# US 9,040,531 B2 · Alpha helix mimetics and methods relating thereto

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- Number: US 9,040,531 B2
- Document ID: US9040531B2
- Status: Granted
- Kind: B2
- Application number: 13/319,071
- Filed: 2010-05-07
- Published: 2012-04-12
- Granted: 2015-05-26
- Earliest claimed: 2009-05-07
- Assignees: PRISM BioLab Co., Ltd.
- Applicants: Takenao Odagami; Yuji Kogami; Hiroyuki Kouji
- Inventors: Takenao Odagami; Yuji Kogami; Hiroyuki Kouji
- Web page: https://patentgrep.com/patent/US9040531B2

## CPC

- C07D 495/14: Ortho-condensed systems
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 13/12: of the kidneys
- A61P 17/14: for baldness or alopecia
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 35/00: Antineoplastic agents
- C07D 401/14: containing three or more hetero rings
- C07D 403/14: containing three or more hetero rings
- C07D 471/14: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 487/14: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Alpha-helix mimetic structures and compounds represented by the formula (I) wherein the general formula and the definition of each symbol are as defined in the specification, a chemical library relating thereto, and methods relating thereto, are disclosed. Applications of these compounds in the treatment of medical conditions, e.g., cancer diseases, fibrotic diseases, and pharmaceutical compositions comprising the mimetics are further disclosed.

## Claims

### Claim 1

A compound having the following general formula (I):
wherein
is single bond or double bond;
A is —CHR7—,
wherein
R7 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl;
B is optionally substituted 3-, 4-, 5-, 6- or 7- membered saturated or unsaturated monocyclic carbocyclic ring formed together with G and Y, or is optionally substituted 4-, 5-, 6- or 7 membered saturated or unsaturated heterocyclic ring formed together with G and Y and the hetero atom is selected from S, N and O and the number of hetero atoms is an integer of 1-3;
G and Y are independently carbon atom or nitrogen atom;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl;
R2 is —W21—W22—Rb—R20,
wherein
W21 is —(CO)—or —(SO2)—,
W22 is bond, —O—, —NH— or optionally substituted lower alkylene,
Rb is bond or optionally substituted alkylene, and
R20 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and
R3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;
with the proviso that
when B is benzene, and R2 is —W21—W22—Rb—R20, wherein W21 is —(CO)—, W22 is —NH—, and Rb is bond, then R20 should not be optionally substituted phenyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1,
wherein
R3 is hydrogen or optionally substituted alkyl.

### Claim 3 (depends on 1)

The compound of claim 1, which has the following general formula (I-d):
wherein
is single bond or double bond;
A is —(CHR)—;
wherein
R7 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl;
B is optionally substituted 3-, 4-, 5-, 6- or 7- membered saturated or unsaturated monocyclic carbocyclic ring formed together with G and Y, or is optionally substituted 4-, 5-, 6- or 7 membered saturated or unsaturated heterocyclic ring formed together with G and Y and the hetero atom is selected from S, N and O and the number of hetero atoms is an integer of 1-3;
G is carbon atom or nitrogen atom;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl;
R2 is —W21—W22—Rb—R20,
wherein
W21 is —(CO)—or —(SO2)—,
W22 is bond, —O—, —NH— or optionally substituted lower alkylene,
Rb is bond or optionally substituted lower alkylene, and
R20 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and
R3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;
with the proviso that
when B is benzene, and R2 is —W21—W22—Rb20, wherein W21 is —(CO)—, W22 is —NH—, and Rb is bond, then R20 should not be optionally substituted phenyl.

### Claim 4 (depends on 1)

The compound of claim 1,
wherein
B is optionally substituted 5-membered saturated or unsaturated monocyclic carbocyclic ring formed together with G and Y.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

### Claim 6

A compound having the following general formula (II):
wherein
is single bond or double bond;
A is —CHR7—,
wherein
R7 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl;
B is optionally substituted 3-, 4-, 5-, 6- or 7- membered saturated or unsaturated monocyclic carbocyclic ring formed together with G and Y, or is optionally substituted 4-, 5-, 6- or 7 membered saturated or unsaturated heterocyclic ring formed together with G and Y and the hetero atom is selected from S, N and O and the number of hetero atoms is an integer of 1-3;
G and Y are independently carbon atom or nitrogen atom;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl;
R2 is —W21—W22—Rb—R20,
wherein
W21 is —(CO)—or —(SO2)—,
W22 is bond, —O—, —NH—or optionally substituted lower alkylene,
Rb is bond or optionally substituted alkylene, and
R20 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;
R3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;
R91 is selected from optionally substituted alkyl, linker and solid support; and
R92 is selected from optionally substituted alkyl, linker and solid support;
with the proviso that
when B is benzene, and R21 is W21—W22—Rb—R20, wherein W21 is —(CO)—, W22 is —NH—, and Rb is bond, then R20 should not be optionally substituted phenyl;
or a salt thereof.

### Claim 7

A process for preparing a compound having the following general formula (I):
wherein
is single bond or double bond;
A is —CHR7—,
wherein
R7 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl;
B is optionally substituted 3-, 4-, 5-, 6- or 7- membered saturated or unsaturated monocyclic carbocyclic ring formed together with G and Y, or is optionally substituted 4-, 5-, 6- or 7 membered saturated or unsaturated heterocyclic ring formed together with G and Y and the hetero atom is selected from S, N and O and the number of hetero atoms is an integer of 1-3;
G and Y are independently carbon atom or nitrogen atom;
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl;
R2 is —W21—W22—Rb—R20,
wherein
W21 is —(CO)—or —(SO2)—,
W22 is bond, —O—, —NH— or optionally substituted lower alkylene,
Rb is bond or optionally substituted alkylene, and
R20 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and
R3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;
with the proviso that
when B is benzene, and R2 is —W21—W22—Rb—R20, wherein W21 is —(CO)—, W22 is —NH—, and Rb is bond, then R20 should not be optionally substituted phenyl;
or a salt thereof, which comprises reacting a compound having the following general formula (II):
wherein
R91 is selected from optionally substituted alkyl, linker and solid support;
R92 is selected from optionally substituted alkyl, linker and solid support; and
the other symbols are as defined above, or a salt thereof, with an acid.