HETEROCYCLIC COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
Provided herein are compounds having the following structure: wherein the substituents are as defined herein, compositions comprising an effective amount of a compound, and methods for modulating activity of KRAS G12D and/or G12V.
1 . A compound of formula (I):
or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof,
wherein:
ring A is
X is N, or C—R 2 ;
Y is N, or C—CN;
Z is N, or C—R 3 ;
W is N, or C—R 5 ;
V is N, or C—R 7 ;
R 1 is —NR 1a R 1b ;
R 2 is halogen, or unsubstituted or substituted alkyl;
R 3 is halogen, or unsubstituted or substituted alkyl;
R 4 is halogen, —NO 2 , or unsubstituted or substituted alkyl;
R 5 is hydrogen, halogen, or —CN;
R 7 is hydrogen, halogen, or —CN;
each of R 8 , R 9 , and R 10 is independently hydrogen, halogen, unsubstituted or substituted alkyl, or —OH;
R 1a and R 1b are each independently hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclylalkyl, provided that R 1a and R 1b are not both hydrogen; or
R 1a and R 1b , together with the nitrogen atom to which they are attached to, form an unsubstituted or substituted heterocyclyl.
2 . The compound of claim 1 ,
wherein ring A is
3 . The compound of claim 2 , wherein Y is N.
4 . The compound of claim 2 , wherein Y is C—CN.
5 . The compound of claim 2 , wherein X is C—R 2 .
6 . The compound of claim 2 , wherein R 2 is halogen, or alkyl which is unsubstituted or substituted by halogen; preferably Cl, or CF 3 ; more preferably CF 3 .
7 . The compound of claim 2 , wherein R 1 is —NHR 1a .
8 . The compound of claim 7 , wherein R 1a is unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl, wherein at least one ring of R 1a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; preferably cyclopropyl.
9 . The compound of claim 1 ,
wherein ring A is
10 . The compound of claim 9 , wherein X is C—R 2 .
11 . The compound of claim 2 , wherein R 1a and R 1b , together with the nitrogen atom to which they are attached to, form an unsubstituted or substituted monocyclic heterocyclyl or an unsubstituted or substituted spiro heterocyclyl, said unsubstituted or substituted monocyclic heterocyclyl or the unsubstituted or substituted spiro heterocyclyl comprises zero or one or two additional heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur, preferably R 1 is unsubstituted or substituted heterocyclyl selected from unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidyl, unsubstituted or substituted piperidyl, unsubstituted or substituted azepanyl, unsubstituted or substituted
unsubstituted or substituted
unsubstituted or substituted
unsubstituted or substituted
or unsubstituted or substituted
12 . The compound of claim 1 ,
wherein ring A is
13 . The compound of claim 12 , wherein X is C—R 2 .
14 . The compound of claim 13 , wherein R 2 is halogen, or alkyl which is unsubstituted or substituted by halogen; preferably Cl, or CF 3 ; more preferably Cl.
15 . The compound of claim 14 , wherein ring A is
16 . The compound of claim 12 , wherein R 1a and R 1b , together with the nitrogen atom to which they are attached to, form an unsubstituted or substituted monocyclic heterocyclyl or an unsubstituted or substituted spiro heterocyclyl, said unsubstituted or substituted monocyclic heterocyclyl or the unsubstituted or substituted spiro heterocyclyl comprises zero, one, or two additional heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur; preferably R 1 is unsubstituted or substituted heterocyclyl selected from unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidyl, unsubstituted or substituted piperidyl, unsubstituted or substituted morpholinyl, or unsubstituted or substituted
17 . The compound of claim 12 , wherein R 1 is
18 . The compound of claim 17 ,
wherein ring A is
19 . The compound of claim 12 , wherein X is N.
20 . The compound of claim 19 , wherein ring A is
21 . The compound of claim 19 , wherein R 1 is —NHR 1a .
22 . The compound of claim 21 , wherein R 1a is unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl, wherein at least one ring of R 1a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; preferably cyclopropyl.
23 . The compound of claim 19 , wherein R 1a and R 1b , together with the nitrogen atom to which they are attached to, form an unsubstituted or substituted monocyclic heterocyclyl or an unsubstituted or substituted spiro heterocyclyl, said unsubstituted or substituted monocyclic heterocyclyl or the unsubstituted or substituted spiro heterocyclyl comprises zero or one or two additional heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur, preferably at least one ring of R 1 is piperidyl, or morpholinyl.
24 . The compound of claim 23 , wherein R 1 is optionally substituted by one or more C 1-4 alkyl, halogen, —CN, or —OH, wherein each of the C 1-4 alkyl is independently optionally substituted by one or more halogen, —CN, or —OH.
25 . The compound of claim 19 , wherein R 1 is
26 . The compound of claim 25 , wherein ring A is
27 . The compound of claim 1 , wherein R 1a and R 1b , together with the nitrogen atom to which they are attached to, form unsubstituted or substituted monocyclic heterocyclyl, unsubstituted or substituted bicyclic heterocyclyl, unsubstituted or substituted tricyclic heterocyclyl, or unsubstituted or substituted spirocyclic heterocyclyl.
28 . The compound of claim 1 , wherein R 1 is not unsubstituted or substituted piperazinyl.
29 . The compound of claim 1 , wherein R 1 is not unsubstituted or substituted
unsubstituted or substituted
unsubstituted or substituted
unsubstituted or substituted
unsubstituted or substituted
, unsubstituted or substituted
or unsubstituted or substituted
30 . The compound of claim 1 , wherein R 1 is not unsubstituted or substituted 3,8-diazabicyclo[3.2.1]octan-3-yl, or unsubstituted or substituted
31 . The compound of claim 1 , wherein the compound is selected from Table 1, Table 2 and Table 3.
32 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, isotopologue, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.
33 . A method for inhibiting the activity of KRAS mutant protein in a cell, comprising contacting said cell with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, isotopologue, stereoisomer, or prodrug thereof, optionally wherein the KRAS mutant protein is KRAS G12D and/or G12V mutant protein.
34 . A method for treatment or prevention of cancer, the method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, isotopologue, stereoisomer, or prodrug thereof, optionally wherein the cancer is mediated by KRAS mutation; preferably KRAS G12D and/or G12V mutation.