# US 9,751,883 B2 · Preparation of certain [((6BR,10AS)-2,3,6B,7,8,9,10, 10A-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo [1,2,3-de]quinoxalines and pharmaceutically acceptable salts thereof

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- Number: US 9,751,883 B2
- Document ID: US9751883B2
- Status: Granted
- Kind: B2
- Application number: 15/066,962
- Filed: 2016-03-10
- Published: 2016-07-07
- Granted: 2017-09-05
- Earliest claimed: 2007-03-12
- Assignees: Intra-Cellular Therapies, Inc.
- Applicants: Intra-Cellular Therapies, Inc.
- Inventors: John Charles Tomesch; Peng Li; Wei Yao; Qiang Zhang; James David Beard; Andrew S. Thompson; Hua Cheng; Lawrence P. Wennogle
- Web page: https://patentgrep.com/patent/US9751883B2

## CPC

- C07D 471/16: Peri-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/10: for impotence
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/26: Psychostimulants, e.g. nicotine, cocaine
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides methods for the preparation of substituted heterocycle fused gamma-carbolines of Formula 2J, as shown below, intermediates useful in producing them and methods for producing such intermediates and such heterocycle fused gamma-carbolines, such methods comprising the preparation of a Compound of Formula 2G, as shown below, and use of said compound to produce the fused gamma-carbolines of Formula 2J, as defined herein:

## Claims

### Claim 1

A method for preparing a Compound of Formula 2J:
or a pharmaceutically acceptable salt thereof, wherein:
(i) k is 1;
(ii) m is 1;
(iii) n is 1;
(iv) X is N;
(v) R5 is H;
(vi) R7, R8 and R9 are H;
(vii) R10 is H or C1-4alkyl;
(viii) R6a a and R6b are H; and
(ix) R1 is 4-(4-fluorophenyl)-4-oxobutyl or 3-(4-fluorophenoxy)propyl;
comprising the steps of:
A) converting a Compound of Formula 2E:
wherein:
(i) k is 1;
(ii) m is 1;
(iii) n is 1;
(iv) A is Cl, Br, F or I;
(v) B is benzyl or triphenylmethyl, or is a moiety of the formula:
wherein:
a) Z is C1-6alkyl, aryl, C1-6alkylaryl or —OR wherein R is C1-6alkyl, aryl, arylC1-6alkyl or heteroarylC1-6alkyl;
b) P is —C(O)—, —C(O)O— or —S(O)2—;
(vi) R5 is H;
(vii) R7, R8 and R9 are H; and
(viii) X—Y— is a H(R′)N—CH2— or H(R′)N—C(O)—, wherein R′ is H or C1-C4alkyl;
by treating the Compound of Formula 2E with (a) a transition metal catalyst selected from a group consisting of palladium, copper, nickel, platinum, ruthenium and rhodium; and (b) a base;
or a Compound of Formula 2E′:
wherein:
(i) k is 1;
(ii) m is 1;
(iii) B is benzyl or triphenylmethyl, or is a moiety of the formula:
wherein:
a) Z is C1-6alkyl, aryl, C1-6alkylaryl or —OR wherein R is C1-6alkyl, aryl, arylC1-6alkyl or heteroarylC1-6alkyl;
b) P is —C(O)—, —C(O)O— or —S(O)2—;
(iv) R5 is H; and
(v) R7, R8 and R9 are H;
by reacting the Compound of Formula 2E′ with:
(a) an alkyl haloacetate having a formula of:
wherein:
i. A is Cl, Br or I; and
ii. R12 is C1-4alkyl; and
(b) a base;
into a Compound of Formula 2G:
wherein:
(i) k, m, n, B, R5, R7, R8, and R9 are as defined for Formula 2E;
(ii) X is N, and Y is —C(O)—; and
(iii) R10 is H or C1-4alkyl; and
B) converting the Compound of Formula 2G into a Compound of Formula 2H:
wherein:
(i) k, m, n, B, R5, R7, R8, R9 and R10 are as defined for Formula 2G;
(ii) X is N; and
(iii) R6a and R6b are H;
by reduction of the ketone of the Compound of Formula 2G to a methylene using a reducing agent;
C) converting the Compound of Formula 2H into a Compound of Formula 2I:
wherein:
(i) k, m, n, R5,R6a, R6b, R7, R8, R9 and Rl0 are as defined for Formula 2H; and
(ii) X is N;
by deprotection of the Compound of Formula 2H using an acid catalyst, a base catalyst or catalytic hydrogenation;
D) reacting the Compound of Formula 2I with (a) 4-chloro-4′-fluorobutyrophenone or 1-(3-chloropropoxy)-4-fluorobenzene, and (b) a base, to give the Compound of Formula 2J, as defined above; and
E) optionally reacting the Compound of Formula 2J with an acid to give a pharmaceutically acceptable salt of the Compound of Formula 2J.

### Claim 2 (depends on 1)

The method according to claim 1, wherein step A) comprises treating the Compound of Formula 2E with (a) a transition metal catalyst selected from a group consisting of palladium, copper, nickel, platinum, ruthenium and rhodium; and (b) a base.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the base for step A) is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate and potassium phosphate.

### Claim 4 (depends on 3)

The method according to claim 3, wherein the base is potassium carbonate.

### Claim 5 (depends on 2)

The method according to claim 2, wherein said transition metal catalyst is a copper catalyst.

### Claim 6 (depends on 5)

The method according to claim 5, further comprising the use of a monodentate ligand or bidentate ligand, wherein such ligand is selected from a group consisting of:
(1) phenolic or amine ligands selected from a group consisting of aryl alcohol, 1,2-diamine, 1,2-aminoalcohol, imidazolium carbene, 4-(dimethylamino)pyridine, 2-(aminomethyl)pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenanthroline, and 5-nitro-1,10-phenanthroline;
(2) ligand represented by structure 1:
wherein
A and B independently represent fused rings selected from the group consisting of monocyclic or polycyclic cycloalkyls, cycloalkenyls, aryls, and heterocyclic rings, said rings having from 4 to 8 atoms in a ring structure;
X represents NR2, P(alkyl)2, P(cycloalkyl)2, AsR2, or OR;
Y represents H, alkyl, NR2, or AsR2;
X and Y are not identical;
R, Ra, Rb, Rc, and Rd, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carboxy, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, formyl, carboxylate ester, sulfonate ester, phosphate ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH2)m—R80;
Re and Rf, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carboxy, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, formyl, carboxylate ester, sulfonate ester, phosphate ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH2)m—R80;
A and B independently are unsubstituted or substituted with Re and Rf respectively, any number of times up to the limitations imposed by stability and the rules of valence;
Ra and Rb, or Rc and Rd, or both, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone;
R80 represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and
the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(3) ligand represented by structure 2:
wherein
X represents PR2;
Y represents H, NR2, OR, or SR;
R represents, independently for each occurrence, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or —(CH2)m —R80;
Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carboxy, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, formyl, carboxylate ester, sulfonate ester, phosphate ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH2)m—R80;
one or more pairs of substituent, with an ortho-relationship therebetween, selected from the group consisting of Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone;
R80 represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and
the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(4) ligand represented by structure 3:
wherein
X represents NR2, P(alkyl)2, P(cycloalkyl)2, AsR2, or OR;
Y represents H, alkyl, NR2, AsR2, or OR;
X and Y are not identical;
R, Ra, Rb, Rc, and Rd, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carboxy, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, formyl, carboxylate ester, sulfonate ester, phosphate ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH2)m—R80;
Re and Rf, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carboxy, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, formyl, carboxylate ester, sulfonate ester, phosphate ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH2)m—R80;
the B and B′ rings of the binaphthyl core independently are unsubstituted or substituted with R5 and R6, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
Ra and Rb, or Rc and Rd, or both, taken together optionally represent a ring consisting of a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone;
R80 represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and
the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(5) ligand represented by structure 4:
wherein:
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and —(CH2)m—R80;
the A and A′ rings of the biphenyl core independently are unsubstituted or substituted with R1 and R2, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
Ra and Rb are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, —SiR3, and —(CH2)m—R80;
R80 represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and
the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(6) ligand represented by structure 5:
wherein
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and —(CH2)m—R80;
the A, B, A′, and B′ rings of the binaphthyl core independently are unsubstituted or substituted with R1, R2, R3, and R4, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
Ra, Rb, Rc, and Rd, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, —SiR3, and —(CH2)mR80;
R80 represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and
the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
provided that when R is cycloalkyl or aryl, there is at least one instance of Ra, Rb, Rc, or Rd;
(7) ligand represented by structure 6:
wherein
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and —(CH2)m—R80;
the A and A′ rings of the biphenyl core independently may be unsubstituted or substituted with Ra and Rb, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
Ra and Rb are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, —SiR3, and —(CH2)m—R80;
R80 represents aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, or a polycyclyl;
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and
the ligand, when chiral, may be provided in the form of a mixture of enantiomers or as a single enantiomer;
(8) ligand represented by structure 7:
wherein
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and —(CH2)m—R80;
P(R)2 represents P(alkyl)2, or P(cycloalkyl)2;
the A, B, A′, and B′ rings of the binaphthyl core independently are unsubstituted or substituted with Ra, Rb, Rc, and Rd, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
Ra, Rb, Rc, and Rd, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, —SiR3, and —(CH2)m—R80;
R80 represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and
the ligand, when chiral, is a mixture of enantiomers or a single enantiomer; and
(9) N,N-dimethylformamide, dimethylsulfoxide and 1-methyl-2-pyrrolidinone.

### Claim 7 (depends on 6)

The method according to claim 6, wherein said ligand is a phenolic ligand or an amine ligand selected from a group consisting of an aryl alcohol, a 1,2-diamine, a 1,2-aminoalcohol, an imidazolium carbene, 4-(dimethylamino)pyridine, 2-(aminomethyl)pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenanthroline and 5-nitro-1,10-phenanthroline.

### Claim 8 (depends on 7)

The method according to claim 7, wherein said ligand is an amine ligand.

### Claim 9 (depends on 7)

The method according to claim 7, wherein said ligand is N,N′-dimethyl-1,2-diaminoethane or 1,8-diazabicyclo[5.4.0]undec-7-ene.

### Claim 10 (depends on 7)

The method according to claim 7, wherein said ligand is 1,8-diazabicyclo[5.4.0]undec-7-ene.

### Claim 11 (depends on 2)

The method according to claim 2, wherein said transition metal catalyst is selected from the group consisting of CuI, CuCl, CuBr, CuBr2, Cu(II) acetate, Cu2Cl2, Cu2O and Cu.

### Claim 12 (depends on 2)

The method according to claim 2, wherein said transition metal catalyst is CuI.

### Claim 13 (depends on 1)

The method according to claim 1, wherein step A) comprises the reaction of the Compound of Formula 2E′ with:
(a) an alkyl haloacetate having a formula of:
wherein:
(i) A is Cl, Br or I; and
(ii) R12 is C1-4alkyl; and
(b) a base.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the alkyl haloacetate is ethyl bromoacetate.

### Claim 15 (depends on 1)

The method according to claim 1, wherein in step B) the reducing agent is selected from the group consisting of metal hydrides, boranes, organoboranes, hydrogen in the presence of a catalyst, hydrazine hydrate in the presence of a base, and zinc amalgam with aqueous mineral acid.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the reducing agent is selected from the group consisting of metal hydrides, boranes, and organoboranes.

### Claim 17 (depends on 15)

The method according to claim 15, wherein the reducing agent is a borane.

### Claim 18 (depends on 15)

The method according to claim 15, wherein the reducing agent is borane-tetrahydrofuran complex.

### Claim 19 (depends on 1)

The method according to claim 1, wherein. in step B), R10 of the Compound of Formula 2G is H, and R10 of the Compound of Formula 2H is methyl, and step B) comprises the N-alkylation of said Compound of Formula 2G using methyl iodide and potassium carbonate to produce said Compound of Formula 2H.

### Claim 20 (depends on 1)

The method according to claim 1, wherein the deprotection of the Compound of Formula 2H uses an aqueous mineral acid catalyst.

### Claim 21 (depends on 20)

The method according to claim 20, wherein the aqueous mineral acid catalyst is aqueous hydrochloric acid.

### Claim 22 (depends on 1)

The method according to claim 1, wherein the base in step D) is potassium carbonate.

### Claim 23 (depends on 1)

The method according to claim 1, wherein the base in step D) is triethylamine.

### Claim 24 (depends on 1)

The method according to claim 1, wherein step D) further comprises the use of sodium iodide or potassium iodide.

### Claim 25 (depends on 1)

The method according to claim 1, wherein the method comprises reacting the Compound of Formula 2J with an acid to give a pharmaceutically acceptable salt of the Compound of Formula 2J, wherein the acid is toluenesulfonic acid.

### Claim 26

A method for preparing a Compound of Formula 2J:
or a pharmaceutically acceptable salt thereof, wherein:
(i) k is 1;
(ii) m is 1;
(iii) n is 1;
(iv) Xis N;
(v) R5 is H;
(vi) R7, R8 and R9 are H;
(vii) R10 is H or C1-4alkyl;
(viii) R6a and R6b are H; and
(ix) R1 is 4-(4-fluorophenyl)-4-oxobutyl or 3-(4-fluorophenoxy)propyl;
comprising the steps of:
A) treating a compound of Formula 2D:
wherein:
(i) k is 1;
(ii) m is 1;
(iii) A is Cl, Br, F or I;
(iv) B is benzyl or triphenylmethyl, or is a moiety of the formula:
wherein:
a) Z is C1-6alkyl, aryl, C1-6alkylaryl or —OR, wherein R is C1-6alkyl, aryl, arylC1-6alkyl or heteroarylC1-6alkyl; and
b) P is —C(O)—, —C(O)O— or —S(O)2—;
(v) R5 is H; and
(vi) R7, R8 and R9 are H;
with (a) a nucleophilic alkyl halide having the formula:
wherein:
(i) A is Cl, Br, F or I;
(ii) X—Y— is H(R′)N—CH2— or H(R′)N—C(O)—, wherein R′ is H or C1-4alkyl; and
(iii) n is 1; and
(b) a base;
to form a Compound of Formula 2E:
wherein:
(i) k, m, A, B, R5, R7, R8 and R9 are as defined for Formula 2D;
(ii) n is 1; and
(iii) X—Y— is H(R′)N—CH2— or H(R′)N—C(O)—, wherein R′ is H or C1-4alkyl;
B) converting the Compound of Formula 2E by treatment with (a) a transition metal catalyst selected from a group consisting of palladium, copper, nickel, platinum, ruthenium and rhodium; and (b) a base; or
converting a compound of Formula 2E′:
wherein:
(i) k is 1;
(ii) m is 1;
(iii) B is benzyl or triphenylmethyl, or is a moiety of the formula:
wherein:
a) Z is C1-6alkyl, aryl, C1-6alkylaryl or —OR wherein R is C1-6alkyl, aryl, arylC1-6alkyl or heteroarylC1-6alkyl;
(b) P is —C(O)—, —C(O)O— or —S(O)2—;
(iv) R5 is H; and
(v) R7, R8 and R9 are H;
by reacting the Compound of Formula 2E′ with:
(a) an alkyl haloacetate having a formula of:
wherein:
i. A is Cl, Br or I; and
ii. R12 is C1-4alkyl; and
(b) a base;
into a Compound of Formula 2G:
wherein:
(i) k, m, n, B, R5, R7, R8, and R9 are as defined for Formula 2E;
(ii) X is N, and Y is —C(O)—; and
(iii) R10 is H or C1-4alkyl; and
(C) converting the Compound of Formula 2G into a Compound of Formula 2H:
wherein:
(i) k, m, n, B, R5, R7, R8, R9 and R10 are as defined for Formula 2G;
(ii) X is N; and
(iii) R6a and R6b are H;
by reduction of the ketone of the Compound of Formula 2G to a methylene using a reducing agent;
(D) converting the Compound of Formula 2H into a Compound of Formula 2I:
wherein:
(i) k, m, n, R5, R6a, R6b, R7, R8, R9 and R10 are as defined for Formula 2H; and
(ii) X is N;
by deprotection of the Compound of Formula 2H using an acid catalyst, a base catalyst or catalytic hydrogenation;
E) reacting the Compound of Formula 2I with (a) 4-chloro-4′-fluorobutyrophenone or 1-(3-chloropropoxy)-4-fluorobenzene, and (b) a base, to give the Compound of Formula 2J, as defined above; and
F) optionally reacting the Compound of Formula 2J with an acid to give a pharmaceutically acceptable salt of the Compound of Formula 2J.

### Claim 27 (depends on 26)

The method according to claim 26, wherein in step A), the nucleophilic alkyl halide is 2-chloroacetamide and the base is diisopropylethylamine.

### Claim 28 (depends on 27)

The method according to claim 27, wherein step A) further comprises the use of potassium iodide.