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WO2023192864A2 - Inhibiteurs de parp16 covalents - Google Patents

Inhibiteurs de parp16 covalents Download PDF

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Publication number
WO2023192864A2
WO2023192864A2 PCT/US2023/065045 US2023065045W WO2023192864A2 WO 2023192864 A2 WO2023192864 A2 WO 2023192864A2 US 2023065045 W US2023065045 W US 2023065045W WO 2023192864 A2 WO2023192864 A2 WO 2023192864A2
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pharmaceutically acceptable
compound
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tautomer
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WO2023192864A3 (fr
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Michael Cohen
Daniel BEJAN
Sunil SUNDALAM
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Oregon Health and Science University
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Oregon Health and Science University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring

Definitions

  • the present invention concerns phthalazinone compounds useful as inhibitors of PARP16 and methods of their use in the treatment of cancers and other diseases and disorders.
  • Phthalazinone compounds have been studied for use as PARP inhibitors, including olaparib, marketed as LYNPARZA® BY AstraZeneca and Merck, and those described in U.S. Pat. No. 6,903,098 (Lubisch et al.), U.S. Patent No. 7,196,085 (Martin et al.), U.S. Patent No. 7,407,957 (Javaid et al.), U.S. Pat. No.
  • PARP16 is an endoplasmic reticulum ⁇ resident (ER ⁇ resident), mono ⁇ ADP ⁇ ribosyl transferase that has been gaining attention as a novel therapeutic target. Recent studies have revealed PARP16 ⁇ dependent vulnerabilities, such as regulation of protein synthesis, can be exploited to treat cancer. Additionally, PARP16 has been identified as an off ⁇ target of talazoparib—an approved PARP1 inhibitor— in small cell lung cancer, suggesting a potential pharmacology ⁇ based mechanism of action for talazoparib. These studies highlight the therapeutic potential for PARP16 inhibition.
  • RNA interference or CRISPR RNA interference
  • first ⁇ in ⁇ class covalent PARP inhibitors targeting PARP16, that elucidate the catalytic function of PARP16 in normal physiology and diseased states.
  • a first embodiment provides a compound of Formula (I): wherein: R 1 is selected from the group of H, halo, ⁇ OH, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, C 3 ⁇ 6 cycloalkyl, C 3 ⁇ 6 heterocyclyl, C 5 ⁇ 6 aryl, C 5 ⁇ 6 heteroaryl, ⁇ O ⁇ C 1 ⁇ 6 alkyl, ⁇ O ⁇ C 2 ⁇ 6 alkenyl, ⁇ O ⁇ C 2 ⁇ 6 alkynyl, ⁇ O ⁇ C 3 ⁇ 6 cycloalkyl, ⁇ O ⁇ C 5 ⁇ 6 heterocyclyl, ⁇ O ⁇ C 5 ⁇ 6 aryl, ⁇ O ⁇ C 5 ⁇ 6 heteroaryl, ⁇ SO 2 ⁇ C 3 ⁇ 6 cycloalkyl, ⁇ NH 2 , ⁇ NH(C 1 ⁇ 3 alkyl), ⁇ N(C 1 ⁇ 3 alkyl) 2 , C 2 ⁇ 6 alkynyl ⁇ NH 2 , C 2 ⁇
  • FIGURE 1A represents the crystal structure of the active site of PARP16 (PDB: 4F0D) overlaid with PARP1 (cyan, PDB: 5DS3) bound to olaparib.
  • FIGURE 1B provides a PARP family sequence alignment generated with T ⁇ Coffee multiple sequence alignment algorithm. The non ⁇ conserved D ⁇ loop cysteine (C169) of PARP16 is highlighted.
  • FIGURE 1C presents the structure of HJ ⁇ 52 and DB008, with the acrylamide warhead shown lighter gray in lighter gray at the lower right, and the dual selectivity/clickable alkyne handle at the left side of the structure.
  • FIGURE 1D graphs a biochemical activity assay to assess potency of olaparib, HJ ⁇ 52, and DB008 against PARP16; n ⁇ 3 biological replicates.
  • FIGURE 1E graphs a biochemical activity assay to assess potency of olaparib, HJ ⁇ 52, and DB008 against PARP16PARP1; n ⁇ 3 biological replicates.
  • FIGURE 2B represents cellular inhibition of PARP1 determined by treating HEK293T cells with a dose response of PARP inhibitors (30 min) followed by PARG inhibitor (15 min) to amplify the PARylation signal. Western blotting for PARylation was done using a Mono/Poly ADPr antibody from Cell Signaling Technology.
  • FIGURE 3A presents a model of DB008 covalently bound to C169 of PARP16 generated using Nir London method.
  • FIGURE 3B represents HEK293T cells transfected with Myc2x ⁇ tagged PARP16 WT or the C169S mutant, treated with a DB008 dose response for 2 hours, followed by lysis and clicking to TAMRA ⁇ azide for in ⁇ gel fluorescence detection of PARP16 labeling.
  • FIGURE 3D represents HEK293T cells transfected with Myc2x ⁇ tagged PARP16 WT, treated with a 300 nM DB008 on a time course, followed by lysis and clicking to TAMRA ⁇ azide for in ⁇ gel fluorescence detection of PARP16 labeling.
  • FIGURE 3F represents HAP1 WT and HAP1 PARP16 KO cells treated with a DB008 dose response for 2 hours, followed by lysis and clicking to TAMRA ⁇ azide for in ⁇ gel fluorescence detection of PARP16 labeling.
  • FIGURE 4A presents chemical structures of talazoparib and epigallocatechin gallate (EGCG).
  • FIGURE 4C represents a cellular competition assay wherein Myc2x ⁇ PARP16 expressing HEK293T cells were dosed with talazoparib and EGCG for 1 hour, then treated with DB008 (0.3 ⁇ M) for 30 min, followed by lysis and clicking to TAMRA ⁇ azide for in gel ⁇ fluorescence detection of PARP16 labeling.
  • a second embodiment provides a compound of Formula (I), as defined above, with the proviso that when R 2 is CN, ⁇ CH 2 CN, CF 3 , or CH 2 ⁇ CF 3 , R 3 is selected from the group of H, F, Cl, Br, I, and CH 3 ; or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • a third embodiment provides a compound of Formula (I), above, wherein: R 1 is selected from the group of H, halo, ⁇ OH, C 1 ⁇ 4 alkyl, C 2 ⁇ 4 alkenyl, C 2 ⁇ 4 alkynyl, C 3 ⁇ 6 cycloalkyl, C 3 ⁇ 6 heterocyclyl, C 5 ⁇ 6 aryl, C 5 ⁇ 6 heteroaryl, ⁇ O ⁇ C 1 ⁇ 4 alkyl, ⁇ O ⁇ C 2 ⁇ 4 alkenyl, ⁇ O ⁇ C 2 ⁇ 4 alkynyl, ⁇ O ⁇ cycloalkyl, ⁇ O ⁇ C 5 ⁇ 6 heterocyclyl, ⁇ O ⁇ C 5 ⁇ 6 aryl, ⁇ O ⁇ C 5 ⁇ 6 heteroaryl, ⁇ SO 2 ⁇ C 3 ⁇ 6 cycloalkyl, ⁇ NH 2 , ⁇ NH(C 1 ⁇ 3 alkyl), ⁇ N(C 1 ⁇ 3 alkyl) 2 , C 2 ⁇ 6 alkynyl ⁇ NH 2 , C 2 ⁇ 4 alkyn
  • a fourth embodiment provides a compound of Formula (I), as defined for the third embodiment, above, with the proviso that, when R 2 is CN, ⁇ CH 2 CN, CF 3 , or CH 2 ⁇ CF 3 , R 3 is selected from the group of H, F, Cl, Br, I, and CH 3 ; or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • a fifth embodiment provides a compound of Formula (I), above, wherein: R 1 is selected from the group of H, C 1 ⁇ 4 alkyl, C 2 ⁇ 3 alkenyl, C 2 ⁇ 3 alkynyl, C 2 ⁇ 6 alkynyl ⁇ NH 2 , C 2 ⁇ 4 alkynyl ⁇ NH(C 1 ⁇ 3 alkyl), and C 2 ⁇ 4 alkynyl ⁇ N(C 1 ⁇ 3 alkyl) 2 ; R 2 and R 3 are each independently selected from the group of H, F, Cl, Br, I, CH 3 , CN, ⁇ CH 2 CN, CF 3 , and CH 2 ⁇ CF 3 ; with the proviso that, when R 2 is CN, ⁇ CH 2 CN, CF 3 , or CH 2 ⁇ CF 3 , R 3 is selected from the group of H, F, Cl, Br, I, and CH 3 ; R 4 is selected from the group of H, F, Cl, Br, I, CH 3 , and CF 3 ; R 5 is
  • a sixth embodiment provides a compound of Formula (I), above, wherein: R 1 is selected from the group of H, C 1 ⁇ 3 alkyl, C 2 ⁇ 3 alkenyl, C 2 ⁇ 3 alkynyl, C 2 ⁇ 3 alkynyl ⁇ NH 2 , C 2 ⁇ 3 alkynyl ⁇ NH(C 1 ⁇ 3 alkyl), and C 2 ⁇ 3 alkynyl ⁇ N(C 1 ⁇ 3 alkyl) 2 ; R 2 and R 3 are each independently selected from the group of H, F, CH 3 , CN, ⁇ CH 2 CN, CF 3 , and CH 2 ⁇ CF 3 ; with the proviso that, when R 2 is CN, ⁇ CH 2 CN, CF 3 , or CH 2 ⁇ CF 3 , R 3 is selected from the group of H, F, Cl, Br, I, and CH 3 ; R 4 is selected from the group of H, F, CH 3 , and CF 3 ; R 5 is selected from the group of H and CH 3 ;
  • a seventh embodiment provides a compound of Formula (II): wherein: R 2 and R 3 are each independently selected from the group of H, F, CH 3 , CN, ⁇ CH 2 CN, CF 3 , and CH 2 ⁇ CF 3 ; with the proviso that, when R 2 is CN, ⁇ CH 2 CN, CF 3 , or CH 2 ⁇ CF 3 , R 3 is selected from the group of H, F, Cl, Br, I, and CH 3 ; R 4 is selected from the group of H, F, CH 3 , and CF 3 ; R 5 and R 7 are each independently selected from the group of H and CH 3 ; and R 6 is selected from the group of H, F, and CH 3 ; or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • R 2 and R 3 are each independently selected from the group of H
  • An eighth embodiment provides a compound of Formula (II), above: wherein: R 2 and R 3 are each independently selected from the group of H, F, and CH 3 ; R 4 is selected from the group of H, F, CH 3 , and CF 3 ; R 5 and R 7 are each independently selected from the group of H and CH 3 ; and R 6 is selected from the group of H, F, and CH 3 ; or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • a ninth embodiment provides a compound of Formula (II), above: wherein: R 2 and R 3 are each independently selected from the group of H and CH 3 ; R 4 is selected from the group of H, F, and CH 3 ; R 5 and R 7 are each independently selected from the group of H and CH 3 ; and R 6 is selected from the group of H, F, and CH 3 ; or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • a tenth embodiment provides a compound of Formula (II), above: wherein: R 2 is H; R 3 is selected from the group of H and CH 3 ; R 4 is selected from the group of H, F, and CH 3 ; R 5 and R 7 are each independently selected from the group of H and CH 3 ; and R 6 is selected from the group of H, F, and CH 3 ; or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • An eleventh embodiment provides a compound of Formula (III):
  • R 4 is selected from the group of H, F, and CH 3 ;
  • R 5 and R 7 are each independently selected from the group of H and CH 3 ;
  • R 6 is selected from the group of H, F, and CH 3 ; or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • a twelfth embodiment provides a compound of Formula (III), above: wherein: R 4 is selected from the group of H, and CH 3 ; R 5 and R 7 are each independently selected from the group of H and CH 3 ; and R 6 is selected from the group of H, F, and CH 3 ; or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • An thirteenth embodiment provides a compound of Formula (III), above: wherein: R 4 is H; R 5 and R 7 are each independently selected from the group of H and CH 3 ; and R 6 is selected from the group of H, F, and CH 3 ; or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • An fourteenth embodiment provides a compound of Formula (III), above: wherein: R 4 is CH 3 ; and R 5 and R 6 are each independently selected from the group of H and CH 3 ; or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • R 4 is CH 3
  • R 5 and R 6 are each independently selected from the group of H and CH 3 ; or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • Another embodiment provides a method of enhancing endoplasmic reticulum (ER) stress ⁇ induced cell apoptosis of cancer cells in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • ER endoplasmic reticulum
  • ER stress ⁇ related conditions that may be treated using a pharmaceutically effective amount of a compound of Formula (I), as defined herein, include those in cancers, protein folding/misfolding disease, diabetes mellitus, Wolcott ⁇ Rallison syndrome, ischemia/reperfusion injury, stroke, neurodegeneration, atherosclerosis, neoplasia, hypoxia, or hypoglycemia.
  • Cancers of this ER stress ⁇ related group include colon adenocarcinoma, esophagus adenocarcinoma, liver hepatocellular carcinoma, squamous cell carcinoma, pancreas adenocarcinoma, islet cell tumor, rectum adenocarcinoma, gastrointestinal stromal tumor, stomach adenocarci noma, adrenal cortical carcinoma, renal cancer, thyroid cancer, melanoma, testicular cancer, follicular carcinoma, papillary carcinoma, breast cancer, ductal carcinoma, lobular carcinoma, intraductal carcinoma, mucinous carcinoma, phyllodes tumor, Ewing’s sarcoma, ovarian adenocarcinoma, endometrium adenocarcinoma, granulose cell tumor, mucinous cystadenocarcinoma, cervix adenocarcinoma, vulva squamous cell carcinoma, basal cell carcinoma, prostate adenocar
  • ER stress ⁇ related protein folding/misfolding diseases include Huntington’s disease, spinobulbar muscular atrophy (Kennedy disease), Machado ⁇ Joseph disease, dentatorubralpallidoluysian atrophy (Haw River Syndrome), spinocerebellar ataxia, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Creutzfeldt ⁇ Jakob disease, bovine spongiform encephalopathy (BSE), and light chain amyloidosis (AL).
  • Huntington’s disease spinobulbar muscular atrophy (Kennedy disease), Machado ⁇ Joseph disease, dentatorubralpallidoluysian atrophy (Haw River Syndrome), spinocerebellar ataxia
  • Alzheimer’s disease Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Creutzfeldt ⁇ Jakob disease, bovine spongiform encephalopathy (BSE
  • each method comprising administering to a subject in need of such treatment a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof. It is understood that such methods also exist for treating the subject in need thereof by administering to the subject a pharmaceutically effective amount of a compound of Formula (II) and/or a compound of Formula (III), as defined herein.
  • Another embodiment provides a method of treating ovarian cancer in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • a further embodiment provides a method of small cell lung cancer in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • Another embodiment provides a method of treating a carcinoid tumor in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • a pharmaceutically effective amount a compound of Formula (I), or a pharmaceutically acceptable salt, co ⁇ crystal, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, prodrug thereof.
  • alkyl refers herein to a straight or branched hydrocarbon.
  • an alkyl group may have from 1 to 6 carbon atoms (i.e., C 1 ⁇ C 6 alkyl or C 1 ⁇ 6 alkyl), 1 to 4 carbon atoms (i.e., C 1 ⁇ C 4 alkyl or C 1 ⁇ 4 alkyl), or 1 to 3 carbon atoms (i.e., C 1 ⁇ C 3 alkyl or C 1 ⁇ 3 alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, ⁇ CH 3 ), ethyl (Et, ⁇ CH 2 CH 3 ), 1 ⁇ propyl (n ⁇ Pr, n ⁇ propyl, ⁇ CH 2 CH 2 CH 3 ), 2 ⁇ propyl (i ⁇ Pr, i ⁇ propyl, ⁇ CH(CH 3 ) 2 ), 1 ⁇ butyl (n ⁇ Bu, n ⁇ butyl, ⁇ CH 2 CH 2 CH 2 CH 3 ), 2 ⁇ methyl ⁇ 1 ⁇ propyl (i ⁇ Bu, i ⁇ butyl, ⁇ CH 2 CH(CH 3 ) 2 ), 2 ⁇ butyl (s ⁇ Bu, s ⁇ butyl, ⁇ CH(CH 3 )CH 2 CH 3 ), 2 ⁇ methyl ⁇ 2 ⁇ propyl (t ⁇ Bu, t ⁇ butyl, ⁇ C(CH 3 ) 3 ), 1 ⁇ pentyl (n ⁇ pentyl, ⁇ CH 2 CH 2 CH 2 CH 3 ),
  • alkenyl refers to a straight or branched hydrocarbon with at least one site of unsaturation, i.e. a carbon ⁇ carbon, sp 2 double bond.
  • an alkenyl group can have 2 to 6 carbon atoms (i.e., C 2 ⁇ C 6 or C 2 ⁇ 6 alkenyl), 2 to 4 carbon atoms (i.e., C 2 ⁇ C 4 or C 2 ⁇ 4 alkenyl), or 2 to 3 carbon atoms (i.e., C 2 ⁇ C 3 or C 2 ⁇ 3 alkenyl).
  • alkynyl refers to a straight or branched hydrocarbon with at least one site of unsaturation, i.e.
  • an alkynyl group can have 2 to 6 carbon atoms (i.e., C 2 ⁇ C 6 or C 2 ⁇ 6 alkynyl).
  • suitable alkynyl groups include, but are not limited to, acetylenic ( ⁇ C ⁇ CH), propargyl ( ⁇ CH 2 C ⁇ CH), and the like.
  • Reference to groups such as C 2 ⁇ 6 alkynyl ⁇ NH 2 indicates an alkynylene chain terminating in another listed moiety, an amino group in this particular example.
  • cycloalkyl refers to a saturated ring having 3 to 6 carbon atoms as a monocycle, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • halo and “halogen” refer to an element or substituent selected from the group of F, Cl, Br, and I.
  • a “heterocyclyl,” “heterocycle,” or “heterocyclic” group herein refers to a chemical ring containing carbon atoms and at least one ring heteroatom selected from O, S, and N.
  • Examples of 5 ⁇ membered and 6 ⁇ membered heterocycles include, by way of example and not limitation, pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, 4 ⁇ piperidinyl, pyrrolidinyl, 2 ⁇ pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, triazinyl, 6H ⁇ 1,2,5 ⁇ thiadiazinyl, 2H,6H ⁇ 1,5,2 ⁇ dithiazinyl, thienyl, thianthrenyl, pyranyl, 2H ⁇ pyrrolyl, isothiazolyl, isoxazoly
  • heteroaryl and “heteroaromatic” refers to an aromatic heterocyclyl having at least one heteroatom in the ring.
  • suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen.
  • Non ⁇ limiting examples of 5 ⁇ and 6 ⁇ membered heteroaryl rings include pyridinyl, pyrrolyl, oxazolyl, furanyl, thienyl (thiophenyl), imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl etc.
  • therapeutically effective amount and “pharmaceutically effective amount” may be used interchangeably and refer to an amount that is sufficient to effect treatment, as defined below, when administered to a subject (e.g., a mammal, such as a human) in need of such treatment.
  • the therapeutically or pharmaceutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • a "therapeutically effective amount” or a “pharmaceutically effective amount” of a compound of Formula I, or a pharmaceutically acceptable salt or co ⁇ crystal thereof is an amount sufficient to modulate PARP16 expression or activity, and thereby treat a subject (e.g., a human) suffering an indication, or to ameliorate or alleviate the existing symptoms of the indication.
  • a therapeutically or pharmaceutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of PARP16 activity.
  • the compound of Formula (I) may be administered to a subject in need thereof at a dose of from about 0.1 mg to about 1000 mg per day in a single dose or in divided doses.
  • each pharmaceutically effective dosage unit contains from 0.1 mg to 1 g, 0.1 mg to 700 mg, or 0.1 mg to 100 mg of a compound of Formula I, or a pharmaceutically acceptable salt or co ⁇ crystal thereof.
  • a therapeutically effective amount or a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof comprises from about 0.1 mg to about 500 mg per dose, given once or twice daily.
  • the individual pharmaceutically effective dose is selected from the group of 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, and 500 mg per dose.
  • salts include, for example, salts with inorganic acids and salts with an organic acid.
  • salts may include hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate (mesylate), benzenesuflonate (besylate), p ⁇ toluenesulfonate (tosylate), 2 ⁇ hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate (such as acetate, HOOC ⁇ (CH 2 ) n ⁇ COOH where n is an integer from 0 ⁇ 4).
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts.
  • a pharmaceutical composition refers to a composition containing a pharmaceutically effective amount of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives, as part of a therapeutic regimen for the treatment of disease in a mammal.
  • Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.
  • pharmaceutically acceptable excipient is a pharmaceutically acceptable vehicle that includes, without limitation, any and all carriers, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • carrier refers to an excipient or vehicle that includes without limitation diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, and the like with which the compound is administered. Carriers are generally described herein and also in “Remington's Pharmaceutical Sciences” by E. W. Martin.
  • Examples of carriers include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, carboxymethylcellulose sodium, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyoctacosanyl hydroxystearate, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, povidone, silicon dioxide, colloidal silicon dioxide, silicone, silicone adhesive 4102, and silicone emulsion.
  • the carriers selected for the pharmaceutical compositions may vary depending on the method of formulation (e.g., dry granulation formulation, solid dispersion formulation).
  • the term "subject” refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in both human therapy and veterinary applications.
  • the subject is a mammal; in some embodiments the subject is human; and in some embodiments the subject is chosen from cats and dogs.
  • Subject in need thereof or “human in need thereof” refers to a subject, such as a human, who may have or is suspected to have diseases or conditions that would benefit from certain treatment; for example treatment with a compound of Formula I, or a pharmaceutically acceptable salt or co ⁇ crystal thereof, as described herein. This includes a subject who may be determined to be at risk of or susceptible to such diseases or conditions, such that treatment would prevent the disease or condition from developing. All ranges disclosed and/or claimed herein are inclusive of the recited endpoint and independently combinable. For example, the ranges of "from 2 to 6" and “2 ⁇ 6” are inclusive of the endpoints, 2 and 6, and all the intermediate values between in context of the units considered.
  • references to “Claims 2 ⁇ 6” or “C 2 ⁇ C 6 alkyl” includes units 2, 3, 4, 5, and 6, as claims and atoms are numbered in sequential numbers without fractions or decimal points, unless described in the context of an average number.
  • Compounds of Formula (I) may be prepared by methods known in the art, including the general scheme below representing synthesis of Compound DB008.
  • Flash column chromatography was conducted using self ⁇ packed columns containing 200 ⁇ 400 mesh silica gel (SiliCycle) on a Teledyne ISCO Combiflash Rf 150. Microwave reactions were performed using a Biotage Initiator+ SP Wave Microwave Reactor. For NMR data, the abbreviation brs is used to define a broad singlet. 2 ⁇ fluoro ⁇ 5 ⁇ ((4 ⁇ oxo ⁇ 7 ⁇ ((triisopropylsilyl)ethynyl) ⁇ 3,4 ⁇ dihydrophthalazin ⁇ 1 ⁇ yl)methyl)benzoic (2).
  • compound 2 80 mg, 0.167 mmol
  • tert ⁇ butyl piperazine ⁇ 1 ⁇ carboxylate 47 mg, 0.251 mmol
  • the reaction mixture was diluted with ethyl acetate (1 mL) and washed once with brine (1 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and the resulting residue was purified on a Teledyne ISCO CombiFlash (0 ⁇ 75% ethyl acetate in hexanes). The produce was isolated as a white solid (36.0 mg, 70% yield).
  • ADP ⁇ ribosylation is a critical post ⁇ translational modification carried out by a family of enzymes known as PARPs.
  • PARPs Upon binding nicotinamide adenine dinucleotide (NAD + ), PARPs cleave the nicotinamide group and transfer the resulting ADP ⁇ ribose (ADPr) to generate ADP ⁇ ribosylated targets— primarily on proteins but also on nucleic acids 1 .
  • the PARP family is divided based on the ability to transfer ADPr in the form of polymers (poly ⁇ ADP ⁇ ribosylation or PARylation) or monomers (mono ⁇ ADP ⁇ ribosylation or MARylation).
  • PARylation has been extensively studied, particularly in cancer, resulting in four clinically approved PARP1/2 inhibitors developed to date (olaparib, rucaparib, niraparib, talazoparib) 3 .
  • the physiological roles of MARylation are far less understood, in large part due to the lack of chemical tools currently available.
  • PARP7 inhibitor RNN ⁇ 2397
  • PARP14 inhibitor RPN ⁇ 3143
  • PARP16 is an example of another MARylating PARP that has been gaining attention as a novel therapeutic target.
  • PARP16 contains a C ⁇ terminal transmembrane (TM) domain that localizes to the endoplasmic reticulum (ER) membrane, with the N ⁇ terminal catalytic domain facing the cytoplasm.
  • PARP16 Upon ER stress, PARP16 has been shown to MARylate two sensors of the unfolded protein response (UPR), PKR ⁇ like ER kinase (PERK) and inositol ⁇ requiring enzyme 1 ⁇ (IRE1 ⁇ ), leading to a suppression of protein synthesis 6 .
  • UPR unfolded protein response
  • PERK PKR ⁇ like ER kinase
  • IRE1 ⁇ inositol ⁇ requiring enzyme 1 ⁇
  • PARP16 ⁇ dependent vulnerabilities that can be exploited to treat cancer.
  • Palve et al. discovered PARP16 as a novel off ⁇ target to the clinically approved PARP1/2 inhibitor, talazoparib, in small cell lung cancer (SCLC) 8 .
  • Talazoparib displayed a half maximal inhibitory concentration (IC 50 ) between 160–289 nM against recombinant PARP16 in a biochemical assay. They also find that transient knockdown of PARP16 reduces SCLC cell viability, and that PARP16 knockdown in combination with olaparib (PARP1/2 inhibitor) treatment, results in a greater decrease in viability.
  • PARP1/2 inhibitor olaparib
  • Challa et al. identify PARP16 as an important driver of ovarian cancer. They show that MARylation of ribosomes by PARP16 attenuates protein synthesis, enabling maintenance of protein homeostasis for cancer cell survival.
  • HJ ⁇ 52 Fig. 2C
  • an olaparib analog in which the cyclopropyl amide is replaced with an acrylamide warhead to promote covalent bond formation with C169.
  • HJ ⁇ 52 inhibited PARP16 about 2.5 ⁇ times more than olaparib in a biochemical assay (Fig. 1D), however, as expected, HJ ⁇ 52 is not selective and inhibits PARP1 with a low nanomolar IC 50 similarly as olaparib (Fig. 1E).
  • Fig. 1D biochemical assay
  • Fig. 1E nanomolar IC 50 similarly as olaparib
  • a first selectivity filter we applied the first selectivity filter and decided to install an ethynyl group on the C6 position of the phthalazinone scaffold. This terminal alkyne serves two functions: i) promotes selective binding to HY ⁇ PARPs over HYE PARPs and ii) provides a clickable handle for assessment of target engagement.
  • DB008 Fig.
  • HAP1 wild ⁇ type (WT) and HAP1 PARP16 knock ⁇ out (KO) cells with a dose response of DB008 and observed selective labeling of a PARP16 ( ⁇ 37 kDa), with saturation occurring at 300 nM DB008 (Fig. 3F), and an apparent K d of 60.9 nM (Fig. 3G).
  • WT wild ⁇ type
  • KO HAP1 PARP16 knock ⁇ out
  • the IC 50 is not the best measure of potency for irreversible inhibitors because it is time ⁇ dependent—longer pre ⁇ incubation times shift the IC 50 to lower values.
  • the more appropriate parameter for measuring potency of covalent inhibitors is K inact /K I , a second ⁇ order rate constant that describes the efficiency of covalent bond formation 19 .
  • the relationship between inhibitor concentration and K obs resulted in a saturation binding curve, indicative of a two ⁇ step, specific binding model wherein the inhibitor binds the protein first, forming a reversible protein ⁇ inhibitor complex, followed by covalent bond formation between the nucleophilic residue and electrophile.
  • the ability to label and visualize cellular PARP16 enables use of DB008 as a probe to validate previously reported PARP16 inhibitors in a competition ⁇ based assay, since PARP16 cellular activity has been difficult to detect.
  • EGCG talazoparib and epigallocatechin ⁇ 3 ⁇ gallate
  • EGCG a major catechin found in tea, was identified as a binder of purified GST ⁇ PARP16 from a high ⁇ throughput optical ⁇ based microarray screen.
  • EGCG used at 100 ⁇ M, was shown to suppress PERK ⁇ mediated UPR in response to ER ⁇ stress in QGY ⁇ 7703 and HeLa cells.
  • EGCG was also used at 30 ⁇ 100 ⁇ M to reduce PARP16 ⁇ dependent ER stress in models of vascular aging 20 and neointimal hyperplasia 21 .
  • talazoparib and EGCG compete labeling in HEK293T cells expressing Myc2x ⁇ PARP16 (Fig. 4C). While talazoparib bound PARP16 with an IC 50 of 949 nM, we observed no competition of labeling with EGCG up to 100 ⁇ M, suggesting that EGCG does not bind the active site of PARP16 in cells (Fig. 4D). Therefore, we caution the use of EGCG as a probe to study PARP16 biology. The effects on the UPR previously observed with EGCG may be due to off ⁇ target binding, especially at 100 ⁇ M, or binding of PARP16 at an allosteric site.

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Abstract

La présente invention concerne un composé inhibiteur de PARP16 de formule (I) : (I) : R1i étant choisi dans le groupe constitué par un H, un halo, un -OH, un alkyle, un alcényle, un alcynyle, un cycloalkyle, un hétérocyclyle, un aryle, un hétéroaryle, un -O-alkyle, un -O-alcényle, un -O-alcynyle, un -O-cycloalkyle, un -O-hétérocyclyle, un -O-aryle, un -O-hétéroaryle, un -SO2-cycloalkyle, un -NH2, un -NH(alkyle), un -N(alkyle)2, un alcynyle-NH2, un alcynyle-N H(alkyle) et un alcynyle-N(alkyle)2 ; R2 et R3 étant chacun sélectionnés dans le groupe de H, F, Cl, Br, I, CH3, CN, -CH2CN, CF3 et CH2-CF3 ; R4 étant choisi dans le groupe constitué par H, F, Cl, Br, I, CH3 et CF3 ; R5 étant choisi dans le groupe constitué par H et CH3 ; et R6 étant choisi dans le groupe constitué par H, F et CH3 ; ou un sel pharmaceutiquement acceptable, un co-cristal, un solvate, un hydrate, un isomère (y compris des isomères optiques, des racémates ou d'autres mélanges de ceux-ci), un tautomère, un isotope, un polymorphe, un promédicament de ceux-ci.
PCT/US2023/065045 2022-03-28 2023-03-28 Inhibiteurs de parp16 covalents Ceased WO2023192864A2 (fr)

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