WO2023067515A1 - Composés thiadiazolyles utilisés comme inhibiteurs de l'adn polymérase thêta - Google Patents

Composés thiadiazolyles utilisés comme inhibiteurs de l'adn polymérase thêta Download PDF

Info

Publication number
WO2023067515A1
WO2023067515A1 PCT/IB2022/060050 IB2022060050W WO2023067515A1 WO 2023067515 A1 WO2023067515 A1 WO 2023067515A1 IB 2022060050 W IB2022060050 W IB 2022060050W WO 2023067515 A1 WO2023067515 A1 WO 2023067515A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
mmol
acceptable salt
thiadiazol
Prior art date
Application number
PCT/IB2022/060050
Other languages
English (en)
Inventor
Chenbo WANG
Firoz Ali JAIPURI
Daniel Lee Severance
Hilary Plake Beck
Brian Thomas Jones
Kevin J. Duffy
Terence John Kiesow
Doo-Hyun Kwon
Paul A. Barsanti
Original Assignee
Ideaya Biosciences, Inc.
Glaxosmithkline Intellectual Property (No.4) Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ideaya Biosciences, Inc., Glaxosmithkline Intellectual Property (No.4) Limited filed Critical Ideaya Biosciences, Inc.
Publication of WO2023067515A1 publication Critical patent/WO2023067515A1/fr

Links

Classifications

    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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

Definitions

  • DNA repair deficient cancers often become dependent on backup DNA repair pathways, which present an “Achilles heel” that can be targeted to eliminate cancer cells, and is the basis of synthetic lethality.
  • Synthetic lethality is exemplified by the success of poly (ADP-ribose) polymerase (PARP) inhibitors in treating BRCA-deficient breast and ovarian cancers (Audeh M. W., et al., Lancet (2010); 376 (9737): 245-51).
  • PARP poly (ADP-ribose) polymerase
  • DNA damage repair processes are critical for genome maintenance and stability, among which, double strand breaks (DSBs) are predominantly repaired by the nonhomologous end joining (NHEJ) pathway in G1 phase of the cell cycle and by homologous recombination (HR) in S-G2 phases.
  • NHEJ nonhomologous end joining
  • HR homologous recombination
  • a less addressed alternative end-joining (alt-EJ), also known as microhomology-mediated end-joining (MMEJ) pathway is commonly considered as a “backup” DSB repair pathway when NHEJ or HR are compromised.
  • MMEJ microhomology-mediated end-joining
  • Numerous genetic studies have highlighted a role for DNA polymerase theta (Pol0, encoded by POLQ) in stimulating MMEJ in higher organisms (Chan S. H., et al., PLoS Genet.
  • Pole is distinct among human DNA polymerases, exhibiting not only a C-terminal DNA polymerase domain but also an N-terminal helicase domain separated by a long and lesser- conserved central domain of unknown function beyond Rad51 binding (Seki eta. Al, 2003, Shima et al 2003; Yousefzadeh and Wood 2013).
  • the N-terminal ATPase/helicase domain belongs to the HELQ class of SF2 helicase super family.
  • HRD homologous recombination deficient
  • the helicase domain of Pol0 causes suppression of HR pathway through disruption of Rad51 nucleoprotein complex formation involved in initiation of the HR-dependent DNA repair reactions following ionizing radiation. This anti-recombinase activity of Pol0 promotes the alt-EJ pathway.
  • the helicase domain of Pol0 contributes to microhomology-mediated strand annealing (Chan SH et al., PLoS Genet. (2010); 6: el001005; and Kawamura K et al., Int. J. Cancer (2004); 109: 9-16).
  • PolO efficiently promotes end-joining in alt-EJ pathway by employing this annealing activity when ssDNA overhangs contain >2 bp of microhomology (Kent T., et al., Elife (2016); 5: el3740), and Kent T., et al., Nat. Struct. Mol. Biol. (2015); 22: 230-237).
  • This reannealing activity is achieved through coupled actions of Rad51 interaction followed by ATPase- mediated displacement of Rad51 from DSB damage sites.
  • the primer strand of DNA can be extended by the polymerase domain of PolO.
  • compositions comprising such compounds and methods of treating and/or preventing diseases treatable by inhibition of PolO such as cancer, including homologous recombination (HR) deficient cancers.
  • HR homologous recombination
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein ring Ar 1 , Z 1 , Z 2 , Z 3 , Z 4 , and R 3 have the meanings provided hereinbelow.
  • pharmaceutical compositions comprising a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • a method for treating and/or preventing a disease characterized by overexpression of PolO in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof.
  • the patient is in recognized need of such treatment.
  • the compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition.
  • the disease is a cancer.
  • a method for treating and/or preventing a homologous recombinant (HR) deficient cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof.
  • the patient is in recognized need of such treatment.
  • the compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition.
  • a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof for use in a method of treating a homologous recombinant (HR) deficient cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof.
  • HR homologous recombinant
  • a method for inhibiting DNA repair by Pol0 in a cancer cell comprising contacting the cell with an effective amount of a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof.
  • the cancer is HR deficient cancer.
  • a method for treating and/orpreventingng a cancer in a patient wherein the cancer is characterized by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.
  • a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof for use in a method of treating a cancer in a patient, wherein the cancer is characterized by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof for use in a method of treating a disease characterized by overexpression of Pol0 in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof for inhibiting DNA repair by Pol0 in a cell in one embodiment, the cell is HR deficient cell.
  • a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a disease in a patient, wherein the disease is characterized by overexpression of Pol0.
  • a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a cancer in a patient, wherein the cancer is characterized by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.
  • a compound of Formula (I), or a subembodiment or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a HR deficient cancer in a patient.
  • a compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a cancer that is resistant to poly(ADP -ribose) polymerase (PARP) inhibitor therapy in a patient.
  • PARP poly(ADP -ribose) polymerase
  • cancers resistant to PARP -inhibitors include, but are not limited to, breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, and colorectal cancer.
  • the cancer is lymphoma, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper aerodigestive cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer (data from large scale drop out screens in cancer cell lines indicate that some cell lines from the above cancers are dependent on polymerase theta for proliferation https : //depmap . org/portal/) .
  • a HR-deficient cancer is breast cancer.
  • Breast cancer includes, but is not limited to, lobular carcinoma in situ (LCIS), a ductal carcinoma in situ (DCIS), an invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget disease of the nipple, Phyllodes tumor, Angiosarcoma, adenoid cystic carcinoma, low- grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, or another breast cancer, including but not limited to triple negative, HER positive, estrogen receptor positive, progesterone receptor positive, HER and estrogen receptor positive, HER and progesterone receptor positive, estrogen and progesterone receptor positive, and HER and estrogen and progesterone receptor positive.
  • HR-deficient cancer is ovarian cancer.
  • Ovarian cancer includes, but is not limited to, epithelial ovarian carcinomas (EOC), maturing teratomas, dysgerminomas, endodermal sinus tumors, granulosa-theca tumors, Sertoli -Leydig cell tumors, and primary peritoneal arcinoma.
  • any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. Ci-8 means one to eight carbons).
  • Alkyl can include any number of carbons, such as Cl-2, Cl-3, Cl-4, Cl-5, Cl-6, C1-7, Cl-8, C1-9, Cl-10, C2-3, C2 , C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • alkenyl by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain hydrocarbon radical with one double bond and having the number of carbon atoms designated (i.e. C2-8 means two to eight carbons). Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10).
  • alkynyl by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain hydrocarbon radical with one triple bond and having the number of carbon atoms designated (i.e. C2-8 means one to eight carbons).
  • Alkynyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10.
  • alkylene refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent hydrocarbon radical.
  • the two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group.
  • a straight chain alkylene can be the bivalent radical of -(CH2) n - where n is 1, 2, 3, 4, 5 or 6.
  • Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, hexylene, and the like.
  • cyano by itself or as part of another substituent, refers to a moiety having the formula -CN, i.e., a carbon atom triple-bonded to nitrogen atom.
  • cycloalkyl refers to a saturated or partially unsaturated hydrocarbon ring having the indicated number of ring atoms (e.g., C3-6 cycloalkyl). Cycloalkyl can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, Ce-8, C3-9, and C3-10. Partially unsaturated cycloalkyl groups have one or more double or triple bonds in the ring, but cycloalkyl groups are not aromatic. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • bridged cyclyl or “bridged cycloalkyl” refer to a cycloalkyl ring (having 5 to 8 ring vertices) in which two non-adjacent ring atoms are linked by a (CRR’) n group where n is 1 to 3 and each R is independently H or methyl (also may be referred to herein as “bridging” group). Bridged cycloalkyl groups do not have any heteroatoms as ring vertices. Additionally, C5-8 refers to a bridged cycloalkyl group having 5-8 ring members. Examples include, but are not limited to, bicyclo [l.l.l]pentane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane, and the like.
  • spirocyclyl or “spirocycloalkyl” refer to a saturated or partially unsaturated bicyclic ring having 6 to 12 ring atoms, where the two rings are connected via a single carbon atom (also called the spiroatom).
  • Partially unsaturated spirocycloalkyl groups have one or more double or triple bonds in the ring, but spirocycloalkyl groups are not aromatic.
  • Representative examples include, but are not limited to, spiro[3.3]heptane, spiro[4.4]nonane, spiro[3.4]octane, and the like.
  • heterocycloalkyl refers to a saturated or partially unsatured monocyclic ring having the indicated number of ring vertices (e.g., a 3- to 7-membered ring) and having from one to five heteroatoms selected from N, O, and S as ring vertices.
  • Partially unsaturated heterocycloalkyl groups have one or more double or triple bonds in the ring, but heterocycloalkyl groups are not aromatic.
  • Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 7, 4 to 7, or 5 to 7 ring members.
  • heterocycloalkyl groups any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4.
  • Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3 -pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like.
  • a heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.
  • the substituent can be attached to any suitable carbon or heteroatom.
  • a pyrrolidin-3-yl is substituted with one or more R groups, each R group will replace a hydrogen on any carbon or nitrogen ring vertex. It is also understood that when the substituent is an oxo group, it will replace two hydrogen atoms.
  • spiroheterocyclyl or “spiroheterocycloalkyl” refer to a saturated or partially unsaturated bicyclic ring having 6 to 12 ring atoms, where the two rings are connected via a single carbon atom (also called the spiroatom).
  • Spiroheterocyclyl groups have from one to five heteroatoms selected from N, O, and S as ring vertices, and the nitrogen atom(s) are optionally quatemized.
  • Partially unsaturated spiroheterocycloalkyl groups have one or more double or triple bonds in the ring, but spiroheterocycloalkyl groups are not aromatic.
  • Representative examples include, but are not limited to, 4-oxaspiro[2.4]heptane, 2,6- diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]- nonane, 2,7-diazaspiro[4.4]nonane, and the like.
  • a spiroheterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom. When spiroheterocycloalkyl groups are substituted, the substituent can be attached to any suitable carbon or heteroatom.
  • each R group will replace a hydrogen on any carbon or nitrogen ring vertex. It is also understood that when the substituent is an oxo group, it will replace two hydrogen atoms.
  • halo or halogen, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • haloalkyl refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms.
  • alkyl group haloalkyl groups can have any suitable number of carbon atoms, such as Ci-6.
  • Ci-6 the term “Ci-4 haloalkyl” is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, and the like.
  • heteroaryl refers to a 5- to 10-membered aromatic ring (or fused ring system) that contains from one to five heteroatoms selected from N, O, and S.
  • Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 5 to 8, 6 to 8, 6 to 9, 9 to 10, 9, 10 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, p
  • heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S).
  • hydroxyalkynyl refers to an alkynyl group where one of the hydrogen atoms is substituted with a hydroxy (-OH) group.
  • hydroxyalkynyl groups can have any suitable number of carbon atoms, such as C3-6, and can be straight or branched.
  • oxo refers to an oxygen atoms that is linked to the reminder of the compound with a double bond
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally- occuring amines and the like, such as arginine, betaine, caffeine, choline, N,N’- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. All potential physical forms are intended to be within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers); the racemates, diastereomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention.
  • a stereochemical depiction it is meant to refer the compound in which one of the isomers is present and substantially free of the other isomer.
  • substantially free of another isomer indicates at least an 80/20 ratio of the two isomers, more preferably 90/10, or 95/5 or more. In some embodiments, one of the isomers will be present in an amount of at least 99%.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atom in question.
  • the compounds may incorporate radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium ( 2 H) or carbon-13 ( 13 C).
  • radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium ( 2 H) or carbon-13 ( 13 C).
  • isotopic variations can provide additional utilities to those described elsewhere within this application.
  • isotopic variants of the compounds of the invention may find additional utility, including but not limited to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutic agents. Additionally, isotopic variants of the compounds of the invention can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or efficacy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • administration refers to contact of, for example, an Pol0 modulator, a pharmaceutical composition comprising same, or a diagnostic agent to the subject, cell, tissue, organ, or biological fluid.
  • administration includes contact (e.g., in vitro or ex vivo) of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • treat refers to a course of action (such as administering a PolO modulator 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 includes inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease.
  • in need of treatment refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s or caregiver's expertise. For example, the patient has been diagonosed as having a disease linked to overexpression of Pole or a homologous recombination (HR)-deficient cancer.
  • HR homologous recombination
  • prevent refers to a course of action (such as administering an PolO modulator or a pharmaceutical composition comprising same) initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom 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.
  • in need of prevention refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from preventative care. This judgment is made based on a variety of factors that are in the realm of a physician’s or caregiver’s expertise.
  • therapeutically effective amount refers to the administration of an agent to a subject, either alone or as part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount capable of having any detectable, positive effect on any symptom, aspect, or characteristic of a disease, disorder or condition when administered to the subject.
  • the therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject’s condition, and the like.
  • measurement of the serum level of an Pol0 modulator (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been used.
  • modulate refers to the ability of a molecule (e.g., an activator or an inhibitor) to increase or decrease the function or activity of Pol0, either directly or indirectly.
  • a modulator may act alone, or it may use a cofactor, e.g., a protein, metal ion, or small molecule. Examples of modulators include small molecule compounds and other bioorganic molecules.
  • the "activity" of a molecule may describe or refer to the binding of the molecule to a ligand or to a receptor; to catalytic activity; to the ability to stimulate gene expression or cell signaling, differentiation, or maturation; to antigenic activity; to the modulation of activities of other molecules; and the like.
  • Certain compounds of the present disclosure can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. For example, certain hydroxy substituted compounds may exist as as tautomers as shown below:
  • “Pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • a wavy line, "• « « « ", that intersects a single, double or triple bond in any chemical structure depicted herein, represent the point attachment of the single, double, or triple bond to the remainder of the molecule.
  • a bond extending to the center of a ring e.g., a phenyl ring
  • a bond extending to the center of a ring is meant to indicate attachment at any of the available ring vertices.
  • multiple substituents shown as being attached to a ring will occupy ring vertices that provide stable compounds and are otherwise sterically compatible.
  • Disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder, " “syndrome, “ and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • Patient is generally synonymous with the term "subject” and as used herein includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.
  • “Inhibiting”, "reducing,” or any variation of these terms in relation of Pol0 includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of Pol0 activity compared to its normal activity.
  • homologous recombination refers to the cellular process of genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA.
  • HR deficient cancer refers to a cancer that is characterized by a reduction or absence of a functional HR repair pathway. HR deficiency may arise from absence of one or more HR-assocated genes or presence of one or more mutations in one or more HR-assocated genes.
  • HR-associated genes include BRCA1, BRCA2, RAD54, RAD51B, CtlP (Choline Transporter-Like Protein), PALB2 (Partner and Localizer of BRCA2), XRCC2 (X-ray repair complementing defective repair in Chinese hamster cells 2), RECQL4 (RecQ Protein-Like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome , one or more HR-assocated genes) Nbs 1 (Nibnn), and genes encoding Fanconi anemia (FA) proteins or FA-like genes e.g, FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF.
  • Polynomen overexpression refers to the increased expression or activity of Pol0 in a diseases cell e.g., cancerous cell, relative to expression or activity of Pol0 in a normal cell (e.g., non-diseased cell of the same kind).
  • the amount of Pol0 can be at least 2-fold, at least 3-fold, at least 4- fold, at least 5- fold, at least 10-fold, or more relative to the Pol0 expression in a normal cell.
  • Pol0 cancers include, but are not limited to, breast, ovarian, cervical, lung, colorectal, gastric, bladder and prostate cancers.
  • Z 1 is N or CR zl ;
  • Z 2 is N or CR z2 ;
  • Z 3 is N or CR z3 ;
  • Z 4 is N or CR z4 , wherein one of Z 1 , Z 2 , Z 3 , and Z 4 is N and the remaining ring vertices are CR zl , CR z2 , CR z3 , and CR z4 , respectively; each R zl , R z2 , R z3 , and R z4 , when present, are independently selected from the group consisting of H, Ci-6 alkyl, halo, Ci-6 haloalkyl, -X'-O-Ci-e alkyl, -O-Ci-6 haloalkyl, -X '-cyano.
  • R a and R b are independently selected from the group consisting of hydrogen, CM alkyl, and C1-6 haloalkyl; and Ar 1 is selected form the group consisting of phenyl and a 5- to 10- membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, wherein Ar 1 is substituted with 0 to 4 R la substituents; each R la is independently selected from Ci-6 alkyl, halo, CM haloalkyl, -X 2 -O-CI-6 alkyl, -X 2 -O-CI-6 haloalkyl, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -C(O)R C , -NR c C(O)R d , -NR c R d , -X 2 -NR c R d , -C(O)NR c R d , -X 2 -S(O)
  • R 3 is a member selected from the group consisting of
  • X 3 is selected from a bond and CM alkylene
  • X 3a is selected from a bond, CM alkylene, and C1-3 alkylene-O-; each R e and R f are independently selected from the group consisting of hydrogen, Ci-4 alkyl, and Ci-4 haloalkyl; or R e and R f together with the nitrogen to which they are attached combine to form a 3- to 6- membered heterocycloalkyl having 0 to 2 additional heteroatom ring vertices independently selected from N, O, and S; each R h and R k is independently selected from the group consisting of hydrogen, Ci-4 alkyl, and Ci-4 haloalkyl;
  • Ri is selected from the group consisting of hydrogen, CM alkyl, CM haloalkyl, and phenyl; each R 3 member of (i) is substituted with 0 to 4 R 3a substituents, each of which is independently selected from -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, -OH, cyano, -S(O)2R g , and oxo; each R 3 member of (iii) is substituted with 0 to 5 R 3b substituents, each of which is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, C1-6 haloalkyl, -O-Ci-6 haloalkyl, -O-Ci-6 alkyl, -X 4 -0H, -X 4 -cyano, -C(O)R g , -S(O)2R g , phenyl, and
  • each R 3 member of (ix) is substituted with 0 to 5 R 3d substituents, each of which is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, C1-6 haloalkyl, -O-Ci-6 haloalkyl, -O-Ci-6 alkyl, -X 4 -0H, -X 4 -cyano, -C(O)R g , -S(O)2R g , and oxo; or two R 3d substituents on adjacent ring vertices combine to form a fused phenyl ring; each X 4 is independently selected from a bond and C1-4 alkylene; and each R g is selected from the group consisting of C1-4 alkyl, and C1-4 haloalkyl or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) and relevant subembodiments thereof are other than
  • R 3 is not benzyl or cyclopropyl.
  • R 3 is not -X 3a -phenyl or C3-6 cycloalkyl.
  • R 3 is not benzyl or cyclopropyl.
  • R 3 is not -X 3a -phenyl or C3-6 cycloalkyl.
  • R 3 is not benzyl or cyclopropyl.
  • R 3 is not -X 3a -phenyl or C3-6 cycloalkyl.
  • R 3 is not -C5-8 bridged cycloalkyl.
  • R 3 is not -X 3 -Cs-8 bridged cycloalkyl.
  • R 3 is not -CH2CH2N(CH3)2.
  • R 3 when Z 3 is N; Z 1 and Z 2 are each CH; Z 4 is CCH3; and Ar 1 is phenyl, then R 3 is not -CM alkylene-NR e R f .
  • R 3 is not -CH2CH2N(CH3)2.
  • R 3 is not -CM alkylene-NR e R f .
  • compounds of Formula (I) are represented by Formula (la): or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) are represented by Formula (lai): or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) are represented by Formula (lb): or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) are represented by Formula (lb 1): or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) are represented by Formula (Ic): or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) are represented by Formula (Ic 1): or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) are represented by Formula (Id): or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) are represented by Formula (Id 1): or a pharmaceutically acceptable salt thereof.
  • each R zl , R z2 , R z3 , and R z4 when present in Formula (I) or a subembodiment thereof are independently selected from the group consisting of Ci-6 alkyl, halo, Ci-6 haloalkyl, -X'-O-Ci-e alkyl, -O-Ci-6 haloalkyl, -X 1 -cyano. -X'-OH. C3-6 cycloalkyl, and -X'-NR ⁇ .
  • each R zl , R z2 , R z3 , and R z4 when present in Formula (I) or a subembodiment thereof, are independently selected from the group consisting of C 1-6 alkyl and -X'-OH.
  • each R zl , R z2 , R z3 , and R z4 when present in Formula (I) or a subembodiment thereof, are independently selected from the group consisting of C 1-4 alkyl and - C1-2 alkylene-OH.
  • each R zl , R z2 , R z3 , and R z4 when present in Formula (I) or a subembodiment thereof are independently selected from the group consisting of C 1-2 alkyl and - C1-2 alkylene-OH.
  • each X 1 in Formula (I) or a subembodiment thereof is a bond.
  • each X 1 in Formula (I) or a subembodiment thereof is Ci-4 alkylene.
  • each X 1 in Formula (I) or a subembodiment thereof is C1-2 alkylene .
  • each X 1 in Formula (I) or a subembodiment thereof is methylene.
  • each R zl , R z2 , R z3 , and R z4 when present in Formula (I) or a subembodiment thereof, are independently selected from the group consisting of methyl and hydroxymethyl.
  • each R zl , R z2 , R z3 , and R z4 when present in Formula (I) or a subembodiment thereof, are methyl.
  • Ar 1 in Formula (I) or a subembodiment thereof is selected from the group consisting of phenyl, pyridinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, pyridazyl, imidazo[l,2-a]pyrimidinyl, oxazolo[4,5-b]pyridinyl, oxazolo[5,4-b]pyridinyl, thiazolo[4,5- b]pyridinyl, benzo [d]thiazole, indazolyl, [l,2,4]triazolo[l,5-a]pyrimidinyl, [l,2,4]triazolo[l,5-b]pyridazinyl, and tetrazolo[l,5-a]pyridinyl, each of which is substituted with 0 to 4 R la .
  • Ar 1 in Formula (I) or a subembodiment thereof is selected from the group consisting of phenyl, pyridinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, and pyridazyl each of which is substituted with 0 to 4 R la , each of which is independently selected.
  • Ar 1 in Formula (I) or a subembodiment thereof is phenyl substituted with 0 to 4 R la , each of which is independently selected.
  • Ar 1 in Formula (I) or a subembodiment thereof is phenyl or a 6- membered heteroaryl substituted with 0 to 4 R la , each of which is independently selected.
  • Ar 1 in Formula (I) or a subembodiment thereof is a 6-membered heteroaryl substituted with 0 to 4 R la , each of which is independently selected.
  • Ar 1 in Formula (I) or a subembodiment thereof is pyridinyl substituted with 0 to 4 R la , each of which is independently selected. In some embodiments, Ar 1 in Formula (I) or a subembodiment thereof is substituted with 0 to 3 R la , each of which is independently selected.
  • Ar 1 in Formula (I) or a subembodiment thereof is substituted with 0 to 2 R la , each of which is independently selected. In some embodiments, Ar 1 in Formula (I) or a subembodiment thereof is substituted with 3 R la , each of which is independently selected.
  • Ar 1 in Formula (I) or a subembodiment thereof is substituted with 2 R la , each of which is independently selected.
  • compounds of Formula (I) are represented by Formula (Ia2): wherein p is an integer from 0 to 4.
  • compounds of Formula (I) are represented by Formula (Ia3):
  • compounds of Formula (I) are represented by Formula (Ia4): wherein p is an integer from 0 to 4.
  • compounds of Formula (I) are represented by Formula (Ia5):
  • compounds of Formula (I) are represented by Formula (Ia6):
  • each R la in Formula (I) or a subembodiment thereof is independently selected from Ci-6 alkyl, halo, Ci-6 haloalkyl, -X 2 -O-CI-6 alkyl, -O-Ci-6 haloalkyl, C3-6 cycloalkyl, -NR a R b , -X 2 -cyano, and -X 2 -OH.
  • each R la in Formula (I) or a subembodiment thereof is independently selected from C1-6 alkyl, halo, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, C3-6 cycloalkyl, -NR a R b , and -X 2 -OH.
  • each R la in Formula (I) or a subembodiment thereof is independently selected from C1-4 alkyl, halo, C1-4 haloalkyl, -O-C1-4 alkyl, -O-C1-4 haloalkyl.
  • each R la in Formula (I) or a subembodiment thereof is independently selected from C1-2 alkyl, halo, C1-2 haloalkyl, -O-C1-2 alkyl, -O-C1-2 haloalkyl.
  • each R la in Formula (I) or a subembodiment thereof is independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1-hydroxyethyl.
  • each R la in Formula (I) or a subembodiment thereof is independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, and cyclopropyl. In some embodiments, each R la is independently selected from fluoro, chloro, and methoxy.
  • each X 2 in Formula (I) or a subembodiment thereof is a bond. In some embodiments, each X 2 in in Formula (I) or a subembodiment thereof is Ci-4 alkylene. In some embodiments, each X 2 in Formula (I) or a subembodiment thereof is C1-2 alkylene. In some embodiments, each X 2 in Formula (I) or a subembodiment thereof is methylene.
  • R 3 in Formula (I) or a subembodiment thereof is
  • R 3 in Formula (I) or a subembodiment thereof is
  • R 3 in Formula (I) or a subembodiment thereof is
  • R 3 in Formula (I) or a subembodiment thereof is
  • R 3 in Formula (I) or a subembodiment thereof is (i) C1-6 alkyl or C1-6 haloalkyl, each of which is substituted with 0 to 4 R 3a , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is Ci-6 alkyl substituted with 0 to 2 R 3a , each of which is independently selected.
  • each R 3a is independently selected from the group consisting of-O- C1-2 alkyl, -O-C1-2 haloalkyl, -OH, cyano, and -S(O)2CH3. In some embodiments, each R 3 is C1-6 haloalkyl. In some embodiments, each R 3 is selected from the group consisting of
  • R 3 in Formula (I) or a subembodiment thereof is (ii) -C alkylene- NR e R f , -X 3 -C(O)NR e R f , -CM alkylene-NR h -C(O)R j , or -X 3 -C(O)OR k .
  • R 3 in Formula (I) or a subembodiment thereof is -CM alkylene-NR e R f .
  • R 3 in Formula (I) or a subembodiment thereof is -X 3 -C(O)NR e R f .
  • R 3 in Formula (I) or a subembodiment thereof is -CM alkylene-NR h - C(O)Ri. In some embodiments, R 3 in Formula (I) or a subembodiment thereof is-X 3 - C(O)OR k .
  • R 3 in Formula (I) or a subembodiment thereof is -C2 alkylene-NR e R f .
  • R 3 in Formula (I) or a subembodiment thereof is -C(O)NR e R f . In some embodiments, R 3 in Formula (I) or a subembodiment thereof is -C(O)OR k .
  • R 3 in Formula (I) or a subembodiment thereof is -C(O)NR e R f and R e and R f are independently selected from the group consisting of hydrogen and C1-2 alkyl.
  • R 3 in Formula (I) or a subembodiment thereof is selected from the group consisting of
  • R 3 in Formula (I) or a subembodiment thereof is selected from the group consisting of
  • R k is CM alkyl. In some embodiments R h is hydrogen. In some embodiments R 1 is C1-4 alkyl or phenyl. In some embodiments, R 3 in Formula (I) or a subembodiment thereof is (iii) -X 3 -Cs-6 cycloalkyl substituted with 0 to 5 R 3b , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is -Ci-4 alkylene -C3-6 cycloalkyl or C4-6 cycloalkyl substituted with 0 to 5 R 3b , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is C3-6 cycloalkyl substituted with 0 to 5 R 3b , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is selected from the group consisting of substituted with 0 to 3 R 3b , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is selected from the group consisting of substituted with 0 to 3 R 3b , each of which is independently selected.
  • R 3b when R 3 is (iii) or a subembodiment thereof is independently selected from the group consisting of C1-3 alkyl, halo, C1-3 haloalkyl, -O-C1-3 haloalkyl, -O- C1-3 alkyl, -X 4 -0H, cyano, -S(O)2Ci-2 alkyl, phenyl, and oxo.
  • each R 3b is independently selected from the group consisting of C1-3 alkyl, halo, C1-3 haloalkyl, -O-C1-3 haloalkyl, -O-C1-3 alkyl, -X 4 -OH, cyano, -S(O)2Cu 2alkyl, and oxo.
  • each R 3b is independently selected from the group consisting of methyl, fluoro, fluoromethyl, difluoromethyl, methoxy, -OH, -CH2-OH, -C(CH3)2-OH, cyano, S(O)2CH3 and oxo.
  • R 3 in Formula (I) or a subembodiment thereof is (iv) -X 3a -phenyl substituted with 0 to 5 R 3c , each of which is independently selected. In some embodiments, R 3 in Formula (I) or a subembodiment thereof is phenyl substituted with 0 to 2 R 3C , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is phenyl or -C2-4 alkylene-phenyl substituted with 0 to 2 R 3c , each of which is independently selected. In some embodiments, R 3 in Formula (I) or a subembodiment thereof is -C1-2 alkylenephenyl substituted with 0 to 2 R 3c , each of which is independently selected.
  • each R 3c when R 3 is (iv) or a subembodiment thereof is independently selected from the group consisting of C1-3 alkyl, halo, C1-6 haloalkyl, -O-C1-3 haloalkyl, and - O-C1-3 alkyl. In some embodiments, each R 3c when R 3 is (iv) or a subembodiment thereof is independently selected from the group consisting of C1-3 alkyl and halo.
  • R 3 in Formula (I) or a subembodiment thereof is
  • R 3 in Formula (I) or a subembodiment thereof is
  • R 3 in Formula (I) or a subembodiment thereof is in some embodiments, R 3 in Formula (I) or a subembodiment thereof is (v) -X 3 -5- to 6- membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, and wherein the 5- to 6- membered heteroaryl is substituted with 0 to 5 R 3c , each of which is independently selected, and when X 3 is a bond, the 5- to 6- membered heteroaryl is linked via a carbon atom to the remainder of the compound.
  • R 3 in Formula (I) or a subembodiment thereof is a 5 - to 6- membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, and wherein the 5- to 6- membered heteroaryl substituted with 0 to 2 R 3c , each of which is independently selected, and the 5- to 6- membered heteroaryl is linked via a carbon atom to the remainder of the compound.
  • R 3 in Formula (I) or a subembodiment thereof is a 5- membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, and wherein the 5- membered heteroaryl substituted with 0 to 2 R 3c , each of which is independently selected, and the 5- membered heteroaryl is linked via a carbon atom to the remainder of the compound.
  • R 3 in Formula (I) or a subembodiment thereof is a 6- membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, and wherein the 6- membered heteroaryl substituted with 0 to 2 R 3c , each of which is independently selected, and the 6- membered heteroaryl is linked via a carbon atom to the remainder of the compound.
  • R 3 in Formula (I) or a subembodiment thereof is HO, H s ] N"° or .
  • R 3 in Formula (I) or a subembodiment thereof is
  • R 3 in Formula (I) or a subembodiment thereof is (vi) -X 3 -Cs-s bridged cycloalkyl substituted with 0 to 5 R 3c , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is C5-8 bridged cycloalkyl substituted with 0 to 5 R 3c , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is substituted with 0 to 2 R 3c , each of which is independently selected.
  • each R 3c when R 3 is (vi) is independently selected from the group consisting of C1-3 alkyl, halo, and C1-3 haloalkyl.
  • each R 3c when R 3 is (vi) is independently selected from the group consisting of methyl and fluoro.
  • R 3 in Formula (I) or a subembodiment thereof is (vii) -X 3 -6- to 12- membered spiroheterocyclyl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, and wherein the 6- to 12-membered spiroheterocyclyl is substituted with 0 to 5 R 3c , each of which is independently selected, and when X 3 is a bond, the 6- to 12- membered spiroheterocyclyl is linked via a carbon atom to the remainder of the compound.
  • R 3 in Formula (I) or a subembodiment thereof is 6- to 12-membered spiroheterocyclyl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, and wherein the 6- to 12-membered spiroheterocyclyl is substituted with 0 to 5 R 3c , each of which is independently selected, and the 6- to 12- membered spiroheterocyclyl is linked via a carbon atom to the remainder of the compound.
  • R 3 is selected from the group consisting of 4-oxaspiro[2.4]heptane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]-nonane, and 2,7- diazaspiro[4.4]nonane, and is substituted with 0 to 4 R 3c .
  • R 3 in Formula (I) or a subembodiment thereof is substituted with 0 to 2 R 3c .
  • each R 3c when R 3 is (vii) is independently selected from the group consisting of C1-3 alkyl, halo, C1-3 haloalkyl, and -OH.
  • each R 3c when R 3 is (vii) is independently selected from the group consisting of methyl, fluoro, and -OH.
  • R 3 in Formula (I) or a subembodiment thereof is (viii) -X 3 -Ce-i2 spirocycloalkyl substituted with 0 to 5 R 3c , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is C6-12 spirocycloalkyl substituted with 0 to 5 R 3c , each of which is independently selected.
  • R 3 in Formula (I) and subembodiments thereof is selected from the group consisting of spiro[3.3]heptane, spiro[4.4]nonane, spiro [3.4] octane substituted with 0 to 5 R 3c , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is substituted with 0 to 2 R 3c , each of which is independently selected.
  • each R 3c when R 3 is (viii) is independently selected from the group consisting of C1-3 alkyl, halo, C1-3 haloalkyl, and -OH.
  • each R 3c when R 3 is (viii) is independently selected from the group consisting of methyl, fluoro, and -OH.
  • R 3 in Formula (I) or a subembodiment thereof is (ix) -X 3 -3- to 6- membered heterocycloalkyl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, wherein ring vertices with an S are substituted with 0 to 2 oxo moieties; the 3- to 6-membered heterocycloalkyl is substituted with 0 to 5 R 3d , each of which is independently selected; and when X 3 is a bond, the 3- to 6- membered heterocycloalkyl is linked via a carbon atom to the remainder of the compound.
  • R 3 in Formula (I) or a subembodiment thereof is 3- to 6-membered heterocycloalkyl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, wherein ring vertices with an S are substituted with 0 to 2 oxo moieties; the 3- to 6- membered heterocycloalkyl is substituted with 0 to 5 R 3d , each of which is independently selected; the 3- to 6- membered heterocycloalkyl is linked via a carbon atom to the remainder of the compound.
  • R 3 in Formula (I) or a subembodiment thereof is a 4- membered heterocycloalkyl substituted with 0 to 5 R 3d , each of which is independently selected. In some embodiments, R 3 in Formula (I) or a subembodiment thereof is a 5 - membered heterocycloalkyl substituted with 0 to 5 R 3d , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is substituted with 0 to 2 R 3d , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is substituted with 0 to 2 R 3d , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is substituted with 0 to 2 R 3d , each of which is independently selected.
  • R 3 in Formula (I) or a subembodiment thereof is selected from the group consisting of substituted with 0 to 3 R 3d , each of which is independently selected.
  • each R 3d when R 3 is (ix) is independently selected from the group consisting of C1-3 alkyl, halo, C1-3 haloalkyl, -C(O)Ci-2alkyl, -S(O)2Ci-2alkyl, and oxo.
  • each R 3d when R 3 is (ix) is independently selected from the group consisting of methyl, fluoro, C(0)CH3, and S(O)2CH3.
  • each X 3 in Formula (I) or a subembodiment thereof is a bond. In some embodiments, each X 3 in Formula (I) or a subembodiment thereof is C1-4 alkylene. In some embodiments, each X 3 in Formula (I) or a subembodiment thereof is C1-2 alkylene. In some embodiments, each X 3 in Formula (I) or a subembodiment thereof is methylene. In some embodiments, each X 3a in Formula (I) or a subembodiment thereof is a bond. In some embodiments, each X 3a in Formula (I) or a subembodiment thereof is C1-4 alkylene.
  • each X 3a in Formula (I) or a subembodiment thereof is C1-2 alkylene. In some embodiments, each X 3a in Formula (I) or a subembodiment thereof is methylene. In some embodiments, each X 3a in Formula (I) or a subembodiment thereof is C1-3 alkylene-O-. In some embodiments, each X 3a in Formula (I) or a subembodiment thereof is C1-2 alkylene- O— . In some embodiments, each X 3a in Formula (I) or a subembodiment thereof is Ci alkylene-O-.
  • each X 4 in Formula (I) or a subembodiment thereof is a bond. In some embodiments, each X 4 in Formula (I) or a subembodiment thereof is C1-4 alkylene. In some embodiments, each X 4 in Formula (I) or a subembodiment thereof is C1-2 alkylene. In some embodiments, each X 4 in Formula (I) or a subembodiment thereof is methylene.
  • the compounds or pharmaceutically acceptable salts thereof is a compound from Table 1.
  • compositions suitable for administration to a subject may be in the form of compositions suitable for administration to a subject.
  • compositions are pharmaceutical compositions comprising a compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • the compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount.
  • the pharmaceutical compositions may be used in all the methods disclosed herein; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic methods and uses described herein.
  • compositions can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein. Furthermore, the pharmaceutical compositions may be used in combination with other therapeutically active agents or compounds as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs.
  • Tablets, capsules and the like contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets, capsules, and the like.
  • excipients can include diluents, granulating agents, disintegrating agents, binding agents, and lubricating agents.
  • the tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture thereof. Such excipients can include suspending agents, dispersing agents and wetting agents.
  • excipients can include suspending agents, dispersing agents and wetting agents.
  • the aqueous suspensions may also contain one or more preservatives.
  • Oily suspensions may be formulated by suspending the active ingredient in an oil. Suitable oils are known in the art.
  • the oily suspensions may contain additional agents such as a thickening agent or a sweetening agent.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, ka
  • the pharmaceutical compositions may also be in the form of oil-in-water emulsions. Suitable emulsifying agents are known in the art.
  • the pharmaceutical compositions typically comprise a therapeutically effective amount of a compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient.
  • Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants, preservatives, emulsifying agents, suspending agents, dispersing agents, solvents, fdlers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants.
  • Those skilled in the art will readily recognize a variety of exipients that can be used in the pharmaceutical compositions and dosage forms contemplated herein.
  • Depot injections which are generally administered subcutaneously or intramuscularly, may also be utilized to release the compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof disclosed herein over a defined period of time.
  • Depot injections are usually either solid- or oil-based and generally comprise at least one of the formulation components set forth herein.
  • One of ordinary skill in the art is familiar with possible formulations and uses of depot injections.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • the suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents mentioned herein.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, which are known in the art.
  • a compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof may also be administered in the form of suppositories for rectal administration or sprays for nasal or inhalation use.
  • the suppositories can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are known in the art.
  • All the compounds and pharmaceutical compositions provided herein can be used in all the methods provided herein.
  • the compounds and pharmaceutical compositions provided herein can be used in all the methods for treatment and/or prevention of all diseases or disorders provided herein.
  • the compounds and pharmaceutical compositions provided herein are for use as a medicament.
  • routes of Administration Compounds of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof and compositions containing the same may be administered in any appropriate manner.
  • Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracistemal, intraarticular, intraperitoneal, intracerebral (intraparenchymal) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal and inhalation.
  • Depot injections which are generally administered subcutaneously or intramuscularly, may also be utilized to administer the compounds of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof over a defined period of time.
  • Particular embodiments of the present invention contemplate oral administration.
  • the present invention contemplates the use of compounds of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation).
  • active therapeutic agents e.g., chemotherapeutic agents
  • prophylactic or therapeutic modalities e.g., radiation
  • the various active agents frequently have different, complementary mechanisms of action.
  • Such combination therapy may be especially advantageous by allowing a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse effects associated with one or more of the agents.
  • such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.
  • “combination” is meant to include therapies that can be administered separately, for example, formulated separately for separate administration (e.g., as may be provided in a kit), and therapies that can be administered together in a single formulation (i.e., a “co-formulation”).
  • the compounds of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof are administered or applied sequentially, e.g., where one agent is administered prior to one or more other agents.
  • the compounds of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof are administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a co-formulation). Regardless of whether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for purposes of the present disclosure.
  • the compounds of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof may be used in combination with at least one other (active) agent in any manner appropriate under the circumstances.
  • treatment with the at least one active agent and at least one compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof is maintained over a period of time.
  • treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), while treatment with the compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof is maintained at a constant dosing regimen.
  • treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), while treatment with a compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof is reduced (e.g., lower dose, less frequent dosing or shorter treatment regimen).
  • treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), and treatment with the compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof is increased (e.g., higher dose, more frequent dosing or longer treatment regimen).
  • treatment with the at least one active agent is maintained and treatment with the compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof is reduced or discontinued (e.g., lower dose, less frequent dosing or shorter treatment regimen).
  • treatment with the at least one active agent and treatment with the compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof are reduced or discontinued (e.g., lower dose, less frequent dosing or shorter treatment regimen).
  • the present disclosure provides methods for treating cancer with a compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof and at least one additional therapeutic or diagnostic agent.
  • the compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent.
  • the additional therapeutic agent is a signal transduction inhibitor (STI) or chemotherapeutic agent.
  • the present disclosure provides methods for treating cancer comprising administration of a compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof described herein in combination with a signal transduction inhibitor (STI) to achieve additive or synergistic suppression of tumor growth.
  • STI signal transduction inhibitor
  • the term “signal transduction inhibitor” refers to an agent that selectively inhibits one or more steps in a signaling pathway. Agents involved in immunomodulation can also be used in combination with one or more compounds of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof described herein for the suppression of tumor growth in cancer patients.
  • the present disclosure provides methods for treating cancer comprising administration of a compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof described herein in combination with a chemotherapeutic agents.
  • Chemotherapeutic agents also include anti-hormonal agents that act to regulate or inhibit hormonal action on tumors such as anti-estrogens.
  • combination therapy comprises administration of a hormone or related hormonal agent.
  • the present disclosure also contemplates the use of the compounds of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof described herein in combination with immune checkpoint inhibitors.
  • immune checkpoint inhibitors The tremendous number of genetic and epigenetic alterations that are characteristic of all cancers provides a diverse set of antigens that the immune system can use to distinguish tumor cells from their normal counterparts.
  • immune checkpoints are crucial for the prevention of autoimmunity (i.e., the maintenance of self-tolerance) and also for the protection of tissues from damage when the immune system is responding to pathogenic infection.
  • the expression of immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism.
  • immune checkpoint inhibitors include but are not limited to CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, 0X40, 4 IBB, VISTA, CD96, TGFp, CD73, CD39, A2AR, A2BR, IDO1, TDO2, Arginase, B7-H3, B7-H4.
  • Cell-based modulators of anti-cancer immunity are also contemplated.
  • modulators include but are not limited to chimeric antigen receptor T-cells, tumor infiltrating T-cells and dendritic-cells.
  • the compounds of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof provided herein may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof.
  • the dosing regimen may also take into consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered. Effective dosage amounts and dosage regimens can readily be determined from, for example, safety and dose-escalation trials, in vivo studies (e.g., animal models), and other methods known to the skilled artisan.
  • dosing parameters dictate that the dosage amount be less than an amount that could be irreversibly toxic to the subject (the maximum tolerated dose (MTD)) and not less than an amount required to produce a measurable effect on the subject.
  • MTD maximum tolerated dose
  • Such amounts are determined by, for example, the pharmacokinetic and pharmacodynamic parameters associated with ADME, taking into consideration the route of administration and other factors.
  • An effective dose is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it.
  • the “median effective dose” or EDso of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population to which it is administered.
  • the ED50 is commonly used as a measure of reasonable expectance of an agent’s effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors. Thus, in some situations the effective amount is more than the calculated ED50, in other situations the effective amount is less than the calculated ED50, and in still other situations the effective amount is the same as the calculated ED50.
  • an effective dose of a compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof, as provided herein may be an amount that, when administered in one or more doses to a subject, produces a desired result relative to a healthy subject.
  • an effective dose may be one that improves a diagnostic parameter, measure, marker and the like of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as the diagnostic parameter, measure, marker and the like exhibited by a normal subject.
  • the compounds of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof disclosed herein may be administered (e.g., orally) at dosage levels of about 0.01 mg/kg to about 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • compositions can be provided in the form of tablets, capsules and the like containing from 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient.
  • the dosage of the compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof is contained in a “unit dosage form”.
  • unit dosage form refers to physically discrete units, each unit containing a predetermined amount of the compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof, either alone or in combination with one or more additional agents, sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the particular agent and the effect to be achieved.
  • kits comprising a compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof.
  • the kits are generally in the form of a physical structure housing various components, as described below, and may be utilized, for example, in practicing the methods described above.
  • a kit can include one or more of the compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof disclosed herein (provided in, e.g., a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject.
  • the compound of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof can be provided in a form that is ready for use (e.g., a tablet or capsule) or in a form requiring, for example, reconstitution or dilution (e.g., a powder) prior to administration.
  • the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, and the like, packaged with or separately from the compounds of Formula (I) or a subembodiment or a pharmaceutically acceptable salt thereof.
  • diluents e.g., sterile water
  • the kit may contain the several agents separately or they may already be combined in the kit.
  • Each component of the kit may be enclosed within an individual container, and all of the various containers may be within a single package.
  • a kit of the present invention may be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing).
  • a kit may contain a label or packaging insert including identifying information for the components therein and instructions fortheir use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s), including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). Labels or inserts can include manufacturer information such as lot numbers and expiration dates.
  • the label or packaging insert may be, e.g., integrated into the physical structure housing the components, contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampule, tube or vial).
  • Labels or inserts can additionally include, or be incorporated into, a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory-type cards.
  • a computer readable medium such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory-type cards.
  • the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g., via the internet, are provided.
  • the compounds of this disclosure may be made by a variety of methods, including well- known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the present disclosure are prepared in the working examples. A skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. In all of the schemes described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M.
  • Pd(dppf)Ch (l,l’-Bis(diphenylphosphino)ferrocene)dichloropalladium(II);
  • Pd(dppf)Ch- DCM (l,l’-Bis(diphenylphosphino)ferrocene)dichloropalladium(II), complex with dichloromethane;
  • BAST N,N-bis(2-methoxyethyl)aminosulfur trifluoride
  • aqueous layer was acidified to pH 6 with HC1 (1 M). A solid formed and mixture was filtered to afford 3-(2- methoxyphenyl) pyridine-4-carboxylic acid as a white solid, which was used to next step without further purification.
  • Step-2 methyl 2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate
  • Step 1 Synthesis of 2-(thiazole-2-carbonyl)hydrazine- 1 -carbothioamide : Into a 50-mL 3-necked round-bottom flask, was placed l,3-thiazole-2-carboxylic acid (1.00 g, 7.744 mmol, 1.00 equiv), DCM (10.00 mb), oxalyl chloride (1081.17 mg, 8.519 mmol, 1.1 equiv), DMF (56.60 mg, 0.774 mmol, 0.1 equiv), The resulting solution was stirred for 30 min at 0 degrees C. The resulting mixture was concentrated under reduced pressure. The crude acyl chloride dissolved with THF (10.00 mb).
  • N-(carbamothioylamino)-l,3-thiazole-2-carboxamide 400.00 mg, 1.978 mmol, 1.00 equiv
  • phosphorus oxychloride 4.00 mb
  • the resulting solution was stirred overnight at 50 degrees C.
  • the reaction was quenched by the addition of Water (50mL) at 0 degree C.
  • the aqueous layer was extracted with EtOAc (50 mb).
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by Prep-TLC (PE/EtOAc 1: 1) to afford 5-(l,3-thiazol-2-yl)-l,3,4-thiadiazol-2-amine (30 mg, yield 8.15%) as a white solid.
  • Step-1 Synthesis of 5-((trans)-2 -phenylcyclopropyl)-!, 3, 4-thiadiazol-2-amine:
  • Step-2 Synthesis of 4-(2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((trans)-2- phenylcyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl)pyridine-3 -carboxamide : To a solution of racemic 5-((trans)-2 -phenylcyclopropyl)- 1, 3, 4-thiadiazol-2-amine (60 mg, 0.276 mmol) in MeCN (2 m ) and DMF (2 m ) were added Intermediate C (73 mg, 0.276 mmol), NMI (68 mg, 0.828 mmol) and TCFH (93 mg, 0.331 mmol). The resulting solution was stirred at room temperature for 2 hours.
  • Step-1 Synthesis of 5-(2-phenylethyl)-l,3,4-thiadiazol-2-amine: To a mixture of 3 -phenylpropionic acid (1.00 g, 6.65 mmol) and thiosemicarbazide (610.00 mg, 6.69 mmol) in dioxane (5.0 mL) was added added POCI3 (1.02 g, 0.007 mmol). The resulting solution was stirred at 90 °C for 16 h before concentrated under vacuum. The residue was quenched by the addition of NaHCCE aqueous solution and extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, fdtered, and concentrated under vacuum.
  • Step-2 Synthesis of 4-(2-fhroro-6-methoxyphenyl)-6-methyl-N-(5-(2-phenylethyl)-l,3,4- thiadiazol -2 -yl)pyridine-3 -carboxamide :
  • Step-2 Synthesis of 2'-chloro-N-(5-cyclobutyl- l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-
  • Step-2 Synthesis of 2'-chloro-N-(5-cyclopentyl-l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-
  • Step-1 Synthesis of 5-(cyclopropylmethyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(cyclopropyhnethyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-
  • the mixture was purified by prep- HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 35% B in 8 min, 35% B to 95% B in 8.2 min, 95% B to 95% B in 10 min, 95% B to 15% B in 10.2 min, 15% B to 15% B in 12 min; Wave Length: 254 nm; RTl(min): 7.6; Injection Volume: 1 mL; Number Of Runs: 4) to afford 2'-chloro-5'- methoxy-N-(5-(methoxymethyl)-l,3,4-thiadiazol-2-yl)-6-methyl-(4,4'-bipyridine)-3- carboxamide (58.7 mg, 26% yield) as a white solid.
  • Step-1 Synthesis of 5-(l-methylcyclopropyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(l-methylcyclopropyl)-l,3,4- thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide:
  • N,N-Dimethylformamide (DMF) (4 mL) were added N-ethyl-N-isopropylpropan-2 -amine (209.0 mg, 1.62 mmol), Intermediate B (150.0 mg, 0.54 mmol) and 2-(3H-TCFH (246.0 mg,
  • Step-1 Synthesis of methyl l-(5-amino-l,3,4-thiadiazol-2-yl)cyclopropane-l-carboxylate:
  • Step-2 Synthesis of methyl l-(5-(2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxamido)- 1 ,3 ,4-thiadiazol-2-yl)cyclopropane- 1 -carboxylate : To a mixture of methyl 1 -(5 -amino- 1, 3, 4-thiadiazol-2-yl)cyclopropane-l -carboxylate (149.0 mg, 0.67 mmol) in Acetonitrile (1 m ) and DMF (1 mL) were added Intermediate B (170.0 mg, 0.61 mmol) and NMI (150.0 mg, 1.83 mmol).
  • Step-3 Synthesis of 2'-chloro-N-(5-( l-(hydroxymethyl)cyclopropyl)- l,3,4-thiadiazol-2-yl)- 5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide:
  • Step-1 Synthesis of ethyl 5-(2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxamido)- 1 ,3 ,4-thiadiazole-2 -carboxylate :
  • Step-2 Synthesis of 2'-chloro-N-(5-(2-hydroxypropan-2-yl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-1 Synthesis of 5-(l-(methylsulfonyl)cyclopropyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(l-(methylsulfonyl)cyclopropyl)- l,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide:
  • Step-1 Synthesis of 5-(tetrahydrofuran-2-yl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-2-yl)-l,3,4- thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide:
  • the resulting mixture was purified by prep-HPLC with the following conditions: (Column: XBridge Shield RP18 OBD Column, 30* 150mm, 5um; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23% B to 32% B in 8 min, 32% B to 95% B in 8.2 min, 95% B to 95% B in 10 min, 95% B to 5% B in 11 min, 5% B; Wave Length: 254 nm; RTl(min): 6.6; Injection Volume: 1 mL; Number Of Runs: 6) to afford 2'-chloro-5'-methoxy- 6-methyl-N-(5-(tetrahydrofuran-2-yl)-l,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide (41.8 mg, 17%) as a white solid.
  • Step-1 Synthesis of 5-(tetrahydrofuran-3-yl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-yl)-l,3,4- thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide:
  • Step-1 Synthesis of 5-(l-fhrorocyclopropyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(l-fluorocyclopropyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-
  • reaction mixture was purified by Combi Flash (Biotage Isolera Prime) which applied to 40 g C18 column with 5-40% acetonitrile in water within 45 min to afford 2'-chloro-N-(5-(l-fluorocyclopropyl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (120.3 mg, 89%) as a white solid.
  • MS (ESI) calc’d for (CisHisClFNsCES) (M+l) + , 420.1, found 420.0.
  • reaction mixture was purified by Combi Flash (Biotage Isolera Prime) which applied to 40 g Cl 8 column with 5-35% acetonitrile in water within 45 min to afford 2'- chloro-5'-methoxy-6-methyl-N-(5-(2,2,2-trifluoroethyl)-l,3,4-thiadiazol-2-yl)-(4,4'- bipyridine)-3 -carboxamide (81.5 mg, 80%) as a white solid.
  • MS (ESI) calc’d for (C17H13CIF3N5O2S) (M+l) + , 444.0, found 444.1.
  • Example 24 and Example 25 2'-chloro-5'-methoxy-6-methyl-N-(5-((lR,2S)-2-methylcyclopropyl)-I,3,4-thiadiazol-2-yl)- (4, 4'-bipyridine)-3 -carboxamide, and 2'-chloro-5'-methoxy-6-methyl-N-(5-((lS,2R)-2- methylcyclopropyl)-I,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide
  • Step-1 Synthesis of re/-5-((lS,2R)-2-methylcyclopropyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of rel- 2'-chloro-5'-methoxy-6-methyl-N-(5-((lS,2R)-2- methylcyclopropyl)-l,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide:
  • Step-3 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-((lR,2S)-2-methylcyclopropyl)- l,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide, and 2'-chloro-5'-methoxy-6-methyl- N-(5-((lS,2R)-2-methylcyclopropyl)-l,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide
  • Step-1 Synthesis of 5-((methylsulfonyl)methyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 2'-chloro-5'-methoxy-6-methyl-N-(5-((methylsulfonyl)methyl)-l,3,4-thiadiazol-2-yl)-
  • reaction mixture was purified by Combi Flash (Biotage Isolera Prime) which applied to 40 g C 18 column with 5 ⁇ 25% acetonitrile in water within 45 min to afford 2'-chloro-5'-methoxy-6-methyl-N-(5-((methylsulfonyl)methyl)-l,3,4-thiadiazol-2-yl)- (4, 4'-bipyridine)-3 -carboxamide (73.6 mg, 60%) as a yellow solid.
  • MS (ESI) calc’d for (C17H16CIN5O4S2) (M+l) + , 454.0, found 454.1.
  • Step-1 Synthesis of methyl 3-(benzyloxy)-2,2-dimethylpropanoate:
  • Step-2 Synthesis of 3-(benzyloxy)-2,2-dimethylpropanoic acid: BnO H HO
  • Step-3 Synthesis of 5-(l-(benzyloxy)-2-methylpropan-2-yl)-l,3,4-thiadiazol-2-amine:
  • Step-4 Synthesis of 2-(5-amino-l,3,4-thiadiazol-2-yl)-2-methylpropan-l-ol:
  • Step-5 Synthesis of 2'-chloro-N-(5-( l-hydroxy-2-methylpropan-2-yl)- l,3,4-thiadiazol-2-yl)- 5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide:
  • Step-1 Synthesis of I-(5-amino-I,3,4-thiadiazol-2-yl)cyclopropane-I-carbonitrile: N H 2 N ' S
  • Step-2 Synthesis of 2'-chloro-N-(5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-
  • reaction mixture was applied to a 40 g C18 column and purified by Combi Flash (Biotage Isolera Prime), eluted with 5-30% acetonitrile in water within 45 min and further purified by prep-HPLC with the following conditions: (Column: XBridge Shield RP18 OBD Column, 30* 150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeOH— HPLC; Flow rate: 60 mL/min; Gradient: 30% B to 52% B in 8 min, 52% B to 95% B in 8.2 min, 95% B to 95% B in 9.5 min, 95% B to 5% B in 11 min, 5% B; Wave Length: 254 nm; RTl(min): 6.2; Injection Volume: 0.3 mL; Number Of Runs: 3) to afford 2'-chloro-N-(5-(l-cyanocyclopropyl)-l,3,4- thiadiazol-2-
  • Step-1 Synthesis of re/-5-((lS,2S)-2-methylcyclopropyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of re/-2'-chloro-5'-methoxy-6-methyl-N-(5-((lS,2S)-2-methylcyclopropyl)- l,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide:
  • Step-3 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-((lS,2S)-2-methylcyclopropyl)- l,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-5'-methoxy-6-methyl-N- (5 -(( 1 R,2R)-2 -methylcyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3 -carboxamide :
  • Step-1 Synthesis of methyl 3-(benzyloxy)cyclobutane-l-carboxylate:
  • Step-2 Synthesis of 3 -(benzyloxy)cyclobutane- 1 -carboxylic acid: To a stirred solution of methyl-3-(benzyloxy)cyclobutane-l -carboxylate (2.2 g, 10.03 mmol) in THF (2 mL) and Water (2 mL) was added LiOH (0.5 g, 20.07 mmol) at 25 °C. The resulting solution was stirred at 25 °C for 1 hr. The organic solvent was removed under vacuum. The aqueous layer was acidified with citric acid to pH ⁇ 5 and extracted with ethyl acetate.
  • Step-3 Synthesis of 5-(3-(benzyloxy)cyclobutyl)-l,3,4-thiadiazol-2-amine:
  • Step-4 Synthesis of 3-(5-amino-l,3,4-thiadiazol-2-yl)cyclobutan-l-ol:
  • Step-5 Synthesis of 2'-chloro-N-(5-(3-hydroxycyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-
  • Step-1 Synthesis of methyl (lr,4r)-4-(5-amino-l,3,4-thiadiazol-2-yl)cyclohexane-l- carboxylate:
  • Step-2 Synthesis of methyl (lr,4r)-4-(5-(2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxamido)- 1 ,3 ,4-thiadiazol-2-yl)cyclohexane- 1 -carboxylate :
  • Step-3 Synthesis of 2'-chloro-N-(5-((lr,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-l,3,4- thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide:
  • Example 33 and Example 34 2'-chloro-N-(5-((lr,4r)-4-hydroxycyclohexyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl- (4, 4'-bipyridine)-3 -carboxamide and 2'-chloro-N-(5-((ls,4s)-4-hydroxycyclohexyl)-l,3,4- thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide
  • Step-1 Synthesis of methyl 4-(benzyloxy)cyclohexane-l -carboxylate:
  • Step-2 Synthesis of 4-(benzyloxy)cyclohexane-l -carboxylic acid:
  • Step-3 Synthesis of 5-(4-(benzyloxy)cyclohexyl)-l,3,4-thiadiazol-2-amine:
  • Step-4 Synthesis of 4-(5-amino-l,3,4-thiadiazol-2-yl)cyclohexan-l-ol:
  • Step-5 Synthesis of 2'-chloro-N-(5-(4-hydroxycyclohexyl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-6 Synthesis of 2'-chloro-N-(5-((lr,4r)-4-hydroxycyclohexyl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-N-(5-(( ls,4s)-4- hydroxycyclohexyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxamide:
  • the racemic compound (260 mg) was further purification by Prep-Chiral HPLC with following condition (Column: XBridge Shield RP18 OBD Column, 30* 150 mm, 5pm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 30% B in 8 min, 30% B to 95% B in 8.2 min, 95% B to 95% B in 9.5 min, 95% B to 5% B in 11 min, 5% B; Wave Length: 254 nm; RTl(min): 7.7; Injection Volume: 0.5 mL; Number Of Runs: 3) to afford 2'-chloro-N-(5-((lr,4r)-4- hydroxycyclohexyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxamide (3.0 mg, 1
  • Step-1 Synthesis of 5-(3-fluorobicyclo(l.l. l)pentan-l-yl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(3-fluorobicyclo(l. l.l)pentan-l-yl)-l,3,4-thiadiazol-2- yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide:
  • the mixture was diluted in DMF (2 mL) and purified by prep-HPLC with the following conditions: (Column: XBridge Shield RP18 OBD Column, 30* 150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 38% B in 8 min, 38% B to 95% B in 8.2 min, 95% B to 95% B in 9.5 min, 95% B to 5% B in 11 min, 5% B; Wave Length: 254 nm; RT1 (min): 7.4; Injection Volume: 0.5 mL; Number Of Runs: 5) to afford 2'-chloro-N-(5-(3-fhrorobicyclo(l .1.
  • Step-1 Synthesis of 5-(l,l-difluoroethyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(l,l-difluoroethyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-(4,4'-bipyridine)-3 -carboxamide: To a solution of 5-(l,l-difluoroethyl)-l,3,4-thiadiazol-2-amine (178.0 mg, 1.07 mmol) in Acetonitrile (1 mL) were added 1 -methyl- IH-imidazole (206.0 mg, 2.51 mmol) and Intermediate B (200.0 mg, 0.71 mmol).
  • Step-1 Synthesis of 5-(l,l,l-trifluoro-2-methylpropan-2-yl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(l,l,l-trifluoro-2-methylpropan-2- yl)-l,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide:
  • the mixture was purified by prep-HPLC with the following conditions: (Column: X Bridge Shield RP18 OBD Column, 30* 150 mm, 5pm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 38% B in 8 min, 38% B to 95% B in 8.2 min, 95% B to 95% B in 9.5 min, 95% B to 5% B in 11 min, 5% B; Wave Length: 254 nm; RTl(min): 7.3; Injection Volume: 0.5 mL; Number Of Runs: 6) to afford 2'-chloro-5'- methoxy-6-methyl-N-(5 -(1,1,1 -trifluoro-2-methylpropan-2-yl)- 1 ,3,4-thiadiazol-2-yl)-(4,4'- bipyridine)-3 -carboxamide (145.9 mg, 57%) as
  • Step-1 Synthesis of 5-propyl-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-propyl-l,3,4-thiadiazol-2-yl)-(4,4'- bipyridine)-3 -carboxamide :
  • Step-1 Synthesis of methyl (ls,4s)-4-(5-amino-l,3,4-thiadiazol-2-yl)cyclohexane-l- carboxylate:
  • Step-2 Synthesis of methyl (ls,4s)-4-(5-(2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxamido)- 1 ,3 ,4-thiadiazol-2-yl)cyclohexane- 1 -carboxylate :
  • Step-3 Synthesis of 2'-chloro-N-(5-((ls,4s)-4-(2-hydroxypropan-2-yl)cyclohexyl)-l,3,4- thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide:
  • Step-1 Synthesis of 5-(2,2-difluoroethyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(2,2-difhroroethyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-1 Synthesis of 5-(2 -cyclopropylethyl)-!, 3 ,4-thiadiazol-2 -amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(2-cyclopropylethyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-(4,4'-bipyridine)-3 -carboxamide: To a solution of 5-(2-cyclopropylethyl)-l,3,4-thiadiazol-2-amine (121.6 mg, 0.71 mmol) in Acetonitrile (1 mb) were added 1 -methyl- IH-imidazole (206.0 mg, 2.51 mmol) and Intermediate B (200.0 mg, 0.71 mmol).
  • Step-1 Synthesis of methyl 3-(5-amino-l,3,4-thiadiazol-2-yl)propanoate:
  • Step-3 Synthesis of 2'-chloro-N-(5-(3-hydroxy-3-methylbutyl)- I,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-1 Synthesis of 5-(2-(methylsulfonyl)ethyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(2-(methylsulfonyl)ethyl)- 1,3,4- thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide:
  • Step-1 Synthesis of 5-(2-fhioropropan-2-yl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(2-fhioropropan-2-yl)-l,3,4-thiadiazol-2-yl)-5'-methoxy- 6-methyl-(4,4'-bipyridine)-3-carboxamide:
  • Step-1 Synthesis of 5-(l-methoxycyclopropyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-5'-methoxy-N-(5-(l-methoxycyclopropyl)-l,3,4-thiadiazol-2- yl)-6-methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-1 Synthesis of 5-(l,l,l-trifhioropropan-2-yl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(l,l,l-trifluoropropan-2-yl)-l,3,4- thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide:
  • Step-1 Synthesis of 3-(5-amino-l,3,4-thiadiazol-2-yl)-l-methylpyrrolidin-2-one:
  • Step-2 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(l-methyl-2-oxopyrrolidin-3-yl)- l,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide:
  • Step-1 Synthesis of 5-(l-fluorocyclobutyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(l-fluorocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-2 Synthesis of 2'-chloro-N-(5-((lR,2S)-2-fluorocyclopropyl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-1 Synthesis of 5-((lS,2R)-2-fluorocyclopropyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-((lS,2R)-2-fluorocyclopropyl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-1 Synthesis of 5-(2,2-difluorocyclopropyl)-l,3,4-thiadiazol-2-amine:
  • Step-1 Synthesis of 5-(3-methyloxetan-3-yl)-l,3,4-thiadiazol-2-amine: To a stirred solution of 3 -methyloxetane-3 -carboxylic acid (500.0 mg, 4.31 mmol) in N,N- dimethylformamide (DMF) (10 mb) were sequentially added TBTU (1.4 g, 4.31 mmol) and DIEA (2 mL, 10.77 mmol) at 23 °C. The resulting solution was stirred at 23 °C for 5 min. To the above was added a solution of hydrazinecarbothioamide (392.0 mg, 4.31 mmol) in DMF (10 mL).
  • DMF N,N- dimethylformamide
  • the resulting solution was stirred at 25 °C for 2 hr. Then a solution of NaOH (22 mL, 1 N) was added thereto. The resulting solution was stirred at 100 °C for 16 hr.
  • the reaction mixture was acidified with citric acid to pH 6 ⁇ 7 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum.
  • Step-2 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(3-methyloxetan-3-yl)- 1,3,4- thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide:
  • the reaction mixture was purified by prep-HPLC with the following conditions: (Column: XBridge Shield RP18 OBD Column, 30* 150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 25% B in 8 min, 25% B to 95% B in 8.2 min, 95% B to 95% B in 9.5 min, 95% B to 5% B in 11 min, 5% B; Wave Length: 254 nm; RTl(min): 6.5; Injection Volume: 1 mb; Number Of Runs: 4) to afford 2'-chloro-5'-methoxy-6-methyl-N-(5-(3-methyloxetan-3-yl)- l,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide (49.0 mg, 19%) as a yellow solid.
  • Step-1 Synthesis of 5-(3,3-difluorocyclobutyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(3,3-difluorocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-1 Synthesis of 5-((lS,2S)-2-fluorocyclopropyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-((lS,2S)-2-fluorocyclopropyl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-1 Synthesis of 5-((lR,2R)-2-fluorocyclopropyl)-l,3,4-thiadiazol-2-amine: To a stirred solution of (lS,2R)-2-fluorocyclopropane-l -carboxylic acid (250.0 mg, 2.40 mmol) in 1,4-Dioxane (10 mL) was added hydrazinecarbothioamide (219.0 mg, 2.40 mmol) at 20 °C under nitrogen atmosphere. To the above solution was added POCI3 (79.2 mg, 2.40 mmol) at 90 °C under nitrogen. The resulting mixture was then stirred at 90 °C for 1 hr. The organic solvent was removed under vacuum.
  • Step-2 Synthesis of 2'-chloro-N-(5-((lR,2R)-2-fluorocyclopropyl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Example 60 and Exmaple 61 2'-chloro-N-(5-((lr,3r)-3-fluorocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'- bipyridine)-3 -carboxamide and 2'-chloro-N-(5-((ls,3s)-3-fluorocyclobutyl)-l,3,4-thiadiazol- 2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide
  • Step-1 Synthesis of 5-(3-fluorocyclobutyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(3-fhiorocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-3 Synthesis of 2'-chloro-N-(5-((lr,3r)-3-fluorocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-N-(5-((ls,3s)-3- fhiorocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxamide:
  • Examples 62, 63 and 64 re/-2'-chloro-N-(5-((lR, 2R)-2 -fluorocyclobutyl)- 1, 3, 4-thiadiazol-2-yl)-5'-methoxy-6-methyl- (4,4'-bipyridine)-3-carboxamide, 2'-chloro-N-(5-((lR,2S)-2-fluorocyclobutyl)-l,3,4- thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-N-(5- ((lS,2R)-2-fluorocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxamide
  • Step-1 Synthesis of 5-(2 -fluorocyclobutyl)-!, 3, 4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(2-fluorocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-3 re/-2'-chloro-N-(5-((lR,2R)-2-fluorocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-N-(5-((lR,2S)-2-fluorocyclobutyl)- l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-N-
  • Step-1 Synthesis of 3-(5-amino-I,3,4-thiadiazol-2-yl)cyclobutane-I-carbonitrile:
  • Step-2 Synthesis of 2'-chloro-N-(5-(3-cyanocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-3 Synthesis of 2'-chloro-N-(5-((lr,3r)-3-cyanocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-N-(5-((ls,3s)-3- cyanocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxamide:
  • the racemic compound (95.0 mg) was separated by prep HPLC with the following conditions: (Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5pm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: MeOH— HPLC; Flow rate: 25 mL/min; Gradient: 60% B to 60% B in 8 min, 60% B to 95% B in 8.2 min, 95% B to 95% B in 10 min, 95% B to 60% B in 11 min, 60% B; Wave Length: 254/220 nm; RTl(min): 7; Injection Volume: 600 mL; Number Of Runs: 4) to afford 2'-chloro-N-(5-((lr,3r)-3-cyanocyclobutyl)-l,3,4- thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide (38.0 mg, 47%) as a white solid with shorter retention time on prep-HP
  • Step-1 Synthesis of re/-(lR,2S)-2-(5-amino-l,3,4-thiadiazol-2-yl)cyclopropane-l- carbonitrile:
  • Step-2 Synthesis of re/-2'-chloro-N-(5-((lR,2S)-2-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl)- 5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide:
  • Step-1 Synthesis of (Z)-2-(oxetan-3-ylmethylene)hydrazine-l -carbothioamide: To a stirred solution of oxetane-3-carbaldehyde (500.0 mg, 5.81 mmol) in methanol (10 mL) was added oxetane-3-carbaldehyde (529.0 mg, 5.81 mmol) at 23 °C. The resulting solution was stirred at 80 °C for 1 hr. The suspension was fdtered.
  • Step-2 Synthesis of 5-(oxetan-3-yl)-l,3,4-thiadiazol-2-amine:
  • Step-3 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(oxetan-3-yl)-l,3,4-thiadiazol-2- yl)-(4,4'-bipyridine)-3 -carboxamide:
  • the reaction mixture was purified by prep-HPLC with the following conditions: (Column: Xselect CSH OBD Column 30* 150mm 5um, n; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 21% B in 12 min, 21% B to 95% B in 12.2 min, 95% B to 95% B in 13.7 min, 95% B to 5% B in 15 min, 5% B; Wave Length: 220 nm; RTl(min): 10.62; Injection Volume: 1 mL; Number Of Runs: 3) to afford 2 -chloro-5 -methoxy-6-methyl-N-(5-(oxetan- 3-yl)-l,3,4-thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide (20.0 mg, 3%) as a white solid.
  • Step-1 Synthesis of 5 -(3 -methylbutyl)- 1, 3, 4-thiadiazol-2 -amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(3-methylbutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-1 Synthesis of 5 -(2 -cyclobutylethyl)- 1, 3, 4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(2-cyclobutylethyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-4,4'-bipyridine-3 -carboxamide :
  • Step-1 Synthesis of 5-(3,3,3-trifluoropropyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(3,3,3-trifluoropropyl)-l,3,4- thiadiazol-2-yl)-(4,4'-bipyridine)-3-carboxamide:
  • Step-1 Synthesis of ethyl 5-(2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxamido)- 1 ,3 ,4-thiadiazole-2 -carboxylate :
  • Step-1 Synthesis of 5-(2,2-difluorocyclobutyl)-l,3,4-thiadiazol-2-amine:
  • Step-2 Synthesis of 2'-chloro-N-(5-(2,2-difhiorocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-1 Synthesis of 3-(5-amino-l,3,4-thiadiazol-2-yl)thietane 1,1-dioxide:
  • Step-2 Synthesis of 2'-chloro-N-(5-(l,l-dioxidothietan-3-yl)-l,3,4-thiadiazol-2-yl)-5'- methoxy-6-methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-1 Synthesis of re/-(lR,2R)-2-(5-amino-l,3,4-thiadiazol-2-yl)cyclopropane-l- carbonitrile:
  • Step-2 Synthesis of re/-2'-chloro-N-(5-((lR,2R)-2-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl)- 5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide:
  • Step-1 Synthesis of tert-butyl (Z)-6-((2-carbamothioylhydrazineylidene)methyl)-2- azaspiro(3.3 )heptane -2-carboxylate :
  • Step-2 Synthesis of tert-butyl 6-(5-amino-l,3,4-thiadiazol-2-yl)-2-azaspiro(3.3)heptane-2- carboxylate:
  • Step-3 Synthesis of tert-butyl 6-(5-(2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxamido)- 1 ,3 ,4-thiadiazol-2-yl)-2-azaspiro(3.3)heptane-2-carboxylate :
  • Step-4 Synthesis ofN-(5-(2-azaspiro(3.3)heptan-6-yl)-l,3,4-thiadiazol-2-yl)-2'-chloro-5'- methoxy-6-methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-1 2-chloro-5-(difluoromethoxy)-4-iodopyridine
  • Step-2 methyl 2'-chloro-5'-(difluoromethoxy)-6-methyl-(4,4'-bipyridine)-3-carboxylate
  • Step-3 2'-chloro-5'-(difluoromethoxy)-6-methyl-(4,4'-bipyridine)-3 -carboxylic acid
  • Step 4 2'-chloro-5'-(difluoromethoxy)-N-(5-(l-fluorocyclopropyl)-l,3,4-thiadiazol-2-yl)-6- methyl-(4,4'-bipyridine)-3-carboxamide
  • Step 5 2'-chloro-3'-fhioro-N-(5-( 1 -fluorocyclopropyl)- l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-(4,4'-bipyridine)-3-carboxamide
  • To a stirred solution of 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxylic acid (100.0 mg, 0.34 mmol) in acetonitrile (1 mL) were added 5-(l- fhiorocyclopropyl)-l,3,4-thiadiazol-2-amine (80.0 mg, 0.51 mmol, Example 21, Step 1) and
  • Examples 81, 82 and 83 2'-chloro-N-(5-((lS,2R)-2-cyanocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl- (4,4'-bipyridine)-3-carboxamide, re/-2'-chloro-N-(5-((lR, 2R)-2 -cyanocyclobutyl)- 1,3,4- thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-N-(5- ((lR,2S)-2-cyanocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3- carboxamide
  • Step-1 Synthesis of 2-(5-amino-l,3,4-thiadiazol-2-yl)cyclobutane-l-carbonitrile: To a stirred solution of 2 -methylcyclobutane- 1 -carboxylic acid (250.0 mg, 2.19 mmol) and hydrazinecarbothioamide (200.0 mg, 2.19 mmol) in 1,4-Dioxane (3 mL) was added POCL (0.20 mL, 2. 19 mmol) at 23°C under nitrogen. The resulting mixture was then stirred at 90°C for 0.5 hr. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution and extracted with ethyl acetate.
  • Step-2 Synthesis of 2'-chloro-N-(5-(2-cyanocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-(4,4'-bipyridine)-3 -carboxamide:
  • Step-3 2'-chloro-N-(5-((lS,2R)-2-cyanocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6- methyl-(4,4'-bipyridine)-3-carboxamide, re/-2'-chloro-N-(5-((lR,2R)-2-cyanocyclobutyl)- l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxamide and 2'-chloro-N- (5-((lR,2S)-2-cyanocyclobutyl)-l,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-(4,4'- bipyridine)-3 -carboxamide :

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne certains dérivés de thiadiazolyle de formule (I) : (I) qui inhibent l'activité de l'ADN polymérase thêta (Polθ), en particulier inhibent l'activité Polθ en inhibant l'activité de domaine hélicase ATP-dépendant de Polθ. L'invention concerne également des compositions pharmaceutiques comprenant de tels composés et des procédés de traitement et/ou de prévention de maladies pouvant être traitées par inhibition de Polθ, telles que le cancer, notamment les cancers déficients en recombinaison homologue (RH).
PCT/IB2022/060050 2021-10-22 2022-10-19 Composés thiadiazolyles utilisés comme inhibiteurs de l'adn polymérase thêta WO2023067515A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163270772P 2021-10-22 2021-10-22
US63/270,772 2021-10-22

Publications (1)

Publication Number Publication Date
WO2023067515A1 true WO2023067515A1 (fr) 2023-04-27

Family

ID=84245821

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2022/060050 WO2023067515A1 (fr) 2021-10-22 2022-10-19 Composés thiadiazolyles utilisés comme inhibiteurs de l'adn polymérase thêta

Country Status (1)

Country Link
WO (1) WO2023067515A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023202623A1 (fr) * 2022-04-20 2023-10-26 南京再明医药有限公司 Composé inhibiteur de polq et son utilisation
WO2023233295A1 (fr) * 2022-06-01 2023-12-07 Ideaya Biosciences, Inc. Dérivés de thiadiazolyle utilisés en tant qu'inhibiteurs d'adn polymérase thêta et leurs utilisations
CN117229260A (zh) * 2023-11-13 2023-12-15 中国药科大学 DNA聚合酶θ与聚ADP核糖聚合酶1双靶点抑制剂及其制备方法和医药用途
WO2024069592A1 (fr) * 2022-09-29 2024-04-04 Repare Therapeutics Inc. Composés de n-([(l, 3,4-thiadiazolyle) substitué en position 5 ou (l,3-thiazolyl)](substitué)carboxamide, compositions pharmaceutiques et procédés de préparation de composés amides et leur utilisation
WO2024099337A1 (fr) * 2022-11-10 2024-05-16 Danatlas Pharmaceuticals Co., Ltd. Dérivés de thiadiazolyle, compositions et utilisations associées

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016039448A1 (fr) * 2014-09-12 2016-03-17 田辺三菱製薬株式会社 Composé aromatique d'amide d'acide carboxylique
WO2020205989A1 (fr) * 2019-04-01 2020-10-08 Cornell University Petite molécule favorisant la différenciation des ostéoblastes
WO2020243459A1 (fr) * 2019-05-31 2020-12-03 Ideaya Biosciences, Inc. Dérivés de thiadiazolyle comme inhibiteurs de l'adn polymérase thêta

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016039448A1 (fr) * 2014-09-12 2016-03-17 田辺三菱製薬株式会社 Composé aromatique d'amide d'acide carboxylique
WO2020205989A1 (fr) * 2019-04-01 2020-10-08 Cornell University Petite molécule favorisant la différenciation des ostéoblastes
WO2020243459A1 (fr) * 2019-05-31 2020-12-03 Ideaya Biosciences, Inc. Dérivés de thiadiazolyle comme inhibiteurs de l'adn polymérase thêta

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
AUDEH M. W ET AL., LANCET, vol. 376, no. 9737, 2010, pages 245 - 51
BERGE, S.M. ET AL.: "Journal of Pharmaceutical Science", vol. 66, 1977, article "Pharmaceutical Salts", pages: 1 - 19
CHAN S. H. ET AL., PLOS GENET, vol. 6, no. 100, 2010, pages el001005
KAWAMURA K ET AL., INT. J. CANCER, vol. 109, 2004, pages 9 - 16
KENT T ET AL., NAT. STRUCT. MOL. BIOL, vol. 22, 2015, pages 230 - 237
KENT T. ET AL., ELIFE, vol. 5, 2016, pages e13740
LEMEE F ET AL., PROC NATL ACAD SCI USA., vol. 107, 2010, pages 13390 - 5
MATEOS-GOMEZ P. A ET AL., NATURE, vol. 518, 2015, pages 254 - 57
ROERINK S. F. ET AL., GENOME RESEARCH, vol. 24, 2014, pages 954 - 962
WYATT D.W. ET AL., MOL. CELL, vol. 63, 2016, pages 662 - 73

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023202623A1 (fr) * 2022-04-20 2023-10-26 南京再明医药有限公司 Composé inhibiteur de polq et son utilisation
WO2023233295A1 (fr) * 2022-06-01 2023-12-07 Ideaya Biosciences, Inc. Dérivés de thiadiazolyle utilisés en tant qu'inhibiteurs d'adn polymérase thêta et leurs utilisations
WO2024069592A1 (fr) * 2022-09-29 2024-04-04 Repare Therapeutics Inc. Composés de n-([(l, 3,4-thiadiazolyle) substitué en position 5 ou (l,3-thiazolyl)](substitué)carboxamide, compositions pharmaceutiques et procédés de préparation de composés amides et leur utilisation
WO2024099337A1 (fr) * 2022-11-10 2024-05-16 Danatlas Pharmaceuticals Co., Ltd. Dérivés de thiadiazolyle, compositions et utilisations associées
CN117229260A (zh) * 2023-11-13 2023-12-15 中国药科大学 DNA聚合酶θ与聚ADP核糖聚合酶1双靶点抑制剂及其制备方法和医药用途
CN117229260B (zh) * 2023-11-13 2024-02-27 中国药科大学 DNA聚合酶θ与聚ADP核糖聚合酶1双靶点抑制剂及其制备方法和医药用途

Similar Documents

Publication Publication Date Title
WO2023067515A1 (fr) Composés thiadiazolyles utilisés comme inhibiteurs de l'adn polymérase thêta
TWI393722B (zh) 吡咯并三激酶抑制劑
ES2663622T3 (es) Novedosas 1H-pirrolo[2,3-b]piridinas 3,4-disustituidas y 7H-pirrolo[2,3-c]piridacinas 4,5-disustituidas como inhibidores de LRRK2
CA2901047A1 (fr) Derives d'octahydro-pyrrolo [3,4-c]-pyrrole et leurs analogues servant d'inhibiteurs de l'autotaxine
AU2016322813A1 (en) Novel imidazo (4,5-c) quinoline and imidazo (4,5-c)(1,5) naphthyridine derivatives as LRRK2 inhibitors
US11319303B2 (en) Compound used as autophagy regulator, and preparation method therefor and uses thereof
CA2935071A1 (fr) Derives de piperidine-dione
JP7044801B2 (ja) Ｃｄｋ４／６阻害剤
KR20180110132A (ko) 무스카린성 아세틸콜린 수용체 m1의 양성 알로스테릭 조절제
AU2022289762A1 (en) O-linked thiadiazolyl compounds as dna polymerase theta inhibitors
CA3181162A1 (fr) Inhibiteurs des kinases receptrices du facteur de croissance des fibroblastes
JP2023506740A (ja) ムスカリン性アセチルコリン受容体ｍ４のアンタゴニスト
CN113164475A (zh) Dyrk1a的大环抑制剂
KR20210027395A (ko) 면역조절 화합물
AU2022203737A1 (en) Imidazo(1,5-a)pyrazine derivatives as PI3Kdelta inhibitors
AU2010260381B2 (en) Substituted -1,3,8-triazaspiro[4.5]decane-2,4-diones
AU2017364807B2 (en) Pyrido[3, 4-d]pyrimidine derivative and pharmaceutically acceptable salt thereof
KR20230039701A (ko) 무스카린성 아세틸콜린 수용체 m4의 양성 알로스테릭 조절제로서의 7-(피페리딘-1-일)-4h-피리미도[1,2-b]피리다진-4-온 유도체
AU2018230236A1 (en) Novel imidazo[4,5-c]quinoline derivatives as LRRK2 inhibitors
JP2019530740A (ja) ピリジン並びに５員芳香環系化合物、その製造方法及び使用
JP2022529575A (ja) ピロールアミドピリドン系化合物、製造方法及び使用
JP2021501778A (ja) ｍＴＯＲＣ１／２二重阻害剤としてのピリドピリミジン系化合物
KR20230104782A (ko) Bcr-abl 티로신 키나제 억제용 7-아자인돌 화합물
TW202214634A (zh) 雜環化合物及其衍生物
WO2023077070A1 (fr) Agonistes de rxfp1

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22800364

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE