2-(pyridin-3-yl)-pyrimidine derivatives as RET inhibitors

Patent metadata

Field	Value
Publication number	US-10774070-B2
Application number	US-201816228381-A
Country	US
Kind code	B2
Filing date	Dec 20, 2018
Priority date	Feb 6, 2015
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

Described herein are compounds, such as compounds of Formula (I) and pharmaceutically acceptable salts thereof, that inhibit wild-type RET and its resistant mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions, e.g., for treating a condition mediated by aberrant RET activity

First claim

The invention claimed is:

1. A method for treating a subject suffering from a cancer, wherein said cancer is selected from papillary thyroid cancer (PTC), medullary thyroid cancer (MTC), pheochromocytoma (PC), pancreatic ductal adenocarcinoma, multiple endocrine neoplasia (MEN2A and MEN2B), metastatic breast cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer, chronic myelomonocytic leukemia, colorectal cancer, ovarian cancer, and cancers of the salivary gland, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

ring A is 1H-pyrazol-3-yl;
ring B is selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;
L 1 is —NH—;
L 2 is selected from —(C 1 -C 6 alkylene)-, —(C 2 -C 6 alkenylene)-, —(C 2 -C 6 alkynylene)-, —(C 1 -C 6 haloalkylene)-, —(C 1 -C 6 heteroalkylene)-, —C(O)—, —O—, —S—, —S(O), —S(O) 2 —, —N(R 1 )—, —O—(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-O—, —N(R 1 )—C(O)—, —C(O)—N(R 1 )—, —(C 1 -C 6 alkylene)-N(R 1 )—, —N(R 1 )—(C 1 -C 6 alkylene)-, —N(R 1 )—C(O)—(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-N(R 1 )—C(O)—, —C(O)—N(R 1 )—(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-C(O)—N(R 1 )—, —N(R 1 )—S(O) 2 —, —S(O) 2 —N(R 1 )—, —N(R 1 )—S(O) 2 —(C 1 -C 6 alkylene)-, and S(O) 2 —N(R 1 )—(C 1 -C 6 alkylene)-, wherein each alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene is independently substituted with 0-5 occurrences of R′;
each R A is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, and —N(R 1 )(R 1 ), wherein each alkyl, alkoxy, haloalkyl, hydroxyalkyl, and hydroxyalkyl is independently substituted with 0-5 occurrences of R a ;
R B is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 hydroxyalkyl;
R C is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 hydroxyalkyl;
each R D is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halo, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, —C(O)R 1 , —OC(O)R 1 , —C(O)OR 1 , —(C 1 -C 6 alkylene)-C(O)R 1 , —SR 1 , —S(O) 2 R 1 , —S(O) 2 —N(R 1 )(R 1 ), —(C 1 -C 6 alkylene)-S(O) 2 R 1 , —(C 1 -C 6 alkylene)-S(O) 2 —N(R 1 )(R 1 ), —N(R 1 )(R 1 ), —C(O)—N(R 1 )(R 1 ), —N(R 1 )—C(O)R 1 , —N(R 1 )—C(O)OR 1 , —(C 1 -C 6 alkylene)-N(R 1 )—C(O)R 1 , —N(R 1 )S(O) 2 R 1 , and —P(O)(R 1 )(R 1 ), wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a , or 2 R C or 2 R D together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R a ;
each R 1 is independently selected from hydrogen, hydroxyl, halo, thiol, C 1 -C 6 alkyl, C 1 -C 6 thioalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, thioalkyl, alkoxy, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R b , or 2 R 1 together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R b ;
each R a and R b is independently C 1 -C 6 alkyl, halo, hydroxyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, cycloalkyl, heterocyclyl, or cyano, wherein each of alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, cycloalkyl, and heterocyclyl is independently substituted with 0-5 occurrences of R′;
each R′ is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, hydroxyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, or cyano, or 2 R′ together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;
m is 0, 1, 2, or 3;
n is 1;
p is 1; and
q is 0, 1, 2, 3, or 4.

2. The method of claim 1 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound having structural Formula I(b):

or a pharmaceutically acceptable salt thereof, wherein L 2 is —C(O)—N(R 1 )—(C 1 -C 6 alkylene)-, and wherein C 1 -C 6 alkylene is substituted with 0-5 occurrences of R′.

3. The method of claim 1 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound having structural Formula I(c):

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein the portion of the compound represented by

is 5-methyl-1H-pyrazol-1-yl.

5. The method of claim 1 , wherein L 2 is selected from *—C(O)—, *—N(R 1 )—C(O)—, and *—(C 1 -C 6 alkylene)-N(R 1 )—C(O)—, wherein the C 1 -C 6 alkylene portion of L 2 is substituted with 0-5 occurrences of R′, and wherein “*” represents a portion of L 2 bound to ring B.

6. The method of claim 5 , wherein L 2 is selected from *—C(O)— and *—(C 1 -C 6 alkylene)-N(R 1 )—C(O)—, wherein the C 1 -C 6 alkylene portion of L 2 is substituted with 0-5 occurrences of R′.

7. The method of claim 1 , wherein L 2 is selected from *—C(O)—, *—CH 2 —NH—C(O)—, *—CH(CH 3 )—NH—C(O)—, and *—CH(CH 2 CH 3 )—NH—C(O)—.

8. The method of claim 3 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound having structural Formula I(d):

or a pharmaceutically acceptable salt thereof.

9. The method of claim 3 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound having structural Formula I(e):

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein R 1 is hydrogen.

11. The method of claim 1 , wherein:
m is 0 or 1; or
q is 0, 1, or 2.

12. The method of claim 11 , wherein:
m is 0, or
m is 1 and R A is methyl or fluoro;
R B is methyl; or
q is 1 or 2 and each R D is independently selected from fluoro, chloro, methyl, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —O—CHF 2 , —O—CF 3 , and 1H-pyrazol-1-yl independently substituted with 0-5 occurrences of R a .

13. The method of claim 12 , wherein each R D is independently selected from fluoro, chloro, methyl, —O—CH 3 , —O—CH 2 CH 3 , —O—CH(CH 3 ) 2 , —O—CHF 2 , —O—CF 3 , 4-methyl-1H-pyrazol-1-yl, 1H-pyrazol-1-yl, 4-fluoro-1H-pyrazol-1-yl, 4-cyano-1H-pyrazol-1-yl, 3,5-dimethyl-1H-pyrazol-1-yl, 3-cyclopropyl-1H-pyrazol-1-yl, 4-cycloprop

Assignees

• Blueprint Medicines Corp

Inventors

• Brooijmans Natasja
• Dipietro Lucian V
• Fleming Paul E
• Kim Joseph L
• Wenglowsky Steven Mark
• Zhang Yulian

Classifications

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title