# US 11,078,161 B2 · Rock-inhibiting compound and uses thereof

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- Number: US 11,078,161 B2
- Document ID: US11078161B2
- Status: Granted
- Kind: B2
- Application number: 16/716,455
- Filed: 2019-12-16
- Published: 2020-06-18
- Granted: 2021-08-03
- Earliest claimed: 2017-06-16
- Assignees: Hitgen Inc.
- Applicants: Hitgen Inc.
- Inventors: Jin Li; Dengyou Zhang; Jingchao Feng; Wei Liao; Li Lin; Si Li
- Web page: https://patentgrep.com/patent/US11078161B2

## CPC

- A61K 31/472: Non-condensed isoquinolines, e.g. papaverine
- C07D 217/02: with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- A61K 31/4725: containing further heterocyclic rings
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein are a compound of formula (I) and a preparation method and uses thereof. The compound shows a good inhibitory activity against ROCK, providing a new medicinal strategy to clinically treat the diseases associated with abnormal ROCK activity.

## Claims

### Claim 1

A compound of formula (II) or a stereoisomer thereof:
wherein:
R1 is selected from the group consisting of hydrogen, hydroxyl, halogen, amino, carboxyl, trifluoromethyl, nitro, cyano and C1-C6 alkyl;
m is 0, 1, 2 or 3;
R2 and R2′ are independently selected from the group consisting of hydrogen and C1-C6 alkyl;
A ring is selected from the group consisting of 5- to 6-membered aromatic ring, 5- to 6-membered heteroaromatic ring and
B ring and C ring are independently selected from the group consisting of 5- to 6-membered aromatic ring and 5- to 6-membered heteroaromatic ring;
R4 is selected from the group consisting of hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, —(CH2)mORa, —(CH2)mOC(O)Ra, —(CH2)mOC(O)NRaRb, —(CH2)mNRaRb, —(CH2)mNRaC(O)Rb, —(CH2)mNRaC(O)ORb, —(CH2)mC(O)Ra, —(CH2)mC(O)ORa and —(CH2)mC(O)NRaRb; and
Ra and Rb are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted and unsubstituted 3- to 6-membered cycloalkyl, substituted and unsubstituted 3- to 6-membered heterocycloalkyl, substituted and unsubstituted 5- to 6-membered aromatic ring and substituted and unsubstituted 5- to 6-membered heteroaromatic ring, wherein the substituted 3- to 6-membered cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, substituted 5- to 6-membered aromatic ring and substituted 5- to 6-membered heteroaromatic ring each comprise 1-2 substituents independently selected from the group consisting of halogen and C1-C6 alkyl.

### Claim 2 (depends on 1)

The compound of claim 1 or a stereoisomer thereof, wherein the compound is selected from the group consisting of:

### Claim 3

A compound of formula (III) or a stereoisomer thereof:
wherein
R1 is selected from the group consisting of hydrogen, hydroxyl, halogen, amino, carboxyl, trifluoromethyl, nitro, cyano and C1-C6 alkyl;
m is 0, 1, 2 or 3;
A ring is an unsubstituted phenyl;
E ring is a substituted or unsubstituted 4- to 5-membered N-containing heterocycloalkyl; wherein the substituted N-containing heterocycloalkyl comprises 1-2 substituents independently selected from the group consisting of halogen and C1-C6 alkyl; and
R4 is absent.

### Claim 4 (depends on 3)

The compound of claim 3 or a stereoisomer thereof, wherein the compound is selected from the group consisting of:

### Claim 5

A method for treating a disease associated with abnormal ROCK activity in a patient in need thereof, comprising:
administering an effective amount of a compound of formula (I), or a stereoisomer thereof to the patient;
wherein:
n is independently 0, 1 or 2;
R1 is independently selected from the group consisting of hydrogen, hydroxyl, halogen, amino, carboxyl, trifluoromethyl, nitro, cyano and C1-C6 alkyl;
m is 0, 1, 2, 3, 4 or 5;
R3 is —NR2R2′ or a substituted or unsubstituted N-containing heterocycloalkyl, wherein the substituted N-containing heterocycloalkyl comprises 1-2 substituents independently selected from the group consisting of halogen and C1-C6 alkyl;
R2 and R2′ are independently hydrogen or C1-C6 alkyl;
A ring is selected from the group consisting of 5- to 6-membered aromatic ring, 5- to 6-membered heteroaromatic ring and
wherein B ring and C ring are independently selected from the group consisting of 5- to 6-membered aromatic ring and 5- to 6-membered heteroaromatic ring;
R4 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, —(CH2)mORa, —(CH2)mOC(O)Ra, —(CH2)mOC(O)NRaRb, —(CH2)mNRaRb, —(CH2)mNRaC(O)Rb, —(CH2)mNRaC(O)ORb, —(CH2)mC(O)Ra, —(CH2)mC(O)ORa and —(CH2)mC(O)NRaRb; and
Ra and Rb are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted and unsubstituted 3- to 6-membered cycloalkyl, substituted and unsubstituted 3- to 6-membered heterocycloalkyl, substituted and unsubstituted 5- to 6-membered aromatic ring and substituted and unsubstituted 5- to 6-membered heteroaromatic ring, wherein the substituted 3- to 6-membered cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, substituted 5- to 6-membered aromatic ring and substituted 5- to 6-membered heteroaromatic ring each comprise 1-2 substituents independently selected from the group consisting of halogen and C1-C6 alkyl.

### Claim 6 (depends on 5)

The method of claim 5, wherein the disease associated with abnormal ROCK activity is associated with cytoskeleton regulation, smooth muscle contraction and nerve regeneration.

### Claim 7 (depends on 6)

The method of claim 6, wherein the disease associated with abnormal ROCK activity is ocular hypertension or glaucoma.

### Claim 8 (depends on 1)

A pharmaceutical composition, comprising the compound of claim 1, or a stereoisomer thereof as an active ingredient and a pharmaceutically-acceptable adjuvant.

### Claim 9 (depends on 3)

A pharmaceutical composition, comprising the compound of claim 3, or a stereoisomer thereof as an active ingredient and a pharmaceutically-acceptable adjuvant.