carb oxamide (Compound No. IV-169) [Chemical Formula 82]

[00559] To a solution of 325 mg (1.58 mmol) of 2-(difluoromethoxy)-6-fluorobenzamide synthesized in the same way as in Reference Example 12 in 10 mL of toluene, 1.02 g (3.17 mmol ) of iodobenzene diacetate were added at room temperature under an argon atmosphere and reacted at room temperature for 10 minutes and subsequently at 60oC for 0.5 hour with stirring. The reaction solution was cooled, and then 400 mg (1.06 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c] Ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 were added at room temperature and reacted at room temperature for 1 hour with stirring.

[00560] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 70:30 (v/v)), and a fraction containing 5-{[2-(difluoromethoxy)-6-fluorophenyl]carbamoyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole Ethyl -2(4H)-carboxylate was concentrated under reduced pressure.

[00561] To a solution of the concentration residue obtained in 5 mL of 1,4-dioxane, 0.395 mL (4.23 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 16 hours with stirring.

[00562] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 40:60 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 367 mg of the title compound (yield: 68%) as a white solid.

[00563] Mass spectrum (IQ, m/z): 510 [M+1]+.

[00564] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.69 (br s, total 1H), 9.59 (s, 1H), 7.96 - 7.71 (m , 1H), 7.31 (dt, J = 6.2, 8.4 Hz, 1H), 7.23 - 7.12 (m, 1H), 7.08 - 7.03 (m, 1H), 7.01 (t, J = 74.3 Hz, 1H), 4.68 - 4.48 (m, 2H), 2.57 - 2.40 (m, 2H), 2.27 - 2.12 ( m, 2H), 1.94 - 1.73 (m, 2H), 1.70 - 1.54 (m, 6H), 0.09 (s, 9H). (Example 65)

[00565] N-(2-Bromo-6-chlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-207) [Chemical Formula 83]

[00566] To a suspension of 374 mg (1.59 mmol) of 2-bromo-6-chlorobenzoic acid in 4.0 mL of dehydrated toluene, 0.370 mL (2.12 mmol) of DIPEA and 0.340 mL (1.58 mmol) of DPPA were added at room temperature under a nitrogen atmosphere and reacted at room temperature for 0.5 hour and subsequently at 90oC for 1 hour with stirring. The reaction solution was cooled, then added to a solution of 398 mg (1.05 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4 -c]pyrazol-2(4H)-ethyl carboxylate synthesized in the same way as in Reference Example 3 in 4.0 mL of dichloromethane dehydrated at 0oC and reacted at 0oC for 3 hours with stirring.

[00567] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction three times with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, n-hexane:ethyl acetate = 80:20 ^ 75:25 ^ 65:35), and a fraction containing 5-[(2 -bromo-6-chlorophenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate of ethyl was concentrated under reduced pressure.

[00568] To a solution of the residue of the concentration obtained in 3.0 mL of THF, 0.450 mL (4.13 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under a nitrogen atmosphere and then reacted at room temperature for 2 hours with stirring.

[00569] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction three times with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, n-hexane:ethyl acetate = 80:20 ^ 65:35 ^ 50:50), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 339 mg of the title compound (yield: 60%) as a white solid.

[00570] Mass spectrum (IQ, m/z): 538 [M+1]+.

[00571] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.71 (br s, total 1H), 9.58 (s, 1H), 8.28 - 7.99 (m , 1H), 7.68 - 7.61 (m, 1H), 7.56 - 7.49 (m, 1H), 7.20 (t, J = 8.1 Hz, 1H), 4.71 - 4.51 (m, 2H), 2.55 - 2.41 (m, 2H), 2.27 - 2.13 (m, 2H), 1.92 - 1.73 (m, 2H), 1, 71 - 1.55 (m, 6H), 0.16 - 0.04 (m, 9H). (Example 66)

[00572] N-(2-Chloro-6-fluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carboxamide (Compound No. IV-703) [Chemical Formula 84]

[00573] To a solution of 299 mg (1.59 mmol) of 2-chloro-6-fluoro-3-methylbenzoic acid [purchased from AOBChem] in 8 mL of toluene, 0.313 mL (1.80 mmol) of DIPEA and 0.353 mL (1.64 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100°C for 1 hour with stirring. The reaction solution was cooled, and then a 400 mg (1.06 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4 Ethyl -c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 1 ml of 1,4-dioxane was added thereto at room temperature and reacted at room temperature for 2 hours with stirring.

[00574] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 70:30 (v/v)), and a fraction containing 5-[(2-chloro-6-fluoro-3-methylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c Ethyl pyrazol-2(4H)-carboxylate was concentrated under reduced pressure.

[00575] To a solution of the residue from the concentration obtained in 3 mL of 1,4-dioxane, 0.494 mL (5.28 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 1 hour with stirring.

[00576] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 40:60 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 407 mg of the title compound (yield: 78%) as a white solid.

[00577] Mass spectrum (IQ, m/z): 492 [M+1]+.

[00578] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.74 (br s, total 1H), 9.58 (s, 1H), 8.06 - 7.82 (m , 1H), 7.25 (dd, J = 5.7, 8.5 Hz, 1H), 7.17 - 7.10 (m, 1H), 4.71 - 4.50 (m, 2H), 2.55 - 2.40 (m, 2H), 2.32 (s, 3H), 2.26 - 2.13 (m, 2H), 1.92 - 1.73 (m, 2H), 1, 70 - 1.54 (m, 6H), 0.09 (s, 9H). (Example 67)

[00579] N-(2-Ethyl-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-137) [Chemical Formula 85]

[00580] To a solution of 267 mg (1.59 mmol) of 2-ethyl-6-fluorobenzoic acid synthesized in the same way as in Reference Example 14 in 8 mL of toluene, 0.313 mL (1.80 mmol) of DIPEA and 0.353 mL (1.64 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a 400 mg (1.06 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4 Ethyl -c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 2 ml of 1,4-dioxane was added thereto at room temperature and reacted at room temperature for 1 hour with stirring.

[00581] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 70:30 (v/v)), and a fraction containing 5-[(2-ethyl-6-fluorophenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2 Ethyl (4H)-carboxylate was concentrated under reduced pressure.

[00582] To a solution of the residue from the concentration obtained in 5 mL of 1,4-dioxane, 0.494 mL (5.28 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 1 hour with stirring.

[00583] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 40:60 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 325 mg of the title compound (yield: 65%) as a white solid.

[00584] Mass spectrum (IQ, m/z): 472 [M+1]+.

[00585] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.74 (br s, total 1H), 9.57 (s, 1H), 7.77 - 7.55 (m , 1H), 7.19 (dt, J = 5.6, 7.9 Hz, 1H), 7.09 - 6.97 (m, 2H), 4.70 - 4.48 (m, 2H), 2.60 (q, J = 7.5 Hz, 2H), 2.54 - 2.39 (m, 2H), 2.27 - 2.13 (m, 2H), 1.92 - 1.74 ( m, 2H), 1.63 (br s, 6H), 1.13 (t, J = 7.5 Hz, 3H), 0.09 (s, 9H). (Example 68)

[00586] N-(2-Bromo-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-121) [Chemical Formula 86]

[00587] To a suspension of 350 mg (1.60 mmol) of 2-bromo-6-fluorobenzoic acid in 2 mL of dehydrated toluene, 0.300 mL (1.72 mmol) of DIPEA and 0.340 mL (1.58 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a 500 mg (1.32 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4 Ethyl -c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 2 ml of dehydrated toluene was added thereto at room temperature and reacted at room temperature for 2 hours with stirring.

[00588] After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing 5-[(2-bromo-6-fluorophenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol- Ethyl 2(4H)-carboxylate was concentrated under reduced pressure.

[00589] To a solution of the concentration residue obtained in 2 mL of dehydrated dichloromethane, 0.340 mL (3.12 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an argon atmosphere and reacted at room temperature for 1 hour with stirring.

[00590] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with dichloromethane. The organic layer obtained was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in that order, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 319 mg of the title compound (yield: 46%) as a white solid.

[00591] Mass spectrum (IQ, m/z): 522 [M+1]+.

[00592] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.26 & 11.73 (br s, total 1H), 9.59 (s, 1H), 8.01 (br s, 1H) , 7.52 - 7.46 (m, 1H), 7.30 - 7.19 (m, 2H), 4.61 (br s, 2H), 2.55 - 2.41 (m, 2H), 2.25 - 2.14 (m, 2H), 1.88 - 1.75 (m, 2H), 1.63 (s, 6H), 0.09 (s, 9H). (Example 69)

[00593] N-(2-Bromo-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-299) [Chemical Formula 87]

[00594] To a solution of 340 mg (1.58 mmol) of 2-bromo-6-methylbenzoic acid in 2 mL of dehydrated toluene, 0.300 mL (1.72 mmol) of DIPEA and 0.340 mL (1.58 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a 500 mg (1.32 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4 Ethyl -c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 2 ml of dehydrated toluene was added thereto at room temperature and reacted at room temperature for 1 hour with stirring.

[00595] After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing 5-[(2-bromo-6-methylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol- Ethyl 2(4H)-carboxylate was concentrated under reduced pressure.

[00596] To a solution of the concentration residue obtained in 2 mL of dehydrated dichloromethane, 0.340 mL (3.12 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour with stirring.

[00597] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with dichloromethane. The organic layer obtained was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in that order, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 507 mg of the title compound (yield: 74%) as a white solid.

[00598] Mass spectrum (IQ, m/z): 518 [M+1]+.

[00599] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.75 (br s, total 1H), 9.57 (s, 1H), 7.82 (br s, 1H) , 7.49 - 7.43 (m, 1H), 7.26 - 7.20 (m, 1H), 7.11 - 7.03 (m, 1H), 4.61 (br s, 2H), 2.56 - 2.41 (m, 2H), 2.27 - 2.13 (m, 5H), 1.89 - 1.74 (m, 2H), 1.64 (s, 6H), 0, 09 (s, 9H). (Example 70)

[00600] N-(2-Chloro-5-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-213) [Chemical Formula 88]

[00601] To a suspension of 270 mg (1.58 mmol) of 2-chloro-5-methylbenzoic acid in 4 mL of dehydrated toluene, 0.368 mL (2.11 mmol) of DIPEA and 0.341 mL (1.58 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a 400 mg (1.06 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4 Ethyl -c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 4 ml of dehydrated dichloromethane was added dropwise thereto at 0oC and reacted at room temperature for 3 hours with stirring.

[00602] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction three times with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 91:9 ^ 70:30 (V/V)), and a fraction containing 5-[(2-chloro-5-methylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2 Ethyl (4H)-carboxylate was concentrated under reduced pressure.

[00603] To a solution of the residue from the concentration obtained in 3 mL of THF and 3 mL of dichloromethane, 0.575 mL (5.28 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 1 hour with stirring.

[00604] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction three times with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 71:29 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 430 mg of the title compound (yield: 86%) as a white solid.

[00605] Mass spectrum (IQ, m/z): 474 [M+1]+.

[00606] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.29 & 11.86 (br s, total 1H), 9.80 - 9.47 (m, 1H), 7.75 - 7 .39 (m, 2H), 7.31 (d, J = 8.2 Hz, 1H), 6.91 (dd, J = 1.6, 8.2 Hz, 1H), 4.62 (br s , 2H), 2.55 - 2.40 (m, 2H), 2.28 (s, 3H), 2.26 - 2.14 (m, 2H), 1.92 - 1.72 (m, 2H) ), 1.67 (br s, 6H), 0.09 (s, 9H). (Example 71)

[00607] N-(6-Fluoro-2,3-dihydrobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3 ,4-c]pyrazol-5(1H)-c arboxamide (Compound No. IV-997) [Chemical Formula 89]

[00608] To a suspension of 289 mg (1.59 mmol) of 6-fluoro-2,3-dihydrobenzofuran-7-carboxylic acid synthesized in the same way as in Reference Example 16 in 4 mL of dehydrated toluene, 0.368 mL (2.11 mmol) of DIPEA and 0.341 mL (1.58 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a 400 mg (1.06 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4 Ethyl -c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 4 ml of dehydrated dichloromethane was added dropwise thereto at 0oC and reacted at room temperature for 1 hour with stirring.

[00609] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction three times with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 47:53 ^ 27:73 (V/V)), and a fraction containing 5-[(6-fluoro-2,3-dihydrobenzofuran-7-yl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3 Ethyl ,4-c]pyrazol-2(4H)-carboxylate was concentrated under reduced pressure.

[00610] To a solution of the concentration residue obtained in 3 mL of dichloromethane, 0.575 mL (5.28 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an argon atmosphere and reacted at room temperature for 1 hour with stirring.

[00611] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction three times with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 44:56 ^ 23:77 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was dissolved in 30 mL of ethyl acetate and washed three times with 5 mL of a 5% aqueous solution of potassium bisulfate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 401 mg of the title compound (yield: 78%) as a white solid.

[00612] Mass spectrum (IQ, m/z): 486 [M+1]+.

[00613] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.67 - 11.22 (m, 1H), 9.54 (s, 1H), 7.59 (br s, 1H), 7 .03 (dd, J = 5.3, 8.1 Hz, 1H), 6.61 (dd, J = 8.1, 10.2 Hz, 1H), 4.65 - 4.47 (m, 4H ), 3.17 (t, J = 8.7 Hz, 2H), 2.57 - 2.40 (m, 2H), 2.26 - 2.13 (m, 2H), 1.89 - 1, 74 (m, 2H), 1.62 (s, 6H), 0.09 (s, 9H). (Example 72)

[00614] N-(2-Cyano-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-185) [Chemical Formula 90]

[00615] To a solution of 4.60 g (25.7 mmol) of methyl 2-cyano-6-fluorobenzoate [purchased from AstaTech Inc.] in 20 mL of methanol, 28.0 mL of an aqueous solution of 1N sodium hydroxide was added at room temperature and reacted at room temperature for 3 hours with stirring.

[00616] After completion of the reaction, the reaction solution was adjusted to pH 3 by adding 1 N hydrochloric acid, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 3.42 g of a concentration residue containing 2-cyano-6-acid. fluorobenzoic.

[00617] To a solution of an aliquot of 0.654 g of the concentration residue obtained in 10 mL of dehydrated toluene, 0.750 mL (4.29 mmol) of DIPEA and 0.850 mL (3.95 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour with stirring. Subsequently, a solution of 1.00 g (2.64 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2 Ethyl (4H)-carboxylate in 2 ml of dehydrated toluene synthesized in the same way as in Reference Example 3 was added thereto at room temperature and reacted at 80oC for 1 hour with stirring.

[00618] After completion of the reaction, water was added to the reaction solution cooled to room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 80:20 (V/V)), and a fraction containing 5-[(2-cyano-6-fluorophenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol- Ethyl 2(4H)-carboxylate was concentrated under reduced pressure.

[00619] To a solution of the concentration residue obtained in 6 mL of dehydrated dichloromethane, 1.15 mL (10.6 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour with stirring.

[00620] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer obtained was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in that order, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was again subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: 1,2-dichloroethane:methanol = 100:0 ^ 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was again subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM aqueous potassium dihydrogen phosphate solution = 40:60 (V/V)), and a fraction containing the compound of interest was collected, followed by extraction with ethyl acetate. The obtained organic layer was washed with water, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 236 mg of the title compound (yield: 19%) as a white solid.

[00621] Mass spectrum (ES TOF MS, m/z): 469 [M+1]+.

[00622] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.29 & 11.71 (br s, total 1H), 9.62 (s, 1H), 8.61 - 8.40 (m , 1H), 7.68 - 7.58 (m, 2H), 7.45 - 7.38 (m, 1H), 4.72 - 4.57 (m, 2H), 2.57 - 2.41 (m, 2H), 2.26 - 2.14 (m, 2H), 1.90 - 1.73 (m, 2H), 1.65 (br s, 6H), 0.09 (s, 9H) . (Example 73)

[00623] N-(2-Chloro-6-cyclopropylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-231) [Chemical Formula 91]

[00624] To a solution of 174 mg (0.885 mmol) of 2-chloro-6-cyclopropylbenzoic acid synthesized in the same way as in Reference Example 17 in 2 mL of dehydrated toluene, 0.212 mL (1.21 mmol) of DIPEA and 0.204 mL (0.949 mmol) of DPPA was added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a solution of 287 mg (0.758 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c Ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 2 mL of dehydrated toluene was added at room temperature and reacted at room temperature for 1 hour with stirring.

[00625] After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing 5-[(2-chloro-6-cyclopropylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol- Ethyl 2(4H)-carboxylate was concentrated under reduced pressure.

[00626] To a solution of the concentration residue obtained in 2 mL of dehydrated dichloromethane, 0.248 mL (2.28 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an argon atmosphere and reacted at room temperature for 1 hour with stirring.

[00627] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with dichloromethane. The organic layer obtained was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in that order, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. An aqueous solution of 5% potassium bisulfate was added to the obtained concentration residue, followed by extraction with dichloromethane. The organic layer obtained was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in that order, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 219 mg of the title compound (yield: 58%) as a white solid.

[00628] Mass spectrum (IQ, m/z): 500 [M+1]+.

[00629] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.71 (br s, total 1H), 9.55 (s, 1H), 7.93 - 7.74 (m , 1H), 7.30 - 7.24 (m, 1H), 7.18 - 7.11 (m, 1H), 6.90 - 6.84 (m, 1H), 4.71 - 4.53 (m, 2H), 2.56 - 2.40 (m, 2H), 2.26 - 2.14 (m, 2H), 2.14 - 2.05 (m, 1H), 1.91 - 1 .73 (m, 2H), 1.69 - 1.56 (m, 6H), 0.92 - 0.84 (m, 2H), 0.64 - 0.57 (m, 2H), 0.09 (s, 9H). (Example 74)

[00630] N-(2-Fluoro-3,6-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide (Compound No. IV-669) [Chemical Formula 92]

[00631] To a solution of 267 mg (1.59 mmol) of 2-fluoro-3,6-dimethylbenzoic acid synthesized in the same way as in Reference Example 20 in 8 mL of toluene, 0.313 mL (1.80 mmol) of DIPEA and 0.353 mL (1.64 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a 400 mg (1.06 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4 Ethyl -c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 2 ml of toluene was added thereto at 0oC and reacted at 0oC for 1 hour with stirring.

[00632] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 70:30 (v/v)), and a fraction containing 5-[(2-fluoro-3,6-dimethylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole Ethyl -2(4H)-carboxylate was concentrated under reduced pressure.

[00633] To a solution of the residue from the concentration obtained in 5 mL of 1,4-dioxane, 0.494 mL (5.28 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 1 hour with stirring.

[00634] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 40:60 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 283 mg of the title compound (yield: 57%) as a white solid.

[00635] Mass spectrum (IQ, m/z): 472 [M+1]+.

[00636] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.25 & 11.73 (br s, total 1H), 9.56 (s, 1H), 7.75 - 7.55 (m , 1H), 7.04 - 6.96 (m, 1H), 6.91 (d, J = 7.8 Hz, 1H), 4.68 - 4.49 (m, 2H), 2.55 - 2.40 (m, 2H), 2.26 - 2.12 (m, 8H), 1.91 - 1.74 (m, 2H), 1.69 - 1.55 (m, 6H), 0, 09 (s, 9H). (Example 75)

[00637] N-(6-Fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-1049) [Chemical Formula 93]

[00638] To a suspension of 287 mg (1.59 mmol) of 6-fluorobenzofuran-7-carboxylic acid synthesized in the same manner as in Reference Example 15 in 4 mL of dehydrated toluene, 0.360 mL (2.11 mmol) of DIPEA, 0.340 mL (1.58 mmol) of DPPA, and 1 mL of dehydrated dichloromethane were added at room temperature under an argon atmosphere and reacted at room temperature for 1 hour and subsequently at 90°C for 1 hour with stirring. The reaction solution was cooled, and then 2 mL of dehydrated dichloromethane was added to it, and the solution was added dropwise to a solution of 403 mg (1.06 mmol) of 6,6-dimethyl-3-[1 Ethyl -(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 4 mL of dichloromethane at 0oC and reacted at 0oC for 1 hour with stirring.

[00639] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction twice with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in that order, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 59:41 ^ 39:61 (V/V)), and a fraction containing 5-[(6-fluorobenzofuran-7-yl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2 Ethyl (4H)-carboxylate was concentrated under reduced pressure.

[00640] To a solution of the concentration residue obtained in 3 mL of dehydrated tetrahydrofuran, 0.540 mL (4.96 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an argon atmosphere and reacted at room temperature for 45 minutes with stirring.

[00641] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction twice with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in that order, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 49:51 ^ 28:72 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 396 mg of the title compound (yield: 77%) as a white solid.

[00642] Mass spectrum (IQ, m/z): 484 [M+1]+.

[00643] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.71 (s, total 1H), 9.58 (s, 1H), 8.23 - 8.04 (m, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 4.8, 8.6 Hz, 1H), 7.14 (dd, J = 8.6 , 10.4 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 4.76 - 4.55 (m, 2H), 2.55 - 2.40 (m, 2H) , 2.28 - 2.12 (m, 2H), 1.94 - 1.74 (m, 2H), 1.72 - 1.55 (m, 6H), 0.09 (s, 9H). (Example 76)

[00644] N-(2-Chloro-3-fluoro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carboxamide (Compound No. IV-747) [Chemical Formula 94]

[00645] To a solution of 180 mg (0.954 mmol) of 2-chloro-3-fluoro-6-methylbenzoic acid synthesized in the same way as in Reference Example 21 in 5 mL of toluene, 0.180 mL (1.03 mmol) of DIPEA and 0.225 mL (1.05 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a solution of 302 mg (0.798 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c Ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 5 ml of toluene was added thereto at room temperature and reacted at room temperature for 0.5 hour with stirring.

[00646] After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 70:30 (V/V)), and a fraction containing 5-[(2-chloro-3-fluoro-6-methylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c Ethyl pyrazol-2(4H)-carboxylate was concentrated under reduced pressure.

[00647] To a solution of the concentration residue obtained in 10 mL of tetrahydrofuran, 0.435 mL (4.00 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and reacted at room temperature for 2 hours with shaking.

[00648] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride in that order, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 301 mg of the title compound (yield: 77%) as a white solid.

[00649] Mass spectrum (IQ, m/z): 492 [M+1]+.

[00650] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.74 (br s, total 1H), 9.59 (br s, 1H), 8.02 - 7.85 ( m, 1H), 7.26 - 7.15 (m, 2H), 4.69 - 4.55 (m, 2H), 2.55 - 2.41 (m, 2H), 2.26 - 2, 14 (m, 5H), 1.91 - 1.73 (m, 2H), 1.69 - 1.56 (m, 6H), 0.09 (s, 9H). (Example 77)

[00651] N-[2-(Difluoromethoxy)-6-fluorophenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide (Compound No. III-169) [Chemical Formula 95]

[00652] To a solution of 42 mg (0.20 mmol) of 2-(difluoromethoxy)-6-fluorobenzamide synthesized in the same way as in Reference Example 12 in 2 mL of toluene, 133 mg (0.413 mmol) of diacetate Iodobenzene were added at room temperature under an argon atmosphere and reacted at room temperature for 10 minutes and subsequently at 60oC for 1 hour with stirring. The reaction solution was cooled, and then 50 mg (0.14 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c] Ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 22 was added thereto at room temperature and reacted at room temperature for 20 minutes with stirring.

[00653] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 60:40 (v/v)), and a fraction containing 5-{[2-(difluoromethoxy)-6-fluorophenyl]carbamoyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole Ethyl -2(4H)-carboxylate was concentrated under reduced pressure.

[00654] To a solution of the residue from the concentration obtained in 3 mL of 1,4-dioxane, 0.051 mL (0.55 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 1 hour with stirring.

[00655] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 40:60 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 37 mg of the title compound (yield: 54%) as a white solid.

[00656] Mass spectrum (IQ, m/z): 496 [M+1]+.

[00657] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.29 & 11.90 (br s, total 1H), 9.78 (br s, 1H), 7.92 - 7.71 ( m, 1H), 7.31 (dt, J = 6.3, 8.3 Hz, 1H), 7.21 - 7.13 (m, 1H), 7.08 - 7.03 (m, 1H) , 7.01 (t, J = 74.3 Hz, 1H), 4.54 (br s, 2H), 1.61 (br s, 6H), 1.07 - 0.94 (m, 2H), 0.80 - 0.59 (m, 2H), 0.03 (s, 9H). (Example 78)

[00658] N-(2,6-Dichlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H )-carboxamide (Compound No. III-199) [Chemical Formula 96]

[00659] To a solution of 100 mg (0.274 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H )-ethyl carboxylate synthesized in the same manner as in Reference Example 22 in 3 mL of toluene, 61.9 mg (0.329 mmol) of 1,3-dichloro-2-isocyanatobenzene were added at room temperature under an argon atmosphere and reacted at room temperature for 1 hour with stirring.

[00660] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 70:30 (v/v)), and a fraction containing 5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H )-ethyl carboxylate was concentrated under reduced pressure.

[00661] To a solution of the residue from the concentration obtained in 5 mL of 1,4-dioxane, 0.128 mL (1.37 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 1 hour with stirring.

[00662] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 40:60 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 89 mg of the title compound (yield: 68%) as a white solid.

[00663] Mass spectrum (IQ, m/z): 480 [M+1]+.

[00664] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.49 - 11.61 (m, 1H), 9.78 (s, 1H), 8.09 (br s, 1H), 7 .49 (d, J = 8.1 Hz, 2H), 7.28 (t, J = 8.1 Hz, 1H), 4.56 (s, 2H), 1.62 (s, 6H), 1 .05 - 0.97 (m, 2H), 0.75 - 0.63 (m, 2H), 0.04 (s, 9H). (Example 79)

[00665] N-(2,6-Dichlorophenyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide (Compound No. II-199) [Chemical Formula 97]

[00666] To a solution of 100 mg (0.273 mmol) of 6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-5,6-dihydropyrrolo[3,4-c]pyrazole Ethyl -2(4H)-carboxylate synthesized in the same way as in Reference Example 25 in 3 mL of toluene, 61.6 mg (0.328 mmol) of 1,3-dichloro-2-isocyanatobenzene were added at 0°C under an atmosphere of argon and reacted at 0oC for 1 hour with stirring.

[00667] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 70:30 (v/v)), and a fraction containing 5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamid]-5,6-dihydropyrrolo[3,4-c]pyrazole Ethyl -2(4H)-carboxylate was concentrated under reduced pressure.

[00668] To a solution of the residue from the concentration obtained in 5 mL of 1,4-dioxane, 0.128 mL (1.37 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 1 hour with stirring.

[00669] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 40:60 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 107 mg of the title compound (yield: 81%) as a white solid.

[00670] Mass spectrum (IQ, m/z): 482 [M+1]+.

[00671] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.53 - 11.57 (m, 1H), 9.30 (br s, 1H), 8.11 (br s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 8.0 Hz, 1H), 4.58 (s, 2H), 1.63 (s, 6H), 1.24 (s, 6H), 0.04 (s, 9H). (Example 80)

[00672] N-[2-(Difluoromethoxy)-6-fluorophenyl]-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-4,6-dihydropyrrolo[3,4- c]pyrazol-5(1H)-carboxamide (Compound No. II-169) [Chemical Formula 98]

[00673] To a solution of 25.2 mg (0.123 mmol) of 2-(difluoromethoxy)-6-fluorobenzamide synthesized in the same way as in Reference Example 12 in 3 mL of toluene, 79 mg (0.25 mmol) of Iodobenzene diacetate were added at room temperature under an argon atmosphere and reacted at room temperature for 10 minutes and subsequently at 60°C for 1 hour with stirring. The reaction solution was cooled, and then 30 mg (0.082 mmol) of 6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-5,6-dihydropyrrolo[3,4- c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 25 were added thereto at room temperature and reacted at room temperature for 20 minutes with stirring.

[00674] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 85:15 ^ 70:30 (v/v)), and a fraction containing 5-{[2-(difluoromethoxy)-6-fluorophenyl]carbamoyl}-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-5,6-dihydropyrrolo[3,4 Ethyl -c]pyrazol-2(4H)-carboxylate was concentrated under reduced pressure.

[00675] To a solution of the residue from the concentration obtained in 3 mL of 1,4-dioxane, 0.031 mL (0.33 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 1 hour with stirring.

[00676] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 40:60 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 8.5 mg of the title compound (yield: 21%) as a white solid.

[00677] Mass spectrum (IQ, m/z): 498 [M+1]+.

[00678] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.43 - 11.62 (m, 1H), 9.31 (br s, 1H), 7.84 (br s, 1H), 7.31 (dt, J = 6.3, 8.3 Hz, 1H), 7.21 - 7.14 (m, 1H), 7.07 - 7.02 (m, 1H), 7.01 ( t, J = 74.3 Hz, 1H), 4.56 (s, 2H), 1.62 (s, 6H), 1.24 (s, 6H), 0.04 (s, 9H). (Example 81)

[00679] N-(2,6-Dichloro-4-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole -5(1H)-carboxamide (Compound No. IV-709) [Chemical Formula 99]

[00680] To a solution of 166 mg (0.794 mmol) of 2,6-dichloro-4-fluorobenzoic acid [purchased from Abamachem Ltd.] in 5 mL of toluene, 0.156 mL (0.896 mmol) of DIPEA and 0.176 mL ( 0.817 mmol) of DPPA was added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a 200 mg (0.528 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c Ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 3 ml of toluene was added dropwise thereto at 0oC and reacted at 0oC for 1 hour with stirring.

[00681] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 70:30 (v/v)), and a fraction containing 5-[(2,6-dichloro-4-fluorophenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole Ethyl -2(4H)-carboxylate was concentrated under reduced pressure.

[00682] To a solution of the residue from the concentration obtained in 5 mL of 1,4-dioxane, 0.247 mL (2.64 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 1 hour with stirring.

[00683] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 40:60 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 149 mg of the title compound (yield: 55%) as a white solid.

[00684] Mass spectrum (IQ, m/z): 512 [M+1]+.

[00685] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.47 - 11.59 (m, 1H), 9.60 (s, 1H), 8.10 (br s, 1H), 7 .55 (d, J = 8.4 Hz, 2H), 4.60 (s, 2H), 2.57 - 2.41 (m, 2H), 2.25 - 2.14 (m, 2H), 1.89 - 1.73 (m, 2H), 1.63 (s, 6H), 0.09 (s, 9H). (Example 82)

[00686] N-(2-Ethyl-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. III-137) [Chemical Formula 100]

[00687] To a solution of 69.2 mg (0.412 mmol) of 2-ethyl-6-fluorobenzoic acid synthesized in the same way as in Reference Example 14 in 5 mL of toluene, 0.081 mL (0.47 mmol) of DIPEA and 0.092 mL (0.43 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a 100 mg (0.274 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c Ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 22 in 2 ml of toluene was added dropwise at 0°C and reacted at 0°C for 1 hour with stirring.

[00688] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 95:5 ^ 80:20 (v/v)), and a fraction containing 5-[(2-ethyl-6-fluorophenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2 Ethyl (4H)-carboxylate was concentrated under reduced pressure.

[00689] To a solution of the concentration residue obtained in 5 mL of 1,4-dioxane, 0.128 mL (1.37 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 2 hours with stirring.

[00690] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 70:30 ^ 50:50 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 98 mg of the title compound (yield: 78%) as a white solid.

[00691] Mass spectrum (IQ, m/z): 458 [M+1]+.

[00692] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.86 (br s, total 1H), 9.75 (br s, 1H), 7.65 (br s, 1H ), 7.19 (dt, J = 5.6, 7.9 Hz, 1H), 7.10 - 6.96 (m, 2H), 4.55 (br s, 2H), 2.60 (q , J = 7.5 Hz, 2H), 1.62 (s, 6H), 1.12 (t, J = 7.5 Hz, 3H), 1.05 - 0.96 (m, 2H), 0 .81 - 0.60 (m, 2H), 0.04 (s, 9H). (Example 83)

[00693] N-(2-Bromo-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. III-299) [Chemical Formula 101]

[00694] To a solution of 88 mg (0.41 mmol) of 2-bromo-6-methylbenzoic acid in 5 mL of toluene, 0.081 mL (0.47 mmol) of DIPEA and 0.092 mL (0.43 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a 100 mg (0.274 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c Ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 22 in 2 ml of toluene was added dropwise thereto at 0oC and reacted at 0oC for 1 hour with stirring.

[00695] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 85:15 ^ 70:30 (v/v)), and a fraction containing 5-[(2-bromo-6-methylphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2 Ethyl (4H)-carboxylate was concentrated under reduced pressure.

[00696] To a solution of the concentration residue obtained in 5 mL of 1,4-dioxane, 0.128 mL (1.37 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 2 hours with stirring.

[00697] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 40:60 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 92 mg of the title compound (yield: 66%) as a white solid.

[00698] Mass spectrum (IQ, m/z): 504 [M+1]+.

[00699] 1H-NMR Spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.85 (br s, total 1H), 9.75 (br s, 1H), 7.80 (br s, 1H ), 7.50 - 7.43 (m, 1H), 7.26 - 7.19 (m, 1H), 7.12 - 7.03 (m, 1H), 4.56 (br s, 2H) , 2.23 (s, 3H), 1.63 (s, 6H), 1.05 - 0.97 (m, 2H), 0.80 - 0.58 (m, 2H), 0.04 (s , 9H). (Example 84)

[00700] N-(2-Chloro-5-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. IV-245) [Chemical Formula 102]

[00701] To a solution of 148 mg (0.793 mmol) of 2-chloro-5-methoxybenzoic acid in 5 mL of toluene, 0.156 mL (0.896 mmol) of DIPEA and 0.176 mL (0.817 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a 200 mg (0.528 mmol) solution of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c Ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 2 ml of toluene was added dropwise thereto at 0oC and reacted at 0oC for 1 hour with stirring.

[00702] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 85:15 ^ 70:30 (v/v)), and a fraction containing 5-[(2-chloro-5-methoxyphenyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2 Ethyl (4H)-carboxylate was concentrated under reduced pressure.

[00703] To a solution of the residue from the concentration obtained in 5 mL of 1,4-dioxane, 0.247 mL (2.64 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an atmosphere of argon and reacted at room temperature for 1 hour with stirring.

[00704] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 50:50 ^ 30:70 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 111 mg of the title compound (yield: 43%) as a white solid.

[00705] Mass spectrum (IQ, m/z): 490 [M+1]+.

[00706] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.42 - 11.71 (m, 1H), 9.63 (br s, 1H), 7.59 - 7.39 (m, 2H), 7.34 (d, J = 8.9 Hz, 1H), 6.68 (dd, J = 3.1, 8.9 Hz, 1H), 4.62 (br s, 2H), 3 .75 (s, 3H), 2.56 - 2.40 (m, 2H), 2.27 - 2.14 (m, 2H), 1.90 - 1.74 (m, 2H), 1.67 (s, 6H), 0.09 (s, 9H). (Example 85)

[00707] N-(2-Ethyl-6-fluorophenyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-4,6-dihydropyrrolo[3,4-c] pyrazole-5(1H)-carboxamide Compound No. II-137) [Chemical Formula 103]

[00708] To a solution of 55.1 mg (0.328 mmol) of 2-ethyl-6-fluorobenzoic acid synthesized in the same way as in Reference Example 14 in 2 mL of dehydrated toluene, 0.076 mL (0.44 mmol) of DIPEA and 0.074 mL (0.34 mmol) DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100°C for 1 hour with stirring. The reaction solution was cooled, and then a 100 mg (0.273 mmol) solution of 6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-5,6-dihydropyrrolo[3 Ethyl ,4-c ]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 25 in 2 ml of dehydrated toluene was added thereto at room temperature and reacted at room temperature for 1 hour with stirring.

[00709] After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing 5-[(2-ethyl-6-fluorophenyl)carbamoyl]-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-5,6-dihydropyrrolo[3,4- Ethyl c]pyrazol-2(4H)-carboxylate was concentrated under reduced pressure.

[00710] To a solution of the concentration residue obtained in 2 mL of dehydrated dichloromethane, 0.089 mL (0.82 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an argon atmosphere and reacted at room temperature for 1 hour with stirring.

[00711] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with dichloromethane. The organic layer obtained was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in that order, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 64 mg of the title compound (yield: 51%) as a white solid.

[00712] Mass spectrum (IQ, m/z): 460 [M+1]+.

[00713] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.31 & 11.74 (br s, total 1H), 9.40 - 9.18 (m, 1H), 7.76 - 7 .56 (m, 1H), 7.19 (dt, J = 5.7, 7.9, 1H), 7.09 - 6.98 (m, 2H), 4.63 - 4.49 (m, 2H), 2.60 (q, J = 7.6 Hz, 2H), 1.71 - 1.53 (m, 6H), 1.24 (s, 6H), 1.13 (t, J = 7 .6Hz, 3H), 0.04 (s, 9H). (Example 86)

[00714] N-(2-Bromo-6-methylphenyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carboxamide (Compound No. II-290) [Chemical Formula 104]

[00715] To a solution of 53.0 mg (0.246 mmol) of 2-bromo-6-methylbenzoic acid in 2 mL of dehydrated toluene, 0.057 mL (0.33 mmol) of DIPEA and 0.055 mL (0.26 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100°C for 1 hour with stirring. The reaction solution was cooled, and then a solution of 75.0 mg (0.205 mmol) of 6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-5,6-dihydropyrrole Ethyl [3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 25 in 2 mL of dehydrated toluene was added thereto at room temperature and reacted at room temperature for 1 hour with stirring .

[00716] After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing 5-[(2-bromo-6-methylphenyl)carbamoyl]-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-5,6-dihydropyrrolo[3,4- Ethyl c]pyrazol-2(4H)-carboxylate was concentrated under reduced pressure.

[00717] To a solution of the concentration residue obtained in 2 mL of dehydrated dichloromethane, 0.067 mL (0.61 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an argon atmosphere and reacted at room temperature for 1 hour with stirring.

[00718] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with dichloromethane. The organic layer obtained was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in that order, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 40 mg of the title compound (yield: 39%) as a white solid.

[00719] Mass spectrum (IQ, m/z): 506 [M+1]+.

[00720] 1H NMR spectrum (400MHz, DMSO-d6) δ: 12.30 & 11.72 (br s, total 1H), 9.40 - 9.15 (m, 1H), 7.82 (br s, 1H), 7.49 - 7.43 (m, 1H), 7.27 - 7.20 (m, 1H), 7.07 (t, J = 7.8, 1H), 4.59 ( s, 2H), 2.24 (s, 3H), 1.64 (br s, 6H), 1.24 (s, 6H), 0.04 (s, 9H). (Example 87)

[00721] N-(6-Fluorobenzofuran-7-yl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carboxamide (Compound No. II-1049) [Chemical Formula 105]

[00722] To a solution of 44.2 mg (0.245 mmol) of 6-fluorobenzofuran-7-carboxylic acid synthesized in the same way as in Reference Example 15 in 2 mL of dehydrated toluene, 0.057 mL (0.33 mmol) of DIPEA and 0.055 mL (0.26 mmol) of DPPA were added at room temperature under an argon atmosphere and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a solution of 75.0 mg (0.205 mmol) of 6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-5,6-dihydropyrrole Ethyl [3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 25 in 2 mL of dehydrated toluene was added thereto at room temperature and reacted at room temperature for 2 hours with stirring .

[00723] After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing 5-[(6-fluorobenzofuran-7-yl)carbamoyl]-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-5,6-dihydropyrrolo[3,4-c Ethyl pyrazol-2(4H)-carboxylate was concentrated under reduced pressure.

[00724] To a solution of the concentration residue obtained in 2 mL of dehydrated dichloromethane, 0.067 mL (0.61 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an argon atmosphere and reacted at room temperature for 1 hour with stirring.

[00725] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with dichloromethane. The organic layer obtained was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in that order, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 14 mg of the title compound (yield: 14%) as a white solid.

[00726] Mass spectrum (IQ, m/z): 472 [M+1]+.

[00727] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.32 & 11.77 (br s, total 1H), 9.43 - 9.20 (m, 1H), 8.14 (br s, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 4.8, 8.5 Hz, 1H), 7.15 (dd, J = 8 .5, 10.5 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 4.63 (s, 2H), 1.65 (br s, 6H), 1.25 ( s, 6H), 0.05 (s, 9H). (Example 88)

[00728] N-(6-Fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide (Compound No. III-1049) [Chemical Formula 106]

[00729] To a solution of 44.5 mg (0.247 mmol) of 6-fluorobenzofuran-7-carboxylic acid synthesized in the same way as in Reference Example 15 in 2 mL of dehydrated toluene, 0.057 mL (0.33 mmol) of DIPEA and 0.055 mL (0.26 mmol) of DPPA were added at room temperature and reacted at room temperature for 0.5 hour and subsequently at 100oC for 1 hour with stirring. The reaction solution was cooled, and then a solution of 75.0 mg (0.206 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3.4 Ethyl -c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 22 in 2 ml of dehydrated toluene was added thereto at room temperature and reacted at room temperature for 1 hour with stirring.

[00730] After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 60:40 (V/V)), and a fraction containing 5-[(6-fluorobenzofuran-7-yl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol- Ethyl 2(4H)-carboxylate was concentrated under reduced pressure.

[00731] To a solution of the concentration residue obtained in 2 mL of dehydrated dichloromethane, 0.067 mL (0.61 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature under an argon atmosphere and reacted at room temperature for 1 hour with stirring.

[00732] After completion of the reaction, a 5% aqueous solution of potassium bisulfate was added to the reaction solution, followed by extraction with dichloromethane. The organic layer obtained was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in that order, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was again subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 35:65 (V/V)), and a fraction containing the compound of interest was collected, followed by extraction with ethyl acetate. The obtained organic layer was washed with water, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 11 mg of the title compound (yield: 11%) as a white solid.

[00733] Mass spectrum (IQ, m/z): 470 [M+1]+.

[00734] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.29 & 11.85 (br s, total 1H), 9.76 (br s, 1H), 8.19 - 8.01 ( m, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.48 (dd, J = 4.9, 8.5 Hz, 1H), 7.14 (dd, J = 8 .5, 10.5 Hz, 1H), 6.97 (d, J = 2.1 Hz, 1H), 4.67 - 4.53 (m, 2H), 1.64 (br s, 6H), 1.08 - 0.96 (m, 2H), 0.80 - 0.60 (m, 2H), 0.04 (s, 9H). (Example 89)

[00735] N,6,6-Trimethyl-N-phenyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazol-5 (1 H)-carboxamide (Compound No. I-965) [Chemical Formula 107]

[00736] A 150 mg solution (including impurities, < 0.340 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3 Ethyl ,4-c]pyrazol-2(4H)-carboxylate synthesized in the same manner as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.180 mL (1.03 mmol) of DIPEA and 0.110 mL (1 .02 mmol) of N-methylaniline were added at room temperature under an argon atmosphere and then reacted at 100oC for 1 hour with stirring. The reaction solution was cooled, and 0.200 mL (1.84 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature for 16 hours with stirring.

[00737] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate = 60:40 ^ 20:80 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol, then water was added to the solution, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 59.6 mg of the title compound (yield: 40% [*value calculation with the purity of the starting material set to 100%]) as a white solid.

[00738] Mass spectrum (IQ, m/z): 440 [M+1]+.

[00739] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.37 - 11.66 (m, 1H), 9.41 (br s, 1H), 7.33 - 7.25 (m, 2H), 7.08 - 7.00 (m, 3H), 3.90 (s, 2H), 3.01 (s, 3H), 2.38 - 2.27 (m, 2H), 2.17 - 2.02 (m, 2H), 1.82 - 1.62 (m, 8H), -0.07 (s, 9H). (Example 90)

[00740] N-(6-Fluoro-3-methylbenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carbo xamide (Compound No. IV-1061) [Chemical Formula 108]

[00741] To a solution of 0.296 g (0.520 mmol) of 5-[(6-fluoro-3-methylbenzofuran-7-yl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]- Ethyl 5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in Reference Example 36 in 5 mL of THF, 0.17 mL (1.6 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature and then reacted at room temperature for 1 hour with stirring.

[00742] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, n-hexane:ethyl acetate = 50:50 ^ 28:72 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 217 mg of the title compound (yield: 84%) as a white solid.

[00743] Mass spectrum (IQ, m/z): 498 [M+1]+.

[00744] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.77 (br s, total 1H), 9.59 (br s, 1H), 8.18 - 8.01 ( m, 1H), 7.80 - 7.74 (m, 1H), 7.41 (dd, J = 4.8, 8.6 Hz, 1H), 7.14 (dd, J = 8.6, 10.5 Hz, 1H), 4.70 - 4.57 (m, 2H), 2.55 - 2.42 (m, 2H), 2.28 - 2.13 (m, 5H), 1.92 - 1.73 (m, 2H), 1.65 (br s, 6H), 0.09 (s, 9H). (Example 91)

[00745] N-(2-Chloro-6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carbo xamide (Compound No. IV-1063) [Chemical Formula 109]

[00746] To a solution of 210 mg (0.356 mmol) of 5-[(2-chloro-6-fluorobenzofuran-7-yl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]- Ethyl 5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate synthesized in Reference Example 40 in 5 mL of THF, 0.12 mL (1.1 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature and then reacted at room temperature for 1 hour with stirring.

[00747] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 164 mg of the title compound (yield: 89%) as a white solid.

[00748] Mass spectrum (IQ, m/z): 518 [M+1]+.

[00749] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.28 & 11.78 (br s, total 1H), 9.61 (br s, 1H), 8.34 - 8.10 ( m, 1H), 7.44 (dd, J = 4.8, 8.6 Hz, 1H), 7.20 (dd, J = 8.6, 10.7 Hz, 1H), 7.05 (s , 1H), 4.72 - 4.57 (m, 2H), 2.58 - 2.41 (m, 2H), 2.28 - 2.13 (m, 2H), 1.92 - 1.73 (m, 2H), 1.66 (br s, 6H), 0.10 (s, 9H). (Example 92)

[00750] N-[5-(Indoline-1-carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1- (trimethylsilyl)cyclobutanecarboxamide (Compound No. I-1000) [Chemical Formula 110]

[00751] To a solution of 187 mg (0.424 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.24 mL (1.4 mmol) of DIPEA and 0.15 mL (1 .3 mmol) of indoline were added at room temperature under an argon atmosphere and then reacted at 100oC for 110 minutes with stirring. The reaction solution was cooled, and 0.24 mL (2.2 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature for 1 hour with stirring. .

[00752] After completion of the reaction, the reaction solution was separated into an organic layer and an aqueous layer by adding ethyl acetate and a 5% aqueous solution of potassium bisulfate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, n-hexane:ethyl acetate = 50:50 ^ 29:71 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 163 mg of the title compound (yield: 85%) as a white solid.

[00753] Mass spectrum (IQ, m/z): 452 [M+1]+.

[00754] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.31 & 11.93 (br s, total 1H), 9.87 - 9.47 (m, 1H), 7.23 - 7 .18 (m, 1H), 7.09 - 7.02 (m, 1H), 6.82 (dt, J = 0.8, 7.4 Hz, 1H), 6.70 - 6.60 (m , 1H), 4.62 - 4.41 (m, 2H), 3.80 - 3.66 (m, 2H), 3.03 - 2.92 (m, 2H), 2.44 - 2.32 (m, 2H), 2.20 - 2.07 (m, 2H), 1.83 - 1.64 (m, 8H), 0.01 (br s, 9H). (Example 93)

[00755] N-[5-(3,4-Dihydro-2H-benz[b][1,4]oxazine-4-carbonyl)-6,6-dimethyl-1,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. I-1036) [Chemical Formula 111]

[00756] To a solution of 192 mg (0.435 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c ]ethyl pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 mL of 1,4-dioxane, 0.24 mL (1.4 mmol) of DIPEA and 180 mg (1.33 mmol) of 3,4-dihydro-2H-1,4-benzoxazine [purchased from Combi-Blocks Inc.] were added at room temperature under an argon atmosphere and then reacted at 100oC for 3 hours with stirring. The reaction solution was cooled, and 0.24 mL (2.2 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature for 1.5 hours with agitation.

[00757] After completion of the reaction, the reaction solution was separated into an organic layer and an aqueous layer by adding ethyl acetate and a 5% aqueous solution of potassium bisulfate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, n-hexane:ethyl acetate = 41:59 ^ 20:80 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 150 mg of the title compound (yield: 74%) as a pale yellow solid.

[00758] Mass spectrum (IQ, m/z): 468 [M+1]+.

[00759] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.30 & 11.99 (br s, total 1H), 9.90 - 9.41 (m, 1H), 6.83 - 6 .74 (m, 4H), 4.53 - 4.42 (m, 2H), 4.34 - 4.26 (m, 2H), 3.50 - 3.46 (m, 2H), 2.43 - 2.33 (m, 2H), 2.19 - 2.07 (m, 2H), 1.83 - 1.66 (m, 8H), 0.09 - -0.09 (m, 9H). (Example 94)

[00760] N-(6-Fluoro-2-methylbenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carbo xamide (Compound No. IV-1059) [Chemical Formula 112]

[00761] To 144 mg (0.742 mmol) of 6-fluoro-2-methylbenzofuran-7-carboxylic acid synthesized in Reference Example 43, 2 mL of toluene were added, followed by azeotropic distillation under reduced pressure. To a suspension of the residue obtained in 2 mL of dehydrated toluene, 0.170 mL (1.22 mmol) of triethylamine and 0.200 mL (0.929 mmol) of DPPA were added at room temperature under an argon atmosphere and then reacted at room temperature for 35 minutes and subsequently at 85°C for 1.5 hours with stirring. The reaction solution was cooled and then added in divided portions to a solution of 232 mg (0.613 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, Ethyl 4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 3 ml of toluene dehydrated at 0°C and reacted at 0°C for 1 hour with stirring.

[00762] After completion of the reaction, the reaction solution was separated into an organic layer and an aqueous layer by adding water and ethyl acetate, and then, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, n-hexane:ethyl acetate = 63:37 ^ 42:58 (V/V)), and a fraction containing 5-[( 6-fluoro-2-methylbenzofuran-7-yl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2( Ethyl 4H)-carboxylate was concentrated under reduced pressure and dried under reduced pressure.

[00763] To a solution of the residue of the concentration obtained in 5 mL of THF, 0.22 mL (2.0 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and then reacted at room temperature for 1 hour with stirring.

[00764] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous solution of potassium bisulfate. After separation into an organic layer and an aqueous layer, the obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, n-hexane:ethyl acetate = 46:54 ^ 25:75 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and the solution was freeze-dried to obtain 230 mg of the title compound (yield: 75%) as a white solid.

[00765] Mass spectrum (IQ, m/z): 498 [M+1]+.

[00766] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.27 & 11.81 (br s, total 1H), 9.69 - 9.49 (m, 1H), 8.16 - 7 .97 (m, 1H), 7.33 (dd, J = 5.0, 8.5 Hz, 1H), 7.06 (dd, J = 8.5, 10.6 Hz, 1H), 6, 60 - 6.55 (m, 1H), 4.64 (br s, 2H), 2.55 - 2.40 (m, 5H), 2.26 - 2.14 (m, 2H), 1.89 - 1.75 (m, 2H), 1.65 (br s, 6H), 0.10 (s, 9H). (Example 95)

[00767] N-[5-(1H-Indole-1-carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]- 1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. I-997) [Chemical Formula 113]

[00768] To a solution of 1.00 g (including impurities, <0.916 mmol) of 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrole Ethyl [3,4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 and 3.52 g (30.0 mmol) of indole in 10 mL of 1,4-dioxane, 1.74 mL (9.99 mmol) of DIPEA was added at room temperature and then reacted at 150oC for 0.5 hour and additionally at 180oC for 1 hour in a microwave-heated reaction apparatus. Subsequently, 1.00 mL (9.19 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction mixture at room temperature and then reacted at room temperature for 16 hours with stirring.

[00769] After completion of the reaction, ethyl acetate was added to the reaction solution, and the resulting solution was washed twice with a 5% aqueous solution of potassium bisulfate and once with a saturated aqueous solution of sodium bicarbonate, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, n-hexane:ethyl acetate = 69:31 ^ 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, CSH OSD silica gel, elution solvent: 0.1% by volume of formate in acetonitrile: 0.1% by volume of aqueous formic acid solution = 45:55 ^ 99:1 (V/V)), and a fraction containing the compound of interest was separated into an organic layer and an aqueous layer by the addition of ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The aqueous layer was subjected to extraction with ethyl acetate, and the entire organic layer thus obtained was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was purified using "VARIAN Bond Elute" (water:acetonitrile = 100:0 ^ 0:100 (V/V)), and water was added to the eluate containing the compound of interest and the solution was freeze-dried to obtain 15.8 mg of the title compound (yield: 2% [*calculation value with starting material purity set to 100%]) as a white solid.

[00770] Mass spectrum (IQ, m/z): 450 [M+1]+.

[00771] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.45 - 11.84 (m, 1H), 11.60 - 11.40 (m, 1H), 9.87 - 9.47 (m, 1H), 7.97 - 7.86 (m, 1H), 7.73 (d, J = 2.6 Hz, 1H), 7.47 - 7.38 (m, 1H), 7, 18 - 7.12 (m, 1H), 7.11 - 7.04 (m, 1H), 4.86 - 4.55 (m, 2H), 2.53 - 2.37 (m, 2H), 2.21 - 2.10 (m, 2H), 1.87 - 1.69 (m, 8H), 0.04 (s, 9H). (Reference Example 1) 1-(Trimethylsilyl)cyclobutanecarboxylic acid [Chemical Formula 114]

[00772] To 200 mL of THF, 214 mL (428 mmol) of a solution of 2 M lithium diisopropylamide in THF was added under an argon atmosphere, and then, 10.1 mL (107 mmol) of cyclobutanecarboxylic acid were added dropwise thereto with stirring under cooling in ice water and reacted for 4 hours while the temperature was increased to room temperature as required. Subsequently, 20 mL (116 mmol) of hexamethylphosphoric triamide was added thereto, 51 mL (490 mmol) of chlorotrimethylsilane was added dropwise thereto with stirring with the internal temperature maintained at -60oC or lower under cooling with an ice coolant. dry/acetone, and then reacted at -78oC for 16.5 hours with stirring.

[00773] After completion of the reaction, 67 mL of methanol was added to the reaction solution, the temperature was raised to 0oC, and then 134 mL of cold water was added to it. The resultant was adjusted to pH 2.1 by adding 2N hydrochloric acid and separated into an organic layer and an aqueous layer by adding 268 mL of diethyl ether, and the organic layer was washed with 268 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was separated into an organic layer and an aqueous layer by adding 50 mL of a 2 N aqueous sodium hydroxide solution and 267 mL of n-hexane. Subsequently, the aqueous layer was adjusted to pH 2.7 by adding 1 N hydrochloric acid, and this solution was separated into an organic layer and an aqueous layer by adding 267 mL of ethyl acetate. The obtained organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. n-hexane was added to the obtained concentration residue and cooled in an ice-water bath. The resulting solid was filtered, washed with cooled n-hexane, and then dried under reduced pressure to obtain 6.24 g of the title compound (yield: 34%) as a white solid. The filtrate was further concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane:methanol = 100:0 ^ 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 4.33 g of the title compound (yield: 23%) as a white solid.

[00774] Mass spectrum (IQ, m/z): 173 [M+1]+.

[00775] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 11.64 br s, 1H), 2.45 - 2.34 (m, 2H), 2.17 - 2.06 (m, 2H ), 1.91 - 1.70 (m, 2H), 0.06 (s, 9H).

[00776] (Reference Example 2) 6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazol-2,5(4H,6H)-dicarboxylate of 2 ethyl and 5 -tert-butyl [Chemical Formula 115]

[00777] To a solution of 13.9 g (80.4 mmol) of 1-(trimethylsilyl)cyclobutanecarboxylic acid synthesized in the same way as in Reference Example 1 in 105 mL of dichloromethane, 6.96 mL (81.2 mmol ) of oxalyl chloride and 0.32 mL (4.14 mmol) of DMF were added dropwise in this order between -25°C and -10°C under an argon atmosphere, then the temperature was raised to 0°C, and the resultant was reacted for 2 hours with shaking. This reaction solution was added dropwise to a solution of 8.74 g (26.9 mmol) of 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazol-2,5(4H,6H)- 2-ethyl and 5-tert-butyl dicarboxylate [synthesized according to the method described in Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739] and 23.5 mL (135 mmol) of DIPEA in 122 mL of dichloromethane at 0°C under an argon atmosphere and reacted at 0°C for 16 hours with stirring.

[00778] After completion of the reaction, the reaction solution was separated into an organic layer and an aqueous layer by adding 486 mL of a 5% aqueous solution of potassium bisulfate, and then, the aqueous layer was subjected to extraction two times with 200 mL of dichloromethane. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate = 86:14 ^ 53:47 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 8.30 g of the title compound (yield: 64%) as a white foam.

[00779] Mass spectrum (IQ, m/z): 479 [M+1]+.

[00780] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 9.98 & 9.72 & 9.71 (s, total 1H), 4.50 - 4.37 (m, 4H), 2, 53 - 2.43 (m, 2H), 2.32 - 2.07 (m, 2H), 2.02 - 1.72 (m, 2H), 1.65 - 1.55 (m, 6H), 1.51 - 1.42 (m, 9H), 1.38 - 1.31 (m, 3H), 0.10 & 0.06 & 0.01 (s, total 9H). (Reference Example 3) 6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-ethyl carboxylate [Chemical Formula 116]

[00781] To a solution of 43.2 g (90.0 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazol-2,5(4H, 2-Ethyl 5-tert-butyl 6H)-dicarboxylate synthesized in the same manner as in Reference Example 2 in 430 mL of dichloromethane, 30 mL (259 mmol) of 2,6-dimethylpyridine and 46 mL (255 mmol) of Trimethylsilyl trifluoromethanesulfonate were added dropwise in this order at 0°C with stirring under an argon atmosphere and reacted at 0°C for 1 hour with stirring.

[00782] After completion of the reaction, 260 mL of a saturated aqueous solution of sodium bicarbonate and 260 mL of dichloromethane were added to the reaction solution, followed by separation into an organic layer and an aqueous layer. The aqueous layer was subjected to extraction twice with 260 mL of dichloromethane, and then, the entire organic layer thus obtained was washed with 260 mL of a saturated aqueous solution of sodium bicarbonate and 260 mL of saturated saline solution in that order, subsequently dried. with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The operation of adding toluene to the obtained concentration residue and concentrating the resultant under reduced pressure was repeated to obtain 39.7 g of the title compound as a pale yellow solid.

[00783] The title compound was also synthesized as follows.

[00784] To a solution of 57.1 g (119 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazol-2,5(4H,6H) 2-ethyl and 5-tert-butyl dicarboxylate synthesized in the same way as in Reference Example 2 in 500 mL of dichloromethane, 28.0 mL (242 mmol) of 2,6-dimethylpyridine and 43.0 mL (238 mmol ) of trimethylsilyl trifluoromethanesulfonate were added dropwise in this order at 0oC under a nitrogen atmosphere and reacted at 0oC for 2 hours with stirring.

[00785] After completion of the reaction, the reaction solution was poured into 1,000 mL of a saturated aqueous solution of sodium bicarbonate, then stirred at room temperature, and subsequently separated into an organic layer and an aqueous layer. The aqueous layer was subjected to extraction twice with 500 mL of ethyl acetate, and then, the entire organic layer thus obtained was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The operation of adding toluene to the residue of the concentration obtained and concentrating the resultant under reduced pressure was carried out three times, then the brown oil obtained was refrigerated overnight, and subsequently, 50 mL of diethyl ether and 100 mL of n-hexane was added and stirred at room temperature for 0.5 hour. The deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 17.0 g of the title compound (yield: 38%) as a white solid.

[00786] Mass spectrum (DUIS, m/z): 379 [M+1]+.

[00787] 1H-NMR spectrum (400MHz, CDCl3) δ: 9.86 (s, 1H), 4.52 (q, J = 7.1 Hz, 2H), 4.23 (s, 2H), 2 .64 - 2.52 (m, 2H), 2.38 - 2.27 (m, 2H), 2.03 - 1.89 (m, 2H), 1.53 - 1.42 (m, 9H) , 0.14 (s, 9H). (Reference Example 4)

[00788] 5-(Chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate ethyl [Chemical Formula 117]

[00789] To a solution of 4.90 g (11.1 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, 4-c]pyrazole Ethyl -2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 50 mL of dichloromethane, 6.80 mL (39.0 mmol) of DIPEA was added at room temperature under a nitrogen atmosphere, and then , a solution of 2.34 g (7.89 mmol) of bis(trichloromethyl) carbonate in 10 ml of dichloromethane was added dropwise thereto at -78°C and reacted at -78°C for 2 hours with stirring.

[00790] After completion of the reaction, 80 mL of a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and it was stirred for 5 minutes. Dichloromethane was added thereto and then stirred while the temperature was increased to room temperature. The reaction solution was separated into an organic layer and an aqueous layer, and then the aqueous layer was subjected to extraction twice with dichloromethane. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 85:15 ^ 75:25 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. n-hexane was added to the obtained concentration residue, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 2.00 g of the title compound (yield: 41%) as a white solid. Also, the obtained filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 2.50 g of the title compound including impurities (yield: 51% [calculation value with purity defined as 100%]) as a pale yellow foam. .

[00791] Mass spectrum (DUIS, m/z): 441 [M+1]+

[00792] 1H-NMR spectrum (400MHz, CDCl3) δ: 9.94 (s, 1H), 4.97 (s, 2H), 4.55 (q, J = 7.1 Hz, 2H), 2 .64 - 2.53 (m, 2H), 2.39 - 2.30 (m, 2H), 2.05 - 1.93 (m, 2H), 1.78 (s, 6H), 1.48 (t, J = 7.1 Hz, 3H), 0.16 (s, 9H). (Reference Example 5) 1-(Ethyldimethylsilyl)cyclobutanecarboxylic acid [Chemical Formula 118]

[00793] To 200 mL of THF, 214 mL (428 mmol) of a solution of 2 M lithium diisopropylamide in THF was added under an argon atmosphere, and then, 10.7 mL (112 mmol) of cyclobutanecarboxylic acid were added dropwise thereto under cooling in ice water and stirred while the temperature was increased to room temperature as the circumstances required. Subsequently, 20 mL (120 mmol) of hexamethylphosphoric triamide was added thereto. After cooling with a dry ice/ethanol coolant, 67.6 mL (485 mmol) of chloro(ethyl)dimethylsilane was added dropwise thereto at -75°C to -69°C and stirred overnight at a temperature of -60OC or lower.

[00794] After completion of the reaction, 67 mL of methanol and subsequently 134 mL of cold water were added dropwise to the reaction solution and then the reaction solution was brought to room temperature. 240 mL of 2N hydrochloric acid was added to it to achieve acidity (pH 2.0), and 200 mL of diethyl ether was added to it, followed by separation into an organic layer and an aqueous layer. The obtained organic layer was washed with 250 ml of a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. 41 mL of a 2N aqueous sodium hydroxide solution was added to the obtained concentration residue, followed by washing with 250 mL of n-hexane. The aqueous layer was made acidic (pH 2.0) again by adding 82 mL of 1 N hydrochloric acid. This solution was subjected to extraction with 250 mL of ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane:methanol = 100:0 ^ 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 11.7 g of the title compound (yield: 59%) as a white solid.

[00795] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 11.71 (br s, 1H), 2.44 - 2.33 (m, 2H), 2.19 - 2.08 (m, 2H), 1.91 - 1.73 (m, 2H), 0.92 (t, J = 7.9 Hz, 3H), 0.55 (q, J = 7.9 Hz, 2H), 0, 05 (s, 6H).

[00796] (Reference Example 6) 3-[1-(Ethyldimethylsilyl)cyclobutanecarboxamido]-6,6-dimethylpyrrolo[3,4-c]pyrazol-2,5(4H,6H)-2-ethyl dicarboxylate and 5-tert-butyl [Chemical Formula 119]

[00797] To a solution of 11.7 g (62.8 mmol) of 1-(ethyldimethylsilyl)cyclobutanecarboxylic acid synthesized in the same way as in Reference Example 5 in 81 mL of dichloromethane, 5.3 mL (62 mmol) of oxalyl chloride and 0.24 mL (3.1 mmol) of DMF were added in this order under cooling in ice water under an argon atmosphere and stirred at the same temperature as above for 2 hours.

[00798] After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentration residue. A solution of the obtained concentration residue in 5 mL of dehydrated dichloromethane was added dropwise to a solution of 6.73 g (20.7 mmol) of 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazol- 2-ethyl and 5-tert-butyl 2,5(4H,6H)-dicarboxylate [synthesized according to the method described in Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739] and 18 mL (100 mmol ) of DIPEA in 94 mL of dichloromethane under cooling in ice water under a nitrogen atmosphere and stirred at the same temperature as above for 16 hours.

[00799] After completion of the reaction, the reaction solution was separated into an organic layer and an aqueous layer by adding 350 mL of a 5% aqueous solution of potassium bisulfate, and then, the aqueous layer was subjected to extraction two times with 150 mL of dichloromethane. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate = 86:14 ^ 53:47 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 7.51 g of the title compound (yield: 74%) as a pale yellow oil.

[00800] Mass spectrum (DUIS, m/z): 493 [M+1]+.

[00801] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 9.82 - 9.69 (m, 1H), 4.51 - 4.36 (m, 4H), 2.49 - 2.42 (m, 2H), 2.32 - 2.23 (m, 2H), 1.95 - 1.84 (m, 2H), 1.62 - 1.55 (m, 6H), 1.49 - 1 .42 (m, 9H), 1.38 - 1.31 (m, 3H), 0.91 (t, J = 7.9 Hz, 3H), 0.57 (q, J = 7.9 Hz, 2H), 0.09 (s, 6H). (Reference Example 7)

[00802] 3-[1-(Ethyldimethylsilyl)cyclobutanecarboxamido]-6,6-dimethyl-5, 6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-ethyl carboxylate [Chemical Formula 120]

[00803] To a solution of 2.87 g (5.79 mmol) of 3-[1-(ethyldimethylsilyl)cyclobutanecarboxamido]-6,6-dimethylpyrrolo[3,4-c]pyrazol-2,5(4H, 2-ethyl and 5-tert-butyl 6H)-dicarboxylate synthesized in the same manner as in Reference Example 6 in 30 mL of dichloromethane, 2.10 mL (18.1 mmol) of 2,6-dimethylpyridine and 3.20 mL (17.8 mmol) of trimethylsilyl trifluoromethanesulfonate were added dropwise in this order at 0°C under a nitrogen atmosphere and reacted at 0°C for 2.5 hours with stirring.

[00804] After completion of the reaction, dichloromethane was added to the reaction solution, followed by washing with a saturated aqueous solution of sodium bicarbonate. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with dichloromethane. The entire organic layer thus obtained was washed with saturated saline, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The operation of adding toluene to the concentration residue obtained and concentrating the resultant under reduced pressure was carried out twice. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: dichloromethane:methanol = 98:2 ^ 95:5 ^ 92:8 (V/V)), and a fraction containing The compound of interest was concentrated under reduced pressure, dried under reduced pressure to obtain 2.17 g of the title compound (yield: 92%) as a pale yellow oil.

[00805] Mass spectrum (DUIS, m/z): 393 [M+1]+.

[00806] 1H-NMR spectrum (400MHz, CDCl3) δ: 9.88 (s, 1H), 4.52 (q, J = 7.1 Hz, 2H), 4.21 (s, 2H), 2 .63 - 2.52 (m, 2H), 2.39 - 2.29 (m, 2H), 2.03 - 1.90 (m, 2H), 1.52 - 1.42 (m, 9H) , 0.96 (t, J = 7.9 Hz, 3H), 0.64 (q, J = 7.9 Hz, 2H), 0.13 (s, 6H). (Reference Example 8) 1-Fluoro-3-(methoxy-d3)-2-nitrobenzene [Chemical Formula 121]

[00807] To a solution of 1.0 g (6.4 mmol) of 3-fluoro-2-nitrophenol in 20 mL of DMF, 0.79 mL (13 mmol) of methyl iodide-(2H3) and 2, 20 g (15.9 mmol) of anhydrous potassium carbonate was added at 0°C under an argon atmosphere and reacted at 0°C for 3 hours with stirring.

[00808] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 95:5 ^ 75:25 (V/V)), and a fraction containing The compound of interest was concentrated under reduced pressure to obtain 1.04 g of the title compound (yield: 94%) as a colorless oil.

[00809] Mass spectrum (IQ, m/z): 175 [M+1]+.

[00810] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 7.64 (dt, J = 6.7, 8.7 Hz, 1H), 7.21 (td, J = 1.0, 8 .7 Hz, 1H), 7.15 (ddd, J = 1.0, 8.7, 9.6 Hz, 1H). (Reference Example 9) 2-Fluoro-6-(methoxy-d3)aniline [Chemical Formula 122]

[00811] To a solution of 1.04 g (5.97 mmol) of 1-fluoro-3-(methoxy-d3)-2-nitrobenzene synthesized in the same way as in Reference Example 8 in 20 mL of ethanol, 200 mg of 10% Pd-C (containing 54.33% water, PE-type manufactured by N.E. Chemcat Corp.) were added at room temperature under an argon atmosphere and after replacing the argon atmosphere with a hydrogen atmosphere, were reacted at room temperature for 4 hours with stirring.

[00812] After completion of the reaction, the reaction solution was diluted with ethyl acetate, subsequently filtered through Celite, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 53:47 ^ 45:55 (V/V)), and a fraction containing The compound of interest was concentrated under reduced pressure to obtain 721 mg of the title compound (yield: 84%) as a white solid.

[00813] Mass spectrum (IQ, m/z): 145 [M+1]+.

[00814] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 6.71 - 6.63 (m, 2H), 6.52 (dt, J = 6.3, 8.3 Hz, 1H), 4.58 (s, 2H). (Reference Example 10) 2-Fluoro-4-methoxy-1-methylbenzene [Chemical Formula 123]

[00815] To a solution of 1.00 g (7.93 mmol) of 3-fluoro-4-methylphenol in 20 mL of dehydrated DMF, 3.30 g (23.9 mmol) of potassium carbonate and 0.750 mL ( 12.0 mmol) of methyl iodide was added at room temperature under an argon atmosphere and reacted at room temperature for 16 hours with stirring.

[00816] After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 80:20 (V/V)), and a fraction containing The compound of interest was concentrated under reduced pressure to obtain 725 mg of the title compound (yield: 65%) as a colorless oil.

[00817] Mass spectrum (IQ, m/z): 141 [M+1]+.

[00818] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.10 - 7.01 (m, 1H), 6.62 - 6.55 (m, 2H), 3.77 (s, 3H), 2.21 - 2.18 (m, 3H). (Reference Example 11) 2-Fluoro-6-methoxy-3-methylbenzoic acid [Chemical Formula 124]

[00819] To a solution of 725 mg (5.17 mmol) of 2-fluoro-4-methoxy-1-methylbenzene synthesized in the same way as in Reference Example 10 in 15 mL of THF, 5.70 mL (6, 21 mmol) of a 1.09 M solution of lithium diisopropylamide in THF and hexane was added dropwise at -78°C under an argon atmosphere and reacted at -78°C for 1 hour with stirring. Subsequently, an excessive amount of dry ice was added thereto at -78°C and the reaction continued at -78°C for 2 hours with stirring.

[00820] After completion of the reaction, the reaction solution whose temperature was raised to room temperature was adjusted to pH 4 by adding 1 N hydrochloric acid, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol = 100:0 ^ 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 276 mg of the title compound (yield: 29%) as a white solid.

[00821] Mass spectrum (IQ, m/z): 185 [M+1]+.

[00822] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.32 - 7.21 (m, 1H), 6.70 (dd, J = 1.0, 8.7 Hz, 1H), 3, 94 (s, 3H), 2.28 - 2.20 (m, 3H). (Reference Example 12) 2-(Difluoromethoxy)-6-fluorobenzamide [Chemical Formula 125]

[00823] To a solution of 400 mg (2.14 mmol) of 2-(difluoromethoxy)-6-fluorobenzonitrile [purchased from Enamina Ltd.] in 5 mL of ethanol and 5 mL of DMSO, 6.41 mL (6 .41 mmol) of a 1 M aqueous sodium hydroxide solution and 1.10 mL (10.7 mmol) of a 30 wt% aqueous hydrogen peroxide solution were added at 0°C under an argon atmosphere and reacted at temperature environment for 2 hours with stirring.

[00824] After completion of the reaction, a saturated aqueous solution of sodium thiosulfate was added to the reaction solution and stirred for 0.5 hour, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 80:20 ^ 60:40 (v/v)), and a fraction containing The compound of interest was concentrated under reduced pressure to obtain 406 mg of the title compound (yield: 93%) as a white solid.

[00825] Mass spectrum (DUIS, m/z): 206 [M+1]+.

[00826] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 8.01 (br s, 1H), 7.75 (br s, 1H), 7.49 (dt, J = 6.7, 8 .4 Hz, 1H), 7.21 (t, J = 73.7 Hz, 1H), 7.20 - 7.14 (m, 1H), 7.11 - 7.06 (m, 1H). (Reference Example 13) Methyl 2-Ethyl-6-fluorobenzoate [Chemical Formula 126]

[00827] To a solution of 2.01 g (8.63 mmol) of methyl 2-bromo-6-fluorobenzoate in 20 mL of 1,4-dioxane and 4.0 mL of water, 2.80 g (26 .4 mmol) of sodium carbonate and 2.90 mL (16.9 mmol) of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane were added under a nitrogen atmosphere and then stirred at room temperature for 10 minutes while argon gas was bubbled into the reaction solution. Subsequently, 1.02 g (0.883 mmol) of tetrakis(triphenylphosphine)palladium (0) was added thereto at room temperature and reacted at 90oC for 4 hours with stirring.

[00828] After completion of the reaction, the reaction solution was diluted with water, followed by extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, n-hexane:ethyl acetate = 99:1 ^ 98:2 ^ 97:3), and a fraction containing 2-fluoro-6 -methyl vinylbenzoate was concentrated under reduced pressure and dried under reduced pressure.

[00829] To a solution of the concentration residue obtained in 16 mL of 1,4-dioxane and 4.0 mL of water, 1.34 g (12.6 mmol) of sodium carbonate and 1.40 mL (8, 16 mmol) of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane was added under a nitrogen atmosphere and then stirred at room temperature for 10 minutes while argon gas was bubbled into the reaction solution. . Subsequently, 446 mg (0.386 mmol) of tetrakis(triphenylphosphine)palladium (0) were added thereto at room temperature and reacted at 90oC for 3 hours with stirring. Subsequently, 1.10 mL (6.41 mmol) of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane and 133 mg (0.115 mmol) of tetrakis(triphenylphosphine)palladium (0) were added to the reaction solution and reacted at 90oC for 3 hours with stirring.

[00830] After completion of the reaction, the reaction solution was diluted with water, followed by extraction twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, n-hexane:ethyl acetate = 99:1 ^ 98:2 ^ 97:3), and a fraction containing 2-fluoro-6 -methyl vinylbenzoate was concentrated under reduced pressure and dried under reduced pressure.

[00831] To a solution of the concentration residue obtained in 20 mL of ethanol, 0.20 g of 10% Pd-C (containing 54% water, type-PE manufactured by N.E. Chemcat Corp.) was added at room temperature under a nitrogen atmosphere. The internal atmosphere of the reaction vessel was replaced by a hydrogen atmosphere, followed by the reaction at room temperature for 0.5 hour with stirring. The internal atmosphere of the reaction vessel was replaced again with a nitrogen atmosphere, and then 0.36 g of 10% Pd-C (containing 54% water, PE-type manufactured by N.E. Chemcat Corp.) was added to the reaction vessel at room temperature. The internal atmosphere of the reaction vessel was replaced again with a hydrogen atmosphere, followed by the reaction at room temperature for 1.5 hours with stirring.

[00832] After completion of the reaction, the internal atmosphere of the reaction vessel was replaced with a nitrogen atmosphere, and subsequently, the reaction solution was filtered using a Celite filter. The removed solid was washed with ethyl acetate, and then the entire filtrate was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, n-hexane:ethyl acetate = 99:1 ^ 98:2 ^ 97:3 ^ 96:4), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 664 mg of the title compound (yield: 42% [2 steps]) as a colorless oil.

[00833] Mass spectrum (IQ, m/z): 183 [M+1]+.

[00834] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.32 (dt, J = 5.8, 8.0 Hz, 1H), 7.07 - 7.01 (m, 1H), 6, 98 - 6.90 (m, 1H), 3.94 (s, 3H), 2.71 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H ). (Reference Example 14) 2-Ethyl-6-fluorobenzoic Acid [Chemical Formula 127]

[00835] To a solution of 659 mg (3.62 mmol) of methyl 2-ethyl-6-fluorobenzoate synthesized in the same way as in Reference Example 13 in 10 mL of ethanol, 4.0 mL (20 mmol) of a 5 N aqueous sodium hydroxide solution were added at room temperature under a nitrogen atmosphere and reacted at room temperature for 3.5 hours with stirring. Subsequently, 2.0 mL (10 mmol) of a 5 N aqueous sodium hydroxide solution was added to the reaction solution and reacted at room temperature for 3.5 hours and at 60°C for 1 hour with stirring.

[00836] After completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethanol was distilled. Water was added to the concentration residue, followed by washing twice with toluene. The aqueous layer was adjusted to pH 2 by addition of 6 N hydrochloric acid, followed by extraction twice with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride, then dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to obtain 558 mg of the title compound (yield: 92 %) as a yellow solid.

[00837] Mass spectrum (IQ, m/z): 169 [M+1]+.

[00838] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.38 (dt, J = 5.7, 8.1 Hz, 1H), 7.11 - 7.05 (m, 1H), 7, 03 - 6.95 (m, 1H), 2.84 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). (Reference Example 15) 6-Fluorobenzofuran-7-carboxylic acid [Chemical Formula 128]

[00839] To a solution of 3.76 g (17.5 mmol) of 7-bromo-6-fluorobenzofuran [synthesized according to the method described in EP1204654, pages 14-16] in 50 mL of dehydrated THF, 12, 3 mL (19.3 mmol) of a 1.57 M n-butyllithium solution in n-hexane was added dropwise at -78°C under a nitrogen atmosphere and reacted at -78°C for 1 hour with stirring. 36.4 g (827 mmol) of dry ice was added in divided portions thereto at -78°C and the reaction continued at -78°C for 1 hour with stirring and subsequently for 6.5 hours while the temperature was raised to room temperature as per the circumstances.

[00840] After completion of the reaction, water was added to the reaction solution and then the reaction solution was concentrated under reduced pressure, and THF was distilled. A 1N aqueous sodium hydroxide solution was added to the obtained concentration residue, followed by washing twice with toluene. The aqueous layer obtained was adjusted to pH 2 by adding 6 N hydrochloric acid, followed by extraction three times with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure and dried under reduced pressure to obtain 2.91 g of the title compound (yield : 92%) as a light orange solid.

[00841] Mass spectrum (IQ, m/z): 181 [M+1]+.

[00842] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.78 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 4.8, 8.6 Hz, 1H) , 7.13 (dd, J = 8.6, 11.0 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H). (Reference Example 16) 6-Fluoro-2,3-dihydrobenzofuran-7-carboxylic acid [Chemical Formula 129]

[00843] To a solution of 729 mg (4.05 mmol) of 6-fluorobenzofuran-7-carboxylic acid synthesized in the same way as in Reference Example 15 in 15 mL of ethanol, 255 mg of 10% Pd-C (containing 54% water, PE-type manufactured by N.E. Chemcat Corp.) was added at room temperature under a nitrogen atmosphere. The internal atmosphere of the reaction vessel was replaced by a hydrogen atmosphere, followed by the reaction at room temperature for 1.5 hours with stirring. The inner atmosphere of the reaction vessel was replaced again with a nitrogen atmosphere, and then 236 mg of 10% Pd-C (containing 54% water, PE-type manufactured by N.E. Chemcat Corp.) was added to the reaction vessel. reaction at room temperature. The internal atmosphere of the reaction vessel was replaced by a hydrogen atmosphere, followed by the reaction at room temperature for 6.5 hours with stirring. The inner atmosphere of the reaction vessel was replaced again with a nitrogen atmosphere, and then 1.03 g of 10% Pd-C (containing 54% water, PE-type manufactured by N.E. Chemcat Corp.) was added to the reaction vessel. reaction vessel at room temperature. The internal atmosphere of the reaction vessel was replaced by a hydrogen atmosphere, followed by the reaction at room temperature for 1 hour with stirring.

[00844] After completion of the reaction, the internal atmosphere of the reaction vessel was replaced with a nitrogen atmosphere, and subsequently, the reaction solution was filtered using a Celite filter. The removed solid was washed with ethyl acetate, and then the entire filtrate was concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: 0.1% by volume of formate in acetonitrile: 0.1% by volume of aqueous formic acid solution = 25 :75 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure, followed by distillation of acetonitrile. The obtained concentration residue was subjected to extraction three times with ethyl acetate, and the entire organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride, then dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to obtain 339 mg of the title compound (yield: 46%) as a pale yellow solid.

[00845] Mass spectrum (IQ, m/z): 183 [M+1]+.

[00846] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.31 - 7.25 (m, 1H), 6.66 (dd, J = 8.2, 11.0 Hz, 1H), 4, 82 (t, J = 8.8 Hz, 2H), 3.28 - 3.19 (m, 2H). (Reference Example 17) 2-Chloro-6-cyclopropylbenzoic acid [Chemical Formula 130]

[00847] To a solution of 495 mg (3.05 mmol) of 2-cyclopropylbenzoic acid [purchased from WuXi AppTec] in 9.0 mL of DMF, 496 mg (3.71 mmol) of N-chlorosuccinimide and 70, 3 mg (0.313 mmol) of palladium (II) acetate were added at room temperature under a nitrogen atmosphere and reacted at 100oC for 2.5 hours with stirring. Subsequently, 70.3 mg (0.313 mmol) of palladium (II) acetate was added thereto and reacted at 100oC for 1.5 hours with stirring. Additionally, 344 mg (2.58 mmol) of N-chlorosuccinimide were added thereto and reacted at 100oC for 1 hour with stirring.

[00848] After completion of the reaction, water was added to the reaction solution, and then, the insoluble matter was filtered using a Celite filter. The filtrate was subjected to filtration three times with ethyl acetate, and then, the entire organic layer thus obtained was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 1.38 g of a concentration residue.

[00849] To a solution of the residue of the concentration obtained in 8.0 mL of DMF, 763 mg (5.71 mmol) of N-chlorosuccinimide and 150 mg (0.668 mmol) of palladium (II) acetate were added at room temperature under a nitrogen atmosphere and reacted at 100oC for 1.5 hours with stirring.

[00850] After completion of the reaction, water was added to the reaction solution, and then, the insoluble matter was filtered using a Celite filter. The filtrate was subjected to filtration three times with ethyl acetate, and then, the entire organic layer thus obtained was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 1.43 g of a concentration residue.

[00851] To a solution of the residue of the concentration obtained in 10 mL of DMF, 227 mg (1.40 mmol) of 2-cyclopropylbenzoic acid [purchased from WuXi AppTec], 956 mg (7.16 mmol) of N-chlorosuccinimide , and 246 mg (1.10 mmol) of palladium (II) acetate were added at room temperature under a nitrogen atmosphere and reacted at 100oC for 1 hour with stirring.

[00852] After completion of the reaction, water was added to the reaction solution, and then, the insoluble matter was filtered using a Celite filter. The filtrate was subjected to filtration three times with ethyl acetate, and then, the entire organic layer thus obtained was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, fluoro-phenyl-silica gel, elution solvent: 0.1% by volume of formate in acetonitrile: 0.1% by volume of aqueous acid solution formic = 40:60), and a fraction containing the compound of interest was concentrated under reduced pressure to distill acetonitrile. The concentration residue obtained was subjected to extraction three times with ethyl acetate, and then, the entire organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and concentrated under pressure. reduced. The concentration residue obtained was again subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: 0.1% by volume of formate in acetonitrile: 0.1% by volume of aqueous formic acid solution = 40:60), and a fraction containing the compound of interest was concentrated under reduced pressure to distill acetonitrile. The obtained concentration residue was subjected to extraction three times with ethyl acetate, and then, the entire organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure. , and dried under reduced pressure to obtain 178 mg of the title compound (yield: 20%).

[00853] Mass spectrum (IQ, m/z): 197 [M+1]+.

[00854] 1H-NMR spectrum (400MHz, CD2Cl2) δ: 7.33 - 7.23 (m, 2H), 6.97 - 6.91 (m, 1H), 2.03 (tt, J = 5 .2, 8.5 Hz, 1H), 1.08 - 0.93 (m, 2H), 0.81 - 0.68 (m, 2H). (Reference Example 18) Methyl 6-Chloro-2-fluoro-3-methylbenzoate [Chemical Formula 131]

[00855] To a solution of 3.00 g (15.9 mmol) of 6-chloro-2-fluoro-3-methylbenzoic acid in 80 mL of DMF, 7.26 g (22.3 mmol) of cesium carbonate and 1.19 mL (19.1 mmol) of methyl iodide were added at room temperature under an argon atmosphere and reacted at room temperature for 2 hours with stirring.

[00856] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 95:5 (v/v)), and a fraction containing The compound of interest was concentrated under reduced pressure to obtain 2.81 g of the title compound (yield: 87%) as a colorless oil.

[00857] Mass spectrum (IQ, m/z): 203 [M+1]+.

[00858] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.22 - 7.15 (m, 1H), 7.14 - 7.07 (m, 1H), 3.97 (s, 3H), 2.30 - 2.24 (m, 3H). (Reference Example 19) Methyl 2-Fluoro-3,6-dimethylbenzoate [Chemical Formula 132]

[00859] A solution of 1.00 g (4.94 mmol) of methyl 6-chloro-2-fluoro-3-methylbenzoate synthesized in the same way as in Reference Example 18 in 20 mL of 1,4-dioxane , 2.07 mL (14.8 mmol) of trimethylboroxine, 2.73 g (19.8 mmol) of anhydrous potassium carbonate, and 336 mg (0.493 mmol) of (1,3-diisopropylimidazole-2) dichloride -ylidene)(3-chloropyridyl)palladium (II) were added at room temperature under an argon atmosphere and reacted at 100oC for 2 hours with stirring.

[00860] After completion of the reaction, the reaction solution was diluted with ethyl acetate and filtered through a membrane filter. A saturated aqueous ammonium chloride solution was added to the filtrate, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 95:5 (v/v)), and a fraction containing The compound of interest was concentrated under reduced pressure to obtain 849 mg of the title compound (yield: 94%) as a colorless oil.

[00861] Mass spectrum (IQ, m/z): 183 [M+1]+.

[00862] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.12 (t, J = 7.8 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 3.93 (s, 3H), 2.34 (s, 3H), 2.27 - 2.22 (m, 3H). (Reference Example 20) 2-Fluoro-3,6-dimethylbenzoic acid [Chemical Formula 133]

[00863] To a solution of 843 mg (4.63 mmol) of methyl 2-fluoro-3,6-dimethylbenzoate synthesized in the same manner as in Reference Example 19 in 5 mL of THF and 10 mL of water, 332 mg (13.9 mmol) lithium hydroxide were added at room temperature under an argon atmosphere and reacted at room temperature for 15 hours and at 80oC for 8 hours with stirring.

[00864] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 50:50 ^ 30:70 (v/v)), and a fraction containing The compound of interest was concentrated under reduced pressure to obtain 565 mg of the title compound (yield: 73%) as a white solid.

[00865] Mass spectrum (IQ, m/z): 169 [M+1]+.

[00866] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 13.42 (br s, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 2.28 (s, 3H), 2.22 - 2.18 (m, 3H). (Reference Example 21) 2-Chloro-3-fluoro-6-methylbenzoic acid [Chemical Formula 134]

[00867] To a solution of 4.00 g (26.0 mmol) of 5-fluoro-2-methylbenzoic acid in 100 mL of DMF, 0.31 g (1.4 mmol) of palladium (II) acetate was added under an argon atmosphere, and then, 4.35 g (32.6 mmol) of N-chlorosuccinimide were added in divided portions thereto at room temperature and reacted at 100oC for 5 hours with stirring.

[00868] After completion of the reaction, the reaction solution was cooled to room temperature, and water was added to it. The resulting solid was filtered using a Celite filter. The filtrate was subjected to extraction with ethyl acetate, and the organic layer obtained was washed with water and a saturated aqueous solution of sodium chloride in that order, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: n-hexane:ethyl acetate = 70:30 ^ 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was again subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: n-hexane:ethyl acetate = 70:30 ^ 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 182 mg of the title compound (yield: 4%) as a white solid.

[00869] Mass spectrum (DUIS, m/z): 187 [M-1]-.

[00870] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 13.91 (br s, 1H), 7.37 (t, J = 8.9 Hz, 1H), 7.32 - 7.26 (m, 1H), 2.29 - 2.25 (m, 3H). (Reference Example 22) Ethyl 6,6-Dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate [Chemical Formula 135]

[00871] To a solution of 9.70 g (61.3 mmol) of 1-(trimethylsilyl)cyclopropanecarboxylic acid [synthesized according to the method described in J. Org. Chem., 1982 (47) 5, 893-895 ] in 120 mL of dehydrated dichloromethane, 6.60 mL (76.9 mmol) of oxalyl chloride and 0.25 mL (3.2 mmol) of dehydrated DMF were added in this order at 0oC under a nitrogen atmosphere and reacted at 0oC for 2.5 hours with stirring.

[00872] After completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure.

[00873] A solution of the concentration residue obtained in 30 mL of dehydrated dichloromethane was added to a solution of 19.0 mL (109 mmol) of DIPEA and 9.94 g (30.6 mmol) of 3-amino-6, 2-Ethyl 5-tert-butyl 6-dimethylpyrrolo[3,4-c]pyrazol-2,5(4H,6H)-dicarboxylate [synthesized according to the method described in Journal of Medicinal Chemistry 2012, 55 (10 ), 4728-4739] in 170 mL of dichloromethane dehydrated at 0oC under a nitrogen atmosphere and reacted at 0oC for 24 hours with stirring.

[00874] After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction once with dichloromethane and twice with ethyl acetate. The entire organic layer thus obtained was dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 70:30 (V/V)), and a fraction containing 2-Ethyl and 5-tert-butyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]pyrrolo[3,4-c]pyrazol-2,5(4H,6H)-dicarboxylate was concentrated under pressure reduced. The residue from the concentration of the fraction containing impurities was subjected again to preparative column chromatography (apparatus 2, silica gel, elution solvent: n-hexane:ethyl acetate = 90:10 ^ 75:25 (V/V)) , combined with the preliminarily obtained fraction, concentrated under reduced pressure, and dried under reduced pressure.

[00875] To a solution of the concentration residue obtained in 100 mL of ethyl acetate, 60.0 mL (240 mmol) of 4 N hydrogen chloride/ethyl acetate were added at room temperature under a nitrogen atmosphere and reacted at room temperature for 5 hours with stirring.

[00876] After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentration residue was suspended in diisopropyl ether, and the suspension was stirred at room temperature. Insoluble matter was collected by filtration and washed with diisopropyl ether. The solid obtained was dissolved in water, and then a saturated aqueous solution of sodium bicarbonate and dichloromethane were added to the dissolved solid solution and stirred at room temperature for 5 minutes. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with dichloromethane. The entire organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride, then dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to obtain 8.15 g of the title compound (yield : 73% [2 steps]) as a light orange solid.

[00877] Mass spectrum (DUIS, m/z): 365 [M+1]+.

[00878] 1H-NMR spectrum (400MHz, CDCl3) δ: 10.02 (s, 1H), 4.53 (q, J = 7.2 Hz, 2H), 4.16 (s, 2H), 1 .50 - 1.43 (m, 9H), 1.14 - 1.08 (m, 2H), 0.84 - 0.77 (m, 2H), 0.12 (s, 9H). (Reference Example 23) 2-methyl-2-(trimethylsilyl)propanoic acid [Chemical Formula 136]

[00879] To 100 mL of dehydrated THF, 200 mL (400 mmol) of a solution of 2 M lithium diisopropylamide in THF was added under an argon atmosphere, and subsequently, 4.7 mL (51 mmol) of acid isobutanoic acid were added dropwise to it at 0oC and reacted at room temperature for 4 hours with stirring. 10 mL (57 mmol) of hexamethylphosphoric triamide was added thereto at room temperature, and subsequently, 29 mL (230 mmol) of chlorotrimethylsilane was added dropwise thereto at -78oC and stirred for 24 hours while the temperature was gradually raised to room temperature.

[00880] After completion of the reaction, the solution was made acidic by adding 25 mL of methanol, 50 mL of water, and 2 N hydrochloric acid in that order to the reaction solution, followed by extraction with diethyl ether. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in a 2N aqueous sodium hydroxide solution and washed with ethyl acetate. The aqueous layer obtained was made acidic by adding 1 N hydrochloric acid, followed by extraction with ethyl acetate. The obtained organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was suspended in n-hexane and ultrasonicated, and then the insoluble matter was collected by filtration. The filtrate was concentrated under reduced pressure, and the concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: 1,2-dichloroethane:methanol = 100:0 ^ 99:1 (V /V)), and a combined fraction containing the compound of interest and the preceding solid collected by filtration, was concentrated under reduced pressure, and dried under reduced pressure to obtain 2.66 g of the title compound (yield: 32%) as a white solid.

[00881] Mass spectrum (IQ, m/z): 161 [M+1]+.

[00882] 1H-NMR spectrum (400MHz, CDCl3) δ: 1.22 (s, 6H), 0.08 (s, 9H). (Reference Example 24) 6,6-Dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]pyrrolo[3,4-c]pyrazol-2,5(4H,6H)-2-ethyl dicarboxylate and 5-tert-butyl [Chemical Formula 137]

[00883] To a solution of 888 mg (5.54 mmol) of 2-methyl-2-(trimethylsilyl)propanoic acid synthesized in the same manner as in Reference Example 23 in 15 mL of dichloromethane, 0.594 mL (6.93 mmol ) of oxalyl chloride and 0.021 mL (0.27 mmol) of DMF were added at 0°C under an argon atmosphere and reacted at 0°C for 1 hour with stirring.

[00884] After completion of the reaction, the reaction solution was concentrated under reduced pressure.

[00885] A solution of the residue from the concentration obtained in 2 mL of 1,4-dioxane was added dropwise to a solution of 899 mg (2.77 mmol) of 3-amino-6,6-dimethylpyrrolo[3,4- c]pyrazol-2,5(4H,6H)-2-ethyl and 5-tert-butyl dicarboxylate [synthesized according to the method described in Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739] and 1 .93 mL (11.1 mmol) of DIPEA in 5 mL of 1,4-dioxane at 0oC and reacted at room temperature for 1 hour with stirring.

[00886] After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 95:5 ^ 80:20 (v/v)), and a fraction containing The compound of interest was concentrated under reduced pressure to obtain 903 mg of the title compound (yield: 70%) as a white solid.

[00887] Mass spectrum (DUIS, m/z): 467 [M+1]+.

[00888] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 10.13 - 10.03 (m, 1H), 4.49 - 4.39 (m, 4H), 1.62 - 1.55 (m, 6H), 1.49 - 1.42 (m, 9H), 1.35 (t, J = 7.1 Hz, 3H), 1.25 (s, 6H), 0.04 (s, 9H). (Reference Example 25) 6,6-Dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate ethyl [Chemical Formula 138]

[00889] To a solution of 903 mg (1.94 mmol) of 6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]pyrrolo[3,4-c]pyrazol-2,5( 2-Ethyl 5-tert-butyl 4H,6H)-dicarboxylate synthesized in the same manner as in Reference Example 24 in 15 mL of dichloromethane, 0.67 mL (5.8 mmol) of 2,6-lutidine and 1 .05 mL (5.82 mmol) of trimethylsilyl trifluoromethanesulfonate were added at 0oC under an argon atmosphere and reacted at 0oC for 1 hour with stirring.

[00890] After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, elution solvent: methanol:1,2-dichloroethane = 0:100 ^ 10:90 (v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 566 mg of the title compound (yield: 80%) as a white solid.

[00891] Mass spectrum (IQ, m/z): 367 [M+1]+.

[00892] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 10.01 (s, 1H), 4.41 (q, J = 7.2 Hz, 2H), 3.91 (s, 2H) , 1.34 (t, J = 7.2 Hz, 3H), 1.28 (s, 6H), 1.23 (s, 6H), 0.03 (s, 9H). (Reference Example 26) Methyl 2-{[(Benzyloxy)carbonyl](2-cyanoethyl)amino}-2-methylpropanoate [Chemical Formula 139]

[00893] In a solution of 5.00 g (29.4 mmol) of methyl 2-[(2-cyanoethyl)amino]-2-methylpropanoate [synthesized according to the method described in J. Med. Chem., 1968, 11 (3), 616-618] in 23 mL of toluene, 15.5 mL (90.7 mol) of DIPEA, and 32.0 mL of a 30% to 35% benzyl chloroformate solution in toluene [purchased with Tokyo Chemical Industry Co., Ltd.] were added in this order at room temperature under an argon atmosphere and reacted at room temperature for 1.5 hours and subsequently at 50oC for 1.5 hours with stirring. The reaction solution was cooled, and then 4.80 mL (44.1 mmol) of N,N-dimethylethane-1,2-diamine was added to it at room temperature and stirred for 2.5 hours with the temperature unchanged. .

[00894] After completion of the reaction, the reaction solution was poured into 2N hydrochloric acid and stirred. An aqueous layer and an organic layer were separated, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in that order, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 84:16 ^ 50:50 (V/V)), and a fraction containing The compound of interest was concentrated under reduced pressure to obtain 8.32 g of the title compound (yield: 93%) as a colorless oil.

[00895] Mass spectrum (IQ, m/z): 305 [M+1]+.

[00896] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 7.43 - 7.28 (m, 5H), 5.07 (s, 2H), 3.64 (t, J = 6.7 Hz, 2H), 3.50 (br s, 3H), 2.76 (t, J = 6.7 Hz, 2H), 1.45 (s, 6H). (Reference Example 27) Benzyl 4-Cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate [Chemical Formula 140]

[00897] To 52 mL (52 mmol) of a solution of 1 mol/L potassium tert-butoxide in THF heated to 60oC, a solution of 12.1 g (39.7 mmol) of 2-{[(benzyloxy) Methyl carbonyl](2-cyanoethyl)amino}-2-methylpropanoate synthesized in the same manner as in Reference Example 26 in 30 mL of dehydrated THF was added dropwise under argon stream and stirred for 1 hour while heated under reflux.

[00898] After completion of the reaction, the reaction solution was allowed to cool to room temperature and was adjusted to pH < 2 by adding 90 mL of water and 2 N hydrochloric acid, followed by extraction twice with 100 mL of acetate of ethyl. The entire organic layer thus obtained was washed with 100 mL of water and 100 mL of a saturated aqueous solution of sodium chloride in this order, then it was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to distill half the amount of solvent. . 12 g of activated carbon was added to the obtained solution, stirred at room temperature for 30 minutes, filtered, and the solution was concentrated under reduced pressure. The obtained concentration residue was diluted with 10 mL of diisopropyl ether, 50 mL of n-hexane was added to the solution, and the deposited solid was triturated and then stirred at room temperature for 30 minutes. The solid component was collected by filtration and dried under reduced pressure at 50°C to obtain 8.27 g of the title compound (yield: 76%) as a pale yellow solid.

[00899] Mass spectrum (DUIS, m/z): 273 [M+1]+.

[00900] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 12.32 (br s, 1H), 7.46 - 7.25 (m, 5H), 5.18 - 5.02 (m, 2H), 4.24 - 4.02 (m, 2H), 1.51 - 1.35 (m, 6H). (Reference Example 28) Benzyl 3-Amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxylate [Chemical Formula 141]

[00901] A solution of 200 mg (0.734 mmol) of benzyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate synthesized in the same way as in Reference Example 27 in 5 mL of ethanol, 0.336 mL (5.87 mmol) of acetic acid was added at room temperature with stirring under an argon stream and stirred at room temperature for 5 minutes. Subsequently, 0.178 mL (3.66 mmol) of hydrazine monohydrate was added dropwise thereto at room temperature with stirring and stirred for 12 hours under heating to reflux.

[00902] After completion of the reaction, the reaction solution was allowed to cool to room temperature and was adjusted to pH 8 by adding 15 mL of water and then an aqueous solution of sodium bicarbonate, followed by extraction three times with acetate of ethyl. The entire organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 50:50 ^ 0:100 (V/V) ^ 1,2-dichloroethane:methanol = 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 141 mg of the title compound (yield: 67%) as a pale yellow foam.

[00903] Mass spectrum (IQ, m/z): 287 [M+1]+.

[00904] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 11.20 (br s, 1H), 7.45 - 7.28 (m, 5H), 5.18 - 5.05 (m, 2H), 5.05 - 4.77 (m, 2H), 4.28 - 4.14 (m, 2H), 1.58- 1.46 (m, 6H). (Reference Example 29) 5-Benzyl 2-ethyl 3-Amino-6,6-dimethylpyrrolo[3,4-c]pyrazol-2,5(4H,6H)-dicarboxylate [Chemical Formula 142]

[00905] To a solution of 400 mg (1.40 mmol) of benzyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxylate synthesized in the same way as in Reference Example 28 in 4 mL of dehydrated THF, 0.594 mL (3.49 mmol) of DIPEA was added at room temperature under argon current and reacted at room temperature for 3 minutes with stirring. Subsequently, 0.133 mL (1.40 mmol) of ethyl chloroformate was added dropwise to the reaction solution at 0°C and reacted at 0°C for 30 minutes with stirring.

[00906] After completion of the reaction, water was added to the reaction solution, and the mixed solution was subjected to extraction twice with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate = 71:29 ^ 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 200 mg of the title compound (yield: 40%) as a white foam and 190 mg of an isomer of the title compound (3-amino-6,6-dimethylpyrrolo[3,4- c]pyrazol-1,5(4H,6H)-5-benzyl 1-ethyl dicarboxylate) (yield: 38%) as a white foam.

[00907] Title compound (5-benzyl and 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazol-2,5(4H,6H)-dicarboxylate)

[00908] Mass spectrum (IQ, m/z): 359 [M+1]+.

[00909] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 7.45 - 7.29 (m, 5H), 6.63 - 6.49 (m, 2H), 5.19 - 5.04 (m, 2H), 4.41 - 4.30 (m, 2H), 4.28 - 4.15 (m, 2H), 1.62 - 1.49 (m, 6H), 1.36 - 1 .28 (m, 3H).

[00910] Isomer of the title compound (3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazol-1,5(4H,6H)-5-benzyl and 1-ethyl dicarboxylate)

[00911] Mass spectrum (IQ, m/z): 359 [M+1]+.

[00912] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 7.45 - 7.29 (m, 5H), 5.78 - 5.65 (m, 2H), 5.19 - 5.05 (m, 2H), 4.36 - 4.17 (m, 4H), 1.79 - 1.66 (m, 6H), 1.33 - 1.25 (m, 3H). (Reference Example 30) 6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazol-2,5(4H,6H)-5-benzyl 2-ethyl dicarboxylate [Chemical Formula 143]

[00913] To a solution of 885 mg (5.14 mmol) of 1-(trimethylsilyl)cyclobutanecarboxylic acid synthesized in the same way as in Reference Example 1 in 20 mL of dehydrated dichloromethane, 0.530 mL (6.17 mmol) of chloride of oxalyl and 0.020 mL (0.26 mmol) of DMF were added in this order at 0oC under an argon atmosphere and reacted at 0oC for 1 hour with stirring.

[00914] After completion of the reaction, the reaction solution was concentrated under reduced pressure.

[00915] A solution of the residue from the concentration obtained in 10 mL of dehydrated dichloromethane was added dropwise to a solution of 2.25 mL (12.9 mmol) of DIPEA and 920 mg (2.57 mmol) of 3-amino- 5-Benzyl and 2-ethyl 6,6-dimethylpyrrolo[3,4-c]pyrazol-2,5(4H,6H)-dicarboxylate synthesized in the same way as in Reference Example 29 in 10 mL of dichloromethane dehydrated at 0oC under an argon atmosphere and reacted at room temperature for 24 hours with stirring.

[00916] After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction twice with dichloromethane. The entire organic layer thus obtained was washed with a 5% aqueous solution of potassium bisulfate and a saturated aqueous solution of sodium chloride in that order, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: n-hexane:ethyl acetate = 100:0 ^ 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 991 mg of the title compound (yield: 75%) as a pale yellow foam.

[00917] Mass spectrum (DUIS, m/z): 513 [M+1]+.

[00918] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 9.78 - 9.70 (m, 1H), 7.45 - 7.29 (m, 5H), 5.20 - 5.08 (m, 2H), 4.63 - 4.50 (m, 2H), 4.47 - 4.37 (m, 2H), 2.58 - 2.41 (m, 2H), 2.31 - 2 .18 (m, 2H), 1.95 - 1.80 (m, 2H), 1.67 - 1.51 (m, 6H), 1.39 - 1.29 (m, 3H), 0.12 - 0.06 (m, 9H). (Reference Example 31) Ethyl 6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-carboxylate [Chemical Formula 144]

[00919] To a solution of 150 mg (0.293 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazol-2,5(4H,6H)-dicarboxylate of 5-benzyl and 2-ethyl synthesized in the same manner as in Reference Example 30 in 4 mL of 2-propanol, 75 mg of 10% Pd-C (containing 50% water, PE-type manufactured by N.E. Chemcat Corp. ) and 1 mL of acetic acid were added in this order at room temperature. The internal atmosphere of the reaction vessel was replaced by a hydrogen atmosphere, followed by the reaction at room temperature for 1 hour with stirring.

[00920] After completion of the reaction, the internal atmosphere of the reaction vessel was replaced with a nitrogen atmosphere, and subsequently, ethyl acetate was added to the reaction solution and the solution was filtered after adding Celite. An aqueous sodium bicarbonate solution was added to the filtrate and stirred, followed by extraction twice with ethyl acetate. The entire organic layer thus obtained was washed with a saturated aqueous solution of sodium bicarbonate, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: 1,2-dichloroethane:methanol = 100:0 ^ 86:14 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 101 mg of the title compound (yield: 91%) as a white foam.

[00921] Mass spectrum (DUIS, m/z): 379 [M+1]+.

[00922] 1H-NMR spectrum (400MHz, CDCl3) δ: 9.86 (s, 1H), 4.52 (q, J = 7.1 Hz, 2H), 4.22 (s, 2H), 2 .65 - 2.52 (m, 2H), 2.38 - 2.26 (m, 2H), 2.03 - 1.88 (m, 2H), 1.50 - 1.43 (m, 9H) , 0.15 (s, 9H). (Reference Example 32) tert-Butyl 2-(2-Acetyl-5-fluorophenoxy)acetate [Chemical Formula 145]

[00923] To a solution of 1.00 g (6.49 mmol) of 4'-fluoro-2'-hydroxyacetophenone in 15 mL of acetonitrile, 1.20 mL (8.18 mmol) of tert-butyl bromoacetate and 1.40 g (10.1 mmol) of potassium carbonate was added with stirring under an argon atmosphere and then reacted at 80oC for 2 hours.

[00924] After completion of the reaction, the cooled reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. n-hexane was added to the obtained concentration residue and concentrated again under reduced pressure. n-hexane was added to the obtained concentration residue and then ultrasonicated, and the deposited solid was collected by filtration. The solid obtained was washed with n-hexane and dried under reduced pressure at room temperature to obtain 1.45 g of the title compound (yield: 83%) as a white solid.

[00925] Mass spectrum (IQ, m/z): 269 [M+1]+.

[00926] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.84 (dd, J = 7.0, 8.8 Hz, 1H), 6.74 (ddd, J = 2.3, 7.7 , 8.8 Hz, 1H), 6.53 (dd, J = 2.3, 10.5 Hz, 1H), 4.60 (s, 2H), 2.70 (s, 3H), 1.50 (s, 9H). (Reference Example 33) 6-Fluoro-3-methylbenzofuran-2-carboxylic acid [Chemical Formula 146]

[00927] To a solution of 0.30 g (1.1 mmol) of tert-butyl 2-(2-acetyl-5-fluorophenoxy)acetate synthesized in Reference Example 32 in 6 mL of dehydrated ethanol, 0.350 mL ( 1.75 mmol) of a 28% sodium methoxide solution in methanol was added with stirring under an argon atmosphere and reacted at 80oC for 20.5 hours.

[00928] After completion of the reaction, the reaction solution was concentrated under reduced pressure, the residue obtained was dissolved by adding water, and then the pH was adjusted to approximately 2 with 2 N hydrochloric acid. The deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 40°C to obtain 106 mg of the title compound (yield: 49%) as an ocher-colored solid.

[00929] Mass spectrum (IQ, m/z): 195 [M+1]+.

[00930] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 14.27 - 12.66 (m, 1H), 7.82 (dd, J = 5.5, 8.8 Hz, 1H), 7.61 (dd, J = 2.3, 9.4 Hz, 1H), 7.25 (ddd, J = 2.3, 8.8, 9.8 Hz, 1H), 2.52 (s, 3H). (Reference Example 34) 6-Fluoro-3-methylbenzofuran [Chemical Formula 147]

[00931] To a solution of 99.0 mg (0.510 mmol) of 6-fluoro-3-methylbenzofuran-2-carboxylic acid synthesized in Reference Example 33 in 1 mL of DMSO, 15.2 mg (0.055 mmol) of carbonate of silver (I) and 3 μL (0.05 mmol) of acetic acid were added and then reacted at 120oC for 18 hours with stirring.

[00932] After completion of the reaction, 2 mL of 2 N hydrochloric acid was added to the cooled reaction solution and stirred, followed by extraction with ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, n-hexane:ethyl acetate = 99:1 ^ 97:3 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 28.4 mg of the title compound (yield: 37%) as a pale yellow oil.

[00933] Mass spectrum (IQ, m/z): 151 [M+1]+.

[00934] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.42 (dd, J = 5.5, 8.5 Hz, 1H), 7.39 (q, J = 1.4 Hz, 1H) , 7.16 (dd, J = 2.3, 9.0 Hz, 1H), 7.00 (ddd, J = 2.3, 8.5, 9.5 Hz, 1H), 2.23 (d , J = 1.4 Hz, 3H). (Reference Example 35) 6-Fluoro-3-methylbenzofuran-7-carboxylic acid [Chemical Formula 148]

[00935] 150 mg (1.00 mmol) of 6-fluoro-3-methylbenzofuran synthesized in the same way as in Reference Example 34 in 5 mL of dehydrated THF, 1.0 mL (1.6 mmol) of a solution of 1.6 M n-butyllithium in n-hexane was added dropwise at -78°C with stirring under an argon atmosphere and then stirred at the same temperature as above for 0.5 hour. Subsequently, 2.00 g (45 mmol) of dry ice was added thereto and then the reaction continued at -78°C for 10 minutes and subsequently for 1 hour while the temperature was increased to room temperature as circumstances required.

[00936] After completion of the reaction, water was added to the reaction solution and then the reaction solution was concentrated under reduced pressure, and THF was distilled. A 2N aqueous sodium hydroxide solution was added to the obtained concentration residue, followed by extraction with toluene. The pH of the obtained aqueous layer was adjusted to approximately 2 by adding 2 N hydrochloric acid, followed by extraction twice with ethyl acetate. The entire organic layer was washed with a saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 3, OSD silica gel, elution solvent: 0.1% by volume of formate in acetonitrile: 0.1% by volume of aqueous formic acid solution = 20 :80^95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 14.6 mg of the title compound (yield: 8%) as a solid white.

[00937] Mass spectrum (IQ, m/z): 195 [M+1]+.

[00938] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 13.56 (br s, 1H), 7.90 - 7.85 (m, 1H), 7.77 (dd, J = 5, 1, 8.6 Hz, 1H), 7.23 (dd, J = 8.6, 11.0 Hz, 1H), 2.22 (d, J = 1.4 Hz, 3H). (Reference Example 36) 5-[(6-Fluoro-3-methylbenzofuran-7-yl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[ Ethyl 3,4-c]pyrazol-2(4H)-carboxylate [Chemical Formula 149]

[00939] To 123 mg (0.634 mmol) of 6-fluoro-3-methylbenzofuran-7-carboxylic acid synthesized in the same way as in Reference Example 35, 2 mL of toluene was added, followed by azeotropic distillation under reduced pressure. To a suspension of the residue obtained in 2 mL of dehydrated toluene, 0.150 mL (1.08 mmol) of triethylamine, 0.171 mL (0.794 mmol) of DPPA, and additionally 0.5 mL of dichloromethane were added at room temperature under an atmosphere of argon and then reacted at room temperature for 40 minutes and subsequently at 85°C for 80 minutes with stirring. The reaction solution was cooled, then added in divided portions to a solution of 203 mg (0.536 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, Ethyl 4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 3 ml of toluene dehydrated at 0°C, and reacted at 0°C for 1 hour with stirring.

[00940] After completion of the reaction, the reaction solution was separated into an organic layer and an aqueous layer by adding water and ethyl acetate, and then, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, n-hexane:ethyl acetate = 70:30 ^ 44:56 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 298 mg of the title compound (yield: 98%) as a white foam.

[00941] Mass spectrum (IQ, m/z): 570 [M+1]+.

[00942] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 9.79 (s, 1H), 8.29 (s, 1H), 7.79 - 7.76 (m, 1H), 7, 43 (dd, J = 4.8, 8.5 Hz, 1H), 7.15 (dd, J = 8.5, 10.5 Hz, 1H), 4.79 (s, 2H), 4.44 (q, J = 7.1 Hz, 2H), 2.56 - 2.45 (m, 2H), 2.32 - 2.23 (m, 2H), 2.21 (d, J = 1.3 Hz, 3H), 1.96 - 1.86 (m, 2H), 1.66 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H), 0.13 (s, 9H ). (Reference Example 37) tert-Butyl 6-Fluorobenzofuran-7-carboxylate [Chemical Formula 150]

[00943] To a solution of 500 mg (2.78 mmol) of 6-fluorobenzofuran-7-carboxylic acid synthesized in Reference Example 15 in 5 mL of pyridine, 1,167 mg (6.12 mmol) of p-toluenesulfonyl chloride were added in divided portions at 0oC under an argon atmosphere and then stirred at 0oC for 15 minutes with stirring. Subsequently, 0.260 mL (2.74 mmol) of tert-butanol was added thereto at 0°C, then the temperature was raised to room temperature, and the resultant was stirred for 1.5 hours. Additionally, 0.270 mL (2.84 mmol) of tert-butanol was added to the reaction solution and then reacted at room temperature for 16 hours.

[00944] After completion of the reaction, the reaction solution was concentrated under reduced pressure, 20 mL of water was added to the obtained concentration residue, and then, the pH was adjusted to 8 with a 2 N aqueous sodium hydroxide solution After separating into an organic layer and an aqueous layer by adding 40 mL of ethyl acetate, the organic layer was washed three times with 10 mL of a 5% aqueous solution of potassium bisulfate and once with 10 mL of an aqueous solution. saturated aqueous sodium chloride solution, then dried with anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 632 mg of the title compound (yield: 96%) as a brown oil .

[00945] Mass spectrum (EI, m/z): 236 [M]+.

[00946] 1H-NMR Spectrum (400MHz, CDCl3) δ: 7.71 (d, J = 2.3 Hz, 1H), 7.61 (dd, J = 4.9, 8.5 Hz, 1H) , 7.05 (dd, J = 8.5, 10.8 Hz, 1H), 6.77 (d, J = 2.3 Hz, 1H), 1.65 (s, 9H). (Reference Example 38) tert-Butyl 2-Chloro-6-fluorobenzofuran-7-carboxylate [Chemical Formula 151]

[00947] To a solution of 632 mg (2.67 mmol) of tert-butyl 6-fluorobenzofuran-7-carboxylate synthesized in Reference Example 37 in 5 mL of dehydrated DMF, 505 mg (3.78 mmol) of N -chlorosuccinimide were added at room temperature with stirring under an argon atmosphere and then reacted at room temperature for 1 hour, at 50oC for 6 hours, and additionally at room temperature for 15.5 hours with stirring.

[00948] After completion of the reaction, the reaction solution was separated into an organic layer and an aqueous layer by adding toluene and water, and then, the aqueous layer was subjected to extraction once with toluene. The entire organic layer thus obtained was washed with a saturated aqueous solution of sodium bicarbonate, a 5% aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in that order, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, n-hexane:ethyl acetate = 99:1 ^ 97:3 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 0.20 g of the title compound (yield: 28%) as a colorless oil.

[00949] Mass spectrum (EI, m/z): 270 [M]+.

[00950] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.51 (dd, J = 4.8, 8.6 Hz, 1H), 7.05 (dd, J = 8.6, 10.9 Hz, 1H), 6.58 (s, 1H), 1.65 (s, 9H). (Reference Example 39) 2-Chloro-6-fluorobenzofuran-7-carboxylic acid [Chemical Formula 152]

[00951] To a solution of 200 mg (0.739 mmol) of tert-butyl 2-chloro-6-fluorobenzofuran-7-carboxylate synthesized in Reference Example 38 in 1.5 mL of dichloromethane, 0.141 mL (1.84 mmol ) of trifluoroacetic acid was added at room temperature under an argon atmosphere and then reacted at room temperature for 20 hours with stirring.

[00952] After completion of the reaction, the reaction solution is purged with nitrogen gas to distill the solvent. Diisopropyl ether/n-hexane = 1/1 (V/V) was added to the obtained concentration residue and then ultrasonicated, and the solid obtained was collected by filtration. The obtained solid was washed with n-hexane and then dried under reduced pressure at 30°C to obtain 120 mg of the title compound (yield: 76%) as a white solid.

[00953] Mass spectrum (IQ, m/z): 215 [M+1]+.

[00954] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.63 (dd, J = 4.8, 8.7 Hz, 1H), 7.13 (dd, J = 8.7, 11.0 Hz, 1H), 6.64 (s, 1H). (Reference Example 40) 5-[(2-Chloro-6-fluorobenzofuran-7-yl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[ Ethyl 3,4-c]pyrazol-2(4H)-carboxylate [Chemical Formula 153]

[00955] To 116 mg (0.541 mmol) of 2-chloro-6-fluorobenzofuran-7-carboxylic acid synthesized in Reference Example 39, 2 mL of toluene were added, followed by azeotropic distillation under reduced pressure. To a suspension of the residue obtained in 2 mL of dehydrated toluene, 0.140 mL (1.00 mmol) of triethylamine, 0.155 mL (0.720 mmol) of DPPA, and additionally 0.5 mL of dichloromethane were added at room temperature under an atmosphere of argon and then reacted at room temperature for 40 minutes and subsequently at 85 °C for 1.5 hours with stirring. The reaction solution was cooled, then added in divided portions to a solution of 182 mg (0.481 mmol) of 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3, Ethyl 4-c]pyrazol-2(4H)-carboxylate synthesized in the same way as in Reference Example 3 in 3 ml of toluene dehydrated at 0°C, and reacted at 0°C for 1 hour with stirring.

[00956] After completion of the reaction, the reaction solution was separated into an organic layer and an aqueous layer by adding water and ethyl acetate, and then, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, n-hexane:ethyl acetate = 70:30 ^ 45:55 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 210 mg of the title compound (yield: 74%) as a white foam.

[00957] Mass spectrum (IQ, m/z): 590 [M+1]+.

[00958] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 9.78 (s, 1H), 8.39 (s, 1H), 7.44 (dd, J = 4.8, 8.6 Hz, 1H), 7.20 (dd, J = 8.6, 10.7 Hz, 1H), 7.05 (s, 1H), 4.78 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 2.57 - 2.42 (m, 2H), 2.31 - 2.20 (m, 2H), 1.95 - 1.84 (m, 2H), 1, 66 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H), 0.12 (s, 9H). (Reference Example 41) tert-Butyl 2-Bromo-6-fluorobenzofuran-7-carboxylate [Chemical Formula 154]

[00959] A solution of 2.26 g (9.57 mmol) of tert-butyl 6-fluorobenzofuran-7-carboxylate synthesized in the same way as in Reference Example 37 in 30 mL of acetonitrile and 10 mL of dehydrated DMF , 1.87 g (10.5 mmol) of N-bromosuccinimide was added at 50°C under an argon atmosphere and then reacted at 50°C for 1 hour with stirring. Subsequently, 1.81 g (10.2 mmol) of N-bromosuccinimide was additionally added to the reaction solution and then reacted at 50°C for 0.5 hour.

[00960] After completion of the reaction, the reaction solution was separated into an organic layer and an aqueous layer by adding ethyl acetate and water. The obtained organic layer was washed once with a 5% aqueous solution of sodium thiosulfate and twice with a saturated aqueous solution of sodium bicarbonate, then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, n-hexane:ethyl acetate = 99:1 ^ 97:3 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue obtained was again subjected to preparative column chromatography (apparatus 1, silica gel, n-hexane:ethyl acetate = 99:1 ^ 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 861 mg of the title compound (yield: 29%) as a pale yellow oil.

[00961] Mass spectrum (EI, m/z): 314 [M]+.

[00962] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.52 (dd, J = 4.8, 8.7 Hz, 1H), 7.05 (dd, J = 8.7, 10.8 Hz, 1H), 6.73 (s, 1H), 1.65 (s, 9H). (Reference Example 42) tert-Butyl 6-Fluoro-2-methylbenzofuran-7-carboxylate [Chemical Formula 155]

[00963] To a heterogeneous solution of 500 mg (1.59 mmol) of tert-butyl 2-bromo-6-fluorobenzofuran-7-carboxylate synthesized in the same way as in Reference Example 41 in 22 mL of toluene and 1, 32 mL of water, 1.50 g (7.07 mmol) of anhydrous potassium phosphate and 290 mg (4.84 mmol) of methylboronic acid were added, and then replacement of the container atmosphere with an argon atmosphere was performed. under reduced pressure under cooling in a dry ice/acetone bath. Subsequently, 10.7 mg (0.048 mmol) of palladium (II) acetate and 35.0 mg (0.098 mmol) of butyl-di-1-adamantyl-phosphine were added to it and then reacted at 100oC for 2 hours with stirring. .

[00964] After completion of the reaction, 5 g of Celite was added to the cooled reaction solution, stirred for 10 minutes, and then filtered, and the solid residue was washed with ethyl acetate. The obtained filtrate was separated into an organic layer and an aqueous layer by adding water, and then, the organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentration residue obtained was subjected to preparative column chromatography (apparatus 1, silica gel, n-hexane:ethyl acetate = 99:1 ^ 96:4 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 240 mg of the title compound (yield: 60%) as a pale yellow oil.

[00965] Mass spectrum (EI, m/z): 250 [M]+.

[00966] 1H-NMR spectrum (400MHz, CDCl3) δ: 7.46 (dd, J = 4.9, 8.5 Hz, 1H), 6.96 (dd, J = 8.5, 10.9 Hz, 1H), 6.35 (q, J = 1.0 Hz, 1H), 2.49 - 2.47 (m, 3H), 1.65 (s, 9H). (Reference Example 43) 6-Fluoro-2-methylbenzofuran-7-carboxylic acid [Chemical Formula 156]

[00967] To a solution of 237 mg (0.947 mmol) of tert-butyl 6-fluoro-2-methylbenzofuran-7-carboxylate synthesized in Reference Example 42 in 1.5 mL of dehydrated dichloromethane, 0.181 mL (2.37 mmol) of trifluoroacetic acid was added at room temperature under an argon atmosphere and then reacted at room temperature for 4 hours with stirring. Subsequently, 1.0 mL of dehydrated dichloromethane and 0.181 mL (2.37 mmol) of trifluoroacetic acid were further added thereto and then further reacted for 13.5 hours.

[00968] After completion of the reaction, the reaction solution was concentrated under reduced pressure. Diisopropyl ether/n-hexane = 1/1 (V/V) was added to the obtained concentration residue and then ultrasonicated, and the solid obtained was collected by filtration, washed with n-hexane, and then dried under reduced pressure at 40oC to obtain 147 mg of the title compound (yield: 80%) as a white solid.

[00969] Mass spectrum (IQ, m/z): 195 [M+1]+.

[00970] 1H-NMR spectrum (400MHz, DMSO-d6) δ: 7.68 (dd, J = 5.2, 8.6 Hz, 1H), 7.15 (dd, J = 8.6, 11 .1Hz, 1H), 6.67 - 6.62 (m, 1H), 2.46 - 2.45 (m, 3H).

[Test Example 1] CDK7 enzyme inhibition test

[00971] The preparation of a buffer solution was carried out by mixing a buffer solution of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES buffer solution) (pH 7.4), dithiothreitol (DTT), Triton X-100, and magnesium chloride (MgCl2). A 500 μM [Y-33P]ATP solution was used by diluting a 10 mM ATP solution and a commercially available [Y-33P]ATP solution (manufactured by PerkinElmer, Inc., Code Number NEG-302H). with the buffer solution. A CDK7 solution was used by diluting commercially available CDK7 (manufactured by Carna Biosciences, Inc., Catalog Number 04-108) with the buffer solution. A substrate solution was used by diluting myelin basic protein (MBP) with the buffer solution. As for preparing a reaction solution, the buffer solution, CDK7 solution, and substrate solution were mixed at 4°C to obtain a reaction solution.

[00972] The CDK5 enzyme reaction was performed by adding 5 μL of a test compound solution prepared with 10% DMSO/90% injectable distilled water, and 40 μL of the reaction solution to a 1.5 microtube. mL at 4OC and pre-incubation of the microtube at 25OC for 60 minutes in an incubator with a water bath. Subsequently, the reaction was carried out at 30°C for 20 minutes by adding 5 μL of 500 μM [Y-33P]ATP solution. After the reaction, a 10% trichloroacetic acid (TCA) aqueous solution was added to each microtube while cooled to 4°C, and mixed on a vortex mixer to finish the reaction. The resultant was left to rest at 4°C for 10 minutes and then centrifuged, and the supernatant was discarded. Next, a 2% aqueous solution of trichloroacetic acid (TCA) was added to it, mixed in a vortex mixer, and then centrifuged, and the supernatant was discarded. The washing operation was performed twice. After washing, the precipitates were dissolved in a 1 N aqueous sodium hydroxide (NaOH) solution, and the amount of energy (radioactivity) of the reaction product was measured with a liquid scintillation counter.

[00973] The calculation of the inhibitory activity of the test compound against CDK7 was performed as a concentration of the test compound with an inhibitory capacity of 50% of the amount of 33P bound to MBP (IC50 value) by using EXSUS (version 8.1.0 , manufactured by CAC Exicare Corp.).

[00974] The calculation of a Ki value was carried out according to the following calculation expression in which S represents the concentration of ATP contained in the reaction solution, and Km represents a Michaelis-Menten constant: Ki = IC50 / (1 + S / Km)

[00975] In this test, the compounds of the present invention showed excellent CDK7 inhibitory activity. For example, the Ki values of compounds represented by compound numbers I-965, II-137, II-169, II-199, II-290, II-1049, III-137, III-169, III-199, III-299, III-1049, IV-1, IV-3, IV-9, IV-7, IV-15, IV-21, IV-23, IV-27, IV-39, IV-45, IV- 51, IV-63, IV-75, IV-79, IV-87, IV-93, IV-99, IV-101, IV-103, IV-105, IV-111, IV-113, IV-121, IV-125, IV-127, IV-129, IV-137, IV-153, IV-161, IV-169, IV-177, IV-185, IV-199, IV-207, IV-215, IV- 299, IV-231, IV-239, IV-247,IV-357, IV-359, IV-361, IV-367, IV-375, IV-377, IV-379, IV-381, IV-389, IV-597, IV-599, IV-609, IV-615, IV-629, IV-689, IV-669, IV-703, IV-709, IV-747, IV-997, IV-1019, IV- 1035, IV-1043, IV-1045, IV-1049, IV-1059, IV-1061, and IV-1063 were 50 nM or less.

[Test Example 2] CDK2 Enzyme Inhibition Test

[00976] The preparation of a buffer solution was carried out by mixing a buffer solution of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES buffer solution) (pH 7.4), dithiothreitol (DTT), Triton X-100, and magnesium chloride (MgCl2). A 500 μM [Y-33P]ATP solution was used by diluting a 10 mM ATP solution and a commercially available [Y-33P]ATP solution (manufactured by Perkin Elmer, Inc., Code Number NEG-302H ) with the buffer solution. A CDK2 solution was used by diluting commercially available CDK2 (manufactured by Invitrogen Corp., Catalog Number PV3267) with the buffer solution. A substrate solution was used by diluting myelin basic protein (MBP) with the buffer solution. As for preparing a reaction solution, the buffer solution, 500 μM [Y-33P]ATP solution, CDK2 solution, and substrate solution were mixed at 4°C to obtain a reaction solution.

[00977] The CDK2 enzyme reaction was carried out by adding 5 μL of a test compound solution prepared with 10% DMSO/90% injectable distilled water, and 45 μL of the reaction solution into a 1.5 microtube. mL at 4OC and reaction in the microtube at 30OC for 20 minutes in an incubator with a water bath. After the reaction, a 10% trichloroacetic acid (TCA) aqueous solution was added to each microtube while cooled to 4°C, and mixed on a vortex mixer to finish the reaction. The resultant was left to rest at 4°C for 10 minutes and then centrifuged, and the supernatant was discarded. Next, a 2% aqueous solution of trichloroacetic acid (TCA) was added to it, mixed in a vortex mixer, and then centrifuged, and the supernatant was discarded. The washing operation was performed twice. After washing, the precipitates were dissolved in a 1 N aqueous sodium hydroxide (NaOH) solution, and the amount of energy (radioactivity) of the reaction product was measured with a liquid scintillation counter.

[00978] The calculation of the inhibitory activity of the test compound against CDK2 was performed as a concentration of the test compound with an inhibitory capacity of 50% of the amount of 33P bound to MBP (IC50 value) by using EXSUS (version 8.1.0 , manufactured by CAC Exicare Corp.).

[00979] The calculation of a Ki value was carried out according to the following calculation expression in which S represents the concentration of ATP contained in the reaction solution, and Km represents a Michaelis-Menten constant: Ki = IC50 / (1 + S / Km)

[00980] In this test, the compounds of the present invention had low CDK2 inhibitory activity. For example, the CDK2 inhibitory activity Ki values of compounds represented by compound numbers I-1000, I-1036, II-137, II-169, II-199, II-1049, III-137, III-169 , III-199, III-1049, IV-1, IV-3, IV-9, IV-15, IV-21, IV-27, IV-39, IV-45, IV-75, IV-87, IV -105, IV-113, IV-127, IV-129, IV-137, IV-161, IV-169, IV-177, IV-185, IV-199, IV-207, IV-215, IV-231 , IV-239, IV-247, IV-299, IV-357, IV-359, IV-361, IV-367, IV-377, IV-379, IV-381, IV-389, IV-597, IV -609, IV-615, IV-629, IV-689, IV-669, IV-703, IV-709, IV-747, IV-997, IV-1043, IV-1045, IV-1049, IV-1059 , IV-1061, and IV-1063 were 1,000 nM or higher. In summary, the compounds of the present invention highly selectively inhibited CDK7 with respect to CDK2.

[Test Example 3] PLK1 (Polo-like kinase 1) enzyme inhibition test

[00981] The preparation of a buffer solution was carried out by mixing a buffer solution of 3-morpholinopropanesulfonic acid (MOPS buffer solution) (pH 7.0), dithiothreitol (DTT), and magnesium acetate (Mg(CH3COO)2 ). A 1 mM [Y-33P]ATP solution was used by diluting a 10 mM ATP solution and a commercially available [Y-33P]ATP solution (manufactured by Perkin Elmer, Inc., Code Number NEG-302H). with the buffer solution. A PLK1 solution was used by diluting commercially available PLK1 (manufactured by Carna Biosciences, Inc., Catalog Number 05-157) with the buffer solution. A substrate solution was used by diluting casein with the buffer solution. As for preparing a reaction solution, the buffer solution, 500 μM [Y-33P]ATP solution, PLK1 solution, and substrate solution were mixed at 4°C to obtain a reaction solution.

[00982] The PLK1 enzyme reaction was carried out by adding 5 μL of a test compound solution prepared with 10% DMSO/90% injectable distilled water, and 45 μL of the reaction solution into a 1.5 microtube. mL at 4OC and reaction in the microtube at 30OC for 20 minutes in an incubator with a water bath. After the reaction, a 10% trichloroacetic acid (TCA) aqueous solution was added to each microtube while cooled to 4°C, and mixed on a vortex mixer to finish the reaction. The resultant was left to rest at 40C for 10 minutes and then centrifuged, and the supernatant was discarded. Next, a 2% aqueous solution of trichloroacetic acid (TCA) was added to it, mixed in a vortex mixer, and then centrifuged, and the supernatant was discarded. The washing operation was performed twice. After washing, the precipitates were dissolved in a 1 N aqueous sodium hydroxide (NaOH) solution, and the amount of energy (radioactivity) of the reaction product was measured with a liquid scintillation counter.

[00983] The calculation of the inhibitory activity of the test compound against PLK1 was carried out as a concentration of the test compound with an inhibitory capacity of 50% of the amount of 33P bound to casein (IC50 value) by using EXSUS (version 8.1.0 , manufactured by CAC Exicare Corp.).

[00984] The calculation of a Ki value was carried out according to the following calculation expression in which S represents the concentration of ATP contained in the reaction solution, and Km represents a Michaelis-Menten constant: Ki = IC50 / (1 + S / Km)

[00985] In this test, the compounds of the present invention had low PLK1 inhibitory activity. For example, the Ki values of the PLK1 inhibitory activity of compounds represented by compound numbers I-1000, I-1036, II-137, II-169, II-199, II-1049, III-137, III-169 , III-199, III-1049, IV-3, IV-15, IV-21, IV-27, IV-39, IV-45, IV-87, IV-105,IV-113, IV-121, IV -127, IV-129, IV-137, IV-153, IV-161, IV-169, IV-177,IV-185, IV-199, IV-207, IV-215, IV-231, IV-239 , IV-247, IV-299, IV-357,IV-359, IV-361, IV-367, IV-377, IV-379, IV-381, IV-389, IV-597, IV-609,IV -615, IV-629, IV-669, IV-689, IV-703, IV-709, IV-747, IV-997, IV-1043, IV-1045, IV-1049, IV-1059, IV-1061 , and IV-1063 were 5,000 nM or higher. In summary, the compounds of the present invention highly selectively inhibited CDK7 with respect to PLK1.

[Test Example 4] Human Large Intestine Cancer Cell Growth Inhibition Test (HCT-116)

[00986] Measurement of an inhibitory effect on the growth of human large intestine cancer cells was carried out by modifying the method of Simak et al. (Cancer Research, 69, 6208 (2009)).

[00987] A human large intestine cancer cell line (HCT-116, obtained from DS Pharma Biomedical Co., Ltd.) was cultured in McCoy's 5A medium (manufactured by Thermo Fisher Scientific, Inc.) containing 10 % fetal bovine serum (FBS) (manufactured by Thermo Fisher Scientific, Inc.) and 1% penicillin/streptomycin/amphotericin B (manufactured by Thermo Fisher Scientific, Inc.) and inoculated at 0.5 to 2.0X 103 cells/well in a 96-well plate. After overnight cultivation in an incubator under an atmosphere containing carbon dioxide, the medium was replaced with fresh medium the next day, and a test compound dissolved in DMSO (final concentration in DMSO: 0.1%) was added to it and left to rest in an incubator under an atmosphere containing carbon dioxide. After culture for 3 days, its absorbance was measured using the Sulforhodamine B based In Vitro Toxicology Assay Kit (manufactured by Sigma-Aldrich Co. LLC.).

[00988] The cell growth inhibition rate at each concentration was calculated from the concentration of the test compound and the absorbance of sulforhodamine B, and the concentration of the test compound required to inhibit 50% of cell growth (value of IG50) was calculated using EXSUS (version 8.1.0, manufactured by CAC Exicare Corp.).

[00989] In this test, the compounds of the present invention showed excellent inhibitory activity on the growth of HCT-116 cells. For example, the IC50 values of compounds represented by compound numbers II-137, II-169, II-199, II-1049, III-137, III-169, III-199, III-299, III-1049, IV-1, IV-3, IV-4, IV-5, IV-9, IV-7, IV-11, IV-15, IV-21, IV-23, IV-25, IV-27, IV- 39, IV-45, IV-51, IV-63, IV-75, IV-79, IV-81, IV-87, IV-93, IV-99, IV-101, IV-103, IV-105, IV-111, IV-113, IV-121, IV-123, IV-125, IV-127, IV-129, IV-137, IV-153, IV-161, IV-169, IV-177, IV- 185, IV-191, IV-197, IV-199, IV-207, IV-213, IV-215, IV-231, IV-239, IV-245, IV-247, IV-299, IV-357, IV-359, IV-361, IV-367, IV-375, IV-377, IV-379, IV-381, IV-389, IV-597, IV-599, IV-609, IV-615, IV- 629, IV-669, IV-689,IV-703, IV-709, IV-747, IV-997, IV-1035, IV-1043, IV-1045, IV-1049, IV-1059, IV-1061, and IV-1063 were 100 nM or lower.

[Test Example 5] Tumor growth inhibition test in nude mice subcutaneously transplanted with human large intestine cancer cells (HCT116)

[00990] A human large intestine cancer cell line (HCT-116) was cultured in McCoy's 5A medium containing 10% FBS and 1% penicilma/streptomycin/amphotericin B and adjusted to 1.0 x 108 cells /mL with PBS or Hanks solution (HBSS(-)). The prepared cell suspension was subcutaneously injected at 0.1 mL/mouse into the right side of the abdomens of BALB female nude mice (supplied by Charles River Laboratories Japan, Inc.). After acclimatization for a certain period, the long diameter (mm) and short diameter (mm) of tumor were measured with electronic calipers, and the tumor volume was calculated with the following expression: Tumor volume (mm3) = ( Long Diameter) x (Short Diameter) x (Short Diameter) x 0.5

[00991] Subjects whose tumor volume was within the range of 50 to 200 mm3 were selected and grouped such that the tumor volume was almost equivalent, then a test compound or just a solvent was orally administered in a repeated manner , and body weights and tumor volume were measured. A test compound was suspended in an aqueous solution of 0.5% methylcellulose (MC 0.5%) (manufactured by Wako Pure Chemical Industries, Ltd.) and the aqueous solution was orally administered at 10 mL/kg in a repeated manner. . When the tumor volume of the control group was set to 100%, the tumor volume suppression rate (%) at each dose of the test compound was calculated.

[00992] In this test, the compounds of the present invention showed excellent tumor growth inhibitory activity. For example, the compounds represented by compound numbers IV-1, IV-3, IV-15, IV-21, IV-113, IV-121, IV-127, IV-199, IV-215, IV-299, IV-359, IV-361, IV-379, IV-389, IV-597, IV-669, IV-1049, and IV-1063 had a tumor volume suppression rate of 50% or greater at a dose of 100 mg/kg.

[Test Example 6] Inhibition test of IL-2 production induced by human PBMC CD3/CD28

[00993] PBMC (Peripheral Blood Mononuclear Cell) was separated and collected by the use of "Ficoll-Paque" (manufactured by GE Healthcare Japan Corp.) from blood collected from a healthy human adult in the presence of heparin. An RPMI1640 medium containing 10% FBS, 1% penicillin/streptomycin/amphoterin B, essential amino acids, and pyruvic acid and containing a test compound dissolved in DMSO and 2 μg/mL CD28 was added at 100 μL/well to the plate. 96-well "T Cell Activation Plate Anti-Human CD3 96-Well Plate" (manufactured by Becton, Dickinson and Company), and subsequently, a PBMC suspension prepared such that the cell number was 2 x 106 cells/mL was added to it at 100 μL/well (final concentration in DMSO: 0.1%). An RPMI1640 medium containing 10% FBS and containing 0.1% DMSO and 2 μg/mL CD28 was similarly added to wells not supplemented with the test compound. After culturing for 2 days in an incubator under an atmosphere containing carbon dioxide, the culture supernatant was collected. The collected culture supernatant was stored at -20OC until measuring the IL-2 content.

[00994] When measuring an IL-2 content in the culture supernatant, a sandwich ELISA kit (Quantikine Human IL-2, manufactured by R&D Systems, Inc.) was used. The IL-2 content of each sample was calculated from the Standard IL-2 calibration curve included in the kit. When the amount of IL-2 produced by CD3/CD28 stimulation in the case of adding DMSO alone was set to 100%, the inhibition rate of IL-2 production at each concentration of the test compound was calculated. A test compound concentration required to inhibit 50% of IL-2 production (IC50 value) was calculated from the concentration of the added test compound and the rate of inhibition of IL-2 production by the test compound by use from EXSUS (version 8.1.0, manufactured by CAC Exicare Corp.).

[00995] In this test, the compounds of the present invention showed excellent inhibitory activity on IL-2 production. For example, the IC50 values of compounds numbered IV-3, IV-21, IV-113, IV-127, IV-161, IV-215, IV-299, IV-361, IV-379, IV-669 , and IV-1049 were 100 nM or lower.

[Test Example 7] Human keratinocyte growth inhibitory assay

[00996] The measurement of an inhibitory effect on the growth of human keratinocytes was carried out by modifying the method of Schafer et al. (British Journal of Pharmacology, 159, 842 (2011)).

[00997] Human keratinocytes (NHEK-Neo Pooled, manufactured by Lonza Group AG) were cultured in "KGM-Gold Keratinocyte Growth Medium Bullet Kit" (manufactured by Lonza Group AG) and inoculated at 2 96 well. After overnight cultivation in an incubator under an atmosphere containing carbon dioxide, a test compound dissolved in DMSO (final concentration in DMSO: 0.1%) was added thereto and allowed to stand in an incubator under an atmosphere. containing carbon dioxide. After culture for 2 days, its absorbance was measured using the cell counting kit "Cell Counting Kit-8" (manufactured by Dojindo Laboratories).

[00998] The rate of inhibition of cell growth at each concentration was calculated from the concentration of the test compound and the absorbance of the "Cell Counting Kit-8", and the concentration of the test compound required to inhibit 50% of growth of cells (IG50 value) was calculated using EXSUS (version 8.1.0, manufactured by CAC Exicare Corp.).

[00999] In this test, the compounds of the present invention showed excellent human keratinocyte growth inhibitory activity, and, for example, the IC50 values of compounds numbered IV-129, IV-215, IV-247, IV-361, and IV-379 were 500 nM or lower.

[Test Example 8] Ear Thickening Suppression Test Using the Imiquimod-Induced Mouse Psoriasis Model

[001000] An imiquimod-induced psoriasis model test was performed by modifying the method of Leslie van der Fits et al. (J. Immunol. 182, 5836 (2009)).

[001001] Female BALB/c mice (supplied by Charles River Laboratories Japan, Inc.) were used as laboratory animals. On the day of testing, the thickness of the mice's right atria was measured with a thickness gauge (manufactured by TECLOCK Corp.). A test compound or a solvent was applied or orally administered to the right atria, and after a certain time, a certain amount of "Beselna Cream 5%" cream (containing 5% imiquimod, manufactured by Mochida Pharmaceutical Co., Ltd.) was applied inside each of the right atria. Application or oral administration of test compound or solvent and application of imiquimod were carried out over a period of time, and the thicknesses of the right atria were measured again on the final day. The thicknesses of the right atria were compared with the solvent administered group and the test compound group, and the inhibition rate was calculated. When the increase in ear thickness of the solvent administered group on the final day was set to 100%, the increase inhibition rate (%) at each dose of the test compound was calculated.

[001002] In this test, the compounds of the present invention showed excellent activity suppressing ear thickening, and, for example, compounds numbered IV-129, IV-137, IV-169, IV-199, IV-215, IV -247, IV-299, and IV-389 showed an inhibition rate of 50% or higher upon application of a 0.01% solution in methanol.

[Test Example 9] Human Breast Cancer Cell Growth Inhibition Test (MCF-7)

[001003] The measurement of an inhibitory effect on the growth of human breast cancer cells is carried out by modifying the method of Simak et al. (Cancer Research, 69, 6208 (2009)).

[001004] A human breast cancer cell line (MCF-7, obtained from DS Pharma Biomedical Co., Ltd.) is cultured in a MEM medium containing 10% FBS and non-essential amino acids and inoculated at 3 x 103 cells/well in a 96-well plate. After overnight cultivation in an incubator under an atmosphere containing carbon dioxide, the medium is replaced with fresh MEM medium containing 10% FBS and non-essential amino acids the next day, and a test compound dissolved in DMSO ( final concentration in DMSO: 0.1%) is added to it and left to rest in an incubator under an atmosphere containing carbon dioxide. After culturing for 3 days, its absorbance is measured using the Sulforhodamine B based In Vitro Toxicology Assay Kit (manufactured by Sigma-Aldrich Co. LLC.).

[001005] The cell growth inhibition rate at each concentration is calculated from the concentration of the test compound and the absorbance of sulforhodamine B, and the concentration of the test compound required to inhibit 50% of cell growth (value of IG50) is calculated using EXSUS (version 8.1.0, manufactured by CAC Exicare Corp.).

[Test Example 10] Test on Reducing the Abundance Ratio of Human Large Intestine Cancer Stem Cells (CD44/CD133 Positive Cells)

[001006] The measurement of human large intestine cancer stem cells was performed by modifying the method of Youzhi et al. (Proceedings of the National Academy of Sciences, 112, 6, 1839 (2015)).

[001007] A human large intestinal cancer cell line (HCT-116) was grown in McCoy's 5A medium containing 10% FBS and 1% penicillin/streptomycin/amphoterin B and inoculated at 1 x 106 cells/well to a 6-well plate. After overnight cultivation in an incubator under an atmosphere containing carbon dioxide, a test compound dissolved in DMSO (final concentration in DMSO: 0.1%) was added thereto and allowed to stand in an incubator under an atmosphere. containing carbon dioxide. After culturing for 7 days, cells were harvested using trypsin/EDTA and treated with a single cell strainer, then FITC-labeled anti-CD44 antibody (Miltenyi Biotec K.K.) and FITC-labeled anti-CD133 antibody. PE (Miltenyi Biotec K.K.) were added to them and reacted at room temperature for 15 minutes in the dark. The abundance ratio of cells positive for both CD44 and CD133 at each concentration was measured by use of flow cytometry. When the abundance ratio of cells positive for both CD44 and CD133 in the solvent-treated sample was set to 100, the concentration of test compound and the reduction rate of the abundance ratio of cells positive for both CD44 and CD133 were calculated, and the concentration of test compound required to inhibit 50% of the abundance ratio (IC50 value) was calculated by using EXSUS (version 8.1.0, manufactured by CAC Exicare Corp.).

[001008] In this test, the compounds of the present invention showed an excellent reduction rate in the abundance ratio of CD44/CD133-positive cells, and, for example, 1 μM solutions of compounds numbered IV-199, IV-215 , IV-299, IV-361, and IV-379 showed a reduction rate of 50% or higher.

[Test Example 11] Test on inhibiting the ability of human large intestine cancer stem cells to self-renew

[001009] Spheroid culture of human large intestine cancer stem cells is performed by modifying the method of Youzhi et al. (Proceedings of the National Academy of Sciences, 112, 6, 1839 (2015)).

[001010] A human colon cancer cell line (HCT-116) was cultured in McCoy's 5A medium containing 10% FBS and 1% penicillin/streptomycin/amphoterin B. The cells are collected from the flask, resuspended in "Cancer Stem Premium" medium (manufactured by ProMab Biotechnologies, Inc.), and inoculated at 1 to 10 x 103 cells/well in a 96-well ultraslow attachment plate. After cultivation for 2 to 7 days in an incubator under an atmosphere containing carbon dioxide, a test compound dissolved in DMSO (final concentration in DMSO: 0.1%) is added thereto and allowed to stand in an incubator under an atmosphere containing carbon dioxide. After culturing for 1 to 3 days, its absorbance is measured using a cell counting kit "Cell Counting Kit-8" (manufactured by Dojindo Laboratories).

[001011] The cell growth inhibition rate at each concentration is calculated from the concentration of the test compound and the absorbance measured using the cell counting kit "Cell Counting Kit-8", and the concentration of the test compound test required to inhibit 50% of cell growth (IG50 value) is calculated by using EXSUS (version 8.1.0, manufactured by CAC Exicare Corp.).

[Test Example 12] Test of inhibition of IL-17 production induced by cocktail of various stimulants in human PBMC

[001012] PBMC was separated and collected by using "Ficoll-Paque" (manufactured by GE Healthcare Japan Corp.) from the blood of a healthy human adult in the presence of heparin. The collected PBMC was further cultured in a flask for a certain time, and then the non-adherent cells in the supernatant were collected and used as a T-cell suspension.

[001013] An RPMI1640 medium containing 10% FBS, 1% penicillin/streptomycin/amphoterin B, essential amino acids, and pyruvic acid and containing a test compound dissolved in DMSO, an anti-human CD28 antibody, an anti-IFN antibody -Y, an antibody anti-human IL-4, human IL-6, human IL-23, human IL-1β, and human TGF-β was added at 100 μL/well to the 96-well T cell Activation Plate Anti-Human CD3 96-Well Plate". Subsequently, 100 μL of a T-cell suspension adjusted to 2 x 105 cells/mL was added to each well (final concentration in DMSO: 0.1%). Only DMSO was added to wells not supplemented with the test compound. After culturing for 5 days in an incubator under an atmosphere containing carbon dioxide, the culture supernatant was collected and stored at -20°C until the IL-17 content was measured.

[001014] In measuring an IL-17 content in the culture supernatant, a sandwich ELISA kit (Quantikine Human IL-17, manufactured by R&D Systems, Inc.) was used. The IL-17 content of each sample was calculated from the Standard IL-17 calibration curve included in the kit. When the amount of IL-17 produced by the cocktail of various stimulants in the case of adding DMSO alone was set to 100%, the inhibition rate of IL-17 production at each concentration of the test compound was calculated. The concentration of the test compound required to inhibit 50% of IL-17 production (IC50 value) was calculated from the concentration of the added test compound and the rate of inhibition of IL-17 production by the test compound by use from EXSUS (version 8.1.0, manufactured by CAC Exicare Corp.).

[001015] In this test, the compounds of the present invention showed excellent inhibitory activity on IL-17 production. For example, the IC50 values of compounds numbered IV-3, IV-129, IV-137, IV-199, IV-215, IV-247, IV-299, IV-361, IV-379, IV-389 , IV-669, and IV-1049 were 100 nM or lower.

[Test Example 13] Paw edema suppression test in rat adjuvant arthritis model

[001016] Female LEW mice (supplied by Charles River Laboratories Japan, Inc.) are used as laboratory animals. An adjuvant prepared from heat-killed Mycobacterium butyricum bacteria (manufactured by Difco Laboratories Ltd.) and liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd.) is administered subcutaneously as a phlogogenic material to the paw pads of the right hind legs. of mice under inhalation anesthesia with isoflurane (manufactured by Wako Pure Chemical Industries, Ltd.) to prepare arthritis models. Also, liquid paraffin containing the dead bacteria is administered by a similar method to obtain an untreated group. A test compound is suspended in an aqueous solution of 0.5% w/v methylcellulose (0.5% MC) (manufactured by Wako Pure Chemical Industries, Ltd.) and orally administered at 10 mL/kg in a repeated manner at from the day of adjuvant injection. Also, only a solvent is administered instead of the test compound to the rat arthritis models in a control group. The volumes of the right hind legs and left hind legs are measured several times after adjuvant administration with a paw volume meter (TK-101CMP manufactured by Unicom Co., Ltd.), and the edema rate is calculated accordingly. with the following expression: Edema rate (%) = [{(Paw pad volume at the time of measurement) - (Paw pad volume at the start of the test)} / (Paw pad volume before the start of the test )] (Edema rate of untreated group)} + {Edema rate of control group) — (Edema rate of untreated group)}] x 100 [Test Example 14] Swelling suppression test using induced arthritis model by mouse collagen A mouse collagen-induced arthritis model test was performed by modifying the method of Mihara et al. (British Journal of Pharmacology, 154, 153 (2008)).

[001017] Male DBA/1J mice (supplied by Japan SLC, Inc.) were used as laboratory animals. An adjuvant prepared from a solution of type II collagen (Collagen Research Center) and Complete Freund's Adjuvant (manufactured by Difco Laboratories Ltd.) was intracutaneously administered twice to the bases of the tails of mice under inhalation anesthesia with isoflurane (manufactured by Wako Pure Chemical Industries, Ltd.) for awareness to prepare friction models.

[001018] Also, Complete Freund's Adjuvant (manufactured by Difco Laboratories Ltd.) not containing type II collagen was administered by a similar method to obtain a control group. A test compound was suspended in an aqueous solution of 0.5% w/v methylcellulose (0.5% MC) (manufactured by Wako Pure Chemical Industries, Ltd.) and orally administered at 10 mL/kg in a repeated manner starting on the booster day after a certain period from the injection day for initial sensitization. Also, only a solvent was administered instead of the test compound to prepare a comparative group.

[001019] During the test period, the swelling score of the limbs (score 0: no disease, score 1: swelling and redness or weak swelling in the small joint of only one of the toes of the hind paws and front paws, score 2: swelling moderate in the small joints of two or more of the toes of the hind paws and forepaws, score 3: severe swelling in the ankle or wrist of the forepaw, score 4: strong total swelling) was performed to evaluate the pharmaceutical efficacy of the test compound . When the total score of the solvent administered group on the final day was set to 100%, the reduction rate as a score (%) at each dose of the test compound was calculated.

[001020] In this test, the compounds of the present invention showed excellent swelling inhibitory activity, and, for example, compound number IV-361 showed an inhibition rate of 50% or higher at a dose of 100 mg/kg.

[Test Example 15] Paralysis Suppression Test Using MOG35-55-Induced Experimental Autoimmune Encephalomyelitis in Mouse (Repeated Administration)

[001021] A model test of experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55 in mice is carried out based on the method of Namiki et al. (The Journal of Biological Chemistry, 287, 29, 24228-24238 (2012)).

[001022] Male C57BL/6J mice (supplied by Charles River Laboratories Japan, Inc.) are used as laboratory animals. An adjuvant prepared from a liquid of M. Tuberculosis H37RA (manufactured by Difco Laboratories Ltd.) ground and suspended in Freund's Incomplete Adjuvant (manufactured by Difco Laboratories Ltd.), and a solution of synthetic MOG35-55 peptide is administered subcutaneously to the 4 limb flanks of the mice, and a pertussis toxin solution (manufactured by List Biological Laboratories, Inc.) is administered to the jugular veins (initial sensitization) to prepare mouse models of EAE.

[001023] The day after preparing the EAE mouse models, a pertussis toxin solution was administered, again, to the jugular veins. A test compound is suspended in an aqueous solution of 5% w/v methylcellulose (MC 0.5% MC) (manufactured by Wako Pure Chemical Industries, Ltd.) and orally administered at 10 mL/kg in a repeated manner from from the day of injection to initial sensitization. Also, only a solvent is administered instead of the test compound to mouse models of EAE to prepare a control group.

[001024] During the testing period, the score based on the pathological conditions of EAE (score 0: no disease, score 0.5: partial tail paralysis, score 1.0: complete tail paralysis, score 1.5: decline of the righting reflex, score 2.0: impairment of the righting reflex, score 2.5: weakness of the hind limbs, score 3.0: paralysis of one hind limb, score 3.5: paralysis of both hind limbs, score 4.0: paralysis of one forelimb, score 4.5: paralysis of both forelimbs, score 5: moribund or dead) was performed to evaluate the pharmaceutical efficacy of the test compound. When the total score of the solvent administered group on the final day is set to 100%, the suppression rate as score (%) at each dose of the test compound is calculated.

[Test Example 16] Cell growth inhibition test for various cancers

[001025] A BT-549 breast cancer cell line (obtained from the American Type Culture Collection (ATCC)), a C-33A uterine cancer cell line (obtained from the ATCC), a PA-1 ovarian cancer cell line (obtained from ATCC), a large cell lung cancer cell line NCI-H460 (obtained from ATCC), a small cell lung cancer cell line NCI-H82 (obtained from ATCC), a kidney cancer cell line ACHN (obtained from ATCC), a pancreatic cancer cell line BxPC-3 (obtained from ATCC), a malignant melanoma cancer cell line A375 (obtained from ATCC), a FaDu throat cancer cell line (obtained from ATCC), a Daoy medulloblastoma cell line (obtained from ATCC), a VA-ES-BJ cutaneous epithelioid sarcoma cell line (obtained from ATCC), a rhabdomyosarcoma cell line A-204 (obtained from ATCC), a prostate cancer cell line DU145 (obtained from ATCC), a bladder cancer cell line T24 (obtained from from ATCC), an SR lymphoma cell line (obtained from ATCC), a neuroblastoma cell line SH-SY5Y (obtained from DS Pharma Biomedical Co., Ltd.), a liver cancer cell line HepG2 (obtained from DS Pharma Biomedical Co., Ltd.), a stomach cancer cell line HGC-27 (obtained from DS Pharma Biomedical Co., Ltd.), and a multiple myeloma cell line NCI-H929 (obtained from DS Pharma Biomedical Co., Ltd.) were used as human cancer cell lines.

[001026] Each cell line was cultivated in a cell culture medium recommended by ATCC or DS Pharma Biomedical Co., Ltd. and was inoculated at 0.3 to 5.0 x 103 cells/well in a plate 96 wells. The cells were cultured overnight in an incubator at 37°C under an atmosphere containing 5% carbon dioxide. The medium was replaced with fresh medium the next day, then replaced with a mixed solution of a DMSO solution of a test compound with varying concentrations and a culture medium (final DMSO concentration: 0.1%), and left at rest in an incubator under an atmosphere containing carbon dioxide (day 0). Compounds IV-361, IV-379, IV-3, IV-215, IV-299, IV-669, IV-1049, and palbociclib (for comparison) were used as test compounds. Regarding a control group, DMSO was added instead of the DMSO solution of the test compound to a cell culture medium (final DMSO concentration: 0.1%).

[001027] After culturing for a predetermined period, the ATP activity of BT-549, C-33A, PA-1, NCI-H460, NCI-H82, ACHN, BxPC-3, A375, FaDu, Daoy, VA- ES-BJ, A-204, DU145, T24, and SR were measured using ATPlite (manufactured by PerkinElmer, Inc.). The ATP activity of SH-SY5Y, HepG2, HGC-27, and NCI-H929 was measured by using CellTiter-Glo (manufactured by Promega Corp.).

[001028] The cell growth inhibition rate (%) was calculated according to the expression provided below. Specifically, in the case in which the difference between the ATP activity before culture (day 0) and the ATP activity after culture in the test compound administered group is equal to the difference between the ATP activity before culture (day 0 ) and the ATP activity after culture in the control group, the cell growth inhibition rate is 0%. The cell growth inhibition rate = (1 -((ATP activity of the group administered with test compound after culture) - (ATP activity of the group administered with test compound on day 0)) / ((ATP activity of the control group after culture) - (ATP activity of the control group on day 0))) x 100 The concentration of test compound required to inhibit 50% of cell growth (IG50 value) was calculated by using EXSUS (version 8.1.0, manufactured by CAC Exicare Corp.).

[001029] In this test, the compounds of the present invention showed excellent cell growth inhibitory activity. Also, the IC50 values of compounds numbers IV-3, IV-215, IV-299, IV-361, IV-379, IV-669, and IV-1049 are shown in Table 50. A = lower than 300 nM; B = 300 nM or higher and lower than 1,000 nM; C = 1,000 nM or higher; NT = not tested

[Test Example 17] Inhibition test of pulmonary neutrophil infiltration induced by LPS inhalation in rats (single administration)

[001030] A lung neutrophil infiltration inhibition test using rats was conducted by partially modifying the method of Spond et al. (Pulmonary Pharmacology and Therapeutics, 14, 157 (2001)). Five male SD rats (provided by Charles River Laboratories Japan, Inc.) fasted for approximately 16 hours were used in each of a test compound administered group and a control group.

[001031] A test compound solution for administration was prepared by dissolving or suspending a test compound in an aqueous solution of 0.5% w/v methylcellulose (MC 0.5%) (manufactured by Wako Pure Chemical Industries, Ltd.).

[001032] The prepared test compound solution was orally administered at 10 mL/kg to the test compound administered group, and 0.5% MC was administered at 10 mL/kg to the control group. 15 minutes after administration, a lipopolysaccharide (LPS) solution (manufactured by Sigma-Aldrich Co. LLC.) (concentration: 0.5 mg/mL) was administered to the rats in each group by inhalation for 30 minutes. In inhalation administration, a two-fluid atomizer was used, and a small air compressor (P0-0.4LES, manufactured by Hitachi Industrial Equipment Systems Co., Ltd.) and an air supply unit (AP-678, manufactured by Shibata Scientific Technology Ltd.) were used for fog generation.

[001033] 4 Hours after LPS administration, bronchoalveolar lavage was performed as described below, and bronchoalveolar lavage fluid (hereinafter, abbreviated as FLBA) was collected.

[001034] Bronchoalveolar lavage method: Rats were anesthetized with isoflurane and subsequently killed due to exsanguination by incision in the inferior vena cava. The trachea was exposed, and a mouse oral tube (manufactured by Fuchigami Kikai Co., Ltd.) connected with a disposable syringe (5 mL, manufactured by Terumo Corp.) was inserted into the trachea, followed by ligation of the trachea. 3.5 mL of saline solution containing BSA (concentration: 1%) was injected into it, and then the injected saline solution was collected to obtain FLBA. The FLBA obtained by additionally repeating this operation four times was centrifuged (420 x g, 10 min, 4°C), then the supernatant was removed until the liquid volume became 1.5 mL, and the precipitated cells were suspended to obtain suspension of cells in FLBA.

[001035] Next, the number of neutrophils in the cell suspension in FLBA was measured by using an automatic multispecies blood cell counter (XT-2000iV, manufactured by Sysmex Corp.). The neutrophil infiltration inhibition rate (%) by administration of the test compound was calculated according to the following expression: Neutrophil infiltration inhibition rate (%) = 100 - [(NEUTc) + (NEUTv)] NEUTv: the number of neutrophils in the cell suspension in FLBA from the control group NEUTc: the number of neutrophils in the cell suspension in FLBA from the test compound administered group

[001036] In this test, the compounds of the present invention showed an excellent inhibitory effect on pulmonary neutrophil infiltration, and, for example, compounds numbers IV-215, IV-299, and IV-379 showed an inhibition rate of 50% or higher at a dose of 100 mg/kg.

[Test Example 18] Swelling Suppression Test Using Oxazolone (OXA)-Induced Mouse Delayed Hypersensitivity Dermatitis Model

[001037] 0.05 mL of an ethanol solution of OXA (manufactured by Sigma-Aldrich Co. LLC.) adjusted to 2% was applied for 2 consecutive days to the abdomens of female BALB/c mice (supplied by Japan SLC, Inc .) dehaired with shaving cream to prepare sensitized animals. Also, mice, in which ethanol was applied instead of 2% OXA, were used as non-sensitized animals.

[001038] 5 Days after application, 0.01 mL of an ethanol solution of a test compound adjusted to 1% was applied to each of both sides (frontal and dorsal surfaces of auricles) of the right ears of the sensitized animals in the group applied with test compound. Also, 0.01 mL of ethanol was applied to each of both sides of the right ears of non-sensitized animals in the control group. In relation to a vehicle group, 0.01 mL of ethanol was applied to each of both sides of the right ears of the sensitized animals. One hour later, 0.015 mL of a 2% OXA ethanol solution was applied to each of both sides of the right ears of the mice in each group. The next day, the thicknesses of the right ears were measured with a thickness gauge (manufactured by TECLOCK Corp.), and the suppression rate (%) was calculated according to the following expression: Suppression rate (%) = (1 - (Ear thickness of the test compound applied group) - (Ear thickness of the control group)) + ((Ear thickness of the vehicle group) — (Ear thickness of the control group))) x 100 Neste test, the compounds of the present invention showed an excellent swelling-suppressing effect, and, for example, compounds IV-215, IV-299, IV-379, and IV-1049 showed 50% or higher suppression with the solution of 1%.

[Test Example 19]

[001039] Evaluation of in vitro cell growth inhibitory activity against human large intestine cancer cell line by combined use with chemotherapeutic agent

[001040] A human colon cancer cell line HCT-116 (obtained from DS Pharma Biomedical Co., Ltd.) was cultured in McCoy's 5A medium (manufactured by Thermo Fisher Scientific, Inc.) containing 10% fetal bovine serum (FBS) (manufactured by Thermo Fisher Scientific, Inc.) and 1% penicillin/streptomycin/amphoterin B (manufactured by Thermo Fisher Scientific, Inc.) and inoculated at 0.5 to 2.0 X 103 cells /well in a 96-well plate. The cells were cultured overnight in an incubator under an atmosphere containing 5% carbon dioxide at 37°C. The medium was replaced with fresh medium the next day, and then a mixed solution of a DMSO solution of a test compound (IV-361, 5-FU or SN-38) with varying concentrations and a culture medium of cells (final concentration in DMSO: 0.2%) was added thereto. The concentration of the test compound was 10 nM, the concentration of 5-FU (manufactured by Wako Pure Chemical Industries, Ltd.) was 1,000 nM, and the concentration of SN-38 (manufactured by Tocris Bioscience) was adjusted 1 nM to perform the test. Regarding a control group, a mixed solution of DMSO and cell culture medium (final DMSO concentration: 0.2%) was used instead of the DMSO solution of the test compound.

[001041] After adding the DMSO solution of the test compound, the cells were cultured for 3 days in an incubator under an atmosphere containing carbon dioxide. Then, the absorbance (measuring wavelength: 565 nm) of the medium in each group was measured by using the Sulforhodamine B based In Vitro Toxicology Assay Kit (manufactured by Sigma-Aldrich Co. LLC.).

[001042] The growth inhibition rate (%) was calculated according to the expression provided below. Specifically, in the case in which the difference between the mean absorbance before culture (day 0) and the mean absorbance after culture in the group administered the test compound is equal to the difference between the mean absorbance before culture (day 0) and the average absorbance after culture in the control group, the cell growth inhibition rate is 0%.

[001043] Growth inhibition rate = (1 - ((Mean absorbance of the group administered with test compound after culture) - (Mean absorbance of the group administered with test compound on day 0)) + ((Mean absorbance of the group control after culture) — (Average absorbance of the control group on day 0))) x 100 In this test, the compound of the present invention showed an excellent inhibitory effect on the growth of cancer cells when used in combination with a chemotherapeutic agent, and , for example, compound number IV-361 showed a synergistic cancer cell growth inhibitory effect, as shown in Table 51, when used in combination with the chemotherapeutic agent (5-FU or SN-38).

[Test Example 20] In vivo tumor growth inhibition test for human large intestine cancer cell line by combined use with chemotherapeutic agent

[001044] A human large intestinal cancer cell line (HCT-116) was cultured in McCoy's 5A medium (manufactured by Thermo Fisher Scientific, Inc.) containing 10% fetal bovine serum (FBS) (manufactured by Thermo Fisher Scientific, Inc.) and 1% penicillin/streptomycin/amphoterin B (manufactured by Thermo Fisher Scientific, Inc.) and adjusted to 1.0 x 108 cells/mL with PBS or Hanks solution (HBSS(-)). The prepared cell suspension was subcutaneously injected at 0.1 mL/mouse into the right side of the abdomens of BALB female nude mice (supplied by Charles River Laboratories Japan, Inc.). After acclimatization for a certain period, the long diameter (mm) and short diameter (mm) of the tumor were measured with electronic calipers (manufactured by Mitsutoyo Corp., Cat. 500-712-10), and the volume of Tumor volume was calculated according to the following expression: Tumor volume (mm3) = (Long diameter) x (Short diameter) x (Short diameter) x 0.5 Subjects whose tumor volume was within the range of 50 to 200 mm3 were selected and grouped in such a way that the tumor volume was almost equivalent. After grouping, a test compound or a solvent alone was administered in a repeated manner to mice in each group as follows: Single-agent administration group: Control group: solvent (administered once a day) Single-agent administration group of IV-361: 25 mg of IV-361/kg (administered only once a day) Group with administration of only 5-Fluorouracil (5-FU): 15 mg of 5-FU/kg (administered twice a week) Group with only Oxaliplatin administration: 3 mg of Oxalapine/kg (administered only once a day) Group with only Irinotecan administration: 12.5 mg of Irotecan/kg (administered once a week) Combined use group: 25 mg of Compound No. IV-361/kg + 15 mg of 5-FU/kg 25 mg of Compound No. IV-361/kg + 3 mg of Oxaliplatin/kg 25 mg of Compound No. IV-361/kg + 12, 5 mg Irinotecan/kg

[001045] Compound number IV-361 was forcibly administered orally (10 mL/kg). 5-FU, oxaliplatin, and irinotecan were administered intraperitoneally (5 mL/kg).

[001046] After a lapse of a predetermined period, the body weights of the mice of each group and the long diameter and short diameter of tumor were measured, and the tumor volume of the group administered with test compound with respect to the tumor volume Control group volume was calculated as the tumor volume suppression rate (%).

[001047] In this test, the compound of the present invention showed excellent tumor growth inhibitory activity when used in combination with a chemotherapeutic agent, and, for example, compound number IV-361 showed an excellent tumor volume suppression rate, as shown in Tables 52 to 54, when used in combination with the chemotherapeutic agent (5-FU, oxaliplatin or irinotecan).

[001048] From Test Examples 1 to 20, it is concluded that the compound of the present invention has excellent CDK7 inhibitory activity and high selectivity and is useful, for example, as a therapeutic drug and/or a prophylactic drug for cancer. , an inflammatory disease, an allergic disease, or a chronic respiratory disease. Also, the compound of the present invention exerts excellent therapeutic effects when used in combination with an additional existing therapeutic drug.

Claims (38)

1. Compound, characterized by the fact that it is represented by formula (Ia) or a pharmacologically acceptable salt thereof: wherein two R moieties are each independently a C1-3 alkyl group; are linked together to form a C2-5 alkylene group; or together with the carbon atom to which they are attached they form an unsubstituted cyclopropyl group or an unsubstituted cyclobutyl group; A is: (i) unsubstituted phenyl; (ii) phenyl substituted with 1 to 3 groups selected from halogen, linear or branched C1-6 alkyl, cyclopropyl, halogenated linear or branched C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, cyano and phenyl; (iii) heteroaryl group selected from benzofuran-7-yl, dihydrobenzofuran-7-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, isothiazol-4-yl, isoxazol-4-yl , thiophen-2-yl and thiophen-3-yl; wherein the heteroaryl group is unsubstituted or substituted with 1 or 2 groups selected from halogen, methyl and methoxy; Z is a hydrogen, methyl, ethyl, propyl, or isopropyl atom, or a group represented by ZNA forms a phenyl-fused pyrrolidine, phenyl-fused pyrroline, phenyl-fused piperidine, or phenyl-fused morpholine; wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents selected from chlorine, fluorine, bromine and methyl; R1, R2 and R3 are each independently methyl or ethyl; and the pharmacologically acceptable salt is a salt of a compound selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, lactic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, lithium, sodium, potassium, calcium, magnesium, ammonia, morpholine, glucosamine, ethylenediamine, guanidine, diethylamine , triethylamine, dicyclohexylamine, diethanolamine and piperazine. 2. Compound according to claim 1, characterized by the fact that Z is hydrogen. 3. Compound according to claim 1 or 2, characterized by the fact that the two R moieties are methyl. 4. Compound according to claim 1 or 2, characterized by the fact that the two R moieties together with the carbon atom to which they are attached form an unsubstituted cyclopropyl group. 5. Compound according to claim 1 or 2, characterized by the fact that the two R moieties together with the carbon atom to which they are attached form an unsubstituted cyclobutyl group 6. Compound according to any one of claims 1 to 5, characterized by the fact that RI, R2 and R3 are methyl. 7. Compound according to any one of claims 1 to 6, characterized by the fact that A is: (i) unsubstituted phenyl or (ii) phenyl substituted with 1 to 3 groups selected from chlorine, fluorine, bromine, methyl, ethyl , isopropyl, tert-butyl, cyano, -CF3, methoxy, ethoxy, -OCHF2, cyclopropyl and phenyl. 8. Compound according to claim 1, characterized by the fact that the compound of formula (Ia) is: 6,6-Dimethyl-N-phenyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6- dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-(p-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-di -hydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(4-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-di- hydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(4-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrole [3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-(pyridin-3-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-di- hydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrole [3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-(o-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[ 3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-(m-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3 ,4-c]pyrazol-5(1H)-carboxamide, N-([1,1'-biphenyl]-3-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4 ,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(3-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4, 6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(3-chlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6 -dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6- dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-chlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-di -hydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-([1,1'-biphenyl]-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutan ocarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-(pyridin-2-yl)-3-[1-(trimethylsilyl) cyclobutanecarb oxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-ethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarb xamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,6-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,3-difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl )cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,3-dimethylphenyl)-6,6-dimethyl-3-[1-( trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-fluoro-6-methylphenyl)-6,6-dimethyl-3-[ 1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-[2-(difluoromethoxy)phenyl]-6,6-dimethyl-3 -[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-ethoxyphenyl)-6,6-dimethyl-3- [1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-[2-(trifluoromethoxy)phenyl]- 3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-fluoro-4-methylphenyl)-6,6 -dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,6-difluorophenyl)-6, 6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-[2-(tert-butyl)phenyl ]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N -[2-(trifluoromethyl)phenyl]-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(3- fluoro-2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N- (2-cyanophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-( 4-fluoro-2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-chloro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide, N-(2-fluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide, N-(2-fluoro-5-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c] pyrazol-5(1H)-carboxamide, N-(5-fluoro-2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4 -c]pyrazol-5(1H)-carboxamide, N-(2,4-difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3, 4-c]pyrazol-5(1H)-carboxamide, N-(2,5-difluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3 ,4-c]pyrazol-5(1H)-carboxamide, N-(2,5-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[ 3,4-c]pyrazol-5(1H)-carboxamide, N-(2-chloro-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-di -hydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,4-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-4,6- dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 3-[1-(Ethyldimethylsilyl)cyclobutanecarboxamido]-N-(2-fluorophenyl)-6,6-dimethyl-4,6-di -hydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-(3-methylisothiazol-4-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4, 6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-(thiophen-2-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-2 ,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N-(thiophen-3-yl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]- 2,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,6-difluoro-4-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl ) cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-fluoro-6-methoxyphenyl)-6,6-dimethyl-3-[1 -(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-[2-fluoro-6-(trifluoromethyl)phenyl]-6,6- dimethyl-3-[1-(trimethylsylyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(5-chloro-2-methylphenyl)- 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,5-dichlorophenyl) -6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-cyclopropylphenyl)- 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,6-dichlorophenyl) -6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutane carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, 6,6-Dimethyl-N- (2,4,6-trifluorophenyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2- ethyl-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N- (2-bromophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanocarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-( 2-chloro-5-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(5-chloro-2-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide, 6,6-Dimethyl-N-(2,3,6-trifluorophenyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide, N-(2-chloro-6-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c] pyrazol-5(1H)-carboxamide, N-[2-(1,1-difluoroethyl)phenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[ 3,4-c]pyrazol-5(1H)-carboxamide, N-(6-chloro-2-fluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4 ,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-fluoro-6-(methoxy-d3)phenyl)-6,6-dimethyl-3-[1 -(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-[2-chloro-6-(trifluoromethyl)phenyl]-6,6- dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-fluoro-6-methoxy-3 -methylphenyl)-6,6-dimethyl-3-[1-(trimethylsylyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2 ,6-difluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide , N-[2-(difluoromethoxy)-6-fluorophenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide, N-(2-bromo-6-chlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c ]pyrazol-5(1H)-carboxamide, N-(2-chloro-6-fluoro-3-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-di- hydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-ethyl-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4, 6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-bromo-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido] -4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-bromo-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-chloro-5-methylphenyl)-6,6-dimethyl-3-[1- (trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(6-fluoro-2,3-dihydrobenzofuran-7-yl)- 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-cyano-6 -fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2- chloro-6-cyclopropylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N- (2-fluoro-3,6-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H) -carboxamide, N-(6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5 (1H)-carboxamide, N-(2-chloro-3-fluoro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3, 4-c]pyrazol-5(1H)-carboxamide, N-[2-(difluoromethoxy)-6-fluorophenyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6- dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4, 6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)pro panoamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-[2-(difluoromethoxy)-6-fluorophenyl]-6,6-dimethyl-3-[2 -methyl-2 -(trimethylsilyl)propaneamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2,6-dichloro-4-fluorophenyl)-6 ,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-ethyl-6-fluorophenyl )-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanocarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-bromo- 6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2 -chloro-5-methoxyphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N -(2-ethyl-6-fluorophenyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanoamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5( 1H)-carboxamide, N-(2-bromo-6-methylphenyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propaneamido]-4,6-dihydropyrrolo[3,4 -c]pyrazol-5(1H)-carboxamide, N-(6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propaneamido]-4,6- dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4 ,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide , N,6,6-trimethyl-N-phenyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6- dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(6-fluoro-3-methylbenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-(2-chloro-6-fluorobenzofuran-7-yl)-6,6-dimethyl-3 -[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide, N-[5-(indoline-1-carbonyl)-6, 6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide, N-[5-(3,4-dihydro -2H-benzo[b][1,4]oxazine-4-carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]- 1-(trimethylsilyl)cyclobutanecarboxamide, N-(6-fluoro-2-methylbenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[ 3,4-c]pyrazol-5(1H)-carboxamide, N-[5-(1H-indol-1-carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[ 3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide, or a pharmacologically acceptable salt of one of the foregoing. 9. Compound according to claim 1, characterized by the fact that the compound of formula (Ia) is N-(2-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4, 6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 10. Compound according to claim 1, characterized by the fact that the compound of formula (Ia) is 6,6-Dimethyl-N-(o-tolyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4, 6-dihydroxydrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 11. Compound according to claim 1, characterized by the fact that the compound of formula (Ia) is N-(2-chloro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxami do]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 12. Compound according to claim 1, characterized by the fact that the compound of formula (Ia) is N-(5-fluoro-2-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxam acid]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 13. Compound according to claim 1, characterized by the fact that the compound of formula (Ia) is N-(2,5-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]- 4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 14. Compound according to claim 1, characterized by the fact that the compound of formula (Ia) is N-(2-chloro-6-fluorophenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxam acid]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 15. Compound according to claim 1, characterized by the fact that the compound of formula (Ia) is N-(2-bromo-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxam acid]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 16. Compound according to claim 1, characterized by the fact that the compound of formula (Ia) is N-(2-fluoro-3,6-dimethylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl )cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 17. Compound according to claim 1, characterized by the fact that the compound of formula (Ia) is N-(6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarbox amido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 18. Compound according to claim 1, characterized by the fact that the compound of formula (Ia) is N-(2-chloro-6-fluorobenzofuran-7-yl)-6,6-dimethyl-3-[1- (trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 19. Compound according to claim 1, characterized by the fact that the compound of formula (Ia) is N-(6-fluoro-2-methylbenzofuran-7-yl)-6,6-dimethyl-3-[1- (trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-carboxamide or a pharmacologically acceptable salt thereof. 20. Pharmaceutical composition, characterized by the fact that it comprises a compound as defined in any one of claims 1 to 19 and a pharmacologically acceptable carrier. 21. Pharmaceutical composition according to claim 20, characterized by the fact that it is for the treatment or prevention of a cancer, an inflammatory disease, an allergic disease or a chronic respiratory disease. 22. Pharmaceutical composition according to claim 21, characterized by the fact that the cancer is a blood cancer or a solid cancer. 23. Pharmaceutical composition according to claim 22, characterized by the fact that the blood cancer is multiple myeloma, chronic myelogenous leukemia, blood tumor, hematological malignancy, childhood leukemia, childhood lymphoma, Hodgkin's disease, lymphocytic lymphoma, cutaneous lymphoma , acute leukemia, chronic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, plasma cell neoplasm, lymphoid neoplasm, or AIDS-related cancer. 24. Pharmaceutical composition according to claim 22, characterized by the fact that said solid cancer is bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, cancer non-small cell lung cancer, head and neck cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, uterine cervical cancer, thyroid cancer, prostate cancer, skin cancer including cell carcinoma squamous cells, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, glioma and neurilemmoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer or Kaposi's sarcoma. 25. Pharmaceutical composition according to claim 21, characterized by the fact that the inflammatory disease is an autoimmune disease. 26. Pharmaceutical composition according to claim 25, characterized by the fact that the autoimmune disease is rheumatoid arthritis. 27. Pharmaceutical composition according to claim 25, characterized by the fact that the autoimmune disease is psoriasis. 28. Pharmaceutical composition according to claim 25, characterized by the fact that the autoimmune disease is multiple sclerosis. 29. Pharmaceutical composition according to claim 25, characterized by the fact that the autoimmune disease is inflammatory bowel disease. 30. Pharmaceutical composition according to claim 21, characterized by the fact that the chronic respiratory disease is chronic obstructive pulmonary disease. 31. Pharmaceutical composition according to claim 21, characterized by the fact that the allergic disease is atopic dermatitis. 32. Pharmaceutical composition according to any one of claims 20 to 31, characterized in that the pharmaceutical composition is administered in combination with one or more additional drug(s) selected from the group consisting of anticancer agents, antirheumatic agents, drugs for the treatment of psoriasis, drugs for the treatment of multiple sclerosis, drugs for the treatment of inflammatory bowel disease, drugs for the treatment of chronic obstructive pulmonary disease and drugs for the treatment of atopic dermatitis. 33. Pharmaceutical composition according to any one of claims 20 to 31, characterized in that the pharmaceutical composition is administered at the same time with or at a different time from a composition comprising, as an active ingredient, one or more drug(s). ) additional selected from the group consisting of anticancer agents, antirheumatic agents, drugs for the treatment of psoriasis, drugs for the treatment of multiple sclerosis, drugs for the treatment of inflammatory bowel disease, drugs for the treatment of pulmonary disease chronic obstructive disease and drugs for the treatment of atopic dermatitis. 34. Pharmaceutical composition according to any one of claims 20 to 31, characterized in that it additionally comprises, as an active ingredient, one or more additional drug(s) selected from the group consisting of anticancer agents , antirheumatic agents, drugs for the treatment of psoriasis, drugs for the treatment of multiple sclerosis, drugs for the treatment of inflammatory bowel disease, drugs for the treatment of chronic obstructive pulmonary disease and drugs for the treatment of atopic dermatitis. 35. Pharmaceutical composition according to any one of claims 32 to 34, characterized in that the additional medicine is nivolumab, ipilimumab, pembrolizumab, durvalumab, atezolizumab or avelumab. 36. Pharmaceutical composition according to any one of claims 32 to 34, characterized by the fact that the additional drug is 5-fluorouracil. 37. Pharmaceutical composition according to any one of claims 32 to 34, characterized by the fact that the additional drug is oxaliplatin. 38. Pharmaceutical composition according to any one of claims 32 to 34, characterized by the fact that the additional drug is irinotecan.