WO2024256574A1

WO2024256574A1 - Process for preparing macrocyclic btk inhibitors

Info

Publication number: WO2024256574A1
Application number: PCT/EP2024/066433
Authority: WO
Inventors: Adrianus Petrus Antonius De Man; Rogier Christian Buijsman; Freek VAN CAUTER; Jan Gerard STERRENBURG; Joeri Johannes Petrus DE WIT; Sander Petrus Wilhelmus VAN GEMERT
Original assignee: Crossfire Oncology Holding BV
Current assignee: Crossfire Oncology Holding BV
Priority date: 2023-06-13
Filing date: 2024-06-13
Publication date: 2024-12-19
Anticipated expiration: 2025-12-13

Abstract

The present invention disclosure provides methods of producing a compound of formula (I-b) or a pharmaceutically acceptable salt hereof. Provided herein are new processes or methods of preparing the compounds of Formula (I-b) as described herein, in particular of preparing a compound of Formula (I). Furthermore, novel intermediates of and processes are disclosed herein.

Description

PROCESS FOR PREPARING MACROCYCLIC BTK INHIBITORS

Field of the invention

The present disclosure relates, in general, to improved processes for the preparation of macrocyclic BTK inhibitor of formula (l-b), particularly processes for preparation of macrocyclic BTK inhibitor of formula (I), and/or intermediates employed in such processes.

Background of the invention

Kinases are enzymes that transfer a phosphate group from ATP to a protein. Kinases play an important role in regulating cellular functions such as cell proliferation, subcellular translocation, apoptosis, inflammation and metabolism (Attwood M.M. et al (2021) Nat Rev Drug Discov). The human kinome is composed of over 500 kinases. The development of small- molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy.

Bruton's tyrosine kinase (BTK) is a member of the Src-related Tec family of protein kinases constituting a large subset of kinases, which play a central role in the regulation of a wide variety of cellular signaling processes. BTK plays a key role in B-cell receptor (BCR) signaling and a critical role in the regulation of survival, proliferation, activation and differentiation of B-lineage cells. Targeting of BTK with small molecule inhibitors such as the FDA approved covalent BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib and tirabrutinib has proven to be efficacious in several B cell malignancies including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), Waldenstrom’s Macroglobulinemia (WM) and Small Lymphocytic Lymphoma SLL.

BTK is also expressed and plays also pro-tumorigenic roles in several solid tumors (Xianhui Wang et al. 2021). In prostate cancer cells BTK inhibition with ibrutinib or acalabrutinib inhibited cell growth (Kokabee et al 2015). Ibrutinib has also been shown to inhibit in vivo (xenograft) breast cancer cell growth (Wang et al., 2016) and inhibition of BTK with ibrutinib blocked gastric cancer cell growth (Wang et al., 2016). BTK inhibitors have also showed inhibition of cellular proliferation and migration, and induced apoptosis and autophagy in glioblastoma cell lines (Wei et al., 2016; Wang et al., 2017).

Where tumors have a strong oncogenic drive from one particular kinase, specific amino acid mutations have been observed as acquired resistance mechanisms of targeted drug molecules. These mutations may naturally occur in very low levels but become more prevalent upon drug treatment (pre-existing mutations), or these can also be produced by random mutation within tumors (acquired mutations) (Barouch-Bentov et al. 2011). Where such mutations have a clear advantage upon drug treatment (i.e. a mutation where the drug is no longer able to bind to the target) then resistance may rapidly develop and patients can relapse quickly. In these cases, the understanding of the impact and mechanism of these mutations has enabled additional drug discovery efforts to develop subsequent “generations” of drug molecules to target such resistance forms.

A drawback of the first generation BTK inhibitor, ibrutinib, is that drug resistance in B- cell malignancies can develop when BTK acquires mutations at the cysteine at position C481 of the kinase domain. This mutation abrogates the covalent binding of ibrutinib hampering its efficacy. Quinquenel et al. performed a ‘snapshot’ screening to determine the prevalence of resistance mutations and found that the presence of the BTK mutation was significantly associated with subsequent CLL progression. The correlation between disease progression, and the emergence and temporal dynamics of the most common resistance inducing C481 S BTK mutation have been determined for CLL patients receiving single-agent ibrutinib treatment (Bodor et al. British Journal of Haematology 2021). Using digital droplet PCR the authors have been able to show that in 72.7% of the patients emergence of the BTK C481 S mutation preceded the symptoms of clinical relapse with a median of nine months. Woyach et al. showed that that detection of the C481 mutation in patients being treated with covalent BTK inhibitors is an indication for imminent relapse, usually within 12-18 months after detection (Woyach et al. (2017) J. Clin. Oncol. 35, 1437-1443). Since ibrutinib resistance confers poor survival, early detection of resistance provides clinically relevant information for the transition of affected patients to alternative treatment strategies.

Second-generation BTK inhibitors, which include acalabrutinib, zanubrutinib, and tirabrutinib, offer greater BTK selectivity and therefore limited off-target toxicity. These inhibitors, however, do not overcome resistance by C481 mutation. To treat patients with relapsed CLL having C481 BTK mutations non-covalent BTK inhibitors have been developed including LOXO- 305 (pirtobrutinib) and ARQ-531 (nemtabrutinib) and vecabrutinib. These agents do not require binding to the BTK C481 residue and effectively inhibit both wild type and mutant BTK with C481 substitutions. In preclinical studies, noncovalent BTK inhibitors including pirtobrutinib (LOXO- 305), ARQ-351 and vecabrutinib, inhibited B-cell-receptor signaling in BTK C481 -mutant cell and animal models. Moreover, the phase 1-2 clinical trial of pirtobrutinib showed promising efficacy for patients with B-cell cancer who had previously been treated with covalent BTK inhibitors (with 62% of patients with CLL having a response), including patients with or without BTK C481 mutations (with a response occurring in 71 % and 66% of the patients, respectively) (Wang et al. (2022) N. Engl. J. Med. 386, 735-43).

Pirtobrutinib was first disclosed in WO2017/103611 , ARQ-531 was disclosed in WO2017/111787 and vecabrutinib is disclosed in WO2013/185084. Further reversible BTK inhibitors are disclosed in WO2017/046604, , WQ2020/015735, WQ2020/239124, WQ2021/093839, WQ2020/043638, WO2013/067274, WQ2018097234, WO2013/010380, WQ2016/161570, WO2016/161571 , WO2016/106624, WO2016/106625, WO2016/106626, WO2016106623, WO2016/106628 and WO2016/109222.

Despite the effective treatment of patients with a C481 mutation with pirtobrutinib new acquired mutations have emerged after treatment with this non-covalent inhibitor. Mutations were identified in these patients that were clustered in the kinase domain of BTK (V416L, A428D, M437R, T474I, and L528W) and that conferred resistance to pirtobrutinib and other non-covalent inhibitors.

The most well-known clinical documented BTK mutations for ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib are given in Figure 1.

PCT Patent Application No. PCT/EP2022/085765, the entire disclosure of which are incorporated herein by reference, including all compounds described therein, discloses macrocyclic inhibitors of Bruton’s tyrosine kinase (BTK). Said macrocyclic BTK inhibitors can, for example, be used to treat various cancers, such as CLL.

Summary of the invention

Provided herein are new processes or methods of preparing the compounds of Formula (l-b) as described below, in particular a compound of Formula (I). Furthermore, novel intermediates and processes are disclosed herein.

In an aspect of the invention there are provided processes and/or intermediates for preparation of a compound according to formula (l-b).

The compounds of Formula (l-b) according to the invention are:

Wherein R¹ is any one of:

wherein R^2w is selected from hydrogen, halogen, (1-2C)alkyl, (1-2C)alkoxy; wherein any said alkyl or alkoxy group is optionally and independently substituted with one, two or three fluoro; wherein R^3u is selected from hydrogen, halogen, cyano, (1-4C)alkyl, (1-5C)alkoxy, (3- 6C)cycloalkyl or (3-6C)heterocycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro; wherein R² is selected from the group consisting of:

wherein any of said cycloalkyl, heterocycloalkyl and alkyl group is optionally and independently substituted with hydroxy, methyl, acetyl or methoxy; wherein R³ and R⁴ together represent a linker having Formula selected from the group consisting of:

whereby the

marks the position of R³ in Formula l-b, and whereby the marks the position of R⁴ in any one of Formula Il-a3, Il-a4, Il-a5 and to II-

c3; wherein any of said linkers is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD₃, (1-4C)alkyl, (1- 5C)alkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy and (1-6C)alkylcarbonyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; and wherein the process comprises one or more reaction steps according to the invention.

In another aspect of the invention there are provided processes and/or intermediates for preparation of a compound according to Formula (I).

The compound of Formula (I) is defined as:

Compound (I) is of one of the BTK inhibitors disclosed in PCT Patent Application No. PCT/EP2022/085765, also referred to as having subformula 184.

The compounds of Formula (l-b), in particular of formula (I) are highly selective inhibitors of Bruton’s tyrosine kinase. In addition, the compounds of the invention can inhibit with high selectivity BTK mutants including, but not limiting, BTK C481 S, BTK C481 R, BTK C481 F, BTK T474I, BTK T474M, BTK T316A, BTK V416L, BTK A428D, BTK M437R, double mutant BTK C481 S/T474I, and BTK L528W.

In another aspect of the invention is provided a method of preparing a compound of formula (IV):

or a salt thereof, comprising hydrogenation a starting material of formula (IV-3):

in the presence of a Raney nickel hydrogenolysis catalyst under acidic conditions to form the compound of formula (IV).

In another aspect of the invention is provided a method of preparing a compound of formula (V):

comprising reacting a starting material of formula (V-1):

in the presence of a zirconium hydroboration catalyst to form the compound of formula (V); wherein L having Formula selected from the group consisting of:

whereby the marks the connection to the pinacol boronic ester group in Formula

V, and whereby the marks the connection to the carboxylate group in Formula V;

wherein any of said linkers L is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD₃, (1-4C)alkyl, (1-5C)alkoxy, (3- 6C)cycloalkyl, (3-6C)cycloalkoxy and (1-6C)alkylcarbonyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; and wherein L₁ is selected from the group consisting of:

whereby the

marks the connection to the carboxylate group in Formula (V-1); wherein any of said linkers L₁ is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD₃, (1-4C)alkyl, (1- 5C)alkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy and (1-6C)alkylcarbonyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen.

In another aspect of the invention is provided a method of preparing a compound of formula (Va):

comprising reacting a starting material of formula (V-1 c):

in the presence of a zirconium hydroboration catalyst to form the compound of formula (Va).

In another aspect of the invention is provided a compound (IV, Va) selected from the following:

or a salt thereof.

Compound (IV) was surprisingly found to be a suitable intermediate compound for forming a linker between position R³ and R⁴ of the compounds (l-b) according to the invention at high overall yields. Surprisingly, we found that the use of the bromine containing compound of formula IV in subsequent reaction sequence resulted in a high yielding regioselective introduction of the vinylic substituent on position R³.

In known synthesis routes for forming imidazopyrazine compounds, albeit without a macrocycle, different synthesis routes were described, wherein R³ substituents were added starting from the already prepared bicyclic imidazopyrazine structure, using relatively harsh reaction conditions and providing very low yields in substitution at the R³ position.

In another aspect of the invention is provided a method of preparing a compound of formula (VI):

comprising reacting a first starting material of formula (IV):

or a salt thereof, with a second starting material of formula (II):

or a salt thereof, in the presence of a couplings reagent, including optionally an additive and a base, to form the compound of formula (VI); is selected from the group consisting of:

wherein any of said cycloalkyl, heterocycloalkyl and alkyl group is optionally and independently substituted with hydroxy, methyl, acetyl or methoxy.

In another aspect of the invention is provided a method of preparing a compound of formula (VIa):

comprising reacting a first starting material of formula (IV):

or a salt thereof, with a second starting material of formula (Il-a3a):

or a salt thereof, in the presence of a couplings reagent, including optionally an additive and a base, to form the compound of formula (VIa).

In another aspect of the invention is provided a method of preparing a compound of any one of formula (VIla) to (VIId):

comprising reacting a first starting material selected of one of formula (VIa) to (VId):

with a second starting material of formula (V):

in the presence of a palladium catalyst to form the compound of formula (VIla) to (VIId), wherein L having Formula selected from the group consisting of:

whereby the marks the connection to the pinacol boronic ester group in Formula

V, and whereby the

marks the connection to the carboxylate group in Formula V; wherein any of said linkers L is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD₃, (1-4C)alkyl, (1-5C)alkoxy, (3- 6C)cycloalkyl, (3-6C)cycloalkoxy and (1-6C)alkylcarbonyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; and wherein L₂ having Formula selected from the group consisting of:

whereby the

marks the connection to the bicyclic scaffold of Formula (l-b), and whereby the

marks the connection to the carboxylate group in Formula (VIla) - (VI Id); wherein any of said linkers L is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD₃, (1-4C)alkyl, (1-5C)alkoxy, (3- 6C)cycloalkyl, (3-6C)cycloalkoxy and (1-6C)alkylcarbonyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen.

In another aspect of the invention is provided a method of preparing a compound of formula (VII):

comprising reacting a first starting material of formula (VIa):

with a second starting material of formula (Va):

in the presence of a palladium catalyst to form the compound of formula (VII).

In another aspect of the invention is provided a method of preparing a compound of any one of formula (VIlla) to (VIlId):

comprising reacting a starting material of any one of formula (VIla) to (Vlld):

in the presence of a dehydrating reagent, including optionally an additive and a base, to form the compound of formula (VIlla) to (Vllld), wherein L₂ is as defined above.

In another aspect of the invention is provided a method of preparing a compound of formula (VIII):

comprising reacting a starting material of formula (VII):

in the presence of a dehydrating reagent, including optionally an additive and a base, to form the compound of formula (VIII).

In another aspect of the invention is provided a method of preparing a compound of any one of formula (IXa) to (IXd):

comprising reacting a starting material of any one of formula (VIlla) to (Vllld):

with a brominating agent to form the compound of formula (Ixa) to (Ixd), wherein L₂ is as defined above.

In another aspect of the invention is provided a method of preparing a compound of formula (IX):

comprising reacting a starting material of formula (VIII):

with a brominating agent to form the compound of formula (IX).

In another aspect of the invention is provided a method of preparing a compound of any one of formula (Xa) to (Xd):

wherein DMB is dimethoxybenzyl, comprising reacting a starting material of any one of formula (IXa) to (IXd):

With 2,4-dimethoxybenzylamine to form the compound of formula (Xa) to (Xd), wherein L₂ is as defined above.

In another aspect of the invention is provided a method of preparing a compound of formula (X):

comprising reacting a starting material of formula (IX):

with 2,4-dimethoxybenzylamine to form the compound of formula (X).

In another aspect of the invention is provided a method of preparing a compound of any one of formula (Xla) to (Xld):

or a salt thereof, wherein DMB is dimethoxybenzyl, comprising reacting a starting material of any one of formula (Xa) to (Xd):

with an acid to form the compound of formula (Xla) to (Xld) or salt thereof, wherein L₂ is as defined above.

In another aspect of the invention is provided a method of preparing a compound of formula (XI):

or a salt thereof comprising reacting a starting material of formula (X):

with an acid to form the compound of formula (XI) or salt thereof. In another aspect of the invention is provided a method of preparing a compound of any one of formula (Xlla) to (XIId):

wherein DMB is dimethoxybenzyl, comprising reacting a starting material of any one of formula (Xla) to (Xld):

in the presence of a couplings reagent, including optionally an additive and a base, to form the compound of formula (XII), wherein L₂ is as defined above.

In another aspect of the invention is provided a method of preparing a compound of formula (XII):

comprising reacting a starting material of formula (XI):

in the presence of a couplings reagent, including optionally an additive and a base, to form the compound of formula (XII).

In another aspect of the invention is provided a method of preparing a compound of any one of formula (Xllla-1) - (Xllld):

comprising reacting a starting material of formula any one of (Xlla) to (Xlld):

wherein DMB is dimethoxybenzyl, with a second starting material of formula (XIV):

in the presence of a palladium catalyst to form the compound of formula (Xllla-1) - (XIIld); wherein L₂ is as defined above; and wherein Y is any one of:

wherein R^2w is selected from hydrogen, halogen, (1-2C)alkyl, (1-2C)alkoxy; wherein any said alkyl or alkoxy group is optionally and independently substituted with one, two or three fluoro; wherein R^3u is selected from hydrogen, halogen, cyano, (1-4C)alkyl, (1-5C)alkoxy, (3- 6C)cycloalkyl or (3-6C)heterocycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro. In another aspect of the invention is provided a method of preparing a compound of formula

comprising reacting a starting material of formula (XII):

with a second starting material of formula (XIV):

in the presence of a palladium catalyst to form the compound of formula (XIII); wherein Y is any one of:

wherein R^2w is selected from hydrogen, halogen, (1-2C)alkyl, (1-2C)alkoxy; wherein any said alkyl or alkoxy group is optionally and independently substituted with one, two or three fluoro; wherein R^3u is selected from hydrogen, halogen, cyano, (1-4C)alkyl, (1-5C)alkoxy, (3- 6C)cycloalkyl or (3-6C)heterocycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro.

In another aspect of the invention is provided a method of preparing a compound of formula (Xllla):

comprising reacting a starting material of formula (XII):

with a second starting material of formula (XlVa):

in the presence of a palladium catalyst to form the compound of formula (Xllla).

In another aspect of the invention is provided a method of preparing a compound of any one of formula (la) to (Id), selected from:

or a salt thereof, comprising reacting a starting material of any one of formula (XIIla-1 ) to (XIIld):

wherein DMB is dimethoxybenzyl, with an acid to form the compound of formula (la) to (Id) or salt thereof.

In another aspect of the invention is provided a method of preparing a compound of formula (I):

or a salt thereof, comprising reacting a starting material of formula (XIIla):

with an acid to form the compound of formula (I) or salt thereof.

In another aspect of the invention is provided a method of purifying a compound of formula (I):

to form a crystallized product, comprising recrystallizing a compound of formula (I) in a solvent system (e.g. in a solvent comprising acetonitrile and dichloromethane). In another aspect of the invention is provided a compound selected from the following:

or a salt thereof.

Definitions

The term "pharmaceutical composition” as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable.

The term "pharmaceutically acceptable” as used herein has its conventional meaning and refers to compounds, material, compositions and/or dosage forms, which are, within the scope of sound medical judgment suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.

The term "effective amount" as used herein, refers to an amount of the compound of the invention, and/or an additional therapeutic agent, or a composition thereof, that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventive effect when administered to a subject suffering from a BTK-mediated disease or disorder.

A "subject" is a human or non-human mammal. In one embodiment, a subject is a human.

The term "controlling” is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of the diseases and conditions affecting the mammal. However, "controlling” does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatment.

The term "excipient” as used herein has its conventional meaning and refers to a pharmaceutically acceptable ingredient, which is commonly used in the pharmaceutical technology for preparing a granulate, solid or liquid oral dosage formulation.

The term "salt” as used herein has its conventional meaning and includes the acid addition and base salts of the compound of the invention.

The term "solvate” as used herein has its conventional meaning. One or more compounds of the invention or the pharmaceutically acceptable salts thereof may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association Involves varying degrees of ionic and covalent bonding. Including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H₂O and includes any hydrate of the compound or the salt of said compound.

The term "treatment” as used herein has its conventional meaning and refers to curative, disease controlling, palliative and prophylactic treatment.

The term "unit dosage form” has its conventional meaning and refers to a dosage form which has the capacity of being administered to a subject, preferably a human, to be effective, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising the therapeutic agent, i.e. the compound of the invention.

The term "BTK” as used herein has its conventional meaning and refers to Bruton's Tyrosine Kinase. Bruton's tyrosine kinase (BTK) is a member of the Src-related Tec family of protein kinases which are a large subset of kinases which play a central role in the regulation of a wide variety of cellular signaling processes. BTK plays a key role in the B-cell receptor signaling and a critical role in the regulation of survival, proliferation, activation and differentiation of B- lineage cells. Targeting of BTK with small molecule inhibitors such as the FDA approved irreversible BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib and tirabrutinib has proven to be efficacious in several B cell malignancies including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), Waldenstrom’s Macroglobulinemia (WM) and Small Lymphocytic Lymphoma SLL.

The term "BTK inhibitor” as used herein has its conventional meaning and refers to an inhibitor for BTK. A BTK inhibitor may be a small molecule inhibitor. Inhibitors may be irreversible inhibitors, such as by forming a covalent bond, and may be reversible inhibitors, which may form a temporary interaction with BTK.

The term "mutant-BTK” as used herein has its conventional meaning and refers to mutations of BTK. Mutations of BTK may be referred to by an altered amino acid target (such as C as single-letter data-base code for cysteine) at a certain position of the BTK structure (such as 481). Additionally, the amino acid substitution at the mutation position may be referred to by an additional amino acid single-letter data-base code, such as C481S for serine substitution and C481T for threonine substitution of cysteine at the 481 position.

A drawback of the currently approved irreversible inhibitors is that patients treated with these inhibitors can develop drug resistance when proteins with variations at the catalytic site are not able to bind efficiently to irreversible inhibitors in patients. This is a rather common event in patients treated with irreversible inhibitors and who experience relapse. A major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C481) mutations. These mutations hamper binding of irreversible inhibitors such as ibrutinib, acalabrutinib, zanubrutinib and tirabrutinib which form a covalent bond with this amino acid. Other mutations / modifications that can result in acquired resistance of irreversible covalent and reversible non-covalent BTK inhibitors are valine 416 (V416), alanine 428 (A428), methionine 437 (M437), threonine 474 (T474) and leucine 528 (L528) modifications, which can reduce BTK inhibitor binding to BTK. The term "wt-BTK” or “WT-BTK” or “BTK^WT’ as used herein has its conventional meaning and refers to wild-type Bruton’s Tyrosine Kinase. A wild-type BTK has the regular meaning of a phenotype of the typical form of BTK as it occurs in nature. Originally, the wild-type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "mutant" allele. The term "macrocycle” as used herein has its conventional meaning and refers to a part of a molecule containing a ring consisting of 12 or more ring atoms forming said ring. In an example, a twelve membered ring consist of 12 atoms forming said ring.

A bicyclic ringsystem, as used herein, refers to heterocyclic (heterocyclyl) groups, to cyclic groups having carbon groups only, i.e. without hetero atoms, within the cycle, and to combinations of a heterocyclic (heterocyclyl) group and a cyclic group having carbon groups only, i.e. without hetero atoms, within the cycle.

A monocylic ringsystem, as used herein, refers both to a heterocyclic (heterocyclyl) group, and to a cyclic group having carbon groups only, i.e. without hetero atoms, within the cycle.

A heterocyclic (heterocyclyl) group, as used herein, refers to both heteroaryl groups and heterocycloalkyl groups.

A heterobicyclic group, as used herein, refers to a bicyclic group having one or more heteroatoms, which is saturated, partially unsaturated or unsaturated.

As used herein, aromatic groups (or aryl groups) include aromatic carbocyclic ring systems (e.g. phenyl) and fused polycyclic aromatic ring systems (e.g. naphthyl and 1,2,3,4- tetrahydronaphthyl).

The term "alkyl," as used herein, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond having the specified number of carbon atoms. In different embodiments, an alkyl group contains, for example, from 1 to 6 carbon atoms (1- 6C)Alkyl or from 1 to 3 carbon atoms (1-3C)Alkyl. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched.

Unless specified otherwise, "alkyl" includes both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms; for example, "(1-6C)Alkyl" includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. "Alkylene" refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbons, and having two terminal end chain attachments; for example, the term "A-C4 alkylene-B" represents, for example, A-CH₂-CH₂-CH₂-CH₂-B, A-CH₂- CH₂-CH(CH₃)-CH₂-B, A-CH₂-CH(CH₂CH₃)-B, A-CH₂-C(CH₃)(CH₃)-B, and the like.

The term "alkylcarbonyl," as used herein, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond attached to a carbonyl group, wherein the aliphatic hydrocarbon group has the specified number of carbon atoms. In different embodiments, an alkyl group or aliphatic hydrocarbon group contains, for example, from 1 to 6 carbon atoms (1-6C)Alkyl or from 1 to 3 carbon atoms (1-3C)Alkyl. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched.

Cycloalkyl means a cycloalkyl group having the recited number of carbon atoms, with the same meaning as previously defined, such as cyclopropyl, cyclobutyl, or cyclopentyl. "Cycloalkyl" refers to a cycloalkyl-group represented by an indicated number of carbon atoms; for example "(3-6C)cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

Heterocycloalkyl means a cycloalkyl group having the recited number of carbon atoms, and 1-3 heteroatoms selected from N, O and/or S, with the same meaning as previously defined.

Haloalkyl means a branched or unbranched alkyl group having the recited number of carbon atoms, in which one and up to all hydrogen atoms are replaced by a halogen; halogen is as defined herein. Examples of such branched or straight chained haloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n- butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo and iodo.

For example, a halo(1-3C)alkyl means a branched or unbranched alkyl group having 1 ,2, or 3 carbon atoms, in which at least one hydrogen atom is replaced by a halogen. Examples of "haloalkyl" include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 1- fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and perfluoro-n-propyl.

Alkoxy means an alkoxy group having the recited number of carbon atoms, the alkyl moiety having the same meaning as previously defined, e.g., "Alkoxy" refers to an alkyl-O-group represented by a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge; for example "(1-6C)Alkoxy" includes -OCH3, -O-CH₂CH3, - OCH(CH₃)₂, -O(CH₂)₅CH3, and the like.

Cycloalkoxy means a cycloalkyl group having the recited number of carbon atoms, with the same meaning as previously defined, attached via a ring carbon atom to an exocyclic oxygen atom, such as cyclopropoxyl, cyclobutoxyl,or cyclopentoxyl. "Cycloalkoxy" refers to a cycloalkyl- O-group represented by a cycloalkyl group of indicated number of carbon atoms attached through an oxygen bridge; for example "(3-6C)cycloalkoxy" includes cyclopropyl-O-, cyclobutyl- O-, cyclopentyl-O-, or cyclohexyl-O-.

Heterocycloalkoxy means a cycloalkyl group having the recited number of carbon atoms, and 1-3 heteroatoms selected from N, O and/or S, with the same meaning as previously defined, attached via a ring carbon atom to an exocyclic oxygen atom.

Unless otherwise specifically noted as only "unsubstituted" or only "substituted", alkyl groups are unsubstituted or substituted with 1 to 3 substituents on each carbon atom.

It should be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

The terms first, second, third and the like in the description and in the claims, are used for distinguishing between for example similar elements, compositions, constituents in a composition, or separate method steps, and not necessarily for describing a sequential or chronological order. The terms are interchangeable under appropriate circumstances and the embodiments of the invention can operate in other sequences than described or illustrated herein, unless specified otherwise.

Furthermore, the various embodiments, although referred to as “preferred” or “e.g.” or “for example” or “in particular” and the like are to be construed as exemplary manners in which the invention may be implemented rather than as limiting the scope of the invention.

The term “comprising”, used in the claims, should not be interpreted as being restricted to for example the elements or the method steps or the constituents of a compositions listed thereafter; it does not exclude other elements or method steps or constituents in a certain composition. It needs to be interpreted as specifying the presence of the stated features, integers, (method) steps or components as referred to, but does not preclude the presence or addition of one or more other features, integers, steps or components, or groups thereof. Thus, the scope of the expression “a method comprising steps A and B” should not be limited to a method consisting only of steps A and B, rather with respect to the present invention, the only enumerated steps of the method are A and B, and further the claim should be interpreted as including equivalents of those method steps. Thus, the scope of the expression “a composition comprising components A and B” should not be limited to a composition consisting only of components A and B, rather with respect to the present invention, the only enumerated components of the composition are A and B, and further the claim should be interpreted as including equivalents of those components.

In addition, reference to an element or a component by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element or component are present, unless the context clearly requires that there is one and only one of the elements or components. The indefinite article "a" or "an" thus usually means "at least one".

Detailed description of the invention

Disclosed herein are processes or methods of preparing the compounds of Formula (I- b) as described above, in particular embodiments a compound of Formula (I). Furthermore, novel intermediates of and processes are disclosed herein.

Compounds according to the invention

The compounds of Formula (l-b) according to the invention are:

Wherein R¹ is any one of:

whereby the

The compound of Formula (I) is defined as:

In further aspects there are provided processes and/or intermediates for preparation of a compound according to Formula (la) to (Id).

The compound of Formula (la) to (Id) is defined as:

wherein R^2w is selected from hydrogen, halogen, (1-2C)alkyl, (1-2C)alkoxy; wherein any said alkyl or alkoxy group is optionally and independently substituted with one, two or three fluoro; wherein R^3u is selected from hydrogen, halogen, cyano, (1-4C)alkyl, (1-5C)alkoxy, (3- 6C)cycloalkyl or (3-6C)heterocycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro, and wherein L₂ having Formula selected from the group consisting of:

whereby the marks the connection to the bicyclic scaffold of Formula (la) - (Id), and whereby the

marks the connection to the amide group in Formula (la) - (Id); wherein any of said linkers L is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD₃, (1-4C)alkyl, (1-5C)alkoxy, (3- 6C)cycloalkyl, (3-6C)cycloalkoxy and (1-6C)alkylcarbonyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen, and wherein Y is any one of:

Intermediates of the invention

Intermediates of compound Formula (I)

In preferred embodiments, the compound of Formula (I) is prepared based on one or more of the intermediate compounds selected from:

or a salt thereof.

Intermediates of compound Formula (l-b) In preferred embodiments, the compound of Formula (l-b) is prepared based on one or of more of the intermediate compounds selected from:

wherein DMB is dimethoxybenzyl, wherein L₂ having Formula selected from the group consisting of:

whereby the

marks the connection to the bicyclic scaffold of Formula (l-b), and whereby the

marks the connection to the carboxylate group in Formula (VII) - (XI) or the amide group in Formula (XII) - (XIII); wherein any of said linkers L₂ is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD₃, (1-4C)alkyl, (1-5C)alkoxy, (3- 6C)cycloalkyl, (3-6C)cycloalkoxy and (1-6C)alkylcarbonyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen, and wherein Y is any one of:

Process of preparation of compound (IV)

In preferred embodiments, the reaction is carried out in acetic acid, preferably at 20 °C to 30 °C, more preferably at 1-4 atm.

Process of preparation of compound (V) or (Va)

In preferred embodiments, the zirconium catalyst is bis(cyclopentadienyl)zirconium chloride hydride (Schwartz’ reagent) and wherein the reaction is carried out in triethylamine in the presence of 4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolane (pinacolborane), preferably at 50 °C to 60 °C.

Process of preparation of compound (VI) or (VIa)

In preferred embodiments, the couplings reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N ’,N ’-dimethylamino)- propylcarbodiimide hydrochloride (EDC), (benzotriazol-1-yloxy)tris(dimethylamino)phospho- nium hexafluorophosphate (BOP), (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), bis(2- oxo-3-oxazolidinyl)phosphinic chloride (BOP-CI), O-(benzotriazol-1-yl)-N ,N ,N ’,N ’-tetramethyl- uronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N ,N ,N ’,N ’-tetramethyluro- nium hexafluorophosphate (HATU), O-(7-azabenzotriazole-1-yl)-N ,N ,N ’,N ’-tetramethyluronium tetrafluoroborate (TATU), O-(6-chlorobenzotriazol-1-yl)-N ,N ,N ’,N ’-tetramethyluronium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-N ,N ,N ’,N ’-tetramethyluronium tetrafluoroborate (TBTU), 2-(2-pyridon-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TPTU), 2-(5-norbore- ne-2,3-dicarboximido)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TNTU), N , N ,N ’, N ’-tetra- methyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU), N ,N ,N ’,N ’-tetramethyl-O-(3,4- dihydro-4-oxo-1 ,2,3-benzotriazin-3-yl)uronium tetrafluoroborate (TDBTU), O-[(ethoxycarbonyl)- cyanomethyleneamino]-N ,N ,N ’N ’-tetramethyluronium tetrafluoroborate (TOTU), (1-cyano-2- ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), 1 ,1 ’-carbonyldiimidazole (CDI), tetramethylfluoroformamidinium hexafluorophosphate (TFFH), N ,N ,N ’,N ’-tetramethylchloroformamidinium hexafluorophosphate (TCFH), 2,4,6-tripropyl- 1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P), 3-(diethylphosphoryloxy)-1 ,2,3- benzotriazin-4(3/-/)-one (DEPBT), N-ethyl-2-[(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]- amino]-N-(3-pyridinylmethyl)-acetamide (EMPA), diphenylphosphinic chloride (DPPCI), chloro- 1 ,3-dimethylimidazolinium chloride (DMC), oxalylchloride (COCI₂), thiony Ichloride (SOCI₂), ethyl chloroformate (ECF) and isobutyl chloroformate (IBCF).

In preferred embodiments, the additive is selected from the group consisting of 1-hy- droxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), ethyl 2-cyano-2-(hydroxyamino)- acetate (Oxyma Pure) and 1-hydroxy-7-azabenzotriazole (HOAt).

In preferred embodiments, the base is selected from the group consisting of triethylamine (TEA), N ,N-diisopropylethylamine (DiPEA), N-ethylmorpholine (NEM), N-methylmorpholine (NMM), pyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2,6-lutidine.

In preferred embodiments, the couplings reagent is O-(7-azabenzotriazol-1-yl)-N ,N ,N ’,N ’- tetramethyluronium hexafluorophosphate (HATU) and wherein the reaction is carried out in ethyl acetate in the presence of triethylamine at 20 °C to 30 °C.

Process of preparation of compound (VII), (VIla), (Vllb), (VIle) or (Vlld) In preferred embodiments, the palladium catalyst is selected from the group consisting of Pd(dppe)₂ (Bis[1 ,2-bis(diphenylphosphino)ethane]palladium(0)), CX-11 (1 ,3-Bis(2,6- diisopropylphenyl)imidazol-2-ylidene(1 ,4-naphthoquinone)palladium(0)dimer), CX-12 (1 ,3-

Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene(1 ,4-naphthoquinone)palladium(0)dimer), Pd(t- BU₃P)₂ (Bis(tri-tert-butylphosphine)palladium(0)),Pd(PCy3)₂ (Bis(tricyclohexylphosphine)- palladium(O)), Pd(PPh3)4 (Tetrakis(triphenylphosphine)palladium(O)), Pd2(dba)3 (Tris(dibenzyli- deneacetone)dipalladium(O)), Pd(OAc)₂ (Palladium(ll)acetate), PdCI₂(PPh3)₂ Dichlorobis(tri- phenylphosphine)palladium(ll)),PdCI₂(Amphos)₂ (Bis(di-te/Y-butyl(4-dimethylaminophenyl)- phosphine)dichloropalladium(ll)), Pd(MeCN)2CI₂ (Bis(acetonitrile)dichloropalladium(ll)), PdCI₂(P-o-Tol)₃)₂ (Dichlorobis(tri-o-tolylphosphine)palladium(ll)), Pd(dppf)CI₂ (1 ,1 '-Bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll)),Pd(MeCN)₄(BF₄)₂ (Tetrakis(acetonitrile)palladium(ll) tetrafluoroborate), Pd-PEPPSI-IPent (Dichloro[1 ,3-bis(2,6-di-3-pentylphenyl)imidazol-2- ylidene](3-chloropyridyl)palladium(ll)), Pd-PEPPSI-IPr ([1 ,3-Bis(2,6-Diisopropylphenyl)imidazol- 2-ylidene](3-chloropyridyl)palladium(ll) dichloride), Pd-PEPPSI-SIPr ((1 ,3-Bis(2,6-

Diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(ll)dichloride), Pd(dba)₂ bis(dibenzylideneacetone)palladium(0)) and cataCXium A Pd G3 (Methanesulfonato(di- adamantyl-n-butylphosphino)-2’-amino-1 ,1 ’-biphenyl-2-yl)palladium(ll)).

In preferred embodiments, the palladium catalyst is 1 ,1 '-bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll) (Pd(dppf)CI₂).

In preferred embodiments, the reaction further comprises a base.

In preferred embodiments, the base is selected from the group consisting of potassium carbonate (K2CO3), cesium carbonate (CS2CO3), potassium hydroxide (KOH) and sodium tert-butoxide (NaOfBu).

In preferred embodiments, the base is potassium carbonate and wherein the reaction is carried out in a solvent mixture of dioxane/water, preferably at 80 °C.

Process of preparation of compound (VIII), (VIlla), (Vlllb), (VIlle) or (Vllld)

In preferred embodiments, the dehydrating reagent is selected from the group consisting of phosphorous pentachloride (PCI5), phosphorous oxychloride (POCI3), trifluoroacetic anhydride (TFAA), polyphosphoric acid (PPA), methyl N-(triethylammonium-sulfonyl)carbamate (Burgessreagent) and 1-chloro-N ,N-dimethylmethaniminium chloride (VIlsmeier reagent).

In preferred embodiments, the additive is selected from the group consisting of N,N,- dimethylformamide (DMF), 1 ,1 ,3,3-tetramethylurea (TMU) and 1 ,3-dimethyl-2-imidazolidinone (DMI).

In preferred embodiments, the base is selected from the group of pyridine, triethylamine, 2- chloropyridine and 2-fluoropyridine.

In preferred embodiments, the dehydrating reagent is phosphorous oxychloride (POCI3) and wherein the reaction is carried out in acetonitrile, N , N , -dimethylformamide (DMF), 1 ,3-di-methyl- 2-imidazolidinone (DMI) or mixtures thereof in the presence of pyridine, preferably at -15°C to 10°C.

Process of preparation of compound (IX), (IXa), (IXb), (IXc) or (IXd)

In preferred embodiments, the brominating agent is N-bromosuccinimide (NBS) and wherein the reaction is carried out in acetonitrile, preferably at 5 °C to 25 °C.

Process of preparation of compound (X), (Xa), (Xb), (Xc) or (Xd)

In preferred embodiments, the reaction is carried out in 2-butanol (sec-BuOH) at 90 °C. Process of preparation of compound (XI), (Xla), (Xlb), (Xlc) or (Xld)

In preferred embodiments, the acid is selected from the group of hydrochloric acid (HCI), hydrobromic acid (HBr), hydroiodic acid (HI), methanesulfonic acid (MsOH) and trifluoroacetic acid (TFA).

In preferred embodiments, the acid is hydrochloric acid (HCI) and wherein the reaction is carried out in dioxane, acetonitrile, or mixtures thereof.

Process of preparation of compound (XII), (Xlla), (Xllb), (Xllc) or (Xlld)

In preferred embodiments, wherein the couplings reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N ’,N ’-dimethylamino)- propylcarbodiimide hydrochloride (EDC), (benzotriazol-l-yloxy)tris(dimethyl- amino)phosphonium hexafluorophosphate (BOP), (benzotriazol-l-yloxy)tripyrrolidinophos- phonium hexafluorophosphate (PyBOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-CI), O-(benzotriazol-l-yl)- N ,N ,N ’,N ’-tetramethyl-uronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)- N ,N ,N ’,N ’-tetramethyluro-nium hexafluorophosphate (HATU), O-(7-azabenzotriazole-1-yl)- N ,N ,N ’,N ’-tetramethyluronium tetrafluoroborate (TATU), O-(6-chlorobenzotriazol-1-yl)- N ,N ,N ’,N ’-tetramethyluronium hexa-fluorophosphate (HCTU), O-(benzotriazol-1-yl)-N ,N ,N ’,N ’- tetramethyluronium tetrafluoroborate (TBTU), 2-(2-pyridon-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TPTU), 2-(5-norbore-ne-2,3-dicarboximido)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TNTU), N ,N ,N ’,N ’-tetra-methyl-O-(N-succinimidyl)uronium tetrafluoro bo rate (TSTU), N ,N ,N ’,N ’-tetramethyl-O-(3,4-dihydro-4-oxo-1 ,2,3-benzotriazin-3-yl)uronium tetrafluoroborate (TDBTU), O-[(ethoxycarbonyl)-cyanomethyleneamino]-N ,N ,N ’N ’-tetramethyl- uronium tetrafluoroborate (TOTU), (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino- morpholino-carbenium hexafluorophosphate (COMU), (7-azabenzotriazol-1-yloxy)tri- pyrrolidinophosphonium hexafluorophosphate (PyAOP), 1 ,1 ’-carbonyldiimidazole (CDI), tetramethylfluoroformamidinium hexafluorophosphate (TFFH), N ,N ,N ’,N ’-tetramethylchloro- formamidinium hexafluorophosphate (TCFH), 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinane- 2,4,6-trioxide (T3P), 3-(diethylphosphoryloxy)-1 ,2,3-benzotriazin-4(3/7)-one (DEPBT), N-ethy I-2- [(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]-amino]-N-(3-pyridinylmethyl)-acetamide (EMPA), diphenylphosphinic chloride (DPPCI), chloro-1 ,3-dimethylimidazolinium chloride (DMC), oxalylchloride (COCI₂), thionylchloride (SOCI₂), ethyl chloroformate (ECF) and isobutyl chloroformate (IBCF).

In preferred embodiments, the additive is selected from the group consisting of 1-hy- droxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), ethyl 2-cyano-2-(hydroxyamino)- acetate (Oxyma Pure) and 1-hydroxy-7-azabenzotriazole (HOAt). In preferred embodiments, the base is selected from the group consisting of triethylamine (TEA), N ,N-diisopropylethylamine (DiPEA), N-ethylmorpholine (NEM), N-methylmorpholine (NMM), pyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2,6-lutidine.

In preferred embodiments, the couplings reagent is O-(7-azabenzotriazol-1-yl)-N ,N ,N ’,N ’- tetramethyluronium hexafluorophosphate (HATU) and wherein the reaction is carried out in N,N,- dimethylformamide (DMF), ethyl acetate, dichloromethane, or mixtures thereof, in the presence of N-ethylmorpholine (NEM), preferably at 20 °C to 30 °C.

Process of preparation of compound (XIII), (Xllla), (Xllla-1), (Xlllb), (Xlllc) or (Xllld) In preferred embodiments, the palladium catalyst is selected from the group consisting of Pd(dppe)₂ (Bis[1 ,2-bis(diphenylphosphino)ethane]palladium(0)), CX-11 (1 ,3-Bis(2,6- diisopropylphenyl)imidazol-2-ylidene(1 ,4-naphthoquinone)palladium(0)dimer), CX-12 (1 ,3-

Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene(1 ,4-naphthoquinone)palladium(0)dimer), Pd(t- BU₃P)₂ (Bis(tri- tert-butylphosphine)palladium(0)),Pd(PCy3)₂ (Bis(tricyclohexylphosphine)- palladium(O)), Pd(PPh₃)₄ (Tetrakis(triphenylphosphine)palladium(O)), Pd2(dba)3 (Tris(dibenzyli- deneacetone)dipalladium(O)), Pd(OAc)₂ (Palladium(ll)acetate), PdCI₂(PPh3)₂ Dichlorobis(tri- phenylphosphine)palladium(ll)),PdCI₂(Amphos)₂ (Bis(di-tert-butyl(4-dimethylaminophenyl)- phosphine)dichloropalladium(ll)), Pd(MeCN)2CI₂ (Bis(acetonitrile)dichloropalladium(ll)), PdCI₂(P-o-Tol)₃)₂ (Dichlorobis(tri-o-tolylphosphine)palladium(ll)), Pd(dppf)CI₂ (1 ,1 '-Bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll)),Pd(MeCN)4(BF4)₂ (Tetrakis(acetonitrile)palladium(ll) tetrafluoroborate), Pd-PEPPSI-IPent (Dichloro[1 ,3-bis(2,6-di-3-pentylphenyl)imidazol-2- ylidene](3-chloropyridyl)palladium(ll)), Pd-PEPPSI-IPr ([1 ,3-Bis(2,6-Diisopropylphenyl)imidazol- 2-ylidene](3-chloropyridyl)palladium(ll) dichloride), Pd-PEPPSI-SIPr ((1 ,3-Bis(2,6- Diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(ll)dichloride), Pd(dba)2 bis(dibenzylideneacetone)palladium(0)) and cataCXium A Pd G3 (Methanesulfonato(di- adamantyl-n-butylphosphino)-2'-amino-1 , 1 '-bipheny l-2-yl)palladium(l I)).

In preferred embodiments, the reaction further comprises a base.

In preferred embodiments, the base is selected from the group consisting of potassium carbonate (K₂CO₃), cesium carbonate (CS₂CO₃), potassium hydroxide (KOH) and sodium fert-butoxide (NaOfBu). In preferred embodiments, the base is potassium carbonate (K₂CO₃), and wherein the reaction is carried out in dioxane, water, or mixtures thereof, preferably at 80 °C.

Process of preparation of compound (I), (la), (Ib-a), (Ic) or (Id) from any one of compound (XIII), (Xllla), (Xllla-1), (Xlllb), (Xlllc) or (Xllld)

In preferred embodiments, the acid is selected from the group of hydrochloric acid (HCI), hydrobromic acid (HBr), hydroiodic acid (HI), methanesulfonic acid (MsOH) and trifluoroacetic acid (TFA). In preferred embodiments, the reaction is carried out at (about) 60 °C, preferably wherein the acid is trifluoroacetic acid (TFA).

Synthesis of compounds

The invention is illustrated by the following examples.

Examples

The following examples are illustrative embodiments of the invention, not limiting the scope of the invention in any way. Reagents are either commercially available or are prepared according to procedures known in the literature.

The following abbreviations are used throughout the application with respect to chemical terminology:

TFA Trifluoracetic acid

HATU O-(7-Azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluroniumhexafluorophosphate

DMF N,N-Dimethylformamide

THF Tetra hydrofuran

DCM Dichloromethane

LCMS Liquid Chromatography with Mass Spectrometry detection

Boc tert-Butyloxy carbonyl

DBU 1 ,8-Diazabicyclo[5.4.0]undec-7-ene

DIAD Diisopropyl azodicarboxylate o/n Overnight

Pd(dppf)CI₂ 1 ,1 '-bis(diphenylphosphino)ferrocene palladium(ll) chloride

ZrCp₂(H)CI zirconocene hydrochloride (Schwartz Reagent)

¹H-NMR Proton nuclear magnetic resonance

¹³C-NMR Carbon nuclear magnetic resonance

PPm Parts per million

BOC2O Di-tert-butyl decarbonate

NBS N-Bromosuccinimide

MTBE Methyl-tert-butylether

J Coupling-constant

EtOAc Ethyl acetate

Na₂S₂O₃ Sodium thiosulfate

NaHCO₃ Sodium bicarbonate

EtOH Ethanol

2-BuOH 2-Butanol

K₂CO₃ Potassium carbonate

POCb Phosphorous oxychloride

SOCI₂ Thionylchloride

PPh₃ Triphenyl phosphine MeOH Methanol

LiOH Lithium hydroxide rT Room temperature

CuCN Copper(l)cyanide

NaCN Sodium cyanide

CuCI₂ Copper(ll)chloride tBuONO tert-Butyl nitrite

MeCN Acetonitrile

HOAc Acetic acid

DMSO Dimethyl sulfoxide

HCI Hydrogen chloride

NaOH Sodium hydroxide

Pd/C Palladium on activated carbon

NEM N-ethyl morpholine

CDCh Deuterated chloroform

DMSO-d₆ Deuterated dimethyl sulfoxide

KI Potassium iodide I₂ Iodine

DMB Dimethoxybenzyl

TBA-CI Tetrabutylammonium chloride

The names of the final products in the intermediates and examples are generated using Biovia Draw (version 16.1). In cases were Biovia Draw could not generate a name, molecular structures are given.

Method LCMS (A)

LC-MS system equipped with a Waters 2998 Photodiode Array Detector, Waters Acquity QDa Detector, Waters 2767 autosampler and Waters 2545 binary gradient module was used for sample analyses with a XTerra® MS C18 column (2.5 μm, 4.6 x 50 mm) for 10 min measure- ments.

The eluents used for this system are A (95/5 v/v% Milli-Q water/acetonitrile + 0.1 % formic acid) and B (acetonitrile + 0.1 % formic acid).

Method LCMS (A): 95% A to 95% B in 7 min, then 95% A.

Method LCMS (B)

LC-MS system equipped with a Waters 2998 Photodiode Array Detector, Waters Acquity QDa Detector, Waters 2767 autosampler and Waters 2545 binary gradient module was used for sample analyses with a XBridge® MS C18 column (5 μm, 4.6 x 50 mm) for 30 min measurements. The eluents used for this system are A (95/5 v/v% Milli-Q water/acetonitrile + 0.1 % formic acid) and B (acetonitrile + 0.1 % formic acid).

Method LCMS (B): 95% A to 95% B in 22 min, then switched to 95% A. NMR

NMR spectra were recorded on a Bruker Avance III 400 MHz and the compounds were assigned using ¹H NMR and ¹³C NMR spectra. Chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane. NMR data are presented in the following way: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, dd = doublet of doublets, ddd = doublet of doublet of doublets, td = triplet of doublets, tdd = triplet of doublet of doublets qd = quartet of doublets, dp = doublet of quintets m = multiplet and/or multiple resonances) and coupling constants J in Hz.

Example 1 : Synthesis of (6-bromo-3-chloro-pyrazin-2-yl)methanamine hydrochloride (IV)

(6-Bromo-3-chloro-pyrazin-2-yl)methanamine hydrochloride (IV)

(a) 3-Amino-6-bromo-pyrazine-2-carbonitrile (IV-2)

To a solution of commercially available 2-amino-3,5-dibromopyrazine (IV-1) (25.12 g, 99.3 mmol) in DMF (160 mL) was added sodium cyanide (4.97 g, 101.3 mmol) and copper(l)cyanide (9.07 g, 101.3 mmol) at room temperature. The mixture was stirred at 95 °C for 32 h. After cooling the mixture was and poured in a thoroughly stirred mixture of 5% sodium bicabonate solution (1 L) and ethyl acetate (500 mL) to give a black suspension. The mixture was filtered over Decalite®, flushed with warm ethyl acetate (2 x 150 mL). The organic layer from the biphasic filtrate was separated. The waterlayer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 15.6 g of the crude title compound (yield: 78.9%).

TLC (ethyl acetate/heptane=1/1 v/v%): R_f = 0.50.

LC-MS (A): R_t = 3.71 min; m/z 198.9 [M+H]⁺ mono-bromide pattern.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm] 8.45 (s, 1 H), 7.63 (s, 2H).

(b) 6-Bromo-3-chloro-pyrazine-2-carbonitrile (IV-3)

To a solution of 3-amino-6-bromo-pyrazine-2-carbonitrile (IV-2) (15.6 g, 78.4 mmol) in acetonitrile (350 mL) was added copper(ll)chloride (12.65 g, 94.1 mmol) and the mixture was heated to 60 °C and stirred for 15 min. A solution of tert-butyl nitrite (1 1.75 mL, 98 mmol) in acetonitrile (50 mL) was added dropwise at 60 °C to the reaction mixture. The mixture was stirred at 60 °C o/n. After cooling, the mixture was filtered over Decalite®, washed with acetonitrile. The filtrate was added dropwise to a 1 N HCI-solution (250 mL) and ethyl acetate (250 mL) and stirred for 10 min. The layers were separated and the water layer was extracted with ethyl acetate (2x 100 mL). The combined organic layers were washed with 1 N-HCl-solution, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (plug filtration) using SiO₂ and heptane/ethyl acetate = 95/5 to 9/1 to 8/2 v/v%. All fractions containing the title compound were collected and concentrated in vacuo to give 10.4 g of the title compound (yield 60.7%).

TLC (ethyl acetate/heptane=1/1 v/v%): Rf = 0.80.

LC-MS (A): R_t = 4.81 min; bad mass respons.

¹H-NMR (400 MHz, CDCI₃) δ [ppm] 8.69 (s, 1 H). ¹³C NMR (101 MHz, CDCb) δ [ppm] 150.50, 149.81 , 138.24, 129.71 , 112.59.

(c) (6-Bromo-3-chloro-pyrazin-2-yl)methanamine hydrochloride (IV)

To a solution of 6-bromo-3-chloro-pyrazine-2-carbonitrile (IV-3) (10.4 g, 47.62 mmol) in acetic acid (160 mL) was added under nitrogen Raney-Nickel (50% slurry in water, 1 .96 mL, -16.7 mmol). The resulting mixture was shaken in a Parr-vessel under 4 bar hydrogen at room temperature o/n. Raney-Nickel was removed by filtration over Decalite® and the filtrate was concentrated under reduced pressure and co-evaporated with toluene. The remaining green solid (12.6 g) was suspended in ethyl acetate at 50 °C and filtered. The filtrate was cooled on an ice-bath, 2N HCI_gas in diethyl ether (48 mL) was added dropwise and the resulting suspension was stirred at room temperature o/n. The solids formed were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40 °C to give 6.21 g (50%) of (6-bromo-3- chloro-pyrazin-2-yl)methanamine hydrochloride (VI).

LC-MS (A): R_t = 0.76 min; m/z 221 .9/223.9 [M+H]⁺ mono-bromide pattern.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm] 8.82-8.80 (m, 1 H), 8.72 (s, 3H), 4.32 (d, J = 1.0

Hz, 2H).

Example 2: Synthesis of tert-butyl (E)-8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)oct- 7 -enoate (lb)

tert-Butyl (E)-8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)oct-7-enoate (Va)

(a) Oct-7-ynoic acid (V1-b)

To a cold (5 °C) suspension of lithium acetylide ethylenediamine complex (techn. 85%, 36.08 g, 333 mmol) in anhydrous DMSO (83 mL) placed under a nitrogen flush, was added dropwise a solution of 6-bromohexanoic acid (25 g, 128 mmol) in anhydrous DMSO (43 mL) keeping the temperature below 15 °C (exothermic reaction). The reaction mixture was stirred at 5 °C for 15 min and then allowed to come to room temperature and stirred for another 2.5 h. The mixture was cooled to 5 °C and quenched by slow addition of 50% brine (200 mL). The mixture was flushed with nitrogen to remove all acetylene formed. The mixture was transferred to a 2 L Erlenmeyer flask and additional 50% brine (200 mL) was added. The mixture was stirred for 30 min at room temperature and then acidified by addition of 3N HCI-solution (386 mL). The product was extracted with ethyl acetate/heptane = 1/1 v/v% (3x250 mL). The combined organic layers were washed with water (3x200 mL), 50% brine (100 mL), dried over sodium sulfate for 30 min, filtered and concentrated in vacuo to give 16.75 g (93%) of oct-7-ynoic acid (V1-b) as an oil which solidifies upon standing.

TLC (ethyl acetate/heptane=1/1 v/v%): Rf = 0.50.

¹H-NMR (400 MHz, CDCb) δ [ppm] 2.37 (t, J = 7.5 Hz, 2H), 2.20 (td, J = 6.9, 2.7 Hz, 2H), 1 .94 (t, J = 2.6 Hz, 1 H), 1 .66 (p, J = 7.5 Hz, 2H), 1 .60 - 1 .40 (m, 4H).

(b) tert-Butyl oct-7-ynoate (V1-c)

To a solution of oct-7-ynoic acid (V1-b) (16.75 g, 120 mmol) in anhydrous THF (239 mL) was added dropwise trifluoroacetic anhydride (29.9 mL, 215 mmol) keeping the temperature between 20-25 °C. The reaction mixture was stirred at room temperature for 3 h. te/Y-Butanol (119 mL) was added slowly and the mixture was stirred at room temperature for 72 hours. The mixture was quenched by addition of 1 N NaOH-solution (200 mL). The mixture was extracted with ethyl acetate/heptane = 1/1 v/v% (2x150 mL). The combined organic layers were washed with 0.5N NaOH-solution (150 mL), water (100 mL), brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 23.13 g of te/Y-butyl oct-7-ynoate (V1- c) as a slightly coloured liquid. Yield: 98%.

TLC (ethyl acetate/heptane=1/1 v/v%): Rf = 0.90.

¹H-NMR (400 MHz, CDCb) δ [ppm] 2.20 (dddd, J = 11 .7, 7.1 , 5.0, 1 .9 Hz, 4H), 1 .93 (t, J = 2.6 Hz, 1 H), 1 .66 - 1 .36 (m, 15H).

(c) tert-Butyl (E)-8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)oct-7-enoate (Va)

To a cold (5 °C) oven-dried 250 mL round bottom flask equipped with a magnetic stirring bar were added te/Y-butyl oct-7-ynoate (V1-c) (21.02 g, 107 mmol), Schwartz’s reagent (1.38 g, 5.35 mmol), EtaN (745 pL, 5.35 mmol) and pinacolborane (15.53 mL, 13.7 g, 107 mmol), under an inert nitrogen atmosphere. The cooling bath was removed and the mixture was stirred at 30 °C for 16 hours. The reaction was allowed to cool to room temperature, diluted with heptane, passed through a pad of silica gel (300 g) using heptane/ethyl acetate = 97.5/2.5 v/v%. All fractions containing the title compound were collected and concentrated in vacuo to give 29 g of the title compound as a clear liquid oil (yield: 83%).

TLC (petane/diethyl ether = 9/1 v/v%): Rf = 0.40.

¹H-NMR (400 MHz, CDCb) δ [ppm] 6.62 (dt, J = 17.9, 6.4 Hz, 1 H), 5.42 (dt, J = 17.9, 1.6 Hz, 1 H), 2.26 - 2.10 (m, 4H), 1.65 - 1.18 (m, 27H).

¹³C NMR (101 MHz, CDCb) δ [ppm] 173.37, 154.57, 83.13, 80.08, 35.71 , 35.64, 28.74,

28.25, 28.00, 24.91 .

Example 3a: Synthesis of ethyl (1R,5R)-5-hydroxycyclohex-3-ene-1-carboxylate

Ethyl (1 R,,5R)-5-hvdroxycyclohex-3-ene-1-carboxylate (c-4)

(a) (1 R,4R,5R)-4-iodo-6-oxabicyclo[3.2.11octan-7-one (c-2)

(R)-(+)-3-Cyclohexenecarboxylic acid (c-1) (50.7 g, 0.4 mol) was suspended in H2O (400 mL) under nitrogen. The reaction mixture was cooled to 4 °C and sodium bicarbonate (101 g, 1.2 mol) was added, followed by a solution of potassium iodide (333 g, 2 mol) and iodine (107 g, 0.42 mol) in H2O (400 mL). The reaction was allowed to come to room temperature and stirred o/n and then extracted with DCM (4x150 mL). The combined organic layers were washed with a solution of Na₂S₂O₃ (120 g) in H₂O (600 mL). The aqueous layer was extracted with DCM (2x150 mL). The combined organic layers were protected from light, dried over sodium sulfate, filtered and concentrated (20 mbar) to afford (1 R,4R,5R)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (c-2) (95.22 g, 94.5 %) as an off-white solid.

TLC (ethyl acetate/heptane=1/3 v/v%): Rf = 0.50.

¹H-NMR (400 MHz, CDCI₃) δ [ppm] 4.83 (dd, J = 5.9, 4.1 Hz, 1 H), 4.51 (tt, J = 4.2, 1.3 Hz, 1 H), 2.80 (d, J = 12.3 Hz, 1 H), 2.68 (td, J = 5.2, 2.0 Hz, 1 H), 2.52 - 2.39 (m, 1 H), 2.43 - 2.34 (m, 1 H), 2.18 - 2.07 (m, 1 H), 1 .98 - 1 .76 (m, 2H).

¹³C NMR (101 MHz, CDCI₃) δ [ppm] 177.80, 80.24, 38.62, 34.53, 29.73, 23.81 , 23.14.

(b) (1 R,5R)-6-oxabicyclo[3.2.11oct-3-en-7-one (c-3)

(1 R,4R,5R)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (c-2) (95.22 g, 377.9 mmol) was dissolved in dry THF (700 mL). Then, DBU (86.3 g, 566.9 mmol) was added and the mixture was refluxed o/n. The reaction mixture was cooled to room temperature, diluted with diethylether (500 mL) and extracted with aq. HCI (1 L, 1 M) and brine (250 mL). The aqueous layers were extracted with diethyl ether (2 x 480 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated (350 mbar to afford (1 R,5R)-6-oxabicyclo[3.2.1]oct-3-en-7-one (c-3) quantitatively as a yellowish oil which was used directly in the next step.

TLC (ethyl acetate/heptane=1/1 v/v%): R_f = 0.60.

(c) Ethyl (1 R,5R)-5-hvdroxycyclohex-3-ene-1-carboxylate (c-4)

To a stirred solution of (1 R,5R)-6-oxabicyclo[3.2.1]oct-3-en-7-one (c-3) (377.9 mmol, theor.) in ethanol (750 mL) was added potassium carbonate (10.45 g, 75.6 mmol) at room temperature and the mixture stirred o/n. The reaction mixture was filtered through a Celite pad. Removal of ethanol under reduced pressure afforded the crude product that was purified by column chromatography plug filtration (eluent 40% EtOAc/heptane) to afford the title compound (41 .38 g, 60.8% over 3 steps and column) as a yellow liquid.

TLC (ethyl acetate/heptane=1/3 v/v%): R_f = 0.30. ¹H-NMR (400 MHz, CDCb) δ [ppm] 5.90 - 5.61 (m, 2H), 4.30 (d, J = 7.5 Hz, 1 H), 4.15 (q, J = 7.1 Hz, 2H), 2.79 - 2.58 (m, 1 H), 2.42 (s, 1 H), 2.36 - 2.16 (m, 3H), 1.81 - 1.63 (m, 1 H), 1.27 (t, J = 7.1 Hz, 3H).

¹³C NMR (101 MHz, CDCb) δ [ppm] 175.30, 130.90, 126.87, 66.01 , 60.72, 37.91 , 34.18, 27.43, 14.17.

Example 3b: Synthesis of (1R,3R)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (Il-3a3)

(1 R,3R)-3-(tert-butoxycarbonylamino)cvclohexanecarboxylic acid (Il-a3a)

(a) Ethyl (1 R,,5S)-5-(1 ,3-dioxoisoindolin-2-yl)cyclohex-3-ene-1-carboxylate (c-5)

To an ice-cold (0 °C) solution of ethyl (1 R,5R)-5-hydroxycyclohex-3-ene-1-carboxylate (c-4, 15.0 g, 88.13 mmol), phthalimide (14.26 g, 96.94 mmol) and triphenylphosphine (34.67 g, 132.2 mmol) in toluene (264 mL) was added dropwise diisopropyl azodicarboxylate (26.02 mL, 132.2 mmol) in 10 min. The reaction mixture was stirred at 0 °C for 30 min and then allowed to come to room temperature and stirred for 3 h. The mixture was evaporated under reduced pressure to give a yellow oil. Heptane/ethyl acetate = 7/3 v/v% (500 mL) was added and the mixture was heated to 70 °C. After cooling, the mixture was stirred for 72 h at room temperature. The solids were filtered, washed with heptane/ethyl acetate = 9/1 v/v% (2x50 mL) and the filtrate was evaporated under reduced pressure. The resulting residue was purified by column chromatography (heptane/ethyl acetate = 9/1 to 6/4 v/v%) to give 21 .96 g of the title compound (Yield: 83.0%) as an off-white solid.

TLC (ethyl acetate/hexane=1/3 v/v%): R_t = 0.40.

LC-MS (A): R_t = 5.47 min; m/z 300.0 [M+H]⁺.

¹H-NMR (400 MHz, CDCb) δ [ppm] 7.88 - 7.78 (m, 2H), 7.77 - 7.67 (m, 2H), 6.03 (dddd, J = 10.1 , 4.2, 3.6, 2.3 Hz, 1 H), 5.61 (ddt, J = 10.0, 3.5, 2.2 Hz, 1 H), 5.07 - 4.94 (m, 1 H), 4.18 (qq, J = 10.8, 7.1 Hz, 2H), 3.13 (dddd, J = 9.5, 6.8, 5.8, 3.8 Hz, 1 H), 2.58 - 2.46 (m, 1 H), 2.46 - 2.26 (m, 2H), 2.19 (ddd, J = 13.5, 8.7, 6.4 Hz, 1 H), 1 .28 (t, J = 7.1 Hz, 3H).

¹³C NMR (101 MHz, CDCb) δ [ppm] 174.83, 168.25, 133.99, 131.96, 129.26, 124.53, 123.18, 60.63, 44.36, 36.69, 29.76, 26.46, 14.25.

(b) Ethyl (1 R,,3R),-3-(1 ,3-dioxoisoindolin-2-yl)cvclohexanecarboxylate (c-6)

To a solution of ethyl (1 R,5S)-5-(1 ,3-dioxoisoindolin-2-yl)cyclohex-3-ene-1-carboxylate (c-5) (18 g, 60.1 mmol) in methanol/ethyl acetate=9/1 v/v% (1 L) was added 1 .8 g of 10% Pd/C. Catalytic hydrogenation was performed for 3 h at room temperature. The palladium-catalyst was filtered and the filtrate was concentrated in vacuo to afford 18.24 g the title compound (Yield: quantitative, crude).

TLC (ethyl acetate/hexane=1/3 v/v%): Rf = 0.50.

LC-MS (A): R_t = 5.91 min; m/z 302.1 [M+H]⁺.

¹H-NMR (400 MHz, CDCb) δ [ppm] 7.87 - 7.77 (m, 2H), 7.70 (dd, J = 5.4, 3.1 Hz, 2H), 4.42 (tt, J = 12.1 , 3.7 Hz, 1 H), 4.32 - 4.07 (m, 2H), 2.89 (q, J = 3.4 Hz, 1 H), 2.47 (td, J = 12.8, 5.1 Hz, 1 H), 2.27 - 2.12 (m, 3H), 1 .76 (tt, J = 9.9, 4.0 Hz, 2H), 1.64 - 1.42 (m, 2H), 1.37 - 1.20 (m, 3H).

¹³C NMR (101 MHz, CDCb) δ [ppm] 174.38, 168.33, 133.80, 132.03, 123.05, 60.56, 47.27, 39.79, 30.10, 29.32, 26.37, 22.41 , 21 .65, 14.30.

(c) Ethyl (1 R,,3R),-3-aminocvclohexanecarboxylate (c-7)

To a solution (heating for complete solvation) of ethyl (1 R,3R)-3-(1 ,3-dioxoisoindolin-2- yl)cyclohexanecarboxylate (c-6) (40.54 g, 134.6 mmol) in ethanol (675 mL) was added dropwise hydrazine hydrate (6.67 mL, 137.2 mmol). The reaction mixture was stirred for 30 min. at room temperature and then refluxed for 3 h. After cooling the mixture to room temperature, additional hydrazine hydrate (667 pL) was added and stirring under reflux was continued for 2 h. The mixture was concentrated under reduced pressure and dried in vacuo to give the title compound in quantitative crude yield, which was used directly into the next step.

LC-MS (A): R_t = 1.31 min; m/z 172.1 [M+H]⁺.

(d) Ethyl (1R ,3R),-3-( tert-butoxycarbonylamino)cvclohexanecarboxylate (c-8)

To a cold (0 °C) stirred suspension of ethyl (1 R,3R)-3-aminocyclohexanecarboxylate (c- 7) (134.76 mmol, theor.) in dichloromethane (500 mL) was added drop-wise a solution of di-tert- butyl dicarbonate (30.8 g, 141.3 mmol) in dichloromethane (100 mL). The reaction mixture was stirred for 15 min at 0 °C, then allowed to come to room temperature and stirred o/n. The solids were filtered, washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by plug filtration chromatography (heptane/ethyl acetate = 8/2 v/v%) to give 34.88 g of the title compound (Yield: 95.6% over two steps) as a white solid.

TLC (ethyl acetate/heptane=1/1 v/v%): Rf = 0.40.

LC-MS (A): R_t = 5.60 min; m/z 443.3 [2M+H]⁺, 216.1 [M-tBu+H]⁺. ¹H-NMR (400 MHz, CDCb) δ [ppm] 4.58 (s, 1 H), 4.13 (q, J = 7.1 Hz, 2H), 3.84 (s, 1 H), 2.55 (s, 1 H), 1.98 - 1.35 (m, 19H), 1 .35 - 1 .15 (m, 4H).

¹³C NMR (101 MHz, CDCI₃) δ [ppm] 175.15, 60.38, 45.61 , 38.65, 33.30, 30.90, 28.43, 28.16, 27.80, 20.62, 14.23.

(e) (1 R,,3R),-3-(tert-butoxycarbonylamino)cvclohexanecarboxylic acid (Il-a3a)

To a solution of ethyl (1 R,3R)-3-(te/Y-butoxycarbonylamino)cyclohexanecarboxylate (c- 8) (34.88 g, 128.6 mmol) in THF (450 mL) was added a solution of lithium hydroxide (3.1 g, 128.6 mmol) in water (225 mL) and the reaction mixture was stirred at room temperature o/n. Additional lithium hydroxide (0.5 g) was added and stirring was continued for 24 h. at room temperature. Again additional lithium hydroxide (0.5 g) was added and stirring was continued for 24 h. at room temperature. The mixture was transferred to a separation funnel and ice was added . The mixture was acidified (pH < 2) by addition of 1 M HCI-solution (300 mL). The water layer was separated and extracted with dichloromethane (2x100 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure and dried in vacuo to give 30.8 g (98.4%) of (1 R,3R)-3-(te/Y-butoxycarbonylamino)cyclo- hexanecarboxylic acid (Il-a3a).

TLC (dichloromethane/methanol=9/1 v/v%): Rf = 0.75.

LC-MS (A): R_t = 4.22 min; m/z 242.0 [M-H]-, 188.0 [M-tBu+H]⁺.

¹H-NMR (400 MHz, CDCb) δ [ppm] 6.80 - 6.73 (m, 1 H), 3.53 (s, 1 H), 2.61 (td, J = 6.6, 3.6 Hz, 1 H), 2.50 (p, J = 1 .9 Hz, 1 H), 1 .80 - 1 .72 (m, 1 H), 1 .60 - 1 .45 (m, 3H), 1 .45 - 1 .34 (m, 2H), 1 .37 (s, 9H), 1 .27 (td, J = 17.7, 8.8 Hz, 1 H).

¹³C NMR (101 MHz, CDCb) δ [ppm] 181.51 , 160.06, 82.60, 50.59, 43.07, 38.21 , 36.44, 33.50, 32.37, 25.81.

Example 4: [4-[(4-cyano-2-pyridyl)carbamoyl]phenyl]boronic acid (XlVa)

[4-[(4-Cvano-2-pyridyl)carbamoyl1phenyl1boronic acid (XlVa)

4-Carboxyphenylboronic acid (25.0 g, 150.7 mmol) was suspended in toluene (376 mL) and Tetrabutylammonium chloride (2.09 g, 7.53 mmol) was added. The reaction mixture was heated to 70 °C, at which point thionyl chloride (32.84 mL, 452 mmol) was added slowly. The reaction mixture was heated to 80 °C and stirred o/n. After cooling to room temperature a white suspension occurred. The mixture was then concentrated under vacuum to remove solvent. Toluene was added and the mixture was concentrated to remove excess thionyl chloride and co-evaporated with toluene (2x250 mL) and used directly in the next step. The crude product was added portion-wise to a solution of 2-aminopyridine-4-carbonitrile (31 .04 g, 263.7 mmol) in pyridine (301 mL) at 30 °C. After addition, the reaction mixture was heated to 70°C and stirred for 4h. The mixture was cooled to 50 °C and water was added (301 mL). The resulting turbid solution was allowed to come to room temperature and stirred o/n. The solids were filtered, washed with water (2x150 mL) and dried under vacuum at 60 °C to give 33.9 g [4-[(4-cyano-2- pyridyl)carbamoyl]phenyl]boronic acid (Id) as off-white fluffy solids. Yield: 84%

LC-MS (B): R_t = 6.82 min; m/z 268.0 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm] 11 .26 (s, 1 H), 8.66 (dd, J = 5.1 , 0.9 Hz, 1 H), 8.52 (dd, J = 1 .4, 0.9 Hz, 1 H), 8.29 (s, 2H), 8.03 - 7.96 (m, 2H), 7.95 - 7.88 (m, 2H), 7.63 (dd, J = 5.0, 1.4 Hz, 1 H).

¹³C NMR (101 MHz, DMSO-d₆) δ [ppm] 166.73, 152.89, 149.70, 134.69, 134.02, 127.05, 121.18, 120.90, 117.00, 116.34.

Example 5a: Synthesis of tert-butyl (E)-8-[1-bromo-3-[(1R,3R)-3-(tert-butoxycarbonyl- amino)cyclohexyl]-8-[(2,4-dimethoxyphenyl)methylamino]imidazo[1,5-a]pyrazin-5-yl]oct- 7 -enoate (X)

5.1 Synthesis of tert-butyl N-[(1R,3R),-3-[(6-bromo-3-chloro-pyrazin-2-yl)methylcarba- moyljcyclohexyljcarbamate (VIa)

To a cold 5 °C suspension of with (6-bromo-3-chloro-pyrazin-2-yl)methanamine hydrochloride (IV) (19.21 g, 74.19 mmol), (1 R,3R)-3-(tert-butoxycarbonylamino)cyclohexane- carboxylic acid (Il-a3a (17.86 g, 73.44 mmol) in ethyl acetate (556 mL) was added subsequently, triethylamine (31.01 mL, 222.6 mmol) and portion-wise HATU (29.05 g, 76.41 mmol). The resulting mixture was stirred at room temperature o/n. To the mixture was added ethyl acetate (150 mL), heptane (50 mL) and 0.5N aq. HCI-solution (200 mL). The biphasic system was stirred for 15 min at room temperature and the layers were separated. The organic layer was washed with 0.5N aq. HCI-solution (200 mL), 5% aq. NaHCOs-solution (2x200 mL) and brine (100 mL). The organic layers was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (VIa) (36.92 g, 98% yield (corrected for solvents present), >95% purity) as a cream coloured solid, which was confirmed by LCMS and ¹H-NMR.

TLC (heptane/ethyl acetate = 1/1 v/v%): Rf = 0.40.

LC-MS (B): R_t = 11 .46 min; m/z 391 .2/393.2 [M-tBu+H]⁺.

¹H-NMR (400 MHz, CDCI₃) δ [ppm] 8.65 (s, 1 H), 8.22 (s, 1 H), 6.66 (d, J = 7.1 Hz, 1 H), 4.51 - 4.34 (m, 2H), 3.68 (s, 1 H), 2.56 (s, 1 H), 1 .70 - 1 .42 (m, 8H), 1 .38 (s, 9H).

5.2 Synthesis of tert-butyl (E)-8-[6-[[[(1R,3R)-3-(tert-butoxycarbonylamino)cyclohexane- carbonyl]amino]methyl]-5-chloro-pyrazin-2-yl]oct-7 -enoate (VII)

A mixture of tert-butyl N-[(1 R,3R)-3-[(6-bromo-3-chloro-pyrazin-2-yl)methylcarbamoyl]- cyclohexyl]carbamate (VIa, 36.92 g, 82.46 mmol), tert-butyl (E)-8-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)oct-7-enoate (Va, 25.12 g, 77.51 mmol) and potassium carbonate (34.18 g, 247.4 mmol) in dioxane/water = 4/1 v/v% (620 mL) was degassed with nitrogen for 5 min at 30 °C. Pd(dppf)CI₂.CH₂CI₂ (3.36 g, 4.12 mmol) was added and the mixture was again degassed with nitrogen for 5 min at 30 °C. The reaction mixture was stirred at 80 °C for 4 h. After cooling the mixture was concentrated in vacuo until a volume of -300 mL. This residue was added to a stirred mixture of ethyl acetate/water = 4/1/ v/v% (1 .2 L). Heptane (100 mL) was added and the bi-phasic mixture was stirred for 30 min at room temperature. The layers were separated and the organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude product was further purified by silica filtration (500 g silica). The compound was dissolved in DCM (50ml +25ml) and charged onto the column. The column was eluted with heptane/ethyl acetate = 80/20 v/v% (1 L), then heptane/ethyl acetate = 1/1 v/v% (4 L). Fractions (1 liter each) were collected and fractions 2-4 were collected and concentrated under reduced pressure. The product was dried in vacuo (4 mbar, 3 h, 50°C). Compound (VII, 43.03 g, 90% yield) as a brown oil, which was confirmed by LCMS and ¹H-NMR.

TLC (heptane/ethyl acetate = 1/1 v/v%): Rf = 0.45.

LC-MS (B): R_t = 16.53 min; m/z 409.4 [M-tBu-Boc+H]⁺, 453.1 [M-2xtBu+H]⁺, 565.3 [M+H]⁺.

¹H-NMR (400 MHz, CDCb) δ [ppm] 8.21 (s, 1 H), 6.97 - 6.75 (m, 2H), 6.47 (dt, J = 15.7, 1.5 Hz, 1 H), 4.72 - 4.56 (m, 3H), 3.94 (s, 1 H), 2.50 (dq, J = 10.1 , 4.9 Hz, 1 H), 2.31 (qd, J = 7.1 , 1 .5 Hz, 2H), 2.22 (t, J = 7.4 Hz, 2H), 1 .88 (td, J = 1 1 .7, 3.5 Hz, 3H), 1 .75 - 1 .63 (m, 5H), 1 .63 - 1 .54 (m, 3H), 1 .54 - 1 .48 (m, 2H), 1 .43 (d, J = 4.6 Hz, 19H), 1 .40 - 1 .32 (m, 2H).

5.3 Synthesis of tert-butyl (E)-8-[3-[(1R,3R)-3-(tert-butoxycarbonylamino)cyclohexyl]-8- chloro-imidazo[1 ,5-a]pyrazin-5-yl]oct-7 -enoate (VIII)

To a cold (-10 °C) solution of tert-butyl (E)-8-[6-[[[(1 R,3R)-3-(tert-butoxycarbonylamino)- cyclohexanecarbonyl]amino]methyl]-5-chloro-pyrazin-2-yl]oct-7-enoate (VII) (24.18 g, 42.78 mmol) in acetonitrile/DMF = 95/5 v/v% (128 mL) was added subsequently pyridine (13.83 mL, 171 .1 mmol) and phosphorus oxychloride (7.17 mL, 77.0 mmol) at a rate to keep the temperature at -10 °C to -15 °C, and the mixture was stirred for 3 h. at -10 °C. The mixture was added carefully to 25% ammonia (54 mL) and crushed ice (540 mL) keeping the temperature below 0 °C. MTBE (270 mL) was added and the resulting mixture was stirred for 30 min. The water layer was separated and extracted with MTBE (180 mL). The combined organic layers were washed with 1 N aq. HCI-solution (2x90 mL), 5% aq. NaHCOs-solution (90 mL) and water/brine (90 mL), dried over sodium sulfate and concentrated in vacuo. Compound (VIII, 22.61 g, 97% yield) as a brown oil, which was confirmed by LCMS and ¹H-NMR.

TLC (heptane/ethyl acetate = 1/1 v/v%): R_t = 0.55.

LC-MS (B): R_t = 18.43 min; m/z 547.2/549.2 [M+H]⁺ (chloride pattern).

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm] 7.81 (s, 1 H), 7.18 (d, J = 1.1 Hz, 1 H), 6.95 (dd, J = 15.2, 1 .4 Hz, 1 H), 6.89 (d, J = 6.5 Hz, 1 H), 6.32 (dt, J = 15.3, 7.0 Hz, 1 H), 3.78 (s, 1 H), 2.40 - 2.23 (m, J = 7.2 Hz, 2H), 2.20 (t, J = 7.3 Hz, 2H), 1 .93 - 1 .78 (m, 3H), 1 .58 (dd, J = 23.1 , 7.6 Hz, 5H), 1 .53 - 1 .44 (m, 4H), 1 .43 - 1 .29 (m, 21 H).

5.4 Synthesis of tert-butyl (E)-8-[1-bromo-3-[(1R,3/?)-3-(tert-butoxycarbonylamino)cyclo- hexyl]-8-chloro-imidazo[1 ,5-a]pyrazin-5-yl]oct-7 -enoate (IX)

N-Bromosuccinimide (8.60 g, 48.33 mmol) was added to a cold (0 °C) solution of tert- butyl (E)-8-[3-[(1 R,3R)-3-(tert-butoxycarbonylamino)cyclohexyl]-8-chloro-imidazo[1 ,5-a]pyrazin- 5-yl]oct-7-enoate (VIII) (27.84 g, 50.88 mmol) in DMF (150 mL). The reaction mixture was stirred o/n allowing the temperature to come to room temperature. The mixture was added to a mixture of 1 % aq. Na2S2O3-solution (150 mL) and 1 % aq. NaHCOs-solution (150 mL) and ethanol (25 mL). The solids formed were separated from the mixture by decantation of the liquid. Ethyl acetate/heptane = 9/1 v/v% (250 mL) was added and the mixture was washed with water (50 mL). The phases were separated and the water layer was extracted with ethyl acetate/heptane = 9/1 v/v% (50 mL). The combined organic phases were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Crude product was isolated, compound (IX, 30.19 g, 95% yield) as a sticky dark oil, which was confirmed by LCMS and ¹H-NMR.

TLC (toluene/ethanol = 8/2 v/v%): R_f = 0.60.

LC-MS (B): R_t = 20.40 min; m/z 625.2/627.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ [ppm] 7.18 (d, J = 1.1 Hz, 1 H), 7.01 - 6.79 (m, 2H), 6.32 (dt, J = 15.2, 7.0 Hz, 1 H), 3.91 - 3.69 (m, 2H), 2.43 - 2.24 (m, J = 12 Hz, 2H), 2.20 (t, J = 7.3 Hz, 2H), 1.86 (ddt, J = 23.5, 10.0, 7.1 Hz, 3H), 1.71 - 1.46 (m, 10H), 1.39 (d, J = 6.1 Hz, 19H).

5.5 Synthesis of tert-butyl (E)-8-[1-bromo-3-[(1R,3R)-3-(tert-butoxycarbonylamino)cyclo- hexyl]-8-[(2,4-dimethoxyphenyl)methylamino]imidazo[1 ,5-a]pyrazin-5-yl]oct-7-enoate (X)

To a suspension of tert-butyl (E)-8-[1-bromo-3-[(1 R,3R)-3-(tert-butoxycarbonylamino)- cyclohexyl]-8-chloro-imidazo-[1 ,5-a]pyrazin-5-yl]oct-7-enoate (IX, 35.77 g, 57.14 mmol) in 2- butanol (171 mL) was added 2,4-dimethoxybenzylamine (25.75 mL, 28.66 g, 171 .4 mmol) and the mixture was stirred for 30 min at 50 °C and then warmed to 90 °C and stirred for 2 h. After cooling, 1 N aq. HCI-solution (200 mL) and ethyl acetate/heptane = 9/1 v/v% (250 mL) was added to slurry formed. The bi-phasic mixture was stirred for 30 min during which all precipitates were dissolved. The organic layer was separated and washed with water (50 mL). The water layer was separated and the water layer was extracted with ethyl acetate/heptane = 9/1 v/v% (50 mL). The combined organic phases were washed with sat. aq. NaHCOs-solution (150 mL), water/brine=1/1 v/v% (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was further purified by silica filtration (250 g silica). The compound was dissolved in DCM and charged onto the column. The column was eluted with heptane/ethyl acetate = 70/30 v/v% (3L). Fractions (500 mL each) were collected and fractions 1-5 were collected and concentrated under reduced pressure to give 38 g of the crude product. The crude product was dissolved ethyl acetate (200 mL) and the mixture was warmed to 60 °C. Heptane (800 mL) was added dropwise under warming at 60 °C. After cooling the mixture was held in the freezer at -20 °C for 4 h. The mixture was concentrated to half of the volume and placed again in the freezer at -20 °C for 24 h. The precipitate formed was filtered, washed with cold (5 °C) heptane/ethyl acetate = 4/1 v/v % (200 mL) and dried in vacuo at 40 °C. Compound (X, 29.7 g, 68% yield over three steps, >97% purity, content 94% (qNMR)) was isolated as an off-white fluffy solid, which was confirmed by LCMS and ¹H-NMR. TLC (heptane/ethyl acetate = 1/1 v/v%): Rf = 0.50.

LC-MS (B): R_t = 16.94 min; m/z 756.3/758.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm] 7.14 (d, J = 8.3 Hz, 1 H), 6.88 - 6.79 (m, 3H), 6.73 (dd, J = 15.2, 1 .5 Hz, 1 H), 6.59 (d, J = 2.4 Hz, 1 H), 6.45 (dd, J = 8.3, 2.4 Hz, 1 H), 6.07 - 5.96 (m, 1 H), 4.55 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 1 H), 3.74 (s, 3H), 3.67 (s, 1 H), 2.22 (dt, J = 24.2, 7.1 Hz, 4H), 1.89 (d, J = 13.8 Hz, 1 H), 1.80 (s, 2H), 1.68 - 1.42 (m, 9H), 1.38 (d, J = 5.7 Hz, 20H).

¹³C NMR (101 MHz, DMSO-d₆) δ [ppm] 172.20, 159.89, 158.11 , 148.90, 146.32, 135.30, 129.24, 127.32, 121.25, 120.32, 118.56, 114.94, 106.00, 104.18, 98.33, 79.29, 77.48, 55.44, 55.14, 34.66, 31.89, 31.49, 31.30, 29.93, 28.25, 27.99, 27.68, 24.52, 22.08, 19.96, 13.92.

Example 5b: Synthesis of Compound of formula (I)

5.6 Synthesis of (E)-8-[3-[(1R,3R)-3-aminocyclohexyl]-1-bromo-8-[(2,4-dimethoxyphenyl)- methylamino]imidazo[1,5-a]pyrazin-5-yl]oct-7-enoic acid dihydrochloride (XI)

tert-ButyI (E)-8-[1-bromo-3-[(1 R,3R)-3-(te/Y-butoxycarbonylamino)cyclohexyl]-8-[(2,4- dimethoxyphenyl)methylamino]imidazo[1 ,5-a]pyrazin-5-yl]oct-7-enoate (X, 21.8 g, 28.80 mmol) was added to a pre-mixed solution of 4N HCIgas in dioxane/acetonitrile = 3/1 v/v% (115 mL) and the reaction mixture was stirred for 4.5 h at room temperature. The mixture was added dropwise to MTBE (1.15 L) and the resulting mixture, containing a strong precipitate was stirred vigorously for 2 h. at room temperature. The precipitate was filtered, washed with MTBE (100 mL) and dried in vacuo at 40 °C. Compound (XI, 20.89 g, 107% yield over three steps, >99% purity, contains 5% of MTBE) was isolated as an off-white solid, which was confirmed by LCMS and ¹H-NMR. LC-MS (B): R_t = 7.48 min; m/z 600.1/602.1 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm] 8.19 (s, 3H), 7.95 (s, 1 H), 7.39 (d, J = 8.3 Hz, 1 H), 6.90 - 6.79 (m, 1 H), 6.74 (s, 1 H), 6.63 (d, J = 2.4 Hz, 1 H), 6.49 (dd, J = 8.4, 2.4 Hz, 1 H), 6.17 (dt, J = 14.6, 6.9 Hz, 1 H), 4.90 - 4.68 (m, 2H), 3.87 (s, 4H), 3.75 (s, 4H), 2.35 - 2.17 (m, 5H), 1 .93 - 1 .80 (m, 2H), 1 .70 - 1 .39 (m, 9H), 1 .33 (ddt, J = 14.6, 9.6, 5.6 Hz, 2H).

(E)-8-[3-[(1 R,3R)-3-aminocyclohexyl]-1-bromo-8-[(2,4-dimethoxyphenyl)methylamino]- imidazo[1 ,5-a]pyrazin-5-yl]oct-7-enoic acid dihydrochloride (XI, 15.6 g, 23.16 mmol) was dissolved in DMF (772 mL) and N-ethylmorpholine (9.65 mL, 92.64 mmol) was added. This solution was added slowly to a heavily stirred suspension of HATU (26.41 g, 69.48 mmol) and N-ethylmorpholine (11.79 mL, 92.64 mmol) in dichloromethane (1.54 L) over a 11 h period to obtain a clear solution. Stirring was continued for another 10 h. at room temperature. The mixture was poured into stirred cold water (2.5 L) and stirring was continued for 15 min. The layers were separated and the water layer was extracted with dichloromethane (300 mL). The combined organic layer was washed with washed with 2.5% aq. citric acid solution (500 mL), 5% aq. NaHCOs-solution (500 mL), water (500 mL) and water/brine = 1/1 v/v% (2x500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in refluxing dichloromethane (50 mL) and acetonitrile (100 mL) was added drop-wise. The mixture was cooled to room temperature and stirred for 72 h. The precipitate formed was filtered, washed with cold (5 °C) acetonitrile, dried in vacuo at 40 °C. Compound (XII, 10.04 g, 74% yield, >95% purity) was isolated as a white solid, which was confirmed by LCMS and ¹H- NMR.

TLC (toluene/ethanol = 8/2 v/v%): Rf = 0.60.

LC-MS (A): R_t = 4.16 min; m/z 582.1/584.1 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm] 7.45 (d, J = 4.1 Hz, 1 H), 7.13 (d, J = 8.3 Hz, 1 H), 6.87 - 6.77 (m, 2H), 6.58 (d, J = 2.4 Hz, 1 H), 6.48 - 6.38 (m, 2H), 5.98 (ddd, J = 15.2, 9.3, 4.5 Hz, 1 H), 4.55 (d, J = 5.8 Hz, 2H), 3.85 (s, 4H), 3.73 (s, 3H), 3.44 (s, 1 H), 2.31 (dt, J = 12.8, 9.7 Hz, 3H), 2.16 - 2.04 (m, 1 H), 2.02 - 1 .87 (m, 2H), 1 .84 - 1 .70 (m, 3H), 1 .55 (q, J = 10.8 Hz, 6H), 1.36 (s, 3H).

5.8 Synthesis of Compound (Xllla)

A mixture of compound XII (10.77 g, 18.48 mmol), [4-[(4-cyano-2-pyridyl)carbamoyl]- phenyl]boronic acid (XlVa, 5.42 g, 20.32 mmol) and potassium carbonate (7.66 g, 55.44 mmol) in dioxane/water = 4/1 v/v% (130 mL) was degassed with nitrogen for 5 min at 30 °C. Pd(dppf)CI₂.CH₂CI₂ (751 mg, 0.92 mmol) was added and the mixture was again degassed with nitrogen for 5 min at 30 °C. The reaction mixture was stirred at 80 °C for 4 h. After cooling the mixture was added to a stirred mixture of ethyl acetate/water = 4/1/ v/v% (500 mL). The mixture was filtered over Decalite® and washed with ethyl acetate/methanol = 9/1 v/v% (100 mL). The filtrate was washed with 1 N aq. NaOH-solution (200 mL), water (100 mL), water/brine = 1/1 v/v% (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (330 g silica, eluents: dichloromethane/methanol = 99.5/0.5 to 95/5 v/v%) to give compound Xllla. The product was dried in vacuo (40°C). Compound (Xllla, 12.32 g, 92% yield, >95% purity, contains 4.5% dichloromethane) as a light yellow/brown solid, which was confirmed by LCMS and NMR.

TLC (dichloromethane/methanol = 9/1 v/v%): Rf = 0.70.

LC-MS (B): R_t = 9.58 min; m/z 725.3 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm] 11 .40 (s, 1 H), 8.68 (dd, J = 5.0, 0.9 Hz, 1 H), 8.56 (t, J = 1 .2 Hz, 1 H), 8.24 - 8.08 (m, 2H), 7.79 - 7.61 (m, 3H), 7.47 (d, J = 4.1 Hz, 1 H), 7.09 (d, J = 8.3 Hz, 1 H), 6.96 (d, J = 1 .0 Hz, 1 H), 6.61 - 6.45 (m, 2H), 6.41 (dd, J = 8.3, 2.4 Hz, 1 H), 6.03 (ddd, J = 14.7, 9.3, 4.5 Hz, 1 H), 5.70 (t, J = 5.7 Hz, 1 H), 4.45 (d, J = 5.7 Hz, 2H), 3.87 (s, 1 H), 3.69 (s, 3H), 3.57 (s, 4H), 2.44 (d, J = 12.2 Hz, 1 H), 2.33 (t, J = 6.9 Hz, 2H), 2.14 (d, J = 11.6 Hz, 1 H), 2.05 - 1 .87 (m, 3H), 1 .80 (t, J = 16.1 Hz, 2H), 1 .72 - 1 .49 (m, 6H), 1 .49 - 1 .27 (m, 3H).

¹³C NMR (101 MHz, DMSO-d₆) δ [ppm] 172.59, 166.11 , 159.88, 158.00, 152.90, 149.70, 149.62, 147.13, 138.50, 135.75, 132.89, 132.33, 129.54, 129.37, 128.41 , 127.34, 121.67, 121.23, 120.92, 120.17, 118.56, 116.98, 116.43, 114.09, 104.10, 98.21 , 55.22, 55.14, 45.40, 36.18, 32.98, 31 .63, 28.99, 27.40, 26.98, 25.08.

DMB-protected compound Xllla (18.03 g, 24.87 mmol) was dissolved in TFA (124 mL) and the mixture was stirred at 60 °C for 16 h. under nitrogen. After cooling to room temperature, dichloromethane (1 L) was added to the mixture followed by the addition of cold (5 °C) water (500 mL). The bi-phasic mixture was stirred for 10 min. The layers were separated and the water layer was extracted with dichloromethane (250 mL). To the combined organic layer was added slowly under stirring 12.5% NH4OH (250 mL). The layers were separated and the organic layer was washed with 5% NH4OH (250 mL) and water/brine = 1/1 v/v% (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was further purified by silica filtration (250 g silica). The compound was dry-loaded onto the column. The column was eluted with dichloromethane/methanol = 98/2 to 96/4 v/v%. Fractions containing the product were collected and concentrated under reduced pressure to give 13.01 g of the product. The product was dissolved refluxing acetonitrile/dichloromethane = 9/1 v/v% (200 mL) for 5 min, then stirred o/n allowing mixture to come to room temperature, filtered, washed with acetonitrile (200 mL) and dried (4 mbar, 5 h, 60 °C) to give the product. Compound (I, 12.03 g, 84% yield, >99% purity) as a yellow solid, which was confirmed by LCMS and NMR.

TLC (dichloromethane/methanol = 9/1 v/v%): Rf = 0.60.

LC-MS (B): R_t = 6.90 min; m/z 575.2 [M+H]⁺.

Mass Analysis (ESI): m/z 288.1500 [M+2H]²⁺, 575,290δ [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm] 11 .35 (s, 1 H), 8.67 (dd, J = 5.0, 0.9 Hz, 1 H), 8.55 (dd, J = 1.4, 0.9 Hz, 1 H), 8.22 - 8.10 (m, 2H), 7.78 - 7.70 (m, 2H), 7.64 (dd, J = 5.0, 1 .4 Hz, 1 H), 7.47 (d, J = 4.1 Hz, 1 H), 6.91 (d, J = 1.1 Hz, 1 H), 6.55 (d, J = 15.2 Hz, 1 H), 6.15 - 5.91 (m, 3H), 3.87 (d, J = 5.1 Hz, 1 H), 3.55 (s, 1 H), 2.44 (d, J = 14.0 Hz, 1 H), 2.39 - 2.27 (m, 2H), 2.23 - 2.05 (m, 1 H), 1 .97 (tdd, J = 15.4, 1 1 .6, 4.0 Hz, 3H), 1 .81 (t, J = 15.3 Hz, 2H), 1 .73 - 1 .50 (m, 6H), 1.39 (dt, J = 22.8, 8.3 Hz, 3H).

¹³C NMR (101 MHz, DMSO-d₆) δ [ppm] 172.5, 166.2, 152.9, 151.1 , 149.6, 147.0, 138.5, 135.6, 133.4, 132.2, 129.3, 128.3, 127.7, 121.7, 121.1 , 120.9, 120.4, 116.9, 116.3, 113.9, 45.4, 36.1 , 34.3, 32.9, 31.6, 31.6, 29.0, 27.3, 26.9, 25.0, 20.0.

REFERENCES

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• Wang, E. W., Mi, X., Thompson, M. C., Montoya, S., Notti, R. Q., Afaghani, J., Durham, B. H., Penson, A. V., Witkowski, M. T., Lu, S. X., Bourcier, J., Hogg, S. J., Erickson, C., Cui, D., Cho, H., Singer, M. B., Totiger, T. M., Chaudhry, S., Geyer, M. A., . . . Abdel-Wahab, O. (2022). Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors. The New England Journal of Medicine, 386(8), 735-743.

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Claims

1 . A process for preparation of a compound according to formula (l-b):

Wherein R¹ is any one of:

whereby the

marks the position of R³ in Formula l-b, and whereby the

marks the position of R⁴ in any one of Formula Il-a3, Il-a4, Il-a5 and to Il-c3; wherein any of said linkers is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD₃, (1-4C)alkyl, (1- 5C)alkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy and (1-6C)alkylcarbonyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; and wherein the process comprises reaction steps according to any one or more of claims 2 - 3 and claims 5 - 46.

2. A method of preparing a compound of formula (IV):

3. The method of claim 2, wherein the reaction is carried out in acetic acid, preferably at 20 °C to 30 °C, more preferably at 1-4 atm.

4. A compound selected from the following:

or a salt thereof.

5. A method of preparing a compound of formula (VI):

comprising reacting a first starting material of formula (IV):

or a salt thereof, with a second starting material of formula (II):

or a salt thereof, in the presence of a couplings reagent, including optionally an additive and a base, to form the compound of formula (VI); wherein is selected from the group consisting of:

6. A method of preparing a compound of formula (VIa):

comprising reacting a first starting material of formula (IV):

or a salt thereof, with a second starting material of formula (Il-a3a):

7. The method of claim 5 or claim 6, wherein the couplings reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N ’,N ’- dimethylamino)-propylcarbodiimide hydrochloride (EDC), (benzotriazol-1- yloxy)tris(dimethylamino)phospho-nium hexafluorophosphate (BOP), (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluoro-phosphate (PyBOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOP-CI), O-(benzotriazol-1-yl)-N ,N ,N ’,N ’-tetramethyl- uronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N ,N ,N ’,N ’-tetramethyluro- nium hexafluorophosphate (HATU), O-(7-azabenzotriazole-1-yl)-N ,N ,N ’,N ’- tetramethyluronium tetrafluoroborate (TATU), O-(6-chlorobenzotriazol-1-yl)-N ,N ,N ’,N ’- tetramethyluronium hexa-fluorophosphate (HCTU), O-(benzotriazol-1-yl)-N ,N ,N ’,N ’- tetramethyluronium tetrafluoroborate (TBTU), 2-(2-pyridon-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TPTU), 2-(5-norbore-ne-2,3-dicarboximido)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TNTU), N ,N ,N ’,N ’-tetra-methyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU), N ,N ,N ’,N ’-tetramethyl-O-(3,4-dihydro-4-oxo-1 ,2,3-benzotriazin-3- yl)uronium tetrafluoroborate (TDBTU), O-[(ethoxycarbonyl)-cyanomethyleneamino]- N ,N ,N ’N ’-tetramethyluronium tetrafluoroborate (TOTU), (1-cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), 1 ,1 ’-carbonyldiimidazole (CDI), tetramethylfluoroformamidinium hexafluorophosphate (TFFH), N ,N ,N ’,N ’-tetramethylchloroformamidinium hexafluorophosphate (TCFH), 2,4,6-tripropy 1-1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6- trioxide (T3P), 3-(diethylphosphoryloxy)-1 ,2,3-benzotriazin-4(3/7)-one (DEPBT), N -ethyl-2- [(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]-amino]-N-(3-pyridinylmethyl)-acetamide (EMPA), diphenylphosphinic chloride (DPPCI), chloro-1 ,3-dimethylimidazolinium chloride (DMC), oxalylchloride (COCI₂), thiony Ichloride (SOCI₂), ethyl chloroformate (ECF) and isobutyl chloroformate (IBCF).

8. The method of claim 5 - 7, wherein the additive is selected from the group consisting of 1- hy-droxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), ethyl 2-cyano-2- (hydroxyamino)-acetate (Oxyma Pure) and 1-hydroxy-7-azabenzotriazole (HOAt).

9. The method of claim 5 or claim 6, wherein the base is selected from the group consisting of triethylamine (TEA), N ,N-diisopropylethylamine (DiPEA), N-ethylmorpholine (NEM), N- methylmorpholine (NMM), pyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2,6- lutidine.

10. The method of claim 5 - 9, wherein the couplings reagent is O-(7-azabenzotriazol-1-yl)- N ,N ,N ’,N ’-tetramethyluronium hexafluorophosphate (HATU) and wherein the reaction is carried out in ethyl acetate in the presence of triethylamine at 20 °C to 30 °C.

11. A method of preparing a compound of formula (VII):

comprising reacting a first starting material of formula (VIa):

with a second starting material of formula (Va):

in the presence of a palladium catalyst to form the compound of formula (VI I).

12. The method of claim 11 , wherein the palladium catalyst is selected from the group consisting of Pd(dppe)₂ (Bis[1 ,2-bis(diphenylphosphino)ethane]palladium(0)), CX-11 (1 ,3- Bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1 ,4-naphthoquinone)palladium(0)dimer), CX- 12 (1 ,3-Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene(1 ,4- naphthoquinone)palladium(O)dimer), Pd(t-Bu₃P)₂ (Bis(tri-tert- butylphosphine)palladium(0)),Pd(PCy3)₂ (Bis(tricyclohexylphosphine)-palladium(O)), Pd(PPh₃)₄ (Tetrakis(triphenylphosphine)palladium(O)), Pd2(dba)3 (Tris(dibenzyli- deneacetone)dipalladium(O)), Pd(OAc)₂ (Palladium(ll)acetate), PdCI₂(PPh3)₂ Dichlorobis(tri- phenylphosphine)palladium(ll)),PdCI₂(Amphos)₂ (Bis(di- tert-butyl(4-dimethylaminophenyl)- phosphine)dichloropalladium(ll)), Pd(MeCN)2CI₂ (Bis(acetonitrile)dichloropalladium(ll)), PdCI₂(P-o-Tol)₃)₂ (Dichlorobis(tri-o-tolylphosphine)palladium(ll)), Pd(dppf)CI₂ (1 ,1'- Bis(diphenyl-phosphino)ferrocene]dichloropalladium(ll)),Pd(MeCN)4(BF4)2 (Tetrakis(acetonitrile)palladium(ll) tetrafluoro borate), Pd-PEPPSI-IPent (Dichloro[1 ,3- bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll)), Pd-PEPPSI-IPr ([1 ,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride), Pd-PEPPSI-SIPr ((1 ,3-Bis(2,6-Diisopropylphenyl)imidazolidene)(3- chloropyridyl)palladium(ll)dichloride), Pd(dba)₂ bis(dibenzylideneacetone)palladium(0)) and cataCXium A Pd G3 (Methanesulfonato(di-adamantyl-n-butylphosphino)-2’-amino-1 ,T- biphenyl-2-yl)palladium(ll)).

13. The method of any of claims 11 - 12, wherein the palladium catalyst is 1 ,1 '-bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll) (Pd(dppf)CI2).

14. The method of any of claims 11 - 13, wherein the reaction further comprises a base.

15. The method of claim 14, wherein the base is selected from the group consisting of potassium carbonate (K₂CO₃), cesium carbonate (CS₂CO₃), potassium hydroxide (KOH) and sodium tert -butoxide (NaOtBu).

16. The method of any of claims 1 1 - 15, wherein the base is potassium carbonate and wherein the reaction is carried out in a solvent mixture of dioxane/water, preferably at 80 °C.

17. A method of preparing a compound of formula (VIII):

comprising reacting a starting material of formula (VII):

18. The method of claim 17, wherein the dehydrating reagent is selected from the group consisting of phosphorous pentachloride (PCI5), phosphorous oxychloride (POCI3), trifluoroacetic anhydride (TFAA), polyphosphoric acid (PPA), methyl N-(triethylammonium- sulfonyl)carbamate (Burgess-reagent) and 1-chloro-N ,N-dimethylmethaniminium chloride (VIlsmeier reagent).

19. The method of claim 17 or claim 18, wherein the additive is selected from the group consisting of N , N , -dimethylformamide (DMF), 1 ,1 ,3,3-tetramethylurea (TMU) and 1 ,3- dimethyl-2-imidazolidinone (DMI).

20. The method of any one of claims 17 - 19, wherein the base is selected from the group of pyridine, triethylamine, 2-chloropyridine and 2-fluoropyridine.

21 . The method of any one of claims 17 - 20, wherein the dehydrating reagent is phosphorous oxychloride (POCI₃) and wherein the reaction is carried out in acetonitrile, N ,N ,- dimethylformamide (DMF), 1 ,3-di-methyl-2-imidazolidinone (DMI) or mixtures thereof in the presence of pyridine, preferably at -15°C to 10°C.

22. A method of preparing a compound of formula (IX):

comprising reacting a starting material of formula (VIII):

with a brominating agent to form the compound of formula (IX).

23. The method of claim 22, wherein the brominating agent is N-bromosuccinimide (NBS) and wherein the reaction is carried out in acetonitrile, preferably at 5 °C to 25 °C.

24. A method of preparing a compound of formula (X):

with 2,4-dimethoxybenzylamine to form the compound of formula (X).

25. The method of claim 24, wherein the reaction is carried out in 2-butanol (sec-BuOH) at 90 °C.

26. A method of preparing a compound of formula (XI):

or a salt thereof comprising reacting a starting material of formula (X):

with an acid to form the compound of formula (XI) or salt thereof.

27. The method of claim 26, wherein the acid is selected from the group of hydrochloric acid (HCI), hydrobromic acid (HBr), hydroiodic acid (HI), methanesulfonic acid (MsOH) and trifluoroacetic acid (TFA).

28. The method of claim 26 or claim 27, wherein the acid is hydrochloric acid (HCI) and wherein the reaction is carried out in dioxane, acetonitrile, or mixtures thereof.

29. A method of preparing a compound of formula (XII):

comprising reacting a starting material of formula (XI):

30. The method of claim 29, wherein the couplings reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N ’,N ’- dimethylamino)-propylcarbodiimide hydrochloride (EDC), (benzotriazol-l-yloxy)tris(dimethyl- amino)phosphonium hexafluorophosphate (BOP), (benzotriazol-l-yloxy)tripyrrolidinophos- phonium hexafluorophosphate (PyBOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-CI), O-(benzotriazol-l-yl)- N ,N ,N ’,N ’-tetramethyl-uronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)- N ,N ,N ’,N ’-tetramethyluro-nium hexafluorophosphate (HATU), O-(7-azabenzotriazole-1-yl)- N ,N ,N ’,N ’-tetramethyluronium tetrafluoroborate (TATU), O-(6-chlorobenzotriazol-1-yl)- N ,N ,N ’,N ’-tetramethyluronium hexa-fluorophosphate (HCTU), O-(benzotriazol-1-yl)-N ,N ,N ’,N ’- tetramethyluronium tetrafluoroborate (TBTU), 2-(2-pyridon-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TPTU), 2-(5-norbore-ne-2,3-dicarboximido)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TNTU), N ,N ,N ’,N ’-tetra-methyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU), N ,N ,N ’,N ’-tetramethyl-O-(3,4-dihydro-4-oxo-1 ,2,3-benzotriazin-3-yl)uronium tetra fluoroborate (TDBTU), O-[(ethoxycarbonyl)-cyanomethyleneamino]-N ,N ,N ’N ’-tetramethyl- uronium tetrafluoroborate (TOTU), (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino- morpholino-carbenium hexafluorophosphate (COMU), (7-azabenzotriazol-1-yloxy)tri- pyrrolidinophosphonium hexafluorophosphate (PyAOP), 1 ,1 ’-carbonyldiimidazole (CDI), tetramethylfluoroformamidinium hexafluorophosphate (TFFH), N ,N ,N ’,N ’-tetramethylchloro- formamidinium hexafluorophosphate (TCFH), 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinane-

2.4.6-trioxide (T3P), 3-(diethylphosphoryloxy)-1 ,2,3-benzotriazin-4(3/7)-one (DEPBT), N-ethyl- 2-[(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]-amino]-N-(3-pyridinylmethyl)-acetamide (EMPA), diphenylphosphinic chloride (DPPCI), chloro-1 ,3-dimethylimidazolinium chloride (DMC), oxalylchloride (COCI₂), thiony Ichloride (SOCI₂), ethyl chloroformate (ECF) and isobutyl chloroformate (IBCF).

31 . The method of claim 29 or claim 30, wherein the additive is selected from the group consisting of 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), ethyl 2-cyano-2- (hydroxyamino)-acetate (Oxyma Pure) and 1-hydroxy-7-azabenzotriazole (HOAt).

32. The method of any one of claims 29 - 31 , wherein the base is selected from the group consisting of triethylamine (TEA), N ,N-diisopropylethylamine (DiPEA), N-ethylmorpholine (NEM), N-methylmorpholine (NMM), pyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and

2.6-lutidine.

33. The method of any one of claims 29 - 32, wherein the couplings reagent is O-(7- azabenzotriazol-1-yl)-N ,N ,N ’,N ’-tetramethyluronium hexafluorophosphate (HATU) and wherein the reaction is carried out in N , N , -dimethylformamide (DMF), ethyl acetate, dichloromethane, or mixtures thereof, in the presence of N-ethylmorpholine (NEM), preferably at 20 °C to 30 °C.

34. A method of preparing a compound of formula (XIII):

comprising reacting a starting material of formula (XII):

with a second starting material of formula (XIV):

35. A method of preparing a compound of formula (Xllla):

comprising reacting a starting material of formula (XII):

with a second starting material of formula (XlVa):

36. The method of claim 34 or claim 35, wherein the palladium catalyst is selected from the group consisting of Pd(dppe)₂ (Bis[1 ,2-bis(diphenylphosphino)ethane]palladium(0)), CX-11 (1 ,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1 ,4-naphthoquinone)palladium(0)dimer), CX-

12 (1 ,3-Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene(1 ,4-naphthoquinone)palladium(0)dimer), Pd(t-Bu₃P)₂ (Bis(tri-tert-butylphosphine)palladium(0)),Pd(PCy3)₂ (Bis(tricyclohexylphosphine)- palladium(O)), Pd(PPh₃)4 (Tetrakis(triphenylphosphine)palladium(O)), Pd2(dba)3 (Tris(dibenzyli- deneacetone)dipalladium(O)), Pd(OAc)₂ (Palladium(ll)acetate), PdCI₂(PPh3)₂ Dichlorobis(tri- phenylphosphine)palladium(ll)),PdCI₂(Amphos)₂ (Bis(di-tert-butyl(4-dimethylaminophenyl)- phosphine)dichloropalladium(ll)), Pd(MeCN)2CI₂ (Bis(acetonitrile)dichloropalladium(ll)), PdCI₂(P-o-Tol)₃)₂ (Dichlorobis(tri-o-tolylphosphine)palladium(ll)), Pd(dppf)CI₂ (1 ,1 '-Bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll)),Pd(MeCN)4(BF4)₂ (Tetrakis(acetonitrile)palladium(ll) tetrafluoroborate), Pd-PEPPSI-IPent (Dichloro[1 ,3-bis(2,6-di-3-pentylphenyl)imidazol-2- ylidene](3-chloropyridyl)palladium(ll)), Pd-PEPPSI-IPr ([1 ,3-Bis(2,6-Diisopropylphenyl)imidazol- 2-ylidene](3-chloropyridyl)palladium(ll) dichloride), Pd-PEPPSI-SIPr ((1 ,3-Bis(2,6- Diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(ll)dichloride), Pd(dba)2 bis(dibenzylideneacetone)palladium(0)) and cataCXium A Pd G3 (Methanesulfonato(di- adamantyl-n-butylphosphino)-2'-amino-1 , 1 '-bipheny l-2-yl)palladium(l I)).

37. The method of any of claims 34 - 36, wherein the palladium catalyst is 1 ,1 '-bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll) (Pd(dppf)CI₂).

38. The method of any of claims 34 - 37, wherein the reaction further comprises a base.

39. The method of claim 38, wherein the base is selected from the group consisting of potassium carbonate (K₂CO₃), cesium carbonate (CS₂CO₃), potassium hydroxide (KOH) and sodium tert-butoxide (NaOtBu).

40. The method of claim 38, wherein the base is potassium carbonate (K₂CO₃), and wherein the reaction is carried out in dioxane, water, or mixtures thereof, preferably at 80 °C.

41. A method of preparing a compound of formula (I):

or a salt thereof, comprising reacting a starting material of formula (XIIla):

with an acid to form the compound of formula (I) or salt thereof.

42. The method of claim 41 , wherein the acid is selected from the group of hydrochloric acid (HCI), hydrobromic acid (HBr), hydroiodic acid (HI), methanesulfonic acid (MsOH) and trifluoroacetic acid (TFA).

43. The method of claim 41 or claim 42, wherein the reaction is carried out at (about) 60 °C, preferably wherein the acid is trifluoroacetic acid (TFA).

44. A method of purifying a compound of formula (I):

to form a crystallized product, comprising recrystallizing a compound of formula (I) in a solvent system (e.g. in a solvent comprising acetonitrile and dichloromethane).

45. The method of claim 44, wherein the compound of formula (I) is isolated as a wet cake.

46. The method of claim 44 or claim 45, wherein the compound of formula (I) is obtainable / obtained from the method of any one of claims 1-43.

47. A compound selected from the following:

or a salt thereof.