# US 11,370,796 B2 · Substituted pyrazoles as LRRK2 inhibitors

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- Number: US 11,370,796 B2
- Document ID: US11370796B2
- Status: Granted
- Kind: B2
- Application number: 16/769,667
- Filed: 2018-12-03
- Published: 2021-11-25
- Granted: 2022-06-28
- Earliest claimed: 2017-12-05
- Assignees: Oscotec Inc.
- Applicants: Oscotec Inc.
- Inventors: Jung-Ho Kim; Jang-Sik Choi; Song-Eun Park; Hwa Sil Kim; Dong-Sik Jung; Jong-Sung Koh; Se-Won Kim; Jaekyoo Lee
- Web page: https://patentgrep.com/patent/US11370796B2

## CPC

- 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
- C07D 487/04: Ortho-condensed systems
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A pyrrolo(pyrazolo)pyrimidine compound of Formula 1, a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug, and an isomer, and pharmaceutical compositions containing the compound are disclosed. The compound of Formula 1 shows excellent LRRK2 inhibitory activity. Method for manufacturing the compound and uses thereof as an LRRK2 inhibitor and methods for treating or preventing degenerative brain diseases employing the compound are disclosed:

## Claims

### Claim 1

A compound of Formula 1:
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
X is CH or N;
R1 is hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, or OC1-4 haloalkyl;
R2 is C1-6 alkyl, C1-6 alkylene-OC1-3 alkyl, C1-6 alkylene-C3-6 cycloalkyl, OC1-6 alkyl, C3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, or C6-10 aryl;
wherein the 4- to 7-membered heterocycloalkyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
wherein the 4- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-4 alkyl, C(O)C1-4 alkyl, C(O)C1-4 haloalkyl, C(O)C3-6 cycloalkyl, C(O)-(4- to 7-membered heterocycloalkyl), S(O)2C1-4 alkyl, S(O)2C3-6 cycloalkyl, and oxetanyl;
wherein each 4- to 7-membered heterocycloalkyl of each C(O)-(4- to 7-membered heterocycloalkyl) substituent of the 4- to 7-membered heterocycloalkyl is optionally substituted with one or more independently selected C1-4 alkyl substituents; and
wherein the C6-10 aryl is optionally substituted with one or more independently selected halogen substituents;
R3 is hydrogen, halogen, or C1-4 alkyl;
R4 is C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl;
wherein the C3-6 cycloalkyl is optionally substituted with one or more independently selected halogen substituents; and
R5 is halogen, C1-4 alkyl, or C1-4 haloalkyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of a benzenesulfonate salt, a ethanesulfonate salt, a hydrobromide salt, a hydrochloride salt, a hydroiodide salt, a methanesulfonate salt, a nitrate salt, a sulfate salt, and a toluenesulfonate salt.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is hydrogen, halogen, C1-4 alkyl, C1-4 trifluoroalkyl, or OC1-4 alkyl.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is C1-4 alkyl, C1-4 alkylene-OC1-3 alkyl, C1-4 alkylene-C3-6 cycloalkyl, OC1-4 alkyl, C3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, or C6-10 aryl;
wherein the 4- to 7-membered heterocycloalkyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
wherein the 4- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-4 alkyl, C(O)C1-4 alkyl, C(O)C1-4 trifluoroalkyl, C(O)C3-6 cycloalkyl, C(O)-(4- to 7-membered heterocycloalkyl), S(O)2C1-4 alkyl, S(O)2C3-6 cycloalkyl, and oxetanyl;
wherein the C(O)-(4- to 7-membered heterocycloalkyl) substituent of the 4- to 7-membered heterocycloalkyl is optionally substituted with one or more independently selected C1-4 alkyl substituents; and
wherein the C6-10 aryl is optionally substituted with one or more substituents independently selected from the group consisting of F and Cl.

### Claim 5 (depends on 4)

The compound of claim 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is selected from the group consisting of:
wherein:
---- is the point of attachment to the nitrogen atom of the pyrazolyl ring.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is C1-4 alkyl, C1-4 trifluoroalkyl, or C3-6 cycloalkyl.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is halogen, C1-4 alkyl, or C1-4 trifluoroalkyl.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

A pharmaceutical composition comprising at least one pharmaceutically acceptable additive and the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, as an active ingredient.

### Claim 10 (depends on 8)

A pharmaceutical composition comprising at least one pharmaceutically acceptable additive and the compound of claim 8, or a pharmaceutically acceptable salt or stereoisomer thereof, as an active ingredient.

### Claim 11 (depends on 1)

A method for selectively inhibiting leucine rich repeat kinase 2 activity in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 12 (depends on 8)

A method for selectively inhibiting leucine rich repeat kinase 2 activity in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of the compound of claim 8, or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 13 (depends on 1)

A method for treating a degenerative brain disease in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 14 (depends on 13)

The method of claim 13, wherein the degenerative brain disease is associated with leucine rich repeat kinase 2 hyperactivity in the subject.

### Claim 15 (depends on 13)

The method of claim 13, wherein the degenerative brain disease is Parkinson's disease.

### Claim 16 (depends on 8)

A method for treating a degenerative brain disease in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of the compound of claim 8, or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 17 (depends on 16)

The method of claim 16, wherein the degenerative brain disease is associated with leucine rich repeat kinase 2 hyperactivity in the subject.

### Claim 18 (depends on 16)

The method of claim 16, wherein the degenerative brain disease is Parkinson's disease.