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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/18—Bridged systems

Definitions

• compositions comprising such compounds and methods of treating and/or preventing diseases treatable by inhibition of Ro ⁇ q such as cancer, including homologous recombination deficient (HRD) cancers.
• Ro ⁇ q DNA Polymerase Theta
• pharmaceutical compositions comprising such compounds and methods of treating and/or preventing diseases treatable by inhibition of Ro ⁇ q such as cancer, including homologous recombination deficient (HRD) cancers.
• HRD homologous recombination deficient
• 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 (Ro ⁇ q, encoded by POLQ ) in stimulating MMEJ in higher organisms (Chan S.
• Ro ⁇ q 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,
• the N-terminal ATPase/helicase domain belongs to the JJELQ class of SF2 helicase super family.
• HRD homologous recombination deficient
• Ro ⁇ q can carry out error-prone DNA synthesis at DNA damage sites through alt-EJ pathway.
• HRD homologous recombination deficient
• the helicase domain of Ro ⁇ q 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 Ro ⁇ q promotes the alt-EJ pathway.
• the helicase domain of Ro ⁇ q contributes to microhomology-mediated strand annealing (Chan SH et al., PLoS Genet. (2010);
• Ro ⁇ q 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. Once annealed, the primer strand of DNA can be extended by the polymerase domain of Ro ⁇ q.
• Ro ⁇ q The expression of Ro ⁇ q is largely absent in normal cells but upregulated in breast, lung, and ovarian cancers (Ceccaldi R., et al., Nature (2015); 518, 258-62). Additionally, the increase of Ro ⁇ q expression correlates with poor prognosis in breast cancer (Le ee F et a!., Proc Natl Acad Sci USA. (2010) ;107: 13390-5).
• compositions comprising such compounds and methods of treating and/or preventing diseases treatable by inhibition of Ro ⁇ q such as cancer, including homologous recombination (HR) deficient cancers.
• HR homologous recombination
• X is -N- or -C-;
• alk is alkylene
• ring A is phenyl or a five to ten membered heteroaryl ring containing, inclusive of X, one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• Ar 1 is phenyl, heteroaryl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl, wherein each of the aforementioned ring is substituted with R a , R b , and/or R c , wherein R a and R b are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, acyl, acylamino, monoalkylamino, dialkylamino, alkylsulfonyl, cyano, and hydroxy; or R a and R b , when on adjacent ring vertices, combine to form a C3-6 cycloalkyl or R a and R b , when on the same ring vertex, combine to form oxo, and R c is selected from hydrogen, alkyl, halo, haloalkyl, alkoxy,
• Ar 2 is phenyl, heteroaryl, or cycloalkyl, wherein said phenyl and heteroaryl are substituted with R d , R e and/or R f , wherein R d and R e are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, and cyano and R f is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl,
• heteroaryl and heterocyclyl of R f are unsubstituted or substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, and hydroxy;
• R 1 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, cyanoalkyl, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl ⁇ optionally substituted heteroaryl, hydroxyalkyl, cycloalkyl, hydroxyalkynyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, sulfonylalkyl, aminosulfonylalkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl; and
• R 2 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, or cyano;
• a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable thereof and at least one pharmaceutically acceptable excipient.
• a method for treating and/or preventing a disease characterized by overexpression of Ro ⁇ q in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (or an embodiment thereof disclosed herein).
• the patient is in recognized need of such treatment.
• the compound of Formula (I) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof is administered in a
• 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 an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof.
• the patient is in recognized need of such treatment.
• the compound of Formula (I) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition.
• a method for inhibiting DNA repair by Ro ⁇ q in a cancer cell comprising contacting the cell with an effective amount of a compound of Formula (I) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof.
• the cancer is HR deficient cancer.
• a method for treating and/orpreventing a cancer in a patient comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (or an
• a compound of Formula (I) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof for inhibiting DNA repair by Ro ⁇ q in a cell.
• the cell is HR deficient cell.
• a compound of Formula (I) (or an embodiment thereof disclosed herein), 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 Ro ⁇ q.
• a compound of Formula (I) (or an embodiment thereof disclosed herein), 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 an embodiment thereof disclosed herein), 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 an embodiment thereof disclosed herein), 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, soft tissue, rhabdoid, multiple myeloma, uterus, gastric, peripheral nervous system, rhabdomyosarcoma, bone, colorectal, mesothelioma, breast, ovarian, lung, fibroblast, central nervous system, urinary tract, upper aerodigestive, leukemia, kidney, skin, esophagus, and pancreas (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.
• the composite group alkoxyalkyl means that an alkoxy group is attached to the parent molecule through an alkyl group.
• Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like. It will be recognized by a person skilled in the art that the term“alkyl” may include“alkylene” groups.
• Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
• Alkyl sulfonyl means a -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, 2-propylsulfonyl, and the like.
• Alkoxy means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, //-, /.so-, or tert- butoxy, and the like.
• Alkoxycarbonyl means a -COOR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, propoxy, or 2-propoxycarbonyl, //-, /.so-, or tert- butoxycarbonyl, and the like.
• Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one alkoxy group, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.
• Acyl means a -C(0)R radical where R is alkyl as defined herein, e.g.,
• Acylamino means a -NHC(0)R radical where R is alkyl as defined herein, e.g., methylcarbonylamino, ethylcarbonylamino, and the like.
• Amino means a -NH2.
• Aminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with - NR’R” where R’ and R” are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,
• alkoxyalkyl or acyl, each as defined herein, e.g., aminomethyl, aminoethyl, methylaminomethyl, and the like.
• Aminocarbonyl means a -CONRR’ radical wherein R and R’ are independently hydrogen or alkyl as defined herein, e.g., -CONH2, methylaminocarbonyl,
• Aminocarbonylalkyl means alkyl radical as defined above that is substituted with - CONRR’ radical wherein R and R’ are independently hydrogen or alkyl as defined herein, e.g., - (CH 2 ) 2 CONH 2 , methylaminocarbonylmethyl, dimethylaminocarbonylethyl, and the like.
• Aminocarbonylmethyl means a -CH 2 CONRR’ radical wherein R and R’ are independently hydrogen or alkyl as defined herein, e.g., -CH 2 CONH 2 ,
• Aminosulfonylalkyl means alkyl radical as defined above that is substituted with - S0 2 NRR’ radical wherein R and R’ are independently hydrogen or alkyl as defined herein, e.g., - (CH 2 ) 2 S0 2 NH 2 , methylaminosulfonylmethyl, dimethylaminosulfonyl ethyl, and the like.
• Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
• Bicyclic heterocyclyl means a saturated monocyclic ring having 4 to 7 ring carbon ring atoms wherein one or two ring carbon atoms is(are) replaced by a heteroatom selected from N, O, or S(0) n , (where n is an integer from 0 to 2) that is fused to phenyl, five or six-membered heteroaryl or heterocyclyl, each as defined herein.
• Exemplary bicyclic heterocyclyl groups include, but are not limited to, [0046] "Bridged heterocyclyl” means a saturated monocyclic ring having 5 to 7 ring carbon ring atoms 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) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, or S(0) n , where n is an integer from 0 to 2.
• Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinuclidine, 7-oxabicyclo[2.2.1]heptane, and the like.
• Cycloalkyl means a monocyclic monovalent hydrocarbon radical of three to six carbon atoms which may be saturated or contains one double bond. Cycloalkyl may be unsubstituted or substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocycloprop-l-yl, 1-cyanomethylcycloprop-l-yl, 3- fluorocyclohexyl, and the like. When cycloalkyl contains a double bond, it may be referred to herein as cycloalkenyl.
• Cycloalkyloxy means -O-R radical where R is cycloalkyl as defined above.
• Examples include, but are not limited to, cyclopropyl oxy, cyclobutyl oxy, and the like.
• Cyanoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one cyano, as defined above, e.g., cyanomethyl, 2-cyanoethyl, and the like.
• Deuteroalkyl means an alkyl radical as defined above wherein one to six hydrogen atoms in the alkyl radical are replaced by deuterium, e.g., -CD 3 , -CH 2 CD 3 , and the like.
• Dialkylamino means -NRR’ radical where R and R’ are independently alkyl as defined herein.
• Halo means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
• Haloalkyl means alkyl radical as defined above, which is substituted with one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2CI, -CF3, -CHF 2 , -CH2CF3, -CF2CF3, -CF(CH ) 2 , and the like.
• halogen atoms such as fluorine or chlorine
• Haloalkoxy means a -OR radical where R is haloalkyl as defined above e.g., -OCF3, -OCHF2, and the like.
• R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy.
• Hydroalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both on the same carbon atom.
• Representative examples include, but are not limited to, hydroxymethyl, 2- hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2- hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, l-(hydroxymethyl)-2- hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxy ethyl, 2,3-dihydroxypropyl, and l-(hydroxymethyl)-2 -hydroxy ethyl.
• Hydroalkynyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms that contains a triple bond and is substituted with a hydroxy group.
• Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon, unless stated otherwise.
• heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl,
• Heterocyclyl means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(0) n , where n is an integer from 0 to 2, the remaining ring atoms being C. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group.
• heterocyclyl includes, but is not limited to, azetidinyl, oxetanyl, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like.
• the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
• Heterocyclyloxy means a -O-R radical where R is heterocyclyl, as defined above.
• Heterocyclylalkyl means a -(alkylene)-R radical where R is heterocyclyl, each group as defined herein.
• “Monoalkyl amino” means a -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.
• Optionally substituted heteroaralkyl means -(alkylene)-heteroaryl, each as defined above, wherein heteroaryl is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano, unless stated otherwise.
• Optionally substituted heterocyclyl means -(alkylene)-heterocyclyl, each as defined above, wherein heterocyclyl is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl, haloalkoxy, and cyano, unless stated otherwise.
• “Sulfonylalkyl” means alkyl radical as defined above that is substituted with -SO2R radical wherein R is alkyl as defined herein, e.g., methylsulfonylmethyl, ethylsulfonylethyl, and the like.
• “Spiroheterocyclyl” means a saturated bicyclic ring having 6 to 10 ring atoms in which one, two, or three ring atoms are heteroatom selected from N, O, or S(0) n , where n is an integer from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”).
• Examples include, but are not limited to, 2,6-diazaspiro[3.3]heptane, 2,6- diazaspiro[3.4]octane, 4-oxa-7-azaspiro[2.5]octane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]- nonane, 2,7-diazaspiro[4.4]nonane, and the like.
• “Pharmaceutically acceptable salts” as used herein is 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’ -dibenzyl ethyl enedi amine, 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.
• suitable inert solvent examples include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogen carbonic, phosphoric,
• 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 can differ 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.
• the present disclosure also includes protected derivatives of compounds of the present disclosure.
• compounds of the present disclosure contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s)
• these groups can be protected with a suitable protecting groups.
• a comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5 th Ed., John Wiley & Sons, Inc. (2014) , the disclosure of which is incorporated herein by reference in its entirety.
• the protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.
• the present disclosure also includes prodrugs of the compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) or a pharmaceutically acceptable salt thereof.
• Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
• An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity.
• prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
• Certain compounds of Formulae (I) can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of Formulae (I) may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
• Certain compounds of Formulae (I) possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers 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 to 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.
• one of the isomers will be present in an amount of at least
• 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.
• certain hydroxy substituted compound of Formula (I) may exist as as tautomers as shown below:
• the compounds of Formulae (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds.
• Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question that differ only in the presence of one or more isotopically enriched atoms.
• Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 ⁇ 4, U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I, and 125 1, respectively.
• Isotopically labeled compounds e.g., those labeled with 3 H and 14 C
• Tritiated (i.e., 3 ⁇ 4) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
• one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon.
• Positron emitting isotopes such as 15 0, 13 N, U C, and 15 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
• Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
• “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.
• “About,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ⁇ 10%, preferably ⁇ 5%, the recited value and the range is included.
• “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.
• “In need of treatment” as used herein means the patient is being treated by a physician or other caregiver after diagnoses of the disease. For example, the patient has been diagonosed as having a disease linked to overexpression of Ro ⁇ q or a homologous recombination (HR)- deficient cancer.
• HR homologous recombination
• administer refers to contact of, for example, a compound of Formula (I), 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.
• “Therapeutically effective amount” as used herein means the amount of a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease either alone or as part of a pharmaceutical composition and either in a single dose or as part of a series of doses, is sufficient to affect such treatment for the disease.
• The“therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
• 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 a compound of Formula (I) (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been used.
• Treating” or“treatment” of a disease includes:
• “Inhibiting”, "reducing,” or any variation of these terms in relation of Ro ⁇ q 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 Ro ⁇ q activity compared to its normal activity.
• the term“preventing” refers to causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease.
• homologous recombination refers to the cellular process of genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA.
• the term“homologous recombination (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-assocated 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 (Nibrin), 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.
• Ro ⁇ q overexpression refers to the increased expression or activity of Ro ⁇ q in a diseases cell e.g., cancerous cell, relative to expression or activity of Ro ⁇ q in a normal cell (e.g., non-diseased cell of the same kind).
• the amount of PolGcan 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 Ro ⁇ q expression in a normal cell.
• Ro ⁇ q cancers include, but are not limited to, breast, ovarian, cervical, lung, colorectal, gastric, bladder and prostate cancers.
• the present disclosure includes:
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof where R 1 , R 2 , X, alk, ring A, Ar 1 , and Ar 2 are as described in the Summary above.
• alk is methylene or ethylene
• alk is C 1-3 alkylene.
• alk is methylmethylene.
• the compound of embodiment 1, or a pharmaceutically acceptable salt thereof is wherein the compound has a structure of formula (la):
• the compound of embodiment 1 or 2 or embodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein ring A is phenyl or a five or six membered heteroaryl ring.
• ring A is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl or imidazo[l,2-a]pyridinyl.
• ring A is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, imidazo[l,2-a]pyridinyl, [l,2,3]triazolo[l,5- a] pyridinyl, imidazo[l,5-a]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrazolo[l,5-a]pyridinyl, [l,2,4]triazolo[l,5-a]pyridinyl, 1,6-naphthyridinyl, or 1,7- naphthyridinyl.
• ring A is a nine or ten membered heteroaryl ring.
• the compound of embodiment 1 or 2 or embodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein ring A is a five or six membered heteroaryl ring.
• ring A is pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, or triazolyl.
• ring A is:
• ring A is:
• ring A is:
• ring A is:
• ring A is:
• ring A is:
• ring A is:
• ring A is:
• ring A is:
• the compound of any one of embodiments 1 to 4 and subembodiment contained therein, or a pharmaceutically acceptable salt thereof is wherein ring A is phenyl.
• the compound of any one of embodiments 1 to 5 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein Ar 1 is heterocyclyl substituted with R a , R b , and/or R c .
• Ar 1 is piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, 2-oxopiperazinyl, 2- oxohomopiperazinyl, tetrahydropyranyl, 3,6-dihydro-2H-pyranyl, 2-oxo-l,2-dihydropyridinyl, thiomorpholinyl, or 1,1-dioxothiomorpholinyl substituted with R a , R b , and/or R c .
• Ar 1 is piperidin-l-yl, piperazin-l-yl, morpholin-4-yl, homomorpholin-4-yl, 3-oxopiperazin-l-yl, 3-oxohomopiperazin-l-yl, 5-oxohomopiperazin-l-yl, tetrahydropyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, 6-oxo-l,6-dihydropyri din-3 -yl, 6-oxo-l,6- dihydropyridin-4-yl, thiomorpholin-4-yl, or l,l-dioxothiomorpholin-4-yl substituted with R a , R b , and/or R c .
• Ar 1 is morpholin-4-yl substituted with R a , R b , and/or R c .
• R a is hydrogen or alkyl
• R b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy
• R c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl.
• R a and R b when on adjacent ring vertices, combine to form a cyclopropyl or cyclobutyl ring, and
• R a and R b when on adjacent ring vertices, combine to form a cyclopropyl ring, and R c is hydrogen.
• Ar 1 is substituted with R b and/or R c wherein R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl and R c is hydrogen, methyl, ethyl, fluoro, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2- morpholin-l-yl ethyl, -CONH2, methylaminocarbonyl, or
• Ar 1 is morpholin-4-yl, homomorpholin-4-yl, 2- methylmorpholin-4-yl, 3-methylmorpholin-4-yl, 3R-methylmorpholin-4-yl, 3S- methylmorpholin-4-yl, 3-oxopiperazin-l-yl, 4-methyl-3-oxo-piperazin-l-yl, 2 -m ethyl-3 - oxopiperazin-l-yl, 6-m ethyl-3 -ox opiperazin-l-yl, 5-methyl-3-oxopiperazin-l-yl, 3- oxohomopiperazin- 1 -yl, 5-oxohomopiperazin- 1 -yl, 4-dimethylaminocarbonylpiperazin- 1 -yl, tetrahydropyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, 4-(2-hydroxy
• the compound of any one of embodiments 1 to 6 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein Ar 1 is bicyclic heterocyclyl substituted with R a , R b , and/or R c .
• Ar 1 is 6-oxohexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl or 2,3-dihydro-4H- benzo[b][l,4]oxazin-4-yl, each ring substituted with R a , R b , and/or R c .
• Ar 1 is selected from the group consisting of 6-ox ohexahydropyrrolo[ 1,2- a]pyrazin-2(lH)-yl 3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl, benzo[d][l,3]dioxol-4-yl, (3,4-dihydro-2H-l,4-benzoxazin-8-yl), [5H,6H,7H-pyrazolo[l,5-a]pyrimidin-4-yl] and 2,3- dihydro-4H-benzo[b][l,4]oxazin-4-yl, each ring substituted with R a , R b , and/or R c .
• R a is hydrogen
• R b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy
• R c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl.
• Ar 1 is substituted with R b and/or R c wherein R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl and R c is hydrogen, methyl, ethyl, fluoro, difluorom ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2- methoxyethyl, 2-aminoethyl, 2-morpholin-l-yl ethyl, -CONH2, methylaminocarbonyl, or dimethylaminocarbonyl.
• R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl
• R c is hydrogen, methyl, ethyl, fluoro, difluorom ethy
• the compound of any one of embodiments 1 to 7 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein Ar 1 is spiroheterocyclyl substituted with R a , R b , and/or R c .
• Ar 1 is 4-oxa-7-azaspiro[2.5]octan-7-yl substituted with R a , R b , and/or R c .
• R a is hydrogen
• R b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy
• R c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl.
• Ar 1 is substituted with R b and/or R c wherein R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl and R c is hydrogen, methyl, ethyl, fluoro, difluorom ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2- methoxyethyl, 2-aminoethyl, 2-morpholin-l-yl ethyl, -CONH2, methylaminocarbonyl, or dimethylaminocarbonyl.
• R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl
• R c is hydrogen, methyl, ethyl, fluoro, difluorom ethy
• the compound of any one of embodiments 1 to 8 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein Ar 1 is phenyl substituted with R a , R b , and/or R c .
• Ar 1 is phenyl substituted with R a , R b , and/or R c .
• R a is hydrogen or alkyl
• R b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy
• R c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl.
• Ar 1 is substituted with R b and/or R c wherein R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl and R c is hydrogen, methyl, ethyl, fluoro, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxy, 2- hydroxy ethyl, 2-methoxy ethyl, 2-aminoethyl, 2-morpholin-l-yl ethyl, -CONH2,
• Ar 1 is phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2-chlorophenyl, 2-cyanophenyl, or 2-cyclopropyl- oxyphenyl.
• Ar 1 is 2-methoxyphenyl.
• Ar 1 is 3-methoxyphenyl.
• Ar 1 is 2,4-dimethoxyphenyl.
• the compound of any one of embodiments 1 to 9 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein Ar 1 is heteroaryl substituted with R a , R b , and/or R c .
• Ar 1 is benzo[c][l,2,5]thiadiazolyl, benzo[d]oxazolyl, l //-indazolyl, substituted with R a , R b , and/or R c
• R a is hydrogen or alkyl
• R b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy
• R c is selected from hydrogen alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbony.
• Ar 1 is pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, or triazolyl substituted with R a , R b , and/or R c where R a is hydrogen or alkyl, R b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy, and R c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl.
• Ar 1 is substituted with R b and/or R c wherein R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl and R c is hydrogen, methyl, ethyl, fluoro, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2- morpholin-l-yl ethyl, -CONH2, methylaminocarbonyl, or dimethylaminocarbonyl.
• R b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl
• R c is hydrogen, methyl, ethyl, fluoro, difluoromethyl, trifluoromethyl
• the compound of any one of embodiments 1 to 10 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein Ar 2 is phenyl substituted with R d , R e and/or R f .
• R d is hydrogen
• R e is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, or cyano
• R f is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl, aminocarbonylmethyl, heteroaryl, and heterocyclyl, wherein said heteroaryl and heterocyclyl of R f are unsubstituted or substituted with one, two, or three substituents
• Ar 2 is phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 2-chloro-4- fluorophenyl, 4-cyanophenyl, 4-bromophenyl, 4-oxetan— 3-ylphenyl, 4-chloro-3- methoxyphenyl, 4-cyclopropylphenyl, or 4-oxazol-2-ylphenyl.
• Ar 2 is
• Ar 2 is 4-fluorophenyl. In a fourth subembodiment of embodiment 11, Ar 2 is 4-chlorophenyl.
• the compound of any one of embodiments 1 to 11 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein Ar 2 is heteroaryl substituted with R d , R e and/or R f .
• R d is hydrogen
• R e is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, or cyano
• R f is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl, aminocarbonylmethyl, heteroaryl, and heterocyclyl, wherein said heteroaryl and heterocyclyl of R f are unsubstituted or substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, and hydroxy.
• R f is cycloalkyl optionally substituted with cyano.
• Ar 2 is heteroaryl selected from pyridinyl or pyrimidinyl. In a subembodiment of embodiment 12 and subembodiments contained therein Ar 2 is
• Ar 2 is 6-chl oropyri din-3 -yl, 6-brom opyri din-3 -yl, or 5-chloropyazin-2-yl.
• the compound of any one of embodiments 1 to 12 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein Ar 2 cycloalkyl.
• Ar 2 is cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• the compound of any one of embodiments 1 to 13 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein R 1 is hydrogen, cyano, -CONH2, methylaminocarbonyl, dimethylaminocarbonyl, imidazol-2-yl, methoxy, hydroxy, bromo, carboxy, or fluoro.
• R 1 is hydrogen, alkyl, halo, haloalkyl, or cyano.
• the compound of any one of embodiments 1 to 14 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein R 1 is hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, sulfonylalkyl, aminosulfonylalkyl, optionally substituted heteroaralkyl, or optionally substituted heterocyclylalkyl.
• the compound of any one of embodiments 1 to 14 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof is wherein R 2 is hydrogen, cyano, or fluoro, preferably hydrogen.
• embodiments set forth above include combinations of one or more of embodiments and/or subembodiments listed therein.
• the Ar 1 group listed in embodiment 10 and subembodiment therein can independently combine with one or more of the embodiments 1-9, and 11-16 and/or subembodiments contained therein.
• 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 pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable or physiologically acceptable excipients.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount.
• the pharmaceutical compositions may be used in 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.
• 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.
• Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
• 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 may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
• 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.
• a time-delay material such as glyceryl monostearate or glyceryl di-stearate may be employed.
• the tablets may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release.
• Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide and glycolide copolymers, polylactide and glycolide copolymers, or ethylene vinyl acetate copolymers in order to control delivery of an administered composition.
• a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide and glycolide copolymers, polylactide and glycolide copolymers, or ethylene vinyl acetate copolymers in order to control delivery of an administered composition.
• the oral agent can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, by the use of hydroxymethyl cellulose or gelatin-microcapsules or poly (methyl methacrylate) microcapsules, respectively, or in a colloid drug delivery system.
• Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, microbeads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for the preparation of the above-mentioned formulations are known in the art.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose
• water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
• Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture thereof.
• excipients can be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, (hydroxypropyl)methyl cellulose, sodium alginate, pol yvi nyl -pyrrol i done, gum tragacanth and gum acacia; dispersing or wetting agents, for example a naturally-occurring phosphatide (e.g., lecithin), or condensation products of an alkylene oxide with fatty acids (e.g., poly-oxy ethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., for heptdecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
• 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. Suitable dispersing or wetting agents and suspending agents are exemplified herein.
• the pharmaceutical compositions may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures of these.
• Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
• compositions typically comprise a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient.
• suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants.
• antioxidants e.g., ascorbic acid and sodium bisulfate
• preservatives e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate
• emulsifying agents suspending agents, dispersing agents, solvents,
• a suitable vehicle may be physiological saline solution or citrate buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration.
• Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
• Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof.
• the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof.
• Acceptable buffering agents include, for example, a Tris buffer, N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid) (HEPES), 2-(N-Morpholino)ethanesulfonic acid (MES), 2-(N- Morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-Morpholino)propanesulfonic acid (MOPS), and N-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).
• HEPES N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid)
• MES 2-(N-Morpholino)ethanesulfonic acid
• MES 2-(N- Morpholino)ethanesulfonic acid sodium salt
• MOPS 3-(N-Morpholino)propanes
• a pharmaceutical composition After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form.
• the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas a multi-use container (e.g., a multi-use vial) is provided in other embodiments.
• a single-use container e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, e.g., an EpiPen®)
• a multi-use container e.g., a multi-use vial
• Formulations can also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including liposomes, hydrogels, prodrugs and microencapsulated delivery systems.
• a controlled release formulation including liposomes, hydrogels, prodrugs and microencapsulated delivery systems.
• a time delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed.
• Any drug delivery apparatus may be used to deliver a compound of Formula (I), or a pharmaceutically acceptable salt thereof, including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are well known to the skilled artisan.
• Depot injections which are generally administered subcutaneously or intramuscularly, may also be utilized to release the compound of Formula (I), 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 non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butane diol.
• Acceptable diluents, solvents and dispersion media include water, Ringer's solution, isotonic sodium chloride solution, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed, including synthetic mono- or diglycerides.
• fatty acids such as oleic acid, find use in the preparation of injectables. Prolonged absorption of particular injectable formulations can be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin).
• a compound of Formula (I), 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.
• suitable non irritating excipient include, but are not limited to, cocoa butter and polyethylene glycols.
• Compounds of Formula (I), 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 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 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
• other prophylactic or therapeutic modalities e.g., radiation
• the various active agents frequently have different, complementary mechanisms of action.
• Such combination therapy may be especially
• 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 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 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 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 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 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
• 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 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 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 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 pharmaceutically acceptable salt thereof and at least one additional therapeutic or diagnostic agent.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent, selected from Temozolomide, Pemetrexed, Pegylated liposomal doxorubicin (Doxil), Eribulin (Halaven), Ixabepilone (Ixempra), Protein-bound paclitaxel (Abraxane), Oxaliplatin, Irinotecan, Venatoclax (bcl2 inhibitor), 5-azacytadine, Anti-CD20 therapeutics, such as Rituxan and obinutuzumab, Hormonal agents (anastrozole, exemestand, letrozole, zoladex, lupon eligard), CDK4/6 inhibitors, Palbociclib, Abemaciclib, CPI (Avelumab, Cemiplimab-rwlc, and Bevacizumab.
• additional therapeutic agent selected from Temozolomide, Pemetrexed,
• the present disclosure provides methods for treating cancer comprising administration of a compound of Formula (I), 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.
• a signal transduction inhibitor refers to an agent that selectively inhibits one or more steps in a signaling pathway.
• STIs signal transduction inhibitors
• bcr/abl kinase inhibitors e.g., GLEEVEC
• EGF epidermal growth factor
• HERCEPTIN her- 2/neu receptor inhibitors
• inhibitors of Akt family kinases or the Akt pathway e.g., rapamycin
• cell cycle kinase inhibitors e.g., flavopiridol
• phosphatidyl inositol kinase inhibitors phosphatidyl inositol kinase inhibitors.
• Agents involved in immunomodulation can also be used in combination with one or more compounds of Formula (I), 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 pharmaceutically acceptable salt thereof described herein in combination with a chemotherapeutic agents.
• chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethio- phosphaoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine,
• mechlorethamine oxide hydrochloride melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin,
• elliptinium acetate etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and doxetaxel; chlorambucil;
• methotrexate platinum and platinum coordination complexes such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11;
• topoisomerase inhibitors difluoromethylornithine (DMFO); retinoic acid; esperamicins;
• compounds of the present disclosure are coadministered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C.
• the cytostatic compound is doxorubicin.
• Chemotherapeutic agents also include anti-hormonal agents that act to regulate or inhibit hormonal action on tumors such as anti-estrogens, including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and antiandrogens such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
• 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 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.
• TCR T-cell receptor
• 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- Ll, BTLA, TIM3, LAG3, 0X40, 41BB, VISTA, CD96, TGF , CD73, CD39, A2AR, A2BR, IDOl, TD02, Arginase, B7-H3, B7-H4.
• Cell-based modulators of anti-cancer immunity include but are not limited to chimeric antigen receptor T-cells, tumor infiltrating T-cells and dendritic-cells.
• the present disclosure contemplates the use of compounds of Formula (I), or a pharmaceutically acceptable salt thereof described herein in combination with inhibitors of the aforementioned immune-checkpoint receptors and ligands, for example ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab, and durvalumab.
• inhibitors of the aforementioned immune-checkpoint receptors and ligands for example ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab, and durvalumab.
• Additional treatment modalities that may be used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof disclosed herein include radiotherapy, a monoclonal antibody against a tumor antigen, a complex of a monoclonal antibody and toxin, a T-cell adjuvant, bone marrow transplant, or antigen presenting cells (e.g., dendritic cell therapy).
• the present disclosure contemplates the use of compounds of Formula (I), or a pharmaceutically acceptable salt thereof described herein for the treatment of glioblastoma either alone or in combination with radiation and/or temozolomide (TMZ), avastin or lomustine.
• TTZ temozolomide
• the present disclosure encompasses pharmaceutically acceptable salts, acids or derivatives of any of the above.
• the compounds of Formula (I), 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 ED50 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.
• 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 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 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 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 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 pharmaceutically acceptable salt thereof, and pharmaceutical compositions 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 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 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 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).
• kits may contain a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s), including mechanism of action, pharmacokinetics and
• 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 title compound was prepared using General Procedure B employing 1, 4- oxazepane. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column Cis silica gel; mobile phase, with 5-100% MeCN in water). The residue was further purified using reverse phase Prep-HPLC[(XBridge Prep OBD Ci 8 column; gradient elution 2 to 15% ACN in (0.16% NH4HCO3 in water)] to afford 2-(l,4- oxazepan-4-yl)nicotinic acid as a light yellow solid.
• DMSO-de d 0.53-0.56 (m, 2H), 0.66-0.69 (m, 2H), 3.31-3.32 (m, 2H), 3.35-3.37 (m, 2H), 3.68- 3.70 (m, 2H), 5.51 (s, 2H), 7.47-7.50 (m, 3H), 7.54-7.56 (m, 2H), 8.00-8.02 (m, 1H), 13.04 (s, 1H) ppm. m/z 483 (M+H + ).
• the title compound was prepared using General Procedure A employing 5-[(4- cyclopropylphenyl)methoxy]-l,3,4-thiadiazol-2-amine and 2-morpholinonicotinic acid. The mixture was diluted with water. The aqueous layer was extracted with EtOAc (3 x). The combined organic layer was concentrated under reduced pressure. The residue was triturated with MeOH to afford N-(5-((4-cyclopropylbenzyl)oxy)-l,3,4-thiadiazol-2-yl)-2- morpholinonicotinamide as off-white solid.
• Example 35 The title compound was prepared using similar procedure as Example 21 employing N- (5-((4-chlorobenzyl)oxy)-l,3,4-thiadiazol-2-yl)-6-cyano-4-morpholinonicotinamide, Example 35. The mixture was stirred at room temperature for 2 h. The mixture was cooled room temperature and diluted with water. The mixture was extracted with EtOAc (3 x). The combined organic layers were concentrated under reduced pressure.
• Step 1 Preparation of (R) 2-(2-methyl-3-oxopiperazin-l-yl)pyridine-3 -carboxylic acid and (S) 2-(2-methyl-3-oxopiperazin-l-yl)pyridine-3 -carboxylic acid
• Step 2 Preparation of (R) N-(5-((4-chlorobenzyl)oxy)-l,3,4-thiadiazol-2-yl)-2-(2-methyl-3- oxopiperazin-l-yl)nicotinamide and (S) N-(5-((4-chlorobenzyl)oxy)-l,3,4-thiadiazol-2-yl)- 2-(2 -methyl-3 -ox opiperazin-l-yl)nicotinamide
• the title compound was prepared using General Procedure A employing a racemic mixture of (R) 2-(2-methyl-3-oxopiperazin-l-yl)pyridine-3-carboxylic acid and (S) 2-(2-methyl- 3-oxopiperazin-l-yl)pyridine-3-carboxylic acid and 5-((4-chlorobenzyl)oxy)-l,3,4-thiadiazol-2- amine (Intermediate B). The mixture was stirred at 50 °C 4 h. The mixture was cooled room temperature and diluted with water. The mixture was extracted with EtOAc (3 x). The combined organic layers were concentrated under reduced pressure.
• DMSO-de d 1.24-1.32 (m, 3H), 3.10-3.14 (m, 1H), 3.35-3.41 (m, 2H), 3.51-3.57 (m, 1H), 4.25- 4.32 (m, 1H), 5.51 (s, 2H), 6.93-6.98 (m, 1H), 7.48-7.57 (m, 4H), 7.86-7.89 (m, 2H), 8.32-8.35 (m, 1H), 12.97 (s, 1H) ppm. m/z 459 (M+H + ).
• the title compound was prepared using General Procedure F employing methyl 2-(3,6- dihydro-2H-pyran-4-yl)pyridine-3-carboxylate. The mixture was stirred at room temperature for 5 h and then diluted with water. The mixture was extracted with EtOAc (3 x). The aqueous layer was neutralized to pH 6 with HO Ac and the mixture was extracted with EtOAc (5 x). The combined organic layers were concentrated under reduced pressure.
• Step 5 Preparation of 5-((4-(oxetan-3-yl)benzyl)oxy)-l,3,4-thiadiazol-2-amine [0275]
• the title compound was prepared using similar procedure as Intermediate B, Step 2, replacing 0-(4-chlorobenzyl) S-methyl carbonodithioate with S-methyl 0-(4-(oxetan-3- yl)benzyl) carbonodithioate
• Example 47 The title compound was prepared using similar procedure as Example 50 employing 5- [(4-cyclopropylphenyl)methoxy]-l,3,4-thiadiazol-2-amine (Example 47, Step 1) in Step 2.
• the mixture was diluted with water and extracted with DCM.
• the combined organic layers were concentrated under reduced pressure.
• the residue was triturated with MeOH to afford N-(5-((4- cyclopropylbenzyl)oxy)-l,3,4-thiadiazol-2-yl)-l-(2-methoxyphenyl)-lH-imidazole-5- carboxamide as a white solid.
• Example 69 Further elution of Example 69 afforded to title compound as the second eluting isomer.
• the title compound was prepared using General Procedure C employing 4-cyano-2- fluorobenzoic acid. The mixture was cooled to room temperature and concentrated under reduce pressure. The residue was purified by silica gel column eluted with 0.9 - 2% MeOH in (0.05% AcOH in DCM). The residue was further purified by triturating with DCM give 4-cyano-2- morpholinobenzoic acid as a white solid.
• the title compound was prepared using General Procedure F employing methyl 6- methoxy-4-morpholinonicotinate.
• the mixture was acidified to pH 3 with HC1 (1 M).
• the mixture was concentrated.
• the residue was purified by Prep-HPLC (column, Cis; mobile phase, 10 - 50% MeCN and water, with both eluents containing 0.05% TFA) to afford 6-methoxy-4- morpholinonicotinic acid as an off-white oil.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Public Health (AREA)
• General Chemical & Material Sciences (AREA)
• Hematology (AREA)
• Oncology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Priority Applications (9)

Applications Claiming Priority (4)

Related Child Applications (2)

Publications (1)

Family

ID=72179163

Family Applications (1)

Country Status (10)

Cited By (29)

Families Citing this family (13)

Citations (3)

Family Cites Families (2)

• 2020
  • 2020-05-29 AU AU2020282768A patent/AU2020282768B2/en active Active
  • 2020-05-29 WO PCT/US2020/035165 patent/WO2020243459A1/en not_active Ceased
  • 2020-05-29 CA CA3141134A patent/CA3141134A1/en active Pending
  • 2020-05-29 CN CN202080050232.1A patent/CN114127062A/zh active Pending
  • 2020-05-29 TW TW109118207A patent/TW202110834A/zh unknown
  • 2020-05-29 BR BR112021024101A patent/BR112021024101A2/pt unknown
  • 2020-05-29 US US17/615,123 patent/US12509454B2/en active Active
  • 2020-05-29 JP JP2021570943A patent/JP7655863B2/ja active Active
  • 2020-05-29 ES ES20760608T patent/ES2968796T3/es active Active
  • 2020-05-29 EP EP20760608.8A patent/EP3976608B1/en active Active
• 2025
  • 2025-10-28 US US19/370,959 patent/US20260049074A1/en active Pending

Patent Citations (3)

Non-Patent Citations (12)

Also Published As

Similar Documents

Legal Events