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 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-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 method of claim 1 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is selected from any one of the following compounds and pharmaceutically acceptable salts thereof:
Compound
Structure
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