Compounds useful for treating disorders related to RET
Described herein are compounds that inhibit wild-type RET and its resistant mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.
1. A compound of structural formula (I) or a pharmaceutically acceptable salt thereof, 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 );
Z is
—CD(R 5 )—, or —CH(R 5 )—, wherein “1” represents a point of attachment to N(R 8 ); and “2” represents a point of attachment to ring A;
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 3 , and R 4 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 8 is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 heteroalkyl, wherein each alkyl and heteroalkyl is independently substituted with 0-5 occurrences of R a ;
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 or a pharmaceutically acceptable salt thereof having the structural formula (Ia):
wherein:
R 1 is halo, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy; and
R 1 is substituted with 0-3 occurrences of R a .
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from hydrogen, C 1 -C 4 alkyl substituted with 0-5 occurrences of R a , C 1 -C 6 alkoxy substituted with 0-5 occurrences of R a , hydroxyl, and halo;
R 3 is hydrogen; or
R 4 is selected from hydrogen, hydroxyl, halo, cyano, C 1 -C 4 alkyl, and O—C 1 -C 4 alkyl, wherein each alkyl portion of R 4 is substituted with 0-3 occurrences of R a .
4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein:
R 2 is hydrogen, fluoro, —CH 3 , —CH 2 CH 3 , —CH 2 OH, —CH 2 CN, —OCH 2 CF 3 , —OCH 2 CH 2 , or OMe; or
R 4 is selected from hydrogen, fluoro, cyano, hydroxyl, —CH 3 , —CH 2 CN, —CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —OCH 3 , —OCH 2 CF 3 , and —OCH 2 CH 3 .
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is selected from
—CH 2 —, and —CH(C 1 -C 4 alkyl)-, wherein the C 1 -C 4 alkyl is substituted with 0-3 occurrences of R a .
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
each R 6 is independently selected from hydrogen, halo, cyano, and C 1 -C 4 alkyl substituted with 0-3 occurrences of R a ; or
R 8 is hydrogen and —CH 3 .
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or a 6-membered monocyclic heteroaryl comprising at least one nitrogen ring atom.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
ring A is selected from
n is 1;
R 7 is selected from 1H-pyrazol-1-yl, azetidin-1-yl, and pyrrolidin-1-yl; and
R 7 is substituted with 0-3 occurrences of R a .
10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from 3-fluoroazetidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, 3-difluoromethyl-1H-pyrazol-1-yl, 4-fluoro-1H-pyrazol-1-yl, 4-chloro-1H-pyrazol-1-yl, 3-difluoromethyl-1H-pyrazol-1-yl, 4-difluoromethyl-1H-pyrazol-1-yl, 4-cyclopropyl-1H-pyrazol-1-yl, 4-fluoro-1H-pyrazol-1-yl, 3,5-bis(difluoromethyl)-1H-pyrazolyl, 3-methyl-1H-pyrazol-1-yl, 4-methyl-1H-pyrazol-1-yl, 3,5-dimethyl-1H-pyrazol-1-yl, and pyrazol-1-yl.
11. A compound having the structural formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is selected from N and C(R 13 );
each Y 1 and Y 2 is independently selected from N and CH, wherein no more than one of Y 1 and Y 2 is N;
Q is selected from N, CH, and CH 2 ;
R 11 is C 1 -C 4 alkyl;
R 12 is selected from hydrogen and C 4 alkyl;
R 13 is selected from hydrogen, cyano, and halo;
R 14 is selected from hydrogen, halo, cyano, hydroxyl, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy;
R 15 is selected from hydrogen and C 1 -C 4 alkyl;
R 16 is selected from hydrogen, and C 1 -C 4 alkyl optionally substituted with 1 or more independently selected halo;
R 17 is selected from hydrogen and C 1 -C 4 alkyl;
each of R 18a , R 19a , R 18b , and R 19b is independently selected from hydrogen, halo, C 1 -C 4 alkyl optionally substituted with one or more halo, and C 3 -C 6 cycloalkyl;
p is 0 or 1; and
each represents a single or a double bond, wherein when is a double bond, one of R 18a or R 18b , and one of R 19a or R 19b , is present.
12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein:
R 11 is —CH 3 ;
R 12 is selected from hydrogen and —CH 3 ;
R 13 is selected from hydrogen, cyano and fluoro;
R 14 is selected from hydrogen, fluoro, cyano, hydroxyl, —CH 3 , —CH 2 CH 3 , —OCH 3 , and —OCH 2 CH 3 ;
R 15 is selected from hydrogen and —CH 3 ;
R 16 is selected from hydrogen, —CH 3 , and —CHF 2 ;
R 17 is selected from hydrogen and —CH 3 ;
each of R 18a and R 19a is independently selected from hydrogen and fluoro, wherein at least one of R 18a or R 19a is hydrogen;
each of R 18b and R 19b is independently selected from hydrogen, fluoro, chloro, —CH 3 , —CHF 2 , and cyclopropyl, wherein at least one of R 18b or R 19b is hydrogen; and
each is the same.
13. A compound having structural formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is selected from N and CH;
Z′ is selected from
or —CH(R 28 )—, wherein “1” represents a point of attachment to N(R 26 ); and “2” represents a point of attachment to ring B;
ring B is selected from phenyl, pyridinyl, 1H-pyrazolyl, and pyrazinyl;
R 21 is selected from C 3 -C 6 cycloalkyl and C 1 -C 4 alkyl;
R 22 is selected from hydrogen and C 1 -C 4 alkyl;
R 23 is selected from hydrogen and cyano;
R 24 is selected from hydrogen, hydroxy, and halo;
R 25 is selected from hydrogen, halo, hydroxy, C 1 -C 4 alkoxy, —C 1 -C 4 alkyl, and —C 1 -C 4 alkyl-O—C 1 -C 4 alkyl, wherein each C 1 -C 4 alkyl is optionally substituted with 1 or more substituents independently selected from halo and cyano;
R 26 is selected from hydrogen and C 1 -C 4 alkyl;
R 27 is independently selected from 1H-pyrazolyl, pyridinyl, and C 1 -C 4 alkoxy, wherein the 1H-pyrazol-1-yl is optionally substituted with up to 2 substituents independently selected from C 1 -C 4 alkyl and halo;
R 28 is selected from hydrogen and C 1 -C 4 alkyl; and
o is 0 or 1.
14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein:
Z′ is selected from
—CH 2 , or —CH(CH 3 )—;
the portion of the molecule represented by
is selected from
R 21 is selected from —CH 3 and cyclopropyl;
R 22 is selected from hydrogen and —CH 3 ;
R 23 is selected from hydrogen and cyano;
R 24 is selected from hydrogen, hydroxy, and fluoro;
R 25 is selected from hydrogen, fluoro, hydroxy, —OCH 3 , —OCH 2 CF 3 , —CH 2 CH 2 OCH 3 , —CH 3 , —CH 2 CH 3 , and —CH 2 CN;
R 26 is selected from hydrogen and —CH 3 ; and
R 37 is selected from hydrogen, —OCH 3 , —OCH 2 CH 3 , 1 H-pyrazol-1-yl, 4-fluoro-1H-pyrazol-1-yl, 3,5-dimethyl-1H-pyrazol-1-yl, and pyridin-2-yl.
15. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. A compound selected from
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and pharmaceutically acceptable salts thereof.
17. 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 pharmaceutically acceptable salt thereof.
18. 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 pharmaceutically acceptable salt thereof.
19. 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 pharmaceutically acceptable salt thereof.
20. 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 pharmaceutically acceptable salt thereof.
21. 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 pharmaceutically acceptable salt thereof.