Heterocyclic compounds and methods of use thereof

摘要

Provided herein are heterocyclic compounds for treatment of CSF1R, FLT3, KIT, and/or PDGFRβ kinase mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions.

主权项

1. A compound having formula VIIb:or a pharmaceutically acceptable salt, a single stereoisomer, a mixture of stereoisomers or a racemic mixture of stereoisomers thereof, wherein:
R1 and R2 are each independently selected from hydrogen or halogen; R3 is hydrogen or alkyl; each Q1 is independently deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, —RuORx, —RuORuN(Ry)(Rz), —RuN(Ry)(Rz), —RuSRx, —RuC(J)Rx, —RuC(J)ORx, —RuC(J)N(Ry)(Rz), —RuS(O)tRw, —RuN(Rx)C(J)Rx, —RuN(Rx)C(J)ORx, —RuN(Rx)S(O)tRw, ═NORd, or —C(═NRy)N(Ry)ORx, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one to three Q3 groups; each Q3 is independently selected from deuterium, halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is —(CR5R6)q—; R5 and R6 are each independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl; Z is O, S, or NH; each W is independently CR8; R8 is hydrogen; W1 is N or C; W2 is N or CR9b; R9b is hydrogen or alkyl; W4 is N or CR11b; W5 is N or CR13; R11b and R13 are each independently hydrogen or Q2; Q2 is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, —RuORx, —RuORuORx, —RuORuN(Ry)(Rz), —RuN(Ry)(Rz), —RuC(J)Rx, —RuC(J)Rx, —RuC(J)ORx, —RuC(J)N(Ry)(Rz), —RuC(J)RuN(Ry)(Rz), —RuC(J)N(Ry)ORx, —C(═NORx)Rx, —RuS(P)tRw, —RuN(Rx)C(J)Rx, —RuN(Rx)C(J)ORx, —RuN(Rx)S(O)tRw or —C(═NRy)N(Ry)ORx, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one to three Q4 groups, each Q4 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Q5 and Q6 are each independently hydrogen, deuterium, halo, cyano, oxo, thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, —RuORx, —RuORuORx, —RuORuN(Ry)(Rz), —RuN(Ry)(Rz), —RuSRx, —RuC(J)Rx, —RuC(J)ORx, —RuC(J)N(Ry)(Rz), —RuC(J)RuN(Ry)(Rz), —RuC(J)N(Ry)ORx, —C(═NORx)Rx, —RuS(O)tRw, —RuN(Rx)C(J)Rx, —RuN(Rx)C(J)ORx, —RuN(Rx)S(O)tRw or —C(═NRy)N(Ry)ORx, where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionally substituted with a Q8 group; each Q8 is independently selected from halo, deuterium, hydroxyl, alkyl, haloalkyl and hydroxyalkyl; each Rd is independently hydrogen or alkyl; each Ru is independently alkylene, alkenylene or a direct bond; Rw is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and Rz are each independently selected from (i) or (ii) below: (i) Ry and Rz are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or (ii) Ry and Rz, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, optionally substituted with one, two or three Q7 groups; each Q7 is independently selected from halo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NRx or S; each t is independently an integer from 0-2; n is 1 or 2; and q is an integer from 0-4.