Fluorinated cyclopropylamine compound, preparation method therefor, pharmaceutical composition thereof, and uses thereof

Patent metadata

Field	Value
Publication number	US-10836743-B2
Application number	US-201716085311-A
Country	US
Kind code	B2
Filing date	Mar 16, 2017
Priority date	Mar 16, 2016
Publication date	Nov 17, 2020
Grant date	Nov 17, 2020

Abstract

Provided is a fluorinated cyclopropylamine compound represented by formula I, a racemate thereof, an R-isomer thereof, an S-isomer thereof, a pharmaceutical salt thereof, and a mixture thereof. Also provided are pharmaceutical compositions containing the compound, a preparation method for the compound, and uses thereof as a lysine specific demethylase 1 (LSD1) inhibitor, and in the treatment of cancers.

First claim

The invention claimed is:

1. A fluorine-substituted cyclopropylamine compound having a structure represented by the following general formula I, and a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt, or a mixture thereof:

wherein:
A is selected from the group consisting of a substituted or unsubstituted aromatic ring and a substituted or unsubstituted 5-12 membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein each of the substituted benzene ring or substituted aromatic heterocycles comprises 1 to 3 substituents;
wherein the substituent on the substituted aromatic ring or substituted aromatic heterocyclic ring is independently selected from hydrogen, isotope of hydrogen, halogen, an unsubstituted or substituted C1-C12 straight or branched alkyl, unsubstituted or substituted C1-C12 straight or branched alkoxy, unsubstituted or substituted C2-C12 straight or branched unsaturated hydrocarbon group, unsubstituted C3-C6 cycloalkyl, C1-C6 straight or branched alkyl substituted by C1-C6 alkoxy, C1-C6 straight or branched alkyl substituted by C3-C6 cycloalkyl, hydroxy, cyano, nitro, C1-C6 straight or branched hydroxyalkyl or thiol, oxygen (═O), unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted C6-C12 aryloxy, unsubstituted or substituted phenyloxy, carboxy, acetyl, and sulfonyl; the substituent is selected from the group consisting of halogen, a C1-C4 straight or branched alkyl, halogen-substituted C1-C4 straight or branched alkyl, C1-C4 alkyloxy, cyano-substituted phenyl;
or any two substituents on the substituted aromatic ring or substituted aromatic heterocyclic ring may be linked together with their adjacent carbon or hetero atom to form a 5-7 membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O or S, and the 5-7 membered heterocyclic ring is optionally substituted by substituents selected from the group consisting of hydrogen, hydrogen isotope, halogen, C1-C6 straight or branched alkyl unsubstituted or substituted with 1-3 halogens, C1-C6 straight or branched alkoxy unsubstituted or substituted by 1 to 3 halogens, and hydroxyl;
each R 1 is independently selected from the group consisting of a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydrogen, substituted or unsubstituted C1-C6 alkyl, —SO 2 Ra, —NC(O)Ra, —(CH 2 ) m C(O)ORa, —C(O)O(CH 2 ) m Ra, —C(O)ORa, —C(O)Ra, —(CH 2 ) m ORa, —C(O)NRaRb, —C(S)NRaRb, —CORa, —NRcRd, substituted or unsubstituted amino, substituted or unsubstituted urea, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl, wherein m is an integer from 1 to 3; the substituent is selected from the group consisting of halogen, hydroxy, carboxy, cyano, amino, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl ester group, C1-C4 alkylsulfonyl, aminophenylamide

arylalkyl, and aryl;
each Ra is independently hydrogen, a substituted or unsubstituted phenyl, substituted or unsubstituted phenylmethyl, 3,5-dimethylisoxazol-4-yl, 1,2-dimethyl-1H-imidazol-4-yl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocyclic group, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C3 alkylamino, —NHPh, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl; the substituent is selected from the group consisting of: a C1-C4 alkyl, halogen-substituted C1-C4 alkyl, phenyl-substituted C1-C4 alkyl, C1-C4 alkyl ester group, C3-C7 cyclic group, C3-C7 cyclic group alkyl, C3-C7 heterocyclic group, benzyl-substituted C3-C7 heterocycloalkyl, aryl, halogen, C1-C4 alkoxy, C1-C4 halogenoalkyl, carboxyl, and a carboxyl-substituted benzyl group;
Rb is hydrogen or a C1-C3 alkyl, or when attached to the same atom,
Ra and Rb together form a 5- or 6-membered heterocycloalkyl ring;
Rc and Rd are each independently selected from hydrogen, a substituted or unsubstituted C1-C3 straight or branched alkyl, substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted 4- to -6-membered heterocyclic group, substituted or unsubstituted C1-C3 alkylacyl, substituted or unsubstituted arylacyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted benzyl, substituted or unsubstituted aryl; the C1-C3 straight or branched alkyl is optionally substituted by one or more selected from the group consisting of methylsulfonyl, a C1-C3 alkoxy, C1-C3 alkoxycarbonyl group, aryl; and the heterocyclic group contains one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen;
R 2 is hydrogen or COOH;
R 3 is a C1-C4 alkyl, acyl, —C(O)CF 3 or hydrogen;
W is —(CH 2 ) 1-4 or —CH(Re)(CH 2 ) 0-3 , wherein Re is CN or C1-C4 alkyl;
Y is N, C or none;
X is N or C;
Z is O or (CH 2 ) q , wherein q is 0-2, and when q is 0, Z represents a bond;
n is 0-3;
with the proviso that when Z is O, Y is N and X is C.

2. The fluorine-substituted cyclopropylamine compound, or a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt, or a mixture thereof of claim 1 , wherein A is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-12 membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein each of the substituted benzene ring or substituted aromatic heterocycles comprises 1 to 3 substituents;
wherein the substituent on the substituted aromatic ring or substituted aromatic heterocyclic ring is independently selected from the group consisting of hydrogen, hydrogen isotope, halogen, carboxyl, nitro, a C1-C4 alkyl, C1-C4 alkanoyl, C1-C4 alkoxy, cyano, oxygen (═O), sulfonyl.

3. The fluorine-substituted cyclopropylamine compound, or a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt, or a mixture thereof of claim 1 , wherein each R 1 is independently selected from: a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydrogen, substituted or unsubstituted C1-C4 alkyl, —SO 2 Ra, —NC(O)Ra, —(CH 2 ) m C(O)ORa, —C(O)ORa, —C(O)Ra, —(CH 2 ) m ORa, —C(O)NRaRb, —NRcRd, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl, wherein m is an integer of 1-3;
each Ra is independently hydrogen, a substituted or unsubstituted phenyl, substituted or unsubstituted phenylmethyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkenyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C3 alkylamino, —NHPh, or substituted or unsubstituted 5-10 membered heteroaryl;
Rb is hydrogen or C1-C3 alkyl;
Rc and Rd are each independently selected from hydrogen, a C1-C3 straight or branched alkyl, substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted 4- to -6-membered heterocyclic group, substituted or unsubstituted C1-C3 alkylacyl, substituted or unsubstituted arylacyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted benzyl, substituted or unsubstituted aryl; the heterocyclic group contains one heteroatom selected from the group consisting of oxygen, sulfur and

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

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

Classifications

• C07D417/12

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

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D409/12

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

• C07D405/12

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

• C07D401/14

  containing three or more hetero rings · CPC title