SYNTHESIS OF RAS INHIBITORS

1 . A method of separating enantiomers of a compound of Formula I

the method comprising the steps of:

a) contacting the compound of Formula I with a chiral acid to form a diastereomeric salt of the compound of Formula I; and

b) separating each diastereomer of the diastereomeric salt, thereby separating enantiomers of a compound of Formula I

wherein

n and m are each, independently, 0, 1, 2, 3, 4, or 5;

PG is a nitrogen protecting group; and

X 1 , X 2 , and X 3 are each, independently, —CH 2 —, —CHF—, —CF 2 —, —C(O)—, or —O—.

2 . The method of claim 1 , wherein the chiral acid comprises a chiral carboxylic acid.

3 . The method of claim 1 or 2 , wherein the separating step (b) comprises recrystallization.

4 . The method of any one of claims 1 to 3 , wherein the compound of Formula I is further described by Formula Ia:

5 . A barium salt of a compound of Compound A:

6 . The barium salt of claim 5 , wherein the barium salt is a 2:1 (compound A: barium) salt.

7 . A method of preparing the barium salt of claim 5 or 6 , the method comprising the steps of:

a) condensing a compound of Formula IIa and Compound C to form a compound of Formula IIb:

b) cyclizing the compound of Formula IIb and a compound of Formula IIc to form a compound of Formula IId:

c) hydrolyzing the compound of Formula IId to form a compound of Formula IIe:

d) methylating the compound of Formula IIe to form a compound of Formula IIf:

and

e) hydrolyzing the compound of Formula IIf to form the barium salt of Compound A:

wherein

R 2 and R 3 are each, independently, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted C 6 -C 10 aryl, and

LG is a leaving group selected from the group consisting of halogen, triflate, mesylate, and tosylate.

8 . The method of claim 7 , wherein the methylating step (d) comprises contacting the compound of Formula IIe with MeB(OH) 2 .

9 . The method of claim 7 or 8 , wherein the hydrolyzing step (e) comprises contacting the compound of Formula IIf with barium hydroxide.

10 . A method of preparing a compound, or a salt thereof, of Formula III:

the method comprising the steps of:

a) coupling a compound of Formula IIId with a compound of Formula I to form a compound of Formula IIIe:

and

b) deprotecting the compound of Formula IIIe to form the compound of Formula III:

wherein

n and m are each, independently, 0, 1, 2, 3, 4, or 5;

PG is a nitrogen protecting group;

each R 4 is independently, optionally substituted C 1 -C 6 alkyl or optionally substituted C 6 -C 10 aryl;

R 5 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; and

X 1 , X 2 , and X 3 are each, independently, —CH 2 —, —CHF—, —CF 2 —, —C(O)—, or —O—.

11 . The method of claim 10 , wherein the compound of Formula IIId is prepared by a method comprising the steps of:

A1) combining a compound of Formula IIIa and a compound of Formula IIIb to form a compound of Formula IIIc:

B1) reducing the compound of Formula IIIc to form the compound of Formula IId:

wherein Q is MgBr, MgCl, MgI, or Li.

12 . The method of claim 11 , wherein the reducing step (B1) comprises contacting the compound of Formula IIIc with a ketoreductase enzyme.

13 . The method of claim 10 , wherein the compound of Formula IIId is prepared by the steps of:

A2) converting a compound of Formula IIIf to form a compound of Formula IIIg:

B2) reacting (e.g., esterifying) the compound of Formula IIIg to form the compound of Formula IIId:

14 . The method of claim 13 , wherein the converting step (A2) comprises forming a diazonium salt of the compound of Formula IIIf.

15 . A method of preparing a compound, or a salt thereof, of Formula IV:

the method comprising the steps of:

a) coupling a compound of Formula III and a barium salt of compound A to form a compound of Formula IVa:

and

b) hydrolyzing the compound of Formula IVa to form the compound of Formula IV:

wherein

n and m are each, independently, 0, 1, 2, 3, 4, or 5;

R 4 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 6 -C 10 aryl;

R 5 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; and

X 1 , X 2 , and X 3 are each, independently, —CH 2 —, —CHF—, —CF 2 —, —C(O)—, or —O—.

16 . The method of claim 15 , wherein the coupling step (a) comprises contacting the compound of Formula III and the Compound A barium salt with chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH).

17 . A method of preparing a compound, or a salt thereof, of Formula VIII:

the method comprising the steps of:

a) esterifying and N-alkylating a compound of Formula VIIIa to form a compound of Formula VIIIb:

b) reducing the compound of Formula VIIIb to form a compound of Formula VIIIc as a mixture of atropisomers:

c) separating the mixture of atropisomers of Formula VIIIc to obtain a stereochemically pure compound of Formula VIII;

wherein R 12 is halogen; and

R 13 is optionally substituted C 1 -C 6 alkyl.

18 . A method of preparing a compound, or a salt thereof, of Formula VIII:

the method comprising the steps of:

a) esterifying a compound of Formula VIIIa to form a compound of Formula VIIId:

b) N-alkylating the compound of Formula VIIId to form the compound of Formula VIIIb:

c) reducing the compound of Formula VIIIb to form a compound of Formula VIIIc as a mixture of atropisomers:

and

d) separating the mixture of atropisomers of Formula VIIIc to obtain the stereochemically pure compound of Formula VIII;

wherein R 12 is halogen; and

R 13 is optionally substituted C 1 -C 6 alkyl.

19 . A method of preparing a compound, or a salt thereof, of Formula IX:

the method comprising the steps of:

a) borylating a compound of Formula VIII to form a compound Formula X:

and

b) coupling the compound of Formula X with the compound of Formula XI to form a compound of Formula XII:

wherein R 12 is halogen;

R 13 is optionally substituted C 1 -C 6 alkyl; and

R 14 is optionally substituted 3- to 6-membered cycloalkyl.

20 . A method of preparing a compound, or a salt thereof, of Formula XIV:

the method comprising the steps of:

a) reacting a compound of Formula XV with a compound of Formula XII to form a compound of Formula XVI:

b) removing PG a of the compound of Formula XVI to form a compound of Formula XVII:

c) cyclizing the compound of Formula XVII with a transitional metal catalyst to form a compound of Formula XVIII:

d) removing PG b of the compound of Formula XVIII to form a compound of Formula XIX:

and

e) coupling the compound of Formula XIX with the compound of Formula IV to form a compound of Formula XIV:

wherein n and m are each, independently, 0, 1, 2, 3, 4, or 5;

X 1 , X 2 , and X 3 are each, independently, —CH 2 —, —CHF—, —CF 2 —, —C(O)—, or —O—;

R 12 is halogen;

R 13 is optionally substituted C 1 -C 6 alkyl;

R 14 is optionally substituted 3- to 6-membered cycloalkyl;

PG a is an acid-labile protecting group; and

PG b is an acid-stable protecting group.

21 . The method of claim 20 , wherein step (a) comprises reacting the compound of Formula XII and the compound of Formula XV in the presence of a carbodiimide coupling reagent, an anti-racemization agent, and a base.

22 . The method of claim 20 or 21 , wherein step (c) further comprises contacting the compound of Formula XVIII with hydrochloric acid to form a hydrochloride salt of the compound of Formula XVIII.

23 . The method of any one of claims 20 to 22 , wherein step (e) comprises coupling the compound of Formula XIX and the compound of Formula IV in the presence of a coupling reagent, an anti-racemization reagent, and a base.

24 . A compound of Formula IIf-1:

or a salt thereof, wherein

R 2 is optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted C 6-10 aryl;

R 20 is hydrogen or C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from CN, OH, C 1-6 alkoxy, and C 1-6 haloalkyl;

R 21 is OH, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl; and

q is 0, 1, or 2.

25 . A method of preparing a compound of Formula IIf:

the method comprising alkylating a compound of Formula IIe with a methylating agent:

wherein R 2 is optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted C 6-10 aryl.

26 . The method of claim 25 , wherein the methylating agent comprises trimethylboroxine.

27 . A method of preparing a compound of Formula IVa:

the method comprising coupling a compound of Formula III with a compound of Formula IIf

wherein n and m are each, independently, 0, 1, 2, 3, 4, or 5;

each R 4 is independently optionally substituted C 1 -C 6 alkyl or optionally substituted C 6 -C 10 aryl;

each R 5 is independently optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl; and

X 1 , X 2 , and X 3 are each, independently, —CH 2 —, —CHF—, —CF 2 —, —C(O)—, or —O—.

28 . The method of claim 27 , wherein the coupling comprises contacting the compound of Formula III and the compound of Formula IIf with a base.

29 . A method of preparing a compound of Formula VIIIc:

the method comprising N-alkylating a compound of Formula VIIIe with a compound having the structure of R 13 -LG 1 :

wherein each R 12 is halogen;

each R 13 is optionally substituted C 1 -C 6 alkyl; and

LG 1 is a leaving group.

30 . A method of preparing a compound of Formula Ville:

the method comprising reducing a compound of Formula VIIIf with a reducing agent:

wherein R 12 is halogen; and

R 13 is optionally substituted C 1 -C 6 alkyl.

31 . The method of claim 30 , wherein the reducing agent is NaBH 4 .