WO2022214645A1

WO2022214645A1 - Processes and intermediates for the preparation of relugolix

Info

Publication number: WO2022214645A1
Application number: PCT/EP2022/059393
Authority: WO
Inventors: Pablo ETAYO PÉREZ; Mª Gema BALLANO BALLANO; Xavier PUJOL Ollé; Pedro Angel GOMOLLÓN FRANCO
Original assignee: Farmhispania Group, S.L.
Priority date: 2021-04-09
Filing date: 2022-04-08
Publication date: 2022-10-13

Abstract

The invention relates to processes for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof. It also relates to intermediates of formula (IX), (X), and (XI) as defined herein useful in the synthesis of this molecule.

Description

Processes and intermediates for the preparation of relugolix

This application claims the benefit of European Patent Application EP21382304.0 filed April 9^th, 2021.

Technical Field

The invention relates to processes for the preparation of relugolix and to intermediates useful in the preparation of this compound. Background Art

Relugolix is a small molecule GnRH receptor antagonist which was approved in Japan in 2019 for relief symptoms associated with uterine fibroids. Relugolix’s chemical name is 1- (2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6-methoxypyridazin-3-yl)-5- (dimethylaminomethyl)thieno[2,3-c(]pyrimidine-2,4(1/-/,3/-/)-dione and it was first disclosed in EP1591446.

A uterine fibroid is a benign tumor that originates from the smooth muscle of the myometrium, and its growth depends on sex hormones. The clinical symptoms associated with uterine fibroids include menorrhagia and accompanying anemia and pain. Early in the treatment, therefore, GnRH agonist therapy increases the secretion of LH and FSH via the stimulation of GnRH receptors and thereby causes a transient increase (flare-up) in blood levels of sex hormones.

Several synthetic processes for preparing Relugolix and intermediates thereof have been disclosed. Preparation of Relugolix was first disclosed in EP1591446. The process disclosed therein requires several synthetic steps and it is characterized in that the introduction of 3-amino-6-methoxypyridazine, and the intramolecular cyclization are carried out during the last steps of the synthesis. J Med. Chem. 2011, 54, 4998-5012, discloses the same synthetic process including more details:

WO201 4/051164 refers to a process wherein the introduction of 3-amino-6-methoxy- pyridazine and intramolecular cyclization are carried out before the formation of the methoxyurea of the final product:

EP3660017 discloses a process that goes through the last intermediates of the process of the patent application W0’164, but wherein the intramolecular cyclization occurs before the introduction of difluorobenzyl group:

CN111925379 also discloses a similar process wherein the introduction of the dimethylamino group takes place after the intramolecular cyclization and the introduction of difluorobenzyl group:

CN111333633 discloses a process wherein the formation of the methoxyurea of the final product occurs prior to the introduction of 3-amino-6-methoxypyridazine and intramolecular cyclization. This process involves the protection/deprotection of the amino group as a carbamate thereof that supposes additional steps. The above processes for the preparation of relugolix require many synthetic steps and/or give rise to the desired product in low yield, which is not desirable from an industrial point of view. Additionally, the introduction of the 3-amino-6-methoxypyridazine building block and/or the intramolecular cyclization reaction is carried out in advanced steps of these linear syntheses. That makes necessary to use precursors such as nitro groups or protecting groups for the amino group and, consequently, involves additional operations of protection/deprotection. Besides, the above processes involve the use of the toxic chemical ethyl chloroformate in the first step of the synthesis. This product can affect people when breathed, irritating the nose and throat, and may be absorbed through the skin, irritating and burn the tissues and eyes with possible damage. Therefore, there is still the need to develop an alternative process for obtaining relugolix which overcomes the problems associated with the known processes belonging to the state of the art, and which can be implemented on an industrial scale. Summary of Invention

The inventors have developed a new and safer process for the preparation of relugolix which involves fewer synthetic steps than the processes cited above. Besides, some of the steps may be advantageously applied in one-pot mode, which simplifies the process and reduces the number of reactors needed. The process proceeds with good yields and purities. These features make the process of the invention especially suitable to be industrially implemented.

Thus, a first aspect of the invention relates to a process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof,

which comprises

(b) reacting a compound of formula (VII),

wherein Y is selected from the group consisting of halogen, -OSO2R1, and -OCOR1 and Ri is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, and (C6-C12)aryl optionally substituted with (C1-C4)alkyl or (C1-C4)haloalkyl, with dimethylamine in a suitable solvent, and

(c) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof. More particularly, the process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof, comprises (a) reacting a compound of formula (VI),

with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen,

(b) reacting the compound of formula (VII) with dimethylamine in a suitable solvent, and (c) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof.

The present invention also relates to new intermediates of formula (IX), formula (X), and formula (XI) which can be efficiently used in the process for the preparation of relugolix.

Accordingly, a further aspect of the invention relates to a compound of formula (IX)

wherein R2 is hydrogen and R represents (C1-C4)alkyl, or alternatively, R2 is halogen and R represents (C1-C4)alkyl. A further aspect of the invention relates to a compound of formula (X) or a salt thereof

wherein R₃ and R₄ are hydrogen, or alternatively, R₃ is halogen and R₄ is hydrogen, or alternatively, R₃ is hydrogen and R₄ is 2,6-difluorobenzyl, or alternatively, R₃ is halogen and R₄ is 2,6-difluorobenzyl. A further aspect of the invention relates to a compound of formula (XI)

wherein R₅ is hydrogen and Rs is -NR₆R₇ wherein R₆ and R₇ are hydrogen; or alternatively R₅ is hydrogen, and Rs is -NR₆R₇ wherein R₆ is an amino protective group, and R₇ is hydrogen or an amino protective group; or alternatively R₅ is hydrogen and Rs is -NR₆R₇ wherein R₆ is hydrogen and R₇ is methoxycarbamoyl; or alternatively R₅ is hydroxyl, and and Rs is -NR₆R₇ wherein R₆ is hydrogen, and R₇ is methoxycarbamoyl; or alternatively R₅ is -OSO₂R₁, being Ri is as previously defined, and Rs is -NR₆R₇ wherein R₆ is hydrogen, and R₇ is methoxycarbamoyl; or alternatively R₅ is -OCO₂R₁, being Ri is as previously defined, and Rs is -NR₆R₇ wherein R₆ is hydrogen, and R₇ is methoxycarbamoyl.

Processes for the preparation of a compound of formula (VII), a compound if formula (VI) and a compound of formula (I) as defined herein also form part of the invention.

Brief Description of Drawings

Fig. 1 shows an embodiment of the invention for the preparation of relugolix of formula (VIII).

Fig. 2 shows an embodiment of the invention for the preparation of an intermediate of formula (VI).

Fig. 3 shows an embodiment of the invention for the preparation of an intermediate of formula (IV).

Fig. 4 shows the XRPD powder diffractogram of crude relugolix oxalate as obtained in example 12.

Fig. 5 shows the DSC thermogram of crude relugolix oxalate obtained in example 12.

Fig. 6 shows the TGA thermogram of crude relugolix oxalate obtained in example 12.

Fig. 7 shows the XRPD powder diffractogram of purified relugolix oxalate (purification from MeOH) as obtained in example 13. Fig. 8 shows the XRPD powder diffractogram of relugolix Form I (crystallization from methyl ethyl ketone, MEK) as obtained in example 14.

Detailed description of the invention

All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply throughout the description and claims.

The term "about" or “around” as used herein refers to a range of values ± 10% of a specified value. For example, the expression "about 10" or “around 10” includes ± 10% of 10, i.e. from 9 to 11.

For the purposes of the invention, the expression “room temperature” means a temperature from 20 to 25 °C.

"Protective group" refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. An amino protective group gives protection to an amine. By way of example, mention may be made of the amino protective groups carbobenzyloxy (Cbz), te/f-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) and benzyl (Bn).

The term halogen or halide means fluoro, chloro, bromo or iodo.

The term “(C1-C4)alkyl” refers to a linear or branched saturated hydrocarbon group having from 1 to 4 carbon atoms. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or te/f-butyl groups. The term "(C1- C4)haloalkyl" refers to a (C1-C4)alkyl group as previously defined in which one or more hydrogen atoms are replaced by same or different halogen atoms. By way of example, mention may be made of -CF3, - CH2CF3, -CH2CI, or -CFhCCh.

The term “(C6-C12)aryl” refers to an aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 12 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl.

The term “phase-transfer catalyst (PTC)” refers to a catalyst that facilitates the migration of a reactant from one phase into another phase where reaction occurs. Phase-transfer catalysis is a special form of heterogeneous catalysis. By way of example, mention may be made of quaternary ammonium or phosphonium salts.

The term “radical initiator” refers to a substance that can produce radical species under mild conditions and promote radical reactions. By way of example, mention may be made of azobisisobutyronitrile (AIBN), 2,2’-azobis(2,4-dimethylvaleronitrile) (AMVN, V-65) or dibenzoyl peroxide (BPO).

The term “halogenating agent” refers to a substance that can transfer one halogen atom to the compound with which they are reacting. By way of example, mention may be made of /V-bromosuccinimide (NBS), bromine, /V-bromophthalimide, /V-iodosuccinimide or N- chlorosuccinimide (NCS), /V-chlorophthalimide (NCP), trifluoromethanesulfonyl chloride, or 1 ,3-dichloro-5,5-dimethylhydantoin.

The term “carbonyl source” refers to a substance that can transfer one carbonyl group to the compound with which it is reacting. By way of example, mention may be made of 1 ,1'- carbonyldiimidazole (CDI), L/,L/'-disuccinimidyl carbonate (DSC) or bis(trichloromethyl) carbonate (BTC).

The term “allylic oxidation” means oxidation of an allylic compound by replacing the allylic hydrogen(s) with oxygen. The term “allylic compound” refers to an organic compound having at least one hydrogen at a contiguous carbon to a doble bond.

The term “-OTf” refers to triflate or trifluoromethanesulfonate, which means -OSO₂CF₃, which is the anion of trifluoromethanesulfonic acid. The term “-OTs” refers to tosylate, which means the anion -OSO₂C₇H₇, which is the anion of p-toluenesulfonic acid. The term “-OMs” refers to mesylate which means the anion -OSO₂CH₃, which is the anion of methanesulfonic acid.

The term “telescoped process” refers to a sequential one-pot synthesis whereby the reagents are added to the reactor one at a time and without work-up.

As mentioned above the first aspect of the invention relates to a process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof. Relugolix of formula (VIII) may be converted into a pharmaceutically acceptable salt thereof. The term “pharmaceutically acceptable salts” encompasses any salt formed from pharmaceutically acceptable non-toxic acids including inorganic or organic acids such as for example acetic, trifluoroacetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethansulfonic, oxalic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, orthophosphoric, lactic, maleic, malic, mandelic, methanesulfonic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, glutamic, aspartic acid, and the like. There is no limitation regarding the salts, except that if used for therapeutic purposes, they must be pharmaceutically acceptable.

The preparation of pharmaceutically acceptable salts of relugolix can be carried out by methods known in the art. For instance, appropriate relugolix salt (e.g. acetate, maleate, oxalate, succinate, phosphate, etc.) can be prepared by reacting relugolix with a stoichiometric amount (0.7-2.0 equiv., typically 1.0 equiv.) of the appropriate pharmaceutically acceptable acid in water, in an organic solvent or in a mixture of them.

If desired, the salts can be further crystallized from a suitable organic solvent such as for example isopropanol, acetone, acetonitrile, ethyl acetate, and the like. Additionally, crude relugolix salts can be purified by slurring them in a suitable organic solvent such as for example methanol, ethanol, acetonitrile, and the like or in suitable mixtures of solvents. Such a purification strategy enables to introduce a significant purity upgrade of the relugolix salt. Furthermore, relugolix salts may be used to purify relugolix.

Relugolix and/or salts may be in crystalline form either as free solvation compound or as solvate (e.g. hydrate). All these forms are within the scope of the present invention. Methods of solvation are generally known within the art. In general, the solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated form for the purposes of the invention. According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process of the first aspect of the invention comprises after step (b), step (c) of converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof, more particularly relugolix oxalate. In a more particular embodiment, the pharmaceutically acceptable salt of relugolix, in particular relugolix oxalate, is crystallized from a suitable organic solvent selected from the group consisting of isopropanol, acetone, acetonitrile, ethyl acetate, and mixtures thereof, more particularly acetonitrile. In another more particular embodiment, the pharmaceutically acceptable salt of relugolix, in particular relugolix oxalate, optionally crystallised from a suitable organic solvent as described above, is purified by slurring them in a suitable organic solvent selected from the group consisting of methanol, ethanol, acetonitrile, and mixtures thereof, more particularly methanol.

The inventors have found that crude relugolix salt as isolated after crystallization in a suitable organic solvent (e.g., crude relugolix oxalate from acetonitrile crystallization) leads to a typical and characteristic XRPD pattern in a reproducible manner (Fig. 4). On the other hand, a given purified relugolix salt as isolated after slurry in a suitable organic solvent (e.g., purified relugolix oxalate from methanol purification) leads to a distinct XRPD pattern (Fig. 7) in comparison to that of the same relugolix salt obtained before purification.

Relugolix salts obtained as defined above may be converted into relugolix of high purity. Generally, relugolix free base can be readily obtained from crude or purified relugolix salts after neutralization of an aqueous solution thereof with a suitable inorganic base such as sodium hydroxide, sodium carbonate, sodium hydrogenphosphate, sodium bicarbonate, and the like, followed by extraction into an organic solvent such as ethyl acetate, dichloromethane, and the like. In addition, the thus obtained relugolix (free base) after salt release can be further subjected to an adequate crystallization from a suitable organic solvent such as acetonitrile, methyl ethyl ketone, ethanol, tetrahydrofuran, dimethyl sulfoxide, and the like, or from suitable mixtures of solvents.

Thus, according to another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process of the invention further comprises after step (c), step (d) of converting the pharmaceutically acceptable salt of relugolix obtained in step (c), in particular relugolix oxalate, into relugolix of formula (VIII) free base.

In a more particular embodiment, the obtained relugolix in step (d) is crystallized from a suitable organic solvent selected from the group consisting of acetonitrile, methyl ethyl ketone, ethanol, tetrahydrofuran, dimethyl sulfoxide, and mixtures thereof, more particularly methyl ethyl ketone. Such a crystallization procedure provides a well-defined polymorphic form of relugolix in a reproducible manner, which is consistent with relugolix Form I which is shown in Fig. 8 and is further defined in the patent applications W02021/069700 and W02021/069711. Thus, in a more particular embodiment, the obtained relugolix in step (d) is relugolix Form I having a XRPD shown in Fig. 8. In another more particular embodiment, the obtained relugolix in step (d) is relugolix Form I characterized by a XRPD that comprises the following characteristic peaks:

It also forms part of the invention a process for the purification of relugolix of formula (VIII) which comprises step (c) converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof, more particularly relugolix oxalate, and step (d) converting the pharmaceutically acceptable salt of relugolix obtained in step (c) into relugolix of formula (VIII) free base. The invention also relates to the use of a pharmaceutically acceptable salt of relugolix for purifying relugolix of formula (VIII) as free base. In a particular embodiment, the pharmaceutically acceptable salt of relugolix used for purifying relugolix is relugolix oxalate. In a more particularly relugolix oxalate in the crystalline form having a XRPD shown in Fig. 4. In another more particular embodiment, the pharmaceutically acceptable salt of relugolix used for purifying relugolix is relugolix oxalate in a crystalline form characterized by a XRPD that comprises the following characteristic peaks:

In another more particular embodiment, the pharmaceutically acceptable salt of relugolix used for purifying relugolix is relugolix oxalate in a crystalline form characterized by having the DSC thermogram shown in Fig. 5.

In another more particular embodiment, the pharmaceutically acceptable salt of relugolix used for purifying relugolix is relugolix oxalate in a crystalline form characterized by having the TGA thermogram shown in Fig. 6. In a more particularly relugolix oxalate in the crystalline form having a XRPD shown in Fig. 7. In another more particular embodiment, the pharmaceutically acceptable salt of relugolix used for purifying relugolix is relugolix oxalate in a crystalline form characterized by a XRPD that comprises the following characteristic peaks:

As mentioned above the invention relates to a process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof, which comprises (b) reacting a compound of formula (VII),

wherein Y is as previously defined, with dimethylamine in a suitable solvent, and

(c) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof.

More particularly, the process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof, comprises (a) reacting a compound of formula (VI),

(b) reacting the compound of formula (VII) with dimethylamine in a suitable solvent, and

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amount of dimethylamine used in step (b) is from 2 to 6 molar equivalents, more particularly is about 3 equivalents, relative to the compound of formula (VII).

Reaction (b) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example at room temperature. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the solvent of step (b) is a polar aprotic solvent, more particularly the solvent is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate and mixtures thereof, and even more particularly is chloroform. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (VII) Y is halogen, more particularly Cl. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (VII) Y is -OSO2R1 or -OCORi, more particularly Ri is selected from trifluoromethyl, p-tolyl, phenyl and methyl, that is, Y is selected from -OTf, -OTFA (i.e. -OCOCF3), -OTs, -OBz (i.e. -OCOPh), -OAc (i.e. -OCOCH3) and -OMs.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (b), the process comprises: (a) reacting a compound of formula (VI),

with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen.

Alternatively, a compound of formula (VII) wherein Y is -OSO2R1 or -OCOR1, may be prepared by a process comprising:

(a’) subjecting a compound of formula (VI) to an allylic oxidation in the presence of an oxidising agent and a suitable solvent to give a compound of formula (VII’), and

(a”) reacting the compound of formula (VII’) obtained in step (a’) with a sulfonylating compound of formula X’SC>2R_I or formula (R_ISC>₂)₂0, wherein X’ is a halogen, in a suitable solvent to give a compound of formula (VII) wherein Y is -OSO2R1, or alternatively reacting the compound of formula (VII’) obtained in step (a’) with an acylating compound of formula R1COX’ or formula (R_ICC>₂)₂0, wherein X’ is a halogen, in a suitable solvent to give a compound of formula (VII) wherein Y is -OCOR1.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (b), the process comprises: (a) reacting a compound of formula (VI) with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen, more particularly Cl.

The halogenating agent used in step (a) is not particularly limited. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in step (a) the halogenating agent is selected from the group consisting of /V-bromosuccinimide (NBS), bromine, /V-bromophthalimide, /V-iodosuccinimide, N- chlorosuccinimide (NCS), /V-chlorophthalimide (NCP), trifluoromethanesulfonyl chloride, and 1,3-dichloro-5,5-dimethylhydantoin, more particularly the halogenating agent is N- chlorosuccinimide (NCS), and in the compound of formula (VII) obtained in step (a) Y is Cl.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amount of halogenating agent used in step (a) is from 1 to 1.3 molar equivalents, more particularly is about 1 equivalent, relative to the compound of formula (VI).

Step (a) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 50 °C, more particularly from 0 to 5 °C, and with a reaction time generally from 1 to 24 h, more particularly 1 h. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the solvent of step (a) is selected from the group consisting of carbon tetrachloride, dichloromethane, dichloroethane, chloroform, chlorobenzene, trifluoromethylbenzene, toluene, ethyl acetate and mixtures thereof, more particularly the solvent is chloroform.

The halogenation reaction (a) may be carried out in the presence of a radical initiator, which is not particularly limited. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step (a) is carried out in the presence of a radical initiator. More particularly, the radical initiator is selected from the group consisting of azobisisobutyronitrile (AIBN), 2,2’-azobis(2,4-dimethylvalero- nitrile) (AMVN, V-65), dibenzoyl peroxide (BPO), even more particularly the radical initiator is azobisisobutyronitrile (AIBN). The amount of the radical initiator is generally from 0.05 to 0.2 molar equivalents, more particularly is about 0.1 equivalents, relative to compound of formula (VI).

The oxidising agent used in step (a’) is not particularly limited. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in step (a’) the oxidising agent is SeC>2 or MnC>2.

Step (a’) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, and with a reaction time generally from 1 to 24 h. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the solvent of step (a’) is selected from the group consisting of toluene, benzene, and mixtures thereof.

The compound of formula (VII’) obtained in step (a’) is reacted with a sulfonylating compound of formula X’SC>2R_I or formula (R_ISC>₂)₂0 to give a compound of formula (VII) wherein Y is -OSO2R1, or alternatively with an acylating compound of formula R1COX’ or formula (R_ICC>₂)₂0, to give a compound of formula (VII) wherein Y is -OCOR1. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, Ri is selected from trifluoromethyl, p-tolyl, phenyl and methyl, and thus, in the compound of formula (VII) obtained in step (a’’) Y is selected from -OTf, -OTFA, -OTs, -OBz, -OAc and -OMs. Step (a’’) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from -20 to 50 ºC, and with a reaction time generally from 1 to 24 h. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the solvent of step (a’’) is selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, and mixtures thereof. It also forms part of the invention a telescoped process for the preparation of relugolix from a compound of formula (VI). Thus, in one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process for the preparation of relugolix of formula (VIII) from a compound of formula (VI) is one- pot. More particularly, previously to step (b), the process comprises: (a) reacting a compound of formula (VI) with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen, more particularly Cl. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (a) or alternatively step (a’), the process comprises: (i) reacting a compound of formula (V),

with R’’’O-CO-NH-OCH3, wherein R’’’ is (C6-C12)aryl optionally substituted with -NO2 in a suitable solvent to give a compound of formula (VI), or alternatively, (i’) reacting a compound of formula (V) with methoxyamine, in the presence of a carbonyl source and in a suitable solvent to give a compound of formula (VI). In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (a) or alternatively step (a’), the process comprises (i) reacting a compound of formula (V) with R’’’O-CO-NH-OCH3 as previously defined. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amount of R’”0-C0-NH-0CH_{3 U}sed in step (i) is from 1 to 1.5 molar equivalents, more particularly about 1.1 equivalents, relative to compound of formula (V). In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, R’” is phenyl or 4- nitrophenyl. 4-Nitrophenyl methoxycarbamate may be prepared according to the literature procedure ( Org . Process Res. Dev. 2012, 16, 109-116).

Step (i) may be carried out in the presence of a base which is not particularly limited. The amount of the base may be generally from 1 to 2 molar equivalents, particularly about 1.1 equivalents, relative to compound of formula (V). In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step (i) is carried out in the presence of a base, more particularly, the base is selected from the group consisting of triethylamine, A/./V-diisopropylethylamine, pyridine, and /V-methylmorpholine, even more particularly the base is A/./V-diisopropylethylamine (DIPEA).

Step (i) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 50 °C, more particularly from 20 to 25 °C, and with a reaction time generally from 1 to 24 h, more particularly from 1 to 2 h. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the solvent of step (i) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetonitrile, tetrahydrofuran, toluene, and mixtures thereof, more particularly the solvent is dichloromethane.

Step (i’) is carried out with methoxyamine which can be supplied e.g. in the form of its hydrochloride salt (CH₃ONH₂ HCI), in the presence of a carbonyl source which is not particularly limited. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the carbonyl source used in step (i’) is selected from the group consisting of 1,T-carbonyldiimidazole (CDI), N,N'- disuccinimidyl carbonate (DSC) and bis(trichloromethyl) carbonate (BTC). The amount of carbonyl source may be generally from 0.3 to 2 molar equivalents relative to compound of formula (V), particularly from 1 to 2 equivalents, even more particularly about 1.2 equivalents in the case of CDI and DSC; and more particularly from 0.3 to 0.8 equivalents, even more particularly about 0.4 equivalents in the case of BTC. Step (i’) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 100 °C, more particularly from 70 to 80 °C for DSC or CDI and 40 to 50 °C for BTC, and with a reaction time generally from 1 to 24 h. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the solvent used in step (i’) is selected from the group consisting of acetonitrile, tetrahydrofuran, 1,4- dioxane, and toluene, more particularly is acetonitrile, especially wherein DSC or CDI is used, or is 1,4-dioxane, especially wherein BTC is used.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (i) or alternatively step (i’), the process comprises:

(ii) reacting a compound of formula (IV),

wherein X is halogen, with a compound (B)

wherein R^IV is -IMH2, and each R” independently represents H, (C1-C4)alkyl or the two R” are linked together to form a R”-R” moiety which is a (C1-C4)alkyl optionally substituted with one or more (C1-C4)alkyl groups, in a suitable solvent to give a compound of formula (V), or alternatively

(ii’) reacting a compound of formula (IV) wherein X is halogen, with a compound (B) wherein R^IV is -NO2 or -NR’R’ wherein one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group, and each R” independently represents H, (C1-C4)alkyl or the two R” are linked together to form a R”-R” moiety which is a (C1- C4)alkyl optionally substituted with one or more (C1-C4)alkyl groups, in a suitable solvent to give a compound of formula (V’)

wherein R^IV is -NO2 or -NR’R’ wherein one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group, and (ii”) reducing the nitro group or removing the protective group from the obtained compound of formula (V’) to give a compound of formula (V).

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (IV) used in step (ii) or alternatively in step (ii’) Y is halogen, more particularly Cl.

Step (ii) or alternatively step (ii’) is a Suzuki-Miyaura cross-coupling reaction which is typically carried out with a boronic acid derivative in the presence of a palladium catalyst in an amount generally from 0.02 to 0.2 molar equivalents, particularly about 0.1 equivalents, relative to compound of formula (IV). In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step (ii) or alternatively step (ii’) is carried out in the presence of a catalyst, more particularly, the catalyst is selected from the group consisting of Pd(OAc)2, Pd(PPh3)2Cl2, Pd(PPhi3)4, Pd(dba)2 and Pd(dppf)Cl2, even more particularly the catalyst is Pd(PPhi3)4.

Step (ii) or alternatively step (ii’) may be carried out in the presence of a base which is not particularly limited. The amount of the base may be generally from 1 to 2 molar equivalents, particularly about 1 equivalent, relative to compound of formula (B). In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step (ii) or alternatively step (ii’) is carried out in the presence of a base, more particularly, the base is selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, potassium phosphate, and potassium hydrogen phosphate, even more particularly the base is cesium carbonate.

Step (ii) or alternatively step (ii’) may be carried out in the presence of a phase-transfer catalyst (PTC) such as a quaternary ammonium salt or a phosphonium salt which is not particularly limited. The amount of PTC may be generally from 0.02 to 0.2 molar equivalents, particularly about 0.1 equivalents, relative to compound of formula (IV). In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step (ii) or alternatively step (ii’) is carried out in the presence of a phase-transfer catalyst (PTC), more particularly, the phase-transfer catalyst (PTC) is tetra-n-butylammonium bromide (TBAB).

Step (ii) or alternatively step (ii’) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 25 to 100 °C, more particularly at about 80 °C, and with a reaction time generally from 1 to 24 h, more particularly from 1 to 2 h. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the solvent of step (ii) or alternatively step (ii’) is selected from the group consisting of toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethanol, methanol, A/./V-dimethylformamide, isopropyl acetate, water and mixtures thereof, particularly the solvent is a mixture 1,4-dioxane/water.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (i) or alternatively step (i’), the process comprises step (ii). More particularly, the compound (B) is 4-aminophenylboronic acid pinacol ester, 4-aminophenylboronic acid or a salt thereof.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (i) or alternatively step (i’), the process comprises steps (ii’) and (ii”), wherein in compound (B) R^IV is -NR’R’ wherein one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group, and each R” independently represents H, (C1-C4)alkyl or the two R” are linked together to form a R”-R” moiety which is a (C1-C4)alkyl optionally substituted with one or more (C1-C4)alkyl groups. More particularly, the compound (B) is 4-aminophenylboronic acid pinacol ester, 4-aminophenylboronic acid or a salt thereof.

When in the compound (B) R^IV is -NR’R’ and one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group the process further comprises removing the protective group from the obtained compound (V’) to obtain a compound of formula (V) (step (ii”). In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amino protective groups are selected from the group consisting of carbobenzyloxy (Cbz), te/f-butyloxycarbonyl (Boc), 9- fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) and benzyl (Bn). More particularly, one R’ is H and the other R’ is selected from the group consisting of carbobenzyloxy (Cbz), te/f-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) and benzyl (Bn).

The removal of the amino protective group of the hydroxamic acid is carried out by standard methods well-known in the art as described for example in T. W. Green and P. G. M. Wuts, Protective Groups in Organic Chemistry (Wiley, 3rd ed. 1999, Chapter 7, pp. 495-653). For example, Cbz and Bn may be removed by hydrogenolysis; Boc can be removed by concentrated strong acid (such as HCI or CF3COOH); Fmoc can be removed by base, such as piperidine; and Ac and Bz can be removed by treatment with a base, most often, with aqueous or gaseous ammonia or methylamine.

When in the compound (B) R^IV is -NO2 the process further comprises reducing the nitro group from the obtained compound (V’) to obtain a compound of formula (V), for example by hydrogenation (step (ii”). This reaction can be carried out in the presence of catalyst palladium/platinum (Pd/C or Pt/C), in a suitable solvent such as methanol or ethanol, and at a suitable temperature, for example in the range from 20 to 40 °C.

According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (ii) or alternatively step (ii’), the process comprises:

(iii) reacting a compound of formula (III)

with a halogenating agent in a suitable solvent to give a compound of formula (IV) wherein X is halogen.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (ii) or alternatively step (ii’), the process comprises:

(iv) reacting a compound of formula (I),

wherein R represents (C1-C4)alkyl under intramolecular cyclization conditions to obtain a compound of formula (II),

(v) reacting the compound of formula (II) obtained in step (iv) with a 2,6-difluorobenzyl halide in a suitable solvent to give a compound of formula (III),

(iii) reacting the compound of formula (III) obtained in step (v) with a halogenating agent in a suitable solvent to give a compound of formula (IV) wherein X is halogen. The cyclization of step (iv) may be carried out in the presence of a base which is not particularly limited. The amount of the base may be generally from 1 to 3 molar equivalents, particularly about 2 equivalents, relative to compound of formula (I). In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step (iv) is carried out in the presence of a base, more particularly, the base is sodium methoxide or sodium ethoxide.

Step (iv) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 60 °C, more particularly at about 20 to 25 °C, and with a reaction time generally from 1 to 24 h, more particularly from 4 to 6 h. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the solvent of step (iv) is a polar aprotic solvent such as a (C1-C4)alcohol, in particular the solvent is selected from the group consisting of methanol, ethanol, isopropanol, 1-butanol, 2-butanol and 1 -propanol, more particularly the solvent is methanol or ethanol.

Step (v) is carried out with a 2,6-difluorobenzyl halide. The alkylating agent is not particularly limited. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, 2,6-difluorobenzyl halide is selected from 2,6-difluorobenzyl bromide or 2,6-difluorobenzyl chloride, wherein 2,6-difluorobenzyl chloride can be used in combination with potassium iodide. More particularly the 2,6-difluorobenzyl halide is 2,6-difluorobenzyl bromide.

Step (v) may be carried out in the presence of a base which is not particularly limited. The amount of the base may be generally from 1 to 1.5 molar equivalents, particularly about 1.1 equivalents, relative to compound of formula (II). In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step (v) is carried out in the presence of a base, more particularly, the base is selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, and even more particularly the base is potassium carbonate. Step (v) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 25 to 80 °C, more particularly at about 60 to 80 °C, and with a reaction time generally from 1 to 24 h, more particularly from 1 to 2 h. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the solvent of step (v) is selected from the group consisting of acetonitrile, tetrahydrofuran, 1,4-dioxane, A/./V-dimethylformamide, toluene and mixtures thereof, particularly the solvent is acetonitrile.

The halogenating agent used in step (iii) is not particularly limited. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in step (iii) the halogenating agent is selected from the group consisting of /V-bromosuccinimide (NBS), bromine, /V-bromophthalimide, /V-iodosuccinimide, N- chlorosuccinimide (NCS), /V-chlorophthalimide (NCP), trifluoromethanesulfonyl chloride, and 1,3-dichloro-5,5-dimethylhydantoin, more particularly the halogenating agent is N- bromosuccinimide (NBS), and in the compound of formula (IV) obtained in step (iii) X is Br. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amount of halogenating agent used in step (iii) is from 1 to 1.5 molar equivalents, more particularly is about 1.1 equivalents, relative to the compound of formula (III).

Step (iii) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 80 °C, more particularly from 20 to 25 °C, and with a reaction time generally from 1 to 24 h, more particularly 2 to 4 h. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the solvent of step (iii) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate, toluene and mixtures thereof, more particularly the solvent is dichloromethane. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (ii) or alternatively step (ii’), the process comprises:

(vi) reacting a compound of formula (I) with a halogenating agent in a suitable solvent to give a compound of formula

wherein X is halogen and R represents (C1-C4)alkyl; (vii) reacting the compound of formula (G) obtained in step (vi) under intramolecular cyclization conditions to obtain a compound of formula (II’),

wherein X is halogen, and

(viii) reacting the compound of formula (II’) obtained in step (vii) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (IV). Step (vi) can be carried out under the same conditions indicated above for step (iii). Thus, all embodiments indicated above for step (iii) and forX in a compound of formula (IV) also apply to step (vi) and for X in a compound of formula (I’). Step (vii) can be carried out under the same conditions indicated above for step (iv). Thus, all embodiments indicated above for obtaining a compound of formula (II) in step (iv) also apply to step (vii) for obtaining a compound of formula (II’).

Step (viii) can be carried out under the same conditions indicated above for step (v). Thus, all embodiments indicated above for obtaining a compound of formula (III) in step (v) also apply to step (viii) for obtaining a compound of formula (IV).

(ix) reacting a compound of formula (I),

(x) reacting a compound of formula (II) with a halogenating agent in a suitable solvent to give a compound of formula (IG)

wherein X is halogen; and (xi) reacting the compound of formula (IG) obtained in step (x) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (IV).

Step (ix) corresponds to step (iv) as previously defined, i.e. step (iv) and (ix) are used herein interchangeably. Thus, all embodiments indicated above for obtaining a compound of formula (II) in step (iv) also apply to step (ix) for obtaining a compound of formula (II).

Step (x) can be carried out under the same conditions indicated above for step (iii). Thus, all embodiments indicated above for step (iii), and for X in a compound of formula (IV) also apply to step (x) and for X in a compound of formula (IG).

Step (xi) corresponds to step (viii) as previously defined, i.e. step (viii) and (xi) are used herein interchangeably. Step (xi) can be carried out under the same conditions indicated above for step (v). Thus, all embodiments indicated above for obtaining a compound of formula (III) in step (v) also apply to step (xi) for obtaining a compound of formula (IV).

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (ii) or alternatively step (ii’), the process comprises step (iii) as previously defined, to give a compound of formula (IV) wherein X is halogen, more particularly, previously to step (ii) or alternatively step (ii’), the process comprises step (iii) to give a compound of formula (IV) wherein X is halogen, particularly Br.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (iii), the process comprises step (v) as previously defined, to give a compound of formula (III).

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (v), the process comprises step (iv) as previously defined, to give a compound of formula (II).

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (iv), the process comprises step (xii) as previously defined, to give a compound of formula (I).

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (ii) or alternatively step (ii’), the process comprises step (viii) as previously defined, to give a compound of formula (IV). In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (viii), the process comprises step (vii) to give a compound of formula (II’).

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (vii), the process comprises step (vi) as previously defined, to give a compound of formula (I’), more particularly, previously to step (vii), the process comprises step (vi) to give a compound of formula (I’) wherein X is halogen, particularly Br.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (ii) or alternatively step (ii’), the process comprises step (xi) as previously defined, to give a compound of formula (IV).

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (xi), the process comprises step (x) as previously defined, to give a compound of formula (II’), more particularly, previously to step (xi), the process comprises step (x) to give a compound of formula (II’) wherein X is halogen, particularly Br.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (x) the process comprises step (iv) to give a compound of formula (II).

It also forms part of the invention a telescoped process for the preparation of a compound of formula (IV) from a compound of formula (I). Thus, in one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process for the preparation of a compound of formula (IV) from a compound of formula (I) is one-pot. More particularly, the process for the preparation of a compound of formula (IV) from a compound of formula (I) comprises steps (iv), (v), and (iii) to give a compound of formula (IV) wherein X is halogen, more particularly Br; or alternatively, the process for the preparation of a compound of formula (IV) from a compound of formula (I) comprises steps (vi), (vii), and (viii) to give a compound of formula (IV) wherein X is halogen, more particularly Br, or alternatively, the process for the preparation of a compound of formula (IV) from a compound of formula (I) comprises steps (ix), (x), and (xi) to give a compound of formula (IV) wherein X is halogen, more particularly Br. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, previously to step (iv), the process comprises: (xii) reacting a compound of formula (A)

wherein R represents (C1-C4)alkyl with a carbonyl source, and subsequently reacting the compound obtained with 3-amino-6-methoxypyridazine, to give a compound of formula (I).

Step (xii) is carried out in the presence of a carbonyl source which is not particularly limited. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the carbonyl source used in step (xii) is selected from the group consisting of 1,T-carbonyldiimidazole (CDI), L/,L/'-disuccinimidyl carbonate (DSC) and bis(trichloromethyl) carbonate (BTC). The amount of carbonyl source may be generally from 1 to 2 equivalents, even more particularly about 1.2 equivalents in the case of CDI and DSC, and from 0.3 to 0.8 equivalents, even more particularly about 0.4 equivalents in the case of BTC. Step (xii) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 100 °C, more particularly from 70 to 80 °C when DSC or CDI is used, and about 45 °C when BTC is used. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the solvent used in step (xii) is selected from the group consisting of acetonitrile, tetrahydrofuran, 1,4-dioxane and toluene, more particularly is acetonitrile, especially when DSC or CDI is used, or is 1,4- dioxane, especially when BTC is used.

As mentioned above the present invention also relates to the intermediates used in the processes disclosed herein. Processes for the preparation of these intermediates also form part of the invention.

The invention also relates to a compound of formula (IX)

wherein R2 is hydrogen and R represents (C1-C4)alkyl, i.e. a compound of formula (I) wherein R represents (C1-C4)alkyl, more particularly it relates to a compound of formula (I) wherein R is ethyl. It also forms part of the present invention a process for the preparation of a compound of formula (I), which comprises step (xii) as previously defined.

The invention also relates to a compound of formula (IX) wherein R2 is halogen and R represents (C1-C4)alkyl, i.e. a compound of formula (G) wherein X is halogen and R represents (C1-C4)alkyl; more particularly it relates to a compound of formula (G) wherein X is Br and R is ethyl. It also forms part of the present invention a process for the preparation of a compound of formula (I’), which comprises step (vi) as previously defined.

The invention also relates to a compound of formula (X) or a salt thereof

wherein R3 and R₄ are hydrogen, i.e., a compound of formula (II). Examples of salts of the compound of formula (X), when possible, include without limitation salts with alkaline metals such as sodium, potassium, lithium or cesium. It also forms part of the present invention a process for the preparation of a compound of formula (II) which comprises step (iv) as previously defined. The invention also relates to a compound of formula (X) wherein R3 is halogen and R₄ is hydrogen, i.e., a compound of formula (II’) wherein X is halogen. It also forms part of the present invention a process for the preparation of a compound of formula (II’) which comprises step (vii) as previously defined. It also forms part of the present invention a process for the preparation of a compound of formula (II’) which comprises which comprises step (x) as previously defined.

The invention also relates to a compound of formula (X) wherein R3 is hydrogen and R₄ is 2,6-difluorobenzyl, i.e., a compound of formula (III). It also forms part of the present invention a process for the preparation of a compound of formula (III) which comprises step (v) as previously defined.

The invention also relates to a compound of formula (X) wherein R3 is halogen and R₄ is 2,6-difluorobenzyl, i.e., a compound of formula (IV) wherein X is halogen. It also forms part of the present invention a process for the preparation of a compound of formula (IV) which comprises step (iii) as previously defined. It also forms part of the present invention a process for the preparation of a compound of formula (IV) which comprises step (viii) as previously defined. The invention also relates to a compound of formula (XI)

wherein R5 is hydrogen and R8 is -NR6R7 wherein R6 and R7 are hydrogen, i.e. a compound of formula (V). It also forms part of the present invention a process for the preparation of a compound of formula (V) which comprises step (ii) as previously defined. It also forms part of the present invention a process for the preparation of a compound of formula (V) which comprises steps (ii’) and (ii’’) as previously defined. It also forms part of the present invention a process for the preparation of a compound of formula (V’) which comprises step (ii’) as previously defined. The invention also relates to a compound of formula (XI), wherein R5 is hydrogen, and R8 is -NR6R7 wherein R6 is an amino protective group, and R7 is hydrogen or an amino protective group, i.e. a compound of formula (V’) wherein R^IV is -NR’R’ wherein one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group. More particularly, it relates to a compound of formula (V’) wherein one R’ is H and the other R’ is selected from the group consisting of carbobenzyloxy (Cbz), tert- butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) and benzyl (Bn), or alternatively both R’ are independently selected from the group consisting of carbobenzyloxy (Cbz), tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxy- carbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) and benzyl (Bn). More particularly, one R’ is H and the other R’ is selected from the group consisting of carbobenzyloxy (Cbz), tert- butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) and benzyl (Bn). It also forms part of the present invention a process for the preparation of a compound of formula (V’) which comprises (ii’) reacting a compound of formula (IV) with a compound (B) in a suitable solvent wherein R^IV is -NR’R’ wherein one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group. The invention also relates to a compound of formula (XI), wherein R5 and R6 are hydrogen and R7 is methoxycarbamoyl, i.e. a compound of formula (VI). It also forms part of the present invention a process for the preparation of a compound of formula (VI) which comprises step (i), or alternatively step (i’) as previously defined. The invention also relates to a compound of formula (XI), wherein R5 is -OSO2R1 or -OCOR1, being R1 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, and R1 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, and (C6-C12)aryl optionally substituted with (C1-C4)alkyl or (C1-C4)haloalkyl, R6 is hydrogen, and R7 is methoxycarbamoyl i.e. a compound of formula (VII) wherein Y is -OSO2R1 or -OCOR1, more particularly it relates to a compound of formula (VII) wherein Y is -OTf, -OTFA, -OTs, -OBz, -OAc or -OMs. It also forms part of the present invention a process for the preparation of a compound of formula (VII) which comprises step (a’’) as previously defined. The invention also relates to a compound of formula (XI), wherein R5 is hydroxyl, R6 is hydrogen, and R7 is methoxycarbamoyl, i.e. a compound of formula (VII’). It also forms part of the present invention a process for the preparation of a compound of formula (VII’), which comprises step (a’) as previously defined. In one embodiment, the process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof, comprises: (xii) reacting a compound of formula (A) as previously defined with a carbonyl source, and subsequently reacting the compound obtained with 3-amino-6-methoxypyridazine, to give a compound of formula (I) as previously defined, (iv) reacting the compound of formula (I) under intramolecular cyclization conditions to obtain a compound of formula (II), (v) reacting the compound of formula (II) with a 2,6-difluorobenzyl halide in a suitable solvent to give a compound of formula (III), (iii) reacting the compound of formula (III) with a halogenating agent in a suitable solvent to give a compound of formula (IV) wherein X is halogen, (ii) reacting the compound of formula (IV) wherein X is halogen with a compound (B) in a suitable solvent, to give a compound of formula (V), (i) reacting the compound of formula (V) with a compound R’’’O-CO-NH-OCH3 as previously defined, in a suitable solvent to give a compound of formula (VI), or alternatively, (i’) reacting a compound of formula (V) with methoxyamine, in the presence of a carbonyl source and in a suitable solvent to give a compound of formula (VI), (a) reacting the compound of formula (VI) with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen, (b) reacting the compound of formula (VII) wherein Y is halogen with dimethylamine in a suitable solvent, and (c) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof. In another embodiment, the process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof, comprises: (xii) reacting a compound of formula (A) as previously defined with a carbonyl source, and subsequently reacting the compound obtained with 3-amino-6-methoxypyridazine, to give a compound of formula (I) as previously defined, (vi) reacting a compound of formula (I) with a halogenating agent in a suitable solvent to give a compound of formula (I’) wherein X is halogen and R represents (C1-C4)alkyl, (vii) reacting the compound of formula (I’) under intramolecular cyclization conditions to obtain a compound of formula (II’) wherein X is halogen and R represents (C1-C4)alkyl, (viii) reacting the compound of formula (II’) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (IV), (ii) reacting the compound of formula (IV) wherein X is halogen with a compound (B) in a suitable solvent, to give a compound of formula (V), (i) reacting the compound of formula (V) with a compound R’’’O-CO-NH-OCH3 as previously defined, in a suitable solvent to give a compound of formula (VI), or alternatively, (i’) reacting a compound of formula (V) with methoxyamine, in the presence of a carbonyl source and in a suitable solvent to give a compound of formula (VI), (a) reacting the compound of formula (VI) with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen, (b) reacting the compound of formula (VII) wherein Y is halogen with dimethylamine in a suitable solvent, and (c) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof. In another embodiment, the process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof, comprises: (xii) reacting a compound of formula (A) as previously defined with a carbonyl source, and subsequently reacting the compound obtained with 3-amino-6-methoxypyridazine, to give a compound of formula (I) as previously defined, (ix) reacting the compound of formula (I) under intramolecular cyclization conditions to obtain a compound of formula (II), (x) reacting the compound of formula (II) with a halogenating agent in a suitable solvent to give a compound of formula (II’) wherein X is halogen, (xi) reacting the compound of formula (II’) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (IV) wherein X is halogen, (ii) reacting the compound of formula (IV) wherein X is halogen with a compound (B) in a suitable solvent, to give a compound of formula (V), (i) reacting the compound of formula (V) with a compound R’’’O-CO-NH-OCH3 as previously defined, in a suitable solvent to give a compound of formula (VI), or alternatively, (i’) reacting a compound of formula (V) with methoxyamine, in the presence of a carbonyl source and in a suitable solvent to give a compound of formula (VI), (a) reacting the compound of formula (VI) with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen, (b) reacting the compound of formula (VII) wherein Y is halogen with dimethylamine in a suitable solvent, and (c) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof. It also forms part of the present invention a process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof, which comprises steps (a) or alternatively steps (a’) and (a’’) as previously defined, further comprising steps (b1) converting the compound of formula (VII) obtained in step (a) or alternatively obtained in step (a’’) into relugolix of formula (VIII), and (c1) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof. More particularly, the process comprises steps (a), (b1) and (c1) as previously defined. It also forms part of the present invention a process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof, which comprises step (ii) or alternatively steps (ii’) and (ii’’) as previously defined, further comprising steps (b2) converting the compound of formula (V) obtained in step (ii) or alternatively in step (ii’’) into relugolix of formula (VIII), and (c2) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof. It also forms part of the present invention a process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof, which comprises step (xii) as previously defined, further comprising (b3) converting the compound of formula (I) obtained in step (xii) into relugolix of formula (VIII), and (c3) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof. Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein. Examples Nuclear Magnetic Resonance (NMR) NMR spectra were acquired on a Bruker AV-400 instrument operating at 400 MHz for ¹H NMR, 100 MHz for ¹³C NMR and 376 MHz for ¹⁹F NMR using the residual solvent signal as the internal standard. Chemical shifts (δ) are expressed in ppm and coupling constants (J) in Hertz. The following abbreviations are used: bs, broad singlet; s, singlet; d, doublet; t, triplet; q, quartet, m, multiplet. High-resolution mass High-resolution mass spectra were obtained on a Bruker Daltonics MicroTof-Q electrospray instrument from methanolic solutions using the positive electrospray ionization mode (ESI⁺). High Performance Liquid Chromatography (HPLC) HPLC chromatography analyses were performed using a Waters Alliance e2695 HPLC instrument equipped with a Waters 2487 Dual λ Absorbance Detector using YMC Triart PFP column, 4.6 x 150 mm, 3 µm, using the following conditions: - Column temperature: 25 ºC - Detection: 230 nm - Injection volume: 10 μL - Flow: 1.0 mL/min - Diluent: Acetonitrile or methanol - Mobile phase: Solution A: Acetonitrile; Solution B: Dissolve 1 mL of trifluoroacetic acid in 1000 mL of water and filter through 0.45 μm filter. - Mode: Gradient

Powder X-Ray Diffraction (XRD) - Instrument: Model Aeris Research edition from MALVERN PANALYTICAL. - Sample holder support: Sampler spinner. - Sample holder: Sample holder for air-sensitive samples with Polycarbonate dome and zero-background silicon insert with 16 mm opening. - X-ray emitter: Empyrean Cu Kα1 emitting tube from MALVERN PANALYTICAL, 1.54060 Å. - Detector: PIXcel1D radiation detector from MALVERN PANALYTICAL. - Optical accessories:

- Instrument settings:

Differential scanning calorimetry (DSC) - Equipment: DSC 821e Mettler Toledo. - Crucible: Aluminium crucible with a capacity of 40 µL with pierced lid. - Gas: Dry nitrogen 50 mL/min. - Method: Heating from 25 ºC to 250 ºC at a rate of 10 ºC/min. Thermogravimetric analysis (TGA): - Equipment: TGA2 Mettler Toledo. - Crucible: Open Aluminium crucible with a capacity of 100 µL. - Gas: Dry nitrogen 50 mL/min. - Method: Heating from 25 ºC to 250 ºC at a rate of 10 ºC/min. A blank curve was previously performed by using the same methodology and it was subtracted. Example 1. Preparation of ethyl 2-[3-(6-methoxypyridazin-3-yl)ureido]-4-methylthiophene- 3-carboxylate (Ia) To a stirred solution of 1,1'-carbonyldiimidazole (CDI; 4.38 g, 26.99 mmol) in acetonitrile (50 mL) at 45-55 °C, a solution of ethyl 2-amino-4-methylthiophene-3-carboxylate (5.0 g, 26.99 mmol) in acetonitrile (30 mL) was slowly added at the same temperature. The resulting reaction mixture was stirred overnight under refluxing conditions. Then, the mixture was slowly cooled down to room temperature (time during which product precipitation was observed) and further stirred for 2 h at room temperature. After that, the slurry was filtered under vacuum. The filter cake was washed with acetonitrile and dried to give a crude activated intermediate (an imidazolyl urea derivative) as a solid which was used in the next step without purification. The previous solid was suspended in acetonitrile (60 mL) and stirred at 60 °C until getting a clear solution. Then, a solution of 3-amino-6- methoxypyridazine (2.62 g, 20.93 mmol) in acetonitrile (20 mL) was slowly added at the same temperature, and the reaction mixture was heated to reflux for an additional 3 h (product precipitation observed during heating). After slowly cooling down to room temperature, the resulting slurry was filtered under vacuum. The filter cake was washed with acetonitrile and then dried to render (Ia) as a white solid (5.75 g, 63% overall yield; HPLC Purity: 99% a/a).¹H NMR (400 MHz, DMSO-d6, 333 K) δ 1.35 (t, J = 7.0, 3H, OCH2CH3), 2.31 (s, 3H, CH3), 3.99 (s, 3H, CH3O ^C4H2N2), 4.50 (q, J = 7.0, 2H, OCH2CH3), 6.56 [s, 1H, HAr (C4HS)], 7.21 [d, 1H, J = 9.4, HAr (C4H2N2)], 7.68 [d, 1H, J = 9.4, HAr (C4H2N2)], 10.53 (bs, 1H, NH), 12.18 (bs, 1H, NH); ¹³C{¹H} NMR (100 MHz, DMSO-d6, 333 K) δ 14.2 (OCH2CH3), 17.1 (CH3), 54.0 (CH3O ^C4H2N2), 59.9 (OCH2CH3), 111.5 (CAr), 112.6 (CHAr), 119.8 (CHAr), 122.2 (CHAr), 134.4 (CAr), 149.3 (C=O), 151.0 (CAr), 151.7 (CAr), 161.6 (CAr), 163.5 (CO2CH2CH3); HRMS (ESI⁺): m/z [M+Na]⁺ calcd for C14H16N4NaO4S 359.0784, found 359.0785. Example 2. Preparation of 3-(6-methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione (II) To a suspension of ethyl 2-[3-(6-methoxypyridazin-3-yl)ureido]-4-methylthiophene-3- carboxylate (Ia) (5.33 g, 15.85 mmol) in ethanol (55 mL), sodium ethoxide was added (21 wt. % in ethanol solution, 11.83 mL, 10.27 g, 31.69 mmol). After stirring at room temperature for 4 h, solvent was evaporated, and the resulting mixture was dissolved in water (60 mL) and acidified with aqueous 1 N HCl until pH 4-5 (product precipitation was observed during acidification). The precipitate was collected by filtration, washed with water, and dried to obtain (II) as a light brown solid (4.03 g, 88% yield; HPLC Purity: 95% a/a).¹H NMR (400 MHz, DMSO-d6, 298 K) δ 2.32 (s, 3H, CH3), 4.08 (s, 3H, CH3O ^C4H2N2), 6.76 [s, 1H, HAr (C4HS)], 7.43 [d, 1H, J = 9.1, HAr (C4H2N2)], 7.76 [d, 1H, J = 9.1, HAr (C4H2N2)], 12.53 (bs, 1H, NH); ¹³C{¹H} NMR (100 MHz, DMSO-d6, 298 K) δ 15.7 (CH3), 55.0 (CH3O ^C4H2N2), 112.3 (CHAr), 113.1 (CAr), 119.5 (CHAr), 131.9 (CHAr), 134.2 (CAr), 150.0 (C=O), 150.2 (C=O), 152.9 (CAr), 159.1 (CAr), 164.9 (CAr ^OMe); HRMS (ESI⁺): m/z [M+Na]⁺ calcd for C12H10N4NaO3S 313.0366, found 313.0352. Example 3. Preparation of ethyl 5-bromo-2-[3-(6-methoxypyridazin-3-yl)ureido]-4- methylthiophene-3-carboxylate (I’a) N-Bromosuccinimide (NBS; 0.32 g, 1.78 mmol) was added to a stirred suspension of ethyl 2-[3-(6-methoxypyridazin-3-yl)ureido]-4-methylthiophene-3-carboxylate (Ia) (0.60 g, 1.78 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred for 2 h. After that, the resultant precipitate was filtered under vacuum. The filter cake was washed with water and dried to render (I’a) as a light brown solid (0.59 g, 80% yield; HPLC Purity: 93% a/a). Example 4. Preparation of 1-(2,6-difluorobenzyl)-3-(6-methoxypyridazin-3-yl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (III) To a suspension of 3-(6-methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione (II) (4.03 g, 13.88 mmol) in acetonitrile (55 mL), 2,6-difluorobenzyl bromide (3.16 g, 15.27 mmol) and potassium carbonate (2.11 g, 15.27 mmol) were subsequently added. The resulting suspension was heated to reflux and stirred under refluxing conditions for 1 h. Then, the reaction mixture was slowly cooled down to room temperature and the solvent was concentrated in vacuo. The resulting residue was dissolved in dichloromethane (40 mL), and the solution cooled to 0-5 °C and washed with aqueous 1 N HCl (30 mL) and water (30 mL). After evaporation of the solvent in vacuo, the crude was purified by silica gel column chromatography (eluent: 1:1 n-heptane/ethyl acetate) to render (III) as a white solid (4.02 g, 70% yield; HPLC Purity: >99% a/a).¹H NMR (400 MHz, DMSO-d6, 298 K) δ 2.32 (d, 3H, J = 1.2, CH3), 4.08 (s, 3H, CH3O ^C4H2N2), 5.15 [d, 1H, J = 14.6, (CH2 ^2,6-F2C6H3)], 5.37 [d, 1H, J = 14.6, (CH2 ^2,6- F2C6H3)], 6.90 [d, 1H, J = 1.2, HAr (C4HS)], 7.09 ^7.15 [m, 2H, HAr (2,6-F2C6H3)], 7.41 ^7.49 [m, 1H, HAr (2,6-F2C6H3)], 7.44 [d, 1H, J = 9.1, HAr (C4H2N2)], 7.74 [d, 1H, J = 9.1, HAr (C4H2N2)]; ¹³C{¹H} NMR (100 MHz, DMSO-d6, 298 K) δ 15.9 (CH3), 40.4 [t, ³JC-F = 3.2, CH2 ^(2,6-F2C6H3)], 55.0 (CH3O ^C4H2N2), 110.5 (t, ²JC-F = 17.6, CAr), 111.8 ^112.0 (m, 2CHAr), 113.3 (CHAr), 113.6 (CAr), 119.6 (CHAr), 131.1 (t, ³JC-F = 10.6, CHAr), 131.7 (CHAr), 135.3 (CAr), 149.8 (C=O), 150.0 (C=O), 154.4 (CAr), 158.2 (CAr), 161.00 (d, ¹JC-F = 249.1, CAr ^F), 161.04 (d, ¹JC-F = 241.5, CAr ^F), 165.0 (CAr ^OMe); ¹⁹F{¹H} NMR (376 MHz, DMSO- d6, 298 K ) δ ^113.1 (s, 2F); HRMS (ESI⁺): m/z [M+Na]⁺ calcd for C19H14F2N4NaO3S 439.0647, found 439.0636. Example 5. Preparation of 6-bromo-3-(6-methoxypyridazin-3-yl)-5-methylthieno[2,3- d]pyrimidine-2,4(1H,3H)-dione (II’a). To a suspension of ethyl 5-bromo-2-[3-(6-methoxypyridazin-3-yl)ureido]-4- methylthiophene-3-carboxylate (I’a) (0.59 g, 1.42 mmol) in ethanol (5 mL), sodium ethoxide was added (21 wt. % in ethanol solution, 1.3 mL, 0.24 g, 3.56 mmol). After stirring at room temperature for 12 h, solvent was evaporated, and the resulting mixture was dissolved in water (5 mL) and acidified with aqueous 1 N HCl until pH 4-5 (product precipitation was observed during acidification). The precipitate was collected by filtration, washed with water, and dried to obtain (II’a) as a light brown solid (0.48 g, 91% yield; HPLC Purity: 89% a/a). MS (ESI^): m/z [M-H]^ calcd for C12H8BrN4O3S 367.0, found 366.9. Example 6. Preparation of 6-bromo-3-(6-methoxypyridazin-3-yl)-5-methylthieno[2,3- d]pyrimidine-2,4(1H,3H)-dione (II’a). N-Bromosuccinimide (NBS; 0.061 g, 1.78 mmol) was added to a stirred suspension of 3- (6-Methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (II) (0.1 g, 0.34 mmol) in dichloromethane (4 mL) and the resulting mixture was stirred for 2 h. After that, the resultant precipitate was filtered under vacuum. The filter cake was washed with water and dried to render (III’a) as a white solid (0.094 g, 75% yield; HPLC Purity: 94% a/a). MS (ESI^): m/z [M-H]^ calcd for C12H8BrN4O3S 367.0, found 366.9. Example 7. Preparation of 1-(2,6-difluorobenzyl)-6-bromo-3-(6-methoxypyridazin-3-yl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (IVa) N-Bromosuccinimide (NBS; 1.30 g, 7.32 mmol) was added to a stirred solution of 1-(2,6- difluorobenzyl)-3-(6-methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)- dione (III) (3.05 g, 7.32 mmol) in dichloromethane (30 mL) and the resulting mixture was stirred for 2 h. After that, the resultant precipitate was filtered under vacuum. The filter cake was washed with water and dried to render (IVa) as a white solid (3.20 g, 88% yield; HPLC Purity: 98% a/a).¹H NMR (400 MHz, DMSO-d6, 373 K) δ 2.36 (s, 3H, CH3), 4.12 (s, 3H, CH3O ^C4H2N2), 5.26 [bs, 2H, CH2 ^(2,6-F2C6H3)], 7.08 ^7.14 [m, 2H, HAr (2,6 ^F2C6H3)], 7.37 [d, 1H, J = 9.1, HAr (C4H2N2)], 7.43 ^7.51 [m, 1H, HAr (2,6 ^F2C6H3)], 7.66 [d, 1H, J = 9.1, HAr (C4H2N2)]; ¹³C{¹H} NMR (100 MHz, DMSO-d6, 373 K) δ 13.8 (CH3), 40.3 [t, ³JC-F = 3.3, CH2 ^(2,6-F2C6H3)], 54.3 (CH3O ^C4H2N2), 100.2 (CAr), 109.5 (t, ²JC-F = 17.4, CAr), 111.2 ^111.5 (m, 2CHAr), 112.9 (CAr), 118.6 (CHAr), 130.69 (t, ³JC-F = 10.4, CHAr), 130.76 (CHAr), 134.8 (CAr), 148.8 (C=O), 149.2 (C=O), 153.2 (CAr), 156.7 (CAr), 160.57 (d, ¹JC-F = 249.5, CAr ^F), 160.64 (d, ¹JC-F = 249.5, CAr ^F), 164.6 (CAr ^OMe); ¹⁹F{¹H} NMR (376 MHz, DMSO-d6, 373 K ) δ ^112.9 (s, 2F); HRMS (ESI⁺): m/z [M+Na]⁺ calcd for C19H13BrF2N4NaO3S 516.9752, found 516.9768. Example 8. Preparation of 1-(2,6-difluorobenzyl)-6-bromo-3-(6-methoxypyridazin-3-yl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (IVa) To a 6-bromo-3-(6-methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)- dione (II’a) (0.48 g, 1.29 mmol) in acetonitrile (6 mL), 2,6-difluorobenzyl bromide (0.29 g, 1.42 mmol) and potassium carbonate (0.20 g, 1.42 mmol) were subsequently added. The resulting suspension was heated to reflux and stirred under refluxing conditions for 1 h. Then, the reaction mixture was slowly cooled down to room temperature and the solvent was concentrated in vacuo. The resulting residue was dissolved in dichloromethane (6 mL), and the solution cooled to 0-5 °C and washed with aqueous 1 N HCl (3 mL) and water (3 mL). After evaporation of the solvent in vacuo, the crude was purified by silica gel column chromatography (eluent: 1:1 n-heptane/ethyl acetate) to render (IVa) as a white solid (0.38 g, 60% yield; HPLC Purity: >94% a/a). HRMS (ESI⁺): m/z [M+Na]⁺ calcd for C19H13BrF2N4NaO3S 516.9752, found 516.9768. Example 9. Preparation of 1-(2,6-difluorobenzyl)-6-(4-aminophenyl)-3-(6- methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Va) A solution of p-aminophenylboronic acid hydrochloride (1.13 g, 6.51 mmol) in water (8 mL) is pre-treated with cesium carbonate (2.12 g, 6.51 mmol) at room temperature. The previous solution is loaded over a stirred suspension of 1-(2,6-difluorobenzyl)-6-bromo-3- (6-methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (IVa) (2.15 g, 4.34 mmol) in 1,4-dioxane (43 mL) at room temperature. Then, a solution of cesium carbonate (4.67 g, 14.32 mmol) and tetra-n-butylammonium bromide (TBAB; 0.14 g, 0.43 mmol) in water (8 mL) was subsequently added. Finally, tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.43 mmol) was added and the resulting mixture is heated to reflux (80°C) and stirred under such conditions for 1 h. After that period, the reaction mixture was cooled down to 40-45 °C, extracted with ethyl acetate (20 mL) and then washed with water (2 x 10 mL) at 40-45°. Removal of the solvent under reduced pressure furnished a solid, which was purified by silica gel column chromatography (eluent: 3:7 n-heptane/ethyl acetate) on silica gel to release (Va) as a white solid (1.98 g, 90% yield; HPLC Purity: 99% a/a) ¹H NMR (400 MHz, CDCl3, 298 K) δ 2.44 [s, 3H, CH3], 3.90 (bs, 2H, NH2), 4.19 (s, 3H, CH3O ^C4H2N2), 5.09 ^5.53 [m, 2H, CH2 ^(2,6-F2C6H3)], 6.63 ^6.79 [m, 2H, HAr (C6H4)], 6.84 ^7.00 [m, 2H, HAr (2,6-F2C6H3)], 7.07 ^7.22 [m, 3H, HAr (C6H4 and C4H2N2)], 7.24 ^7.36 [m, 1H, HAr (2,6-F2C6H3)], 7.41 [d, 1H, J = 9.1, HAr (C4H2N2)]; ¹³C{¹H} NMR (100 MHz, CDCl3, 298 K) δ 14.4 (CH3), 40.3 [t, ³JC-F = 3.2, CH2 ^(2,6-F2C6H3)], 55.3 (CH3O ^C4H2N2), 110.1 (t, ²JC-F = 17.2, CAr), 111.6 ^112.0 (m, 2CHAr), 114.9 (2CHAr), 115.5 (CAr), 119.3 (CHAr), 121.7 (CAr), 130.1 (CAr), 130.5 (t, ³JC-F = 5.2, CHAr), 130.60 (CHAr), 130.64 (2CHAr), 146.8 (2CAr), 149.6 (C=O), 150.1 (C=O), 151.9 (C ), 158.9 (C ), 161.56 (d, ^J = 251.0, C ^ Ar Ar C-F Ar ^F), 161.63 (d, JC-F = 251.0, CAr ^F), 165.1 (CAr ^OMe); ¹⁹F{¹H} NMR (376 MHz, CDCl3, 298 K) δ ^112.8 (s, 2F); HRMS (ESI⁺): m/z [M+Na]⁺ calcd for C25H19F2N5NaO3S 530.1069, found 530.1054. Example 10. Preparation of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (VI) To a solution of 1-(2,6-difluorobenzyl)-6-(4-aminophenyl)-3-(6-methoxypyridazin-3-yl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)dione (Va) (1.56 g, 3.07 mmol) in dichloromethane (15 mL), 4-nitrophenyl N-methoxycarbamate (0.72 g, 3.38 mmol) was added as a solid in one-portion. N,N-Diisopropylethylamine (DIPEA; 0.59 mL, 0.44 g, 3.38 mmol) was then syringed dropwise into the reaction mixture and the resulting solution was stirred for 2 h. Then, the organic layer was washed with saturated aqueous sodium bicarbonate (2 x 10 mL) and water (2 x 10 mL). After evaporation of the solvent under vacuum, the crude was purified by silica gel column chromatography (eluent: 1:2 n- heptane/ethyl acetate) to release (VI) as a white solid (1.60 g, 90% yield; HPLC Purity: 96% a/a).¹H NMR (400 MHz, CDCl3, 298 K) δ 2.42 [s, 3H, CH3], 3.79 (s, 3H, CH3O ^NHCONH), 4.20 (s, 3H, CH3O ^C4H2N2), 5.18 ^5.43 [m, 2H, CH2 ^(2,6-F2C6H3)], 6.85 ^6.96 [m, 2H, HAr (2,6-F2C6H3)], 7.17 [d, 1H, J = 9.1, HAr (C4H2N2)], 7.20 ^7.29 [m, 2H, HAr (C6H4)], 7.25 ^7.36 [m, 1H, HAr (2,6-F2C6H3)], 7.44 [d, 1H, J = 9.1, HAr (C4H2N2)], 7.51 ^7.58 [m, 2H, HAr (C6H4)], 7.91 (bs, 2H, 2NH); ¹³C{¹H} NMR (100 MHz, CDCl3, 298 K) δ 14.4 (CH3), 40.3 [t, ³JC-F = 3.2, CH2 ^(2,6-F2C6H3)], 55.4 (CH3O ^C4H2N2), 64.7 (CH3O ^NHCONH), 109.9 (t, ²JC-F = 17.2, CAr), 111.6 ^112.1 (m, 2CHAr), 115.5 (CAr), 119.7 (3CHAr), 127.2 (CAr), 129.1 (CAr), 130.1 (2CHAr), 130.7 (t, ³JC-F = 10.5, CHAr), 130.8 (CHAr), 131.6 (CAr), 137.7 (CAr), 149.5 (C=O), 150.0 (C=O), 152.4 (C=O), 157.0 (CAr), 158.8 (CAr), 161.54 (d, ¹JC-F = 251.1, CAr ^F), 161.61 (d, ¹JC-F = 251.1, CAr ^F), 165.1 (CAr ^OMe); ¹⁹F{¹H} NMR (376 MHz, CDCl3, 298 K) δ ^112.8 (s, 2F); HRMS (ESI⁺): m/z [M+Na]⁺ calcd for C27H22F2N6NaO5S 603.1233, found 603.1207. Example 11. Preparation of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)- 5-(dimethylaminomethyl)thieno [2,3-d]pyrimidine-2,4(1H,3H)- dione [Relugolix] To a solution of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (VI) (1.00 g, 1.72 mmol) in chloroform (10 mL) at 0 °C, N-chlorosuccinimide (NCS; 0.23 g, 1.72 mmol) and azobisisobutyronitrile (AIBN; 28 mg, 0.17 mmol) were subsequently added. The resulting reaction mixture was stirred for 1 h at 0 °C. Then, dimethylamine (2.0 M solution in THF, 2.58 mL, 5.16 mmol) was added at 0 °C. The reaction mixture was initially stirred for 1 h at 0°C and further stirred overnight at room temperature. After that, the organic layer was washed first twice with aqueous saturated sodium bicarbonate solution (2 x 10 mL) and afterwards twice with water (2 x 10 mL). The final organic layer was concentrated in vacuo to give crude relugolix, which was purified by silica gel column chromatography (eluent: 95:5 dichloromethane/ethanol) to render relugolix as a white solid (0.59 g, 55% overall yield; HPLC Purity: 96% a/a).¹H NMR (400 MHz, CDCl3, 298 K) δ 2.14 [s, 6H, N(CH3)2], 3.45 ^3.75 [m, 2H, CH2N(CH3)2], 3.79 (s, 3H, CH3O ^NHCONH), 4.18 (s, 3H, CH3O ^C4H2N2), 5.13 ^5.56 [m, 2H, CH2 ^(2,6-F2C6H3)], 6.85 ^6.99 [m, 2H, HAr (2,6- F2C6H3)], 7.14 [d, 1H, J = 9.1, HAr (C4H2N2)], 7.26 ^7.36 [m, 1H, HAr (2,6-F2C6H3)], 7.38 ^7.47 [m, 2H, HAr (C6H4)], 7.47 [d, 1H, J = 9.1, HAr (C4H2N2)], 7.53 ^7.60 [m, 2H, HAr (C6H4)], 7.84 (bs, 2H, 2NH); ¹³C{¹H} NMR (100 MHz, CDCl3, 298 K) δ 40.3 [t, ³JC-F = 3.1, CH2 ^(2,6-F2C6H3)], 44.9 [N(CH3)2], 53.1 [CH2N(CH3)2], 55.3 (CH3O ^C4H2N2), 64.7 (CH3O ^NHCONH), 109.9 (t, ²JC-F = 17.2, CAr), 111.6 ^112.0 (m, 2CHAr), 115.3 (CAr), 119.48 (2CHAr), 119.51 (CHAr), 127.0 (CAr), 130.7 (t, ³JC-F = 10.4, CHAr), 130.81 (CHAr), 130.86 (2CHAr), 132.4 (CAr), 133.5 (CAr), 138.1 (CAr), 149.6 (C=O), 150.0 (C=O), 152.7 (C=O), 156.9 (CAr), 158.3 (CAr), 161.55 (d, ¹JC-F = 251.2, CAr ^F), 161.62 (d, ¹JC-F = 251.1, CAr ^F), 165.1 (CAr ^OMe); ¹⁹F{¹H} NMR (376 MHz, CDCl3, 298 K) δ ^112.6 (s, 2F); HRMS (ESI⁺): m/z [M+H]⁺ calcd for C29H28F2N7O5S 624.1835, found 624.1815. Example 12. Preparation of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)-5-(dimethylaminomethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, ethanedioate [crude relugolix oxalate] To a solution of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (VI) (1.00 g, 1.72 mmol) in chloroform (10 mL) at 0 °C, N-chlorosuccinimide (NCS; 0.23 g, 1.72 mmol) and azobisisobutyronitrile (AIBN; 28 mg, 0.17 mmol) were subsequently added. The resulting reaction mixture was stirred for 1 h at 0 °C. Then, dimethylamine (2.0 M solution in THF, 2.58 mL, 5.16 mmol) was added at 0 °C. The reaction mixture was initially stirred for 1 h at 0°C and further stirred overnight at room temperature. After that, the organic layer was washed first twice with aqueous saturated sodium bicarbonate solution (2 x 10 mL) and afterwards twice with water (2 x 10 mL). The final organic layer was concentrated in vacuo to give crude relugolix, which was suspended in acetonitrile (10 mL) and further, heated to reflux and stirred until complete dissolution. A previously prepared solution of oxalic acid dihydrate (0.131 g, 1.04 mmol) in acetonitrile (5.0 mL) was slowly added over the previous solution under refluxing conditions. The resulting mixture was stirred at such conditions for around 0.5 h. Then, the mixture was slowly cooled down to room temperature and stirred at such temperature for around 2 h. The thus formed suspension was filtered under vacuum and washed twice with acetonitrile (2 x 2 mL) to render crude relugolix oxalate as a white solid (0.56 g, 40% overall yield; HPLC Purity: 97% a/a).¹H NMR (400 MHz, DMSO-d6, 298 K) δ 2.33 [s, 6H, N(CH3)2], 3.64 (s, 3H, CH3O ^NHCONH), 3.88 ^4.10 [m, 2H, CH2N(CH3)2], 4.09 (s, 3H, CH3O ^C4H2N2), 4.95 ^5.65 [bs, 2H, 2(N ^H)⁺], 5.20 [bd, 1H, J = 16.0, CHH ^(2,6-F2C6H3)], 5.43 [bd, 1H, J = 16.0, CHH ^(2,6-F2C6H3)], 7.07 ^7.23 [m, 2H, HAr (2,6-F2C6H3)], 7.39 ^7.57 [m, 4H, 1HAr (C4H2N2), 1HAr (2,6-F2C6H3), 2HAr (C6H4)], 7.70 ^7.86 [m, 3H, 1HAr (C4H2N2), 2HAr (C6H4)], 9.39 [s, 1H, NH, (CH3O ^NHCONH)], 9.93 [s, 1H, NH, (CH3O ^NHCONH)]; ¹³C{¹H} NMR (100 MHz, DMSO- d6, 298 K) δ 41.0 [CH2 ^(2,6-F2C6H3)], 43.5 [N(CH3)2], 52.5 [CH2N(CH3)2], 55.0 (CH3O ^C4H2N2), 63.9 (CH3O ^NHCONH), 110.3 (t, ²JC-F = 18.0, CAr), 111.5 ^112.4 (m, 2CHAr), 114.1 (CAr), 119.4 (2CHAr), 119.7 (CHAr), 124.1 (CAr), 130.1 (2CHAr), 131.2 (t, ³JC-F = 10.0, CHAr), 131.6 (CHAr), 134.8 (CAr), 140.4 (CAr), 149.3 (C=O), 149.8 (C=O), 152.9 (C=O), 156.8 (CAr), 158.3 (CAr), 161.0 (d, ¹JC-F = 248.0, CAr ^F), 161.1 (d, ¹JC-F = 247.0, CAr ^F), 164.9 (CAr ^OMe), 165.0 [2(C=O), oxalate]; ¹⁹F{¹H} NMR (376 MHz, DMSO-d6, 298 K) δ ^112.8 (s, 2F); HRMS (ESI⁺): m/z [M+H]⁺ calcd for C29H28F2N7O5S 624.1835, found 624.1819. Example 13. Preparation of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)-5-(dimethylaminomethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, ethanedioate [purified relugolix oxalate] Purification of crude relugolix oxalate salt by means of a slurry thereof in methanol enables to introduce significant purity upgrade (from 97% to 99%) To this aim a suspension of crude relugolix oxalate (0.56 g, 0.78 mmol, 97% purity) in methanol (5.60 mL) was prepared at room temperature and further heated to reflux temperature. After stirring for at least 1 h under refluxing conditions, the resulting suspension was slowly cooled down to room temperature and stirred at such temperature for at least 1 h before filtration. The thus formed slurry was filtered under vacuum and washed twice with methanol (2 x 1.12 mL) to render purified relugolix oxalate as a white solid (0.49 g, 87% yield; HPLC Purity: 99% a/a). Example 14. Preparation of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)-5-(dimethylaminomethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione [Relugolix Form I] A solution of crude or purified relugolix oxalate (2.0 g, 2.80 mmol) in water (60 mL) at 25 ^30 ºC was diluted with DCM (70 mL) and then, treated with 0.5 M aqueous sodium bicarbonate solution (16 mL, 8.01 mmol). After stirring the resulting biphasic mixture for at least 15 min, phases were separated. The firstly generated organic layer was further washed twice with water (2 x 20 mL) to render a solution of relugolix (free base) in DCM. This solution was subsequently microfiltered and then, concentrated up to approx.12 mL. MEK (20 mL) was added followed by seeding with 1% w/w of Relugolix Form I (20 mg) followed by vacuum distillation up to a final volume of approx.12 mL. After that, MEK (17 mL) addition and vacuum distillation to a final volume of approx.12 mL were repeated twice. Finally, MEK (24 mL) was added, and the resulting suspension was slowly cooled down to 20 ºC, and further stirred under such conditions for around 1 h before filtration. The thus formed slurry was filtered under vacuum and washed twice with MEK (2 x 2.0 mL) to render Relugolix Form I (0.87 g, 50% yield, HPLC Purity: 97 ^99% a/a). Citation List EP1591446 J Med. Chem.2011, 54, 4998-5012 WO2014/051164 EP3660017 CN111333633 WO2021/069700 WO2021/069711 Org. Process Res. Dev.2012, 16, 109-116 Green and P. G. M. Wuts, Protective Groups in Organic Chemistry (Wiley, 3rd ed.1999, Chapter 7, pp.495-653) For reasons of completeness, various aspects of the invention are set out in the following numbered clauses: Clause 1. A process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof,

which comprises (b) reacting a compound of formula (VII),

wherein Y is selected from the group consisting of halogen, -OSO2R1, and -OCOR1, and R1 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, and (C6-C12)aryl optionally substituted with (C1-C4)alkyl or (C1-C4)haloalkyl, with dimethylamine in a suitable solvent, and (c) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof. Clause 2. The process according to clause 1, wherein previously to step (b), the process comprises: (a) reacting a compound of formula (VI),

with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen, or alternatively, (a’) subjecting a compound of formula (VI) to an allylic oxidation in the presence of an oxidising agent and a suitable solvent to give a compound of formula (VII’), and

(a’’) reacting the compound of formula (VII’) obtained in step (a’) with a sulfonylating compound of formula X’SO2R1 or formula (R1SO2)2O, wherein X’ is a halogen, in a suitable solvent to give a compound of formula (VII) wherein Y is -OSO2R1, or alternatively reacting the compound of formula (VII’) obtained in step (a’) with an acylating compound of formula R1COX’ or formula (R1CO2)2O, wherein X’ is a halogen, in a suitable solvent to give a compound of formula (VII) wherein Y is -OCOR1. Clause 3. The process according to clause 2, wherein the process for the preparation of relugolix of formula (VIII) from a compound of formula (VI) is one-pot. Clause 4. The process according to any of clauses 2 to 3, wherein previously to step (a) or alternatively step (a’), the process comprises: (i) reacting a compound of formula (V),

with a compound R’’’O-CO-NH-OCH3, wherein R’’’ is (C6-C12)aryl optionally substituted with -NO2 in a suitable solvent to give a compound of formula (VI), or alternatively, (i’) reacting a compound of formula (V) with methoxyamine, in the presence of a carbonyl source and in a suitable solvent to give a compound of formula (VI). Clause 5. The process according to clause 4, wherein previously to step (i) or alternatively step (i’), the process comprises: (ii) reacting a compound of formula (IV),

( ) wherein X is halogen, with a compound (B)

wherein R^IV is -NH2, and each R’’ independently represents H, (C1-C4)alkyl or the two R’’ are linked together to form a R’’-R’’ moiety which is a (C1-C4)alkyl optionally substituted with one or more (C1-C4)alkyl groups, in a suitable solvent to give a compound of formula (V), or alternatively (ii’) reacting a compound of formula (IV) wherein X is halogen, with a compound (B) wherein R^IV is -NO2 or -NR’R’ wherein one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group, and each R’’ independently represents H, (C1-C4)alkyl or the two R’’ are linked together to form a R’’-R’’ moiety which is a (C1- C4)alkyl optionally substituted with one or more (C1-C4)alkyl groups, in a suitable solvent to give a compound of formula (V’)

wherein R^IV is -NO2 or -NR’R’ wherein one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group, and (ii’’) reducing the nitro group or removing the protective group from the obtained compound of formula (V’) to give a compound of formula (V). Clause 6. The process according to clause 5, wherein previously to step (ii) or alternatively step (ii’), the process comprises: (iv) reacting a compound of formula (I),

(iii) reacting the compound of formula (III) obtained in step (v) with a halogenating agent in a suitable solvent to give a compound of formula (IV) wherein X is halogen. Clause 7. The process according to clause 5, wherein previously to step (ii) or alternatively step (ii’), the process comprises: (vi) reacting a compound of formula (I) with a halogenating agent in a suitable solvent to give a compound of formula (I’),

wherein X is halogen and R represents (C1-C4)alkyl; (vii) reacting the compound of formula (I’) obtained in step (vi) under intramolecular cyclization conditions to obtain a compound of formula (II’),

wherein X is halogen, and (viii) reacting the compound of formula (II’) obtained in step (vii) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (IV). Clause 8. The process according to clause 5, wherein previously to step (ii) or alternatively step (ii’), the process comprises: (ix) reacting a compound of formula (I),

(x) reacting a compound of formula (II) with a halogenating agent in a suitable solvent to give a compound of formula (II’) wherein X is halogen; and

(xi) reacting the compound of formula (II’) obtained in step (x) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (IV). Clause 9. The process according to any of clauses 6 to 8, wherein previously to step (iv), the process comprises: (xii) reacting a compound of formula (A)

wherein R represents (C1-C4)alkyl with a carbonyl source, and subsequently reacting the compound obtained with 3-amino-6-methoxypyridazine, to give a compound of formula (I). Clause 10. A process for the preparation of a compound of formula (VII)

wherein Y is selected from the group consisting of halogen, -OSO2R1, and -OCOR1, and R1 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, and (C6-C12)aryl optionally substituted with (C1-C4)alkyl or (C1-C4)haloalkyl, which comprises: (a) reacting a compound of formula (VI),

(a’’) reacting the compound of formula (VII’) obtained in step (a’) with a sulfonylating compound of formula X’SO2R1 or formula (R1SO2)2O, wherein X’ is a halogen, in a suitable solvent to give a compound of formula (VII) wherein Y is -OSO2R1, or alternatively reacting the compound of formula (VII’) obtained in step (a’) with an acylating compound of formula R1COX’ or formula (R1CO2)2O, wherein X’ is a halogen, in a suitable solvent to give a compound of formula (VII) wherein Y is -OCOR1. Clause 11. A compound of formula (XI)

wherein R5 is hydrogen and R8 is -NR6R7 wherein R6 and R7 are hydrogen; or alternatively R5 is hydrogen, and R8 is -NR6R7 wherein R6 is an amino protective group, and R7 is hydrogen or an amino protective group; or alternatively R5 is hydrogen and R8 is -NR6R7 wherein R6 is hydrogen and R7 is methoxycarbamoyl; or alternatively R5 is hydroxyl, and R8 is -NR6R7 wherein R6 is hydrogen, and R7 is methoxycarbamoyl; or alternatively R5 is -OSO2R1, being R1 selected from the group consisting of (C1-C4)alkyl, (C1- C4)haloalkyl, and (C6-C12)aryl optionally substituted with (C1-C4)alkyl or (C1-C4)haloalkyl, and R8 is -NR6R7 wherein R6 is hydrogen, and R7 is methoxycarbamoyl; or alternatively R5 is -OCO2R1, being R1 selected from the group consisting of (C1-C4)alkyl, (C1- C4)haloalkyl, and (C6-C12)aryl optionally substituted with (C1-C4)alkyl or (C1-C4)haloalkyl, and R8 is -NR6R7 wherein R6 is hydrogen, and R7 is methoxycarbamoyl.

Claims

Claims 1. A process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof,

which comprises (a) reacting a compound of formula (VI),

with a halogenating agent in a suitable solvent to give a compound of formula (VII)

wherein Y is halogen, (b) reacting the compound of formula (VII) with dimethylamine in a suitable solvent, and (c) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof.

2. The process according to claim 1, wherein the process for the preparation of relugolix of formula (VIII) from a compound of formula (VI) is one-pot.

3. The process according to any of claims 1 to 2, wherein previously to step (a), the process comprises: (i) reacting a compound of formula (V),

with a compound R’’’O-CO-NH-OCH3, wherein R’’’ is (C6-C12)aryl optionally substituted with -NO2 in a suitable solvent to give a compound of formula (VI), or alternatively, (i’) reacting a compound of formula (V) with methoxyamine, in the presence of a carbonyl source and in a suitable solvent to give a compound of formula (VI).

4. The process according to claim 3, wherein previously to step (i) or alternatively step (i’), the process comprises: (ii) reacting a compound of formula (IV),

wherein X is halogen, with a compound (B)

wherein R^IV is -NH2, and each R’’ independently represents H, (C1-C4)alkyl or the two R’’ are linked together to form a R’’-R’’ moiety which is a (C1-C4)alkyl optionally substituted with one or more (C1-C4)alkyl groups, in a suitable solvent to give a compound of formula (V), or alternatively (ii’) reacting a compound of formula (IV) wherein X is halogen, with a compound (B) wherein R^IV is -NO2 or -NR’R’ wherein one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group, and each R’’ independently represents H, (C1-C4)alkyl or the two R” are linked together to form a R”-R” moiety which is a (C1- C4)alkyl optionally substituted with one or more (C1-C4)alkyl groups, in a suitable solvent to give a compound of formula (V’)

wherein R^IV is -NO2 or -NR’R’ wherein one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group, and

(ii”) reducing the nitro group or removing the protective group from the obtained compound of formula (V’) to give a compound of formula (V).

5. The process according to claim 4 wherein previously to step (ii) or alternatively step (ii’), the process comprises:

(iii) reacting a compound of formula (III)

6. The process according to claim 5, wherein previously to step (iii), the process comprises:

(iv) reacting a compound of formula (I),

(v) reacting the compound of formula (II) obtained in step (iv) with a 2,6-difluorobenzyl halide in a suitable solvent to give a compound of formula (III).

7. The process according to claim 4, wherein previously to step (ii) or alternatively step (ii’), the process comprises: (vi) reacting a compound of formula (I)

with a halogenating agent in a suitable solvent to give a compound of formula (I’),

wherein X is halogen and R represents (C1-C4)alkyl; (vii) reacting the compound of formula (I’) obtained in step (vi) under intramolecular cyclization conditions to obtain a compound of formula (II’), wherein X is halogen, and

(viii) reacting the compound of formula (II’) obtained in step (vii) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (IV).

8. The process according to claim 4, wherein previously to step (ii) or alternatively step (ii’), the process comprises: (ix) reacting a compound of formula (I),

(x) reacting a compound of formula (II) with a halogenating agent in a suitable solvent to give a compound of formula (II’)

wherein X is halogen; and (xi) reacting the compound of formula (II’) obtained in step (x) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (IV).

9. The process according to any of claims 7 to 8, wherein previously to step (iv), the process comprises: (xii) reacting a compound of formula (A)

10. A process for the preparation of a compound of formula (VII)

wherein Y is halogen, which comprises: (a) reacting a compound of formula (VI),

11. A process for the preparation of a compound of formula (V)

which comprises: (ii) reacting a compound of formula (IV),

wherein X is halogen, with a compound (B)

12. A process for the preparation of a compound of formula (I),

wherein R represents (C1-C4)alkyl, which comprises: (xii) reacting a compound of formula (A)

13. A compound of formula

wherein R₂ is hydrogen and R represents (C1-C4)alkyl, or alternatively, R₂ is halogen and R represents (C1-C4)alkyl.

14. A compound of formula (X) or a salt thereof

wherein

R₃ and R₄ are hydrogen, or alternatively,

R₃ is halogen and R₄ is hydrogen, or alternatively,

R₃ is hydrogen and R₄ is 2,6-difluorobenzyl, or alternatively, R₃ is halogen and R₄ is 2,6-difluorobenzyl.

15. A compound of formula (XI)

wherein

R₅ is hydrogen and Rs is -NR₆R₇ wherein R₆ and R₇ are hydrogen; or alternatively R₅ is hydrogen, and Rs is -NR₆R₇ wherein R₆ is an amino protective group, and R₇ is hydrogen or an amino protective group; or alternatively

Rs is hydrogen and Rs is -NR₆R₇ wherein R₆ is hydrogen and R₇ is methoxycarbamoyl.