WO2026033475A1 - Dérivés de composés aryle ou hétéroaryle substitués et leur utilisation pharmaceutique - Google Patents

Dérivés de composés aryle ou hétéroaryle substitués et leur utilisation pharmaceutique

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Publication number
WO2026033475A1
WO2026033475A1 PCT/IB2025/058084 IB2025058084W WO2026033475A1 WO 2026033475 A1 WO2026033475 A1 WO 2026033475A1 IB 2025058084 W IB2025058084 W IB 2025058084W WO 2026033475 A1 WO2026033475 A1 WO 2026033475A1
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Prior art keywords
alkyl
group
optionally substituted
hydrogen
membered
Prior art date
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PCT/IB2025/058084
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English (en)
Inventor
Young Whan Park
Soongyu Choi
Ja Heouk Khoo
Younglok CHOI
A Ra Kwon
Sang Hyun Lee
Haeyeon JANG
Seong Heon Kim
Suk Ho Lee
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Avelos Therapeutics Inc
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Avelos Therapeutics Inc
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Publication of WO2026033475A1 publication Critical patent/WO2026033475A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
    • C07D421/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present disclosure belongs to a technical field of medicine, and particularly relates to aryl or heteroaryl compound derivates with inhibitory effects on PARG, pharmaceutical compositions comprising the same, and preparation methods and uses thereof.
  • Background Art DNA repair is essential for the regulation of cell growth and survival. Thus, DNA repair pathways have been targeted for manipulation by medical therapeutics. Single- strand breaks (SSBs) are the most common type of lesion that occurs in cells.
  • PARG Poly(ADP- ribose) glycohydrolase
  • PARP poly(ADP-ribose) polymerase
  • PARP detects single-strand breaks and begins to synthesize poly ADP-ribose (PAR) itself.
  • PAR poly ADP-ribosylation
  • PARylation serves as a signal to recruit DNA repair proteins, such as XRCC1(X-ray repair cross-complementing protein 1), and the DNA repair proteins subsequently proceed to repair the SSBs.
  • PARG reverses the action of PARP enzymes by hydrolysing ribose-ribose bonds present in PAR, which is a process referred to as depoly(ADP- ribosyl)ation (dePARylation).
  • depoly(ADP- ribosyl)ation dePARylation
  • PARP is bound to PAR, its catalytic activity is reduced and therefore PARG activity helps to restore PARP to its catalytically active form (Curtin, N. J., & Szabo, C., 2013, Molecular aspects of medicine, 34(6), 1217-1256). Therefore, a sequential event of PARylation and dePARylation should be well-regulated since imbalance between PARylation and dePARylation can lead to DNA damage.
  • Cancer is a result of uncontrolled and unregulated cellular proliferation.
  • a rapid proliferation can cause a high level of oxidative stress within tumor cells, which leads to DNA damage and increased rate of mutation.
  • the mutation can cause deficiencies in 2 DNA repair mechanisms, and accordingly, cancer cells with the deficiencies tend to heavily rely on specific DNA repair mechanisms.
  • several therapeutic agents have been developed to target cancer cells that rely on specific DNA repair mechanisms. For example, it has been shown that tumor cells carrying a mutation in BRCA1 and BRCA2 genes often harbor defects in DNA double brand break (DSB) repair and such BRCA1/BRCA2 deficient tumor cells are more sensitive to PARP inhibitors.
  • DSB DNA double brand break
  • ADP-HPD adenosine diphosphate (hydroxymethy1)pyrrolidinediol
  • ADP-HPD adenosine diphosphate (hydroxymethy1)pyrrolidinediol
  • FIG. 1 Another PARG inhibitor, adenosine diphosphate (hydroxymethy1)pyrrolidinediol (ADP-HPD), which is an analog of ADP-ribose, showed good selectivity in inhibiting PARG at a low concentration (Slama, J. T., Aboul-Ela, N., & Jacobson, M. K. (1995)., Journal of medicinal chemistry, 38(21), 4332-4336).
  • existing PARG inhibitors have drawbacks of limited PARG inhibition capabilities or being difficult to obtain, etc. [0006] Therefore, there is still need to develop novel PARG inhibitors with improved efficacy that can be used for treating cancer.
  • the present disclosure relates to a compound of the following Formula (I): 3 I) [0013] is a single bond or double bond; [0014] each of W 1 , W 2 and W 3 is independently selected from carbon and nitrogen, provided that only one of W 1 , W 2 and W 3 is nitrogen; [0015] X is selected from the following: ); [0018] R x1 is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen; [0019] R x2 is selected from the group consisting of hydrogen and C1-C6 alkyl; [0020] R x3 is selected from the group consisting of hydrogen and halogen; [0021] R 1 is selected from the group consisting of hydrogen, deuter
  • R x1 is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;
  • R 1 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6 alkyl), and -C(O)NR 11 R 12 , wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and
  • the present disclosure provides a pharmaceutical composition for treating or preventing diseases or disorders, such as diseases or disorders mediated by PARG, which comprises one or more of the compounds disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier(s) or excipient(s).
  • the composition comprises one or more of the compounds in a therapeutically effective amount.
  • the composition comprises one or more of the compounds in a prophylactically effective amount.
  • the present disclosure provides the use of the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for the treatment or prevention of diseases or disorders mediated by PARG.
  • the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by PARG, in a subject, comprising administering to the subject at least one compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.
  • C 1 -C 6 alkyl is intended to encompass C 1 , C 2 , C 3 , C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.
  • C 1 -C 6 alkyl refers to a saturated hydrocarbon group which is straight-chained or branched, and has 1 to 6 carbon atoms.
  • the term “lower alkyl” also refers to this group.
  • the alkyl group may have 1 to 4 carbon atoms (C1-4 alkyl) or 3 to 6 carbon atoms (C3-6 alkyl).
  • Examples 15 of C 1-6 alkyl group include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n- butyl, tert-butyl, sec-butyl, iso-butyl, n-pentyl, 3-pentyl, 2-pentyl, neo-pentyl, 3-methyl-2- butyl, tert-pentyl, n-hexyl, 2-hexyl, 3-hexyl, and the like.
  • C 2 -C 6 alkenyl refers to a hydrocarbon group which is straight-chained or branched, and has 2-6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds).
  • One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl).
  • the alkenyl group may have 2 to 4 carbon atoms.
  • C 2-6 alkenyl group examples include, but are not limited to, vinyl, 1-propenyl, 2- propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, etc.
  • C2-C6 alkynyl refers to a hydrocarbon group which is straight-chained or branched, and has 2-6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2 or 3 carbon-carbon triple bonds) and optionally one or more carbon-carbon double bonds (e.g., 1, 2 or 3 carbon-carbon double bonds).
  • C1-C6 alkoxy refers to a -OR group, wherein R is substituted or unsubstituted C 1- -C 6 alkyl.
  • the alkoxy group may have 1 to 4 carbon atoms.
  • C1-6 alkoxyl includes, but is not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, sec-butoxy, n- pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.
  • halo refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I).
  • the halo group is F, Cl or Br.
  • the halo group is F or Cl.
  • the halo group is F.
  • C 3- C 14 cycloalkyl or “3- to 14- membered cycloalkyl” or “3- to 14-membered carbocyclic” refers to a saturated or 16 unsaturated cyclic hydrocarbon group which is aromatic or non-aromatic and has 3-14 ring carbon atoms and zero heteroatoms.
  • the cycloalkyl group may have 3 to 14, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 10, 4 to 8, 4 to 7, 4 to 6, 5 to 10, 5 to 8, 5 to 7, or 5 to 6 ring carbon atoms.
  • the cycloalkyl also includes a ring system in which the above mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring.
  • the cycloalkyl group include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, phenyl, naphtyl, anthracyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, cyclonony
  • heterocyclic group refers to a radical of a 3- to 14-membered ring system which is aromatic or non-aromatic and has ring carbon atoms and at least one ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur and phosphorus. The point of attachment of the heterocyclic group is on carbon or heteroatom.
  • the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and includes a fused, spiro, or bridged ring system.
  • the heterocyclyl group may have 2 to 7, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7, or 5 to 6 ring carbon atoms, and 1 to 4 heteroatoms.
  • the heterocyclic group may be an 8- to 14-(e.g., 9) membered bicyclic spiro heterocyclic group.
  • the heterocyclic group may be an 8- to 14-membered bicyclic fused heterocyclic group.
  • the heterocyclic group may be an 8-14 membered bicyclic bridged heterocyclic group.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, 17 tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, oxazolidin-2-one, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, thiadiazolinyl, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heterocyclyl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl and pyridinyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridinonyl, dithianyl, dioxanyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinanyl, triazinyl (e.g., 1,2,4-triazinyl, 1,3,5-triazinyl).
  • Exemplary 6-membered heterocyclyl groups containing four heteroatoms include, without limitation, tetrazinyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, thiepanyl, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Exemplary 6-membered heterocyclyl groups with substituted with oxo include, without limitation, pyridinonyl.
  • Exemplary 5,6-bicyclic heterocyclyl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heterocyclyl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • the heterocyclic group includes a saturated or unsatuated ring radical that comprises carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus.
  • the heterocyclic group may have a 3-14 membered heterocyclic group.
  • the heterocyclic group may have an 8-14 (e.g., 9) membered bicyclic spiro heterocyclic group.
  • the heterocyclic group may have 2 to 10, , 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 4 to 10, 4 to 9, 4 to 8, 5 to 9, 5 to 8, or 5 to 6 ring carbon atoms, and 1 to 4 heteroatoms.
  • heterocyclic group examples include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholin
  • spiro heterocyclic group examples include 2-oxa-7-azaspiro[3.5]nonan-7-yl and 2- oxa-8-azaspiro[4.5]decan-8-yl.
  • 8-14 membered polycylic heterocyclic group refers to a monovalent heterocyclic group, which is polycyclic (where there are two or more rings) (e.g, bicyclic) ring system having 7-11 ring atoms, including carbon and one or more heteroatom (e.g., nitrogen, oxygen and sulfur).
  • a polycyclic ring system may be a fused ring ring system, a bridged ring system and a spiro ring system.
  • a fused ring ring system is a system in which the two or more rings share a covalent bond and have two bridgehead carbons.
  • a bridged ring system is a system in which there is a carbon that is part of two or more rings and the two or more rings are connected by a bridge containing two bridegehead carbons and there are one or more carbons between the two bridegehead carbons.
  • a spiro ring system is a system in which the two or more rings are joined with a single bridgehead carbon. Examples of the polycyclic heterocyclic group include 19 .
  • -membered aryl refers to a radical of a carbocyclic aromatic group, whether or not fused to one or more groups, having 6 to 14 ring carbon atoms and zero heteroatoms. In one embodiment, the aryl may have 6-10 membered ring carbon atoms.
  • the aryl group may be monocylic or polycylic (e.g., bicyclic or tricyclic). Examples of the aryl group include, but are not limited to, phenyl, naphtyl, anthracyl, and the like.
  • the aryl group also includes ring systems wherein the aryl ring, as defined herein, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment is on the aryl ring.
  • the term “5- to 14-membered heteroaryl” refers to any monocyclic or polycyclic (e.g., bi-, or tricyclic) aromatic ring system which has ring carbon atoms and at least one heteroatom (e.g., nitrogen, oxygen, and sulfur). The point of attachment of the heroaryl is on carbon or heteroatom.
  • the heteroaryl group also includes ring systems wherein the heteroaryl ring, as defined herein, is fused with one or more cycloalkyl, heterocyclyl or aryl groups wherein the point of attachment is on the heteroaryl ring.
  • the heteroaryl group may have 3 to 10, 3 to 8, 3 to 7, 4 to 7, 5 to 12, 5 to 10, 5 to 7, or 5 to 6 ring carbon atoms or heteroatoms.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups 20 containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6- membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl (e.g., 1,2,4- triazinyl, 1,3,5-triazinyl), and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • the term “deuterated”, “deuteration”, or “D” means that one or more hydrogens in a compound or group are replaced by deuterium. Deuteration can be mono-, di-, tri-, poly-, or fully-substituted. The term “substituted with one or more deuteriums” can be used interchangeably with “deuterated one or more times”.
  • non-deuterated compound refers to a compound whose content of deuterium atoms is not higher than the natural content (0.015%) of deuterium isotope.
  • the content of deuterium isotope at a deuterated position is at least greater than the natural content of deuterium isotope (0.015%), alternatively greater than 30%, yet alternatively greater than 50%, yet alternatively greater than 75%, yet alternatively greater than 95%, or yet alternatively greater than 99%.
  • C 1- C 6 alkylene refers to a divalent alkyl linking group, which is a linear or branched, saturated hydrocarbon group having 1 to 6 carbon atoms.
  • An alkylene group formally corresponds to an alkane with two C-H bonds replaced by points of attachment of the alkylene group to the remainder of the compound.
  • the alkylene group may have 1 to 4 carbon atoms (C1-4 alkylene) or 1 to 2 carbon atoms (C1-2 alkylene).
  • alkynylene group formally corresponds to an alkyne with two C-H bonds replaced by points of attachment of the alkynylene group to the remainder of the compound.
  • the alkynylene group may have 1 to 4 carbon atoms (C1-C4 alkynylene) or 1 to 2 carbon atoms (C1-C2 alkynylene).
  • a w avy line( ) is used to indicate that the stereochemistry at the designated position is not specified, and may be either the R- or S-configuration, or a mixture thereof.
  • the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
  • “optionally substituted” refers to the event or circumstance that a chemical group (for example, the groups defined herein) may be substituted as well as the event or circumstance where a chemical group is not substituted.
  • substituted refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, it is contemplated that the term “substituted” includes all permissible substituents of organic compounds.
  • substituents on carbon atoms include, but are not limited to, C 1 -C 6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), 3-10 membered (e.g., 3-8 membered, 5-6 membered, 3-5 membered) cycloalkyl, hydroxy, amino, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), carbamoyl, oxo, a 3-8 membered heterocyclic or heteroaryl group, -COR z1 (wherein R z1 is selected from C
  • the number of substituents may be any number as long as valence of the substituted atom and the substituent permit, for example 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5, 3 to 4, and the like.
  • [0103] [0104]
  • the term “about”, when used with a corresponding numeric value, is meant to encompass variations within ⁇ 20% of the numeric value, typically ⁇ 10% of the numeric value, often ⁇ 5% of the numeric value, and most often ⁇ 2% of the numeric value. In some embodiments, the term “about” can mean the numeric value itself.
  • the concept of any expression in singular form should be considered to encompass the concept of the expression in plural form.
  • a compound of Formula (I) (including subsets of each formula), a compound of Formula (II) (including subsets of each formula) and a compound of Formula (III) (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.
  • compound of the present disclosure refers to the following compounds represented by Formula (I) (including subsets of each formula), Formula (II) (including subsets of each formula) and Formula (III) (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the present disclosure comprises a compound of Formula (I): I) [ ] w eren, [0116] is a single bond or double bond; 24 [0117] each of W 1 , W 2 and W 3 is independently selected from carbon and nitrogen, provided that only one of W 1 , W 2 and W 3 is nitrogen; [0118] X is selected from the following: [0119] ); [0120] [0121] R x1 is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen; [0122] R x2 is selected from the group consisting of hydrogen and C1-C6 alkyl; [0123] R x3 is selected from the group consisting of hydrogen and halogen; [0124
  • R x1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 1 is selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C 1 -C 6 alkyl), and -C(O)NR 11 R 12 , wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, 3-8 membered
  • R x1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 2 is a 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C 1 -C 6 alkoxy, -(C 1 -C 6 alkylene)-OH, -(C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(
  • X in Formula (I) is selected from the following: ); [0173] Y is absent or oxygen; [0174] R x1 is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen; [0175] preferably, R x1 is selected from the group consisting of C1-C6 alkyl, halogen and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen; [0176] more preferably, R x1 is selected from the group consisting of C1-C3 alkyl, halogen and cyano, wherein each of said alkyl is independently optional
  • X in Formula (I) is selected from the following: ); [0186] Y is absent or oxygen; [0187] R x1 is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine; [0188] preferably, R x1 is selected from the group consisting of C1-C6 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine; [0189] more preferably, R x1 is selected from the group consisting of C1-C3 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C3 alkyl
  • X in Formula (I) is selected from the group consisting of [0197] and, [0198] W-W an - are as e ne eren. [0199] [0200] In one embodiment, X in Formula (II) and Formula (III) i A), [0201] wherein: [0202] Y is absent or oxygen; 32 [0203] R x1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen; [0204] preferably, R x1 is selected from the group consisting of C 1 -C 6 alkyl, halogen and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen
  • X in Formula (II) and Formula (III) is selected from the group consisting of and, .
  • R 1 in Formulae (I) and (II) is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6 alkyl), and -C(O)NR 11 R 12 , wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, -O(C 1 -C 6 alkyl
  • R 1 is selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, fluorine, -O(C 1 -C 6 alkyl) and a 3-8 membered heterocyclic group, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, -O(C 1 -C 6 alkyl) and fluorine; [0234] preferably, R 1 is selected from the following: [0235] (R 1 -A) or (
  • R 1 is selected from the group consisting of nd , .
  • R 2 in Formulae (I) to (III) [0254]
  • R 2 is selected from the following: ); [0281] each of R z11 and R z12 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl), or R z11 and R z12 , taken together with the carbon atom to which they are attached, form a 3-8 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from C1-C6 alkyl and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl; 41 [0282] preferably, each of R z11 and R z12 is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene
  • R 2 is selected from the following: -A- [ ] w eren: [0321] each of R z11 and R z12 is independently selected from the group consisting of hydrogen, C1-C6 alkyl and -(C1-C3 alkylene)-O-(C1-C3 alkyl); 45 [0322] preferably, each of R z11 and R z12 is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(C1-C2 alkyl); [0323] more preferably, each of R z11 and R z12 is independently selected from the group consisting of hydrogen, methyl and -CH 2 -O-CH 3 ; [0324] R z13 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, -(C 1 -C 3 alkylene)- O-(C1-C3 alkyl
  • each of R 3 , R 4 , R 5 and R 6 in Formula (I), Formula (II) and/or Formula (III) is independently selected from the group consisting of hydrogen and halogen; preferably, each of R 3 , R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen and fluorine; and [0364] X, W 1 -W 3 and R 1 -R 2 are as defined herein.
  • the present disclosure relates to a compound of Formula (Ia-1), (Ia-2), (Ia-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), (Ic-2) or (Ic-3): -2) -2) 51 -2)
  • X is selected from the following: [0375] ); [0376] yg [0377] R x1 is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen; [0378] R x2 is selected from the group consisting of hydrogen and C1-C6 alkyl; [0379] R x3 is selected from the group consisting of hydrogen and halogen; 52 [0380] R 1 is selected from the group consisting of hydrogen,
  • the present disclosure relates to a compound of Formula (II-1), (II-2) or (II-3): -2)
  • Y is absent or oxygen
  • R x1 is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen
  • R 1 is selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6 alkyl), and -C(O)NR 11 R 12 , wherein each of said alky
  • the present disclosure relates to a compound of Formula (III-1), (III-2) or (III-3): -2)
  • Y is absent or oxygen
  • R x1 is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen
  • R 2 is a 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), mercapto, -S(C1-C
  • Non-limiting exemplary embodiments [0424] 57 [0425] the present disclosure relates to a compound of Formula (Ia-1), (Ia-2) or (Ia-3): -2) [0429] X is selected from the following: ); [0432] Y is absent or oxygen; [0433] R x1 is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine; [0434] preferably, R x1 is selected from the group consisting of C1-C6 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine; [0435] more preferably, R x1 is selected from the
  • the present disclosure relates to a compound of Formula (Ib-1), (Ib-2) or (Ib-3): -2)
  • X is selected from the following: ); [ ] s a sen or oxygen; [0553] R x1 is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl and fluorine; 71 [0554] preferably, R x1 is selected from the group consisting of C 1 -C 6 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine; [0555] more preferably, R x1 is selected from the group consisting of C 1 -C 3 alkyl
  • the present disclosure relates to a compound of Formula (Ic-1), (Ic-2) or (Ic-3): 83 -2)
  • X is selected from the following: );
  • Y is absent or oxygen;
  • R x1 is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine;
  • R x1 is selected from the group consisting of C 1 -C 6 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine;
  • R x1 is selected from the group consisting of C1-C3 alkyl, fluorine
  • the present disclosure relates to a compound of Formula (II-1), (II-2) or (II-3): -2)
  • Y is absent or oxygen
  • R x1 is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl and fluorine
  • R x1 is selected from the group consisting of C1-C6 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl and fluorine
  • R x1 is selected from the group consisting of C1-C3 alkyl, fluorine and cyano, wherein each of said alkyl is independently
  • the present disclosure relates to a compound of Formula (III), which is selected from the group consisting of the following compounds: 103 [08 , , , , rm, pharmaceutically acceptable salt, hydrate or solvate thereof.
  • exemplary compounds of Formula (I), Formula (II) and Formula (III) are shown below:
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • stereoisomers refers to compounds that are identical in chemical constitution, but different in arrangement of atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.
  • diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may be separated into each stereoisomer through high resolution analytical procedures such as electrophoresis and chromatography such as HPLC. 149 [0842] As used herein, the term “enantiomers” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • the organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates.” Where the solvent is water, the complex is known as “hydrate.”
  • solvates are known as “solvates.” Where the solvent is water, the complex is known as “hydrate.”
  • the present disclosure encompasses all solvates of the compounds disclosed herein.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc.
  • the compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvates will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • “Solvate” means both solution-phase and isolatable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • the term “hydrate” refers to a compound that is associated with water. Generally, the number of water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, hydrates of a compound can be represented, for example, by a general formula R ⁇ x H 2 O, wherein R denotes the compound, and x is a number greater than 0.
  • Given compounds can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, for example, hemihydrates (R ⁇ 0.5 H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R ⁇ 2 H2O) and hexahydrates (R ⁇ 6 H 2 O)).
  • Compounds disclosed herein may be in an amorphous or crystalline form (crystal form or polymorph).
  • the compounds disclosed herein may exist in one or more crystalline forms. Therefore, the scope of the present disclosure includes all amorphous or crystalline forms of the compounds disclosed herein.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shapes, optical and electrical properties, stability, 150 and solubility. Recrystallization solvents, rate of crystallization, storage temperatures, and other factors may cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • isotopically labeled form refers to a compound that contains an isotopic form of one or more atoms in the compound that is different from the naturally occurring isotopic distribution of the atom in nature. All isotopic forms are included as options, unless a specific isotopic form is indicated.
  • An “isotopically label form” of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium ( 2 H or D), carbon- 13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • prodrug refers to substances that can be converted, under physiological conditions or through solvolysis, into the compound of the present disclosure having biological activity.
  • the prodrug of the present disclosure is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or removed in vivo, to obtain the compound of the present disclosure.
  • the prodrug includes a compound which is formed by connecting a hydroxyl group or amino group in the compound of the present disclosure to any group.
  • the prodrug of the compound of the present disclosure is administered to a mammalian individual, the prodrug is dissociated to form a free hydroxyl or amino group.
  • pharmaceutically acceptable salt refers to a salt which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and is commensurate with a reasonable benefit/risk ratio.
  • Certain compounds disclosed herein can exist in the form of salts, for example acid addition salts, or salts with organic or inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds disclosed herein include the salt forms of the compounds. 151 [0850]
  • the salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • such salts can be prepared by reacting the free acid or base form of the parent compound with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • Acid addition salts e.g., mono - or di- salts
  • acids may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di- salts formed with an acid selected from the group consisting of acetic, trifluoroacetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g.
  • D-glucuronic D-glucuronic
  • glutamic e.g. L-glutamic
  • a-oxoglutaric glycolic, hippuric
  • hydrohalic acids e.g. hydrobromic, hydrochloric, hydriodic
  • isethionic lactic (e.g.
  • One particular group of salts consists of salts formed from acetic, trifluoroacetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
  • One particular salt is a hydrochloride salt.
  • One particular salt is a trifluoroacetic acid salt.
  • the compound disclosed herein may form quaternary ammonium salts, for example by reaction with an alkylating agent 152 according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the compounds disclosed herein.
  • the compounds of the invention may exist as mono- or di- salts depending upon the pKa of the acid from which the salt is formed.
  • Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci.1977, 66, pp.1-19.
  • Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g., hydrochloric, hydrobromic, sulfuric, nitric acid, phosphoric acid sulfuric acid, and perchloric acid and organic acids e.g., succinic, maleic, acetic, oxalic, malonic, fumaric, citric, tartaric, benzoic, p- toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • Other salts e.g., oxalates or formates may be used, for example in the isolation of compounds disclosed herein and are included within the scope of this invention.
  • salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts.
  • Such non-pharmaceutically acceptable salts forms which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.
  • Salts formed using conventional methods in the art such as ion exchange are also included.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1-4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic 153 ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • the compounds disclosed herein may form acid addition salts with one or more equivalents of the acid.
  • a process of preparing the compound of Formula (Ia-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof comprises any one of Processes A and A': [0862] [0863] - Process A produces the compound of Formula (Ia-1): 154 1) [0866] R 2 is selected from the following: ); ein.
  • Process A prepares the compound of Formula (Ia-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises: [0878] (i) preparing a compound of Formula (A-1): [0879] ); [0880] Formula (A-1) with oxidative halogenation reagent such as NCS (N-Chlorosuccinimide), NBS (N-Bromosuccinimide), and 1,3-dichloro-5,5- dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (A-2): ); ormula (A-2) with X-NH 2 to obtain a compound of Formula (A-3): ); 156 [0884] (iv) reacting the compound of Formula (A-3) wit to obtain the compound
  • Process A' prepares the compound of Formula (Ia-1') as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises: [0891] (i) preparing a compound of Formula (A-1): ); Formula (A-1) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (A-2): ); 157 [0895] (iii) reacting the compound of Formula (A-2) with X-NH 2 to obtain a compound of Formula (A-3): ); [0897] (iv) reacting the compound of Formula (A-3) with (Boc: tert- Butyloxycarbonyl) to obtain the compound of Formula (A ); ula (A-4) with
  • an exemplary reaction scheme of Process A may be shown as Scheme I-1 and Scheme I-2: [0905] Scheme I-1 158 [0906] [0907] [0908] X, R 1 , R z11 -R z13 , Z and R 5 are as described herein; [0909] Hal a and Hal c are halogens; preferably, fluoro, chloro, bromo or iodo.
  • an exemplary reaction scheme of Process A' may be shown as Scheme II: [0919] Scheme II [0922] X, R 1 , R z11 -R z13 and R 5 are as described herein; [0923] Hal a and Hal c are halogens; preferably, fluoro, chloro, bromo or iodo.
  • the step (i) of Processes A and A' comprises: [0926] (i-1) preparing the compound of Formula (a-1) ); [ ] (- ) (- a) reactng t e compound of Formula (a-1) with NH2NH2•H2O to obtain a compound of Formula (a-2), then reacting the compound of Formula (a-2) with 160 o obtain a compound of Formula (a-3), then reacting the compound of selenadiazole formation reagent such as SeO2, Se, SeCl4, SeOCl, and Woollins Reagent to obtain the compound of Formula (a-4), and then reacting the compound of Formula (a-4) with BnSH (Benzyl mercaptan) to obtain the compound of Formula (A-1): ), g p Formula (a-1) with BnSH to obtain a compound of Formula (a-2'), then reacting the compound of Formula (a-2') with NH 2 NH 2 •H 2 O to
  • R 1 and R 5 are as described herein; [0945] Hal a and Hal b are halogens; preferably, fluoro, chloro, bromo or iodo. [0946] [0947] Scheme III-2 , [0950] R 1 and R 5 are as described herein; [0951] Hal a and Hal b are halogens; preferably, fluoro, chloro, bromo or iodo.
  • an exemplary reaction scheme of step (i-1) of Processes A and A' may be shown as Scheme IV-1 and Scheme IV-2: [0973] Scheme IV-1 [0976] R 1 is as described herein; and [0977] Hal a , Hal b and Hal d are halogens; preferably, fluoro, chloro, bromo or iodo. [0978] [0979] Scheme IV-2 [0980] [0981] w eren, [0982] Hal a , Hal b and Hal d are halogens; preferably, fluoro, chloro, bromo or iodo.
  • the step (i) of Process B comprises: [1025] (i-1) preparing a compound of Formula (b-1): ); f Formula (b-1) with halogenation reagent such as NBS, NIS, NCS, Selectfluor, NFSI, Cl2, Br2, I2, HF, 2-Chloro-1,3- bis(methoxycarbonyl)guanidine and 1,2-Dibromotetrachloroethane to obtain a compound of Formula (b-2): ); f Formula (b-2) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (b-3): ); [ ] (- ) reactng t e compoun o Formula (b-3) with X-NH2 to obtain a compound of Formula (b-3)
  • the step (i) of Process B comprises: [1040] (i-1) preparing a compound of Formula (b-1): [1041] ); [1042] g p of Formula (b-1) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (b-2'): '); 170 [1044] (i-3') reacting the compound of Formula (b-2') with X-NH 2 to obtain a compound of Formula (B-1) [1045] wherein, [1046] X and R 5 are as described herein; [1047] Hal a and Hal c are halogens; preferably, fluoro, chloro, bromo or iodo.
  • an exemplary reaction scheme of Process B may be shown as Scheme VI-1 to Scheme VI-4: [1050] Scheme VI-1 , [1053] R 1 is as described herein except hydrogen; [1054] X, R z11 -R z13 , Z and R 5 are as described herein; [1055] Hal a , Hal b and Hal c are halogens; preferably, fluoro, chloro, bromo or iodo.
  • the step (i-1) of Process B comprises: [1080] (i-1-a) preparing a compound of Formula (b-5): ); [1082] (i-1-b) reacting the compound of Formula (b-5) wit to obtain a compound of Formula (b-6): ); [1084] (i-1-c) reacting the compound of Formula (b-6) with to obtain a compound of Formula (b-7): ); - - reac ng e compound of Formula (b-7) with BnSH to obtain a compound of Formula (b-8): 174 ); nd of Formula (b-8) with base such as LiOH, NaOH and KOH to obtain a compound of Formula (b-9): ); [1090] (i-1-f) reacting the compound of Formula (b-9) with to obtain a compound of Formula (b-10): ); ormula (b-10) with selenadiazole formation reagent such as SeO2, Se, SeCl4, Se
  • an exemplary reaction scheme of step (i-1) of Process B may be shown as Scheme VII: 175 [1098]
  • Scheme VII [1101]
  • R 5 is as described herein;
  • Hal a and Hal d are halogens; preferably, fluoro, chloro, bromo or iodo.
  • a process of preparing the compound of Formula (Ic-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof comprises one of Process C: [1105] [1106] - Process C produces the compound of Formula (Ic-1): X N O S O ed froNm N N th Se R Fe f1olF Rlo5176 1) [1110] R 2 isH select R2 Nwing: ); ein.
  • the step (i) of Process C comprises: [1126] (i-1) preparing a compound of Formula (c-1): ); pound of Formula (c-1) with HCOOH to obtain a compound of Formula (c-2): ); [1130] (i-3) reacting the compound of Formula to obtain a compound of Formula (c-3): 178 ); d of Formula (c-3) with BnSH to obtain a compound of Formula (c-4): [1133] ); [1134] of Formula (c-4) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (c-5): [1135] ); [1136] g p Formula (c-5) with X-NH2 to obtain a compound of Formula (C-1); [1137] wherein, [1138] X and R
  • R B is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl; [1169] X, R z21 and R 5 are as described herein; [1170] Hal a , Hal b , Hal c and Hal d are halogens; preferably, fluoro, chloro, bromo or iodo. [1171] [1172] Scheme VIII-3
  • R 1 is as described herein except hydrogen;
  • R B is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;
  • X, R z21 and R 5 are as described herein;
  • Hal a , Hal b , Hal c , Hal d and Hal e are halogens; preferably, fluoro, chloro, bromo or iodo.
  • a process of preparing the compound of Formula (II-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof comprises one of Process D: [1188] [1189] - Process D produces the compound of Formula (II-1): 185 1) [1195] R 2 is selected from the following: ); , , , .
  • Process D prepares the compound of Formula (II-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises: [1202] (i) preparing a compound of Formula (D-1): 186 [1203] ); [1204] (ii) reacting the compound of Formula (D-1) with to obtain the compound of Formula (II-1); [1205] wherein, ); ed herein; [1208] R 1 , R z11 -R z13 , R z21 , Z and R 5 are as described herein; [1209] R B is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl; and [1210] Hal a is halogen; preferably, fluoro, chloro, bromo or iodo.
  • the step (i) of Process D comprises: [1213] (i-1) preparing a compound of Formula (d-1): [1214] ); 187 [1215] (i-2) reacting the compound of Formula (d-1) with halogenation reagent such as NBS, NIS, NCS, Selectfluor, NFSI, Cl2, Br2, I2, HF, 2-Chloro-1,3- bis(methoxycarbonyl)guanidine and 1,2-Dibromotetrachloroethane to obtain a compound of Formula (d-2): [1216] ); [1217] f Formula (d-2) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (d-3): [1218] ); [1219] Formula (d-3) with
  • the step (i) of Process D comprises: [1230] (i-1) preparing a compound of Formula (d-1): ); of Formula (d-1) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (d-2'): [1233] '); [1234] - reac ng e compoun o Formula (d-2') with X-NH2 to obtain a compound of Formula (d-1) [1235] wherein, 189 1236 X i XA); ed herein; [1238] R 5 is as described herein; [1239] Hal a and Hal c are halogens; preferably, fluoro, chloro, bromo or iodo.
  • an exemplary reaction scheme of Process D may be shown as Scheme IX-1 and Scheme IX-4: [1242] Scheme IX-1 , 190 124 X i XA); ed herein; [1247] R 1 is as described herein but is not hydrogen; [1248] R z11 -R z13 , Z and R 5 are as described herein; [1249] Hal a , Hal b and Hal c are halogens; preferably, fluoro, chloro, bromo or iodo.
  • the step (i-1) of Process D comprises: [1279] (i-1-a) preparing a compound of Formula (d-5): [1280] ); [1281] (- -b) reactng t e compound of Formula (d-5) with BnSH to obtain a compound of Formula (b-6): 193 [1282] ); [1283] nd of Formula (d-6) with base such as LiOH, NaOH and KOH to obtain a compound of Formula (d-7): ); [1285] (i-1-d) reacting the compound of Formula (d-7) with to obtain a compound of Formula (d-8): ); Formula (d-9) with selenadiazole formation reagent such as SeO 2 , Se, SeCl 4 , SeOCl, and Woollins' Reagent to obtain a compound of Formula (d-1); [1288] wherein, [1289] R 5 is as described herein; [1290] Hal a and Hal
  • an exemplary reaction scheme of step (i-1) of Process D may be shown as Scheme X: 194 [1293]
  • R 5 is as described herein;
  • Hal a and Hal d are halogens; preferably, fluoro, chloro, bromo or iodo.
  • a process of preparing the compound of Formula (III) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof comprises one of Process E: [1300] [1301] - Process E produces the compound of Formula (III-1): 1) [ ] w eren: 195 130 X i XA); ed herein; [1307] R 2 is selected from the following: ); .
  • Process E prepares the compound of Formula (III-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises: [1314] (i) preparing a compound of Formula (E-1): ); [1317] (ii) reacting the compound of Formula (E-1) wit to obtain the compound of Formula (III-1); 196 [1318] wherein, 1 1 i A); ed herein; [1321] Z, R z11 - R z13 , R z21 , R 5 and R 6 are as described herein; [1322] R B is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl; and [1323] Hal a is halogen; preferably, fluoro, chloro, bromo or iodo.
  • the step (i) of Process E comprises: [1326] (i-1) preparing a compound of Formula (e-1): [1327] ); [1328] f Formula (e-1) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (e-2): [1329] ); [1330] (- ) reactng t e compoun o Formula (e-2) with X-NH2 to obtain a compound of Formula (e-3): 197 ); ormula (e-3) with dehalogenation reagent such as Pd/C H 2, Grignard reagent, n-BuLi, Zn, and NH 4 Cl to obtain a compound of Formula (E- 1); [1333] wherein, ); ed herein; [1336] R 5 is as
  • the step (i) of Process E comprises: [1340] (i-1) preparing a compound of Formula (e-1): [1341] ); [1342] - reac ng e compoun of Formula (e-2') with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (e-3'): 198 [1343] ); [1344] Formula (e-3') with X-NH2 to obtain a compound of Formula (E-1): [1345] wherein, ); ed herein; [1348] R 5 is as described herein; and [1349] Hal a , Hal b and Hal c are halogens; preferably, fluoro, chloro, bromo or iodo.
  • an exemplary reaction scheme of Process E may be shown as Scheme XI-1 and Scheme XI-4: [1352] Scheme XI-1 [1353] 199 [1354] wherein, 13 X i XA); ed herein; [1357] R z11 -R z13 , Z and R 5 are as described herein; [1358] Hal a , Hal b and Hal c are halogens; preferably, fluoro, chloro, bromo or iodo.
  • R z21 and R 5 are as described herein; [1383] R B is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl; [1384] Hal a , Hal b and Hal c are halogens; preferably, fluoro, chloro, bromo or iodo.
  • the step (i-1) of Process E comprises: [1387] (i-1-a) preparing a compound of Formula (e-4): ); [ ] (- - ) reactng t e compound of Formula (e-4) with i) Phthalimide, DIAD, PPh3 and ii) Hydrazine hydrate to obtain a compound of Formula (e-5): 202 ); [1391] (i-1-c) reacting the compound of Formula (e-5) with n a compound of Formula (e-6): ); Formula (e-6) with POCl 3 to obtain a compound of Formula (e-7): ); ound of Formula (e-7) with NH 2 NH 2 •H 2 O to obtain a compound of Formula (e-8): [1396] ); [1397] (i-1-f) reacting the compound of Formula (e-8) with to obtain a compound of Formula (e-9): 203 [1398] ); [1399] Formula
  • an exemplary reaction scheme of step (i-1) of Process E may be shown as Scheme XII: [1409] Scheme XII [1410] [1411] wherein, [1412] R 5 is as described herein; [1413] Hal a , Hal b , Hal d and Hal e are halogens; preferably, fluoro, chloro, bromo or iodo.
  • a process of preparing the compound of Formula (Ia-2), (Ia-3), (Ib-2), (Ib-3), (Ic-2), (Ic-3), (II-2), (II-3), (III-2) and (III-3) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof comprises any one of Process F, G, H, I and J: [1416] [1417] - Process F produces the compound of Formula (Ia-2) and Formula (Ia-3): -3) [1420]
  • R 2 is selected from the following: ); , , , , ein.
  • Process J produces the compound of Formula (III-2) and Formula (III-3): -3) 208 [1451] Y and R x1 are as defined herein; [1452] R 2 is selected from the following: ); [1455] [1456] Process F [1457] [1458] Process F prepares the compound of Formula (Ia-2) and (Ia-3) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises: [1459] (i) preparing a compound of Formula (Ia-1); and [1460] (ii) reacting the compound of Formula (Ia-1) with Selectfluor (1-Chloromethyl-4- fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), F-TEDA-BF 4 ) to obtain the compound of Formula (Ia-
  • an exemplary reaction scheme of Process F may be shown as Scheme XIII: [1463] Scheme XIII , 209 [1466]
  • R 2 is selected from the following: ); ein.
  • Process G [1471]
  • Process G prepares the compound of Formula (Ib-2) and (Ib-3) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises: [1473] (i) preparing a compound of Formula (Ib-1); and [1474] (ii) reacting the compound of Formula (Ib-1) with Selectfluor to obtain the compound of Formula (Ib-2) and (Ib-3).
  • an exemplary reaction scheme of Process G may be shown as Scheme XIV: [1477] Scheme XIV , [1480] R 2 is selected from the following: 210 ); ein. [1483] [1484] Process H [1485] [1486] Process H prepares the compound of Formula (Ic-2) and (Ic-3) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises: [1487] (i) preparing a compound of Formula (Ic-1); and [1488] (ii) reacting the compound of Formula (Ic-1) with Selectfluor to obtain the compound of Formula (Ic-2) and (Ic-3).
  • an exemplary reaction scheme of Process H may be shown as Scheme XV: [1491] Scheme XV , [1494] R 2 is selected from the following: 211 ); ein. [1497] [1498] Process I [1499] [1500] Process I prepares the compound of Formula (II-2) and (II-3) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises: [1501] (i) preparing a compound of Formula (II-1); and [1502] (ii) reacting the compound of Formula (II-1) with Selectfluor to obtain the compound of Formula (II-2) and (II-3).
  • an exemplary reaction scheme of Process I may be shown as Scheme XVI: [1505] Scheme XVI , [1508] Y and R x1 are as defined herein; [1509] R 2 is selected from the following: 212 ); .
  • Process J prepares the compound of Formula (III-2) and (III-3) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises: [1516] (i) preparing a compound of Formula (III-1); and [1517] (ii) reacting the compound of Formula (III-1) with Selectfluor to obtain the compound of Formula (III-2) and (III-3).
  • an exemplary reaction scheme of Process J may be shown as Scheme XVII: [1520] Sch Rx1 Yem NH O e S X , [1523] Y and R x O VII 1 a Rr2e NN as N R N6 d Se FefiFn R5ed se hleecrtfeluionr; [1524] R 2 is selected from the followin,g A:CN, 0 oC Rx1 Y NH O S F O R2 NN N R N6 S FeF R5 Rx1 Y NH O S O R F2 NN N R N6 S FeF R5
  • the term “dehalogenation reagent” includes, but is not limited to, Pd/C H2, Grignard reagent, n-BuLi, Zn, NH4Cl.
  • the term “selenadiazole formation reagent” includes, but is not limited to, SeO2, Se, SeCl4, SeOCl, and Woollins' Reagent.
  • halogenation reagent includes, but is not limited to, NBS, NIS, NCS, Selectfluor, NFSI, Cl2, Br2, I2, HF, 2-Chloro-1,3- bis(methoxycarbonyl)guanidine and 1,2-Dibromotetrachloroethane.
  • oxidative halogenation reagent includes, but is not limited to, NBS, NCS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione.
  • treatment refers to a course of action (such as administering an inhibitor of PARG or a pharmaceutical composition comprising same) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition afflicting a subject, or at least one of the symptoms associated with a disease, disorder, condition afflicting a subject.
  • treatment may also refer to inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease.
  • prevent refers to a course of action (such as administering a PARG inhibitor or a pharmaceutical composition comprising same) initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom 214 thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition.
  • a course of action such as administering a PARG inhibitor or a pharmaceutical composition comprising same
  • the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting the progression of the disease, disorder or condition such that it does not reach a harmful or otherwise undesired state.
  • the terms “inhibiting” and “reducing,” or any variation of these terms in relation to PARG may refer to any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease in PARG activity of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, compared to a control group.
  • the term “about” as used herein means variations within ⁇ 20%, preferably, within ⁇ 10%, more preferably within ⁇ 5% of a given value.
  • Disease disease
  • disorder disorder
  • condition condition
  • the present disclosure provides a compound that prevents or treats a disease or disorder mediated by PARG or a disease or disorder in which PARG activity is implicated.
  • the present disclosure also provides a compound that selectively inhibits PARG enzyme activity over PARP1 or ARH3 enzyme activity in vitro or in vivo.
  • the disease or disorder mediated by PARG is any of proliferative disorders.
  • proliferative disorders is used interchangeably herein and pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
  • proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis.
  • Any type of cell including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin, may be treated.
  • the proliferative condition to be treated is cancer, such as lung cancer (Dai W et al., Front Pharmacol.2019;10:338), colon cancer (Shirai et al., Cell Death Dis.2013 Jun; 4(6): e656), breast cancer (Chen et al., Sci Adv.2019 Apr; 5(4): eaav4340), ovarian cancer (N. Pillay, R.M. Brady, M.
  • the therapeutically effective amount of the compound of Formula (I), Formula (II) or Formula (III) provided herein is an amount sufficient to provide therapeutic benefits during the course of the treatment, or to delay or minimize one or more symptoms associated with cancer.
  • the therapeutically effective amount of a compound is the amount of the therapeutic agent that, when used alone or in combination with other therapies, provides such therapeutic benefits during the course of the treatment.
  • Effective amounts of the compound of the present disclosure vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, whether treatment is prophylactic or therapeutic, as well as the specific activity of the composition itself and its ability to elicit the desired response in the individual.
  • the patient can be a human or non-human mammal.
  • dosage regimens are adjusted to provide an optimum therapeutic response, i.e., to optimize safety and efficacy. Accordingly, a therapeutically effective amount is also one of which any undesired collateral effects are outweighed by the beneficial effects of administering the compound as described herein.
  • a therapeutically effective amount is also one of which any undesired collateral effects are outweighed by the beneficial effects of administering the compound as described herein.
  • Pharmaceutical compositions [1543] The terms “combination”, “combined”, and related terms refer to the simultaneous, separate or sequential administration of two or more therapeutic agents or therapies.
  • the compound disclosed herein may be administered with another therapeutic agent or therapy simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.
  • the another therapy may be radiotherapy.
  • the another therapeutic agent may be an anti-cancer agent.
  • the anti-cancer agent may include a DNA damage response (DDR) targeting anti-cancer agent.
  • DDR DNA damage response
  • the term DNA damage response is a collective term for the plethora of different intra- and inter-cellular signaling events and enzyme activities that result from the induction and detection of DNA damage.
  • DDR DNA damage response
  • anti-cancer agents targeting DDR have been known and developed, e.g., PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1/2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC- 0575,
  • a pharmaceutical composition including the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a 217 pharmaceutical acceptable carrier, wherein the composition may be administered simultaneously, separately or sequentially with additional DDR targeting anti-cancer agent described above.
  • a method of treating or preventing diseases or disorders mediated by PARG, in a subject comprising administering to the subject the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the method may further comprise administering additional DDR targeting anti-cancer agent described above to the subject.
  • kits comprising: [1547] - a first pharmaceutical composition or dosage form comprising the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers; and [1548] - a second pharmaceutical composition or dosage form comprising additional DDR targeting anti-cancer agent described above, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers.
  • the kit is for use in a method of treating and/or preventing diseases or disorders mediated by PARG.
  • the first pharmaceutical composition or dosage form may be administered simultaneously, separately or sequentially with second pharmaceutical composition or dosage form.
  • the kit may further comprise a package insert comprising an instruction for simultaneous, sequential or separate use in the treatment and/or prevention of diseases or disorders mediated by PARG.
  • the present disclosure further relates to a pharmaceutical composition, comprising a pharmaceutically effective amount of one or more of the compounds disclosed herein, and a pharmaceutically acceptable carrier(s) and/or excipient(s).
  • the composition may further comprise at least one of additional therapeutic agents in amounts effective for achieving the treatment or prevention of diseases or disorders disclosed herein.
  • the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by PARG, in a subject in need of treatment or prevention, comprising administering to the subject at least one compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)
  • a non-human animal e.g., a mammal such as primates (e.g.,
  • the subject is a human. In some embodiments, the subject is a non-human animal.
  • the pharmaceutical composition of the present disclosure can be administered via various routes, including, but not limited to, oral, parenteral (injected), (e.g., intravenous, subcutaneous, intramuscular, intravascular administration, or infusion), sublingual, topical, transdermal, ocular, rectal, nasal, and vaginal administration.
  • the pharmaceutical composition provided herein is administered in a pharmaceutically effective amount.
  • the pharmaceutically effective amount of the pharmaceutical composition may be in the range of about 0.01 mg to about 500 mg/kg of body weight, or about 10 mg to about 500 mg/kg of body weight.
  • the amount may be in the range of about 0.1 mg to about 250 mg/kg of body weight, or 219 about 0.1 mg to about 10 mg/kg of body weight, or about 0.1 mg to about 1 mg/kg of body weight. In another embodiment, the amount be in the range of about 1 mg to about 100 mg/kg of body weight, preferably, about 10 mg to about 100 mg/kg of body weight.
  • the amount of the composition to be administered will typically be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound to be administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
  • the pharmaceutical composition may, for example, be in a form suitable for oral administration such as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection such as a sterile solution, suspension or emulsion, for topical administration such as an ointment or cream, or for rectal administration such as a suppository.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient, and a compound of the present disclosure as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring 220 matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • the pharmaceutical composition of the present disclosure may be administered in a single dose or in multiple doses. Dosing may occur one time, two times, three times, four times, five times, six times, or more than six times per day. Dosing may occur once a month, once every two weeks, once a week, or once every other day. In some cases, continuous dosing is achieved and maintained as long as necessary. In some embodiments, the pharmaceutical composition of the present disclosure is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days.
  • the pharmaceutical composition of the present disclosure is administered for less than 28, 14, 7, 6, 5, 4, 3, or 2 days, or for less than 1 day. In some embodiments, the pharmaceutical composition of the present disclosure is administered chronically on an ongoing basis. [1566] [1567] It is noted that the compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention should be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed herein (including any accompanying claims, and abstract), and/or all of the steps of any method or process disclosed herein, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted by the details of any of the foregoing embodiments.
  • each reaction is carried out in an inert solvent at a temperature from room temperature to reflux temperature (e.g., 0 o C to 100 o C, or alternatively 0 o C to 80 o C).
  • the reaction time is usually 0.1-60 hours, or alternatively 0.5- 24 hours.
  • N- methoxymethanamine;hydrochloride (26.94 g, 276.17 mmol) was added to the above mentioned solution, and the resulting mixture was warmed to 20 °C and stirred at 20 °C for 12.5 h.
  • the reaction mixture was concentrated under reduced pressure to obtain a residue.
  • the residue was dissolved in EtOAc (800 mL), then washed with 10% aqueous citric acid 225 (500 mL ⁇ 3), 10% aqueous NaHCO 3 (500 mL ⁇ 3), saturated aqueous sodium chloride (500 mL ⁇ 3), and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue.
  • Solution 1 tert-butyl N-[(1S)-1-[methoxy(methyl)carbamoyl]-2-methyl- propyl]carbamate (45 g, 172.86 mmol) was added to THF (675 mL) under N2;
  • Solution 2 MeMgCl (3 M in THF, 230.48 mL) under N2;
  • Solution 1 was pumped by Pump 1 ⁇ S1, P1, 3 mL/min ⁇ to flow reactor 1 ⁇ FLR1, Others, CSTRs, 12 mL, -10 °C ⁇ .
  • Solution 2 was pumped by Pump 2 ⁇ S2, P2, 3 mL/min ⁇ to flow reactor 1 ⁇ FLR1, Others, CSTRs, 12 mL, -10 °C ⁇ . [1627] The resulting solution was further stirred at flow reactor 2 ⁇ FLR2, Others, CSTRs, 60 mL, 15 °C ⁇ . [1628] The residence time of flow reactor 1 was ⁇ FLR1, 2 min ⁇ . [1629] The residence time of flow reactor 2 was ⁇ FLR2, 10.000 min ⁇ . [1630] The mixture was collected with a bottle (containing sat. NH4Cl) at 0 °C under N2. [1631] Pump 1 and Pump 2 were started at the same time.
  • Step 3 Synthesis of tert-butyl N-[(1S)-2,2-difluoro-1-isopropyl-propyl]carbamate [1639] To a solution of tert-butyl N-[(1S)-1-acetyl-2-methyl-propyl]carbamate (6.0 g, 27.87 mmol) in DCM (60 mL) was added BAST (30.83 g, 139.35 mmol, 30.52 mL) at 0 °C under nitrogen atmosphere, then the reaction mixture was warmed to 25 °C and stirred at 25 °C for 36 h.
  • reaction mixture was stirred at 25 °C for 1 h under N2 atmosphere.
  • the reaction mixture was poured into H2O (150 mL) and extracted with Ethyl acetate (150 mL ⁇ 3).
  • the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a tert-butyl N-[2-(benzylamino)-1,1-dimethyl-ethyl]carbamate (15 g, 50.65 mmol, 95% yield) as a white solid.
  • Step 2 Synthesis of tert-butyl N-[2-[benzyl-(2-chloroacetyl)amino]-1,1-dimethyl- ethyl]carbamate
  • TEA 7.27 g, 71.84 mmol, 10.00 mL
  • Step 3 Synthesis of tert-butyl 4-benzyl-2,2-dimethyl-5-oxo-piperazine-1-carboxylate [1657] To a solution of tert-butyl N-[2-[benzyl-(2-chloroacetyl)amino]-1,1-dimethyl- ethyl]carbamate (19.12 g, 53.88 mmol) in MeCN (260 mL) was added Cs2CO3 (35.11 g, 107.76 mmol). The mixture was degassed and purged with N 2 3 times. The reaction mixture was stirred at 60 °C for 4 h under N2 atmosphere.
  • Step 4 Synthesis of tert-butyl 4-benzyl-6-(benzyloxymethyl)-2,2-dimethyl-5-oxo- piperazine-1-carboxylate
  • tert-butyl 4-benzyl-2,2-dimethyl-5-oxo-piperazine-1-carboxylate (2.23 g, 7.00 mmol) in THF (35 mL) was added dropwise LiHMDS (1 M, 10.51 mL, in hexane solution) at -70 °C.
  • the mixture was degassed and purged with N23 times.
  • the reaction mixture was stirred at -70 °C for 30 min under N2 atmosphere.
  • chloromethoxymethylbenzene (1.65 g, 10.51 mmol, 1.45 mL) was added dropwise to the above mentioned mixture.
  • the mixture was degassed and purged with N 2 3 times.
  • the reaction mixture was stirred at -70 °C for 1 h under N2 atmosphere.
  • the reaction mixture was quenched with HCl aq. (1 M, 25 mL) and diluted with H2O (100 mL).
  • the mixture was extracted with Ethyl acetate (100 mL ⁇ 3).
  • the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue.
  • the reaction mixture was stirred at 20 °C for 1 h and 50 °C for 2 h under N2 atmosphere.
  • the reaction mixture was quenched with MeOH (15 mL) at 0 °C.
  • the reaction mixture was stirred at 20 °C for 1 h and 50 °C for 2 h under N2 atmosphere.
  • the reaction mixture was concentrated under reduced pressure to obtain a residue.
  • the residue was triturated with commercial hexanes (3 mL) at 20 °C for 0.5 h.
  • the suspension was filtered and the filter cake was collected and concentrated under reduced pressure to obtain the crude product.
  • Step 6 Synthesis of 1-benzyl-5-(benzyloxymethyl)-3,3-dimethyl-piperazine [1673] To a solution of tert-butyl 4-benzyl-6-(benzyloxymethyl)-2,2-dimethyl-piperazine-1- carboxylate (1.128 g, 2.66 mmol) in DCM (12 mL) was added TFA (3 mL). The mixture was degassed and purged with N 2 3 times. The reaction mixture was stirred at 25 °C for 1 h under N2 atmosphere.
  • the suspension was degassed and purged with Ar 3 times. Then the suspension was degassed and purged with H23 times. The mixture was stirred under H2 (50 Psi) at 50 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was slurried with commercial hexanes (5 mL) at 25 °C for 30 min. The mixture was filtered. The filter cake was washed with commercial hexanes (2 mL ⁇ 2) and concentrated under reduced pressure to obtain (6,6-dimethylpiperazin-2-yl)methanol (673 mg, 2.48 mmol, 94% yield, TFA) as a white solid.
  • Step 2 Synthesis of (2S,2'S)-(benzylazanediyl)bis(3-methoxypropane-1,2-diyl) diethanesulfonate
  • (2S)-1-[benzyl-[(2S)-2-hydroxy-3-methoxy-propyl]amino]-3- methoxy-propan-2-ol (4.0 g, 14.12 mmol) in DCM (40 mL) were added TEA (4.29 g, 42.35 mmol, 5.89 mL) and ethanesulfonyl chloride (5.45 g, 42.35 mmol, 4.01 mL) dropwise at 0 °C under nitrogen atmosphere.
  • Step 3 Synthesis of (2R,6R)-1,4-dibenzyl-2,6-bis(methoxymethyl)piperazine & (2R,6S)-1,4-dibenzyl-2,6-bis(methoxymethyl)piperazine [1693] To a solution of [(1S)-1-[[benzyl-[(2S)-2-ethylsulfonyloxy-3-methoxy- propyl]amino]methyl]-2-methoxy-ethyl] ethanesulfonate (6.60 g, crude) in EtOH (94 mL) were added TEA (5.71 g, 56.46 mmol, 7.86 mL) and BnNH 2 (8.10 g, 21.17 mmol, 8.24 mL).
  • reaction mixture was heated to 80 °C and stirred for 2 hr under nitrogen atmosphere to obtain a brown suspension.
  • the reaction mixture was concentrated under reduced pressure to obtain a residue.
  • the residue was purified by flash silica gel 233 chromatography to obtain a crude product (1.32 g, the mixture of (2R,6R)-1,4-dibenzyl- 2,6-bis(methoxymethyl)piperazine & (2R,6S)-1,4-dibenzyl-2,6- bis(methoxymethyl)piperazine.
  • the reaction mixture was stirred for 4 h at this temperature, and then was warmed to 25 °C and stirred for further 8 h under N2 atmosphere.
  • the reaction mixture was filtered and the filter cake was washed with EtOAc (30 mL ⁇ 3).
  • the combined filtrate was diluted with EtOAc (50 mL) and washed with saturated aqueous Na2S2O3 (160 mL ⁇ 2), 10 % aqueous citric acid (160 mL), brine (160 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue.
  • Step 4 Synthesis of (6S)-8-benzyl-6-methyl-2-oxa-5,8-diazaspiro[3.5]nonane
  • Step 1 To a 40 mL vial were added bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridyl]phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (8.96 mg, 7.99 ⁇ mol) and 4A MS (100 mg).
  • Step 2 (2S)-N1-benzyl-N1-(trimethylsilylmethyl)propane-1,2-diamine (200 mg, 798.55 ⁇ mol) + oxetan-3-one (200 mg, 2.78 mmol) was dissolved in MeCN (12 mL) : CF 3 CH 2 OH (4 mL); [1721] Step 3: The reaction vial was capped, and the capped vial was placed in a Penn OC reactor for 16 hr at 25 °C. [450 nm, 1000 rpm stirring, 100% intensity of light, max fan cooling] [1722] The reaction mixture was concentrated under reduced pressure to obtain a residue.
  • reaction mixture was stirred at 25 °C for 1 hr under nitrogen atmosphere. Then the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in DCM (204 mL) and the reaction 238 mixture was cooled to -78 °C. TEA (10.36 g, 102.34 mmol, 14.24 mL) was added, then followed by the dropwise addition of a solution of methylsulfonyl methanesulfonate (9.36 g, 53.73 mmol) in DCM (54 mL). The reaction mixture was stirred at -78 °C for 1.5 hr under nitrogen atmosphere.
  • Step 3 Synthesis of 5-benzyl 2-(tert-butyl) (S)-6-methyl-7-oxo-2,5,8- triazaspiro[3.5]nonane-2,5-dicarboxylate [1743] To a solution of tert-butyl (6S)-6-methyl-7-oxo-2,5,8-triazaspiro[3.5]nonane-2- carboxylate (2.67 g, crude) in THF (30 mL) and H 2 O (10 mL) were added NaHCO 3 (2.64 g, 31.37 mmol) and CbzCl (2.68 g, 15.69 mmol, 2.24 mL).
  • reaction mixture was stirred at 25 °C for 12 hr under nitrogen atmosphere.
  • the reaction mixture was poured into water (50 mL) and extracted with EtOAc (80 mL ⁇ 3). The combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue.
  • the residue was purified by flash silica gel chromatography to obtain 5-benzyl 2-(tert-butyl) (S)-6-methyl-7-oxo-2,5,8-triazaspiro[3.5]nonane-2,5- dicarboxylate (3.03 g, 7.22 mmol, 69% yield) as a light yellow oil.
  • Step 4 Synthesis of 5-benzyl 2-(tert-butyl) (S)-6-methyl-2,5,8-triazaspiro[3.5]nonane- 2,5-dicarboxylate
  • the reaction was a flow chemistry: [1749] Solution 1: 5-benzyl 2-(tert-butyl) (S)-6-methyl-7-oxo-2,5,8-triazaspiro[3.5]nonane- 2,5-dicarboxylate (3.03 g, 7.78 mmol) in THF (30 mL); [1750] Solution 2: BH 3 -Me 2 S (10 M, 2.33 mL) in THF (2.33 mL).
  • Solution 1 was pumped by Pump 1 ⁇ S1, P1, 2.952 mL/min ⁇ to flow reactor 1 ⁇ FLR1, PFA, Coils reactor, 3.175(1/8")mm, 59.84055 mL, 60.0°C ⁇ .
  • Solution 2 was pumped by Pump 2 ⁇ S2, P2, 3.032 mL/min ⁇ to flow reactor 1 ⁇ FLR1, PFA, Coils reactor, 3.175(1/8")mm, 59.84055 mL, 60.0°C ⁇ .
  • the residence time of flow reactor 1 ⁇ FLR1, 10.0 min ⁇ . 240 [1754] The mixture was collected with a bottle (Quenched by MeOH (40 mL) at 0 °C).
  • Step 2 Synthesis of 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2- carbonitrile
  • Et3N 8.78 g, 86.78 mmol, 12.08 mL
  • 4-nitrobenzenesulfonyl chloride 243 (12.50 g, 56.41 mmol
  • Step 3 Synthesis of 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2-carboxylic acid
  • HCl 6 M, 16.60 mL
  • Step 4 Synthesis of benzyl 1-benzyl-6,6-dimethyl-4-(4-nitrophenyl)sulfonyl- piperazine-2-carboxylate
  • Step 4 Synthesis of benzyl 1-benzyl-6,6-dimethyl-4-(4-nitrophenyl)sulfonyl- piperazine-2-carboxylate
  • 692 To a solution of 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2-carboxylic acid (920 mg, crude, HCl) in CH3CN (20 mL) were added bromomethylbenzene (1.60 g, 9.38 mmol, 1.11 mL), K 2 CO 3 (2.96 g, 21.44 mmol) and KI (1.11 g, 6.70 mmol) under N 2 244 atmosphere.
  • the reaction mixture was stirred at 85 °C for 12 h under N 2 atmosphere.
  • the reaction mixture was poured into water (50 mL) and extracted with EtOAc (80 mL ⁇ 3). The combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue.
  • the residue was purified by flash silica gel chromatography to obtain benzyl 1-benzyl-6,6-dimethyl-4-(4- nitrophenyl)sulfonyl-piperazine-2-carboxylate (848 mg, 983.07 ⁇ mol, 36.69% yield, 60.7% purity) as a brown oil.
  • Step 5 Synthesis of benzyl 1-benzyl-6,6-dimethyl-piperazine-2-carboxylate [1797] To a solution of benzyl 1-benzyl-6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine- 2-carboxylate (848 mg, 1.62 mmol) in CH3CN (12 mL) and DMF (1.2 mL) were added K 2 CO 3 (447.68 mg, 3.24 mmol) and 4-methoxybenzenethiol (681.20 mg, 4.86 mmol) under N2 atmosphere.
  • Step 6 Synthesis of 6,6-dimethylpiperazine-2-carboxylic acid [1801] To a solution of benzyl 1-benzyl-6,6-dimethyl-piperazine-2-carboxylate (200 mg, 590.94 ⁇ mol) in HFIP (10 mL) was added wet Pd/C (60 mg, 10% purity) under Ar 2 atmosphere. The suspension was degassed and purged with Ar 3 times. Then the suspension was degassed and purged with H 2 3 times. The reaction mixture was stirred under H2 (50 Psi) at 50 °C for 12 h.
  • Step 7 Synthesis of methyl 6,6-dimethylpiperazine-2-carboxylate
  • SOCl2 300.81 mg, 2.53 mmol
  • the reaction mixture was stirred at 50 °C for 12 h under N2 atmosphere.
  • the reaction mixture was concentrated under reduced pressure to obtain methyl 6,6-dimethylpiperazine- 2-carboxylate (125 mg, crude, 2HCl) as a brown solid, which was directly used for the next step without further purification.
  • Step 2 Synthesis of Ethyl 6-bromo-8-chloroimidazo[1,2-a]pyridine-3-carboxylate [1818] To a solution of 5-bromo-3-chloro-pyridin-2-amine (2.14 g, 10.32 mmol) and potassium (Z)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (7.79 g, 41.27 mmol) in EtOH (120 mL) at 25 °C was added H 2 SO 4 (3.04 g, 31.95 mmol, 1.66 mL). The reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to 25 °C.
  • Step 3 Synthesis of 6-bromo-8-chloro-imidazo[1,2-a]pyridine-3-carbohydrazide
  • ethyl 6-bromo-8-chloro-imidazo[1,2-a]pyridine-3-carboxylate (1.76 g, 5.81 mmol) in EtOH (35 mL) was added NH2NH2 ⁇ H2O (3.49 g, 69.73 mmol) at 25 °C.
  • the mixture was heated to 80 °C and stirred at 80 °C under an N 2 atmosphere for 12 h.
  • the mixture was cooled to 25 °C.
  • Step 4 Synthesis of 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,2-a]pyridine- 3-carbohydrazide
  • 6-bromo-8-chloro-imidazo[1,2-a]pyridine-3-carbohydrazide (1.24 g, 4.27 mmol) in THF (30 mL) was added TEA (864 mg, 8.54 mmol) and (2,2-difluoroacetyl) 2,2-difluoroacetate (817.4 mg, 8.54 mmol). The mixture was stirred at 25 °C under an N 2 atmosphere for 1 h.
  • Step 5 Synthesis of 2-(6-Bromo-8-chloroimidazo[1,2-a]pyridin-3-yl)-5- (difluoromethyl)-1,3,4-selenadiazole
  • 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,2-a]pyridine-3- carbohydrazide 514 mg, 1.40 mmol
  • Wollin’s reagent 7.44 mg, 1.40 mmol
  • the reaction mixture was diluted with H 2 O (20 mL), and extracted with DCM (30 mL x 3). The organic phases were dried over anhydrous Na2SO4, filtered and concentrated to obtain a residue.
  • the crude residue was purified by column chromatography on silica gel eluting with 0 ⁇ 40% EtOAc in petroleum ether to obtain 2-(6- Bromo-8-chloroimidazo[1,2-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-selenadiazole (205 mg, 0.50 mmol, 35% yield) as a yellow solid.
  • the suspension was degassed under vacuum and purged with N 2 three times.
  • the mixture was heated to 100 °C and stirred at 100 °C under an N 2 atmosphere for 2 h.
  • the mixture was diluted with H2O (10 mL) and extracted with DCM (30 mL ⁇ 3), the combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the residue.
  • Step 7 Synthesis of 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride [1843] To a mixture of 2-(6-benzylsulfanyl-8-chloro-imidazo[1,2-a]pyridin-3-yl)-5- (difluoromethyl)-1,3,4-selenadiazole (34.6 mg, 0.08 mmol) in AcOH (0.54 mL) and H2O (0.18 mL) was added NCS (40.5 mg, 0.30 mmol) at 5 °C.
  • Step 9 Synthesis of tert-butyl (2S,6S)-4-[3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]-6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6-dimethyl- piperazine-1-carboxylate [1852] To a solution of 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-N-(1- methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (65.5 mg, 0.14 mmol) in dioxane (1.4 mL) was added tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (60.1 mg, 0.28 mmol), Cs2CO3 (
  • the suspension was degassed under vacuum and purged with N2 three times.
  • the mixture was heated to 100 °C and stirred at 100 °C under an N2 atmosphere for 16 h.
  • the mixture was 251 diluted with H 2 O (10 mL) and extracted with DCM (30 mL ⁇ 3), the combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the residue.
  • Step 10 Synthesis of 3-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide
  • the suspension was degassed under vacuum and purged with an N2 atmosphere three times.
  • the mixture was heated to 100 °C and stirred at 100 °C under an N 2 atmosphere for 2 h.
  • the mixture was cooled to 25 °C and diluted with H2O (50 mL) and extracted with EtOAc (30 mL ⁇ 3). The organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue.
  • Step 2 Synthesis of 6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl) imidazo [1, 2-a] pyridine
  • Step 2 Synthesis of 6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl) imidazo [1, 2-a] pyridine
  • To a mixture of 5-benzylsulfanyl-3-chloro-pyridin-2-amine (5.0 g, 19.94 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (4.76 g, 21.93 mmol) in EtOH (100 mL) was added NaHCO 3 (2.01 g, 23.93 mmol) at 25 °C. The mixture was heated to 85°C and stirred at 85°C under an N2 atmosphere for 12 h.
  • Step 3 Synthesis of 2-[6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl)imidazo[1,2- a]pyridin-3-yl]-5-(difluoromethyl)-1,3,4-selenadiazole
  • Solution 1 6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (2.2 g, 5.96 mmol) , 2-bromo-5-(difluoromethyl)-1,3,4-selenadiazole (3.12 g, 11.93 mmol), bis[2-(2-pyridyl)phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (272.56 mg, 298.22 ⁇ mol), N-cyclohe
  • Step 4 Synthesis of 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-2-(4- fluorophenyl)imidazo[1,2-a]pyridine-6-sulfonyl chloride
  • 2-[6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl)imidazo[1,2- a]pyridin-3-yl]-5-(difluoromethyl)-1,3,4-selenadiazole (163.99 mg, 298.23 ⁇ mol) in CH3CN (5 mL), H2O (200 ⁇ L) and AcOH (100 ⁇ L) was added 1,3-dichloro-5,5-dimethyl- imidazolidine-2,4-dione (88.14 mg, 447.35 ⁇ mol) at 0-5 °C in an ice-bath.
  • Step 7 Synthesis of 3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-8-[(3S,5S)-3,5- dimethylpiperazin-1-yl]-2-(4-fluorophenyl)-N-(1-methylcyclopropyl)imidazo[1,2- a]pyridine-6-sulfonamide TFA salt
  • Step 2 Synthesis of ethyl 6-bromo-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridine-3- carboxylate
  • the reaction mixture was concentrated under reduced pressure to obtain a residue, the residue was dissolved in EtOAc (1000 mL), then washed with HCl (1 M, 600 mL ⁇ 3) and saturated aqueous sodium chloride (800 mL), then dried over anhydrous Na 2 SO4, filtered and concentrated under reduced pressure to obtain a residue.
  • the residue was purified by flash silica gel chromatography to obtain a crude product (10.5 g), the crude product was slurred with EtOAc (8 mL) at 25 °C for 0.5 hr, then filtered, the filter cake was washed with EtOAc (2 mL) and collected the white solid.
  • Step 3 Synthesis of ethyl 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2- a]pyridine-3-carboxylate
  • ethyl 6-bromo-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridine-3- carboxylate 2.3 g, 6.69 mmol
  • phenylmethanethiol 997.1 mg, 8.03 mmol, 940.6 ⁇ L
  • Xantphos (774.20 mg, 1.34 mmol
  • DIEA 4.33 g, 33.47 mmol, 263 5.83 mL
  • Pd 2 (dba) 3 (1.23 g,1.34 mmol).
  • Step 4 Synthesis of 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridine- 3-carbohydrazide
  • ethyl 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2- a]pyridine-3-carboxylate (2 g, 5.17 mmol) in EtOH (35 mL) was added NH2NH2 ⁇ H2O (16.74 g, 284.31 mmol, 16.23 mL, 85% purity) dropwise at 25 °C.
  • the mixture was heated and stirred at 80 °C under N2 atmosphere for 12 h.
  • Step 5 Synthesis of 6-benzylsulfanyl-8-chloro-2-cyclopropyl-N'-(2,2- difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide 264
  • 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridine-3- carbohydrazide (1.87 g, 5.02 mmol) in THF (33 mL) were added TEA (1.27 g, 12.54 mmol, 1.75 mL) and (2,2-difluoroacetyl) 2,2-difluoroacetate (1.05 g, 6.02 mmol).
  • Step 7 Synthesis of 8-chloro-2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol- 2-yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride
  • 2-(6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridin-3- yl)-5-(difluoromethyl)-1,3,4-selenadiazole 243 mg, 490.08 ⁇ mol
  • AcOH 3.517 mL
  • H2O (1.1506 mL
  • Step 8 Synthesis of tert-butyl (2S,6S)-4-[2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4- selenadiazol-2-yl]-6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6- dimethyl-piperazine-1-carboxylate [1946] To a solution of 8-chloro-2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride (53 mg, 112.25 ⁇ mol) in DCM (0.6 mL) were added 4A MS (0.05 g, 112.25 ⁇ mol), TEA (34.08 mg, 336.75 ⁇ mol, 46.87 ⁇ L) and 1- methylcyclopropyl chloride (53 mg,
  • Step 9 Synthesis of tert-butyl (2S,6S)-4-[2-cyclopropyl-6-[[(1S)-2,2-difluoro-1- isopropyl-propyl]sulfamoyl]-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]imidazo[1,2- a]pyridin-8-yl]-2,6-dimethyl-piperazine-1-carboxylate [1950] To a solution of 8-chloro-2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (20 mg, 39.46 ⁇ mol) in dioxane (1.5 mL) were added tert-butyl (2S,6S)-2,6-
  • Step 4 Synthesis of 6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2-a]pyridine-3- carbohydrazide
  • ethyl 6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2- a]pyridine-3-carboxylate 822 mg, 2.05 mmol
  • EtOH 12 mL
  • NH 2 NH 2 .H 2 O 2.57 g, 51.26 mmol, 2.49 mL, 100% purity
  • Step 5 Synthesis of 6-benzylsulfanyl-8-chloro-2-cyclobutyl-N'-(2,2- difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide
  • 6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2-a]pyridine-3- carbohydrazide 928 mg, 2.40 mmol
  • THF 20 mL
  • Step 8 Synthesis of 8-chloro-2-cyclobutyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol- 2-yl]-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide
  • 8-chloro-2-cyclobutyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride (93 mg, 191.29 ⁇ mol) in DCM (3 mL) were added 4A MS (0.1 g, 191.29 ⁇ mol), 1-methylcyclopropanamine;hydrochloride (30.87 mg, 286.93 ⁇ mol) and TEA (58.07 mg, 573.86 ⁇ mol, 79.87 ⁇ L) at 5 °C.
  • Step 9 Synthesis of tert-butyl (2S,6S)-4-[2-cyclobutyl-3-[5-(difluoromethyl)-1,3,4- selenadiazol-2-yl]-6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6- dimethyl-piperazine-1-carboxylate [1997] To a solution of 8-chloro-2-cyclobutyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (50 mg, 96.00 ⁇ mol) in dioxane (2.5 mL) were added tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate 284 (41
  • Step 2 Synthesis of 2-(6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2- a]pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-selenadiazole
  • 6-benzylsulfanyl-8-chloro-2-cyclopropyl-N'-(2,2,2- trifluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide 843 mg, 1.80 mmol
  • toluene 22 mL
  • 2,4-diphenyl-2,4-diselenoxo-1,3,2,4diselenadiphosphetane (1.15 g, 2.16 mmol).
  • Step 3 Synthesis of 8-chloro-2-cyclopropyl-3-[5-(trifluoromethyl)-1,3,4-selenadiazol- 2-yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride [2021] To a solution of 2-(6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridin-3- yl)-5-(trifluoromethyl)-1,3,4-selenadiazole (200 mg, 389.24 ⁇ mol) in AcOH (2.8943 mL) and H2O (0.947 mL) was added NCS (207.90 mg, 1.56 mmol) at 5 °C.
  • Step 4 Synthesis of 8-chloro-2-cyclopropyl-N-(1-methylcyclopropyl)-3-[5- (trifluoromethyl)-1,3,4-selenadiazol-2-yl]imidazo[1,2-a]pyridine-6-sulfonamide
  • 8-chloro-2-cyclopropyl-3-[5-(trifluoromethyl)-1,3,4-selenadiazol-2- yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride 158 mg, 322.35 ⁇ mol
  • 4A MS 0.2 g
  • 1-methylcyclopropanamine;hydrochloride 52.02 mg, 483.53 ⁇ mol
  • TEA 97.86 mg, 967.06 ⁇ mol, 134.60 ⁇ L
  • Step 5 Synthesis of tert-butyl (2S,6S)-4-[2-cyclopropyl-6-[(1- methylcyclopropyl)sulfamoyl]-3-[5-(trifluoromethyl)-1,3,4-selenadiazol-2- yl]imidazo[1,2-a]pyridin-8-yl]-2,6-dimethyl-piperazine-1-carboxylate [2030] To a solution of 8-chloro-2-cyclopropyl-N-(1-methylcyclopropyl)-3-[5- (trifluoromethyl)-1,3,4-selenadiazol-2-yl]imidazo[1,2-a]pyridine-6-sulfonamide (50 mg, 95.27 ⁇ mol) in dioxane (2 mL) were added tert-butyl (2S,6S)-2,6-dimethylpiperazine-1- carboxylate (40.83
  • Step 3 Synthesis of ethyl 5-(benzylthio)-7-fluoropyrazolo[1,5-a]pyridine-3- carboxylate
  • ethyl 5-bromo-7-fluoropyrazolo[1,5-a]pyridine-3-carboxylate 1.15 g, 3.35 mmol
  • dioxane 30 mL
  • phenylmethanethiol 498.55 mg, 4.01 mmol, 470.3 ⁇ L
  • Xantphos 387.1 mg, 0.67 mmol
  • DIEA (2.17 g, 16.7 mmol, 2.91 mL
  • Pd2(dba)3 (0.62 g, 0.67 mmol).
  • Step 4 Synthesis of 5-(benzylthio)-7-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid
  • ethyl 5-(benzylthio)-7-fluoropyrazolo[1,5-a]pyridine-3-carboxylate 919 mg, 2.78 mmol
  • LiOH 133 mg, 5.56 mmol
  • the mixture was stirred at 80 °C under N 2 atmosphere for 6 h.
  • the mixture was extracted with EtOAc (50 mL ⁇ 3).
  • Step 5 Synthesis of 5-(benzylthio)-N'-(2,2-difluoroacetyl)-7-fluoropyrazolo[1,5- a]pyridine-3-carbohydrazide
  • Step 7 Synthesis of 3-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-7- fluoropyrazolo[1,5-a]pyridine-5-sulfonyl chloride [2081] To a solution of 2-(5-(benzylthio)-7-fluoropyrazolo[1,5-a]pyridin-3-yl)-5- (difluoromethyl)-1,3,4-selenadiazole (543 mg, 1.24 mmol) in AcOH (2.0 mL) and H2O (1.0 mL) was added NCS (660.5 mg, 4.94 mmol) at 5 °C.
  • Step 8 Synthesis of N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4- selenadiazol-2-yl)-7-fluoropyrazolo[1,5-a]pyridine-5-sulfonamide
  • Step 8 Synthesis of N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4- selenadiazol-2-yl)-7-fluoropyrazolo[1,5-a]pyridine-5-sulfonamide
  • Step 9 Synthesis of N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4- selenadiazol-2-yl)-7-((3S,5S)-3,5-dimethylpiperazin-1-yl)pyrazolo[1,5-a]pyridine-5- sulfonamide
  • N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-selenadiazol-2- yl)-7-fluoropyrazolo[1,5-a]pyridine-5-sulfonamide 420.7 mg, 0.914 mmol
  • DMSO 2 mL
  • (2S,6S)-2,6-dimethylpiperazine 208.77 mg, 1.828 mmol
  • N,N- diisopropyl ethylamine 0.478 mL, 2.7
  • Step 4 Synthesis of 2-bromo-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4- selenadiazol-2-yl)-7-fluoropyrazolo[1,5-a]pyridine-5-sulfonamide
  • 2-bromo-3-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-7- fluoropyrazolo[1,5-a]pyridine-5-sulfonyl chloride 811 mg, 1.64 mmol) in DCM (5 mL) were added 4A MS (0.8 g), 1-aminocyclopropane-1-carbonitrile hydrochloride (233 mg, 1.97 mmol) and TEA (0.671 mL, 4.92 mmol) at 5 °C.
  • Step 5 Synthesis of N-(1-cyanocyclopropyl)-2-cyclopropyl-3-(5-(difluoromethyl)- 1,3,4-selenadiazol-2-yl)-7-fluoropyrazolo[1,5-a]pyridine-5-sulfonamide
  • 2-bromo-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4- selenadiazol-2-yl)-7-fluoropyrazolo[1,5-a]pyridine-5-sulfonamide 700 mg, 1.30 mmol
  • dioxane 2 mL
  • H2O 2 mL
  • cyclopropylboronic acid 129 mg, 1.94 mmol
  • XPhos-Pd-G3 55 mg, 64.78 ⁇ mol
  • K3PO4 825 mg, 3.89 mmol
  • the mixture was degassed and purged with N 2 3 times, and then the mixture was stirred at 100 °C under N 2 atmosphere for 2 h.
  • the mixture was filtered with celite and extracted with EtOAc (50 mL ⁇ 3).
  • the combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and and concentrated under reduced pressure to obtain a residue.
  • Step 2 Synthesis of ethyl 5-bromo-7-chloropyrazolo[1,5-a]pyridine-3-carboxylate [2130] To a solution of ethyl propiolate (53 mg, 0.543 mmol) and 1-amino-4-bromo-2- fluoropyridin-1-ium 2,4,6-trimethylbenzenesulfonate (185 mg, 0.452 mmol) in ACN (2.0 mL) was added K2CO3 (67 mg, 484.97 ⁇ mol) at 10 °C. The mixture was stirred at 10 °C under N 2 atmosphere for 12 h. The mixture was concentrated under reduced pressure to obtain a residue.
  • Step 3 Synthesis of ethyl 5-(benzylthio)-7-chloropyrazolo[1,5-a]pyridine-3- carboxylate
  • ethyl 5-bromo-7-chloropyrazolo[1,5-a]pyridine-3-carboxylate 117 mg, 0.385 mmol
  • dioxane 3 mL
  • phenylmethanethiol 57 mg, 0.462 mmol
  • Xantphos 22 mg, 0.04 mmol
  • DIEA 149 mg, 1.16 mmol, 202 ⁇ L
  • Pd 2 (dba) 3 (0.62 g, 0.67 mmol).
  • Step 4 Synthesis of 5-(benzylthio)-7-chloropyrazolo[1,5-a]pyridine-3-carboxylic acid 322 [2138] To a solution of ethyl 5-(benzylthio)-7-chloropyrazolo[1,5-a]pyridine-3-carboxylate (115 mg, 0.33 mmol) in THF/water (1 mL / 1mL) was added was added LiOH (16 mg, 0.66 mmol) at 0 °C. The mixture was stirred at 80 °C under N2 atmosphere for 6 h. The mixture was extracted with EtOAc (5 mL ⁇ 3).
  • Step 5 Synthesis of 5-(benzylthio)-7-chloro-N'-(2,2-difluoroacetyl)pyrazolo[1,5- a]pyridine-3-carbohydrazide
  • Step 9 Synthesis of 2-bromo-7-chloro-3-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)- N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyridine-5-sulfonamide
  • To a solution of 3-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-7-fluoropyrazolo[1,5- a]pyridine-5-sulfonyl chloride (53 mg, 0.10 mmol) in DCM (4 mL) were added 4A MS (100 mg), 1-aminocyclopropane-1-carbonitrile hydrochloride (15 mg, 0.13 mmol) and TEA ( 43 ⁇ L, 0.31 mmol) at 5 °C.
  • Step 2 Synthesis of 2-(6-bromo-4-fluoro-1H-benzo[d]imidazol-1-yl)-5- (difluoromethyl)-1,3,4-selenadiazole 328
  • 6-bromo-4-fluoro-1H-benzo[d]imidazole (2.91 g, 13.53 mmol) in DMF (40 mL) was added 2-bromo-5-(difluoromethyl)-1,3,4-selenadiazole (4.25 g, 16.24 mmol), K2CO3 (5.61 g, 40.60 mmol). The mixture was stirred at 55 °C under N2 atmosphere for 2 h.
  • Step 3 Synthesis of 2-(6-(benzylthio)-4-fluoro-1H-benzo[d]imidazol-1-yl)-5- (difluoromethyl)-1,3,4-selenadiazole
  • 2-(6-bromo-4-fluoro-1H-benzo[d]imidazol-1-yl)-5-(difluoromethyl)- 1,3,4-selenadiazole (4.89 g, 12.34 mmol) in dioxane (40 mL) were added phenylmethanethiol (1.84 g, 14.81 mmol), Xantphos (714 mg, 1.23 mmol), DIEA (4.79 g, 37.04 mmol, 6.45 mL) and Pd2(dba)3 (565 m g, 0.61 mmol).
  • Step 4 Synthesis of 1-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-4-fluoro-1H- benzo[d]imidazole-6-sulfonyl chloride [2187] To a solution of 2-(6-(benzylthio)-4-fluoro-1H-benzo[d]imidazol-1-yl)-5- (difluoromethyl)-1,3,4-selenadiazole (3.54 g, 8.05 mmol) in AcOH (12.0 mL) and H2O (4.0 329 mL) was added NCS (4.3 g, 32.2 mmol) at 5 °C.
  • Step 5 Synthesis of N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4- selenadiazol-2-yl)-4-fluoro-1H-benzo[d]imidazole-6-sulfonamide
  • N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4- selenadiazol-2-yl)-4-fluoro-1H-benzo[d]imidazole-6-sulfonamide [2191] To a solution of 1-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-4-fluoro-1H- benzo[d]imidazole-6-sulfonyl chloride (2.52 g, 6.07 mmol) in DCM (20 mL) were added 4A MS (2.0 g), 1-aminocyclopropane-1-carbonitrile hydrochloride (864 mg, 7.29
  • Step 4 Synthesis of N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4- selenadiazol-2-yl)-4-fluoro-1H-benzo[d]imidazole-6-sulfonamide
  • 2-chloro-1-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-4-fluoro-1H- benzo[d]imidazole-6-sulfonyl chloride 575.58 g, 1.28 mmol
  • 4A MS 0.5 g
  • 1-aminocyclopropane-1-carbonitrile hydrochloride 182 mg, 1.54 mmol
  • TEA 0.525 mL, 3.84 mmol
  • Step 5 Synthesis of N-(1-cyanocyclopropyl)-2-cyclopropyl-1-(5-(difluoromethyl)- 1,3,4-selenadiazol-2-yl)-4-fluoro-1H-benzo[d]imidazole-6-sulfonamide
  • N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)- 4-fluoro-1H-benzo[d]imidazole-6-sulfonamide 558 mg, 1.13 mmol) in dioxane (2 mL) /H2O (2 mL) were added cyclopropylboronic acid (145 mg, 1.70 mmol), XPhos-Pd-G3 (48 mg, 0.06 mmol), K3PO4 (720 mg, 3.39 mmol).
  • Step 5 Synthesis of N-(1-cyanocyclopropyl)-2-cyclopropyl-1-(5-(difluoromethyl)- 1,3,4-selenadiazol-2-yl)-4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-1H-benzo[d]imidazole-6- sulfonamide
  • N-(1-cyanocyclopropyl)-2-cyclopropyl-3-(5-(difluoromethyl)-1,3,4- selenadiazol-2-yl)-7-fluoropyrazolo[1,5-a]pyridine-5-sulfonamide (238 mg, 0.47 mmol) in DMSO (5 mL) were added (2S,6S)-2,6-dimethylpiperazine (107 mg, 0.94 mmol) and N,N- diisopropyl ethylamine (0.246
  • Step 2 Synthesis of 2-(6-(benzylthio)-2-chloro-4-fluoro-1H-benzo[d]imidazol-1-yl)- 5-(difluoromethyl)-1,3,4-selenadiazole
  • 2-(6-(benzylthio)-2-chloro-4-fluoro-1H-benzo[d]imidazol-1-yl)-5-(difluoromethyl)- 1,3,4-selenadiazole 751 mg, 2.27 mmol) in THF/water (5 mL / 5mL) was added was added LiOH (109 mg, 4.54 mmol) at 0 °C.
  • Step 3 Synthesis of 7-(benzylthio)-N'-(2,2-difluoroacetyl)-5-fluoroimidazo[1,5- a]pyridine
  • 2-(6-(benzylthio)-2-chloro-4-fluoro-1H-benzo[d]imidazol-1-yl)-5- (difluoromethyl)-1,3,4-selenadiazole (659 mg, 2.18 mmol) in THF was added 2,2- difluoroacetohydrazide (288 mg, 2.62 mmol), Triphenyl phosphine (858 mg, 3.27 mmol), Triethyl amine (0.894 mL, 6.54 mmol) at 25 °C.
  • Step 4 Synthesis of 2-(7-(benzylthio)-5-fluoroimidazo[1,5-a]pyridin-1-yl)-5- (difluoromethyl)-1,3,4-selenadiazole
  • Step 5 Synthesis of 2-(7-(benzylthio)-3-chloro-5-fluoroimidazo[1,5-a]pyridin-1-yl)-5- (difluoromethyl)-1,3,4-selenadiazole
  • 2-(7-(benzylthio)-5-fluoroimidazo[1,5-a]pyridin-1-yl)-5- (difluoromethyl)-1,3,4-selenadiazole (487 mg, 1.11 mmol) was added 2-Chloro-1,3- bis(methoxycarbonyl)guanidine (210 mg, 1.66 mmol) in CHCl3 (5 mL) .
  • Step 3 Synthesis of ethyl 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carboxylate
  • POCl3 124 g, 809.0 mmol
  • Equal volume of 2X substrate mix (200 uM TFMU-ADPr, 25 mM Tris-HCl pH 7.5, 12.5 mM NaCl, 0.5 mM MgCl 2 , 5% Glycerol, 0.01% BSA(w/v), 0.01% Triton X-100, 1 mM DTT) was added.
  • DMSO without a test compound was used as control for 100% activity.
  • Reactions without PARG enzyme were used as control for 100% inhibition.
  • the reaction mixture was incubated at room temperature for 30 minutes and the fluorescence was measured (Excitation 385nm, Emission 502nm) using a multi plate reader, EnSight (PerkinElmer).

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Abstract

L'invention concerne de nouveaux dérivés de composés aryle ou hétéroaryle, des compositions contenant les composés, et des procédés de préparation et des utilisations de ceux-ci. Les dérivés aryle ou hétéroaryle sont des composés représentés par la formule (I), la formule (II) et la formule (III) ou des tautomères, des stéréoisomères, des promédicaments, des formes cristallines, des formes marquées isotopiquement, des sels pharmaceutiquement acceptables, des hydrates ou des solvates de ceux-ci. Les composés et les compositions selon la présente divulgation peuvent être utilisés pour traiter des maladies ou des troubles médiés par PARG, en particulier, le cancer. Formule (I) ; Formule (II) ; Formule (III).
PCT/IB2025/058084 2024-08-09 2025-08-08 Dérivés de composés aryle ou hétéroaryle substitués et leur utilisation pharmaceutique Pending WO2026033475A1 (fr)

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