# US 10,370,379 B2 · Compounds and compositions useful for treating disorders related to NTRK

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- Number: US 10,370,379 B2
- Document ID: US10370379B2
- Status: Granted
- Kind: B2
- Application number: 15/355,425
- Filed: 2016-11-18
- Published: 2017-05-25
- Granted: 2019-08-06
- Earliest claimed: 2015-11-19
- Assignees: Blueprint Medicines Corporation
- Applicants: Blueprint Medicines Corporation
- Inventors: Steven Mark Wenglowsky; Chandrasekhar V. Miduturu; Neil Bifulco, Jr.; Joseph L. Kim
- Web page: https://patentgrep.com/patent/US10370379B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This disclosure relates to inhibitors of NTRK that are active against wild-type NTRK and its resistant mutants, such as compounds of Formula I:

## Claims

### Claim 1

A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from cycloalkyl and heterocyclyl;
each RA is independently selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, C1-C6 alkyl, C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, —N(R1)(R1), cyano, —C(O)R1, —OC(O)R1, —C(O)OR1, —SR1, —S(O)2R1, —S(O)2—N(R2)(R2), —(C1-C6 alkylene)—S(O)2—N(R2)(R2), —C(O)—N(R2)(R2), —N(R2)(R2)—C(O)R1, —(C1-C6 alkylene)—N(R2)—C(O)R1, —NR2S(O)2R1, —P(O)(R1)(R1), and —OR1, wherein:
each of aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 heteroalkyl is independently substituted with 0-5 occurrences of Ra; and
wherein at least one RA is halo;
each RB is independently selected from halo;
each R1 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Rb;
each R2 is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 heteroalkyl; or 2 R2 together with the nitrogen to which they are attached form a heterocyclyl ring substituted with 0-5 occurrences of Rb;
each Ra is independently selected from halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, —N(R″)(R″), —C(O)—N(R″)(R″), —N(R″)(R″)—C(O)R′, and —(C1-C6 alkylene)—N(R″)—C(O)R′;
each Rb is independently selected from halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, —N(R″)(R″), —C(O)—N(R″)(R″), N(R″)(R″)—C(O)R′, and —(C1-C6 alkylene)-N(R″)—C(O)R′;
each R′ is independently selected from hydrogen, C1-C6 alkyl and C1-C6 hydroxyalkyl;
each R″ is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 hydroxyalkyl;
m is 1, 2, 3, 4 or 5; and
n is 0, 1 or 2.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula (Ia-1):

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula (Ib):

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein one RA is halo and one R A is monocyclic or bicyclic arl or monocyclic or bicyclic heteroaryl.

### Claim 5 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds in the table below:
Compound
Number
Structure
1
2
3
4
6
7
8
9
10
11
12
13
15
17
18

### Claim 6

A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein:
Ring A is selected from cycloalkyl and heterocyclyl;
each RA is independently selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, C1-C6 alkyl, C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, —N(R1)(R1), cyano, —C(O)R1, —OC(O)R1, —C(O)OR1, —SR1, —S(O)2R1, —S(O)2—N(R2)(R2), —(C1-C6 alkylene)—S(O)2—N(R2)(R2), —C(O)—N(R2)(R2), —N(R2)(R2)—C(O)R1, —(C1-C6 alkylene)—N(R2)—C(O)R1, —NR2S(O)2R1, —P(O)(R1)(R1), and —OR1, wherein:
each of aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 heteroalkyl is independently substituted with 0-5 occurrences of Ra; and
wherein at least one RA is halo;
each RB is independently selected from halo;
each R1 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Rb;
each R2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl; or 2 R2 together with the nitrogen to which they are attached form a heterocyclyl ring substituted with 0-5 occurrences of Rb;
each Ra is independently selected from halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, —N(R″)(R″), —C(O)—N(R″)(R″), —N(R″)(R″)—C(O)R′, and —(C1-C6 alkylene)—N(R″)—C(O)R′;
each Rb is independently selected from halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, —N(R″)(R″), —C(O)—N(R″)(R″), N(R″)(R″)—C(O)R′, and —(C1-C6 alkylene) —N(R″) —C(O)R′;
each R′ is independently selected from hydrogen and C1-C6 alkyl or C1-C6 hydroxyalkyl;
each R″ is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 hydroxyalkyl;
m is 1, 2, 3, 4 or 5; and
n is 0, 1 or 2.

### Claim 7

A compound selected from
and pharmaceutically acceptable salts thereof.

### Claim 8

A compound selected from
and pharmaceutically acceptable salts thereof.

### Claim 9

A compound selected from
and pharmaceutically acceptable salts thereof.

### Claim 10

A compound selected from
and pharmaceutically acceptable salts thereof.

### Claim 11

A compound selected from
and pharmaceutically acceptable salts thereof.

### Claim 12 (depends on 2)

The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein each RA is independently selected from halo.