WO2024256574A1 - Procédé de préparation d'inhibiteurs de btk macrocycliques - Google Patents

Procédé de préparation d'inhibiteurs de btk macrocycliques Download PDF

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WO2024256574A1
WO2024256574A1 PCT/EP2024/066433 EP2024066433W WO2024256574A1 WO 2024256574 A1 WO2024256574 A1 WO 2024256574A1 EP 2024066433 W EP2024066433 W EP 2024066433W WO 2024256574 A1 WO2024256574 A1 WO 2024256574A1
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formula
compound
palladium
bis
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Adrianus Petrus Antonius De Man
Rogier Christian Buijsman
Freek VAN CAUTER
Jan Gerard STERRENBURG
Joeri Johannes Petrus DE WIT
Sander Petrus Wilhelmus VAN GEMERT
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Crossfire Oncology Holding BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/16—Halogen atoms; Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • 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.
  • 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.
  • BTK Bruton's tyrosine kinase
  • BCR B-cell receptor
  • BTK small molecule inhibitors
  • small molecule inhibitors such as the FDA approved covalent BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib and tirabrutinib
  • CLL Chronic Lymphocytic Leukemia
  • MCL Mantle Cell Lymphoma
  • WM Macroglobulinemia
  • SLL Small Lymphocytic Lymphoma
  • BTK is also expressed and plays also pro-tumorigenic roles in several solid tumors (Xianhui Wang et al. 2021).
  • BTK inhibition with ibrutinib or acalabrutinib inhibited cell growth (Kokabee et al 2015).
  • 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).
  • 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.
  • 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.
  • 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.
  • noncovalent BTK inhibitors including pirtobrutinib (LOXO- 305), ARQ-351 and vecabrutinib, inhibited B-cell-receptor signaling in BTK C481 -mutant cell and animal models.
  • 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.
  • PCT Patent Application No. PCT/EP2022/085765 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.
  • the compounds of Formula (l-b) according to the invention are:
  • R 1 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 R 2 is selected from the group consisting of:
  • any of said cycloalkyl, heterocycloalkyl and alkyl group is optionally and independently substituted with hydroxy, methyl, acetyl or methoxy; wherein R 3 and R 4 together represent a linker having Formula selected from the group consisting of: whereby the marks the position of R 3 in Formula l-b, and whereby the marks the position of R 4 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, CD 3 , (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 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.
  • 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.
  • 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).
  • 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:
  • any of said linkers L is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD 3 , (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 L 1 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 L 1 is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD 3 , (1-4C)alkyl, (1- 5C)alkoxy, (
  • 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).
  • 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 R 3 and R 4 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 R 3 .
  • 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.
  • 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).
  • 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 L 2 is as defined above.
  • 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).
  • 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 L 2 is as defined above.
  • 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.
  • DMB 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 L 2 is as defined above.
  • 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.
  • a method of preparing a compound of formula comprising reacting a starting material of formula (XII):
  • 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.
  • a solvent system e.g. in a solvent comprising acetonitrile and dichloromethane.
  • composition as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable.
  • pharmaceutically acceptable 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.
  • an effective amount 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.
  • 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.
  • 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.
  • salt as used herein has its conventional meaning and includes the acid addition and base salts of the compound of the invention.
  • 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 H 2 O and includes any hydrate of the compound or the salt of said compound.
  • treatment has its conventional meaning and refers to curative, disease controlling, palliative and prophylactic treatment.
  • 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.
  • BTK Bruton's Tyrosine Kinase
  • BTK Bruton's tyrosine kinase
  • 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.
  • BTK small molecule inhibitors
  • 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.
  • CLL Chronic Lymphocytic Leukemia
  • MCL Mantle Cell Lymphoma
  • WM Macroglobulinemia
  • SLL Small Lymphocytic Lymphoma SLL.
  • 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.
  • mutant-BTK 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.
  • an altered amino acid target such as C as single-letter data-base code for cysteine
  • 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.
  • valine 416 V416)
  • alanine 428 A428)
  • methionine 437 M437)
  • threonine 474 T474
  • leucine 528 L528, modifications, which can reduce BTK inhibitor binding to BTK.
  • 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.
  • 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 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 refers both to a heterocyclic (heterocyclyl) group, and to a cyclic group having carbon groups only, i.e. without hetero atoms, within the cycle.
  • heterocyclic (heterocyclyl) group refers to both heteroaryl groups and heterocycloalkyl groups.
  • a heterobicyclic group refers to a bicyclic group having one or more heteroatoms, which is saturated, partially unsaturated or unsaturated.
  • aromatic groups include aromatic carbocyclic ring systems (e.g. phenyl) and fused polycyclic aromatic ring systems (e.g. naphthyl and 1,2,3,4- tetrahydronaphthyl).
  • alkyl refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond having the specified number of carbon atoms.
  • 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.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • an alkyl group is linear. In another embodiment, an alkyl group is branched.
  • 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-CH 2 -CH 2 -CH 2 -CH 2 -B, A-CH 2 - CH 2 -CH(CH 3 )-CH 2 -B, A-CH 2 -CH(CH 2 CH 3 )-B, A-CH 2 -C(CH 3 )(CH 3 )-B, and the like.
  • alkylcarbonyl 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.
  • 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.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • 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.
  • 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.
  • 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.
  • 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-CH 2 CH3, - OCH(CH 3 ) 2 , -O(CH 2 ) 5 CH3, 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.
  • alkyl groups are unsubstituted or substituted with 1 to 3 substituents on each carbon atom.
  • compositions comprising components A and B
  • the only enumerated components of the composition are A and B, and further the claim should be interpreted as including equivalents of those components.
  • 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”.
  • the compounds of Formula (l-b) according to the invention are:
  • R 1 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 R 2 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 R 3 and R 4 together represent a linker having Formula selected from the group consisting of:
  • any of said linkers is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD 3 , (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.
  • the compound of Formula (I) is defined as:
  • 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 L 2 having Formula selected from the group consisting of:
  • any of said linkers L is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD 3 , (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:
  • the compound of Formula (I) is prepared based on one or more of the intermediate compounds selected from:
  • the compound of Formula (l-b) is prepared based on one or of more of the intermediate compounds selected from:
  • DMB is dimethoxybenzyl
  • L 2 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 L 2 is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, CD 3 , (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:
  • 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.
  • the reaction is carried out in acetic acid, preferably at 20 °C to 30 °C, more preferably at 1-4 atm.
  • 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.
  • 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
  • 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).
  • 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.
  • TAA triethylamine
  • DIPEA N ,N-diisopropylethylamine
  • NEM N-ethylmorpholine
  • NMM N-methylmorpholine
  • pyridine 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • DBU 1,6-lutidine
  • 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.
  • HATU tetramethyluronium hexafluorophosphate
  • 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-
  • Pd G3 Metalhanesulfonato(di- adamantyl-n-butylphosphino)-2’-amino-1 ,1 ’-biphenyl-2-yl)palladium(ll)).
  • the palladium catalyst is 1 ,1 '-bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll) (Pd(dppf)CI 2 ).
  • the reaction further comprises a base.
  • the base is selected from the group consisting of potassium carbonate (K2CO3), cesium carbonate (CS2CO3), potassium hydroxide (KOH) and sodium tert-butoxide (NaOfBu).
  • the base is potassium carbonate and wherein the reaction is carried out in a solvent mixture of dioxane/water, preferably at 80 °C.
  • 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).
  • PCI5 phosphorous pentachloride
  • POCI3 phosphorous oxychloride
  • TFAA trifluoroacetic anhydride
  • PPA polyphosphoric acid
  • Degessreagent 1-chloro-N ,N-dimethylmethaniminium chloride
  • 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).
  • DMF N,N,- dimethylformamide
  • TNU 1 ,1 ,3,3-tetramethylurea
  • DI 1 ,3-dimethyl-2-imidazolidinone
  • the base is selected from the group of pyridine, triethylamine, 2- chloropyridine and 2-fluoropyridine.
  • 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.
  • POCI3 phosphorous oxychloride
  • the brominating agent is N-bromosuccinimide (NBS) and wherein the reaction is carried out in acetonitrile, preferably at 5 °C to 25 °C.
  • reaction is carried out in 2-butanol (sec-BuOH) at 90 °C.
  • the acid is selected from the group of hydrochloric acid (HCI), hydrobromic acid (HBr), hydroiodic acid (HI), methanesulfonic acid (MsOH) and trifluoroacetic acid (TFA).
  • HCI hydrochloric acid
  • HBr hydrobromic acid
  • HI hydroiodic acid
  • MsOH methanesulfonic acid
  • TFA trifluoroacetic acid
  • the acid is hydrochloric acid (HCI) and wherein the reaction is carried out in dioxane, acetonitrile, or mixtures thereof.
  • HCI hydrochloric acid
  • 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 ’-t
  • 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).
  • 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.
  • TAA triethylamine
  • DIPEA N ,N-diisopropylethylamine
  • NEM N-ethylmorpholine
  • NMM N-methylmorpholine
  • pyridine 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • DBU 1,6-lutidine
  • 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.
  • DMF N,N,- dimethylformamide
  • NEM N-ethylmorpholine
  • 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-
  • the palladium catalyst is 1 ,1 '-bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll) (Pd(dppf)CI 2 ).
  • the reaction further comprises a base.
  • the base is selected from the group consisting of potassium carbonate (K 2 CO 3 ), cesium carbonate (CS 2 CO 3 ), potassium hydroxide (KOH) and sodium fert-butoxide (NaOfBu).
  • the base is potassium carbonate (K 2 CO 3 ), and wherein the reaction is carried out in dioxane, water, or mixtures thereof, preferably at 80 °C.
  • the acid is selected from the group of hydrochloric acid (HCI), hydrobromic acid (HBr), hydroiodic acid (HI), methanesulfonic acid (MsOH) and trifluoroacetic acid (TFA).
  • HCI hydrochloric acid
  • HBr hydrobromic acid
  • HI hydroiodic acid
  • MsOH methanesulfonic acid
  • TFA trifluoroacetic acid
  • the reaction is carried out at (about) 60 °C, preferably wherein the acid is trifluoroacetic acid (TFA).
  • 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).
  • 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 ⁇ m, 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).
  • 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).
  • 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)
  • 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.
  • 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)
  • 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.
  • 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 1 H-NMR.
  • 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).
  • 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).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne des procédés de production d'un composé de formule (I-b) ou d'un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne de nouveaux procédés ou de nouveaux procédés de préparation des composés de formule (I-b) tels que décrits dans la description, en particulier de préparation d'un composé de formule (I). En outre, l'invention concerne de nouveaux intermédiaires et des procédés.
PCT/EP2024/066433 2023-06-13 2024-06-13 Procédé de préparation d'inhibiteurs de btk macrocycliques Pending WO2024256574A1 (fr)

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