# US 2023/0056631 A1 · Tricyclic compounds as inhibitors of kras

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- Number: US 2023/0056631 A1
- Document ID: US20230056631A1
- Status: Published application
- Kind: A1
- Application number: 17/810,915
- Filed: 2022-07-06
- Published: 2023-02-23
- Earliest claimed: 2021-07-07
- Assignees: Incyte Corporation
- Applicants: Incyte Corporation
- Inventors: Pei Gan; Jeffrey Yang; Yong Li; Le Zhao; Chunhong He; Chunyin Marshall Law; Xiaozhao Wang; Wenqing Yao
- Web page: https://patentgrep.com/patent/US20230056631A1

## CPC

- C07D 471/04: Ortho-condensed systems
- 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 37/00: Drugs for immunological or allergic disorders
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are compounds of Formula I, methods of using the compounds for inhibiting KRAS activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with KRAS activity such as cancer.

## Claims

### Claim 1

A compound having Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y is N or OH;
R1 is selected from Cl, CH3, CH2F, CHF2, and OF3;
Cy1 is selected from
R2 is selected from F and Cl;
R3 is selected from
and,
Cy2 is selected from
provided that the compound of Formula I is other than,
2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-4-(3-(dimethylamino)-3-
methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-
1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile,
2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(2,3-
dimethylphenyl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-
yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile, and
2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(6-
fluoro-5-methyl-1H-indazol-4-yl)-8-methyl-1H-[1,2,3]triazolo[4,5-
c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound of Formula I is a compound of Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from Cl and CH3;
Cy1 is selected from
R3 is selected from
and,
Cy2 is selected from

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
Y is N or OH;
R1 is selected from Cl, CH3, CH2F, CHF2, and OF3;
Cy1 is selected from
R2 is selected from F and Cl;
R is selected from
and,
Cy2 is selected from
provided that the compound of Formula I is other than
2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-4-(3-(dimethylamino)-3-
methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-
1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile and
2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(2,3-
dimethylphenyl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-
yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
Y is N or OH;
R1 is selected from Cl, CH3, CH2F, CHF2, and OF3;
Cy1 is selected from
R2 is selected from F and Cl;
R3 is selected from
and,
Cy2 is selected from

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is N.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy1 is selected from Cy1-a, Cy1-b, Cy1-c, Cy1-d, and Cy1-e.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy1 is selected from Cy1-f, Cy1-g, Cy1-h, Cy1-i, Cy1-j, and Cy1-k.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy1 is selected from Cy1-a and Cy1-b.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy1 is selected from Cy1-1, Cy1-m, Cy1-n, Cy1-o, Cy1-p, Cy1-q, Cy1-r, Cy1-s, and Cy1-t.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy1 is selected from Cy1-c, Cy1-m, Cy1-n, Cy1-o, Cy1-p, Cy1-q, Cy1-r, Cy1-s, and Cy1-t.

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CH3, CH2F, CHF2, and CF3.

### Claim 13 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CH3 and CF3.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is F.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is Cl.

### Claim 16 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from R3-a and R3-b.

### Claim 17 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from R3-b and R3-c.

### Claim 18 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy2 is selected from Cy2-a, Cy2-b, and Cy2-d.

### Claim 19 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy2 is selected from Cy2-a and Cy2-b.

### Claim 20 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy2 is selected from Cy2-b and Cy2-d.

### Claim 21 (depends on 1)

The compound of claim 1, wherein the compound of Formula I is selected from
2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(2-methoxy-3-methylphenyl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(7-(3-chloro-2-methoxyphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;
1-(4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)piperidin-1-yl)prop-2-en-1-one;
2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(2,3-dimethylphenyl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-6-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6-fluoro-8-methyl-7-(6-methylpyridin-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6-fluoro-7-(4-fluorophenyl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;
8-(1-(1-acryloylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile;
2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;
8-(1-((2R,4S)-1-acryloyl-2-methylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile;
2-((2S,4S)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)azetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;
8-(6-fluoro-1-(1-((E)-4-fluorobut-2-enoyl)piperidin-4-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile;
8-(1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile;
2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; and
2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

The compound of claim 1, wherein the compound of Formula I is selected from:
2-((2S,4S)-4-(6-fluoro-7-(4-fluoroisoquinolin-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6-fluoro-7-(4-fluoroisoquinolin-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6-fluoro-8-methyl-7-(3-methylisoquinolin-4-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6-fluoro-8-methyl-7-(3-methylisoquinolin-4-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6-fluoro-7-(7-fluoro-2-methylquinolin-8-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methylisoquinolin-4-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6-fluoro-7-(7-fluoroquinolin-8-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;
2-(4-(1-((2R,4S)-1-acryloyl-2-methylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-methyl-1H-indazol-3-yl)acetonitrile;
2-((2S,4S)-4-(4-(3-(ethyl(methyl)amino)-3-methylazetidin-1-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;
2-(4-(1-((2R,4S)-1-acryloyl-2-methylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-methyl-1H-indol-3-yl)acetonitrile;
2-(4-(1-(1-acryloylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-methyl-1H-indol-3-yl)acetonitrile;
2-((2S,4S)-4-(8-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)-3-methylazetidin-1-yl)-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;
2-((2S,4S)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; and
2-((2S,4S)-4-(8-chloro-4-(3-(ethyl(methyl)amino)-3-methylazetidin-1-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

### Claim 24 (depends on 1)

A method of inhibiting KRAS activity, said method comprising contacting a compound of claim 1, with KRAS.

### Claim 25 (depends on 24)

The method of claim 24, wherein the contacting comprises administering the compound to a patient.

### Claim 26 (depends on 1)

A method of treating a disease or disorder associated with inhibition of KRAS interaction, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

### Claim 27 (depends on 1)

A method of treating a disease or disorder associated with inhibiting a KRAS protein harboring a G12C mutation, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

### Claim 28 (depends on 1)

A method for treating a cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of the compound of claim 1.

### Claim 29 (depends on 28)

The method of claim 28, wherein the cancer is selected from carcinomas, hematological cancers, sarcomas, and glioblastoma.

### Claim 30 (depends on 29)

The method of claim 29, wherein the hematological cancer is selected from myeloproliferative neoplasms, myelodysplastic syndrome, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, and multiple myeloma.

### Claim 31 (depends on 29)

The method of claim 29, wherein the carcinomas is selected from pancreatic, colorectal, lung, bladder, gastric, esophageal, breast, head and neck, cervical, skin, and thyroid.

### Claim 32 (depends on 26)

The method of claim 26, wherein the disease or disorder is an immunological or inflammatory disorder.

### Claim 33 (depends on 31)

The method of claim 31, wherein the immunological or inflammatory disorder is Ras-associated lymphoproliferative disorder and juvenile myelomonocytic leukemia caused by somatic mutations of KRAS.