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WO2025244014A1 - Composé ayant une action inhibitrice de la kinase aurkb ou sel de celui-ci, et composition pharmaceutique le contenant - Google Patents

Composé ayant une action inhibitrice de la kinase aurkb ou sel de celui-ci, et composition pharmaceutique le contenant

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Publication number
WO2025244014A1
WO2025244014A1 PCT/JP2025/018170 JP2025018170W WO2025244014A1 WO 2025244014 A1 WO2025244014 A1 WO 2025244014A1 JP 2025018170 W JP2025018170 W JP 2025018170W WO 2025244014 A1 WO2025244014 A1 WO 2025244014A1
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WO
WIPO (PCT)
Prior art keywords
carboxamide
pent
amino
benzodiazole
imidazo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/JP2025/018170
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English (en)
Japanese (ja)
Inventor
友裕 永沢
明 菅野又
悠人 藤林
渚沙 ▲吉▼田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Shinyaku Co Ltd
Original Assignee
Nippon Shinyaku Co Ltd
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Publication date
Application filed by Nippon Shinyaku Co Ltd filed Critical Nippon Shinyaku Co Ltd
Publication of WO2025244014A1 publication Critical patent/WO2025244014A1/fr
Pending legal-status Critical Current
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Definitions

  • the present disclosure relates to a compound or a salt thereof that has AURKB kinase inhibitory activity, and a pharmaceutical composition containing the same.
  • Aurora kinase (sometimes referred to as AURK) in mammalian cells has three homologs: AURKA, AURKB, and AURKC.
  • AURKA and AURKB are expressed in all proliferating cells, but AURKC is expressed specifically in the testis.
  • AURKA kinase inhibitors have been reported to resolve megakaryocytic differentiation abnormalities in myelofibrosis (MF) and serve as a therapeutic target for myelofibrosis (Non-Patent Document 1). Furthermore, aliselitib, known as a selective AURKA kinase inhibitor, improved splenomegaly, systemic symptom scores, and bone marrow fibrosis in a Phase 1 trial targeting myelofibrosis (Non-Patent Document 2).
  • Myelofibrosis is an intractable disease in which megakaryocytes and granulocyte cells proliferate in the bone marrow due to a genetic abnormality at the hematopoietic stem cell level.
  • Various cytokines produced by the proliferating megakaryocytes and monocytes act on bone marrow stromal cells, causing bone marrow fibrosis, splenomegaly due to extramedullary hematopoiesis, and ineffective hematopoiesis.
  • Aurora kinase B (also known as AURKB) is a serine/threonine kinase and a component of the chromosomal passenger complex, a regulator of mitosis.
  • the chromosomal passenger complex localizes to chromosomes during mitosis and plays an important role in regulating mitotic processes such as chromosome formation, chromosome segregation, and cytokinesis.
  • AURKB has been widely reported to be important for cancer survival. Its importance in hematological cancers has been reported in, for example, acute myeloid leukemia (Non-Patent Document 3), B-cell acute lymphoblastic leukemia (Non-Patent Document 4), T-cell acute lymphoblastic leukemia (Non-Patent Document 5), diffuse large B-cell lymphoma (Non-Patent Document 6), chronic myeloid leukemia (Non-Patent Document 7), Hodgkin's lymphoma (Non-Patent Document 8), Burkitt's lymphoma (Non-Patent Document 8), and multiple myeloma (Non-Patent Document 9).
  • Non-Patent Document 3 acute myeloid leukemia
  • B-cell acute lymphoblastic leukemia Non-Patent Document 4
  • T-cell acute lymphoblastic leukemia Non-Patent Document 5
  • diffuse large B-cell lymphoma Non-P
  • Non-Patent Document 10 thyroid cancer
  • Non-Patent Document 11 non-small cell lung cancer
  • Non-Patent Document 12 squamous cell carcinoma
  • Non-Patent Document 13 colorectal cancer
  • breast cancer Non-Patent Document 14
  • gastric cancer Non-Patent Document 15
  • prostate cancer Non-Patent Document 16
  • cutaneous melanoma Non-Patent Document 17
  • neuroblastoma Non-Patent Document 18
  • bladder cancer Non-Patent Document 19
  • intrahepatic bile duct cancer Non-Patent Document 20
  • pancreatic ductal adenocarcinoma Non-Patent Document 21
  • hepatocellular carcinoma Non-Patent Document 22
  • uveal melanoma Non-Patent Document 23
  • retinoblastoma Non-Patent Document
  • AURKB has also been reported to be involved in pathological conditions such as osteoarthritis (Non-Patent Document 25), diabetic nephropathy (Non-Patent Document 26), neuropathic pain (Non-Patent Document 27), and ocular neovascular disease (Non-Patent Document 28).
  • AURKB Treatment for these diseases in which AURKB is reported to be involved is often limited to symptomatic treatment, suppression of disease progression, and improvement of quality of life, making effective treatment extremely difficult. Therefore, the inventors investigated new therapies that target AURKB.
  • the main objective of this disclosure is to provide novel compounds that have AURKB kinase inhibitory activity.
  • the inventors conducted extensive research to provide a novel compound that has AURKB kinase inhibitory activity. During this process, they discovered that a compound represented by the following general formula (I) or a salt thereof has AURKB kinase inhibitory activity. Further research led to the completion of the present disclosure.
  • R 1 and R 2 are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group having 1 to 5 carbon atoms, or an optionally substituted phenyl group
  • R 3 is a hydrogen atom or an optionally substituted alkyl group having 1 to 3 carbon atoms, or R 1 and R 2 , or R 1 and R 3 form an optionally substituted 5- or 6-membered aromatic ring together with each adjacent carbon atom
  • R 4 is a hydrogen atom or an optionally substituted alkyl group having 1 to 5 carbon atoms
  • R 7 and R 8 are each independently a hydrogen atom or an optionally substituted alkyl group having 1 to 3 carbon atoms
  • R 4 and R 7 is R 4
  • the nitrogen atom adjacent to R 5 and R 6 the carbon atom adjacent to R 7 together with the carbon atom adjacent to may form an optionally substituted 5- or 6-membered heterocycloalkyl ring
  • R 5 and R 6 each independently a hydrogen atom adjacent to R
  • R 1 , and R 2 are each independently a hydrogen atom, a halogen atom, an alkyl group having 1 or 2 carbon atoms which may be substituted with a halogen atom, or a phenyl group
  • R 3 is a hydrogen atom or an alkyl group having 1 or 2 carbon atoms, or R 1 and R 2 , or R 2 and R 3 and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37
  • R 4 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms
  • R 7 and R 8 are each independently a hydrogen atom or an alkyl group having 1 or 2 carbon atoms
  • R 4 and R 7 is R 4
  • the nitrogen atom adjacent to R 5 and R 6 the carbon atom adjacent to R 7 together with the carbon atom adjacent to may form a 5-membered heterocycloalkyl ring containing one nitrogen atom in the ring
  • R 5 and R 6 are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a phenyl group, Here, R 5 and R 6 may together with the adjacent carbon atoms form a 3- or 4-membered cycloalkyl ring
  • L is a divalent group obtained by removing two hydrogen atoms from ethane, ethylene, or acetylene, When L is a divalent group (ethylene group) formed by removing two hydrogen atoms from ethane, one
  • R D1 and R D2 are each independently a hydrogen atom or an alkyl group having 1 or 2 carbon atoms. or a group represented by the following formula: (In the formula, R D1 and R D2 are each independently a hydrogen atom, a halogen atom, or an amino group.
  • R D3 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or —CH 2 -R D4 (R D4 is a cycloalkyl group having 3 to 5 carbon atoms) or a group represented by the following formula: or a group represented by the following formula: or a group represented by the following formula: A compound or salt thereof described in any one of items 1 to 3, wherein the compound is a group represented by the formula: Item 5.
  • a compound or a salt thereof represented by the formula: Section 7. At least one compound or a salt thereof selected from the group consisting of the following compounds (31), (37), (50), and (215): (31) N-[(2S,4E)-5-(2-amino-4-methoxypyrimidin-5-yl)pent-4-en-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide, (37) N-[(2S,4E)-5-(6-amino-4-fluoropyridin-3-yl)pent-4-en-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide, (50) N-[(2S)-5-(6-aminopyridin-3-yl)pentan-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide, and (215) N-[(2S,4E)-5-(5-aminopyrazin-2-yl)p
  • An AURKB kinase inhibitor comprising a compound or a salt thereof described in any one of items 1 to 7.
  • Item 9. A pharmaceutical composition containing the compound or salt thereof described in any one of items 1 to 7 as an active ingredient.
  • Item 10. A therapeutic agent for at least one disease selected from the group consisting of myelofibrosis, acute myeloid leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, chronic myeloid leukemia, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, thyroid cancer, non-small cell lung cancer, squamous cell carcinoma, colorectal cancer, breast cancer, gastric cancer, prostate cancer, cutaneous melanoma, neuroblastoma, bladder cancer, intrahepatic bile duct cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, uveal
  • Item 11 Use of the compound or salt thereof according to any one of items 1 to 7 for the manufacture of a therapeutic agent for at least one disease selected from the group consisting of myelofibrosis, acute myeloid leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, chronic myeloid leukemia, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, thyroid cancer, non-small cell lung cancer, squamous cell carcinoma, colorectal cancer, breast cancer, gastric cancer, prostate cancer, cutaneous melanoma, neuroblastoma, bladder cancer, intrahepatic bile duct cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, uveal melanoma, retinoblastoma, osteoarthritis, diabetic nephropathy, neuropathic pain, and ocular n
  • Item 12. A compound or salt thereof described in any one of items 1 to 7 for use as a pharmaceutical.
  • Item 13 A compound or salt thereof described in any one of items 1 to 7 for use in the treatment of at least one disease selected from the group consisting of myelofibrosis, acute myeloid leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, chronic myeloid leukemia, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, thyroid cancer, non-small cell lung cancer, squamous cell carcinoma, colorectal cancer, breast cancer, gastric cancer, prostate cancer, cutaneous melanoma, neuroblastoma, bladder cancer, intrahepatic bile duct cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, uveal melanoma, retinoblastoma, osteoarthritis
  • Section 14 A compound or salt thereof described in any one of items 1 to 7 for use in the treatment of myelofibrosis.
  • Item 15. A method for treating at least one disease selected from the group consisting of myelofibrosis, acute myeloid leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, chronic myeloid leukemia, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, thyroid cancer, non-small cell lung cancer, squamous cell carcinoma, colorectal cancer, breast cancer, gastric cancer, prostate cancer, cutaneous melanoma, neuroblastoma, bladder cancer, intrahepatic bile duct cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, uveal melanoma, retinoblastoma, osteoarthritis, diabetic nephropathy,
  • the compound represented by general formula (I) may be a tautomer.
  • the term “tautomer” refers to a structural isomer that is reversibly interconvertible. Tautomers have the same molecular formula but a different bonding sequence of atoms, and under certain conditions, multiple tautomers may coexist in equilibrium.
  • a compound represented by general formula (I) or a salt thereof included in this disclosure may be referred to simply as a "compound of the present disclosure.” Note that, in this disclosure, “salt” refers to a pharmaceutically acceptable salt.
  • the term “compound of the present disclosure” also includes solvates of the compound of the present disclosure.
  • the term "compound of the present disclosure” in this specification encompasses the compound represented by general formula (I) and its tautomers, as well as salts thereof and solvates thereof.
  • the compound of the present disclosure possesses AURKB kinase inhibitory activity, as shown in the test examples described below. Furthermore, because the compound of the present disclosure possesses AURKB kinase inhibitory activity, it may also have antimitotic and antitumor effects.
  • AURKB is also involved in regulating megakaryocyte differentiation, and it has been reported that AURKB expression decreases during the differentiation and maturation process of megakaryocytes (Non-Patent Document 29), and that compounds with AURKB kinase inhibitory activity promote the multinucleation of megakaryocytes (Non-Patent Document 30). However, it was unclear whether AURKB kinase inhibitors are effective against myelofibrosis.
  • other diseases to which the compounds of the present disclosure can be applied include, for example, acute myeloid leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, chronic myeloid leukemia, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, thyroid cancer, non-small cell lung cancer, squamous cell carcinoma, colorectal cancer, breast cancer, gastric cancer, prostate cancer, cutaneous melanoma, neuroblastoma, bladder cancer, intrahepatic bile duct cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, uveal melanoma, retinoblastoma, osteoarthritis, diabetic nephropathy, neuropathic pain, and ocular neovascular disease.
  • halogen atoms include, for example, fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.
  • the alkyl group may be straight-chain or branched. Specific examples of alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, 1-methylethyl, tert-butyl, and 2-methylbutyl groups.
  • Alkoxy groups may also be straight-chain or branched. Specific examples of alkoxy groups include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, 1-methylethoxy, tert-butoxy, and 2-methylbutoxy.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • Specific examples of cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl rings.
  • Heteroatoms contained in the heterocycle include, for example, oxygen atoms, nitrogen atoms, and sulfur atoms.
  • the number of heteroatoms contained in the heterocycle may be, for example, 1, 2, 3, 4, or 5.
  • aromatic ring includes aromatic carbocycles and aromatic heterocycles.
  • R1 and R2 are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group of 1 to 5 carbon atoms, or an optionally substituted phenyl group
  • R3 is a hydrogen atom or an optionally substituted alkyl group of 1 to 3 carbon atoms, or R1 and R2 , or R1 and R3 , together with their adjacent carbon atoms, form an optionally substituted 5- or 6-membered aromatic ring.
  • R1 and R2 are each independently a hydrogen atom, a halogen atom, an alkyl group of 1 or 2 carbon atoms which may be substituted with a halogen atom, or a phenyl group
  • R3 is a hydrogen atom, a methyl group, or an ethyl group, or R1 and R2 , or R1 and R3 , together with their adjacent carbon atoms, form a benzene ring or a 6-membered heterocycle containing at least one nitrogen atom in the ring, which may be substituted with at least one group selected from the group consisting of a halogen atom, an alkyl group of 1 or 2 carbon atoms, and an alkoxy group of 1 or 2 carbon atoms.
  • R1 and R2 are each independently a hydrogen atom, a halogen atom, a methyl group, an ethyl group, an n-propyl group, a 1-methylethyl group, a trifluoromethyl group, or a phenyl group
  • R3 is a hydrogen atom, a methyl group, or an ethyl group, or R1 and R2 , or R1 and R3, together with their adjacent carbon atoms, form a benzene ring which may be substituted with at least one group selected from the group consisting of a halogen atom, a methyl group, and a methoxy group, or form a 6-membered heterocycle containing one nitrogen atom in the ring.
  • R4 is a hydrogen atom or an optionally substituted alkyl group having 1 to 5 carbon atoms
  • R7 and R8 are each independently a hydrogen atom or an optionally substituted alkyl group having 1 to 3 carbon atoms
  • R4 and R7 together with the nitrogen atom adjacent to R4 , the carbon atoms adjacent to R5 and R6 , and the carbon atom adjacent to R7 , may form an optionally substituted 5- or 6-membered heterocycloalkyl ring.
  • R4 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms
  • R7 and R8 are each independently a hydrogen atom or an alkyl group having 1 or 2 carbon atoms
  • R4 and R7 together with the nitrogen atom adjacent to R4 , the carbon atoms adjacent to R5 and R6 , and the carbon atom adjacent to R7 , may form a 5-membered heterocycloalkyl ring containing one nitrogen atom in the ring.
  • R4 is a hydrogen atom
  • R7 and R8 are each independently a hydrogen atom or a methyl group, or R4 and R7 , together with the nitrogen atom adjacent to R4 , the carbon atoms adjacent to R5 and R6 , and the carbon atom adjacent to R7 , form a 5-membered heterocycloalkyl ring containing one nitrogen atom
  • R8 is a hydrogen atom
  • R5 and R6 are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 5 carbon atoms, or an optionally substituted phenyl group, where R5 and R6 , together with the adjacent carbon atom, may form an optionally substituted 3- to 6-membered cycloalkyl ring.
  • R5 and R6 are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a phenyl group, where R5 and R6 , together with the adjacent carbon atom, may form a 3- or 4-membered cycloalkyl ring.
  • R5 and R6 are each independently a hydrogen atom, a methyl group, an ethyl group, or a 1-methylethyl group, or R5 and R6 , together with the adjacent carbon atom, may form a 3- or 4-membered cycloalkyl ring.
  • L is a divalent group formed by removing two hydrogen atoms from an alkane, alkene, or alkyne having 2 to 4 carbon atoms
  • L when L is a divalent group (alkylene group) formed by removing two hydrogen atoms from an alkane having 2 to 4 carbon atoms, it may have a structure in which one or more methylene groups (-CH 2 -) of the alkylene group are substituted with -NH- or -O-.
  • L is a divalent group formed by removing two hydrogen atoms from ethane, ethylene, or acetylene, and when L is a divalent group (ethylene group) formed by removing two hydrogen atoms from ethane, it may have a structure in which one methylene group (-CH 2 -) of the ethylene group is substituted with -NH- or -O-.
  • Het is General formula (II): [In the formula, represents a single or double bond; X 1 to X 4 each independently represent a carbon atom or a nitrogen atom; R A1 to R A4 each independently represent a hydrogen atom, a halogen atom, an amino group, a group represented by —NH—(CH 2 ) n A —O—CH 3 (n A is a natural number of 1 to 4), a group represented by the following formula: (wherein R A5 is an optionally substituted alkyl group having 1 to 3 carbon atoms), or a group represented by the following formula: (wherein R A6 is an optionally substituted alkyl group having 1 to 3 carbon atoms) (provided that when X 2 is a nitrogen atom, R A1 does not exist, and when X 3 is a nitrogen atom, R A3 does not exist) or General formula (III): [In the formula, represents a single or double bond; R B1 , R B2
  • R A1 to R A4 each independently represent a hydrogen atom, a halogen atom, an amino group, a group represented by —NH—(CH 2 ) 2 —O—CH 3 , a group represented by the following formula: (wherein R A5 is an alkyl group having 1 or 2 carbon atoms), or a group represented by the following formula: (wherein R A6 is an alkyl group having 1 or 2 carbon atoms) (provided that R A1 does not exist when X 2 is a nitrogen atom, and R A3 does not exist when X 3 is a nitrogen atom).
  • R A1 to R A4 are each independently a hydrogen atom, a halogen atom, an amino group, a group represented by -NH-(CH 2 ) 2 -O-CH 3 , a group represented by the following formula: or a group represented by the following formula: It is a group represented by the formula:
  • the group represented by the above general formula (II) is preferably represented by the following formula: (R A1 to R A4 are as described above).
  • R C1 to R C3 are each independently a hydrogen atom, a halogen atom, an amino group, a hydroxy group, a cyano group, an alkoxy group having 1 to 3 carbon atoms which may be substituted with a halogen atom, a cycloalkyl group having 3 to 5 carbon atoms, a phenyl group, a 6-membered aromatic heterocyclic group having one nitrogen atom in the ring, or a 5-membered heterocycloalkyl group having one nitrogen atom in the ring, -NH-R C8 , -SO 2 -R C11 , -CO-NR C14 R C15 , or ⁇ O, where R C8 is an alkyl group having 1 or 2 carbon atoms, a group represented by -SO 2 -R C9 or -CO-R C10 , R C9 is an alkyl group having 1 or 2
  • R C1 to R C3 are each independently a hydrogen atom, a halogen atom, an amino group, a methoxy group, an ethoxy group, a trifluoromethoxy group, a phenyl group, a 6-membered aromatic heterocyclic group having one nitrogen atom in the ring, or a 5-membered heterocycloalkyl group having one nitrogen atom in the ring, or form a ring as described above; and R C4 is a hydrogen atom, a halogen atom, or an amino group.
  • the group represented by the above general formula (IV) is preferably a group represented by the following formula: (R C1 to R C4 are as described above).
  • a preferred embodiment of the group represented by the general formula (IV) is a group represented by the following formula: a group represented by the following formula: (wherein R C5 is a hydrogen atom or a halogen atom), a group represented by the following formula: (wherein R C6 and R C7 each independently represent a hydrogen atom, a halogen atom, or an alkyl group having 1 or 2 carbon atoms), and a group represented by the following formula: Examples of the group include a group represented by the following formula:
  • Het is a group represented by the above general formula (V), it is preferably a group represented by the following formula: (wherein R D1 is a hydrogen atom or an alkoxy group having 1 or 2 carbon atoms), or a group represented by the following formula: or a group represented by the following formula: or a group represented by the following formula: (In the formula, R D1 and R D2 each independently represent a hydrogen atom or an alkyl group having 1 or 2 carbon atoms.) or a group represented by the following formula: (In the formula, R D1 and R D2 each independently represent a hydrogen atom or an alkyl group having 1 or 2 carbon atoms.) or a group represented by the following formula: (In the formula, R D1 and R D2 each independently represent a hydrogen atom, a halogen atom, or an amino group.) or a group represented by the following formula: or a group represented by the following formula: or a group represented by the following formula: (wherein R D3 is a hydrogen atom
  • Het is a group represented by the above general formula (V), it is preferably a group represented by the following formula: It is a group represented by the formula:
  • a preferred embodiment of the compound represented by the general formula (I) or a salt thereof is a compound represented by the general formula (VII):
  • L is a divalent group obtained by removing two hydrogen atoms from ethane, ethylene, or acetylene;
  • L is a divalent group (ethylene group) formed by removing two hydrogen atoms from ethane
  • the ethylene group may have a structure in which one methylene group (—CH 2 —) is substituted with —O—;
  • Y 1 and Y 2 each independently represent a carbon atom or a nitrogen atom;
  • R Y1 to R Y3 each independently represent a hydrogen atom, a halogen atom, an amino group, an alkyl group having 1 or 2 carbon atoms which may be substituted with a halogen atom, or an alkoxy group having 1 or 2 carbon atoms. or a salt thereof.
  • a more preferred embodiment of the compound represented by the general formula (I) or a salt thereof is a compound represented by the general formula (VII'):
  • L is a divalent group obtained by removing two hydrogen atoms from ethane, ethylene, or acetylene
  • L is a divalent group (ethylene group) formed by removing two hydrogen atoms from ethane
  • the ethylene group may have a structure in which one methylene group (—CH 2 —) is substituted with —O—
  • Y is a carbon atom or a nitrogen atom
  • R and Y are a hydrogen atom, a halogen atom, or an alkoxy group having 1 or 2 carbon atoms. or a salt thereof.
  • a preferred embodiment of the compound represented by the general formula (I) or a salt thereof is at least one compound or a salt thereof selected from the group consisting of the following compounds (1) to (360): (1) 4,5-dibromo-N- ⁇ 4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]but-3-yn-1-yl ⁇ -1H-imidazole-2-carboxamide, (2) 4,5-dibromo-N-(4- ⁇ 8-[(1-methyl-1H-pyrazol-4-yl)amino]imidazo[1,2-a]pyridin-3-yl ⁇ but-3-yn-1-yl)-1H-imidazole-2-carboxamide, (3) N-(4- ⁇ 8-aminoimidazo[1,2-a]pyridin-3-yl ⁇ -2-methylbut-3-yn-1-yl)-7-chloro-1H-1,3-benzodiazole-2-carbox
  • a more preferred embodiment of the compound represented by the above general formula (I) or a salt thereof is at least one compound selected from the group consisting of the above compounds (31), (37), (50), and (215) or a salt thereof.
  • the compounds of the present disclosure can be used as they are, or mixed with a pharmaceutically acceptable carrier or the like to form a pharmaceutical composition containing, for example, 0.001% to 99.5% by weight, preferably 0.1% to 90% by weight, and can be used as a therapeutic agent for the various diseases mentioned above in mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys.
  • the carrier may be one or more selected from the group consisting of solid, semi-solid, or liquid diluents, fillers, and other formulation auxiliaries.
  • the pharmaceutical composition according to the present disclosure is preferably administered in a dosage unit form.
  • the pharmaceutical composition may be administered intratissue, orally, intravenously, topically (transdermally, ophthalmically, intraperitoneally, intrapleurally, etc.), or rectally.
  • the dosage form of the pharmaceutical composition may be adjusted appropriately depending on the method of administration.
  • the pharmaceutical dosage taking into consideration the patient's condition, such as age, weight, type and severity of disease, the route of administration, the type of compound disclosed herein, whether it is a salt or not, and the type of salt.
  • the amount of active ingredient of the compound disclosed herein is in the range of 0.01 mg to 5 g per adult per day, preferably 1 mg to 500 mg per adult. In some cases, a lower dose may be sufficient, or conversely, a higher dose may be required.
  • the compound is administered once a day or in divided doses, or in the case of intravenous administration, it can be administered as a bolus or continuously over a period of no more than 24 hours.
  • One or more atoms constituting the compound of the present disclosure may be substituted with an isotope of the atom. That is, the term "compound of the present disclosure” also includes any isotope-labeled compound (preferably a radioisotope-labeled compound) of the compound represented by general formula (I) or a salt thereof. Examples of isotopes include 2H , 3H , 11C , 13C , 14C , 15N , 18O , 17O , 31P , 32P , 35S , 18F , 123I and 36Cl .
  • isotopes include 2H , 3H , 11C , 13C , 14C , 15N , 18O , 17O , 31P , 32P , 35S , 18F , 123I and 36Cl .
  • the compounds of the present disclosure can be produced from known compounds or intermediates that can be easily synthesized from known compounds, for example, by methods described herein or in accordance with known methods.
  • the compound represented by general formula (I) can be used as a pharmaceutical directly, but can also be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt by known methods.
  • pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; salts of organic acids such as acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; salts of alkali metals such as lithium, potassium, and sodium; salts of alkaline earth metals such as magnesium and calcium; and salts of inorganic bases such as ammonium salts. These salts can be formed by conventional methods.
  • the compound of the present disclosure when it is a hydrochloride salt, it can be obtained by dissolving the compound represented by general formula (I) in an alcohol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a cyclopentyl methyl ether solution of hydrogen chloride, or a diethyl ether solution of hydrogen chloride.
  • the solvate may be a solvate with an organic solvent or a hydrate.
  • Specific solvates include, for example, alcohol solvates such as methanol solvates and ethanol solvates, and ethyl acetate solvates. Hydrates include, for example, monohydrates and dihydrates.
  • the compounds of the present disclosure consist of only a single stereoisomer.
  • a single stereoisomer can be separated from a mixture of stereoisomers by optical resolution using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.).
  • an optically active acid tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.
  • compounds of the present disclosure consisting of only a single stereoisomer can also be produced.
  • compounds can be produced by optical resolution using a chiral column or asymmetric synthesis.
  • the compound represented by general formula (I) in the present disclosure may be a tautomer thereof.
  • R3 is a hydrogen atom
  • the compound represented by general formula (I) may be the following tautomer:
  • the solvents, reagents, and raw materials used in each step of the following manufacturing methods are commercially available, these commercially available products can be used as is.
  • the compounds obtained in each step of the following manufacturing methods and the raw materials used may form salts, which can be converted into other types of salts or into their free forms by known methods. If the compounds obtained in each step of the following manufacturing methods and the raw materials used are in their free forms, they can be converted into the desired salts by known methods. Examples of such salts include the same salts as those used for the compounds disclosed above.
  • protecting groups may be introduced into these substituents in advance by known methods.
  • the target compound can be obtained by removing the protecting groups as necessary after the reaction.
  • protecting groups include those described in "Greene's Protective Groups in Organic Synthesis” by Wuts and Greene, 4th Edition; John Wiley & Sons Inc., 2006; or "Protecting Groups” by P.J. Kocienski, 3rd Edition; Thieme, 2005.
  • Protecting groups can be selected appropriately depending on the properties of the raw materials and the reaction conditions.
  • the compounds obtained in each step of the manufacturing methods below can be isolated or purified using conventional methods such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, and chromatography, or can be used in the next step as a reaction mixture or crude product.
  • This step is a step of reacting a compound 1a, which is commercially available or can be prepared by a known method, with a compound 2a, which is commercially available or can be prepared by a known method, in an appropriate solvent in the presence of a transition metal catalyst such as palladium, a copper catalyst, and a base at 0°C to 100°C, preferably 20°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain a compound 3a.
  • This step is known as the Sonogashira coupling reaction, and compound 3a can be obtained by applying the method described in the literature (Sonogashira et al., J. Organomet. Chem. 2002, 653, 46-49.; Negishi et al., Chem. Rev., 2003, 103, 1979-2017.).
  • Solvents used in this step include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and 1,2-dimethoxyethane (also known as "DME”), amides such as DMF, dimethylacetamide (also known as “DMA”), and NMP, and DMSO. Two or more of these solvents can also be mixed and used. The reaction can also be carried out using the following organic bases as solvents.
  • palladium catalyst used in this step examples include tris(dibenzylideneacetone)bispalladium-chloroform adduct (hereinafter referred to as "Pd 2 (dba) 3.CHCl 3 "), tris(dibenzylideneacetone)bispalladium (hereinafter referred to as “Pd 2 (dba) 3 "), tetrakistriphenylphosphinepalladium (hereinafter referred to as “Pd(PPh 3 ) 4 "), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichloromethane adduct (hereinafter referred to as "Pd(dppf)Cl 2.CH 2 Cl 2 "), and bis(triphenylphosphine)palladium(II) dichloride (hereinafter referred to as "PdCl 2 (PPh 3 ) 2 "), [1,1'-
  • the base used in this step can include, for example, organic bases such as triethylamine (hereinafter referred to as "TEA”), diisopropylethylamine (hereinafter referred to as "DIPEA”), diethylamine, diisopropylamine, and piperidine, and inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, and tripotassium phosphate.
  • organic bases such as triethylamine (hereinafter referred to as "TEA”), diisopropylethylamine (hereinafter referred to as "DIPEA”), diethylamine, diisopropylamine, and piperidine
  • inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, and tripotassium phosphate.
  • This step is a step of deprotecting the protecting group PG1 of compound 3a to obtain compound 4a, and can be performed with reference to, for example, Wuts and Greene, “Greene's Protective Groups in Organic Synthesis,” 4th Edition, John Wiley & Sons Inc., 2006, or P.J. Kocienski, "Protecting Groups,” 3rd Edition, Thieme, 2005.
  • This step is a step of reacting compound 4a with compound 5, which is commercially available or can be prepared by a known method, in an appropriate solvent in the presence of a condensing agent and a base at 0°C to 100°C, preferably 20°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain compound IA.
  • Solvents used in this process include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and DME, amides such as DMF and DMA, halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile and propionitrile, and mixed solvents of these.
  • Condensing agents used in this step include, for example, 1,1'-carbonyldiimidazole (hereinafter referred to as "CDI”), 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (hereinafter referred to as "BOP”), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (also referred to as “EDCI”), diisopropylcarbodiimide (also referred to as "DIC”), diethyl cyanophosphonate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HBTU”), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (
  • the base used in this step may be, for example, an organic base such as TEA, DIPEA, N,N-dimethylaniline, or diazabicycloundecene (also known as "DBU").
  • organic base such as TEA, DIPEA, N,N-dimethylaniline, or diazabicycloundecene (also known as "DBU").
  • the reaction can be carried out by adding additives as needed.
  • additives that can be used include 1-hydroxybenzotriazole (hereinafter referred to as "HOBt”), N-hydroxysuccinimide, and 1-hydroxy-7-azabenzotriazole (hereinafter referred to as "HOAt").
  • compound 1a which is commercially available or can be prepared by a known method, is hydroborated with boron compound 6a or 6b to give compound 7.
  • This reaction can be carried out in a solvent such as THF, diethyl ether, dichloromethane, dichloroethane, hexane, cyclohexane, or toluene, with compound 1 and compound 6a or 6b at 0°C to 200°C, preferably 20°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain compound 7.
  • a catalyst such as zirconium, rhodium or ruthenium or a base such as TEA or sodium t-butoxide may be added to the reaction.
  • This step is a step of reacting compound 7 with compound 2a, which is commercially available or can be prepared by a known method, in an appropriate solvent in the presence of a transition metal catalyst such as palladium and a base at 0°C to 100°C, preferably 20°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain compound 3b.
  • a transition metal catalyst such as palladium and a base at 0°C to 100°C, preferably 20°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours.
  • This step is known as the Suzuki coupling reaction, and compound 3b can be obtained by applying a method described in the literature (Suzuki et al., Chem. Rev., 1995, 95, 2457-2483).
  • solvents examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and DME, amides such as DMF, DMA, and NMP, alcohols such as ethanol, 2-propanol, and tert-butanol, and water. Two or more of these solvents can also be used in combination.
  • the palladium catalyst used in this step includes those mentioned in the above Production Method 1, Step 1.
  • Examples of the base used in this step include inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium acetate, potassium acetate, trisodium phosphate, and tripotassium phosphate.
  • an appropriate ligand may be used, if necessary.
  • usable ligands include 1,1'-bis(diphenylphosphino)ferrocene (hereinafter referred to as "dppf"), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (hereinafter referred to as "Xantphos”), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (hereinafter referred to as "XPhos”), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP”), 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl (hereinafter referred to as "RuPhos”), triphenylphosphine (hereinafter referred to as "PPh 3 "), and tricycl
  • This step is a step of deprotecting PG 1 of compound 3b, and compound 4b can be obtained by the same method as in step 2 of Production Method 1 above.
  • This step is a step for obtaining compound I-B from compound 4b and compound 5, which is commercially available or can be prepared by a known method, and compound IC can be obtained by the same method as in step 3 of Production Method 1 above.
  • This step is a step of reacting compound 3a or 3b in a suitable solvent in the presence of a metal catalyst such as palladium and a hydrogen source under a hydrogen pressure of 1 to 20 atmospheres at 0°C to 100°C, preferably 20°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain compound 3c.
  • a metal catalyst such as palladium and a hydrogen source under a hydrogen pressure of 1 to 20 atmospheres at 0°C to 100°C, preferably 20°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain compound 3c.
  • the metal catalyst used in this step is not limited as long as it is a metal catalyst commonly used in the reduction of unsaturated carbon bonds, and examples thereof include heterogeneous catalysts such as palladium-carbon, palladium black, palladium chloride, palladium hydroxide, rhodium-carbon, platinum oxide, platinum black, platinum-palladium, Raney nickel, and palladium-carbon ethylenediamine complex.
  • heterogeneous catalysts such as palladium-carbon, palladium black, palladium chloride, palladium hydroxide, rhodium-carbon, platinum oxide, platinum black, platinum-palladium, Raney nickel, and palladium-carbon ethylenediamine complex.
  • the hydrogen source used in this step include hydrogen gas and ammonium formate.
  • the solvent to be used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include hydrocarbons such as toluene and xylene; ethers such as 1,4-dioxane, THF, and DME; amides such as DMF, DMA, and NMP; alcohols such as ethanol, 2-propanol, and tert-butanol; water; and mixed solvents thereof.
  • hydrocarbons such as toluene and xylene
  • ethers such as 1,4-dioxane, THF, and DME
  • amides such as DMF, DMA, and NMP
  • alcohols such as ethanol, 2-propanol, and tert-butanol
  • water and mixed solvents thereof.
  • This step is a step of deprotecting PG 1 of compound 3c, and compound 4c can be obtained by the same method as in step 2 of Production Method 1 above.
  • This step is a step for obtaining compound IC from compound 4c and compound 5, which is commercially available or can be prepared by a known method, and compound IC can be obtained by the same method as in step 3 of Production Method 1 above.
  • This step is a step of reacting compound 1b, which can be prepared by a known method, with compound 2b, which is commercially available or can be prepared by a known method, in an appropriate solvent in the presence of an azodicarboxylic acid ester reagent and a phosphine reagent at 0°C to 100°C, preferably 20°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain ether compound 3d.
  • This step is known as the Mitsunobu reaction, and compound 3d can be obtained by applying the method described in the literature (Mitsunobu, O. Synthesis 1981, 1.).
  • Examples of the azodicarboxylate reagent used in this step include diethyl azodicarboxylate (hereinafter referred to as “DEAD”), diisopropyl azodicarboxylate (hereinafter referred to as “DIAD”), and bis(2-methoxyethyl)azodicarboxylate (hereinafter referred to as "DMEAD”).
  • Examples of the phosphine reagent used in this step include PPh 3 and tributylphosphine.
  • the solvent used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF and DME, and mixed solvents thereof.
  • This step is a step of deprotecting PG 1 of compound 3d, and compound 4d can be obtained by the same method as in step 2 of Production Method 1 above.
  • This step is a step for obtaining compound ID from compound 4d and compound 5, which is commercially available or can be prepared by a known method.
  • Compound ID can be obtained by the same method as in step 3 of Production Method 1 above.
  • This step is a step of reacting compound 1c, which can be prepared by a known method, with compound 2c, which is commercially available or can be prepared by a known method, in an appropriate solvent in the presence of a base at 0°C to 200°C, preferably 20°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain ether compound 3e.
  • Examples of the base used in this step include sodium hydride, potassium hydride, potassium carbonate, etc.
  • the solvent used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include DMF, DMA, and acetonitrile.
  • This step is a step of deprotecting PG 1 of compound 3e, and compound 4e can be obtained by the same method as in step 2 of Production Method 1 above.
  • This step is a step for obtaining compound IE from compound 4e and compound 5, which is commercially available or can be prepared by a known method.
  • Compound IE can be obtained by the same method as in step 3 of Production Method 1 above.
  • This step is a step of reacting compound 2d, which can be prepared by a known method, with compound 1d, which can also be prepared by a known method, in an appropriate solvent in the presence of a reducing agent at 0°C to 200°C, preferably 20°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain amino compound 3f, and can be carried out in accordance with a known method for reductive amination reaction.
  • the reducing agent used in this step includes, for example, sodium triacetoxyborohydride, sodium cyanoborohydride, etc.
  • the solvent to be used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and DME, halogenated hydrocarbons such as dichloromethane, and mixed solvents thereof.
  • an acid or a suitable Lewis acid may be used as needed. Examples of acids that can be used in the reaction include acetic acid, and examples of Lewis acids that can be used include tetraisopropyl orthotitanate.
  • This step is a step of deprotecting PG 1 of compound 3f, and compound 4f can be obtained by the same method as in step 2 of Production Method 1 above.
  • This step is a step of obtaining compound IF from compound 4f and compound 5, which is commercially available or can be prepared by a known method, and compound IF can be obtained by the same method as in step 3 of Production Method 1 above.
  • Pd-C Palladium-carbon
  • Pd-Fib Palladium-fibroin
  • Pd-PEI Palladium-polyethyleneimine
  • Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0)
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium(0)
  • PdCl 2 (PPh 3 ) 2 bis(triphenylphosphine)palladium(II) dichloride
  • Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct Boc 2 O: di-tert-butyl dicarbonate
  • BOP 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro
  • MS was measured by LCMS.
  • ESI was used as the ionization method.
  • the observed mass spectrometry values are expressed as m/z.
  • the measurement conditions for the specific rotation [ ⁇ ] 589 are as follows: Analytical equipment: Automatic polarimeter SEPA-500 (manufactured by Horiba, Ltd.) Optical path length: 50mm
  • Step 1 Preparation of methyl 4,5-dibromo-1H-imidazole-2-carboxylate A solution of bromine (2.72 g) in acetic acid (15 mL) was slowly added to a solution of methyl 1H-imidazole-2-carboxylate (1.00 g) in acetic acid (15 mL), and the mixture was stirred at room temperature over the weekend. The reaction mixture was neutralized with 10% aqueous sodium carbonate solution and extracted with ethyl acetate.
  • Step 2 Preparation of tert-butyl N-(pent-4-yn-2-yl)carbamate Sodium azide (1.71 g) was added to a solution of pent-4-yn-2-yl methanesulfonate (1.42 g) in DMF (10 mL), and the mixture was stirred at 70°C for 4 hours and at room temperature over the weekend. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • PPh 3 (4.21 g) was added to a diethyl ether (10 mL) solution of the residue obtained by distilling off the solvent under reduced pressure, and the mixture was stirred in an ice bath for 3 hours. Water (1 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. Boc 2 O (1.75 mL) was then added to the reaction mixture, and the mixture was stirred at room temperature over the weekend. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture to quench the reaction, and the mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound (331 mg).
  • Step 2 Preparation of methyl 2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ (3,3,3- 2 H 3 )propanoate TEA (7.60 mL) and Boc 2 O (6.26 mL) were added to a solution of methyl 2-amino(3,3,3- 2 H 3 )propanoate hydrochloride (3.11 g) in dichloromethane (40 mL), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated, and the resulting residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Step 4 Preparation of tert-butyl N-[1-(methanesulfonyloxy)(3,3,3- 2 H 3 )propan-2-yl]carbamate Methanesulfonyl chloride (1.71 mL) was added to a solution of tert-butyl N-[1-hydroxy(3,3,3- 2 H 3 )propan-2-yl]carbamate (3.59 g) and TEA (4.21 mL) in dichloromethane (30 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with dichloromethane.
  • Step 5 Preparation of tert-butyl N-[1-cyano(3,3,3- 2 H 3 )propan-2-yl]carbamate Sodium cyanide (1.97 g) was added to a solution of tert-butyl N-[1-(methanesulfonyloxy)(3,3,3- 2 H 3 )propan-2-yl]carbamate (4.79 g) in DMSO (20 mL), and the mixture was stirred at 40°C for 35 hours and at room temperature over the weekend. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate.
  • Step 9 Preparation of tert-butyl N-[( 1,1,1-2H3 ) pent-4-yn-2-yl]carbamate 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-( 1H )-one (2.44 g) was added to a solution of tert-butyl N-[4 - hydroxy(1,1,1-2H3)butan-2-yl]carbamate (960 mg) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the resulting residue was diluted with ethyl acetate.
  • Step 3 Preparation of tert-butyl N-[(2R)-1,1,1-trifluoropent-4-yn-2-yl]carbamate 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (531 mg) was added to a solution of tert-butyl N-[(2R)-1,1,1-trifluoro-4-hydroxybutan-2-yl]carbamate (265 mg) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was quenched by adding saturated aqueous sodium bicarbonate and 20% aqueous sodium hydrogen thiosulfate, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and to a solution of the residue obtained in methanol (5 mL) were added potassium carbonate (452 mg) and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.20 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and insoluble matter was filtered off. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography to give the title compound (228 mg).
  • But-3-yn-1-amine (33 mg), DIPEA (0.27 mL), and HATU (181 mg) were further added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was purified by reverse-phase column chromatography to give the title compound (70 mg). MS (ESI+) m/z 335.9 (M+H)+
  • the reaction mixture was concentrated, and the resulting residue was diluted with ethyl acetate. After that, a saturated aqueous solution of sodium bicarbonate and a 20% aqueous solution of sodium hydrogen thiosulfate were added to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (763 mg).
  • NCS (87 mg) was further added to the reaction solution, and the mixture was stirred at 75°C for 14 hours.
  • a saturated aqueous solution of sodium bicarbonate and a 20% aqueous solution of sodium hydrogen thiosulfate were added to the reaction solution to quench the reaction, and the mixture was diluted with water and extracted with a mixed solvent of ethyl acetate and THF.
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography to give the title compound (116 mg).
  • a saturated aqueous solution of sodium bicarbonate and a 20% aqueous solution of sodium hydrogen thiosulfate were added to the reaction mixture to quench the reaction, diluted with water, and extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was washed with acetonitrile to give the title compound (551 mg).
  • a saturated aqueous solution of sodium bicarbonate and a 20% aqueous solution of sodium hydrogen thiosulfate were added to the reaction mixture to quench the reaction, diluted with water, and extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was washed with methanol to give the title compound (135 mg).
  • a saturated aqueous solution of sodium hydrogen carbonate and a 20% aqueous solution of sodium hydrogen thiosulfate were added to the reaction solution to quench the reaction, and the mixture was extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was washed with acetonitrile to give the title compound (871 mg).
  • a saturated aqueous solution of sodium bicarbonate and a 20% aqueous solution of sodium hydrogen thiosulfate were added to the reaction mixture to quench the reaction, diluted with water, and extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was washed with acetonitrile to give the title compound (137 mg).
  • a saturated aqueous solution of sodium bicarbonate and a 20% aqueous solution of sodium hydrogen thiosulfate were added to the reaction mixture to quench the reaction, and the mixture was diluted with water and extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was washed with acetonitrile to give the title compound (952 mg).
  • a saturated aqueous solution of sodium bicarbonate and a 20% aqueous solution of sodium hydrogen thiosulfate were added to the reaction mixture to quench the reaction, diluted with water, and extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was washed with acetonitrile to give the title compound (158 mg).
  • a saturated aqueous solution of sodium hydrogen carbonate and a 20% aqueous solution of sodium hydrogen thiosulfate were added to the reaction mixture to quench the reaction, and the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (237 mg).
  • Methyl iodide (0.37 mL) was added to the reaction solution and stirred at room temperature for 30 minutes and then at 60°C for 2 hours.
  • the reaction solution was diluted with water in an ice bath and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (267 mg).
  • Reference Example 103 4-bromo-6-iodopyridazin-3-amine NBS (254 mg) was added to a solution of 6-iodopyridazin-3-amine (300 mg) and ammonium acetate (10 mg) in acetonitrile (5 mL), and the mixture was stirred at room temperature over the weekend. A saturated aqueous solution of sodium hydrogen carbonate and a 20% aqueous solution of sodium hydrogen thiosulfate were added to the reaction mixture to quench the reaction. The mixture was diluted with water, and insoluble matter was filtered off through Celite (registered trademark). The resulting filtrate was extracted with ethyl acetate.
  • Example 1 4,5-Dibromo-N- ⁇ 4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]but-3-yn-1-yl ⁇ -1H-imidazole-2-carboxamide
  • 4- ⁇ 3-iodopyrazolo[1,5-a]pyridin-6-yl ⁇ -1-methyl-1H-pyrazole (38 mg) obtained in Step 2 of Reference Example 79 and 4,5-dibromo-N-(but-3-yn-1-yl)-1H-imidazole-2-carboxamide (30 mg) obtained in Reference Example 57, PdCl 2 (PPh 3 ) 2 (6.5 mg), copper(I) iodide (2.7 mg), and piperidine (0.5 mL) were added and degassed, followed by stirring under an argon atmosphere at 50° C. for 90 minutes.
  • the reaction mixture was purified by reverse-phase column chromatography to obtain a crude
  • reaction solution was diluted with ethyl acetate, and insoluble matter was filtered off through Celite (registered trademark).
  • the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography to give a crude residue.
  • the resulting residue was purified by reverse phase column chromatography to give the title compound (92 mg).
  • N-(but-3-yn-1-yl)carbamate (30 mg) and TEA (0.12 mL) were added and degassed, followed by stirring at room temperature for 1 hour under an argon atmosphere.
  • TEA TEA
  • tert-butyl N-(but-3-yn-1-yl)carbamate 7.5 mg was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography to give the title compound (93 mg).
  • N-[1-(prop-2-yn-1-yl)cyclobutyl]carbamate (136 mg) and TEA (0.30 mL) were added, and the mixture was degassed and then stirred for 2 hours under an argon atmosphere at 50° C.
  • the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography to obtain the title compound (224 mg).
  • Example 13 N-(4- ⁇ 8-aminoimidazo[1,2-b]pyridazin-3-yl ⁇ but-3-yn-1-yl)-1-methyl-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[4-(8- ⁇ bis[(tert-butoxy)carbonyl]amino ⁇ imidazo[1,2-b]pyridazin-3-yl)but-3-yn-1-yl]carbamate
  • Example 27 N-[4-(8-fluoroisoquinolin-4-yl)but-3-yn-1-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • Step 1 To a mixture of tert-butyl N-[4-(8-fluoroisoquinolin-4-yl)but-3-yn-1-yl]carbamate (80 mg), Pd(PPh 3 ) 4 (41 mg), and copper(I) iodide (10 mg), DMF (2.5 mL), tert-butyl N-(but-3-yn-1-yl)carbamate (75 mg), and TEA (0.25 mL) were added and degassed, followed by stirring for 2 hours under an argon atmosphere at 75° C.
  • Example 28 N-[(2S)-5- ⁇ 8-aminoimidazo[1,2-b]pyridazin-3-yl ⁇ pent-4-yn-2-yl]-5-ethyl-1H-imidazole-2-carboxamide
  • 3-[(4S)-4-aminopent-1-yn-1-yl]imidazo[1,2-b]pyridazin-8-amine trihydrochloride (15 mg) obtained in Step 2 of Example 24, 5-ethyl-1H-imidazole-2-carboxylic acid (8.1 mg), and DIPEA (0.080 mL) in DMF (0.5 mL), BOP (26 mg) was added and stirred at room temperature for 1 hour.
  • Example 30 N-[(3E)-4-(2-amino-4-methoxypyrimidin-5-yl)but-3-en-1-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • Example 33 N-(4- ⁇ 6-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-(4- ⁇ 6-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl ⁇ but-3-yn-1-yl)carbamate DMF (2.5 mL), tert-butyl N-(but- 3 -yn-1-yl)carbamate (91 mg), and TEA (0.45 mL) were added to a mixture of 5 -bromo-6-chloro-1H-pyrazolo[3,4-b]pyridine (100 mg), Pd(PPh 3 ) 4 (50 mg), and copper(I) iodide (12 mg).
  • Example 34 7-chloro-N-[4-(4-phenylpyridin-3-yl)but-3-yn-1-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[4-(4-chloropyridin-3-yl)but-3-yn-1-yl]carbamate
  • Pd(PPh 3 ) 4 60 mg
  • copper(I) iodide 9.9 mg
  • DMF (2 mL
  • tert-butyl N-(but-3-yn-1-yl)carbamate 211 mg
  • TEA 2.1 mL
  • Example 38 N-[(2S,4E)-5-(5-methoxypyridin-3-yl)pent-4-en-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • Example 39 N-[(2S,4E)-5-(6-aminopyrazin-2-yl)pent-4-en-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • 6-chloropyrazin-2-amine 55 mg
  • tert-butyl N-[(2S,4E)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl]carbamate 165 mg
  • Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 52 mg
  • potassium carbonate 176 mg
  • 1,4-dioxane 1.5 mL
  • water 0.5 mL
  • the reaction mixture was quenched by adding saturated aqueous sodium bicarbonate and 20% aqueous sodium hydrogen thiosulfate, followed by extraction with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the solvent was evaporated under reduced pressure, and the resulting residue, 5-fluoropyridin-3-amine (75 mg), and acetic acid (0.038 mL) were dissolved in 1,2-dichloroethane (2.5 mL) to which sodium triacetoxyborohydride (425 mg) was added, followed by stirring at room temperature for 2 hours.
  • the reaction mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate.
  • Example 57 4,5-Dibromo-N- ⁇ 4-[5-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]but-3-yn-1-yl ⁇ -1H-imidazole-2-carboxamide
  • 4- ⁇ 3-iodopyrazolo[1,5-a]pyridin-5-yl ⁇ -1-methyl-1H-pyrazole (44 mg) obtained in Step 2 of Reference Example 80 4- ⁇ 3-iodopyrazolo[1,5-a]pyridin-6-yl ⁇ -1-methyl-1H-pyrazole (38 mg), and 4,5-dibromo-N-(but-3-yn-1-yl)-1H-imidazole-2-carboxamide (35 mg) obtained in Reference Example 57, PdCl 2 (PPh 3 ) 2 (7.7 mg), copper(I) iodide (3.1 mg), and piperidine (0.5 mL) were added
  • Example 58 N-(4- ⁇ 8-[(1-methyl-1H-pyrazol-4-yl)amino]imidazo[1,2-a]pyridin-3-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • N-[3-(4-aminobut-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-1-methyl-1H-pyrazol-4-amine trihydrochloride (30 mg) obtained in Step 3 of Example 2, 1H-1,3-benzodiazole-2-carboxylic acid (10 mg), and DIPEA (0.11 mL) in DMF (0.5 mL), HATU (35 mg) was added and stirred at room temperature for 1 hour.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with methanol to obtain the title compound (12 mg).
  • Example 60 N-(4- ⁇ 8-aminoimidazo[1,2-a]pyridin-3-yl ⁇ but-3-yn-1-yl)-6-methyl-1H-1,3-benzodiazole-2-carboxamide
  • 3-(4-aminobut-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine trihydrochloride (18 mg) obtained in Step 2 of Example 59
  • 6-methyl-1H-1,3-benzodiazole-2-carboxylic acid (10 mg) obtained in Step 2 of Reference Example 5
  • DIPEA 0.098 mL
  • DMF 0.5 mL
  • HATU 32 mg
  • Example 61 N-(4- ⁇ 8-aminoimidazo[1,2-a]pyridin-3-yl ⁇ but-3-yn-1-yl)-6-fluoro-1H-1,3-benzodiazole-2-carboxamide
  • 3-(4-aminobut-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine trihydrochloride (20 mg) obtained in Step 2 of Example 59
  • 6-fluoro-1H-1,3-benzodiazole-2-carboxylic acid (15 mg) obtained in Step 2 of Reference Example 7, and DIPEA (0.11 mL) in DMF (0.5 mL)
  • HATU 37 mg
  • Example 62 N-(4- ⁇ 8-amino-6-chloroimidazo[1,2-b]pyridazin-3-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[4-(8- ⁇ bis[(tert-butoxy)carbonyl]amino ⁇ -6-chloroimidazo[1,2-b]pyridazin-3-yl)but-3-yn-1-yl]carbamate
  • N-(but-3-yn-1-yl)carbamate (103 mg) and TEA (0.28 mL) were added, and the mixture was degassed and then stirred under an argon atmosphere at 50° C. for 1 hour.
  • the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography to obtain the title compound (143 mg).
  • N-(but-3-yn-1-yl)carbamate (66 mg) and TEA (0.26 mL) were added, and the mixture was degassed and then stirred under an argon atmosphere at 50° C. for 1 hour. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (115 mg).
  • Example 65 N-(4- ⁇ 8-amino-6,7-dichloroimidazo[1,2-b]pyridazin-3-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[4-(8- ⁇ bis[(tert-butoxy)carbonyl]amino ⁇ -6,7-dichloroimidazo[1,2-b]pyridazin-3-yl)but-3-yn-1-yl]carbamate
  • N-(but-3-yn-1-yl)carbamate (72 mg) and TEA (0.28 mL) were added, and the mixture was degassed and then stirred under an argon atmosphere at 50° C. for 1 hour.
  • the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography to obtain the title compound (147 mg).
  • Example 66 7-fluoro-N-(4- ⁇ imidazo[1,2-b]pyridazin-3-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • 4- ⁇ imidazo[1,2-b]pyridazin-3-yl ⁇ but-3-yn-1-amine dihydrochloride 29 mg obtained in Step 2 of Example 5
  • 7-fluoro-1H-1,3-benzodiazole-2-carboxylic acid (18 mg) obtained in Step 2 of Reference Example 6, and DIPEA (0.17 mL) in DMF (0.5 mL)
  • HATU 43 mg was added and stirred at room temperature overnight.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with methanol to obtain the title compound (6.9 mg).
  • Example 68 7-chloro-N-(4- ⁇ 2-[(4-fluorophenyl)amino]pyrimidin-5-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-(4- ⁇ 2-[(4-fluorophenyl)amino]pyrimidin-5-yl ⁇ but-3-yn-1-yl)carbamate
  • PdCl 2 (PPh 3 ) 2 27 mg
  • copper(I) iodide 11 mg
  • THF 2.5 mL
  • tert-butyl N-(but-3-yn-1-yl)carbamate 97 mg
  • TEA TEA
  • Example 70 7-chloro-N-[4-(2- ⁇ [4-(4-methylpiperazin-1-yl)phenyl]amino ⁇ pyrimidin-5-yl)but-3-yn-1-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[4-(2- ⁇ [4-(4-methylpiperazin-1-yl)phenyl]amino ⁇ pyrimidin-5-yl)but-3-yn-1-yl]carbamate
  • PdCl 2 (PPh 3 ) 2 24 mg
  • copper(I) iodide 9.8 mg
  • THF 2.5 mL
  • tert-butyl N-(but-3-yn-1-yl)carbamate 87 mg
  • Example 72 N-[1-(3- ⁇ 8-aminoimidazo[1,2-b]pyridazin-3-yl ⁇ prop-2-yn-1-yl)cyclopropyl]-7-methoxy-1H-1,3-benzodiazole-2-carboxamide
  • 3-[3-(1-aminocyclopropyl)prop-1-yn-1-yl]imidazo[1,2-b]pyridazin-8-amine trihydrochloride (20 mg) obtained in Step 2 of Example 8, 7-methoxy-1H-1,3-benzodiazole-2-carboxylic acid (14 mg) obtained in Step 2 of Reference Example 8, and DIPEA (0.10 mL) in DMF (0.5 mL), BOP (33 mg) was added and stirred at room temperature for 1 hour.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with methanol to obtain the title compound (16 mg).
  • Example 74 N-[1-(3- ⁇ 8-amino-7-chloroimidazo[1,2-b]pyridazin-3-yl ⁇ prop-2-yn-1-yl)cyclopropyl]-7-chloro-1H-1,3-benzodiazole-2-carboxamide
  • 3-[3-(1-aminocyclopropyl)prop-1-yn-1-yl]-7-chloroimidazo[1,2-b]pyridazin-8-amine trihydrochloride (20 mg) obtained in Step 2 of Example 73, 7-chloro-1H-1,3-benzodiazole-2-carboxylic acid (13 mg) obtained in Step 2 of Reference Example 2, and DIPEA (0.093 mL) in DMF (0.5 mL), BOP (30 mg) was added and stirred at room temperature for 2 hours.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with methanol to obtain the title compound (18
  • Example 75 N-[1-(3- ⁇ 8-amino-7-chloroimidazo[1,2-b]pyridazin-3-yl ⁇ prop-2-yn-1-yl)cyclopropyl]-7-methyl-1H-1,3-benzodiazole-2-carboxamide
  • 3-[3-(1-aminocyclopropyl)prop-1-yn-1-yl]-7-chloroimidazo[1,2-b]pyridazin-8-amine trihydrochloride (20 mg) obtained in Step 2 of Example 73, 7-methyl-1H-1,3-benzodiazole-2-carboxylic acid (12 mg) obtained in Step 2 of Reference Example 4, and DIPEA (0.093 mL) in DMF (0.5 mL), BOP (30 mg) was added and stirred at room temperature for 2 hours.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with methanol to obtain the title compound (19 mg).
  • Example 76 N-[1-(3- ⁇ 8-amino-7-chloroimidazo[1,2-b]pyridazin-3-yl ⁇ prop-2-yn-1-yl)cyclopropyl]-7-methoxy-1H-1,3-benzodiazole-2-carboxamide
  • 3-[3-(1-aminocyclopropyl)prop-1-yn-1-yl]-7-chloroimidazo[1,2-b]pyridazin-8-amine trihydrochloride (20 mg) obtained in Step 2 of Example 73, 7-methoxy-1H-1,3-benzodiazole-2-carboxylic acid (13 mg) obtained in Step 2 of Reference Example 8, and DIPEA (0.093 mL) in DMF (0.5 mL), BOP (30 mg) was added and stirred at room temperature for 2 hours.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with methanol to obtain the title compound (20
  • Example 80 N-[1-(3- ⁇ 8-amino-7-chloroimidazo[1,2-b]pyridazin-3-yl ⁇ prop-2-yn-1-yl)cyclopropyl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • 3-[3-(1-aminocyclopropyl)prop-1-yn-1-yl]-7-chloroimidazo[1,2-b]pyridazin-8-amine trihydrochloride (15 mg) obtained in Step 2 of Example 73, 3H-imidazo[4,5-b]pyridine-2-carboxylic acid (8.2 mg), and DIPEA (0.070 mL) in DMF (0.5 mL), BOP (22 mg) was added and stirred at room temperature for 2 hours.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with methanol to obtain the title compound (15 mg).
  • Example 88 N-[1-(3- ⁇ 8-amino-7-chloroimidazo[1,2-b]pyridazin-3-yl ⁇ prop-2-yn-1-yl)cyclopropyl]-7-ethoxy-1H-1,3-benzodiazole-2-carboxamide
  • 3-[3-(1-aminocyclopropyl)prop-1-yn-1-yl]-7-chloroimidazo[1,2-b]pyridazin-8-amine trihydrochloride (18 mg) obtained in Step 2 of Example 73, 7-ethoxy-1H-1,3-benzodiazole-2-carboxylic acid (12 mg) obtained in Step 2 of Reference Example 9, and DIPEA (0.082 mL) in DMF (0.5 mL), BOP (26 mg) was added and stirred at room temperature for 1 hour.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with methanol to obtain the title compound (18
  • Example 90 N-[1-(3- ⁇ 8-aminoimidazo[1,2-b]pyridazin-3-yl ⁇ prop-2-yn-1-yl)cyclopropyl]-6-fluoro-7-methyl-1H-1,3-benzodiazole-2-carboxamide
  • 3-[3-(1-aminocyclopropyl)prop-1-yn-1-yl]imidazo[1,2-b]pyridazin-8-amine trihydrochloride 13 mg
  • 6-fluoro-7-methyl-1H-1,3-benzodiazole-2-carboxylic acid 9.0 mg) obtained in Step 2 of Reference Example 20
  • DIPEA 0.064 mL
  • DMF 0.5 mL
  • BOP 21 mg
  • Example 95 N-[(2S)-5- ⁇ 8-aminoimidazo[1,2-b]pyridazin-3-yl ⁇ pent-4-yn-2-yl]-7-methoxy-N-methyl-1H-1,3-benzodiazole-2-carboxamide
  • 3-[(4S)-4-(methylamino)pent-1-yn-1-yl]imidazo[1,2-b]pyridazin-8-amine trihydrochloride (15 mg) obtained in Step 2 of Example 14, 7-methoxy-1H-1,3-benzodiazole-2-carboxylic acid (11 mg) obtained in Step 2 of Reference Example 8, and DIPEA (0.077 mL) in DMF (0.5 mL), BOP (24 mg) was added and stirred at room temperature for 1 hour.
  • Example 97 N-[(2S)-5- ⁇ 8-aminoimidazo[1,2-b]pyridazin-3-yl ⁇ pent-4-yn-2-yl]-6-chloro-1-methyl-1H-1,3-benzodiazole-2-carboxamide
  • 3-[(4S)-4-aminopent-1-yn-1-yl]imidazo[1,2-b]pyridazin-8-amine trihydrochloride (15 mg) obtained in Step 2 of Example 24, sodium 6-chloro-1-methyl-1H-1,3-benzodiazole-2-carboxylate (13 mg) obtained in Step 4 of Reference Example 27, and DIPEA (0.080 mL) in DMF (0.5 mL), BOP (26 mg) was added and stirred at room temperature for 1 hour.
  • Example 99 N-[(2S)-5- ⁇ 8-aminoimidazo[1,2-b]pyridazin-3-yl ⁇ pent-4-yn-2-yl]-4-chloro-1-methyl-1H-1,3-benzodiazole-2-carboxamide
  • 3-[(4S)-4-aminopent-1-yn-1-yl]imidazo[1,2-b]pyridazin-8-amine trihydrochloride (15 mg) obtained in Step 2 of Example 24, sodium 4-chloro-1-methyl-1H-1,3-benzodiazole-2-carboxylate (13 mg) obtained in Step 4 of Reference Example 29, and DIPEA (0.080 mL) in DMF (0.5 mL), BOP (26 mg) was added and stirred at room temperature for 1 hour.
  • Example 100 7-chloro-N-(4- ⁇ imidazo[1,2-a]pyrazin-3-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-(4- ⁇ imidazo[1,2-a]pyrazin-3-yl ⁇ but-3-yn-1-yl)carbamate
  • PdCl 2 (PPh 3 ) 2 29 mg
  • copper(I) iodide (12 mg
  • THF 2.5 mL
  • tert-butyl N-(but-3-yn-1-yl)carbamate 86 mg
  • TEA TEA
  • Example 104 N-[1-(3- ⁇ 8-amino-7-bromoimidazo[1,2-b]pyridazin-3-yl ⁇ prop-2-yn-1-yl)cyclopropyl]-7-methoxy-N-methyl-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N- ⁇ 1-[3-(8- ⁇ bis[(tert-butoxy)carbonyl]amino ⁇ -7-bromoimidazo[1,2-b]pyridazin-3-yl)prop-2-yn-1-yl]cyclopropyl ⁇ -N-methylcarbamate
  • PdCl 2 (PPh 3 ) 2 20 mg
  • Example 105 N-[4-(5-bromopyridin-3-yl)but-3-yn-1-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of 4-(5-bromopyridin-3-yl)but-3-yn-1-amine dihydrochloride
  • tert-butyl N-[4-(5-bromopyridin-3-yl)but-3-yn-1-yl]carbamate (20 mg) obtained in Step 1 of Example 17, in dichloromethane (1.5 mL) and methanol (1.5 mL)
  • hydrogen chloride (4 M solution in 1,4-dioxane, 0.31 mL) was added and the mixture was stirred for 1 hour at 45° C.
  • Example 106 N-[4-(6-amino-5-phenylpyridin-3-yl)but-3-yn-1-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[4-(6-amino-5-bromopyridin-3-yl)but-3-yn-1-yl]carbamate
  • PdCl 2 (PPh 3 ) 2 23 mg
  • copper(I) iodide 9.6 mg
  • THF 2.5 mL
  • tert-butyl N-(but-3-yn-1-yl)carbamate 71 mg
  • TEA TEA (0.23 mL
  • the mixture was degassed and then stirred at 100°C under an argon atmosphere for 5 hours.
  • the reaction mixture was purified by silica gel column chromatography to obtain a crude residue.
  • the resulting residue was washed with diethyl ether to obtain the title compound (66 mg).
  • Example 108 N-[4-(6-amino-5-bromo-4-methoxypyridin-3-yl)but-3-yn-1-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[4-(6-amino-5-bromo-4-methoxypyridin-3-yl)but-3-yn-1-yl]carbamate
  • PdCl 2 (PPh 3 ) 2 10 mg
  • copper(I) iodide 4.1 mg
  • THF 1.5 mL
  • tert-butyl N-(but-3-yn-1-yl)carbamate 31 mg
  • TEA TEA
  • Example 109 N-[4-(6-aminopyridazin-3-yl)but-3-yn-1-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[4-(6-aminopyridazin-3-yl)but-3-yn-1-yl]carbamate
  • 6-iodopyridazin-3-amine 100 mg
  • PdCl 2 (PPh 3 ) 2 32 mg
  • copper(I) iodide 13 mg
  • THF 2.5 mL
  • tert-butyl N-(but-3-yn-1-yl)carbamate 100 mg
  • TEA TEA
  • Example 110 N-[(2S)-5-(6-amino-5-bromopyridin-3-yl)pent-4-yn-2-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(2S)-5-(6-amino-5-bromopyridin-3-yl)pent-4-yn-2-yl]carbamate
  • Example 112 N-[4-(6-amino-5-bromopyridin-3-yl)but-3-yn-1-yl]-7-chloro-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of 5-(4-aminobut-1-yn-1-yl)-3-bromopyridin-2-amine dihydrochloride
  • tert-butyl N-[4-(6-amino-5-bromopyridin-3-yl)but-3-yn-1-yl]carbamate 105 mg
  • Example 106 in a mixture of dichloromethane (1.5 mL) and methanol (1.5 mL) was added hydrogen chloride (4 M solution in 1,4-dioxane, 1.2 mL), and the mixture was stirred for 2 hours at 45° C.
  • Example 120 N-[4-(5-cyclopropylpyridin-3-yl)but-3-yn-1-yl]-1H-1,3-benzodiazole-2-carboxamide
  • PdCl 2 (PPh 3 ) 2 11 mg
  • copper(I) iodide 4.3 mg
  • piperidine 3 mL
  • Example 122 N-[(2S,4E)-5-(6-amino-5-chloropyridin-3-yl)pent-4-en-2-yl]-7-chloro-1H-1,3-benzodiazole-2-carboxamide
  • 5-[(1E,4S)-4-aminopent-1-en-1-yl]-3-chloropyridin-2-amine dihydrochloride (20 mg) obtained in Step 2 of Example 121
  • 7-chloro-1H-1,3-benzodiazole-2-carboxylic acid 17.
  • DIPEA 0.12 mL
  • DMF 0.5 mL
  • Example 128 N-[(3S)-6-(6-amino-5-chloropyridin-3-yl)hex-5-yn-3-yl]-7-chloro-1H-1,3-benzodiazole-2-carboxamide
  • 5-[(4S)-4-aminohex-1-yn-1-yl]-3-chloropyridin-2-amine dihydrochloride 15 mg obtained in Step 2 of Example 127
  • DIPEA 0.087 mL
  • DMF 0.5 mL
  • BOP 28 mg
  • Example 129 N-[(3E)-4-(6-amino-5-chloropyridin-3-yl)but-3-en-1-yl]-N-methyl-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(3E)-4-(6-amino-5-chloropyridin-3-yl)but-3-en-1-yl]-N-methylcarbamate Pd(dppf)Cl 2.CH 2 Cl 2 (36 mg), potassium carbonate (122 mg), 1,4-dioxane (1.5 mL), and water (0.5 mL) were added to a mixture of 3-chloro-5-iodopyridin-2-amine (75 mg) and tert-butyl N-methyl- N -[(3E) -4- ( 4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl]carba
  • Example 130 7-chloro-N-[1-(3- ⁇ 1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ prop-2-yn-1-yl)cyclopropyl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[1-(3- ⁇ 1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ prop-2-yn-1-yl)cyclopropyl]carbamate
  • 5-iodo-1H-pyrrolo[2,3-b]pyridine 56 mg
  • PdCl 2 (PPh 3 ) 2 (16 mg)
  • copper(I) iodide 6.6 mg
  • THF 2.5 mL
  • tert-butyl N-[1-(prop-2-yn-1-yl)cyclopropyl]carbamate 67 mg) obtained in Reference Example 41, and TEA (0.16 mL) were added and the mixture
  • Example 131 7-chloro-N-(4- ⁇ 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-(4- ⁇ 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl ⁇ but-3-yn-1-yl)carbamate THF (2.5 mL), tert-butyl N- (but- 3 -yn - 1-yl)carbamate (104 mg), and TEA (0.33 mL) were added to a mixture of 6-bromo-3-methyl-3H-imidazo[4,5-b]pyridine (100 mg), PdCl 2 (PPh 3 ) 2 (33 mg), and copper(I) iodide (13 mg).
  • the mixture was degassed and then stirred overnight at 60°C under an argon atmosphere.
  • the reaction solution was concentrated, and the resulting residue was purified by reverse-phase column chromatography to give a crude residue.
  • the resulting residue was purified by silica gel column chromatography to give the title compound (28 mg).
  • Example 136 7-chloro-N-(4- ⁇ 5H-pyrrolo[2,3-b]pyrazin-2-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-(4- ⁇ 5H-pyrrolo[2,3-b]pyrazin-2-yl ⁇ but-3-yn-1-yl)carbamate DMF (1 mL), tert-butyl N-(but- 3 -yn-1-yl)carbamate (128 mg), and TEA (1.0 mL) were added to a mixture of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (100 mg), Pd(PPh 3 ) 4 (29 mg), and copper(I) iodide (4.8 mg).
  • the mixture was degassed and then stirred at 90° C. for 2 hours under an argon atmosphere.
  • the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography to give a crude residue.
  • the resulting residue was purified by reverse-phase column chromatography to give the title compound (37 mg).
  • Example 137 N-[(2S)-5- ⁇ 8-aminoimidazo[1,2-b]pyridazin-3-yl ⁇ pent-4-yn-2-yl]-5-bromo-1H-imidazole-2-carboxamide
  • 3-[(4S)-4-aminopent-1-yn-1-yl]imidazo[1,2-b]pyridazin-8-amine trihydrochloride (15 mg) obtained in Step 2 of Example 24, 5-bromo-1H-imidazole-2-carboxylic acid (11 mg), and DIPEA (0.080 mL) in DMF (0.5 mL), BOP (26 mg) was added and stirred at room temperature for 1 hour.
  • Example 138 N-[(2S)-5- ⁇ 8-aminoimidazo[1,2-b]pyridazin-3-yl ⁇ pent-4-yn-2-yl]-4,5-dichloro-1H-imidazole-2-carboxamide
  • 3-[(4S)-4-aminopent-1-yn-1-yl]imidazo[1,2-b]pyridazin-8-amine trihydrochloride (18 mg) obtained in Step 2 of Example 24, 4,5-dichloro-1H-imidazole-2-carboxylic acid (12 mg), and DIPEA (0.093 mL) in DMF (0.5 mL), BOP (30 mg) was added and stirred at room temperature over the weekend.
  • the reaction mixture was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with acetonitrile to obtain the title compound (5.2 mg).
  • Example 139 7-chloro-N-(4- ⁇ 3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-(4- ⁇ 3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl ⁇ but-3-yn-1-yl)carbamate DMF (2 mL), tert-butyl N-(but- 3 -yn-1-yl)carbamate (221 mg), and TEA (2.0 mL) were added to a mixture of 6 -bromo-3H-[1,2,3]triazolo[4,5-b]pyridine (200 mg), Pd(PPh 3 ) 4 (58 mg), and copper(I) iodide (9.6 mg).
  • Example 140 N-(4- ⁇ 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl ⁇ but-3-yn-1-yl)-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • Step 1 Preparation of tert-butyl N-(4- ⁇ 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl ⁇ but-3-yn-1-yl)carbamate DMF (2 mL), tert-butyl N- (but- 3 -yn-1-yl)carbamate (207 mg), and TEA (1.9 mL) were added to a mixture of 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (200 mg), Pd(PPh 3 ) 4 (54 mg), and copper(I) iodide (9.0 mg).
  • Example 142 N-[(3R)-6- ⁇ 8-aminoimidazo[1,2-b]pyridazin-3-yl ⁇ -2-methylhex-5-yn-3-yl]-7-methoxy-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(3R)-6-(8- ⁇ bis[(tert-butoxy)carbonyl]amino ⁇ imidazo[1,2-b]pyridazin-3-yl)-2-methylhex-5-yn-3-yl]carbamate
  • PdCl 2 (PPh 3 ) 2 27 mg
  • copper(I) iodide 11 mg
  • THF 2.5 mL
  • Example 143 7-chloro-N-[4-(5-methanesulfonamidopyridin-3-yl)but-3-yn-1-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[4-(5-methanesulfonamidopyridin-3-yl)but-3-yn-1-yl]carbamate
  • N-(5-bromopyridin-3-yl)methanesulfonamide 150 mg
  • Pd(PPh 3 ) 4 35 mg
  • copper(I) iodide 5.7 mg
  • DMF (1 mL
  • tert-butyl N-(but-3-yn-1-yl)carbamate 126 mg
  • TEA 1.2 mL
  • Example 144 N-[(2S)-5-(2-amino-4-methoxypyrimidin-5-yl)pent-4-yn-2-yl]-7-chloro-1H-1,3-benzodiazole-2-carboxamide
  • 5-[(4S)-4-aminopent-1-yn-1-yl]-4-methoxypyrimidin-2-amine dihydrochloride (16 mg) obtained in Step 2 of Example 26, 7-chloro-1H-1,3-benzodiazole-2-carboxylic acid (14 mg) obtained in Step 2 of Reference Example 2, and DIPEA (0.099 mL) in DMF (0.5 mL), BOP (32 mg) was added and the mixture was stirred at room temperature overnight.
  • Example 145 N-[(2S)-5-(2-amino-4-ethoxypyrimidin-5-yl)pent-4-yn-2-yl]-7-chloro-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of 5-[(4S)-4-aminopent-1-yn-1-yl]-4-ethoxypyrimidin-2-amine dihydrochloride
  • tert-butyl N-[(2S)-5-(2-amino-4-chloropyrimidin-5-yl)pent-4-yn-2-yl]carbamate (57 mg) obtained in Step 1 of Example 26 in a mixture of dichloromethane (0.5 mL) and ethanol (0.5 mL) was added hydrogen chloride (4 M solution in 1,4-dioxane, 0.92 mL), and the mixture was stirred at room temperature for 6 hours.
  • Example 146 N-[(2S)-5-(2-amino-4-ethoxypyrimidin-5-yl)pent-4-yn-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • 5-[(4S)-4-aminopent-1-yn-1-yl]-4-ethoxypyrimidin-2-amine dihydrochloride 17.0 mg
  • 3H-imidazo[4,5-b]pyridine-2-carboxylic acid (12 mg)
  • DIPEA 0.10 mL
  • DMF 0.5 mL
  • BOP 32 mg
  • Example 149 7-chloro-N- ⁇ 4-[2-(methylamino)pyrimidin-5-yl]but-3-yn-1-yl ⁇ -1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N- ⁇ 4-[2-(methylamino)pyrimidin-5-yl]but-3-yn-1-yl ⁇ carbamate
  • PdCl 2 (PPh 3 ) 2 22 mg
  • copper(I) iodide 9.1 mg
  • THF 2.5 mL
  • tert-butyl N-(but-3-yn-1-yl)carbamate 67 mg
  • TEA TEA
  • Example 150 7-chloro-N- ⁇ 4-[2-(ethylamino)pyrimidin-5-yl]but-3-yn-1-yl ⁇ -1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N- ⁇ 4-[2-(ethylamino)pyrimidin-5-yl]but-3-yn-1-yl ⁇ carbamate
  • PdCl 2 (PPh 3 ) 2 21 mg
  • copper(I) iodide 8.6 mg
  • THF 2.5 mL
  • tert-butyl N-(but-3-yn-1-yl)carbamate 64 mg
  • TEA TEA (0.21 mL
  • Example 151 7-chloro-N- ⁇ 4-[2-(cyclopropylamino)pyrimidin-5-yl]but-3-yn-1-yl ⁇ -1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N- ⁇ 4-[2-(cyclopropylamino)pyrimidin-5-yl]but-3-yn-1-yl ⁇ carbamate
  • PdCl 2 (PPh 3 ) 2 (20 mg
  • copper(I) iodide 8.2 mg
  • THF 2.5 mL
  • tert-butyl N-(but-3-yn-1-yl)carbamate 61 mg
  • TEA TEA
  • Example 152 N-[(2S)-5- ⁇ 8-aminoimidazo[1,2-b]pyridazin-3-yl ⁇ pent-4-yn-2-yl]-5-methyl-1H-imidazole-2-carboxamide
  • 3-[(4S)-4-aminopent-1-yn-1-yl]imidazo[1,2-b]pyridazin-8-amine trihydrochloride (15 mg) obtained in Step 2 of Example 24, 5-methyl-1H-imidazole-2-carboxylic acid (7.3 mg), and DIPEA (0.080 mL) in DMF (0.5 mL), BOP (26 mg) was added and stirred at room temperature for 3 hours.
  • the mixture was degassed and then stirred under an argon atmosphere at 100°C for 2 hours.
  • the reaction mixture was purified by silica gel column chromatography to give a crude residue, which was washed with a mixed solvent of diethyl ether and ethyl acetate to give the title compound (27 mg).
  • Example 155 7-chloro-N-(4- ⁇ 2-methyl-2H-pyrazolo[3,4-c]pyridin-4-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-(4- ⁇ 2-methyl-2H-pyrazolo[3,4-c]pyridin-4-yl ⁇ but-3-yn-1-yl)carbamate DMF (1 mL), tert-butyl N-(but- 3 -yn-1-yl)carbamate (93 mg), and TEA (0.85 mL) were added to a mixture of 4- bromo-2-methyl-2H-pyrazolo[3,4-c]pyridine (90 mg), Pd(PPh 3 ) 4 (25 mg), and copper(I) iodide (4.0 mg).
  • Example 156 7-chloro-N-(4- ⁇ 1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-(4- ⁇ 1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl ⁇ but-3-yn-1-yl)carbamate DMF (1 mL), tert-butyl N-(but- 3 -yn-1-yl)carbamate (128 mg), and TEA (1.2 mL) were added to a mixture of 4- bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (123 mg), Pd(PPh 3 ) 4 (34 mg), and copper(I) iodide (5.5 mg).
  • Example 157 7-chloro-N-(4- ⁇ 1H-pyrazolo[3,4-c]pyridin-4-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl 4-(4- ⁇ [(tert-butoxy)carbonyl]amino ⁇ but-1-yn-1-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate
  • Pd(PPh 3 ) 4 29 mg
  • copper(I) iodide 4.8 mg
  • DMF (1 mL
  • tert-butyl N-(but-3-yn-1-yl)carbamate 106 mg
  • TEA 1.0 mL
  • Example 158 N-[4-(5-bromo-6-cyclopropaneamidopyridin-3-yl)but-3-yn-1-yl]-1H-1,3-benzodiazole-2-carboxamide
  • N-(3-bromo-5-iodopyridin-2-yl)cyclopropanecarboxamide 62 mg
  • Pd(PPh 3 ) 4 8.1 mg
  • copper(I) iodide 1.3 mg
  • DMF 0.5 mL
  • N-(but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide (30 mg) obtained in Reference Example 58
  • DIPEA (0.14 mL) were added and degassed, followed by stirring under an argon atmosphere at 80° C.
  • Example 160 7-chloro-N-[(2S)-5- ⁇ 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl ⁇ pent-4-yn-2-yl]-1H-1,3-benzodiazole-2-carboxamide
  • (2S)-5- ⁇ 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl ⁇ pent-4-yn-2-amine trihydrochloride (20 mg) obtained in Step 2 of Example 159
  • 7-chloro-1H-1,3-benzodiazole-2-carboxylic acid (15 mg) obtained in Step 2 of Reference Example 2, and DIPEA (0.11 mL) in DMF (0.5 mL), BOP (34 mg) was added and stirred at room temperature overnight.
  • Example 161 N-[(2S)-5- ⁇ 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl ⁇ pent-4-yn-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • (2S)-5- ⁇ 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl ⁇ pent-4-yn-2-amine trihydrochloride (20 mg) obtained in Step 2 of Example 159, 3H-imidazo[4,5-b]pyridine-2-carboxylic acid (13 mg), and DIPEA (0.11 mL) in DMF (0.5 mL), BOP (34 mg) was added and stirred at room temperature overnight.
  • Example 166 N-(4- ⁇ 6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-(4- ⁇ 6-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl ⁇ but-3-yn-1-yl)carbamate DMF (2.5 mL), tert-butyl N-(but- 3 -yn-1-yl)carbamate (93 mg), and TEA (0.46 mL) were added to a mixture of 5 -bromo-6-methoxy-1H-pyrazolo[3,4-b]pyridine (100 mg), Pd(PPh 3 ) 4 (51 mg), and copper(I) iodide (13 mg).
  • Example 167 7-chloro-N-(4- ⁇ 2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ but-3-yn-1-yl)-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-(4- ⁇ 2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ but-3-yn-1-yl)carbamate DMF (1 mL), tert-butyl N-(but- 3 -yn-1-yl)carbamate (96 mg), and TEA (0.95 mL) were added to a mixture of 5 -bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (100 mg), Pd(PPh 3 ) 4 (27 mg), and copper(I) iodide (4.5 mg).
  • Example 168 N-(4- ⁇ 2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ but-3-yn-1-yl)-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • 4- ⁇ 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ but-3-yn-1-amine dihydrochloride (20 mg) obtained in Step 2 of Example 167, 3H-imidazo[4,5-b]pyridine-2-carboxylic acid (15 mg), and DIPEA (0.13 mL) in DMF (0.5 mL), BOP (41 mg) was added and the mixture was stirred at room temperature overnight.
  • Example 170 N-[(2S)-5-(6-amino-5-chloro-4-methoxypyridin-3-yl)pent-4-yn-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(2S)-5-(6-amino-5-chloro-4-methoxypyridin-3-yl)pent-4-yn-2-yl]carbamate
  • Example 171 N-[(2S)-5-(6-amino-5-chloro-4-methylpyridin-3-yl)pent-4-yn-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • 5-[(4S)-4-aminopent-1-yn-1-yl]-3-chloro-4-methylpyridin-2-amine dihydrochloride (20 mg) obtained in Step 2 of Example 169, 3H-imidazo[4,5-b]pyridine-2-carboxylic acid (14 mg), and DIPEA (0.12 mL) in DMF (0.5 mL) was added BOP (37 mg) and stirred at room temperature for 1 hour.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with methanol to obtain the title compound (22 mg).
  • Example 172 N-[(2S)-5-(5-amino-4-chloropyridin-3-yl)pent-4-yn-2-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(2S)-5-(5-amino-4-chloropyridin-3-yl)pent-4-yn-2-yl]carbamate
  • 5-bromo-4-chloropyridin-3-amine 85 mg
  • Pd(PPh 3 ) 4 47 mg
  • copper(I) iodide (12 mg
  • DMF 1.5 mL
  • tert-butyl N-[(2S)-pent-4-yn-2-yl]carbamate 113 mg
  • Reference Example 32 and TEA (0.43 mL) were added and the mixture was degassed, followed by stirring for 10 hours at 85° C.
  • Example 173 N-[(2S)-5-(5-amino-4-methoxypyridin-3-yl)pent-4-yn-2-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(2S)-5-(5-amino-4-methoxypyridin-3-yl)pent-4-yn-2-yl]carbamate
  • 5-bromo-4-methoxypyridin-3-amine 85 mg
  • Pd(PPh 3 ) 4 48 mg
  • copper(I) iodide (12 mg
  • DMF 1.5 mL
  • tert-butyl N-[(2S)-pent-4-yn-2-yl]carbamate 115 mg
  • Reference Example 32 and TEA (0.44 mL) were added and the mixture was degassed, followed by stirring for 10 hours at 85° C.
  • Example 175 N-[(2S)-5-(5-amino-4-methoxypyridin-3-yl)pent-4-yn-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • 5-[(4S)-4-aminopent-1-yn-1-yl]-4-methoxypyridin-3-amine trihydrochloride (20 mg) obtained in Step 2 of Example 173, 3H-imidazo[4,5-b]pyridine-2-carboxylic acid (13 mg), and DIPEA (0.11 mL) in DMF (0.5 mL) was added BOP (35 mg) and stirred at room temperature for 1 hour.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with acetonitrile to obtain the title compound (8.5 mg).
  • Example 176 N-[4-(5-amino-4-hydroxypyridin-3-yl)but-3-yn-1-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-(4- ⁇ [1,3]oxazolo[4,5-c]pyridin-7-yl ⁇ but-3-yn-1-yl)carbamate DMF (1 mL), tert-butyl N-(but- 3 -yn-1-yl)carbamate (106 mg), and TEA (1.0 mL) were added to a mixture of 7 -bromo-[1,3]oxazolo[4,5-c]pyridine (100 mg), Pd(PPh 3 ) 4 (29 mg), and copper(I) iodide (4.8 mg).
  • Example 178 N-[(2S,4E)-5-(6-amino-4,5-dichloropyridin-3-yl)pent-4-en-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • 5-[(1E,4S)-4-aminopent-1-en-1-yl]-3,4-dichloropyridin-2-amine dihydrochloride 25 mg
  • 3H-imidazo[4,5-b]pyridine-2-carboxylic acid (16 mg)
  • DIPEA 0.14 mL
  • DMF 0.5 mL
  • BOP 43 mg
  • Example 180 N-[(2S,4E)-5-[4-methoxy-2-(methylamino)pyrimidin-5-yl]pent-4-en-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(2S,4E)-5-[4-methoxy-2-(methylamino)pyrimidin-5-yl]pent-4-en-2-yl]carbamate Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (42 mg), potassium carbonate (143 mg), 1,4-dioxane (1.5 mL), and water (0.5 mL) were added to a mixture of 5-bromo-4-methoxy-N-methylpyrimidin-2-amine (75 mg) obtained in Step 3 of Reference Example 94 and tert-butyl N-[(2S,4E) -5- ( 4,4,5,5 -tetramethyl-1,3,2-dio
  • Example 182 N-[4-(4-chloropyridin-3-yl)but-3-yn-1-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of 4-(4-chloropyridin-3-yl)but-3-yn-1-amine dihydrochloride
  • tert-butyl N-[4-(4-chloropyridin-3-yl)but-3-yn-1-yl]carbamate (100 mg) obtained in Step 1 of Example 34 in a mixture of dichloromethane (1.5 mL) and methanol (1.5 mL) was added hydrogen chloride (4 M solution in 1,4-dioxane, 1.8 mL), and the mixture was stirred at room temperature for 3 hours.
  • Example 188 N-[(2S)-5-(6-amino-5-fluoropyridin-3-yl)pent-4-yn-2-yl]-7-chloro-1H-1,3-benzodiazole-2-carboxamide
  • 5-[(4S)-4-aminopent-1-yn-1-yl]-3-fluoropyridin-2-amine dihydrochloride (20 mg) obtained in Step 2 of Example 187
  • 7-chloro-1H-1,3-benzodiazole-2-carboxylic acid (18 mg) obtained in Step 2 of Reference Example 2, and DIPEA (0.13 mL) in DMF (0.5 mL), BOP (42 mg) was added and stirred at room temperature for 1 hour.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with acetonitrile to obtain the title compound (21 mg).
  • Example 190 N-[(2S,4E)-5-(6-amino-5-fluoropyridin-3-yl)pent-4-en-2-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(2S,4E)-5-(6-amino-5-fluoropyridin-3-yl)pent-4-en-2-yl]carbamate Pd(dppf)Cl 2.CH 2 Cl 2 (48 mg), potassium carbonate (163 mg), 1,4-dioxane (1.5 mL), and water (0.5 mL) were added to a mixture of 5-bromo-3-fluoropyridin-2-amine (75 mg) and tert-butyl N-[(2S, 4E ) -5- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl]carbamate (
  • Example 192 N-[(2S,4E)-5-(6-amino-5-fluoropyridin-3-yl)pent-4-en-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • 5-[(1E,4S)-4-aminopent-1-en-1-yl]-3-fluoropyridin-2-amine dihydrochloride (20 mg) obtained in Step 2 of Example 190, 3H-imidazo[4,5-b]pyridine-2-carboxylic acid (15 mg), and DIPEA (0.13 mL) in DMF (0.5 mL), BOP (41 mg) was added and stirred at room temperature for 1 hour.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with acetonitrile to obtain the title compound (24 mg).
  • Example 196 N-[(2S)-5-(6-amino-4-chloro-5-methoxypyridin-3-yl)pent-4-yn-2-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(2S)-5-(6-amino-4-chloro-5-methoxypyridin-3-yl)pent-4-yn-2-yl]carbamate
  • Pd(PPh 3 ) 4 39 mg
  • copper(I) iodide 9.6 mg
  • DMF 2.5 mL
  • tert-butyl N-[(2S)-pent-4-yn-2-yl]carbamate (77 mg) obtained in Reference Example 32, and TEA (0.35 mL) were added and the mixture was degas
  • Example 198 N-[(2S)-5-(6-amino-4-chloro-5-methoxypyridin-3-yl)pent-4-yn-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • 5-[(4S)-4-aminopent-1-yn-1-yl]-4-chloro-3-methoxypyridin-2-amine dihydrochloride (20 mg) obtained in Step 2 of Example 196, 3H-imidazo[4,5-b]pyridine-2-carboxylic acid (13 mg), and DIPEA (0.11 mL) in DMF (0.5 mL), BOP (35 mg) was added and stirred at room temperature for 1 hour.
  • the reaction solution was purified by reverse-phase column chromatography to obtain a crude residue. The resulting residue was washed with acetonitrile to obtain the title compound (23 mg).
  • Example 201 N-[(2S,4E)-5-(5-amino-4-methoxypyridin-3-yl)pent-4-en-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • 5-[(1E,4S)-4-aminopent-1-en-1-yl]-4-methoxypyridin-3-amine tritrifluoroacetate 40 mg
  • 3H-imidazo[4,5-b]pyridine-2-carboxylic acid 15 mg
  • DIPEA 0.19 mL
  • BOP 40 mg
  • Example 202 N-[(2S,4E)-5-(5-amino-4-ethoxypyridin-3-yl)pent-4-en-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(2S,4E)-5-(5-amino-4-ethoxypyridin-3-yl)pent-4-en-2-yl]carbamate Pd(dppf)Cl 2.CH 2 Cl 2 (45 mg), potassium carbonate (153 mg), 1,4-dioxane (1.5 mL), and water (0.5 mL) were added to a mixture of 5-bromo-4-ethoxypyridin-3-amine (80 mg) obtained in Step 2 of Reference Example 121 and tert - butyl N-[(2S,4E)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4
  • Example 204 N-[(2S,4E)-5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]pent-4-en-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(2S,4E)-5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]pent-4-en-2-yl]carbamate Pd(dppf)Cl 2.CH 2 Cl 2 (43 mg), potassium carbonate (146 mg), 1,4-dioxane (1.5 mL), and water (0.5 mL) were added to a mixture of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (85 mg) and tert-butyl N-[(2S,4E) -5- ( 4,4,5,5-tetramethyl- 1,3,2 -dioxaborolan-2-y
  • Example 205 N-[(2S,4E)-5-(6-amino-5-methoxypyridin-3-yl)pent-4-en-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(2S,4E)-5-(6-amino-5-methoxypyridin-3-yl)pent-4-en-2-yl]carbamate Pd(dppf)Cl 2.CH 2 Cl 2 (48 mg), potassium carbonate (163 mg), 1,4-dioxane (1.5 mL), and water (0.5 mL) were added to a mixture of 5-bromo-3-methoxypyridin-2-amine (80 mg) and tert-butyl N-[(2S, 4E ) -5- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl]c
  • Example 206 N-[(2S,4E)-5-(5-aminopyridin-3-yl)pent-4-en-2-yl]-1H-1,3-benzodiazole-2-carboxamide
  • Step 1 Preparation of tert-butyl N-[(2S,4E)-5-(5-aminopyridin-3-yl)pent-4-en-2-yl]carbamate Pd(dppf)Cl.CH.sub.2Cl.sub.2 (57 mg), potassium carbonate (192 mg), 1,4-dioxane (1.5 mL), and water ( 0.5 mL) were added to a mixture of 5-bromopyridin- 3 -amine (80 mg) and tert-butyl N-[(2S,4E)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en- 2 -yl]carbamate (180 mg) obtained in
  • Example 207 N-[(2S,4E)-5-(5-aminopyridin-3-yl)pent-4-en-2-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide
  • 5-[(1E,4S)-4-aminopent-1-en-1-yl]pyridin-3-amine trihydrochloride 25 mg
  • 3H-imidazo[4,5-b]pyridine-2-carboxylic acid 18 mg
  • DIPEA 0.15 mL
  • BOP 48 mg

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Abstract

La présente divulgation concerne un nouveau composé ayant une action inhibitrice de la kinase AURKB. La kinase AURKB peut être inhibée par un composé représenté par la formule générale (I) ci-jointe ou un sel de celui-ci.
PCT/JP2025/018170 2024-05-20 2025-05-20 Composé ayant une action inhibitrice de la kinase aurkb ou sel de celui-ci, et composition pharmaceutique le contenant Pending WO2025244014A1 (fr)

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JP2024-081975 2024-05-20
JP2024081975 2024-05-20

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WO2025244014A1 true WO2025244014A1 (fr) 2025-11-27

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