Analogues of 4H-pyrazolo[1,5-a] benzimidazole compound as PARP inhibitors

Patent metadata

Field	Value
Publication number	US-9856262-B2
Application number	US-201515302588-A
Country	US
Kind code	B2
Filing date	Mar 30, 2015
Priority date	Apr 10, 2014
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

Abstract

Disclosed is a series of analogs of 4H-pyrazolo[1,5-α]benzimidazole compound as PARP inhibitors. In particular, disclosed in the invention is a compound as shown by formula (I) or a pharmaceutically acceptable salt thereof as a PARP inhibitor.

First claim

What is claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein,
D is selected from the group consisting of —C(R d1 )(R d2 )—, —C(═O)N(R d3 )—, —N(R d4 )—, —C(═NR d5 )—, —S(═O) 2 N(R d6 )—, —S(═O) N(R d7 )—, —O—, —S—, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—, and —S(═O) 2 —;
R 1-3 , R d1 , and R d2 are separately and independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, and NH 2 , or selected from the group, optionally substituted by R 01 , consisting of C 1-10 alkyl, C 1-10 heteroalkyl, C 3-10 cyclohydrocarbyl, C 3-10 heterocyclohydrocarbyl, C 1-10 alkyl substituted by C 3-10 cyclohydrocarbyl or C 3-10 heterocyclohydrocarbyl, and C 1-10 heteroalkyl substituted by C 3-10 cyclohydrocarbyl or C 3-10 heterocyclohydrocarbyl;
R 01 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , and R 02 ;
R 02 is selected from the group consisting of C 1-10 alkyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl) amino, C 1-10 alkyloxyl, C 1-10 alkylacyl, C 1-10 alkyloxylcarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxyl, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxylcarbonyl, C 3-10 cycloalkylsulfonyl, and C 3-10 cycloalkylsulfinyl;
heteroatom or heteroatomic group is separately and independently selected from the group consisting of —C(═O)N(R d3 )—, —N(R d4 )—, —C(═NR d5 )—, —S(═O) 2 N(R d6 )—, —S(═O) N(R d7 )—, —O—, —S—, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—, and/or —S(═O) 2 —;
R d3-d7 are separately and independently selected from the group consisting of H, and R 03 ;
R 03 is selected from the group consisting of C 1-10 alkyl, C 1-10 alkylacyl, C 1-10 alkyloxylcarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkyl, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxylcarbonyl, C 3-10 cycloalkylsulfonyl, and C 3-10 cycloalkylsulfinyl;
R 02 , and R 03 are optionally substituted by R 001 ;
R 001 is selected from the group consisting of F, Cl, Br, I, CN, OH, N(CH 3 ) 2 , NH(CH 3 ), NH 2 , CF 3 , (NH 2 )CH 2 , (HO)CH 2 , CH 3 , CH 3 O, CH 3 C(═O), CH 3 O C(═O), CH 3 S(═O) 2 , and CH 3 S(═O); and
the number of R 01 , R 001 , the heteroatom, or heteroatomic group is separately and independently selected from 0, 1, 2, and 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the D is selected from —NH—, —N(CH 3 )—, —C(F) 2 —, —C(H) (F)— and —C(H)(OH)—.

3. The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 1-3 are separately and independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, NH 2 , C 1-6 alkyl, C 1-6 alkyloxyl, benzyloxyl, —CH 2 N(R 21 )(R 22 ),

in which,
L and D 21 are separately and independently selected from the group consisting of —C(R d1 )(R d2 )—, —C(═O)N(R d3 )—, —N(R d4 )—, —C(═NR d6 )—, —S(═O) 2 N(R d6 )—, —S(═O) N(R d7 )—, —O—, —S—, —C(═O)—, —C(═O)O—, —C(═S)—, —S(═O)—, and —S(═O) 2 —;
L may also be a single bond for a linkage purpose only;
T 21-22 are separately and independently selected from the group consisting of C(R t ) and N;
X is selected from (CH2) n optionally substituted by R 01 , and n is selected from 0, 1, 2, or 3;
Y is selected from (CH2) m optionally substituted by R 01 , and m is selected from 0, 1, 2, or 3;
R 21-23 and R d3-d7 are separately and independently selected from the group consisting of H and R 03 ;
R 24-27 , R d1 , R d2 , and R t are separately and independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, and NH 2 , or selected from the group, optionally substituted by R 01 , consisting of C 1-10 alkyl, C 1-10 heteroalkyl, C 3-10 cyclohydrocarbyl, C 3-10 heterocyclohydrocarbyl, C 1-10 alkyl substituted by C 3-10 cyclohydrocarbyl or C 3-10 heterocyclohydrocarbyl, and C 1-10 heteroalkyl substituted by C 3-10 cyclohydrocarbyl or C 3-10 heterocyclohydrocarbyl;
R 01 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , and R 02 ;
R 02 is selected from the group consisting of C 1-10 alkyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl) amino, C 1-10 alkyloxyl, C 1-10 alkylacyl, C 1-10 alkyloxylcarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxyl, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxylcarbonyl, C 3-10 cycloalkylsulfonyl, and C 3-10 cycloalkylsulfinyl;
the heteroatom or heteroatomic group is separately and independently selected from the group consisting of —C(═O)N(R d3 )—, —N(R d4 )—, —C(═NR d5 )—, —S(═O) 2 N(R d6 )—, —S(═O)N(R d7 )—, —O—, —S—, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—, and/or —S(═O) 2 —;
R d3-d7 are separately and independently selected from the group consisting of H, and R 03 ;
R 03 is selected from the group consisting of C 1-10 alkyl, C 1-10 alkylacyl, C 1-10 alkyloxylcarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkyl, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxylcarbonyl, C 3-10 cycloalkylsulfonyl, and C 3-10 cycloalkylsulfinyl;
R 02 , and R 03 are optionally substituted by R 001 ;
R 001 is selected from the group consisting of F, Cl, Br, I, CN, OH, N(CH 3 ) 2 , NH(CH 3 ), NH 2 , CF 3 , (NH 2 )CH 2 , (HO)CH 2 , CH 3 , CH 3 O, HC(═O), CH 3 O C(═O), CH 3 S(═O) 2 , and CH 3 S(═O); and
the number of R 01 , R 001 , the heteroatom, or heteroatomic group is separately and independently selected from 0, 1, 2, or 3.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein the R 1 and R 3 are separately and independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, NH 2 , C 1-3 alkyl, C 1-3 alkyloxyl, benzyloxyl, and

in which R 101 is selected from the group consisting of H, methyl, ethyl, n-propyl, or isopropyl.

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from —CH 2 N(R 201 )(R 202 ), in which R 201 and R 202 are separately and independently selected from the group consisting of H, C 1-3 alkyl, C 1-3 alkylacyl, C 3-6 cycloalkylacyl, or C 3-6 cycloalkyl.

6. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of

in which R 203 , R 204 , R 217 , and R 218 are separately and independently selected from the group consisting of H, substituted or unsubstituted C 1-3 alkyl, cyclopropyl, or cyclopropylmethylene, the substituent is selected from the group consisting of F, Cl, Br, I, CN, OH, NH 2 , methyl, or methyloxyl, and the number of substituents is 0, 1, 2, or 3.

7. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from

in which R 205 and R 206 are separately and independently selected from the group consisting of H, substituted or unsubstituted C 1-3 alkyl, cyclopropyl, and cyclopropylmethylene, wherein the substituent is selected from the group consisting of F, Cl, Br, I, CN, OH, NH 2 , methyl, or methyloxyl, and the number of substituents is 0, 1, 2, or 3.

8. The compound of claim 3 or a pharmaceutically acceptable salt thereo

Assignees

• Hubei Bio-Pharmaceutical Industrial Tech Institute Inc
• Humanwell Healthcare (Group) Co Ltd
• Medshine Discovery Inc

Inventors

• Wang Xuehai
• Ding Zhaozhong
• Xu Yong
• Chen Shuhui
• Li Lie
• Li Gang
• Tu Ronghua
• Wang Cailin
• Yue Yang
• Zhang Zhibo
• Chen Hailiang
• Sun Wenjie
• Huang Lu

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title