7-azaindole or 4,7-diazaindole derivatives as IKKϵ epsilon and TBK1 inhibitor and pharmaceutical composition comprising same

Patent metadata

Field	Value
Publication number	US-10239873-B2
Application number	US-201615080068-A
Country	US
Kind code	B2
Filing date	Mar 24, 2016
Priority date	Apr 3, 2015
Publication date	Mar 26, 2019
Grant date	Mar 26, 2019

Abstract

Provided are 7-azaindole or 4,7-diazaindole derivatives as an IKKε (I-kappa-B kinase epsilon) and TBK1 (TANK-binding kinase 1) inhibitor. The 7-azaindole or 4,7-diazaindole derivative effectively inhibits IKKε and TBK1, and thus is useful not only as an anticancer agent for the treatment of various cancers including colorectal cancer, breast cancer, CNS cancer, colon cancer, non-small cell lung cancer, kidney cancer, prostate cancer, ovarian cancer, uterus cancer, stomach cancer, liver cancer, skin cancer, lung cancer, brain cancer, bladder cancer, esophageal cancer, pancreatic cancer, thyroid cancer, head and neck cancer, squamous cell carcinoma, osteosarcoma, B-cell or T-cell lymphoma, acute or chronic leukemia and multiple myeloma, but as a therapeutic agent for chronic inflammation.

First claim

What is claimed is:

1. A compound selected from the group consisting of a 7-azaindole or 4,7-diazaindole compound of formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof, and a solvate thereof:

wherein,
X is C or N,
ring A is unsaturated 5-membered heterocycle containing at least one N, or saturated or unsaturated 6- or 7-membered heterocycle containing at least one N;
R 1 is halogen, substituted or unsubstituted C 5-14 aryl, substituted or unsubstituted 5- to 13-membered heteroaryl, or -NHY wherein Y is substituted or unsubstituted C 5-14 aryl, wherein when said C 5-14 aryl or 5- to 13-membered heteroaryl is substituted, the substituent is one or more substituents selected from the group consisting of 5- to 10-membered heterocycloalkyl-C 1-7 alkyl, C 1-7 alkoxy, halogen, C 1-7 alkyl, C 1-7 alkylamido, C 1-7 alkyl-5- to 10-membered heterocycloalkyl-C 1-7 alkyl, C 3-10 cycloalkyl-5- to 10-membered heterocycloalkyl-C 1-7 alkyl, 5- to 10-membered heterocycloalkyl-C 1-7 alkyl, C 1-7 alkyl-5- to 10-membered heterocycloalkyl-carbonyl, 5- to 10-membered heterocycloalkyl-amino, 5- to 10-membered heterocycloalkyl-oxy, C 1-7 alkyl-sulfonyl, C 3-10 cycloalkyl-sulfonyl, sulfamoyl, C 1-7 alkyl-sulfamoyl, 5- to 10-membered heterocycloalkyl-sulfonyl, amino, oxo, 5- to 13-membered heteroaryl-C 1-7 alkyl-carbamoyl, 5- to 10-membered heterocycloalkyl-C 1-7 alkoxy, 5- to 10-membered heterocycloalkyl-carbonyl, C 1-7 alkoxy-carbonyl-5- to 10-membered heterocycloalkyl-C 1-7 alkyl, 5- to 10-membered heterocycloalkyl, C 1-7 alkyl-carbonyl, C 1-7 alkoxy-carbonyl, cyano, C 1-7 alkyl-5- to 13-membered heteroaryl, di C 1-7 alkyl-sulfonyl, and C 1-7 alkyl-amino-sulfonyl;
R 2 is H or —NH 2 ;
R 3 is H or C 1-7 alkyl;
R 4 is C 1-7 alkyl, —C(═O)—R 7 , —C(═O)—O—R 8 , —C(═O)—N(—R 9 )—R 10 , —CH 2 —C(═O)—NH—R 11 or —CH 2 —C(═O)—R 12 ; R 7 to R 12 are each independently H, hydroxy, C 1-7 alkyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted 5- to 10-membered heterocycloalkyl or substituted or unsubstituted 5- to 13-membered heteroaryl; and each of said cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with C 1-7 alkyl; and
R 5 and R 6 are each independently H, halogen, C 1-7 alkyl or substituted or unsubstituted C 5-14 aryl; when said R 5 and R 6 are C 1-7 alkyl, said R 5 and R 6 are optionally connected to each other.

2. The compound of claim 1 , wherein the ring A is a heterocycle ring selected from the group consisting of:

R 4 is substituted at N position; and
each of R 5 and R 6 is substituted at other positions.

3. The compound of claim 1 , wherein R 1 is halogen, substituted or unsubstituted phenyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted isoindolinonyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted furanyl, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted indazolyl or substituted or unsubstituted oxoisoindolinyl.

4. The compound of claim 3 , wherein the phenyl, thiophenyl, isoindolinonyl, pyridinyl, furanyl, benzodioxolyl, thiadiazolyl, indazolyl or oxoisoindolinyl is substituted with one or more substituents selected from the group consisting of fluoro, chloro, amino, tetrahydro-2H-pyran-amino, cyano, acetyl, acetamido, methylsulfonamido, methyl, morpholinomethyl, piperazinylmethyl, methylpiperazinylmethyl, ethylpiperazinylmethyl, pyrrolidinylmethyl, cyclopropylpiperazinylmethyl, tertbutyloxycarbonylpiperazinylmethyl, morpholinoethyl, methoxy, propoxy, morpholinoethoxy, morpholinopropoxy, tetrahydro-2H -pyran-oxy, methylpiperazinylcarbonyl, methoxycarbonyl, morpholinocarbonyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, morpholinosulfonyl, sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, furanylmethylcarbamoyl, morpholino, piperidine, and sulfonamido.

5. The compound of claim 1 , wherein R 4 is methyl, ethyl, propyl, isobutyl, —C(═O)—R 7 , —C(═O)—O—R 8 , —C(═O)—N(—R 9 )—R 10 , —CH 2 —C(═O)—NH—R 11 or —CH 2 —C(═O)—R 12 ; said R 7 to R 12 are each independently H, hydroxy, methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopropyl, isopentyl, isohexyl, tert-butyl, pentan-3-yl, sec-butyl, cyclopropyl, cyclopentyl, cyclohexyl, oxetan-3-yl, tetrahydrofuran-3-yl, pyrrolidin-1-yl, cyclobutyl, thiophen-2-yl or 5-methylthiophen-2-yl.

6. A compound selected from the group consisting of:
(1) 4-((5-(3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2-yl)methyl)morpholine;
(2) 5-(3,4-dimethoxyphenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)- 1H-pyrrolo[2,3-b]pyridine;
(3) 5-(3,4-dimethoxyphenyl)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1 H-pyrrolo[2,3 -b]pyridine;
(4) 5-(3,4-dimethoxyphenyl)-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine;
(5) 5-(3,4-dimethoxyphenyl)-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine;
(6) 4-((5-(3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2-yl)methyl)morpholine;
(7) 4-((5-(3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2-yl)methyl)morpholine;
(8) 1-(4-(5-(5-(morpholinomethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one;
(9) 1-(4-(5-(5-(morpholinomethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridin-1(2H)-yl)pentan-1-one;
(10) 3-methyl-1-(4-(5-(5-(morpholinomethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridin-1(2H)-yl)butan-1-one;
(11) N-isopropyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxamide;
(12) N-isopropyl-4-(5-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxamide;
(13) 4-(5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-isopropyl-3,6-dihydropyridine-1(2H)-carboxamide;
(14) N-isopropyl-4-(5-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxamide;
(15) 4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-isopropyl-3,6-dihydropyridine-1(2H)-carboxamide;
(16) N-isopropyl-4-(5-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxamide;
(17) 4-(5-(4-acetamidophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-isopropyl-3,6-dihydropyridine-1(2H)-carboxamide;
(18) 4-(5-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-isopropyl-5,6-dihydropyridine-1(2H)-carboxamide;
(19) 4-(5-(3-acetamidophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-isopropyl-3,6-dihydropyridine-1(2H)-carboxamide;
(20) 4-(5-(2-fluoro-4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-isopropyl-3,6-dihydropyridine-1(2H)-carboxamide;
(21) 4-(5-(2-fluoro-5-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-isopropyl-3,6-dihydropyridine-1(2H)-carboxamide;
(22) 4-(5-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-isopropyl-3,6-dihydropyridine-1(2H)-carboxamide;
(23) 4-(5-(4-((4-cyclopropylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-isopropyl-3,6-dihydropyridine-1(2H)-carboxamide;
(24) 4-(5-(3-((4-ethylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-isopropyl-3,6-dihydropyridine-1(2H)-carboxamide;
(25) N-isopropyl-4-(5-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxamide;
(26) 4-(5-(5-((4-ethylpiperazin-1-yl)methyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-isopropyl-3,6-dihydropyrid

Assignees

• Green Cross Corp

Inventors

• Choi Soongyu
• Song Kwang-Seop
• Seo Hee Jeong
• Ma Sang-Ho
• Park Eun-Jung
• Kong Younggyu
• Park So Ok
• Park Kisoo
• Son Ickhwan
• Kim Min Ju
• Cha Man-Young
• Kim Mi-Soon
• Kang Sang Mi
• Jang Dong Hyuk
• Hong Jangwon

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title