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

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 R1a and R1b is independently hydrogen, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, —CN, C3-6 cycloalkyl, or C3-6 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 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 hydroxyalkyl, —CN, C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, C3-6 heteroaryl, or C3-6 spirocycloalkyl, and
• the asterisk represents a chiral center when R3a and R3b are different.

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
• 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
• 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.

A process for preparing a compound of formula (VIII) or a salt thereof, the process comprising reacting a reaction mixture comprising a compound of formula (IX) or a compound of formula (XI), a compound of formula (IV) and an organic solvent to form the compound of formula (VIII) or a salt thereof according to step 1 below

• 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, halogen, —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, halogen, —OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, —CN, C3-6 cycloalkyl, 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;
• 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;
• R6 is halogen or —CN;
• R10 is H or C1-3 alkyl;
• the CHO moiety and the nitrogen atom linking J and G are located in the para position with respect to each other on J on the compound of formula (IX);
• PG is an aldehyde protecting group,
• CH-PG and the nitrogen atom linking J and G are located in the para position with respect to each other on J on the compound of formula (XI);
• 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.

A process for preparing a compound of formula (IX) or a salt thereof, the process comprising:

• (1) reacting a reaction mixture comprising a compound of formula (X), a compound of formula (VII) or a salt thereof, an organic solvent and a catalyst to form a compound of formula (XI) according to step 1 below
• wherein
• 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,
• PG is an aldehyde protecting group,
• LG and CH-PG are located in the para position with respect to each other on J,
• 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,
• R6 is halogen or —CN, and
• R10 is hydrogen or C1-C3 alkyl;
• and
• (2) deprotecting the compound of formula (XI) to form the compound of formula (IX) according to step 2 below

A process for preparing a compound of formula (III) or a salt thereof, the process comprising:

• (1) reacting a reaction mixture comprising a compound of formula (XII), a compound B and an organic solvent to form the compound of formula (XIII) according to step 1 below
• wherein:
• B is selected from substituted or unsubstituted indolyl, benzofuranyl, benzothiophenyl, aza-indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, and furopyrazinyl,
• each of R2a and R2b is independently selected from hydrogen, halogen, —OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, —CN, C3-6 cycloalkyl, and C3-6 spirocycloalkyl,
• R3a and R3b are independently selected from hydrogen, halogen, —OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, —CN, C3-6 cycloalkyl, and C3-6 spirocycloalkyl,
• PG is an amine protecting group, and
• each asterisk represents a chiral center when R3a and R3b are different;
• and
• (2) deprotecting the compound of formula (XIII) to form the compound of formula (III) according to step 2 below

A compound of formula (XVI)

• wherein:
• each R4 is independently selected from hydrogen, halogen and C1-3 alkyl;
• s is an integer from 0 to 2;
• G is C1-3 alkyl;
• p is 0 or 1;
• each R7a and R7b is independently selected from hydrogen, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, and —CN;
• each R8a and R8b is independently selected from hydrogen, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, and —CN;
• R10 is hydrogen or C1-3 alkyl;
• y is an integer selected from 1 and 2, x is an integer selected from 1 and 2, and the total of x and y is 2 or 3;
• M is substituted or unsubstituted C1-5 alkyl;
• r is 0 or 1;
• and
• R9 is halogen or —CN.

A process for preparing a compound having formula (XX):

• the process comprising:
• contacting a compound of formula (XXI)
• with a protein transaminase to form a compound of formula (3):
• contacting the compound of formula (3) with a compound of formula (II) to form compound formula (XX)
• wherein
• n is 3;
• and
• each of R1a and R1b is independently selected from hydrogen, halogen, —OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, —CN, C3-6 cycloalkyl, and C3-6 spirocycloalkyl.