Pyrrolo-pyrimidine derivative compound, preparation method therefor, and pharmaceutical composition comprising same compound as effective ingredient for preventing or treating protein kinase-related disease

Patent metadata

Field	Value
Publication number	US-11208412-B2
Application number	US-201816488194-A
Country	US
Kind code	B2
Filing date	Feb 22, 2018
Priority date	Feb 22, 2017
Publication date	Dec 28, 2021
Grant date	Dec 28, 2021

Abstract

The present invention relates to a novel pyrrolo-pyrimidine derivative compound, a preparation method therefor, and a pharmaceutical composition comprising the same compound as an effective ingredient for preventing or treating a protein kinase-related disease. The compound represented by Chemical Formula 1 according to the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same as an effective ingredient has outstanding inhibitory activity against LRRK2 kinase and against phosphorylation in the NIH-3T3 cell line, which is an LRRK2-expressing cell line, and NCC01 and 448T cell lines, which are both derived from patients with brain tumors. Verified to have inhibitory activity against various protein kinases in addition to LRRK2, the compound can find effective applications in the treatment or prevention of protein kinase-related diseases.

First claim

What is claimed is:

1. A compound represented by formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,
X is —NH—;
Z is cyano (—CN); or straight or branched C1-C3 alkyl substituted with one or more halogens;
R 1 is straight or branched unsubstituted C1-C6 alkyl; C3-C6 cycloalkyl nonsubstituted or substituted with one or more straight or branched C1-C3 alkyls; or unsubstituted 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O; and

is

wherein, R 2 is one or more substituents selected from the group consisting of halogen and straight or branched C1-C3 alkoxy,
R 4 , R 6 , R 8 , R 11 , R 17 , and R 23 are independently one or more substituents selected from the group consisting of hydrogen, halogen, straight or branched C1-C3 alkyl and straight or branched C1-C3 alkoxy,
R 3 is methoxy,

R 5 , R 7 and R 9 are independently straight or branched C1-C3 alkyl; straight or branched C1-C3 alkoxy; straight or branched C1-C3 alkyl substituted with one or more substituents selected from the group consisting of hydroxy, straight or branched C1-C3 alkyl, straight or branched C1-C3 alkoxy, aminocarboxy group (—(C═O)NH 2 ) and —CN; 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O nonsubstituted or substituted with one or more substituents selected from the group consisting of halogen and 3-5 membered heterocycloalkyl containing one or more oxygen atoms; 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O nonsubstituted or substituted with one or more straight or branched C1-C3 alkyls; or —(C═O)NR 24 R 25 ,
wherein, R 24 and R 25 are independently hydrogen; 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O substituted with straight or branched C1-C3 alkyl or 3-5 membered heterocycloalkyl containing one or more oxygen atoms; or R 24 and R 25 form 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O along with nitrogen atom to which they are attached, wherein, the substituted heterocycloalkyl is substituted with one or more substituents selected from the group consisting of halogen; straight or branched C1-C3 alkyl; and 3-6 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O nonsubstituted or substituted with one or more straight or branched C1-C3 alkyls,
R 10 is —CR 26 R 27 —CN, wherein R 26 and R 27 are independently hydrogen, or straight or branched C1-3 alkyl,
R 12 , R 13 , R 14 , R 15 , R 18 , R 19 , R 20 , and R 21 are independently hydrogen, or straight or branched C1-3 alkyl, or two of R 12 , R 13 , R 14 , R 15 , R 18 , R 19 , R 20 , and R 21 bonded to the same carbon can form carbonyl along with the carbon to which they are attached, and
R 16 and R 22 are independently hydrogen, or straight or branched C1-3 alkyl, and wherein when Z is CF 3 , R 3 is not OCH 3 .

2. The compound, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein:
X is —NH—;
Z is —CN or methyl substituted with one or more halogens;
R 1 is straight or branched unsubstituted C1-C3 alkyl; C3-C5 cycloalkyl nonsubstituted or substituted with one or more methyls; or unsubstituted 5-6 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O; and

is

wherein, R 2 is one or more substituents selected from the group consisting of fluoro, chloro, bromo, methoxy and ethoxy,
R 4 , R 6 , R 8 , R 11 , R 17 , and R 23 are independently one or more substituents selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy and ethoxy,
R 5 , R 7 and R 9 are independently methyl; isopropyl; methoxy; straight or branched C1-C3 alkyl substituted with one or more substituents selected from the group consisting of hydroxy, methoxy, methyl, aminocarboxy group (—(C═O)NH 2 ) and —CN; piperidinyl substituted with one or more substituents selected from the group consisting of fluoro, chloro and oxetanyl; piperazinyl or morpholinyl nonsubstituted or substituted with one or more methyls; or —(C═O)NR 24 R 25 ,
wherein, R 24 and R 25 are independently hydrogen; piperidinyl substituted with methyl, isopropyl or oxetanyl; or R 24 and R 25 form nonsubstituted or substituted piperazinyl, morpholinyl or piperidinyl along with nitrogen atom to which they are attached, wherein, the substituted piperazinyl, morpholinyl or piperidinyl can be substituted with one or more substituents selected from the group consisting of fluoro, methyl, oxetanyl, piperazinyl and morpholinyl,
R 10 is —CR 26 R 27 —CN, wherein R 26 and R 27 are independently hydrogen, methyl or ethyl,
R 12 , R 13 , R 14 , R 15 , R 18 , R 19 , R 20 , and R 21 are independently hydrogen, methyl or ethyl, or two of R 12 , R 13 , R 14 , R 15 , R 18 , R 19 , R 20 , and R 21 bonded to the same carbon can form carbonyl along with the carbon to which they are attached, and
R 16 and R 22 are independently hydrogen, methyl or ethyl.

3. The compound, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein:
X is —NH—;
Z is —CN or —CF 3 ;
R 1 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 1-methylcyclopropyl, tetrahydropyranyl or tetrahydrofuranyl;

is

wherein, R 2 is one or more substituents selected from the group consisting of chloro, fluoro, bromo, and methoxy,
R 4 , R 6 , R 8 , R 11 , R 17 , and R 23 are independently one or more substituents selected from the group consisting of hydrogen, chloro, fluoro, bromo, methyl and methoxy;
R 7 is methoxy,

and
R 5 and R 9 are independently methyl, isopropyl,

R 10 is —CR 26 R 27 —CN, wherein R 26 and R 27 are independently hydrogen or methyl,
R 12 , R 13 , R 14 , R 15 , R 18 , R 19 , R 20 , and R 21 are independently hydrogen or methyl, or two of R 12 , R 13 , R 14 , R 15 , R 18 , R 19 , R 20 , and R 21 bonded to the same carbon can form carbonyl along with the carbon to which they are attached, and
R 16 and R 22 are independently hydrogen or methyl.

4. The compound, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to

Assignees

• Daegu Gyeongbuk Medical Innovation Found
• Nat Cancer Ct
• Samsung Life Public Welfare Foundation

Inventors

• Choi Hwan Geun
• Park Jong Bae
• Ko Eunhwa
• Son Jung Beom
• Cho Joong-Heui
• Ko Yi Kyung
• Park Jin-Hee
• Kim So Young
• Kang Seock Yong
• Lee Seungyeon
• Kim Nam Doo
• Lee Yunho
• Lee Sun-Hwa
• Kim Dayea
• Lee Sun Joo
• Bae Jae Hyun
• Hong Eunmi
• Jang Tae-Ho
• Kim Sang Bum
• Lee Seung Hoon
• Nam Do-Hyun

Classifications

• A23L33/10 Primary

  using additives (addition of substantially indigestible substances A23L33/21) · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A23V2002/00

  Food compositions, function of food ingredients or processes for food or foodstuffs · CPC title