# US 6,297,233 B1 · Lactam inhibitors of FXa and method

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- Number: US 6,297,233 B1
- Document ID: US6297233B1
- Status: Granted
- Kind: B1
- Application number: 09/496,571
- Filed: 2000-02-02
- Granted: 2001-10-02
- Earliest claimed: 1999-02-09
- Assignees: Bristol-Myers Squibb Company
- Inventors: Philip D. Stein; Gregory S. Bisacchi; Yan Shi; Stephen P. O'Connor; Chi Li
- Web page: https://patentgrep.com/patent/US6297233B1

## CPC

- C07D 207/273: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- 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
- C07D 211/76: attached in position 2 or 6
- C07D 223/12: Nitrogen atoms not forming part of a nitro radical
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Caprolactam inhibitors are provided which have the structure including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrugs thereof, wherein n is 1 to 5; and and Y R1, R2, R3, R5, R5a, R6, R7, R8, R9 and R10 are as defined herein. These compounds are inhibitors of Factor Xa and thus are useful as anticoagulants. A method for treating cardiovascular diseases associated with thromboses is also provided.

## Claims

### Claim 1

A compound having the formula
or a pharmaceutically acceptable salt thereof, or all stereoisomers thereof, wherein
n is 3;
Y is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, heteroaryl, cycloheteroalkyl, cyano, nitro, hydroxy, amino, —ORa, —SRa,
R1, R2, R4, R6, R8, and R9 are the same or different and are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloheteroalkyl, cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, substituted alkylcarbonyl, cycloheteroalkylcarbonyl and heteroarylcarbonyl;
R3 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, cyano, nitro, hydroxy, —ORa, —SRa,
R5, R5a, and R7 are the same or different and are independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroaryl, cycloalkyl, aryl, cycloheteroalkyl,
R10 is selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloalkylcarbonyl, substituted alkyl-carbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl,
or when R9 is hydrogen and R8 and R10 are on adjacent carbons they join to complete a cycloalkyl or phenyl ring;
Ra and Rb are the same or different and are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloheteroalkyl, cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, substituted alkylcarbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl;
Rc is hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, cycloheteroaryl,
and wherein R1 and R2, and/or Ra and Rb can be taken together with the nitrogen to which they are attached to form a cycloheteroalkyl ring or a heteroaryl ring; and
R5 and R5a can be taken together to the carbon to which they are attached to form a cycloalkyl ring, a heteroaryl ring or a cycloheteroalkyl ring; and
where one or more of R3, R4 or R6 are H, then double bond isomers which may be formed.

### Claim 2 (depends on 1)

A compound of claim 1 wherein:
R1 and R2 are the same or different and are selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, and cycloheteroalkyl or R1 and R2 taken together with the nitrogen to which they are attached form a cycloheteroalkyl ring;
R3 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl or cycloheteroalkyl;
Y is cyano, nitro, aryl, heteroaryl, cycloheteroalkyl,
Ra and Rb are the same or different and are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl or cycloheteroalkyl;
R4, R5, R5a, R6, R7, R8, R9 and R10 are each hydrogen; and
the configuration at the chiral center is S— (as judged where R7 is hydrogen).

### Claim 3 (depends on 2)

A compound of claim 2 wherein:
R1 and R2 taken together with nitrogen to which they are attached complete a pyrrolidyl, substituted pyrrolidyl, or pyrrolidyl having a fused cycloalkyl ring;
R3 is aryl;
Y is cyano, heteroaryl,
Ra and Rb are the same or different and are hydrogen, alkyl, aminocarbonyl, heteroaryl, aryl, or cycloheteroalkyl;
R4, R5, R5a, R6, R7, R8, R9 and R10 are each hydrogen; and the configuration at the chiral center is S— (as judged where R7 is hydrogen).

### Claim 4 (depends on 3)

A compound of claim 3 wherein:
R3 is a substituted benzofuranyl ring.

### Claim 5 (depends on 4)

A compound of claim 4 wherein:
R3 is

### Claim 6 (depends on 3)

A compound of claim 3 wherein:
R1 and R2 taken together with the nitrogen to which they are attached are
R30 is H3C—C(O)—N(CH3)—
H2N—CH2—, H3C—C(O)—NH—CH2—, and H2N—C(O)—NH—CH2—.

### Claim 7 (depends on 6)

A compound of claim 6 wherein:
R1 and R2 taken together with the nitrogen to which they are attached are

### Claim 8 (depends on 3)

A compound of claim 3 wherein:
Y is cyano.

### Claim 9 (depends on 3)

A compound of claim 3 wherein:
Y is a heteroaryl ring selected from
R40 is hydrogen or H3C—NH—C(O)—.

### Claim 10 (depends on 3)

A compound of claim 3 wherein:
Ra is heteroaryl, aryl or cycloheteroaryl.

### Claim 11 (depends on 10)

A compound of claim 10 wherein:
Ra is

### Claim 12 (depends on 11)

A compound of claim 11 wherein: Ra is

### Claim 13 (depends on 3)

A compound of claim 3 wherein:
Y is SO2NH2 or SO2—CH3.

### Claim 14 (depends on 1)

A compound of claim 1 of the formula:

### Claim 15 (depends on 1)

The compound of claim 1 of the formula

### Claim 16 (depends on 1)

A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.

### Claim 17 (depends on 1)

A method for treating cardiovascular diseases associated with thromboses, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

### Claim 18 (depends on 1)

A method for treating thromboses, coronary artery disease or cerebrovascular disease, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in claim 1.