Granted Patent B2

US 12,655,115 · App. 18/253,306 · Granted Jun 16, 2026

Inventor: Fritz Andreae (Raaba-Grambach, AT)

Assignee: NOVARTIS AG

C07D257/02

Abstract

Claims (52)

1 . A method for synthesizing a compound of formula (I), or a pharmaceutically acceptable salt thereof, using solid phase synthesis:

wherein said method comprises at least one of the following steps:

a) contacting a supported compound of formula (II)

with a compound of formula (III)

to provide a supported compound of formula (IV)

b) contacting the supported compound of formula (IV) with a deprotecting agent to provide a supported compound of formula (V)

c) contacting the supported compound of formula (V) with a compound of formula (VI)

to provide a supported compound of formula (VII)

d) contacting the supported compound of formula (VII) with a deprotecting agent to provide a supported compound of formula (VIII)

e) contacting the supported compound of formula (VIII) with a compound of formula (IX)

to provide a supported compound of formula (X)

f) contacting the supported compound of formula (X) with a deprotecting agent to provide a supported compound of formula (XI)

g) contacting the supported compound of formula (XI) with a compound (XII)

to provide a supported compound of formula (XIII)

h) contacting the support compound of formula (XIII) with a cleavage reagent, and optionally with a deprotecting agent, to provide the compound of formula (I), or a pharmaceutically acceptable salt thereof;

wherein

PG, PG1, PG5, PG6 and PG7 are each independently a carboxyl protecting group;

L is a linker;

PG2, PG3 and PG4 are each independently an amino protecting group;

R1, R2 and R3 are each independently H, or an activating ester group, and

LG is a leaving group selected from the group consisting of imidazole, halogens and activating ester groups.

2 . The method according to claim 1 , wherein said method comprises all the steps a)-h).

3 . The method according to claim 1 , wherein PG, PG1, PG5, PG6, and PG7, are independently selected from the group consisting of benzyl, p-methoxybenzyl (PMB), tertiary butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl, Tr).

4 . The method according to claim 1 , wherein PG2, PG3 and PG4 are independently selected from the group consisting of t-butyloxycarbonyl (Boc), 9-fluorenyl methoxycarbonyl (Fmoc), allyloxycarbonyl (alloc), N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) (Dde), monomethoxytrityl (MMt), 1-(1-Adamantyl)-1-Methylethoxycarbonyl (Adpoc), N-(1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl) (ivDde), and 4-methyltrityl (Mtt).

5 . The method according to claim 1 , wherein at least one of the steps a)-h) is performed using a polar aprotic solvent.

6 . The method according to claim 1 , wherein at least one of the step a), c), e) or g) is performed using a coupling agent and/or a base.

7 . A method for synthesizing a compound of formula (I), or a pharmaceutically acceptable salt thereof, using solid phase synthesis:

wherein said method comprises at least one of the following steps:

a′) contacting a supported compound of formula (II′)

with a compound of formula (III′)

to provide a supported, compound of formula (IV′)

b′) contacting the supported compound of formula (IV′) with a deprotecting agent to provide a supported, compound of formula (V′)

c′) contacting the supported, compound of formula (V′) with a compound of formula (VI′)

to provide a supported, compound of formula (VII′)

d′) contacting the supported compound of formula (VII′) with a deprotecting agent to provide a supported, compound of formula (VIII′)

e′) contacting the supported, compound of formula (VIII′) with a compound of formula (IX′)

to provide a supported compound of formula (X′)

f′) contacting the supported compound of formula (X′) with a deprotecting agent to provide a supported, compound of formula (XI′)

g′) contacting the supported, compound of formula (XI′) with a compound (XII′)

to provide a supported, compound of formula (XIII′)

h′) contacting the supported compound of formula (XIII′) with a cleavage reagent, and optionally with a deprotecting agent, to provide the compound of formula (I), or a pharmaceutically acceptable salt thereof;

wherein

PG′, PG1′, PG5′, PG6′ and PG7′ are each independently a carboxyl protecting group;

L′ is a linker;

PG2′, PG3′ and PG4′ are each independently an amino protecting group;

R1′, R2′ and R3′ are each independently H or an activating ester group, and

LG′ is a leaving group selected from the group consisting of imidazole, halogens and activating ester groups.

8 . The method according to claim 7 , wherein said method comprises all the steps a′)-h′).

9 . The method according to claim 7 , wherein PG′, PG1′, PG5′, PG6′, and PG7′, are independently selected from the group consisting of benzyl, p-methoxybenzyl (PMB), tertiary butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl, Tr).

10 . The method according to claim 7 , wherein PG2′, PG3′ and PG4′ are independently selected from the group consisting of t-butyloxycarbonyl (Boc), 9-fluorenyl methoxycarbonyl (Fmoc), allyloxycarbonyl (alloc), N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) (Dde), monomethoxytrityl (MMt), 1-(1-Adamantyl)-1-Methylethoxycarbonyl (Adpoc), N-(1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl) (ivDde) and 4-methyltrityl (Mtt).

11 . The method according to claim 7 , wherein at least one of the steps a′)-h′) is performed using a polar aprotic solvent.

12 . The method according to claim 7 , wherein at least one of the step a′), c′), e′) and g′) is performed using a coupling agent and/or a base.

Priority Claims (1)

Continuity (1)

References Cited (400)