# US 11,993,596 B2 · Fused tri-cyclic compound as PDE3/PDE4 dual inhibitor

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- Number: US 11,993,596 B2
- Document ID: US11993596B2
- Status: Granted
- Kind: B2
- Application number: 17/259,089
- Filed: 2019-07-12
- Published: 2021-10-21
- Granted: 2024-05-28
- Earliest claimed: 2018-07-13
- Assignees: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
- Applicants: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
- Inventors: Yunfu Luo; Jianfeng Pan; Guoli Zhang; Sheng Su; Yong Wang; Shuhui Chen
- Web page: https://patentgrep.com/patent/US11993596B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/08: Bronchodilators
- C07D 487/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided is a fused tri-cyclic compound as PDE3/PDE4 dual inhibitor, and a use thereof in the preparation of drugs for PDE3/PDE4 associated diseases, particularly in medicinal functions such as chronic obstructive pulmonary disease (COPD). Provided are specifically a compound of formula (I) and a pharmaceutically acceptable salt thereof.

## Claims

### Claim 1

A compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
wherein,
a ring Cy is selected from the group consisting of 5-membered heterocyclyl and 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted by one or more of the following groups: amino, hydroxy, ═O, halogen, cyano, C1-12 alkyl, —C(O)NH2, —C(O)NH(C1-6 alkyl), —C(O)N(C1-6 alkyl)2, —COOH, —C(O)O(C1-6 alkyl) or C1-12 alkoxy, wherein the C1-12 alkyl or C1-12 alkoxy is optionally substituted by one or more groups selected from the group consisting of halogen, amino and hydroxy;
ring atoms of the ring Cy comprise at least one nitrogen atom;
L is selected from the group consisting of —N(R6)—, —N(R6)C(O)—, —C(O)N(R6)—, —O—, —S—, —OC(O)—, —C(O)O—, —CH2N(R6)C(O)—, —CH2C(O)N(R6)—, —S(O)2NH—, —NHS(O)2— and a single bond;
n is 1, 2, 3 or 4;
E1 is —(CH2)m—, wherein m is 1, 2 or 3;
E2 is selected from the group consisting of —O—, —NH—, —S— and a single bond;
R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halogen and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more groups selected from the group consisting of halogen, amino and hydroxy; and
each R6 is independently selected from the group consisting of hydrogen, hydroxy and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by one or more groups selected from the group consisting of halogen, amino and hydroxy.

### Claim 2 (depends on 1)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the ring Cy is selected from the group consisting of 5-membered heterocyclyl and 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted by one or more of the following groups: amino, hydroxy, ═O, halogen, cyano, C1-6alkyl, —C(O)NH2, —C(O)NH(C1-3 alkyl), —C(O)N(C1-3 alkyl)2, —COOH, —C(O)O(C1-3 alkyl), C1-6 alkoxy, or C1-6 alkyl substituted by one or more halogens.

### Claim 3 (depends on 1)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the ring Cy is selected from the group consisting of structural units
wherein
represents a single bond or double bond;
T1, T2, T3 and T4 are each independently selected from the group consisting of C═O, C(R1), C(R1)2, O, N(R2), N and S;
each R1 is independently selected from the group consisting of hydrogen, amino, hydroxy, halogen, cyano, C1-12 alkyl, —C(O)NH2, —C(O)NH(C1-6 alkyl), —C(O)N(C1-6 alkyl)2, —COOH, —C(O)O(C1-6 alkyl) and C1-12 alkoxy, wherein the C1-12 alkyl or C1-12 alkoxy is optionally substituted by one or more groups selected from the group consisting of halogen, amino and hydroxy;
each R2 is independently selected from the group consisting of hydrogen, hydroxy and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by one or more groups selected from the group consisting of halogen, amino and hydroxyl.

### Claim 4 (depends on 3)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 3, wherein the structural unit
is selected from the group consisting of

### Claim 5 (depends on 1)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein L is selected from the group consisting of —N(R6)—, —N(R6)C(O)—, —C(O)N(R6)—, —CH2N(R6)C(O)—, —CH2C(O)N(R6)—, —S(O)2NH—, —NHS(O)2— and a single bond.

### Claim 6 (depends on 1)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein n is selected from the group consisting of 1, 2 and 3.

### Claim 7 (depends on 1)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein R3, R4 and R5 are each independently selected from the group consisting of halogen and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, amino or hydroxyl.

### Claim 8 (depends on 1)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein each R6 is independently selected from the group consisting of hydrogen, hydroxy and methyl, wherein the methyl is optionally substituted by 1, 2 or 3 halogens, amino or hydroxyl.

### Claim 9 (depends on 1)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein E1 is selected from the group consisting of —(CH2)2— and —(CH2)3—.

### Claim 10 (depends on 1)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein E2 is selected from the group consisting of —O— and a bond.

### Claim 11 (depends on 3)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 3, wherein the compound of formula (I) is a compound of formula (II)

### Claim 12 (depends on 1)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound selected from

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 1)

A method for treating a disease related to PDE3 and/or PDE4 in a mammal, the disease being asthma or COPD, comprising administering to the mammal in need thereof a therapeutically effective amount of the compound, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1.

### Claim 15 (depends on 2)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 2, wherein the ring Cy is selected from the group consisting of 5-membered heterocyclyl and 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted by one or more of the following groups: amino, hydroxy, C1-6 alkyl, C1-6 alkoxy, wherein the 5-membered heterocyclyl is optionally substituted by one or more ═O.

### Claim 16 (depends on 2)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 2, wherein the ring Cy is selected from the group consisting of oxazolidin-2-one, imidazolyl, pyrazolyl, oxazolyl, triazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl and isoxazolyl, wherein the imidazolyl, pyrazolyl, oxazolyl, triazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl or isoxazolyl is optionally substituted by one or more of the following groups: amino, hydroxy, halogen, cyano, C1-6 alkyl, —C(O)NH2, —C(O)NH(C1-3 alkyl), —C(O)N(C1-3 alkyl)2, —COOH, —C(O)O(C1-3 alkyl), C1-6 alkoxy, or C1-6 alkyl substituted by one or more halogens.

### Claim 17 (depends on 3)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 3, wherein T1 is selected from the group consisting of C(R1), C(R1)2 and N, and T2, T3 and T4 are each independently selected from the group consisting of C═O, C(R1), C(R1)2, O, N(R2), N and S; each R1 is independently selected from the group consisting of hydrogen, amino, hydroxy, halogen, cyano, C1-6 alkyl, —C(O)NH2, —C(O)NH(C1-3 alkyl), —C(O)N(C1-3 alkyl)2, —COOH, —C(O)O(C1-3 alkyl) and C1-6 alkoxy, wherein the C1-6 alkyl or C1-6 alkoxy is optionally substituted by one or more groups selected from the group consisting of halogen, amino and hydroxyl; and each R2 is independently selected from the group consisting of hydrogen, hydroxy and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, amino or hydroxyl.

### Claim 18 (depends on 4)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 4, wherein the structural unit
is selected from the group consisting of

### Claim 19 (depends on 4)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 4, wherein the structural unit
is selected from the group consisting of

### Claim 20 (depends on 1)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein L is selected from the group consisting of —N(R6)—, —N(R6)C(O)—, —C(O)N(R6)—, —CH2N(R6)C(O)—, —CH2C(O)N(R6)— and a single bond.

### Claim 21 (depends on 1)

The compound of formula (I), the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the ring Cy is selected from the group consisting of structural units
the structural unit
and the structural unit
is selected from the group consisting of
L is selected from the group consisting of —N(R6)—, —N(R6)C(O)—, —C(O)N(R6)—, —CH2N(R6)C(O)—, —CH2C(O)N(R6)— and a single bond;
n is selected from the group consisting of 1, 2 and 3;
E1 is —(CH2)m—, wherein m is 2 or 3;
E2 is —O— or a single bond;
R3, R4 and R5 are each independently C1-3 alkyl; and
each R6 is independently selected from the group consisting of hydrogen and hydroxyl.