US 11,780,834 B2
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
Cheol Keun Chung, South San Francisco, CA (US); Jie Xu, South San Francisco, CA (US); Hans Iding, Basel (CH); Kyle Clagg, South San Francisco, CA (US); Michael Dalziel, South San Francisco, CA (US); Alec Fettes, Basel (CH); Francis Gosselin, South San Francisco, CA (US); Ngiap-Kie Lim, South San Francisco, CA (US); Andrew McClory, South San Francisco, CA (US); Haiming Zhang, South San Francisco, CA (US); Paroma Chakravarty, South San Francisco, CA (US); Karthik Nagapudi, South San Francisco, CA (US); and Sarah Robinson, South San Francisco, CA (US)
Assigned to Genentech, Inc., South San Francisco, CA (US); and Hoffmann-La Roche Inc., Little Falls, NJ (US)
Filed by Hoffmann-La Roche Inc., Little Falls, NJ (US); and GENENTECH, INC., South San Francisco, CA (US)
Filed on Dec. 3, 2020, as Appl. No. 17/110,607.
Application 17/110,607 is a division of application No. 16/443,515, filed on Jun. 17, 2019, granted, now 10,954,234.
Claims priority of provisional application 62/719,896, filed on Aug. 20, 2018.
Claims priority of provisional application 62/687,930, filed on Jun. 21, 2018.
Prior Publication US 2022/0041587 A1, Feb. 10, 2022
Int. Cl. C07D 471/04 (2006.01); C07D 403/14 (2006.01)
CPC C07D 471/04 (2013.01) [C07D 403/14 (2013.01); C07B 2200/13 (2013.01)] 72 Claims
 
1. A process for preparing a compound of formula (VIII) or a salt thereof, the process comprising:
(a) reacting a reaction mixture comprising a compound of formula (IV), a compound of formula (V) or a compound of formula (X), and an organic solvent to form a compound of formula (VI) according to step 1 below

OG Complex Work Unit Chemistry
wherein
B is substituted or unsubstituted indolyl, benzofuranyl, benzothiophenyl, aza-indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl;
each of R1a and R1b is independently hydrogen, fluorine, chlorine, —OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, and —CN, C3-6 cycloalkyl, or C3-6 spirocycloalkyl,
n is an integer of 2 or 3,
each of R2a and R2b is independently hydrogen, halogen, —OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, —CN, C3-6 cycloalkyl, or C3-6 spirocycloalkyl,
R3a and R3b are independently hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, —CN, C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, C3-6 heteroaryl, or C3-6 spirocycloalkyl,
J is phenyl or pyridinyl;
each R4 is independently hydrogen, halogen or C1-3 alkyl,
s is an integer from 0 to 2,
LG is a leaving group,
LG and CHO are located in the para position with respect to each other on J on the compound of formula (V),
PG is an aldehyde protecting group,
LG and CH-PG are located in the para position with respect to each other on J on the compound formula (X), and
each asterisk independently represents a chiral center wherein the carbon bearing R3a and R3b is a chiral center when R3a and R3b are different; and
(b) reacting a reaction mixture comprising the compound of formula (VI), an organic solvent, and a compound of formula (VII) or a salt thereof to form a compound of formula (VIII) or a salt thereof according to step 2 below

OG Complex Work Unit Chemistry
wherein
G is C1-3 alkyl,
p is 0 or 1,
E is substituted or unsubstituted azetidinyl or pyrrolidinyl,
each R5 is independently hydrogen, halogen, —OH, —CN, C1-5 alkoxy, or C1-5 hydroxyalkyl,
v is an integer from 1 to 5, and
R6 is halogen or —CN;
R10 is hydrogen or C1-3 alkyl.