# US 12,110,289 B2 · Heterocyclic compounds, preparation methods and uses thereof

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- Number: US 12,110,289 B2
- Document ID: US12110289B2
- Status: Granted
- Kind: B2
- Application number: 17/365,503
- Filed: 2021-07-01
- Published: 2021-11-18
- Granted: 2024-10-08
- Earliest claimed: 2020-05-20
- Assignees: Inventisbio Co., Ltd.
- Applicants: InventisBio Co., Ltd.
- Inventors: Xing Dai; Yaolin Wang; Yueheng Jiang; Yanqin Liu; Zhe Shi; Zhenwu Wang; Liangshan Tao; Zixing Han; Haotao Niu; Jifang Weng
- Web page: https://patentgrep.com/patent/US12110289B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/282: Platinum compounds
- A61K 31/438: The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 33/243: Platinum; Compounds thereof
- A61P 35/00: Antineoplastic agents
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are novel compounds, for example, compounds having a Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. Also provided herein are methods of preparing the compounds and methods of using the compounds, for example, in inhibiting KRAS G12C in a cell, and/or in treating various cancer such as pancreatic cancer, endometrial cancer, colorectal cancer, or lung cancer (e.g., non-small cell lung cancer).

## Claims

### Claim 1

A compound of Formula I-1 or I-2, or a pharmaceutically acceptable salt thereof:
wherein:
X is O, S, N, or NR10,
wherein R10 is hydrogen, an optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C1-4 heteroalkyl, optionally substituted C3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group;
each of A3, A4, and A5 is independently CR30 or N,
wherein R30 at each occurrence is independently hydrogen, F, Cl, C1-4 alkyl, or C1-4 alkoxy;
R2 and R3 are each independently hydrogen, halogen, —OH, —CN, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or optionally substituted C1-4 alkoxy;
Het is a 4-10 membered heterocyclic ring, optionally substituted with independently selected R4 group(s), (R4)n, wherein n is 0, 1, 2, or 3, and R4 at each occurrence is independently C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3 or 4 membered ring, fluorine substituted C1-4 alkyl, hydroxyl substituted C1-4 alkyl, or cyano substituted C1-4 alkyl;
or two R4 groups can join together to form a 3-6 membered ring structure;
R7 is hydrogen, halogen, CN, a 3-4 membered ring, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, or optionally substituted C1-4 alkoxy;
R8 is an optionally substituted aryl or optionally substituted heteroaryl;
each of J1 and J2 is independently selected from O, S, N, CR40, and NR41, wherein each of R40 and R41 at each occurrence is independently hydrogen, OH, CN, halogen, an optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, an optionally substituted C1-4 alkoxy, optionally substituted C1-4 heteroalkyl, optionally substituted C3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring,
R5 and R6 are each independently hydrogen, halogen, —CN, —COOR23A, —CONR21AR22A, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 carbocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 4 to 7 membered heterocyclic ring, or R5 and R6 can join together to form an optionally substituted C3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring, wherein each of R21A and R22A at each occurrence is independently hydrogen, an optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C1-4 heteroalkyl, optionally substituted C3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group; and R23A at each occurrence is independently hydrogen, an optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C1-4 heteroalkyl, optionally substituted C3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group;
wherein the dotted line indicates that the respective connection is a single or double bond, provided that the bicyclic ring as a whole is aromatic.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized as having Formula I-3A, I-3B, I-3C, I-4A, I-4B, or I-4C:
wherein A2 is CH or N, and each of R10, R40 and R41 at each occurrence is independently hydrogen or a C1-4 alkyl.

### Claim 3 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are independently selected from hydrogen, C1-4 alkyl optionally substituted with 1-3 fluorine, C3-6 cycloalkyl, and halogen.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are both isopropyl or both cyclopropyl.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,
the moiety of
is represented by
wherein n is 0, 1, or 2, wherein when n is 1 or 2, R4 at each occurrence is independently methyl, ethyl, —CF3, —CF2H, —CH2OH, or —CH2CN.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A3 is N, A4 is CH, and A5 is N.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is hydrogen, F, Cl, methyl, or CF3.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R8 is a phenyl optionally substituted with 1-3 groups each independently selected from F, C1, —OH, NH2, protected hydroxyl group, protected amino group, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3 or 4 membered ring, C1-4 alkoxy, fluorine substituted C1-4 alkyl, and fluorine substituted C1-4 alkoxy.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R8 is a bicyclic heteroaryl optionally substituted with 1-3 groups each independently selected from F, Cl, —OH, NH2, protected hydroxyl group, protected amino group, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3 or 4 membered ring, C1-4 alkoxy, fluorine substituted C1-4 alkyl, and fluorine substituted C1-4 alkoxy.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R8 is selected from:

### Claim 11 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

### Claim 12 (depends on 1)

A method of inhibiting KRAS G12C mutant protein in a cell, the method comprising contacting the cell with the compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 13)

The method of claim 13, wherein the cancer is a hematologic malignancy, lung cancer, pancreatic cancer, endometrial cancer, gall bladder cancer, thyroid cancer, bile duct cancer, and/or colorectal cancer.

### Claim 15 (depends on 13)

The method of claim 13, further comprising treating the subject with an additional therapy.

### Claim 16 (depends on 15)

The method of claim 15, wherein the additional therapy is a chemotherapeutic agent, therapeutic antibody, radiation, cell therapy, or immunotherapy.

### Claim 17 (depends on 13)

The method of claim 13, wherein the subject has a G12C mutation of KRAS, HRAS and/or NRAS.