CD73 inhibitor compound

Abstract

The present invention relates to a compound of formula I shown below, wherein R1, X2, X3, X4, X5, X6, X7, X8, and X9 are each as defined in the present application. The present invention also relates to a method for preparing these compounds, pharmaceutical compositions containing them, and their use in the treatment of diseases or conditions in which adenosine CD73 activity is involved, such as cancer. [Chemical Formula 1] JPEG2025521173000296.jpg42170

Description

Technical Field

[0001] Introduction The present invention relates to certain compounds that function as inhibitors of CD73, also known as 5'-nucleotidase or ecto-5'-nucleotidase. The present invention also relates to methods for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of diseases or conditions in which CD73 activity is involved, such as cancer.

Background Art

[0002] Purinergic signaling plays a critically important role in physiological processes, and imbalances can lead to various pathophysiological states. The levels of extracellular adenosine triphosphate and adenosine are controlled by a complex network of enzymes and transporters. Downstream signaling is mediated by ligand-gated ion channels and through G protein-coupled receptors. The cell surface protein CD39 acts at an early point in the pathway by catalyzing the hydrolysis of adenosine triphosphate (ATP) to adenosine diphosphate (ADP), followed by the conversion of ADP to AMP. CD73 is a cell surface ecto-5'-nucleotidase encoded by the NT5E gene. CD73 is widely expressed and is responsible for the conversion of adenosine monophosphate (AMP) to adenosine. Abnormalities in purinergic signaling have been observed in various diseases, including cancer, autoimmune disorders, inflammation, fibrosis, bleeding disorders, and atherosclerosis. Inhibition of CD73 enzyme activity is seen as a promising approach to balance ATP-mediated immune cell activation and adenosine-induced immunosuppression.

[0003] In cancer, an immunosuppressive microenvironment is created by increased levels of adenosine within the tumor. CD73 expression levels are increased in a variety of human tumor types, including ovarian cancer, melanoma, prostate cancer, breast cancer, colon cancer, head and neck cancer, leukemia, hepatocellular carcinoma, and glioblastoma [Arab and Hadjati, 2019]. High expression of CD73 is associated with poor cancer outcomes [Leone and Emens, 2018; Hammami et al, 2019]. CD73 expression can change in response to treatment with chemotherapy and targeted therapy and is also regulated by hypoxic conditions through activation by the transcription factor HIF1a. In addition to expression in tumor cells, an overview of CD73 expression in leukocytes and myeloid cells has been shown by Roh et al (Roh et al, 2020). CD73 is expressed in regulatory T cells and exhausted or anergic effector T cells. Increased expression of CD73 has been observed in myeloid-derived suppressor cells in cancer patients.

[0004] Tumor growth is altered in mice lacking the gene encoding CD73 [Yegutkin et al, 2011]. Loss of CD73 significantly inhibits the growth of MC38 colon cancer cells, EG7 lymphoma, and AT-3 breast tumor cells, as well as B16F10 melanoma in syngeneic models [Stagg et al, 2011]. Studies using adoptive transfer have shown that the tumor-promoting effect of CD73 is due, in part, to its expression in hematopoietic cells (e.g., regulatory T cells) and, in part, to its expression in non-hematopoietic cells such as endothelial cells. Furthermore, this study showed that the use of monoclonal antibodies targeting CD73 can reduce tumor growth and metastasis. Blockade using the CD73 inhibitor α,β-methylene adenosine 5'-diphosphate has also been shown to reduce tumor growth and metastasis in mouse models [Stagg t et al. 2011]. Several therapeutic antibodies targeting CD73 with distinct mechanisms of action are in clinical development [Allard et al 2018]. MEDI9447 (AstraZeneca) is a human monoclonal antibody that non-competitively inhibits the function of CD73 by blocking dimerization and preventing CD73 from transitioning to its catalytically active higher-order structure [Geoghegan J.C.et al]. MEDI9447 has been shown to inhibit tumor growth as a single agent and in combination with anti-PD-1 antibodies in animal studies using syngeneic tumors [Hay C.M.et al 2016]. Another antibody, BMS-986179, enhances the internalization of CD73.

[0005] Small-molecule chemical inhibitors of CD73, including AB680 (Arcus Biosiences) and LY3475070 (Eli Lilly), have also entered clinical trials. AB680 is a potent and reversible inhibitor of CD73 catalytic activity [Lawson K.V.et al 2020]. OP-5244 (Oric Pharmaceuticals) is a sub-nanomolar CD73 inhibitor that has been shown to inhibit adenosine production by both cancer cells and T cells in vitro and to reverse immunosuppression in mouse models [Du X.et al 2020].

[0006] However, there is still a need for additional compounds that are potent CD73 inhibitors. In particular, there is a need for compounds that are potent and selective CD73 inhibitors for oral administration.

[0007] The present invention has been devised in view of the above.

[0008] References Allard D. et al. (2019) Immunol Lett 205; 31-39. Arab S. and Hadjait J. (2019) Immune Netw 19 (4) e23 Du, X. et al. (2020) J Med Chem 63; 10433-10459 Geoghegan J.C. et al (2016) MAbs 8; 454-67 Hammami A. et al. (2019) Seminars in Immunology 42 Hay C.M. et al (2016) Oncoimmunology 5; e1208875 Lawson K.V. et al (2020) J Med Chem 63, 20, 11448 Leone R.D. and Emens L.A. (2018) J Immunother Cancer 6(57) Roh M. et al. (2020) Current Opinion in Pharmacology 53, 1-11 Stagg J. et al. (2011) Cancer Research 71, 2892-900 Yegutkin G.G. et al. (2011) Eur J Immunol 41 (5); 1231-41

Summary of the Invention

[0009] Summary of the Invention According to a first aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0010] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0011] According to a further aspect of the present invention, there is provided a method of inhibiting CD73 in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0012] According to a further aspect of the present invention, there is provided a method of selectively inhibiting CD73 in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0013] According to a further aspect of the present invention, there is provided a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (such as checkpoint inhibitors and / or cytotoxic agents).

[0014] According to a further aspect of the present invention, there is provided a method of performing said treatment in a patient in need of treating a disease or disorder associated with CD73 activity, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0015] According to a further aspect of the present invention, there is provided a method of performing said treatment in a patient in need of treating a proliferative disorder, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (such as checkpoint inhibitors and / or cytotoxic agents).

[0016] According to a further aspect of the present invention, there is provided a method of performing said treatment in a patient in need of treating cancer, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (such as checkpoint inhibitors and / or cytotoxic agents).

[0017] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition for use in therapy.

[0018] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition for use in treating a proliferative condition. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (such as checkpoint inhibitors and / or cytotoxic agents).

[0019] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the treatment of cancer. In certain embodiments, the cancer is human cancer. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (such as checkpoint inhibitors and / or cytotoxic agents).

[0020] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use as a CD73 activity inhibitor. Certain compounds of the present invention are selective CD73 inhibitors.

[0021] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in the treatment of a disease or disorder in which CD73 activity is involved.

[0022] According to a further aspect of the present invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative condition. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (such as checkpoint inhibitors and / or cytotoxic agents).

[0023] According to a further aspect of the present invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for the treatment of cancer. Preferably, the cancer is human cancer. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (such as checkpoint inhibitors and / or cytotoxic agents).

[0024] According to a further aspect of the invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for use as a CD73 activity inhibitor.

[0025] According to a further aspect of the invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which CD73 activity is involved.

[0026] According to a further aspect of the invention, there is provided a method for preparing a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0027] According to a further aspect of the invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which can be obtained, or is obtained, or is directly obtained, by a method for preparing a compound as defined herein.

[0028] According to a further aspect of the invention, there is provided a novel intermediate as defined herein, which is suitable for use in any one of the synthetic methods described herein.

[0029] Features, including optional features, suitable features, and preferred features, relating to one aspect of the invention can also be features, including optional features, suitable features, and preferred features, relating to any other aspect of the invention.

Mode for Carrying Out the Invention

[0030] Detailed Description of the Invention Definition Unless otherwise specified, the following terms used in this specification and the claims have the meanings described below.

[0031] References to "treating" or "treatment" should be understood to include the prevention of a condition and the alleviation of existing symptoms of a condition. Thus, "treating" or "treatment" with respect to a situation, disorder, or condition includes (1) preventing or delaying the onset of clinical symptoms of a situation, disorder, or condition that may or is likely to be suffered by a human who has not yet experienced or manifested the clinical or preclinical symptoms of the situation, disorder, or condition, (2) inhibiting a situation, disorder, or condition, i.e., stopping, reducing, or delaying the development of a disease, or its recurrence (in the case of maintenance treatment), or at least one of its clinical or preclinical symptoms, or (3) reducing or attenuating a disease, i.e., causing regression of a situation, disorder, or condition, or at least one of its clinical or preclinical symptoms.

[0032] "Therapeutically effective amount" means an amount of a compound that is sufficient to effect the treatment of a disease when administered to a mammal for treating the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0033] As used herein, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups such as "propyl" specifically refer only to the straight-chain form, and references to individual branched-chain alkyl groups such as "isopropyl" specifically refer only to the branched-chain form. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and t-butyl, as well as pentyl and hexyl isomers. A similar convention applies to other groups, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl, etc.

[0034] The term “(m~nC)” or “(m~nC) group” used alone or as a prefix means any group having m to n carbon atoms.

[0035] An “alkylene”, “alkenylene”, or “alkynylene” group is an alkyl, alkenyl, or alkynyl group that is located between two other chemical groups and serves to connect them. Thus, “(1~6C) alkylene” means a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group having 3 to 6 carbon atoms, such as methylene, ethylene, propylene, 2-methylpropylene, pentylene, etc.

[0036] “(2~6C) alkenylene” means a straight-chain divalent hydrocarbon group having 2 to 6 carbon atoms or a branched divalent hydrocarbon group having 3 to 6 carbon atoms that contains at least one double bond, such as ethenylene, 2,4-pentadienylene, etc.

[0037] “(2~6C) alkynylene” means a straight-chain divalent hydrocarbon group having 2 to 6 carbon atoms or a branched divalent hydrocarbon group having 3 to 6 carbon atoms that contains at least one triple bond, such as ethynylene, propynylene, and butynylene, etc.

[0038] “(3~8C) cycloalkyl” means a hydrocarbon ring containing 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or bicyclo[2.2.1]heptyl.

[0039] “(3~8C) cycloalkenyl” means a hydrocarbon ring containing at least one double bond, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl, such as 3-cyclohexen-1-yl, or cyclooctenyl.

[0040] "(3 to 8C) cycloalkyl-(1 to 6C) alkyl" means a (3 to 8C) cycloalkyl group as defined herein covalently bonded to a (1 to 6C) alkylene group as defined herein.

[0041] The term "halo" or "halogeno" means fluoro, chloro, bromo, and iodo.

[0042] The terms "heterocyclyl", "heterocyclic", or "heterocycle" mean a non-aromatic saturated or partially saturated monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic heterocyclic system. The monocyclic heterocycle contains about 3 to 12 (preferably 3 to 7) ring atoms and has 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. The bicyclic heterocycle contains 7 to 17 member atoms, preferably 7 to 12 member atoms in the ring. The bicyclic heterocycle can be a fused ring system, a spiro ring system, or a bridged ring system. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Examples of heterocycles containing nitrogen include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Sulfur-containing heterocycles also include sulfur oxide heterocycles containing an SO or SO2 group. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values for heterocyclyl groups having one or two oxo (=O) or thioxo (=S) substituents include, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl, or 2,6-dioxopiperidinyl.Examples of specific heterocyclic groups include saturated monocyclic 3- to 7-membered heterocyclyls containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As will likely be recognized by those skilled in the art, any heterocycle can be linked to another group through any suitable atom, for example, through a carbon atom or a nitrogen atom. However, references herein to piperidino or morpholino refer to a piperidin-1-yl or morpholin-4-yl ring linked through the ring nitrogen.

[0043] The term "bridged ring system" means a ring system in which two rings share three or more atoms. See, for example, Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0044] The term "spiro bicyclic system" means that two ring systems share one common spiro carbon atom, i.e., a heterocycle is linked to a further carbocyclic or heterocyclic ring through one common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azaspiro[3.5]nonane.

[0045] "Heterocyclyl(1-6C)alkyl" means a heterocyclyl group as defined herein covalently bonded to an alkylene group (1-6C) as defined herein.

[0046] The terms "heteroaryl" or "aromatic heterocyclic" mean an aromatic monocyclic, bicyclic, or polycyclic ring containing one or more (e.g., 1-4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The term heteroaryl includes both monovalent and divalent species. Examples of heteroaryl groups include monocyclic and bicyclic groups containing 5-12 ring members, more usually 5-10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring, or a 9- or 10-membered bicyclic ring, e.g., a bicyclic structure formed from fused 5- and 6-membered rings, or from fused 2 6-membered rings. Each ring can contain up to about 4 heteroatoms usually selected from nitrogen, sulfur, and oxygen. Generally, a heteroaryl ring contains up to 3 heteroatoms, more usually up to 2, e.g., 1 heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. A nitrogen atom in a heteroaryl ring can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents of the ring, is less than 5.

[0047] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno[2,3b]-furanyl-, 2H-furo[3,2b]-pyranyl-, 5H-pyrido[2,3-d]-oxazinyl-, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5d]thiazolyl, pyrazino[2,3d]pyridazinyl, -imidazo[2,1b]thiazolyl, -imidazo[1,2b][1,2,4]-triazinyl. "Heteroaryl" encompasses partially aromatic bicyclic or polycyclic systems in which at least one ring is an aromatic ring and one or more other rings are saturated or partially saturated non-aromatic rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or -sulfur-. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl.

[0048] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0049] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0050] Bicyclic heteroaryl groups include, for example, a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; A cyclohexyl ring fused to a 5- or 6-membered aromatic heterocycle containing 1, 2, or 3 ring heteroatoms; and A cyclopentyl ring fused to a 5- or 6-membered aromatic heterocycle containing 1, 2, or 3 ring heteroatoms can be a group selected from.

[0051] Specific examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guanylinyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0052] Specific examples of bicyclic heteroaryl groups containing two fused 6-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0053] "Heteroaryl(1-6C)alkyl" means a heteroaryl group as defined herein covalently bonded to an alkylene group (1-6C) as defined herein. Examples of heteroalkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

[0054] The term "aryl" means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In certain embodiments, aryl is phenyl.

[0055] The term "aryl(1-6C)alkyl" means an aryl group as defined herein covalently bonded to an alkylene group (1-6C) as defined herein. Examples of aryl-(1-6C)alkyl groups include benzyl, phenylethyl, and the like.

[0056] In this specification, several compound words are also used to describe groups containing two or more functional groups. These terms will be understood by those skilled in the art. For example, heterocyclyl(m-nC)alkyl includes (m-nC)alkyl substituted with heterocyclyl.

[0057] The term "optionally substituted" means a substituted group, structure, or molecule, as well as an unsubstituted group, structure, or molecule. "R 1 One / any CH, CH2, CH3 group or heteroatom (i.e., NH) within the group may be optionally substituted" preferably means that one (any) hydrogen group of the R 1 group is substituted with a group as defined by the relevant regulations.

[0058] When an optional substituent is selected from "one or more" groups, this definition should be understood to include that all substituents are selected from one specified group or that the substituents are selected from two or more specified groups.

[0059] The phrase "the compounds of the present invention" means the compounds generally and specifically disclosed herein.

[0060] The compounds of the present invention In a first aspect, the present invention relates to a compound having the following structural formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof: [Chemical formula] Wherein, R1 is (i) -NR 1A R 1B ; (wherein R 1A and R 1B are each independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl; or, or, R 1A and R 1B are linked so as to form a heterocyclic ring together with the nitrogen atom to which they are attached; any (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl (including those formed by R 1A and R 1B ), or heterocyclyl(1-2C)alkyl group may be substituted with one or more R x ); (ii) a carbon-bonded heterocyclyl which may be substituted with one or more R x ; (iii) -O-R 1C ; (wherein R 1C are each independently selected from (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, each of which may be substituted with one or more R x ); (iv) (1-6C)alkyl which may be substituted with one or more R x ; (v) A (3 - 6C) cycloalkyl optionally substituted with one or two substituents independently selected from fluoro, (1 - 4C) alkyl, (1 - 4C) haloalkyl, (1 - 4C) alkoxy, (1 - 4C) haloalkoxy, hydroxy, (1 - 4C) hydroxyalkyl, (3 - 6C) cycloalkyl, (3 - 6C) cycloalkyl(1 - 2C) alkyl, aryl, aryl(1 - 2C) alkyl, heteroaryl, heteroaryl(1 - 2C) alkyl, heterocyclyl, or heterocyclyl(1 - 2C) alkyl, provided that any alkyl, (3 - 6C) cycloalkyl, (3 - 6C) cycloalkyl(1 - 2C) alkyl, aryl, aryl(1 - 2C) alkyl, heteroaryl, heteroaryl(1 - 2C) alkyl, heterocyclyl, or heterocyclyl(1 - 2C) alkyl group is substituted with one or more R x and is a (3 - 6C) cycloalkyl optionally substituted with; (vi) A carbon - linked or nitrogen - linked heteroaryl ring optionally substituted with one or two substituents independently selected from fluoro, (1 - 4C) alkyl, (1 - 4C) haloalkyl, (1 - 4C) alkoxy, (1 - 4C) haloalkoxy, hydroxy, or (1 - 4C) hydroxyalkyl selected from; each R x is independently halo, cyano, (1 - 4C) alkyl, (CH2) q1 NR 1D R 1E 、(CH2) q1 OR 1D 、(CH2) q1 C(O)R 1D 、(CH2) q1 C(O)OR 1D 、O(CH2) q1 C(O)R 1D 、(CH2) q1 OC(O)R 1D 、(CH2) q1 C(O)N(R 1E )R 1D 、O(CH2) q1 C(O)N(R 1E )R 1D 、(CH2) q1 N(R1E )C(O)R 1D 、(CH2) q1 S(O) p R 1D (p is 0, 1, or 2), (CH2) q1 SO2N(R 1E )R 1D 、(CH2) q1 N(R 1E )SO2R 1D 、(3 - 6C) cycloalkyl, (3 - 6C) cycloalkyl(1 - 4C) alkyl, aryl, aryl(1 - 4C) alkyl, heteroaryl, heteroaryl(1 - 4C) alkyl, heterocyclyl, heterocyclyl(1 - 4C) alkyl, or spiro - fused (3 - 6C) cycloalkyl or heterocyclyl; q1 is 0, 1, 2, or 3; R 1D is selected from hydrogen, (1 - 4C) alkyl, (3 - 6C) cycloalkyl, (3 - 6C) cycloalkyl(1 - 4C) alkyl, aryl, aryl(1 - 4C) alkyl, heteroaryl, heteroaryl(1 - 4C) alkyl, heterocyclyl, or heterocyclyl(1 - 4C) alkyl; R 1E is selected from hydrogen, (1 - 4C) alkyl, (3 - 6C) cycloalkyl, (3 - 6C) cycloalkyl(1 - 4C) alkyl, aryl, or aryl(1 - 4C) alkyl; or, R 1D and R 1E are linked such that together with one or more atoms to which they are attached they form a 4 - to 10 - membered heterocycle; R x 、R 1D 、and R 1E any (1 - 4C) alkyl, (3 - 6C) cycloalkyl, (3 - 6C) cycloalkyl(1 - 4C) alkyl, aryl, aryl(1 - 4C) alkyl, heteroaryl, heteroaryl(1 - 4C) alkyl, heterocyclyl, heterocyclyl(1 - 4C) alkyl groups present in the substituents, or, R 1D and R 1EThe heterocyclic group formed when it is linked is halo, cyano, hydroxy, oxo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)hydroxyalkyl, (CH2) q2 NR 1F R 1G , (CH2) q2 OR 1F , (CH2) q2 C(O)R 1F , (CH2) q2 C(O)OR 1F , (CH2) q2 OC(O)R 1F , (CH2) q2 C(O)N(R 1G )R 1F , (CH2) q2 N(R 1G )C(O)R 1F , (CH2) q2 S(O) p R 1F (p is 0, 1, or 2), (CH2) q2 SO2N(R 1G )R 1F , (CH2) q2 N(R 1G )SO2R 1F and may be further substituted with; q2 is 0, 1, 2, or 3; R 1F and R 1G are each independently selected from hydrogen or (1-4C)alkyl optionally substituted with halo; X2 is selected from N or CR2; R2 is selected from hydrogen, halo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, or cyano; X3 is selected from N or CR3; R3 is selected from hydrogen, halo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, or cyano; X4 is selected from N or CR4; R4 is selected from hydrogen, halo (e.g., fluoro or chloro), (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, or cyano; X5 is selected from N or C; X6 is selected from N or C; X7 is N, NR 7N , CR7, O, or S; R7 is selected from hydrogen, halo, methyl, or methoxy; R 7N is selected from hydrogen or methyl; X8 is N, NR 8N , CR8, O, or S; R8 is selected from hydrogen, halo, methyl, or methoxy; R 8N is selected from hydrogen or methyl; X9 is selected from N or C, provided that (i) X5 and X6 cannot both be N; (ii) only one of X7 and X8 may be O or S; (iii) among the atoms of the X2, X3, X4, X5, X6, X7, X8, and X9 groups that together with the carbon atom to which R1 is attached form a bicyclic ring, no more than 4 may be heteroatoms.

[0061] In one aspect, the present invention relates to a compound having the following structural formula I-I (a sub-formula of formula I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof:

Chemical formula

[0062] Specific compounds of the invention include, for example, compounds of formula I or I-I, or pharmaceutically acceptable salts, hydrates, and / or solvates thereof, wherein R1, X2, X3, X4, X5, X6, X7, X8, and X9, and any relevant derived groups, each have, unless otherwise specified, any of the meanings defined above or any of the meanings defined in any of paragraphs (1)-(24) below.

[0063] (1) R1 is (i) -NR 1A R 1B ; (wherein R 1A and R 1B are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, or, R 1A and R 1Bare linked together with the nitrogen atom to which they are attached to form a heterocyclic ring; Any (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl(R 1A and R 1B formed by), or the heterocyclyl(1-2C)alkyl group may be substituted with one or more R x ; (ii) Carbon-bonded heterocyclyl which may be substituted with one or more R x ; (iii) -O-R 1C ; (wherein R 1C are each independently selected from (1-6C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl which may be substituted with one or more R x ); (iv) (1-6C) alkyl which may be substituted with one or more R x ; (v) (3-6C) cycloalkyl which may be substituted with one or two substituents independently selected from fluoro, (1-4C) alkyl, (1-4C) haloalkyl, (1-4C) alkoxy, (1-4C) haloalkoxy, hydroxy, (1-4C) hydroxyalkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C)alkyl, aryl, heteroaryl, or heterocyclyl; (vi) Carbon-bonded or nitrogen-bonded monocyclic heteroaryl ring which may be substituted with one or two substituents independently selected from fluoro, (1-3C) alkyl, (1-3C) haloalkyl, (1-3C) alkoxy, (1-3C) haloalkoxy, hydroxy, or (1-3C) hydroxyalkyl selected from, Each R x is independently halo, cyano, (1-4C)alkyl, (CH2) q1 NR 1D R 1E , (CH2) q1 OR 1D , (CH2) q1 C(O)R 1D , O(CH2) q1 C(O)R 1D , (CH2) q1 C(O)OR 1D , (CH2) q1 OC(O)R 1D , (CH2) q1 C(O)N(R 1E )R 1D , O(CH2) q1 C(O)N(R 1E )R 1D , (CH2) q1 N(R 1E )C(O)R 1D , (CH2) q1 S(O) p R 1D (p is 0, 1, or 2), (CH2) q1 SO2N(R 1E )R 1D , (CH2) q1 N(R 1E )SO2R 1D , (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, heterocyclyl(1-4C)alkyl, or spiro-fused(3-6C)cycloalkyl or heterocyclyl; q1 is 0, 1, or 2; R 1D is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, or heterocyclyl(1-4C)alkyl; R 1Eis selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, aryl, or aryl(1-4C)alkyl; or, R 1D and R 1E are linked so as to form, together with one or more atoms to which they are attached, a 4- to 10-membered heterocyclic ring; R x , R 1D , and R 1E Any (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, heterocyclyl(1-4C)alkyl group present in the substituent, or the heterocyclyl group formed when R 1D and R 1E are linked may be further substituted with halo, cyano, hydroxy, oxo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)hydroxyalkyl, (CH2) q2 NR 1F R 1G , (CH2) q2 OR 1F , (CH2) q2 C(O)R 1F , (CH2) q2 C(O)OR 1F , (CH2) q2 OC(O)R 1F , (CH2) q2 C(O)N(R 1G )R 1F , (CH2) q2 N(R 1G )C(O)R 1F , (CH2) q2 S(O) p R 1F (p is 0, 1, or 2), (CH2) q2 SO2N(R 1G )R 1F , (CH2) q2 N(R 1G )SO2R 1F and may be further substituted; q2 is 0, 1, or 2; R 1F and R 1G are each independently selected from hydrogen or (1-4C) alkyl optionally substituted with halo.

[0064] (2) R1 is (i) -NR 1A R 1B ; (wherein R 1A and R 1B are each independently selected from hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl, or R 1A and R 1B are linked so as to form a heterocycle together with the nitrogen atom to which they are attached; any (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl group, or the heteroseryl group formed by R 1A and R 1B may be substituted with one or more R x ); (ii) a carbon-bonded heterocyclyl optionally substituted with one or more R x ; (iii) -O-R 1C ; (wherein R 1C are each selected from (1-6C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, phenyl, or phenyl(1-2C) alkyl, each of which may be optionally substituted with one or more R x ); (iv) (3C) cycloalkyl optionally substituted with one or two substituents independently selected from fluoro, (1-4C) alkyl, (1-2C) fluoroalkyl, methoxy, trifluoromethoxy, hydroxy, hydroxymethyl, or phenyl selected from each R x is independently halo, cyano, (1-4C) alkyl, (CH2) q1 NR 1D R 1E 、(CH2) q1 OR 1D 、(CH2) q1 C(O)R 1D 、O(CH2) q1 C(O)R 1D 、(CH2) q1 C(O)OR 1D 、(CH2) q1 OC(O)R 1D 、(CH2) q1 C(O)N(R 1E )R 1D 、O(CH2) q1 C(O)N(R 1E )R 1D 、(CH2) q1 N(R 1E )C(O)R 1D 、(3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, phenyl, phenyl(1-4C) alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-4C) alkyl, 4-10-membered heterocyclyl, (4-10-membered) heterocyclyl(1-4C) alkyl, or spiro-fused (3-6C) cycloalkyl or 4-6-membered heterocyclyl; q1 is 0, 1, or 2; R 1D is hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, phenyl, phenyl(1-4C) alkyl, heteroaryl, heteroaryl(1-4C) alkyl, heterocyclyl, or heterocyclyl(1-4C) alkyl; R 1Eis selected from hydrogen or (1-4C) alkyl; or, R 1D and R 1E are linked together with one or more atoms to which they are attached to form a 4- to 10-membered heterocyclic ring; R x , R 1D , and R 1E any (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C)alkyl, phenyl, phenyl(1-4C)alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-4C)alkyl, 4- to 10-membered heterocyclyl, (4- to 10-membered) heterocyclyl(1-4C)alkyl group present in the substituent, or, R 1D and R 1E when linked, the heterocyclyl group formed is halo, cyano, hydroxy, oxo, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, (CH2) q2 NR 1F R 1G , (CH2) q2 OR 1F , (CH2) q2 C(O)R 1F , (CH2) q2 C(O)OR 1F , (CH2) q2 OC(O)R 1F , (CH2) q2 C(O)N(R 1G )R 1F , (CH2) q2 N(R 1G )C(O)R 1F , (CH2) q2 S(O) p R 1F (p is 0, 1, or 2), (CH2) q2 SO2N(R 1G )R 1F , (CH2) q2 N(R 1G )SO2R 1F may be further substituted with; q2 is 0 or 1; R 1F and R1G is independently selected from hydrogen or (1-2C) alkyl.

[0065] (3) R1 is (i) -NR 1A R 1B ; (wherein one of R 1A and R 1B is hydrogen and the other is selected from (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl; or R 1A and R 1B are linked together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclic system (including 4-, 5-, or 6-membered monocyclic heterocycles, 5- to 9-membered bridged heterocycles, 5- to 10-membered bridged condensed heterocycles, and 5- to 10-membered bridged spirocyclic heterocycles); any (1-4C) alkyl, (3-6C) cycloalkyl, aryl, aryl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl group, or 4- to 10-membered heterosilyl group (including those formed by R 1A and R 1B ) may be substituted with one or more R x ; one or more R x may be substituted); (ii) a carbon-bonded 4- to 10-membered heterosilyl (including 4-, 5-, or 6-membered monocyclic heterocycles, condensed heterocycles, and spirocyclic heterocycles) optionally substituted with one or more R x ; (iii) -O-R 1C ; (wherein R 1C is selected from (1-6C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, phenyl, or phenyl(1-2C) alkyl, each optionally substituted with one or more R x ); (iv) (3C) cycloalkyl optionally substituted with one or two substituents independently selected from fluoro, (1-4C) alkyl, (1-2C) fluoroalkyl, methoxy, trifluoromethoxy, hydroxy, hydroxymethyl, or phenyl selected from each R x is independently halo, cyano, (1-4C) alkyl, (CH2) q1 NR 1D R 1E 、(CH2) q1 OR 1D 、(CH2) q1 C(O)R 1D 、O(CH2) q1 C(O)R 1D 、(CH2) q1 C(O)OR 1D 、(CH2) q1 OC(O)R 1D 、(CH2) q1 C(O)N(R 1E )R 1D 、O(CH2) q1 C(O)N(R 1E )R 1D 、(CH2) q1 N(R 1E )C(O)R 1D 、(3-6C) cycloalkyl(1-4C) alkyl, phenyl, phenyl(1-4C) alkyl, (5- or 6-membered) heteroaryl(1-4C) alkyl, 4-9-membered heterocyclyl, (4-9-membered) heterocyclyl(1-3C) alkyl, or spiro-fused (3-6C) cycloalkyl or 4-6-membered heterocyclyl; q1 is 0 or 1; R 1D is hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, phenyl, phenyl(1-4C) alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-4C) alkyl, 4-9-membered heterocyclyl, or (4-9-membered) heterocyclyl(1-4C) alkyl; R 1E is selected from hydrogen or (1-4C) alkyl; or R 1D and R 1E are linked together with one or more atoms to which they are attached to form a 4- to 10-membered heterocyclic ring; R x 、R 1D 、and R 1E any (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, phenyl, phenyl(1-4C)alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered)heteroaryl(1-4C)alkyl, 4- to 9-membered heterocyclyl, or (4- to 9-membered)heterocyclyl(1-4C)alkyl group present in the substituent, or the heterocyclyl group formed when R 1D and R 1E are linked is further substituted by halo, cyano, hydroxy, oxo, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, NR 1F R 1G 、OR 1F 、C(O)R 1F 、C(O)OR 1F 、OC(O)R 1F 、C(O)N(R 1G )R 1F 、N(R 1G )C(O)R 1F 、or S(O) p R 1F (p is 0, 1, or 2) and may be further substituted; R 1F and R 1G are each independently selected from hydrogen or (1-2C)alkyl.

[0066] (4) R1 is (i) -NR 1A R 1B ; (wherein one of R 1A and R 1B is hydrogen and the other is each independently one or more R xwhich may be replaced by (1-4C)alkyl, aryl(1-2C)alkyl, or heteroaryl(1-2C)alkyl; or, R 1A and R 1B together with the nitrogen atom to which they are attached, each form one or more R x optionally substituted 4-membered, 5-membered, or 6-membered monocyclic heterocycle, 5-10 membered fused heterocycle, 5-10 membered bridged heterocycle, or 5-10 membered spirocyclic heterocycle; (ii) a carbon-bonded 4-10 membered heterocyclyl (including 4-membered, 5-membered, or 6-membered monocyclic heterocycles, fused heterocycles, bridged heterocycles, and spirocyclic heterocycles), optionally substituted with one or more R x ; (iii) (3C)cycloalkyl optionally substituted with one or two substituents independently selected from fluoro, (1-4C)alkyl, (1-2C)fluoroalkyl, methoxy, trifluoromethoxy, hydroxy, hydroxymethyl, or phenyl selected from, each R x is independently halo, cyano, (1-4C)alkyl, (CH2) q1 NR 1D R 1E 、(CH2) q1 OR 1D 、(CH2) q1 C(O)R 1D 、O(CH2) q1 C(O)R 1D 、(CH2) q1 C(O)OR 1D 、(CH2) q1 OC(O)R 1D 、(CH2) q1 C(O)N(R 1E )R 1D 、O(CH2) q1 C(O)N(R 1E )R 1D 、(CH2) q1 N(R 1E )C(O)R 1D, selected from (3 - 6C) cycloalkyl(1 - 3C)alkyl, phenyl, phenyl(1 - 3C)alkyl, (5 - or 6 - membered) heteroaryl(1 - 3C)alkyl, (4 - 6 - membered) heterocyclyl(1 - 3C)alkyl, or spiro - fused (3 - 6C) cycloalkyl or 4 - 6 - membered heterocyclyl; q1 is 0 or 1; R 1D is selected from hydrogen, (1 - 4C) alkyl, (3 - 6C) cycloalkyl, (3 - 6C) cycloalkyl(1 - 4C)alkyl, phenyl, phenyl(1 - 3C)alkyl, 5 - or 6 - membered heteroaryl, (5 - or 6 - membered) heteroaryl(1 - 3C)alkyl, 4 - 9 - membered heterocyclyl, or (4 - 9 - membered) heterocyclyl(1 - 3C)alkyl; R 1E is selected from hydrogen or (1 - 2C) alkyl; or, R 1D and R 1E are linked such that, together with one or more atoms to which they are attached, they form a 4 - 9 - membered heterocycle; R x 、R 1D 、and R 1E Any (1 - 4C) alkyl, (3 - 6C) cycloalkyl, (3 - 6C) cycloalkyl(1 - 4C)alkyl, phenyl, phenyl(1 - 3C)alkyl, 5 - or 6 - membered heteroaryl, (5 - or 6 - membered) heteroaryl(1 - 3C)alkyl, 4 - 9 - membered heterocyclyl, or (4 - 9 - membered) heterocyclyl(1 - 3C)alkyl group present in the substituents, or, the heterocyclyl group formed when R 1D and R 1E are linked may be further substituted with halo, cyano, hydroxy, oxo, (1 - 4C) alkyl, (1 - 4C) haloalkyl, (1 - 4C) hydroxyalkyl, NR 1F R 1G 、OR 1F 、C(O)R 1F 、and C(O)OR 1F (e.g., halo, cyano, hydroxy, or (1 - 4C) alkyl); R 1Fand R 1G is each independently selected from hydrogen or (1-2C) alkyl.

[0067] (5) R1 is (i) -NR 1A R 1B ; (wherein one of R 1A and R 1B is hydrogen and the other is each independently selected from (1-4C) alkyl or phenyl(1-2C) alkyl, which may be substituted with one or more R x ; or R 1A and R 1B are linked together with the nitrogen atom to which they are attached to form a 4-membered, 5-membered, or 6-membered monocyclic heterocycle, 6-10 membered fused heterocycle, 6-10 membered bridged heterocycle, or 6-10 membered spirocyclic heterocycle, each of which may be substituted with one or more R x ; or (ii) a carbon-bonded 4-membered, 5-membered, or 6-membered monocyclic heterocycle, 6-10 membered fused heterocycle, 6-10 membered bridged heterocycle, or 6-10 membered spirocyclic heterocycle, each of which may be substituted with one or more R x ; (iii) (3C) cycloalkyl optionally substituted with one or two substituents independently selected from fluoro, (1-4C) alkyl, (1-2C) fluoroalkyl, methoxy, trifluoromethoxy, hydroxy, hydroxymethyl, or phenyl selected from each R x is independently halo, cyano, (1-4C) alkyl, (CH2) q1 NR 1D R 1E , (CH2) q1 OR 1D , (CH2) q1 C(O)R 1D , O(CH2) q1 C(O)R 1D , (CH2) q1 C(O)OR 1D , (CH2) q1 OC(O)R1D 、 (CH2) q1 C(O)N(R 1E )R 1D 、 O(CH2) q1 C(O)N(R 1E )R 1D 、 or (CH2) q1 N(R 1E )C(O)R 1D selected from; q1 is 0 or 1; R 1D is selected from (1-4C) alkyl, phenyl, phenyl(1-3C)alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered)heteroaryl(1-3C)alkyl, 4-9-membered heterocyclyl, or (4-9-membered)heterocyclyl(1-3C)alkyl; R 1E is selected from hydrogen or (1-2C) alkyl; or, R 1D and R 1E are linked together with one or more atoms to which they are attached to form a 4-8-membered heterocyclic ring; R x 、 R 1D 、 and R 1E any (1-4C) alkyl, phenyl, phenyl(1-3C)alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered)heteroaryl(1-3C)alkyl, 4-9-membered heterocyclyl, or (4-9-membered)heterocyclyl(1-3C)alkyl group present in the substituent, or, R 1D and R 1E the heterocyclyl group formed when they are linked may be further substituted with halo, cyano, hydroxy, oxo, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, NR 1F R 1G 、 OR 1F 、 C(O)R 1F 、 and C(O)OR 1F (e.g., halo, cyano, hydroxy, or (1-4C) alkyl); R 1F and R 1GEach is independently selected from hydrogen or (1-2C) alkyl.

[0068] (6) R1 is (i) -NR 1A R 1B ; (wherein one of R 1A and R 1B is hydrogen, and the other is each independently selected from (1-4C) alkyl or phenyl(1-2C) alkyl, which may be substituted with one or more R x ; or, R 1A and R 1B are linked together with the nitrogen atom to which they are attached to form a 4-membered, 5-membered, or 6-membered monocyclic heterocycle, 7-9 membered fused heterocycle, or 7-9 membered spirocyclic heterocycle, each of which may be substituted with one or more R x ); or, (ii) a carbon-bonded 4-membered, 5-membered, or 6-membered monocyclic heterocycle, 7-9 membered fused heterocycle, or 7-9 membered spirocyclic heterocycle, each of which may be substituted with one or more R x ; (iii) (3C) cycloalkyl, which may be substituted with one or two substituents independently selected from fluoro, (1-4C) alkyl, (1-2C) fluoroalkyl, methoxy, trifluoromethoxy, hydroxy, hydroxymethyl, or phenyl selected from, each R x is independently selected from halo, cyano, (1-4C) alkyl, (CH2) q1 OR 1D , O(CH2) q1 C(O)R 1D , or O(CH2) q1 C(O)N(R 1E )R 1D ; q1 is 0 or 1; R 1Dis selected from (1-4C)alkyl, phenyl, phenyl(1-2C)alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered)heteroaryl(1-2C)alkyl, 4-9-membered heterocyclyl, or (4-9-membered)heterocyclyl(1-2C)alkyl; R 1E is selected from hydrogen or methyl; or, R 1D and R 1E are linked such that together with one or more atoms to which they are attached form a 4-8-membered heterocyclic ring; R x 、R 1D 、and R 1E any (1-4C)alkyl, phenyl, phenyl(1-2C)alkyl, (5- or 6-membered)heteroaryl, (5- or 6-membered)heteroaryl(1-2C)alkyl, (4-9-membered)heterocyclyl, or (4-9-membered)heterocyclyl(1-2C)alkyl group present in the substituent, or, R 1D and R 1E the heterocyclyl group formed when they are linked may be further substituted with halo, cyano, or hydroxy, (1-2C)alkyl, or (1-2C)haloalkyl.

[0069] (7)R1 is -NR 1A R 1B ; R 1A and R 1B one of is hydrogen and the other is each independently selected from (1-4C)alkyl or phenyl(1-2C)alkyl which may be substituted with one or more R x ; or, R 1A and R 1B are linked such that together with the nitrogen atom to which they are attached form a 4- or 5-membered heterocyclic ring system, 7-9-membered fused heterocyclic ring, or 7-9-membered spirocyclic heterocyclic ring, each of which may be substituted with one or more R x ; each R x is independently halo, cyano, (1-2C)alkyl, OR 1D, OC(O)R 1D , or OC(O)N(R 1E )R 1D selected from; R 1D is selected from (1-4C) alkyl, phenyl, phenyl(1-3C)alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered)heteroaryl(1-3C)alkyl, 4-9-membered heterocyclyl, or (4-9-membered)heterocyclyl(1-3C)alkyl; R 1E is selected from hydrogen or methyl; or, R 1D and R 1E are linked together with one or more atoms to which they are attached to form a 4-8 membered heterocyclic ring; R x or R 1D any (1-4C)alkyl, phenyl, phenyl(1-3C)alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered)heteroaryl(1-3C)alkyl, 4-9-membered heterocyclyl, or (4-9-membered)heterocyclyl(1-3C)alkyl group present in the substituent, or, R 1D and R 1E the heterocyclyl group formed when they are linked may be further substituted with halo, cyano, or hydroxy, (1-2C)alkyl, or (1-2C)haloalkyl.

[0070] (8) R1 is -NR 1A R 1B ; R 1A and R 1B are linked together with the nitrogen atom to which they are attached to form a 4- or 5-membered nitrogen-linked heterocyclic ring, 7-9 membered fused heterocyclic ring, or 7-9 membered spirocyclic heterocyclic ring, any of which may be substituted with one or more R x ; each R x is independently halo, (1-2C)alkyl, OR 1D , OC(O)R 1D , or OC(O)N(R 1E )R 1Dselected from; R 1D is selected from (1-4C) alkyl, phenyl(1-2C)alkyl, 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-2C)alkyl, 6-9 membered heterocyclyl, or (6-9 membered) heterocyclyl(1-2C)alkyl; R 1E is hydrogen; or, R 1D and R 1E are linked together with one or more atoms to which they are attached to form a 4-8 membered heterocyclic ring; R x or R 1D any (1-4C) alkyl, phenyl(1-2C)alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-2C)alkyl, 4-9 membered heterocyclyl, or (4-9 membered) heterocyclyl(1-2C)alkyl group present in the substituent, or, R 1D and R 1E the heterocyclyl group formed when they are linked may be further substituted with halo, cyano, or hydroxy, (1-2C) alkyl, or (1-2C) haloalkyl.

[0071] (9) R1 is a group of the following formula:

Chemical formula

[0072] (10) R1 is a group of the following formula: [Chemical formula] In the formula, R x1 and R x2 are independently selected from hydrogen or halo; R x3 and R x4 are independently selected from hydrogen, halo, methyl, or methoxy; or, one of R x3 and R x4 is hydrogen and the other is OR 1D ; R 1D is selected from phenyl(1-2C)alkyl, (5- or 6-membered)heteroaryl(1-2C)alkyl, or (4-6-membered)heterocyclyl(1-2C)alkyl; said phenyl(1-2C)alkyl, (5- or 6-membered)heteroaryl(1-2C)alkyl, or (4-6-membered)heterocyclyl(1-2C)alkyl may each be substituted with one or more halo, cyano, hydroxy, or methyl; Ring A is a spiro-fused 3-6 membered cycloalkyl or heterocyclyl ring which may be substituted with one or more substituents each independently selected from halo, methyl, or methoxy.

[0073] (11) R1 is a group of the following formula: [Chemical formula] In the formula, R x1 and R x2 are independently selected from hydrogen or fluoro; R x3 and R x4 are independently selected from hydrogen, halo, or methyl; or, one of R x3 and R x4 is hydrogen and the other is OR 1D ; R 1Dis (6-membered) heterocyclyl(C1-2)alkyl; said (6-membered) heterocyclyl(C1-2)alkyl may be substituted with one or more halo, cyano, or methyl; Ring A is a spiro-fused 3- to 5-membered cycloalkyl or heterocyclyl ring, which may be substituted with one or more substituents each independently selected from halo or methyl.

[0074] (12) R1 is a group of the following formula: [Chemical formula] In the formula, R x1 and R x2 are both hydrogen or both fluoro; R x3 and R x4 are each independently selected from hydrogen, halo, or methyl; or, one of R x3 and R x4 is hydrogen and the other is OR 1D ; R 1D is (6-membered) heterocyclyl(C1-2)alkyl; said (6-membered) heterocyclyl(C1-2)alkyl may be substituted with one or more halo, cyano, or methyl.

[0075] (13) R1 is [Chemical formula] [Chemical formula] [Chemical formula] selected from

[0076] (14) R1 is [Chemical formula] [Chemical formula] [Chemical formula] selected from the following.

[0077] (15) X2 is selected from N or CR2; R2 is selected from hydrogen, halo, methyl, methoxy, halomethyl, halomethoxy, or cyano; X3 is selected from N or CR3; R3 is selected from hydrogen, halo, methyl, methoxy, halomethyl, halomethoxy, or cyano; X4 is selected from N or CR4; R4 is selected from hydrogen, halo, (1-2C) alkyl, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, or cyano; X5 is selected from N or C; X6 is selected from N or C; X7 is selected from N, NR 7N , CR7, O, or S; R7 is selected from hydrogen, halo, methyl, or methoxy; R 7N is selected from hydrogen or methyl; X8 is selected from N, NR 8N , CR8, O, or S; R8 is selected from hydrogen or halo; R 8N is selected from hydrogen or methyl; X9 is selected from N or C, provided that (i) X5 and X6 cannot both be N; (ii) Only one of X7 and X8 can be O or S; (iii) Among the atoms in the X2, X3, X4, X5, X6, X7, X8, and X9 groups that together with the carbon atom bonded to R1 form a bicyclic ring, no more than 4 atoms can be heteroatoms.

[0078] (15a) X2 is selected from N or CR2; R2 is selected from hydrogen or cyano; X3 is selected from N or CR3; R3 is selected from hydrogen, halo, or cyano; X4 is selected from N or CR4; R4 is selected from hydrogen, fluoro, chloro, iodo, methyl, methoxy, fluoromethyl (e.g., CH2F, CHF2, or CF3), or cyano; X5 is C; X6 is selected from N or C; X7 is selected from N, CR7, or S; R7 is selected from hydrogen, halo, or methyl; X8 is selected from N, NR 8N , CR8, O, or S; R8 is selected from hydrogen or halo; R 8N is hydrogen or methyl; X9 is selected from N or C, provided that (i) X5 and X6 cannot both be N; (ii) only one of X7 and X8 may be O or S; (iii) among the atoms in the X2, X3, X4, X6, X7, X8, and X9 groups that together with the carbon atom to which R1 is attached form a bicyclic ring, four or fewer may be heteroatoms.

[0079] (16) X2 is selected from N or CR2; R2 is selected from hydrogen or cyano; X3 is selected from N or CR3; R3 is selected from hydrogen, halo, or cyano; X4 is selected from N or CR4; R4 is selected from hydrogen, fluoro, chloro, methyl, methoxy, fluoromethyl (e.g., CH2F, CHF2, or CF3), or cyano; X5 is C; X6 is selected from N or C; X7 is selected from N, CR7, or S; R7 is selected from hydrogen, halo, or methyl; X8 is selected from N, NR 8N , CR8, O, or S; R8 is selected from hydrogen or halo; R 8N is hydrogen or methyl; X9 is selected from N or C, provided that (i) X5 and X6 cannot both be N; (ii) only one of X7 and X8 may be O or S; (iii) among the atoms of the X2, X3, X4, X6, X7, X8, and X9 groups that together with the carbon atom to which R1 is attached form a bicyclic ring, four or fewer may be heteroatoms.

[0080] (16a) X2 is selected from N or CR2; R2 is selected from hydrogen or cyano; X3 is selected from N or CR3; R3 is selected from hydrogen, halo, or cyano; X4 is selected from N or CR4; R4 is selected from hydrogen, fluoro, chloro, iodo, methyl, or fluoromethyl (e.g., CH2F, CHF2, or CF3); X5 is C; X6 is C or N; X7 is N or CR7, and R7 is hydrogen; X8 is selected from N, CR8, or S; R8 is hydrogen; X9 is selected from N or C, provided that (i) X5 and X6 cannot both be N; (ii) only one of X7 and X8 may be O or S; (iii) among the atoms of the X2, X3, X4, X6, X8, and X9 groups that together with the carbon atom to which R1 is attached form a bicyclic ring, four or fewer may be heteroatoms.

[0081] (17) X2 is selected from N or CR2; R2 is selected from hydrogen or cyano; X3 is selected from N or CR3; R3 is selected from hydrogen, halo, or cyano; X4 is selected from N or CR4; R4 is selected from hydrogen, fluoro, chloro, methyl, or fluoromethyl (e.g., CH2F, CHF2, or CF3); X5 is C; X6 is C or N; X7 is N or CR7, and R7 is hydrogen; X8 is selected from N, CR8, or S; R8 is hydrogen; X9 is selected from N or C, provided that, (i) X5 and X6 cannot both be N; (ii) Only one of X7 and X8 may be O or S; (iii) Among the atoms of the X2, X3, X4, X6, X8, and X9 groups that together with the carbon atom bonded to R1 form a bicyclic ring, no more than 4 may be heteroatoms.

[0082] (17a) X2 is selected from CR2 or N; R2 is selected from hydrogen or cyano; X3 is selected from N or CR3; R3 is selected from hydrogen, halo, or cyano; X4 is selected from N or CR4; R4 is selected from hydrogen, fluoro, chloro, iodo (e.g., hydrogen or fluoro), methyl, or fluoromethyl (e.g., CH2F, CHF2, or CF3); X5 is C; X6 is N or C; X7 is CR7; R7 is hydrogen; X8 is N; X9 is selected from N or C, provided that, i) One of X2 and X3 is N and the other is optionally CR2 or CR3; ii) One of X6 and X9 is N and the other is C.

[0083] (18) X2 is selected from CR2 or N; R2 is selected from hydrogen or cyano; X3 is selected from N or CR3; R3 is selected from hydrogen, halo, or cyano; X4 is selected from N or CR4; R4 is selected from hydrogen, fluoro, chloro (e.g., hydrogen or fluoro), methyl, or fluoromethyl (e.g., CH2F, CHF2, or CF3); X5 is C; X6 is N or C; X7 is CR7; R7 is hydrogen; X8 is N; X9 is selected from N or C, provided that, i) one of X2 and X3 is N and the other is optionally CR2 or CR3; ii) one of X6 and X9 is N and the other is C.

[0084] (19) X2 is N; X3 is CR3; R3 is selected from hydrogen, halo, or cyano; X4 is selected from N or CR4; R4 is selected from hydrogen, chloro, or fluoro (e.g., hydrogen or fluoro); X5 is C; X6 is C or N; X7 is CR7; R7 is hydrogen; X8 is selected from N, CR8, or S; R8 is hydrogen; X9 is selected from N or C.

[0085] (20) X2 is N; X3 is CR3; R3 is selected from hydrogen, halo, or cyano; X4 is selected from N or CR4; R4 is selected from hydrogen, chloro, or fluoro (e.g., hydrogen or fluoro); X5 is C; X6 is C or N; X7 is CR7; R7 is hydrogen; X8 is N; X9 is selected from N or C.

[0086] (21) X2 is N; X3 is CR3; R3 is hydrogen; X4 is CR4; R4 is selected from hydrogen, chloro, or fluoro; X5 is C; X6 is N; X7 is CR7; R7 is hydrogen; X8 is N; X9 is C.

[0087] (22) X2 is N; X3 is CR3; R3 is hydrogen; X4 is CR4; R4 is hydrogen; X5 is C; X6 is N; X7 is CR7; R7 is hydrogen; X8 is N; X9 is C.

[0088] (23) X2 is N; X3 is CR3; R3 is hydrogen; X4 is CR4; R4 is chloro; X5 is C; X6 is N; X7 is CR7; R7 is hydrogen; X8 is N; X9 is C.

[0089] (24) X2 is N; X3 is CR3; R3 is hydrogen; X4 is CR4; R4 is fluoro; X5 is C; X6 is N; X7 is CR7; R7 is hydrogen; X8 is N; X9 is C.

[0090] Preferably, the heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl group, or a monocyclic, bicyclic, or bridged heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S.

[0091] Preferably, the heteroaryl is a 5- or 6-membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from N, O, or S.

[0092] Preferably, the heterocyclyl group is a 4-, 5-, 6-, 7-, 8-, or 9-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms selected from N, O, or S. Most preferably, the heterocyclyl group is a 5-, 6-, or 7-membered monocyclic or bicyclic [e.g., morpholinyl (e.g., 4-morpholinyl), pyridinyl, piperazinyl, homopiperazinyl, or pyrrolidinonyl] containing 1, 2, or 3 heteroatoms selected from N, O, or S.

[0093] Preferably, the aryl group is phenyl.

[0094] Preferably, R1 is as defined in any one of paragraphs (1) to (14) above. Most preferably, R1 is as defined in paragraph (8) or (9) above.

[0095] Preferably, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in any one of paragraphs (15) to (18), or (19) to (21) above. More preferably, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in any one of paragraphs (17), (17a), (18), or (19) above. Most preferably, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (19) above.

[0096] Preferably, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in any one of paragraphs (15) to (21) above. More preferably, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in any one of paragraphs (18) to (21) above. Even more preferably, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (19), (20), or (21) above.

[0097] Preferably, R2 is as defined in any one of paragraphs (15) to (18) above. Most preferably, R2 is as defined in paragraph (18) above.

[0098] Preferably, R3 is as defined in any one of paragraphs (15) to (21) above. Most preferably, R3 is as defined in paragraph (21) above.

[0099] Preferably, R4 is as defined in any one of paragraphs (15) to (21) above. Preferably, R4 is as defined in any one of paragraphs (15a) to (21) above. More preferably, R4 is as defined in any one of paragraphs (18) to (21) above. Most preferably, R4 is as defined in paragraph (21) above.

[0100] Preferably, R4 is as defined in any one of paragraphs (15) to (24) above. Preferably, R4 is as defined in any one of paragraphs (15a) to (24) above. More preferably, R4 is as defined in any one of paragraphs (18) to (24) above. Most preferably, R4 is as defined in paragraph (21) above.

[0101] Preferably, R4 is as defined in any one of paragraphs (22), (23), or (24) above.

[0102] Preferably, R7 is as defined in any one of paragraphs (15) to (21) above. Most preferably, R7 is as defined in paragraph (21) above.

[0103] Preferably, R8 is as defined in any one of paragraphs (15)-(19) above. Most preferably, R8 is as defined in paragraph (19) above.

[0104] In certain groups of the compounds of formula I above, R1 is as defined in any one of paragraphs (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), or (14) above, and X2, X3, X4, X5, X6, X7, X8, and X9 each represent any one of the definitions herein.

[0105] In certain groups of the compounds of formula I above, R1 is as defined in paragraph (1) above, and X2, X3, X4, X5, X6, X7, X8, and X9 each represent any one of the definitions herein.

[0106] In certain groups of the compounds of formula I above, R1 is as defined in paragraph (2) above, and X2, X3, X4, X5, X6, X7, X8, and X9 each represent any one of the definitions herein.

[0107] In certain groups of the compounds of formula I above, R1 is as defined in paragraph (3) above, and X2, X3, X4, X5, X6, X7, X8, and X9 each represent any one of the definitions herein.

[0108] In certain groups of the compounds of formula I above, R1 is as defined in paragraph (4) above, and X2, X3, X4, X5, X6, X7, X8, and X9 each represent any one of the definitions herein.

[0109] In certain groups of the compounds of formula I above, R1 is as defined in paragraph (5) above, and X2, X3, X4, X5, X6, X7, X8, and X9 each represent any one of the definitions herein.

[0110] In certain groups of the compounds of formula I above, R1 is as defined in paragraph (6) above, and X2, X3, X4, X5, X6, X7, X8, and X9 each represent any one of the definitions herein.

[0111] In a particular group of compounds of formula I above, R1 is as defined in paragraph (7) above, and X2, X3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0112] In a particular group of compounds of formula I above, R1 is as defined in paragraph (8) above, and X2, X3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0113] In a particular group of compounds of formula I above, R1 is as defined in paragraph (9) above, and X2, X3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0114] In a particular group of compounds of formula I above, R1 is as defined in paragraph (10) above, and X2, X3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0115] In a particular group of compounds of formula I above, R1 is as defined in paragraph (11) above, and X2, X3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0116] In a particular group of compounds of formula I above, R1 is as defined in paragraph (12) above, and X2, X3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0117] In a particular group of compounds of formula I above, R1 is as defined in paragraph (13) above, and X2, X3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0118] In a particular group of compounds of formula I above, R1 is as defined in paragraph (14) above, and X2, X3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0119] In certain groups of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in any one of paragraphs (15)-(18) or (19)-(21) above, and R1 represents any one of the definitions herein.

[0120] In certain groups of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (15) above, and R1 represents any one of the definitions herein.

[0121] In certain groups of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (16) above, and R1 represents any one of the definitions herein.

[0122] In certain groups of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (17) above, and R1 represents any one of the definitions herein.

[0123] In certain groups of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (15a) above, and R1 represents any one of the definitions herein.

[0124] In certain groups of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (16a) above, and R1 represents any one of the definitions herein.

[0125] In certain groups of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (17a) above, and R1 represents any one of the definitions herein.

[0126] In a particular group of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (18) above, and R1 represents any one of the definitions herein.

[0127] In a particular group of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (19) above, and R1 represents any one of the definitions herein.

[0128] In a particular group of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (20) above, and R1 represents any one of the definitions herein.

[0129] In a particular group of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (21) above, and R1 represents any one of the definitions herein.

[0130] In a particular group of the compounds of formula I, R1 is as defined in any one of paragraphs (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) above, and X2, X3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0131] In a particular group of the compounds of formula I-I, R1 is as defined in paragraph (1) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0132] In a particular group of the compounds of formula I-I, R1 is as defined in paragraph (2) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0133] In a specific group of the compounds of formula I-I, R1 is as defined in paragraph (3) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0134] In a specific group of the compounds of formula I-I, R1 is as defined in paragraph (4) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0135] In a specific group of the compounds of formula I-I, R1 is as defined in paragraph (5) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0136] In a specific group of the compounds of formula I-I, R1 is as defined in paragraph (6) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0137] In a specific group of the compounds of formula I-I, R1 is as defined in paragraph (7) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0138] In a specific group of the compounds of formula I-I, R1 is as defined in paragraph (8) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0139] In a specific group of the compounds of formula I-I, R1 is as defined in paragraph (9) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0140] In a specific group of the compounds of formula I-I, R1 is as defined in paragraph (10) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0141] In a specific group of the compounds of formula I-I, R1 is as defined in paragraph (11) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0142] In a specific group of the compounds of formula I-I, R1 is as defined in paragraph (12) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0143] In a specific group of the compounds of formula I-I, R1 is as defined in paragraph (13) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0144] In a specific group of the compounds of formula I-I, R1 is as defined in paragraph (14) above, and X2, R3, X4, X5, X6, X7, X8, and X9 represent any one of the definitions herein.

[0145] In a specific group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in any one of paragraphs (15)-(18) or (19)-(21) above, and R1 represents any one of the definitions herein.

[0146] In a specific group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (15) above, and R1 represents any one of the definitions herein.

[0147] In a specific group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (16) above, and R1 represents any one of the definitions herein.

[0148] In a specific group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (17) above, and R1 represents any one of the definitions herein.

[0149] In a particular group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (15a) above, and R1 represents any one of the definitions herein.

[0150] In a particular group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (16a) above, and R1 represents any one of the definitions herein.

[0151] In a particular group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (17a) above, and R1 represents any one of the definitions herein.

[0152] In a particular group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (18) above, and R1 represents any one of the definitions herein.

[0153] In a particular group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (19) above, and R1 represents any one of the definitions herein.

[0154] In a particular group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (20) above, and R1 represents any one of the definitions herein.

[0155] In a particular group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in paragraph (21) above, and R1 represents any one of the definitions herein.

[0156] In a specific group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in the above paragraph (22), and R1 represents any one of the definitions herein.

[0157] In a specific group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in the above paragraph (23), and R1 represents any one of the definitions herein.

[0158] In a specific group of the compounds of formula I-I, X2, R3, X4, X5, X6, X7, X8, and X9 are as defined in the above paragraph (24), and R1 represents any one of the definitions herein.

[0159] In a specific group of the compounds of the present invention, the compound, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, has the following structural formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip [sub-definitions of formula (I)]:

Chemical formula

[0160] In a specific group of the compounds of the above formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in the above paragraph (1), and R2, R3, and R4 represent any one of the definitions herein.

[0161] In a specific group of the compounds of the above formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in the above paragraph (2), and R2, R3, and R4 represent any one of the definitions herein.

[0162] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in paragraph (3) above, and R2, R3, and R4 represent any one of the definitions in this specification.

[0163] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in paragraph (4) above, and R2, R3, and R4 represent any one of the definitions in this specification.

[0164] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in paragraph (5) above, and R2, R3, and R4 represent any one of the definitions in this specification.

[0165] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in paragraph (6) above, and R2, R3, and R4 represent any one of the definitions in this specification.

[0166] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in paragraph (7) above, and R2, R3, and R4 represent any one of the definitions in this specification.

[0167] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in paragraph (8) above, and R2, R3, and R4 represent any one of the definitions in this specification.

[0168] In a specific group of the compounds of the above formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in the above paragraph (9), and R2, R3, and R4 each represent any one of the definitions in this specification.

[0169] In a specific group of the compounds of the above formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in the above paragraph (10), and R2, R3, and R4 each represent any one of the definitions in this specification.

[0170] In a specific group of the compounds of the above formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in the above paragraph (11), and R2, R3, and R4 each represent any one of the definitions in this specification.

[0171] In a specific group of the compounds of the above formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in the above paragraph (12), and R2, R3, and R4 each represent any one of the definitions in this specification.

[0172] In a specific group of the compounds of the above formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in the above paragraph (13), and R2, R3, and R4 each represent any one of the definitions in this specification.

[0173] In a specific group of the compounds of the above formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in the above paragraph (14), and R2, R3, and R4 each represent any one of the definitions in this specification.

[0174] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are as defined in any one of paragraphs (15) to (18) or (19) to (21) above, and R1 represents any one of the definitions herein.

[0175] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are as defined in paragraph (15) above, and R1 represents any one of the definitions herein.

[0176] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are as defined in paragraph (16) above, and R1 represents any one of the definitions herein.

[0177] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are as defined in paragraph (17) above, and R1 represents any one of the definitions herein.

[0178] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are as defined in paragraph (15a) above, and R1 represents any one of the definitions herein.

[0179] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are as defined in paragraph (16a) above, and R1 represents any one of the definitions herein.

[0180] In certain groups of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are as defined in paragraph (17a) above, and R1 represents any one of the definitions herein.

[0181] In certain groups of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are as defined in paragraph (18) above, and R1 represents any one of the definitions herein.

[0182] In certain groups of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are each independently as defined in paragraph (19) above, and R1 represents any one of the definitions herein.

[0183] In certain groups of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are each independently as defined in paragraph (20) above, and R1 represents any one of the definitions herein.

[0184] In certain groups of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are each independently as defined in paragraph (21) above, and R1 represents any one of the definitions herein.

[0185] In certain groups of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are each independently as defined in paragraph (22) above, and R1 represents any one of the definitions herein.

[0186] In a particular group of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are each independently as defined in paragraph (23) above, and R1 represents any one of the definitions herein.

[0187] In a particular group of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R2, R3, and R4 are each independently as defined in paragraph (24) above, and R1 represents any one of the definitions herein.

[0188] In a particular group of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in any one of paragraphs (1) to (14); R2, R3, and R4 are each independently as defined in any one of paragraphs (15) to (21) above.

[0189] In a particular group of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in any one of paragraphs (7) to (14); R2, R3, and R4 are each independently as defined in any one of paragraphs (18) to (21) above.

[0190] In a particular group of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in any one of paragraphs (9) to (14) above; R2, R3, and R4 are each independently as defined in any one of paragraphs (18) to (21) above.

[0191] In a particular group of compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in any one of paragraphs (12), (13), or (14); R2, R3, and R4 are each independently as defined in any one of paragraphs (19) to (21) above.

[0192] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in any one of paragraphs (12), (13), or (14); R2, R3, and R4 are each independently as defined in any one of paragraphs (19) to (21) above.

[0193] In a specific group of the compounds of the present invention, the compound has the structural formula Ia [sub - definition of formula (I)] as defined herein.

[0194] In a specific group of the compounds of the present invention, the compound has the structural formula Ib [sub - definition of formula (I)] as defined herein.

[0195] In a specific group of the compounds of the present invention, the compound has the structural formula Ic [sub - definition of formula (I)] as defined herein.

[0196] In a specific group of the compounds of the present invention, the compound has the structural formula Id [sub - definition of formula (I)] as defined herein.

[0197] In a specific group of the compounds of the present invention, the compound has the structural formula Ie [sub - definition of formula (I)] as defined herein.

[0198] In a specific group of the compounds of the present invention, the compound has the structural formula If [sub - definition of formula (I)] as defined herein.

[0199] In a specific group of the compounds of the present invention, the compound has the structural formula Ig [sub - definition of formula (I)] as defined herein.

[0200] In certain groups of the compounds of the present invention, the compound has the structural formula Ih [sub - definition of formula (I)] as defined herein.

[0201] In certain groups of the compounds of the present invention, the compound has the structural formula Ij [sub - definition of formula (I)] as defined herein.

[0202] In certain groups of the compounds of the present invention, the compound has the structural formula Ik [sub - definition of formula (I)] as defined herein.

[0203] In certain groups of the compounds of the present invention, the compound has the structural formula Im [sub - definition of formula (I)] as defined herein.

[0204] In certain groups of the compounds of the present invention, the compound has the structural formula In [sub - definition of formula (I)] as defined herein.

[0205] In certain groups of the compounds of the present invention, the compound has the structural formula Io [sub - definition of formula (I)] as defined herein.

[0206] In certain groups of the compounds of the present invention, the compound has the structural formula Ip [sub - definition of formula (I)] as defined herein.

[0207] In certain groups of the compounds of the present invention, the compound, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, has the following structural formula Ia [sub - definition of formula (I)]:

Chemical formula

[0208] In certain groups of the compounds of formula Ia above, R1 is as defined in paragraph (1) above, and R3 represents any one of the definitions herein.

[0209] In certain groups of the compounds of formula Ia above, R1 is as defined in paragraph (2) above, and R3 represents any one of the definitions herein.

[0210] In a specific group of the compounds of formula Ia, R1 is as defined in paragraph (3) above, and R3 represents any one of the definitions herein.

[0211] In a specific group of the compounds of formula Ia, R1 is as defined in paragraph (4) above, and R3 represents any one of the definitions herein.

[0212] In a specific group of the compounds of formula Ia, R1 is as defined in paragraph (5) above, and R3 represents any one of the definitions herein.

[0213] In a specific group of the compounds of formula Ia, R1 is as defined in paragraph (6) above, and R3 represents any one of the definitions herein.

[0214] In a specific group of the compounds of formula Ia, R1 is as defined in paragraph (7) above, and R3 represents any one of the definitions herein.

[0215] In a specific group of the compounds of formula Ia, R1 is as defined in paragraph (8) above, and R3 represents any one of the definitions herein.

[0216] In a specific group of the compounds of formula Ia, R1 is as defined in paragraph (9) above, and R3 represents any one of the definitions herein.

[0217] In a specific group of the compounds of formula Ia, R1 is as defined in paragraph (10) above, and R3 represents any one of the definitions herein.

[0218] In a specific group of the compounds of formula Ia, R1 is as defined in paragraph (11) above, and R3 represents any one of the definitions herein.

[0219] In a specific group of the compounds of formula Ia, R1 is as defined in paragraph (12) above, and R3 represents any one of the definitions herein.

[0220] In a particular group of the compounds of formula Ia, R1 is as defined in paragraph (13) above, and R3 represents any one of the definitions herein.

[0221] In a particular group of the compounds of formula Ia, R1 is as defined in paragraph (14) above, and R3 represents any one of the definitions herein.

[0222] In a particular group of the compounds of formula Ia, R3 is as defined in any one of paragraphs (15)-(18) or (19)-(21) above, and R1 represents any one of the definitions herein.

[0223] In a particular group of the compounds of formula Ia, R3 is as defined in paragraph (15) above, and R1 represents any one of the definitions herein.

[0224] In a particular group of the compounds of formula Ia, R3 is as defined in paragraph (16) above, and R1 represents any one of the definitions herein.

[0225] In a particular group of the compounds of formula Ia, R3 is as defined in paragraph (17) above, and R1 represents any one of the definitions herein.

[0226] In a particular group of the compounds of formula Ia, R3 is as defined in paragraph (15a) above, and R1 represents any one of the definitions herein.

[0227] In a particular group of the compounds of formula Ia, R3 is as defined in paragraph (16a) above, and R1 represents any one of the definitions herein.

[0228] In a particular group of the compounds of formula Ia, R3 is as defined in paragraph (17a) above, and R1 represents any one of the definitions herein.

[0229] In a specific group of the compounds of formula Ia, R3 is as defined in paragraph (18) above, and R1 represents any one of the definitions herein.

[0230] In a specific group of the compounds of formula Ia, R3 is as defined in paragraph (19) above, and R1 represents any one of the definitions herein.

[0231] In a specific group of the compounds of formula Ia, R3 is as defined in paragraph (20) above, and R1 represents any one of the definitions herein.

[0232] In a specific group of the compounds of formula Ia, R3 is as defined in paragraph (21) above, and R1 represents any one of the definitions herein.

[0233] In a specific group of the compounds of formula Ia, R3 is hydrogen, and R1 represents any one of the definitions herein.

[0234] In a specific group of the compounds of formula Ia, R1 is as defined in any one of paragraphs (1) to (14); R3 is as defined in any one of paragraphs (15) to (21) above.

[0235] In a specific group of the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, Im, In, Io, or Ip, R1 is as defined in any one of paragraphs (7) to (14); R3 is as defined in any one of paragraphs (18) to (21) above.

[0236] In a specific group of the compounds of formula Ia, R1 is as defined in any one of paragraphs (9) to (14); R3 is as defined in any one of paragraphs (18) to (21) above.

[0237] In a specific group of the compounds of formula Ia, R1 is as defined in any one of paragraphs (12), (13), or (14); R3 is as defined in any one of paragraphs (19) to (21) above.

[0238] In a specific group of the compounds of the present invention, the compound, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, has the following structural formula Ik [sub-definition of formula (I)]:

Chemical formula

[0239] In a specific group of the compounds of formula Ik above, R1 is as defined in paragraph (1) above, and R3 and R4 represent any one of the definitions herein.

[0240] In a specific group of the compounds of formula Ik above, R1 is as defined in paragraph (2) above, and R3 and R4 represent any one of the definitions herein.

[0241] In a specific group of the compounds of formula Ik above, R1 is as defined in paragraph (3) above, and R3 and R4 represent any one of the definitions herein.

[0242] In a specific group of the compounds of formula Ik above, R1 is as defined in paragraph (4) above, and R3 and R4 represent any one of the definitions herein.

[0243] In a specific group of the compounds of formula Ik above, R1 is as defined in paragraph (5) above, and R3 and R4 represent any one of the definitions herein.

[0244] In a specific group of the compounds of formula Ik above, R1 is as defined in paragraph (6) above, and R3 and R4 represent any one of the definitions herein.

[0245] In a specific group of the compounds of formula Ik, R1 is as defined in paragraph (7) above, and R3 and R4 represent any one of the definitions herein.

[0246] In a specific group of the compounds of formula Ik, R1 is as defined in paragraph (8) above, and R3 and R4 represent any one of the definitions herein.

[0247] In a specific group of the compounds of formula Ik, R1 is as defined in paragraph (9) above, and R3 and R4 represent any one of the definitions herein.

[0248] In a specific group of the compounds of formula Ik, R1 is as defined in paragraph (10) above, and R3 and R4 represent any one of the definitions herein.

[0249] In a specific group of the compounds of formula Ik, R1 is as defined in paragraph (11) above, and R3 and R4 represent any one of the definitions herein.

[0250] In a specific group of the compounds of formula Ik, R1 is as defined in paragraph (12) above, and R3 and R4 represent any one of the definitions herein.

[0251] In a specific group of the compounds of formula Ik, R1 is as defined in paragraph (13) above, and R3 and R4 represent any one of the definitions herein.

[0252] In a specific group of the compounds of formula Ik, R1 is as defined in paragraph (14) above, and R3 and R4 represent any one of the definitions herein.

[0253] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in any one of paragraphs (15) to (18) or (19) to (21) above, and R1 represents any one of the definitions herein.

[0254] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in any one of paragraphs (22)-(24) above, and R1 represents any one of the definitions herein.

[0255] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (15) above, and R1 represents any one of the definitions herein.

[0256] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (16) above, and R1 represents any one of the definitions herein.

[0257] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (17) above, and R1 represents any one of the definitions herein.

[0258] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (15a) above, and R1 represents any one of the definitions herein.

[0259] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (16a) above, and R1 represents any one of the definitions herein.

[0260] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (17a) above, and R1 represents any one of the definitions herein.

[0261] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (18) above, and R1 represents any one of the definitions herein.

[0262] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (19) above, and R1 represents any one of the definitions herein.

[0263] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (20) above, and R1 represents any one of the definitions herein.

[0264] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (21) above, and R1 represents any one of the definitions herein.

[0265] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (22) above, and R1 represents any one of the definitions herein.

[0266] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (23) above, and R1 represents any one of the definitions herein.

[0267] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (24) above, and R1 represents any one of the definitions herein.

[0268] In a specific group of the compounds of formula Ik, R3 is hydrogen, R4 is as defined in any one of paragraphs (15) to (20) above, and R1 represents any one of the definitions herein.

[0269] In a specific group of the compounds of formula Ik, R3 is hydrogen, R4 is as defined in paragraph (15) above, and R1 represents any one of the definitions herein.

[0270] In a specific group of the compounds of formula Ik, R3 is hydrogen, R4 is as defined in paragraph (16) above, and R1 represents any one of the definitions herein.

[0271] In a specific group of the compounds of formula Ik, R3 is hydrogen, R4 is as defined in paragraph (17) above, and R1 represents any one of the definitions herein.

[0272] In a specific group of the compounds of formula Ik, R3 is hydrogen, R4 is as defined in paragraph (15a) above, and R1 represents any one of the definitions herein.

[0273] In a specific group of the compounds of formula Ik, R3 is hydrogen, R4 is as defined in paragraph (16a) above, and R1 represents any one of the definitions herein.

[0274] In a specific group of the compounds of formula Ik, R3 is hydrogen, R4 is as defined in paragraph (17a) above, and R1 represents any one of the definitions herein.

[0275] In a specific group of the compounds of formula Ik, R3 is hydrogen, R4 is as defined in paragraph (18) above, and R1 represents any one of the definitions herein.

[0276] In a specific group of the compounds of formula Ik, R3 is hydrogen, R4 is as defined in paragraph (19) above, and R1 represents any one of the definitions herein.

[0277] In a specific group of the compounds of formula Ik, R3 is hydrogen, R4 is as defined in paragraph (20) above, and R1 represents any one of the definitions herein.

[0278] In a specific group of the compounds of formula Ik, R3 is hydrogen, R4 is as defined in paragraph (21) above, and R1 represents any one of the definitions herein.

[0279] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (22) above, and R1 represents any one of the definitions herein.

[0280] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (23) above, and R1 represents any one of the definitions herein.

[0281] In a specific group of the compounds of formula Ik, R3 and R4 are as defined in paragraph (24) above, and R1 represents any one of the definitions herein.

[0282] In a specific group of the compounds of formula Ik, R1 is as defined in any one of paragraphs (1) to (14); R3 is as defined in any one of paragraphs (15) to (21) above; R4 is as defined in any one of paragraphs (15) to (21) above.

[0283] In a specific group of the compounds of formula Ik, R1 is as defined in any one of paragraphs (7) to (14); R3 is as defined in any one of paragraphs (18) to (21) above; R4 is as defined in any one of paragraphs (18) to (21) above.

[0284] In a specific group of the compounds of formula Ik, R1 is as defined in any one of paragraphs (9) to (14) above; R3 is as defined in any one of paragraphs (18) to (21) above; R4 is as defined in any one of paragraphs (18) to (21) above.

[0285] In a specific group of the compounds of formula Ik, R1 is as defined in any one of paragraphs (12), (13), or (14); R3 is hydrogen; R4 is as defined in any one of paragraphs (19) to (21) above.

[0286] In a specific group of the compounds of the present invention, the compound, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, has the following structural formula Im [sub - definition of formula (I)]:

Chemical formula

[0287] In a specific group of the compounds of the above formula Im, R1 is as defined in the above paragraph (1), and R3 and R4 represent any one of the definitions in the present specification.

[0288] In a specific group of the compounds of the above formula Im, R1 is as defined in the above paragraph (2), and R3 and R4 represent any one of the definitions in the present specification.

[0289] In a specific group of the compounds of the above formula Im, R1 is as defined in the above paragraph (3), and R3 and R4 represent any one of the definitions in the present specification.

[0290] In a specific group of the compounds of the above formula Im, R1 is as defined in the above paragraph (4), and R3 and R4 represent any one of the definitions in the present specification.

[0291] In a specific group of the compounds of the above formula Im, R1 is as defined in the above paragraph (5), and R3 and R4 represent any one of the definitions in the present specification.

[0292] In a specific group of the compounds of the above formula Im, R1 is as defined in the above paragraph (6), and R3 and R4 represent any one of the definitions in the present specification.

[0293] In a specific group of the compounds of the above formula Im, R1 is as defined in the above paragraph (7), and R3 and R4 represent any one of the definitions in the present specification.

[0294] In a specific group of the compounds of the above formula Im, R1 is as defined in the above paragraph (8), and R3 and R4 represent any one of the definitions in the present specification.

[0295] In a specific group of the compounds of the above formula Im, R1 is as defined in the above paragraph (9), and R3 and R4 represent any one of the definitions in the present specification.

[0296] In a specific group of the compounds of formula Im, R1 is as defined in paragraph (10) above, and R3 and R4 represent any one of the definitions herein.

[0297] In a specific group of the compounds of formula Im, R1 is as defined in paragraph (11) above, and R3 and R4 represent any one of the definitions herein.

[0298] In a specific group of the compounds of formula Im, R1 is as defined in paragraph (12) above, and R3 and R4 represent any one of the definitions herein.

[0299] In a specific group of the compounds of formula Im, R1 is as defined in paragraph (13) above, and R3 and R4 represent any one of the definitions herein.

[0300] In a specific group of the compounds of formula Im, R1 is as defined in paragraph (14) above, and R3 and R4 represent any one of the definitions herein.

[0301] In a specific group of the compounds of formula Im, R3 and R4 are as defined in any one of paragraphs (15) to (18) or (19) to (21) above, and R1 represents any one of the definitions herein.

[0302] In a specific group of the compounds of formula Im, R3 and R4 are as defined in any one of paragraphs (22) to (24) above, and R1 represents any one of the definitions herein.

[0303] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (15) above, and R1 represents any one of the definitions herein.

[0304] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (16) above, and R1 represents any one of the definitions herein.

[0305] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (17) above, and R1 represents any one of the definitions herein.

[0306] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (18) above, and R1 represents any one of the definitions herein.

[0307] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (19) above, and R1 represents any one of the definitions herein.

[0308] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (20) above, and R1 represents any one of the definitions herein.

[0309] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (21) above, and R1 represents any one of the definitions herein.

[0310] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (22) above, and R1 represents any one of the definitions herein.

[0311] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (23) above, and R1 represents any one of the definitions herein.

[0312] In a specific group of the compounds of formula Im, R3 and R4 are as defined in paragraph (24) above, and R1 represents any one of the definitions herein.

[0313] In a specific group of the compounds of formula Im, R3 is hydrogen, R4 is as defined in paragraph (18) above, and R1 represents any one of the definitions herein.

[0314] In a specific group of the compounds of formula Im, R3 is hydrogen, R4 is as defined in paragraph (19) above, and R1 represents any one of the definitions herein.

[0315] In a specific group of the compounds of formula Im, R3 is hydrogen, R4 is as defined in paragraph (20) above, and R1 represents any one of the definitions herein.

[0316] In a specific group of the compounds of formula Im, R3 is hydrogen, R4 is as defined in paragraph (21) above, and R1 represents any one of the definitions herein.

[0317] In a specific group of the compounds of formula Im, R3 is hydrogen, R4 is as defined in paragraph (22) above, and R1 represents any one of the definitions herein.

[0318] In a specific group of the compounds of formula Im, R3 is hydrogen, R4 is as defined in paragraph (23) above, and R1 represents any one of the definitions herein.

[0319] In a specific group of the compounds of formula Im, R3 is hydrogen, R4 is as defined in paragraph (24) above, and R1 represents any one of the definitions herein.

[0320] In a specific group of the compounds of formula Im, R1 is as defined in any one of paragraphs (7) to (14); R3 is as defined in any one of paragraphs (18) to (21); R4 is as defined in any one of paragraphs (18) to (21).

[0321] In a specific group of the compounds of formula Im, R1 is as defined in any one of paragraphs (9) to (14); R3 is as defined in any one of paragraphs (18) to (21); R4 is as defined in any one of the above paragraphs (18) to (21).

[0322] In a specific group of the compounds of the above formula Im, R1 is as defined in any one of paragraphs (12), (13), or (14); R3 is hydrogen; R4 is as defined in any one of the above paragraphs (19) to (21).

[0323] In a specific group of the compounds of the present invention, the compound, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, has the following structural formula II [sub-definition of formula (I)]:

Chemical formula

[0324] In a specific group of the compounds of the above formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in the above paragraph (15), and R x1 , R x2 , R x3 , and R x4 represents any one of the definitions herein.

[0325] In a specific group of the compounds of the above formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in the above paragraph (16), and R x1 , R x2 , R x3 , and R x4 represents any one of the definitions herein.

[0326] In a specific group of the compounds of the above formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in the above paragraph (17), and R x1 , R x2 , R x3, and R x4 represents any one of the definitions in this specification.

[0327] In a specific group of the compounds of formula I above, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in the above paragraph (18), and R x1 , R x2 , R x3 , and R x4 represents any one of the definitions in this specification.

[0328] In a specific group of the compounds of formula I above, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in the above paragraph (19), and R x1 , R x2 , R x3 , and R x4 represents any one of the definitions in this specification.

[0329] In a specific group of the compounds of formula I above, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in the above paragraph (20), and R x1 , R x2 , R x3 , and R x4 represents any one of the definitions in this specification.

[0330] In a specific group of the compounds of formula I above, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in the above paragraph (21), and R x1 , R x2 , R x3 , and R x4 represents any one of the definitions in this specification.

[0331] In a specific group of the compounds of formula I above, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined anywhere in this specification, and R x1 , R x2 , R x3 , and R x4 is as defined in the above paragraph (10).

[0332] In certain groups of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined anywhere in this specification, and R x1 , R x2 , R x3 , and R x4 are as defined in paragraph (11) above.

[0333] In certain groups of the compounds of formula I, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined anywhere in this specification, and R x1 , R x2 , R x3 , and R x4 are as defined in paragraph (12) above.

[0334] Certain compounds of the invention include any of the compounds described in the Examples section of this application, or a pharmaceutically acceptable salt or solvate thereof, particularly 5-[4-[3-(Hydroxymethyl)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-(2-Hydroxyethyl)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Dimethylazetidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione 5-[4-[3-(2-Hydroxyethoxy)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Dimethylpyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 6-[1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-3-carbonitrile; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-(2-Pyridylmethoxy)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3-Benzyloxypyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-[(4-methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[(4-methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[7-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thiazolo[4,5-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)thiazolo[4,5-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]pyrimidine-2,4-diol; 5-[4-[3-[2-(4,4-Difluoro-1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione; 2-(2,4-Dioxo-1H-pyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-b]pyridine-5-carbonitrile; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(4,4-Difluoro-2-azaspiro[4.4]nonan-2-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(3aR,6aS)-3,3a,4,5,6,6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3-Ethyl-3-methyl-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Dimethylpyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Diethylpyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3,4,4-Tetrafluoropyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(3aR,6aR)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-5H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4-methoxy-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)thieno[2,3-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[6-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]-9H-purin-8-yl]-1H-pyrimidine-2,4-dione; 5-[7-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione; 5-[2-Chloro-4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-5H-pyrimidine-2,4-dione; 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(4,4-Difluoro-2-azaspiro[4.4]nonan-2-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(4-Chlorophenyl)methylamino]furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; [3-[[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]amino]-2,2-difluoro-propyl] N-isopropylcarbamate; 5-[4-[3-[2-[4-(Trifluoromethyl)-1-piperidyl]ethoxy]]pyrrolidin-1-yl]furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl]morpholine-4-carboxylate; [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl]8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate; [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl]N-isopropylcarbamate; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-methyl-pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 6-[1-[2-(2,4-Dioxo-1H-pyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]]pyrrolidin(63yrrolidine)-3-yl]oxypyridine-3-carbonitrile; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4-methoxy-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(2-Oxa-7-azaspiro[3.4]octan-7-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4-hydroxy-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-[(4-methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-(2-morpholinoethoxy)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Chloro-4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-7-fluoro-pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-7-methyl-pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4-methoxy-pyrrolidin-1-yl)-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4-hydroxy-pyrrolidin-1-yl)-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Fluoro-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-[(4-methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Chloro-4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Chloro-4-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Chloro-4-(8,8-difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-2-(2,4-dioxo-1H-pyrimidin-5-yl)pyrazolo[4,3-c]pyridine-7-carbonitrile; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[3,4-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[3,4-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-7-iodo-pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Chloro-4-(3,3-difluoro-4-hydroxy-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Chloro-4-(3,3-difluoro-4-methoxy-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Chloro-4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-methyl-pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Chloro-4-(3,3-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; and any one of 5-[4-(3,3-dimethylpyrrolidin-1-yl)-7-fluoro-pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione is included.

[0335] As specific compounds of the present invention, any of the compounds described in the Examples section of this application, or their pharmaceutically acceptable salts or solvates, particularly 5-[4-[3-(Hydroxymethyl)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-(2-Hydroxyethyl)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Dimethylazetidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione 5-[4-[3-(2-Hydroxyethoxy)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Dimethylpyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 6-[1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-3-carbonitrile; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-(2-Pyridylmethoxy)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3-Benzyloxypyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-[(4-methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[(4-Methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[7-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thiazolo[4,5-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)thiazolo[4,5-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]pyrimidine-2,4-diol; 5-[4-[3-[2-(4,4-Difluoro-1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione; 2-(2,4-Dioxo-1H-pyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-b]pyridine-5-carbonitrile; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(4,4-Difluoro-2-azaspiro[4.4]nonan-2-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(3aR,6aS)-3,3a,4,5,6,6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3-Ethyl-3-methyl-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Dimethylpyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Diethylpyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3,4,4-Tetrafluoropyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(3aR,6aR)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-5H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4-methoxy-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)thieno[2,3-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[6-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]-9H-purin-8-yl]-1H-pyrimidine-2,4-dione; 5-[7-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione; 5-[2-chloro-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-5H-pyrimidine-2,4-dione; 5-[4-(8,8-difluoro-6-azaspiro[3.4]octan-6-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(4,4-difluoro-2-azaspiro[4.4]nonan-2-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(4-chlorophenyl)methylamino]furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; [3-[[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]amino]-2,2-difluoro-propyl] N-isopropylcarbamate; 5-[4-[3-[2-[4-(Trifluoromethyl)-1-piperidyl]ethoxy]]pyrrolidin-1-yl]furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] morpholine-4-carboxylate; [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] 8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate; [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] N-isopropylcarbamate; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-methyl-pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 6-[1-[2-(2,4-Dioxo-1H-pyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]] pyrrolidine(68yrrolidine)-3-yl]oxypyridine-3-carbonitrile; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octane-6-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptane-5-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4-methoxy-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(2-Oxa-7-azaspiro[3.4]octan-7-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4-hydroxy-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-[(4-methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-(2-morpholinoethoxy)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Chloro-4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-7-fluoro-pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-7-methyl-pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4-methoxy-pyrrolidin-1-yl)-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4-hydroxy-pyrrolidin-1-yl)-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Fluoro-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-[(4-methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Chloro-4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Chloro-4-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-Chloro-4-(8,8-difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-2-(2,4-dioxo-1H-pyrimidin-5-yl)pyrazolo[4,3-c]pyridine-7-carbonitrile; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[3,4-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione; and Either 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[3,4-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione is included.

[0336] As specific compounds of the present invention, any of the compounds described in the Examples section of this application, or their pharmaceutically acceptable salts or solvates, particularly 5-[4-[3-(Hydroxymethyl)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-(2-Hydroxyethyl)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Dimethylazetidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-(2-Hydroxyethoxy)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Dimethylpyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 6-[1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-3-carbonitrile; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-(2-Pyridylmethoxy)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3-Benzyloxypyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-[(4-methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[(4-methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[7-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thiazolo[4,5-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-furo[2,3-d]pyrimidin-6-yl)-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]pyrimidine-2,4-diol; 5-[4-[3-[2-(4,4-Difluoro-1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione; 2-(2,4-Dioxo-1H-pyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-b]pyridine-5-carbonitrile; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione hydrochloride; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(4,4-Difluoro-2-azaspiro[4.4]nonan-2-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(3aR,6aS)-3,3a,4,5,6,6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3-Ethyl-3-methyl-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Dimethylpyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Diethylpyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3,4,4-Tetrafluoropyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(3aR,6aR)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-5H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4-methoxy-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)thieno[2,3-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[6-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]-9H-purin-8-yl]-1H-pyrimidine-2,4-dione; 5-[7-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-Difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione; 5-[2-Chloro-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-5H-pyrimidine-2,4-dione; 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)furo[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(4,4-Difluoro-2-azaspiro[4.4]nonan-2-yl)furo[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(4-Chlorophenyl)methylamino]furo[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)furo[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; [3-[[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]amino]-2,2-difluoro-propyl] N-isopropylcarbamate; 5-[4-[3-[2-[4-(Trifluoromethyl)-1-piperidyl]ethoxy]pyrrolidin-1-yl]furo[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] morpholine-4-carboxylate; [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] 8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate; [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] N-isopropylcarbamate; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-methyl-pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione; 6-[1-[2-(2,4-Dioxo-1H-pyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-3-carbonitrile; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; and Any one of 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione is included.

[0337] Generally, various functional groups and substituents constituting the compound of formula (I) are selected so that the molecular weight of the compound of formula (I) does not exceed 1000. More usually, the molecular weight of this compound is less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, for example 550 or less.

[0338] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention that are sufficiently basic, and examples include acid addition salts with inorganic acids or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Further, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, ammonium salts, or salts with organic bases that yield pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0339] Compounds having the same molecular formula but different in the nature or order of atomic bonds or the arrangement of atoms in space are called "isomers". Isomers with different arrangements of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers can exist. Enantiomers can be characterized by the absolute configuration of the asymmetric center and are described by the R and S ranking rules of Cahn and Prelog or by the manner in which the molecule rotates the plane of polarization, and are called dextrorotatory or levorotatory (i.e., the (+)-isomer or (-)-isomer, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal ratios of enantiomers is called a "racemic mixture".

[0340] The compounds of the present invention may have one or more chiral centers and, accordingly, these compounds can occur as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the present specification and claims is intended to include both the individual enantiomers and their racemic or other mixtures. Methods for the determination of stereochemical configuration and the separation of stereoisomers, such as synthesis from optically active starting materials or separation of racemates, are well known in the art (see the discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomer centers (E and Z isomers). It should be understood that the present invention encompasses all optical isomers, diastereoisomers, and geometric isomers having antiproliferative activity, as well as mixtures thereof.

[0341] The present invention also encompasses compounds of the invention as defined herein that contain one or more isotope substitutions. For example, H can be any isotope including 1H, 2H (D), and 3H (T); C can be any isotope including 12C, 13C, and 14C; O can be any isotope including 16O and 18O; and so on for others.

[0342] It should also be understood that certain compounds of formula (I) can exist in solvated and non-solvated forms, such as hydrated forms. It should be understood that the present invention encompasses all such solvated forms having antiproliferative activity.

[0343] It should also be understood that certain compounds of formula I can exhibit polymorphism and that the present invention encompasses all such forms having antiproliferative activity.

[0344] The compounds of formula I can exist in several different tautomeric forms, and references to the compounds of formula I include all these forms. To be clear, if a compound can exist as one of several tautomeric forms and only one is specifically described or illustrated, all other tautomeric forms are nonetheless included in formula I. Examples of tautomeric forms include keto, enol, and enolate forms, such as the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acyinitro.

[0345] [Chemical formula]

[0346] Compounds of formula I containing an amine functionality may also form N-oxides. References herein to compounds of formula I containing an amine functionality include N-oxides. When a compound contains several amine functionalities, one or more nitrogen atoms may be oxidized to form N-oxides. Specific examples of N-oxides include N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid). See, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514) in which an amine compound is reacted with, for example, m-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0347] The compounds of formula (I) can be administered in the form of prodrugs that are decomposed in the human or animal body so as to release the compounds of the present invention. Prodrugs may be used to change the physical properties and / or pharmacokinetic properties of the compounds of the present invention. When the compounds of the present invention contain suitable groups or substituents to which a property-modifying group can be attached, prodrugs can be formed. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at the carboxy group or hydroxy group in the compounds of formula (I), and in vivo cleavable amide derivatives that can be formed at the carboxy group or amino group in the compounds of formula (I).

[0348] Accordingly, the present invention includes the compounds of formula (I) as defined above when made available by organic synthesis and when made available in the human or animal body by cleavage of their prodrugs. Accordingly, the present invention includes compounds of formula I produced by means of organic synthesis and compounds of formula I produced in the human or animal body by metabolism of precursor compounds, i.e., the compounds of formula (I) can be compounds produced by synthesis or compounds produced by metabolism.

[0349] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) are prodrugs based on reasonable medical judgment that are suitable for administration to the human or animal body, have no undesirable pharmacological activity, and have no excessive toxicity.

[0350] Various forms of prodrugs are, for example, a)Methods in Enzymology,Vol.42,p.309-396,edited by K.Widder,et al.(Academic Press,1985); b)Design of Pro-drugs,edited by H.Bundgaard,(Elsevier,1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987 and other such literature.

[0351] Suitable pharmaceutically acceptable prodrugs of the compounds of formula I having a carboxy group are, for example, those that are cleavable in vivo esters. Pharmaceutically acceptable esters of the compounds of formula I containing a carboxy group that are cleavable in vivo are, for example, pharmaceutically acceptable esters that are cleaved in the human or animal body to yield the parent acid. Suitable pharmaceutically acceptable esters of carboxy include C1-6 alkyl esters such as methyl, ethyl, and tert-butyl; C1-6 alkoxymethyl esters such as methoxymethyl ester; C1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl ester; 3-phthalidyl esters; C3-8 cycloalkylcarbonyl-oxy-C1-6 alkyl esters such as cyclopentylcarbonyl-oxymethyl and 1-cyclohexylcarbonyl-oxyethyl ester; 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester; and C1-6 alkoxycarbonyl-oxy-C1-6 alkyl esters such as methoxycarbonyl-oxymethyl and 1-methoxycarbonyl-oxyethyl ester.

[0352] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) having a hydroxy group are, for example, esters or ethers cleavable in vivo thereof. In vivo cleavable esters or ethers of the compounds of formula I containing a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body so as to yield the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include inorganic acid esters such as phosphate esters (including phosphoramidic acid cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include C1-10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl groups, and substituted benzoyl and phenylacetyl groups; C1-10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-6)2 carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents in the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0353] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) having a carboxy group are, for example, amides cleavable in vivo thereof, for example, amides formed with amines such as ammonia; C1-4 alkylamines such as methylamine; (C1-4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine, or diethylamine; C1-4 alkoxy-C2-4 alkylamines such as 2-methoxyethylamine; phenyl-C1-4 alkylamines such as benzylamine, and amides formed with amino acids such as glycine or esters thereof.

[0354] Suitable pharmaceutically acceptable prodrugs of the compounds of formula I having an amino group are, for example, amide derivatives cleavable in vivo. Suitable pharmaceutically acceptable amides derived from the amino group include, for example, amides formed with acetyl, benzoyl, phenylacetyl groups, and C1-10 alkanoyl groups such as substituted benzoyl and phenylacetyl groups. Examples of ring substituents in the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-4 alkyl)piperazin-1-ylmethyl.

[0355] The in vivo effects of the compounds of formula (I) may be exerted, in part, by one or more metabolites formed in the body of a human or animal after administration of the compounds of formula (I). As described above, the in vivo effects of the compounds of formula (I) may also be exerted by metabolism of the precursor compound (prodrug).

[0356] The present invention may relate to any compound or any specific group of compounds as defined herein by optional features, preferred features, or suitable features, or other features of particular embodiments, but the present invention may also relate to any compound or any specific group of compounds that specifically exclude the said optional features, preferred features, or suitable features, or particular embodiments.

[0357] Preferably, the present invention excludes any individual compound that does not have the biological activity as defined herein.

[0358] Synthesis The compounds of the present invention can be prepared by any suitable technique known in the art. Specific methods for the preparation of the compounds of the present invention are described in the Examples section below.

[0359] In the descriptions regarding the synthetic methods described herein and any reference-described synthetic methods used to prepare the starting materials, one should understand that those skilled in the art can select all of the presented reaction conditions, including the selection of solvents, reaction atmospheres, reaction temperatures, experimental durations, and work-up procedures.

[0360] Those skilled in organic synthesis will understand that the functional groups present in various parts of the molecule must be compatible with the reagents and reaction conditions utilized.

[0361] It will be recognized that during the synthesis of the compounds of the present invention or during the synthesis of specific starting materials in the methods defined herein, it may be desirable to protect certain substituents to prevent unwanted reactions. A skilled chemist will recognize when such protection is necessary and how these protecting groups can be introduced and later removed.

[0362] For examples of protecting groups, refer to one of many general texts on the subject, such as "Protective Groups in Organic Synthesis" by Theodora Green (Publisher: John Wiley & Sons). The protecting groups can be removed as appropriate by any convenient method described in the literature for the removal of the protecting group in question or known to skilled chemists, and these methods are selected to effect the removal of the protecting group while minimizing interference with groups elsewhere in the molecule.

[0363] Thus, when the reactants contain groups such as, for example, amino, carboxy, or hydroxy, it may be desirable to protect this group in some of the reactions referred to herein.

[0364] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups such as alkanoyl groups such as acetyl; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups; arylmethoxycarbonyl groups such as benzyloxycarbonyl; or aroyl groups such as benzoyl. The deprotection conditions for the above protecting groups necessarily vary depending on the choice of the protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group can be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be removed by hydrogenation over a catalyst such as palladium on carbon or by treatment with a Lewis acid such as boron tris(trifluoroacetate). Another suitable protecting group for a primary amino group is, for example, a phthaloyl group that can be removed by treatment with an alkylamine such as dimethylaminopropylamine or with hydrazine.

[0365] Suitable protecting groups for hydroxy groups are, for example, acyl groups such as alkanoyl groups such as acetyl; aroyl groups such as benzoyl; or arylmethyl groups such as benzyl. The deprotection conditions for the above protecting groups necessarily vary depending on the choice of the protecting group. Thus, for example, an acyl group such as an alkanoyl or aroyl group can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide, or ammonia. Alternatively, an arylmethyl group such as a benzyl group can be removed by hydrogenation over a catalyst such as palladium on carbon.

[0366] Suitable protecting groups for the carboxy group are, for example, esterifying groups, such as methyl or ethyl groups, which are removable, for example, by hydrolysis with a base, such as sodium hydroxide, or a t-butyl group, which is removable, for example, by treatment with an acid, such as an organic acid, such as trifluoroacetic acid, or a benzyl group, which is removable, for example, by hydrogenation over palladium on carbon.

[0367] A resin may be used as a protecting group.

[0368] The methodology used to synthesize the compounds of formula (I) varies depending on the nature of R1 and R2, and any substituents associated therewith. Suitable methods for the preparation of the compounds of formula (I) are further described in the accompanying examples.

[0369] When the compound of formula (I) is synthesized by any one of the methods defined herein, the method may (i) further comprise the step of removing any protecting groups present; (ii) the step of converting the compound of formula (I) into another compound of formula (I); (iii) the step of forming a pharmaceutically acceptable salt, hydrate, or solvate of the compound of formula I; and / or (iv) further comprise one or more of the further steps such as the step of forming a prodrug of the compound of formula I.

[0370] An example of (ii) above is the case where, after synthesizing the compound of formula (I), one or more of the R1 or R2 groups are further reacted to change the nature of this group to obtain another compound of formula (I).

[0371] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0372] Biological activity To measure the pharmacological effects of the compounds of the present invention, the biological assays described in the Examples section (Biological Examples A, B, and C) can be used.

[0373] The pharmacological properties of the compounds of formula I vary as expected depending on the structural changes, but the compounds of the present invention were found to be active in the assays described in Biological Examples A, B, and C.

[0374] Generally, with respect to CD73 inhibitory activity, the compounds of the present invention show an IC 50 of 3 μM or less in the assay described in Biological Example A of the present invention, the preferred compounds of the present invention show an IC 50 of 500 nM or less, and the most preferred compounds of the present invention show an IC 50 of 200 nM or less.

[0375] Pharmaceutical composition According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a combination of a compound of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0376] The compositions of the present invention can be in a form suitable for oral use (for example, tablets, troches, hard or soft capsules, aqueous or oily suspensions or emulsions, dispersible powders or granules, syrups, or elixirs), in a form suitable for topical use (for example, creams, ointments, gels, or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (for example, as fine powders or liquid aerosols), in a form suitable for administration by insufflation (for example, as fine powders), or in a form suitable for parenteral administration (for example, as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as suppositories for rectal administration).

[0377] The composition of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well-known in the art. Thus, compositions intended for oral use can contain, for example, one or more colorants, sweeteners, flavorants, and / or preservatives.

[0378] An effective amount of the compound of the present invention for use in therapy is an amount sufficient to treat or prevent the proliferative conditions referred to herein, slow their progression, and / or reduce the symptoms associated with this condition.

[0379] The amount of active ingredient combined with one or more excipients to produce one dosage form will necessarily vary depending on the individual being treated and the particular route of administration. For example, generally, a formulation intended for oral administration to humans will contain, for example, from 0.5 mg to 0.5 g (more preferably from 0.5 to 100 mg, for example from 1 to 30 mg) of the active agent as a mixture with a suitable and convenient amount of excipient which can vary from about 5 to about 98 weight percent of the total composition.

[0380] According to well-known medical principles, the magnitude of the dosage of the compound of formula I for therapeutic or prophylactic purposes will necessarily vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0381] When using the compounds of the present invention for therapeutic or prophylactic purposes, generally, a daily dose in the range of, for example, from 0.1 mg / kg body weight to 75 mg / kg body weight is received and administered in divided doses if necessary. Generally, when a parenteral route is used, a lower dose is administered. Thus, for example, for intravenous or intraperitoneal administration, doses in the range of, for example, from 0.1 mg / kg body weight to 30 mg / kg body weight are generally used. Similarly, for administration by inhalation, doses in the range of, for example, from 0.05 mg / kg body weight to 25 mg / kg body weight are used. Oral administration can also be suitable, especially in the form of tablets. Usually, a unit dosage form contains from about 0.5 mg to 0.5 g of the compound of the present invention.

[0382] Therapeutic use and application The present invention provides a compound that functions as a CD73 inhibitor.

[0383] According to a further aspect of the present invention, there is provided a method of inhibiting CD73 in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0384] According to a further aspect of the present invention, there is provided a method of selectively inhibiting CD73 in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0385] According to a further aspect of the present invention, there is provided a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (such as checkpoint inhibitors and / or cytotoxic agents).

[0386] According to a further aspect of the present invention, there is provided a method of performing said treatment in a patient in need of treating a disease or disorder associated with CD73 activity, the method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0387] According to a further aspect of the present invention, there is provided a method of performing said treatment in a patient in need of treating a proliferative disorder, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0388] According to a further aspect of the present invention, there is provided a method of performing said treatment in a patient in need of treating cancer, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0389] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition for use in therapy.

[0390] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0391] According to a further aspect of the invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the treatment of cancer. In certain embodiments, the cancer is a human cancer. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (such as checkpoint inhibitors and / or cytotoxic agents).

[0392] According to a further aspect of the invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use as a CD73 activity inhibitor. Certain compounds of the invention are selective CD73 inhibitors.

[0393] According to a further aspect of the invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in the treatment of a disease or disorder in which CD73 activity is involved.

[0394] According to a further aspect of the invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative condition. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (such as checkpoint inhibitors and / or cytotoxic agents).

[0395] According to a further aspect of the invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for the treatment of cancer. Preferably, the cancer is a human cancer. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (such as checkpoint inhibitors and / or cytotoxic agents).

[0396] According to a further aspect of the present invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for use as a CD73 activity inhibitor.

[0397] According to a further aspect of the present invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which CD73 activity is involved.

[0398] The term "proliferative disorder" is used interchangeably herein and relates to unwanted or uncontrolled cell proliferation of undesirable or abnormal cells, such as neoplastic or hyperplastic proliferation, whether in vitro or in vivo. Examples of proliferative states include, but are not limited to, pre-malignant and malignant cell proliferation, such as malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissue), and atherosclerosis. Any type of cell can be treated, including, but not limited to, cells of the lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

[0399] The anti-proliferative effect of the compounds of the present invention is particularly applicable to the treatment of human cancer.

[0400] More specifically, there is provided a compound of general formula (I) for use in the treatment of cancer, particularly solid tumors such as non-small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma.

[0401] Also provided is the use of a compound of general formula (I) in the manufacture of a medicament for the treatment of cancer, particularly solid tumors such as non-small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma.

[0402] The present invention further provides a method for the treatment of cancer, particularly solid tumors such as non-small cell lung cancer, head and neck squamous cell cancer, and urothelial cancer, the method comprising administering to a patient in need of said treatment an effective amount of a compound of general formula (I).

[0403] The patient to be treated is preferably a mammal, more preferably a human.

[0404] Route of administration The compounds of the present invention, or pharmaceutical compositions containing these compounds, can be administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (i.e., at the site where the action is desired).

[0405] Routes of administration include oral (e.g., by oral ingestion); buccal; sublingual; transdermal (including those by patch, plaster, etc.); transmucosal (including those by patch, plaster, etc.); intranasal (e.g., by nasal drops); intraocular (e.g., by eye drops); intrapulmonary (e.g., by inhalation therapy or insufflation therapy through the mouth or nose using, for example, an aerosol); rectal (e.g., by suppository or enema); intravaginal (e.g., by pessary); parenteral, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, intrathecal, and intrasternal, for example by injection; routes including, but not limited to, subcutaneous or intramuscular depot or reservoir implantation.

[0406] Combination therapy The compounds of formula I are useful for the treatment and / or prevention of proliferative disorders such as cancer. The compounds of formula I as defined herein can be used in combination with one or more additional anti-proliferative / anti-cancer treatments, such as chemotherapy with one or more additional anti-proliferative / anti-cancer agents, radiation therapy, and / or conventional surgery.

[0407] Additional anti-proliferative / anticancer agents may be included in pharmaceutical compositions with the compounds of formula (I) as defined herein, or may be administered alone, simultaneously with, before or after the compounds of formula (I).

[0408] Accordingly, in a further aspect of the invention, there is provided a product comprising a compound of general formula (I) and a further agent useful in the treatment or prevention of cancer, as a combined preparation for simultaneous, sequential or separate use in the treatment of cancer.

[0409] The invention also provides a combination of a compound of general formula (I) and one or more additional anti-proliferative / anticancer agents for use in the treatment of cancer, as a combined preparation for simultaneous, sequential or separate use in the treatment of cancer.

[0410] In particular, the combination therapy as defined herein is suitable for the treatment of solid tumors such as non-small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma.

[0411] Suitable additional anti-proliferative / anticancer agents that can be used in combination with the compounds of formula I as defined herein (either alone or as part of a combined pharmaceutical composition or combined preparation with a compound of general formula (I)) include 1) other forms of cancer immunotherapeutic agents and anticancer chemotherapeutic agents; 2) A2b antagonists; 3) anti-PD-1 and PDL-1 antibodies including, but not limited to, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab; and 4) anti-CTLA4 antibodies including, but not limited to, ipilimumab.

[0412] The compounds of formula I as defined herein are particularly suitable for use in combination with anti-PD-1 and PDL-1 antibodies including, but not limited to, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab.

[0413] The CD73 inhibitor of general formula (I) can also be used in combination with cell-based immunotherapeutic agents and cancer vaccines, including but not limited to CAR-T cell therapeutics.

[0414]

[0415] As described above, the combination therapy of the present invention can be carried out by administering the individual components of the treatment agent simultaneously, sequentially, or separately. In these combination preparations, the compounds of the present invention within the dosage ranges described above, and other pharmaceutically active agents within the approved dosage ranges are used.

[0416] According to this aspect of the present invention, there is provided a combination for use in the treatment of cancer (e.g., cancer including solid tumors), comprising a compound of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and one or more additional anti-proliferative / anti-cancer agents.

[0417] According to this aspect of the present invention, there is also provided a combination for use in the treatment of a proliferative condition, e.g., cancer (e.g., cancer including solid tumors), comprising a compound of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and one or more additional anti-proliferative / anti-cancer agents selected from those listed above.

[0418] In a further aspect of the present invention, there is provided a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in the treatment of cancer in combination with another anti-tumor agent optionally selected from those listed above.

[0419] It should be understood that when the term "combination" is used herein, this means simultaneous administration, separate administration, or sequential administration. In one aspect of the present invention, "combination" means simultaneous administration. In another aspect of the present invention, "combination" means separate administration. In a further aspect of the present invention, "combination" means sequential administration. When the administration is sequential or separate administration, the delay in the administration of the second component should not be such as to lose the beneficial effects of the combination.

[0420] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a combination of a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and an anti-tumor agent (optionally selected from those listed above), in combination with a pharmaceutically acceptable diluent or carrier.

Examples

[0421] General conditions: Mass spectra were run on an LC-MS system using electrospray ionization. These were run using a Waters Acquity H-Class UPLC equipped with a PDA and QDa mass detector, or an Acquity UPLC (binary pump / PDA detector) + ZQ mass spectrometer or an Acquity i-Class (quaternary pump / PDA detector) + Quattro Micro mass spectrometer, or a Waters Acquity uPLC system equipped with Waters PDA and ELS detectors, or a Shimadzu LC-MS-2010EV system. [M+H]+ means the monoisotopic molecular weight.

[0422] NMR spectra were run on a Bruker Ultrashield 500 MHz NMR spectrometer or a Bruker Avance III HD 400 MHz NMR spectrometer. Spectra were recorded at 298 K and referenced to the solvent peak.

[0423] The following examples are intended to illustrate the present invention and should not be construed as limiting the present invention. Temperatures are indicated in degrees Celsius. Unless otherwise stated, all evaporations are carried out under reduced pressure, preferably at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods, such as microanalysis, and spectroscopic properties, such as MS and NMR. Abbreviations used are those customary in the art. Where not defined, terms have their generally accepted meanings.

[0424] Abbreviations br broad CDI 1,1'-carbonyldiimidazole d doublet DCM dichloromethane dd doublet of doublets DIPEA diisopropylethylamine DMA dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HPLC high performance liquid chromatography LC-MS liquid chromatography and mass spectrometry LDA lithium diisopropylamide m multiplet mCPBA m-chloroperbenzoic acid MeCN acetonitrile MeOH MeOH MS mass spectrometry min(s) minute(s) mL milliliter m / z mass-to-charge ratio NBS N-bromosuccinimide NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride pTSA p-toluenesulfonic acid Rt retention time s singlet t triplet TBAB tetrabutylammonium bromide TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran X-phos 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl

[0425] For the following examples, compounds of preferred embodiments were synthesized using the methods described herein or other methods known in the art.

[0426] Various starting materials, intermediates, and compounds of preferred embodiments can be isolated and purified as appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without purification. Salts can be prepared from the compounds by known salt formation procedures.

[0427] Unless otherwise indicated, the analytical HPLC conditions are as follows.

[0428] Instrument: LC-MS-1: Method 2A Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm Column temperature: 50°C Flow rate: 0.8 mL / min Eluent: A: H2O, 0.1% formic acid, B: MeCN Gradient: 0.0 - 1.8 min 2 - 98% B, 1.8 - 2.1 min 98% B, 2.1 - 2.5 98% A

[0429] Method 2B Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm Column temperature: 50°C Flow rate: 0.8 mL / min Eluent: A: H2O, 0.1% ammonia, B: MeCN Gradient: 0.0 - 1.8 min 2 - 98% B, 1.8 - 2.1 min 98% B, 2.1 - 2.5 98% A

[0430] Method 8A Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm Column temperature: 50 °C Eluent: A: H2O, 0.1% formic acid, B: MeCN Flow rate: 0.6 mL / min Gradient: 0.5 - 6.5 min 2 - 98% B, 6.5 - 7.6 min 98% B, 7.6 - 8.0 98% A

[0431] Method 8B Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm Column temperature: 50 °C Eluent: A: H2O, 0.1% ammonia, B: MeCN Flow rate: 0.6 mL / min Gradient: 0.5 - 6.5 min 2 - 98% B, 6.5 - 7.6 min 98% B, 7.6 - 8.0 98% A

[0432] Method 8B[0 - 10%] Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm Column temperature: 50 °C Eluent: A: H2O, 0.1% ammonia, B: MeCN Flow rate: 0.6 mL / min Gradient: 0.0 - 0.5 min 2% B; 0.5 - 6.5 min 2 - 10% B; 6.5 - 7.5 min 98% B; 7.5 - 7.6 min 2% B; 7.6 - 8.0 2% B

[0433] Instrument: LC - MS - 2: Method 2A Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm Column temperature: 50 °C Flow rate: 0.8 mL / min Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 2.0% formic acid Gradient: 0.0 - 1.7 minutes, 0 - 95% B, 5% C; 1.7 - 2.1 minutes, 95% B, 5% C; 2.1 - 2.5 minutes, 95% A, 5% C

[0434] Method 2B Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm Column temperature: 50°C Flow rate: 0.8 mL / min Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 2.0% ammonia (aqueous) Gradient: 0.0 - 1.7 minutes, 0 - 95% B, 5% D; 1.7 - 2.1 minutes, 95% B, 5% D; 2.1 - 2.5 minutes, 95% A, 5% D

[0435] Method 8A Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm Column temperature: 50°C Flow rate: 0.8 mL / min Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 2.0% formic acid Gradient: 0.0 - 0.5 minutes, 95% A, 5% C; 0.5 - 6.5 minutes, 0 - 95% B, 5% C; 6.6 - 7.5 minutes, 95% B, 5% C; 7.5 - 7.6 minutes, 0 - 95% A, 5% C; 7.6 - 8.0 minutes, 95% A, 5% C

[0436] Method 8B Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm Column temperature: 50°C Flow rate: 0.8 mL / min Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 2.0% ammonia (aqueous) Gradient: 0.0 - 0.5 minutes, 95% A, 5% D; 0.5 - 6.5 minutes, 0 - 95% B, 5% D; 6.6 - 7.5 minutes, 95% B, 5% D; 7.5 - 7.6 minutes, 0 - 95% A, 5% D; 7.6 - 8.0 minutes, 95% A, 5% D

[0437] Machine: LC-MS Method 7A Column: Phenomenex Kinetix-XB C18 2.1×100mm, 1.7μm Column temperature: 40°C Eluent: A: H2O, 0.1% formic acid, B: acetonitrile, 0.1% formic acid Flow rate: 0.6 mL / min Gradient: 0 - 5.3 min 5 - 100% B, 5.3 - 5.8 min 100% B, 5.8 - 5.82 min 100 - 5% B, 5.82 - 7.00 min 5% B

[0438] Method 7B Column: Waters UPLC® BEH™ C18, 2.1mm×100mm, 1.7μm column Column temperature: 55°C Eluent: A: 2 mM ammonium bicarbonate buffered to pH10, B: acetonitrile Flow rate: 0.6 mL / min Gradient: 0 - 5.3 min 5 - 100% B, 5.3 - 5.8 min 100% B, 5.8 - 5.82 min 100 - 5% B, 5.82 - 7.00 min 5% B

[0439] Method 2A Column: Waters UPLC® BEH™ C18 2.1×50mm, 1.7μm Column temperature: 40°C Eluent: A: H2O, 0.1% formic acid, B: acetonitrile, 0.1% formic acid Flow rate: 0.9 mL / min Gradient: 0 - 1.10 min 5 - 100% B, 1.10 - 1.35 min 100% B, 1.35 - 1.40 min 100 - 5% B, 1.40 - 1.50 min 5% B

[0440] Method 2B Column: Waters UPLC® BEH™ C18 2.1×30mm, 1.7μm Column temperature: From September 21, 2020 is 55°C, before that is 40°C Eluent: A: 2 mM ammonium bicarbonate buffered to pH 10, B: acetonitrile Flow rate: 1 mL / min Gradient: 0 - 1.10 min 1 - 100% B, 1.10 - 1.35 min 100% B, 1.35 - 1.40 min 100% B, 1.40 - 1.80 min 1% B

[0441] [Example 1] 5-[4-[3-(Hydroxymethyl)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0442] [Chemical formula]

[0443] 5-(4-Chlorothieno[2,3-d]pyrimidin-6-yl)-1H-pyrimidine-2,4-dione (Intermediate D) (80 mg, 0.24 mmol), pyrrolidin-3-ylmethanol (37 mg, 0.36 mmol), and DIPEA (0.13 mL, 0.73 mmol) were dissolved in MeCN (3 mL) and heated at 70 °C overnight. The resulting mixture was cooled to room temperature and then filtered. The collected solid was washed with MeCN (5 mL) and diethyl ether (5 mL) and purified by C18 reverse-phase chromatography eluting with a gradient of 5 - 35% MeCN in water (+0.1% formic acid). The product was lyophilized and then azeotroped with MeCN to give the title compound as a yellow solid. LC-MS-1 (Method 8A): Rt 1.52 min; MS m / z 346.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 2H), 8.28 (s, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 4.76 (t, J = 5.3 Hz, 1H), 3.98 - 3.72 (m, 3H), 3.56 (s, 1H), 3.50 - 3.43 (m, 2H), 2.07 (s, 1H), 1.86 - 1.75 (m, 1H).

[0444] [Example 1.1] 5-[4-[3-(2-Hydroxyethyl)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0445] [Chemical formula]

[0446] The title compound was prepared in a similar manner to Example 1 from 5-(4-chlorothieno[2,3-d]pyrimidin-6-yl)-1H-pyrimidine-2,4-dione (Intermediate D) and 2-pyrrolidin-3-ylethanol. LC-MS-2 (Method 8A): Rt 1.91 min; MS m / z 360.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6 @ 70°C) δ 11.53 (s, 2H), 8.29 (s, 1H), 8.25 (s, 1H), 7.90 (s, 1H), 4.51 (t, J = 5.1 Hz, 1H), 4.06 - 3.86 (m, 2H), 3.75 (s, 1H), 3.56 - 3.47 (m, 2H), 2.35 (s, 1H), 2.16 (s, 1H), 1.69 - 1.53 (m, 3H).

[0447] [Example 1.2] 5-[4-(3,3-Dimethylazetidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0448] [Chemical formula]

[0449] The title compound was prepared in a similar manner to Example 1 from 5-(4-chlorothieno[2,3-d]pyrimidin-6-yl)-1H-pyrimidine-2,4-dione (Intermediate D) and 3,3-dimethylazetidine hydrochloride. LC-MS-1 (Method 8A): Rt 1.93 min; MS m / z 330.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 2H), 8.31 (s, 1H), 8.26 (s, 1H), 7.65 (s, 1H), 4.08 (s, 4H), 1.34 (s, 6H).

[0450] [Example 1.3] 5-[4-[3-(2-Hydroxyethoxy)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0451] [Chemical Structure]

[0452] The title compound was prepared in a similar manner to Example 1 from 5-(4-chlorothieno[2,3-d]pyrimidin-6-yl)-1H-pyrimidine-2,4-dione (Intermediate D) and 2-pyrrolidin-3-yloxyethanol hydrochloride. LC-MS-1 (Method 8A): Rt 1.53 min; MS m / z 376.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 2H), 8.34 (s, 1H), 8.27 (s, 1H), 7.91 (s, 1H), 4.67 - 4.56 (m, 1H), 4.26 (s, 1H), 3.88 (s, 4H), 3.55 - 3.44 (m, 4H), 2.21 - 2.00 (m, 2H).

[0453] [Example 2] 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0454] [Chemical Structure]

[0455] Step 1: 6-Bromo-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidine

[0456]

Chem.

[0457] To a stirred solution of 6-bromo-4-chloro-thieno[2,3-d]pyrimidine (330 mg, 1.32 mmol) and 1-(2-pyrrolidin-3-yloxyethyl)piperidine dihydrochloride (430 mg, 1.59 mmol) in 1,4-dioxane (7 mL) was added DIPEA (0.92 mL, 5.29 mmol), and the solution was heated at 80 °C for 3 h. Additional DIPEA (0.46 mL, 2.65 mmol) was added and stirring was continued at 80 °C for 30 min. The resulting mixture was cooled to room temperature, the solution was concentrated under reduced pressure, and then partitioned between DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 × 20 mL). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. Purification by silica chromatography eluting with a gradient of 2 - 10% MeOH in DCM afforded the title compound as a peach-colored solid. LC-MS-2 (Method 2B): Rt 1.66 min; MS m / z 411.0 / 413.0 = [M+H]+ 1H NMR (500 MHz, methanol-d4) δ 8.27 (s, 1H), 7.73 (s, 1H), 4.33 (s, 1H), 4.06 - 3.93 (m, 2H), 3.93 - 3.74 (m, 4H), 3.09 - 2.83 (m, 6H), 2.31 (s, 1H), 2.17 (s, 1H), 1.71 (s, 4H), 1.56 (s, 2H).

[0458] Step 2: 6-(2,4-Dimethoxypyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidine

[0459]

Chem.

[0460] 6-Bromo-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidine (Step 1) (70 mg, 0.17 mmol) and cesium carbonate (78 mg, 0.51 mmol) in a degassed solution of 1,4-dioxane (1 mL) and water (0.25 mL) were added with Pd(dppf)Cl2 (12 mg, 0.02 mmol) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (47 mg, 0.26 mmol). The flask was evacuated and filled with nitrogen (3 × cycles), and the solution was heated at 100 °C for 1 hour. The resulting mixture was cooled to room temperature and partitioned between DCM (30 mL) and water (30 mL). The layers were separated, and the aqueous layer was further extracted with DCM (2 × 30 mL). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. Purification by silica chromatography eluting with a gradient of 2 - 8% 1M NH3MeOH in DCM gave the title compound as a brown solid. LC-MS-1 (Method 2B): Rt 1.47 min; MS m / z 471.3 = [M+H]+ 1H NMR (500 MHz, methanol-d4) δ 8.56 (s, 1H), 8.17 (s, 1H), 7.81 (s, 1H), 4.19 (s, 1H), 4.06 (s, 3H), 3.95 (s, 3H), 3.92 (s, 1H), 3.80 (s, 3H), 3.65 - 3.53 (m, 2H), 2.49 (t, J = 5.7 Hz, 2H), 2.38 (s, 4H), 2.19 (s, 1H), 2.10 - 2.03 (m, 1H), 1.45 (p, J = 5.6 Hz, 4H), 1.36 - 1.27 (m, 2H).

[0461] Step 3: 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione A stirred solution of 6-(2,4-dimethoxypyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidine (Step 2) (58 mg, 0.12 mmol) in 1M HCl (2 mL, 2 mmol) and MeOH (1 mL) was heated at 70 °C overnight. After cooling to room temperature and stirring for 2 days, the mixture was concentrated under reduced pressure. Purification by C18 reverse-phase chromatography eluting with a gradient of 2 - 30% MeCN in water (+0.1% NH4OH) afforded the title compound as an off-white solid. LC-MS-2 (Method 8B): Rt 2.21 min; MS m / z 443.1 = [M+H]+ 1H NMR 70 °C (500 MHz, DMSO-d6) δ 11.25 (s, 2H), 8.28 (s, 1H), 8.20 - 8.15 (m, 1H), 7.91 (s, 1H), 4.25 (p, J = 3.8 Hz, 1H), 4.00 - 3.76 (m, 4H), 3.66 - 3.51 (m, 2H), 2.46 (t, J = 6.1 Hz, 2H), 2.40 - 2.34 (m, 4H), 2.16 - 2.07 (m, 2H), 1.46 (p, J = 5.6 Hz, 4H), 1.38 - 1.31 (m, 2H).

[0462] [Example 2.1] 5-[4-(3,3-Dimethylpyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0463] [Chemical Structure]

[0464] Step 1: 6-Bromo-4-(3,3-dimethylpyrrolidin-1-yl)thieno[2,3-d]pyrimidine

[0465] [Chemical formula]

[0466] The title compound was prepared from 6-bromo-4-chloro-thieno[2,3-d]pyrimidine and 3,3-dimethylpyrrolidine hydrochloride in a similar manner to Step 1 of Example 2. LC-MS-2 (Method 2A): Rt 1.70 min; MS m / z 311.8 / 313.8 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.79 (s, 1H), 3.82 (m, 2H), 3.52 (m, 2H), 1.78 (m, 2H), 1.12 (s, 6H).

[0467] Step 2: 6-(2,4-Dimethoxypyrimidin-5-yl)-4-(3,3-dimethylpyrrolidin-1-yl)thieno[2,3-d]pyrimidine

[0468] [Chemical formula]

[0469] The title compound was prepared from 6-bromo-4-(3,3-dimethylpyrrolidin-1-yl)thieno[2,3-d]pyrimidine (Step 1) and (2,4-dimethoxypyrimidin-5-yl)boronic acid in a similar manner to Step 2 of Example 2. LC-MS-2 (Method 2A): Rt 1.53 min; MS m / z 372.0 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.30 (s, 1H), 7.98 (s, 1H), 4.02 (m, 8H), 3.58 (s, 2H), 1.82 (s, 2H), 1.14 (s, 6H).

[0470] Step 3: 5-[4-(3,3-Dimethylpyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione 6-(2,4-Dimethoxypyrimidin-5-yl)-4-(3,3-dimethylpyrrolidin-1-yl)thieno[2,3-d]pyrimidine (Step 2) and 1M HCl were used to prepare the title compound in a similar manner to Step 3 of Example 2. LC-MS-2 (Method 8A): Rt 2.32 min; MS m / z 344.0 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 11.51 (s, 1H), 11.44 (s, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.34 (d, J = 5.6 Hz, 1H), 7.97 (s, 1H), 4.07 - 3.96 (m, 2H), 3.69 (s, 2H), 1.88 (t, J = 7.1 Hz, 2H), 1.18 (s, 6H).

[0471] [Example 3] 6-[1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-3-carbonitrile

[0472] [Chemical Structure]

[0473] Step 1: 1-(6-Bromothieno[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ol

[0474] [Chemical Structure]

[0475] A stirred suspension of 6-bromo-4-chloro-thieno[2,3-d]pyrimidine (3.00 g, 12.02 mmol) and pyrrolidin-3-ol (1.26 g, 14.43 mmol) in MeCN (50 mL) was treated with DIPEA (8.38 mL, 48.09 mmol) under nitrogen and the reaction mixture was heated at 70 °C for 30 minutes. After cooling to room temperature, the resulting suspension was filtered and the collected solid was washed with diethyl ether (5 mL) and then dried under reduced pressure to afford the title compound as a cream-colored solid. LC-MS-2 (Method 2A): Rt 1.12 min; MS m / z 299.9 / 301.9 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.79 (s, 1H), 5.08 - 5.01 (m, 1H), 4.41 (s, 1H), 3.99 - 3.59 (m, 4H), 2.06 - 1.86 (m, 2H).

[0476] Step 2: 6-[1-(6-Bromothieno[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]oxypyridine-3-carbonitrile

[0477]

Chemical formula

[0478] 1-(6-Bromothieno[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (Step 1) (300 mg, 1.0 mmol) was added to a stirred suspension in DMF (3 mL), and sodium hydride (60% mineral oil dispersion) (44 mg, 1.1 mmol) was added. The mixture was stirred at room temperature for 30 minutes. 6-Fluoropyridine-3-carbonitrile (146 mg, 1.2 mmol) was added, and stirring was continued for 20 minutes. The reaction mixture was quenched with water (15 mL), and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with water (4 × 10 mL) and brine (10 mL), dried over magnesium sulfate, and concentrated under reduced pressure. Purification by silica chromatography eluting with a gradient of 0 to 75% EtOAc in petroleum ether gave the title compound as a colorless solid. LC-MS-2 (Method 2A): Rt 1.60 min; MS m / z 402.0 / 404.0 = [M+H]+ 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 2.3 Hz, 1H), 8.41 (s, 1H), 7.81 (dd, J = 8.7, 2.3 Hz, 1H), 7.46 (s, 1H), 6.81 (d, J = 8.7 Hz, 1H), 5.83 (s, 1H), 4.18 - 3.95 (m, 4H), 2.50 - 2.31 (m, 2H).

[0479] Step 3: 6-[1-[6-(2,4-Dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-3-carbonitrile

[0480]

Chemical Structure

[0481] 6-[1-(6-Bromothieno[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]oxypyridine-3-carbonitrile (Step 2) (306 mg, 0.76 mmol), (2,4-Dimethoxypyrimidin-5-yl)boronic acid (210 mg, 1.14 mmol), and cesium carbonate (347 mg, 2.28 mmol) in a stirred mixture were degassed with nitrogen for 10 minutes. Pd(dppf)Cl2 (56 mg, 0.08 mmol) was added and the reaction mixture was heated at 100 °C for 10 minutes. The resulting mixture was cooled to room temperature and partitioned between EtOAc (20 mL) and water (15 mL). The layers were separated and the aqueous portion was further extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. Purification by silica chromatography eluting with a gradient of 25 - 100% EtOAc in DCM afforded the title compound as a pale brown solid. LC-MS-1 (Method 2A): Rt 1.40 min; MS m / z 462.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6 @ 343K) δ 8.85 - 8.78 (m, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.34 (s, 1H), 8.13 (dd, J = 8.7, 2.3 Hz, 1H), 7.98 (s, 1H), 7.01 (dd, J = 8.7, 0.8 Hz, 1H), 5.84 - 5.79 (m, 1H), 4.25 - 4.18 (m, 1H), 4.15 - 4.10 (m, 1H), 4.09 (s, 3H), 4.07 - 4.01 (m, 2H), 3.99 (s, 3H), 2.46 - 2.41 (m, 1H), 2.36 - 2.31 (m, 1H).

[0482] Step 4: 6-[1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-3-carbonitrile 6-[1-[6-(2,4-Dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-3-carbonitrile (Step 3) (303 mg, 0.66 mmol) was heated at 70 °C for 7 hours in a stirred solution of 1 M HCl (6.57 mL, 6.57 mmol) and MeOH (6 mL). The mixture was cooled to room temperature and the resulting suspension was collected by filtration. The solid was washed with water (20 mL), MeCN (20 mL), diethyl ether (20 mL) and dried under reduced pressure to give the title compound as a yellow solid. LC-MS-2 (Method 8A): Rt 2.46 min; MS m / z 434.1 = [M+H]+ 1H NMR (500 MHz, acetic acid-d4 @ 343K) δ 8.67 - 8.56 (m, 2H), 8.38 (s, 1H), 8.19 (s, 1H), 7.97 (dd, J = 8.8, 2.3 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 5.97 (s, 1H), 4.58 - 4.24 (m, 4H), 2.58 (s, 2H).

[0483] [Example 4] 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0484] [Chemical Formula]

[0485] Step 1: 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidine

[0486] [Chemical Formula]

[0487] A suspension of 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidine (Intermediate A) (200 mg, 0.65 mmol), 3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride (133 mg, 0.78 mmol), and DIPEA (0.45 mL, 2.59 mmol) in MeCN (3.5 mL) was stirred at 80 °C for 16 h. When the solution was cooled to room temperature, a suspension was formed. The solid was filtered off and washed with MeCN (3 × 3 mL). The filtrate was concentrated under reduced pressure and purified by silica chromatography eluting with a gradient of 20 - 60% EtOAc in petroleum ether to give the title compound as a yellow solid. LC-MS-1 (Method 2A): Rt 1.57 min; MS m / z 408.3 = [M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.39 (s, 1H), 8.00 (s, 1H), 4.54 - 4.20 (m, 2H), 4.08 (s, 3H), 3.97 (s, 3H), 3.95 - 3.82 (m, 2H), 1.21 (s, 6H).

[0488] Step 2: 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione A suspension of 4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidine (Step 1) (141 mg, 0.35 mmol) in 1M HCl (3.5 mL, 3.5 mmol) and EtOH (3.5 mL) was stirred at 70 °C for 3 h. When the solution was cooled to room temperature, a suspension was formed. The solid was collected by filtration, washed with water (3 × 3 mL), MeCN (3 × 3 mL), and diethyl ether (3 × 3 mL), and dried under reduced pressure. Purification by C18 reverse phase chromatography eluting with a gradient of 15 - 40% MeCN in water (+0.1% formic acid) gave the title compound as a colorless solid. LC-MS-2 (Method 8A): Rt 2.87 min; MS m / z 380.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 2H), 8.40 (s, 1H), 8.34 (s, 1H), 7.86 (s, 1H), 4.45 - 4.27 (m, 2H), 3.94 - 3.76 (m, 2H), 1.21 (s, 6H).

[0489] [Example 4.1] 5-[4-[3-(2-Pyridylmethoxy)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione formate

[0490] [Chemical Structure]

[0491] Step 1: 6-(2,4-Dimethoxypyrimidin-5-yl)-4-[3-(2-pyridylmethoxy)pyrrolidin-1-yl]thieno[2,3-d]pyrimidine

[0492] [Chemical Structure]

[0493] The title compound was prepared from 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidine (Intermediate A) and 2-(pyrrolidin-3-yloxymethyl)pyridine dihydrochloride in a similar manner to Step 1 of Example 4. LC-MS-2 (Method 2A): Rt 1.15 min; MS m / z 451.1 = [M+H]+ 11H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.50 (d, J = 4.3 Hz, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.77 (td, J = 7.7, 1.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.28 (dd, J = 7.6, 4.9 Hz, 1H), 4.67 (s, 2H), 4.42 (br s, 1H), 4.20 - 3.70 (m, 10H), 2.27 (br s, 1H), 2.15 (br s, 1H).

[0494] Step 2: 5-[4-[3-(2-Pyridylmethoxy)pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione formate 6-(2,4-Dimethoxypyrimidin-5-yl)-4-[3-(2-pyridylmethoxy)pyrrolidin-1-yl]thieno[2,3-d]pyrimidine (Step 1) and 1M HCl were used to prepare the title compound in a similar manner to Step 2 of Example 4. LC-MS-2 (Method 8A): Rt 1.78 min; MS m / z 423.1 = [M+H]+ 1 1H NMR (400 MHz, DMSO-d6) δ 11.97 - 11.25 (m, 2H), 8.51 (dd, J = 5.0, 1.8 Hz, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.77 (td, J = 7.8, 1.8 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.28 (dd, J = 7.5, 4.8 Hz, 1H), 4.74 - 4.59 (m, 2H), 4.42 (s, 1H), 3.97 (br s, 4H), 2.31 - 2.21 (m, 1H), 2.14 (br s, 1H).

[0495] [Example 4.2] 5-[4-(3-Benzyloxypyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0496]

Chem.

[0497] Step 1: 4-(3-Benzyloxypyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidine

[0498]

Chem.

[0499] The title compound was prepared in a similar manner to Step 1 of Example 4 from 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidine (Intermediate A) and 3-benzyloxypyrrolidine. LC-MS-1 (Method 2A): Rt 1.51 min; MS m / z 450.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 7.54 - 7.14 (m, 4H), 7.32 - 7.15 (m, 1H), 4.60 (s, 2H), 4.46 - 4.25 (m, 1H), 4.14 - 4.03 (m, 4H), 3.97 (s, 6H), 2.30 - 2.20 (m, 1H), 2.19 - 2.10 (m, 1H).

[0500] Step 2: 5-[4-(3-Benzyloxypyrrolidin-1-yl)thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione 4-(3-Benzyloxypyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidine (Step 1) and the title compound was prepared in a similar manner to Step 2 of Example 4 from 1M HCl. LC-MS-1 (Method 8A): Rt 2.57 min; MS m / z 422.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 11.28 (s, 2H), 8.28 (s, 1H), 8.18 - 8.15 (m, 1H), 7.90 (s, 1H), 7.40 - 7.22 (m, 5H), 4.64 - 4.57 (m, 2H), 4.39 - 4.32 (m, 1H), 3.99 - 3.86 (m, 4H), 2.27 - 2.19 (m, 1H), 2.19 - 2.11 (m, 1H).

[0501] [Example 4.3] 5-[4-[3,3-Difluoro-4-[(4-methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione formate

[0502] [Chemical formula]

[0503] Step 1: 2-[[1-[6-(2,4-Dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl]oxymethyl]-4-methyl-morpholine

[0504] [Chemical formula]

[0505] The title compound was prepared from 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidine (Intermediate A) and 2-[(4,4-difluoropyrrolidin-3-yl)oxymethyl]-4-methyl-morpholine dihydrochloride (Intermediate H) in a similar manner to Step 1 of Example 4. LC-MS-2 (Method 2A): Rt 1.16 min; MS m / z 509.1 = [M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.41 (s, 1H), 8.02 (s, 1H), 4.44 (br s, 1H), 4.38 - 4.13 (m, 3H), 4.08 (s, 3H), 4.05 - 3.91 (m, 4H), 3.78 - 3.56 (m, 4H), 3.53 - 3.42 (m, 1H), 2.71 - 2.63 (m, 1H), 2.60 - 2.54 (m, 1H), 2.17 - 2.12 (m, 3H), 1.99 - 1.86 (m, 1H), 1.79 - 1.70 (m, 1H).

[0506] Step 2: 5-[4-[3,3-Difluoro-4-[(4-methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione formate The title compound was prepared from 2-[[1-[6-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl]oxymethyl]-4-methyl-morpholine (Step 1) and 1M HCl in a similar manner to Step 2 of Example 4. LC-MS-2 (Method 8A): Rt 2.02 min; MS m / z 481.0 = [M+H]+ 1H NMR (400 MHz, deuterated acetic acid - d4) δ 8.46 (s, 1H), 8.10 (d, J = 3.8 Hz, 1H), 8.06 (s, 1H), 7.92 - 7.85 (m, 1H), 4.41 - 4.02 (m, 7H), 4.02 - 3.79 (m, 3H), 3.65 (t, J = 14.1 Hz, 1H), 3.54 (d, J = 12.4 Hz, 1H), 3.12 - 2.91 (m, 2H), 2.87 (s, 3H).

[0507] [Example 4.4] 5-[4-[3-[(4-Methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0508] [Chemical Structure]

[0509] Step 1: 2-[[1-[6-(2,4-Dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxymethyl]-4-methyl-morpholine

[0510] [Chemical Structure]

[0511] The title compound was prepared from 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidine (Intermediate A) and 4-methyl-2-(pyrrolidin-3-yloxymethyl)morpholine (Intermediate I) in a manner similar to Step 1 of Example 4. LC-MS-1 (Method 2A): Rt 0.87 min; MS m / z 473.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 4.26 (s, 1H), 4.12 - 3.62 (m, 10H), 3.61 - 3.40 (m, 4H), 2.72 - 2.63 (m, 1H), 2.59 - 2.53 (m, 2H), 2.18 - 2.04 (m, 5H), 1.98 - 1.86 (m, 1H), 1.72 (q, J = 9.8 Hz, 1H).

[0512] Step 2: 5-[4-[3-[(4-Methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione formate 2-[[1-[6-(2,4-Dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxymethyl]-4-methyl-morpholine (Step 1) and 1M HCl were used to prepare the title compound in a similar manner to Step 2 of Example 4. LC-MS-1 (Method 8B): Rt 1.47 min; MS m / z 445.3 = [M+H]+ 1H NMR (400 MHz, acetic acid-d4) δ 8.49 (s, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 8.01 (d, J = 3.2 Hz, 1H), 4.39 (s, 1H), 4.24 - 3.81 (m, 7H), 3.82 - 3.60 (m, 3H), 3.60 - 3.48 (m, 1H), 3.20 - 2.91 (m, 2H), 2.88 (s, 3H), 2.47 - 2.30 (m, 1H), 2.28 - 2.15 (m, 1H).

[0513] [Example 5] 5-[4-[3,3-Difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione formate

[0514] [Chemistry]

[0515] Step 1: 1-(6-Bromothieno[2,3-d]pyrimidin-4-yl)-4,4-difluoro-pyrrolidin-3-ol

[0516] [Chemistry]

[0517] The title compound was prepared from 6-bromo-4-chloro-thieno[2,3-d]pyrimidine and 4,4-difluoropyrrolidin-3-ol hydrochloride in a manner similar to Step 1 of Example 3. LC-MS-1 (Method 2A): Rt 1.20 min; MS m / z 336.1 / 338.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.87 (s, 1H), 6.26 (m, 1H), 4.57 - 4.31 (m, 1H), 4.31 - 3.96 (m, 3H), 3.90 - 3.58 (m, 1H).

[0518] Step 2: 6-Bromo-4-[3,3-difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidine

[0519] [Chemistry]

[0520] 1-(6-Bromo-thieno[2,3-d]pyrimidin-4-yl)-4,4-difluoro-pyrrolidin-3-ol (Step 1) (200 mg, 0.59 mmol), 1-(2-chloroethyl)piperidine (Intermediate J, Step 1) (108 mg, 0.73 mmol), TBAB (108 mg, 0.34 mmol), and a mixture of 5 M aqueous sodium hydroxide solution (2 mL, 10 mmol) in toluene (6 mL) were heated at 80 °C for 100 minutes. After the reaction mixture was cooled to room temperature, it was partitioned between EtOAc (50 mL) and water (50 mL). The phases were separated and the aqueous portion was further extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. Purification by silica chromatography eluting with a gradient of 0 - 10% MeOH in DCM gave the title compound as a yellow oil. LC-MS-2 (Method 2A): Rt 1.17 min; MS m / z 447.0 / 449.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.88 (s, 1H), 4.41 (p, J = 6.2 Hz, 1H), 4.27 - 4.13 (m, 3H), 4.09 (q, J = 5.3 Hz, 2H), 4.00 - 3.89 (m, 1H), 3.79 (t, J = 5.9 Hz, 2H), 2.46 - 2.34 (m, 4H), 1.51 - 1.44 (m, 4H), 1.38 - 1.32 (m, 2H).

[0521] Step 3: 4-[3,3-Difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidine

[0522]

Chemical Structure

[0523] 4-[2-[1-(6-Bromothieno[2,3-d]pyrimidin-4-yl)-4,4-difluoro-pyrrolidin-3-yl]oxyethyl]morpholine (Step 2) and 2,4-dimethoxypyrimidin-5-yl)boronic acid were used to prepare the title compound in a similar manner to Step 3 of Example 3. LC-MS-2 (Method 2A): Rt 1.18 min; MS m / z 507.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.41 (s, 1H), 8.01 (s, 1H), 4.45 (s, 1H), 4.39 - 4.15 (m, 3H), 4.08 (s, 3H), 4.05 - 3.99 (m, 1H), 3.97 (s, 3H), 3.83 (s, 2H), 2.63 - 2.53 (m, 2H), 2.42 (s, 4H), 1.56 - 1.42 (m, 4H), 1.41 - 1.30 (m, 2H).

[0524] Step 4: 5-[4-[3,3-Difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione formate 4-[3,3-Difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-d]pyrimidine (Step 3) and 1M HCl were used to prepare the title compound in a similar manner to Step 4 of Example 3. LC-MS-2 (Method 8A): Rt 2.04 min; MS m / z 479.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 2H), 8.42 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 4.44 (d, J = 7.3 Hz, 1H), 4.28 (s, 2H), 4.18 (s, 1H), 3.97 (d, J = 12.1 Hz, 1H), 3.83 - 3.76 (m, 2H), 2.58 - 2.56 (m, 2H), 2.46 - 2.35 (m, 4H), 1.52 - 1.41 (m, 4H), 1.39 - 1.29 (m, 2H).

[0525] [Example 6] 5-[7-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thiazolo[4,5-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0526] [Chemical formula]

[0527] Step 1: 7-Chloro-2-methylsulfanyl-thiazolo[4,5-d]pyrimidine

[0528] [Chemical formula]

[0529] To a solution of 2-methylsulfanyl-6H-thiazolo[4,5-d]pyrimidin-7-one (500 mg, 2.51 mmol) in phosphorus oxychloride (V) (5.0 mL, 68.55 mmol) was added N,N-dimethylaniline (0.74 mL, 5.88 mmol), and the reaction mixture was stirred at 80 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and azeotroped with chloroform (2 × 15 mL). The residue was triturated with MeCN (about 3 mL), and the resulting solid was collected by filtration and washed with MeCN (2 × 1 mL) to obtain the title compound as a pale yellowish-white solid. LC-MS (Method 2A): Rt 0.74 min; MS m / z 218.5 = [M+H]+ 1H NMR (500 MHz, DMSO) δ 9.01 (s, 1H), 2.89 (s, 3H).

[0530] Step 2: 2-Methylsulfanyl-7-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thiazolo[4,5-d]pyrimidine

[0531]

Chem.

[0532] The title compound was prepared from 7-chloro-2-methylsulfanyl-thiazolo[4,5-d]pyrimidine (Step 1) and 1-(2-pyrrolidin-3-yloxyethyl)piperidine (Intermediate J) in a similar manner to Step 1 of Example 2. LC-MS (Method 2A): Rt 0.46 min; MS m / z 380.1 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 8.39 (s, 1H), 4.26 - 4.18 (m, 1H), 3.92 - 3.62 (m, 4H), 3.61 - 3.50 (m, 2H), 2.80 (s, 3H), 2.47 - 2.41 (m, 2H), 2.41 - 2.23 (m, 4H), 2.18 - 1.99 (m, 2H), 1.51 - 1.38 (m, 4H), 1.38 - 1.26 (m, 2H).

[0533] Step 3: 2-(2,4-Dimethoxypyrimidin-5-yl)-7-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thiazolo[4,5-d]pyrimidine

[0534]

Chem.

[0535] A solution of 2-methylsulfanyl-7-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thiazolo[4,5-d]pyrimidine (100 mg, 0.25 mmol), copper(I) thiophene-2-carboxylate (117 mg, 0.61 mmol), and Pd(PPh3)4 (28 mg, 0.02 mmol) in THF (2 mL) was stirred at room temperature under nitrogen for 10 minutes. (2,4-Dimethoxypyrimidin-5-yl)boronic acid (90 mg, 0.49 mmol) was added and the reaction mixture was heated at 60 °C overnight. Additional Pd(PPh3)4 (28 mg, 0.02 mmol) was added and heating was continued at 60 °C for 4 hours. After cooling the mixture to room temperature, it was partitioned between EtOAc (5 mL) and water (1 mL). The mixture was filtered through a glass fiber filter paper and the precipitate was washed with water (3 mL) and EtOAc (10 mL). The filtrate layer was separated and the organic layer was further washed with 10% aqueous NH4OH (20 mL). The combined aqueous layers were extracted with EtOAc (30 mL) and the combined organic extracts were washed with 10% aqueous NH4OH (3 × 20 mL) until the aqueous layer was no longer blue. The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified by C18 reverse phase chromatography eluting with MeCN in water (+0.1% NH4OH) and then the column was washed with 100% MeOH. The fractions of the MeOH washings containing the desired product were concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS (method 7B): Rt 3.07 min; MS m / z 472.3 = [M+H]+

[0536] Step 4: 5-[7-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thiazolo[4,5-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione The title compound was prepared in a similar manner to Step 3 of Example 2 from 2-(2,4-dimethoxypyrimidin-5-yl)-7-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thiazolo[4,5-d]pyrimidine (Step 3) and 1M HCl. LC-MS (Method 7B): Rt 1.51 min; MS m / z 444.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 2H), 8.62 (s, 1H), 8.40 (s, 1H), 4.28 - 4.23 (m, 1H), 3.96 - 3.88 (m, 1H), 3.88 - 3.82 (m, 2H), 3.80 - 3.72 (m, 1H), 3.65 - 3.55 (m, 2H), 2.55 (t, J = 6.0 Hz, 2H), 2.48 - 2.41 (m, 4H), 2.20 - 2.05 (m, 2H), 1.52 - 1.42 (m, 4H), 1.38 - 1.30 (m, 2H).

[0537] [Example 6.1] 5-[7-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)thiazolo[4,5-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0538] [Chemical Formula]

[0539] Step 1: 7-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-2-methylsulfanyl-thiazolo[4,5-d]pyrimidine

[0540] [Chemical Formula]

[0541] The title compound was prepared in a manner similar to Step 2 of Example 6 from 7-chloro-2-methylsulfanyl-thiazolo[4,5-d]pyrimidine (Example 6, Step 1) and 3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride. LC-MS-1 (Method 2A): Rt 1.37 min; MS m / z 317.5 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 4.23 (t, J = 13.6 Hz, 2H), 3.80 (s, 2H), 2.82 (s, 3H), 1.19 (s, 6H).

[0542] Step 2: 7-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)thiazolo[4,5-d]pyrimidine

[0543]

Chem.

[0544] The title compound was prepared from 7-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-2-methylsulfanyl-thiazolo[4,5-d]pyrimidine (Step 1) and (2,4-dimethoxypyrimidin-5-yl)boronic acid in a similar manner to Step 3 of Example 6. LC-MS-2 (Method 2A): Rt 1.45 min; MS m / z 409.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.55 (s, 1H), 4.39 - 4.28 (m, 2H), 4.22 (s, 3H), 4.04 (s, 3H), 3.92 - 3.84 (m, 2H), 1.23 (s, 6H).

[0545] Step 3: 5-[7-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)thiazolo[4,5-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione The title compound was prepared from 7-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)thiazolo[4,5-d]pyrimidine (Step 2) and 1M HCl in a similar manner to Step 4 of Example 6. LC-MS-2 (Method 8B): Rt 2.48 min; MS m / z 381.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 12.04 (br s, 1H), 11.92 (s, 1H), 8.63 (br s, 1H), 8.50 (s, 1H), 4.28 (t, J = 11.8 Hz, 2H), 3.89 (s, 2H), 1.23 (s, 6H).

[0546] [Example 7] 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione formate

[0547] [Chemical formula]

[0548] Step 1: 6-(2,4-Dimethoxypyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]furo[2,3-d]pyrimidine

[0549] [Chemical formula]

[0550] To a stirred suspension of 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidine (Intermediate C) (200 mg, 0.68 mmol) and 1-(2-pyrrolidin-3-yloxyethyl)piperidine (Intermediate J) (163 mg, 0.82 mmol) in MeCN (5 mL) was added DIPEA (0.48 mL, 2.73 mmol), and the reaction mixture was heated at 70 °C for 90 min. The resulting mixture was cooled to room temperature, filtered, and the solid was washed with MeCN (50 mL). The filtrate was concentrated under reduced pressure and purified by silica chromatography eluting with a gradient of 0-10% 1M NH3 MeOH solution in DCM to give the title compound as a yellow solid. LC-MS-1 (Method 2A): Rt 0.90 min; MS m / z 455.4 = [M+H]+ 1H NMR (500 MHz, acetic acid-d4) δ 8.83 (s, 1H), 8.42 (s, 1H), 7.25 (s, 1H), 4.53 - 4.33 (m, 1H), 4.21 (s, 3H), 4.10 - 3.87 (m, 8H), 3.83 - 3.59 (m, 3H), 3.46 - 3.35 (m, 2H), 3.00 - 2.86 (m, 2H), 2.49 - 2.08 (m, 2H), 1.93 - 1.70 (m, 5H), 1.52 - 1.37 (m, 1H).

[0551] Step 2: 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione formate To a stirred solution of 6-(2,4-dimethoxypyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]furo[2,3-d]pyrimidine (170 mg, 0.37 mmol) in MeOH (4 mL) was added 1 M HCl (3.74 mL, 3.74 mmol), and the mixture was heated at 70 °C for 6 h. After the resulting mixture was cooled to room temperature, it was concentrated under reduced pressure. Purification by C18 reverse-phase chromatography eluting with a gradient of 5 - 30% MeCN in water (+0.1% formic acid) afforded the title compound as a pale yellowish-white solid. LC-MS-2 (Method 8A): Rt 1.73 min; MS m / z 427.1 = [M+H]+ 1H NMR (500 MHz, DMSO-d6 + D2O, @ 343K) δ 8.28 (s, 1H), 8.17 (d, J = 2.3 Hz, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 4.29 (s, 1H), 3.87 - 3.76 (m, 3H), 3.75 - 3.65 (m, 3H), 2.95 - 2.88 (m, 2H), 2.86 - 2.76 (m, 4H), 2.21 - 2.08 (m, 2H), 1.62 - 1.54 (m, 4H), 1.46 - 1.37 (m, 2H).

[0552] [Example 7.1] 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0553] [Chemical Structure]

[0554] Step 1: 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidine

[0555] [Chemical Structure]

[0556] The title compound was prepared in a similar manner to Step 1 of Example 7 from 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidine (Intermediate C) and 3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride. LC-MS-1 (Method 2A): Rt 1.54 min; MS m / z 392.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.31 (s, 1H), 7.28 (s, 1H), 4.48 - 4.17 (m, 2H), 4.11 (s, 3H), 3.96 (s, 3H), 3.87 - 3.66 (m, 2H), 1.22 (s, 6H).

[0557] Step 2: 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidine (Step 1) and 1M HCl were used to prepare the title compound in a similar manner to Step 2 of Example 7. LC-MS-2 (Method 8A): Rt 2.99 min; MS m / z 364.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.61 - 11.43 (m, 2H), 8.29 (s, 1H), 7.95 (s, 1H), 7.37 (s, 1H), 4.23 (s, 2H), 3.91 - 3.70 (m, 2H), 1.21 (s, 6H).

[0558] [Example 8] 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0559] [Chemical Structure]

[0560] Step 1: 4-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)thieno[3,2-d]pyrimidine

[0561] [Chemical Structure]

[0562] The title compound was prepared from 6-bromo-4-chloro-thieno[3,2-d]pyrimidine and (2,4-dimethoxypyrimidin-5-yl)boronic acid in a manner similar to Step 2 of Example 2. LC-MS (Method 7A): Rt 3.29 min; MS m / z 309.5 / 311.4 = [M+H]+ 1H NMR (500 MHz, CDCl3) δ 8.96 (s, 1H), 8.73 (s, 1H), 7.91 (s, 1H), 4.21 (s, 3H), 4.09 (s, 3H).

[0563] Step 2: 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0564]

Chemical formula

[0565] The title compound was prepared from 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)thieno[3,2-d]pyrimidine (Step 1) and 1-(2-pyrrolidin-3-yloxyethyl)piperidine (Intermediate J) in a manner similar to Step 1 of Example 2. The reaction was carried out in NMP at 130 °C to obtain a 3:7 mixture of 2-methoxy-5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-d]pyrimidin-6-yl]-1H-pyrimidin-6-one and 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione.

[0566] The above mixture of 2-methoxy-5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-d]pyrimidin-6-yl]-1H-pyrimidin-6-one and 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione was treated with 1 M HCl similarly to Step 3 of Example 2. LC-MS (Method 7B): Rt 1.56 min; MS m / z 443.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 2H), 8.39 (s, 1H), 8.31 (s, 1H), 7.72 (s, 1H), 4.26 - 4.17 (m, 1H), 3.97 - 3.90 (m, 1H), 3.90 - 3.82 (m, 2H), 3.80 - 3.73 (m, 1H), 3.61 - 3.50 (m, 2H), 2.42 (t, J = 6.1 Hz, 2H), 2.37 - 2.29 (m, 4H), 2.18 - 2.02 (m, 2H), 1.48 - 1.38 (m, 4H), 1.34 - 1.26 (m, 2H).

[0567] [Example 9] 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione

[0568] [Chemical Structure]

[0569] Step 1: 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)thieno[3,2-c]pyridine

[0570] [Chemical Structure]

[0571] The title compound was prepared from 2-bromo-4-chloro-thieno[3,2-c]pyridine and (2,4-dimethoxypyrimidin-5-yl)boronic acid in a similar manner to Step 2 of Example 2. LC-MS-2 (Method 2A): Rt 1.59 min; MS m / z 308.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.23 (d, J = 5.5 Hz, 1H), 8.11 (d, J = 5.5 Hz, 1H), 7.99 (s, 1H), 4.11 (s, 3H), 3.99 (s, 3H).

[0572] Step 2: 5-(4-chlorothieno[3,2-c]pyridin-2-yl)-1H-pyrimidine-2,4-dione

[0573]

Chemical Structure

[0574] The title compound was prepared from 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)thieno[3,2-c]pyridine (Step 1) and 1M HCl in a similar manner to Step 3 of Example 2. LC-MS-2 (Method 2A): Rt 1.05 min; MS m / z 279.9 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.71 (d, J = 5.8 Hz, 1H), 11.66 (s, 1H), 8.52 (d, J = 5.9 Hz, 1H), 8.15 (d, J = 5.4 Hz, 1H), 8.03 (d, J = 5.5 Hz, 1H), 7.98 (s, 1H).

[0575] Step 3: 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione 4-Chloro-2-(2,4-dimethoxypyrimidin-5-yl)thieno[3,2-c]pyridine (Step 2) and 1-(2-pyrrolidin-3-yloxyethyl)piperidine (Intermediate J) were used to prepare the title compound in a similar manner to Step 1 of Example 2. The reaction was carried out at 120 °C in NMP. LC-MS-2 (Method 8B): Rt 2.29 min; MS m / z 442.1 = [M+H]+ 1H NMR (400 MHz, acetic acid-d4) δ 8.47 (s, 1H), 8.31 (s, 1H), 7.70 (d, J = 6.9 Hz, 1H), 7.40 (d, J = 6.9 Hz, 1H), 4.51 (s, 1H), 4.27 - 4.09 (m, 4H), 4.02 - 3.91 (m, 2H), 3.65 (d, J = 12.2 Hz, 2H), 3.45 - 3.34 (m, 2H), 3.01 - 2.86 (m, 2H), 2.50 - 2.39 (m, 1H), 2.31 - 2.21 (m, 1H), 1.87 - 1.78 (m, 4H), 1.78 - 1.68 (m, 1H), 1.55 - 1.38 (m, 1H).

[0576] [Example 10] 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]pyrimidine-2,4-diol

[0577] [Chemical formula]

[0578] Step 1: 6-Bromo-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine

[0579] [Chemical formula]

[0580] A solution of 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.32 mmol), 1-(2-pyrrolidin-3-yloxyethyl)piperidine (Intermediate J) (70 mg, 0.35 mmol), and DIPEA (112 μL, 0.65 mmol) in EtOH (0.5 mL) was stirred at room temperature for 1 hour. The resulting solid was removed by vacuum filtration, and the filtrate was concentrated under reduced pressure. Purification by silica chromatography eluting with a gradient of 0 - 15% MeOH in DCM gave the title compound as a colorless glassy solid. LC-MS (Method 2B): Rt 0.81 min; MS m / z 394.2 / 396.2 = [M+H]+ 1H NMR (500 MHz, CDCl3) δ 7.80 (s, 1H), 7.52 (d, J = 1.6 Hz, 1H), 6.74 (s, 1H), 4.38 - 4.20 (m, 1H), 4.05 - 3.93 (m, 4H), 3.88 - 3.81 (m, 1H), 3.78 - 3.67 (m, 1H), 2.94 - 2.75 (m, 6H), 2.41 - 1.97 (m, 2H), 1.88 - 1.78 (m, 4H), 1.58 - 1.47 (m, 2H).

[0581] Step 2: 6-(2,4-Dimethoxypyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine

[0582]

Chemical Structure

[0583] 6-Bromo-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine (Step 1) (30 mg, 0.08 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (21 mg, 0.11 mmol), and cesium carbonate (74 mg, 0.23 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) were degassed for 5 minutes and treated with Pd(dppf)Cl2·DCM (3 mg, 3.8 μmol). The reaction mixture was heated at 100 °C overnight and then cooled to room temperature. The resulting mixture was diluted with EtOAc and filtered through a magnesium sulfate plug. The filtrate was concentrated under reduced pressure and purified by silica chromatography eluting with a gradient of 0 - 20% 1M NH3 MeOH in DCM to give the title compound as a brown oil. LC-MS (Method 7B): Rt 3.33 min; MS m / z 454.7 = [M+H]+ 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.85 (s, 1H), 7.00 (s, 1H), 4.32 - 4.13 (m, 3H), 4.11 (s, 3H), 4.03 (s, 3H), 4.01 - 3.96 (m, 2H), 3.67 - 3.59 (m, 2H), 2.58 - 2.51 (m, 2H), 2.46 - 2.37 (m, 4H), 2.34 - 2.00 (m, 2H), 1.60 - 1.52 (m, 4H), 1.45 - 1.34 (m, 2H).

[0584] Step 3: 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]pyrimidine-2,4-diol 6-(2,4-Dimethoxypyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine (Step 2) (37 mg, 0.04 mmol) was heated overnight at 70 °C in a solution of 1 M HCl (500 μL, 0.5 mmol) and MeOH (0.5 mL). The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was dissolved in 3:1:1 DMSO:MeCN:H2O (1.4 mL) and purified by preparative HPLC under basic conditions (details below) to give the title compound as a colorless powder. LC-MS (Method 7B): Rt 1.87 min; MS m / z 426.3 = [M+H]+ 1H NMR (500 MHz, methanol-d4) δ 8.10 (d, J = 1.7 Hz, 1H), 7.88 (s, 1H), 7.71 (s, 1H), 7.27 (d, J = 1.7 Hz, 1H), 4.60 - 4.56 (m, 1H), 4.28 - 4.04 (m, 4H), 3.72 - 3.66 (m, 2H), 2.60 (t, J = 5.7 Hz, 2H), 2.56 - 2.42 (m, 4H), 2.25 - 2.16 (m, 1H), 2.14 - 2.02 (m, 1H), 1.60 - 1.53 (m, 4H), 1.47 - 1.39 (m, 2H).

[0585] Purification conditions: Waters XBridge C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature). Flow rate 40 mL / min with an injection volume of 1500 μL. 10% B (A = 0.2% ammonium hydroxide in water, B = 0.2% ammonium hydroxide in acetonitrile) for 2.0 min, then a gradient of 10 - 95% B over 14.0 min, held for 2.0 min. Next, a second gradient of 95 - 10% B was applied over 0.2 min and held for 0.9 min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0586] [Example 10.1] 5-[4-[3-[2-(4,4-Difluoro-1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione

[0587]

Chem.

[0588] Step 1: 6-Bromo-4-[3-[2-(4,4-difluoro-1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine

[0589]

Chem.

[0590] The title compound was prepared in a manner similar to Step 1 of Example 10 from 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine and 4,4-difluoro-1-(2-pyrrolidin-3-yloxyethyl)piperidine dihydrochloride (Intermediate B). LC-MS-2 (Method 2B): Rt 1.59 min; MS m / z 430.0 / 431.9 = [M+H]+ 1H NMR (400 MHz, methanol-d4) δ 7.74 (s, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.00 (d, J = 1.7 Hz, 1H), 4.41 - 4.19 (m, 1H), 4.15 - 3.80 (m, 3H), 3.77 - 3.60 (m, 3H), 2.70 - 2.55 (m, 6H), 2.44 - 2.00 (m, 2H), 2.00 - 1.85 (m, 4H).

[0591] Step 2: 4-[3-[2-(4,4-Difluoro-1-piperidyl)ethoxy]pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine

[0592] [Chem.]

[0593] 6-Bromo-4-[3-[2-(4,4-difluoro-1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine (Step 1) and (2,4-dimethoxypyrimidin-5-yl)boronic acid were used to prepare the title compound in a similar manner to Step 2 of Example 10. LC-MS-1 (Method 2A): Rt 0.95 min; MS m / z 490.4 = [M+H]+ 1H NMR (400 MHz, methanol-d4) δ 8.67 (br s, 1H), 8.04 - 7.99 (m, 1H), 7.75 (s, 1H), 7.35 - 7.28 (m, 1H), 4.40 - 4.11 (m, 6H), 4.06 - 3.83 (m, 4H), 3.81 - 3.63 (m, 3H), 2.43 - 2.04 (m, 2H), 2.70 - 2.57 (m, 6H), 2.02 - 1.85 (m, 4H).

[0594] Step 3: 5-[4-[3-[2-(4,4-difluoro-1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione 4-[3-[2-(4,4-difluoro-1-piperidyl)ethoxy]pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine (Step 2) and 1M HCl were used to prepare the title compound in a similar manner to Step 3 of Example 10. LC-MS-1 (Method 8A): Rt 1.48 min; MS m / z 462.3 = [M+H]+ 1H NMR (400 MHz, deuterated acetic acid) δ 8.35 - 8.27 (m, 1H), 8.07 (d, J = 3.5 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 5.5 Hz, 1H), 4.55 - 4.40 (m, 1H), 4.35 - 4.14 (m, 2H), 4.14 - 3.85 (m, 4H), 3.78 - 3.35 (m, 6H), 2.53 - 2.22 (m, 6H).

[0595] [Example 10.2] 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione

[0596] [Chemical formula]

[0597] Step 1: 6-Bromo-4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine

[0598] [Chemical formula]

[0599] The title compound was prepared in a similar manner to Step 1 of Example 10 from 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine and 3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride. LC-MS-1 (Method 2A): Rt 1.46 min; MS m / z 331.1 / 333.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 1.7 Hz, 1H), 7.90 (s, 1H), 7.12 (d, J = 1.7 Hz, 1H), 4.50 (m, 1H), 4.17 - 4.10 (m, 1H), 4.01 (s, 1H), 3.67 (s, 1H), 1.18 (s, 6H).

[0600] Step 2: 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine

[0601]

Chem.

[0602] The title compound was prepared in a similar manner to Step 2 of Example 10 from 6-bromo-4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine (Step 1) and (2,4-dimethoxypyrimidin-5-yl)boronic acid. LC-MS-2 (Method 2A): Rt 1.69 min; MS m / z 391.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.89 (s, 1H), 7.45 (d, J = 1.7 Hz, 1H), 4.58 (s, 1H), 4.06 (m, 5H), 3.94 (s, 3H), 3.73 (s, 1H), 1.21 (s, 6H).

[0603] Step 3: 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine (Step 2) and 1M HCl were used to prepare the title compound in a similar manner to Step 3 of Example 10. LC-MS-2 (Method 8A): Rt 2.79 min; MS m / z 363.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 2H), 8.18 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.28 (d, J = 1.6 Hz, 1H), 4.41 - 4.25 (m, 2H), 3.88 (s, 2H), 1.22 (s, 6H).

[0604] [Example 11] 2-(2,4-Dioxo-1H-pyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-b]pyridine-5-carbonitrile

[0605]

Chemical Structure

[0606] Step 1: 4-Chloro-2-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-b]pyridine-5-carbonitrile

[0607]

Chemical Structure

[0608] The title compound was prepared from 4-chloro-2-iodo-thieno[2,3-b]pyridine-5-carbonitrile and (2,4-dimethoxypyrimidin-5-yl)boronic acid in a similar manner to Step 2 of Example 2. LC-MS (Method 2A): Rt 1.01 min; MS m / z 332.9 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.98 (s, 1H), 8.09 (s, 1H), 4.12 (s, 3H), 4.00 (s, 3H).

[0609] Step 2: 2-(2,4-Dimethoxypyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-b]pyridine-5-carbonitrile

[0610]

Chem.

[0611] The title compound was prepared in a similar manner to Step 1 of Example 2 from 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)thieno[2,3-b]pyridine-5-carbonitrile (Step 1) and 1-(2-pyrrolidin-3-yloxyethyl)piperidine (Intermediate J). The reaction was carried out at 80 °C in DMA. LC-MS (Method 2A): Rt 0.71 min; MS m / z 495.5 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 4.38 - 4.34 (m, 1H), 4.29 (dd, J = 11.4, 3.8 Hz, 1H), 4.25 - 4.17 (m, 1H), 4.10 - 4.03 (m, 5H), 3.97 (s, 3H), 3.90 - 3.82 (m, 2H), 3.39 (s, 2H), 3.25 (s, 2H), 2.93 - 2.83 (m, 2H), 2.30 - 2.22 (m, 1H), 2.14 - 2.04 (m, 1H), 1.81 - 1.59 (m, 6H).

[0612] Step 3: 2-(2,4-Dioxo-1H-pyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-b]pyridine-5-carbonitrile 2-(2,4-Dimethoxypyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-b]pyridine-5-carbonitrile (Step 2) and the title compound was prepared in a similar manner to Step 3 of Example 2 from 1M HCl. LC-MS (Method 7A): Rt 1.38 min; MS m / z 467.5 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 2H), 8.33 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 4.27 - 4.18 (m, 2H), 4.18 - 4.04 (m, 1H), 4.02 - 3.95 (m, 1H), 3.94 - 3.87 (m, 1H), 3.63 - 3.52 (m, 2H), 2.45 - 2.39 (m, 2H), 2.36 - 2.25 (m, 4H), 2.17 - 2.10 (m, 1H), 2.08 - 1.98 (m, 1H), 1.48 - 1.36 (m, 4H), 1.35 - 1.26 (m, 2H).

[0613] [Example 12] 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione hydrochloride

[0614] [Chemical Structure]

[0615] Step 1: 2-(2,4-Dimethoxypyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrazolo[3,4-d]pyrimidine

[0616] [Chem.]

[0617] A solution of 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) (100 mg, 0.34 mmol), 1-(2-pyrrolidin-3-yloxyethyl)piperidine (Intermediate J) (75 mg, 0.38 mmol), and DIPEA (0.18 mL, 1.03 mmol) in MeCN (1.5 mL) was stirred at 80 °C for 5 hours and 45 minutes. After cooling to room temperature, the resulting suspension was filtered, and the collected solid was dried under reduced pressure to obtain the title compound as a colorless solid. LC-MS (Method 7B): Rt 2.56 min; MS m / z 455.6 = [M+H]+ 1H NMR (500 MHz, CDCl3) δ 9.03 - 8.87 (m, 1H), 8.50 - 8.39 (m, 2H), 4.40 - 4.21 (m, 1H), 4.15 (s, 3H), 4.11 - 4.04 (m, 3H), 4.06 - 3.58 (m, 6H), 2.65 - 2.02 (m, 8H), 1.60 - 1.52 (m, 4H), 1.46 - 1.36 (m, 2H).

[0618] Step 2: 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione hydrochloride 2-(2,4-Dimethoxypyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrazolo[3,4-d]pyrimidine (Step 1) (47 mg, 0.1 mmol) was dissolved in MeOH (1 mL). 1M HCl (1 mL, 1.03 mmol) was added, and the mixture was stirred at 70 °C overnight. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to obtain the title compound as an orange solid. LC-MS (Method 7B): Rt 1.37 min; MS m / z 427.4 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.96 - 11.85 (m, 1H), 11.86 - 11.68 (m, 1H), 10.67 - 10.39 (m, 1H), 9.37 - 9.17 (m, 1H), 8.75 - 8.56 (m, 1H), 8.32 - 8.16 (m, 1H), 4.54 - 4.33 (m, 1H), 4.21 - 4.04 (m, 3H), 4.02 - 3.77 (m, 3H), 3.42 - 3.30 (broad m, 2H), 3.26 - 3.14 (m, 2H), 2.95 - 2.80 (m, 2H), 2.43 - 2.09 (m, 2H), 1.89 - 1.54 (m, 5H), 1.44 - 1.21 (m, 1H).

[0619] [Example 13] 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0620] [Chemical Structure]

[0621] Step 1: 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine

[0622] [Chemical Structure]

[0623] A stirred suspension of 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) (150 mg, 0.51 mmol) and 3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride (106 mg, 0.62 mmol) in MeCN (3 mL) was added with DIPEA (0.27 mL, 1.54 mmol) under nitrogen, and the reaction mixture was heated at 70 °C for 5 minutes. When the mixture was cooled to room temperature, a solid precipitated. The solid was collected by filtration and washed with water (10 mL). The crude material was purified by silica chromatography eluting with a gradient of 0 - 10% MeOH in DCM to give the title compound as a pale yellowish-white solid. LC-MS-1 (Method 2A): Rt 1.09 min; MS m / z 392.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.72 (s, 1H), 8.32 (s, 1H), 4.40 (t, J = 13. Hz, 1H), 4.17 (t, J = 13.5 Hz, 1H), 4.05 - 3.98 (m, 6H), 3.89 (s, 1H), 3.74 (s, 1H), 1.28 - 1.13 (m, 6H).

[0624] Step 2: 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione A stirred solution of 4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Step 1) (182 mg, 0.47 mmol) in MeOH (3 mL) and 1M HCl (4.65 mL, 4.65 mmol) was heated at 70 °C for 4.5 hours. The resulting mixture was concentrated under reduced pressure, and the crude material was treated with water (30 mL) to precipitate a solid. The solid was collected by filtration and washed with water (20 mL), MeCN (2 × 20 mL), and diethyl ether (2 × 20 mL) to give the title compound as a peach-colored solid. LC-MS-1 (Method 8A): Rt 1.94 min; MS m / z 364.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 11.76 - 11.65 (m, 1H), 9.22 (d, J = 9.8 Hz, 1H), 8.66 (d, J = 3.6 Hz, 1H), 8.25 - 8.17 (m, 1H), 4.57 (t, J = 13.1 Hz, 1H), 4.36 (t, J = 13.1 Hz, 1H), 4.01 (s, 1H), 3.90 (s, 1H), 1.25 (s, 3H), 1.21 (s, 3H).

[0625] [Example 13.1] 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0626] [Chemical Formula]

[0627] Step 1: 4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine

[0628] [Chemical Formula]

[0629] The title compound was prepared in a manner similar to Step 1 of Example 13 from 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) and 7,7-difluoro-5-azaspiro[2.4]heptane hydrochloride. LC-MS-2 (Method 2A): Rt 1.17 min; MS m / z 390.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 9.01 - 8.82 (m, 1H), 8.73 (s, 1H), 8.34 (s, 1H), 4.54 - 4.44 (m, 1H), 4.33 - 4.23 (m, 1H), 4.12 (s, 1H), 4.05 - 3.99 (m, 6H), 3.94 (s, 1H), 1.12 - 1.03 (m, 2H), 1.02 - 0.96 (m, 2H).

[0630] Step 2: 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione 4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Step 1) and 1M HCl were used to prepare the title compound in a similar manner to Step 2 of Example 13. LC-MS-2 (Method 8A): Rt 1.89 min; MS m / z 362.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 11.36 (s, 1H), 8.98 (s, 1H), 8.37 (s, 1H), 8.14 (d, J = 5.4 Hz, 1H), 4.38 (t, J = 11.9 Hz, 2H), 4.06 (s, 2H), 1.12 - 1.05 (m, 2H), 1.05 - 0.98 (m, 2H).

[0631] [Example 13.2] 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0632] [Chemical Structure]

[0633] Step 1: 4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine

[0634]

Chem.

[0635] The title compound was prepared from 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) and 8,8-difluoro-6-azaspiro[3.4]octane hydrochloride in a similar manner to Step 1 of Example 13. LC-MS-1 (Method 2B): Rt 1.29 min; MS m / z 404.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 9.05 - 8.88 (m, 1H), 8.72 (d, J = 3.6 Hz, 1H), 8.32 (d, J = 5.8 Hz, 1H), 4.31 (t, J = 12.8 Hz, 1H), 4.23 - 3.92 (m, 9H), 2.41 - 2.28 (m, 2H), 2.14 - 1.94 (m, 3H), 1.94 - 1.75 (m, 1H).

[0636] Step 2: 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione The title compound was prepared from 4-(8,8-difluoro-6-azaspiro[3.4]octan-6-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Step 1) and 1M HCl in a similar manner to Step 2 of Example 13. LC-MS-1 (Method 8A): Rt 2.05 min; MS m / z 376.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 11.55 (s, 1H), 9.06 - 8.92 (m, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 4.35 - 4.23 (m, 1H), 4.17 - 3.93 (m, 3H), 2.37 - 2.30 (m, 2H), 2.16 - 1.95 (m, 3H), 1.93 - 1.82 (m, 1H).

[0637] [Example 13.3] 5-[4-(4,4-Difluoro-2-azaspiro[4.4]nonan-2-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0638] [Chemical formula]

[0639] Step 1: 4-(4,4-Difluoro-2-azaspiro[4.4]nonan-2-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine

[0640] [Chemical formula]

[0641] The title compound was prepared from 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) and 4,4-difluoro-2-azaspiro[4.4]nonane hydrochloride in a similar manner to Step 1 of Example 13. LC-MS-1 (Method 2A): Rt 1.20 min; MS m / z 418.5 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 9.00 - 8.91 (m, 1H), 8.74 - 8.65 (m, 1H), 8.32 (s, 1H), 4.36 (t, J = 13.0 Hz, 1H), 4.12 (t, J = 13.0 Hz, 1H), 4.06 - 3.99 (m, 6H), 3.93 (s, 1H), 3.80 (s, 1H), 2.02 - 1.87 (m, 2H), 1.77 - 1.58 (m, 6H).

[0642] Step 2: 5-[4-(4,4-Difluoro-2-azaspiro[4.4]nonan-2-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione 4-(4,4-Difluoro-2-azaspiro[4.4]nonan-2-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Step 1) and 1M HCl were used to prepare the title compound in a similar manner to Step 2 of Example 13. LC-MS-1 (Method 8A): Rt 2.27 min; MS m / z 390.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 11.67 (d, J = 5.9 Hz, 1H), 9.19 (s, 1H), 8.60 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 4.49 (t, J = 12.6 Hz, 1H), 4.28 (t, J = 12.9 Hz, 1H), 4.02 (s, 1H), 3.93 (s, 1H), 2.02 - 1.86 (m, 2H), 1.79 - 1.61 (m, 6H).

[0643] [Example 13.4] 5-[4-[(3aR,6aS)-3,3a,4,5,6,6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0644] [Chemical formula]

[0645] Step 1: 4-[(3aR,6aS)-3,3a,4,5,6,6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine

[0646] [Chemical formula]

[0647] The title compound was prepared from 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) and (3aR,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole hydrochloride in a similar manner to Step 1 of Example 13. LC-MS-1 (Method 2A): Rt 1.01 min; MS m / z 368.5 = [M+H]+ 1H NMR (400 MHz, methanol-d4) δ 8.78 (s, 1H), 8.71 (s, 1H), 8.24 (s, 1H), 4.22 - 4.10 (m, 4H), 4.09 (s, 3H), 4.07 - 3.97 (m, 1H), 3.74 - 3.59 (m, 2H), 3.06 - 2.95 (m, 1H), 2.95 - 2.80 (m, 1H), 2.09 - 1.94 (m, 2H), 1.94 - 1.84 (m, 1H), 1.80 - 1.72 (m, 1H), 1.72 - 1.57 (m, 2H).

[0648] Step 2: 5-[4-[(3aR,6aS)-3,3a,4,5,6,6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione 4-[(3aR,6aS)-3,3a,4,5,6,6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Step 1) and the title compound was prepared from 1M HCl in a similar manner to Step 2 of Example 13. LC-MS-1 (Method 8A): Rt 1.70 min; MS m / z 340.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 11.57 (d, J = 6.4 Hz, 1H), 9.03 (s, 1H), 8.36 (s, 1H), 8.19 (d, J = 6.2 Hz, 1H), 4.12 - 4.02 (m, 1H), 4.02 - 3.92 (m, 1H), 3.67 - 3.51 (m, 2H), 2.98 - 2.88 (m, 1H), 2.84 - 2.74 (m, 1H), 1.94 - 1.73 (m, 3H), 1.68 - 1.46 (m, 3H).

[0649] [Example 13.5] 5-[4-(3-Ethyl-3-methyl-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0650] [Chemical Structure]

[0651] Step 1: 2-(2,4-Dimethoxypyrimidin-5-yl)-4-(3-ethyl-3-methyl-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidine

[0652] [Chemical Structure]

[0653] 4-Chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) and 3-ethyl-3-methyl-pyrrolidine were used to prepare the title compound in a similar manner to Step 1 of Example 13. LC-MS-2 (Method 2A): Rt 1.18 min; MS m / z 370.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.70 (s, 1H), 8.24 (s, 1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.93 - 3.69 (m, 2H), 3.64 - 3.43 (m, 2H), 1.87 (m, 2H), 1.51 (q, J = 7.5 Hz, 2H), 1.09 (s, 3H), 0.94 (t, J = 7.5 Hz, 3H).

[0654] Step 2: 5-[4-(3-Ethyl-3-methyl-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione 2-(2,4-Dimethoxypyrimidin-5-yl)-4-(3-ethyl-3-methyl-pyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidine (Step 1) and 1M HCl were used to prepare the title compound in a similar manner to Step 2 of Example 13. LC-MS-2 (Method 8A): Rt 2.01 min; MS m / z 342.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 11.53 (s, 1H), 9.19 (s, 1H), 8.51 (s, 1H), 8.15 (s, 1H), 4.08 - 3.88 (m, 2H), 3.74 - 3.61 (m, 2H), 2.11 - 1.80 (m, 2H), 1.61 - 1.45 (m, 2H), 1.18 - 1.05 (m, 3H), 1.02 - 0.88 (m, 3H).

[0655] [Example 13.6] 5-[4-(3,3-Dimethylpyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0656]

Chem.

[0657] Step 1: 2-(2,4-Dimethoxypyrimidin-5-yl)-4-(3,3-dimethylpyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidine

[0658]

Chem.

[0659] The title compound was prepared in a similar manner to Step 1 of Example 13 from 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) and 3,3-dimethylpyrrolidine hydrochloride. LC-MS-2 (Method 2A): Rt 1.10 min; MS m / z 356.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.70 (s, 1H), 8.24 (s, 1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.95 - 3.73 (m, 2H), 3.54 (s, 2H), 1.87 (m, 2H), 1.16 (s, 6H).

[0660] Step 2: 5-[4-(3,3-Dimethylpyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione The title compound was prepared in a similar manner to Step 2 of Example 13 from 2-(2,4-dimethoxypyrimidin-5-yl)-4-(3,3-dimethylpyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidine (Step 1) and 1M HCl. LC-MS-2 (Method 8A): Rt 1.80 min; MS m / z 328.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 11.29 (s, 1H), 8.90 (s, 1H), 8.21 (d, J = 5.0 Hz, 1H), 8.12 (s, 1H), 3.87 - 3.71 (m, 2H), 3.52 (s, 2H), 2.01 - 1.76 (m, 2H), 1.15 (s, 6H).

[0661] [Example 13.7] 5-[4-(3,3-Diethylpyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0662] [Chemical Structure]

[0663] Step 1: 4-(3,3-Diethylpyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine

[0664] [Chemical Structure]

[0665] The title compound was prepared in a manner similar to Step 1 of Example 13 from 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) and 3,3-diethylpyrrolidine. LC-MS-2 (Method 2A): Rt 1.24 min; MS m / z 384.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.71 (s, 1H), 8.25 (s, 1H), 4.05 (s, 3H), 4.04 (s, 3H), 3.91 - 3.69 (m, 2H), 3.56 (s, 2H), 1.99 - 1.78 (m, 2H), 1.50 (q, J = 7.6 Hz, 4H), 0.90 (t, J = 7.6 Hz, 6H).

[0666] Step 2: 5-[4-(3,3-Diethylpyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione 4-(3,3-Diethylpyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Step 1) and 1M HCl were used to prepare the title compound in a similar manner to Step 2 of Example 13. LC-MS-2 (Method 8A): Rt 2.29 min; MS m / z 356.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 2H), 8.91 (s, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 3.86 - 3.75 (m, 2H), 3.53 (s, 2H), 1.99 - 1.75 (m, 2H), 1.48 (q, J = 7.6 Hz, 4H), 0.89 (t, J = 7.6 Hz, 6H).

[0667] [Example 13.8] 5-[4-(3,3,4,4-Tetrafluoropyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0668] [Chemical Structure]

[0669] Step 1: 2-(2,4-Dimethoxypyrimidin-5-yl)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidine

[0670]

Chem.

[0671] The title compound was prepared from 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) and 3,3,4,4-tetrafluoropyrrolidine hydrochloride in a similar manner to Step 1 of Example 13. LC-MS-2 (Method 2B): Rt 1.36 min; MS m / z 400.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.74 (s, 1H), 8.41 (s, 1H), 4.78 - 4.57 (m, 2H), 4.57 - 4.35 (m, 2H), 4.04 (s, 3H), 4.02 (s, 3H).

[0672] Step 2: 5-[4-(3,3,4,4-Tetrafluoropyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione The title compound was prepared from 2-(2,4-dimethoxypyrimidin-5-yl)-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidine (Step 1) and 1M HCl in a similar manner to Step 2 of Example 13. LC-MS-2 (Method 8A): Rt 2.09 min; MS m / z 371.9 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 11.45 - 11.34 (m, 1H), 9.09 (s, 1H), 8.43 (s, 1H), 8.15 (d, J = 5.9 Hz, 1H), 4.57 (t, J = 13.9 Hz, 4H).

[0673] [Example 13.9] 5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0674] [Chemical Formula]

[0675] Step 1: (3aR,6aS)-5-[2-(2,4-Dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrole

[0676] [Chemical Formula]

[0677] The title compound was prepared from 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) and (3aS,6aR)-3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride in a similar manner to Step 1 of Example 13. LC-MS-2 (Method 2A): Rt 0.93 min; MS m / z 370.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.71 (s, 1H), 8.26 (s, 1H), 4.04 (m, 8H), 3.91 - 3.84 (m, 2H), 3.74 (dd, J = 12.2, 3.3 Hz, 2H), 3.68 (dd, J = 9.0, 2.9 Hz, 2H), 3.17 - 3.12 (m, 2H).

[0678] Step 2: 5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione (3aR,6aS)-5-[2-(2,4-Dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrole (Step 1) and the title compound was prepared in a similar manner to Step 2 of Example 13 from 1M HCl. LC-MS-1 (Method 8B): Rt 1.14 min; MS m / z 342.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 2H), 8.92 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 4.06 - 3.96 (m, 2H), 3.91 - 3.83 (m, 2H), 3.75 - 3.62 (m, 4H), 3.18 - 3.12 (m, 2H).

[0679] [Example 13.10] 5-[4-[(3aR,6aR)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-5H-pyrimidine-2,4-dione

[0680] [Chemical Structure]

[0681] Step 1: (3aR,6aR)-5-[2-(2,4-Dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrole

[0682] [Chemical Structure]

[0683] The title compound was prepared from 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) and (3aR,6aR)-3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride in a similar manner to Step 1 of Example 13. LC-MS-1 (Method 2A): Rt 0.73 min; MS m / z 370.2 = [M+H]+ 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 4.48 - 4.39 (m, 1H), 4.18 (s, 3H), 4.13 (dt, J = 7.0, 3.8 Hz, 2H), 4.09 (s, 3H), 3.78 (t, J = 10.1 Hz, 1H), 3.69 - 3.62 (m, 3H), 3.13 - 3.05 (m, 1H), 2.87 - 2.77 (m, 1H), 2.75 - 2.66 (m, 1H).

[0684] Step 2: 5-[4-[(3aR,6aR)-1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl]pyrazolo[3,4-d]pyrimidin-2-yl]-5H-pyrimidine-2,4-dione (3aR,6aR)-5-[2-(2,4-Dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrole (Step 1) and 1M HCl were used to prepare the title compound in a similar manner to Step 2 of Example 13. LC-MS-1 (Method 8B [0-10%]): Rt 0.38 min; MS m / z 342.2 = [M+H]+ 1H NMR (400 MHz, deuterated acetic acid - d4) δ 9.36 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 4.49 - 4.42 (m, 1H), 4.31 (dd, J = 10.2, 6.9 Hz, 1H), 4.21 (q, J = 6.7 Hz, 2H), 3.93 (t, J = 10.7 Hz, 1H), 3.79 - 3.60 (m, 3H), 2.95 - 2.86 (m, 1H), 2.84 - 2.76 (m, 1H).

[0685] [Example 13.11] 5 - [4 - (3,3 - Difluoro - 4 - methoxypyrrolidin - 1 - yl)pyrazolo[3,4 - d]pyrimidin - 2 - yl] - 1H - pyrimidine - 2,4 - dione

[0686] [Chemical Structure]

[0687] Step 1: 4 - (3,3 - Difluoro - 4 - methoxypyrrolidin - 1 - yl) - 2 - (2,4 - dimethoxypyrimidin - 5 - yl)pyrazolo[3,4 - d]pyrimidine

[0688] [Chemical Structure]

[0689] The title compound was prepared from 4 - chloro - 2 - (2,4 - dimethoxypyrimidin - 5 - yl)pyrazolo[3,4 - d]pyrimidine (Intermediate E) and 3,3 - difluoro - 4 - methoxypyrrolidine hydrochloride in a similar manner to Step 1 of Example 13. LC - MS - 1 (Method 2A): Rt 0.95 min; MS m / z 394.4 = [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 11.9 Hz, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 4.52 - 4.22 (m, 3H), 4.22 - 4.10 (m, 1H), 4.07 - 3.89 (m, 7H), 3.29 (s, 3H).

[0690] Step 2: 5-[4-(3,3-Difluoro-4-methoxypyrrolidin-1-yl)pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione 4-(3,3-Difluoro-4-methoxypyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Step 1) and 1M HCl were used to prepare the title compound in a similar manner to Step 2 of Example 13. LC-MS-2 (Method 8A): Rt 1.70 min; MS m / z 366.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 2H), 8.99 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 4.39 - 4.30 (m, 1H), 4.27 - 4.04 (m, 3H), 3.93 - 3.83 (m, 1H), 3.51 (s, 3H).

[0691] [Example 14] 5-[4-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[2,3-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione

[0692] [Chemical Structure]

[0693] The title compound was prepared in a similar manner to Step 1 of Example 13 from 5-(4-chlorothieno[2,3-b]pyridin-2-yl)-1H-pyrimidine-2,4-dione hydrochloride (Intermediate F) and 1-(2-pyrrolidin-3-yloxyethyl)piperidine (Intermediate J). The reaction was carried out in NMP at 120 °C. LC-MS-2 (Method 8B): Rt 2.29 min; MS m / z 442.1 = [M+H]+ 1H NMR (400 MHz, acetic acid-d4) δ 8.39 (s, 1H), 8.21 (d, J = 7. Hz, 1H), 8.05 (s, 1H), 6.68 (d, J = 7.2 Hz, 1H), 4.51 (s, 1H), 4.33 - 3.86 (m, 6H), 3.76 - 3.63 (m, 2H), 3.50 - 3.40 (m, 2H), 3.05 - 2.88 (m, 2H), 2.51 - 2.39 (m, 1H), 2.33 - 2.20 (m, 1H), 1.94 - 1.72 (m, 5H), 1.55 - 1.40 (m, 1H).

[0694] [Example 14.1] 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)thieno[2,3-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione

[0695] [Chemical Structure]

[0696] The title compound was prepared in a similar manner to Step 1 of Example 13 from 5-(4-chlorothieno[2,3-b]pyridin-2-yl)-1H-pyrimidine-2,4-dione hydrochloride (Intermediate F) and 3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride. The reaction was carried out in NMP at 120 °C. LC-MS-1 (Method 8A): Rt 2.05 min; MS m / z 379.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 2H), 8.29 (s, 1H), 8.06 (d, J = 5.7 Hz, 1H), 7.85 (s, 1H), 6.38 (d, J = 5.7 Hz, 1H), 4.26 (t, J = 13.8 Hz, 2H), 3.65 (s, 2H), 1.21 (s, 6H).

[0697] [Example 15] 5-[6-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]-9H-purin-8-yl]-1H-pyrimidine-2,4-dione

[0698] [Chemical formula]

[0699] Step 1: 8-Bromo-6-chloro-9-tetrahydropyran-2-yl-purine

[0700] [Chemical formula]

[0701] A solution of 6-chloro-9-tetrahydropyran-2-yl-purine (1.50 g, 6.28 mmol) in THF (10 mL) was added to a solution of 2M LDA in THF / n-heptane / ethylbenzene (4.71 mL, 9.43 mmol) in THF (10 mL) at -78 °C, and the resulting mixture was stirred at this temperature for 1 hour. A solution of 1,2-dibromo-1,1,2,2-tetrachloro-ethane (4.09 g, 12.57 mmol) in THF (10 mL) was added to this mixture, and the reaction mixture was stirred at -78 °C for an additional 1 hour. Saturated aqueous NH4Cl (10 mL) was added, and the reaction mixture was warmed to room temperature and stirred for 30 minutes. The resulting mixture was concentrated under reduced pressure to remove THF, and the aqueous mixture was extracted with DCM (3 × 15 mL). The combined organic extracts were passed through a hydrophobic frit and concentrated under reduced pressure. Purification by silica chromatography eluting with a gradient of 0 - 50% EtOAc in heptane afforded the title compound as an orange oil. LC-MS (Method 2A): Rt 0.78 min; MS m / z 319.4 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 5.73 (dd, J = 11.1, 2.3 Hz, 1H), 4.12 - 4.02 (m, 1H), 3.76 - 3.63 (m, 1H), 3.05 - 2.88 (m, 1H), 2.06 - 1.92 (m, 2H), 1.83 - 1.56 (m, 3H).

[0702] Step 2: 6-Chloro-8-(2,4-dimethoxypyrimidin-5-yl)-9-tetrahydropyran-2-yl-purine

[0703]

Chem.

[0704] 8-Bromo-6-chloro-9-tetrahydropyran-2-yl-purine (Step 1) (500 mg, 1.57 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (319 mg, 1.73 mmol), and Pd(dppf)Cl2 (115 mg, 0.16 mmol) were suspended in an aqueous solution of 1 M sodium carbonate (3.94 mL, 3.94 mmol) and 1,4-dioxane (10 mL), degassed with nitrogen for 5 minutes, and heated at 60 °C for 2 hours. The mixture was diluted with water (20 mL), and the resulting suspension was collected by filtration. The solid was washed with water (2 × 10 mL) to obtain an orange solid. The filtrate was extracted with EtOAc (2 × 25 mL), the combined organic extracts were washed with brine (30 mL), dried over magnesium sulfate, and concentrated under reduced pressure to obtain an orange oil. The oil was combined with the already isolated orange solid and purified by silica chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to obtain the title compound as a colorless solid. LC-MS (Method 2A): Rt 0.73 min; MS m / z 377.4 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.63 (s, 1H), 5.35 (dd, J = 10.9, 2.2 Hz, 1H), 4.04 (s, 3H), 3.99 (s, 3H), 3.97 - 3.92 (m, 1H), 3.60 - 3.53 (m, 1H), 2.92 - 2.81 (m, 1H), 1.97 - 1.84 (m, 2H), 1.72 - 1.46 (m, 3H).

[0705] Step 3: 8-(2,4-Dimethoxypyrimidin-5-yl)-6-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]-9-tetrahydropyran-2-yl-purine

[0706]

Chemical Structure

[0707] 6-Chloro-8-(2,4-dimethoxypyrimidin-5-yl)-9-tetrahydropyran-2-yl-purine (Step 2) and 1-(2-pyrrolidin-3-yloxyethyl)piperidine (Intermediate J) were used to prepare the title compound in a similar manner to Step 1 of Example 7. The reaction was carried out in DMA at 70 °C. LC-MS (Method 2A): Rt 0.62 min; MS m / z 539.6 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 8.50 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 5.22 (dd, J = 10.9, 2.2 Hz, 1H), 4.42 - 4.19 (m, 2H), 4.14 - 4.06 (m, 1H), 4.01 (s, 3H), 3.96 (s, 3H), 3.94 - 3.88 (m, 2H), 3.86 - 3.55 (m, 6H), 3.54 - 3.46 (m, 2H), 2.88 - 2.80 (m, 2H), 2.23 - 1.97 (m, 2H), 1.93 - 1.86 (m, 1H), 1.79 - 1.73 (m, 1H), 1.69 - 1.55 (m, 6H), 1.49 - 1.43 (m, 2H), 1.29 - 1.25 (m, 2H).

[0708] Step 4: 5-[6-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]-9H-purin-8-yl]-1H-pyrimidine-2,4-dione 8-(2,4-Dimethoxypyrimidin-5-yl)-6-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]-9-tetrahydropyran-2-yl-purine (Step 3) and 1M HCl were used to prepare the title compound in a similar manner to Step 2 of Example 7. LC-MS (Method 7A): Rt 0.74 min; MS m / z 427.6 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 12.11 - 11.75 (m, 1H), 8.52 (s, 1H), 8.07 (s, 1H), 4.21 (s, 1H), 3.92 - 3.50 (m, 6H), 2.45 - 2.38 (m, 2H), 2.37 - 2.29 (m, 4H), 2.16 - 1.96 (m, 2H), 1.53 - 1.37 (m, 4H), 1.37 - 1.26 (m, 2H).

[0709] [Example 16] 5-[7-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione

[0710] [Chemical Structure]

[0711] Step 1: 7-Chloro-2-(2,4-dimethoxypyrimidin-5-yl)thieno[3,2-b]pyridine

[0712] [Chemical Structure]

[0713] The title compound was prepared from 2-bromo-7-chloro-thieno[3,2-b]pyridine and (2,4-dimethoxypyrimidin-5-yl)boronic acid in a similar manner to Step 2 of Example 15. LC-MS (Method 7A): Rt 3.49 min; MS m / z 308.0 = [M+H]+ 1H NMR (500 MHz, CDCl3) δ 8.67 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H), 7.94 (s, 1H), 7.27 (m, 1H), 4.18 (s, 3H), 4.08 (s, 3H).

[0714] Step 2: 5-(7-Chlorothieno[3,2-b]pyridin-2-yl)-1H-pyrimidine-2,4-dione

[0715]

Chemical formula

[0716] 7-Chloro-2-(2,4-dimethoxypyrimidin-5-yl)thieno[3,2-b]pyridine (Step 1) and 1M HCl were used to prepare the title compound in a similar manner to Step 2 of Example 9. LC-MS (Method 2A): Rt 0.56 min; MS m / z 280.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.82 (d, J = 6.2 Hz, 1H), 11.73 (d, J = 1.9 Hz, 1H), 8.63 (d, J = 5.3 Hz, 1H), 8.55 (d, J = 6.2 Hz, 1H), 8.10 (s, 1H), 7.54 (d, J = 5.3 Hz, 1H).

[0717] Step 3: 5-[7-[3-[2-(1-Piperidyl)ethoxy]pyrrolidin-1-yl]thieno[3,2-b]pyridin-2-yl]-1H-pyrimidine-2,4-dione 5-(7-Chlorothieno[3,2-b]pyridin-2-yl)-1H-pyrimidine-2,4-dione (Step 2) and 1-(2-pyrrolidin-3-yloxyethyl)piperidine (Intermediate J) were used to prepare the title compound in a similar manner to Step 1 of Example 7. The reaction was carried out at 120 °C in NMP. LC-MS (Method 7B): Rt 1.95 min; MS m / z 442.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.10 (d, J = 5.6 Hz, 1H), 7.73 (s, 1H), 6.22 (d, J = 5.6 Hz, 1H), 4.27 - 4.20 (m, 1H), 3.83 (dd, J = 10.5, 4.7 Hz, 1H), 3.74 (td, J = 8.6, 3.9 Hz, 1H), 3.71 - 3.65 (m, 2H), 3.59 - 3.52 (m, 2H), 2.42 (td, J = 6.1, 1.3 Hz, 2H), 2.35 - 2.31 (m, 4H), 2.14 - 2.06 (m, 2H), 1.45 - 1.40 (m, 4H), 1.35 - 1.28 (m, 2H).

[0718] [Example 17] 5-[4-[3,3-Difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione formate

[0719] [Chemical formula]

[0720] Step 1: 1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-4,4-difluoro-pyrrolidin-3-ol

[0721] [Chemical formula]

[0722] The title compound was prepared from 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine and 4,4-difluoropyrrolidin-3-ol hydrochloride in a similar manner to Step 1 of Example 10. LC-MS-2 (Method 2A): Rt 1.33 min; MS m / z 319.0 / 320.9 = [M+H]+ 1 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.91 (s, 1H), 7.13 (s, 1H), 6.45 - 6.21 (m, 1H), 1H), 4.38 (s, 2H), 4.15 - 3.58 (m, 3H).

[0723] Step 2: 6-Bromo-4-[3,3-difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine

[0724]

Chem.

[0725] A mixture of 1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-4,4-difluoro-pyrrolidin-3-ol (Step 1) (150 mg, 0.47 mmol), 1-(2-chloroethyl)piperidine (Intermediate J, Step 1) (85 mg, 0.58 mmol), TBAB (85 mg, 0.26 mmol), and 5 M aqueous sodium hydroxide solution (1.6 mL, 7.9 mmol) in toluene (9 mL) was heated at 80 °C for 90 minutes. After the resulting mixture was cooled to room temperature, it was partitioned between EtOAc (50 mL) and water (50 mL). The phases were separated and the aqueous portion was further extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. Purification by silica chromatography eluting with a gradient of 0 - 10% MeOH in DCM gave the title compound as a clear oil. LC-MS-2 (Method 2A): Rt 1.12 min; MS m / z 430.1, 432.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 1.7 Hz, 1H), 7.91 (s, 1H), 7.16 (d, J = 1.7 Hz, 1H), 4.42 (br s, 3H), 4.14 - 3.90 (br m, 3H), 3.81 (br s, 3H), 2.59 (br s, 2H), 2.40 (br s, 2H), 1.57 - 1.47 (br m, 4H), 1.39 - 1.32 (br m, 2H).

[0726] Step 3: 4-[3,3-Difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine

[0727]

Chem.

[0728] The title compound was prepared from 6-bromo-4-[3,3-difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine (Step 2) and (2,4-dimethoxypyrimidin-5-yl)boronic acid in a similar manner to Step 2 of Example 10. LC-MS-2 (Method 2A): Rt 1.15 min; MS m / z 490.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.91 (s, 1H), 7.47 (d, J = 1.7 Hz, 1H), 4.63 - 4.31 (m, 3H), 4.27 - 3.96 (m, 6H), 3.94 (s, 3H), 3.92 - 3.70 (m, 3H), 2.67 - 2.54 (m, 2H), 2.45 - 2.34 (m, 2H), 1.60 - 1.43 (m, 4H), 1.43 - 1.29 (m, 2H).

[0729] Step 4: 5-[4-[3,3-Difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-1H-pyrimidine-2,4-dione formate The title compound was prepared in a manner similar to Step 2 of Example 7 from 4-[3,3-difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine (Step 3) and 2M HCl. LC-MS-2 (Method 8A): Rt 2.02 min; MS m / z 462.1 = [M+H]+ 1H NMR (400 MHz, acetic acid-d4) δ 8.27 (d, J = 1.5 Hz, 1H), 8.08 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.35 (d, J = 1.5 Hz, 1H), 4.63 - 3.98 (br m, 8H), 3.71 (d, J = 12.0 Hz, 2H), 3.44 (apr t, J = 4.8 Hz, 2H), 3.01 - 2.84 (m, 2H), 1.93 - 1.78 (br m, 4H), 1.52 - 1.37 (br m, 1H).

[0730] [Example 18] 5-[2-Chloro-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-5H-pyrimidine-2,4-dione

[0731] [Chemical Structure Diagram]

[0732] Step 1: 6-Bromo-2-chloro-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine

[0733]

Chem.

[0734] The title compound was prepared in a similar manner to Step 1 of Example 10 from 6-bromo-2,4-dichloro-pyrrolo[2,1-f][1,2,4]triazine and 1-(2-pyrrolidin-3-yloxyethyl)piperidine (Intermediate J). LC-MS-1 (Method 2A): Rt 1.06 min; MS m / z 428.2, 430.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 1.7 Hz, 1H), 7.21 - 7.12 (m, 1H), 4.29 - 4.14 (m, 1H), 4.07 - 3.74 (m, 3H), 3.67 - 3.47 (m, 3H), 2.43 - 2.37 (m, 2H), 2.37 - 2.29 (m, 4H), 2.20 - 1.92 (m, 2H), 1.47 - 1.39 (m, 4H), 1.36 - 1.26 (m, 2H).

[0735] Step 2: 2-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine

[0736]

Chem.

[0737] The title compound was prepared in a similar manner to Step 2 of Example 10 from 6-bromo-2-chloro-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine (Step 1) and (2,4-dimethoxypyrimidin-5-yl)boronic acid. LC-MS-2 (Method 2B): Rt 1.88 min; MS m / z 488.1 = [M+H]+

[0738] Step 3: 5-[2-Chloro-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]-5H-pyrimidine-2,4-dione The title compound was prepared in a similar manner to Step 3 of Example 10 from 2-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidin-1-yl]pyrrolo[2,1-f][1,2,4]triazine (Step 2) and 2M HCl. LC-MS-2 (Method 8B): Rt 2.53 min; MS m / z 460.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 2H), 8.14 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.41 (dd, J = 4.0, 1.7 Hz, 1H), 4.33 - 4.15 (m, 1H), 4.14 - 3.90 (m, 2H), 3.86 - 3.77 (m, 1H), 3.68 - 3.50 (m, 3H), 2.45 - 2.37 (m, 2H), 2.36 - 2.29 (m, 4H), 2.24 - 2.12 (m, 1H), 2.11 - 1.96 (m, 1H), 1.48 - 1.38 (m, 4H), 1.37 - 1.26 (m, 2H).

[0739] [Example 19] 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0740] [Chemical Structure]

[0741] A mixture of 5-(4-chlorofuro[2,3-d]pyrimidin-6-yl)-1H-pyrimidine-2,4-dione (Intermediate G) (80 mg, 0.30 mmol), 8,8-difluoro-6-azaspiro[3.4]octane hydrochloride (57 mg, 0.31 mmol), and DIPEA (0.26 mL, 1.51 mmol) in MeCN (3 mL) was heated at 80 °C overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by C18 reverse-phase chromatography eluting with a gradient of 15 - 55% MeCN in water (+0.1% formic acid), and then subjected to a second chromatographic purification by C18 reverse-phase chromatography eluting with a gradient of 20 - 55% MeCN in water (+0.1% formic acid) to afford the title compound as a colorless solid. LC-MS-1 (Method 8A): Rt 2.55 min; MS m / z 376.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 2H), 8.28 (s, 1H), 7.96 (s, 1H), 7.38 (s, 1H), 4.08 (m, 4H), 2.38 - 2.27 (m, 2H), 2.15 - 1.81 (m, 4H).

[0742] [Example 19.1] 5-[4-(4,4-Difluoro-2-azaspiro[4.4]nonan-2-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0743] [Chemical Structure]

[0744] The title compound was prepared in a similar manner to Example 19 from 5-(4-chlorofuro[2,3-d]pyrimidin-6-yl)-1H-pyrimidine-2,4-dione (Intermediate G) and 4,4-difluoro-2-azaspiro[4.4]nonane hydrochloride. LC-MS-2 (Method 8A): Rt 3.38 min; MS m / z 390.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 2H), 8.28 (s, 1H), 7.95 (s, 1H), 7.36 (s, 1H), 4.20 (s, 2H), 3.84 (s, 2H), 2.01 - 1.87 (m, 2H), 1.77 - 1.58 (m, 6H).

[0745] [Example 19.2] 5-[4-[(4-Chlorophenyl)methylamino]furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0746] [Chemical formula]

[0747] The title compound was prepared in a similar manner to Example 19 from 5-(4-chlorofuro[2,3-d]pyrimidin-6-yl)-1H-pyrimidine-2,4-dione (Intermediate G) and (4-chlorophenyl)methanamine. LC-MS-1 (Method 8A): Rt 2.00 min; MS m / z 370.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.64 - 11.22 (m, 2H), 8.54 (t, J = 6.1 Hz, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.52 (s, 1H), 7.43 - 7.31 (m, 4H), 4.68 (d, J = 5.7 Hz, 2H).

[0748] [Example 19.3] 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0749] [Chemical formula]

[0750] The title compound was prepared from 5-(4-chlorofuro[2,3-d]pyrimidin-6-yl)-1H-pyrimidine-2,4-dione (Intermediate G) and 7,7-difluoro-5-azaspiro[2.4]heptane hydrochloride in a similar manner to Example 19. LC-MS-2 (Method 8A): Rt 2.87 min; MS m / z 362.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6 @ 343K) δ 11.28 (s, 2H), 8.29 (s, 1H), 7.90 (s, 1H), 7.36 (s, 1H), 4.31 (t, J = 12.5 Hz, 2H), 4.02 (s, 2H), 1.09 - 0.99 (m, 4H).

[0751] [Example 20] [3-[[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]amino]-2,2-difluoro-propyl] N-isopropylcarbamate

[0752] [Chemical Structure]

[0753] Step 1: 3-[[6-(2,4-Di-tert-butoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]amino]-2,2-difluoro-propan-1-ol

[0754] [Chemical Structure]

[0755] 4-Chloro-6-(2,4-di-tert-butoxypyrimidin-5-yl)furo[2,3-d]pyrimidine (Intermediate G, Step 1) (283 mg, 0.75 mmol), 3-amino-2,2-difluoropropan-1-ol (125 mg, 1.13 mmol), and DIPEA (0.65 mL, 3.75 mmol) in NMP (3 mL) were heated in a sealed vial at 120 °C for 3.5 h. The reaction mixture was cooled to room temperature and added dropwise to stirred water (50 mL). The precipitate was collected by filtration and then concentrated in vacuo from MeCN (20 mL) to give the title compound as a beige solid. LC-MS-2 (Method 2A): Rt 1.71 min; MS m / z 452.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.39 (m, 1H), 8.29 (s, 1H), 7.33 (s, 1H), 5.62 (t, J = 6.3 Hz, 1H), 4.09 (td, J = 15.1, 6.1 Hz, 2H), 3.67 (td, J = 13.6, 6.3 Hz, 2H), 1.73 (s, 9H), 1.60 (s, 9H).

[0756] Step 2: [3-[[6-(2,4-Di-tert-butoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]amino]-2,2-difluoropropyl] N-isopropylcarbamate

[0757]

Chem.

[0758] 3-[[6-(2,4-Di-tert-butoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]amino]-2,2-difluoro-propan-1-ol (Step 1) (200 mg, 0.44 mmol), 2-isocyanatopropane (0.44 mL, 4.43 mmol), and DIPEA (0.39 mL, 2.21 mmol) were dispersed in DCM (8 mL) and heated at 50 °C for 5 h. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was suspended in DCM (8 mL), and then DIPEA (0.39 mL, 2.21 mmol) and 2-isocyanatopropane (0.24 mL, 2.44 mmol) were added. After the reaction solution was heated at 50 °C for 6 h, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica chromatography eluting with a gradient of 20 - 40% EtOAc in petroleum ether, and then subjected to a second chromatographic purification by silica chromatography eluting with a gradient of 20 - 30% EtOAc in petroleum ether to obtain the title compound as a pale yellowish-white solid. LC-MS-1 (Method 2B): Rt 1.77 min; MS m / z 537.3 = [M+H]+

[0759] Step 3: [3-[[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]amino]-2,2-difluoro-propyl] N-isopropylcarbamate [3-[[6-(2,4-Di-tert-butoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]amino]-2,2-difluoro-propyl] N-isopropylcarbamate (Step 2) (60 mg, 0.09 mmol) was dispersed in DCM (1 mL), cooled to 0 °C, and then TFA (0.07 mL, 0.89 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 3 h, and then concentrated under reduced pressure. The residue was recrystallized from DMSO (2 mL) to obtain the title compound as a colorless solid. LC-MS-2 (Method 8A): Rt 2.77 min; MS m / z 425.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.55 - 11.38 (m, 2H), 8.34 (t, J = 6.3 Hz, 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.60 (s, 1H), 7.40 (d, J = 7.7 Hz, 1H), 4.33 (t, J = 14.2 Hz, 2H), 4.09 (td, J = 14.8, 6.0 Hz, 2H), 3.63 - 3.53 (m, 1H), 1.05 (d, J = 6.5 Hz, 6H).

[0760] [Example 21] 5-[4-[3-[2-[4-(Trifluoromethyl)-1-piperidyl]ethoxy]pyrrolidin-1-yl]furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione

[0761] [Chemical formula]

[0762] Step 1: 2-[1-[6-(2,4-Dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxyethanol

[0763] [Chemical formula]

[0764] A mixture of 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidine (Intermediate C) (250 mg, 0.85 mmol), 2-pyrrolidin-3-yloxyethanol hydrochloride (186 mg, 1.11 mmol), and DIPEA (0.74 mL, 4.27 mmol) in MeCN (5 mL) was heated at 70 °C for 1 hour. The reaction mixture was cooled to room temperature, and the solid was collected by filtration and washed with MeCN (2 × 5 mL). The solid was dried under reduced pressure to obtain the title compound as a gray solid. LC-MS-1 (Method 2A): Rt 1.00 min; MS m / z 388.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.26 (s, 1H), 7.32 (s, 1H), 4.42 - 4.37 (m, 1H), 4.31 (m, 1H), 4.15 (s, 3H), 4.01 (s, 3H), 3.94 - 3.75 (m, 4H), 3.60 - 3.48 (m, 4H), 2.26 - 2.10 (m, 2H).

[0765] Step 2: 2-[1-[6-(2,4-Dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxyethyl 4-methylbenzenesulfonate

[0766]

Chem.

[0767] To a mixture of 2-[1-[6-(2,4-Dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]ethanol (260 mg, 0.67 mmol) and triethylamine (0.37 mL, 2.68 mmol) in DCM (4 mL) was added tosyl chloride (128 mg, 0.67 mmol). The suspension was stirred at room temperature for 16 h, then additional tosyl chloride (64 mg, 0.34 mmol) was added and the suspension was stirred for an additional 4 h. After the resulting suspension was filtered, MeOH (0.4 mL) and water (10 mL) were added to the filtrate. The organic phase was separated and the aqueous phase was back-extracted with DCM (2×5 mL) containing 10% MeOH. The organic fractions were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica chromatography eluting with a gradient of 0 - 5% MeOH in DCM to afford the title compound as a yellow solid. LC-MS-1 (Method 2A): Rt 1.47 min; MS m / z 542.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.27 (s, 1H), 7.78 - 7.72 (m, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.30 (s, 1H), 4.35 - 4.13 (m, 3H), 4.12 (s, 3H), 3.97 (s, 3H), 3.91 - 3.74 (m, 2H), 3.72 - 3.59 (m, 4H), 2.32 (s, 3H), 2.20 - 2.00 (m, 2H).

[0768] Step 3: 6-(2,4-Dimethoxypyrimidin-5-yl)-4-[3-[2-[4-(trifluoromethyl)-1-piperidyl]ethoxy]pyrrolidin-1-yl]furo[2,3-d]pyrimidine

[0769] [Chemical Structure]

[0770] A mixture of 2-[1-[6-(2,4-dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxyethyl 4-methylbenzenesulfonate (Step 2) (200 mg, 0.37 mmol), potassium carbonate (153 mg, 1.11 mmol), and 4-(trifluoromethyl)piperidine (113 mg, 0.74 mmol) in MeCN (3 mL) was heated at 75 °C for 24 h, then the mixture was concentrated under reduced pressure. The residue was triturated with MeCN (5 mL), the solid was collected by filtration and dried under reduced pressure. The residue was purified by silica chromatography eluting with a gradient of 1 - 10% 1M NH3MeOH in DCM to give the title compound as a pale yellow solid. LC-MS-2 (Method 2A): Rt 1.12 min; MS m / z 523.1 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.32 (s, 1H), 7.37 (s, 1H), 4.42 - 4.26 (m, 1H), 4.17 (s, 3H), 4.04 (s, 3H), 4.00 - 3.83 (m, 3H), 3.79 - 3.52 (m, 4H), 3.02 - 2.95 (m, 2H), 2.68 - 2.60 (m, 1H), 2.33 - 2.11 (m, 3H), 2.09 - 1.95 (m, 2H), 1.80 - 1.69 (m, 2H), 1.52 - 1.34 (m, 2H).

[0771] Step 4: 5-[4-[3-[2-[4-(Trifluoromethyl)-1-piperidyl]ethoxy]pyrrolidin-1-yl]furo[2,3-d]pyrimidin-6-yl]-1H-pyrimidine-2,4-dione A solution of 6-(2,4-dimethoxypyrimidin-5-yl)-4-[3-[2-[4-(trifluoromethyl)-1-piperidyl]ethoxy]pyrrolidin-1-yl]furo[2,3-d]pyrimidine (Step 3) (140 mg, 0.27 mmol) in 1 M HCl (2.68 mL, 2.68 mmol) and methanol (2 mL) was heated at 70 °C for 7.5 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by C18 reverse-phase chromatography eluting with a gradient of 5 - 25% MeCN in water (+0.1% formic acid) to give the title compound as a colorless solid. LC-MS-1 (Method 8A): Rt 1.88 min; MS m / z 495.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.37 - 11.13 (m, 2H), 8.21 (s, 1H), 7.86 (s, 1H), 7.38 (s, 1H), 4.30 - 4.22 (m, 1H), 3.89 - 3.76 (m, 3H), 3.76 - 3.68 (m, 1H), 3.66 - 3.52 (m, 2H), 2.93 (d, J = 11.7 Hz, 2H), 2.48 - 2.39 (m, 2H), 2.20 - 2.08 (m, 3H), 2.07 - 1.98 (m, 2H), 1.75 - 1.65 (m, 2H), 1.48 - 1.34 (m, 2H).

[0772] [Example 22] [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] morpholine-4-carboxylate

[0773] [Chemical formula]

[0774] Step 1: [1-[6-(2,4-Dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] morpholine-4-carboxylate

[0775] [Chemical formula]

[0776] DIPEA (0.14 mL, 0.79 mmol), 1-[6-(2,4-dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-ol (Intermediate K) (100 mg, 0.26 mmol), and CDI mmol) in THF (5 mL) was heated at 50 °C for 2 h. Next, morpholine (0.09 mL, 1.05 mmol) was added at this temperature, and the reaction mixture was stirred for 1 h 20 min, then cooled to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (2 × 10 mL). The aqueous phase was extracted with 10% MeOH DCM solution (2 × 10 mL), and the combined organic fractions were dried over magnesium sulfate and concentrated under reduced pressure. After purification by silica chromatography eluting with a gradient of 0 - 12% 1M NH3 MeOH in DCM, it was subjected to a second purification by silica chromatography eluting with a gradient of 0 - 100% EtOAc in DCM to obtain the title compound as a pale yellowish-white solid. LC-MS-1 (Method 2A): Rt 1.32 min; MS m / z 493.4 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.36 (s, 1H), 7.38 (s, 1H), 5.52 (s, 1H), 4.45 - 4.26 (m, 3H), 4.12 (s, 3H), 4.06 - 4.02 (m, 1H), 3.98 (s, 3H), 3.63 - 3.51 (m, 4H), 3.45 - 3.36 (m, 4H).

[0777] Step 2: [1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] morpholine-4-carboxylate [1-[6-(2,4-Dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] morpholine-4-carboxylate (Step 1) (141 mg, 0.29 mmol) in chloroform (10 mL) was added trimethylsilyl iodide (0.2 mL, 1.43 mmol), and the reaction mixture was stirred at room temperature for 90 minutes. After adding water (2 mL), the mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (2 mL), and water (5 mL) was added. The solid was collected by filtration and purified by C18 reverse-phase chromatography eluting with a gradient of 10 - 60% MeCN in water (+0.1% NH4OH) to obtain the title compound as a colorless solid. LC-MS-1 (Method 8B): Rt 1.81 min; MS m / z 465.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 11.49 (s, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 7.39 (s, 1H), 5.57 - 5.47 (m, 1H), 4.39 - 4.22 (m, 3H), 3.99 (d, J = 12.3 Hz, 1H), 3.63 - 3.51 (m, 4H), 3.47 - 3.35 (m, 4H).

[0778] [Example 22.1] [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] 8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate

[0779] [Chemical formula]

[0780] Step 1: [1-[6-(2,4-Dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] 8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate

[0781]

Chem.

[0782] The title compound was prepared from 1-[6-(2,4-dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-ol (Intermediate K) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride in a similar manner to Step 1 of Example 22. LC-MS-2 (Method 2A): Rt 1.53 min; MS m / z 519.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.36 (s, 1H), 7.38 (s, 1H), 4.45 - 4.20 (m, 5H), 4.13 (s, 3H), 3.98 (s, 3H), 3.67 - 3.56 (m, 2H), 3.14 - 3.00 (m, 2H), 2.45 - 2.42 (m, 2H), 1.87 - 1.72 (m, 2H), 1.69 - 1.60 (m, 2H).

[0783] Step 2: [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] 8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate [1-[6-(2,4-Dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] 8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate (Step 1) and trimethylsilyl iodide were used to prepare the title compound in a similar manner to Step 2 of Example 22. LC-MS-2 (Method 8A): Rt 2.27 min; MS m / z 490.9 = [M+H]+

[0784] 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 11.48 (s, 1H), 8.32 (s, 1H), 7.96 (s, 1H), 7.39 (s, 1H), 5.52 (s, 1H), 4.37 - 4.29 (m, 2H), 4.28 - 4.19 (m, 2H), 4.05 - 3.93 (m, 1H), 3.66 - 3.56 (m, 2H), 3.14 - 3.00 (m, 2H), 2.45 - 2.38 (m, 1H), 1.84 - 1.73 (m, 2H), 1.68 - 1.62 (m, 2H).

[0785] [Example 22.2] [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] N-isopropylcarbamate

[0786] [Chemical formula]

[0787] Step 1: [1-[6-(2,4-Dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] N-isopropylcarbamate

[0788] [Chemical formula]

[0789] The title compound was prepared from 1-[6-(2,4-dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-ol (Intermediate K) and propan-2-amine in a similar manner to Step 1 of Example 22. LC-MS-1 (Method 2A): Rt 1.41 min; MS m / z 465.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.36 (s, 1H), 7.38 (s, 1H), 4.45 - 4.17 (m, 4H), 4.14 - 4.11 (m, 4H), 4.00 - 3.96 (m, 4H), 3.67 - 3.58 (m, 1H), 1.09 - 1.04 (m, 6H).

[0790] Step 2: [1-[6-(2,4-Dioxo-1H-pyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] N-isopropylcarbamate [1-[6-(2,4-Dimethoxypyrimidin-5-yl)furo[2,3-d]pyrimidin-4-yl]-4,4-difluoro-pyrrolidin-3-yl] N-isopropylcarbamate and trimethylsilyl iodide were used to prepare the title compound in a similar manner to Step 2 of Example 22. LC-MS-2 (Method 8B): Rt 2.05 min; MS m / z 437.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.51 - 11.12 (m, 2H), 8.31 (s, 1H), 7.91 (s, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 5.54 - 5.37 (m, 1H), 4.37 - 4.24 (m, 2H), 4.21 - 4.09 (m, 1H), 3.97 - 3.87 (m, 1H), 3.68 - 3.57 (m, 1H), 1.14 - 1.00 (m, 6H).

[0791] [Example 23] 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-methyl-pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione

[0792]

Chem.

[0793] Step 1: 4-Chloro-2-(2,4-dimethoxypyrimidin-5-yl)-6-methyl-pyrazolo[3,4-d]pyrimidine

[0794]

Chem.

[0795] (2,4-Dimethoxypyrimidin-5-yl)hydrazine hydrochloride (Intermediate E, Step 1a) (1.5 g, 5.44 mmol) and 4,6-dichloro-2-methyl-pyrimidine-5-carbaldehyde (988 mg, 5.17 mmol) were dispersed in THF (30 mL), and triethylamine (2.85 mL, 20.42 mmol) was added. The resulting suspension was heated at 65 °C for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was triturated with DCM (20 mL), cooled to 0 °C, and then filtered. The filtrate was concentrated and purified by silica chromatography eluting with a gradient of 0 - 100% EtOAc in DCM to obtain a solid, which was triturated with diethyl ether (10 mL) to obtain the title compound as a yellow solid. LC-MS-2 (Method 2A): Rt 1.33 min; MS m / z 306.9 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.82 (s, 1H), 4.05 (s, 3H), 4.02 (s, 3H), 2.69 (s, 3H).

[0796] Step 2: 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)-6-methyl-pyrazolo[3,4-d]pyrimidine

[0797]

Chem.

[0798] A stirred suspension of 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)-6-methyl-pyrazolo[3,4-d]pyrimidine (94 mg, 0.31 mmol) and 3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride (63 mg, 0.37 mmol) in MeCN (2 mL) was added with DIPEA (0.27 mL, 1.53 mmol) under nitrogen. The reaction mixture was then heated at 70 °C for 20 minutes and then cooled to room temperature. Water (10 mL) was added and the mixture was extracted with DCM (2 × 15 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by silica column chromatography eluting with a gradient of 0 - 5% MeOH in DCM gave the title compound as a yellow solid. LC-MS-2 (Method 2A): Rt 1.27 min; MS m / z 406.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.69 (s, 1H), 4.37 (t, J = 13.4 Hz, 1H), 4.21 - 4.11 (m, 1H), 4.02 (d, J = 3.7 Hz, 3H), 4.00 (s, 3H), 3.86 (s, 1H), 3.72 (s, 1H), 2.41 (s, 3H), 1.21 (s, 3H), 1.19 (s, 3H).

[0799] Step 3: 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-methyl-pyrazolo[3,4-d]pyrimidin-2-yl]-1H-pyrimidine-2,4-dione 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)-6-methyl-pyrazolo[3,4-d]pyrimidine (Step 2) (64 mg, 0.16 mmol) in MeOH (2 mL) was added 2M HCl (0.79 mL, 1.58 mmol). The resulting solution was heated at 70 °C for 165 minutes, then the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by C18 reverse-phase chromatography eluting with a gradient of 2 - 45% MeCN in water (+0.1% formic acid) to give the title compound as a pale yellow solid. LC-MS-1 (Method 8A): Rt 2.04 min; MS m / z 378.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 2H), 8.90 (s, 1H), 8.14 (s, 1H), 4.42 - 4.28 (m, 1H), 4.19 - 4.08 (m, 1H), 3.84 (s, 1H), 3.70 (s, 1H), 2.40 (s, 3H), 1.26 - 1.14 (m, 6H).

[0800] [Example 24] 6-[1-[2-(2,4-Dioxo-1H-pyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-3-carbonitrile

[0801] [Chemical Structure]

[0802] Step 1: 1-[2-(2,4-Dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidin-3-ol

[0803] [Chemical Structure]

[0804] The title compound was prepared from 4-chloro-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidine (Intermediate E) and pyrrolidin-3-ol in a similar manner to Step 1 of Example 13. LC-MS-1 (Method 2A): Rt 0.68 min; MS m / z 344.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 5.07 - 4.82 (m, 1H), 4.57 - 4.36 (m, 1H), 4.06 (s, 3H), 4.03 (s, 3H), 3.95 - 3.81 (m, 2H), 3.81 - 3.60 (m, 2H), 2.18 - 1.96 (m, 2H).

[0805] Step 2: 6-[1-[2-(2,4-Dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-3-carbonitrile

[0806]

Chemical Structure

[0807] Sodium hydride (60% mineral oil dispersion) (210 mg, 0.51 mmol) was added to a stirred suspension of 1-[2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidin-3-ol (160 mg, 0.47 mmol) from Step 1 in DMF (2.5 mL). After stirring the reaction mixture at room temperature for 30 minutes, 6-fluoropyridine-3-carbonitrile (68.28 mg, 0.56 mmol) was added. After stirring the reaction mixture at room temperature for 2 hours, water (10 mL) was added, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica chromatography eluting with a gradient of 0 - 10% MeOH in DCM gave the title compound as a yellow oil. LC-MS-2 (Method 2A): Rt 1.16 min; MS m / z 445.9 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.94 - 8.82 (m, 1H), 8.76 - 8.70 (m, 2H), 8.30 - 8.23 (m, 1H), 8.20 - 8.14 (m, 1H), 7.07 - 7.00 (m, 1H), 5.94 - 5.72 (m, 1H), 4.30 - 4.20 (m, 1H), 4.08 - 3.91 (m, 8H), 3.79 - 3.69 (m, 1H), 2.50 - 2.45 (m, 2H).

[0808] Step 3: 6-[1-[2-(2,4-Dioxo-1H-pyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-3-carbonitrile 6-[1-[2-(2,4-Dimethoxypyrimidin-5-yl)pyrazolo[3,4-d]pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-3-carbonitrile (Step 2) and 1M HCl were used to prepare the title compound in a similar manner to Step 2 of Example 13. LC-MS-2 (Method 8B): Rt 1.72 min; MS m / z 418.0 = [M+H]+ 1H NMR (400 MHz, acetic acid-d4) δ 9.40 - 9.30 (m, 1H), 8.67 - 8.50 (m, 3H), 8.02 - 7.95 (m, 1H), 6.98 - 6.89 (m, 1H), 6.05 - 5.90 (m, 1H), 4.56 - 4.05 (m, 4H), 2.70 - 2.49 (m, 2H).

[0809] [Example 25] 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione

[0810] [Chemical formula]

[0811] Step 1: 2-Bromo-4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazine

[0812] [Chemical formula]

[0813] A mixture of 2-bromo-4-chloro-pyrazolo[1,5-a]pyrazine (intermediate L) (110 mg, 0.47 mmol), 3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride (97 mg, 0.57 mmol), and DIPEA (0.25 mL, 1.42 mmol) in MeCN (3 mL) was heated at 70 °C for 3 hours. Then, additional 3,3,4,4-tetramethylpyrrolidine hydrochloride (50 mg, 0.31 mmol) was added. After an additional 6 hours at 70 °C, a third addition of 3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride (98 mg, 0.57 mmol) was made, and the reaction mixture was heated at 70 °C for an additional 18 hours. The reaction mixture was cooled to room temperature, diluted with DCM (50 mL), and washed with saturated aqueous NH4Cl (40 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to obtain the title compound as an orange solid. LC-MS-2 (Method 2B): Rt 1.70 min; MS m / z 330.9 / 332.9 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 4.7 Hz, 1H), 7.37 (d, J = 4.7 Hz, 1H), 7.26 (s, 1H), 4.23 (t, J = 13.8 Hz, 2H), 3.79 (s, 2H), 1.18 (s, 6H).

[0814] Step 2: 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrazine

[0815]

Chem.

[0816] A mixture of 2-bromo-4-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazine (170 mg, 0.51 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (113 mg, 0.62 mmol), and cesium carbonate (502 mg, 1.54 mmol) in dioxane (4 mL) and water (1 mL) was degassed under a nitrogen stream. Pd(dppf)Cl2 (38 mg, 0.05 mmol) was added, and the reaction mixture was heated at 100 °C for 10 minutes. The mixture was cooled to room temperature, diluted with DCM (50 mL), washed with water (40 mL), dried over magnesium sulfate, and the solvent was removed under reduced pressure. Purification by silica chromatography eluting with a gradient of 0 - 100% EtOAc in petroleum ether afforded the title compound as a beige solid. LC-MS-2 (Method 2B): Rt 1.69 min; MS m / z 391.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.09 (d, J = 4.7 Hz, 1H), 7.38 (d, J = 4.7 Hz, 1H), 7.34 (s, 1H), 4.31 (t, J = 13.7 Hz, 2H), 4.08 (s, 3H), 3.97 (s, 3H), 3.83 (s, 2H), 1.21 (s, 6H).

[0817] Step 3: 5-[4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione 4-(3,3-Difluoro-4,4-dimethyl-pyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrazine (Step 2) (165 mg, 0.42 mmol) was heated in a mixture of 1 M HCl (4.2 mL, 4.2 mmol) and MeOH (2 mL) at 70 °C for 14 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification by C18 reverse-phase chromatography eluting with a gradient of 5 - 35% MeCN in water (+0.1% formic acid) gave the title compound as a colorless solid. LC-MS-2 (Method 8A): Rt 2.50 min; MS m / z 363.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 11.29 (s, 1H), 8.02 (s, 1H), 8.00 (d, J = 4.7 Hz, 1H), 7.43 (s, 1H), 7.34 (d, J = 4.7 Hz, 1H), 4.24 (t, J = 13.7 Hz, 2H), 3.82 (s, 2H), 1.21 (s, 6H).

[0818] [Example 25.1] 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione

[0819] [Chemical formula]

[0820] Step 1: 2-Bromo-4-(8,8-difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[1,5-a]pyrazine

[0821] [Chemical formula]

[0822] The title compound was prepared from 2-bromo-4-chloro-pyrazolo[1,5-a]pyrazine (Intermediate L) and 8,8-difluoro-6-azaspiro[3.4]octane hydrochloride in a similar manner to Step 1 of Example 25. LC-MS-2 (Method 2A): Rt 1.75 min; MS m / z 342.6 / 344.9 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 4.7 Hz, 1H), 7.36 (d, J = 4.7 Hz, 1H), 7.29 (s, 1H), 4.11 (t, J = 13.1 Hz, 2H), 4.05 (s, 2H), 2.35 - 2.27 (m, 2H), 2.07 - 2.00 (m, 2H), 1.92 - 1.72 (m, 2H).

[0823] Step 2: 4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrazine

[0824]

Chemical formula

[0825] The title compound was prepared from 2-bromo-4-(8,8-difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[1,5-a]pyrazine (Step 1) and (2,4-dimethoxypyrimidin-5-yl)boronic acid in a similar manner to Step 2 of Example 25. LC-MS-2 (Method 2A): Rt 1.65 min; MS m / z 403.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.09 (d, J = 4.7 Hz, 1H), 7.37 (d, J = 4.7 Hz, 1H), 7.35 (s, 1H), 4.19 (t, J = 13.1 Hz, 2H), 4.09 (s, 3H), 4.07 (s, 2H), 3.97 (s, 3H), 2.37 - 2.29 (m, 2H), 2.14 - 2.04 (m, 2H), 2.03 - 1.83 (m, 2H).

[0826] Step 3: 5-[4-(8,8-Difluoro-6-azaspiro[3.4]octan-6-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione The title compound was prepared in a similar manner to Step 3 of Example 25 from 4-(8,8-difluoro-6-azaspiro[3.4]octan-6-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrazine (Step 2) and 1M HCl. LC-MS-2 (Method 8A): Rt 2.62 min; MS m / z 375.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 11.23 (s, 1H), 8.02 (s, 1H), 8.00 (d, J = 4.8 Hz, 1H), 7.44 (s, 1H), 7.34 (d, J = 4.8 Hz, 1H), 4.14 (t, J = 13.0 Hz, 2H), 4.06 (s, 2H), 2.37 - 2.28 (m, 2H), 2.13 - 2.03 (m, 2H), 2.02 - 1.94 (m, 1H), 1.93 - 1.84 (m, 1H).

[0827] [Example 25.2] 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione

[0828]

Chem.

[0829] Step 1: 2-Bromo-4-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrazine

[0830]

Chem.

[0831] The title compound was prepared from 2-bromo-4-chloro-pyrazolo[1,5-a]pyrazine (Intermediate L) and 7,7-difluoro-5-azaspiro[2.4]heptane hydrochloride in a similar manner to Step 1 of Example 25. LC-MS-1 (Method 2A): Rt 1.51 min; MS m / z 329.4 / 331.4 = [M+H]+ 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 4.7 Hz, 1H), 7.34 (d, J = 4.7 Hz, 1H), 6.72 (s, 1H), 4.28 (t, J = 12.2 Hz, 2H), 4.00 (s, 2H), 1.22 - 1.16 (m, 2H), 0.87 - 0.81 (m, 2H).

[0832] Step 2: 4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrazine

[0833]

Chem.

[0834] 2-Bromo-4-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrazine (Step 1) and (2,4-dimethoxypyrimidin-5-yl)boronic acid were used to synthesize the title compound in a similar manner to Step 2 of Example 25. LC-MS-2 (Method 2A): Rt 1.57 min; MS m / z 389.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.39 (d, J = 4.7 Hz, 1H), 7.33 (s, 1H), 4.36 (t, J = 12.5 Hz, 2H), 4.07 (d, J = 4.4 Hz, 5H), 3.97 (s, 3H), 1.10 - 0.95 (m, 4H).

[0835] Step 3: 5-[4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione 4-(7,7-Difluoro-5-azaspiro[2.4]heptan-5-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrazine and 1M HCl were used to synthesize the title compound in a similar manner to Step 3 of Example 25. LC-MS-2 (Method 8A): Rt 2.40 min; MS m / z 361.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 2H), 8.02 (d, J = 5.5 Hz, 2H), 7.41 (s, 1H), 7.35 (d, J = 4.7 Hz, 1H), 4.30 (t, J = 12.5 Hz, 2H), 4.05 (s, 2H), 1.09 - 0.93 (m, 4H).

[0836] [Example 25.3] 5-[4-(3,3-Difluoro-4-methoxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione

[0837]

Chem.

[0838] Step 1: 2-Bromo-4-(3,3-difluoro-4-methoxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrazine

[0839]

Chem.

[0840] The title compound was prepared in a similar manner to Step 1 of Example 25 from 2-bromo-4-chloro-pyrazolo[1,5-a]pyrazine (Intermediate L) and 3,3-difluoro-4-methoxypyrrolidine hydrochloride. LC-MS-2 (Method 2A): Rt 1.46 min; MS m / z 334.8 = [M+H]+ 1H NMR (400 MHz, chloroform-d) δ 7.77 (d, J = 4.8 Hz, 1H), 7.36 (d, J = 4.8 Hz, 1H), 6.78 (s, 1H), 4.28 - 3.95 (m, 5H), 3.58 (s, 3H).

[0841] Step 2: 4-(3,3-Difluoro-4-methoxypyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrazine

[0842]

Chem.

[0843] 2-Bromo-4-(3,3-difluoro-4-methoxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrazine (Step 1) and (2,4-dimethoxypyrimidin-5-yl)boronic acid were used to synthesize the title compound in a similar manner to Step 2 of Example 25. LC-MS-2 (Method 2A): Rt 1.43 min; MS m / z 393.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.39 (d, J = 4.7 Hz, 1H), 7.35 (s, 1H), 4.34 - 4.15 (m, 4H), 4.08 (s, 3H), 3.97 (s, 3H), 3.94 - 3.86 (m, 1H), 3.50 (s, 3H).

[0844] Step 3: 5-[4-(3,3-Difluoro-4-methoxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione 4-(3,3-Difluoro-4-methoxypyrrolidin-1-yl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrazine (Step 2) and 1M HCl were used to synthesize the title compound in a similar manner to Step 3 of Example 25. LC-MS-1 (Method 8A): Rt 2.02 min; MS m / z 365.2 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 11.32 (d, J = 6.1 Hz, 1H), 8.06 (d, J = 4.9 Hz, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.51 (s, 1H), 7.35 (d, J = 4.8 Hz, 1H), 4.39 - 4.10 (m, 4H), 3.94 - 3.86 (m, 1H), 3.47 (s, 3H).

[0845] [Example 25.4] 5-[4-(2-Oxa-7-azaspiro[3.4]octan-7-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione

[0846]

Chem.

[0847] Step 1: 7-(2-Bromopyrazolo[1,5-a]pyrazin-4-yl)-2-oxa-7-azaspiro[3.4]octane

[0848]

Chem.

[0849] The title compound was prepared in a similar manner to Step 1 of Example 25 from 2-bromo-4-chloro-pyrazolo[1,5-a]pyrazine (Intermediate L) and 2-oxa-7-azaspiro[3.4]octane oxalic acid. LC-MS-2 (Method 2A): Rt 0.91 min; MS m / z 310.9 = [M+H]+ 1H NMR (400 MHz, chloroform-d) δ 7.70 (d, J = 4.7 Hz, 1H), 7.33 (d, J = 4.7 Hz, 1H), 6.82 (s, 1H), 4.74 (d, J = 6.2 Hz, 2H), 4.67 (d, J = 6.2 Hz, 2H), 4.06 (s, 2H), 3.88 (t, J = 7.1 Hz, 2H), 2.37 (t, J = 7.0 Hz, 2H).

[0850] Step 2: 7-[2-(2,4-Di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-oxa-7-azaspiro[3.4]octane

[0851]

Chem.

[0852] 7-(2-Bromopyrazolo[1,5-a]pyrazin-4-yl)-2-oxa-7-azaspiro[3.4]octane (Step 1) and (2,4-Di-tert-butoxypyrimidin-5-yl)boronic acid were used to prepare the title compound in a similar manner to Step 2 of Example 25. LC-MS-1 (Method 2A): Rt 1.27 min; MS m / z 453.3 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 7.95 (d, J = 4.7 Hz, 1H), 7.40 (s, 1H), 7.32 (d, J = 4.7 Hz, 1H), 4.61 (d, J = 6.1 Hz, 2H), 4.55 (d, J = 6.1 Hz, 2H), 4.06 (s, 2H), 3.79 (t, J = 6.9 Hz, 2H), 2.29 (t, J = 6.8 Hz, 2H), 1.71 (s, 9H), 1.60 (s, 9H).

[0853] Step 3: 5-[4-(2-Oxa-7-azaspiro[3.4]octan-7-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione 7-[2-(2,4-Di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-oxa-7-azaspiro[3.4]octane (Step 2) (103 mg, 0.23 mmol) was dispersed in DCM (2.5 mL) and cooled to 0 °C. TFA (0.17 mL, 2.28 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 20 minutes and then at room temperature for 40 minutes. The reaction mixture was then concentrated under reduced pressure. The residue was purified by C18 reverse-phase chromatography eluting with a gradient of 5-20% MeCN in water (+0.1% NH4OH) to give the title compound as a white solid. LC-MS-2 (Method 8B): Rt 1.99 min; MS m / z 341.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.52 - 11.04 (m, 2H), 8.02 (s, 1H), 7.89 (d, J = 4.6 Hz, 1H), 7.46 (s, 1H), 7.30 (d, J = 4.7 Hz, 1H), 4.64 (d, J = 6.1 Hz, 2H), 4.54 (d, J = 6.1 Hz, 2H), 4.00 (s, 2H), 3.78 (t, J = 6.9 Hz, 2H), 2.29 (t, J = 6.9 Hz, 2H).

[0854] [Example 25.5] 5-[4-(3,3-Difluoro-4-hydroxy-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione

[0855] [Chemical formula]

[0856] Step 1: 1-(2-Bromopyrazolo[1,5-a]pyrazin-4-yl)-4,4-difluoro-pyrrolidin-3-ol

[0857] [Chemical formula]

[0858] The title compound was prepared from 2-bromo-4-chloro-pyrazolo[1,5-a]pyrazine (Intermediate L) and 4,4-difluoropyrrolidin-3-ol hydrochloride in a similar manner to Step 1 of Example 25. LC-MS-2 (Method 2A): Rt 1.19 min; MS m / z 320.8 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 4.7 Hz, 1H), 7.38 (d, J = 4.7 Hz, 1H), 7.27 (s, 1H), 6.22 (d, J = 5.1 Hz, 1H), 4.36 (m, 1H), 4.23 - 4.03 (m, 3H), 3.80 - 3.70 (m, 1H).

[0859] Step 2: 1-[2-(2,4-Dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrazin-4-yl]-4,4-difluoro-pyrrolidin-3-ol

[0860]

Chem.

[0861] The title compound was synthesized from 1-(2-bromopyrazolo[1,5-a]pyrazin-4-yl)-4,4-difluoro-pyrrolidin-3-ol (Step 1) and (2,4-dimethoxypyrimidin-5-yl)boronic acid in a similar manner to Step 2 of Example 25. LC-MS-2 (Method 2A): Rt 1.21 min; MS m / z 379.0 = [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.40 (d, J = 4.7 Hz, 1H), 7.35 (s, 1H), 6.25 (d, J = 5.0 Hz, 1H), 4.47 - 4.37 (m, 1H), 4.24 - 4.15 (m, 3H), 4.09 (s, 3H), 3.98 (s, 3H), 3.88 - 3.79 (m, 1H).

[0862] Step 3: 5-[4-(3,3-Difluoro-4-hydroxy-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione 1-[2-(2,4-Dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrazin-4-yl]-4,4-difluoro-pyrrolidin-3-ol (Step 2) and 1M HCl were used to synthesize the title compound in a similar manner to Step 3 of Example 25. LC-MS-1 (Method 8A): Rt 1.53 min; MS m / z 351.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 11.21 (s, 1H), 11.11 (s, 1H), 8.02 (d, J = 6.0 Hz, 1H), 7.99 (d, J = 4.7 Hz, 1H), 7.49 (s, 1H), 7.34 (d, J = 4.7 Hz, 1H), 4.46 - 4.40 (m, 1H), 4.22 - 4.14 (m, 3H), 3.87 - 3.83 (m, 1H).

[0863] [Example 25.6] 5-[4-[3,3-Difluoro-4-[(4-methylmorpholin-2-yl)methoxy]pyrrolidin-1-yl]pyrazolo[1,5-a]pyrazin-2-yl]-1H-pyrimidine-2,4-dione

[0864]

Chemical Structure

[0865] Step 1: 2-[[1-(2-Bromopyrazolo[1,5-a]pyrazin-4-yl)-4,4-difluoro-pyrrolidin-3-yl]oxymethyl]-4-methyl-morpholine

[0866]

Chemical Structure

[0867] 1-(2-Bromopyrazolo[1,5-a]pyrazin-4-yl)-4,4-difluoro-pyrrolidin-3-ol (Example 25.5, Step 1) (300 mg, 0.94 mmol), (4-Methylmorpholin-2-yl)methyl 4-methylbenzenesulfonate (Intermediate H, Step 1) (295 mg, 1.03 mmol), and TBAB (90 mg, 0.2800 mmol) in toluene (6 mL) were stirred, and 50% aqueous NaOH solution (1.13 mL, 14.1 mmol) was added. The reaction mixture was heated at 80 °C for 18 hours. 50% aqueous NaOH solution (1.13 mL, 14.1 mmol), TBAB (90.92 mg, 0.28 mmol), and (4-Methylmorpholin-2-yl)methyl 4-methylbenzenesulfonate (Intermediate H, Step 1) (295 mg, 1.03 mmol) were added to the reaction mixture, and it was heated at 80 °C for 22 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (5...

Claims

1. Compounds having structural formula I shown below, or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula, R １ teeth (i)-NR １Ａ R １Ｂ ; (In the formula, R １Ａ and R １Ｂ Each is independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, and heterocyclyl(1-2C)alkyl; or Or, R １Ａ and R １Ｂ They are linked together with the nitrogen atoms to which they are bonded to form a heterocycle; Any (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl, heterocyclyl (R １Ａ and R １Ｂ formed by), or the heterocyclyl(1-2C) alkyl group may be substituted with one or more R ｘ ); (ii) One or more R ｘ A carbon-bonded heterocyclyl which may be substituted with; (iii)-mR １Ｃ ; (In the formula, R １Ｃ Each of these is one or more R ｘ (Selected from (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl); (iv) One or more R ｘ (1-6C) alkyl groups which may be substituted with; (v) A (3-6C) cycloalkyl which may be substituted with one or two substituents independently selected from (v) fluoro, (1-4C) alkyl, (1-4C) haloalkyl, (1-4C) alkoxy, (1-4C) haloalkoxy, hydroxy, (1-4C) hydroxyalkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl (1-2C) alkyl, aryl, aryl (1-2C) alkyl, heteroaryl, heteroaryl (1-2C) alkyl, heterocyclyl, heterocyclyl (1-2C) alkyl, and heterocyclyl (1-2C) alkyl, wherein one or more R ｘ (3-6C)cycloalkyl, which may be substituted with; (vi) A carbon-bonded or nitrogen-bonded heteroaryl ring which may be substituted with one or two substituents independently selected from fluoro, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, hydroxy, or (1-4C)hydroxyalkyl. Selected from, Each R ｘ These are independently halo, cyano, (1-4C) alkyl, and (CH ２ ) ｑ１ NR １Ｄ R １Ｅ , (CH ２ ) ｑ１ OR １Ｄ , (CH ２ ) ｑ１ C(O)R １Ｄ , (CH ２ ) ｑ１ C(O)OR １Ｄ , O(CH ２ ) ｑ１ C(O)R １Ｄ , (CH ２ ) ｑ１ OC(O)R １Ｄ , (CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , O(CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , (CH ２ ) ｑ１ N(R) １Ｅ ) C(O)R １Ｄ , (CH ２ ) ｑ１ S(O) ｐ R １Ｄ (p is 0, 1, or 2), (CH ２ ) ｑ１ SO ２ N(R) １Ｅ ) R １Ｄ , (CH ２ ) ｑ１ N(R) １Ｅ ) SO ２ R １Ｄ Selected from (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, aryl, aryl(1-4C) alkyl, heteroaryl, heteroaryl(1-4C) alkyl, heterocyclyl, heterocyclyl(1-4C) alkyl, or spirocondensed (3-6C) cycloalkyl or heterocyclyl; q1 is 0, 1, 2, or 3; R １Ｄ is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, or heterocyclyl(1-4C)alkyl; R １Ｅ is selected from hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, aryl, or aryl(1-4C) alkyl; Or, R １Ｄ and R １Ｅ They are linked together with one or more atoms to which they are bonded to form a 4- to 10-membered heterocycle; R ｘ 、 R １Ｄ 、 and R １Ｅ any (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, heterocyclyl(1-4C)alkyl group present in the substituent, or, R １Ｄ and R １Ｅ when linked, the heterocyclyl group formed is halo, cyano, hydroxy, oxo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)hydroxyalkyl, (CH ２ ) ｑ２ NR １Ｆ R １Ｇ 、(CH ２ ) ｑ２ OR １Ｆ 、(CH ２ ) ｑ２ C(O)R １Ｆ 、(CH ２ ) ｑ２ C(O)OR １Ｆ 、(CH ２ ) ｑ２ OC(O)R １Ｆ 、(CH ２ ) ｑ２ C(O)N(R １Ｇ )R １Ｆ 、(CH ２ ) ｑ２ N(R １Ｇ )C(O)R １Ｆ 、(CH ２ ) ｑ２ S(O) ｐ R １Ｆ (p is 0, 1, or 2), (CH ２ ) ｑ２ SO ２ N(R １Ｇ )R １Ｆ 、(CH ２ ) ｑ２ N(R １Ｇ )SO ２ R １Ｆ and may be further substituted; q2 is 0, 1, 2, or 3; R １Ｆ and R １Ｇ Each of these is independently selected from (1-4C) alkyl groups which may be substituted with hydrogen or a halo; X ２ is N or CR ２ Selected from; R ２ is selected from hydrogen, halo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, or cyano; X ３ is N or CR ３ Selected from; R ３ is selected from hydrogen, halo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, or cyano; X ４ is N or CR ４ Selected from; R ４ is selected from hydrogen, halo (e.g., fluoro or chloro), (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, or cyano; X ５ is selected from N or C; X ６ is selected from N or C; X ７ N, NR ７Ｎ CR ７ Selected from , O, or S; R ７ is selected from hydrogen, halo, methyl, or methoxy; R ７Ｎ is selected from hydrogen or methyl; X ８ N, NR ８Ｎ CR ８ Selected from , O, or S; R ８ is selected from hydrogen, halo, methyl, or methoxy; R ８Ｎ is selected from hydrogen or methyl; X ９ It is selected from N or C, however, (i) X ５ and X ６ It is not possible for both to be N; (ii) X ７ and X ８ Only one of them may be O or S; (iii) R １ X, together with the bonded carbon atoms, forms a bicyclic ring. ２ , X ３ , X ４ , X ５ , X ６ , X ７ , X ８ , and X ９ (Four or fewer atoms in the group may be heteroatoms.)

2. The compound according to claim 1, having the following structural formula I-I, or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 (In the formula, R １ teeth (i)-NR １Ａ R １Ｂ ; (In the formula, R １Ａ and R １Ｂ Each is independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, and heterocyclyl(1-2C)alkyl; or Or, R １Ａ and R １Ｂ They are linked together with the nitrogen atoms to which they are bonded to form a heterocycle; Any (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl, heterocyclyl(R) １Ａ and R １Ｂ (including those formed by), or heterocyclyl(1-2C) alkyl groups are one or more R ｘ (May be replaced by ); (ii) One or more R ｘ A carbon-bonded heterocyclyl which may be substituted with; (iii)-mR １Ｃ ; (In the formula, R １Ｃ Each of these is one or more R ｘ (Selected from (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl); (iv) One or more R ｘ (1-6C) alkyl groups which may be substituted with; (v) A (3-6C) cycloalkyl which may be substituted with one or two substituents independently selected from (v) fluoro, (1-4C) alkyl, (1-4C) haloalkyl, (1-4C) alkoxy, (1-4C) haloalkoxy, hydroxy, (1-4C) hydroxyalkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl (1-2C) alkyl, aryl, aryl (1-2C) alkyl, heteroaryl, heteroaryl (1-2C) alkyl, heterocyclyl, heterocyclyl (1-2C) alkyl, and heterocyclyl (1-2C) alkyl, wherein one or more R ｘ (3-6C)cycloalkyl, which may be substituted with; (vi) A carbon-bonded or nitrogen-bonded heteroaryl ring which may be substituted with one or two substituents independently selected from fluoro, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, hydroxy, or (1-4C)hydroxyalkyl. Selected from, Each R ｘ These are independently halo, cyano, (1-4C) alkyl, and (CH ２ ) ｑ１ NR １Ｄ R １Ｅ , (CH ２ ) ｑ１ OR １Ｄ , (CH ２ ) ｑ１ C(O)R １Ｄ , (CH ２ ) ｑ１ C(O)OR １Ｄ , O(CH ２ ) ｑ１ C(O)R １Ｄ , (CH ２ ) ｑ１ OC(O)R １Ｄ , (CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , O(CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , (CH ２ ) ｑ１ N(R) １Ｅ ) C(O)R １Ｄ , (CH ２ ) ｑ１ S(O) ｐ R １Ｄ (p is 0, 1, or 2), (CH ２ ) ｑ１ SO ２ N(R) １Ｅ ) R １Ｄ , (CH ２ ) ｑ１ N(R) １Ｅ ) SO ２ R １Ｄ Selected from (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, aryl, aryl(1-4C) alkyl, heteroaryl, heteroaryl(1-4C) alkyl, heterocyclyl, heterocyclyl(1-4C) alkyl, or spirocondensed (3-6C) cycloalkyl or heterocyclyl; q1 is 0, 1, 2, or 3; R １Ｄ is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, or heterocyclyl(1-4C)alkyl; R １Ｅ is selected from hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, aryl, or aryl(1-4C) alkyl; Or, R １Ｄ and R １Ｅ They are linked together with one or more atoms to which they are bonded to form a 4- to 10-membered heterocycle; R ｘ , R １Ｄ , and R １Ｅ Any (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, aryl, aryl(1-4C) alkyl, heteroaryl, heteroaryl(1-4C) alkyl, heterocyclyl, heterocyclyl(1-4C) alkyl, or R １Ｄ and R １Ｅ The heterocyclyl groups formed when these are linked are halo, cyano, hydroxy, oxo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)hydroxyalkyl, (CH ２ ) ｑ２ NR １Ｆ R １Ｇ , (CH ２ ) ｑ２ OR １Ｆ , (CH ２ ) ｑ２ C(O)R １Ｆ , (CH ２ ) ｑ２ C(O)OR １Ｆ , (CH ２ ) ｑ２ OC(O)R １Ｆ , (CH ２ ) ｑ２ C(O)N(R) １Ｇ ) R １Ｆ , (CH ２ ) ｑ２ N(R) １Ｇ ) C(O)R １Ｆ , (CH ２ ) ｑ２ S(O) ｐ R １Ｆ (p is 0, 1, or 2), (CH ２ ) ｑ２ SO ２ N(R) １Ｇ ) R １Ｆ , (CH ２ ) ｑ２ N(R) １Ｇ ) SO ２ R １Ｆ It may also be further replaced with; q2 is 0, 1, 2, or 3; R １Ｆ and R １Ｇ Each of these is independently selected from (1-4C) alkyl groups which may be substituted with hydrogen or a halo; X ２ is N or CR ２ Selected from; R ２ is selected from hydrogen, halo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, or cyano; R ３ is selected from hydrogen, halo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, or cyano; X ４ is N or CR ４ Selected from; R ４ is selected from hydrogen, halo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy, or cyano; X ５ is selected from N or C; X ６ is selected from N or C; X ７ N, NR ７Ｎ CR ７ Selected from , O, or S; R ７ is selected from hydrogen, halo, methyl, or methoxy; R ７Ｎ is selected from hydrogen or methyl; X ８ N, NR ８Ｎ CR ８ Selected from , O, or S; R ８ is selected from hydrogen, halo, methyl, or methoxy; R ８Ｎ is selected from hydrogen or methyl; X ９ It is selected from N or C, however, (i) X ５ and X ６ It is not possible for both to be N; (ii) X ７ and X ８ Only one of them may be O or S; (iii) CR １ and CR ３ X, together with the others, forms a biring ring. ２ , X ４ , X ５ , X ６ , X ７ , X ８ , and X ９ (Four or fewer atoms in the group may be heteroatoms.)

3. The following (A) to (C) (A)R １ but (i)-NR １Ａ R １Ｂ ; (In the formula, R １Ａ and R １Ｂ Each is independently selected from hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl, heterocyclyl, and heterocyclyl(1-2C) alkyl. Or, R １Ａ and R １Ｂ They are linked together with the nitrogen atoms to which they are bonded to form a heterocycle; Any (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl, heterocyclyl(R) １Ａ and R １Ｂ (including those formed by), or heterocyclyl(1-2C) alkyl groups are one or more R ｘ (May be replaced by ); (ii) One or more R ｘ A carbon-bonded heterocyclyl which may be substituted with; (iii)-mR １Ｃ ; (In the formula, R １Ｃ Each of these is one or more R ｘ (Selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl); (iv) One or more R ｘ (1-6C) alkyl groups which may be substituted with; (v) (3-6C)cycloalkyl, which may be substituted with one or two substituents independently selected from fluoro, (1-4C)alkyl, (1-3C)haloalkyl, (1-3C)alkoxy, (1-3C)haloalkoxy, hydroxy, or (1-3C)hydroxyalkyl; (vi) (3-6C) cycloalkyl, which may be substituted with one or two substituents independently selected from (vi) fluoro, (1-4C) alkyl, (1-4C) haloalkyl, (1-4C) alkoxy, (1-4C) haloalkoxy, hydroxy, (1-4C) hydroxyalkyl, (3-6C) cycloalkyl, aryl, heteroaryl, or heterocyclyl; (vii) A carbon-bonded or nitrogen-bonded monocyclic heteroaryl ring, which may be substituted with one or two substituents independently selected from (vii) fluoro, (1-3C) alkyl, (1-3C) haloalkyl, (1-3C) alkoxy, (1-3C) haloalkoxy, hydroxy, or (1-3C) hydroxyalkyl. Selected from, Each R ｘ These independently form halo, cyano, (1-4C) alkyl, and (CH ２ ) ｑ１ NR １Ｄ R １Ｅ , (CH ２ ) ｑ１ OR １Ｄ , (CH ２ ) ｑ１ C(O)R １Ｄ , O(CH ２ ) ｑ１ C(O)R １Ｄ , (CH ２ ) ｑ１ C(O)OR １Ｄ , (CH ２ ) ｑ１ OC(O)R １Ｄ , (CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , O(CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , (CH ２ ) ｑ１ N(R) １Ｅ ) C(O)R １Ｄ , (CH ２ ) ｑ１ S(O) ｐ R １Ｄ (p is 0, 1, or 2), (CH ２ ) ｑ１ SO ２ N(R) １Ｅ ) R １Ｄ , (CH ２ ) ｑ１ N(R) １Ｅ ) SO ２ R １Ｄ Selected from (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, aryl, aryl(1-4C) alkyl, heteroaryl, heteroaryl(1-4C) alkyl, heterocyclyl, heterocyclyl(1-4C) alkyl, or spirocondensed (3-6C) cycloalkyl or heterocyclyl; q1 is 0, 1, or 2; R １Ｄ is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, or heterocyclyl(1-4C)alkyl; R １Ｅ is selected from hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, aryl, or aryl(1-4C) alkyl; R ｘ , R １Ｄ , and R １Ｅ Any (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, aryl, aryl(1-4C) alkyl, heteroaryl, heteroaryl(1-4C) alkyl, heterocyclyl, heterocyclyl(1-4C) alkyl, or R １Ｄ and R １Ｅ The heterocyclyl groups formed when these are linked are halo, cyano, hydroxy, oxo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)hydroxyalkyl, (CH ２ ) ｑ２ NR １Ｆ R １Ｇ , (CH ２ ) ｑ２ OR １Ｆ , (CH ２ ) ｑ２ C(O)R １Ｆ , (CH ２ ) ｑ２ C(O)OR １Ｆ , (CH ２ ) ｑ２ OC(O)R １Ｆ , (CH ２ ) ｑ２ C(O)N(R) １Ｇ ) R １Ｆ , (CH ２ ) ｑ２ N(R) １Ｇ ) C(O)R １Ｆ , (CH ２ ) ｑ２ S(O) ｐ R １Ｆ (p is 0, 1, or 2), (CH ２ ) ｑ２ SO ２ N(R) １Ｇ ) R １Ｆ , (CH ２ ) ｑ２ N(R) １Ｇ ) SO ２ R １Ｆ It may also be further replaced with; q2 is 0, 1, or 2; R １Ｆ and R １Ｇ Each of these may be independently substituted with hydrogen or a halo, selected from (1-4C) alkyl groups. (B)R １ but (i)-NR １Ａ R １Ｂ ; (In the formula, R １Ａ and R １Ｂ Each of these is independently selected from hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, heteroaryl, and heteroaryl(1-2C) alkyl. Or, R １Ａ and R １Ｂ They are linked together with the nitrogen atoms to which they are bonded to form a heterocycle; Any (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl, or R １Ａ and R １Ｂ The heterocyclyl group formed by this is one or more R ｘ (May be replaced by ); (ii) One or more R ｘ A carbon-bonded heterocyclyl which may be substituted with; (iii)-mR １Ｃ ; (In the formula, R １Ｃ Each of these is one or more R ｘ (Selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl, or phenyl(1-2C)alkyl, which may be substituted with; (iv) cycloalkyl (3-6C) which may be substituted with one or two substituents independently selected from (iv) fluoro, (1-4C) alkyl, (1-4C) haloalkyl, (1-4C) alkoxy, (1-4C) haloalkoxy, hydroxy, (1-4C) hydroxyalkyl, or phenyl Selected from, Each R ｘ These independently form halo, cyano, (1-4C) alkyl, and (CH ２ ) ｑ１ NR １Ｄ R １Ｅ , (CH ２ ) ｑ１ OR １Ｄ , (CH ２ ) ｑ１ C(O)R １Ｄ , O(CH ２ ) ｑ１ C(O)R １Ｄ , (CH ２ ) ｑ１ C(O)OR １Ｄ , (CH ２ ) ｑ１ OC(O)R １Ｄ , (CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , O(CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , (CH ２ ) ｑ１ N(R) １Ｅ ) C(O)R １Ｄ Selected from (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, phenyl, phenyl(1-4C) alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-4C) alkyl, 4- to 10-membered heterocyclyl, (4- to 10-membered) heterocyclyl(1-4C) alkyl, or spiro-condensed (3-6C) cycloalkyl or 4- to 6-membered heterocyclyl; q1 is 0, 1, or 2; R １Ｄ is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, phenyl, phenyl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, or heterocyclyl(1-4C)alkyl; R １Ｅ is selected from hydrogen or (1-4C) alkyl; R ｘ , R １Ｄ , and R １Ｅ Any (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, phenyl, phenyl(1-4C) alkyl, 5-membered or 6-membered heteroaryl, (5-membered or 6-membered) heteroaryl(1-4C) alkyl, 4-10 membered heterocyclyl, (4-10 membered) heterocyclyl(1-4C) alkyl, or R １Ｄ and R １Ｅ The heterocyclyl groups formed when these are linked are halo, cyano, hydroxy, oxo, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, (CH ２ ) ｑ２ NR １Ｆ R １Ｇ , (CH ２ ) ｑ２ OR １Ｆ , (CH ２ ) ｑ２ C(O)R １Ｆ , (CH ２ ) ｑ２ C(O)OR １Ｆ , (CH ２ ) ｑ２ OC(O)R １Ｆ , (CH ２ ) ｑ２ C(O)N(R) １Ｇ ) R １Ｆ , (CH ２ ) ｑ２ N(R) １Ｇ ) C(O)R １Ｆ , (CH ２ ) ｑ２ S(O) ｐ R １Ｆ (p is 0, 1, or 2), (CH ２ ) ｑ２ SO ２ N(R) １Ｇ ) R １Ｆ , (CH ２ ) ｑ２ N(R) １Ｇ ) SO ２ R １Ｆ It may also be further replaced with; q2 is 0 or 1; R １Ｆ and R １Ｇ Each is independently selected from hydrogen or (1-2C) alkyl. (C) R １ but (i)-NR １Ａ R １Ｂ ; (In the formula, R １Ａ and R １Ｂ One of them is hydrogen, and the other is one or more R ｘ Selected from (1-4C)alkyl, aryl(1-2C)alkyl, or heteroaryl(1-2C)alkyl, which may be substituted with; or R １Ａ and R １Ｂ Together with the nitrogen atom to which they are bonded, each has one or more R ｘ (May be substituted with, linked to form a 4-membered, 5-membered, or 6-membered monocyclic heterocycle, a 5- to 10-membered fused heterocycle, a 5- to 10-membered bridged heterocycle, or a 5- to 10-membered spirocyclic heterocycle); (ii) One or more R ｘ Carbon-bonded 4- to 10-membered heterocyclines (including 4-membered, 5-membered, or 6-membered monocyclic heterocycles, fused heterocycles, bridging heterocycles, and spirocyclic heterocycles), which may be substituted with; (iii) (3C)cycloalkyl, which may be substituted with one or two substituents independently selected from (iii) fluoro, (1-4C) alkyl, (1-4C) haloalkyl, (1-4C) alkoxy, (1-4C) haloalkoxy, hydroxy, (1-4C) hydroxyalkyl, or phenyl. Selected from, Each R ｘ These independently form halo, cyano, (1-4C) alkyl, and (CH ２ ) ｑ１ NR １Ｄ R １Ｅ , (CH ２ ) ｑ１ OR １Ｄ , (CH ２ ) ｑ１ C(O)R １Ｄ , O(CH ２ ) ｑ１ C(O)R １Ｄ , (CH ２ ) ｑ１ C(O)OR １Ｄ , (CH ２ ) ｑ１ OC(O)R １Ｄ , (CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , O(CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , (CH ２ ) ｑ１ N(R) １Ｅ ) C(O)R １Ｄ Selected from (3-6C) cycloalkyl(1-3C) alkyl, phenyl, phenyl(1-3C) alkyl, (5- or 6-membered) heteroaryl(1-3C) alkyl, (4-6-membered) heterocyclyl(1-3C) alkyl, or spirocondensed(3-6C) cycloalkyl or 4-6-membered heterocycline; q1 is 0 or 1; R １Ｄ is selected from hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, phenyl, phenyl(1-3C) alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-3C) alkyl, 4- or 9-membered heterocyclyl, or (4- or 9-membered) heterocyclyl(1-3C) alkyl; R １Ｅ is selected from hydrogen or (1-2C) alkyl; R ｘ , R １Ｄ , and R １Ｅ Any (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, phenyl, phenyl(1-3C) alkyl, 5-membered or 6-membered heteroaryl, (5-membered or 6-membered) heteroaryl(1-3C) alkyl, 4-9 membered heterocyclyl, or (4-9 membered) heterocyclyl(1-3C) alkyl, or R １Ｄ and R １Ｅ The heterocyclyl groups formed when these are linked are halo, cyano, hydroxy, oxo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)hydroxyalkyl, NR １Ｆ R １Ｇ , OR １Ｆ , C(O)R １Ｆ , and C(O)OR １Ｆ They may be further substituted with (for example, halo, cyano, hydroxy, or (1-4C) alkyl); R １Ｆ and R １Ｇ Each is independently selected from hydrogen or (1-2C) alkyl. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, that falls under any one or more of the following categories.

4. The following (A) to (D) (A)R １ but (i)-NR １Ａ R １Ｂ ; (In the formula, R １Ａ and R １Ｂ One of them is hydrogen, and the other is one or more R ｘ Selected from (1-4C)alkyl, aryl(1-2C)alkyl, or heteroaryl(1-2C)alkyl, which may be substituted with; or R １Ａ and R １Ｂ Together with the nitrogen atom to which they are bonded, each has one or more R ｘ (May be substituted with, linked to form a 4-membered, 5-membered, or 6-membered monocyclic heterocycle, a 5- to 10-membered fused heterocycle, a 5- to 10-membered bridged heterocycle, or a 5- to 10-membered spirocyclic heterocycle); (ii) One or more R ｘ Carbon-bonded 4- to 10-membered heterocyclines (including 4-membered, 5-membered, or 6-membered monocyclic heterocycles, fused heterocycles, bridging heterocycles, and spirocyclic heterocycles), which may be substituted with; (iii) (3C)cycloalkyl, which may be substituted with one or two substituents independently selected from (iii) fluoro, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy, hydroxy, (1-2C) hydroxyalkyl, or phenyl. Selected from, Each R ｘ These independently form halo, cyano, (1-4C) alkyl, and (CH ２ ) ｑ１ NR １Ｄ R １Ｅ , (CH ２ ) ｑ１ OR １Ｄ , (CH ２ ) ｑ１ C(O)R １Ｄ , O(CH ２ ) ｑ１ C(O)R １Ｄ , (CH ２ ) ｑ１ C(O)OR １Ｄ , (CH ２ ) ｑ１ OC(O)R １Ｄ , (CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , O(CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , (CH ２ ) ｑ１ N(R) １Ｅ ) C(O)R １Ｄ Selected from (3-6C) cycloalkyl(1-3C) alkyl, phenyl, phenyl(1-3C) alkyl, (5- or 6-membered) heteroaryl(1-3C) alkyl, (4-6-membered) heterocyclyl(1-3C) alkyl, or spirocondensed(3-6C) cycloalkyl or 4-6-membered heterocycline; q1 is 0 or 1; R １Ｄ is selected from hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, phenyl, phenyl(1-3C) alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-3C) alkyl, 4- or 9-membered heterocyclyl, or (4- or 9-membered) heterocyclyl(1-3C) alkyl; R １Ｅ is selected from hydrogen or (1-2C) alkyl; R ｘ , R １Ｄ , and R １Ｅ Any (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-4C) alkyl, phenyl, phenyl(1-3C) alkyl, 5-membered or 6-membered heteroaryl, (5-membered or 6-membered) heteroaryl(1-3C) alkyl, 4-9 membered heterocyclyl, or (4-9 membered) heterocyclyl(1-3C) alkyl, or R １Ｄ and R １Ｅ The heterocyclyl groups formed when these are linked are halo, cyano, hydroxy, oxo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)hydroxyalkyl, NR １Ｆ R １Ｇ , OR １Ｆ , C(O)R １Ｆ , and C(O)OR １Ｆ They may be further substituted with (for example, halo, cyano, hydroxy, or (1-4C) alkyl); R １Ｆ and R １Ｇ Each is independently selected from hydrogen or (1-2C) alkyl. (B)R １ but (i)-NR １Ａ R １Ｂ ; (In the formula, R １Ａ and R １Ｂ One of them is hydrogen, and the other is one or more R ｘ Selected from (1-4C)alkyl or phenyl(1-2C)alkyl, which may be substituted with; or R １Ａ and R １Ｂ Together with the nitrogen atom to which they are bonded, each has one or more R ｘ (which may be substituted with, linked to form a 4-membered, 5-membered, or 6-membered monocyclic heterocycle, a 6- to 10-membered fused heterocycle, a 6- to 10-membered bridging heterocycle, or a 6- to 10-membered spirocyclic heterocycle); or, (ii) In each case, one or more R ｘ A four-, five-, or six-membered monocyclic heterocycle, a six- to ten-membered fused heterocycle, a six- to ten-membered bridging heterocycle, or a six- to ten-membered spirocyclic heterocycle, which may be substituted with a carbon bond; (iii) (3C)cycloalkyl, which may be substituted with one or two substituents independently selected from (iii) fluoro, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy, hydroxy, (1-2C) hydroxyalkyl, or phenyl. Selected from, Each R ｘ These independently form halo, cyano, (1-4C) alkyl, and (CH ２ ) ｑ１ NR １Ｄ R １Ｅ , (CH ２ ) ｑ１ OR １Ｄ , (CH ２ ) ｑ１ C(O)R １Ｄ , O(CH ２ ) ｑ１ C(O)R １Ｄ , (CH ２ ) ｑ１ C(O)OR １Ｄ , (CH ２ ) ｑ１ OC(O)R １Ｄ , (CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , O(CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ , or (CH ２ ) ｑ１ N(R) １Ｅ ) C(O)R １Ｄ Selected from; q1 is 0 or 1; R １Ｄ is selected from (1-4C) alkyl, phenyl, phenyl(1-3C)alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-3C)alkyl, 4- or 9-membered heterocyclyl, or (4- or 9-membered) heterocyclyl(1-3C)alkyl; R １Ｅ is selected from hydrogen or (1-2C) alkyl; R ｘ , R １Ｄ , and R １Ｅ Any (1-4C) alkyl, phenyl, phenyl(1-3C)alkyl, 5-membered or 6-membered heteroaryl, (5-membered or 6-membered) heteroaryl(1-3C)alkyl, 4-9 membered heterocyclyl, or (4-9 membered) heterocyclyl(1-3C)alkyl, or R １Ｄ and R １Ｅ The heterocyclyl groups formed when these are linked are halo, cyano, hydroxy, oxo, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, NR １Ｆ R １Ｇ , OR １Ｆ , C(O)R １Ｆ , and C(O)OR １Ｆ They may be further substituted with (for example, halo, cyano, hydroxy, or (1-4C) alkyl); R １Ｆ and R １Ｇ Each is independently selected from hydrogen or (1-2C) alkyl. (C) R １ but (i)-NR １Ａ R １Ｂ ; (In the formula, R １Ａ and R １Ｂ One of them is hydrogen, and the other is one or more R ｘ Selected from (1-4C)alkyl or phenyl(1-2C)alkyl, which may be substituted with; or R １Ａ and R １Ｂ Together with the nitrogen atom to which they are bonded, each has one or more R ｘ (which may be substituted with, linked to form a 4-membered, 5-membered, or 6-membered monocyclic heterocycle, a 7- to 9-membered fused heterocycle, or a 7- to 9-membered spirocyclic heterocycle); or, (ii) In each case, one or more R ｘ A four-, five-, or six-membered monocyclic heterocycle, a seven- to nine-membered fused heterocycle, or a seven- to nine-membered spirocyclic heterocycle, which may be substituted with a carbon bond; (iii) (3C)cycloalkyl, which may be substituted with one or two substituents independently selected from (iii) fluoro, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy, hydroxy, (1-2C) hydroxyalkyl, or phenyl. Selected from, Each R ｘ These independently form halo, cyano, (1-4C) alkyl, and (CH ２ ) ｑ１ OR １Ｄ , O(CH ２ ) ｑ１ C(O)R １Ｄ , or O(CH ２ ) ｑ１ C(O)N(R) １Ｅ ) R １Ｄ Selected from; q1 is 0 or 1; R １Ｄ is selected from (1-4C) alkyl, phenyl, phenyl(1-2C)alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-2C)alkyl, 4- or 9-membered heterocyclyl, or (4- or 9-membered) heterocyclyl(1-2C)alkyl; R １Ｅ is selected from hydrogen or methyl; R ｘ or R １Ｄ Any (1-4C) alkyl, phenyl, phenyl(1-2C)alkyl, (5- or 6-membered) heteroaryl, (5- or 6-membered) heteroaryl(1-2C)alkyl, (4- or 9-membered) heterocyclyl, or (4- or 9-membered) heterocyclyl(1-2C)alkyl, or R １Ｄ and R １Ｅ The heterocyclyl group formed when the two are linked may be further substituted with a halo, cyano, or hydroxy, (1-2C)alkyl, or (1-2C)haloalkyl group. (D)R １ ga-NR １Ａ R １Ｂ And; R １Ａ and R １Ｂ One of them is hydrogen, and the other is one or more R ｘ Selected from (1-4C)alkyl or phenyl(1-2C)alkyl, which may be substituted with; or R １Ａ and R １Ｂ However, together with the nitrogen atom to which they are bonded, each of them has one or more R ｘ Linked to form a four- or five-membered heterocyclic system, a seven- to nine-membered fused heterocyclic system, or a seven- to nine-membered spirocyclic heterocyclic system, which may be substituted with; Each R ｘ These independently form halo, cyano, (1-2C) alkyl, OR １Ｄ OC(O)R １Ｄ , or OC(O)N(R １Ｅ ) R １Ｄ Selected from; R １Ｄ is selected from (1-4C) alkyl, phenyl, phenyl(1-3C)alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-3C)alkyl, 4- or 9-membered heterocyclyl, or (4- or 9-membered) heterocyclyl(1-3C)alkyl; R １Ｅ is selected from hydrogen or methyl; R ｘ or R １Ｄ Any (1-4C) alkyl, phenyl, phenyl(1-3C)alkyl, 5-membered or 6-membered heteroaryl, (5-membered or 6-membered) heteroaryl(1-3C)alkyl, 4-9 membered heterocyclyl, or (4-9 membered) heterocyclyl(1-3C)alkyl, or R １Ｄ and R １Ｅ The heterocyclyl group formed when the two are linked may be further substituted with a halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)haloalkyl group; Optionally, R １Ａ and R １Ｂ However, together with the nitrogen atom to which they are bonded, each of them has one or more R ｘ Linked to form a four- or five-membered nitrogen-bonded heterocycle, a seven- to nine-membered condensed heterocycle, or a seven- to nine-membered spirocyclic heterocycle, which may be substituted with; Each R ｘ These independently form halo, (1-2C)alkyl, OR １Ｄ OC(O)R １Ｄ , or OC(O)N(R １Ｅ ) R １Ｄ Selected from; R １Ｄ The selected elements are (1-4C) alkyl, phenyl(1-2C) alkyl, 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-2C) alkyl, 6-9 membered heterocyclyl, or (6-9 membered) heterocyclyl(1-2C) alkyl; R １Ｅ is hydrogen; R ｘ or R １Ｄ Any (1-4C) alkyl, phenyl(1-2C)alkyl, 5- or 6-membered heteroaryl, (5- or 6-membered) heteroaryl(1-2C)alkyl, 4- to 9-membered heterocyclyl, or (4-9-membered) heterocyclyl(1-2C)alkyl, or R １Ｄ and R １Ｅ The heterocyclyl group formed when the two are linked may be further substituted with a halo, cyano, or hydroxy, (1-2C)alkyl, or (1-2C)haloalkyl group. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, that falls under any one or more of the following categories.

5. (A) or (B) below (A)R １ The basis of the following equation is: 【Transformation 3】 In the formula, n is 0, 1, 2, 3, or 4; R ｘ Each that exists independently is defined as in any one of the paragraphs above; Ring A, together with the carbon atoms to which it is bonded, forms one or more R ｘ The spirocondensed 3-6 membered cycloalkyl or heterocyclyl ring may be substituted with; Ring B, together with the carbon atoms to which it is bonded, forms one or more R ｘ The resulting condensed 3-6 member cycloalkyl or heterocyclyl ring may be substituted with; Optionally, R １ The basis of the following formula: 【Chemistry 4】 That is, (B)R １ The basis of the following equation is: 【Transformation 5】 During the ceremony, R ｘ１ and R ｘ２ The hydrogen or halo is independently selected; R ｘ３ and R ｘ４ This is independently selected from hydrogen, halo, methyl, or methoxy; Or, R ｘ３ and R ｘ４ One of them is hydrogen, and the other is OR １Ｄ And; R １Ｄ is selected from phenyl(1-2C)alkyl, (5- or 6-membered) heteroaryl(1-2C)alkyl, or (4- or 6-membered) heterocyclyl(1-2C)alkyl; the phenyl(1-2C)alkyl, (5- or 6-membered) heteroaryl(1-2C)alkyl, or (4- or 6-membered) heterocyclyl(1-2C)alkyl may each be substituted with one or more halo, cyano, hydroxy, or methyl groups; Ring A is a spiro-condensed 3- to 6-membered cycloalkyl or heterocyclyl ring, each of which may be substituted with one or more substituents selected from halo, methyl, or methoxy; Optionally, R ｘ１ and R ｘ２ This is independently selected from hydrogen or fluoro; R ｘ３ and R ｘ４ These are independently selected from hydrogen, halo, or methyl; Or, R ｘ３ and R ｘ４ One of them is hydrogen, and the other is OR １Ｄ And; R １Ｄ is a (6-membered) heterocyclyl(1-2C)alkyl; the (6-membered) heterocyclyl(1-2C)alkyl may be substituted with one or more halo, cyano, or methyl groups; Ring A is a spiro-condensed 3- to 5-membered cycloalkyl or heterocyclyl ring, each of which may be substituted with one or more substituents selected from halo, methyl, or methoxy. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, that falls under the category of [the compound].

6. (A) or (B) below (A)R １ but 【Chemistry 6-1】 【Chemistry 6-2】 Selected from, Optionally, R １ but 【Chemistry 7-1】 【Chemistry 7-2】 Selected from, (B)R １ but 【Chemistry 8-1】 【Chemistry 8-2】 Selected from, A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, that falls under the category of [the compound].

7. X ２ is N or CR ２ Selected from; R ２ is selected from hydrogen, halo, methyl, methoxy, halomethyl, halomethoxy, or cyano; X ３ is N or CR ３ Selected from; R ３ is selected from hydrogen, halo, methyl, methoxy, halomethyl, halomethoxy, or cyano; X ４ is N or CR ４ Selected from; R ４ is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, or cyano; X ５ is selected from N or C; X ６ is selected from N or C; X ７ N, NR ７Ｎ CR ７ Selected from , O, or S; R ７ is selected from hydrogen, halo, methyl, or methoxy; R ７Ｎ is selected from hydrogen or methyl; X ８ N, NR ８Ｎ CR ８ Selected from , O, or S; R ８ is selected from hydrogen or halo; R ８Ｎ is selected from hydrogen or methyl; X ９ is selected from N or C, however, (i) X ５ and X ６ It is not possible for both to be N; (ii) X ７ and X ８ Only one of them may be O or S; (iii) R １ X, together with the bonded carbon atoms, forms a bicyclic ring. ２ , X ３ , X ４ , X ５ , X ６ , X ７ , X ８ , and X ９ Four or fewer of the atoms in the group may be heteroatoms; Optionally, X ２ is N or CR ２ Selected from; R ２ is selected from hydrogen or cyano; X ３ is N or CR ３ Selected from; R ３ is selected from hydrogen, halo, or cyano; X ４ is N or CR ４ Selected from; R ４ is hydrogen, fluoro, chloro, methyl, methoxy, fluoromethyl (e.g., CH ２ F, CHF ２ , or CF ３ ), or selected from cyano; X ５ C is; X ６ is selected from N or C; X ７ N, CR ７ , or selected from S; R ７ is selected from hydrogen, halo, or methyl; X ８ N, NR ８Ｎ CR ８ Selected from , O, or S; R ８ is selected from hydrogen or halo; R ８Ｎ is hydrogen or methyl; X ９ is selected from N or C. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

8. X ２ is N; X ３ CR ３ And; R ３ is selected from hydrogen, halo, or cyano; X ４ is N or CR ４ Selected from; R ４ is selected from hydrogen, chloro, or fluoro (e.g., hydrogen or fluoro); X ５ C is; X ６ is C or N; X ７ CR ７ And; R ７ is hydrogen; X ８ N, CR ８ , or selected from S; R ８ is hydrogen; X ９ is selected from N or C; Optionally, X ２ is N; X ３ CR ３ And; R ３ is selected from hydrogen, halo, or cyano; X ４ is N or CR ４ And; R ４ is selected from hydrogen, chloro, or fluoro (e.g., hydrogen or fluoro); X ５ C is; X ６ is C or N; X ７ CR ７ And; R ７ is hydrogen; X ８ is N; X ９ is selected from N or C; Furthermore, optionally, X ２ is N; X ３ CR ３ And; R ３ is hydrogen; X ４ CR ４ And; R ４ is selected from hydrogen, chloro, or fluoro; X ５ C is; X ６ is N; X ７ CR ７ And; R ７ is hydrogen; X ８ is N; X ９ C is The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

9. Compounds of formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Im, In, Io, or Ip: 【Chemistry 9】 In the formula, R １ , R ２ , R ３ , and R ４ is as defined in any one of the claims above; or a pharmaceutically acceptable salt thereof.

10. 5-[4-[3-(hydroxymethyl)pyrrolidine-1-yl]thieno[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-(2-hydroxyethyl)pyrrolidine-1-yl]thieno[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-dimethylazetidine-1-yl)thieno[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione 5-[4-[3-(2-hydroxyethoxy)pyrrolidine-1-yl]thieno[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidine-1-yl]thieno[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-dimethylpyrrolidine-1-yl)thieno[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 6-[1-[6-(2,4-dioxo-1H-pyrimidine-5-yl)thieno[2,3-d]pyrimidine-4-yl]pyrrolidine-3-yl]oxypyridine-3-carbonitrile; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrrolidine-1-yl)thieno[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-(2-pyridylmethoxy)pyrrolidine-1-yl]thieno[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3-benzyloxypyrrolidine-1-yl)thieno[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-difluoro-4-[(4-methylmorpholine-2-yl)methoxy]pyrrolidine-1-yl]thieno[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[(4-methylmorpholine-2-yl)methoxy]pyrrolidine-1-yl]thieno[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-difluoro-4-[2-(1-piperidyl)ethoxy]pyrrolidine-1-yl]thieno[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[7-[3-[2-(1-piperidyl)ethoxy]pyrrolidine-1-yl]thiazolo[4,5-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-(3,3-difluoro-4,4-dimethyl-pyrrolidine-1-yl)thiazolo[4,5-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidine-1-yl]flo[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrrolidine-1-yl)flo[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidine-1-yl]thieno[3,2-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrroridine-1-yl]thieno[3,2-c]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrroridine-1-yl]pyrrolo[2,1-f][1,2,4]triazine-6-yl]pyrimidine-2,4-diol; 5-[4-[3-[2-(4,4-difluoro-1-piperidyl)ethoxy]pyrroridine-1-yl]pyrrolo[2,1-f][1,2,4]triazine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrroridine-1-yl)pyrrolo[2,1-f][1,2,4]triazine-6-yl]-1H-pyrimidine-2,4-dione; 2-(2,4-dioxo-1H-pyrimidine-5-yl)-4-[3-[2-(1-piperidyl)ethoxy]pyrrolidine-1-yl]thieno[2,3-b]pyridine-5-carbonitrile; 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrrolidine-1-yl]pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrrolidine-1-yl)pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-difluoro-5-azaspiro[2,4]heptan-5-yl)pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(8,8-difluoro-6-azaspiro[3,4]octan-6-yl)pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(4,4-difluoro-2-azaspiro[4.4]nonane-2-yl)pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(3aR,6aS)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-yl]pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3-ethyl-3-methyl-pyrrolidine-1-yl)pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-dimethylpyrrolidine-1-yl)pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-diethylpyrrolidine-1-yl)pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3,4,4-tetrafluoropyrrolidine-1-yl)pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-hexahydrofloxacin[3,4-c]pyrrole-5-yl]pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(3aR,6aR)-1,3,3a,4,6,6a-hexahydrofl[3,4-c]pyrrole-5-yl]pyrazolo[3,4-d]pyrimidine-2-yl]-5H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4-methoxy-pyrroridine-1-yl)pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3-[2-(1-piperidyl)ethoxy]pyrroridine-1-yl]thieno[2,3-b]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrrolidine-1-yl)thieno[2,3-b]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[6-[3-[2-(1-piperidyl)ethoxy]pyrrolidine-1-yl]-9H-purine-8-yl]-1H-pyrimidine-2,4-dione; 5-[7-[3-[2-(1-piperidyl)ethoxy]pyrroridine-1-yl]thieno[3,2-b]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-difluoro-4-[2-(1-piperidyl)ethoxy]pyrroridine-1-yl]pyrrolo[2,1-f][1,2,4]triazine-6-yl]-1H-pyrimidine-2,4-dione; 5-[2-chloro-4-[3-[2-(1-piperidyl)ethoxy]pyrroridine-1-yl]pyrrolo[2,1-f][1,2,4]triazine-6-yl]-5H-pyrimidine-2,4-dione; 5-[4-(8,8-difluoro-6-azaspiro[3.4]octan-6-yl)flo[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(4,4-difluoro-2-azaspiro[4.4]nonane-2-yl)flo[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-[(4-chlorophenyl)methylamino]fl[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-difluoro-5-azaspiro[2,4]heptan-5-yl)flo[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; [3-[[6-(2,4-dioxo-1H-pyrimidine-5-yl)flo[2,3-d]pyrimidine-4-yl]amino]-2,2-difluoropropyl]N-isopropylcarbamate; 5-[4-[3-[2-[4-(trifluoromethyl)-1-piperidyl]ethoxy]]pyrrolidine(290yrrolidine)-1-yl]flo[2,3-d]pyrimidine-6-yl]-1H-pyrimidine-2,4-dione; [1-[6-(2,4-dioxo-1H-pyrimidine-5-yl)flo[2,3-d]pyrimidine-4-yl]-4,4-difluoropyrrolidine-3-yl]morpholine-4-carboxylate; [1-[6-(2,4-dioxo-1H-pyrimidine-5-yl)flo[2,3-d]pyrimidine-4-yl]-4,4-difluoropyrrolidine-3-yl]8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate; [1-[6-(2,4-dioxo-1H-pyrimidine-5-yl)flo[2,3-d]pyrimidine-4-yl]-4,4-difluoropyrrolidine-3-yl]N-isopropylcarbamate; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrrolidine-1-yl)-6-methyl-pyrazolo[3,4-d]pyrimidine-2-yl]-1H-pyrimidine-2,4-dione; 6-[1-[2-(2,4-dioxo-1H-pyrimidine-5-yl)pyrazolo[3,4-d]pyrimidine-4-yl]]pyrrolidine-3-yl]oxypyridine-3-carbonitrile; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrroridine-1-yl)pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(8,8-difluoro-6-azaspiro[3,4]octan-6-yl)pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-difluoro-5-azaspiro[2,4]heptan-5-yl)pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4-methoxy-pyrroridine-1-yl)pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(2-oxa-7-azaspiro[3,4]octan-7-yl)pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4-hydroxy-pyrroridine-1-yl)pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-difluoro-4-[(4-methylmorpholine-2-yl)methoxy]pyrrolidine-1-yl]pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-difluoro-4-(2-morpholinoethoxy)pyrrolidine-1-yl]pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-chloro-4-(3,3-difluoro-4,4-dimethyl-pyrrolin-1-yl)pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrroridine-1-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrrolidine-1-yl)-7-fluoro-pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrrolidine-1-yl)-7-methyl-pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrrolidine-1-yl)-7-fluoro-pyrazolo[4,3-c]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(8,8-difluoro-6-azaspiro[3,4]octan-6-yl)-7-fluoropyrazolo[4,3-c]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4-methoxy-pyrroridine-1-yl)-7-fluoropyrazolo[4,3-c]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4-hydroxypyrrolidine-1-yl)-7-fluoropyrazolo[4,3-c]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-fluoro-4-(2-oxa-7-azaspiro[3,4]octan-7-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(7,7-difluoro-5-azaspiro[2,4]heptan-5-yl)-7-fluoropyrazolo[4,3-c]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-[3,3-difluoro-4-[(4-methylmorpholine-2-yl)methoxy]pyrrolidine-1-yl]-7-fluoropyrazolo[4,3-c]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrroridine-1-yl)pyrazolo[4,3-c]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-chloro-4-(3,3-difluoro-4,4-dimethyl-pyrroridine-1-yl)pyrazolo[4,3-c]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-chloro-4-(7,7-difluoro-5-azaspiro[2,4]heptan-5-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-chloro-4-(8,8-difluoro-6-azaspiro[3,4]octan-6-yl)pyrazolo[4,3-c]pyridin-2-yl]-1H-pyrimidine-2,4-dione; 4-(3,3-difluoro-4,4-dimethyl-pyrroridine-1-yl)-2-(2,4-dioxo-1H-pyrimidine-5-yl)pyrazolo[4,3-c]pyridine-7-carbonitrile; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrrolidine-1-yl)pyrazolo[3,4-b]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-[4-(3,3-difluoro-4,4-dimethyl-pyrroridine-1-yl)pyrazolo[3,4-c]pyridine-2-yl]-1H-pyrimidine-2,4-dione; 5-4-(3,3-difluoro-4,4-dimethyl-pyrroridine-1-yl)-7-iodopyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-chloro-4-(3,3-difluoro-4-hydroxypyrrolidine-1-yl)pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-chloro-4-(3,3-difluoro-4-methoxy-pyrroridine-1-yl)pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-chloro-4-(3,3-difluoro-4,4-dimethyl-pyrrolin-1-yl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; 5-[7-chloro-4-(3,3-dimethylpyrrolidine-1-yl)pyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione; and 5-[4-(3,3-dimethylpyrrolidine-1-yl)-7-fluoropyrazolo[1,5-a]pyrazine-2-yl]-1H-pyrimidine-2,4-dione A compound selected from any one of the following, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a mixture of the compound described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

12. (i) Therapy; (ii) Treatment of the proliferative state; (iii) Cancer treatment; (iv) Treatment of cancer administered in combination with one or more additional anticancer drugs; (v) 1) Other forms of cancer immunotherapy agents and anticancer chemotherapy agents; 2) A2b Antagonist; 3) Anti-PD-1 and PDL-1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab); and 4) Anti-CTLA4 antibody (e.g., ipilimumab) Cancer treatment administered in combination with one or more additional anticancer drugs selected from the group consisting of: The pharmaceutical composition according to claim 11 for use in [the specified area].

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