2-(pyridin-3-yl)-pyrimidine derivatives as RET inhibitors
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
1. 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 compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the portion of the compound represented by
is 5-methyl-1H-pyrazol-1-yl.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 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.
4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, 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′.
5. The compound of claim 1 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′.
6. The compound of claim 3 or a pharmaceutically acceptable salt thereof, 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)—.
7. The compound of claim 5 having structural Formula I(c):
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7 having structural Formula I(d):
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 7 having structural Formula I(e):
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
m is 0 or 1; or
q is 0, 1, or 2.
12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, 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 compound of claim 12 or a pharmaceutically acceptable salt thereof, 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-cyclopropyl-1H-pyrazol-1-yl, 4-(1-hydroxyethyl)-1H-pyrazol-1-yl, 4-difluoromethyl-1H-pyrazol-1-yl, and 3-methyl-4-difluoromethyl-1H-pyrazol-1-yl.
14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound or the pharmaceutically acceptable salt thereof is selected from any one of the following compounds and pharmaceutically acceptable salts thereof:
Compound
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
15. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.