Optically active bridged piperidine derivative
The present invention relates to the compound of formula (1a) wherein a-d and p are 1 or 2, R 1 -R 4 are hydrogen atom or the like, and R 18 is —CF 3 or the like, or a pharmaceutically acceptable salt thereof, which has an anticancer effect by inhibiting the binding between a MLL fusion protein that is fused with AF4, AF9, or the like, which is a representative fusion partner gene causing MLL leukemia, and menin.
1 . A compound selected from the group consisting of
[(1S,3S,4R)-5-( 2 H 2 )methylidene-2-azabicyclo[2.2.2]octan-3-yl]{2-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl}methanone,
4-{7-[(1S,3S,4R)-5-( 2 H 2 )methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octan-3-yl]{2-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl}methanone, and
4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile or pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 where the compound is [(1S,3S,4R)-5-( 2 H 2 )methylidene-2-azabicyclo[2.2.2]octan-3-yl]{2-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl}methanone, or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 where the compound is 4-{7-[(1S,3S,4R)-5-( 2 H 2 )methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile, or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 where the compound is [(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octan-3-yl]{2-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl}methanone, or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 where the compound is 4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile, or a pharmaceutically acceptable salt thereof.
6 . A compound selected from the group consisting of [(1S,3S,4R)-5-( 2 H 2 )methylidene-2-azabicyclo[2.2.2]octan-3-yl]{2-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl}methanone, or a pharmaceutically acceptable salt thereof and 4-{7-[(1S,3S,4R)-5-( 2 H 2 )methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile, or a pharmaceutically acceptable salt thereof.
7 . A method for treating a tumor selected from MLL acute leukemia, MLL partial tandem duplicate acute leukemia, NPM mutated acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, chronic myeloid leukemia, B-cell lymphoma, or multiple myeloma, comprising administering a compound of claim 6 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
8 . The method of claim 7 , wherein the tumor is MLL acute leukemia, or NPM mutated acute leukemia.
9 . A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with at least one different agent or a pharmaceutically acceptable salt thereof, wherein the different agent is at least one agent selected from the group consisting of an antitumor alkylating agent, an antitumor antimetabolite, an antitumor antibiotic, a plant-derived antitumor medicament, an antitumor platinum complex compound, an antitumor camptothecin derivative, an antitumor tyrosine kinase inhibitor, an antitumor serine/threonine kinase inhibitor, an antitumor phospholipid kinase inhibitor, an antitumor monoclonal antibody, interferon, an biological response modifier, a hormone preparation, an angiogenic inhibitor, an immune checkpoint inhibitor, an epigenetics-associated molecular inhibitor, a protein post-translational modification inhibitor, a proteasome inhibitor, and other antitumor medicaments.
10 . A method of treating a subject with a tumor comprising administering to a subject with a tumor the compound of claim 1 , and at least one different agent or a pharmaceutically acceptable salt thereof, wherein the different agent is at least one agent selected from an antitumor alkylating agent, an antitumor antimetabolite, an antitumor antibiotic, a plant-derived antitumor medicament, an antitumor platinum complex compound, an antitumor camptothecin derivative, an antitumor tyrosine kinase inhibitor, an antitumor serine/threonine kinase inhibitor, an antitumor phospholipid kinase inhibitor, an antitumor monoclonal antibody, interferon, a biological response modifier, a hormone preparation, an angiogenic inhibitor, an immune checkpoint inhibitor, an epigenetics-associated molecular inhibitor, a protein post-translational modification inhibitor, a proteasome inhibitor, and other antitumor medicaments, wherein the tumor is acute leukemia (including MLL acute leukemia, MLL partial tandem duplicate acute leukemia, NPM mutated acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, liver cancer, hepatocellular cancer, colon cancer, rectal cancer, ovarian cancer, bladder cancer, renal cancer, renal cell cancer, prostate cancer, malignant melanoma, Ewing's sarcoma.