# US 12,180,211 B2 · Compounds, compositions and methods

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- Number: US 12,180,211 B2
- Document ID: US12180211B2
- Status: Granted
- Kind: B2
- Application number: 17/350,581
- Filed: 2021-06-17
- Published: 2021-10-28
- Granted: 2024-12-31
- Earliest claimed: 2016-12-09
- Assignees: Denali Therapeutics Inc.
- Applicants: Denali Therapeutics Inc.
- Inventors: Anthony A. Estrada; Jianwen A. Feng; Brian Fox; Cheng Hu; Maksim Osipov; Zachary K. Sweeney; Javier de Vicente Fidalgo; Arun Thottumkara
- Web page: https://patentgrep.com/patent/US12180211B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/00: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- G01N 33/50: Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing (measuring or testing processes involving enzymes or microorganisms, compositions or test papers therefor; processes for forming such compositions, condition responsive control in microbiological or enzymological processes C12Q)
- G01N 33/5091: {for testing the pathological state of an organism}
- G01N 33/575: for cancer
- G01N 33/6893: {related to diseases not provided for elsewhere}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present disclosure relates generally to methods and compositions for preventing or arresting cell death and/or inflammation.

## Claims

### Claim 1

A method for treating a necrotic cell disease, the method comprising administering an effective amount of a compound of Formula I,
or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof to a subject in need thereof, wherein:
Y is N or CH;
n is 1 or 2;
m is 0, 1, 2, 3, 4, or 5;
p is 0, 1, 2, or 3;
A is aryl, heteroaryl, C3-10 cycloalkyl, or heterocyclyl;
each of R1 and R2 is independently hydrogen, deuterium, halo, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, heteroaryl or aryl;
wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z1; or
R1 and R2 taken together with the atoms to which they are attached form a C3-10 cycloalkyl;
wherein the C3-10 cycloalkyl is optionally substituted with one, two, three, four, or five Z2;
R3 in each instance is independently deuterium, halo, hydroxy, cyano, nitro, azido, oxo, C1-12 alkyl, —OR5, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R4, —C(═O)OR4, —OC(═O)OR4, —OC(═O)R4, —C(═O)NR4R5, —OC(═O)NR4R5, —NR4C(═O)NR5R6, —S(═O)1-2R4, —S(═O)1-2OR4, —OS(═O)1-2R4, —S(═O)1-2NR4, —NR4S(═O)1-2R5, —NR4S(═O)1-2NR4R5, —NR4R5, —NR4C(═O)R5, or —NR4C(═O)OR5;
wherein each C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, three, four, or five Z3;
R4, R5, and R6 in each instance are independently C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 haloalkyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 haloalkyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z4; or
two of R4, R5, and R6 taken together with the atoms to which they are attached form a heterocyclyl;
wherein the heterocyclyl is optionally substituted with one, two, three, four, or five Z5;
R14 is bonded to either ring of the fused bicyclic ring and, in each instance, is independently halo or haloalkyl, or two R14 bonded to the same carbon atom may be taken together with the atom to which they are attached to form a C3-10 cycloalkyl or heterocyclyl;
wherein the C3-10 cycloalkyl or heterocyclyl is optionally substituted with one, two, three, four, or five Z6;
each of Z1, Z2, Z3, Z4, Z5, and Z6 are independently deuterium, halo, hydroxy, cyano, nitro, azido, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R11, —C(═O)OR11, —OC(═O)OR11, —OC(═O)R11, —C(═O)NR11R12, —OC(═O)NR11R12, —NR11C(═O)NR12R13, —S(═O)1-2R11, —S(═O)1-2OR11, —S(═O)1-2NR11, —NR11S(═O)1-2R12, —NR11S(═O)1-2NR12R13, —NR11R12, —NR11C(═O)R12, or —NR11C(═O)OR12;
wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three substituents independently selected from deuterium, halo, hydroxy, cyano, amino, nitro, azido, oxo, C1-12 alkyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
R11, R12, and R13 in each instance are independently C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C3-10 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z11; or
two of R11, R12, and R13 are taken together with the atoms to which they are attached to form a heterocyclyl; wherein the heterocyclyl is optionally substituted with one, two, three, four or five Z12;
wherein each of Z11 and Z12 is independently deuterium, halo, hydroxy, cyano, oxo, amino or C1-12 alkyl; wherein the C1-12 alkyl is optionally substituted with one, two or three halo, hydroxyl, amino or oxo, provided that
when n is 1, Y is CH, and both of R1 and R2 are hydrogen, then A is not heterocyclyl substituted with oxo; and
when n is 2, Y is CH, and one of R1 or R2 is iodo, or both of R1 or R2 are hydrogen, then A is not 4-chlorophenyl, 2,6-difluoropyridin-3-yl, phenyl, or phenyl substituted with 1, 2 or 3 fluoro; and
the compound is not chosen from (3R,8aR)-6-chloro-3-(4-fluorophenyl)hexahydroindolizin-5(1H)one: (3R,6S,8aS)-6-methyl-3-phenylhexahydroindolizin-5(1H)-one; hexahydro-6-methyl-3-phenyl-5(1H)-indolizinone; and 6-[(2-bromo-1H-indol-3-yl)methyl]hexahydro-3-(4-hydroxyphenyl)-5(1H)-indolizinone.

### Claim 2 (depends on 1)

The method of claim 1, wherein the necrotic cell disease is selected from at least one of trauma, ischemia, stroke, cardiac infarction, infection, Gaucher's disease, Krabbe disease, sepsis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, HIV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis, and inflammatory bowel disease.

### Claim 3

A method for treating an inflammatory disorder, the method comprising administering an effective amount of a compound of Formula I,
or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof to a subject in need thereof, wherein:
Y is N or CH;
n is 1 or 2;
m is 0, 1, 2, 3, 4, or 5;
p is 0, 1, 2, or 3;
A is aryl, heteroaryl, C3-10 cycloalkyl, or heterocyclyl;
each of R1 and R2 is independently hydrogen, deuterium, halo, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, heteroaryl or aryl;
wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z1; or
R1 and R2 taken together with the atoms to which they are attached form a C3-10 cycloalkyl; wherein the C3-10 cycloalkyl is optionally substituted with one, two, three, four, or five Z2;
R3 in each instance is independently deuterium, halo, hydroxy, cyano, nitro, azido, oxo, C1-12 alkyl, —OR5, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R4, —C(═O)OR4, —OC(═O)OR4, —OC(═O)R4, —C(═O)NR4R5, —OC(═O)NR4R5, —NR4C(═O)NR5R6, —S(═O)1-2R4, —S(═O)1-2OR4, —OS(═O)1-2R4, —S(═O)1-2NR4, —NR4S(═O)1-2R5, —NR4S(═O)1-2NR4R5, —NR4R5, —NR4C(═O)R5, or —NR4C(═O)OR5;
wherein each C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, three, four, or five Z3;
R4, R5, and R6 in each instance are independently C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 haloalkyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 haloalkyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z4; or
two of R4, R5, and R6 taken together with the atoms to which they are attached form a heterocyclyl;
wherein the heterocyclyl is optionally substituted with one, two, three, four, or five Z5; R14 is bonded to either ring of the fused bicyclic ring and, in each instance, is independently halo or haloalkyl, or two R14 bonded to the same carbon atom may be taken together with the atom to which they are attached to form a C3-10 cycloalkyl or heterocyclyl;
wherein the C3-10 cycloalkyl or heterocyclyl is optionally substituted with one, two, three, four, or five Z6;
each of Z1, Z2, Z3, Z4, Z5, and Z6 are independently deuterium, halo, hydroxy, cyano, nitro, azido, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R11, —C(═O)OR11, —OC(═O)OR11, —OC(═O)R11, —C(═O)NR11R12, —OC(═O)NR11R12, —NR11C(═O)NR12R13, —S(═O)1-2R11, —S(═O)1-2OR11, —S(═O)1-2NR11, —NR11S(═O)1-2R12, —NR11S(═O)1-2NR12R13, —NR11R12, —NR11C(═O)R12, or —NR11C(═O)OR12;
wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three substituents independently selected from deuterium, halo, hydroxy, cyano, amino, nitro, azido, oxo, C1-12 alkyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
R11, R12, and R13 in each instance are independently C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C3-10 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z11; or
two of R11, R12, and R13 are taken together with the atoms to which they are attached to form a heterocyclyl; wherein the heterocyclyl is optionally substituted with one, two, three, four or five Z12;
wherein each of Z11 and Z12 is independently deuterium, halo, hydroxy, cyano, oxo, amino or C1-12 alkyl; wherein the C1-12 alkyl is optionally substituted with one, two or three halo, hydroxyl, amino or oxo, provided that
when n is 1, Y is CH, and both of R1 and R2 are hydrogen, then A is not heterocyclyl substituted with oxo; and
when n is 2, Y is CH, and one of R1 or R2 is iodo, or both of R1 or R2 are hydrogen, then A is not 4-chlorophenyl, 2,6-difluoropyridin-3-yl, phenyl, or phenyl substituted with 1, 2 or 3 fluoro; and
the compound is not chosen from (3R,8aR)-6-chloro-3-(4-fluorophenyl)hexahydroindolizin-5(1H)one: (3R,6S,8aS)-6-methyl-3-phenylhexahydroindolizin-5(1H)-one; hexahydro-6-methyl-3-phenyl-5(1H)-indolizinone; and 6-[(2-bromo-1H-indol-3-yl)methyl]hexahydro-3-(4-hydroxyphenyl)-5(1H)-indolizinone.

### Claim 4 (depends on 3)

The method of claim 3, wherein the inflammatory disorder is inflammatory bowel disease.

### Claim 5 (depends on 4)

The method of claim 4, wherein the inflammatory disorder is Crohn's disease or ulcerative colitis.