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US 2021/0198283 A1Published application
Optically active bridged piperidine derivative
AssigneeSumitomo Dainippon Pharma Co., Ltd.
InventorsSeiji KAMIOKA, Naoaki SHIMADA, Hitoshi BAN, Kazuto YAMAZAKI, Akihiko ARAKAWA, Wataru HIROSE
Life of this patent
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Abstract
The present invention relates to the compound of formula (Ia) wherein a-d and p are 1 or 2, R1-R4 are hydrogen atom or the like, and R18 is —CF3 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.
Claims47
A compound of formula (1a):
- or a pharmaceutically acceptable salt thereof, wherein
- p is 1 or 2;
- a, b, c, and d are each independently 1 or 2;
- R1 and R2 are each independently hydrogen atom or -M-Q;
- or R1 and R2 may be combined together to form ═CR5AR6A;
- M is, each independently if there are plural, C1-6 alkylene which may be independently substituted with the same or different 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C2-4 alkynyl, C1-3 alkoxy, —CONR22AR23A, —NR22AR23A, —NR22ACOR21A, —NR22ASO2R21A, —SO2R21A, —SO2NR22AR23A, and cyano;
- Q is, each independently if there are plural, C3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C6-10 aryl, or 5- to 12-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be independently substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C1-3 alkyl, C2-4 alkynyl, C1-3 alkoxy, —CONR22CR23C, —NR22CR23C, —NR22CCOR21C, —NR22CSO2R21C, —SO2R21C, —SO2NR22CR23C, and cyano;
- R5A and R6A are each independently hydrogen atom, C1-6 alkyl, C3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C6-10 aryl, or 5- to 12-membered heteroaryl, wherein the alkyl may be each independently substituted with the same or different 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C2-4 alkynyl, C1-3 alkoxy, —CONR22ER23E, —NR22ER23E, —NR22ECOR21E, —NR22ESO2R21E, —SO2R21E, —SO2NR22ER23E, and cyano;
- the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C1-3 alkyl, C1-4 alkynyl, C1-3 alkoxy, —CONR22ER23E, —NR22ER23E, —NR22ECOR21E, —NR22ESO2R21E, —SO1R21E, —SO2NR22ER23E, and cyano, and if there are plural R5A or R6A, each R5A or R6A may be the same or different, or when R5A and R6A are both C1-6 alkyl, they may be combined with the carbon atom to which they are each attached to form 3- to 8-membered saturated carbocycle;
- R21A is, each independently if there are plural, C1-6 alkyl;
- R22A and R23A are each independently hydrogen atom or C1-6 alkyl, and if there are plural R22A or R23A, each R22A or R23A may be the same or different, or when R22A and R23A are both C1-6 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocycle;
- R21C is, each independently if there are plural, C1-6 alkyl;
- R22C and R23C are each independently hydrogen atom or C1-6 alkyl, and if there are plural R22C or R23C, each R22C or R23C may be the same or different, or when R22C and R23C are both C1-6 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocycle;
- R21E is, each independently if there are plural, C1-6 alkyl;
- R22E and R23E are each independently hydrogen atom or C1-6 alkyl, and if there are plural R22E or R23E, each R22E or R23E may be the same or different, or when R22E and R23E are both C1-6 alkyl, they may be combined with the nitrogen atom to which they are each attached to form 3- to 6-membered nitrogen-containing saturated heterocycle;
- R3 and R4 are each independently hydrogen atom, hydroxy, or fluorine atom, or R3 and R4 may be combined together to form ═O or ═CR5AR6A;
- R18 is —CF3 or cyano;
- provided that when both of R1 and R2 are hydrogen atom, then R3 and R4 are ═CR5AR6A.
15 more elements
2:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein a and c are 1, and b and d are 1 or 2.
4:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein a and c are 1, and b and d are 2.
5:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein M is, each independently if there are plural, C1-3 alkylene which may be independently substituted with the same or different 1 to 3 substituents selected from the group consisting of fluorine atom, C2-4 alkynyl, C1-3 alkoxy, —NR22AR23A, and cyano.
6:
- The compound of any claim 1 or a pharmaceutically acceptable salt thereof, wherein M is, each independently if there are plural, C1-3 alkylene.
7:
- The compound of any claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is, each independently if there are plural, C3-6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the phenyl, and the heteroaryl may be independently substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, C1-3 alkyl, C2-4 alkynyl, C1-3 alkoxy, —CONR22CR23C, —NR22CR23C, —NR22CCOR21C, —NR22CSO2R21C, —SO2R21C, —SO2NR22CR23C, and cyano.
8:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is, each independently if there are plural, C3-6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the phenyl, and the heteroaryl may be independently substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atom C1-3 alkyl, —NR22CSO2R21C, —SO2NR22CR23C, and cyano.
9:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is, each independently if there are plural, C3-6 cycloalkyl which may be independently substituted with the same or different 1 to 2 substituents selected from the group consisting of fluorine atom, C1-3 alkyl, —NR22CSO2R21C, —SO2NR22CR23C, and cyano.
10:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R5A and R6A are each independently hydrogen atom, C1-3 alkyl or C3-6 cycloalkyl, wherein the alkyl may be each independently substituted with the same or different 1 to 2 substituents selected from the group consisting of fluorine atom, —NR22ESO2R21E, —SO2NR22ER23E, and cyano;
- and the cycloalkyl may be each independently substituted with the same or different 1 to 2 substituents selected from the group consisting of fluorine atom, C1-3 alkyl, —NR22ESO2R21E, —SO2NR22R23, and cyano, and if there are plural R5A or R6A, each R5A or R6A may be the same or different, or when R5A and R6A are both C1-3 alkyl, they may be combined with the carbon atom to which they are each attached to form 3- to 6-membered saturated carbocycle.
11:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R5A and R6A are each independently hydrogen atom or C3-6 cycloalkyl which may be each independently substituted with the same or different 1 to 2 substituents selected from the group consisting of fluorine atom, C1-3 alkyl, —NR22ESO2R21E, —SO2NR22ER23E, and cyano, and if there are plural R5A or R6A, each R5A or R6A may be the same or different.
12:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein formula (1a) is the following formula (1b):
- wherein
- p is 1 or 2;
- R1 and R2 are each independently hydrogen atom or -M-Q;
- or R1 and R2 may be combined together to form ═CR5AR6A;
- M is, each independently if there are plural, C1-3 alkylene;
- Q is, each independently if there are plural, C3-6 cycloalkyl which may be independently substituted with the same or different 1 to 2 substituents selected from the group consisting of fluorine atom, C1-3 alkyl, —NR22CSO2R21C, —SO2NR22CR23C, and cyano;
- R5A and R6A are each independently hydrogen atom or C3-6 cycloalkyl which may be independently substituted with the same or different 1 to 2 substituents selected from the group consisting of fluorine atom, C1-3 alkyl, —NR22ESO2R21E, —SO2NR22ER23E, and cyano, and if there are plural R5A or R6A, each R5A or R6A may be the same or different;
- R21C is, each independently if there are plural, C1-6 alkyl;
- R22C and R23C are each independently hydrogen atom or C1-6 alkyl, and if there are plural R22C or R23C, each R22C or R23C may be the same or different, or when R22C and R23C are both C1-6 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 8-membered nitrogen-containing saturated heterocycle;
- R21E is, each independently if there are plural, C1-6 alkyl;
- R22E and R23E are each independently hydrogen atom or C1-6 alkyl, and if there are plural R22E or R23E, each R22E or R23E may be the same or different, or when R22E and R23E are both C1-6 alkyl, they may be combined with the nitrogen atom to which they are each attached to form 3- to 6-membered nitrogen-containing saturated heterocycle;
- R3 and R4 are each independently hydrogen atom or fluorine atom, or R3 and R4 may be combined together to form ═O or ═CR5AR6A;
- R18 is —CF3 or cyano;
- provided that when both of R1 and R2 are hydrogen atom, then R3 and R4 are ═CR5AR6A.
12 more elements
13:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein formula (1a) is the following formula (1c):
- wherein
- p is 1 or 2;
- R1 and R2 are each independently hydrogen atom or -M-Q;
- or R1 and R2 may be combined together to form ═CR5AR6A;
- M is, each independently if there are plural, C1-3 alkylene;
- Q is, each independently if there are plural, C3-6 cycloalkyl which may be independently substituted with the same or different 1 to 2 substituents selected from the group consisting of fluorine atom, C1-3 alkyl, —NR22CSO2R21C, —SO2NR22CR23C, and cyano;
- R5A and R6A are each independently hydrogen atom or C3-6 cycloalkyl which may be independently substituted with the same or different 1 to 2 substituents selected from the group consisting of fluorine atom, C1-3 alkyl, —NR22ESO2R21E, —SO2NR22ER23E, and cyano, and if there are plural R5A or R6A, each R5A or R6A may be the same or different;
- R21C is, each independently if there are plural, C1-6 alkyl;
- R22C and R23C are each independently hydrogen atom or C1-6 alkyl, and if there are plural R22C or R23C, each R22C or R23C may be the same or different, or when R22C and R23C are both C1-6 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 8-membered nitrogen-containing saturated heterocycle;
- R21E is, each independently if there are plural, C1-6 alkyl;
- R22E and R23E are each independently hydrogen atom or C1-6 alkyl, and if there are plural R22E or R23E, each R22E or R23E may be the same or different, or when R22E and R23E are both C1-6 alkyl, they may be combined with the nitrogen atom to which they are each attached to form 3- to 6-membered nitrogen-containing saturated heterocycle;
- R3 and R4 are each independently hydrogen atom or fluorine atom, or R3 and R4 may be combined together to form ═O or ═CR5AR6A;
- R18 is —CF3 or cyano;
- provided that when both of R1 and R2 are hydrogen atom, then R3 and R4 are ═CR5AR6A.
12 more elements
14:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently hydrogen atom or -M-Q.
15:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein M is methylene.
16 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is, each independently if there are plural, C3-6 cycloalkyl.
17:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R5A and R6A are each independently hydrogen atom or C3-6 cycloalkyl, and if there are plural R5A or R6A, each R5A or R6A may be the same or different.
18:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R5A and R6A are hydrogen atom.
19:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
- p is 1 or 2;
- R1 and R2 are each independently hydrogen atom or -M-Q;
- M is methylene;
- Q is, each independently if there are plural, C3-6 cycloalkyl;
- R3 and R4 are each independently hydrogen atom or fluorine atom, or R3 and R4 may be combined together to form ═CH2;
- R18 is —CF3 or cyano;
- provided that when both of IV and R2 are hydrogen atom, then R3 and R4 are ═CH2.
5 more elements
20:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
- R1 is hydrogen atom,
- R2 is -M-Q,
- M is methylene,
- Q is C3-6 cycloalkyl,
- R3 is hydrogen atom,
- R4 is hydrogen atom or fluorine atom, and
- R18 is —CF3 or cyano.
5 more elements
21:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
- R1 is -M-Q,
- R2 is hydrogen atom,
- M is methylene,
- Q is C3-6 cycloalkyl,
- R3 is hydrogen atom or fluorine atom,
- R4 is hydrogen atom, and
- R18 is —CF3 or cyano.
5 more elements
22:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
- R1 and R2 are hydrogen atom,
- R3 and R4 are combined together to form ═CH2, and
- R18 is —CF3 or cyano.
1 more element
23:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein p is 1.
24:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein p is 2.
25:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from:
- [(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
- 4-{6-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbony]-2,6-diazaspiro[3.3]heptan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
- [(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
- 4-{6-[(1S,3S,4R,6R)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbony]-2,6-diazaspiro[3.3]heptan-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]{6-[2-(2,2,2-Trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
- 4-{6-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbony]-2,6-diazaspiro[3.3]heptan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
- [(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
- 4-{6-[(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbony]-2,6-diazaspiro[3.3]heptan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
- [(1S,3S,4S,5S,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
- 4-{6-[(1S,3S,4S,5S,6S)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbony]-2,6-diazaspiro[3.3]heptan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
- [(1S,3S,4R)-5-(2H2)methylidene-2-azabicyclo[2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5- (trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
- [(1S,3S,4R)-5-(2H2)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,
- [(1S,3S,4R,6S)-6-(cyclopropylmethyl)-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,
- [(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptan-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-(2H2)methylidene-2-azabicyclo[2.2.2]octane-3-carbony]-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,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbony]-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-carbony]-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-carbony]-2,7-diazaspiro[3.5]nonan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile.
17 more elements
26:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from:
- [(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
- [(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
- 4-{6-[(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbony]-2,6-diazaspiro[3.3]heptan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
- [(1S,3S,4R)-5-(2H2)methylidene-2-azabicyclo[2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
- [(1S,3S,4R)-5-(2H2)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,
- [(1S,3S,4R,6S)-6-(cyclopropylmethyl)-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,
- [(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptan-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-(2H2)methylidene-2-azabicyclo[2.2.2]octane-3-carbony]-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,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbony]-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-carbony]-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-carbony]-2,7-diazaspiro[3.5]nonan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile.
10 more elements
27:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from:
- [(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
- [(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octan-3-yl]{6-[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)thieno[2,3-b]pyridin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}methanone,
- 4-{6-[(1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbony]-2,6-diazaspiro[3.3]heptan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile,
- [(1S,3S,4R,6S)-6-(cyclopropylmethyl)-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,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbony]-2,7-diazaspiro[3.5]nonan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile.
3 more elements
28:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from:
- [(1S,3S,4R)-5-(2H2)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-(2H2)methylidene-2-azabicyclo[2.2.2]octane-3-carbony]-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-carbony]-2,7-diazaspiro[3.5]nonan-2-yl}-2-(2,2,2-trifluoroethyl)thieno[2,3-b]pyridine-5-carbonitrile.
2 more elements
(canceled)
30:
- A method for treating a tumor comprising administering the compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
31:
- The method of claim 30, 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, cancer of the head and neck, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, gallbladder and bile duct cancer, liver cancer, hepatocellular cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer, chorionepithelioma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, renal cancer, renal cell cancer, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.
32:
- The method of claim 30, 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 myeloid leukemia, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, prostate cancer, breast cancer, neuroblastoma, Ewing's sarcoma, or liver cancer.
33:
- The method of claim 30, wherein the tumor is 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, multiple myeloma, neuroblastoma, or prostate cancer.
34:
- The method of claim 30, wherein the tumor is 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.
35:
- The method of claim 30, wherein the tumor is MLL acute leukemia, or NPM mutated acute leukemia.
36:
- The method of claim 30, wherein the tumor is accompanied by high expression of HOXa gene cluster, or MEIS gene cluster.
37:
- The method of claim 30, wherein the tumor is accompanied by p53 gain-of-function mutation.
(canceled)
39:
- The method of claim 30, wherein the tumor is involved in menin-MLL.
(canceled)
(canceled)
42:
- 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.
43:
- The compound of claim 1 or a pharmaceutically acceptable salt thereof for treating a tumor, which is used 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 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.
44:
- The compound of claim 1 where the compound is [(1S,3S,4R)-5-(2H2)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.
45:
- The compound of claim 1 where the compound is 4-{7-[(1S,3S,4R)-5-(2H2)methylidene-2-azabicyclo[2.2.2]octane-3-carbony]-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.
46:
- 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.
47:
- The compound of claim 1 where the compound is 4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbony]-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.
Dependencies are inferred from the claim text.