Trans-indoline cyclopropylamine chemical compound, and method for preparation, pharmaceutical composition, and use thereof

Patent metadata

Field	Value
Publication number	US-11873292-B2
Application number	US-201716306751-A
Country	US
Kind code	B2
Filing date	Jun 2, 2017
Priority date	Jun 3, 2016
Publication date	Jan 16, 2024
Grant date	Jan 16, 2024

Abstract

The present invention relates to the fields of medicinal chemistry and pharmacotherapy, and specifically relates to the chemical compound of formula (I), and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt, and mixtures thereof, as well as its method for preparation, a pharmaceutical composition containing said chemical compound, and use as a lysine-specific demethylase 1 (LSD 1) inhibitor. The cyclopropylamine chemical compound to which the present invention relates may be used in the treatment of cancer.

First claim

The invention claimed is:

1. A compound of the following formula I, or a enantiomer, diastereomer, racemate or mixture thereof, or a pharmaceutically acceptable salt, crystalline hydrate, or solvate thereof:

wherein:
n=1 or 2;
X is none or —(CH 2 ) 1-4 , —CH(Ra)(CH 2 ) 0-3 , —C(Ra) 2 (CH 2 ) 0-3 , C3-C6 cycloalkane, carbonyl, or carbonyl-oxo, wherein each Ra of X is independently C1-C4 alkyl;
Y is sulfonyl, carbonyl or carbonyl-oxo;
R 1 is selected from —H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group (which comprises monocyclic, cyclo, spiro or bridged ring), substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered aromatic heterocyclic group, wherein R1 has 0, 1, 2, or 3 substituents selected from the group consisting of halogen, aryl, heteroaryl, C1-C6 alkyl, —SO 2 Ra, —NC(O)Ra, —CH 2 C(O)ORa, —C(O)ORa, —C(O)Ra, —C(O)NRaRb, substituted amino, amino, carbamido, amide, sulfonamide, aralkyl and heteroarylalkyl, wherein said heterocyclic group comprises 1-3 heteroatoms selected from the group consisting of N, O and S, wherein
each Ra of R 1 is independently hydrogen, phenyl, phenylmethyl, 3,5-dimethylisoxazol-4-yl, 1,2-dimethyl-1H-imidazol-4-yl, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C3 alkylamino or —NHPh,
Rb is hydrogen or C1-C3 alkyl, or when Ra and Rb are attached to the same atom, Ra and Rb together form 5- or 6-membered heterocycloalkyl ring;
R 2 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C6-C10 aromatic ring or substituted or unsubstituted 3-12 membered aromatic heterocyclic ring containing 1-4 hetero atoms selected from oxygen, sulfur or nitrogen;
wherein the substituents is/are selected from the group consisting of deuterium, tritium, halogen, C1-C12 alkyl which is unsubstituted or substituted by 1-3 halogen, C1-C12 alkoxy which is unsubstituted or substituted by 1-3 halogens or phenyls, C2-C12 alkenyl which is unsubstituted or substituted by 1-3 halogens, C3-C6 cycloalkyl which is unsubstituted or substituted by 1-3 halogens, C1-C6 alkyl which is substituted by C1-C6 alkoxy, C1-C6 alkyl substituted by C3-C6 cycloalkyl, hydroxy, cyano, nitro, C1-C6 straight or branched hydroxyalkyl, amino group which is unsubstituted or substituted by 1 or 2 C1-C6 alkyls, carboxyl, hydrosulfuryl, or benzyl group which is unsubstituted or substituted by one or more substituents selected from the group consisting of carboxyl, C2-C6 ester group; or any two substituents on the substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted benzene ring or substituted aromatic heterocyclic ring may be bonded together with the adjacent carbon or hetero atom to form a 5-7 membered heterocyclic ring comprising 1 to 3 heteroatoms selected from the group consisting of N, O and S, and the 5-7 membered heterocyclic ring is optionally substituted with a substituent selected from the group consisting of hydrogen, hydrogen isotopes, halogen, trifluoromethyl, methoxy, C1-C6 straight or branched alkyl which is unsubstituted or substituted with 1-3 halogen, C1-C6 straight or branched alkoxy which is unsubstituted or substituted with 1-3 halogen, or hydroxy,
wherein the halogen is F, Cl, Br or I.

2. The compound of claim 1 , wherein R 1 is selected from substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group (which comprises monocyclic, cyclo, spiro or bridged ring), substituted or unsubstituted C6-C10 aryl, wherein R1 has 0, 1, 2, or 3 substituents selected from the group consisting of halogen, aryl, heteroaryl, C1-C6 alkyl, —SO 2 Ra, —NC(O)Ra, —CH 2 C(O)ORa, —C(O)ORa, —C(O)Ra, —C(O)NRaRb, substituted amino, amino, carbamido, amide, sulfonamide, aralkyl and heteroarylalkyl; wherein said heterocyclic ring comprises 1-3 heteroatoms selected from N or O.

3. The compound of claim 1 wherein R 2 is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 3-7 membered cycloalkyl; wherein when substituted one or more hydrogen atoms are substituted with a substituent selected from the group consisting of halogen, C1-4 alkyl, fluoro C1-4 alkyl and C1-4 alkoxy.

4. The compound of claim 1 , wherein Y is sulfonyl or carbonyl.

5. The compound of claim 1 , wherein the compound is selected from the following group:

No.
Name
Structure

A1
Trans-2-(1-(phenylsulfonyl)indolin-5- yl)cyclopropylamine

A2
trans-N-phenyl-2-(1- (phenylsulfonyl)indolin-5- yl)cyclopropylamine

A3
trans-N-benzyl-2-(1- (phenylsulfonyl)indolin-5- yl)cyclopropylamine

A4
trans-N-(1-phenylethyl)-2-(1- (phenylsulfonyl)indolin-5- yl)cyclopropylamine

A5
trans-N-(4-dimethylamino-benzyl)-2-(1- (phenylsulfonyl)indolin-5- yl)cyclopropylamine

A6
trans-N-(4-pyridine-methylene)-2-(1- (phenylsulfonyl)indolin-5- yl)cyclopropylamine

A7
trans-N-(5-indolylmethylene)-2-(1- (phenylsulfonyl)indolin-5- yl)cyclopropylamine

A8
trans-N-(3-indolylmethylene)-2-(1- (phenylsulfonyl)indolin-5- yl)cyclopropylamine

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

• Liu Hong
• Li Jia
• Zhu Wei
• Zhou Yubo
• Wang Jiang
• Su Mingbo
• Wang Shuni
• Xu Wei
• Li Chunpu
• Kan Weijuan
• Jiang Hualiang
• Chen Kaixian

Classifications

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D209/04

  Indoles; Hydrogenated indoles · CPC title

• C07D209/08 Primary

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• C07D215/00

  Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems · CPC title