Heterocyclic compound

Patent metadata

Field	Value
Publication number	US-10787462-B2
Application number	US-201615769201-A
Country	US
Kind code	B2
Filing date	Oct 21, 2016
Priority date	Oct 23, 2015
Publication date	Sep 29, 2020
Grant date	Sep 29, 2020

Abstract

The present invention provides a heterocyclic compound having an RIP1 kinase inhibitory action, which is useful for the prophylaxis or treatment of Gaucher's disease, Niemann-Pick disease, inflammatory bowel disease, multiple sclerosis, chronic kidney disease, acute kidney injury, acute hepatic failure, autoimmune hepatitis, hepatitis B, hepatitis C, alcohol steatohepatitis, non-alcohol steatohepatitis and the like.
The present invention relates to a compound represented by the following formula (I):

wherein each symbol is as defined in the specification, or a salt thereof.

First claim

The invention claimed is:

1. A compound represented by the following formula (I):

wherein
Ring A and Ring B are each independently an optionally further substituted 5- to 6-membered aromatic ring,
Ring C is an optionally further substituted ring,
Ring D is an optionally further substituted 5- to 7-membered nitrogen-containing heterocycle,
R 1 is a C 1-6 alkyl group or a hydrogen atom,
X is (a) an oxygen atom, (b) a sulfur atom, (c) —SO—, (d) —SO 2 —, (e) an optionally substituted methylene group or (f) —NR 2 —,
R 2 is a hydrogen atom or a substituent, or R 2 is optionally bonded to R 1 to form a bridge,
Y 1 and Y 2 are each independently a carbon atom or a nitrogen atom,
L is (a) an optionally substituted C 1-3 alkylene group, (b) an oxygen atom, (c) a sulfur atom, (d) —SO—, (e) —SO 2 — or (f) —NR 3 —, and
R 3 is a hydrogen atom or a substituent,
or a salt thereof.

2. The compound or salt according to claim 1 , wherein Ring D is piperidine, pyrrolidine, pyrroline, piperazine, tetrahydropyridine or diazepane, each optionally further substituted.

3. The compound or salt according to claim 1 , wherein Ring B is pyrazole, triazole, imidazole, triazole or pyridine, each optionally further substituted.

4. The compound or salt according to claim 1 , wherein the partial structure represented by the formula:

is a partial structure represented by the formula (1)-(4), (6)-(9), (11), (16), 9) or (21):

wherein R b1 and R b2 are each independently a substituent or a hydrogen atom.

5. The compound or salt according to claim 1 , wherein
Ring A is benzene, pyridine or pyrazole, each optionally further substituted,
X is an oxygen atom, a sulfur atom, —SO 2 —, an optionally substituted methylene group or —NR 2 — wherein R 2 is a C 1-6 alkyl group or a hydrogen atom,
L is an optionally substituted C 1-2 alkylene group, and
Ring C is benzene, furan, oxazole, pyrazole, pyridine, pyrimidine, pyrazine, dioxane, tetrahydropyran, tetrahydrofuran, piperidine, pyrrolidine, oxetane, 1,1-dioxidotetrahydrothiophene, 1,1-dioxidotetrahydrothiopyran or a C 3-6 cycloalkane, each optionally further substituted.

6. The compound or salt according to claim 1 , wherein
Ring A is an optionally further substituted benzene,
R 1 is a C 1-6 alkyl group,
X is an oxygen atom,
Ring D is an optionally further substituted piperidine,
Ring B is an optionally further substituted pyrazole,
L is an optionally substituted methylene, and
Ring C is an optionally further substituted benzene.

7. (3S)-3-(2-(2-fluorobenzyl)-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-8-carbonitrile, or a salt thereof.

8. (3S)-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-N,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-8-carboxamide, or a salt thereof.

9. (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-8-carbonitrile, or a salt thereof.

10. A medicament comprising the compound or salt according to claim 1 .

11. The medicament according to claim 10 , which is an RIP1 kinase inhibitor.

12. The medicament according to claim 10 , which is an agent for the treatment of Gaucher's disease, Niemann-Pick disease, inflammatory bowel disease, multiple sclerosis, chronic kidney disease, acute kidney injury, acute hepatic failure, autoimmune hepatitis, hepatitis B, hepatitis C, alcohol steatohepatitis or non-alcohol steatohepatitis.

13. A method of inhibiting RIP1 kinase in a mammal, which comprises administering an effective amount of the compound or salt according to claim 1 to the mammal.

14. A method for the treatment of Gaucher's disease, Niemann-Pick disease, inflammatory bowel disease, multiple sclerosis, chronic kidney disease, acute kidney injury, acute hepatic failure, autoimmune hepatitis, hepatitis B, hepatitis C, alcohol steatohepatitis or non-alcohol steatohepatitis in a mammal, which comprises administering an effective amount of the compound or salt according to claim 1 to the mammal.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Yogo Takatoshi
• Yoshikawa Masato
• Saitoh Morihisa
• Katoh Taisuke
• Seki Tomohiro
• Nakada Yoshihisa

Classifications

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61K31/554

  having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title