JPWO2020100027A5

JPWO2020100027A5 -

Info

Publication number: JPWO2020100027A5
Application number: JP2021525702A
Authority: JP
Publication date: 2022-05-24
Anticipated expiration: 2039-11-12

Claims

Compound of formula I

Or its pharmaceutically acceptable salt [in the formula,
R ¹ is hydrogen, halogen, (C ₁ to C ₆ ) alkyl, halo (C ₁ to C ₆ ) alkyl, (C ₁ to C ₆ ) alkoxy, halo (C ₁ to C ₆ ) alkoxy, -N (R). ⁶ ) Selected from the group consisting of (R ⁷ ) and (C ₃ to C ₆ ) cycloalkyl, said (C ₁ to C ₆ ) alkyl, halo (C ₁ to C ₆ ) alkyl and (C ₃ to C ₆ ). The cycloalkyl may be substituted with 1 to 3 substituents selected from the group consisting of halogens, hydroxys, cyanos, (C ₁ -C ₆ ) alkyls and (C ₁ -C ₆ ) alkoxys.
R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen and (C ₁ to C ₆ ) alkyl, respectively, where the (C ₁ to C ₆ ) alkyl is halogen, (C ₁ to C ₆ ) alkoxy, respectively. It may be substituted with 1 to 3 substituents selected from the group consisting of cyano and hydroxy, or R ⁶ and R ⁷ together with the nitrogen to which they are attached are halogens, (C ₁ ). Substituent with 1 to 3 substituents selected from the group consisting of ~ C ₆ ) alkyl, halo (C ₁ ~ C ₆ ) alkyl, (C ₁ ~ C ₆ ) alkoxy and halo (C ₁ ~ C ₆ ) alkoxy. The (4 to 8 member) heterocycloalkyl may be formed, and the (C ₁ to C ₆ ) alkyl and the halo (C ₁ to C ₆ ) alkyl may be halogen, hydroxy, cyano, (C ₁ to C 1 to). It may be substituted with 1 to 3 substituents selected from the group consisting of C ₆ ) alkyl and (C ₁ to C ₆ ) alkoxy.
R ^1a is selected from the group consisting of hydrogen and halogen.
R ² is
i)-(CH ₂ ) _m N (R ⁸ ) (R ⁹ ), where m is an integer selected from 0, 1, 2 or 3, where R ⁸ and R ⁹ are hydrogen and (C). ₁ to C ₆ ) Independently selected from the group consisting of alkyl, the (C ₁ to C ₆ ) alkyl is selected from the group consisting of halogen, (C ₁ to C ₆ ) alkoxy, cyano and hydroxy 1 _May be substituted with 3 substituents from, or R ⁸ and R ⁹ together with the nitrogen to which they are attached are halogen, hydroxy, (C _1-6 ) alkyl, halo (C). It may be substituted with 1 to 3 substituents selected from the group consisting of ₁ to C ₆ ) alkyl, (C ₁ to C ₆ ) alkoxy and halo (C ₁ to C ₆ ) alkoxy. The (member) heterocycloalkyl is formed, and the (C ₁ to C ₆ ) alkyl and the halo (C ₁ to C ₆ ) alkyl are selected from the group consisting of halogen, hydroxy, cyano and (C ₁ to C ₆ ) alkoxy. May be substituted with 1 to 3 substituents.
ii) (C ₁ to C ₆ ) alkyl, said (C ₁ to C ₆ ) alkyl is a group consisting of halogen, (C ₁ to C ₆ ) alkoxy, -N (R ⁶ ) (R ⁷ ), cyano and hydroxy. May be substituted with 1 to 3 substituents selected from, where R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen and (C ₁ to C ₆ ) alkyl, respectively. , Or iii) (4 to 6 members) heterocycloalkyl, said heterocycloalkyl is halogen, hydroxy, cyano, (C ₁ to C ₆ ) alkyl, halo (C ₁ to C ₆ ) alkyl, (C ₁ to C 1 to). It may be substituted with 1 to 3 substituents selected from the group consisting of C ₆ ) alkoxy and halo (C ₁ to C ₆ ) alkoxy, as described above (C ₁ to C ₆ ) alkyl and halo (C ₁ ). ~ C ₆ ) Alkyl may be substituted with ₁ to 3 substituents selected from the group consisting of halogens, hydroxys, cyanos and (C1 ~ C6) _alkoxys .
R ³ is a group consisting of hydrogen, halogen, hydroxy, (C ₁ to C ₆ ) alkyl, halo (C ₁ to C ₆ ) alkyl, (C ₁ to C ₆ ) alkoxy and halo (C ₁ to C ₆ ) alkoxy. Selected from
X is carbon or nitrogen,
^R4 is a (4 to 6 member) heterocycloalkyl or (5 to 10 member) heterocycloalkyl and the (4 to 6 member) heterocycloalkyl and (5 to 10 member) heteroaryl are Halogen, cyano, oxo, hydroxy, -N (R ¹⁰ ) (R ¹¹ ), (C ₁ to C ₆ ) alkyl, halo (C ₁ to C ₆ ) alkyl, (C ₁ to C ₆ ) alkoxy, halo (C) It may be substituted with 1 to 3 substituents selected from the group consisting of ₁ to C ₆ ) alkoxy and-(CH ₂ ) _n (C ₃ to C ₆ ) cycloalkyl, as described above (C ₁ to C). ₆ ) Alkyl and halo (C ₁ to C ₆ ) alkyl may be substituted with 1 to 3 substituents selected from the group consisting of halogens, hydroxys, cyanos and (C ₁ to C ₆ ) alkoxys. , N are integers selected from 0, 1 or 2, and R ¹⁰ and R ¹¹ are independently selected from the group consisting of hydrogen and (C ₁ to C ₆ ) alkyl, respectively, as described above (C ₁ to C 6). C ₆ ) Alkyl may be substituted with 1 to 3 substituents selected from the group consisting of halogens and hydroxys.
R ⁵ is a group consisting of hydrogen, halogen, hydroxy, (C ₁ to C ₆ ) alkyl, halo (C ₁ to C ₆ ) alkyl, (C ₁ to C ₆ ) alkoxy and halo (C ₁ to C ₆ ) alkoxy. Selected from
a is an integer selected from 0 or 1, where a is 0 if X is nitrogen].

R ¹ is -N (R ⁶ ) (R ⁷ ), and R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen and (C ₁ to C ₆ ) alkyl, respectively, as described above (C ₁ to C 6). C ₆ ) The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the alkyl may be substituted with 1 to 3 halogens.

R ¹ is -N (R ⁶ ) (R ⁷ ), and R ⁶ and R ⁷ together with the nitrogen to which they are bound are halogen, (C ₁ to C ₆ ) alkyl, halo (C ₁ ). It may be substituted with 1 to 3 substituents selected from the group consisting of ~ C ₆ ) alkyl, (C ₁ ~ C ₆ ) alkoxy and halo (C ₁ ~ C ₆ ) alkoxy (4 to 8 members). The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which forms a heterocycloalkyl.

^R1 is a (4-8 member) heterocycloalkyl selected from the group consisting of azetidinyl, pyrrolidinyl and azabicyclo [2.2.1] heptyl, said azetidinyl, pyrrolidinyl and azabicyclo [2.2.1]. Heptyl is selected from the group consisting of halogen, (C ₁ to C ₆ ) alkyl, halo (C ₁ to C ₆ ) alkyl, (C ₁ to C ₆ ) alkoxy and halo (C ₁ to C ₆ ) alkoxy 1 The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, which may be substituted with 3 substituents from the above.

R ¹ is selected from the group consisting of halogens, (C ₁ to C ₆ ) alkyl, halo (C ₁ to C ₆ ) alkyl, (C ₁ to C ₆ ) alkoxy and halo (C ₁ to C ₆ ) alkoxy. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, which is pyrrolidinyl which may be substituted with 1 to 3 substituents.

Claim 1 where R ² is − (CH ₂ ) _m N (R ⁸ ) (R ⁹ ), m is 1, one of R ⁸ and R ⁹ is hydrogen and the other is methyl. 5. The compound according to any one of 5 or a pharmaceutically acceptable salt thereof.

One of claims 1 to 5 , wherein R ² is − (CH ₂ ) _m N (R ⁸ ) (R ⁹ ), m is 1, and R ⁸ and R ⁹ are both hydrogen. The compound according to paragraph 1, or a pharmaceutically acceptable salt thereof.

The compound according to any one of claims 1 to 7 , wherein R ³ is hydrogen, or a pharmaceutically acceptable salt thereof.

R ⁴ is halogen, cyano, hydroxy, -N (R ¹⁰ ) (R ¹¹ ), (C ₁ to C ₆ ) alkyl, halo (C ₁ to C ₆ ) alkyl, (C ₁ to C ₆ ) alkoxy, halo. It may be substituted with 1 to 3 substituents selected from the group consisting of (C ₁ to C ₆ ) alkoxy and-(CH ₂ ) _n (C ₃ to C ₆ ) cycloalkyl (5 to 6 members). ) Heteroaryl, where n is an integer selected from 0, 1 or 2, and R ¹⁰ and R ¹¹ are independently selected from the group consisting of hydrogen and (C ₁ to C ₆ ) alkyl, respectively. , The said (C ₁ to C ₆ ) alkyl may be substituted with 1 to 3 substituents selected from the group consisting of halogens and hydroxys, according to any one of claims 1-8 . A compound, or a pharmaceutically acceptable salt thereof.

The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein the heteroaryl (5 to 6 members) is 1,2,3-triazolyl, 1,2,4-triazolyl or pyrazolyl.

The compound according to any one of claims 1 to 10 , wherein X is carbon, a is ¹ , and R5 is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.

R ^１ａ1a Is hydrogen, R ^３3 Is hydrogen, a is 1, X is carbon, and R ^５5 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

4-[(Methylamino) Methyl] -6- [Methyl (Propane-2-yl) Amino] -2- [6- (4-propyl-4H-1,2,4-Triazole-3-yl) Pyridine- 2-yl] -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one;
4-[(Methylamino) Methyl] -6-[(2R) -2-Methylpyrrolidine-1-yl] -2- [6- (4-propyl-4H-1,2,4-triazole-3-yl] ) Pyridine-2-yl] -2,3-dihydro-1H-pyrrolo [3,4-c] Pyridine-1-one;
4-[(Methylamino) Methyl] -2- [6- (5-Methyl-4-propyl-4H-1,2,4-Triazole-3-yl) Pyridine-2-yl] -6-[(2R) ) -2-Methylpyrrolidin-1-yl] -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one;
4-[(Methylamino) Methyl] -6- [Methyl (Propane-2-yl) Amino] -2- [6- (5-Methyl-4-propyl-4H-1,2,4-Triazole-3-) Il) Pyridine-2-yl] -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one; and 4- (aminomethyl) -2- [6- (4-ethyl-5) -Methyl-4H-1,2,4-triazole-3-yl) Pyridine-2-yl] -6-[(2S) -2-Methylpyrrolidine-1-yl] -2,3-dihydro-1H-pyrrolo [3,4-c] The compound according to claim 1 selected from the group consisting of pyridine-1-one, or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.

The pharmaceutical composition of claim 14, for use in the treatment of abnormal cell growth in a subject in need thereof.

The pharmaceutical composition according to claim 15, wherein the cell growth is abnormal.

The pharmaceutical composition according to any one of claims 14 to 16, for use in combination with an additional anti-cancer therapeutic agent or pain-relieving agent.