WO2024256568A1 - Formes salines et formes cristallines d'un inhibiteur de btk macrocyclique - Google Patents

Formes salines et formes cristallines d'un inhibiteur de btk macrocyclique Download PDF

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WO2024256568A1
WO2024256568A1 PCT/EP2024/066423 EP2024066423W WO2024256568A1 WO 2024256568 A1 WO2024256568 A1 WO 2024256568A1 EP 2024066423 W EP2024066423 W EP 2024066423W WO 2024256568 A1 WO2024256568 A1 WO 2024256568A1
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acid salt
compound
crystalline
ray powder
powder diffraction
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Adrianus Petrus Antonius De Man
Rogier Christian Buijsman
Freek VAN CAUTER
Petrus Jozef Cornelis Maria VAN HOOF
Irina Andreevna NIKOLAEVA
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Crossfire Oncology Holding BV
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Crossfire Oncology Holding BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to novel salts and crystalline forms of a macrocyclic Bruton’s Tyrosine Kinase (BTK) inhibitor, to pharmaceutical compositions comprising the crystalline forms, to methods of using the crystalline forms to treat conditions treatable by the inhibition of (mutant) BTK, such as B-cell malignancies, in particular B-cell lymphomas, even more particular marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), non-Hodgkin lymphoma, Burkitt lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), hairy cell leukemia, B- cell non-Hodgkin lymphoma, B-cell prolymphocytic leukemia, Waldenstrom’s macroglobulinemia (WM), multiple myeloma (MM), arthritis, in particular rheuma
  • 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 smallmolecule 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 covalent 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.
  • 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, WO2018097234, WO2013/010380, W02016/161570, 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 cancer, such as CLL.
  • the compound (I) is one of the BTK inhibitors disclosed in PCT Patent Application No. PCT/EP2022/085765, also referred to as having subformula 184.
  • the present disclosure is directed to i) novel pharmaceutically acceptable salts of compound (I) (e.g., compound (I) hydrochloric acid, compound (I) maleate, compound (I) semisulfate, compound (I) sulfate, compound (I) semi-edisylate, compound (I) hydrobromic acid) including the corresponding solid forms; and ii) a novel solid form of the free base of compound (I) (hereinafter collectively referred to as “Salt or Solid Forms of the Disclosure”).
  • the present disclosure provides a hydrochloric acid addition salt of compound (I).
  • the molar ratio between compound (I) and hydrochloric acid is about 1 :1 , in particular between 0.95 : 1 .05 and 1 .05 : 0.95, more preferably the molar ratio is 1 :1.
  • this salt is also referred herein as “compound (I) hydrochloric acid” or as “hydrochloric acid addition salt of compound (I)”.
  • the present disclosure provides a maleic acid addition salt of compound (I).
  • the molar ratio between compound (I) and maleic acid is about 1 :1 , in particular between 0.95 : 1 .05 and 1 .05 : 0.95, more preferably the molar ratio is 1 :1.
  • this salt is also referred herein as “compound (I) maleate” or as “maleic acid addition salt of compound (I)”.
  • the present disclosure provides a semi-sulfate addition salt of compound (I).
  • the molar ratio between compound (I) and sulfuric acid is about 1 :0.5, in particular between 0.95 : 0.55 and 1.05 : 0.45, more preferably the molar ratio is 1 :0.5.
  • this salt is also referred herein as “compound (I) semi-sulfate” or as “1 :0.5 sulphuric acid addition salt of compound (I)”.
  • the present disclosure provides a sulfate addition salt of compound (I).
  • the molar ratio between compound (I) and sulfuric acid is about 1 :1 , in particular between 0.95 : 1 .05 and 1 .05 : 0.95, more preferably the molar ratio is 1 :1 .
  • this salt is also referred herein as “compound (I) sulfate” or as “1 :1 sulphuric acid addition salt of compound (I)”.
  • the present disclosure provides a semi-edisylate addition salt of compound (I).
  • the molar ratio between compound (I) and ethane 1 ,2 sulfonic acid is about 1 :0.5, in particular between 0.95 : 0.55 and 1.05 : 0.45, more preferably the molar ratio is 1 :0.5.
  • this salt is also referred herein as “compound (I) semi- edisylate” or as “1 :0.5 ethane 1 ,2 sulfonic acid addition salt of compound (I)”.
  • the present disclosure provides a hydrobromic acid addition salt of compound (I).
  • the molar ratio between compound (I) and hydrobromic acid is about 1 :1 , in particular between 0.95 : 1 .05 and 1 .05 : 0.95, more preferably the molar ratio is 1 :1.
  • this salt is also referred herein as “compound (I) hydrobromic acid” or as “hydrobromic acid addition salt of compound (I)”.
  • the present disclosure provides a crystalline form of the free base of compound (I), having a crystalline Form G.
  • This crystalline form is also referred herein as compound (I) free base Form G.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of an addition salt of compound (I) according to the invention or a freebase of compound (I) according to the invention, in particular embodiments comprising at least one of a compound (I) hydrochloric acid salt, compound (I) maleate, compound (I) semisulfate, compound (I) sulfate, compound (I) semi-edisylate, compound (I) hydrobromic acid, compound (I) free base Form G or compound (I) and a pharmaceutically acceptable carrier or diluent.
  • BTK Tyrosine Kinase
  • an addition salt of compound (I) according to the invention or a freebase of compound (I) according to the invention or a pharmaceutical composition according to the invention for use in the treatment of Bruton’s Tyrosine Kinase (BTK) mediated disorders wherein the Bruton’s Tyrosine Kinase (BTK) mediated disorder is selected from the group consisting of an allergic disease, an autoimmune disease, an inflammatory disease, a thromboembolic disease, a bone-related disease, and cancer.
  • a method for treating of cancer in a subject in need thereof comprising administering to the subject the compound according to the invention in an amount effective to treat cancer.
  • a method for treating a subject suffering with a Bruton's Tyrosine Kinase (BTK) mediated disorder comprising administering to the subject the compound the invention or pharmaceutical composition according to the invention in an amount effective to treat the BTK mediated disorder.
  • BTK Bruton's Tyrosine Kinase
  • 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 H2O 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 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 reversible interaction with BTK.
  • covalent BTK inhibitor has its conventional meaning and refers to a BTK inhibitor that reacts with its target protein (BTK) to form a covalent complex in which the protein has lost its function.
  • BTK target protein
  • Covalent inhibitors can be reversible or irreversible, depending on the rate of the reverse reaction.
  • 'covalent inhibitor' and 'irreversible inhibitor' are often used interchangeably.
  • irreversible BTK inhibitor has its conventional meaning and refers to a BTK inhibitor that possesses an off-rate that is slow relative to the rate of re-synthesis of the target protein (BTK) in vivo, so that once the target protein is inhibited, it does not regain activity.
  • rate of re-synthesis has its conventional meaning and refers to the rate at which a cell and/or organism replaces a protein target with freshly synthesized functional protein.
  • the re-synthesis rate defines the rate at which an irreversibly inhibited protein target will recover activity in vivo, once the inhibitor is no longer present.
  • reversible BTK inhibitor has its conventional meaning and refers to a BTK inhibitor that inactivates the BTK enzyme through non-covalent, transcient, interactions. Unlike an irreversible inhibitor, a reversible inhibitor can dissociate from the enzyme.
  • mutant-BTK has its conventional meaning and refers to mutations of BTK. Mutations of BTK may be referred to by an altered or modified amino acid target (such as C as single-letter amino acid code for cysteine) at a certain position of the BTK structure (such as 481). Additionally, the amino acid substitution at the modification position may be referred to by an additional amino acid single-letter amino acid code, such as C481 S for serine substitution and C481T for threonine substitution of cysteine at the 481 position.
  • an altered or modified amino acid target such as C as single-letter amino acid code for cysteine
  • an additional amino acid single-letter amino acid code such as C481 S for serine substitution and C481T for threonine substitution of cysteine at the 481 position.
  • modification has its conventional meaning and refers to modification of a sequence of amino acids of a polypeptide, protein or a sequence of nucleotides in a nucleic acid molecule and includes deletions, insertions, and replacements of amino acids and nucleotides, respectively.
  • the term "resistance to BTK inhibitor” as used herein has its conventional meaning and refers to a BTK inhibitor, which shows a reduction in effectiveness, after being effective initially in treating a hyperproliferative disease, in particular a B-cell hematological malignancy.
  • a drawback of the currently approved irreversible inhibitors is that patients treated with these inhibitors can develop drug resistance when BTK 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)
  • A428 alanine 428
  • M437 methionine 437
  • T474 threonine 474
  • L528 leucine 528
  • drug resistance is meant the major cause of cancer treatment failure. While a treatment may be effective initially, the heterogeneity of cancer and its ability to adapt can allow the cancer to become resistant to the treatment and regrow.
  • relapse as used herein has the conventional meaning and refers to evidence of disease progression in a patient who has previously achieved criteria of a complete response or partial remission.
  • disease progression has the conventional meaning and refers to a measured increase in tumor size or tumor burden.
  • recurrent or refractory form of a hyperproliferative disease has the conventional meaning and refers to a particular cancer that is resistant, or non-responsive to therapy with a particular therapeutic agent.
  • a cancer can be refractory to therapy with a particular therapeutic agent either from the onset of treatment (i.e., non-responsive to initial exposure to the therapeutic agent), or as a result of developing resistance to the therapeutic agent, either over the course of a first treatment period with the therapeutic agent or during a subsequent treatment period with the therapeutic agent.
  • the term ‘’acquired drug resistance” as used herein has the conventional meaning and refers to resistance of a drug caused by mutations in the target protein.
  • the mutations in the target protein hamper the binding of drug resulting in a regrowth of the tumor
  • clinical drug resistance refers to growth of a tumour while the patient is on treatment, that develops following after an initial clinical benefit (a clinical response or prolonged stable disease).
  • 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.
  • microcycle 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.
  • 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”.
  • Figure 1 shows the X-ray Powder Diffraction (XRPD) pattern of 1 :1 compound (I) hydrochloric acid Form A.
  • FIG. 2 shows the Thermogravimetric Analysis (TGA) of 1 :1 compound (I) hydrochloric acid Form A.
  • FIG. 3 shows the Differential Scanning Calorimetry Analysis (DSC) thermogram of 1 :1 compound (I) hydrochloric acid Form A.
  • Figure 4 shows the X-ray Powder Diffraction (XRPD) pattern of 1 :1 compound (I) maleate Form B.
  • FIG. 5 shows the Thermogravimetric Analysis (TGA) of 1 :1 compound (I) maleate Form B.
  • FIG. 6 shows the Differential Scanning Calorimetry Analysis (DSC) thermogram of 1 :1 compound (I) maleate Form B.
  • Figure 7 shows the X-ray Powder Diffraction (XRPD) pattern of 1 :0.5 compound (I) semisulfate Form C.
  • Figure 8 shows the Thermogravimetric Analysis (TGA) of 1 :0.5 compound (I) semisulfate Form C.
  • FIG. 9 shows the Differential Scanning Calorimetry Analysis (DSC) thermogram of 1 :0.5 compound (I) semi-sulfate Form C.
  • Figure 10 shows the X-ray Powder Diffraction (XRPD) pattern of 1 :1 compound (I) sulfate Form D.
  • FIG 11 shows the Thermogravimetric Analysis (TGA) of 1 :1 compound (I) sulfate Form D.
  • Figure 12 shows the Differential Scanning Calorimetry Analysis (DSC) thermogram of 1 :1 compound (I) sulfate Form D.
  • Figure 13 shows the X-ray Powder Diffraction (XRPD) pattern of 1 :0.5 compound (I) semi-edisylate Form E.
  • FIG 14 shows the Thermogravimetric Analysis (TGA) of 1 :0.5 compound (I) semi- edisylate Form E.
  • FIG. 15 shows the Differential Scanning Calorimetry Analysis (DSC) thermogram of 1 :0.5 compound (I) semi-edisylate Form E.
  • Figure 16 shows the X-ray Powder Diffraction (XRPD) pattern of 1 :1 compound (I) hydrobromic acid Form F.
  • Figure 17 shows the Thermogravimetric Analysis (TGA) of 1 :1 compound (I) hydrobromic acid Form F.
  • Figure 18 shows the Differential Scanning Calorimetry Analysis (DSC) thermogram of 1 :1 compound (I) hydrobromic acid Form F.
  • Figure 19 shows the X-ray Powder Diffraction (XRPD) pattern of compound (I) free base Form G.
  • FIG. 20 shows the Thermogravimetric Analysis (TGA) of compound (I) free base Form G.
  • FIG. 21 shows the Differential Scanning Calorimetry Analysis (DSC) thermogram of compound (I) free base Form G.
  • Figure 22 shows the X-ray Powder Diffraction (XRPD) pattern of compound (I) free base Form O.
  • FIG. 23 shows the Thermogravimetric Analysis (TGA) of compound (I) free base Form O.
  • FIG. 24 shows the Differential Scanning Calorimetry Analysis (DSC) thermogram of compound (I) free base Form O.
  • the present disclosure provides a hydrochloric acid addition salt of compound (I).
  • the molar ratio between compound (I) and hydrochloric acid is about 1 :1 , in particular between 0.95 : 1 .05 and 1 .05 : 0.95, more preferably the molar ratio is 1 :1.
  • this salt is also referred herein as “compound (I) hydrochloric acid”.
  • the present disclosure provides a maleic acid addition salt of compound (I).
  • the molar ratio between compound (I) and maleic acid is about 1 :1 , in particular between 0.95 : 1 .05 and 1 .05 : 0.95, more preferably the molar ratio is 1 :1 .
  • this salt is also referred herein as “compound (I) maleate”.
  • the present disclosure provides a semi-sulfate addition salt of compound (I).
  • the molar ratio between compound (I) and sulfuric acid is about 1 :0.5, in particular between 0.95 : 0.55 and 1.05 : 0.45, more preferably the molar ratio is 1 :0.5.
  • this salt is also referred herein as “1 :1 compound (I) semi-sulfate”.
  • the present disclosure provides a sulfate addition salt of compound (I).
  • the molar ratio between compound (I) and sulfuric acid is about 1 :1 , in particular between 0.95 : 1 .05 and 1 .05 : 0.95, more preferably the molar ratio is 1 :1 .
  • this salt is also referred herein as “compound (I) sulfate”.
  • the present disclosure provides a semi-edisylate addition salt of compound (I).
  • the molar ratio between compound (I) and ethane 1 ,2 sulfonic acid is about 1 :0.5, in particular between 0.95 : 0.55 and 1.05 : 0.45, more preferably the molar ratio is 1 :0.5.
  • this salt is also referred herein as “compound (I) semi- edisylate”.
  • the present disclosure provides a hydrobromic acid addition salt of compound (I).
  • the molar ratio between compound (I) and hydrobromic acid is about 1 :1 , in particular between 0.95 : 1 .05 and 1 .05 : 0.95, more preferably the molar ratio is 1 :1.
  • this salt is also referred herein as “compound (I) hydrobromic acid”.
  • the present disclosure provides a crystalline form of the free base of compound (I), having a crystalline Form G.
  • This crystalline form is also referred herein as compound (I) free base Form G.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of an addition salt of compound (I) according to the invention or a freebase of compound (I) according to the invention, in particular embodiments comprising at least one of a compound (I) hydrochloric acid salt, compound (I) maleate, compound (I) semisulfate, compound (I) sulfate, compound (I) semi-edisylate, compound (I) hydrobromic acid, or compound (I) free base Form G, and a pharmaceutically acceptable carrier or diluent.
  • the hydrochloric acid salt is at least partly crystalline.
  • said crystalline hydrochloric acid salt has Form A, having an X-ray powder diffraction pattern which comprises at least three, four, five, six, seven or eight peaks chosen from 4.2°, 8.4°, 9.0°, 14.9°, 18.0°, 23.0°, 23.8° and 25.4° ⁇ 0.2 in 20.
  • said crystalline hydrochloric acid salt is has Form A, having an X-ray powder diffraction pattern substantially similar to Figure 1 .
  • hydrochloric acid addition salt of compound (I) said hydrochloric acid salt has a differential scanning calorimeter thermogram substantially similar to Figure 3.
  • At least 90% by weight of the hydrochloric acid salt is crystalline Form A.
  • the X- ray powder diffraction pattern is substantially stable during at least 2 days at 40°C / 75 % RH.
  • the hydrochloride acid addition is obtained or obtainable by a process comprising: combining compound (I) and hydrochloric acid in acetone; collecting said hydrochloric acid salt of compound (I).
  • the molar ratio between compound (I) and maleic acid is 1 :1.
  • the maleic acid salt is at least partly crystalline.
  • said crystalline maleic acid salt has crystalline Form B, having an X-ray powder diffraction pattern which comprises at least three or four peaks chosen from 9.7°, 10.7°, 12.2°, 16.5°, 23.5 and 25.4° ⁇ 0.2 in 20.
  • said crystalline maleic acid salt has Form B, having an X-ray powder diffraction pattern which comprises peaks at 9.7°, 10.7°, 12.2°, 16.5°, 23.5 and 25.4° ⁇ 0.2 in 20.
  • said crystalline maleic acid salt has Form B, having an X-ray powder diffraction pattern which comprises at least three, four, five, six, seven, eight, nine, or ten peaks chosen from 8.1 °, 9.7°, 10.7°, 12.2°, 15.1 °, 16.5°, 17.7°, 19.6°, 20.5°, 21.2°, 22.4°, 23.5°, 23.9°, 25.4° and 30.0° ⁇ 0.2 in 20.
  • said crystalline maleic acid salt is Form B, having an X-ray powder diffraction pattern which comprises peaks at 8.1 °, 9.7°, 10.7°, 12.2°, 13.1 °, 15.1 °, 16.5°, 17.2°, 17.7°, 18.8°, 19.0°, 19.6°, 20.5°, 21.2°, 22.4°, 23.5°, 23.9°, 24.4°, 25.4°, 26.3°, 28.7°, 29.0° and 30.0° ⁇ 0.2 in 20.
  • said crystalline maleic acid salt is Form 1 , having an X-ray powder diffraction pattern substantially similar to Figure 4.
  • said maleic acid salt has a differential scanning calorimeter thermogram substantially similar to Figure 6.
  • said maleic acid salt has a thermogravimetric analysis (TGA) thermogram substantially similar to Figure 5.
  • the X-ray powder diffraction pattern is substantially stable during at least 2 days at 40°C / 75 % RH.
  • the maleic acid salt is obtained or obtainable by a process comprising: combining compound (I) and maleic acid in dioxane; collecting said maleic acid salt of compound (I).
  • the molar ratio between compound (I) and sulphuric acid is 1 :0.5.
  • the sulphuric acid salt is at least partly crystalline.
  • said crystalline sulphuric acid salt has crystalline Form C, having an X-ray powder diffraction pattern which comprises at least two peaks chosen from 4.8°, 9.6° and 20.8° ⁇ 0.2 in 20.
  • said crystalline sulphuric acid salt has Form C, having an X-ray powder diffraction pattern which comprises peaks at 4.8°, 9.6° and 20.8° ⁇ 0.2 in 20.
  • said crystalline sulphuric acid salt has Form C, having an X-ray powder diffraction pattern which comprises peaks at 4.8°, 6.0°, 9.6°, 10.3, 11.6°, 15.7°, 17.9°, 19.1 °, 19.9°, 20.8°, 21.6°, 21.8°, 22.4°, 23.4°, 24.0° and 25.7° ⁇ 0.2 in 20.
  • said crystalline sulphuric acid salt has Form C, having an X-ray powder diffraction pattern substantially similar to Figure 7.
  • said sulphuric acid salt has a differential scanning calorimeter thermogram substantially similar to Figure 9.
  • thermogravimetric analysis (TGA) thermogram substantially similar to Figure 8.
  • At least 90% by weight of the sulphuric acid salt is crystalline Form C.
  • the X-ray powder diffraction pattern is substantially stable during at least 2 days at 40°C / 75 % RH.
  • the sulphuric acid salt is obtained or obtainable by a process comprising: combining compound (I) and sulphuric acid in ethanol; collecting said sulphuric acid salt of compound (I).
  • the sulphuric acid salt is at least partly crystalline.
  • said crystalline sulphuric acid salt has crystalline Form D, having an X-ray powder diffraction pattern which comprises at least two peaks chosen from 4.2°, 23.7°, and 25.4° ⁇ 0.2 in 20.
  • said crystalline sulphuric acid salt has Form D, having an X-ray powder diffraction pattern which comprises peaks at 4.2°, 23.7°, and 25.4° ⁇ 0.2 in 20.
  • said crystalline sulphuric acid salt has Form D, having an X-ray powder diffraction pattern which comprises at least three, four, five, six or seven peaks chosen from 4.2°, 14.8°, 15.2°, 18.0°, 21 .0°, 23.7°, and 25.4° ⁇ 0.2 in 20.
  • said crystalline sulphuric acid salt has Form D, having an X-ray powder diffraction pattern substantially similar to Figure 10.
  • said sulphuric acid salt has a differential scanning calorimeter thermogram substantially similar to Figure 12.
  • thermogravimetric analysis (TGA) thermogram substantially similar to Figure 11 .
  • At least 90% by weight of the sulphuric acid salt is crystalline Form D.
  • the X-ray powder diffraction pattern is substantially stable during at least 2 days at 40°C / 75 % RH.
  • the sulphuric acid salt is obtained or obtainable by a process comprising: combining compound (I) and sulphuric acid in acetone; collecting said sulphuric acid salt of compound (I).
  • Ethane 1 ,2-disulfonic acid addition salt of compound (I) In preferred embodiments of the ethane 1 ,2-disulfonic acid addition salt of compound (I), the molar ratio between compound (I) and ethane 1 ,2-disulfonic acid is 1 :0.5.
  • the ethane 1 ,2-disulfonic acid salt is at least partly crystalline.
  • said crystalline ethane 1 ,2-disulfonic acid salt has crystalline Form E, having an X-ray powder diffraction pattern which comprises at least two peaks chosen from 4.2°, 17.4° and 24.7° ⁇ 0.2 in 20.
  • said crystalline ethane 1 ,2-disulfonic acid salt has Form E, having an X-ray powder diffraction pattern which comprises peaks at 4.2°, 17.4° and 24.7° ⁇ 0.2 in 20.
  • said crystalline ethane 1 ,2-disulfonic acid salt has Form E, having an X-ray powder diffraction pattern which comprises at least three, four or five peaks chosen from 4.2°, 14.9°, 17.4°, 21.3° and 24.7° ⁇ 0.2 in 20.
  • said crystalline ethane 1 ,2-disulfonic acid salt has Form E, having an X-ray powder diffraction pattern which comprises peaks at 4.2°, 14.9°, 15.5°, 17.4°, 21 .3° and 24.7° ⁇ 0.2 in 20.
  • said crystalline ethane 1 ,2-disulfonic acid salt has Form E, having an X-ray powder diffraction pattern substantially similar to Figure 13.
  • said ethane 1 ,2-disulfonic acid salt has a differential scanning calorimeter thermogram substantially similar to Figure 15.
  • thermogravimetric analysis (TGA) thermogram substantially similar to Figure 14.
  • At least 90% by weight of the ethane 1 ,2-disulfonic acid salt is crystalline Form E.
  • the X-ray powder diffraction pattern is substantially stable during at least 2 days at 40°C / 75 % RH.
  • the ethane 1 ,2-disulfonic acid salt is obtained or obtainable by a process comprising: combining compound (I) and ethane 1 ,2-disulfonic acid in ethanol; collecting said ethane 1 ,2- disulfonic acid salt of compound (I).
  • Hydrobromic acid addition salt of compound (I) In preferred embodiments of the hydrobromic acid addition salt of compound (I), the molar ratio between compound (I) and hydrobromic acid is 1 :1 .
  • the hydrobromic acid salt is at least partly crystalline.
  • said crystalline hydrobromic acid salt has crystalline Form F, having an X-ray powder diffraction pattern which comprises at least three, four or five peaks chosen from 4.2°, 14.9°, 17.9°, 21.5°, 23.9°, 24.3° and 25.4° ⁇ 0.2 in 20.
  • said crystalline hydrobromic acid salt has Form F, having an X-ray powder diffraction pattern which comprises peaks at 4.2°, 14.9°, 17.9°, 21 .5°, 23.9°, 24.3° and 25.5° ⁇ 0.2 in 20.
  • said crystalline hydrobromic acid salt has Form F, having an X-ray powder diffraction pattern which comprises at least three, four, five, six, seven, eight, nine, or ten peaks chosen from 4.2°, 8.4°, 9.0°, 9.8°, 12.6°, 14.9°, 15.4°, 16.3°, 17.3°, 17.9°, 19.9°, 20.7°, 21.5°, 23.0°, 23.9°, 24.3°, 25.5°, 26.4°, 27.1 ° and 27.9° ⁇ 0.2 in 20.
  • said crystalline hydrobromic acid salt has Form F, having an X-ray powder diffraction pattern which comprises peaks at 4.2°, 8.4°, 9.0°, 9.8°, 12.6°, 14.9°, 15.4°, 16.3°, 17.3°, 17.9°, 18.6°, 19.9°, 20.7°, 21.5°, 23.0°, 23.9°, 24.3°, 25.5°, 26.4°, 27.1 °, 27.9°, 29.6° and 30.0° ⁇ 0.2 in 20.
  • said crystalline hydrobromic acid salt has Form F, having an X-ray powder diffraction pattern substantially similar to Figure 16.
  • said hydrobromic acid salt has a differential scanning calorimeter thermogram substantially similar to Figure 18.
  • thermogravimetric analysis (TGA) thermogram substantially similar to Figure 17.
  • At least 90% by weight of the hydrobromic acid salt is crystalline Form F.
  • the X- ray powder diffraction pattern is substantially stable during at least 2 days at 40°C / 75 % RH.
  • the hydrobromic acid salt is obtained or obtainable by a process comprising: combining compound (I) and hydrobromic acid in acetone; collecting said hydrobromic acid salt of compound (I).
  • Freebase crystalline Form G of compound (I) In preferred embodiments ofthe freebase crystalline Form G of compound (I), said Form G has an X-ray powder diffraction pattern which comprises at least three or four peaks chosen from 4.2°, 9.3°, 22.0° and 25.2° ⁇ 0.2 in 20.
  • said Form G having an X-ray powder diffraction pattern which comprises peaks at 4.2°, 9.3°, 22.0° and 25.2° ⁇ 0.2 in 20.
  • said Form G has an X-ray powder diffraction pattern which comprises at least three, four, five, six, seven or eight peaks chosen from 4.2°, 9.3°, 13.0°, 13.5°, 16.4°, 22.0°, 24.7° and 25.2° ⁇ 0.2 in 20.
  • said Form G has an X-ray powder diffraction pattern which comprises peaks at 4.2°, 9.3°, 13.0°, 13.5°, 16.4°, 22.0°, 24.7° and 25.2° ⁇ 0.2 in 20.
  • said Form G has an X-ray powder diffraction pattern substantially similar to Figure 19.
  • said crystalline freebase form has a differential scanning calorimeter thermogram substantially similar to Figure 21 .
  • said Form G has a thermogravimetric analysis (TGA) thermogram substantially similar to Figure 20.
  • the freebase crystalline Form G of compound (I) at least 90% by weight of the freebase is crystalline Form G.
  • the X-ray powder diffraction pattern is substantially stable during at least 2 days at 40°C / 75 % RH.
  • the freebase crystalline Form G of compound (I) is obtained or obtainable by a process comprising: combining compound (I) to dioxane to form a mixture; collecting said freebase crystalline Form G of compound (I).
  • said Form O has an X-ray powder diffraction pattern which comprises at least three or four peaks chosen from at least three or four peaks chosen from 5.9°, 6.9°, 9.9° and 11 .7° ⁇ 0.2 in 20.
  • said Form O has an X-ray powder diffraction pattern which comprises peaks at 5.9°, 6.9°, 9.9° and 11 .7° ⁇ 0.2 in 20.] In preferred embodiments ofthe freebase crystalline Form O of compound (I), said Form O has an X-ray powder diffraction pattern which comprises at least three, four, five or six peaks chosen from 5.9°, 6.2°, 6.9°, 9.9°, 11 .7° and 17.6° ⁇ 0.2 in 20.
  • said Form O having an X-ray powder diffraction pattern which comprises peaks at 5.9°, 6.2°, 6.9°, 9.9°, 11.7° and 17.6° ⁇ 0.2 in 20.
  • said Form O has an X-ray powder diffraction pattern substantially similar to Figure 22.
  • said crystalline freebase form has a differential scanning calorimeter thermogram substantially similar to Figure 24.
  • said Form O has a thermogravimetric analysis (TGA) thermogram substantially similar to Figure 23.
  • the compounds and the pharmaceutical compositions of the present invention are useful as inhibitors of tyrosine kinases, in particular of BTK.
  • compounds of this invention are useful as inhibitors of tyrosine kinases that are important in hyper-proliferative diseases, especially in cancer, such as a B-cell hematological malignancy.
  • a compound according to the invention or pharmaceutical composition according to the invention for use in therapy.
  • a compound according to the invention or pharmaceutical composition according to the invention for use in the treatment of Bruton’s Tyrosine Kinase (BTK) mediated disorders.
  • the Bruton’s Tyrosine Kinase (BTK) mediated disorder is selected from the group consisting of an allergic disease, an autoimmune disease, an inflammatory disease, a thromboembolic disease, a bone-related disease, and a hyperproliferative disease, such as cancer.
  • a compound according to the invention or pharmaceutical composition according to the invention for use in the treatment of cancer, lymphoma or leukemia.
  • a compound according to the invention or pharmaceutical composition according to the invention for use in the treatment of a disease selected from the group consisting of B-cell malignancy, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, Richter transformation, multiple myeloma, bone cancer, bone metastasis, chronic lymphocytic lymphomas, B-cell prolymphocyte leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma,
  • a compound according to the invention or pharmaceutical composition according to the invention for use in the treatment of a disease selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, deforming arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter’s syndrome, polychondritis, acute synovitis and spondylitis, glomerulonephritis (with or without 40 nephrotic syndrome), autoimmune hematologic disorders, hemolytic anemia, aplasic anemia, idiopathic thrombocytopenia, and neutropenia, autoimmune gastritis, and autoimmune inflammatory bowel diseases, ulcerative colitis, Crohn’s disease, host versus graft disease, allograft rejection, chronic thyroiditis, Graves’ disease, schleroderma, diabetes (type I and type II), active hepatitis (acute and chronic), pancreatitis, primary billiary cirrhos
  • Behcet’s disease chronic renal insufficiency, Stevens-Johnson syndrome, inflammatory pain, idiopathic sprue, cachexia, sarcoidosis, Guillain-Barre syndrome, uveitis, conjunctivitis, kerato conjunctivitis, otitis media, periodontal disease, pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema, pulmonary fibrosis, silicosis, chronic inflammatory pulmonary disease, and chronic obstructive pulmonary disease.
  • the hyperproliferative disease is a B-cell hematological malignancy.
  • the B-cell hematological malignancy is any one of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), primary mediastinal B-cell lymphoma (PMBL), nonHodgkin lymphoma, Burkitt’s lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, precursor B-cell acute lymphoblastic leukemia, hairy cell leukemia, mantle cell lymphoma, B-cell prolymphocytic leukemia, lym- phoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma
  • CLL
  • the B-cell hematological malignancy is mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), diffuse large B- cell lymphoma (DLBCL), Waldenstrom macroglobulinemia (WM), follicular lymphoma (FL) and marginal zone lymphoma (MZL).
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • DLBCL diffuse large B- cell lymphoma
  • WM Waldenstrom macroglobulinemia
  • FL follicular lymphoma
  • MZL marginal zone lymphoma
  • the B-cell malignancy is Mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).
  • composition/Formulation (Pharmaceutical composition)
  • a pharmaceutical composition comprising a salt of compound (I) according to the invention, or a freebase of compound (I) according to the invention, and a pharmaceutically acceptable carrier or a diluent.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks’s solution, Ringer’s solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks’s solution, Ringer’s solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection).
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be the VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD cosolvent system (VPD:5W) consists of VPD diluted 1 :1 with a 5% dextrose in water solution.
  • This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • the invention is illustrated by the following examples.
  • Methyl (1 R,3/?)-3-aminocyclohexanecarboxylate hydrochloride (1.06 g, 5.47 mmol) was suspended in 10 mL water.
  • Sodium bicarbonate (1.38 g, 16.4 mmol) in 10 mL water was added followed by a drop-wise addition of a solution A/-(benzyloxycarbonyloxy)succinimide (1 .50 g, 6.01 mmol) in dioxane (30 mL).
  • the reaction mixture was stirred at room temperature o/n.
  • the mixture was diluted with ethyl acetate (50 mL) and water (50 mL) and the bi-phasic system was stirred 30 minutes at room temperature.
  • Triethylamine (10.4 mL, 74.62 mmol), 4-dimethylaminopyridine (605 mg, 4.95 mmol) and di-te/Y-butyl dicarbonate (13.5 g, 61.86 mmol) were added sequentially to a solution of 4- nitrobenzene sulfonamide (10 g, 49.46 mmol) in dichloromethane (100 mL).
  • the reaction mixture was stirred for 30 minutes at room temperature.
  • hydrochloric acid (1 N aqueous solution) until it becomes acidic.
  • the organic layer was separated and washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered and then concentrated under reduced pressure.
  • Lithium (E)-8-[3-[(1 R,3/?)-3-aminocyclohexyl]-1 -bromo-8-[(2,4-dimethoxyphenyl)- methylamino]imidazo[1 ,5-a]pyrazin-5-yl]oct-7-enoate (9.14 g, 15.07 mmol) was suspended dissolved in DMF (520 mL) and A/-ethylmorpholine (3.83 mL, 30.14 mmol) was added.
  • HT-XRPD patterns were obtained using the Ardena T2 high-throughput XRPD set-up.
  • the plates were mounted on a Bruker General Area Detector Diffraction System (GADDS) equipped with a VANTEC-500 gas area detector corrected for intensity and geometric variations.
  • GADDS General Area Detector Diffraction System
  • the calibration of the measurement accuracy (peaks position) was performed using NIST SRM1976 standard (Corundum).
  • Data collection was carried out at room temperature using monochromatic Cu Ka radiation in the 20 region between 1 .5° and 41 .5°, which is the most distinctive part of the XRPD pattern.
  • the diffraction pattern of each well was collected in two 20 ranges (1 .5° ⁇ 20 ⁇ 21 .5° for the first frame, and 19.5° ⁇ 20 ⁇ 41.5° for the second) with an exposure time of 90s for each frame. No background subtraction or curve smoothing was applied to the XRPD patterns.
  • the polarized light microscopy pictures were collected with a Leica DM 2500M optical microscope.
  • Mass loss due to solvent or water loss from the crystals was determined by TGA/DSC. Monitoring the sample weight, during heating in a TGA/DSC 3+ STARe system (Mettler-Toledo GmbH, Switzerland), resulted in a weight vs. Temperature curve and a heat flow signal.
  • the TGA/DSC 3+ was calibrated for temperature with samples of indium and aluminum. Samples (circa 2 mg) were weighed into 100 pL aluminum crucibles and sealed. The seals were pin- holed, and the crucibles heated in the TGA from 25 to 300 °C at a heating rate of 10 °C/min. Dry N2 gas was used for purging.
  • the gases coming from the TGA samples were analyzed by a mass spectrometer Omnistar GSD 301 T2 (Pfeiffer Vacuum GmbH, Germany).
  • the latter is a quadrupole mass spectrometer, which analyzes masses in the temperature range of 0-200 amu.
  • Detector 1 UV detector set at 240 nm
  • the compound integrity is expressed as a peak-area percentage, calculated from the area of each peak in the chromatogram, except the ‘injection peak’, and the total peak-area, as follows:
  • peak area peak area (%) - — - — - - — ⁇ 100% total area of all peaks
  • the peak area percentage of the compound of interest is employed as an indication of the purity of the component in the sample.
  • a UPLC-CAD method was used for the determination of the ratio of compound (I) and bromide, chloride and sulphate counterions in the respectively salts.
  • a calibration line was measured for bromide, chloride and sulphate, using a stock solution with a concentration of 0.1 mg/mL and 10 different injection volumes (from 1 pL to 5.5 pL in 0.5 pL steps).
  • the amount of compound (l)-salts used for the analysis was calculated, so that the concentration of the counterion would be about 0.05 mg/mL.
  • the ratio was then calculated using the expected area and the actual measured area considering the amount of water/solvent observed in TGMS.
  • the ratios determined using the UPLC-CAD method were all close to the expected ratios. The slight deviation that was observed was likely due to the hygroscopicity of the samples.
  • the salt screen experiments were carried out in 1 ,4-dioxane, acetone or ethanol.
  • the salt formation experiments were performed according to the “saturated solution” methodology for 1 ,4-dioxane and the solvent equilibrium method for acetone and ethanol.
  • the solids were separated from the liquid phases by centrifugation and analysed by HT-XRPD as vacuum-dried solids. Solvents from mother liquors were evaporated at ambient conditions and further dried under vacuum at 50°C. The obtained solids were also harvested and analysed by HT-XRPD.
  • PCT/EP2022/085765 was poorly crystalline and comprises a crystalline Form O, which is different from the freebase crystalline Form G, as obtained according to the invention.
  • Compound (l)-semi-sulfate salt (Form C) was physically stable after 2 days at 40°C/75% RH.
  • Compound (l)-sulfate salt (Form D) was physically stable for at least 2 days at 40°C/75% RH. Table 5. Peak list for solids of Compound (l)-sulfate salt (Form D).
  • Compound (l)-semi-edisylate salt (Form E) was physically stable for at least 2 days at 40°C/75% RH.
  • the HT-XRPD pattern of freebase crystalline Form G is shown in Figure 19 and the peak list is in Table 8.
  • Compound (I) freebase crystalline Form G was physically stable for at least 2 days at 40°C/75% RH.
  • the HT-XRPD pattern of freebase crystalline Form O is shown in Figure 22 and the peak list is in Table 9.
  • IMAP® assay (Molecular Devices) was used. Compounds were serially diluted in dimethylsulfoxide (DMSO) and subsequently in 4% DMSO in IMAP reaction buffer, which consists of 10 mM Tris- HCI, pH 15 7.5, 10 mM MgCL, 0.01 % Tween-20, 0.1 % NaNs and 1 mM freshly prepared dithiotreitol (DTT). Compound solution was mixed with an equal volume of full-length wt-BTK enzyme (Carna Biosciences, cat. no. 08-180) in IMAP reaction buffer.
  • DMSO dimethylsulfoxide
  • IMAP reaction buffer which consists of 10 mM Tris- HCI, pH 15 7.5, 10 mM MgCL, 0.01 % Tween-20, 0.1 % NaNs and 1 mM freshly prepared dithiotreitol (DTT).
  • DTT dithiotreitol
  • fluorescein-labeled MBP-derived substrate peptide (Molecular Devices, cat. no. RP 7123) was added, followed by ATP to start the reaction.
  • Final enzyme concentration was 1.2 nM, final substrate concentration 50 nM, and final ATP concentration was 4 pM.
  • the reaction was allowed to proceed for 2 hours at room temperature in the dark.
  • the reaction was stopped by quenching with IMAP progressive binding solution according to the protocol of the manufacturer (Molecular Devices). Fluorescence polarization was measured on an Envision multimode reader (Perkin Elmer, Waltham, MA, U.S.A.). ICso were calculated using XLfitTM5 software (ID Business Solutions, Ltd., Surrey, U.K.).
  • Compound (I) showed an IC50 value of ⁇ 5 nM.
  • IMAP® assay (Molecular Devices) was used. Compounds were serially diluted in dimethylsulfoxide (DMSO) and subsequently in 4 % DMSO in IMAP reaction buffer, which consists of 10 mM Tris-HCI, pH 15 7.5, 10 mM MgCh, 0.01 % Tween-20, 0.1 % NaNs and 1 mM freshly prepared dithiotreitol (DTT). Compound solution was mixed with an equal volume of full- length BTK C481 S enzyme (Carna Biosciences, cat. no. 08-547) in IMAP reaction buffer.
  • DMSO dimethylsulfoxide
  • IMAP reaction buffer which consists of 10 mM Tris-HCI, pH 15 7.5, 10 mM MgCh, 0.01 % Tween-20, 0.1 % NaNs and 1 mM freshly prepared dithiotreitol (DTT).
  • DTT dithiotreitol
  • REC-1 mantle cell lymphoma cells were purchased from American Type Culture Collection via Synthego Corporation (cat. no. CRL-3004, ATCC). Frozen stocks were thawed and cells were diluted in RPMI-1640 cell culture medium (cat. no. 61870036, Life Technologies), supplemented with 10% (v/v) fetal calf serum and 1 % penicillin/streptomycin. 3200 cells per well (in 45 pl) were seeded in a white 384-well culture plate (cat. no. 781080, Greiner Bio-One) and allowed to rest for 24 hours at 37 °C, 95 % humidity, and 5 % CO2.
  • Compound (I) showed an IC50 value of ⁇ 100 nM.
  • REC-1 cell lines expressing mutant BTK were created at Synthego Corporation.
  • a cell line expressing BTK T474I was generated via CRISPR/Cas9.
  • a clonal REC-1 BTK T474I cell line was obtained by single cell cloning.
  • the mutation status of BTK was confirmed via sequencing.
  • frozen cell stocks were thawed and cells were diluted in RPMI-1640 cell culture medium (cat. no. 61870036, Life Technologies), supplemented with 10% (v/v) fetal calf serum and 1 % penicillin/streptomycin. 3200 cells per well (in 45 pl) were seeded in a white 384-well culture plate (cat. no.
  • Compound (I) showed an IC50 value of ⁇ 100 nM.
  • Streptavidin-coated chips (Cat. No. BR100531), disposables and maintenance kits for Biacore were purchased from Cytiva (Eindhoven, The Netherlands).
  • Biotinylated wt-BTK enzym (Carna Biosciences, cat. no. 08-480-20N), BTK C481 S (Carna Biosciences, cat. no. 08-417- 20N), BTK T474I (Carna Biosciences, cat. no. 08-419-20N) or BTK T474S (Carna Biosciences, cat. no.
  • the kinetic constants of the compounds were determined with single cycle kinetics with five consecutive injections with an increasing compound concentration with ranges of 3.16 - 316 nM. Experiments were performed with an association time of 100 s per concentration and a dissociation time of 1200 s, except for compounds with a long target residence time, such as irreversible inhibitors, where dissociation time was increased. To circumvent problems of mass transport limitation, a flow rate of 30 pl/min was used. A blank run with the same conditions was performed before the compound was injected. The SPR sensorgrams were analyzed with Biacore Evaluation Software by using a method of double referencing. First the reference channel was subtracted from the channel containing immobilized protein. Subsequently, the reference curve obtained with buffer injections was subtracted.
  • the resulting curve was fitted with a 1 :1 binding model.
  • Compounds that bound according to an induced fit model were fitted with a two-state reaction model.
  • the kinetic constants (k a , kd, KD) of duplicates were geometrically averaged.
  • Compound (I) showed a KD (wt-BTK) value of ⁇ 5 nM.
  • Compound (I) showed a KD (BTK C481 S) value of ⁇ 5 nM.
  • Compound (I) showed a KD (BTK T474I) value of ⁇ 10 nM.
  • Compound (I) showed a KD (BTK T474S) value of ⁇ 5 nM.
  • wt-TMD8 diffuse large B-cell lymphoma cells were purchased from Tokyo Medical and Dental University and cultured in RPMI-1640 cell culture medium (cat. no. 61870036, Life Technologies), supplemented with 10% (v/v) heat-inactivated fetal bovine calf serum and 1 % penicillin/streptomycin. 1600 cells per well (in 45 pl) were seeded in a white 384-well culture plate (cat. no. 781080, Greiner Bio-One) and allowed to rest for at least 5 hours at 37 °C, 95 % humidity, and 5 % CO2.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Sont divulguées diverses formes salines et cristallines d'un composé macrocyclique (I) représenté par la formule développée suivante, composé (I) et leurs compositions pharmaceutiques correspondantes. Des formes cristallines particulières du composé (I) acide chlorhydrique, composé (I) maléate, composé (I) semi-sulfate, composé (I) sulfate, composé (I) semi-édisylate et composé (I) acide bromhydrique, ainsi qu'une forme cristalline à base libre sont caractérisées par une variété de propriétés et de caractéristiques physiques. Sont divulgués également des procédés de préparation de formes cristallines spécifiques. La présente divulgation concerne également des compositions pharmaceutiques et des méthodes de traitement du cancer par inhibition de BTK, comprenant lesdits composés.
PCT/EP2024/066423 2023-06-13 2024-06-13 Formes salines et formes cristallines d'un inhibiteur de btk macrocyclique Pending WO2024256568A1 (fr)

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