Parg inhibitoring compounds

Abstract

The present invention relates to a pharmaceutically acceptable crystalline form of a compound of formula (I): wherein the pharmaceutically acceptable crystal is obtainable by recrystallizing the compound of formula (I) from ethanol. The crystalline forms are characterized by outstanding stability, good solubility and low hygroscopicity, and are particularly suitable for long-term storage and clinical development.

Description

Technical Field

[0001] This invention relates to a pharmaceutically acceptable crystalline form of a compound of formula (I), wherein the pharmaceutically acceptable crystals can be obtained by recrystallizing the compound of formula (I) from ethanol. The crystalline form is characterized by outstanding stability, good solubility, and low hygroscopicity, and is particularly suitable for long-term storage and clinical development. Background Technology

[0002] Cancer is a leading cause of death worldwide. Although progression-free survival and overall survival have improved over the past two decades, millions of cancer patients still have limited treatment options and poor survival outcomes (Jemal et al., Journal of the National Cancer Institute, 2017, 109, 1975).

[0003] DNA replication stress (DRS) is a hallmark of cancer cells and a major source of genomic instability (a) Halazonetis et al., Science 2008, 319, 1352; b) Negrini et al., Nature Reviews Molecular Cell Biology 2010, 11, 220. Broadly speaking, DRS refers to the dysregulation of DNA replication and cell cycle progression. DRS can be induced by endogenous or exogenous factors such as oncogene activation and chemotherapy agents (Zeman and Cimprich, Nature Cell Biology 2013, 16, 2). At the replication fork level, DRS leads to replication fork arrest, replicon disengagement, and eventual collapse. Under DRS conditions, several DNA repair proteins are involved in replication fork stability, protection, and restart (a) Costantino et al., Science 2014, 343, 88; b) Scully et al., Current Perspectives on Genetics and Development (Curr. Opin. Genet. Dev.) 2021 71, 154).

[0004] Poly(ADP)ribosylation is a transient and reversible post-translational modification that occurs at DNA damage sites and is catalyzed by the poly(ADP-ribose) polymerase (PARP) protein family (Cohen and Chang, *Nature Chemical Biology*, 2018, 14, 236). PARylation of various DNA repair proteins leads to its activation. Degradation of the poly(ADP)ribose chain is primarily mediated by poly(ADP-ribose)hydrolases (PARG) proteins. DNA damage-dependent PARylation / dePARylation is a rapid and dynamic process that requires careful regulation, as imbalances between these two processes can lead to DNA damage.

[0005] Human PARG encodes a 111 kDa protein of 976 amino acids. It contains an N-terminal regulatory domain, a catalytic domain, and an ADP-ribose-binding macrodomain. Five human PARG transcripts have been identified. The full-length PARG is predominantly nuclear; smaller isoforms are mainly located in the cytoplasm. PARG primarily acts as an exonuclease, releasing a single (ADP-ribose) mainly by hydrolyzing the α-O-glycosidic-ribose bond in PAR. PARG can also function as an endonuclease. PARG preferentially degrades long and linear PAR chains, while its activity towards small and branched PAR chains is significantly reduced (O'Sullivan et al., Nature Communications 2019, 10, 1182).

[0006] Although PARG is the primary cellular PAR-degrading enzyme, it does not act on terminal protein-ribose bonds. Other hydrolases, such as terminal ADP-riboprotein hydrolase (TARG1) and ADP-riboprotein hydrolase 3 (ARH3), are also known to catalyze PAR degradation. TARG1 and ARH3 reverse PARylation by removing the protein-bound mono(ADP-ribose) moiety (a) Fontana et al., eLife 2017, doi: 10.7554 / eLife.28533; b) Rack et al., Genes & Development 2020, 34, 263. TARG1 is located in the nucleus and cytoplasm. ARH3 is primarily found in the cytoplasm, but is also present in mitochondria and the nucleus (Rack et al., Genes & Development 2020, 34, 263).

[0007] Genomic aberrations targeting tumor suppressor genes or oncogenes often render cancer cells dependent on specific DNA repair pathways. For example, PARP inhibitors are known to be particularly effective against tumors carrying mutations in the BRCA1 and BRCA2 genes (a) Bryant et al., Nature 2005, 434, 913; b) Farmer et al., Nature 2005, 434, 917). Targeting synthetic lethal interactions, such as the interaction between PARP and BRCA, is an attractive new therapeutic approach for cancer treatment.

[0008] PARG is involved in DNA replication and various DNA repair mechanisms, including single-strand break (SSB) repair and replication fork restart. PARG inhibitors exhibit a synthetic lethal phenotype in cells with high DRS levels, which is caused by low expression of genes involved in DNA replication and / or replication fork stability (Pillay et al., Cancer Cell. 2019, 35, 519). Furthermore, PARG inactivation, depletion, or inhibition sensitizes cells to radiation and DNA-damaging agents such as alkylating agents (e.g., temozolomide and methyl mesylate) (a) Fujihara et al., Current Cancer Drug Targets 2009, 9, 953; b) Gogola et al., Cancer Cell 2018, 33, 1078; c) Houl et al., Nature Communications 2019, 10, 5654.

[0009] Given the therapeutic potential of PARG inhibitors in cancer treatment, there is an increasing need to develop highly potent and selective PARG inhibitors in addition to those already described (a) James et al., ACS Chemical Biology 2016, 11, 3179; b) Waszkowycz et al., Journal of Medicinal Chemistry 2018, 61, 10767.

[0010] Some compounds that can be used as PARG inhibitors are further disclosed in WO 2016 / 092326, WO 2016 / 097749 and WO 2021 / 055744.

[0011] The document US 2019 / 233411 discloses certain Gcn2 inhibitors and their uses.

[0012] Document WO 2009 / 050183 discloses certain imidazo[1,2-a]pyridine derivatives that can be used to treat diseases mediated by ALK-5 and / or ALK-4 receptors.

[0013] Document WO 2023 / 057389 discloses another effective PARG inhibitor based on imidazo[1,5-a]pyridine scaffold. Summary of the Invention

[0014] The objective technical problem of this invention is to provide a compound as a cell permeability inhibitor of PARG in a form capable of long-term storage and particularly suitable for future clinical use. This technical problem is solved by the embodiments described herein and characterized as claimed.

[0015] In one embodiment, the present invention provides a pharmaceutically acceptable crystalline form of a compound of formula (I):

[0016]

[0017] The pharmaceutically acceptable crystalline form of said compound (I) can be obtained by recrystallization from ethanol.

[0018] Another embodiment of the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable crystalline form of a compound of formula (I) of the present invention and a pharmaceutically acceptable carrier.

[0019] In another embodiment, the present invention relates to a pharmaceutically acceptable crystalline form of the compound of formula (I) of the present invention or a pharmaceutical composition of the present invention for use in therapy.

[0020] The compound of formula (I) can be used to treat diseases or conditions involving PARG activity.

[0021] The compound of formula (I) can be used in methods for treating proliferative disorders. In a preferred embodiment of the invention, the proliferative disorder is cancer, preferably human cancer.

[0022] definition

[0023] Unless otherwise expressly stated, the following definitions apply throughout this specification and claims.

[0024] The term “hydrogen” is used herein to refer to protium, deuterium, and / or tritium, preferably protium. Therefore, the term “non-hydrogen atom” refers to any atom that is not hydrogen (i.e., not protium, deuterium, or tritium).

[0025] The term "hydrocarbon group" refers to a group composed of carbon and hydrogen atoms.

[0026] The term "alicyclic" is used in conjunction with a cyclic group and indicates that the corresponding cyclic group is non-aromatic.

[0027] As used herein, the term "alkyl" refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group, which can be straight-chain or branched. Therefore, "alkyl" does not contain any carbon-carbon double bonds or any carbon-carbon triple bonds. 1-5 "alkyl" refers to an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless otherwise defined, the term "alkyl" preferably refers to C14. 1-4 Alkyl, more preferably methyl or ethyl, and even more preferably methyl.

[0028] As used herein, the term "carbocyclic" refers to a hydrocarbon cyclic group, including monocyclic and bridged, spirocyclic, and / or fused ring systems (which may consist of, for example, two or three rings), wherein the cyclic group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic), or aromatic. Unless otherwise defined, "carbocyclic" preferably refers to an aryl, cycloalkyl, or cycloalkenyl group.

[0029] As used herein, the term "heterocyclic group" refers to a cyclic group, including monocyclic and bridged, spirocyclic and / or fused ring systems (which may consist of, for example, two or three rings), wherein the cyclic group comprises one or more (e.g., one, two, three or four) cyclic heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein the cyclic group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring included in the cyclic group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbocyclic atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. Unless otherwise defined, "heterocyclic group" preferably refers to a heteroaryl, heterocyclic alkyl, or heterocyclic alkenyl group.

[0030] As used herein, the term "aryl" refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings and bridged and / or fused ring systems containing at least one aromatic ring (e.g., a ring system consisting of two or three fused rings, wherein at least one of these fused rings is aromatic; or a bridged ring system consisting of two or three rings, wherein at least one of these bridged rings is aromatic). "Aryl" may, for example, refer to phenyl, naphthyl, tetralinyl (i.e., 1,2-dihydronaphthyl), tetrahydronaphthyl (i.e., 1,2,3,4-tetrahydronaphthyl), indenyl, indenyl (e.g., 1H-indenyl), anthracene, phenanthryl, 9H-fluorenyl, or azulenyl. Unless otherwise defined, "aryl" preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably phenyl or naphthyl, and most preferably phenyl.

[0031] As used herein, the term "heteroaryl" refers to an aromatic cyclic group, including monocyclic aromatic rings and bridged and / or fused ring systems containing at least one aromatic ring (e.g., a ring system consisting of two or three fused rings, wherein at least one of these fused rings is aromatic; or a bridged ring system consisting of two or three rings, wherein at least one of these bridged rings is aromatic), wherein the aromatic cyclic group comprises one or more (e.g., one, two, three or four) cyclic heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring included in the aromatic cyclic group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring."Heteroaryl" can refer to, for example, thiophene (i.e., phenylthio), benzo[b]thiophene, naphtho[2,3-b]thiophene, thianyl, furanyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, benzodihydropyranyl, benzopyranyl (e.g., 2H-1-benzopyranyl or 4H-1-benzopyranyl), isobenzopyranyl (e.g., 1H-2-benzopyranyl), cronone, xanthonyl, phenoxathioyl, pyrroleyl (e.g., 1H-pyrroleyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridyl; e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, and indoleyl (e.g., 3H-indoleyl). Isoindolyl, indazole, indoleazinyl, purine, quinolinyl, isoquinolinyl, phthalazinyl, naphthidyl, quinoxalinyl, cyclolinyl, pteridinyl, carbazolyl, β-carbazolyl, phenanthridine, acridineyl, naphthalene-diazaphenyl, phenanthrolinyl (e.g., [1,10]phenanthrolinyl, [1,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (i.e., furazonyl) or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl or 1,3,4-thiadiazolyl). ), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidin-3-yl), 1,2-benzisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzo[b]thiophene (i.e., benzothiophene), triazolyl (e.g., 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl or 4H-1,2,4-triazolyl), benzotriazolyl, 1H-tetrazole, 2H-tetrazole, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl), furanyl [2,3-c]pyridyl, dihydrofuranopyridyl (e.g., 2,3-dihydrofurano[2,3-c]pyridyl or 1,3-dihydrofurano[3,4-c]pyridyl), imidazopyridyl (e.g., imidazo[1,2-a]pyridyl or imidazo[3,2-a]pyridyl), quinazolinyl, thienopyridyl, tetrahydrothienopyridyl (e.g., 4,5,6,7-tetrahydrothienopyridyl), dibenzofuranyl, 1,3-benzodioxanepentyl, benzodioxane (e.g., 1,3-benzodioxane or 1,4-benzodioxane), or coumarinyl.Unless otherwise defined, the term "heteroaryl" preferably refers to a 5- to 14-membered (more preferably, 5- to 10-membered) monocyclic or fused-ring system comprising one or more (e.g., one, two, three, or four) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbide ring atoms are optionally oxidized; even more preferably, "heteroaryl" refers to a 5- or 6-membered monocyclic ring comprising one or more (e.g., one, two, or three) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbide ring atoms are optionally oxidized.

[0032] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon cyclic group, including monocyclic and bridged, spirocyclic, and / or fused ring systems (which may consist of, for example, two or three rings; for example, a fused ring system consisting of two or three fused rings). "Cycloalkyl" may refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl) or adamantyl. Unless otherwise defined, "cycloalkyl" preferably refers to C14. 3-11 Cycloalkyl, and more preferably C 3-7 Cycloalkyl. Particularly preferred “cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).

[0033] As used herein, the term "cycloalkenyl" refers to an unsaturated alicyclic (non-aromatic) hydrocarbon cyclic group, including monocyclic and bridged, spirocyclic, and / or fused ring systems (which may consist of, for example, two or three rings; e.g., a fused ring system consisting of two or three fused rings), wherein the hydrocarbon cyclic group contains one or more (e.g., one or two) carbon-carbon double bonds and does not contain any carbon-carbon triple bonds. "Cycloalkenyl" may refer to, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless otherwise defined, "cycloalkenyl" preferably refers to C 3-11 Cycloalkenyl, and more preferably C 3-7 Cycloalkenyl. Particularly preferred “cycloalkenyl” is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two; preferably one) carbon-carbon double bonds.

[0034] As used herein, the term "heterocyclic alkyl" refers to a saturated cyclic group, including monocyclic and bridged, spirocyclic, and / or fused-ring systems (which may consist of, for example, two or three rings; e.g., a fused-ring system consisting of two or three fused rings), wherein the cyclic group contains one or more (e.g., one, two, three, or four) cyclic heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring included in the saturated cyclic group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. "Heterocyclic alkyl" can refer to, for example, aziridinyl, aziridine, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, piperazinyl, aziridine-heptyl, diazacycloheptyl (e.g., 1,4-diazacycloheptyl), oxazolyl, isoxazolyl, thiazoalkyl, isothiazolyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazolidine-heptyl, and ethylene oxide. alkyl, oxetane, tetrahydrofuranyl, 1,3-dioxopentane, tetrahydropyranyl, 1,4-dioxhexane, oxetane heptyl, thioheptanepropyl, thioheptanebutyl, tetrahydrothiophene (i.e., thioheptanepentyl), 1,3-dithioheptanepentyl, thiaalkyl, 1,1-dioxetanethiaalkyl, thioheptane, decahydroquinolinyl, decahydroisoquinolinyl or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless otherwise defined, “heterocyclic alkyl” preferably refers to a 3- to 11-membered saturated cyclic group, which is a monocyclic or fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the cyclic group contains one or more (e.g., one, two, three, or four) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbide ring atoms are optionally oxidized; more preferably, “heterocyclic alkyl” refers to a 5- to 7-membered saturated monocyclic group containing one or more (e.g., one, two, or three) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbide ring atoms are optionally oxidized.

[0035] As used herein, the term "heterocyclic alkenyl" refers to an unsaturated alicyclic (non-aromatic) cyclic group, including monocyclic and bridged, spirocyclic and / or fused ring systems (which may consist of, for example, two or three rings; e.g., a fused ring system consisting of two or three fused rings), wherein the cyclic group contains one or more (e.g., one, two, three or four) cyclic heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein the cyclic group contains at least one double bond between adjacent ring atoms and does not contain any triple bonds between adjacent ring atoms. For example, each heteroatom-containing ring included in the unsaturated alicyclic cyclic group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbocyclic atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. "Heterocyclic alkenyl" can refer to, for example, imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1H-imidazolinyl), 3-imidazolinyl or 4-imidazolinyl), tetrahydropyridyl (e.g., 1,2,3,6-tetrahydropyridyl), dihydropyridyl (e.g., 1,2-dihydropyridyl or 2,3-dihydropyridyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1,2,3,4,4a,5,6,7-octahydroquinolinyl) or octahydroisoquinolinyl (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl).Unless otherwise defined, "heterocyclic alkenyl" preferably refers to a 3- to 11-membered unsaturated alicyclic cyclic group, which is a monocyclic or fused-ring system (e.g., a fused-ring system consisting of two fused rings), wherein the cyclic group contains one or more (e.g., one, two, three, or four) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbide ring atoms are optionally oxidized, and wherein the cyclic group comprises at least one [unclear] ring between adjacent ring atoms. The double bond does not contain any triple bond between adjacent ring atoms; more preferably, "heterocyclic alkenyl" refers to a 5- to 7-membered monocyclic unsaturated non-aromatic cyclic group containing one or more (e.g., one, two, or three) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbide ring atoms are optionally oxidized, and wherein the cyclic group contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms.

[0036] As used in this article, the term "halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

[0037] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms, said halogen atoms being independently selected from fluorine, chlorine, bromine, and iodine, and preferably all of them being fluorine atoms. It should be understood that the maximum number of halogen atoms is limited by the number of available linking sites, and therefore depends on the number of carbon atoms contained in the alkyl portion of the haloalkyl group. "Haloalkyl" can refer to, for example, -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A particularly preferred "haloalkyl" is -CF3.

[0038] Unless otherwise explicitly stated or contradicted by the context, the terms “key” and “covalent bond” are used synonymously in this document.

[0039] As used herein, unless otherwise expressly indicated or contradicted by the context, the terms “a / an” and “the” are used interchangeably with “one or more” and “at least one”. Thus, for example, a composition comprising “one” of formula (I) can be interpreted as a composition comprising “one or more” of formula (I) compounds.

[0040] It should be understood that regardless of the numerical ranges provided / disclosed herein, all values ​​and subranges covered by the corresponding numerical ranges are implied to be covered by the present invention. Therefore, the present invention specifically and exclusively relates to each value falling within the numerical ranges disclosed herein, and each subrange covered by the numerical ranges disclosed herein.

[0041] As used herein, the term "about" preferably refers to ±10% of the indicated value, more preferably ±5% of the indicated value, and particularly to the exact indicated value. If the term "about" is used in conjunction with the endpoints of a range, it preferably refers to the range from -10% of the lower endpoint of its indicated value to +10% of the upper endpoint of its indicated value, more preferably the range from -5% of the lower endpoint to +5% of the upper endpoint, and even more preferably the range defined by the exact values ​​of the lower and upper endpoints.

[0042] As used herein, unless otherwise explicitly stated or contradicted by the context, the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”) means “containing, especially,” that is, “containing…” among other optional elements. In addition, the term also includes the narrower meanings of “consistently composed of” and “composed of.” For example, the term “A comprises B and C” means “A contains, especially B and C,” where A may contain other optional elements (e.g., it would also cover “A contains B, C, and D”), but the term also includes the meanings of “A is essentially composed of B and C” and “A is composed of B and C” (i.e., A contains no other components besides B and C). Attached Figure Description

[0043] The present invention is illustrated using the accompanying drawings, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0044] Figure 1 The results of testing the compound of Example 1 in the MDA-MB-436 xenograft model are presented.

[0045] Figure 2 The XRPD diffraction pattern of the pharmaceutically acceptable crystalline form 1 of the obtained compound of formula (I) is presented.

[0046] Figure 3 DSC and TGA thermographs obtained from measurements of pharmaceutically acceptable crystalline form 1 of compound (I) are presented.

[0047] Figure 4The XRPD diffraction pattern of the pharmaceutically acceptable crystalline form 2 of the obtained compound of formula (I) is presented.

[0048] Figure 5 DSC and TGA thermographs obtained from measurements of pharmaceutically acceptable crystalline form 2 of compound (I) are presented.

[0049] Figure 6 A comparison of the XRPD diffraction patterns of pharmaceutically acceptable crystalline forms 1 and 2 of the obtained compound (I) is presented.

[0050] Figure 7 shows the superposition of XRPD diffraction patterns of form 1 (black) and form 2 (gray) (Part 1); the extension of the superposition of XRPD diffraction patterns of form 1 (black) and form 2 (gray) (0 to 17 °2θ) (Part 2); and the extension of the superposition of XRPD diffraction patterns of form 1 (black) and form 2 (gray) (17 to 35 °2θ) (Part 3).

[0051] Figure 8 shows the XRPD spectra of solids separated from Form 1 and Form 2 in competitive equilibrium in ethanol, sampled at different temperatures after 4 hours and 24 hours, compared to Form 1 and Form 2 references.

[0052] Figure 9 shows the XRPD spectra of solids separated from Form 1 and Form 2 in competitive equilibrium in ethyl acetate, sampled at different temperatures after 4 hours and 24 hours, compared to Form 1 and Form 2 references.

[0053] Figure 10 shows the XRPD spectra of solids separated from acetonitrile in competitive equilibrium of Form 1 and Form 2, sampled at different temperatures after 4 hours and 24 hours, compared to Form 1 and Form 2 references.

[0054] Figure 11 presents the XRPD spectra of solids separated from Form 1 and Form 2 in competitive equilibrium in water, sampled at different temperatures after 4 hours and 24 hours, compared to Form 1 and Form 2 references.

[0055] Figure 12 The slow heating DSC of Form 2 (at 2 °C / min) resolved to a broad melting endothermic peak to show the sequence of melting-recrystallization-melting events.

[0056] Figure 13 The DSC recycling experiment starting from crystal form 2 is shown. Detailed Implementation

[0057] The present invention is described in detail below. It should be understood that the present invention relates in particular to every combination of the features and embodiments described herein, including any combination of general and / or preferred features / embodiments.

[0058] In a first embodiment, the present invention relates to a pharmaceutically acceptable crystalline form of a compound of formula (I):

[0059]

[0060] It should be understood that the compound of formula (I) exists in crystalline form as a free base (or, in other words, as a non-salt). It should be understood that the pharmaceutically acceptable crystalline form can be obtained by recrystallizing the compound of formula (I) from ethanol.

[0061] The specific crystalline form of the compound of formula (I) referred to herein is characterized by outstanding stability, high solubility, and negligible hygroscopicity. Therefore, these particular properties of the claimed crystalline form allow it to be formulated for both clinical use and long-term storage. It should be understood that there are no particular limitations on formulations for clinical use, and it can refer to, for example, formulations in tablet form. Importantly, the crystalline form referred to herein is not a single (i.e., unique) crystalline form formed by the compound of formula (I) in its free base form. Therefore, the inventors have also discovered and obtained compounds of formula (I) exhibiting polycrystalline form phenomena and other crystalline forms. However, none of these crystalline forms exhibits stability, hygroscopicity, and / or solubility properties comparable to those of the crystalline form claimed herein. Furthermore, crystalline form screening was conducted not only on the free base of the compound of formula (I) but also on pharmaceutically acceptable salts of the compound of formula (I), yielding substances with properties inferior to those of the crystalline form claimed herein. Therefore, correspondingly, compared with other available forms of compounds of formula (I), including other crystalline forms of the free base of compounds of formula (I) and crystalline forms of salts of compounds of formula (I), the crystalline form of the present invention surprisingly exhibits improved properties. Thus, the crystalline form provided herein, referred to as form 1, is characterized by its outstanding properties compared with other available solid forms of compounds of formula (I). Therefore, crystalline form 1 should not be considered merely an arbitrary choice of one crystalline form relative to another. Specifically, the inventors have identified a second crystalline form, referred to as crystalline form 2, which has lower stability than form 1 and, under certain conditions, transforms into the more stable form 1.

[0062] When discussing specific crystalline forms of the compounds of formula (I) of the present invention, the terms “crystalline form,” “polycrystalline form,” or simply “crystal” or “polymorph” are used interchangeably as used herein.

[0063] As shown in this article, the compound of formula (I), also known as 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide, is a highly potent PARG inhibitor. The compound exhibits the IC50 values ​​determined in the PARG enzymatic assay. 50 = 11 nM, and showed low nanomolar levels of activity against many cancer cell lines, including NCIH-460 and MDA-MB-436 cells. Simultaneously, the compound has shown selectivity, and therefore, its EC50 was determined in U2OS cells. 50 > 5.0 µM indicates that the compound exhibits outstanding selectivity. Finally, the compound of formula (I) also showed activity in animal xenograft models of cancer, such as, for example, in... Figure 1 As shown in the document.

[0064] Therefore, as understood herein, the crystalline form of the present invention is the crystalline form of the compound of formula (I). For this purpose, the compound of formula (I) exists as a free base, rather than as a salt of the crystalline form of the present invention. Thus, crystalline form 1 of the present invention comprises the compound of formula (I) in the form of a free base.

[0065] Furthermore, as provided by this invention, the crystalline form of this invention is not a crystalline form as a hydrate (or more generally, a solvate). Therefore, the crystalline form of this invention contains no or substantially no solvent, including water. It should be understood that the term "substantially solvent-free" preferably refers to the case where the crystal contains no more than 2% w / w of solvent, more preferably no more than 1% w / w of solvent, and even more preferably no more than 0.5% w / w of water. This is evident when thermogravimetric analysis, or in other words TGA, is performed on the crystalline form of this invention (i.e., crystalline form 1), which reveals only a slight weight loss of the solid substance (i.e., crystalline form 1) upon heating. This slight weight loss indicates that the form is not a solvate form. It should be further noted that further weight loss is observed at temperatures exceeding 230°C, which is attributed to the post-melting decomposition of the compound of formula (I).

[0066] Therefore, the crystalline form is essentially composed of the compound of formula (I). In other words, the compound of formula (I) preferably constitutes a crystalline form of at least 95% w / w, more preferably at least 96% w / w, even more preferably at least 97% w / w, still more preferably at least 98% w / w, and still more preferably at least 99% w / w.

[0067] As described herein, the crystalline form of the present invention can be obtained by recrystallizing the compound of formula (I) from ethanol. This recrystallization may involve providing a pure (or substantially pure, such as at least 90%, 95%, or 97% pure, where purity is defined on a w / w basis) compound of formula (I), dissolving it in ethanol to obtain a supersaturated solution, and obtaining the crystalline form of the compound of formula (I) of the present invention once crystallization occurs. For example, experiments as described in the experimental procedure for obtaining the crystalline form provided in the Examples section necessarily produce the crystalline form of the present invention. Recrystallization from ethanol involves complete dissolution in ethanol followed by cooling to room temperature for 12 hours. Preferably, the step of complete dissolution in ethanol is carried out under stirring, mixing, or agitation of the solution or suspension in any manner. Furthermore, the step of cooling the resulting solution to room temperature is carried out under stirring (or mixing or agitation of the thus obtained solution in any manner known to those skilled in the art). Preferably, the dissolution step is carried out at an elevated temperature. Therefore, this step is preferably carried out under reflux. Alternatively and preferably, the dissolution of the compound of formula (I) in ethanol is carried out at a temperature of 110°C. It will be immediately apparent to those skilled in the art that the 110°C temperature provided herein refers to the temperature of a heating element (such as an oil batch) in which the reaction vessel containing the ethanol is heated. It will be immediately apparent to those skilled in the art that the ethanol can be boiled under these conditions (such as under reflux). Therefore, and preferably, the dissolution step is carried out in boiling ethanol.

[0068] Preferably, seeding is not performed in the method for obtaining the pharmaceutically acceptable crystalline form of the present invention by recrystallization of the compound of formula (I) from ethanol.

[0069] It should be noted that the current definition of the crystal form obtained by the method of obtaining the crystal form does not limit the crystal form to the crystal obtained entirely according to the above-described scheme based on recrystallization from ethanol. Rather, it provides a scheme that necessarily produces the claimed crystal form, thereby defining the crystal form. According to the invention, the same crystal form can also be obtained according to other crystallization schemes, such as crystallization from a mixture of tetrahydrofuran / n-heptane (optionally involving seeding using crystal form 1).

[0070] Preferably, within the scope of the invention, as described above, the recrystallization of compound (I) from ethanol is carried out after a deprotection reaction of the Boc group using formic acid (referred to as FA), as depicted in the following scheme:

[0071]

[0072] It should be understood that the reaction will be carried out in pure formic acid.

[0073] Preferably, after the deprotection reaction, the formic acid is concentrated under vacuum to obtain a residue diluted with water, wherein the pH is adjusted to 9 with a saturated NaHCO3 solution. The product is then extracted with DCM. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue thus obtained by recrystallization from ethanol is as described herein.

[0074] For informational purposes only, the acquisition of the crystal form 1 of the reference example—formula (I) compound—is described in the examples section.

[0075] It will be apparent to those skilled in the art that the characteristics of a crystalline form may lie in its structural properties and / or its physicochemical properties. Specifically, the characteristics of a crystalline form may lie in its X-ray diffraction properties, its melting point, and / or its enthalpy of fusion.

[0076] Crystal forms are usually characterized by their X-ray powder diffraction patterns. Figure 1 The X-ray powder diffraction pattern of the crystalline form of the present invention obtained using CuKα radiation is shown.

[0077] Further preferably, the crystalline form of the present invention is characterized by an X-ray powder diffraction pattern obtained using CuKα radiation containing at least one peak selected from peaks at 12.24 ± 0.2 °2θ, 20.04 ± 0.2 °2θ, 20.40 ± 0.2 °2θ, and 24.02 ± 0.2 °2θ. These peaks are characteristics of the currently claimed crystalline form of the present invention, and not of other crystalline forms, specifically not of form 2 of the compound of formula (I). Preferably, the X-ray powder diffraction pattern of the claimed crystalline form (also referred to as crystalline form 1) obtained using CuKα radiation contains at least two or at least three peaks selected from peaks at 12.24 ± 0.2 °2θ, 20.04 ± 0.2 °2θ, 20.40 ± 0.2 °2θ, and 24.02 ± 0.2 °2θ. Even more preferably, the X-ray powder diffraction pattern of the claimed crystal form obtained using CuKα radiation further includes peaks at 12.24 ± 0.2 °2θ, 20.04 ± 0.2 °2θ, 20.40 ± 0.2 °2θ, and 24.02 ± 0.2 °2θ.

[0078] It should be understood that whenever an angle value provided as a specific numerical value x ± 0.2 ° is mentioned, it preferably means the value x ± 0.1 °, and more preferably means the precise value x.

[0079] Preferably, the crystalline form is characterized by an X-ray powder diffraction pattern obtained using CuKα radiation that additionally includes a peak at 18.71 ± 0.2 °2θ, preferably at 18.71 ± 0.1 °2θ, and / or at 6.86 ± 0.2 °2θ. The peak at 18.71 ± 0.2 °2θ is the most prominent peak in the X-ray powder diffraction pattern of the compound, as seen from... Figure 1 It can be clearly and explicitly seen from this.

[0080] Further preferably, in addition to the peaks discussed above, the X-ray powder diffraction pattern further includes at least one peak selected from the peaks at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ. More preferably, the X-ray powder diffraction pattern further includes at least two peaks selected from the peaks at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ. Even more preferably, the X-ray powder diffraction pattern further includes at least three peaks selected from those at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ. Even more preferably, the X-ray powder diffraction pattern further includes at least four peaks selected from those at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ. More preferably, the X-ray powder diffraction pattern further includes at least five peaks selected from those at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ. Still more preferably, the X-ray powder diffraction pattern further includes at least six peaks selected from those at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ.Most preferably, the X-ray powder diffraction pattern further includes peaks at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ.

[0081] In one embodiment, such as Figure 2 As shown, the crystal form of the present invention preferably has an X-ray powder diffraction pattern obtained using CuKα radiation.

[0082] The crystalline form can also be characterized by its melting-related properties. An example of such a property is its melting point. Preferably, crystalline form 1, as claimed in this invention, is characterized by a melting point of 207.5 ± 4.0 °C. More preferably, crystalline form 1 is characterized by a melting point of 207.5 ± 2.0 °C. Even more preferably, crystalline form 1 is characterized by a melting point of 207.5 ± 1.0 °C. Still more preferably, crystalline form 1 is characterized by a melting point of 207.5 ± 0.5 °C. This melting point determined for crystalline form 1 is significantly different from the melting points determined for other crystalline forms, for example, particularly for crystalline form 2, which is measured to be 199 °C (specifically, the specific measured value is 199 °C ± 2.0 °C). Alternatively or additionally, the crystalline form can be characterized by its enthalpy of fusion. Preferably, crystalline form 1 is characterized by an enthalpy of fusion between 115 J / g and 125 J / g. More preferably, crystalline form 1 is characterized by a melting enthalpy between 118 J / g and 120 J / g. Even more preferably, crystalline form 1 is characterized by a melting enthalpy of 119 J / g.

[0083] Figure 3 Experimental data on the melting properties of the crystalline form 1 of the compound of formula (I) of the present invention are shown. For comparative purposes only, such data are not included. Figure 5 As shown, the experimental data summarize the melting properties of the crystalline form 2 of compound (I).

[0084] Therefore, and preferably, the pharmaceutically acceptable crystalline form of the present invention is characterized by a melting point of 207.5 ± 4.0 °C and an X-ray powder diffraction pattern obtained using CuKα radiation containing at least one, at least two, at least three, or four peaks selected from those at 12.24 ± 0.2 °2θ, 20.04 ± 0.2 °2θ, 20.40 ± 0.2 °2θ, and 24.02 ± 0.2 °2θ. More preferably, crystalline form 1 is characterized by a melting point of 207.5 ± 2.0 °C and an X-ray powder diffraction pattern obtained using CuKα radiation containing at least one, at least two, at least three, or four peaks selected from those at 12.24 ± 0.2 °2θ, 20.04 ± 0.2 °2θ, 20.40 ± 0.2 °2θ, and 24.02 ± 0.2 °2θ. Even more preferably, crystal form 1 is characterized by a melting point of 207.5 ± 1.0 °C and an X-ray powder diffraction pattern obtained using CuKα radiation containing at least one, at least two, at least three, or four peaks selected from those at 12.24 ± 0.2 °2θ, 20.04 ± 0.2 °2θ, 20.40 ± 0.2 °2θ, and 24.02 ± 0.2 °2θ. More preferably, crystal form 1 is characterized by a melting point of 207.5 ± 0.5 °C and an X-ray powder diffraction pattern obtained using CuKα radiation containing at least one, at least two, at least three, or four peaks selected from those at 12.24 ± 0.2 °2θ, 20.04 ± 0.2 °2θ, 20.40 ± 0.2 °2θ, and 24.02 ± 0.2 °2θ. Preferably, the crystalline form is characterized by an X-ray powder diffraction pattern obtained using CuKα radiation that additionally includes a peak at 18.71 ± 0.2 °2θ, preferably at 18.71 ± 0.1 °2θ, and / or at 6.86 ± 0.2 °2θ. More preferably, in addition to the peaks discussed above, the X-ray powder diffraction pattern further includes at least one peak selected from those at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ. More preferably, the X-ray powder diffraction pattern further includes at least two peaks selected from those at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ.Even more preferably, the X-ray powder diffraction pattern further includes at least three peaks selected from the peaks at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ. Even more preferably, the X-ray powder diffraction pattern further includes at least four peaks selected from the peaks at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ. More preferably, the X-ray powder diffraction pattern further includes at least five peaks selected from those at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ. Still more preferably, the X-ray powder diffraction pattern further includes at least six peaks selected from those at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ. Most preferably, the X-ray powder diffraction pattern further includes peaks at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ.

[0085] The present invention further relates to a method for preparing a pharmaceutically acceptable crystalline form 1 of the present invention. The method comprises the step of crystallizing a compound of formula (I) as depicted herein from ethanol or a mixture of THF / n-heptane. Preferably, the compound is crystallized from ethanol. Experimental details of exemplary embodiments of the method are described herein. However, in one embodiment of the invention, the method for preparing a pharmaceutically acceptable crystalline form 1 of the present invention comprises the step of crystallizing a compound of formula (I) from a mixture of THF / n-heptane. Optionally, the crystallization is carried out with inoculation using crystalline form 1.

[0086] For illustrative purposes only, the crystalline form 2 provided as a reference example can be obtained as described in the experimental section below. Specifically, crystalline form 2 can be obtained by grinding compound (I) from DCM. Detailed experimental protocols are provided herein.

[0087] This specification relates to pharmaceutically acceptable salts of compounds of formula (I). The term covers all pharmaceutically acceptable salt forms of compounds of formula (I) that can be formed, for example, by protonation of an atom carrying a protonation-sensitive lone pair of electrons (such as an amino group) with an inorganic or organic acid, or as a salt with an acidic group (such as a carboxylic acid group) of a physiologically acceptable cation. Exemplary base addition salts include, for example: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts, such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkylamine salts, such as N,N-dibenzylethylenediamine salts, benzylamine salts, phenethylbenzylamine salts; heterocyclic aromatic amine salts, such as pyridine salts, methylpyridine salts, quinoline salts, or isoquinoline salts; quaternary ammonium salts, such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, or tetrabutylammonium salts; and basic amino acid salts, such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts include, for example: inorganic acid salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate (e.g., sulfate or hydrogen sulfate), nitrate, phosphate (e.g., phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, perchlorate, borate, or thiocyanate; and organic acid salts, such as acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipic acidate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, bis(hydroxynaphthyl)ate (sparganate), and camphorate. , glucoheptanate or neopentanoate; sulfonates, such as methanesulfonate / mesylate, ethanesulfonate / esylate, hydroxyethanesulfonate / isethionate, benzenesulfonate / besylate, p-toluenesulfonate (toluenesulfonate), 2-naphthalenesulfonate / napsylate, 3-benzenesulfonate or camphorsulfonate; glycerophosphates; and acidic amino acid salts, such as aspartate or glutamate. Preferred pharmaceutically acceptable salts of compounds of formula (I) include hydrochloride, hydrobromide, methanesulfonate, sulfate, tartrate, fumarate, acetate, citrate, and phosphate. Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are hydrochloride.Therefore, it is preferred that the compound of formula (I) (including any of the specific compounds of formula (I) described herein) be in the form of a hydrochloride, hydrobromide, methanesulfonate, sulfate, tartrate, fumarate, acetate, citrate, or phosphate, and particularly preferred that the compound of formula (I) be in the form of a hydrochloride. In one embodiment, the compound of formula (I) may be in the form of a formate. In a preferred form, the compound of formula (I) is in a non-salt form. In other words, in the crystalline form 1 of the invention, the compound of formula (I) is in its free base form. It should be noted that when referring to a salt, specific reference is made to a composition comprising both an acid and a base that form said salt.

[0088] Furthermore, compounds of formula (I) can exist in various isomers, particularly stereoisomers (including, for example, geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers (particularly including proton shift tautomers, such as ketone / enol tautomers or thionone / thiol tautomers). All such isomers of compounds of formula (I) are considered part of the invention in mixtures or in pure or substantially pure form. As for stereoisomers, the invention covers the isolated optical isomers of compounds according to the invention and any mixtures thereof (particularly including racemic mixtures / racemates). Racemates can be resolved by physical methods (e.g., fractional crystallization, separation or crystallization of diastereomer derivatives, or separation by chiral column chromatography). Individual optical isomers can also be obtained from racemates by forming salts with optically active acids, followed by crystallization. The invention further covers any tautomers of compounds of formula (I). It should be understood that some compounds may exhibit tautomerism. In such cases, the formulas provided herein explicitly depict only one of the possible tautomers. As the formulas and chemical names provided herein are intended to cover any tautomer of the corresponding compound, and not only the specific tautomer depicted in the figures or identified by the compound name.

[0089] The scope of this invention also covers compounds of formula (I), wherein one or more atoms are replaced by specific isotopes of the corresponding atoms. For example, this invention covers compounds of formula (I), wherein one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by deuterium atoms (i.e., 2 H; also known as "D"). Therefore, the present invention also covers deuterium-rich compounds of formula (I). Naturally occurring hydrogen is a compound containing about 99.98 mol-% hydrogen-1 ( 1 H) and approximately 0.0156 mol-% deuterium ( 2A mixture of isotopes of H or D. The deuteration content at one or more hydrogen sites in a compound of formula (I) can be increased using deuteration techniques known in the art. For example, a compound of formula (I) or a reactant or precursor used to synthesize a compound of formula (I) can be subjected to an H / D exchange reaction using, for example, heavy water (D2O). Other suitable deuteration techniques are described in the following literature: Atzrodt J et al., BioorgMed Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The deuterium content can be determined, for example, using mass spectrometry or NMR spectroscopy. Unless otherwise specifically indicated, it is preferred that the compound of formula (I) is not rich in deuterium. Therefore, the compound of formula (I) contains naturally occurring hydrogen atoms or 1 H hydrogen atoms are preferred.

[0090] The present invention also covers compounds of formula (I), wherein one or more atoms are emitted by positron-emitting isotopes of the corresponding atoms, for example... 18 F, 11 C 13 N、 15 O、 76 Br、 77 Br、 120 I and / or 124 I is substituted. Such compounds can be used as tracers, tracking agents, or imaging probes in positron emission tomography (PET). Therefore, the present invention includes compounds of formula (i), wherein one or more fluorine atoms (or, for example, all fluorine atoms) are replaced with fluorine. 18 F atom substitution, (ii) compounds of formula (I) wherein one or more carbon atoms (or, for example, all carbon atoms) are... 11 C atom substitution, (iii) of the compound of formula (I), wherein one or more nitrogen atoms (or, for example, all nitrogen atoms) are replaced. 13 N atom substitution, (iv) of the compound of formula (I), wherein one or more oxygen atoms (or, for example, all oxygen atoms) are... 15 O atom substitution, in compounds of formula (v) (I), wherein one or more bromine atoms (or, for example, all bromine atoms) are... 76 Br atom substitution, (vi) of formula (I) compounds, wherein one or more bromine atoms (or, for example, all bromine atoms) are substituted.77 Br atom substitution, (vii) of formula (I) compounds, wherein one or more iodine atoms (or, for example, all iodine atoms) are substituted. 120 I atom substitution, and (viii) compounds of formula (I), wherein one or more iodine atoms (or, for example, all iodine atoms) are... 124 I atom substitution. Generally, it is preferred that none of the atoms in the compound of formula (I) are substituted by a specific isotope.

[0091] Pharmaceutical Composition

[0092] The compounds provided herein in the pharmaceutically acceptable crystalline form of the present invention may be administered as compounds on their own or may be formulated into pharmaceuticals. Pharmaceutical / pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubilizers. As understood herein, whenever a compound of formula (I) is mentioned, it means that the claimed formula (I) is in pharmaceutically acceptable crystalline form.

[0093] The pharmaceutical composition may contain one or more solubilizers, such as polyethylene glycol, including polyethylene glycols with a molecular weight in the range of about 200 Da to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerin, nonionic surfactants, tyloxapol, polysorbate 80, polyethylene glycol-15-hydroxystearate (e.g., Kolliphor). ® HS 15, CAS 70142-34-6), phospholipids, lecithin, myristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearyl phosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl ether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin Cyclodextrin, disaccharido-β-cyclodextrin, maltodextrin-α-cyclodextrin, maltodextrin-β-cyclodextrin, maltodextrin-γ-cyclodextrin, maltotrisyl-β-cyclodextrin, maltotrisyl-γ-cyclodextrin, disaccharido-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl sulfides, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, sodium dioctyl succinate sulfonate, or any combination thereof.

[0094] The pharmaceutical composition may also contain one or more preservatives, particularly one or more antimicrobial preservatives, such as benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methylphenol or 4-chloro-3-methylphenol), benzalkonium chloride, benzyl chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

[0095] Pharmaceutical compositions can be formulated using techniques known to those skilled in the art, such as those described in Remington: The Science and Practice of Pharmacy, Pharmaceutical Press, 22nd edition. Pharmaceutical compositions can be formulated into dosage forms for oral, parenteral (e.g., intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, topical, aerosol, or vaginal) administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, sugar tablets, lozenges, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, pharmaceutical gum, chewable tablets, and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions, and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and oval-shaped tablets. Dosage forms for nasal administration can be administered via inhalation and blowing, for example, through a metered-dose inhaler. Dosage forms for topical administration include creams, gels, ointments, balms, patches, and transdermal delivery systems.

[0096] The compound of formula (I) or the pharmaceutical composition comprising the above-described formula (I) may be administered to a subject via any convenient route of administration, whether systemic / peripheral or at the site of desired action, including but not limited to one or more of the following: oral (e.g., as a tablet, capsule or as an ingestible solution), topical (e.g., percutaneously, intranasally, ocularly, buccally and sublingually), parenteral (e.g., using injection or infusion techniques, including, for example, by injection, such as subcutaneously, intradermally, intramuscularly, intravenously, intraarterially, intracardiacly, intrathecally, intraspinously, intracapsularly, intraorbitally, intra-orbitally, subarachnoidly or intrasternally, by, for example, implantation of a depot, such as subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or blowing therapy, such as via aerosol, such as via mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ocular (including intravitreal or anterior chamber), rectal or vaginal administration.

[0097] If the compound or pharmaceutical composition is administered parenterally, examples of such administration include one or more of the following: intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracardiac, intramuscular, or subcutaneous administration, and / or administration by means of infusion techniques. For parenterally administration, the compound is preferably used in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salt or glucose, to make the solution isotonic with blood. If necessary, the aqueous solution should be appropriately buffered (preferably at a pH of 3 to 9). Suitable parenteral formulations can be readily prepared under sterile conditions using standard pharmaceutical techniques well known to those skilled in the art.

[0098] The compound or pharmaceutical composition may also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, and may contain flavoring or coloring agents for immediate release, delayed release, modulated release, sustained release, pulsatile release or controlled release applications.

[0099] Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, and glycine; disintegrants such as starch (preferably corn, potato, or cassava starch), sodium hydroxyacetic acid starch, croscarmellose sodium, and certain complex silicates; and granulation binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin, and gum arabic. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl docosanoate, and talc may be included. Similar types of solid compositions may also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, or high molecular weight polyethylene glycol. For aqueous suspensions and / or elixirs, the formulation may be combined with various sweeteners or flavorings, coloring substances or dyes, emulsifiers and / or suspending agents, and diluents such as water, ethanol, propylene glycol, and glycerin, and combinations thereof.

[0100] For oral administration, the compound or pharmaceutical composition is preferably ingested orally, particularly by swallowing. Therefore, the compound or pharmaceutical composition can be administered through the oral cavity into the gastrointestinal tract, which can also be referred to as "oral-gastrointestinal" administration.

[0101] Alternatively, the compounds or pharmaceutical compositions may be administered in the form of suppositories or vaginal suppositories, or topically in the form of gels, hydrogels, lotions, solutions, creams, ointments, or powders. The compounds of the present invention may also be administered through the skin or transdermally, for example, by using skin patches.

[0102] The compounds or pharmaceutical compositions described herein can also be administered via a sustained-release system. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of molded articles, such as membranes or microcapsules. Sustained-release matrices include, for example, copolymers of polylactide, L-glutamic acid and γ-ethyl-L-glutamic acid, poly(2-hydroxyethyl methacrylate), ethylene-vinyl acetate, or poly-D-(–)-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include compounds encapsulated in liposomes. Therefore, the present invention also relates to liposomes containing compounds of the present invention.

[0103] The compounds or pharmaceutical compositions may also be administered via the pulmonary, rectal, or ocular routes. For ocular use, they may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they may be formulated in ointments such as petrolatum.

[0104] It is also envisioned to prepare dry powder formulations of compounds of formula (I) for pulmonary administration, particularly inhalation. Such dry powders can be prepared by spray drying under conditions that produce substantially amorphous, glassy, ​​or substantially crystalline bioactive powders. Therefore, dry powders of the compounds of the present invention can be prepared according to an emulsification / spray drying method.

[0105] For topical application to the skin, the compound or pharmaceutical composition may be formulated as a suitable ointment containing an active compound suspended or dissolved in, for example, a mixture with one or more of the following substances: mineral oil, liquid paraffin, white petrolatum, polyethylene glycol, emulsified wax, and water. Alternatively, they may be formulated as a suitable lotion or cream suspended or dissolved in, for example, a mixture with one or more of the following substances: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, hexadecyl ester wax, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0106] Therefore, this invention relates to the compounds or pharmaceutical compositions provided herein, wherein the corresponding compounds or pharmaceutical compositions are administered via any of the following routes: oral administration; local administration, including percutaneous, intranasal, ocular, buccal, or sublingual routes; parenteral administration using injection or infusion techniques, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrasheathal, intraspinal, intracapsular, subcapsular, orbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, intrasternal, intravenous, intraurethral, ​​or intracranial routes; pulmonary administration, including inhalation or blowing therapy; gastrointestinal administration; intrauterine administration; intraocular administration; subcutaneous administration; ocular administration, including intravitreal or intra-anterior chamber administration; rectal administration; or vaginal administration. Preferred routes of administration are oral or parenteral administration. For each of the compounds or pharmaceutical compositions provided herein, it is particularly preferred that the corresponding compound or pharmaceutical composition be administered orally (especially by oral ingestion).

[0107] Typically, the physician will determine the actual dose most suitable for the individual subject. The specific dose level and frequency of administration for any particular individual subject can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, weight, general health condition, sex, diet, administration pattern and time, excretion rate, drug combination, severity of the specific condition, and the individual subject's prior therapy experience.

[0108] Recommended, but not limiting, doses of the compounds according to the invention administered orally to humans (approximately 70 kg body weight) may be 0.05 mg to 2000 mg, preferably 0.1 mg to 1500 mg, and more preferably 0.1 mg to 1000 mg of the active ingredient per unit dose. The unit dose may be administered, for example, 1 to 3 times daily. The unit dose may also be administered 1 to 7 times weekly, for example, no more than once daily. It should be understood that dose adjustments may be necessary depending on the patient's / subject's age and weight, as well as the severity of the condition to be treated. The precise dosage and route of administration are ultimately determined by the attending physician or veterinarian.

[0109] Therapeutic uses

[0110] In one embodiment, the present invention relates to a pharmaceutically acceptable crystalline form or pharmaceutical composition of a compound of formula (I) as defined herein for therapeutic purposes.

[0111] This invention provides pharmaceutically acceptable crystalline forms of compounds that act as PARG inhibitors. Therefore, this invention provides a method for inhibiting PARG enzyme activity in vitro or in vivo, the method comprising contacting cells with an effective amount of a pharmaceutically acceptable crystalline form of a compound of formula (I) as defined herein.

[0112] The present invention also provides a method for selectively inhibiting PARG enzyme activity relative to PARP1 or ARH3 enzyme activity in vitro or in vivo. The method comprises contacting cells with an effective amount of a pharmaceutically acceptable crystalline form of a compound as defined herein.

[0113] In another embodiment, the present invention relates to a pharmaceutically acceptable crystalline form of a compound of formula (I) as disclosed herein, for use in a method of treating a subject or patient requiring such treatment for a disease or condition involving PARG activity. The treatment method comprises administering to the subject / patient a therapeutically effective amount of a pharmaceutically acceptable crystalline form of a compound of formula (I) as defined herein, or a pharmaceutical composition thereof. In other words, in one embodiment, the present invention relates to a pharmaceutically acceptable crystalline form of a compound of formula (I) as disclosed herein, for use in treating a disease or condition involving PARG activity.

[0114] In another embodiment, the present invention relates to a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of a pharmaceutically acceptable crystalline form of a compound of formula (I) as defined herein. Therefore, the present invention relates to a pharmaceutically acceptable crystalline form of a compound of formula (I) or a pharmaceutically acceptable salt thereof for inhibiting cell proliferation in vitro or in vivo.

[0115] Therefore, in another embodiment, the present invention relates to a method for treating a proliferative condition in a subject or patient requiring such treatment. The method of treating a proliferative condition in a subject or patient includes administering to the subject / patient a therapeutically effective amount of a pharmaceutically acceptable crystalline form or pharmaceutical composition of a compound of formula (I) as defined herein. Preferably, as disclosed herein, the proliferative condition is cancer. Therefore, the present invention relates to a method for treating cancer in a subject or patient requiring treatment. The method of treating cancer in a subject or patient requires administering to the subject / patient a therapeutically effective amount of a pharmaceutically acceptable crystalline form or pharmaceutical composition of a compound of formula (I) as defined herein. In a particular embodiment, the cancer is human cancer.

[0116] In one embodiment, the present invention relates to a pharmaceutically acceptable crystalline form of a compound of formula (I) for treating a proliferative disease. Preferably, as disclosed herein, the proliferative disease is cancer. Therefore, the present invention relates to a pharmaceutically acceptable crystalline form of a compound of formula (I) for treating cancer. In a particular embodiment, the cancer is human cancer.

[0117] In another embodiment, the present invention relates to a pharmaceutically acceptable crystalline form of a compound of formula (I) as defined herein for the preparation of a medicament for treating proliferative conditions. In a preferred embodiment, the proliferative condition is cancer, more preferably human cancer. Therefore, preferably, the present invention relates to a pharmaceutically acceptable crystalline form of a compound of formula (I) as defined herein for the preparation of a medicament for treating cancer, preferably for treating human cancer.

[0118] In another embodiment, the present invention relates to a pharmaceutically acceptable crystalline form of a compound of formula (I) as defined herein, used for preparing a medicament for inhibiting PARG enzyme activity. Preferably, the inhibition of PARG enzyme activity is a selective inhibition of PARG enzyme activity relative to PARP1 or ARH3 enzyme activity. Therefore, the present invention relates to a pharmaceutically acceptable crystalline form of a compound of formula (I) as defined herein, used for preparing a medicament for selectively inhibiting PARG enzyme activity relative to PARP1 or ARH3 enzyme activity.

[0119] The present invention further provides a pharmaceutically acceptable crystalline form of a compound of formula (I) as defined herein for preparing a medicament for treating a disease or condition involving PARG activity as defined herein.

[0120] As understood herein, the term "proliferative disorder" is used interchangeably and refers to unwanted or uncontrolled cell proliferation of undesirable excess or abnormal cells, such as tumor growth or hyperplasia, whether in vitro or in vivo. Examples of proliferative disorders include, but are not limited to, pre-malignant and malignant cell proliferation, including but not limited to malignant growths and tumors, cancer, leukemia, psoriasis, bone diseases, (e.g., connective tissue) fibroproliferative disorders, and atherosclerosis. Treatment can be administered to any type of cell, including but not limited to the stomach, lungs, colon, breast, ovary, prostate, liver, pancreas, brain, and skin, preferably the lungs, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

[0121] Preferably, as understood herein, the cancer to be treated is selected from gastric cancer, lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, and skin cancer; more preferably, lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, and skin cancer.

[0122] The antiproliferative effects of the compounds of formula (I) of this invention have particular applications in the treatment of human cancers (due to their inhibition of PARG enzyme activity). The anticancer effects can be produced through one or more mechanisms, including but not limited to regulating cell proliferation, inhibiting angiogenesis (formation of new blood vessels), inhibiting metastasis (spread of tumors from their origin), inhibiting invasion (spread of tumor cells into adjacent normal structures), or promoting apoptosis (programmed cell death).

[0123] Antiproliferative therapy using pharmaceutically acceptable crystalline forms of compounds of formula (I) as defined above can be administered as a monotherapy, or may involve conventional surgery, radiation therapy, or chemotherapy in addition to the compounds of the present invention. Such chemotherapy may include one or more antitumor agents of the following classes:

[0124] (i) Other antiproliferative / anti-proliferative agents and combinations thereof used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolomide, and nitrosourea); antimetabolites (e.g., gemcitabine) and antifolate agents such as fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytarabine, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin). Pirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin; antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine) and taxanes (e.g., taxol and taxotere and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxin such as etoposide and teniposide), amsacrine, topotecan, and camptothecin);

[0125] (ii) Cell growth inhibitors, such as anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5oc-reductase inhibitors such as finasteride.

[0126] (iii) Anti-invasive agents [e.g., c-Src kinase family inhibitors, such as 4-(6-chloro-2,3-methylenedioxyaniline)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazolyl-5-carboxamide (dasatinib, BMS-354825; Journal of Medicinal Chemistry, 2004, 47, ] 6658-6661) and bosutinib (SKI-606), as well as metalloproteinase inhibitors such as marimastat, urokinase plasminogen activator receptor function inhibitors or heparanase antibodies;

[0127] (iv) Inhibitors of growth factor function: Such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin™], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225], and Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, ...). Any growth factor or growth factor receptor antibody disclosed in pages 11-29); such inhibitors also include tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoline-4-amine (CI). 1033), ERB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors, such as farnesyltransferase inhibitors, such as sorafenib (BAY 43-9006), tipifarnib (R115777), and lonafarnib (SCH66336)), inhibitors of cell signaling via MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (e.g., AZD1). 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors;

[0128] (v) Anti-angiogenic agents, such as anti-angiogenic agents that inhibit the action of vascular endothelial growth factor, [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU1 1248), axitinib (AG-013736), pazopanib (GW786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidone-1-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00 / 47212), as in International Patent Application WO97 / 22596, WO Compounds disclosed in WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354, as well as compounds that act through other mechanisms (e.g., linolamine, inhibitors of integrin ανβ3 function and angiostatin));

[0129] (vi) Vascular disruptors, such as Combretastatin A4 and compounds disclosed in international patent applications WO 99 / 02166, WO 00 / 40529, WO00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213; (vii) Endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan.

[0130] (viii) Antisense therapies, such as antisense therapies involving the targets listed above, such as the antiras antisense ISIS2503;

[0131] (ix) Gene therapy approaches, including, for example, methods that replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2; GDEPT (gene-guided enzyme prodrug therapy) approaches such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase; and methods that increase patient tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; and

[0132] (x) Immunotherapy methods, including, for example, in vitro and in vivo methods to increase the immunogenicity of the patient’s tumor cells, such as transfection with cytokines such as interleukin-2, interleukin-4 or granulocyte-macrophage colony-stimulating factor, methods to reduce T cell unresponsiveness, methods using transfected immune cells such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cell lines, and methods using anti-idiotype antibodies.

[0133] In certain embodiments, in addition to the compounds of formula (I) of the present invention, the antiproliferative treatment as defined above may involve conventional surgery, radiation therapy, or chemotherapy. Such combination therapies can be achieved by administering the individual components of the treatment simultaneously, sequentially, or individually. Such combination products use compounds of the present invention within the dosage range described above and other pharmaceutically active agents within their approved dosage ranges.

[0134] Accordingly, the invention further relates to pharmaceutically acceptable crystalline forms of compounds of formula (I) as defined herein, for use in combination with another antitumor agent to treat cancer (e.g., cancers involving solid tumors). The antitumor agent is preferably selected from the antitumor agents listed above.

[0135] As understood herein, the term "combination" means simultaneous, separate, or sequential application. In one aspect of the invention, "combination" means simultaneous application. In another aspect of the invention, "combination" means separate application. In yet another aspect of the invention, "combination" means sequential application. When applied sequentially or separately, a delay in the application of the second component should not result in the loss of the beneficial effects of the combination.

[0136] Example

[0137] The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention as defined by the appended claims.

[0138] Synthesis of compound (I)

[0139] The synthesis of compounds of formula (I) according to the invention is preferably carried out as described or analogously as in the specific synthetic procedures described in the following synthetic examples.

[0140] Preparation Examples

[0141] General considerations

[0142] The abbreviations used in the following descriptions are: AcOH (acetic acid); aq. (aqueous solution); Ar (argon); Atm (atmosphere); BH3.THF (boranetetrahydrofuran complex); br. (wide, 1H NMR signal); Boc2O (di-tert-butyl dicarbonate); (CataxiumAPdG3 (palladium(II) methanesulfonic acid [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]); CDCl3 (deuterated chloroform); cHex (cyclohexane); CMPB (cyanomethylenetrimethylphosphine); Cs2CO3 (cesium carbonate); CuI (copper iodide); DABCO (1,4-diazabicyclo[2.2.2]octane); DAST (diethylaminosulfur trifluoride); DBU (1,8-diazabicyclo(5.4.0)undec-7-ene); DCE (dichloroethane); d (doublet state, 1 H NMR signal); DCM (dichloromethane); DIBAL-H (diisobutylaluminum hydrogen); DIPEA or DIEA (diisopropylethylamine); DMAP (4-NN-dimethylaminopyridine), DME (1,2-dimethoxyethane), DMEDA (dimethylethylenediamine); DMF (NN-dimethylformamide); DMSO (dimethyl sulfoxide); DPPA (diphenyl azidophosphate); dtbbpy (bis(1,1-dimethylethyl)-2,2'-bipyridine); ES (electro-injection); EtOAc or EA (ethyl acetate); EtOH (ethanol); h (hours); FA (formic acid); HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide); HFIP (hexafluoroisopropanol); 1 H NMR (proton nuclear magnetic resonance spectroscopy); HPLC (high performance liquid chromatography); iPrOH (isopropanol); K3PO4 (tripotassium phosphate); Ir[dF(CF3)(dtbbpy)PF6 ((4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III)hexafluorophosphate); LiOH (lithium hydroxide); m (multiplexed, 1H NMR signal); mCPBA (m-chloroperoxybenzoic acid), MeCN (acetonitrile), MeOH (methanol); min (minutes); MnO2 (manganese oxide (IV)); MS (mass spectrometry); MTBE (methyl tert-butyl ether); NaBH4 (sodium borohydride); NaHCO3 (sodium bicarbonate); Na2S2O3 (sodium thiosulfate); NCS (N-chlorosuccinimide); NH3 (ammonium); NH4Cl (ammonium fluoride); NiCl2 (nickel dichloride); NIS (N-iodosuccinimide); NMP (N-methylpyrrolidone); NMR (nuclear magnetic resonance); Pd / C (carbon-supported palladium); Pd2dba3 (tris(dibenzylacetone)dipalladium); Pd(dppf)C l2 (1,1-bis(phenylphosphino)ferrocene palladium dichlorochloride); Pd(Ph3)2Cl2 (bis(triphenylphosphino)palladium(II) dichloride); PE (petroleum ether); Pd-PEPPSI-IPentCl o-methylpyridine ([1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-yl]-dichloro-(2-methylpyridin-1-onthiol-1-yl)palladium); Pd(OH)2 (palladium hydroxide); Pd(Ph3)4 (palladium-tetra(triphenylphosphine)); PhI(OAc)2 ((diacetoxyiodine)benzene); P(tBu)3 (tri-tert-butylphosphine); Py (pyridine); q (quadbit, 1H NMR signal); quin (quintbit, 1H NMR signal); rac (racemic); RT (retention time); s (singlet, 1 H NMR signal); sat. (saturation); t (triple state, 1H NMR signal); TBAF (tetrabutylammonium chloride); tert-BuBrettPhos-Pd-G3 ([(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate); tBuXPhos Pd G3 (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), TBDMSCl or TBSCl (tert-butyldimethylsilyl chloride); tBuOH (tert-butanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); TLC (thin-layer chromatography); TMSCHN2 (trimethylsilyldiazomethane); TMSCN (trimethylsilylcyanide); TMSOTf (trimethylsilyltrifluoromethanesulfonate); TTMSS (trimethylsilane); UPLC (ultra-high performance liquid chromatography); UV (ultraviolet); wt-% (weight); Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene); Xantphos Pd G4 (methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphino)oxanthene](2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)).

[0143] General Procedure: All starting materials and solvents were obtained from commercial sources or prepared according to literature references. Commercially available reagents and anhydrous solvents were used directly as supplied, without further purification. All reactions were stirred unless otherwise specified. Organic solutions were routinely dried over anhydrous sodium sulfate. Column chromatography was performed in the indicated amounts on pre-packed silica (100-1000 mesh, 40-63 µm) columns. All air- and moisture-sensitive reactions were carried out in dry (120°C) glassware under an inert atmosphere of nitrogen or argon. Compound names were generated using ChemDraw Prime (PerkinElmer). In some cases, the names of commercially available reagents that are generally accepted were used instead of those generated by ChemDraw.

[0144] Reversed-phase HPLC method for LCMS analysis of compounds:

[0145] Method 1: SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30mm, 5 µm, at 50℃; Mobile phase: A: water (v / v) containing 0.0375% TFA; B: MeCN (v / v) containing 0.01875% TFA; Flow rate maintained at 1.5 mL / min; Elution with mobile phase for 1.55 min, detection using UV at 220 nm and 254 nm. Gradient information: 0–0.80 min, slope from 95% A–5% B to 5% A–95% B; 0.80–1.20 min, maintained at 5% A–95% B; 1.20–1.21 min, recovered to 95% A–5% B; 1.21–1.55 min, maintained at 95% A–5% B.

[0146] Method 2: SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30mm, 5 µm, at 40℃; mobile phase: A: water (v / v) containing 0.025% NH3·H2O, B: MeCN; flow rate maintained at 1.5 mL / min; elution with mobile phase for 1.55 min, detection using UV at 220 nm and 254 nm. Gradient information: 0–0.80 min, from 95% A–5% B to 5% A–95% B; 0.80–1.20 min, maintained at 5% A–95% B; 1.20–1.21 min, returned to 95% A–5% B; 1.21–1.55 min, maintained at 95% A–5% B.

[0147] Method 3: SHIMADZU LCMS-2020 Kinetex EVO C18 2.1 x 30 mm, 5 µm, at 50 °C; Mobile phase: A: Water (v / v) containing 0.0375% TFA; B: MeCN (v / v) containing 0.01875% TFA; Flow rate maintained at 2.0 mL / min; Elution with mobile phase for 0.80 min, detection using UV at 220 nm and 254 nm. Gradient information: 0–0.80 min, slope from 95% A–5% B to 5% A–95% B; 0.80–1.20 min, maintained at 5% A–95% B; 1.20–1.21 min, recovered to 95% A–5% B; 1.21–1.55 min, maintained at 95% A–5% B.

[0148] Method 4: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1 x 20 mm, 2.6 μm, at 50 °C; Mobile phase: A: Water (v / v) containing 0.0375% TFA; B: MeCN (v / v) containing 0.01875% TFA; Flow rate maintained at 2.0 mL / min; Elution with mobile phase for 1.00 min, UV detection at 220 nm and 254 nm. Gradient information: 0.01–0.60 min, slope from 95% A–5% B to 5% A–95% B; 0.61–0.78 min, maintained at 5% A–95% B; 0.78–0.79 min, recovered to 95% A–5% B; 0.79–0.80 min, maintained at 95% A–5% B.

[0149] Reversed-phase HPLC method for compound analysis:

[0150] Method 1: Agilent 1100 / 1200 series liquid chromatograph, Xselect Premier CSH C18, 150 x 4.6 mm, 2.5 µm particle size, at 30 °C; mobile phase: A: deionized water:trifluoroacetic acid (100:0.1%); B: acetonitrile:trifluoroacetic acid (100:0.1%); flow rate maintained at 1.0 mL / min; elution with mobile phase for 30.00 min, detection with 268 nm UV. Gradient information: 0 – 2.00 mn, maintained at 75% A-25% B; 2.00 – 12.00 mn, slope from 75% A-25% B to 60% A-40% B; 12.00 – 25.00, slope from 60% A-40% B to 5% A-95% B; 25.00 – 29.5 mn, maintained at 5% A-95% B; 29.5 – 30.00 mn, returned to 75% A-25% B; maintained at 75% A-25% B for 5 mn.

[0151] 1 1H NMR spectroscopy:

[0152] The results were obtained at 400 MHz using the residual undeuterated solvent as a reference on a Bruker Avance III spectrometer. 1 H NMR spectrum. 1 H NMR signals are specified by their multiplicity / combined multiplicity, as is evident from the spectrum; possible higher-order effects are not considered. The chemical shift (δ) of the signal is expressed in ppm (parts per million).

[0153] Salt stoichiometry :

[0154] In this document, particularly in the experimental section, for the synthesis of intermediates and examples of the invention, when a compound is referred to as a salt of the corresponding base or acid, the precise stoichiometric composition of the salt form obtained by the corresponding preparation and / or purification methods is, in most cases, unknown. Unless otherwise stated, suffixes in chemical names or structural formulas (such as “hydrochloride,” “trifluoroacetate,” “sodium salt,” or “x HO,” “x CF3COOH,” “x Na+”) should be understood not as stoichiometric specifications, but only as indicating the form of the salt. This similarly applies to cases where synthetic intermediates or example compounds or their salts have been obtained as solvates by the stated preparation and / or purification methods, such as hydrates with (if defined) unknown stoichiometric compositions.

[0155] Preparation of intermediate 1.1

[0156] (5-Bromo-3-chloropyridin-2-yl)methylamine

[0157]

[0158] BH3 was added to a mixture of 5-bromo-3-chloropyridinecarboxynitrile (2.0 g, 9.20 mmol) in THF (10 mL) after 5 minutes of cooling in ice water. . THF (1 M, 11.04 mL). The mixture was stirred at 0 °C for 30 min, then heated to 20 °C and stirred at that temperature for another 30 min. After 5 min, the mixture was cooled to 0 °C and quenched by dropwise addition of MeOH (10 mL). The mixture was heated to 70 °C and stirred at that temperature for 30 min. The reaction solution was concentrated under vacuum to give a crude product (2.2 g) as a light brown solid. The crude product was dissolved in HCl (aq. 2 M, 20 mL), washed with DCM (20 mL; twice), and the aqueous phase was finally concentrated under vacuum to give a product (5-bromo-3-chloro-2-pyridyl)methylamine (1.5 g, 4.07 mmol, 44.26% yield, 70% purity, HCl salt) as a light brown solid.

[0159] LC / MS retention time: 0.18 minutes (Method 2); m / z: 222.9 (M+H) + (ESI + ), 1 H NMR (400MHz, DMSO-d6) δ = 8.78 (d, J = 2.0 Hz, 1H), 8.69 (br, 3H), 8.47 (d, J = 2.0Hz, 1H), 4.24 (d, J = 6.2 Hz, 2H).

[0160] Preparation of intermediate 1.2

[0161] 2-(((5-bromo-3-chloropyridin-2-yl)methyl)amino)-2-oxoethyl acetate

[0162]

[0163] Under ice-water cooling, DIPEA (2.25 g, 17.45 mmol) was added to a mixture of (5-bromo-3-chloro-2-pyridyl)methylamine (1.5 g, 5.82 mmol, HCl salt) in DCM (30 mL). Then, after 5 minutes, ethyl 2-chloro-2-oxoacetate (952.77 mg, 6.98 mmol) was added, and the mixture was stirred at 0 °C for 30 minutes. The mixture was then heated to 20 °C and stirred at that temperature for 30 minutes. The mixture was quenched with an aqueous solution of NaHCO3 (50 mL) and extracted with DCM (50 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give ethyl 2-(((5-bromo-3-chloropyridin-2-yl)methyl)amino)-2-oxoethyl acetate as a white solid (1300 mg, 3.64 mmol, 62.57% yield, 65.6% purity). Retention time 0.61 min (Method 1); m / z 322.8 (M+H) + (ESI + The product is used in the next step without further purification.

[0164] Preparation of intermediate 1.3

[0165] 6-Bromo-8-chloroimidozolo[1,5-a]pyridine-3-carboxylic acid ethyl ester

[0166]

[0167] Phosphorus pentoxide (2.87 g, 20.21 mmol) was added to a mixture of ethyl 2-(((5-bromo-3-chloropyridin-2-yl)methyl)amino)-2-oxoethyl acetate (1300 mg, 4.04 mmol) in POCl3 (15 mL) under ice-water cooling. The mixture was heated to 110 °C and stirred at that temperature for 5 hours. The mixture was cooled to 25 °C and concentrated under vacuum to give a residue. The residue was dissolved in EtOAc (50 mL) and washed with water (30 mL) and an aqueous solution of NaHCO3 (30 mL). It was then concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the product ethyl 6-bromo-8-chloroimidazolo[1,5-a]pyridine-3-carboxylic acid (900 mg, 2.97 mmol, 73.34% yield) as a white solid.

[0168] LC / MS retention time: 0.718 minutes (Method 1), m / z: 304.8 (M+H) + (ESI + ), 1 ¹H NMR (400MHz, chloroform-d) δ = 9.47 (s, 1H), 7.77 (s, 1H), 7.20 (s, 1H), 4.65–4.42 (m, 2H), 1.57–1.42 (m, 3H)

[0169] Preparation of intermediate 1.4

[0170] 6-Bromo-8-chloroimidazole[1,5-a]pyridine-3-carbazide

[0171]

[0172] Add NH2NH2 to a mixture of ethyl 6-bromo-8-chloroimidazole[1,5-a]pyridine-3-carboxylate (900 mg, 2.97 mmol) in EtOH (20 mL). . H2O (1.48 g, 29.65 mmol, 98%). The mixture was heated to 80 °C and stirred at that temperature for 2 hours. The reaction was cooled to 25 °C and the precipitated solid was separated. The crude product was ground with EtOH (5 mL) to give 6-bromo-8-chloroimidazolo[1,5-a]pyridine-3-carbazide as a white solid (650 mg, 2.25 mmol, 75.72% yield).

[0173] LC / MS retention time: 0.56 minutes (Method 1); m / z: 290.8 (M+H)+ (ESI + ); 1 H NMR (400MHz, DMSO-d6) δ = 10.02 (s, 1H), 9.50 (s, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 4.58 (d, J = 4.0 Hz, 2H).

[0174] Preparation of intermediate 1.5

[0175] 6-Bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,5-a]pyridine-3-carbazide

[0176]

[0177] Add ethyl 2,2-difluoroacetate (3.10 g, 22.45 mmol) and DBU (683.58 mg, 4.49 mmol) to a mixture of 6-bromo-8-chloroimidazole[1,5-a]pyridine-3-carbazide (650 mg, 2.25 mmol) in EtOH (20 mL). Heat the mixture to 100 °C and stir at this temperature for 16 hours. Cool the mixture to 25 °C and concentrate under vacuum. Dissolve the residue in DCM (50 mL), wash with aqueous NH4Cl solution (30 mL; twice), and concentrate under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (PE / EtOAc = 1:1 to MeOH:EtOAc = 1:10) to give the product 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,5-a]pyridine-3-carbazide (650 mg, 1.56 mmol, 69.32% yield, 88% purity) as a white solid.

[0178] LC / MS retention time: 0.62 minutes (Method 1); m / z: 368.8 (M+H) + (ESI + ); 1 H NMR (400MHz, DMSO-d6) δ = 10.95 (br, 2H), 9.44 (s, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 6.38 (t, J = 53.2, 1H).

[0179] Preparation of intermediate 1.6

[0180] 2-(6-bromo-8-chloroimidazole[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole

[0181]

[0182] Under a nitrogen atmosphere, Lawson's reagent (665.80 mg, 1.65 mmol) was added to a mixture of 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,5-a]pyridin-3-carbazide (550 mg, 1.50 mmol) and toluene (20 mL). The reaction mixture was heated to 120 °C and stirred at this temperature for 2 hours. The reaction mixture was cooled to 25 °C and concentrated under vacuum. The residue was ground with MeOH (10 mL) at 70 °C for 1 hour, filtered, and the filter cake was collected and dried under vacuum to give the product 2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (530 mg, 1.45 mmol, 96.88% yield) as a pale yellow solid.

[0183] LC / MS retention time: 0.806 minutes (Method 1); m / z: 366.8 (M+H) + (ESI + ); 1 H NMR (400MHz, DMSO-d6) δ = 9.62 (s, 1H), 8.64 (s, 1H), 8.09 (s, 1H), 7.70 (t, J =53.2, 1H).

[0184] Preparation of intermediate 1.7

[0185] 2-(6-(benzylthio)-8-chloroimidazole[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole

[0186]

[0187] Under nitrogen atmosphere, Pd2(dba)3 (112.72 mg, 123.09 µmol), Xantphos (71.22 mg, 123.09 µmol), and DIEA (477.26 mg, 3.69 mmol) were added to a mixture of 2-(6-bromo-8-chloroimidazolo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (450 mg, 1.23 mmol) and phenylmethanethiol (168.17 mg, 1.35 mmol) in dioxane (10 mL). The mixture was heated to 90 °C and stirred at that temperature for 16 hours. The mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 5:1) to give the product 2-(6-(benzylthio)-8-chloroimidazolo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (250 mg, 489.15 µmol, 39.74% yield, 80% purity) as a pale yellow solid.

[0188] LC / MS retention time: 0.99 minutes (Method 1); m / z: 409.0 (M+H) + (ESI + ); 1 H NMR (400MHz, CHLOROFORM-d) δ = 9.35 (s, 1H), 7.69 - 7.67 (m, 1H), 7.39 - 7.28 (m,2H), 7.25 - 7.12 (m, 3H), 7.05 (t, J = 53.2, 1H), 7.00 (s, 1H), 6.90 (s, 1H), 4.10 (s, 2H)

[0189] Preparation of intermediate 1.8

[0190] 2-(6-(benzylthio)-8-chloro-1-iodoimidazole[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole

[0191]

[0192] At 0 °C, NIS (78.68 mg, 349.74 µmol) was added to a mixture of 2-(6-(benzylthio)-8-chloroimidazole[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (130 mg, 317.95 µmol) in MeCN (5 mL). The mixture was stirred at 25 °C for 5 hours. The reaction mixture was used directly for the next step.

[0193] LC / MS retention time: 0.99 minutes (Method 1); m / z: 535.0 (M+H) + (ESI + )

[0194] Preparation of intermediate 1.9

[0195] 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ioimidazole[1,5-a]pyridine-6-sulfonyl chloride

[0196]

[0197] A mixture of 2-(6-(benzylthio)-8-chloro-1-iodoimidazole[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (170 mg, 317.95 µmol) in MeCN (5 mL) was cooled to 0 °C, and then H₂O (5.73 mg, 317.95 µmol), AcOH (38.19 mg, 635.89 µmol), and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (125.28 mg, 635.89 µmol) were added. The mixture was stirred at 0 °C for 2 hours. The mixture was diluted with THF (8 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ioimidazolo[1,5-a]pyridine-6-sulfonyl chloride (160 mg, 219.14 µmol, 68.92% yield, 70% purity), which was a light brown oil.

[0198] It should be noted that the formation of dichloro compounds, such as 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride, during this process cannot be ruled out.

[0199] Preparation of intermediate 1.10

[0200] 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

[0201]

[0202] At 0 °C, MeCN (2 mL) containing 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodomidazo[1,5-a]pyridine-6-sulfonyl chloride (90 mg, 176.09 µmol) was added to a mixture of 1-methylcyclopropyl-1-amine (37.80 mg, 531.49 µmol) in pyridine (1 mL) and NMP (N-methyl-2-pyrrolidone) (1 mL). The reaction mixture was stirred at 0 °C for 50 min. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL; twice). The organic phase was collected, dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by preparative TLC (PE:EtOAc = 3:1) to obtain a pale yellow solid product, 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (25 mg, 45.81 µmol, 26.01% yield).

[0203] It should be noted that the possibility of forming the dichloro compound 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide during this process cannot be ruled out.

[0204] LC / MS retention time: 0.5-10 minutes (Method 3); m / z: 545.8 (M+H) + (ESI + )

[0205] Preparation of intermediate 1.11

[0206] 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide

[0207]

[0208] Pd / C (5 mg, 10% purity) was added to a mixture of 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (25 mg, 45.81 µmol) in tetrahydrofuran (3 mL). The reaction mixture was degassed three times with H2 (15 Psi), and then stirred at 20 °C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the product 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (20 mg, 30.96 µmol, 67.59% yield, 65% purity) as a brown solid.

[0209] It should be noted that the formation of dichloro compound 1,8-dichloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide during this process cannot be ruled out.

[0210] LC / MS retention time: 0.468 minutes (Method 3); m / z: 420.0 (M+H) + (ESI + )

[0211] Preparation of intermediate 1.12

[0212] (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester

[0213]

[0214] To a mixture of 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (30 mg, 0.0715 mmol) in dioxane (0.5 mL), tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (15 mg, 0.0715 mmol), Cs₂CO₃ (70 mg, 0.214 mmol), and Pd-PEPPSI-IPentCl o-methylpyridine (7.0 mg, 0.00715 mmol) were added. The reaction mixture was degassed with N₂ (3 times) and then stirred at 98 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was subjected to preparative TLC (petroleum ether: ethyl acetate = 1:2) to give the product (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (16 mg, 0.0238 mmol, 33.34% yield) as a yellow solid.

[0215] LC / MS retention time 0.573 minutes (Method 4); m / z 598.1 (M+H) + (ESI) + ); 1 H NMR(CDCl3, 400 MHz): 9.74 (s, 1H), 7.83 (s, 1H), 7.08 (t, J = 53.6 Hz, 1H), 6.36(s, 1H), 5.06 (s, 1H), 4.20-4.37 (m, 2H), 4.14-4.11 (m, 2H), 3.67-3.48 (m,2H), 1.52 (s, 9H), 1.40 (s, 3H), 1.34 (d, J = 6.8 Hz, 6H), 0.98-0.96 (m, 2H), 0.63-0.58 (m, 2H).

[0216] Preparation of Example 1

[0217] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (crystal form 1)

[0218]

[0219] The reaction mixture was carried out twice on 29 g of (2S,6S)-4-[3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-[(1-methylcyclopropyl)aminosulfonyl]imidazo[1,5-a]pyridin-8-yl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester, and the reaction mixtures were then combined for post-treatment.

[0220] A mixture of (2S,6S)-4-[3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-[(1-methylcyclopropyl)aminosulfonyl]imidazo[1,5-a]pyridin-8-yl]-2,6-dimethyl-piperazin-1-carboxylic acid tert-butyl ester (29.00 g, 48.5 mmol) in formic acid (290 mL, 7686 mmol, 158 equivalents) was stirred at 20 °C for 2 h. The two reaction mixtures were combined and the formic acid was concentrated under vacuum to give a residue diluted with water (500 mL). The pH was adjusted to 9 with saturated NaHCO3 solution and the product was extracted with DCM (500 mL × 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting yellow solid was absorbed with EtOH (1.4 L) and stirred at 110 °C until completely dissolved. The resulting clear solution was stirred for 12 hours and cooled to room temperature. The precipitate was filtered and dried under vacuum to give fraction A 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)-8-[(3S,5S)-3,5-dimethylpiperazin-1-yl]imidazo[1,5-a]pyridine-6-sulfonamide (33.00 g, 66.3 mmol, 68.6% yield) as a yellow solid.

[0221] The filtrate was concentrated under vacuum to give a residue (15 g), which was recrystallized in EtOH according to the same procedure as described to give fraction A. The precipitate was filtered off and dried under vacuum to give fraction B (7.6 g, 15.3 mmol, 15.7% yield) of 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)-8-[3S,5S)-3,5-dimethylpiperazin-1-yl]imidazo[1,5-a]pyridine-6-sulfonamide as a yellow solid.

[0222] Fractions A and B both correspond to crystal form 1.

[0223] Grade A

[0224] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (s, 1 H), 8.43 (s, 1 H), 7.86 (s,1 H), 7.67 (t, J = 53.2 Hz, 1H), 6.65 (s, 1 H), 3.25 - 3.31 (m, 2 H), 3.17-3.25 (m, 2 H), 3.00 (m, 2 H), 2.15 (br s, 1 H), 1.13 - 1.22 (m, 9 H), 0.66 -0.77 (m, 2 H), 0.41 - 0.49 (m, 2 H)

[0225] Class B

[0226] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (s, 1 H), 8.43 (s, 1 H), 7.86 (s,1 H), 7.67 (t, J = 53.2 Hz, 1H), 6.65 (s, 1 H), 3.25 - 3.31 (m, 2 H), 3.17-3.25 (m, 2 H), 2.95-3.07 (m, 2 H), 2.15 (br s, 1 H), 1.13 - 1.22 (m, 9 H), 0.66 - 0.77 (m, 2 H), 0.41 - 0.49 (m, 2 H)

[0227] Table 1 below provides an overview of the compounds described in the Examples section.

[0228] Table 1

[0229]

[0230] Alternative recrystallization experiment to produce crystal form 1

[0231] Alternative preparation of crystal form 1

[0232] Under nitrogen atmosphere, 10¹⁰ g (2.03 mol) of 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)-8-[(3S,5S)-3,5-dimethylpiperazin-1-yl]imidazo[1,5-a]pyridine-6-sulfonamide and 5.55 L of THF were added to container 1. The mixture was heated to 65 °C to obtain a solution, which was then filtered into container 2 at 60–70 °C. Container 1 was rinsed with 0.5 L of THF and transferred to container 2. Container 2 was heated to 60°C, and then n-heptane (0.5 L) was slowly added, followed by 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)-8-[(3S,5S)-3,5-dimethylpiperazin-1-yl]imidazo[1,5-a]pyridine-6-sulfonamide form 1 seed crystals (1 g, 0.002 mol). The mixture was maintained at 55–65°C, and then another 4 L of n-heptane was slowly added to the container. The mixture was slowly cooled to 5°C, stirred overnight, and filtered. The container and filter cake were washed with the filtrate (1 L). The filter cake was washed with cold 6:4 THF:n-heptane (1 L) and cold n-heptane (1 L). The solids were dried to give 868 g (85.9% recovery; 99% purity (HPLC method 1). XRPD indicated the desired crystalline form, i.e., crystalline form 1).

[0233] HPLC retention time: 11.9 minutes (Method 1)

[0234] Reference Example - Crystal Form 2

[0235] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (crystal form 2)

[0236]

[0237] To a solution of (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (13.00 g, 21.8 mmol) in DCM (130 mL), HCl / dioxane (130 mL, 326 mmol, 2 N) was added. The mixture was stirred at 20 °C for 8 hours. The reaction mixture was combined with another reaction carried out on 2 g of (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester, and then alkalized with saturated NaHCO3 (aqueous solution) until pH=10, and extracted with DCM (200 mL, 3 times). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting yellow solid (10 g) was ground with DCM (50 mL) at 20 °C for 20 minutes, filtered, and dried under vacuum to give 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (8.00 g, 16.1 mmol, 80.00% yield) as a yellow solid.

[0238] Then, a mixture of 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (7.10 g, 14.3 mmol, Pd residue 95 ppm) and mercapto resin (4.30 g) in THF (150 mL) was stirred at 60 °C for 2 hours. The reaction mixture was cooled to 20 °C and filtered. Mercapto resin (4.30 g) was added to the filtrate, and the mixture was stirred at 60 °C for 16 hours. The reaction mixture was cooled to 20 °C, filtered, and the filtrate was concentrated under reduced pressure.

[0239] The obtained 7.0 g of 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide was ground and stirred in DCM (50 mL) for 2 hours. The precipitate was then filtered and dried under vacuum to give 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (4.30 g, 8.64 mmol, 60.5% yield, form 2). The obtained analytical data ( 1 The ¹H NMR and LC / MS results were consistent with the chemical structure of the compound.

[0240] X-ray powder diffraction pattern analysis

[0241] X-ray powder diffraction patterns were collected on a PANalytical diffractometer using Cu Kα radiation (45 kV, 40 mA), an θ-θ goniometer, a focusing lens, a diverging slit (1 / 2''), a Soler slit at both the incident and diverging beams (4 mm), and a PIXcel detector. The software used for data acquisition was X'Pert Data Collector version 7.4 and PanalyticalX'Pert Operator Interface version 1.2. Data were presented using High Score Plus version 5.2. XRPD patterns were obtained under ambient conditions using a transmission foil stage (polyimide-Kapton, 12.7 µm thick film) on a PANalytical X'Pert PRO. The data acquisition range was 2.994 – 35 °2θ, with a continuous scan rate of 0.202004 °s. -1 .

[0242] Tables 2 and 3 show the measured values ​​for crystal form 1 and crystal form 2, respectively. Furthermore, Figure 2 and 4 The complete map is presented, and Figure 6 Their comparison is shown in Figures 7 and 8.

[0243] Table 2: A list of peaks from XRPD measurements performed on the crystalline form 1 of compound (I).

[0244]

[0245]

[0246] Table 3: Peak values ​​from XRPD measurements of crystalline form 2 of compound (I)

[0247]

[0248]

[0249] Differential scanning calorimetry (DSC)

[0250] DSC data were collected on a TA Instruments Discovery DSC equipped with a 54-position sample holder. The instrument's energy and temperature calibrations were validated using certified indium. Pre-calculated sample volumes (0.5–2.0 mg) were placed in a Tzero tray with a Tzero-sealed cap and incubated at 20 °C for [time missing]. -1 Heat from 30°C to 350°C or as specified in the experiment. Hold over the sample for 50 mL min. -1 The instrument was purged with dry nitrogen. Instrument control, data acquisition, and analysis were performed using TAInstruments TRIOS software v5.5.0.323. All results are characterized by an upward endothermic pattern. Figure 3 The measurement results for crystal form 1 are shown in the figure. Figure 5 Reference results for crystal form 2 are shown.

[0251] Figure 12 Further experiments on the melt-recrystallization-melt sequence starting from form 2 are presented. Slow heating of DSC improves resolution but affects overall sensitivity and causes slight changes in relative peak positions (which can vary with sample presentation and sample and particle size variations, potentially causing a thermal lag type effect). The melt endothermic reaction obtained at a higher heating rate (10 °C / min) is resolved into a melt-recrystallization-melt sequence. It shows the melting of form 2, followed by recrystallization from the molten material to form 1, and then continued melting. This data further demonstrates that form 1 has better stability than form 2. Therefore, after melting of form 2, it can recrystallize at least partially into form 1, identified here based on its melting point.

[0252] Finally, it was carried out Figure 13 The DSC recirculation experiment shown in the diagram involves heating the Form 2 sample to just above the peak melting point of Form 2. In short, cooling the sample back to ambient temperature reveals a recrystallization event, and reheating it reveals a single melting event associated with Form 1. This further confirms that Form 1 recrystallizes from the melt of Form 2, suggesting that Form 1 has higher thermodynamic stability.

[0253] Thermogravimetric analysis (TGA)

[0254] TGA data were collected on a TA Instruments Discovery TGA equipped with a 25-position autosampler. The instrument's temperature was calibrated using certified weights and certified nickel-silicon alloy (Alumel) and nickel. A predetermined sample volume (approximately 5 mg) was loaded into a pre-balanced aluminum ACCUPIK sample pan and platinum crucible, and incubated at 20 °C for [time missing]. -1 Heat from ambient temperature to 400 °C unless otherwise specified. Incubate above the sample for 25 mL min. -1 Nitrogen purging was performed. Instrument control, data acquisition, and analysis were performed using TA Instruments TRIOS software v5.5.0.323. Figure 3 The measurement results for crystal form 1 are shown in the figure. Figure 5 Reference results for crystal form 2 are shown.

[0255] Competitive equilibrium between crystal form 1 and crystal form 2 of compound (I)

[0256] In order to investigate the relationship between crystal form 1 and crystal form 2 of the compound of formula (I), a series of solvent-based maturations have been carried out to determine whether a crystal form is dominant under various conditions.

[0257] Experiment: A saturated solution of compound (I) was prepared by equilibrating the API (approximately 100 mg) in the relevant solvent (Table 4, 5 mL) for 4 hours. The suspension was filtered, and the filtrate was used as the medium for competitive equilibration.

[0258] Equal amounts of crystal form 1 and crystal form 2 (10 mg to 20 mg) were loaded into crystallization tubes, and the corresponding saturated solution (1 mL) was added. The mixture was equilibrated at the relevant temperature, and samples were taken for XPRD analysis at 4 hours and 24 hours. At the 24-hour time point, the solids were analyzed as a wet filter cake and after drying at 45 °C.

[0259] The results are summarized in Table 4. XRPD data are presented in Figures 7 through 10. The data presented are for the dried solids; XRPD analysis of the wet filter cake showed no difference from the dried solids.

[0260] Data confirms that when the API reaches a certain solubility, XRPD reveals that form 1 is the dominant form, while there is no evidence for form 2. Note that in several entries, the conversion from form 2 to form 1 is completed within four hours, and as the equilibrium temperature increases, XRPD shows a significant decrease in the level of form 2. It is also noted that in each solvent tested, form 2 converts to form 1 at higher temperatures.

[0261] For entries where solubility remains low and a thicker suspension is obtained, a mixture of form 1 and form 2 can still be observed via XRPD. This assumes that the solubility in these solvents (e.g., water) is very low at ambient and below ambient temperatures, making it difficult to promote form conversion.

[0262] There are no instances of form 1 transforming into form 2 in any solvent or at any temperature.

[0263] Data supports that form 1 is the preferred stable crystalline form of the compound of formula (I).

[0264] Table 4:

[0265]

[0266]

[0267] Solubility data for crystal form 1

[0268]

[0269]

[0270]

[0271]

[0272] The table below reports the solubility data for Form 1.

[0273]

[0274] The solubility data obtained herein support the possibility of formulating oral formulations in the pharmaceutically acceptable crystalline form of this invention.

Claims

1. A pharmaceutically acceptable crystalline form of a compound of formula (I): The pharmaceutically acceptable crystals described herein can be obtained by recrystallizing the compound of formula (I) from ethanol.

2. The pharmaceutically acceptable crystalline form according to claim 1, wherein the recrystallization from ethanol involves complete dissolution in ethanol under stirring, followed by cooling to room temperature under stirring for 12 hours.

3. The pharmaceutically acceptable crystalline form according to claim 1 or 2, wherein the X-ray powder diffraction pattern obtained using CuKα radiation contains at least one peak selected from those at 12.24 ± 0.2 °2θ, 20.04 ± 0.2 °2θ, 20.40 ± 0.2 °2θ, and 24.02 ± 0.2 °2θ.

4. The pharmaceutically acceptable crystalline form according to claim 1 or 2, wherein the X-ray powder diffraction pattern obtained using CuKα radiation contains peaks at 12.24 ± 0.2 °2θ, 20.04 ± 0.2 °2θ, 20.40 ± 0.2 °2θ, and 24.02 ± 0.2 °2θ.

5. The pharmaceutically acceptable crystalline form according to claim 3 or 4, wherein the X-ray powder diffraction pattern obtained using CuKα radiation further includes a peak at 18.71 ± 0.2 °2θ and / or a peak at 6.86 ± 0.2 °2θ.

6. The pharmaceutically acceptable crystalline form according to any one of claims 3 to 5, wherein the X-ray powder diffraction pattern obtained using CuKα radiation further comprises at least one peak selected from the peaks at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ.

7. The pharmaceutically acceptable crystalline form according to any one of claims 3 to 5, wherein the X-ray powder diffraction pattern obtained using CuKα radiation further includes peaks at 15.42 ± 0.2 °2θ, 19.04 ± 0.2 °2θ, 21.59 ± 0.2 °2θ, 23.19 ± 0.2 °2θ, 23.58 ± 0.2 °2θ, 28.01 ± 0.2 °2θ, and 29.18 ± 0.2 °2θ.

8. The pharmaceutically acceptable crystalline form according to any one of claims 1 to 7, wherein the crystalline form is characterized by a melting point of 207.5 ± 4.0 °C.

9. The pharmaceutically acceptable crystalline form according to claim 8, wherein the crystalline form is characterized by a melting point of 207.5 ± 2.0 °C.

10. The pharmaceutically acceptable crystalline form according to claim 9, wherein the crystalline form is characterized by a melting point of 207.5 ± 1.0 °C.

11. A pharmaceutical composition comprising pharmaceutically acceptable crystals according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

12. A pharmaceutically acceptable crystal according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11, used in a therapeutic manner.

13. A pharmaceutically acceptable crystal according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11, used in a method of treating a disease or condition involving PARG activity.

14. The pharmaceutically acceptable crystals according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11, used in a method of treating proliferative disorders.

15. The pharmaceutically acceptable crystalline form or pharmaceutical composition for use according to claim 14, wherein the proliferative condition is cancer.

16. The pharmaceutically acceptable crystalline form or pharmaceutical composition for use according to claim 15, wherein the cancer is selected from gastric cancer, lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, and skin cancer.

17. Use in a pharmaceutically acceptable crystalline form according to any one of claims 1 to 10 for the preparation of a medicament for inhibiting PARG enzyme activity.

18. Use in a pharmaceutically acceptable crystalline form according to any one of claims 1 to 10 for the preparation of a medicament for treating proliferative symptoms.

19. The use according to claim 18, wherein the proliferative symptom is cancer.

20. The use according to claim 19, wherein the cancer is selected from gastric cancer, lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, and skin cancer.

21. A method of treating a subject with a disease or condition involving PARG activity, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable crystalline form according to any one of claims 1 to 10.

22. A method of treating a proliferative disorder in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable crystalline form according to any one of claims 1 to 10.

23. The method of claim 22, wherein the proliferative condition is cancer.

24. The method of claim 23, wherein the cancer is selected from gastric cancer, lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, and skin cancer.

25. A method for preparing a pharmaceutically acceptable crystalline form according to any one of claims 1 to 10, the method comprising the step of crystallizing a compound of formula (I) according to claim 1 from ethanol or a mixture of tetrahydrofuran / n-heptane.

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