Compounds useful for treating disorders related to RET

1. A compound having the structural formula (I):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

ring A is an aryl or heteroaryl ring;

each of X 1 and X 2 is independently selected from N and C(R 6′ );

each R 1 and each R 7 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, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, —C(O)R c , —OC(O)R c , —C(O)OR d , —(C 1 -C 6 alkylene)-C(O)R c , —SR d , —S(O) 2 R c , —S(O) 2 —N(R d )(R d ), —(C 1 -C 6 alkylene)-S(O) 2 R c , —(C 1 -C 6 alkylene)-S(O) 2 —N(R d )(R d ), —N(R d )(R d ), —C(O)—N(R d )(R d ), —N(R d )—C(O)R c , —N(R d )—C(O)OR c , —(C 1 -C 6 alkylene)-N(R d )—C(O)R c , —N(R d )S(O) 2 R c , and —P(O)(R c )(R c ), wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a , or two R 1 or two R 7 are taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R b ;

each of R 2 , R 3a , R 3b , R 4 , R 8a , R 8b , R 10a , and R 10b is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, hydroxyl, cyano, C 1 -C 6 heteroalkyl, and —N(R d )(R d ), wherein each of alkyl, alkoxy, and heteroalkyl is independently substituted with 0-5 occurrences of R a ;

each of R 5 and R 9 is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 heteroalkyl, wherein each of alkyl and heteroalkyl is independently substituted with 0-5 occurrences of R a ;

R 6 and each R 6′ is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, cyano, C 1 -C 6 heteroalkyl, and —N(R d )(R d ), wherein each alkyl, alkoxy, and heteroalkyl is independently substituted with 0-5 occurrences of R a ;

each R a and each R b is independently selected from C 1 -C 6 alkyl, halo, hydroxyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, cycloalkyl, heterocyclyl, and cyano, wherein each of alkyl, heteroalkyl, alkoxy, cycloalkyl, and heterocyclyl is independently substituted with 0-5 occurrences of R′;

each R′ is independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, hydroxyl, cycloalkyl, and cyano, or two R′ together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;

each R c 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 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, thioalkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a , or two R c 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 d is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a , or two R d 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 ;

m is 0, 1, or 2; and

n is 0, 1, 2, or 3.

2. The compound of claim 1 having the structural formula (Ia):

or structural formula (Ib):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing,

wherein ring A, X 1 , X 2 , R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9 , R 10a , R 10b , m, and n are as defined in claim 1 .

3. The compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

m is 1;

R 1 is located at the 5-position; and

R 1 is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, wherein R 1 is substituted with 0-3 occurrences of R a .

4. The compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

R 1 is CH 3 or cyclopropyl;

R 2 is hydrogen or hydroxyl;

each of R 3a , R 3b , R 8a , R 8b , R 10a , and R 10b is hydrogen;

R 4 is hydrogen or C 1 -C 4 alkyl substituted with 0-3 occurrences of R a ;

R 5 is hydrogen or C 1 -C 4 alkyl substituted with 0-3 occurrences of R a ; or

R 6 is C 1 -C 4 alkyl substituted with 0-3 occurrences of R a .

5. The compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

R 4 is hydrogen or CH 3 ;

R 5 is hydrogen or CH 3 ;

R 6 is CH 3 ;

each R 6′ is hydrogen; or

R 9 is hydrogen.

6. The compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein ring A is a 6-membered monocyclic heteroaryl comprising at least one nitrogen ring atom or phenyl.

7. The compound of claim 6 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein ring A is selected from:

8. The compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

n is 0 or 1; and

R 7 is selected from pyrazol-1-yl substituted with 0-3 occurrences of R a and C 1 -C 4 alkoxy substituted with 0-3 occurrences of R a .

9. The compound of claim 8 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

n is 0; or

n is 1 and R 7 is selected from 4-fluoropyrazol-1-yl, 4-chloropyrazol-1-yl, 3,5-dimethylpyrazol-1-yl, pyrazol-1-yl, and ethoxy.

10. The compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

X 1 is C(R 6′ ) and X 2 is N; or

X 1 is C(R 6′ ) and X 2 is C(R 6′ ).

11. A compound having the structural formula (II):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

X 2 is selected from N and CH;

X 3 is selected from N and CH;

each R 11 is independently selected from halo and C 1 -C 4 alkyl substituted with 0-3 occurrences of R a ;

R 12 is hydrogen or hydroxyl;

R 13 is selected from C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl, wherein R 13 is substituted with 0-3 occurrences of R a ;

R 14 is selected from hydrogen and C 1 -C 4 alkyl substituted with 0-3 occurrences of R a ;

R 15 is selected from hydrogen and C 1 -C 4 alkyl substituted with 0-3 occurrences of R a ;

R 16 is selected from hydrogen and C 1 -C 4 alkyl substituted with 0-3 occurrences of R a ;

q is 0, 1, or 2;

each R a is independently selected from C 1 -C 6 alkyl, halo, hydroxyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, cycloalkyl, heterocyclyl, and cyano, wherein each of alkyl, heteroalkyl, alkoxy, cycloalkyl, and heterocyclyl is independently substituted with 0-5 occurrences of R′; and

each R′ is independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, hydroxyl, cycloalkyl, and cyano, or two R′ together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring.

12. The compound of claim 11 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

each R 11 is independently selected from fluoro and CH 3 ;

R 13 is selected from CH 3 and cyclopropyl;

R 14 is selected from hydrogen and CH 3 ;

R 15 is selected from hydrogen and CH 3 ; and

R 16 is CH 3 .

13. A compound having the structural formula (III):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

X 2 is selected from N and CH;

R 12 is hydrogen or hydroxyl;

R 13 is selected from C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, wherein R 13 is substituted with 0-3 occurrences of R a ;

R 14 is selected from hydrogen and C 1 -C 4 alkyl substituted with 0-3 occurrences of R a ;

R 15 is selected from hydrogen and C 1 -C 4 alkyl substituted with 0-3 occurrences of R a ;

R 16 is selected from hydrogen and C 1 -C 4 alkyl substituted with 0-3 occurrences of R a ;

R 17 is selected from hydrogen, C 1 -C 4 alkyl substituted with 0-3 occurrences of R a , and O—C 1 -C 4 alkyl substituted with 0-3 occurrences of R a ;

each R a is independently selected from C 1 -C 6 alkyl, halo, hydroxyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, cycloalkyl, heterocyclyl, and cyano, wherein each of alkyl, heteroalkyl, alkoxy, cycloalkyl, and heterocyclyl is independently substituted with 0-5 occurrences of R′; and

each R′ is independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, hydroxyl, cycloalkyl, and cyano, or two R′ together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring.

14. The compound of claim 13 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:

R 13 is selected from CH 3 and cyclopropyl;

R 14 is selected from hydrogen and CH 3 ;

R 15 is selected from hydrogen and CH 3 ;

R 16 is CH 3 ; and

R 17 is selected from hydrogen and OCH 3 .

15. A pharmaceutical composition comprising:

a compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing; and

a pharmaceutically acceptable carrier.

16. A method for treating a subject suffering from non-small cell lung cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing.

17. A method for treating a subject suffering from papillary thyroid cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing.

18. A method for treating a subject suffering from medullary thyroid cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing.

19. A method for treating a subject suffering from colorectal cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing.

20. A method for treating a subject suffering from multiple endocrine neoplasia, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of either of the foregoing.

21. A compound selected from:

Compound

#

Structure

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

and pharmaceutically acceptable salts thereof.