# US 2023/0054883 A1 · MTA-Cooperative PRMT5 Inhibitors

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- Number: US 2023/0054883 A1
- Document ID: US20230054883A1
- Status: Published application
- Kind: A1
- Application number: 17/942,367
- Filed: 2022-09-12
- Published: 2023-02-23
- Earliest claimed: 2019-09-12
- Assignees: Mirati Therapeutics, Inc.
- Applicants: Mirati Therapeutics, Inc.
- Inventors: Thomas P. Bobinski; Christopher Ronald Smith; Matthew Arnold Marx; John Michael Ketcham; Aaron Craig Burns; John David Lawson; Svitlana Kulyk; Jon Kuehler; Anthony Ivetac
- Web page: https://patentgrep.com/patent/US20230054883A1

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 237/32: with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/14: containing three or more hetero rings
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/10: linked by a carbon chain containing aromatic rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/14: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C12N 9/1007: {Methyltransferases (general) (2.1.1.)}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention relates to compounds that inhibit Protein Arginine N-Methyl Transferase 5 (PRMT5) activity. In particular, the present invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the present invention.

## Claims

### Claim at position 1

1-33. (canceled)

### Claim 34

A compound of Formula (I-D):
or a pharmaceutically acceptable salt thereof, wherein:
R2 is —X-aryl optionally substituted with one or more R5;
each R5 is independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, —X-haloalkyl, —Z-cycloalkyl, —X-arylC1-C3alkyl, —X-arylC1-C3alkyl substituted with cyano, —X-L-cycloalkyl, —X-L-heteroaryl optionally substituted with one or more C1-C3alkyl or oxo, or —X-aryl;
each X is independently a bond, O, S, —NR4— or —NR4C(O)—;
each Z is independently a bond, —SO—, —SO2—, —CH(OH)— or —C(O)—;
each L is independently a bond or C1-C3 alkylene;
each R4 is independently hydrogen or C1-C3 alkyl; and
R6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

### Claim 35 (depends on 34)

A compound according to claim 34, wherein the X in —X-aryl is a bond and the aryl is phenyl or naphthyl substituted with one, two or three R5.

### Claim 36 (depends on 35)

A compound according to claim 35, wherein the aryl is naphthyl and the naphthyl is substituted with two R5 groups.

### Claim 37 (depends on 36)

A compound according to claim 36, wherein one R5 is cyano and the second R5 is halogen, alkoxy or cyano.

### Claim 38 (depends on 36)

A compound according to claim 36, wherein one R5 is cyano and the second R5 is halogen or cyano.

### Claim 39 (depends on 36)

A compound according to claim 36, wherein one R5 is cyano and the second R5 is halogen.

### Claim 40 (depends on 35)

A compound according to claim 35, wherein the aryl is naphthyl and the naphthyl is substituted with three R5 groups.

### Claim 41 (depends on 40)

A compound according to claim 40, wherein one R5 is cyano, the second R5 is X-haloalkyl and the third R5 is —X-L-cycloalkyl.

### Claim 42 (depends on 35)

A compound according to claim 35, wherein R6 is hydrogen.

### Claim 43 (depends on 34)

A compound according to claim 34, wherein —X-aryl is phenyl and the phenyl is substituted with one or more R5.

### Claim 44 (depends on 43)

A compound according to claim 43, wherein each R5 is selected from the group consisting of cyano, halogen, —X-L-cycloalkyl, —X-haloalkyl, heterocyclyl, X-heteroaryl, C1-C3 alkyl and alkoxy, wherein each X is a bond or O.

### Claim 45 (depends on 43)

A compound according to claim 43, wherein each R5 is selected from the group consisting of cyano, halogen, —O-cycloalkyl.

### Claim 46 (depends on 45)

A compound according to claim 45, wherein R6 is hydrogen.

### Claim 47 (depends on 34)

A pharmaceutical composition comprising a compound according to claim 34.

### Claim 48 (depends on 34)

A compound according to claim 34, which is 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthonitrile.

### Claim 49 (depends on 34)

A compound which is a salt of the compound of claim 34, wherein the compound is 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthonitrile.

### Claim 50 (depends on 34)

A pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (I) according to claim 34 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

### Claim 51 (depends on 34)

A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula (I) according to claim 34 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents.

### Claim 52 (depends on 51)

The method according to claim 51, wherein the cancer wherein the cancer is selected from the group consisting of bladder cancer, bone cancer, brain cancer, blood cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer and uterine cancer.

### Claim 53 (depends on 51)

The method according to claim 51, wherein the cancer is selected from the group consisting of ovarian serous cystadenocarcinoma, squamous cell lung cancer, lung adenocarcinoma, mesothelioma; esophageal squamous cell carcinoma, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, kidney adenocarcinoma, bladder transitional cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, cholangiocarcinoma; osteosarcoma, multiple myeloma, astrocytoma, glioma, glioblastoma, uterine sarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, malignant melanoma, endometrial carcinoma and thyroid carcinoma.

### Claim 54 (depends on 52)

The method according to claim 52, wherein the cancer is a MTAP-associated cancer.

### Claim 55 (depends on 51)

The method of claim 51, wherein the cancer is hepatocellular carcinoma breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

### Claim 56

A compound of the formula:
wherein
R2 is —X-aryl optionally substituted with one or more R5;
each R5 is independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, —X-haloalkyl, —Z-cycloalkyl, —X-arylC1-C3alkyl, —X-arylC1-C3alkyl substituted with cyano, —X-L-cycloalkyl, —X-L-heteroaryl optionally substituted with one or more C1-C3alkyl or oxo, or —X-aryl;
each X is independently a bond, O, S, —NR4— or —NR4C(O)—;
each Z is independently a bond, —SO—, —SO2—, —CH(OH)— or —C(O)—;
each L is independently a bond or C1-C3 alkylene;
each R4 is independently hydrogen or C1-C3 alkyl;
R6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy; and
Protect represents a nitrogen protecting group.

### Claim 57 (depends on 56)

A compound according to claim 56, wherein R6 is fluoro or chloro.