Solid forms of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-B]indol-2-yl)-2,2-difluoropropan-1-ol and processes for preparing fused tricyclic compounds comprising a substituted phenyl or pyridinyl moiety, including methods of their use
Provided herein are solid forms, salts, and formulations of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, processes and synthesis thereof, and methods of their use in the treatment of cancer.
1 . A process for preparing a compound of formula (IV) or a salt thereof, the process comprising:
(a) reacting a reaction mixture comprising a compound of formula (I), an organic solvent and thionyl chloride to form a compound of formula (IIa) according to step 1 below, and reacting a reaction mixture comprising the compound of formula (IIa), a catalyst, an oxidant and a solvent to form a compound of formula (II) according to step 2 below
wherein
each of R 1a and R 1b is independently hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, —CN, C 3-6 cycloalkyl, or C 3-6 spirocycloalkyl, and
n is an integer of 2 or 3; and
(b) reacting a reaction mixture comprising the compound of formula (II) and a compound of formula (III) in an organic solvent to form a compound of formula (IV) or a salt thereof according to step 3 below
wherein
B is substituted or unsubstituted indolyl, benzofuranyl, benzothiophenyl, indazolyl, aza-indolyl, benzimidazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl,
each of R 2a and R 2b is independently hydrogen, halogen, —OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, —CN, C 3-6 cycloalkyl, or C 3-6 spirocycloalkyl,
R 3a and R 3b are independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, —CN, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl, C 3-6 heteroaryl, or C 3-6 spirocycloalkyl, and
the asterisk represents a chiral center when R 3a and R 3b are different.
2 . The process of claim 1 , wherein B is a substituted or unsubstituted indolyl, benzofuranyl, or benzothiophenyl.
3 . The process of claim 2 , wherein B is a substituted or unsubstituted indolyl.
4 . The process of claim 1 , wherein B is a substituted or unsubstituted pyrrolopyridazinyl, pyrrolopyrimidinyl, or pyrrolopyrazinyl.
5 . The process of claim 1 , wherein B is substituted with one or two substituents independently selected from F, Cl, C 1-3 alkyl, C 1-3 haloalkyl, —CN, —OH, C 1-3 alkoxy, or C 1-3 hydroxyalkyl.
6 . The process of claim 1 , wherein each of R 2a and R 2b is hydrogen.
7 . The process of claim 1 , wherein R 3a and R 3b are independently hydrogen or —CH 3 .
8 . The process of claim 1 , wherein each of R 1a and R 1b is independently hydrogen, F, —Cl, —CN, —CH 3 , —CF 3 , —CHF 2 , —CH 2 F, or spirocyclopropyl.
9 . The process of claim 8 , wherein n is 3.
10 . The process of claim 1 , wherein the compound of formula (I) is:
including stereoisomers thereof.
11 . The process of claim 1 , wherein the compound of formula (I) is:
including stereoisomers thereof.
12 . The process of claim 1 , wherein the compound of formula (I) is:
13 . The process of claim 1 , wherein the compound of formula (II) is:
including stereoisomers thereof.
14 . The process of claim 1 , wherein the compound of formula (II) is:
including stereoisomers thereof.
15 . The process of claim 1 , wherein the compound of formula (II) is:
16 . The process of claim 1 , wherein the compound of formula (III) is:
wherein X is —NH—, —N—C 1 -C 3 unsubstituted alkyl, —O— or —S—.
17 . The process of claim 16 , wherein the compound of formula (III) is:
18 . The process of claim 17 , wherein the compound of formula (III) is:
19 . The process of claim 1 , wherein the compound of formula (IV) is:
or salt or stereoisomers thereof.
20 . The process of claim 19 , wherein B is an indolyl.
21 . The process of claim 1 , wherein the compound of formula (IV) is:
22 . The process of claim 1 , wherein the compound of formula (IV) is:
23 . The process of claim 1 , wherein:
the compound of formula (I) is
the compound of formula (II) is
the compound of formula (III) is
and
the compound of formula (IV) is
24 . The process of claim 1 , wherein the compound of formula (I) in step 1 is present in the organic solvent at a concentration of about 25 g/L, about 50 g/L, about 100 g/L, about 150 g/L, about 200 g/L, or about 250 g/L.
25 . The process of claim 1 , wherein the catalyst of step 2 is a redox active metal catalyst selected from NiCl 2 , RuCl 3 , CoCl 2 , FeCl 3 , FeCl 2 , or MnCl 2 .
26 . The process of claim 25 , wherein the catalyst is FeCl 3 .
27 . The process of claim 1 , wherein the oxidant of step 2 is NaIO 4 , NaOCl, or Oxone.
28 . The process of claim 27 , wherein the ratio of oxidant is present at a ratio of about 1.1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1 or 5:1 to the compound formula (IIa).
29 . The process of claim 1 , wherein the mole ratio of the compound formula (II) to the compound formula (III) of step 3 is about 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, or 1.5:1.
30 . The process of claim 1 , wherein step 3 further comprises an acid catalyst selected from sulfuric acid, p-toluene sulfonic acid (p-TsOH), or methansulfonic acid, or combinations thereof.