# US 11,111,235 B2 · Compounds, compositions, and methods

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- Number: US 11,111,235 B2
- Document ID: US11111235B2
- Status: Granted
- Kind: B2
- Application number: 16/818,745
- Filed: 2020-03-13
- Published: 2021-01-07
- Granted: 2021-09-07
- Earliest claimed: 2016-06-16
- Assignees: Denali Therapeutics Inc.
- Applicants: Denali Therapeutics Inc.
- Inventors: Javier de Vicente Fidalgo; Anthony A. Estrada; Jianwen A. Feng; Joseph P. Lyssikatos; Zachary K. Sweeney
- Web page: https://patentgrep.com/patent/US11111235B2

## CPC

- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 59/002: {Heterocyclic compounds}
- C07D 401/14: containing three or more hetero rings
- C07D 403/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07D 491/20: Spiro-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present disclosure relates generally to LRRK2 inhibitors, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, and methods of making and using thereof.

## Claims

### Claim 1

A method for treating a disease or condition mediated, at least in part, by LRRK2, wherein the disease or condition is selected from the group consisting of kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, and ankylosing spondylitis, the method comprising administering to a subject in need thereof an effective amount of a compound of formula Ia:
or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein:
R1 is optionally substituted cycloalkyl or C1-6 alkyl optionally substituted with halo;
R2 is halo, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted cycloalkoxy, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylsulfonyl, —C(O)R10, or —C(O)N(R11)(R12);
R3 is optionally substituted C1-6 alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylsulfonyl, or —N(R11)(R12);
R4 is hydrogen or halo;
R6 and R7 are each independently hydrogen or C1-6 alkyl optionally substituted with halo;
R8 and R9 are each independently hydrogen, cyano, halo, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or optionally substituted heteroaryl;
R10 is optionally substituted C1-6 alkyl or optionally substituted C1-6 alkoxy; and
R11 and R12 are each independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted cycloalkyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein R6 and R7 are methyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein at least one of R8 and R9 is hydrogen.

### Claim 4 (depends on 3)

The method of claim 3, wherein both R8 and R9 are hydrogen.

### Claim 5 (depends on 1)

The method of claim 1, wherein R1 is optionally substituted cyclopropyl or optionally substituted cyclobutyl.

### Claim 6 (depends on 5)

The method of claim 5, wherein R1 is cyclopropyl independently substituted with one or more halo, hydroxy, cyano, or heteroaryl.

### Claim 7 (depends on 5)

The method of claim 5, wherein R1 is cyclopropyl, cyclobutyl, hydroxycylobut-3-yl, cyanocylobut-3-yl, triazol-2yl-cyclobut-3-yl, triazol-1-yl-cyclobut-3-yl, or fluorocyclobut-3-yl.

### Claim 8 (depends on 1)

The method of claim 1, wherein R1 is CD3, ethyl, prop-2-yl, or methyl optionally substituted with halo.

### Claim 9 (depends on 1)

The method of claim 1, wherein R2 is halo, cyano, or C1-6 alkyl optionally substituted with one or more halo.

### Claim 10 (depends on 9)

The method of claim 9, wherein R2 is bromo.

### Claim 11 (depends on 9)

The method of claim 9, wherein R2 is —CF3.

### Claim 12 (depends on 1)

The method of claim 1, wherein R3 is optionally substituted cycloalkyl, optionally substituted C1-6 alkoxy, or —N(R11)(R12).

### Claim 13 (depends on 12)

The method of claim 12, wherein R12 is optionally substituted C1-6 alkyl.

### Claim 14 (depends on 12)

The method of claim 12, wherein R11 is H and R12 is ethyl.

### Claim 15 (depends on 1)

The method of claim 1, wherein R3 is cyclopropyl, methoxy, 1,1-difluoroeth-2-ylamino, cyclopropylamino, —NH(CH3), or —NH(CH2CH3).

### Claim 16 (depends on 1)

The method of claim 1, wherein R4 is hydrogen.

### Claim 17 (depends on 1)

The method of claim 1, wherein R1 is cycloalkyl independently substituted with one or more hydroxy, cyano, or heteroaryl; R2 is halo or C1-6 haloalkyl; R3 is —N(R11)(R12) or C1-6 alkoxy; and R4 is H.

### Claim 18

A method for treating a disease or condition mediated, at least in part, by LRRK2, wherein the disease or condition is selected from the group consisting of kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, and ankylosing spondylitis, the method comprising administering to a subject in need thereof an effective amount of a compound selected from:
or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof.

### Claim 19

A method for treating a disease or condition mediated, at least in part, by LRRK2, wherein the disease or condition is selected from the group consisting of kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, and ankylosing spondylitis, the method comprising administering to a subject in need thereof an effective amount of a compound selected from:
or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof.

### Claim 20 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 1)

The method of claim 1, wherein the disease or condition is kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, or multiple myeloma.

### Claim 26 (depends on 1)

The method of claim 1, wherein the disease or condition is leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, or ankylosing spondylitis.