# US 2023/0056541 A1 · Egfr inhibitors

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- Number: US 2023/0056541 A1
- Document ID: US20230056541A1
- Status: Published application
- Kind: A1
- Application number: 17/514,457
- Filed: 2021-10-29
- Published: 2023-02-23
- Earliest claimed: 2019-12-23
- Assignees: Blueprint Medicines Corporation
- Applicants: Blueprint Medicines Corporation
- Inventors: John Emmerson Campbell; Thomas A. Dineen; Natasja Brooijmans; Jason D. Brubaker; Meredith Suzanne Eno; Joseph L. Kim; Aysegül Özen; Emanuele Perola; Brett D. Williams; Douglas Wilson; Kevin J. Wilson; Christopher De Savi
- Web page: https://patentgrep.com/patent/US20230056541A1

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- C07D 471/04: Ortho-condensed systems
- C07D 471/08: Bridged systems
- C07D 491/04: Ortho-condensed systems
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 491/08: Bridged systems
- C07D 491/10: Spiro-condensed systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D 491/113: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- C07D 498/08: Bridged systems
- 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
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07B 2200/07: Optical isomers
- 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 provides a compound represented by structural formula (I): or a pharmaceutically acceptable salt thereof useful for treating a cancer.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Z is O or NH;
each A1, A2, and A3 is independently N or CR; wherein each R is independently H, halogen, or CH3;
Ring A is 4-12 membered heterocyclyl;
each R1 is independently halogen, CN, OH, NRaRb, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or —O—C3-C6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl represented by R1 or in the group represented by R1 is optionally substituted with 1 to 3 groups selected from deuterium, halogen, OH, NRaRb, C1-C2 alkyl, and C1-C2 alkoxy; and/or
m is 0, 1, 2, 3, 4, 5, or 6;
R2 is H, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl represented by R2 is optionally substituted with 1 to 3 groups selected from halogen and OH;
R3 is H or methyl;
R4 is H or methyl;
R5 is H, C1-C4 alkyl, C3-C6 cycloalkyl or 4-6 membered monocyclic heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl represented by R5 is optionally substituted with 1 to 3 three groups selected from halogen, CN, OH, NRaRb, C1-C2 alkyl, and C1-C2 alkoxy;
R6 is H or C1-C4 alkyl optionally substituted with 1 to 3 three groups selected from halogen, CN, OH, NRaRb, and C1-C2 alkoxy; and
each Ra and Rb is independently H or C1-C4 alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is represented by structural formula (II-A), (II-B), (II-C), (II-D), or (II-E):
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound is represented by structural formula (II-A):
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein Z is O.

### Claim 5 (depends on 4)

The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R2 is H, fluorine, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl represented by R2 is optionally substituted with 1 to 3 groups selected from halogen and OH.

### Claim 6 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R6 is H, methyl, ethyl, C1-C2 haloalkyl, or C1-C2 aminoalkyl.

### Claim 7 (depends on 6)

The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R5 is H; C1-C4 alkyl optionally substituted with 1 to 3 three groups selected from halogen, CN, and NRaRb; C3-C6 cycloalkyl; or 4-6 membered monocyclic heterocyclyl optionally substituted with C1-C4 alkyl; and wherein Ra and Rb are each independently selected from H, methyl and ethyl.

### Claim 8 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Ring A is 4-7 membered monocyclic heterocyclyl optionally substituted with 1-6 R1.

### Claim 9 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Ring A is 7-12 membered bicyclic heterocyclyl optionally substituted with 1-6 R1.

### Claim 10 (depends on 8)

The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, 4, or 5; and
each R1 is independently halogen, CN, OH, NRaRb, C1-C4 alkyl, C1-C4 alkoxy, —O—C3-C6 cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl represented by R1 or in the group represented by R1 is optionally substituted with 1 to 3 groups selected from deuterium, halogen, OH, NRaRb, C1-C2 alkyl, and C1-C2 alkoxy.

### Claim 11 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R2 is H, F, methyl, ethyl, isopropyl, CH(CH3)CH2F, CH(CH3)CH2OH, CF3, OCH3, OCH2CH3, or cyclopropyl.

### Claim 12 (depends on 11)

The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R6 is H, CH3, or CH2NH2.

### Claim 13 (depends on 12)

The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with 1-6 R1, and Ring A is pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, 6-oxa-2-azabicyclo[3.2.1]octanyl, 6-oxa-3-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, hexahydro-1H-furo[3,4-b]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl or 1,4-dioxa-9-azaspiro[5.5]undecan-9-yl.

### Claim 14 (depends on 13)

The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein at least one R1 is OH, C1-C4 alkoxy, or —O—C3-C6 cycloalkyl, wherein the alkoxy or cycloalkyl represented by R1 or in the group represented by R1 is optionally substituted with 1 to 3 groups selected from deuterium, halogen, OH, NRaRb, C1-C2 alkyl, and C1-C2 alkoxy.

### Claim 15 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently F, CN, OH, NH2, CH3, CH2CH3, CHF2, CH(OH)CH3, CH2OH, CH2NH2, CH2CH2NH2, OCH3, OCD3, OCH2CH2OH, OCH2CH(OH)CH3, OCH2C(OH)(CH3)2, OCH2CH2OCH3, OCH2CH2NH2, OCH2CH2NHCH3, OCH2CH2N(CH3)2, —O-cyclopropyl, NHCH3, or N(CH3)2.

### Claim 16 (depends on 15)

The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein

### Claim 17 (depends on 16)

The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R2 is H or isopropyl.

### Claim 18 (depends on 17)

The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidinyl optionally substituted with 1-6 R1.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

A method of treating a cancer, comprising administering a subject in need thereof an effective amount of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim at position 21

21-25. (canceled)

### Claim 26 (depends on 1)

A method of inhibiting epidermal growth factor receptor (EGFR), comprising administering to a subject in need thereof an effective amount of claim 1, or a pharmaceutically acceptable salt thereof.