JP2017048214A5

JP2017048214A5 -

Info

Publication number: JP2017048214A5
Application number: JP2016211244A
Authority: JP
Filing date: 2016-10-28
Publication date: 2017-08-31
Anticipated expiration: 2031-12-31

Claims

Cancer, cytotoxic cancer, ischemia reperfusion injury, reperfusion, inflammatory disease, immune disease or disorder, degeneration, comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof Pharmaceuticals for the treatment of disease, hypoglycemia, retroviral infection, hepatotoxicity after acetaminophen overdose, cardiac and nephrotoxicity with doxorubicin and platinum-based antineoplastic agents, or skin damage secondary to sulfa mustard Composition :

Where
R _N is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is at least one substituted Optionally independently substituted by the group R ¹² ;
X is selected from the group consisting of C, N, O, and S;
m and n may be the same or different and are each an integer of 0, 1, 2, or 3;
t is an integer of 0, 1, 2, or 3;
R ¹ is in each case halogen, CN, NO ₂ , OR ⁹ , NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COOR ⁹ , SO ₂ R ⁹ , alkyl , Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is at least one substituent R ¹² May be independently substituted;
R ² is selected from hydrogen, COR ⁹ , CONR ⁹ R ¹⁰ , CO ₂ R ⁹ , SO ₂ R ⁹ , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl Each of, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be independently substituted with at least one substituent R ¹² ;
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ may be the same or different and are each hydrogen, halogen, -NR ⁹ R ¹⁰ , -OR ⁹ , oxo, -COR ⁹ ,- CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹¹ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ R ⁹ , alkyl, alkenyl, cycloalkyl, aryl, Independently selected from heterocyclyl, alkynyl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl may be independently substituted with at least one substituent R ¹² ,
Or (R ³ and R ⁴ ), and / or (R ⁴ and R ⁵ ), and / or (R ⁵ and R ⁶ ), and / or (R ⁶ and R ⁷ ), and / or (R ⁷ and R ⁸ ) is 0, 1 or 2 hetero, independently selected from —NR ¹³ —, —O—, —S—, —SO— or —SO ₂ —, together with the atoms to which they are attached. Forms a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having atoms, and the ring may be substituted with at least one substituent R ¹² ;
However,
When X is O, R ⁵ and R ⁶ are not present,
When X is N, R ⁶ is not present,
When X is S, R ⁵ and R ⁶ are absent or at least one of R ⁵ and R ⁶ is oxo;
When one of R ³ and R ⁴ is oxo, the other is absent,
If one of R ⁷ and R ⁸ is oxo, the other is absent and
When X is C and one of R ⁵ and R ⁶ is oxo, the other is absent;
R ⁹ , R ¹⁰ , and R ¹¹ may be the same or different and are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl Each of, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be independently substituted with at least one substituent R ¹² ;
R ¹² is CN, halogen, haloalkyl, NO ₂ , -NR'R '', -OR ', oxo, -COR', -CO ₂ R ', -CONR'R'',-NR'CONR''R' ``, -NR'CO ₂ R '', -NR'SO ₂ R '', -SO ₂ R ', selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where R ', R'', and R''' are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or (R 'and R'') and / or (R''andR'''), together with the atoms to which they are ^{attached, -NR 13 -, - O -} , - S -, - SO- and -SO ₂ - from Forming a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 additional heteroatoms independently selected;
R ¹³ is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
Of these, cycloalkyl is a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, including monocyclic, bicyclic, and tricyclic groups, having 3 to 12 carbon atoms. Including;
Among them, heteroaryl is a group selected from the following:
A 5- to 7-membered aromatic monocyclic ring containing at least one heteroatom selected from N, O, and S, the remaining ring atoms being carbon,
An 8- to 12-membered bicyclic ring comprising at least one heteroatom selected from N, O, and S, the remaining ring atoms being carbon, wherein at least one ring is aromatic; And a ring having at least one heteroatom in the aromatic ring, and
An 11 to 14 membered tricyclic ring comprising at least one heteroatom selected from N, O and S, the remaining ring atoms being carbon, wherein at least one ring is aromatic; And a ring having at least one heteroatom in the aromatic ring; and
Wherein heterocyclyl is a 4- to 12-membered monocyclic, bicyclic, and tricyclic containing at least one carbon atom in addition to at least one heteroatom selected from oxygen, sulfur, and nitrogen, A ring selected from saturated and partially unsaturated rings .

The compound is a compound of Formula (II), its stereoisomers, or a pharmaceutically acceptable salt, pharmaceutical composition according to claim 1:

Where
R _N is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is at least one substituted Optionally independently substituted by the group R ¹² ;
m and n may be the same or different and are each an integer of 0, 1, 2, or 3;
t is an integer of 0, 1, 2, or 3;
R ¹ is in each case halogen, CN, NO ₂ , OR ⁹ , NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COOR ⁹ , SO ₂ R ⁹ , alkyl , Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is at least one substituent R ¹² May be independently substituted;
R ² is selected from hydrogen, COR ⁹ , CONR ⁹ R ¹⁰ , CO ₂ R ⁹ , SO ₂ R ⁹ , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl Each of, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be independently substituted with at least one substituent R ¹² ;
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ may be the same or different and are each hydrogen, halogen, -NR ⁹ R ¹⁰ , -OR ⁹ , oxo, -COR ⁹ ,- CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹¹ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ R ⁹ , alkyl, alkenyl, cycloalkyl, aryl, Independently selected from heterocyclyl, alkynyl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl may be independently substituted with at least one substituent R ¹² Or (R ³ and R ⁴ ), and / or (R ⁴ and R ⁵ ), and / or (R ⁵ and R ⁶ ), and / or (R ⁶ and R ⁷ ), and / or (R ⁷ and R ⁸ ), together with the atoms to which they are attached, —NR ¹³ —, —O Forming a 3- to 8-membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 heteroatoms independently selected from-, -S-, -SO- and -SO _2- ; And the ring may be substituted with at least one substituent R ¹² provided that
When one of R ³ and R ⁴ is oxo, the other is absent,
If one of R ⁷ and R ⁸ is oxo, the other is absent and
When one of R ⁵ and R ⁶ is oxo, the other is absent;
R ⁹ , R ¹⁰ , and R ¹¹ may be the same or different and are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl Each of, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be independently substituted with at least one substituent R ¹² ;
R ¹² is CN, halogen, haloalkyl, NO ₂ , -NR'R '', -OR ', oxo, -COR', -CO ₂ R ', -CONR'R'',-NR'CONR''R' ``, -NR'CO ₂ R '', -NR'SO ₂ R '', -SO ₂ R ', selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where R ', R'', and R''' are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or (R 'and R'') and / or (R''andR'''), together with the atoms to which they are ^{attached, -NR 13 -, - O -} , - S -, - SO- or -SO ₂ - from Forming a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 additional heteroatoms independently selected;
R ¹³ is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

The compound is a compound of formula (III), its stereoisomers, or a pharmaceutically acceptable salt, pharmaceutical composition according to claim 1:

Where
R _N is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is at least one substituted Optionally independently substituted by the group R ¹² ;
m and n may be the same or different and are each an integer of 0, 1, 2, or 3;
t is an integer of 0, 1, 2, or 3;
R ¹ is in each case halogen, CN, NO ₂ , OR ⁹ , NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COOR ⁹ , SO ₂ R ⁹ , alkyl , Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is at least one substituent R ¹² May be independently substituted;
R ² is selected from hydrogen, COR ⁹ , CONR ⁹ R ¹⁰ , CO ₂ R ⁹ , SO ₂ R ⁹ , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl Each of, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be independently substituted with at least one substituent R ¹² ;
R ³ , R ⁴ , R ⁵ , R ⁷ and R ⁸ may be the same or different and are each hydrogen, halogen, —NR ⁹ R ¹⁰ , —OR ⁹ , oxo, —COR ⁹ , —CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹¹ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ R ⁹ , alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl And independently selected from heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl may be independently substituted with at least one substituent R ¹² , or ( R ³ and R ⁴ ), and / or (R ⁴ and R ⁵ ), and / or (R ⁵ and R ⁷ ), and / or (R ⁷ and R ⁸ ), together with the atom to which they are attached ^{a, -NR 13 -, - O -} , - S -, - SO- and -SO ₂ - independently selected of from Form a 3- to 8-membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 heteroatoms, and the ring may be substituted with at least one substituent R ¹² ;
However,
If one of R ³ and R ⁴ is oxo, the other is not present and
When one of R ⁷ and R ⁸ is oxo, the other is absent;
R ⁹ , R ¹⁰ , and R ¹¹ may be the same or different and are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl Each of, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be independently substituted with at least one substituent R ¹² ;
R ¹² is CN, halogen, haloalkyl, NO ₂ , -NR'R '', -OR ', oxo, -COR', -CO ₂ R ', -CONR'R'',-NR'CONR''R' ``, -NR'CO ₂ R '', -NR'SO ₂ R '', -SO ₂ R ', selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where R ', R'', and R''' are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or (R 'and R'') and / or (R''andR'''), together with the atoms to which they are ^{attached, -NR 13 -, - O -} , - S -, - SO- or -SO ₂ - from Forming a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having independently selected 0, 1 or 2 additional heteroatoms; and
R ¹³ is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

4. A pharmaceutical composition according to claim 3, wherein m and n are both integers of one.

t is 0, or t is 1 and R ¹¹ 4. The pharmaceutical composition according to claim 3, wherein is halogen.

R _NN 4. The pharmaceutical composition according to claim 3, wherein is hydrogen.

R ^２2 4. The pharmaceutical composition according to claim 3, wherein is hydrogen or alkyl.

R ^3Three , R ^4Four , R ^5Five , R ⁶⁶ , R ⁷⁷ And R ⁸⁸ May be the same or different, hydrogen, -OR respectively ⁹⁹ , -COR ⁹⁹ , -CO ₂₂ R ⁹⁹ 4. A pharmaceutical composition according to claim 3, independently selected from: alkyl, cycloalkyl, or aryl.

R ^4Four And R ^5Five Together with the atom to which they are attached, ¹³¹³ -, -O-, -S-, -SO- or -SO ₂₂ Form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 heteroatoms independently selected from- The pharmaceutical composition according to claim 3.

R ^４4 And R ^５5 Together with the atom to which they are attached, ¹³¹³ -, -O-, -S-, -SO- or -SO ₂₂ The pharmaceutical composition according to claim 3, which forms a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered saturated ring having 0 heteroatoms independently selected from-.

The above compounds are the following compounds

Or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof .

The pharmaceutical composition according to claim 1, wherein the cancer is selected from the group consisting of leukemia, colon cancer, glioblastoma, lymphoma, melanoma, breast cancer, and cervical cancer.