WO2012145617A2 - Aminopyrimidine kinase inhibitors - Google Patents

Aminopyrimidine kinase inhibitors Download PDF

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Publication number
WO2012145617A2
WO2012145617A2 PCT/US2012/034436 US2012034436W WO2012145617A2 WO 2012145617 A2 WO2012145617 A2 WO 2012145617A2 US 2012034436 W US2012034436 W US 2012034436W WO 2012145617 A2 WO2012145617 A2 WO 2012145617A2
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WIPO (PCT)
Prior art keywords
compound
methyl
pyrimidin
piperidin
amino
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PCT/US2012/034436
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French (fr)
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WO2012145617A3 (en
WO2012145617A9 (en
Inventor
Carmen M. Baldino
Justin L. Caserta
Chee-Seng Lee
Stephane A. Dumas
Yvonne L. Flanders
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Jasco Pharmaceuticals, LLC
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Application filed by Jasco Pharmaceuticals, LLC filed Critical Jasco Pharmaceuticals, LLC
Priority to EP12774599.0A priority Critical patent/EP2699569B1/en
Priority to AU2012245344A priority patent/AU2012245344B2/en
Priority to CA2832865A priority patent/CA2832865C/en
Publication of WO2012145617A2 publication Critical patent/WO2012145617A2/en
Publication of WO2012145617A3 publication Critical patent/WO2012145617A3/en
Priority to IL228928A priority patent/IL228928A/en
Publication of WO2012145617A9 publication Critical patent/WO2012145617A9/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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

Definitions

  • Casein kinase 1 is a family of evolutionarily conserved serine/threonine kinases including seven known members in vertebrates (CKla, - ⁇ , - ⁇ , - ⁇ 2, - ⁇ 3, - ⁇ and - ⁇ ).
  • the CKls contain a typical kinase domain followed by a C-terminal tail region, which has been implicated in the regulation of CK1 localization, substrate selectivity and kinase activity.
  • CK1 family members (- ⁇ , - ⁇ / ⁇ and - ⁇ ) modulate the activities of major signaling pathways (for example, Wnt and Shh) through several mechanisms (Peters et al., 1999; Liu et al., 2002; Price and Kalderon, 2002; Davidson et al., 2005; Zeng et al., 2005 and reviewed by Price (2006)).
  • CK1 isoforms namely CKla, ⁇ , ⁇ _3, ⁇ and ⁇ , and several splice variants have been described. They all contain a highly conserved kinase domain, a short N-terminal domain of 6 to 76 amino acids and a highly variable C-terminal domain of 24 to more than 200 amino acids.
  • the constitutive phosphotransferase activity of CK1 isoforms is tightly controlled by several mechanisms.
  • the closely related isoforms CK1 ⁇ and ⁇ which share a 98% identity at the amino acid level in their catalytic domain, are regulated by autophosphorylation, dephosphorylation and proteolytic cleavage.
  • CK1 CK1 family proteins are found in the nucleus, the cytoplasm and in the plasma membrane. By phosphorylating many different substrates bearing either a canonical or non-canonical consensus sequence, they modulate the activity of key regulator proteins involved in many cellular processes such as cell differentiation, cell proliferation, apoptosis, circadian rhythm, chromosome segregation, and vesicle transport.
  • Pim kinase family contains three isoforms, Pim-1, Pim-2 and Pim-3, and has recently emerged as targets of interest in oncology and immune regulation. Ongoing studies have identified a role for these proteins in cell survival and proliferation, both functionally and mechanistically, and overexpression has been observed in a number of human cancers and inflammatory states.
  • Pim kinases suppress apoptosis and regulate cell-cycle progression. Elevated levels of Pim kinases have been reported in solid tumors such as prostate cancer and pancreatic cancer. Pim-1 was initially discovered in murine leukemia and several independent studies have shown this kinase to be upregulated in human prostate cancer. Pim-1 , 2 and 3 make up a distinct and highly homologous family of serine/threonine kinases belonging to the calmodulin-dependent protein kinase-related (CAMK) family. In addition to the three gene-encoded proteins, translational variants have also been reported for Pim-1 and 2 resulting from utilization of alternative start codons.
  • CAMK calmodulin-dependent protein kinase-related
  • Pim refers to the original identification of the pim-1 gene as a frequent proviral insertion site in Moloney murine leukemia virus-induced T-cell lymphomas, and the gene encoding Pim-2 was subsequently found to have similar susceptibility.
  • Pim-3 originally designated kinase induced by depolarization (KID)-l, was later renamed due to high sequence similarity to Pim-1 (71% identity at the amino acid level). Considering all three isoforms, Pim proteins are widely expressed with high levels in hematopoietic tissue and are aberrantly expressed in a variety of human malignancies. Pim kinases positively regulate cell survival and proliferation, affording therapeutic opportunities in oncology. The Pim protein kinases are frequently overexpressed in prostate cancer and certain forms of leukemia and lymphoma.
  • Pim-2 has been reported to have enhanced levels of expression in a variety of inflammatory states and may function as a positive regulator of interleukin-6 (IL-6), whereby overexpression of the kinase augments stimulus-induced IL-6 levels.
  • IL-6 interleukin-6
  • Pim-1 and 2 have also been implicated in cytokine-induced T-cell growth and survival. Comparing the sensitivity of stimulated T cells from Pim-r /" Pim-2 " " mice to wild-type mice following treatment with the
  • Pirn kinases have been reported to play a role in the protection of the ATP- binding cassette (ABC) transporter P-glycoprotein (Pgp; ABCB1) from proteolytic and proteasomal degradation.
  • Pgp is known to mediate drug efflux, and, as such, inhibitors of Pirn kinases may provide a novel approach to abrogating drug resistance.
  • An aspect of the present invention relates to compounds that inhibit casein kinase 1 and/or casein kinase 2 and/or a PIM kinase.
  • an embodiment relates to a compound of formula 1 or a pharmaceutically acceptable salt thereof:
  • W is C(R CCR ⁇ CCR 1 ) ⁇ C( 1 ) 2 C( 1 ) 2 C(R 1 ) 2 , or S(0) 2;
  • X is nitrogen or CR 2 ;
  • Y is nitrogen or CR 3 ;
  • Z is nitrogen or CR 4 ;
  • R 1 is hydrogen or alkyl
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl,
  • R 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
  • any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted; wherein the compound is not
  • An embodiment relates to a compound of formula 2 or a pharmaceutically acceptable salt thereof:
  • X is nitrogen or CR 2 ;
  • B4002959vl - 4 - Y is nitrogen or CR 3 ;
  • Z is nitrogen or CR 4 ;
  • R 1 is hydrogen or alkyl
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl; or R 3 and R 4 are joined together to form an optionally substituted heterocyclic ring;
  • R 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
  • any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.
  • An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of C 1, CKlyl, CKly2, or CKly3.
  • the compound has an IC 50 of less than 5000 nM for CK1, CKlyl, CKly2, or CKly3.
  • the compound has an IC5 0 of less than 1000 nM for CK1, CKlyl, CKly2, or CKly3.
  • the compound has an IC50 of less than 500 nM for CK1, CKlyl, CKly2, or CKly3.
  • An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of CK2.
  • the compound has an IC5 0 of less than 5000 nM for CK2.
  • the compound has an IC5 0 of less than 1000 nM for CK2.
  • the compound has an IC5 0 of less than 500 nM for CK2.
  • An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of Pim-1, Pim-2, or Pim-3. In one embodiment the compound has
  • An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the Wnt pathway.
  • An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the TGF pathway.
  • An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the JAK/STAT pathway.
  • An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the mTOR pathway.
  • An embodiment relates to any one of the aforementioned compounds, wherein the compound is a modulator of Pgp degradation, drug efflux, or drug resistance.
  • An embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising any one or combination of the aforementioned compounds, and a pharmaceutically acceptable carrier.
  • Another embodiment relates to a method of inhibiting CKl activity, comprising contacting CKl, CKlyl, CKly2, or CKly3 with any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of inhibiting CK2 activity, comprising contacting CK2 with any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of treating or preventing a condition associated with aberrant CKl, CKlyl, CKly2, or CKly3 activity, comprising
  • Another embodiment relates to a method of treating or preventing a condition associated with aberrant CK2 activity, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of treating cancer, comprising
  • the cancer is a cancer of a system selected from the group consisting of the hematopoietic system, immune system, endocrine system, pulmonary system, gastrointestinal system, musculoskeletal system, reproductive system, central nervous system, and urologic system.
  • the cancer is located in the mammal's myeloid tissues, lymphoid tissues, pancreatic tissues, thyroid tissues, lung tissues, colon tissues, rectal tissues, anal tissues, liver tissues, skin, bone, ovarian tissues, uterine tissues, cervical tissues, breast, prostate, testicular tissues, brain, brainstem, meningeal tissues, kidney or bladder.
  • the cancer is selected from the group consisting of breast cancer, colon cancer, multiple myeloma, prostate cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, hematologic malignancy, renal cell carcinoma, renal cancer, malignant melanoma, pancreatic cancer, lung cancer, colorectal carcinoma, brain cancer, head and neck cancer, bladder cancer, thyroid cancer, ovarian cancer, cervical cancer, and myelodysplastic syndrome.
  • Another embodiment relates to a method of treating leukemia, multiple myeloma, or other hematologic malignancies, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of treating Alzheimer's disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of treating a Wnt-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of treating a TGFP-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of treating a JAK/STAT-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • B4002959vl - 17 - Another embodiment relates to a method of treating an mTOR-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of treating or preventing inflammation, inflammatory diseases (e.g., osteoarthritis and rheumatoid arthritis), neurological conditions (e.g., Alzheimer's disease) and neurodegeneration, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • inflammatory diseases e.g., osteoarthritis and rheumatoid arthritis
  • neurological conditions e.g., Alzheimer's disease
  • neurodegeneration comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of treating or preventing bone -related diseases and conditions, including osteoporosis and bone formation, or facilitating bone restoration, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of treating or preventing hypoglycemia, metabolic syndrome and diabetes, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of influencing apoptosis (e.g., increasing the rate of apoptosis in cancerous cells), comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of treating or preventing aberrant embryonic development, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of inhibiting PIM activity, comprising contacting Pirn- 1 , Pim-2 or Pim-3 with any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method for treating or preventing a condition associated with aberrant PIM activity, comprising administering to a mammal in need
  • B4002959vl - 18 - thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method of modulating Pgp degradation and/or drug efflux activity, comprising contacting a cell with any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method for treating a malignancy based upon modulation of Pgp, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
  • Another embodiment relates to a method for treating a malignancy based upon modulation of Pgp, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions, in conjunction with another drug, compound, or material, to abrogate resistance to the drug, compound, or material.
  • isolated in connection with a compound of the present invention means the compound is not in a cell or organism and the compound is separated from some or all of the components that typically accompany it in nature.
  • the term "pure" in connection with an isolated sample of a compound of the present invention means the isolated sample contains at least 60% by weight of the compound. In certain embodiments, the isolated sample contains at least 70% by weight of the compound. In certain embodiments, the isolated sample contains at least 80% by weight of the compound. In certain embodiments, the isolated sample contains at least 90% by weight of the compound. In certain embodiments, the isolated sample contains at least 95% by weight of the compound.
  • the purity of an isolated sample of a compound of the present invention may be assessed by a number of methods or a combination of them; e.g., thin-layer, preparative or flash chromatography, mass spectrometry, HPLC, NMR analysis, and the like.
  • heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C 30 for straight chain, C 3 -C30 for branched chain), and alternatively, about 20 or fewer.
  • cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
  • lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • aralkyl is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aryl is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene,
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or “heteroaromatics.”
  • the aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, - CF 3 , -CN, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively.
  • 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
  • heterocyclyl refers to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be poly cycles.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, piperonyl, furazan, phenoxazine,
  • the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • optionally substituted refers to a chemical group, such as alkyl, cycloalkyl aryl, and the like, wherein one or more hydrogen may be replaced with a
  • polycyclyl or “polycyclic group” are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, si
  • carrier is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • nitro is art-recognized and refers to -NO 2 ;
  • halogen is art- recognized and refers to -F, -CI, -Br or -I;
  • sulfhydryl is art-recognized and refers to -SH;
  • hydroxyl means -OH;
  • sulfonyl is art-recognized and refers to -S0 2 ⁇ .
  • Halide designates the corresponding anion of the halogens, and
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:
  • R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
  • R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and
  • m is zero or an integer
  • R50 and R51 each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH 2 ) m -R61.
  • alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
  • acylamino is art-recognized and refers to a moiety that may be represented by the general formula:
  • R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R61, where m and R61 are as defined above.
  • amino is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2) m -R61, wherein m and R61 are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • X50 is a bond or represents an oxygen or a sulfur
  • R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(C]3 ⁇ 4)m-R61or a pharmaceutically acceptable salt
  • R56 represents a hydrogen, an alkyl, an alkenyl or -(CH2) m -R61, where m and R61 are defined above.
  • X50 is an oxygen and R55 or R56 is not hydrogen
  • the formula represents an "ester”.
  • X50 is an oxygen
  • R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid".
  • X50 is an oxygen, and R56 is hydrogen
  • the formula represents a "formate".
  • the oxygen atom of the above formula is replaced by sulfur
  • the formula represents a "thiolcarbonyl” group.
  • X50 is a sulfur and R55 or R56 is not hydrogen
  • the formula represents a "thiolester.”
  • X50 is a sulfur and R55 is hydrogen
  • the formula represents a "thiolcarboxylic acid.”
  • X50 is a sulfur and R56 is hydrogen
  • the formula represents a "thiolformate.”
  • X50 is a bond, and R55 is not hydrogen
  • the above formula represents a "ketone” group.
  • X50 is a bond, and R55 is hydrogen
  • the above formula represents an "aldehyde” group.
  • oxime and "oxime ether” are art-recognized and refer to moieties that may be represented by the general formula:
  • R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH 2 ) m -R61.
  • the moiety is an "oxime” when R is H; and it is an "oxime ether” when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(C]3 ⁇ 4) m -R61.
  • alkoxyl or "alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -0-(CH 2 ) m -R61 , where m and R61 are described above.
  • R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • R57 is as defined above.
  • sulfamoyl is art-recognized and refers to a moiety that may be represented by the general formula:
  • sulfonyl is art-recognized and refers to a moiety that may be represented by the general formula:
  • R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
  • sulfoxido is art-recognized and refers to a moiety that may be represented by the general formula:
  • phosphoryl is art-recognized and may in general be represented by the formula:
  • Q50 represents S or O
  • R59 represents hydrogen, a lower alkyl or an aryl.
  • the phosphoryl group of the phosphorylalkyl may be represented by the general formulas:
  • Q50 and R59 each independently, are defined above, and Q51 represents O, S or N.
  • Q50 is S
  • the phosphoryl moiety is a "phosphorothioate”.
  • R60 represents a lower alkyl or an aryl.
  • Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • each expression e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • triflyl, tosyl, mesyl, and nonafiyl are art-recognized and refer to trifluoromethanesulfonyl, /?-toluenesulfonyl, methanesulfonyl, and
  • nonafluorobutanesulfonyl groups respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, /?-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, /?-toluenesulfonyl and
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, E- and Z-isomers, R- and ⁇ S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • the enantiomers may be separated using a chiral
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • pharmaceutically acceptable salt refers to a salt of one or more compounds.
  • Suitable pharmaceutically acceptable salts of compounds include acid addition salts, such as those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and also those formed with organic acids such as maleic acid.
  • acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids.
  • inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid
  • organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascor
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate,
  • methanesulfonate propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate and the like.
  • pharmaceutically acceptable salts may be formed by treatment of a solution of the compound with a solution of a pharmaceutically acceptable base.
  • Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups include, but are not limited to, hydroxides and carbonates of alkali metals such as sodium, potassium, and lithium; alkaline earth metal such as calcium and magnesium; and other metals, such as aluminum and zinc.
  • Suitable bases also incllude ammonia, and organic amines, such as unsubstituted or hydroxy- substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N- methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert- butylamine, or tris-(hydroxymethyl)methylamine, N,N-di alkyl-N-(hydroxy alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl- D-glucamine; and amino acids such as arginine, lysine, and the like.
  • organic amines such as un
  • Certain compounds of the invention and their salts may exist in more than one crystalline form (i.e., polymorph); the present invention includes each of the crystal forms and mixtures thereof.
  • Certain compounds of the invention and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • Certain compounds of the invention may contain one or more chiral centers, and exist in different optically active forms.
  • the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures thereof.
  • the enantiomers may be resolved by methods known to those skilled in the art; for example, enantiomers may be resolved by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid
  • B4002959vl - 30 - chromatography selective reaction of one enantiomer with an enantiomer-specific reagent, for example, via enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support; suitable include chiral supports (e.g., silica with a bound chiral ligand) or in the presence of a chiral solvent.
  • a further step may be used to liberate the desired purified enantiomer.
  • specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • a compound of the invention When a compound of the invention contains more than one chiral center, it may exist in diastereoisomeric forms.
  • the diastereoisomeric compounds may be separated by methods known to those skilled in the art (for example, chromatography or crystallization) and the individual enantiomers may be separated as described above.
  • the present invention includes the various diastereoisomers of compounds of the invention, and mixtures thereof.
  • Compounds of the invention may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of the invention, and mixtures thereof.
  • any olefins present in the compounds may exist as either the E- or Z- geometric isomers or a mixture thereof unless stated otherwise.
  • Compounds of the invention may exist in zwitterionic form.
  • the present invention includes each zwitterionic form of compounds of the invention, and mixtures thereof.
  • pro-drug refers to an agent, which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form).
  • Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
  • pro-drug a compound of the present invention wherein it is administered as an ester (the "pro-drug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial.
  • Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the
  • a pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
  • Exemplary pro-drugs release an amine of a compound of the invention wherein the free hydrogen of an amine or alcohol is replaced by (Ci-C6)alkanoyloxymethyl, l-((Ci- C6)alkanoyloxy)ethyl, 1 -methyl- 1 -((C i-C6)alkanoyloxy)ethyl, (C i -C6)alkoxycarbonyl- oxymethyl, N-(Ci-C6)alkoxycarbonylamino-methyl, succinoyl, (Ci-Ce)alkanoyl, a- amino(Ci-C4)alkanoyl, arylactyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl wherein said a-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, -P(0)(OH) 2 , -P(0)(0(Ci-C6)al
  • exemplary pro-drugs upon cleavage release a corresponding free acid, and such hydrolyzable ester- forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents (e.g., -(CH 2 )C(0)OH or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (Ci-C/i)alkyl, (C 2 - C i 2 )alkanoyloxymethyl, (C4-C9) 1 -(alkanoyloxy)ethyl, 1 -methyl- 1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbony
  • alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C2-C 3 )alkyl (such as ⁇ -dimethylaminoethyl), carbamoyl-(Ci-C 2 )alkyl, N,N-di(Ci-C2)-alkylcarbamoyl-(Ci- C 2 )alkyl and piperidino-, pyrrolidino- or mo ⁇ holino(C2-C 3 )alkyl.
  • subject refers to an animal, typically a mammal or a human, that will be or has been the object of treatment, observation, and/or experiment.
  • subject refers to an animal, typically a mammal or a human, that will be or has been the object of treatment, observation, and/or experiment.
  • the term is used in conjunction with administration of a compound or drug, then the subject has been the object of treatment, observation, and/or administration of the compound or drug.
  • co-administration and “co-administering” refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different
  • B4002959vl - 32 - from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent at the same time.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a cell culture, tissue system, animal, or human that is being sought by a researcher, veterinarian, clinician, or physician, which includes alleviation of the symptoms of the disease, condition, or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable carrier refers to a medium that is used to prepare a desired dosage form of a compound.
  • a pharmaceutically acceptable carrier can include one or more solvents, diluents, or other liquid vehicles; dispersion or suspension aids; surface active agents; isotonic agents; thickening or emulsifying agents; preservatives; solid binders; lubricants; and the like.
  • An aspect of the present invention relates to compounds that inhibit casein kinase 1 and/or casein kinase 2 and/or a PIM kinase.
  • an embodiment relates to a compound of formula 1 or a pharmaceutically acceptable salt thereof,
  • W is C(R% C(R 1 ) 2 C( 1 ) 2 , C(R 1 ) 2 C(R 1 ) 2 C(R 1 ) 2 , or S(0) 2;
  • B4002959vl - 33 - X is nitrogen or CR 2 ;
  • Y is nitrogen or CR 3 ;
  • Z is nitrogen or CR 4 ;
  • R 1 is hydrogen or alkyl
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl; or R 3 and R 4 are joined together to form an optionally substituted heterocyclic ring;
  • R 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
  • any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted; wherein the compound is not
  • R 1 is hydrogen
  • R 1 is methyl
  • W is S(0) 2 .
  • W is CH 2 .
  • R 2 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
  • R 2 is hydrogen
  • R 2 is methyl
  • R 2 is fluorine
  • R 2 is an optionally substituted heteroaryl.
  • R 2 is an optionally substituted aryl.
  • R 3 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
  • R 3 is hydrogen
  • R 3 is methyl
  • R 3 is fluorine
  • R 3 is an optionally substituted heteroaryl.
  • R 3 is an optionally substituted aryl.
  • R 3 is an optionally substituted heterocyclylalkyl.
  • R 3 and R 4 are joined together to form an optionally substituted aryl.
  • R 3 and R 4 are joined together to form an optionally substituted heterocyclyl.
  • R 3 and R 4 are joined together to form an optionally substituted heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
  • R 4 is hydrogen
  • R 4 is methyl
  • R 4 is fluorine
  • R 4 is an optionally substituted heteroaryl.
  • R 4 is an optionally substituted aryl.
  • R 4 is an optionally substituted heterocyclylalkyl.
  • R 5 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
  • R 5 is hydrogen
  • R 5 is methyl
  • R 5 is fluorine
  • R 5 is an optionally substituted heteroaryl.
  • R 5 is an optionally substituted aryl.
  • R 5 is an optionally substituted heterocyclylalkyl.
  • R 6 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
  • R 6 is hydrogen
  • R 6 is methyl
  • R 6 is fluorine
  • R 6 is an optionally substituted heteroaryl.
  • R 6 is an optionally substituted aryl.
  • R 6 is an optionally substituted heterocyclylalkyl.
  • An aspect of the present invention relates to compounds that inhibit casein kinase 1 and/or casein kinase 2 and/or a PIM kinase.
  • an embodiment relates to a compound of formula 2 or a pharmaceutically acceptable salt thereof,
  • X is nitrogen or CR 2 ;
  • Y is nitrogen or CR 3 ;
  • Z is nitrogen or CR 4 ;
  • R 1 is hydrogen or alkyl
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl; or R 3 and R 4 are joined together to form an optionally substituted heterocyclic ring;
  • R 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
  • any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.
  • R 1 is hydrogen
  • R 1 is methyl
  • R 2 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
  • R 2 is hydrogen
  • R 2 is methyl
  • R 2 is fluorine
  • R 2 is an optionally substituted heteroaryl.
  • R 2 is an optionally substituted aryl.
  • R 3 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
  • R 3 is hydrogen
  • R 3 is methyl
  • R 3 is fluorine
  • R 3 is an optionally substituted heteroaryl.
  • R 3 is an optionally substituted aryl.
  • R 3 is an optionally substituted heterocyclylalkyl.
  • R 3 and R 4 are joined together to form an optionally substituted aryl.
  • R 3 and R 4 are joined together to form an optionally substituted heterocyclyl.
  • R 3 and R 4 are joined together to form an optionally substituted heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
  • R 4 is hydrogen
  • R 4 is methyl
  • R 4 is fluorine
  • R 4 is an optionally substituted heteroaryl.
  • R 4 is an optionally substituted aryl.
  • R 4 is an optionally substituted heterocyclylalkyl.
  • R is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
  • R 5 is hydrogen
  • R 5 is methyl
  • R 5 is fluorine
  • R 5 is an optionally substituted heteroaryl.
  • R 5 is an optionally substituted aryl.
  • R 5 is an optionally substituted heterocyclylalkyl.
  • R 6 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
  • R 6 is hydrogen
  • R 6 is methyl
  • R 6 is fluorine
  • R 6 is an optionally substituted heteroaryl.
  • R 6 is an optionally substituted aryl.
  • R 6 is an optionally substituted heterocyclylalkyl.
  • a compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • a compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • a compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • any one of the aforementioned compounds may exist as the isomer, the Z-geometric isomer, or mixtures thereof.
  • ⁇ 3 ⁇ 4 ⁇ in the aforementioned structures represents the ⁇ -isomer of the particular compound.
  • any one of the aforementioned compounds is an inhibitor of CKlyl, CKly2, or CKly3.
  • any one of the aforementioned compounds is an inhibitor of
  • any one of the aforementioned compounds is an inhibitor of the Wnt pathway.
  • any one of the aforementioned compounds is an inhibitor of the JAK/STAT pathway.
  • any one of the aforementioned compounds is an inhibitor of the mTOR pathway.
  • any one of the aforementioned compounds is a mediator of Pgp degradation and/or drug efflux.
  • any one of the aforementioned compounds is an inhibitor of the TGF pathway.
  • the compound has an IC5 0 of less than 5000 nM for CKlyl, CKly2, or CKly3.
  • the compound has an IC50 of less than 1000 nM for CKlyl, CKly2, or CKly3.
  • the compound has an IC5 0 of less than 500 nM for CKlyl, CKly2, or CKly3.
  • any one of the aforementioned compounds is an inhibitor of
  • the compound has an IC5 0 of less than 5000 nM for CK2.
  • the compound has an IC5 0 of less than 1000 nM for CK2.
  • the compound has an IC5 0 of less than 500 nM for CK2.
  • any on of the aforementioned compounds is an inhibitor of
  • Pim-1 Pim-2, or Pim-3.
  • the compound has an IC5 0 of less than 5000 nM for Pim-1, Pim-2 or Pim-3.
  • the compound has an IC5 0 of less than 1000 nM for Pim-1, Pim-2 or Pim-3.
  • the compound has an IC50 of less than 500 nM for Pim-1, Pim- 2 or Pim-3.

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Abstract

Disclosed are compounds, pharmaceutical compositions containing those compounds, and uses of the compounds and compositions as modulators of casein kinase 1 (e.g., CKlϒ), casein kinase 2 (CK2), Pim-1, Pim-2, Pim-3, the TGFPβ pathway, the Wnt pathway, the JAK/STAT pathway, and/or the mTOR pathway. Uses are also disclosed for the treatment or prevention of a range of therapeutic indications due at least in part to aberrant physiological activity of casein kinase 1 (e.g., CKlϒ), casein kinase 2 (CK2), Pim- 1, Pim-2, Pim-3, the TGFPβ pathway, the Wnt pathway, the JAK/STAT pathway, and/or the mTOR pathway.

Description

AMINOPYRIMIDINE KINASE INHIBITORS
RELATED APPLICATIONS
This application claims benefit of priority under 35 U.S.C. 119(e) to U.S.
Provisional Patent Application No. 61/478,302, filed April 22, 2011; and U.S. Provisional Patent Application No. 61/555,617, filed November 4, 2011.
BACKGROUND OF THE INVENTION
Casein kinase 1 (CK1) is a family of evolutionarily conserved serine/threonine kinases including seven known members in vertebrates (CKla, -β, -γΐ, -γ2, -γ3, -δ and -ε). The CKls contain a typical kinase domain followed by a C-terminal tail region, which has been implicated in the regulation of CK1 localization, substrate selectivity and kinase activity. Myriad proteins have been found to be phosphorylated by CKls, which are involved in a wide range of cellular functions including vesicular trafficking, DNA damage repair, cell cycle progression, cytokinesis and circadian rhythms (reviewed by Gross and Anderson (1998); Vielhaber and Virshup (2001); Knippschild et al. (2005)). Moreover, CK1 family members (-α, -δ/ε and -γ) modulate the activities of major signaling pathways (for example, Wnt and Shh) through several mechanisms (Peters et al., 1999; Liu et al., 2002; Price and Kalderon, 2002; Davidson et al., 2005; Zeng et al., 2005 and reviewed by Price (2006)).
In mammals seven CK1 isoforms, namely CKla, β, γι_3, δ and ε, and several splice variants have been described. They all contain a highly conserved kinase domain, a short N-terminal domain of 6 to 76 amino acids and a highly variable C-terminal domain of 24 to more than 200 amino acids. The constitutive phosphotransferase activity of CK1 isoforms is tightly controlled by several mechanisms. For example, the closely related isoforms CK1 δ and ε, which share a 98% identity at the amino acid level in their catalytic domain, are regulated by autophosphorylation, dephosphorylation and proteolytic cleavage.
Members of the CK1 family are found in the nucleus, the cytoplasm and in the plasma membrane. By phosphorylating many different substrates bearing either a canonical or non-canonical consensus sequence, they modulate the activity of key regulator proteins involved in many cellular processes such as cell differentiation, cell proliferation, apoptosis, circadian rhythm, chromosome segregation, and vesicle transport.
B4002959vl The Pim kinase family contains three isoforms, Pim-1, Pim-2 and Pim-3, and has recently emerged as targets of interest in oncology and immune regulation. Ongoing studies have identified a role for these proteins in cell survival and proliferation, both functionally and mechanistically, and overexpression has been observed in a number of human cancers and inflammatory states.
Pim kinases suppress apoptosis and regulate cell-cycle progression. Elevated levels of Pim kinases have been reported in solid tumors such as prostate cancer and pancreatic cancer. Pim-1 was initially discovered in murine leukemia and several independent studies have shown this kinase to be upregulated in human prostate cancer. Pim-1 , 2 and 3 make up a distinct and highly homologous family of serine/threonine kinases belonging to the calmodulin-dependent protein kinase-related (CAMK) family. In addition to the three gene-encoded proteins, translational variants have also been reported for Pim-1 and 2 resulting from utilization of alternative start codons. The name Pim refers to the original identification of the pim-1 gene as a frequent proviral insertion site in Moloney murine leukemia virus-induced T-cell lymphomas, and the gene encoding Pim-2 was subsequently found to have similar susceptibility. Pim-3, originally designated kinase induced by depolarization (KID)-l, was later renamed due to high sequence similarity to Pim-1 (71% identity at the amino acid level). Considering all three isoforms, Pim proteins are widely expressed with high levels in hematopoietic tissue and are aberrantly expressed in a variety of human malignancies. Pim kinases positively regulate cell survival and proliferation, affording therapeutic opportunities in oncology. The Pim protein kinases are frequently overexpressed in prostate cancer and certain forms of leukemia and lymphoma.
A role for Pim kinases in immune regulation has also been observed. Pim-2 has been reported to have enhanced levels of expression in a variety of inflammatory states and may function as a positive regulator of interleukin-6 (IL-6), whereby overexpression of the kinase augments stimulus-induced IL-6 levels. Pim-1 and 2 have also been implicated in cytokine-induced T-cell growth and survival. Comparing the sensitivity of stimulated T cells from Pim-r/"Pim-2" " mice to wild-type mice following treatment with the
immunosuppressant rapamycin, it was found that T-cell activation was significantly impaired by Pim-1 /Pim-2 deficiency, suggesting that Pim kinases promote lymphocyte growth and survival through a PI3K/AKT (PKB, protein kinase B)/mammalian target of rapamycin (mTOR)-independent pathway. Other parallel but independent functions and overlapping substrate specificity for proteins in these pathways have been reported as well,
B4002959vl - 2 - including the positive regulation of transcription of nuclear factor kappa-B (NF-KB)- responsive genes, which have implications in both inflammation and oncology. Therefore, Pirn kinases are attractive targets for both therapeutic areas.
Further, Pirn kinases have been reported to play a role in the protection of the ATP- binding cassette (ABC) transporter P-glycoprotein (Pgp; ABCB1) from proteolytic and proteasomal degradation. Pgp is known to mediate drug efflux, and, as such, inhibitors of Pirn kinases may provide a novel approach to abrogating drug resistance.
SUMMARY OF THE INVENTION
An aspect of the present invention relates to compounds that inhibit casein kinase 1 and/or casein kinase 2 and/or a PIM kinase. For example, an embodiment relates to a compound of formula 1 or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
1
wherein independently for each occurrence:
W is C(R CCR^CCR1)^ C( 1)2C( 1)2C(R1)2, or S(0)2;
X is nitrogen or CR2;
Y is nitrogen or CR3;
Z is nitrogen or CR4;
R1 is hydrogen or alkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl,
B4002959vl - 3 - heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl; or R3 and R4 are joined together to form an optionally substituted heterocyclic ring;
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted; wherein the compound is not
Figure imgf000005_0001
An embodiment relates to a compound of formula 2 or a pharmaceutically acceptable salt thereof:
Figure imgf000005_0002
2
wherein independently for each occurrence:
X is nitrogen or CR2;
B4002959vl - 4 - Y is nitrogen or CR3;
Z is nitrogen or CR4;
R1 is hydrogen or alkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl; or R3 and R4 are joined together to form an optionally substituted heterocyclic ring;
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.
An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure imgf000006_0001
B4002959vl
Figure imgf000007_0001
B4002959vl -6-
Figure imgf000008_0001
B4002959vl -7-
Figure imgf000009_0001
An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
B4002959vl - 8 -
Figure imgf000010_0001
Figure imgf000011_0001
B4002959vl - 10-
Figure imgf000012_0001
B4002959vl - 11 -
Figure imgf000013_0001
Figure imgf000014_0001
B4002959vl - 13 -
Figure imgf000015_0001
B4002959vl - 14-
Figure imgf000016_0001
An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure imgf000016_0002
An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of C 1, CKlyl, CKly2, or CKly3. In one embodiment the compound has an IC50 of less than 5000 nM for CK1, CKlyl, CKly2, or CKly3. In one embodiment the compound has an IC50 of less than 1000 nM for CK1, CKlyl, CKly2, or CKly3. In one embodiment the compound has an IC50 of less than 500 nM for CK1, CKlyl, CKly2, or CKly3.
An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of CK2. In one embodiment the compound has an IC50 of less than 5000 nM for CK2. In one embodiment the compound has an IC50 of less than 1000 nM for CK2. In one embodiment the compound has an IC50 of less than 500 nM for CK2.
An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of Pim-1, Pim-2, or Pim-3. In one embodiment the compound has
B4002959vl - 15 - an IC50 of less than 5000 nM for Pim-1, Pim-2, or Pim-3. In one embodiment the compound has an IC50 of less than 1000 nM for Pim-1, Pim-2, or Pim-3. In one embodiment the compound has an IC50 of less than 500 nM for Pim-1, Pim-2, or Pim-3.
An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the Wnt pathway.
An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the TGF pathway.
An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the JAK/STAT pathway.
An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the mTOR pathway.
An embodiment relates to any one of the aforementioned compounds, wherein the compound is a modulator of Pgp degradation, drug efflux, or drug resistance.
An embodiment relates to a pharmaceutical composition comprising any one or combination of the aforementioned compounds, and a pharmaceutically acceptable carrier.
Another embodiment relates to a method of inhibiting CKl activity, comprising contacting CKl, CKlyl, CKly2, or CKly3 with any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of inhibiting CK2 activity, comprising contacting CK2 with any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of treating or preventing a condition associated with aberrant CKl, CKlyl, CKly2, or CKly3 activity, comprising
administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of treating or preventing a condition associated with aberrant CK2 activity, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
B4002959vl - 16 Another embodiment relates to a method of treating cancer, comprising
administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions. In one embodiment the cancer is a cancer of a system selected from the group consisting of the hematopoietic system, immune system, endocrine system, pulmonary system, gastrointestinal system, musculoskeletal system, reproductive system, central nervous system, and urologic system. In one embodiment the cancer is located in the mammal's myeloid tissues, lymphoid tissues, pancreatic tissues, thyroid tissues, lung tissues, colon tissues, rectal tissues, anal tissues, liver tissues, skin, bone, ovarian tissues, uterine tissues, cervical tissues, breast, prostate, testicular tissues, brain, brainstem, meningeal tissues, kidney or bladder. In one embodiment the cancer is selected from the group consisting of breast cancer, colon cancer, multiple myeloma, prostate cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, hematologic malignancy, renal cell carcinoma, renal cancer, malignant melanoma, pancreatic cancer, lung cancer, colorectal carcinoma, brain cancer, head and neck cancer, bladder cancer, thyroid cancer, ovarian cancer, cervical cancer, and myelodysplastic syndrome.
Another embodiment relates to a method of treating leukemia, multiple myeloma, or other hematologic malignancies, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of treating Alzheimer's disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of treating a Wnt-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of treating a TGFP-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of treating a JAK/STAT-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
B4002959vl - 17 - Another embodiment relates to a method of treating an mTOR-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of treating or preventing inflammation, inflammatory diseases (e.g., osteoarthritis and rheumatoid arthritis), neurological conditions (e.g., Alzheimer's disease) and neurodegeneration, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of treating or preventing bone -related diseases and conditions, including osteoporosis and bone formation, or facilitating bone restoration, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of treating or preventing hypoglycemia, metabolic syndrome and diabetes, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of influencing apoptosis (e.g., increasing the rate of apoptosis in cancerous cells), comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of treating or preventing aberrant embryonic development, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of inhibiting PIM activity, comprising contacting Pirn- 1 , Pim-2 or Pim-3 with any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method for treating or preventing a condition associated with aberrant PIM activity, comprising administering to a mammal in need
B4002959vl - 18 - thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method of modulating Pgp degradation and/or drug efflux activity, comprising contacting a cell with any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method for treating a malignancy based upon modulation of Pgp, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.
Another embodiment relates to a method for treating a malignancy based upon modulation of Pgp, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions, in conjunction with another drug, compound, or material, to abrogate resistance to the drug, compound, or material.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
The definitions of terms used herein are meant to incorporate the present state-of- the-art definitions recognized for each term in the chemical and pharmaceutical fields. Where appropriate, illustration is provided. The definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
Where stereochemistry is not specifically indicated, all stereoisomers of the inventive compounds are included within the scope of the invention, as pure compounds as well as mixtures thereof. Unless otherwise indicated, individual enantiomers,
diastereomers, geometrical isomers, and combinations and mixtures thereof are all encompassed by the present invention. Polymorphic crystalline forms and solvates are also encompassed within the scope of this invention.
As used herein, the term "isolated" in connection with a compound of the present invention means the compound is not in a cell or organism and the compound is separated from some or all of the components that typically accompany it in nature.
B4002959vl - 19 - As used herein, the term "pure" in connection with an isolated sample of a compound of the present invention means the isolated sample contains at least 60% by weight of the compound. In certain embodiments, the isolated sample contains at least 70% by weight of the compound. In certain embodiments, the isolated sample contains at least 80% by weight of the compound. In certain embodiments, the isolated sample contains at least 90% by weight of the compound. In certain embodiments, the isolated sample contains at least 95% by weight of the compound. The purity of an isolated sample of a compound of the present invention may be assessed by a number of methods or a combination of them; e.g., thin-layer, preparative or flash chromatography, mass spectrometry, HPLC, NMR analysis, and the like.
The term "heteroatom" is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
The term "alkyl" is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
Unless the number of carbons is otherwise specified, "lower alkyl" refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.
The term "aralkyl" is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
The term "aryl" is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene,
B4002959vl - 20 - naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics." The aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, - CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
The terms ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
The terms "heterocyclyl", "heteroaryl", or "heterocyclic group" are art-recognized and refer to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be poly cycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, piperonyl, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
The term "optionally substituted" refers to a chemical group, such as alkyl, cycloalkyl aryl, and the like, wherein one or more hydrogen may be replaced with a
B4002959vl - 21 - substituent as described herein, including but not limited to halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like.
The terms "polycyclyl" or "polycyclic group" are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
The term "carbocycle" is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
The term "nitro" is art-recognized and refers to -NO2; the term "halogen" is art- recognized and refers to -F, -CI, -Br or -I; the term "sulfhydryl" is art-recognized and refers to -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" is art-recognized and refers to -S02 ~. "Halide" designates the corresponding anion of the halogens, and
"pseudohalide" has the definition set forth on 560 of Advanced Inorganic Chemistry by Cotton and Wilkinson.
The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:
R50
R50 I
N / N I + R53
\
R51 R52
wherein R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer
B4002959vl - 22 - in the range of 1 to 8. In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m-R61. Thus, the term "alkylamine" includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
The term "acylamino" is art-recognized and refers to a moiety that may be represented by the general formula:
O
-N- -R54
R50
wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R61, where m and R61 are as defined above.
The term "amido" is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:
O
R51
R50
wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable.
The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In certain embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-R61, wherein m and R61 are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like.
The term "carboxyl" is art recognized and includes such moieties as may be represented by the general formulas:
Figure imgf000024_0001
B4002959vl - 23 - wherein X50 is a bond or represents an oxygen or a sulfur, and R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(C]¾)m-R61or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R61, where m and R61 are defined above. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an "ester". Where X50 is an oxygen, and R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid". Where X50 is an oxygen, and R56 is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a "thiolester." Where X50 is a sulfur and R55 is hydrogen, the formula represents a "thiolcarboxylic acid." Where X50 is a sulfur and R56 is hydrogen, the formula represents a "thiolformate." On the other hand, where X50 is a bond, and R55 is not hydrogen, the above formula represents a "ketone" group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an "aldehyde" group.
The term "carbamoyl" refers to -0(C=0)NRR', where R and R' are independently H, aliphatic groups, aryl groups or heteroaryl groups.
The term "oxo" refers to a carbonyl oxygen (=0).
The terms "oxime" and "oxime ether" are art-recognized and refer to moieties that may be represented by the general formula:
Figure imgf000025_0001
wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH2)m-R61. The moiety is an "oxime" when R is H; and it is an "oxime ether" when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(C]¾)m-R61.
The terms "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -0-(CH2)m-R61 , where m and R61 are described above.
B4002959vl - 24 - The term "sulfonate" is art recognized and refers to a moiety that may be represented by the general formula:
O
-OR57
O
in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
The term "sulfate" is art recognized and includes a moiety that may be represented by the general formula:
O
-O- -OR57
O
in which R57 is as defined above.
The term "sulfonamido" is art recognized and includes a moiety that may be represented by the general formula:
O N S R56
R50 O
in which R50 and R56 are as defined above.
The term "sulfamoyl" is art-recognized and refers to a moiety that may be represented by the general formula:
Figure imgf000026_0001
which R50 and R51 are as defined above.
The term "sulfonyl" is art-recognized and refers to a moiety that may be represented by the general formula:
B4002959vl - 25 - o
S R58
O
in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
The term "sulfoxido" is art-recognized and refers to a moiety that may be represented by the general formula:
Figure imgf000027_0001
in which R58 is defined above.
The term "phosphoryl" is art-recognized and may in general be represented by the formula:
Q50
OR59
wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl or an aryl. When used to substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl may be represented by the general formulas:
Q50 Q50 Q51— -O Q51— P— OR59
OR59 OR59
wherein Q50 and R59, each independently, are defined above, and Q51 represents O, S or N. When Q50 is S, the phosphoryl moiety is a "phosphorothioate".
The term "phosphoramidite" is art-recognized and may be represented in the general formulas:
B4002959vl - 26 - Q 59
Figure imgf000028_0001
wherein Q51, R50, R 1 and R59 are as defined above.
The term "phosphonamidite" is art-recognized and may be represented in the general formulas:
Figure imgf000028_0002
wherein Q51, R50, R 1 and R59 are as defined above, and R60 represents a lower alkyl or an aryl.
Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
The definition of each expression, e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
The terms triflyl, tosyl, mesyl, and nonafiyl are art-recognized and refer to trifluoromethanesulfonyl, /?-toluenesulfonyl, methanesulfonyl, and
nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, /?-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, /?-toluenesulfonyl and
methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the
B4002959vl - 27 - Journal of Organic Chemistry; this list is typically presented in a table entitled "Standard List of Abbreviations."
Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, E- and Z-isomers, R- and <S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Additionally, the enantiomers may be separated using a chiral
chromatographic method including HPLC or SFC approaches.
It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
The term "substituted" is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible
B4002959vl - 28 - substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
The phrase "protecting group" as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. Examples of nitrogen protecting groups include an amide (-N C(=0)R) or a urethane (-NRC(=0)OR), for example, as: a methyl amide (-NHC(=0)CH3); a benzyloxy amide
(-NHC(=0)OCH2C6H5NHCbz); as a t-butoxy amide (-NHC(=0)OC(CH3)3, -NHBoc); a 2- biphenyl-2-propoxy amide (-NHC(=0)OC(CH3)2C6H4C6H5 HBoc), as a 9- fiuorenylmethoxy amide (-NHFmoc), as a 6-nitroveratryloxy amide (-NHNvoc), as a 2- trimethylsilylethyloxy amide (-NHTeoc), as a 2,2,2-trichloroethyloxy amide (-NHTroc), as an allyloxy amide (-NHAlloc), as a 2-(phenylsulfonyl)ethyloxy amide (-NHPsec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention.
The term "pharmaceutically acceptable salt" or "salt" refers to a salt of one or more compounds. Suitable pharmaceutically acceptable salts of compounds include acid addition salts, such as those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and also those formed with organic acids such as maleic acid. For example, acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate,
B4002959vl - 29 - chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate,
methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate and the like.
Where the compounds carry one or more acidic moieties, pharmaceutically acceptable salts may be formed by treatment of a solution of the compound with a solution of a pharmaceutically acceptable base. Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups include, but are not limited to, hydroxides and carbonates of alkali metals such as sodium, potassium, and lithium; alkaline earth metal such as calcium and magnesium; and other metals, such as aluminum and zinc. Suitable bases also incllude ammonia, and organic amines, such as unsubstituted or hydroxy- substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N- methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert- butylamine, or tris-(hydroxymethyl)methylamine, N,N-di alkyl-N-(hydroxy alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl- D-glucamine; and amino acids such as arginine, lysine, and the like.
Certain compounds of the invention and their salts may exist in more than one crystalline form (i.e., polymorph); the present invention includes each of the crystal forms and mixtures thereof.
Certain compounds of the invention and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
Certain compounds of the invention may contain one or more chiral centers, and exist in different optically active forms. When compounds of the invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures thereof. The enantiomers may be resolved by methods known to those skilled in the art; for example, enantiomers may be resolved by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid
B4002959vl - 30 - chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example, via enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support; suitable include chiral supports (e.g., silica with a bound chiral ligand) or in the presence of a chiral solvent. Where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be used to liberate the desired purified enantiomer. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
When a compound of the invention contains more than one chiral center, it may exist in diastereoisomeric forms. The diastereoisomeric compounds may be separated by methods known to those skilled in the art (for example, chromatography or crystallization) and the individual enantiomers may be separated as described above. The present invention includes the various diastereoisomers of compounds of the invention, and mixtures thereof. Compounds of the invention may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of the invention, and mixtures thereof. For example, any olefins present in the compounds may exist as either the E- or Z- geometric isomers or a mixture thereof unless stated otherwise. Compounds of the invention may exist in zwitterionic form. The present invention includes each zwitterionic form of compounds of the invention, and mixtures thereof.
As used herein the term "pro-drug" refers to an agent, which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions over the parent drug. An example, without limitation, of a pro-drug would be a compound of the present invention wherein it is administered as an ester (the "pro-drug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial. Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the
B4002959vl - 31 - drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
Exemplary pro-drugs release an amine of a compound of the invention wherein the free hydrogen of an amine or alcohol is replaced by (Ci-C6)alkanoyloxymethyl, l-((Ci- C6)alkanoyloxy)ethyl, 1 -methyl- 1 -((C i-C6)alkanoyloxy)ethyl, (C i -C6)alkoxycarbonyl- oxymethyl, N-(Ci-C6)alkoxycarbonylamino-methyl, succinoyl, (Ci-Ce)alkanoyl, a- amino(Ci-C4)alkanoyl, arylactyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl wherein said a-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, -P(0)(OH)2, -P(0)(0(Ci-C6)alkyl)2 or glycosyl (the radical resulting from detachment of the hydroxyl of the hemiacetal of a carbohydrate).
Other exemplary pro-drugs upon cleavage release a corresponding free acid, and such hydrolyzable ester- forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents (e.g., -(CH2)C(0)OH or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (Ci-C/i)alkyl, (C2- C i2)alkanoyloxymethyl, (C4-C9) 1 -(alkanoyloxy)ethyl, 1 -methyl- 1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-
(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci-C2)alkyl, N,N-di(Ci-C2)-alkylcarbamoyl-(Ci- C2)alkyl and piperidino-, pyrrolidino- or moφholino(C2-C3)alkyl.
The term "subject" as used herein, refers to an animal, typically a mammal or a human, that will be or has been the object of treatment, observation, and/or experiment. When the term is used in conjunction with administration of a compound or drug, then the subject has been the object of treatment, observation, and/or administration of the compound or drug.
The terms "co-administration" and "co-administering" refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different
B4002959vl - 32 - from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent at the same time.
The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a cell culture, tissue system, animal, or human that is being sought by a researcher, veterinarian, clinician, or physician, which includes alleviation of the symptoms of the disease, condition, or disorder being treated.
The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
The term "pharmaceutically acceptable carrier" refers to a medium that is used to prepare a desired dosage form of a compound. A pharmaceutically acceptable carrier can include one or more solvents, diluents, or other liquid vehicles; dispersion or suspension aids; surface active agents; isotonic agents; thickening or emulsifying agents; preservatives; solid binders; lubricants; and the like. Remington's Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) and Handbook of
Pharmaceutical Excipients, Third Edition, A. H. Kibbe ed. (American Pharmaceutical Assoc. 2000), disclose various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
COMPOUNDS
An aspect of the present invention relates to compounds that inhibit casein kinase 1 and/or casein kinase 2 and/or a PIM kinase. For example, an embodiment relates to a compound of formula 1 or a pharmaceutically acceptable salt thereof,
Figure imgf000034_0001
1
wherein independently for each occurrence:
W is C(R% C(R1)2C( 1)2, C(R1)2C(R1)2C(R1)2, or S(0)2;
B4002959vl - 33 - X is nitrogen or CR2;
Y is nitrogen or CR3;
Z is nitrogen or CR4;
R1 is hydrogen or alkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl; or R3 and R4 are joined together to form an optionally substituted heterocyclic ring;
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted; wherein the compound is not
Figure imgf000035_0001
In one embodiment, R1 is hydrogen.
B4002959vl - 34 - In one embodiment, R1 is methyl.
In one embodiment, W is S(0)2.
In one embodiment, W is CH2.
In one embodiment, R2 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
In one embodiment, R2 is hydrogen.
In one embodiment, R2 is methyl.
In one embodiment, R2 is fluorine.
In one embodiment, R2 is an optionally substituted heteroaryl.
In one embodiment, R2 is an optionally substituted aryl.
In one embodiment, R3 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
In one embodiment, R3 is hydrogen.
In one embodiment, R3 is methyl.
In one embodiment, R3 is fluorine.
In one embodiment, R3 is an optionally substituted heteroaryl.
In one embodiment, R3 is an optionally substituted aryl.
In one embodiment, R3 is an optionally substituted heterocyclylalkyl.
In one embodiment, R3 and R4 are joined together to form an optionally substituted aryl.
In one embodiment, R3 and R4 are joined together to form an optionally substituted heterocyclyl.
In one embodiment, R3 and R4 are joined together to form an optionally substituted heteroaryl.
In one embodiment, R4 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
In one embodiment, R4 is hydrogen.
B4002959vl - 35 - In one embodiment, R4 is methyl.
In one embodiment, R4 is fluorine.
In one embodiment, R4 is an optionally substituted heteroaryl.
In one embodiment, R4 is an optionally substituted aryl.
In one embodiment, R4 is an optionally substituted heterocyclylalkyl.
In one embodiment, R5 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
In one embodiment, R5 is hydrogen.
In one embodiment, R5 is methyl.
In one embodiment, R5 is fluorine.
In one embodiment, R5 is an optionally substituted heteroaryl.
In one embodiment, R5 is an optionally substituted aryl.
In one embodiment, R5 is an optionally substituted heterocyclylalkyl.
In one embodiment, R6 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
In one embodiment, R6 is hydrogen.
In one embodiment, R6 is methyl.
In one embodiment, R6 is fluorine.
In one embodiment, R6 is an optionally substituted heteroaryl.
In one embodiment, R6 is an optionally substituted aryl.
In one embodiment, R6 is an optionally substituted heterocyclylalkyl.
An aspect of the present invention relates to compounds that inhibit casein kinase 1 and/or casein kinase 2 and/or a PIM kinase. For example, an embodiment relates to a compound of formula 2 or a pharmaceutically acceptable salt thereof,
B4002959vl - 36 -
Figure imgf000038_0001
2
wherein independently for each occurrence:
X is nitrogen or CR2;
Y is nitrogen or CR3;
Z is nitrogen or CR4;
R1 is hydrogen or alkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl; or R3 and R4 are joined together to form an optionally substituted heterocyclic ring;
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.
In one embodiment, R1 is hydrogen.
In one embodiment, R1 is methyl.
In one embodiment, R2 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
B4002959vl - 37 - In one embodiment, R2 is hydrogen.
In one embodiment, R2 is methyl.
In one embodiment, R2 is fluorine.
In one embodiment, R2 is an optionally substituted heteroaryl.
In one embodiment, R2 is an optionally substituted aryl.
In one embodiment, R3 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
In one embodiment, R3 is hydrogen.
In one embodiment, R3 is methyl.
In one embodiment, R3 is fluorine.
In one embodiment, R3 is an optionally substituted heteroaryl.
In one embodiment, R3 is an optionally substituted aryl.
In one embodiment, R3 is an optionally substituted heterocyclylalkyl.
In one embodiment, R3 and R4 are joined together to form an optionally substituted aryl.
In one embodiment, R3 and R4 are joined together to form an optionally substituted heterocyclyl.
In one embodiment, R3 and R4 are joined together to form an optionally substituted heteroaryl.
In one embodiment, R4 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
In one embodiment, R4 is hydrogen.
In one embodiment, R4 is methyl.
In one embodiment, R4 is fluorine.
In one embodiment, R4 is an optionally substituted heteroaryl.
In one embodiment, R4 is an optionally substituted aryl.
In one embodiment, R4 is an optionally substituted heterocyclylalkyl.
B4002959vl - 38 - In one embodiment, R is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
In one embodiment, R5 is hydrogen.
In one embodiment, R5 is methyl.
In one embodiment, R5 is fluorine.
In one embodiment, R5 is an optionally substituted heteroaryl.
In one embodiment, R5 is an optionally substituted aryl.
In one embodiment, R5 is an optionally substituted heterocyclylalkyl.
In one embodiment, R6 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
In one embodiment, R6 is hydrogen.
In one embodiment, R6 is methyl.
In one embodiment, R6 is fluorine.
In one embodiment, R6 is an optionally substituted heteroaryl.
In one embodiment, R6 is an optionally substituted aryl.
In one embodiment, R6 is an optionally substituted heterocyclylalkyl.
In one embodiment, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000040_0001
B4002959vl - 39 -
Figure imgf000041_0001
B4002959vl -40-
Figure imgf000042_0001
B4002959vl -41 -
Figure imgf000043_0001
In one embodiment, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
B4002959vl - 42 -
Figure imgf000044_0001
Figure imgf000045_0001
B4002959vl -44-
Figure imgf000046_0001
B4002959vl -45 -
Figure imgf000047_0001
Figure imgf000048_0001
B4002959vl -47-
Figure imgf000049_0001
B4002959vl -48-
Figure imgf000050_0001
In one embodiment, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure imgf000050_0002
Any one of the aforementioned compounds may exist as the
Figure imgf000050_0003
isomer, the Z-geometric isomer, or mixtures thereof. For example, in one embodiment, ^^¾· in the aforementioned structures represents the ^-isomer of the particular compound. In another embodiment, represents the Z-isomer of the particular compound. In yet another embodiment, represents a mixture of E and Z isomers of the particular compound.
In one embodiment, any one of the aforementioned compounds is an inhibitor of CKlyl, CKly2, or CKly3.
In one embodiment, any one of the aforementioned compounds is an inhibitor of
CK2.
In one embodiment, any one of the aforementioned compounds is an inhibitor of the Wnt pathway.
B4002959vl - 49 - In one embodiment, any one of the aforementioned compounds is an inhibitor of the JAK/STAT pathway.
In one embodiment, any one of the aforementioned compounds is an inhibitor of the mTOR pathway.
In one embodiment, any one of the aforementioned compounds is a mediator of Pgp degradation and/or drug efflux.
In one embodiment, any one of the aforementioned compounds is an inhibitor of the TGF pathway.
In some embodiments, the compound has an IC50 of less than 5000 nM for CKlyl, CKly2, or CKly3.
In some embodiments, the compound has an IC50 of less than 1000 nM for CKlyl, CKly2, or CKly3.
In some embodiments, the compound has an IC50 of less than 500 nM for CKlyl, CKly2, or CKly3.
In one embodiment, any one of the aforementioned compounds is an inhibitor of
CK2.
In one embodiment, the compound has an IC50 of less than 5000 nM for CK2.
In one embodiment, the compound has an IC50 of less than 1000 nM for CK2.
In one embodiment, the compound has an IC50 of less than 500 nM for CK2.
In one embodiment, any on of the aforementioned compounds is an inhibitor of
Pim-1, Pim-2, or Pim-3.
In one embodiment, the compound has an IC50 of less than 5000 nM for Pim-1, Pim-2 or Pim-3.
In one embodiment, the compound has an IC50 of less than 1000 nM for Pim-1, Pim-2 or Pim-3.
In one embodiment, the compound has an IC50 of less than 500 nM for Pim-1, Pim- 2 or Pim-3.
B4002959vl - 50 PROPHETIC EMBODIMENTS
Certain compounds of the invention could be made in accordance with the above schemes by reacting an amine (Reactant A) with the hydantoin core (Reactant B). Non- limiting prophetic examples of Reactant A and Reactant B are shown in Table 1 and Table 2, respectively.
Table 1: Reactant A Prophetic Examples.
Figure imgf000052_0001
B4002959vl - 51 - A5 254.004 6-bromo-4-(trifluorometliyl)picolinaldehyde
Figure imgf000053_0001
C7H3BrF3NO
A6 236.065 3 -bromoisoquinoline- 1 -carbaldehyde
Figure imgf000053_0002
C,o¾BrNO
A7 186.006 2-bromonicotinaldehyde
Figure imgf000053_0003
C6H4BrNO
A8 236.065 2-bromoquinoline-3-c arb aldehyde
Figure imgf000053_0004
C10H6BrNO
A9 186.006 6-bromonicotinaldehyde
Figure imgf000053_0005
C6H4BrNO
A10 211.016 2-bromo-5-formylnicotinonitrile
Figure imgf000053_0006
C7H3BrN20
B4002959vl - 52 - Al l 258.069 ethyl 2-bromo-5-formylnicotinate
Figure imgf000054_0001
C9H8BrN03
A12 186.006 2-bromoisonicotinaldehyde
Figure imgf000054_0002
C6H4BrNO
A13 254.004 2-bromo-6-(trifluoromethyl)isonicotinaldehyde
Figure imgf000054_0003
C7H3BrF3NO
A14 203.997 2-bromo-5-fluoroisonicotinaldehyde
Figure imgf000054_0004
C6H3BrFNO
A15 201.021 6-amino-2-bromonicotinaldehyde
Figure imgf000054_0005
B4002959vl - 53 -
Figure imgf000055_0001
Table 2: Reactant B Prophetic Examples.
Figure imgf000055_0002
B4002959vl -54- B4 179.966 2-borono-4-methylbenzoic acid
Figure imgf000056_0001
CgHgB04
B5 165.939 benzo[d][ 1 ,3]dioxol-5-ylboronic acid
Figure imgf000056_0002
C7H7B04
B6 255.077 (3-(benzylcarbamoyl)plienyl)boronic acid
Figure imgf000056_0003
C14H14BN03
B7 164.997 (3-(dimethylamino)phenyl)boronic acid
Figure imgf000056_0004
C8H12BN02
B8 178.981 (3-acetamidophenyl)boronic acid
Figure imgf000056_0005
CSH,„BN<¾
B9 214.025 (4-phenoxyphenyl)boronic acid
Figure imgf000056_0006
B4002959vl - 55 - BIO 160.966 (lH-indol-5-yl)boronic acid
Figure imgf000057_0001
CsHsBNO,
Bl l 172.976 isoquinolin-5-ylboronic acid
B(OH)2
C9H8BN02
B12 127.957 thiophen-3-ylboronic acid
Figure imgf000057_0002
C4H5B02S
B13 178.016 benzo[b]thiophen-3 -ylboronic acid
Figure imgf000057_0003
C8H7B02S
B14 169.994 (5-acetylthiophen-2-yl)boronic acid
Figure imgf000057_0004
C6H7B03S
B15 111.892 furan-2-ylboronic acid
Figure imgf000057_0005
C4H5B03
B4002959vl - 56 - B16 161.95 benzofuran-2-ylboronic acid
Figure imgf000058_0001
C8H7BO3
B17 111.892 furan-3-ylboronic acid
Figure imgf000058_0002
C4H5B03
B18 110.907 (lH-pyrrol-2-yl)boronic acid
Figure imgf000058_0003
C4H6BN02
B19 172.976 isoquinolin-4-ylboronic acid
Figure imgf000058_0004
C9H8BN02
B20 172.976 quinolm-4-ylboronic acid
B(OH)2
C9H8BN02
B21 140.908 (3-fluoropyridin-4-yl)boronic acid
Figure imgf000058_0005
C5H5BFN02
B4002959vl - 57 - B22 158.899 (2,6-difluoropyridin-4-yl)boronic acid
B(OH)2
F
C5H4I 02
B23 165.985 (6-(dimethylamino)pyridin-3 -yl)boronic acid
B24 166.973 (2-(dimethylamino)pyrimidin-5-yl)boronic acid
B25 140.933 (3,5-dimethylisoxazol-4-yl)boronic acid
Figure imgf000059_0001
C5H8BN03
B26 111.895 (lH-pyrazol-4-yl)boronic acid
Figure imgf000059_0002
C3H5BN202
B4002959vl - 58 - Β27 111.895 (lH-pyrazol-5-yl)boronic acid
Figure imgf000060_0001
C3H5BN202
Additional prophetic embodiments of the invention that may be made in accordance with the above reaction schemes using Reactants A and B are listed in Table 3. The geometric isomers listed in Table 3 are believed to reflect the actual geometry of the prophetic compounds if they were to be made; however, final structural assignments may only be made if the compounds are synthesized and subjected to appropriate 2D NMR experiments. Further, although the compounds are listed as the "Z" geometric isomer, both the E and Z geometric isomers and mixtures thereof are contemplated.
Table 3: Additional prophetic embodiments of the invention.
Figure imgf000060_0002
B4002959vl - 59 - (Z)-5-((2-(4-((((6-(2,4- bis(trifluoromethyl)phenyl)pyridm-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H24F6N602S 622.585 A9 Bl
(Z)-2-(2,4-bis(trifluoromethyl)phenyl)-5-(((( 1 -(4- ((2 ,4 -dioxothiazolidin- 5 -ylidene)methyl)pyrimidin-2 - yl)piperidin-4- yl)methyl)amino)metliyl)nicotinonitrile C29H23F6N702S 647.594 A10 Bl
(Z)-ethyl 2-(2,4-bis(trifluoromethyl)plienyl)-5-((((l- (4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)nicotinate C3iH28F6N604S 694.647 Al l Bl
(Z)-5-((2-(4-((((2-(2,4- bis(trifluoromethyl)phenyl)pyridin-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H24F6N602S 622.585 A12 Bl
(Z)-5-((2-(4-((((2-(2,4-bis(triil orometliyl)plienyl)-6- (trifluoromethyl)pyridin-4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C29H23F9N602S 690.583 A13 Bl
(Z)-5-((2-(4-((((2-(2,4-bis(trifluorometliyl)phenyl)-5- fluoropyridin-4-yl)methyl)amino)metliyl)piperidin- 1 - yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C28¾3F7N602S 640.575 A14 Bl
(Z)-5-((2-(4-((((6-amino-2-(2,4- bis(trifluoromethyl)phenyl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H25F6N702S 637.599 A15 Bl
(Z)-5-((2-(4-((((6-(2,4-dimethoxyphenyl)-4- iluoropyridin-2-yl)metliyl)amino)metliyl)piperidin- 1 - yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C28H29FN604S 564.631 Al B2
(Z)-5-((2-(4-((((6-(2,4-dimethoxyplienyl)pyridm-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H30N6O4S 546.641 A2 B2
(Z)-5-((2-(4-((((6-(2,4-dimethoxyphenyl)-4- metliylpyridin-2-yl)methyl)ammo)metliyl)piperidin- l-yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4- dione C29H32N604S 560.667 A3 B2
(Z)-5-((2-(4-((((6-(2,4-dimethoxyphenyl)-3- methoxypyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C29H32N605S 576.667 A4 B2
(Z)-5-((2-(4-((((6-(2,4-dimethoxyphenyl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C29H29F3N604S 614.639 A5 B2
(Z)-5-((2-(4-((((3-(2,4-dimethoxyphenyl)isoquinolin- 1 -yl)metliyl)ammo)methyl)piperidin- 1 -yl)pyrimidin- 4-yl)methylene)thiazolidine-2,4-dione C32H32N604S 596.699 A6 B2
(Z)-5-((2-(4-((((2-(2,4-dimethoxyphenyl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H30N6O4S 546.641 A7 B2
(Z)-5-((2-(4-((((2-(2,4-dimethoxyphenyl)q molin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C32H32N604S 596.699 A8 B2
(Z)-5-((2-(4-((((6-(2,4-dimetlioxyplienyl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H30N6O4S 546.641 A9 B2 959vl - 60 (Z)-2-(2,4-dimethoxyphenyl)-5-((((l-(4-((2,4- dioxothiazolidin-5-ylidene)methyl)pyrimidin-2- yl)piperidin-4- yl)methyl)amino)methyl)nicotinonitrile C29H29N7O4S 571.65 A10 B2
(Z)-ethyl 2-(2,4-dimethoxyphenyl)-5-((((l-(4-((2,4- dioxot azolidin-5-ylidene)methyl)pyrimidin-2- yl)piperidin-4-yl)methyl)amino)met]iyl)nicotinate C31H34N606S 618.703 Al l B2
(Z)-5-((2-(4-((((2-(2,4-dimethoxyp]ienyl)pyridin-4- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H3oN604S 546.641 A12 B2
(Z)-5-((2-(4-((((2-(2,4-dimethoxyphenyl)-6- (trifluoromethyl)pyridin-4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C29H29F3N604S 614.639 A13 B2
(Z)-5-((2-(4-((((2-(2,4-dimethoxyphenyl)-5- fluoropyridin-4-yl)methyl)amino)metliyl)piperidin- 1 - yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione C28H29FN604S 564.631 A14 B2
(Z)-5-((2-(4-((((6-amino-2-(2,4- dimethoxyphenyl)pyridin- 3 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H31N704S 561.655 A15 B2
(Z)-5-((2-(4-((((4-fl oro-6-(2- (trifluoromethoxy)phenyl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C27H24F4N603S 588.576 Al B3
(Z)-5-((2-(4-((((6-(2- (trifluoromethoxy)phenyl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C27H25F3N603S 570.586 A2 B3
(Z)-5-((2-(4-((((4-methyl-6-(2- (trifluoromethoxy)phenyl)pyridin-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H27F3N603S 584.613 A3 B3
(Z)-5-((2-(4-((((3-methoxy-6-(2- (trifluorometlioxy)phenyl)pyridm-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H27F3N604S 600.612 A4 B3
(Z)-5-((2-(4-((((6-(2-(trifluoromethoxy)phenyl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H24F6N603S 638.584 A5 B3
(Z)-5-((2-(4-((((3-(2- (trifluoromethoxy)phenyl)isoquinolin- 1 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C31H27F3N603S 620.645 A6 B3
(Z)-5-((2-(4-((((2-(2- (trifluoromethoxy)phenyl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C27H25F3N603S 570.586 A7 B3
(Z)-5-((2-(4-((((2-(2- (trifluoromethoxy)phenyl)quinolin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C31H27F3N603S 620.645 A8 B3
(Z)-5-((2-(4-((((6-(2- (trifl oromethoxy)phenyl)pyridm-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C27H25F3N603S 570.586 A9 B3 959vl - 61 (Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl) amino)methyl) -2 -(2 - (trifluoromethoxy)phenyl)nicotinonitrile C28H24F3N7O3S 595.595 A10 B3
(Z)-ethyl 5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)metliyl) -2 -(2 - (frifl oromethoxy)phenyl)nicotmate C30H29F3N6O5S 642.649 Al l B3
(Z)-5-((2-(4-((((2-(2- (trifluoromethoxy)phenyl)pyridin-4- yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C27H25F3N603S 570.586 A12 B3
(Z)-5-((2-(4-((((2-(2-(trifluorometlioxy)plienyl)-6- (trifluoromethyl)pyridin-4 - yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H24F6N603S 638.584 A13 B3
(Z)-5-((2-(4-((((5-iluoro-2-(2- (trifluoromethoxy)phenyl)pyridin-4- yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C27H24F4N603S 588.576 A14 B3
(Z)-5-((2-(4-((((6-amino-2-(2- (trifluoromethoxy)phenyl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C27H2 F3N703S 585.601 A15 B3
(Z)-2-(6-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl) ammo)metliyl) -4 -iluoropyridin-2 -yl) -4 - methylbenzoic acid C28H27FN604S 562.615 Al B4
(Z)-2-(6-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)pyridin-2-yl)-4- methylbenzoic acid C2gH28 604S 544.625 A2 B4
(Z)-2-(6-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)methyl) -4 -methylpyridin-2 -yl) -4 - methylbenzoic acid C2gH3o 604S 558.651 A3 B4
(Z)-2-(6-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)-5-methoxypyridin-2-yl)-4- methylbenzoic acid C29H30N6O5S 574.651 A4 B4
(Z)-2-(6-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)-4-(trifluoromethyl)pyridin- 2-yl)-4-methylbenzoic acid C29H27F3N604S 612.623 A5 B4
(Z)-2-(l-((((l-(4-((2,4-dioxothiazohdm-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)isoquinolin-3-yl)-4- methylbenzoic acid C32H30N6O4S 594.683 A6 B4
(Z)-2-(3-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)pyridin-2-yl)-4- methylbenzoic acid C28H28N604S 544.625 A7 B4
(Z)-2-(3-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)quinolin-2-yl)-4- methylbenzoic acid C32H30N6O4S 594.683 A8 B4
959vl - 62 - (Z)-2-(5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)ammo)methyl)pyridin-2-yl)-4- methylbenzoic acid C28H28N604S 544.625 A9 B4
(Z)-2-(3-cyano-5-((((l-(4-((2,4-dioxotliiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)ammo)methyl)pyridin-2-yl)-4- methylbenzoic acid C29H27N704S 569.634 A10 B4
(Z)-2-(5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)methyl) - 3 -(ethoxy c arbonyl)pyridin-
2-yl)-4-methylbenzoic acid C3iH32N606S 616.687 Al l B4
(Z)-2-(4-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)pyridin-2-yl)-4- methylbenzoic acid C28¾8N604S 544.625 A12 B4
(Z)-2-(4-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)-6-(trifluoromethyl)pyridin- 2-yl)-4-methylbenzoic acid C29H27F3N604S 612.623 A13 B4
(Z)-2-(4-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl) amino)methyl) - 5 -fluoropyridin-2 -yl) -4 - methylbenzoic acid C28H27F 604S 562.615 A14 B4
(Z)-2-(6-amino-3-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)ammo)methyl)pyridin-2-yl)-4- methylbenzoic acid C2sH2gN704S 559.639 A15 B4
(Z)-5-((2-(4-((((6-(benzo[d][l,3]dioxol-5-yl)-4- fluoropyridin-2-yl)methyl)amino)methyl)piperidin- 1 - yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione C27H25F 604S 548.589 Al B5
(Z)-5-((2-(4-((((6-(benzo[d][l,3]dioxol-5-yl)pyridin- 2-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin- 4-yl)methylene)thiazolidine-2,4-dione C27H26 604S 530.598 A2 B5
(Z)-5-((2-(4-((((6-(benzo[d][l,3]dioxol-5-yl)-4- methylpyridin-2-yl)methyl)amino)methyl)piperidin- l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione C28H28N604S 544.625 A3 B5
(Z)-5-((2-(4-((((6-(benzo[d][l,3]dioxol-5-yl)-3- methoxypyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H28 605S 560.624 A4 B5
(Z)-5-((2-(4-((((6-(benzo[d][l,3]dioxol-5-yl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)tmazolidine-2,4-dione C28H25F3N604S 598.596 A5 B5
(Z)-5-((2-(4-((((3-(benzo[d][l,3]dioxol-5- yl)isoquinolin- 1 -yl)methyl)amino)methyl)piperidin- l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione C31¾8 604S 580.657 A6 B5
(Z)-5-((2-(4-((((2-(benzo[d] [ 1 ,3]dioxol-5-yl)pyridin- 3 -yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin- 4-yl)methylene)thiazolidine-2,4-dione C27H26 604S 530.598 A7 B5
(Z)-5-((2-(4-((((2-(benzo[d][l,3]dioxol-5- yl)q inolin-3 -yl)methyl)amino)methyl)piperidin- 1 - yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione C31H28N604S 580.657 A8 B5
(Z)-5-((2-(4-((((6-(benzo[d][l,3]dioxol-5-yl)pyridin- 3 -yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin- 4-yl)methylene)thiazolidine-2,4-dione C27H26N604S 530.598 A9 B5 959vl - 63 (Z)-2-(benzo[d][l,3]dioxol-5-yl)-5-((((l-(4-((2,4- dioxothiazolidin-5-ylidene)metliyl)pyrimidin-2- yl)piperidin-4- yl)methyl)amino)methyl)nicotinonitrile C28H25N704S 555.608 A10 B5
(Z)-ethyl 2-(benzo[d][l,3]dioxol-5-yl)-5-((((l-(4- ((2 ,4 -dioxothiazolidin- 5 -ylidene)methyl)pyrimidin-2 - yl)piperidin-4-yl)methyl)amino)metliyl)nicotinate C30H30N6O6S 602.661 Al l B5
(Z)-5-((2-(4-((((2-(benzo[d] [ 1 ,3]dioxol-5-yl)pyridin- 4-yl)metliyl)amino)methyl)piperidin- 1 -yl)pyrimidin- 4-yl)methylene)thiazolidine-2,4-dione C27H26N604S 530.598 A12 B5
(Z)-5-((2-(4-((((2-(benzo[d][l,3]dioxol-5-yl)-6- (triiluoromethyl)pyridin-4 - yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione C28H25F3N604S 598.596 A13 B5
(Z)-5-((2-(4-((((2-(benzo[d][l,3]dioxol-5-yl)-5- fluoropyridin-4-yl)methyl)amino)metliyl)piperidin- 1 - yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C27H25FN604S 548.589 A14 B5
(Z)-5-((2-(4-((((6-amino-2-(benzo[d][l,3]dioxol-5- yl)pyridin-3 -yl)methyl)amino)methyl)piperidin- 1 - yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C27H27N7O4S 545.613 A15 B5
(Z)-N-benzyl-3-(6-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl) amino)metliyl) -4 -iluoropyridin-2 - yl)benzamide C34H32FN703S 637.726 Al B6
(Z)-N-benzyl-3-(6-((((l-(4-((2,4-dioxotMazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)pyridin-2-yl)benzamide C34H33N7O3S 619.736 A2 B6
(Z)-N-benzyl-3-(6-((((l-(4-((2,4-dioxotliiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)methyl) -4 -methylpyridin-2 - yl)benzamide C35H35N703S 633.763 A3 B6
(Z)-N-benzyl-3-(6-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl) amino)metliyl) - 5 -methoxypyridin-2- yl)benzamide C35H35N704S 649.762 A4 B6
(Z)-N-benzyl-3-(6-((((l-(4-((2,4-dioxotliiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)metliyl)amino)metliyl)-4-(trifluorometliyl)pyridin- 2-yl)benzamide C35H32F3 7O3S 687.734 A5 B6
(Z)-N-benzyl-3 -( 1 -(((( 1 -(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)isoquinolin-3-yl)benzamide C38H3 N7O3S 669.795 A6 B6
(Z)-N-benzyl-3 -(3 -(((( 1 -(4-((2,4-dioxotMazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)pyridin-2-yl)benzamide C34H33N7O3S 619.736 A7 B6
(Z)-N-benzyl-3 -(3 -(((( 1 -(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)quinolm-2-yl)benzaniide C38H35N7O3S 669.795 A8 B6
(Z)-N-benzyl-3 -(5-(((( 1 -(4-((2,4-dioxotMazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)pyridin-2-yl)benzamide C34H33N7O3S 619.736 A9 B6
(Z)-N-benzyl-3-(3-cyano-5-((((l-(4-((2,4- dioxot azolidin-5-ylidene)methyl)pyrimidin-2- yl)piperidin-4-yl)methyl)amino)metliyl)pyridin-2- yl)benzamide C35H32N803S 644.745 A10 B6
(Z)-ethyl 2-(3-(benzylcarbamoyl)plienyl)-5-((((l-(4- ((2 ,4 -dioxothiazolidin- 5 -ylidene)methyl)pyrimidin-2 - yl)piperidin-4-yl)methyl)amino)methyl)nicotinate C37H3 N705S 691.799 Al l B6 959vl - 64 (Z)-N-benzyl-3 -(4-(((( 1 -(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4-
87 yl)methyl)amino)metliyl)pyridin-2-yl)benzamide C34H33N7O3S 619.736 A12 B6
(Z)-N-benzyl-3-(4-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)-6-(trifl orometliyl)pyridin-
88 2-yl)benzamide C35H32F3N O3S 687.734 A13 B6
(Z)-N-benzyl-3 -(4-(((( 1 -(4-((2,4-dioxotMazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl) amino)methyl) - 5 -fluoropyridin-2 -
89 yl)benzamide Cj-AzFNyOjS 637.726 A14 B6
(Z)-3-(6-ammo-3-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)metliyl)pyridin-2 -yl) -N-
90 benzylbenzamide C34H34N803S 634.751 A15 B6
(Z)-5-((2-(4-((((6-(3-(dimethylamino)phenyl)-4- fluoropyridin-2-yl)metliyl)amino)metliyl)piperidin- 1 -
91 yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C28H30FN7O2S 547.647 Al B7
(Z)-5-((2-(4-((((6-(3-(dimethylamino)phenyl)pyridin- 2-yl)metliyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
92 4-yl)methylene)thiazolidine-2,4-dione C2SH31N7O2S 529.656 A2 B7
(Z)-5-((2-(4-((((6-(3-(dimethylamino)phenyl)-4- methylpyridin-2-yl)methyl)amino)metliyl)piperidin- l-yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-
93 dione C29H33 702S 543.683 A3 B7
(Z)-5-((2-(4-((((6-(3-(dimethylamino)phenyl)-3- methoxypyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
94 yl)methylene)thiazolidine-2,4-dione C29H33N703 S 559.682 A4 B7
(Z)-5-((2-(4-((((6-(3-(dimethylamino)phenyl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
95 yl)methylene)thiazolidine-2,4-dione C29H3oF3N702S 597.654 A5 B7
(Z)-5-((2-(4-((((3-(3- (dimetliylamino)plienyl)isoq inolin- 1 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
96 yl)methylene)thiazolidine-2,4-dione C32H33 702S 579.715 A6 B7
(Z)-5-((2-(4-((((2-(3-(dimethylamino)phenyl)pyridin- 3 -yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-
97 4-yl)methylene)thiazolidine-2,4-dione C2gH3iN702S 529.656 A7 B7
(Z 5-((2-(4-((((2-(3- (dimethylamino)phenyl)quinolin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
98 yl)methylene)thiazolidine-2,4-dione C32H33N702S 579.715 A8 B7
(Z)-5-((2-(4-((((6-(3-(dimethylamino)phenyl)pyridin- 3 -yl)metliyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
99 4-yl)metliylene)thiazolidine-2,4-dione C28H31N702S 529.656 A9 B7
(Z)-2-(3-(dimethylamino)phenyl)-5-((((l-(4-((2,4- dioxothiazolidin-5-ylidene)methyl)pyrimidin-2- yl)piperidin-4-
100 yl)methyl)amino)methyl)nicotinonitrile C2gH30N8O2S 554.666 A10 B7
(Z)-ethyl 2-(3-(dimethylammo)phenyl)-5-((((l-(4- ((2 ,4 -dioxothiazolidin- 5 -ylidene)methyl)pyrimidin-2 -
101 yl)piperidin-4-yl)methyl)amino)metliyl)nicotinate C3iH35 704S 601.719 Al l B7
(Z)-5-((2-(4-((((2-(3-(dimetliylamino)phenyl)pyridin- 4-yl)metliyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
102 4-yl)methylene)thiazolidine-2,4-dione C28H3i 702S 529.656 A12 B7
B4002959vl - 65 (Z)-5-((2-(4-((((2-(3-(dimethylamino)phenyl)-6- (trifluoromethyl)pyridin-4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
103 yl)methylene)thiazolidine-2,4-dione C29H30F3N7O2S 597.654 A13 B7
(Z)-5-((2-(4-((((2-(3-(dimethylamino)phenyl)-5- fluoropyridin-4-yl)methyl)amino)metliyl)piperidin- 1 -
104 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C28H30FN7O2S 547.647 A14 B7
(Z)-5-((2-(4-((((6-amino-2-(3- (dimethylammo)phenyl)pyridin-3- yl)methyl)amino)methyl)piperidm- 1 -yl)pyrimidin-4-
105 yl)methylene)thiazolidine-2,4-dione C28H32 802S 544.671 A15 B7
(Z)-N-(3-(6-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl) amino)metliyl) -4 -iluoropyridin-2 -
106 yl)plienyl)acetamide C28H28FN703S 561.63 Al B8
(Z)-N-(3-(6-((((l-(4-((2,4-dioxot azolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)pyridin-2-
107 yl)plienyl)acetamide C2sH gN703 S 543.64 A2 B8
(Z)-N-(3-(6-((((l-(4-((2,4-dioxotMazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)methyl) -4 -methylpyridin-2 -
108 yl)phenyl)acetamide C29H31N7O3 s 557.667 A3 B8
(Z)-N-(3-(6-((((l-(4-((2,4-dioxot azolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl) amino)methyl) - 5 -methoxypyridin-2-
109 yl)phenyl)acetamide C29H3 N704S 573.666 A4 B8
(Z)-N-(3-(6-((((l-(4-((2,4-dioxot azolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)metliyl)amino)metliyl)-4-(trifluorometliyl)pyridin-
110 2 -yl)phenyl) acetamide C29H28F3N703S 611.638 A5 B8
(Z)-N-(3-(l-((((l-(4-((2,4-dioxot azolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)isoquinolin-3-
111 yl)phenyl)acetamide C32H31N703S 593.699 A6 B8
(Z)-N-(3-(3-((((l-(4-((2,4-dioxot azolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)pyridin-2-
112 yl)phenyl)acetamide C28H29N703S 543.64 A7 B8
(Z)-N-(3-(3-((((l-(4-((2,4-dioxot azolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl) amino)metliyl) quinolin-2 -
113 yl)phenyl)acetamide C32H31N703S 593.699 A8 B8
(Z)-N-(3-(5-((((l-(4-((2,4-dioxot azolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)metliyl)amino)methyl)pyridin-2-
114 yl)phenyl)acetamide C28H29 703S 543.64 A9 B8
(Z)-N-(3-(3-cyano-5-((((l-(4-((2,4-dioxothiazolidin- 5-ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)pyridin-2-
115 yl)phenyl)acetamide C29H28 803S 568.649 A10 B8
(Z)-ethyl 2-(3-acetamidoplienyl)-5-((((l-(4-((2,4- dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-
116 yl)piperidin-4-yl)methyl)amino)methyl)nicotinate C31H33N705S 615.703 Al l B8
(Z)-N-(3-(4-((((l-(4-((2,4-dioxot azolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)metliyl)amino)metliyl)pyridin-2-
117 yl)phenyl)acetamide C28H29 703S 543.64 A12 B8
B4002959vl - 66 (Z)-N-(3-(4-((((l-(4-((2,4-dioxot azolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)metliyl)amino)metliyl)-6-(trifluorometliyl)pyridin-
118 2 -yl)phenyl) acetamide C29H28F3N7O3S 611.638 A13 B8
(Z)-N-(3-(4-((((l-(4-((2,4-dioxot azolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl) amino)metliyl) - 5 -iluoropyridin-2 -
119 yl)phenyl)acetamide C28H28FN703S 561.63 A14 B8
(Z)-N-(3 -(6-amino-3 -(((( 1 -(4-((2,4-dioxothiazolidin- 5-ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)pyridin-2-
120 yl)phenyl)acetamide C28H30N8O3S 558.655 A15 B8
(Z)-5-((2-(4-((((4-fluoro-6-(4- phenoxyphenyl)pyridin-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
121 yl)methylene)thiazolidine-2,4-dione C32H29FN603S 596.674 Al B9
(Z)-5-((2-(4-((((6-(4-phenoxyphenyl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
122 yl)methylene)thiazolidine-2,4-dione C32H3o i;03S 578.684 A2 B9
(Z)-5-((2-(4-((((4-methyl-6-(4- phenoxyphenyl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
123 yl)methylene)thiazolidine-2,4-dione C33H32 ¾03S 592.711 A3 B9
(Z)-5-((2-(4-((((3-methoxy-6-(4- phenoxyphenyl)pyridin-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
124 yl)methylene)thiazolidine-2,4-dione C33H32N1SO4S 608.71 A4 B9
(Z)-5-((2-(4-((((6-(4-phenoxyphenyl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
125 yl)methylene)thiazolidine-2,4-dione C33H29F3N603S 646.682 A5 B9
(Z)-5-((2-(4-((((3-(4-phenoxyplienyl)isoquinolin- 1 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
126 yl)methylene)thiazolidine-2,4-dione C36H32 603S 628.743 A6 B9
(Z)-5-((2-(4-((((2-(4-phenoxyphenyl)pyridm-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
127 yl)methylene)thiazolidine-2,4-dione C32H30 6O3S 578.684 A7 B9
(Z)-5-((2-(4-((((2-(4-phenoxyphenyl)quinolin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
128 yl)methylene)thiazolidine-2,4-dione C36H32 603S 628.743 A8 B9
(Z)-5-((2-(4-((((6-(4-phenoxyphenyl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
129 yl)methylene)thiazolidine-2,4-dione 32H30 6O3S 578.684 A9 B9
(Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)methyl) -2 -(4 -
130 phenoxyphenyl)mcotinonitrile C33H29N703S 603.693 A10 B9
(Z)-ethyl 5-((((l-(4-((2,4-dioxotliiazolidm-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)methyl) -2 -(4 -
131 phenoxyphenyl)nicotinate C35H34 605S 650.747 Al l B9
(Z)-5-((2-(4-((((2-(4-phenoxyphenyl)pyridin-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
132 yl)methylene)thiazolidine-2,4-dione C32H3o 603S 578.684 A12 B9
(Z)-5-((2-(4-((((2-(4-phenoxyphenyl)-6- (triiluoromethyl)pyridin-4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
133 yl)methylene)thiazolidine-2,4-dione C33H29F3N603S 646.682 A13 B9
B4002959vl - 67 (Z)-5-((2-(4-((((5-iluoro-2-(4- phenoxyphenyl)pyridin-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
134 yl)methylene)thiazolidine-2,4-dione C32H29FN603S 596.674 A14 B9
(Z)-5-((2-(4-((((6-amino-2-(4- phenoxyphenyl)pyridin-3 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
135 yl)methylene)thiazolidine-2,4-dione C32H31N7O3S 593.699 A15 B9
(Z)-5-((2-(4-((((4-fluoro-6-(lH-indol-5-yl)pyridin-2- yl)methyl)amino)methyl)piperidm- 1 -yl)pyrimidin-4-
136 yl)methylene)thiazolidine-2,4-dione C28H26FN702S 543.615 Al BIO
(Z)-5-((2-(4-((((6-(lH-indol-5-yl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
137 yl)methylene)thiazolidine-2,4-dione C28H27N7O2S 525.625 A2 BIO
(Z)-5-((2-(4-((((6-(lH-indol-5-yl)-4-methylpyridin-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
138 yl)methylene)thiazolidine-2,4-dione C29H29N7O2 s 539.651 A3 BIO
(Z)-5-((2-(4-((((6-(lH-indol-5-yl)-3-methoxypyridin- 2-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
139 4-yl)methylene)thiazolidine-2,4-dione C29H29N7O3 s 555.651 A4 BIO
(Z)-5-((2-(4-((((6-(lH-indol-5-yl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
140 yl)methylene)thiazolidine-2,4-dione C29H26F3N702S 593.623 A5 BIO
(Z)-5-((2-(4-((((3-(lH-indol-5-yl)isoquinolin-l- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
141 yl)methylene)thiazolidine-2,4-dione C32H29N702S 575.683 A6 BIO
(Z)-5-((2-(4-((((2-(lH-indol-5-yl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
142 yl)methylene)thiazolidine-2,4-dione C28H27N702S 525.625 A7 BIO
(Z)-5-((2-(4-((((2-(lH-indol-5-yl)quinolin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
143 yl)methylene)thiazolidine-2,4-dione C32H29N702S 575.683 A8 BIO
(Z)-5-((2-(4-((((6-(lH-indol-5-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
144 yl)methylene)thiazolidine-2,4-dione C28H27N702S 525.625 A9 BIO
(Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)-2-( 1 H-indol-5-
145 yl)nicotmonitrile C29H2e 802S 550.634 A10 BIO
(Z)-ethyl 5-((((l-(4-((2,4-dioxotMazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4-
146 yl)metliyl)amino)metliyl)-2-( 1 H-indol-5-yl)nicotinate C31H31N7O4S 597.687 Al l BIO
(Z)-5-((2-(4-((((2-(lH-indol-5-yl)pyridin-4- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
147 yl)methylene)thiazolidine-2,4-dione C2gH27]S[702S 525.625 A12 BIO
(Z)-5-((2-(4-((((2-(lH-indol-5-yl)-6- (trifluorometliyl)pyridm-4 - yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
148 yl)methylene)thiazolidine-2,4-dione C29H 6F3N702S 593.623 A13 BIO
(Z)-5-((2-(4-((((5-fluoro-2-(lH-indol-5-yl)pyridin-4- yl)methyl)amino)methyl)piperidm- 1 -yl)pyrimidin-4-
149 yl)methylene)thiazolidine-2,4-dione C28H26FN702S 543.615 A14 BIO
(Z)-5-((2-(4-((((6-amino-2-(lH-indol-5-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
150 yl)methylene)thiazolidine-2,4-dione C28H28 g02S 540.639 A15 BIO
(Z)-5-((2-(4-((((4-fluoro-6-(isoquinolin-5-yl)pyridin- 2-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
151 4-yl)methylene)thiazolidine-2,4-dione C29H26FN702S 555.626 Al Bl l
B4002959vl - 68 (Z)-5-((2-(4-((((6-(isoquinolin-5-yl)pyridin-2- yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-4-
152 yl)methylene)thiazolidine-2,4-dione C29H27N7O2 S 537.635 A2 Bl l
(Z)-5-((2-(4-((((6-(isoqumolin-5-yl)-4- methylpyridin-2-yl)methyl)ammo)methyl)piperidin- l-yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-
153 dione C3oH2g 702S 551.662 A3 Bl l
(Z)-5-((2-(4-((((6-(isoq inolin-5-yl)-3- methoxypyridin-2- yl)methyl)amino)methyl)piperidm- 1 -yl)pyrimidin-4-
154 yl)methylene)thiazolidine-2,4-dione C30H29N7O3S 567.661 A4 Bl l
(Z)-5-((2-(4-((((6-(isoquinolin-5-yl)-4- (triiluoromethyl)pyridin-2 - yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
155 yl)methylene)thiazolidine-2,4-dione C30H26F3N7O2S 605.633 A5 Bl l
(Z)-5-((2-(4-((([3,5'-biisoquinolin]-l- ylmethyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
156 yl)methylene)thiazolidine-2,4-dione C33H29 702S 587.694 A6 Bl l
(Z)-5-((2-(4-((((2-(isoquinolin-5-yl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
157 yl)methylene)thiazolidine-2,4-dione C29H27N7O2 S 537.635 A7 Bl l
(Z)-5-((2-(4-((((2-(isoquinolin-5-yl)quinolin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
158 yl)methylene)thiazolidine-2,4-dione C33H29 7O2S 587.694 A8 Bl l
(Z)-5-((2-(4-((((6-(isoquinolin-5-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
159 yl)methylene)thiazolidine-2,4-dione C29H27N702 S 537.635 A9 Bl l
(Z)-5-((((l-(4-((2,4-dioxotliiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)-2-(isoquinolm-5-
160 yl)nicotinonitrile C3oH26N802S 562.645 A10 Bl l
(Z)-ethyl 5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)-2-(isoquinolin-5-
161 yl)nicotinate C32H31 704S 609.698 Al l Bl l
(Z)-5-((2-(4-((((2-(isoquinolin-5-yl)pyridin-4- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
162 yl)methylene)thiazolidine-2,4-dione C29H27N7O2 S 537.635 A12 Bl l
(Z)-5-((2-(4-((((2-(isoq inolin-5-yl)-6- (triiluoromethyl)pyridin-4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
163 yl)methylene)thiazolidine-2,4-dione C30H2 F3N7O2S 605.633 A13 Bl l
(Z)-5-((2-(4-((((5-fluoro-2-(isoquinolin-5-yl)pyridin- 4-yl)metliyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
164 4-yl)methylene)thiazolidine-2,4-dione C29H26F 702S 555.626 A14 Bl l
(Z)-5-((2-(4-((((6-amino-2-(isoquinolin-5-yl)pyridin- 3 -yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
165 4-yl)methylene)thiazolidine-2,4-dione C29¾8N802S 552.65 A15 Bl l
(Z)-5-((2-(4-((((4-iluoro-6-(thiophen-3-yl)pyridin-2- yl)methyl)amino)methyl)piperidm- 1 -yl)pyrimidin-4-
166 yl)methylene)thiazolidine-2,4-dione C24H23F 602S2 510.607 Al B12
(Z)-5-((2-(4-((((6-(thiophen-3-yl)pyridm-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
167 yl)methylene)thiazolidine-2,4-dione C24H24 ¾02S2 492.616 A2 B12
(Z)-5-((2-(4-((((4-methyl-6-(thiophen-3-yl)pyridm-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
168 yl)methylene)thiazolidine-2,4-dione C2 H2 N6O2S2 506.643 A3 B12
B4002959vl - 69 (Z)-5-((2-(4-((((3-methoxy-6-(thiophen-3-yl)pyridin- 2-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
169 4-yl)methylene)thiazolidine-2,4-dione C25H2 N6O3S2 522.642 A4 B12
(Z)-5-((2-(4-((((6-(thioplien-3-yl)-4- (triiluoromethyl)pyridin-2 - yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
170 yl)methylene)thiazolidine-2,4-dione C25H23F3N6O2S2 560.614 A5 B12
(Z)-5-((2-(4-((((3-(thioplien-3-yl)isoq inolin- 1 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
171 yl)methylene)thiazolidine-2,4-dione C28H2 N602S2 542.675 A6 B12
(Z)-5-((2-(4-((((2-(t ophen-3-yl)pyridm-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
172 yl)methylene)thiazolidine-2,4-dione C24H24N6O2S2 492.616 A7 B12
(Z)-5-((2-(4-((((2-(thiophen-3-yl)quinolin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
173 yl)methylene)thiazolidine-2,4-dione C28H2 N¾02S2 542.675 A8 B12
(Z)-5-((2-(4-((((6-(tMophen-3-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
174 yl)methylene)thiazolidine-2,4-dione C24H24N6O2S2 492.616 A9 B12
(Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)ammo)methyl)-2-(thiophen-3-
175 yl)nicotinonitrile C25H23N7O2 S2 517.626 A10 B12
(Z)-ethyl 5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4-
176 yl)methyl)amino)metliyl)-2-(tliiophen-3-yl)nicotmate C27H28N604S2 564.679 Al l B12
(Z)-5-((2-(4-((((2-(tMophen-3-yl)pyridm-4- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
177 yl)methylene)thiazolidine-2,4-dione C24H24N6O2S2 492.616 A12 B12
(Z)-5-((2-(4-((((2-(thiophen-3-yl)-6- (triiluoromethyl)pyridin-4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
178 yl)methylene)thiazolidine-2,4-dione C2 H23F3N6O2S2 560.614 A13 B12
(Z)-5-((2-(4-((((5-fluoro-2-(thiophen-3-yl)pyridin-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
179 yl)methylene)thiazolidine-2,4-dione C24H23F 602S2 510.607 A14 B12
(Z)-5-((2-(4-((((6-amino-2-(thiophen-3-yl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
180 yl)methylene)thiazolidine-2,4-dione C24H2 N702S2 507.631 A15 B12
(Z)-5-((2-(4-((((6-(benzo[b]tMophen-3-yl)-4- iluoropyridin-2-yl)methyl)amino)metliyl)piperidin- 1 -
181 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C28H25FN602S2 560.666 Al B13
(Z)-5-((2-(4-((((6-(benzo[b]tMophen-3-yl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
182 yl)methylene)thiazolidine-2,4-dione C28H2 N602S2 542.675 A2 B13
(Z)-5-((2-(4-((((6-(benzo[b]thiophen-3-yl)-4- methylpyridin-2-yl)methyl)ammo)methyl)piperidin- l-yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-
183 dione C29H28N602S2 556.702 A3 B13
(Z)-5-((2-(4-((((6-(benzo[b]thiophen-3-yl)-3- methoxypyridin-2- yl)methyl)amino)methyl)piperidm- 1 -yl)pyrimidin-4-
184 yl)methylene)thiazolidine-2,4-dione C29H28N603S2 572.701 A4 B13
(Z)-5-((2-(4-((((6-(benzo[b]thiophen-3-yl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
185 yl)methylene)thiazolidine-2,4-dione C29H2 F3N6O2S2 610.673 A5 B13
B4002959vl - 70 (Z)-5-((2-(4-((((3-(benzo[b]thiophen-3- yl)isoquinolin- 1 -yl)methyl)amino)methyl)piperidin- l-yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-
186 dione C32H28N602S2 592.734 A6 B13
(Z)-5-((2-(4-((((2-(benzo[b]tMophen-3-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
187 yl)methylene)thiazolidine-2,4-dione C28H26 602S2 542.675 A7 B13
(Z)-5-((2-(4-((((2-(benzo[b]thiophen-3-yl)q inolin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
188 yl)methylene)thiazolidine-2,4-dione C32H28N602S2 592.734 A8 B13
(Z)-5-((2-(4-((((6-(benzo[b]thiophen-3-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
189 yl)methylene)thiazolidine-2,4-dione C28H26N602S2 542.675 A9 B13
(Z)-2-(benzo[b]thiophen-3-yl)-5-((((l-(4-((2,4- dioxot azolidin-5-ylidene)methyl)pyrimidin-2- yl)piperidin-4-
190 yl)methyl)amino)metliyl)nicotinonitrile C29H25N7O2S2 567.685 A10 B13
(Z)-ethyl 2-(benzo[b]thiophen-3-yl)-5-((((l-(4-((2,4- dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-
191 yl)piperidin-4-yl)methyl)amino)methyl)nicotinate C31H30 1SO4S2 614.738 Al l B13
(Z)-5-((2-(4-((((2-(benzo[b]thiophen-3-yl)pyridin-4- yl)methyl)ammo)metliyl)piperidin- 1 -yl)pyrimidin-4-
192 yl)methylene)thiazolidine-2,4-dione C28H26 602S2 542.675 A12 B13
(Z)-5-((2-(4-((((2-(benzo[b]thiophen-3-yl)-6- (trifluoromethyl)pyridin-4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
193 yl)methylene)thiazolidine-2,4-dione C29H25F3N602S2 610.673 A13 B13
(Z)-5-((2-(4-((((2-(benzo[b]thiophen-3-yl)-5- iluoropyridin-4-yl)methyl)amino)metliyl)piperidin- 1 -
194 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione C28H25F 602S2 560.666 A14 B13
(Z)-5-((2-(4-((((6-amino-2-(benzo[b]thiophen-3- yl)pyridin-3 -yl)methyl)amino)methyl)piperidin- 1 -
195 yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C28H27N702S2 557.69 A15 B13
(Z)-5-((2-(4-((((6-(5-acetylthiophen-2-yl)-4- fluoropyridin-2-yl)methyl)amino)metliyl)piperidin- 1 -
196 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C26H25FN603S2 552.644 Al B14
(Z)-5-((2-(4-((((6-(5-acetyltliiophen-2-yl)pyridin-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
197 yl)methylene)thiazolidine-2,4-dione C2 H2 N603S2 534.653 A2 B14
(Z)-5-((2-(4-((((6-(5-acetylthioplien-2-yl)-4- methylpyridin-2-yl)methyl)amino)methyl)piperidin- l-yl)pyrimidin-4-yl)methylene)tliiazolidine-2,4-
198 dione C27H28N603S2 548.68 A3 B14
(Z)-5-((2-(4-((((6-(5-acetylthiophen-2-yl)-3- methoxypyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
199 yl)methylene)thiazolidine-2,4-dione C27H28N604S2 564.679 A4 B14
(Z)-5-((2-(4-((((6-(5-acetyltliiophen-2-yl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)methyl)piperidm- 1 -yl)pyrimidin-4-
200 yl)methylene)thiazolidine-2,4-dione C27H2 F3N603 S2 602.651 A5 B14
(Z)-5-((2-(4-((((3-(5-acetylthiophen-2-yl)isoquinolin- 1 -yl)metliyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
201 4-yl)methylene)thiazolidine-2,4-dione C3oH28N¾03S2 584.712 A6 B14
(Z)-5-((2-(4-((((2-(5-acetyltliiophen-2-yl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
202 yl)methylene)thiazolidine-2,4-dione C2 H2 N603S2 534.653 A7 B14
B4002959vl - 71 (Z)-5-((2-(4-((((2-(5-acetyltliiophen-2-yl)quinolin-3- yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-4-
203 yl)methylene)thiazolidine-2,4-dione C30H28N6O3S2 584.712 A8 B14
(Z)-5-((2-(4-((((6-(5-acetyltliiophen-2-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
204 yl)methylene)thiazolidine-2,4-dione C26H2 N603S2 534.653 A9 B14
(Z)-2-(5-acetylthiophen-2-yl)-5-((((l-(4-((2,4- dioxot azolidin-5-ylidene)metliyl)pyrimidin-2- yl)piperidin-4-
205 yl)methyl)amino)methyl)nicotinonitrile C27H25N7O3S2 559.663 A10 B14
(Z)-ethyl 2-(5-acetylthiophen-2-yl)-5-((((l -(4-((2,4- dioxotliiazolidin-5-ylidene)methyl)pyrimidin-2-
206 yl)piperidin-4-yl)methyl)amino)metliyl)nicotinate C29H3o 6OsS2 606.716 Al l B14
(Z)-5-((2-(4-((((2-(5-acetylthiophen-2-yl)pyridin-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
207 yl)methylene)thiazolidine-2,4-dione C2 H2 N¾03S2 534.653 A12 B14
(Z)-5-((2-(4-((((2-(5-acetyltliiophen-2-yl)-6- (triiluoromethyl)pyridin-4 - yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
208 yl)methylene)thiazolidine-2,4-dione C27H25F3N13O3 S2 602.651 A13 B14
(Z)-5-((2-(4-((((2-(5-acetylthiophen-2-yl)-5- iluoropyridin-4-yl)metliyl)amino)metliyl)piperidin- 1 -
209 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C26H25F 603S2 552.644 A14 B14
(Z)-5-((2-(4-((((2-(5-acetylthiophen-2-yl)-6- aminopyridin-3 -yl)methyl)amino)methyl)piperidin- 1 -
210 yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C26H27 703S2 549.668 A15 B14
(Z)-5-((2-(4-((((4-fl oro-6-(furan-2-yl)pyridin-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
211 yl)methylene)thiazolidine-2,4-dione C24H23F 603S 494.541 Al B15
(Z)-5-((2-(4-((((6-(furan-2-yl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
212 yl)methylene)thiazolidine-2,4-dione C24H24N603S 476.551 A2 B15
(Z)-5-((2-(4-((((6-(furan-2-yl)-4-methylpyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
213 yl)methylene)thiazolidine-2,4-dione C25H26 603S 490.577 A3 B15
(Z)-5-((2-(4-((((6-(furan-2-yl)-3-methoxypyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
214 yl)methylene)thiazolidine-2,4-dione C25H26N604S 506.577 A4 B15
(Z)-5-((2-(4-((((6-(furan-2-yl)-4- (triiluoromethyl)pyridin-2 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
215 yl)methylene)thiazolidine-2,4-dione C25H23F3N603S 544.549 A5 B15
(Z)-5-((2-(4-((((3-(furan-2-yl)isoq inolin- 1 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
216 yl)methylene)thiazolidine-2,4-dione C28H26 603S 526.609 A6 B15
(Z)-5-((2-(4-((((2-(furan-2-yl)pyridm-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
217 yl)methylene)thiazolidine-2,4-dione C24H24N603S 476.551 A7 B15
(Z)-5-((2-(4-((((2-(furan-2-yl)quinolm-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
218 yl)methylene)thiazolidine-2,4-dione C28H26N603S 526.609 A8 B15
(Z)-5-((2-(4-((((6-(furan-2-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
219 yl)methylene)thiazolidine-2,4-dione C24H24N603S 476.551 A9 B15
(Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)-2-(furan-2-
220 yl)nicotinonitrile C25H23 703S 501.56 A10 B15
B4002959vl - 72 (Z)-ethyl -((((l-(4-((2,4-dioxotMazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4-
221 yl)metliyl)amino)metliyl)-2-(furan-2-yl)nicotinate C27H28N605S 548.613 Al l B15
(Z)-5-((2-(4-((((2-(furan-2-yl)pyridm-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
222 yl)methylene)thiazolidine-2,4-dione C24H24N603S 476.551 A12 B15
(Z)-5-((2-(4-((((2-(furan-2-yl)-6- (trifluoromethyl)pyridin-4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
223 yl)methylene)thiazolidine-2,4-dione C25H23F3N603S 544.549 A13 B15
(Z)-5-((2-(4-((((5-fluoro-2-(furan-2-yl)pyridin-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
224 yl)methylene)thiazolidine-2,4-dione C24H23FN603S 494.541 A14 B15
(Z)-5-((2-(4-((((6-amino-2-(furan-2-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
225 yl)methylene)thiazolidine-2,4-dione C24H25N703S 491.565 A15 B15
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)-4-fluoropyridin- 2-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
226 4-yl)methylene)thiazolidine-2,4-dione C28H25FN603S 544.6 Al B16
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)pyridm-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
227 yl)methylene)thiazolidine-2,4-dione C28H26N603S 526.609 A2 B16
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)-4- methylpyridin-2-yl)methyl)ammo)metliyl)piperidin- l-yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-
228 dione C2gH28N603S 540.636 A3 B16
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)-3- methoxypyridin-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
229 yl)methylene)thiazolidine-2,4-dione C29H 8N604S 556.635 A4 B16
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
230 yl)methylene)thiazolidine-2,4-dione C29H25F3N603S 594.607 A5 B16
(Z)-5-((2-(4-((((3-(benzofuran-2-yl)isoquinolin-l- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
231 yl)methylene)thiazolidine-2,4-dione C32H28N603S 576.668 A6 B16
(Z)-5-((2-(4-((((2-(benzofuran-2-yl)pyridm-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
232 yl)methylene)thiazolidine-2,4-dione C28H26N603S 526.609 A7 B16
(Z)-5-((2-(4-((((2-(benzofuran-2-yl)quinolin-3- yl)methyl)ammo)metliyl)piperidin- 1 -yl)pyrimidin-4-
233 yl)methylene)thiazolidine-2,4-dione C32H28 603S 576.668 A8 B16
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)pyridm-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
234 yl)methylene)thiazolidine-2,4-dione C28H26N603S 526.609 A9 B16
(Z)-2-(benzofuran-2-yl)-5-((((l-(4-((2,4- dioxot azolidin-5-ylidene)metliyl)pyrimidin-2- yl)piperidin-4-
235 yl)methyl)amino)methyl)nicotinonitrile C29H 5 703S 551.619 A10 B16
(Z)-ethyl 2-(benzofuran-2-yl)-5-((((l-(4-((2,4- dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-
236 yl)piperidin-4-yl)methyl)amino)metliyl)nicotinate C31H30N6O5S 598.672 Al l B16
(Z)-5-((2-(4-((((2-(benzofuran-2-yl)pyridm-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
237 yl)methylene)thiazolidine-2,4-dione C28H26N603S 526.609 A12 B16
B4002959vl - 73 - (Z)-5-((2-(4-((((2-(benzofuran-2-yl)-6- (trifluoromethyl)pyridin-4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
238 yl)methylene)thiazolidine-2,4-dione C29H25F3N603S 594.607 A13 B16
(Z)-5-((2-(4-((((2-(benzofuran-2-yl)-5-fluoropyridin- 4-yl)metliyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
239 4-yl)methylene)thiazolidine-2,4-dione C28H25FN603S 544.6 A14 B16
(Z)-5-((2-(4-((((6-amino-2-(benzoftu"an-2-yl)pyridin- 3 -yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
240 4-yl)methylene)thiazolidine-2,4-dione C28H 7 703S 541.624 A15 B16
(Z)-5-((2-(4-((((4-fluoro-6-(furan-3-yl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
241 yl)methylene)thiazolidine-2,4-dione C24H23FN603S 494.541 Al B17
(Z)-5-((2-(4-((((6-(furan-3-yl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
242 yl)methylene)thiazolidine-2,4-dione C24H24N603S 476.551 A2 B17
(Z)-5-((2-(4-((((6-(furan-3-yl)-4-methylpyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
243 yl)methylene)thiazolidine-2,4-dione C25H26N603S 490.577 A3 B17
(Z)-5-((2-(4-((((6-(furan-3-yl)-3-methoxypyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
244 yl)methylene)thiazolidine-2,4-dione C25H26N604S 506.577 A4 B17
(Z)-5-((2-(4-((((6-(furan-3-yl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
245 yl)methylene)thiazolidine-2,4-dione C25H23F3N603S 544.549 A5 B17
(Z)-5-((2-(4-((((3-(furan-3-yl)isoquinolin-l- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
246 yl)methylene)thiazolidine-2,4-dione C28H26N603S 526.609 A6 B17
(Z)-5-((2-(4-((((2-(furan-3-yl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
247 yl)methylene)thiazolidine-2,4-dione C24H24N603S 476.551 A7 B17
(Z)-5-((2-(4-((((2-(furan-3-yl)quinolm-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
248 yl)methylene)thiazolidine-2,4-dione C28H26N603S 526.609 A8 B17
(Z)-5-((2-(4-((((6-(furan-3-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
249 yl)methylene)thiazolidine-2,4-dione C24H24N603S 476.551 A9 B17
(Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)-2-(furan-3-
250 yl)mcotinonitrile C25H23N703S 501.56 A10 B17
(Z)-ethyl -((((l-(4-((2,4-dioxotliiazolidm-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4-
251 yl)metliyl)amino)metliyl)-2-(furan-3-yl)nicotinate C27H28N605S 548.613 Al l B17
(Z)-5-((2-(4-((((2-(furan-3-yl)pyridm-4- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
252 yl)methylene)thiazolidine-2,4-dione C24H24N603S 476.551 A12 B17
(Z)-5-((2-(4-((((2-(furan-3-yl)-6- (trilluorometliyl)pyridm-4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
253 yl)methylene)thiazolidine-2,4-dione C25H23F3N603S 544.549 A13 B17
(Z)-5-((2-(4-((((5-fl oro-2-(furan-3-yl)pyridin-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
254 yl)methylene)thiazolidine-2,4-dione C24H23FN603S 494.541 A14 B17
(Z)-5-((2-(4-((((6-amino-2-(furan-3-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
255 yl)methylene)thiazolidine-2,4-dione C24H25N703S 491.565 A15 B17
B4002959vl - 74 (Z)-5-((2-(4-((((4-fluoro-6-(lH-pyrrol-2-yl)pyridin- 2-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
256 4-yl)methylene)thiazolidine-2,4-dione C24H24F 702S 493.556 Al B18
(Z)-5-((2-(4-((((6-(lH-pyrrol-2-yl)pyridm-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
257 yl)methylene)thiazolidine-2,4-dione C24H25N702S 475.566 A2 B18
(Z)-5-((2-(4-((((4-methyl-6-(lH-pyrrol-2-yl)pyridin- 2-yl)metliyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
258 4-yl)methylene)thiazolidine-2,4-dione C25H27N702S 489.593 A3 B18
(Z)-5-((2-(4-((((3-methoxy-6-(lH-pyrrol-2- yl)pyridin-2-yl)methyl)amino)methyl)piperidin- 1 -
259 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C25H 7N7O3 s 505.592 A4 B18
(Z)-5-((2-(4-((((6-(lH-pyrrol-2-yl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
260 yl)methylene)thiazolidine-2,4-dione C25H24F3N702S 543.564 A5 B18
(Z)-5-((2-(4-((((3-(lH-pyrrol-2-yl)isoquinolin-l- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
261 yl)methylene)thiazolidine-2,4-dione C28H27N7O2S 525.625 A6 B18
(Z)-5-((2-(4-((((2-(lH-pyrrol-2-yl)pyridm-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
262 yl)methylene)thiazolidine-2,4-dione C24H25N7O2S 475.566 A7 B18
(Z)-5-((2-(4-((((2-(lH-pyrrol-2-yl)quinolin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
263 yl)methylene)thiazolidine-2,4-dione C28H27N7O2S 525.625 A8 B18
(Z)-5-((2-(4-((((6-(lH-pyrrol-2-yl)pyridm-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
264 yl)methylene)thiazolidine-2,4-dione C24H25N7O2S 475.566 A9 B18
(Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)-2-( 1 H-pyrrol-2-
265 yl)nicotinonitrile C25H24N8O2S 500.575 A10 B18
(Z)-ethyl 5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)-2-( 1 H-pyrrol-2-
266 yl)nicotinate C27H2gN704S 547.629 Al l B18
(Z)-5-((2-(4-((((2-(lH-pyrrol-2-yl)pyridin-4- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
267 yl)methylene)thiazolidine-2,4-dione C24H25N702S 475.566 A12 B18
(Z)-5-((2-(4-((((2-(lH-pyrrol-2-yl)-6- (trifluoromethyl)pyridm-4 - yl)methyl)ammo)metliyl)piperidin- 1 -yl)pyrimidin-4-
268 yl)methylene)thiazolidine-2,4-dione C25H24F3N702S 543.564 A13 B18
(Z)-5-((2-(4-((((5-fluoro-2-(lH-pyrrol-2-yl)pyndin- 4-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
269 4-yl)methylene)thiazolidine-2,4-dione C24H24FN702S 493.556 A14 B18
(Z)-5-((2-(4-((((6-amino-2-(lH-pyrrol-2-yl)pyridin- 3 -yl)metliyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
270 4-yl)methylene)thiazolidine-2,4-dione C24H26N802S 490.581 A15 B18
(Z)-5-((2-(4-((((4-fl oro-6-(isoquinolin-4-yl)pyridin- 2-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
271 4-yl)methylene)thiazolidine-2,4-dione C29H26FN702S 555.626 Al B19
(Z)-5-((2-(4-((((6-(isoquinolin-4-yl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
272 yl)methylene)thiazolidine-2,4-dione C29H2 N702 S 537.635 A2 B19
(Z)-5-((2-(4-((((6-(isoquinolin-4-yl)-4- methylpyridin-2-yl)methyl)ammo)metliyl)piperidin- l-yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-
273 dione C3oH2gN702S 551.662 A3 B19
B4002959vl - 75 - (Z)-5-((2-(4-((((6-(isoquinolin-4-yl)-3- methoxypyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
274 yl)methylene)thiazolidine-2,4-dione C30H29 7O3S 567.661 A4 B19
(Z)-5-((2-(4-((((6-(isoquinolin-4-yl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
275 yl)methylene)thiazolidine-2,4-dione C30H2 F3N7O2S 605.633 A5 B19
(Z)-5-((2-(4-((([3,4'-biisoquinolin]-l- ylmethyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
276 yl)methylene)thiazolidine-2,4-dione C33H29 7O2S 587.694 A6 B19
(Z)-5-((2-(4-((((2-(isoquinolin-4-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
277 yl)methylene)thiazolidine-2,4-dione C29H27N7O2 S 537.635 A7 B19
(Z)-5-((2-(4-((((2-(isoquinolin-4-yl)quinolin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
278 yl)methylene)thiazolidine-2,4-dione C33H29N7O2S 587.694 A8 B19
(Z)-5-((2-(4-((((6-(isoquinolin-4-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
279 yl)methylene)thiazolidine-2,4-dione C29H27N7O2 s 537.635 A9 B19
(Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)-2-(isoquinolin-4-
280 yl)nicotinonitrile C3oH26 802S 562.645 A10 B19
(Z)-ethyl 5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)-2-(isoquinolin-4-
281 yl)nicotinate C32H31N7O4S 609.698 Al l B19
(Z)-5-((2-(4-((((2-(isoquinolin-4-yl)pyridin-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
282 yl)methylene)thiazolidine-2,4-dione C29H27N7O2 S 537.635 A12 B19
(Z)-5-((2-(4-((((2-(isoquinolin-4-yl)-6- (trifluoromethyl)pyridin-4 - yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
283 yl)methylene)thiazolidine-2,4-dione C30H2 F3N7O2S 605.633 A13 B19
(Z)-5-((2-(4-((((5-fluoro-2-(isoquinolin-4-yl)pyridin- 4-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
284 4-yl)methylene)thiazolidine-2,4-dione C29H26F 702S 555.626 A14 B19
(Z)-5-((2-(4-((((6-amino-2-(isoq inolin-4-yl)pyridin- 3 -yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
285 4-yl)methylene)thiazolidine-2,4-dione C29H28N8O2S 552.65 A15 B19
(Z)-5-((2-(4-((((4-fluoro-6-(quinolin-4-yl)pyridm-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
286 yl)methylene)thiazolidine-2,4-dione C29H26F 702S 555.626 Al B20
(Z)-5-((2-(4-((((6-(quinolin-4-yl)pyndin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
287 yl)methylene)thiazolidine-2,4-dione C29H27N7O2 S 537.635 A2 B20
(Z)-5-((2-(4-((((4-methyl-6-(quinolin-4-yl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
288 yl)methylene)thiazolidine-2,4-dione C30H29 7O2S 551.662 A3 B20
(Z)-5-((2-(4-((((3-methoxy-6-(quinolin-4-yl)pyridin- 2-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
289 4-yl)methylene)thiazolidine-2,4-dione C30H29 7O3S 567.661 A4 B20
(Z)-5-((2-(4-((((6-(quinolin-4-yl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
290 yl)methylene)thiazolidine-2,4-dione C30H2 F3N7O2S 605.633 A5 B20
B4002959vl - 76 (Z)-5-((2-(4-((((3-(quinolin-4-yl)isoquinolin-l- yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-4-
291 yl)methylene)thiazolidine-2,4-dione C33H2gN702S 587.694 A6 B20
(Z)-5-((2-(4-((((2-(quinolin-4-yl)pyndin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
292 yl)methylene)thiazolidine-2,4-dione C29H27N7O2 s 537.635 A7 B20
(Z)-5-((2-(4-((([2,4'-biquinolin]-3- ylmethyl)amino)methyl)piperidm- 1 -yl)pyrimidin-4-
293 yl)methylene)thiazolidine-2,4-dione C33H29N702S 587.694 A8 B20
(Z)-5-((2-(4-((((6-(quinolin-4-yl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
294 yl)methylene)thiazolidine-2,4-dione C29H 7N7O2 s 537.635 A9 B20
(Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl) amino)methyl) -2 -(quinolin-4 -
295 yl)nicotinonitrile C30H26N8O2S 562.645 A10 B20
(Z)-ethyl 5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4-
296 yl)methyl)amino)metliyl)-2-(qumolin-4-yl)nicotinate C32H31N704S 609.698 Al l B20
(Z)-5-((2-(4-((((2-(quinolin-4-yl)pyndin-4- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
297 yl)methylene)thiazolidine-2,4-dione C29H27N7O2 S 537.635 A12 B20
(Z)-5-((2-(4-((((2-(quinolin-4-yl)-6- (triiluoromethyl)pyridin-4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
298 yl)methylene)thiazolidine-2,4-dione C3oH26F3N702S 605.633 A13 B20
(Z)-5-((2-(4-((((5-iluoro-2-(quinolin-4-yl)pyridm-4- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
299 yl)methylene)thiazolidine-2,4-dione C29H26F 702S 555.626 A14 B20
(Z)-5-((2-(4-((((6-amino-2-(quinolin-4-yl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
300 yl)methylene)thiazolidine-2,4-dione C29H28N8O2S 552.65 A15 B20
(Z)-5-((2-(4-((((3',4-diiluoro-[2,4'-bipyridin]-6- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
301 yl)methylene)thiazolidine-2,4-dione C2 H23F2N7(¾S 523.558 Al B21
(Z)-5-((2-(4-((((3,-iluoro-[2,4'-bipyridin]-6- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
302 yl)methylene)thiazolidine-2,4-dione C25H24FN702S 505.567 A2 B21
(Z)-5-((2-(4-((((3'-iluoro-4-metliyl-[2,4,-bipyridin]-6- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
303 yl)methylene)thiazolidine-2,4-dione C26H26FN702S 519.594 A3 B21
(Z)-5-((2-(4-((((3,-iluoro-5-methoxy-[2,4'-bipyridin]- 6-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
304 4-yl)methylene)thiazolidine-2,4-dione C26H2(5FN703S 535.593 A4 B21
(Z)-5-((2-(4-((((3'-iluoro-4-(triiluorometliyl)-[2,4'- bipyridin] -6-yl)methyl)amino)methyl)piperidin- 1 -
305 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C26H23F4N702S 573.565 A5 B21
(Z)-5-((2-(4-((((3-(3-iluoropyridin-4-yl)isoquinolin-
306 1 -yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin- 4-yl)methylene)thiazolidine-2,4-dione C29H26FN702S 555.626 A6 B21
(Z)-5-((2-(4-((((3,-iluoro-[2,4'-bipyridin]-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
307 yl)methylene)thiazolidine-2,4-dione C25H24FN702S 505.567 A7 B21
(Z)-5-((2-(4-((((2-(3-iluoropyridin-4-yl)qumolin-3- yl)methyl)ammo)metliyl)piperidin- 1 -yl)pyrimidin-4-
308 yl)methylene)thiazolidine-2,4-dione C29H26F 702S 555.626 A8 B21
(Z)-5-((2-(4-((((3'-iluoro-[2,4'-bipyridin]-5- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
309 yl)methylene)thiazolidine-2,4-dione C25H24F 702S 505.567 A9 B21
B4002959vl - 77 (Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl) amino)methyl) - 3 ' - fluoro- [2 ,4 '-bipyridine] -
310 3-carbonitrile C26H23FN802S 530.577 A10 B21
(Z)-etliyl 5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)methyl) - 3 ' - fluoro- [2 ,4 '-bipyridine] -
311 3-carboxylate C28H28FN704S 577.63 Al l B21
(Z)-5-((2-(4-((((3'-fluoro-[2,4'-bipyridin]-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
312 yl)methylene)thiazolidine-2,4-dione C25H24FN702S 505.567 A12 B21
(Z)-5-((2-(4-((((3,-fluoro-6-(trifluoromethyl)-[2,4'- bipyridin] -4-yl)methyl)amino)methyl)piperidin- 1 -
313 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione C26H23F4N702S 573.565 A13 B21
(Z)-5-((2-(4-((((3',5-difluoro-[2,4'-bipyridin]-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
314 yl)methylene)thiazolidine-2,4-dione C2 H23F2N702S 523.558 A14 B21
(Z)-5-((2-(4-((((6-amino-3'-fluoro-[2,4'-bipyridm]-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
315 yl)methylene)thiazolidine-2,4-dione C25H25FN802S 520.582 A15 B21
(Z)-5-((2-(4-((((2',4,6'-trifluoro-[2,4'-bipyridin]-6- yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-4-
316 yl)methylene)thiazolidine-2,4-dione C25H22F3 7O2S 541.548 Al B22
(Z)-5-((2-(4-((((2',6'-difluoro-[2,4'-bipyridm]-6- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
317 yl)methylene)thiazolidine-2,4-dione C25H23F2N7O2S 523.558 A2 B22
(Z)-5-((2-(4-((((2,,6,-difluoro-4-methyl-[2,4'- bipyridin] -6-yl)methyl)amino)methyl)piperidin- 1 -
318 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione C26H25F2N702S 537.584 A3 B22
(Z)-5-((2-(4-((((2',6'-difluoro-5-methoxy-[2,4'- bipyridin] -6-yl)methyl)amino)methyl)piperidin- 1 -
319 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione C26H25F2N703S 553.584 A4 B22
(Z)-5-((2-(4-((((2,,6,-difluoro-4-(trifluoromethyl)- [2,4 '-bipyridin] - 6 -yl)methyl) amino)methyl)piperidin- l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-
320 dione C26H22F5N702S 591.556 A5 B22
(Z)-5-((2-(4-((((3-(2,6-difluoropyridin-4- yl)isoquinolin- 1 -yl)methyl)amino)methyl)piperidin- l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-
321 dione C29H25F2N7O2S 573.616 A6 B22
(Z)-5-((2-(4-((((2',6'-difluoro-[2,4'-bipyridin]-3- yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-4-
322 yl)methylene)thiazolidine-2,4-dione C25H23F2 7O2S 523.558 A7 B22
(Z)-5-((2-(4-((((2-(2,6-difluoropyridin-4-yl)quinolin- 3 -yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
323 4-yl)methylene)thiazolidine-2,4-dione C29H25F2N7O2S 573.616 A8 B22
(Z)-5-((2-(4-((((2',6'-difluoro-[2,4'-bipyridm]-5- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
324 yl)methylene)thiazolidine-2,4-dione C25H23F2N702S 523.558 A9 B22
(Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)-2',6'-difluoro-[2,4'-
325 bipyridine] -3 -carbonitrile C26H22F2NSO2S 548.567 A10 B22
(Z)-ethyl 5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)-2',6'-difluoro-[2,4'-
326 bipyridine] -3 -carboxylate C28H27F2N7O4S 595.62 Al l B22
B4002959vl - 78 (Z)-5-((2-(4-((((2',6'-difluoro-[2,4'-bipyridin]-4- yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-4-
327 yl)methylene)thiazolidine-2,4-dione C25H23F2 7O2S 523.558 A12 B22
(Z)-5-((2-(4-((((2',6'-difluoro-6-(trifluorometliyl)- [2,4'-bipyridin]-4-yl)methyl)ammo)methyl)piperidin- l-yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-
328 dione C26H22F5Nv02S 591.556 A13 B22
(Z)-5-((2-(4-((((2',5,6'-trifluoro-[2,4'-bipyridin]-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
329 yl)methylene)thiazolidine-2,4-dione C2 H22F3N7O2S 541.548 A14 B22
(Z)-5-((2-(4-((((6-amino-2',6'-difluoro-[2,4'- bipyridin] -3 -yl)methyl)amino)methyl)piperidin- 1 -
330 yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C2 H24F2Ng02S 538.572 A15 B22
(Z)-5-((2-(4-((((6,-(dimethylamino)-4-fluoro-[2,3'- bipyridin] -6-yl)methyl)amino)methyl)piperidin- 1 -
331 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C27H29FNs02S 548.635 Al B23
(Z)-5-((2-(4-((((6'-(dimethylamino)-[2,3,-bipyridin]- 6-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
332 4-yl)methylene)thiazolidine-2,4-dione C27H30 8O2S 530.645 A2 B23
(Z)-5-((2-(4-((((6,-(dimethylamino)-4-methyl-[2,3'- bipyridin] -6-yl)methyl)amino)methyl)piperidin- 1 -
333 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C2gH32N802S 544.671 A3 B23
(Z)-5-((2-(4-((((6'-(dimethylamino)-5-metlioxy-[2,3'- bipyridin] -6-yl)methyl)amino)methyl)piperidin- 1 -
334 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C28H32 803S 560.67 A4 B23
(Z)-5-((2-(4-((((6'-(dimethylamino)-4- (trifluoromethyl) -[2,3' -bipyridin] - 6 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrirnidin-4-
335 yl)methylene)thiazolidine-2,4-dione C28H29F3N802S 598.642 A5 B23
(Z)-5-((2-(4-((((3-(6-(dimethylamino)pyridin-3- yl)isoquinolin- 1 -yl)methyl)amino)methyl)piperidin- l-yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-
336 dione C3iH32N802S 580.703 A6 B23
(Z)-5-((2-(4-((((6,-(dimethylamino)-[2,3,-bipyridin]- 3 -yl)metliyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
337 4-yl)methylene)thiazolidine-2,4-dione C27H3o 802S 530.645 A7 B23
(Z)-5-((2-(4-((((2-(6-(dimethylamino)pyridin-3- yl)quinolin-3 -yl)methyl)amino)methyl)piperidin- 1 -
338 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione C31H32N8O2S 580.703 A8 B23
(Z)-5-((2-(4-((((6,-(dimethylamino)-[2,3,-bipyridin]- 5-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
339 4-yl)methylene)thiazolidme-2,4-dione C27H30N8O2S 530.645 A9 B23
(Z)-6'-(dimetliylamino)-5-((((l-(4-((2,4- dioxothiazolidin-5-ylidene)methyl)pyrimidin-2- yl)piperidin-4-yl)methyl)amino)methyl)-[2,3'-
340 bipyridine] -3 -carbonitrile C2 H29lS[902 S 555.654 A10 B23
(Ζ)-ε 1 6'-(άίηΐ6 1¾ηιίηο)-5-((((1-(4-((2,4- dioxot azolidin-5-ylidene)metliyl)pyrimidin-2- yl)piperidin-4-yl)methyl)amino)methyl)-[2,3'-
341 bipyridine] -3 -carboxylate C3oH34 804S 602.707 Al l B23
(Z)-5-((2-(4-((((6,-(dimethylamino)-[2,3,-bipyridin]- 4-yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-
342 4-yl)methylene)thiazolidine-2,4-dione C27H30 8O2S 530.645 A12 B23
(Z)-5-((2-(4-((((6'-(dimethylamino)-6- (trifluoromethyl) -[2,3' -bipyridin] -4 - yl)methyl)amino)metriyl)piperidin- 1 -yl)pyrimidin-4-
343 yl)methylene)thiazolidine-2,4-dione C28H29F3N8O2S 598.642 A13 B23
B4002959vl - 79 (Z)-5-((2-(4-((((6'-(dimethylamino)-5-fluoro-[2,3'- bipyridin] -4-yl)methyl)amino)methyl)piperidin- 1 -
344 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C27H29F S02S 548.635 A14 B23
(Z)-5-((2-(4-((((6-amino-6,-(dimethylamino)-[2,3'- bipyridin] -3 -yl)methyl)amino)methyl)piperidin- 1 -
345 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione C27H31N9O2 s 545.659 A15 B23
(Z)-5-((2-(4-((((6-(2-(dimethylamino)pyrimidin-5- yl)-4-fluoropyridin-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
346 yl)methylene)thiazolidine-2,4-dione C26H28FN902S 549.623 Al B24
(Z)-5-((2-(4-((((6-(2-(dimethylamino)pyrimidin-5- yl)pyridin-2-yl)methyl)amino)methyl)piperidin- 1 -
347 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione C26H29N9O2 s 531.633 A2 B24
(Z)-5-((2-(4-((((6-(2-(dimethylamino)pyrimidin-5- y 1) - 4 -methy lpyridin- 2 - yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
348 yl)methylene)thiazolidine-2,4-dione C27H31N9O2 s 545.659 A3 B24
(Z)-5-((2-(4-((((6-(2-(dimethylamino)pyrimidin-5- yl)-3 -methoxypyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
349 yl)methylene)thiazolidine-2,4-dione C27H31N9O3 s 561.659 A4 B24
(Z)-5-((2-(4-((((6-(2-(dimethylamino)pynmidin-5- yl) -4 - (trifluoromethyl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
350 yl)methylene)thiazolidine-2,4-dione C27H2SF3N902S 599.631 A5 B24
(Z)-5-((2-(4-((((3-(2-(dimethylamino)pyrimidin-5- yl)isoquinolin- 1 -yl)methyl)amino)methyl)piperidin- l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-
351 dione C30H31N9O2S 581.691 A6 B24
(Z)-5-((2-(4-((((2-(2-(dimethylamino)pyrimidin-5- yl)pyridin-3 -yl)methyl)amino)methyl)piperidin- 1 -
352 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C2 H29N9O2 s 531.633 A7 B24
(Z)-5-((2-(4-((((2-(2-(dimethylamino)pyrimidin-5- yl)quinolin-3 -yl)methyl)amino)methyl)piperidin- 1 -
353 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C30H3 !N902S 581.691 A8 B24
(Z)-5-((2-(4-((((6-(2-(dimethylamino)pyrimidin-5- yl)pyridin-3 -yl)methyl)amino)methyl)piperidin- 1 -
354 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione C26H29N9O2 s 531.633 A9 B24
(Z)-2-(2-(dimethylamino)pyrimidin-5-yl)-5-((((l-(4- ((2 ,4 -dioxothiazolidin- 5 -ylidene)methyl)pyrimidin-2 - yl)piperidin-4-
355 yl)methyl)amino)methyl)nicotinonitrile C27H28N10O2S 556.642 A10 B24
(Z)-ethyl 2 - (2- (dimethyl amino)pyrimidin- 5 -yl) - 5 - ((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4-
356 yl)methyl)amino)metliyl)nicotinate C29H33N9O4 s 603.695 Al l B24
(Z)-5-((2-(4-((((2-(2-(dimethylamino)pyrimidin-5- yl)pyridin-4-yl)metliyl)ammo)methyl)piperidin- 1 -
357 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C26H29N9O2 s 531.633 A12 B24
(Z)-5-((2-(4-((((2-(2-(dimethylamino)pyrimidin-5- yl) - 6 - (trifluoromethyl)pyridin-4- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
358 yl)methylene)thiazolidine-2,4-dione C27H28F3N902S 599.631 A13 B24
(Z)-5-((2-(4-((((2-(2-(dimethylamino)pyrimidin-5- y 1) - 5 - fluoropyridin- 4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
359 yl)methylene)thiazolidine-2,4-dione C26H28FN902S 549.623 A14 B24
B4002959vl - 80 (Z)-5-((2-(4-((((6-amino-2-(2- (dimethylamino)pyrimidin-5-yl)pyridm-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
360 yl)methylene)thiazolidine-2,4-dione C26H30 10O2S 546.647 A15 B24
(Z)-5-((2-(4-((((6-(3,5-dimetliylisoxazol-4-yl)-4- iluoropyridin-2-yl)methyl)amino)metliyl)piperidin- 1 -
361 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C25H26FN703S 523.582 Al B25
(Z)-5-((2-(4-((((6-(3,5-dimetliylisoxazol-4- yl)pyridin-2-yl)methyl)amino)methyl)piperidin- 1 -
362 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C2 H27 7O3S 505.592 A2 B25
(Z)-5-((2-(4-((((6-(3,5-dimethylisoxazol-4-yl)-4- methylpyridin-2-yl)methyl)amino)methyl)piperidin- l-yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-
363 dione C2 H29 7O3S 519.619 A3 B25
(Z)-5-((2-(4-((((6-(3,5-dimethylisoxazol-4-yl)-3- methoxypyridin-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
364 yl)methylene)thiazolidine-2,4-dione C26H29N704S 535.618 A4 B25
(Z)-5-((2-(4-((((6-(3,5-dimethylisoxazol-4-yl)-4- (triiluoromethyl)pyridin-2 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
365 yl)methylene)thiazolidine-2,4-dione C26H26F3N703S 573.59 A5 B25
(Z)-5-((2-(4-((((3-(3,5-dimetliylisoxazol-4- yl)isoquinolin- 1 -yl)methyl)amino)methyl)piperidin- l-yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-
366 dione C2gH2gN703 S 555.651 A6 B25
(Z)-5-((2-(4-((((2-(3,5-dimetliylisoxazol-4- yl)pyridin-3 -yl)methyl)amino)methyl)piperidin- 1 -
367 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C25H27 703S 505.592 A7 B25
(Z)-5-((2-(4-((((2-(3,5-dimethylisoxazol-4- yl)quinolin-3 -yl)methyl)amino)methyl)piperidin- 1 -
368 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C2gH2gN703 S 555.651 A8 B25
(Z)-5-((2-(4-((((6-(3,5-dimethylisoxazol-4- yl)pyridin-3 -yl)methyl)amino)methyl)piperidin- 1 -
369 yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C25H27N703S 505.592 A9 B25
(Z)-2-(3,5-dimethylisoxazol-4-yl)-5-((((l-(4-((2,4- dioxot azolidin-5-ylidene)methyl)pyrimidin-2- yl)piperidin-4-
370 yl)methyl)amino)methyl)nicotinonitrile C26H26 803S 530.601 A10 B25
(Z)-ethyl 2-(3,5-dimethylisoxazol-4-yl)-5-((((l-(4- ((2 ,4 -dioxothiazolidin- 5 -ylidene)methyl)pyrimidin-2 -
371 yl)piperidin-4-yl)methyl)amino)metliyl)nicotinate C28H31N7O5S 577.655 Al l B25
(Z)-5-((2-(4-((((2-(3,5-dimetliylisoxazol-4- yl)pyridin-4-yl)methyl)amino)methyl)piperidin- 1 -
372 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C25H27 703S 505.592 A12 B25
(Z)-5-((2-(4-((((2-(3,5-dimethylisoxazol-4-yl)-6- (triiluoromethyl)pyridin-4 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
373 yl)methylene)thiazolidine-2,4-dione C26H26F3N703S 573.59 A13 B25
(Z)-5-((2-(4-((((2-(3,5-dimethylisoxazol-4-yl)-5- iluoropyridin-4-yl)methyl)amino)metliyl)piperidin- 1 -
374 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C25H26FN703S 523.582 A14 B25
(Z)-5-((2-(4-((((6-amino-2-(3,5-dimethylisoxazol-4- yl)pyridin-3 -yl)methyl)amino)methyl)piperidin- 1 -
375 yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C2 H28N803S 520.607 A15 B25
(Z)-5-((2-(4-((((4-lluoro-6-(lH-pyrazol-4-yl)pyridin- 2-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
376 4-yl)methylene)thiazolidine-2,4-dione C23H23FN802S 494.545 Al B26
B4002959vl - 81 (Z)-5-((2-(4-((((6-(lH-pyrazol-4-yl)pyridin-2- yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-4-
377 yl)methylene)thiazolidine-2,4-dione C23H24NSO2S 476.554 A2 B26
(Z)-5-((2-(4-((((4-methyl-6-(lH-pyrazol-4- yl)pyridin-2-yl)methyl)amino)methyl)piperidin- 1 -
378 yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C24H26N8O2S 490.581 A3 B26
(Z)-5-((2-(4-((((3-methoxy-6-(lH-pyrazol-4- yl)pyridin-2-yl)methyl)amino)methyl)piperidin- 1 -
379 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C24H26N803S 506.58 A4 B26
(Z)-5-((2-(4-((((6-(lH-pyrazol-4-yl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
380 yl)methylene)thiazolidine-2,4-dione C24H23F3N8O2S 544.552 A5 B26
(Z)-5-((2-(4-((((3-(lH-pyrazol-4-yl)isoquinolin-l- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
381 yl)methylene)thiazolidine-2,4-dione C2 H2 N8O2S 526.613 A6 B26
(Z)-5-((2-(4-((((2-(lH-pyrazol-4-yl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
382 yl)methylene)thiazolidine-2,4-dione C23H24N8O2S 476.554 A7 B26
(Z)-5-((2-(4-((((2-(lH-pyrazol-4-yl)quinolin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
383 yl)methylene)thiazolidine-2,4-dione C27H26 802S 526.613 A8 B26
(Z)-5-((2-(4-((((6-(lH-pyrazol-4-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
384 yl)methylene)thiazolidine-2,4-dione C23H24N802S 476.554 A9 B26
(Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)-2-( 1 H-pyrazol-4-
385 yl)nicotinonitrile C24H23N9O2 s 501.564 A10 B26
(Z)-ethyl 5-((((l-(4-((2,4-dioxotMazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)metliyl)amino)methyl)-2-( 1 H-pyrazol-4-
386 yl)nicotinate C26H28N804S 548.617 Al l B26
(Z)-5-((2-(4-((((2-(lH-pyrazol-4-yl)pyridin-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
387 yl)methylene)thiazolidine-2,4-dione C23H24 802S 476.554 A12 B26
(Z)-5-((2-(4-((((2-(lH-pyrazol-4-yl)-6- (trifluoromethyl)pyridin-4 - yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
388 yl)methylene)thiazolidine-2,4-dione C24H23F3N802S 544.552 A13 B26
(Z)-5-((2-(4-((((5-fluoro-2-(lH-pyrazol-4-yl)pyridin- 4-yl)methyl)ammo)methyl)piperidin- 1 -yl)pyrimidin-
389 4-yl)methylene)thiazolidine-2,4-dione C23H23FN802S 494.545 A14 B26
(Z)-5-((2-(4-((((6-amino-2-(lH-pyrazol-4-yl)pyridin- 3 -yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
390 4-yl)methylene)thiazolidine-2,4-dione C23H2 902S 491.569 A15 B26
(Z)-5-((2-(4-((((4-fl oro-6-(lH-pyrazol-5-yl)pyridin- 2-yl)metliyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
391 4-yl)methylene)thiazolidine-2,4-dione C23H23FN802S 494.545 Al B27
(Z)-5-((2-(4-((((6-(lH-pyrazol-5-yl)pyridin-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
392 yl)methylene)thiazolidine-2,4-dione C23H24 8O2S 476.554 A2 B27
(Z)-5-((2-(4-((((4-methyl-6-(lH-pyrazol-5- yl)pyridin-2-yl)methyl)amino)methyl)piperidin- 1 -
393 yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C24H26N8O2S 490.581 A3 B27
(Z)-5-((2-(4-((((3-methoxy-6-(lH-pyrazol-5- yl)pyridin-2-yl)methyl)amino)methyl)piperidin- 1 -
394 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C24H26 8O3S 506.58 A4 B27
B4002959vl - 82 (Z)-5-((2-(4-((((6-(lH-pyrazol-5-yl)-4- (trifluoromethyl)pyridin-2 - yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
395 yl)methylene)thiazolidine-2,4-dione C24H23F3N8O2S 544.552 A5 B27
(Z)-5-((2-(4-((((3-(lH-pyrazol-5-yl)isoquinolin-l- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
396 yl)methylene)thiazolidine-2,4-dione C27H26 802S 526.613 A6 B27
(Z)-5-((2-(4-((((2-(lH-pyrazol-5-yl)pyridin-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
397 yl)methylene)thiazolidine-2,4-dione C23H24 802S 476.554 A7 B27
(Z)-5-((2-(4-((((2-(lH-pyrazol-5-yl)quinolm-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
398 yl)methylene)thiazolidine-2,4-dione C27H26N802S 526.613 A8 B27
(Z)-5-((2-(4-((((6-(lH-pyrazol-5-yl)pyridin-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
399 yl)methylene)thiazolidine-2,4-dione C23H24 802S 476.554 A9 B27
(Z)-5-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)methyl)-2-( 1 H-pyrazol-5-
400 yl)nicotinonitrile C24H23N9O2 S 501.564 A10 B27
(Z)-ethyl -((((l-(4-((2,4-dioxotMazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)metliyl)amino)metliyl)-2-( 1 H-pyrazol-5-
401 yl)nicotinate C26H28N804S 548.617 Al l B27
(Z)-5-((2-(4-((((2-(lH-pyrazol-5-yl)pyridin-4- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
402 yl)methylene)thiazolidine-2,4-dione C23H24 802S 476.554 A12 B27
(Z)-5-((2-(4-((((2-(lH-pyrazol-5-yl)-6- (triiluoromethyl)pyridin-4 - yl)methyl)amino)methyl)piperidm- 1 -yl)pyrimidin-4-
403 yl)methylene)thiazolidine-2,4-dione C24H23F3N802S 544.552 A13 B27
(Z)-5-((2-(4-((((5-fluoro-2-(lH-pyrazol-5-yl)pyridin- 4-yl)metliyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
404 4-yl)methylene)thiazolidine-2,4-dione C23H23FNS02S 494.545 A14 B27
(Z)-5-((2-(4-((((6-amino-2-(lH-pyrazol-5-yl)pyridin- 3 -yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
405 4-yl)methylene)thiazolidine-2,4-dione C23H2 N9O2S 491.569 A15 B27
(Z)-5-((2-(4-((((2',4,-bis(trifluoromethyl)-[ 1 , 1 '- biphenyl] -2-yl)methyl)amino)methyl)piperidin- 1 -
406 yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C29H25F6N502S 621.597 A16 Bl
(Z)-5-((2-(4-((((2',4'-bis(trifluoromethyl)-[ 1 , 1 '- biphenyl]-3-yl)metliyl)amino)methyl)piperidm-l-
407 yl)pyrimidin-4-yl)metliylene)thiazolidine-2,4-dione C29H25F6N502S 621.597 A17 Bl
(Z)-5-((2-(4-((((2',4'-dimethoxy-[l, l'-biplienyl]-2- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
408 yl)methylene)thiazolidine-2,4-dione C29H31N504S 545.653 A16 B2
(Z)-5-((2-(4-((((2,,4,-dimethoxy-[l, l'-biplienyl]-3- yl)methyl)amino)metliyl)piperidin- 1 -yl)pyrimidin-4-
409 yl)methylene)thiazolidine-2,4-dione C29H31N504S 545.653 A17 B2
(Z)-5-((2-(4-((((2'-(trill orometlioxy)-[l,l'- biphenyl] -2-yl)methyl)amino)methyl)piperidin- 1 -
410 yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C28H26F3N503S 569.598 A16 B3
(Z)-5-((2-(4-((((2,-(triί uorometlloxy)-[l,l,- biphenyl]-3-yl)methyl)amino)methyl)piperidm-l-
411 yl)pyrimidin-4-yl)metliylene)tliiazolidine-2,4-dione C28H26F3N503S 569.598 A17 B3
(Z)-2'-((((l-(4-((2,4-dioxotMazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)-5-methyl-[ 1, 1 '-biphenyl]-
412 2-carboxylic acid C29H29N5O4S 543.637 A16 B4
B4002959vl - 83 (Z)-3'-((((l-(4-((2,4-dioxot azolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)metliyl)-5-methyl-[ 1, 1 '-biphenyl]-
413 2-carboxylic acid C29H29N5O4S 543.637 A17 B4
(Z)-5-((2-(4-(((2-(benzo[d][l,3]dioxol-5- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
414 yl)methylene)thiazolidine-2,4-dione C28H27 504S 529.61 A16 B5
(Z)-5-((2-(4-(((3-(benzo[d][l,3]dioxol-5- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
415 yl)methylene)thiazolidine-2,4-dione C28H27 5O4S 529.61 A17 B5
(Z)-N-benzyl-2'-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)methyl) -[1, 1 -biphenyl] - 3 -
416 carboxamide C35H34 603S 618.748 A16 B6
(Z)-N-benzyl-3'-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)methyl) -[1, 1 '-biphenyl] - 3 -
417 carboxamide C35H34 603S 618.748 A17 B6
(Z)-5-((2-(4-((((3'-(dimethylamino)-[l,l'-biphenyl]- 2-yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
418 4-yl)methylene)thiazolidine-2,4-dione C2gH32N602S 528.668 A16 B7
(Z)-5-((2-(4-((((3,-(dimethylammo)-[l,l'-biphenyl]- 3 -yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-
419 4-yl)methylene)thiazolidine-2,4-dione C29H32 602S 528.668 A17 B7
(Z)-N-(2'-((((l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)methyl) -[1, 1 '-biphenyl] - 3 -
420 yl)acetamide C29H30 6O3S 542.652 A16 B8
(Z)-N-(3 '-(((( 1 -(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl) methyl) amino)methyl) -[1, 1 -biphenyl] - 3 -
421 yl)acetamide C29H3o ¾03S 542.652 A17 B8
(Z)-5-((2-(4-((((4'-phenoxy-[l,l'-biphenyl]-2- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
422 yl)methylene)thiazolidine-2,4-dione C33H31N503S 577.696 A16 B9
(Z)-5-((2-(4-((((4,-phenoxy-[l,l'-biphenyl]-3- yl)methyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
423 yl)methylene)thiazolidine-2,4-dione C33H31N503S 577.696 A17 B9
(Z)-5-((2-(4-(((2-( 1 H-indol-5- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
424 yl)methylene)thiazolidine-2,4-dione C29H28N6O2S 524.637 A16 BIO
(Z)-5-((2-(4-(((3-(lH-mdol-5- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
425 yl)methylene)thiazolidine-2,4-dione C29H28N6O2S 524.637 A17 BIO
(Z)-5-((2-(4-(((2-(isoquinolin-5- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
426 yl)methylene)thiazolidine-2,4-dione C3oH2sN602S 536.647 A16 Bl l
(Z)-5-((2-(4-(((3-(isoquinolin-5- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
427 yl)methylene)thiazolidine-2,4-dione C3oH28N602S 536.647 A17 Bl l
(Z)-5-((2-(4-(((2-(thiophen-3- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
428 yl)methylene)thiazolidine-2,4-dione C2 H2 N5O2S2 491.628 A16 B12
(Z)-5-((2-(4-(((3-(thiophen-3- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
429 yl)methylene)thiazolidine-2,4-dione C25H2 502S2 491.628 A17 B12
(Z)-5-((2-(4-(((2-(benzo[b]thiophen-3- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
430 yl)methylene)thiazolidine-2,4-dione C29H27N5O2S2 541.687 A16 B13
B4002959vl - 84 (Z)-5-((2-(4-(((3-(benzo[b]thiophen-3- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
431 yl)methylene)thiazolidine-2,4-dione C29H27N5O2 S2 541.687 A17 B13
(Z)-5-((2-(4-(((2-(5-acetylthioplien-2- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
432 yl)methylene)thiazolidine-2,4-dione C27H27 5O3S2 533.665 A16 B14
(Z)-5-((2-(4-(((3-(5-acetylthiophen-2- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
433 yl)methylene)thiazolidine-2,4-dione C27H27 5O3S2 533.665 A17 B14
(Z)-5-((2-(4-(((2-(furan-2- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
434 yl)methylene)thiazolidine-2,4-dione C25H25 503S 475.563 A16 B15
(Z)-5-((2-(4-(((3-(furan-2- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
435 yl)methylene)thiazolidine-2,4-dione C25H25 503S 475.563 A17 B15
(Z)-5-((2-(4-(((2-(benzofuran-2- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
436 yl)methylene)thiazolidine-2,4-dione C29H2 5O3S 525.621 A16 B16
(Z)-5-((2-(4-(((3-(benzofuran-2- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
437 yl)methylene)thiazolidine-2,4-dione C29H27N5O3S 525.621 A17 B16
(Z)-5-((2-(4-(((2-(furan-3- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
438 yl)methylene)thiazolidine-2,4-dione C25H25 503S 475.563 A16 B17
(Z)-5-((2-(4-(((3-(furan-3- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
439 yl)methylene)thiazolidine-2,4-dione C25H25N503S 475.563 A17 B17
(Z)-5-((2-(4-(((2-(lH-pyrrol-2- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
440 yl)methylene)thiazolidine-2,4-dione C25H26N602S 474.578 A16 B18
(Z)-5-((2-(4-(((3-(lH-Pyrrol-2- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
441 yl)methylene)thiazolidine-2,4-dione C25H26N602S 474.578 A17 B18
(Z)-5-((2-(4-(((2-(isoquinolin-4- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
442 yl)methylene)thiazolidine-2,4-dione C30H2SN6O2S 536.647 A16 B19
(Z)-5-((2-(4-(((3-(isoquinolin-4- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
443 yl)methylene)thiazolidine-2,4-dione C3oH28N6(¾S 536.647 A17 B19
(Z)-5-((2-(4-(((2-(quinolin-4- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
444 yl)methylene)thiazolidine-2,4-dione C3oH28 602S 536.647 A16 B20
(Z)-5-((2-(4-(((3-(quinolin-4- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
445 yl)methylene)thiazolidine-2,4-dione C30H28N6O2S 536.647 A17 B20
(Z)-5-((2-(4-(((2-(3-fluoropyridin-4- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
446 yl)methylene)thiazolidine-2,4-dione C26H25F 602S 504.579 A16 B21
(Z)-5-((2-(4-(((3-(3-fluoropyridin-4- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
447 yl)methylene)thiazolidine-2,4-dione C26H25FN602S 504.579 A17 B21
(Z)-5-((2-(4-(((2-(2,6-difluoropyridin-4- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
448 yl)methylene)thiazolidine-2,4-dione C26H24F2N602S 522.57 A16 B22
(Z)-5-((2-(4-(((3-(2,6-difluoropyridin-4- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
449 yl)methylene)thiazolidine-2,4-dione C26H24F2N602S 522.57 A17 B22
B4002959vl - 85 (Z)-5-((2-(4-(((2-(6-(dimethylamino)pyridin-3- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
450 yl)methylene)thiazolidine-2,4-dione C2SH31N7O2S 529.656 A16 B23
(Z)-5-((2-(4-(((3-(6-(dimethylamino)pyridm-3- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
451 yl)methylene)thiazolidine-2,4-dione C28H31 7O2S 529.656 A17 B23
(Z)-5-((2-(4-(((2-(2-(dimetliylammo)pyrimidm-5- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
452 yl)methylene)thiazolidine-2,4-dione C27H3oN802S 530.645 A16 B24
(Z)-5-((2-(4-(((3-(2-(dimethylamino)pyrimidin-5- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
453 yl)methylene)thiazolidine-2,4-dione C27H30 8O2S 530.645 A17 B24
(Z)-5-((2-(4-(((2-(3,5-dimethylisoxazol-4- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
454 yl)methylene)thiazolidine-2,4-dione C26H28N603S 504.604 A16 B25
(Z)-5-((2-(4-(((3-(3,5-dimethylisoxazol-4- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
455 yl)methylene)thiazolidine-2,4-dione C26H28N603S 504.604 A17 B25
(Z)-5-((2-(4-(((2-( 1 H-pyrazol-4- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
456 yl)methylene)thiazolidine-2,4-dione C24H25N7O2S 475.566 A16 B26
(Z)-5-((2-(4-(((3-(lH-pyrazol-4- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
457 yl)methylene)thiazolidine-2,4-dione C24H25 7O2S 475.566 A17 B26
(Z)-5-((2-(4-(((2-(lH-pyrazol-5- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
458 yl)methylene)thiazolidine-2,4-dione C24H25 702S 475.566 A16 B27
(Z)-5-((2-(4-(((3-(lH-pyrazol-5- yl)benzyl)amino)methyl)piperidin- 1 -yl)pyrimidin-4-
459 yl)methylene)thiazolidine-2,4-dione C24H25N7O2S 475.566 A17 B27
In addition, it may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form. The term "chemically protected form," as used herein, pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions (i.e., they have been modified with a protecting group).
By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1991), and Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=0)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=0)CH3,-OAc).
B4002959vl - 86 - For example, an aldehyde or ketone group may be protected as an acetal or ketal, respectively, in which the carbonyl group (C(=0)) is converted to a diether (C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
For example, an amine group may be protected, for example, as an amide
(-NRC(=0)R) or a urethane (-NRC(=0)OR), for example, as: a methyl amide
(-NHC(=0)CH3); a benzyloxy amide (-NHC(=0)OCH2C6H5NHCbz); as a t-butoxy amide (-NHC(=0)OC(CH3)3, -NHBoc); a 2-biphenyl-2-propoxy amide
(-NHC(=0)OC(CH3)2C6H4C6H5NHBoc), as a 9-fluorenylmethoxy amide (-NHFmoc), as a 6-nitroveratryloxy amide (-NHNvoc), as a 2-trimethylsilylethyloxy amide (-NHTeoc), as a 2,2,2-trichloroethyloxy amide (-NHTroc), as an allyloxy amide (-NHAlloc), as a
2-(phenylsulfonyl)ethyloxy amide (-NHPsec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical.
For example, a carboxylic acid group may be protected as an ester or an amide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide.
For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; or an acetamidomethyl ether (-SCH2NHC(=0)CH3).
PHARMACEUTICAL COMPOSITIONS
One or more compounds of this invention can be administered to a mammal by themselves or in pharmaceutical compositions where they are mixed with suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. For example, one aspect of the invention relates to pharmaceutical composition comprising a therapeutically effective dose of a compound of formula I, or a pharmaceutically acceptable salt, solvate, enantiomer or stereoisomer thereof; and a pharmaceutically acceptable diluent or carrier.
Techniques for formulation and administration of the compounds of the instant application may be found in references well known to one of ordinary skill in the art, such as "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition.
B4002959vl - 87 - Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
Alternatively, one may administer a compound in a local rather than a systemic manner, for example, via injection of the compound directly into an edematous site, often in a depot or sustained release formulation.
Furthermore, one may administer a compound in a targeted drug delivery system, for example, in a liposome coated with endothelial-cell-specific antibody.
The pharmaceutical compositions of the present invention may be manufactured, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants are used in the formulation appropriate to the barrier to be permeated. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth,
B4002959vl - 88 - methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical preparations which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or
B4002959vl - 89 - aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, e.g., sterile pyrogen-free water.
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (for example, as a sparingly soluble salt).
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethysulfoxide also may be employed. Additionally, the compounds may be delivered using a sustained-release system, such as semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
B4002959vl - 90 - The pharmaceutical compositions may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers, such as polyethylene glycols or cyclodextrins.
METHODS OF TREATMENT
Provided herein are methods of modulating the activity of CKl and subtypes thereof, CK2, the Wnt pathway, and/or the TGF pathway. Also provided herein are methods of treating or preventing conditions and diseases the course of which can be influenced by modulating the activity of CKl (e.g., CKly), CK2, the Wnt pathway, and/or the TGFp pathway. Such methods typically comprise administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.
Also provided herein are methods of modulating the activity of PIM, such as PIM 1, PIM 2 or PIM 3, the JAK/STAT pathway, and/or the mTOR pathway, and/or Pgp. Also provided herein are methods of treating or preventing conditions and diseases, the course of which can be influenced by modulating the activity of the PIMs, the JAK/STAT pathway, and/or the mTOR pathway, and/or Pgp. Such methods typically comprise administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.
Various diseases, such as cancers, inflammation, and inflammatory diseases (e.g., osteoarthritis and rheumatoid arthritis), and neurological conditions (e.g., Alzheimer's disease) and neurodegeneration can be treated by administration of modulators of CKl (e.g., CKly), CK2, the Wnt pathway and/or the TGFp pathway. Bone-related diseases and conditions, including osteoporosis and bone formation, also can be treated by
administration of modulators of CKl (e.g., CKly), CK2, the Wnt pathway and/or the TGFp pathway. Bone restoration can be facilitated by administration of modulators of CKl (e.g., CKly), CK2, the Wnt pathway and/or the TGF pathway. Additional conditions that can be treated by administration of modulators of CKl (e.g., CKly), CK2, the Wnt pathway and/or the TGFp pathway include hypoglycemia, metabolic syndrome and diabetes.
Modulators of CKl (e.g., CKly), CK2, the Wnt pathway and/or the TGF pathway are also useful for influencing apoptosis (e.g., increasing the rate of apoptosis in cancerous cells). Modulators of CKl (e.g., CKly), CK2, the Wnt pathway and/or the TGF pathway are also useful in treatment or prevention of aberrant embryonic development.
B4002959vl - 91 - Based at least on the fact that increased CKly has been found to be associated with certain cancers, a method for treating cancer in a subject comprises administering to the subject in need thereof a therapeutically effective amount of a compound that inhibits CKly. Pim-1, Pim-2, Pim-3, the JAK/STAT pathway, and/or the mTOR pathway have also been found to be associated with certain cancers. Therefore, provided herein is a method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound that inhibits Pim-1 and/or Pim-2 and/or Pim-3.
Pim-1, Pim-2, and Pim-3 have also been associated with protecting Pgp from degradation, which can regulate drug efflux and drug resistance. Therefore, provided herein is a method for treating malignancies comprising administering to a subject in need thereof a therapeutically effective amount of a compound that inhibits Pirn- 1 and/or Pim-2 and/or Pim-3 in conjunction with another drug, compound or material to abrogate resistance to the drug, compound or material.
The compounds described herein can be used for modulating cell proliferation, generally. Accordingly, diseases that may be treated include hyperproliferative diseases, such as benign cell growth and malignant cell growth.
Exemplary cancers that may be treated include leukemias, e.g., acute lymphoid leukemia and myeloid leukemia, and carcinomas, such as colorectal carcinoma and hepatocarcinoma. Other cancers include Acute Lymphoblastic Leukemia; Acute
Lymphoblastic Leukemia; Acute Myeloid Leukemia; Acute Myeloid Leukemia;
Adrenocortical Carcinoma Adrenocortical Carcinoma; AIDS-Related Cancers; AIDS- Related Lymphoma; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Basal Cell Carcinoma, see Skin Cancer (non-Melanoma); Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer; Bone Cancer,
osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma; Brain Tumor; Brain Tumor, Brain Stem Glioma; Brain Tumor, Cerebellar Astrocytoma; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma; Brain Tumor, Ependymoma; Brain Tumor,
Medulloblastoma; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors; Brain Tumor, Visual Pathway and Hypothalamic Glioma; Brain Tumor; Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer; Breast Cancer, Male; Bronchial
Adenomas/Carcinoids; Burkitt's Lymphoma; Carcinoid Tumor; Carcinoid Tumor,
Gastrointestinal; Carcinoma of Unknown Primary; Central Nervous System Lymphoma,
B4002959vl - 92 - Primary; Cerebellar Astrocytoma; Cerebral Astrocytoma/Malignant Glioma; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Colon Cancer; Colorectal Cancer;
Cutaneous T-Cell Lymphoma, see Mycosis Fungoides and Sezary Syndrome; Endometrial Cancer; Ependymoma; Esophageal Cancer; Esophageal Cancer; Ewing's Family of Tumors; Extracranial Germ Cell Tumor; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma; Glioma, Childhood Brain Stem; Glioma, Childhood Cerebral Astrocytoma; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hematologic (Blood) Cancer, Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma; Hodgkin's Lymphoma; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma;
Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney (Renal Cell) Cancer; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer;
Leukemia, Acute Lymphoblastic; Leukemia, Acute Lymphoblastic; Leukemia, Acute Myeloid; Leukemia, Acute Myeloid; Leukemia, Chronic Lymphocytic; Leukemia; Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoma, AIDS-Related; Lymphoma, Burkitt's; Lymphoma, Cutaneous T-Cell, see Mycosis Fungoides and Sezary Syndrome; Lymphoma, Hodgkin's; Lymphoma, Hodgkin's; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non- Hodgkin's; Lymphoma, Non-Hodgkin's; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's;
Malignant Fibrous Histiocytoma of Bone/Osteosarcoma; Medulloblastoma; Melanoma; Melanoma, Intraocular (Eye); Merkel Cell Carcinoma; Mesothelioma, Adult Malignant; Mesothelioma; Metastatic Squamous Neck Cancer with Occult Primary; Multiple
Endocrine Neoplasia Syndrome; Multiple Myeloma/Plasma Cell Neoplasm' Mycosis Fungoides; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Adult Acute; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity
B4002959vl - 93 - and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer;
Neuroblastoma; Non-Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer; Oral Cavity Cancer, Lip and; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors; Pituitary Tumor; Plasma Cell
Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell (Kidney) Cancer; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma; Salivary Gland Cancer; Salivary Gland Cancer; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma, Soft Tissue; Sarcoma, Soft Tissue; Sarcoma, Uterine; Sezary Syndrome; Skin Cancer (non-Melanoma); Skin
Cancer; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma; Soft Tissue Sarcoma; Squamous Cell Carcinoma, see Skin Cancer (non-Melanoma); Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer; Supratentorial Primitive Neuroectodermal Tumors; T-Cell Lymphoma, Cutaneous, see Mycosis Fungoides and Sezary Syndrome; Testicular Cancer; Thymoma; Thymoma and Thymic Carcinoma; Thyroid Cancer; Thyroid Cancer; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Carcinoma of; Unknown Primary Site, Cancer of; Unusual Cancers of Childhood; Ureter and Renal Pelvis,
Transitional Cell Cancer; Urethral Cancer; Uterine Cancer, Endometrial; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma; Vulvar Cancer; Waldenstrom's Macroglobulinemia; Wilms' Tumor; and Women's Cancers.
Neurologic diseases that may be treated include epilepsy, schizophrenia, bipolar disorder or other psychological and/or psychiatric disorders, neuropathies, skeletal muscle atrophy, and neurodegenerative diseases, e.g., a neurodegenerative disease. Exemplary neurodegenerative diseases include: Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), and Parkinson's disease. Another class of neurodegenerative diseases includes diseases caused at least in part by aggregation of poly-glutamine. Diseases of this class
B4002959vl - 94 - include: Huntington's Diseases, Spinalbulbar Muscular Atrophy (SBMA or Kennedy's Disease), Dentatorubropallidoluysian Atrophy (DRPLA), Spinocerebellar Ataxia 1 (SCAl), Spinocerebellar Ataxia 2 (SCA2), Machado- Joseph Disease (MJD; SCA3), Spinocerebellar Ataxia 6 (SCA6), Spinocerebellar Ataxia 7 (SCA7), and Spinocerebellar Ataxia 12
(SCA12).
Any other disease in which the Wnt pathway, TGFp pathway, JAK/STAT pathway, the mTOR pathway, Pgp modulation, CK1, CKly, CK2, or PIMs plays a role may be treatable or preventable using compounds and methods described herein.
DOSAGE
As used herein, a "therapeutically effective amount" or "therapeutically effective dose" is an amount of a compound of the invention or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition. A therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount may be determined by methods known to those of skill in the art.
A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED50 (effective dose for 50% maximal response). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED50. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. In the treatment of crises, the administration of an acute bolus or an infusion approaching the MTD may be required to obtain a rapid response.
B4002959vl - 95 - Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the CK1, CKly, CK2, Piml-3, Wnt pathway, TGFp pathway, JAK/STAT pathway, mTOR pathway, or Pgp modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations.
Dosage intervals can also be determined using the MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
KITS
The compounds and compositions of the invention (e.g., compounds and compositions of formula I and formula II) may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labelled for treatment of an indicated condition. Instructions for use may also be provided.
B4002959vl - 96 - EXEMPLIFICATION
The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. The geometric isomers depicted below are believed to be correct, but final structural assignment will be made via 2-D NMR experiments. Although the exemplary compounds described below are believed to be the Z-geometric isomers, the E-geometric isomers and mixtures of the E-and Z-isomers are also contemplated by the present disclosure.
EXAMPLE 1
Figure imgf000098_0001
1
(E)-4-(dimethylamino)-l,l-dimethoxybut-3-en-2-one l,l-dimethoxy-N,N- dimethylmethanamine (100 g, 839 mmol, 1.02 equiv.) and l,l-dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at 110°C for 3 hours. The produced methanol was removed by a Dean-Stark apparatus. After the solution was cooled to room temperature, the remaining volatile materials were removed in vacuo to provide 130 g of the crude product, (E)-4-(dimethylamino)-l,l-dimethoxybut-3-en-2-one (1) (130 g, 143 g theoretical, 91%). LC-MS m/z 283 (M+1). Reference: WO 2006/0097341A1 (incorporated by reference), pg 67. EXAMPLE 2
Figure imgf000098_0002
Sodium 4-(dimethoxymethy])pyrimidine-2-thiolate (2): A solution of thiourea (64.7 g,
B4002959vl - 97 - 850 mmol, 1.13 equiv.), sodium methanolate (95%, 40.5 g, 751 mmol, 1.0 equiv.) in methanol (500 mL, 1.5 M) was stirred at room temperature for 30 minutes. A solution of (E)-4-(dimethylamino)-l,l-dimethoxybut-3-en-2-one (1) (130 g, 751 mmol) in methanol (200 mL) was added and the reaction stirred at room temperature for 2 h. The crude sodium 4-(dimethoxyniethyl)pyrimidine-2-thiolate (2) was used directly in the next step without further purification. LC-MS m/z 209 (M+l). Reference: WO 2006/0097341A1 (incorporated by reference), pg 67.
EXAMPLE 3
Figure imgf000099_0001
2 3 4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3): Iodomethane (128 g, 902 mmol, 1.20 equiv.) was added carefully to the crude solution of sodium 4-
(dimethoxymethyl)pyrimidine-2-thiolate (2) (156 g, 751 mmol) in methanol (700 mL, 1.1 M) while maintaining the reaction temperature below 28°C using an ice-water bath for cooling. The resulting mixture was stirred at room temperature for 16 h. After removal of the solvent under reduced pressure, the residue was diluted with water (300 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layer was concentrated under reduced pressure and the crude residue purified by passing through a short silica gel pad and washing with diethyl ether (200 mL) to afford 4-(dimethoxymethyl)-2- (methylthio)pyrimidine (3) as a brown oil (53.7 g, 150 g theoretical, 35.7%). LC-MS m/z 201 (M+l). Reference: WO 2006/0097341A1 (incorporated by reference), pg 67.
EXAMPLE 4
Figure imgf000099_0002
3 4
2-(methylthio)pyrimidine-4-carbaldehyde (4) : 4-(dimethoxymethyl)-2-
B4002959vl - 98 - (methylthio)pyrimidine (3) (53.7 g, 268 mmol) was added carefully to 1.2 N aqueous HCl (300 mL, 268 mmol, 1.0 equiv.) and stirred at 60°C for 3hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodium bicarbonate. The crude mixture was extracted with diethyl ether (3 x 150 mL) and the combined organic layer was concentrated under reduced pressure to afford 2-
(methylthio)pyrimidine-4-carbaldehyde (4) as a yellow solid (14.2 g, 41.5 g theoretical, 34%). LC-MS m/z 155 (M+l). Reference: WO 2006/009734 Al (incorporated by reference), pg 67.
EXAMPLE 5
Figure imgf000100_0001
(Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5): A 40 mL round-bottomed vial was charged with 2-(methylthio)pyrimidine-4-carbaldehyde (4)
(771 mg, 5 mmol), thiazolidine-2,4-dione (586 mg, 5 mmol, 1.0 equiv.), and piperidine (400 μί, 4 mmol, 0.8 equiv.) in ethanol (20 mL, 0.25 M). The reaction mixture was heated to 80°C and shaken for 20 h. The resulting yellow precipitate was isolated by filtration and washed with ethanol (1 x 20 mL) and dried in vacuo to afford (Z)-5-((2- (methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5) as a yellow solid (550 mg, 898 mg theoretical, 61%). LC-MS m/z 254 (M+l).
EXAMPLE 6
Figure imgf000100_0002
(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (6) : A mixture of (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5)
(3.5 g, 13.82 mmol) in THF (100 mL, 0.13 M) was treated with a solution of oxone (25.8 g,
B4002959vl - 99 - 41.5 mmol, 3.0 equiv.) in water (175 mL). The resulting mixture was stirred at room temperature for 48 h. The resulting precipitate was filtered and washed with water (20 mL) and diethyl ether (20 mL) to afford (Z)-5-((2-(methylsulfonyi)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione (6) as a solid (2.48 g, 3.94 g theoretical, 63%). LC- MS m/z 286 (M+l).
EXAMPLE 7
Figure imgf000101_0001
General Displacement Procedure: 2-dram round-bottomed vials were charged with (Z)- 5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (25 mg, 0.0877 mmol) prepared according to the general procedure, DMSO (1 mL, 0.08 M),
diisopropylethylamine (50 μί, 0.288 mmol, 3.2 equiv.), and the appropriate amine (0.0877 mmol, 1.0 equiv.). The reaction mixture was heated to 110°C and shaken for 24 h. The solvent was removed under reduced pressure (Genvac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an
acetonitrile/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4).
E
Figure imgf000101_0002
Displacenient/De-protection of mono-Boc Diamines
General De-Protection Procedure: The crude protected amine was prepared using the General Displacement Procedure and was then treated with 2 mL DCE and 500 of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4).
B4002959vl - 100 -
Figure imgf000102_0001
Reductive Amination Analogs
General Reductive Amination Procedure: A 2-dram round-bottomed vial was charged with the crude amine/TFA salt prepared using the general displacement procedure followed by the general TFA de-protection procedure (0.115 mmol), DCE (2 mL), DIPEA (6 eq. 0.690 mmol), DMF (1 mL), the aldehyde or ketone (1 equiv., 0.115 mmol), and the reaction mixture was shaken for 1 h at RT. The reaction mixture was then treated with
NaBH(OAc)3 (2.5 equiv., 0.230 mmol) and the reaction was shaken 16 h at RT. The reaction mixture was then diluted with DCE (2 mL) and NaHCC (2 mL). The aqueous layer was back extracted with DCE (2 x 2 mL) and the combined organic layer was concentrated under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to afford the pure products as the TFA salt.
EXAMPLE 10
Figure imgf000102_0002
(Z)-5-((2-(4-((((5-phenylpyridin-2-y])methyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 5-phenylpicolinaldehyde (33.7 mg, 40.4 mg theoretical, 83%). LC-MS m/z 487.6 (M+l).
EXAMPLE 11
B4002959vl - 101 -
Figure imgf000103_0001
(Z)-5-((2-(4-((((8-(trifluoromethyl)quino]in-2-y])methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-y])methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 8-(trifluoromethyl)-2-naphthaldehyde (8.5 mg, 43.9 mg theoretical, 19.3%). LC-MS m/z 529.5 (M+l).
EXAMPLE 12
Figure imgf000103_0002
(Z)-5-((2-(4-((((6-(4-methoxyphenyl)pyridin-2-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 5-phenylpicolinaldehyde (32 mg, 42.9 mg theoretical, 74.6%). LC-MS m/z 517.6 (M+l).
EXAMPLE 13
Figure imgf000103_0003
(Z)-5-((2-(4-((((5-(furan-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 5-(furan-2-yl)picolinaldehyde (24 mg, 39.6 mg theoretical, 60.7%). LC-MS m/z 477.6 (M+l).
B4002959vl - 102 - EXAMPLE 14
Figure imgf000104_0001
(Z)-5-((2-(4-((((5-methylpyridin-2-yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin- 4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 5-methylpicolinaldehyde (25.3 mg, 35.2 mg theoretical, 71.8%). LC-MS m/z 425.5 (M+l).
Figure imgf000104_0002
(Z)-5-((2-(4-(((quinolin-2-ylmethyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)imidazolidine-2,4-dione was prepared using the general reductive amination procedure and quinoline-2-carbaldehyde (3.2 mg, 24.9 mg theoretical, 12.8%). LC-MS m/z 444.5 (M+l).
EXAMPLE 16
Figure imgf000104_0003
(Z)-5-((2-(((l-((6-(thiophen-3-yl)pyridin-2-yl)methy])piperidin-4- yl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-(thiophen-3-yl)picolinaldehyde (38.8 mg 46.8 mg theoretical, 83%). LC-MS m z 493.6 (M+l).
EXAMPLE 17
B4002959vl - 103 -
Figure imgf000105_0001
(Z)-5-((2-(((l-((6-methylpyridin-2-yl)methyl)piperidin-4-yl)methyl)amino)pyrimidin- 4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-methylpicolinaldehyde (40.3 mg, 40.3 mg theoretical, 100%). LC-MS m/z 425.5 (M+l).
EXAMPLE 18
Figure imgf000105_0002
(Z)-5-((2-(((l-((6-fluoropyridin-2-yl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-fluoropicolinaldehyde (16.2 mg, 40.7 mg theoretical, 39.8%). LC-MS m/z 429.5 (M+l).
EXAMPLE 19
Figure imgf000105_0003
(Z)-5-((2-(((l-(pyridin-3-ylmethyl)piperidin-4-yl)methy])amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and nicotinaldehyde (38.6 mg, 39.0 mg theoretical, 99%). LC-MS m/z 411.5 (M+l).
EXAMPLE 20
B4002959vl - 104 -
Figure imgf000106_0001
(Z)-5-((2-(4-((((2-(lH-pyrazol-5-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and tert-butyl 5 -(3 -formylpyridin-2-yl)- 1 H-pyrazole- 1 - carboxylate followed by the general de-protection procedure (6.8 mg, 34.3 mg theoretical, 19.8%). LC-MS m/z 477.6 (M+l).
EXAMPLE 21
Figure imgf000106_0002
(Z)-5-((2-(4-((((2-(furan-3-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(furan-3-yl)nicotinaldehyde (40.5 mg, 42.5 mg theoretical, 95%). LC-MS m/z 477.6 (M+l).
EXAMPLE 22
Figure imgf000106_0003
(Z)-5-((2-(4-((((2-(thiophen-3-yl)pyridin-4-yl)methy])amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(thiophen-3-yl)isonicotinaldehyde (20.8 mg, 35.5 mg theoretical, 58.6%). LC-MS m/z 493.6 (M+l). EXAMPLE 23
B4002959vl - 105 -
Figure imgf000107_0001
(Z)-5-((2-(4-((((2-(furan-3-yl)pyridin-4-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(furan-3-yl)isonicotinaldehyde (22.2 mg, 34.3 mg theoretical, 64.7%). LC-MS m/z 477.6 (M+l).
EXAMPLE 24
Figure imgf000107_0002
(Z)-5-((2-(4-((((2,3-dihydrobenzofuran-5-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-y])methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2,3-dihydrobenzofuran-5-carbaldehyde (2.0 mg, 32.5 mg theoretical, 6.1%). LC-MS m/z 452.5 (M+l).
EXAMPLE 25
Figure imgf000107_0003
(Z)-5-((2-(4-(((4-fluorobenzyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 4-fluorobenzaldehyde (8.7 mg, 30.8 mg theoretical, 28.3%). LC-MS m/z 428.5 (M+l).
EXAMPLE 26
B4002959vl - 106 -
Figure imgf000108_0001
(Z)-5-((2-(4-(((3-chlorobenzyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive animation procedure and 3-chlorobenzaldehyde (13.8 mg, 32.0 mg theoretical, 43.2%). LC-MS m/z 444.9 (M+l).
EXAMPLE 27
Figure imgf000108_0002
(Z)-5-((2-(4-((((2-(furan-2-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(furan-2-yl)nicotinaldehyde (14.0 mg, 34.3 mg theoretical, 40.8%). LC-MS m/z 477.6 (M+l).
EXAMPLE 28
Figure imgf000108_0003
(Z)-5-((2-(4-(((3-(thiophen-2-yl)benzyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 3-(thiophen-2-yl)benzaldehyde (34.0 mg, 46.2 mg theoretical, 73.6%). LC- MS m/z 492.6 (M+l).
EXAMPLE 29
B4002959vl - 107 -
Figure imgf000109_0001
(Z)-5-((2-(4-((((2-(5-(trifluoromethyl)thiophen-2-yl)pyridin-3- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)rnethylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and 2-(5-
(trifluoromethyl)thiophen-2-yl)nicotinaldehyde (19.9 mg, 26.9 mg theoretical, 74%). LC- MS m/z 561.6 (M+l).
EXAMPLE 30
Figure imgf000109_0002
(Z)-5-((2-(4-((((2-(furan-2-yl)pyridin-4-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(furan-2-yl)isonicotinaldehyde (16.0 mg, 34.3 mg theoretical, 46.6%). LC-MS m/z 477.6 (M+l).
EXAMPLE 31
Figure imgf000109_0003
(Z)-5-((2-(4-((methyl((6-(thiophen-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-y])methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-(thiophen-2-yl)picolinaldehyde (14.0 mg, 34.4 mg theoretical, 46.1%). LC-MS m/z 507.6 (M+l).
EXAMPLE 32
B4002959vl - 108 -
Figure imgf000110_0001
(Z)-5-((2-(4-((((6-fluoronaphthalen-2-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-y])methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-fluoro-2-naphthaldehyde (18.7 mg, 22.9 mg theoretical, 82%). LC-MS m/z 478.6 (M+l).
EXAMPLE 33
Figure imgf000110_0002
(Z)-5-((2-(4-((((3-fluoro-6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)piperidin l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 3-fluoro-6-(thiophen-3-yl)picolinaldehyde (13.3 mg, 24.5 mg theoretical, 54.3%). LC-MS m/z 511.6 (M+l).
EXAMPLE 34
Figure imgf000110_0003
(Z)-5-((2-(4-((((2-(thiophen-3-yl)pyridin-3-yl)methy])amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(thiophen-3-yl)nicotinaldehyde (21.0 mg, 26.6 mg theoretical, 79%). LC-MS m/z 555.5 (M+l). EXAMPLE 35
B4002959vl - 109 -
Figure imgf000111_0001
(Z)-5-((2-(4-((((2-(2-(trifluoromethyl)phenyl)pyridin-3- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and 2-(2- (trifluoromethyl)phenyl)nicotinaldehyde (24.5 mg, 26.6 mg theoretical, 92%). LC-MS m/z 555.5 (M+l).
EXAMPLE 36
Figure imgf000111_0002
(Z)-5-((2-(4-((((2-(3-(trifluoromethyl)phenyl)pyridin-3- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and 2-(3- (trifluoromethyl)phenyl)nicotinaldehyde (25.1 mg, 26.6 mg theoretical, 94%). LC-MS m/z 555.5 (M+l).
EXAMPLE 37
Figure imgf000111_0003
(Z)-5-((2-(4-((((2-(4-(trifluoromethyl)phenyl)pyridin-3- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and 2-(4-
B4002959vl - 110 - (trifluoromethyl)phenyl)nicotinaldehyde (9.1 mg, 26.6 mg theoretical, 34.2%). LC-MS m/z 555.5 (M+l).
EXAMPLE 38
Figure imgf000112_0001
(Z)-5-((2-(4-((((2-(benzofuran-2-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-y])methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(benzofuran-2-yl)nicotinaldehyde (8.9 mg, 25.3 mg theoretical, 35.2%). LC-MS m/z 527.6 (M+l).
EXAMPLE 39
Figure imgf000112_0002
(Z)-5-((2-(4-((((6-(furan-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-(furan-2-yl)picolinaldehyde (13.9 mg, 22.8 mg theoretical, 60.8%). LC-MS m/z 477.5 (M+l).
EXAMPLE 40
Figure imgf000112_0003
B4002959vl - I l l - (Z)-5-((2-(4-((((6-(2-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)rnethylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and 6-(2- (trifluoromethyl)phenyl)picolinaldehyde (14 mg, 26.6 mg theoretical, 52.6%). LC-MS m z 555.5 (M+l).
EXAMPLE 41
Figure imgf000113_0001
(Z)-5-((2-(4-((((6-(3-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and 6-(3- (trifluoromethyl)phenyl)picolinaldehyde (21.0 mg, 26.6 mg theoretical, 79%). LC-MS m/z 555.5 (M+l).
EXAMPLE 42
Figure imgf000113_0002
(Z)-5-((2-(4-((((6-(4-(trifluoromethyl)phenyl)pyridin-2- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and 6-(4- (trifluoromethyl)phenyl)picolinaldehyde (13.8 mg, 26.6 mg theoretical, 51.8%). LC-MS m/z 555.5 (M+l).
EXAMPLE 43
B4002959vl - 112 -
Figure imgf000114_0001
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-(benzofuran-2-yl)picolinaldehyde (13.3 mg, 25.3 mg theoretical, 52.6%). LC-MS m/z 527.6 (M+l).
EXAMPLE 44
Figure imgf000114_0002
(Z)-5-((2-(4-(((2-(furan-2-yl)benzyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(furan-2-yl)benzaldehyde (10.2 mg, 22.8 mg theoretical, 44.7%). LC-MS m/z 476.5 (M+l).
EXAMPLE 45
Figure imgf000114_0003
(Z)-5-((2-(4-((((6-(furan-2-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-(furan-2-yl)nicotinaldehyde (18.0 mg, 22.8 mg theoretical, 79%). LC-MS m/z 477.5 (M+l). EXAMPLE 46
B4002959vl - 113 -
Figure imgf000115_0001
(Z)-5-((2-(4-((((3-(thiophen-2-yl)pyridin-2-yl)methy])amino)methyl)piperidin-l- yl)pyrimidin-4-y])methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 3-(thiophen-2-yl)picolinaldehyde (10.9 mg, 23.6 mg theoretical, 46%). LC-MS m/z 493 (M+l).
EXAMPLE 47
Figure imgf000115_0002
(Z)-5-((2-(4-((((2-(5-(trifluoromethyl)thiophen-2-yl)pyridin-4- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and 2-(5- (trifluoromethyl)thiophen-2-yl)isonicotinaldehyde (3.0 mg, 26.9 mg theoretical, 11%). LC- MS m/z 561 (M+l).
EXAMPLE 48
Figure imgf000115_0003
(Z)-5-((2-(4-((((2-(methylthio)pyrimidin-4-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(methylthio)pyrimidine-4-carbaldehyde (12.6 mg, 62.6 mg theoretical, 20.1%). LC-MS m/z 458 (M+l).
B4002959vl - 114 - EXAMPLE 49
Figure imgf000116_0001
(Z)-5-((2-(4-((((2-(3-(trifluoromethoxy)phenyl)pyridin-3- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and 2-(3- (trifluoromethoxy)phenyl)nicotinaldehyde (11.6 mg, 27.4 mg theoretical, 42%). LC-MS m z 571 (M+l).
EXAMPLE 50
Figure imgf000116_0002
(Z)-5-((2-(4-((((2-(trifluoromethyl)quino]in-4-y])methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(trifluoromethyl)quinoline-4-carbaldehyde (5.3 mg, 25.4 mg theoretical, 21%). LC-MS m/z 529 (M+l).
EXAMPLE 1
Figure imgf000116_0003
(Z)-5-((2-(4-((((5-(thiophen-3-yl)furan-2-yl)methy])amino)methyl)piperidin-l- yl)pyrimidin-4-y])methylene)thiazolidine-2,4-dione was prepared using the general
B4002959vl - 115 - reductive animation procedure and 5-(thiophen-3-yl)furan-2-carbaldehyde (12.0 mg, 23.1 mg theoretical, 52%). LC-MS m/z 482 (M+l).
EXAMPLE 52
Figure imgf000117_0001
(Z)-5-((2-(4-((([3,3'-bithiophen]-5-ylmethyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive animation procedure and 3,3'-bithiophene]-5-carbaldehyde (3.5 mg, 23.8 mg theoretical, 14%). LC- MS m/z 498 (M+l).
EXAMPLE 53
Figure imgf000117_0002
(Z)-5-((2-(4-(((4-fluoro-2-(furan-2-yl)benzy])amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 4-fluoro-2-(furan-2-yl)benzaldehyde (9.6 mg, 23.6 mg theoretical, 40%). LC-MS m z 494 (M+l). EXAMPLE 54
Figure imgf000117_0003
(Z)-5-((2-(4-(((2,4-difluorobenzyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2,4-difluorobenzaldehyde (4.2 mg, 21.3 mg theoretical, 20%). LC-MS m/z 446 (M+l).
B4002959vl - 116 - EXAMPLE 55
Figure imgf000118_0001
(Z)-5-((2-(4-((((5-(3,5-bis(trifluoromethyl)phenyl)furan-2- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and 5-(3,5- bis(trifluoromethyl)phenyl)furan-2-carbaldehyde (10.9 mg, 29.4 mg theoretical, 37%). MS m/z 612 (M+l).
EXAMPLE 56
Figure imgf000118_0002
(Z)-5-((2-(4-((([2,2,-bifuran]-5-ylmethyl)amino)methyl)piperidin-l-y])pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2,2'-bifuran-5-carbaldehyde (6.0 mg, 22.3 mg theoretical, 27%). LC-MS m/z 466 (M+l).
EXAMPLE 57
Figure imgf000118_0003
(Z)-5-((2-(4-((((4-(furan-2-yl)thiophen-2-yl)methy])amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 4-(furan-2-yl)thiophene-2-carbaldehyde (3.0 mg, 23.1 mg theoretical, 13%). LC-MS m/z 482 (M+l).
B4002959vl - 117 - EXAMPLE 58
Figure imgf000119_0001
(Z)-5-((2-(4-(((furan-3-ylmethyl)amino)methy])piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive animation procedure and furan-3-carbaldehyde (2.0 mg, 19.1 mg theoretical, 10%). LC-MS m/z 400 (M+l).
EXAMPLE 59
Figure imgf000119_0002
(Z)-5-((2-(4-(((furan-2-ylmethyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive animation procedure and furan-2-carbaldehyde (7.4 mg, 19.1 mg theoretical, 38%). LC-MS m/z 400 (M+l).
EXAMPLE 60
Figure imgf000119_0003
(Z)-5-((2-(4-(((2,3,4-trifluorobenzy])amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2,3,4-trifluorobenzaldehyde (6.6 mg, 22.2 mg theoretical, 30%). LC-MS m/z 464 (M+l).
EXAMPLE 61
B4002959vl - 118 -
Figure imgf000120_0001
(Z)-5-((2-(4-((((5-(2,4-dichlorophenyl)furan-2-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 5-(2,4-dichlorophenyl)furan-2-carbaldehyde (19 mg, 39 mg theoretical, 48%). LC-MS m/z 545.5 (M+l).
EXAMPLE 62
Figure imgf000120_0002
(Z)-5-((2-(4-((((5-(2-chlorophenyl)furan-2-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 5-(2-chlorophenyl)furan-2-carbaldehyde (17.2 mg, 36. mg theoretical, 46.8%). LC-MS m/z 511.5 (M+l).
EXAMPLE 63
Figure imgf000120_0003
(Z)-5-((2-(4-((((5-(2-(trifluoromethyl)phenyl)furan-2- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and 5-(2- (trifluoromethyl)phenyl)furan-2-carbaldehyde (23.9 mg, 39.1 mg theoretical, 66%). LC- MS m/z 544.5 (M+l).
B4002959vl - 119 - EXAMPLE 64
Figure imgf000121_0001
(Z)-5-((2-(4-((((5-(3-(trifluoromethyl)phenyl)furan-2- yl)methyl)amino)methyl)piperidin-l-yl)pyrirnidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and 5-(3- (trifluoromethyl)phenyl)furan-2-carbaldehyde (20.5 mg, 39.1 mg theoretical, 52.4%). LC- MS m/z 544 (M+l).
EXAMPLE 65
Figure imgf000121_0002
(Z)-5-((2-(4-(((thiophen-3-ylmethyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and thiophene-3-carbaldehyde (9.7 mg, 19.5 mg theoretical, 47%). LC-MS m/z 416 (M+l).
EXAMPLE 66
Figure imgf000121_0003
(Z)-5-((2-(4-(((l-(6-(thiophen-3-yl)pyridin-2-yl)ethyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general
B4002959vl - 120 - reductive animation procedure and l-(6-(thiophen-3-yl)pyridin-2-yl)ethanone (3 mg, 37.4 mg theoretical, 8.6%). LC-MS m/z 507 (M+l).
EXAMPLE 67
Figure imgf000122_0001
(Z)-5-((2-(4-((((3-fluoro-6-(furan-2-yl)pyridin-2-yl)methy])amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 3-f uoro-6-(furan-2-yl)picolinaldehyde (13.6 mg, 23.7 mg theoretical, 57%). LC-MS m/z 495 (M+l).
EXAMPLE 68
Figure imgf000122_0002
(Z)-5-((2-(4-(((2-fluoro-5-(thiophen-3-yl)benzyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-fluoro-5-(thiophen-3-yl)benzaldehyde (7.6 mg, 24.4 mg theoretical, 31%). LC-MS m/z 510 (M+l). EXAMPLE 69
Figure imgf000122_0003
(Z)-5-((2-(4-(((2-fluoro-6-(thiophen-3-yl)benzyl)amino)methyl)piperidin-l yl)pyrimidin-4-y])methylene)thiazolidine-2,4-dione was prepared using the
B4002959vl - 121 - reductive animation procedure and 2-fluoro-6-(thiophen-3-yl)benzaldehyde (8.9 mg, 24.4 mg theoretical, 36%). LC-MS m/z 510 (M+l).
EXAMPLE 70
Figure imgf000123_0001
(Z)-5-((2-(4-(((benzofuran-5-ylmethyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and benzofuran-5-carbaldehyde (5.5 mg, 21.5 mg theoretical, 26%). LC-MS m/z 450 (M+l).
EXAMPLE 71
Figure imgf000123_0002
(Z)-5-((2-(4-(((benzo[b]thiophen-5-ylmethyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and benzo[b]thiophene-5-carbaldehyde (14.3 g, 22.3 mg theoretical, 64%). LC- MS m/z 466 (M+l).
EXAMPLE 72
Figure imgf000123_0003
(Z)-5-((6-(4-((((6-fluoroquinolin-2-yl)methyl)amino)methyl)piperidin-l-yl)pyridin-2- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-fluoroquinoline-2-carbaldehyde (6 mg, 18.9 mg theoretical, 31.7%). LC- MS m/z 478 (M+l).
B4002959vl - 122 - EXAMPLE 73
Figure imgf000124_0001
(Z)-5-((2-(4-((((l-methyl-lH-benzo[d]imidazol-5-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and l-methyl-lH-benzo[d]imidazole-5-carbaldehyde (5.6 mg, 22.5 mg theoretical, 25%). LC-MS m/z 464 (M+l). EXAMPLE 74
Figure imgf000124_0002
(Z)-5-((2-(4-((((lH-indol-5-yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and lH-indole-5-carbaldehyde (5.2 mg, 24.5 mg theoretical, 24%). LC-MS m/z 449 (M+l).
EXAMPLE 75
Figure imgf000124_0003
(Z)-5-((2-(4-((((6-fluoroquinolin-2-yl)methyl)amino)methyl)-4-methylpiperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-fluoroquinoline-2-carbaldehyde (25.3 mg, 64.2 mg theoretical, 18%). LC-MS m/z 334 (M+l).
EXAMPLE 76
B4002959vl - 123 -
Figure imgf000125_0001
(Z)-5-((2-(4-((((2-(2-(trifluoromethyl)phenyl)pyridin-3- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and cyclohexanone (18 mg, 28.9 mg theoretical, 63%). LC-MS m/z 402.5 (M+l).
EXAMPLE 77
Figure imgf000125_0002
(Z)-5-((2-(4-(((6-fluoroquinolin-2-yl)methyl)amino)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 6-fluoroquinoline-2-carbaldehyde (5.7 mg, 34.4 mg theoretical, 16.5%). LC-MS m/z 465.5 M+l).
Figure imgf000125_0003
(Z)-5-((2-(4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-(thiophen-3-yl)picolinaldehyde (13.6 mg, 35.4 mg theoretical, 38.4%). LC-MS m/z 479.5 (M+l).
B4002959vl - 124 - EXAMPLE 79
Figure imgf000126_0001
(Z)-5-((2-(7-((2-(pyridin-2-yl)ethyl)amino)-3,4-dihydroisoquinolin-2(lH)-yl)pyrimidin- 4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(pyridin-2-yl)acetaldehyde (18.6 mg, 32.4 mg theoretical, 57.3%). LC-MS m/z 459.5 (M+l).
EXAMPLE 80
Figure imgf000126_0002
(Z)-5-((2-(5-((2-(pyridin-2-yl)ethyl)amino)-3,4-dihydroisoquinolin-2(lH)-yl)pyrimidin- 4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(pyridin-2-yl)acetaldehyde (9.3 mg, 32.4 mg theoretical, 28.7%). LC-MS m/z 459.5 (M+l).
EXAMPLE 81
Figure imgf000126_0003
B4002959vl - 125 - (Z)-5-((2-(4-(((2-methylquinolin-4-yl)methyl)amino)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive animation procedure and 2-methylquinoline-4-carbaldehyde (5.1 mg, 34.1 mg theoretical, 15%). LC- MS m/z 461.5 (M+l).
EXAMPLE 82
Figure imgf000127_0001
(Z)-5-((2-(4-((phenethylamino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-phenylacetaldehyde (9.6 mg, 30.5 mg theoretical, 31.5%). LC-MS m/z 424.5 (M+l).
Figure imgf000127_0002
(Z)-5-((2-(4-(2-(((6-(thiophen-2-yl)pyridin-2-yl)methyl)amino)ethyl)piperidin-l- yl)pyrimidin-4-y])methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-(thiophen-2-yl)picolinaldehyde (2.6 mg, 35 mg theoretical, 7.4%). LC-MS m z 507 (M+l).
EXAMPLE 84
Figure imgf000127_0003
B4002959vl - 126 - (Z)-5-((2-(4-(((l,2,3,4-tetrahydronaphthalen-2-yl)amino)methy])piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 3,4-dihydronaphthalen-2(lH)-one (2.0 mg, 32.4 mg theoretical, 6%). LC-MS m z 450 (M+l).
EXAMPLE 85
Figure imgf000128_0001
(Z)-5-((2-((lR,5S)-8-((((6-fluoroquinolin-2-yl)methyl)amino)methyl)-3- azabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-fluoroquinoline-2- carbaldehyde (4.7 mg, 33.8 mg theoretical, 13.9%). LC-MS m/z 505.5 (M+l).
EXAMPLE 86
Figure imgf000128_0002
(Z)-5-((2-((lR,5S)-8-((((6-(thiophen-3-y])pyridin-2-yl)methyl)amino)methyl)-3- azabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-(thiophen-2- yl)picolinaldehyde (2.3 mg, 34.7 mg theoretical, 6.6%). LC-MS m/z 519.5 (M+l).
EXAMPLE 87
Figure imgf000128_0003
(Z)-5-((2-((lR,5S)-8-(((quinolin-2-ylmethy])amino)methyl)-3-azabicyclo[3.2.1]octan-3- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general
B4002959vl - 127 - reductive animation procedure and quinoline-2-carbaldehyde (1.4 mg, 32.6 mg theoretical, 4.3%). LC-MS m/z 487.5 (M+l).
EXAMPLE 88
Figure imgf000129_0001
(Z)-5-((2-(2-((4-fluoro-2-(furan-2-yl)benzyl)amino)-7-azaspiro[3.5]nonan-7- yl)pyrimidin-4-y])methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 4-f uoro-2-(furan-2-yl)benzaldehyde (9.1 mg, 34.8 theoretical, 26.1%). LC-MS m/z 520.5 (M+l).
EXAMPLE 89
Figure imgf000129_0002
(Z)-5-((2-(2-(((6-fluoronaphthalen-2-yl)methyl)amino)-7-azaspiro[3.5]nonan-7- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 6-fluoro-2-naphthaldehyde (16.9 mg, 33.7 mg theoretical, 50.1%). LC-MS m/z 504.5 (M+l).
EXAMPLE 90
Figure imgf000129_0003
(Z)-5-((6-methoxy-2-(4-((((6-(thiophen-3-yl)pyridin-2- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-
B4002959vl - 128 - clione was prepared using (Z)-5-((2-(4-(aminomethyl)piperidin-l-yl)-6-methoxypyrimidin- 4-yl)methylene)thiazolidine-2,4-dione (Example 153), the general reductive animation procedure and 6-(thiophen-3-yl)picolinaldehyde (34.3 mg, 65 mg theoretical, 52.8%). LC- MS m/z 523 (M+l).
EXAMPLE 91
Figure imgf000130_0001
(Z)-5-((6-methoxy-2-(4-((((2-methylquinolin-4-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-y])methylene)thiazolidine-2,4-dione was prepared using (Z)-5-((2-(4- (aminomethyl)piperidin-l-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Example 153), the general reductive amination procedure and 2-methylquinoline-4- carbaldehyde (45.8 mg, 63 mg theoretical, 72.2%). LC-MS m/z 505 (M+l).
EXAMPLE 92
Figure imgf000130_0002
(Z)-5-((2-(4-((((6-fluoropyridin-2-yl)methyl)amino)methyl)piperidin-l-yl)-6- methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using (Z)-5-((2- (4-(aminomethyl)piperidin-l-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4- dione (Example 153), the general reductive amination procedure and 6- fluoropicolinaldehyde (26.1 mg, 59 mg theoretical, 43.9%). LC-MS m/z 459 (M+l).
EXAMPLE 93
B4002959vl - 129 -
Figure imgf000131_0001
(Z)-5-((6-methoxy-2-(4-((((6-(thiophen-3-yl)pyridin-2- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using (Z)-5-((2-(4-(aminomethyl)piperidin-l-yl)-6-methoxypyrimidin- 4-yl)methylene)thiazolidine-2,4-dione (Example 153), the general reductive amination procedure and 7-fluoroquinoline-2-carbaldehyde (15.1 mg, 64 mg theoretical, 23.7%). LC- MS m/z 509 (M+l).
EXAMPLE 94
Figure imgf000131_0002
(Z)-5-((2-(4-((((5-(pyrrolidin-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and tert-butyl 2-(6-formylpyridin-3-yl)pyrrolidine-l- carboxylate followed by the general de-protection procedure (29.3 mg, 39.8 mg theoretical, 73.6%). LC-MS m/z 480.6 (M+l).
EXAMPLE 95
Figure imgf000131_0003
(Z)-5-((2-(4-((((2-(lH-pyrrol-2-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-l- yl)pyrimidin-4-y])methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and tert-butyl 2-(3-formylpyridin-2-yl)-lH-pyrrole-l- carboxylate followed by the general de-protection procedure (16.5 mg, 17.1 mg theoretical, 96%). LC-MS m/z 476.6 (M+l).
B4002959vl - 130 - EXAMPLE 96
Figure imgf000132_0001
(Z)-5-((2-(4-((methylamino)methyl)piperidin-l-y])pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl methyl(piperidin-4-ylmethyl)carbamate followed by the general de-protection procedure (28.3 mg, 28.5 mg theoretical, 99%). LC-MS m/z 334.4 (M+l). EXAMPLE 97
Figure imgf000132_0002
(Z)-5-((2-(4-(((thiophen-2-ylmethyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive animation procedure and thiophene-2-carbaldehyde followed by the general de-protection procedure (7.6 mg, 19.9 mg theoretical, 38%). LC-MS m/z 416 (M+l).
EXAMPLE 98
Figure imgf000132_0003
(Z)-5-((2-(4-(((2-aminobenzyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and tert-butyl (2-formylphenyl)carbamate followed by the general de-protection procedure (17.4 mg, 18.7 mg theoretical, 93%). LC-MS m/z 425.5 (M+l).
EXAMPLE 99
B4002959vl - 131 -
Figure imgf000133_0001
(Z)-5-((2-(4-((((4-aminopyridin-3-yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive animation procedure and tert-butyl (3-formylpyridin-4-yl)carbamate followed by the general de- protection procedure (4.3 mg, 7.3 mg theoretical, 59%). LC-MS m/z 426.5 (M+l).
EXAMPLE 100
Figure imgf000133_0002
(Z)-5-((2-(4-((((3-aminopyridin-4-yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive animation procedure and tert-butyl (4-formylpyridin-3-yl)carbamate followed by the general de- protection procedure (11.5 mg, 15.3 mg theoretical, 75%). LC-MS m/z 426.5 (M+l).
EXAMPLE 101
Figure imgf000133_0003
(Z)-5-((2-(4-(aminomethyl)-4-methylpiperidin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate followed by the general de-protection procedure (29.9 mg, 168 mg theoretical, 17.8%). LC-MS m/z 334 (M+l). EXAMPLE 102
B4002959vl - 132 -
Figure imgf000134_0001
(Z)-5-((6-(4-(aminomethyl)piperidin-l-y])pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure, (Z)-5-((2- (methylsulfonyl)pyrimidin-4-yl)methylene)-3-(2-(pyridin-2-yl)ethyl)thiazolidine-2,4-dione and tert-butyl (piperidin-4-ylmethyl)carbamate followed by the general de-protection procedure (16 mg, 30.6 mg theoretical, 52.3%). LC-MS m/z 425.5 (M+l).
EXAMPLE 103
Figure imgf000134_0002
(Z)-5-((2-((lR,5S)-8-(aminomethyl)-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and tert-butyl ((lR,5S)-3-azabicyclo[3.2.1]octan-8-ylmethyl)carbamate followed by the general de-protection procedure (15.1 mg, 17.1 mg theoretical, 89%). LC-MS m z 346 (M+l).
EXAMPLE 104
Figure imgf000134_0003
(Z)-5-((2-(4-(2-aminoethyl)piperidin-l-y])pyrimidin-4-yl)methylene)thiazolidine-2,4- clione, was prepared using the general reductive amination procedure and tert-butyl (2- (piperidin-4-yl)ethyl)carbamate followed by the general de-protection procedure (6.8 mg, 23.1 mg theoretical, 29.5%). LC-MS m/z 334 (M+l).
EXAMPLE 105
B4002959vl - 133 -
Figure imgf000135_0001
(Z)-5-((2-(4-(2-aminoacetyl)piperazin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general reductive amination procedure and tert-butyl (2-oxo- 2-(piperazin-l-yl)ethyl)carbamate followed by the general de-protection procedure (3.9 mg, 26.5 mg theoretical, 15%). LC-MS m/z 348 (M+l).
Figure imgf000135_0002
(Z)-5-((2-(2-amino-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-y])methylene)thiazolidine- 2,4-dione was prepared using the general reductive amination procedure and tert-butyl 7- azaspiro[3.5]nonan-2-ylcarbamate followed by the general de-protection procedure (17.2 mg, 11.6 mg theoretical, 148%). LC-MS m/z 346 (M+l).
EXAMPLE 107
Figure imgf000135_0003
(Z)-5-((2-(5-chlorospiro [indoline-3,4 '-piperidin] - 1 '-y])pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 5-chlorospiro[indoline-3,4'-piperidine] (9.1 mg, 27.1 mg theoretical, 33.6%). LC-MS m/z 428 (M+l).
EXAMPLE 108
B4002959vl - 134 -
Figure imgf000136_0001
(Z)-5-((2-(4-(4-aminophenyl)piperidin-l-y])pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general displacement procedure and 4-(piperidin-4-yl)aniline (10.2 mg, 40.1 mg theoretical, 25.4%). LC-MS m/z 382 (M+l).
EXAMPLE 109
Figure imgf000136_0002
(Z)-5-((2-(4-(2-aminophenyl)piperidin-l-y])pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general displacement procedure and 2-(piperidin-4-yl)aniline (24 mg, 40.1 mg theoretical, 59.8%). LC-MS m/z 382 (M+l).
Figure imgf000136_0003
(Z)-5-((2-(4-(2-aminophenyl)piperidin-l-y])pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared using the general displacement procedure and 3-(piperidin-4-yl)aniline (19.7 mg, 40.1 mg theoretical, 49.1%). LC-MS m/z 382 (M+l).
EXAMPLE 111
Synthesized Sulfonamide Analogs
B4002959vl - 135 - General Procedure for the Preparation of Sulfonamides/Amides A 2-dram round- bottomed vial was charged with the appropriate sulfonyl chloride (0.072 mmol, 1 equiv.) in 0.5 mL of DMF, and then treated carefully with a solution of (Z)-5-((2-(4- (aminomethyl)piperidin- 1 -yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione, prepared using the general displacement procedure followed by the general de-protection procedure, (0.072 mmol, 1 equiv.), DIPEA (0.288 mmol, 4 equiv.), and 1 mL of DMF. The reaction mixture was then shaken at room temperature overnight. The reaction mixture was partitioned between 2 mL DCE and 1 mL sat. NaHC03 and the aqueous layer was extracted with DCE (2 x 2 mL). The combined organic layer was the concentrated under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC
(MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to afford the sulfonamide analogs.
EXAMPLE 112
Figure imgf000137_0001
(Z)-N-((l-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)-l-methyl-lH-indole-5-sulfonamide was prepared using General Procedure for the Preparation of Sulfonamides and 1 -methyl- lH-indole-5 -sulfonyl chloride (13.2 mg, 36.9 mg theoretical, 35.8%). LC-MS m/z 513.6 (M+l).
EXAMPLE 113
Figure imgf000137_0002
B4002959vl - 136 - (Z)-N-((l-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)-6-methoxynaphthalene-2-sulfonamide was prepared using General Procedure for the Preparation of Sulfonamides and 6-methoxynaphthalene-2-sulfonyl chloride (15.2 mg, 38.9 mg theoretical, 39.1%). LC-MS m/z 540.6 (M+l).
EXAMPLE 114
Figure imgf000138_0001
(Z)-N-((l-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)naphthalene-2-sulfonamide was prepared using General Procedure for the
Preparation of Sulfonamides naphthalene-2-sulfonyl chloride (7.7 mg, 36.7 mg theoretical, 20.9%). LC-MS m/z 510.6 (M+l).
EXAMPLE 115
Figure imgf000138_0002
(Z)-5-chloro-N-((l-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2- yl)piperidin-4-yl)methyl)naphthalene-2-sulfonamide was prepared using General Procedure for the Preparation of Sulfonamides and 5-chloronaphthalene-2-sulfonyl chloride (9.2 mg, 39.2 mg theoretical, 23.4%). LC-MS m/z 545.0 (M+l).
EXAMPLE 116
B4002959vl - 137 -
Figure imgf000139_0001
(Z)-N-((l-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)quinoline-2-carboxamide was prepared using General Procedure for the Preparation of Sulfonamides/Amides and quinoline-2-carbonyl chloride (8.9 mg, 34.2 theoretical, 26%). LC-MS m/z 475 (M+l).
EXAMPLE 117
Figure imgf000139_0002
(Z)-N-((l-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4- yl)methyl)-6-(trifluoromethyl)picolinamide was prepared using General Procedure for the Preparation of Sulfonamides/Amides and 6-(trifluoromethyl)picolinoyl chloride (15.7 mg, 35.5 mg theoretical, 44.3%). LC-MS m/z 493 (M+l).
EXAMPLE 118
General Boronic Acid Coupling Procedures
Figure imgf000139_0003
A 2-dram round-bottomed vial was charged with 6-bromopicolinaldehyde (100 mg,
0.538 mmol) and the boronic acid (0.538 mmol, 1 equiv.) were added in THF (2 mL). Then 2 M Na2C03 (0.403 mL, 0.806 mmol, 1.5 equiv.) and Pd(Ph3P)4 (31.0 mg, 0.027 mmol, 0.05 equiv.) were added and shaken at 85°C overnight. The solvent was removed in the Genevac and the residue was washed with saturated NaHCCb (1 mL). The aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organic layers were dried on the Genevac and the crude was purified using flash purification with a gradient of 5-40%
B4002959vl - 138 - EtOAc in hexane.
EXAMPLE 119
Figure imgf000140_0001
6-(furan-2-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and furan-2-ylboronic acid (60 mg, 93.2 mg theoretical, 64.4%). LC-MS m/z 174.2 (M+l).
EXAMPLE 120
Figure imgf000140_0002
6-(furan-3-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and furan-3-ylboronic acid (65 mg, 93.2 mg theoretical, 69.8%). LC-MS m/z 174.2 (M+l).
EXAMPLE 121
Figure imgf000140_0003
6-(2-(trifluoromethyl)phenyl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and (2-
(trifluoromethyl)phenyl)boronic acid (43.5 mg, 135.1 mg theoretical, 32.2%). LC-MS m/z 252.2 (M+l). EXAMPLE 122
Figure imgf000140_0004
B4002959vl - 139 - 6-(3-(trifluoromethy])phenyl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and (3-
(trifluoromethyl)phenyl)boronic acid (115 mg, 135.1 mg theoretical, 85.1%). LC-MS m/z 252.2 (M+l).
EXAMPLE 123
Figure imgf000141_0001
6-(4-(trifluoromethyl)phenyl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and (4-
(trifluoromethyl)phenyl)boronic acid (79 mg, 135.1 mg theoretical, 58.5%). LC-MS m/z 252.2 (M+l).
EXAMPLE 124
Figure imgf000141_0002
6-(benzofuran-2-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and benzofuran-2-ylboronic acid (41 mg, 120.1 mg theoretical, 34.1%). LC-MS m/z 224.2 (M+l).
EXAMPLE 125
Figure imgf000141_0003
A 2-dram round-bottomed vial was charged with 2-bromonicotinaldehyde (100 mg, 0.538 mmol) and the boronic acid (0.538 mmol, 1 equiv.) were added in THF (2 mL). Then 2M Na2C03 (0.403 mL, 0.806 mmol, 1.5 equiv.) and Pd(Ph3P)4 (31.0 mg, 0.027 mmol, 0.05 equiv.) were added and shaken at 85°C overnight. The solvent was removed in the Genevac and the residue was washed with saturated NaHCC (1 mL). The aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organic layers were dried on the
B4002959vl - 140 - Genevac and the crude was purified using flash purification with a gradient of 5-40% EtOAc in hexane.
EXAMPLE 126
Figure imgf000142_0001
2-(furan-3-yl)nicotinaldehyde was prepared using the general boronic acid couplin procedure for 2-bromonicotinaldehyde and furan-3-ylboronic acid (40 mg, 93.2 mg theoretical, 42.9%). LC-MS m/z 174.2 (M+l).
EXAMPLE 127
Figure imgf000142_0002
2-(furan-2-yl)nicotinaldehyde was prepared using the general boronic acid couplin procedure for 2-bromonicotinaldehyde and furan-2-ylboronic acid (38 mg, 93.2 mg theoretical, 40.8%). LC-MS m/z 174.2 (M+l).
EXAMPLE 128
Figure imgf000142_0003
2-(5-(trifluoromethyl)thiophen-2-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (5-
(trifluoromethyl)thiophen-2-yl)boronic acid (47.7 mg, 62.3 mg theoretical, 76.6%). LC-MS m/z 258.2 (M+l).
EXAMPLE 129
Figure imgf000142_0004
B4002959vl - 141 - 2-(thiophen-3-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and thiophen-3-ylboronic acid (60 mg, 101.8 mg theoretical 58.9%). LC-MS m/z 190.2 (M+l).
Figure imgf000143_0001
2-(lH-pyrazol-5-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (lH-pyrazol-5-yl)boronic acid (60 mg, 93.2 mg theoretical, 64.4%). LC-MS m/z 174.2 (M+l).
EXAMPLE 131
Figure imgf000143_0002
tert-butyl 2-(3-formylpyridin-2-yl)-lH-pyrrole-l-carboxylate was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (l-(tert- butoxycarbonyl)-lH-pyrrol-2-yl)boronic acid (66 mg, 146.5 mg theoretical, 45.1%). LC- MS m/z 273.3 (M+l).
EXAMPLE 132
Figure imgf000143_0003
2-(2-(trifluoromethy])phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (2-
(trifluoromethyl)phenyl)boronic acid (40 mg, 93.2 mg theoretical, 42.9%). LC-MS m/z 252.2 (M+l).
B4002959vl - 142 - EXAMPLE 133
Figure imgf000144_0001
2-(3-(trifluoromethy])phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (3-
(trifluoromethyl)phenyl)boronic acid (100 mg, 135.1 mg theoretical, 74%). LC-MS m/z 252.2 (M+l). EXAMPLE 134
Figure imgf000144_0002
2-(4-(trifluoromethy])phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (4- (trifluoromethyl)phenyl)boronic acid (93.8 mg, 135.1 mg theoretical, 69.4%). LC-MS m/z 252.2 (M+l).
EXAMPLE 135
Figure imgf000144_0003
2-(benzofuran-2-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and benzofuran-2-ylboronic acid (72 mg, 120.1 mg theoretical, 60%). LC-MS m/z 224.2 (M+l). EXAMPLE 136
Figure imgf000144_0004
B4002959vl - 143 - A 2-dram round-bottomed vial was charged with 2-bromoisonicotinaldehyde (100 mg, 0.538 mmol) and the boronic acid (0.538 mmol, 1 equiv.) were added in THF (2 mL). Then 2M Na2C03 (0.403 mL, 0.806 mmol, 1.5equiv.) and Pd(Ph3P)4 (31.0 mg, 0.027 mmol, 0.05 equiv.) were added and shaken at 85°C overnight. The solvent was removed in the Genevac and the residue was washed with saturated NaHC03 (1 mL). The aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organic layers were dried on the Genevac and the crude was purified using flash purification with a gradient of 5-40% EtOAc in hexane. EXAMPLE 137
Figure imgf000145_0001
2-(thiophen-3-yl)isonicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and thiophen-3-ylboronic acid (89 mg, 101.8 mg theoretical, 87.4%). LC-MS m/z 190.2 (M+l).
EXAMPLE 138
Figure imgf000145_0002
2-(furan-3-yl)isonicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and furan-3-ylboronic acid (67 mg, 93.2 mg theoretical, 61.2%). LC-MS m/z 174.2 (M+l).
EXAMPLE 139
Figure imgf000145_0003
B4002959vl - 144 - tert-butyl 2-(4-formylpyridin-2-yl)-lH-pyrrole-l-carboxylate was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and (l-(tert- butoxycarbonyl)-lH-pyrrol-2-yl)boronic acid (56 mg, 146.5 mg theoretical, 38.2%). LC- MS m/z 273.3 (M+l).
EXAMPLE 140
Figure imgf000146_0001
2-(furan-2-yl)isonicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and furan-2-ylboronic acid (39.6 mg, 93.2 mg theoretical, 42.5%). LC-MS m/z 174.2 (M+l).
EXAMPLE 141
Figure imgf000146_0002
2-(5-(trifluoromethy])thiophen-2-yl)isonicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and (5- (trifluoromethyl)thiophen-2-yl)boronic acid (29.4 mg, 62.3 mg theoretical, 47.2%>). LC-MS m/z 258.2 (M+l).
EXAMP
Figure imgf000146_0003
A 2-dram round-bottomed vial was charged with 6-bromo-3-fluoropicolinaldehyde (100 mg, 0.490 mmol) and thiophen-3-ylboronic acid (62.7 mg, 0.490 mmol, 1 equiv.) were added in THF (2 mL). Then 2 M Na2C03 (0.368 mL, 0.735 mmol, 1.5 equiv.) and
Pd(Pli3P)4 (28.3 mg, 0.025 mmol, 0.05 equiv.) were added and shaken at 85°C overnight. The solvent was removed in the Genevac and the residue was washed with saturated NaHCC>3 (1 mL). The aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organic layers were dried on the Genevac and the crude was purified using flash
B4002959vl - 145 - purification with a gradient of 5-40% EtOAc in hexane.
EXAMPLE 143
Figure imgf000147_0001
3-fluoro-6-(thiophen-3-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromo-3-fiuoropicolinaldehyde and thiophen-3-ylboronic acid (80.5 mg, 101.5 mg theoretical, 79.3%). LC-MS m/z 208.2 (M+l).
Figure imgf000147_0002
2-(3-(trifluoromethoxy)phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure with 2-bromonicotinaldehyde and (3- (trifiuoromethoxy)phenyl)boronic acid (101 mg, 144 mg theoretical, 70.1%). LC-MS m/z 268 (M+l).
EXAMPLE 145
Figure imgf000147_0003
2-(3-(trifluoromethoxy)phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure with 5-bromofuran-2-carbaldehyde and thiophen-3-ylboronic acid (68 mg, 102 mg theoretical, 66.7%). LC-MS m z 179 (M+l).
EXAMPLE 146
B4002959vl - 146 -
Figure imgf000148_0001
[3,3'-bithiophene]-5-carbaldehyde was prepared using the general boronic acid coupling procedure with 4-bromothiophene-2-carbaldehyde and thiophen-3-ylboronic acid (56 mg, 102 mg theoretical, 54.9%). LC-MS m/z 195 (M+l).
Figure imgf000148_0002
4-fluoro-2-(furan-2-yl)benzaldehyde was prepared using the general boronic acid coupling procedure with 2-bromo-4-fluorobenzaldehyde and furan-2-ylboronic acid (20 mg, 94 mg theoretical, 21.3%). LC-MS m/z 191 (M+l).
EXAMPLE 148
Figure imgf000148_0003
[2,2'-bifuran]-5-carbaldehyde was prepared using the general boronic acid coupling procedure with 5-bromofuran-2-carbaldehyde and furan-2-ylboronic acid (24 mg, 93 mg theoretical 25.8%). LC-MS m/z 163 (M+l).
Figure imgf000148_0004
B4002959vl - 147 - 4-(furan-2-yl)thiophene-2-carbaldehyde was prepared using the general boronic acid coupling procedure with 4-bromothiophene-2-carbaldehyde and furan-2-ylboronic acid (26 mg, 93 mg theoretical, 28.0%). LC-MS m/z 179 (M+l). EXAMPLE 150
Figure imgf000149_0001
3-fluoro-6-(furan-2-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure with 6-bromo-3-f uoropicolinaldehyde and furan-2-ylboronic acid (41 mg, 94 mg theoretical, 43.6%). LC-MS m/z 192 (M+l).
EXAMPLE 151
Figure imgf000149_0002
2-fluoro-5-(thiophen-3-yl)benzaldehyde was prepared using the general boronic acid coupling procedure with 5-bromo-2-fluorobenzaldehyde and thiophen-3-ylboronic acid (27 mg, 102 mg theoretical, 26.5%). LC-MS m/z 207 (M+l).
EXAMPLE 152
Figure imgf000149_0003
2-fluoro-6-(thiophen-3-yl)benzaldehyde was prepared using the boronic acid coupling procedure with 2-bromo-6-fluorobenzaldehyde and thiophen-3-ylboronic acid (66 mg, 102 mg theoretical, 64.7%). LC-MS m/z 207 (M+l).
EXAMPLE 153
Preparation of Methoxyaminopyrimidine Intermediate
B4002959vl - 148 - (Z)-5-((2-(4-(aminomethyl)piperidin-l-yl)-6-methoxypyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared as follows.
Figure imgf000150_0001
Figure imgf000150_0002
Methyl 2-chloro-6-methoxypyrimidine-4-carboxylate
A 30 mL round-bottomed vial was charged with methyl 2,6-dichloropyrimidine-4- carboxylate (0.6 g, 2.9 mmol, 1 equiv.), methanol (6 mL, 0.97 M), 2C0 (0.401 g, 2.9 mmol, 1 equiv.), and the reaction mixture was shaken at 65°C for 1.5 h. The solvent was concentrated under reduced pressure and the residue was partitioned between EtOAc (25 mL) and H20 (25 mL) and the water layer was extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure to provide the crude chloropyrimidine (441 mg, 588 mg theoretical, 75%), which was used in the next step without further purification.
B4002959vl - 149 -
Figure imgf000151_0001
Methyl 2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-l-yl)-6- methoxypyrimidine-4-carboxylate
An 8 mL round-bottomed vial was charged with the 2-chloropyrimidine (150 mg,
0.74 mmol, 1.5 equiv.), methanol (1.5 mL, 0.49 M), tert-Butyl (piperidin-4- ylmethyl)carbamate (159 mg, 0.49 mmol, 1 equiv.), DIPEA (258 μί, 0.99 mmol, 2 equiv.), and the reaction mixture was shaken at 65°C for 3 h. The solvent was concentrated under reduced pressure and the residue was partitioned between EtOAc (25 mL) and saturated NaHCCb (10 mL). The organic layer was dried over Na2S04 and dried under reduced pressure to provide the crude product. Purification using the Biotage (Si02, 10 g cartridge, Hexanes/EtOAc 95:5 to 40:60) afforded the desired pyrimidine intermediate as a white solid (219 mg, 281 mg theoretical, 78%).
Figure imgf000151_0002
NHBoc tert-Butyl ((l-(4-formyl-6-methoxypyrimidin-2-yl)piperidin-4-y])methyl)carbamate
A 50 mL 2-neck round-bottomed flask was charged with the methyl ester intermediate (150 mg, 0.39 mmol, 1 equiv.), CH2C12 (2 mL, 0.195 M), and then DIBAL-H 1 M in CH2C12 (0.59 mL, 0.59 mmol, 1.5 equiv.) was added over a 4 minute period at -
78°C. The reaction was then stirred for 1.5 h at -78°C and for 1.5 h between -78°C and RT. LC-MS showed mostly starting material so the reaction mixture was re-cooled to -78°C and DIBAL-H (0.8 mL, 0.8 mmol, 2 equiv.) was added. LC-MS showed mostly starting material. The reaction mixture was stored at -20°C for 3 d. The reaction mixture was cooled to -78°C and treated with 1 M DIBAL-H in hexanes (0.59 mL, 0.59 mmol, 1 equiv.) over a 5 min. period, which produced a white precipitate. After 2.5 h, another equivalent of DiBAL-H (1 M in Hexanes, 0.59 mL) was added over a 15 min. period at -78°C. The reaction was quenched at -78°C after 35 min. with methanol (1 mL). The solvent were
B4002959vl - 150 - concentrated under reduced pressure and the residue was partitioned between CH2CI2 (20 mL) and saturated NaHCC>3 (20 mL). The organic layer was dried over Na2S04 and the solvent was concentrated under reduced pressure to provide the crude product, which was used in the next step without further purification.
Figure imgf000152_0001
(Z)-tert-Butyl ((l-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-methoxypyrimidin-2- yl)piperidin-4-yl)methyl)carbamate
An 8 mL round-bottomed vial was charged with the crude aldehyde (0.2 mmol, estimated), ethanol (2 mL), thiazolidine-2,4-dione (23 mg, 0.2 mmol, 1 equiv.), triethylamine (56 μί, 0.4 mmol, 2 equiv.), purged with Ar, and the reaction mixture was shaken at 80°C for 24 h. The crude mixture was purified using the Biotage (Si02, 10 g cartridge, CH2Cl2/MeOH 99:1 to 94:6) afforded 113 mg of the partially purified product. The sample was re-purified using reverse phase HPLC (methanol/water 10-90%, 0.4% TFA, 3 equal injections) provided the pure product as a TFA salt (47.3 mg, 225 mg theoretical, 21%). LC-MS m/z 450 (M+l).
Figure imgf000152_0002
(Z)-5-((2-(4-(aminomethyl)piperidin-l-y])-6-methoxypyrimidin-4- yl)methylene)thiazolidine-2,4-dione
An 8 mL round-bottomed vial was charged with the MeO-pyrimidine boc protected amine (47.3 mg, 105 μιηοΐ, 1 equiv.), CH2C12 (1.3 mL, 0.08 M), TFA (0.5 mL, 6.5 mmol, 62 equiv.), and the reaction mixture was stirred for 1 h at RT. The solvents were concentrated under reduced pressure and the residue was re-dissolved in DMSO (0.9 mL) and purified by reverse phase HPLC (methanol/water with 0.4% TFA, 10-90 % method, 2 injections of 500 μί) to provide (Z)-5-((2-(4-(aminomethyl)piperidin-l-yl)-6-
B4002959vl - 151 - methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione as the TFA salt (43.9 mg, 48.8 mg theoretical, 90%). LC-MS m/z 350.1 (M+l).
EXAMPLE 154
Figure imgf000153_0001
(Z)-5-((6-methoxy-2-(4-((((6-(thiophen-3-yl)pyridin-2- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)rnethylene)thiazolidine-2,4- dione (4.1 mg, 5.9 mg theoretical, 69%) LC-MS m/z 480 (M+l), was prepared according to the following synthetic scheme using the general boronic acid coupling conditions and other methods similar to those used in the preparation of (Z)-5-((2-(4- aminomethyl)piperidin-l-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4- dione.
Figure imgf000153_0002
B4002959vl - 152 -
Figure imgf000154_0001
General boronic acid coupling conditions for the first step: A 2-dram round-bottom vial was charged with methyl 2,6-dichloropyrimidine-4-carboxylate (100 mg, 0.483 mmol) and (3-(trifluoromethoxy)phenyl)boronic acid (80 mg, 0.386 mmol, 0.8 equiv) were added in THF (2 mL). Then 2M Na2C03 (0.362 mL, 0.725 mmol, 1.5 equiv) and Pd(tetrakis)Ph3P (27.9 mg, 0.024 mmol, 0.05 equiv) were added and shaken at 85°C overnight. The solvent was removed in the Genevac and the residue was washed with saturated NaHC03 (1 mL). The aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organic layers were dried on the Genevac and the crude was purified using flash purification with a gradient of 5-40% EtOAc in hexane to provide methyl 2-chloro-6-(3- (trifluoromethoxy)phenyl)pyrimidine-4-carboxylate.
Figure imgf000154_0002
(Z)-5-((6-methoxy-2-(4-((((6-(thiophen-3-yl)pyridin-2- yl)methyl)amino)methyl)piperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione (292 mg, 360 mg theoretical, 81%) LC-MS m/z 334 (M+l), was prepared according to the following synthetic scheme using methods similar to those used in the preparation of (Z)-5-((2-(4-(aminomethyl)piperidin- 1 -yl)-6-methoxypyrimidin-4- yl)methylene)thiazolidine-2,4-dione (Example 153):
B4002959vl - 153 -
Figure imgf000155_0001
Figure imgf000155_0002
(Z)-5-((2-(4-(aminomethyl)piperidin-l-y])-6-(2,2,2-trifluoroethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione (203 mg, 236 mg theoretical, 86%) LC-MS m/z 418 (M+1), was prepared according to the following synthetic scheme using methods similar to those used in the preparation of (Z)-5-((2-(4-(aminomethyl)piperidin-l-yl)-6- methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Example 153).
B4002959vl - 154 -
Figure imgf000156_0001
EXAMPLE 157
Figure imgf000156_0002
(Z)-N-(l-(4-((2,4-dioxothiazo]idin-5-y]idene)methyl)pyrimidin-2-yl)piperidin-4- yl)furan-2-carboximidamide was prepared using the following procedure (16.6 mg, 29.5 mg theoretical, 56.3%). LC-MS m/z 399.1 (M+l). Step 1.
Figure imgf000156_0003
A 30 mL RB-vial was charged with furan-2-carbonitrile (25 mg, 0.269 mmol), methanol (300 μί, 0.269 mmol), and hydrogen chloride (2 mL, 8.00 mmol) in 4 M in dioxane (Volume: 1 mL) to a 2-dram vial and allowed to shake at RT for 24 h. The
B4002959vl - 155 - reaction was concentrated under reduced pressure and used directly in the next step without further purification.
Step 2.
Figure imgf000157_0001
A 2-dram RB-vial was charged with the crude material from step 1, methyl furan-2- carbimidate (37 mg, 296 μηιοΐ) and then treated with MeOH (Volume: 1.5 mL), (Z)-5-((2- (4-aminopiperidin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (22.6 mg, 74 μιτιοΐ), and 2 mL of DMSO was added providing a homogeneous solution. After 2 h at RT, DIPEA was added (250 μΐ). After 24 h at RT, the reaction was purified using RP-HPLC with TFA as the modifier to provide (Z)-N-(l-(4-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)furan-2-carboximidamide. EXAMPLE 158
Figure imgf000157_0002
(Z)-5-((2-(4-(furan-2-yl(imino)methyl)piperazin-l-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione was prepared using the following procedure (1.8 mg, 29.1 mg theoretical, 6.2%). LC-MS m/z 385.1 (M+l).
Step 1.
Figure imgf000157_0003
A 30 mL RB-vial was charged with furan-2-carbonitrile (25 mg, 0.269 mmol), methanol (300 μί, 0.269 mmol), and hydrogen chloride (2 mL, 8.00 mmol) in 4 M in
B4002959vl - 156 - dioxane (Volume: 1 mL) to a 2-dram vial and allowed to shake at RT for 24 h. The reaction was concentrated under reduced pressure and used directly in the next step without further purification. Step 2.
Figure imgf000158_0001
Crude reaction from Step 1, methyl furan-2-carbimidate (26 mg, 0.208 mmol) was dried down and then diluted in MeOH (Volume: 1 mL) and treated with tert-butyl piperazine-l-carboxylate (122 mg, 0.655 mmol) was added to the solution. N-ethyl-N- isopropylpropan-2-amine (50 mg, 0.387 mmol) was added and the solution shaken at RT for 24 h. The sample was purified by RP-HPLC with TFA as the modifier to provide the Boc-piperazine intermediate. The dry material was then treated with 1 mL MeOH and 1 mL 4.0 M HCI in dioxane. After 30 minutes the final product (M+l = 180) was the only peak in the chromatogram. The reaction was concentrated under reduced pressure and used directly in the next step without further purification.
Step 3.
Figure imgf000158_0002
The crude material from Step 2, furan-2-yl(piperazin-l-yl)methanimine
hydrochloride (16.3 mg, 0.076 mmol) was diluted in DMSO (Volume: 0.75 mL) and added to (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (19.4 mg, 0.068 mmol) in a 2-dram vial. The reaction solution was then treated with N-ethyl-N- isopropylpropan-2-amine (50 mg, 0.387 mmol) and then shaken at 100 °C for 16 h. The
B4002959vl - 157 - reaction was then purified by RP-HPLC using TFA as the modifier to provide (Z)-5-((2-(4- (mran-2-yl(imino)methyl)piperazin-l-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione.
EXAMPLE 159
Figure imgf000159_0001
(Z)-N-((l-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4 yl)methyl)furan-2-carboximidamide was prepared using the following procedure (4 31.4 m theoretical, 15%). LC-MS m/z 413.1 (M+l).
Figure imgf000159_0002
A 30 mL RB-vial was charged with furan-2-carbonitrile (25 mg, 0.269 mmol), methanol (300 μί, 0.269 mmol), and hydrogen chloride (2 mL, 8.00 mmol) in 4 M in dioxane (Volume: 1 mL) to a 2-dram vial and allowed to shake at RT for 24 h. The reaction was concentrated under reduced pressure and used directly in the next step without further purification. Step 2.
Figure imgf000159_0003
The crude material from Step 1, methyl furan-2-carbimidate hydrochloride (12.3 mg, 0.076 mmol) was diluted in DMSO (Volume: 0.5 mL) and added to (Z)-5-((2-(4- (aminomethyl)piperidin- 1 -yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (23 mg,
B4002959vl - 158 - 0.072 mmol) in a 2-dram vial. The reaction solution was then treated with N-ethyl-N- isopropylpropan-2-amine (50 mg, 0.387 mmol) and the reaction was shaken at RT for 16 h. The reaction was then purified by RP-HPLC using TFA as the modifier to provide (Z)-N- ((l-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)furan- 2-carboximidamide.
EXAMPLE 160
Figure imgf000160_0001
(Z)-5-((6-(4-(aminomethyl)piperidin-l-y])pyrimidin-4-yl)methylene)thiazolidine-2,4- dione was prepared as follows (36.0 mg, 104 mg theoretical, 34.6%). LC-MS m/z 320 (M+l).
Figure imgf000160_0002
Step 1: Synthesis of methyl 6-(4-(((tert-butoxycarbonyl)amino)methyl) piperidin- 1 -yl)-2- chloropyrimidine-4-carboxylate.
B4002959vl - 159 -
Figure imgf000161_0001
A 30 mL round-bottomed vial methyl 2,6-dichloropyrimidine-4-carboxylate (300 mg, 1 equiv.) was partially dissolved in anhydrous THF (5 mL). DIEA (278 μί, 1.1 equiv.) was added at once at 0°C. tert-Butyl (piperidin-4-ylmethyl)carbamate (311 mg, 1 equiv.) dissolved in THF (5 mL) was added at 0°C in 5 min. The reaction mixture was warmed to RT in 3hl5. LC-MS showed mostly the desired product (2.77 min, M+l= 385) and a small amount of the other regioisomer (3.28 min, M+l- isobutene = 329). The solvent was evaporated and the residue was purified by biotage (Si02, 10 g, Hex/EtOAc 9:1 to 1 : 1) to give the desired isomer (386.8 mg, 69.4%) as a white solid. LC-MS m/z 385 (M+l).
Step 2: Synthesis of methyl 6-(4-(((tert-butoxycarbonyl)amino)methyl) piperidin-l- yl)pyrim
Figure imgf000161_0002
A 50 mL round-bottomed flask was charged with methyl 6-(4-(((tert- butoxycarbonyl)amino)methyl)piperidin- 1 -yl)-2-chloropyrimidine-4-carboxylate and MeOH (4 mL) and Et3N (0.4 mL). 10% Pd/C (104 mg, 0.25 equiv.) was added under argon. The reaction mixture was stirred for 6h under latm ¾. The catalyst was filtered and the solvent was evaporated to give the crude desired product (150mg, 110% crude yield) which was used directly in the next step. LC-MS m/z 351 (M+l).
Step 3: Synthesis of tert-butyl ((l-(6-formylpyrimidin-4-yl)piperidin-4-yl)methyl)carbamate.
B4002959vl - 160 -
Figure imgf000162_0001
A 25mL round-bottomed flask was charged with methyl 6-(4-(((tert- butoxycarbonyl)amino)methyl) piperidin-l-yl)pyrimidine-4-carboxylate (150 mg, 0.43 mmol, 1 equiv.) and CH2CI2 (2 mL). The reaction mixture was cooled to -78°C. DIBAL-H 1 M in CH2CI2 (0.64 mL, 0.64 mmol, 1.5 equiv.) was added in 3 minutes at -78°C. The reaction was stirred for 4h at -78°C. LC-MS showed some starting material. Another portion of DIBAL-H 1 M in CH2CI2 (0.5 mL, 0.5 mmol, 1.2 equiv.) was added in 1 min at - 78°C. LC-MS after 30 min showed the reaction was complete. The reaction was quenched at -78°C after 40 min with methanol (1 mL). The solvents were concentrated in vacuo.
The residue was partitioned between CH2CI2 (10 mL) and 1 N NaOH (6 mL). The aqueous layer was extracted with CH2CI2 (2 x 10 mL). The organic layer was dried over Na2SC>4. The solvent was evaporated to give the crude desired aldehyde (77.9 mg, 56.8% crude yield) as an yellowish oil. The crude reaction aldehyde was carried on the next step without any further purification. LC-MS m/z 339 (M+1+H20) and 351 (M+l+MeOH).
Step 4: (Z)-tert-butyl ((l-(6-((2,4-dioxothiazoUdin-5-ylidene)methyl)pyrimidin-4- yl)piperidi -4-yl)methyl)carbamate.
Figure imgf000162_0002
An 8 mL round-bottomed vial was charged with tert-butyl ((l-(6-formylpyrimidin- 4-yl)piperidin-4-yl)methyl)carbamate (77.9 mg, 0.24 mmol, 1 equiv.), ethanol (1 mL), thiazolidine-2,4-dione (28.5 mg, 0.24 mmol, 1 equiv.) and triethylamine (68 \\L, 0.48
B4002959vl - 161 - mmol, 2 equiv.). Piperidine (1.04 mg, 23 μί of a solution of 52 μΐ, in 0.95 mL ethanol, 0.012 mmol, 5% eq.) was added and Argon was bubbled through the solution. The reaction mixture was shaken at 85°C for 18 h. LC-MS of the crude reaction mixture showed mostly the desired product. The solvent was evaporated. The residue was partitioned between EtOAc (10 mL) and 10% NH4C1 (5 mL). The organic layer was dried over Na2S04.
Evaporation of solvent gave the crude (Z)-tert-butyl ((l-(6-((2,4-dioxothiazolidin-5- ylidene)methyl)pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate (79.8 mg, 78%). LC-MS: M+ 1=420. EXAMPLE 161
Figure imgf000163_0001
(Z)-5-((2-(4-(aminomethyl)piperidin-l-y])pyrimidin-4-yl)methylene)-3-(2-(pyridin-2- yl)ethyl)thiazolidine-2,4-dione (Example 102) was also prepared using the general displacement procedure with tert-butyl (piperidin-4-ylmethyl)carbamate, alkylation with 2- (2-bromoethyl)pyridine, followed by the general de-protection procedure (16 mg, 30.6 mg theoretical, 52.3%). LC-MS m/z 525.5 (M+l).
EXAMPLE 162 Cell Proliferation Inhibition
Table 4:
Figure imgf000163_0002
All cells were cultured in the media supplemented with 10% FBS in the temperature of 37 °C, 5% C02 and 95% humidity. All culture media were purchased from GIBCO. Reagents:
B4002959vl - 162 - CellTiter 96® Aqueous MTS reagent powder (Cat. No.: Gl 112, Promega. Store MTS Reagent Powder desiccated at 4 °C protected from light.)
Phenazine methosulfate (PMS) (Product No.: P9625, SIGMA. Store PMS Powder desiccated at 4 °C protected from light.)
Equipment:
Synergy2, Gene Company Limited; C02 Water Jacketed Incubator, Thermo (USA). Reverse microscope, Chongguang XDS-IB, Chongqing Guangdian Corp. (Chongqing, P.R.China).
Cytotoxicity and ICso determination:
1. Cells were harvested respectively during the logarithmic growth period and counted with hemocytometer. Cell viability was over 98 % by trypan blue exclusion.
2. Dilute cells with respective medium to achieve 1.11 x 105 cells/mL for LNCaP cells, 2.22 x 105cells/mL for KU812 cells, 5.56 x 104 cells/mL for Panc-1 cells.
3. Add 90 uL cell suspensions to 96-well plate, the final cell densities are 1 x 104
cells/well for LNCaP cells, 2 χ 104 cells/well for KU812 cells, and 4x 103 cells/well for
Panc-1 cells, respectively.
4. The next day, dilute the test article or positive drugs with DMSO or PBS.
5. Dispense 10 drug solution in each well (triplicate for each drug concentration).
6. The plates were cultured for another 72 hours, then measured using MTS assay.
7. Prepare MTS/PMS solution immediately prior to use, pipet 20 of the mixture into each well of the 96 well assay plate containing 100 μΐ^ culture medium. (The final reaction volume is 120 μί).
8. Incubate the plate for 1-4 hours at 37 °C in a humidified, 5% C02 atmosphere.
9. Record the absorbance at 490 nm using Synergy2 Microplate Reader.
Data analysis:
The software of GraphPad Prism version 5 was used to calculate IC50. The graphical curve was fitted using a nonlinear regression model with a sigmoidal dose response.
Results:
Results are shown in Table 5.
B4002959vl 163 - TableS: IC50 values (μΜ)
Figure imgf000165_0001
B4002959vl - 164- Compound LNCaP U812 Panc-1
11220 NA >30 >30
11221 NA 12 >30
11222 NA 22.8 >30
11223 NA 18.2 >30
11224 NA >30 >30
11225 NA >30 >30
11226 NA >30 >30
11227 NA 28.1 >30
11232 NA >30 >30
11234 NA 11.5 >30
11235 NA 13.5 >30
11236 NA 18.8 >30
11237 NA 10.8 >30
11240 NA >30 >30
11241 NA 13.3 >30
11242 NA >30 >30
11243 NA 10.4 >30
11244 NA 15.4 >30
11246 NA 22.3 >30
11247 NA 11.9 >30
11248 NA 14.7 >30
11249 NA 9.7 >30
11250 NA 9.6 >30
11251 NA 20.7 >30
11263 NA 7.1 >30
11264 NA 26.1 >30
11266 NA >30 >30
11267 NA >30 >30
11268 NA >30 >30
11269 NA 13.2 21.5
11271 NA NA NA
11272 NA NA NA
11273 NA NA NA
11274 NA NA NA
11275 NA NA NA
11276 NA NA NA
11279 NA NA NA
11280 NA NA NA
11288 NA NA NA
11289 NA NA NA
11290 NA NA NA
11291 NA NA NA
11293 NA NA NA
11299 NA NA NA 2959vl - 165 - Compound LNCaP U812 Panc-1
11300 NA NA NA
11301 NA NA NA
11303 NA NA NA
11304 NA NA NA
11306 NA NA NA
11307 NA NA NA
11308 NA NA NA
11352 NA NA NA
11355 NA NA NA
11666 NA NA NA
11667 NA NA NA
NA = not available
EXAMPLE 163
Cell Proliferation Inhibition
Table 6:
Figure imgf000167_0001
All cells were cultured in media supplemented with 10% FBS except for which are marked specially, in the temperature of 37 °C, 5% C02 and 95% humidity. All culture media were purchased from GIBCO (USA, IMDM Cat. 12200-036; RPMI Medium 1640 Cat.31800- 022; 2-mercaptoethanol Cat. 21985-023).
Reagents:
CellTiter 96® AQueous MTS reagent powder (Cat. No.: Gl 1 12, Promega. Store MTS Reagent Powder desiccated at 4°C protected from light.)
Phenazine methosulfate (PMS) (Product No.: P9625, SIGMA. Store PMS Powder desiccated at 4°C protected from light.)
Preparation of PMS solution:
B4002959vl - 166 - 0.92 mg/mL PMS in DPBS Filter-sterilize through a 0.2 m filter into a sterile, light-protected container. Store at -20°C.
Preparation of MTS solution:
The following protocol is recommended for the preparation of 21 mL of MTS solution (sufficient for ten 96-well plates).
a. Select a light-protected container or wrap a container with foil.
b. Add 21 mL of DPBS to the container.
c. Weigh out 42 mg of MTS Reagent Powder and add to DPBS .
d. Mix at moderate speed on a magnetic stir plate for 15 minutes or until the MTS
is completely dissolved.
e. Measure the pH of the MTS solution. The optimum pH is between pH 6.0 to 6.5. If the solution is above pH 6.5, adjust to pH 6.5 with 1 N HC1.
f. Filter-sterilize the MTS solution through a 0.2 μιτι filter into a sterile, light
protected container.
g. Store the MTS solution at -20°C, protected from light.
Preparation of the mixture of MTS/PMS:
a. In order to prepare reagents sufficient for one 96-well plate containing cells cultured in a 100 volume, thaw the MTS solution and the PMS solution. It should take approximately 90 minutes at room temperature or 10 minutes in a 37 °C water bath to completely thaw the 20 mL size of MTS solution. (Note: For convenience, the first time the product is thawed, the entire contents of the 1 mL tube of PMS solution can be transferred to the 20 mL bottle of MTS solution. This mixture should be stored at -20 °C between uses. If storing PMS and MTS solutions at 4°C, do not combine these solutions until immediately before addition to the assay plate.)
b. Remove 2.0 mL of MTS solution from the amber reagent bottle using aseptic technique and transfer to a test tube.
c. Add 100 of PMS solution to the 2.0 mL of MTS solution immediately before
addition to the culture plate containing cells.
d. Gently swirl the tube to ensure complete mixing of the combined MTS/PMS solution.
B4002959vl - 167 - Equipment:
SpectraMAX plus microplate spectrophotometer Model 3011, Molecular Devices Corp. (California, USA); CO2 water jacketed incubator, Therma (USA). Reverse microscope, Chongguang XDS-IB, Chongqing Guangdian Corp. (Chongqing, P.R.China). Cytotoxicity and IC50 determination:
1. The cells were harvested respectively during the logarithmic growth period and
counted with hemocytometer. The cell viability was over 98 % by trypan blue exclusion.
2. Cell concentrations were adjusted to 2.22 χ 105 or 1.11 x 105 or 5.56 x 104 cells/mL with respective medium.
3. 90 cell suspensions were added to 96-well plates (triplicates for each cell
concentration), the final cell densities were 2 x 10 4 or lx l04 or 103 cells/well. The density of 5 x 103 cells/well was used for the first test. The appropriate cell density was determined and adjusted according to the results of the first test.
4. The next day, test article or positive drugs were dissolved with DMSO as stock solution at the concentration of 20 mM.
5. 10 drug solution was dispensed in each well (triplicate for each drug concentration).
6. Plates were cultured for another 72 hours, then measured by means of MTS assay.
7. MTS/PMS solution was prepared immediately prior to use. 20 \L of the mixture was introduced into each well of the 96-well assay plate containing 100 culture medium.
(The final reaction volume was 120 \L).
8. Plate was incubated for 1-4 hours at 37 °C in a humidified 5% CO2 atmosphere.
9. Absorbance at 490 nm was recorded using SpectraMAX Plus microplate
spectrophotometer.
Data analysis:
The software of GraphPad Prism version 5 was used to calculate IC50. The graphical curves were fitted using a nonlinear regression model with a sigmoidal dose.
Results
Results are shown in Table 7.
B4002959vl - 168 - Table 7: IC50 values (μΜ)
Figure imgf000170_0001
B4002959vl - 169- Compound MV4-11 RPMI 8226 NCI-H929
11217 NA >30 >30
11220 NA >30 >30
11221 NA 14 17.5
11222 NA 20.3 11.7
11223 NA 25.3 28.7
11224 NA >30 14.3
11225 NA >30 16.1
11226 NA >30 >30
11227 NA 24.8 12.4
11232 NA >30 >30
11234 NA 7.9 22.3
11235 NA 11.5 18.6
11236 NA 12.2 >30
11237 NA 8.9 >30
11240 NA >30 19
11241 NA 5.7 8.7
11242 NA 16 9.1
11243 NA 12.4 6.2
11244 NA 11.4 8.6
11246 NA 21.8 7
11247 NA 11.5 12.3
11248 NA 14.7 9.6
11249 NA 11.1 6
11250 NA 9.9 7.1
11251 NA 15.8 14.9
11263 NA 12.3 4
11264 NA >30 11.3
11266 NA >30 17
11267 NA >30 >30
11268 NA >30 >30
11269 NA 12.7 >30
11271 7.2 NA 7.5
11272 8.3 NA 9
11273 4.7 NA 7.8
11274 >30 NA >30
11275 7.5 NA >30
11276 >30 NA >30
11279 1.4 NA 10.7
11280 >30 NA >30
11288 11.7 NA >30
11289 0.63 NA 2.4
11290 >30 NA >30
11291 >30 NA >30
11293 26.7 NA 8.4 2959vl - 170 - Compound MV4-11 PMI 8226 NCI-H929
11299 5.4 NA 11.1
11300 1.8 NA 12.1
11301 24.5 NA >30
11303 >30 NA >30
11304 >30 NA >30
11306 13.5 NA >30
11307 0.43 NA 3.1
11308 6.8 NA >30
11352 >30 NA >30
11355 4.7 NA 14.7
11666 NA NA NA
11667 NA NA NA
NA = not available
EXAMPLE 164
Table 8: Percent Activity of Enzyme When Treated with 100 nM of Compound (ATP Concentration = Km of Enzyme)
Figure imgf000172_0001
IC50 (nM) for compound 11198 (with ATP concentration = Km of enzyme):
Pim-l(h), 25; Pim-2(h), 15; Pim-3(h), 6.
B4002959vl - 171 - EXAMPLE 165
Table 9: Percent Activity of Enzyme When Treated with 300 nM of Compound (ATP Concentration = Km of Enzyme)
Figure imgf000173_0001
B4002959vl - 172 - Compound CKly2(h) CKl(y) CK2(h) Pim-l(h) Pim-2(h) Pim-3(h)
11235 39 57 86 9 17 28
11236 43 70 86 16 25 38
11237 39 66 94 24 41 52
11240 26 98 77 57 49 40
11241 55 85 88 53 27 86
11242 83 79 64 25 24 7
11243 63 79 80 5 21 10
11244 68 98 80 66 35 69
11246 56 44 67 3 4 4
11247 31 45 83 13 12 37
11248 34 -3 68 3 7 5
11249 72 71 64 17 18 10
11250 32 65 81 11 12 11
11251 92 97 87 4 18 7
11263 75 72 72 30 22 9
11264 33 71 74 24 20 14
11266 75 62 87 21 20 11
11267 58 92 91 8 23 9
11268 95 114 85 115 108 80
11269 105 90 90 105 120 97
11271 102 96 71 51 69 32
11272 67 96 89 83 76 66
11273 60 83 71 52 66 49
11274 108 100 80 95 99 99
11275 106 107 97 116 112 106
11276 90 94 84 98 101 85
11279 73 82 73 94 89 87
11280 107 92 84 87 99 80
11288 94 97 84 39 7 11
11289 85 58 63 6 2 1
11290 -7 99 92 86 90 103
11291 89 86 42 26 15 10
11293 71 92 70 13 17 10
11299 82 67 71 6 27 31
11300 93 93 63 32 20 21
11301 34 106 76 84 89 104
11303 0 89 75 93 91 95
11304 21 104 82 89 71 97
11306 93 94 82 59 30 85
11307 39 73 78 4 3 12
11308 82 105 84 35 14 53
11352 76 77 70 45 48 38
11355 47 67 52 6 5 6
11666 24 42 84 11 4 8 002959vl - 173 - Compound CKly2(h) CKl(y) CK2(h) Pim-l(h) Pim-2(h) Pim-3(h)
11667 -1 22 73 17 8 10
EXAMPLE 166
Table 10: ICS0 (nM) of Compound When ATP Concentration = Km of Enzyme
Compound CKly2(h) CKl(y) CK2(h) Pim-l(h) Pim-2(h) Pim-3(h)
11214 16 38 27
11216 17 5 4
11243 8 57 36
11248 4 2 3
11249 89 27 16
11250 35 18 80
11251 5 33 6
11267 7 27 48
11289 0.7 0.9 1
11290 1
11293 83 60 62
B4002959vl - 174 - INCORPORATION BY REFERENCE
All of the U.S. patents and U.S. published patent applications cited herein are hereby incorporated by reference. EQUIVALENTS
While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or
modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention.
B4002959vl - 175 -

Claims

We claim:
1. A compound of formula 1 or a pharmaceutically acceptable salt thereof,
Figure imgf000177_0001
1
wherein independently for each occurrence:
W is C(R C(R1)2C( 1)2, C(R1)2C(R1)2C(R1)2, or S(0)2;
X is nitrogen or CR2;
Y is nitrogen or CR3;
Z is nitrogen or CR4;
R1 is hydrogen or alkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl; or R3 and R4 are joined together to form an optionally substituted heterocyclic ring;
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted;
B4002959vl - 176 - wherein the compound is not
Figure imgf000178_0001
2. The compound of claim I, wherein R1 is hydrogen.
3. The compound of claim 1, wherein R1 is methyl.
4. The compound of claim 1, wherein W is S(0)2.
5. The compound of claim 1 , wherein W is CH2.
6. The compound of claim 1, wherein R2 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
7. The compound of claim 1, wherein R2 is hydrogen.
8. The compound of claim 1, wherein R2 is methyl.
9. The compound of claim 1, wherein R2 is fluorine.
10. The compound of claim 1, wherein R2 is an optionally substituted heteroaryl.
11. The compound of claim 1 , wherein R2 is an optionally substituted aryl.
12. The compound of claim 1, wherein R3 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
13. The compound of claim 1 , wherein R3 is hydrogen.
14. The compound of claim 1, wherein R3 is methyl.
15. The compound of claim 1, wherein R3 is fluorine.
16. The compound of claim 1, wherein R3 is an optionally substituted heteroaryl.
17. The compound of claim 1, wherein R3 is an optionally substituted aryl.
B4002959vl - 177 -
18. The compound of claim 1 , wherein R3 is an optionally substituted heterocyclylalkyl.
19. The compound of claim 1, wherein R3 and R4 are joined together to form an optionally substituted aryl.
20. The compound of claim 1 , wherein R3 and R4 are joined together to form an optionally substituted heterocyclyl.
21. The compound of claim 1 , wherein R3 and R4 are joined together to form an optionally substituted heteroaryl.
22. The compound of claim 1, wherein R4 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
23. The compound of claim 1 , wherein R4 is hydrogen.
24. The compound of claim 1, wherein R4 is methyl.
25. The compound of claim 1, wherein R4 is fluorine.
26. The compound of claim 1, wherein R4 is an optionally substituted heteroaryl.
27. The compound of claim 1 , wherein R4 is an optionally substituted aryl.
28. The compound of claim 1, wherein R4 is an optionally substituted heterocyclylalkyl.
29. The compound of claim 1, wherein R5 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
30. The compound of claim 1, wherein R5 is hydrogen.
31. The compound of claim 1 , wherein R5 is methyl.
32. The compound of claim 1, wherein R5 is fluorine.
33. The compound of claim 1, wherein R5 is an optionally substituted heteroaryl.
34. The compound of claim 1 , wherein R5 is an optionally substituted aryl.
35. The compound of claim 1 , wherein R5 is an optionally substituted heterocyclylalkyl.
36. The compound of claim 1, wherein R6 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
37. The compound of claim 1, wherein R6 is hydrogen.
38. The compound of claim 1, wherein R6 is methyl.
B4002959vl - 178 -
39. The compound of claim 1, wherein R6 is fluorine.
40. The compound of claim 1, wherein R6 is an optionally substituted heteroaryl.
41. The compound of claim 1 , wherein R6 is an optionally substituted aryl.
42. The compound of claim 1 , wherein R6 is an optionally substituted heterocyclylalkyl.
43. A compound of formula 2 or a pharmaceutically acceptable salt thereof,
Figure imgf000180_0001
2
wherein independently for each occurrence:
X is nitrogen or CR2;
Y is nitrogen or CR3;
Z is nitrogen or CR4;
R1 is hydrogen or alkyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl; or R3 and R4 are joined together to form an optionally substituted heterocyclic ring;
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
B4002959vl - 179 - R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, trifluoromethyl, perfluoroalkyl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, trifluoromethoxy, hydroxyalkyl, and alkoxyalkyl;
wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.
44. The compound of claim 43, wherein R1 is hydrogen.
4 . The compound of claim 43 , wherein R1 is methyl.
46. The compound of claim 43, wherein R2 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
47. The compound of claim 43, wherein R2 is hydrogen.
48. The compound of claim 43, wherein R2 is methyl.
49. The compound of claim 43, wherein R2 is fluorine.
50. The compound of claim 43, wherein R2 is an optionally substituted heteroaryl.
51. The compound of claim 43, wherein R2 is an optionally substituted aryl.
52. The compound of claim 43, wherein R3 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
53. The compound of claim 43 , wherein R3 is hydrogen.
54. The compound of claim 43, wherein R3 is methyl.
55. The compound of claim 43, wherein R3 is fluorine.
56. The compound of claim 43, wherein R3 is an optionally substituted heteroaryl.
57. The compound of claim 43, wherein R3 is an optionally substituted aryl.
58. The compound of claim 43, wherein R3 is an optionally substituted
heterocyclylalkyl.
59. The compound of claim 43, wherein R3 and R4 are joined together to form an optionally substituted aryl.
60. The compound of claim 43, wherein R3 and R4 are joined together to form an optionally substituted heterocyclyl.
B4002959vl - 180 -
61. The compound of claim 43, wherein R3 and R are joined together to form an optionally substituted heteroaryl.
62. The compound of claim 43, wherein R4 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
63. The compound of claim 43, wherein R4 is hydrogen.
64. The compound of claim 43, wherein R4 is methyl.
65. The compound of claim 43, wherein R4 is fluorine.
66. The compound of claim 43, wherein R4 is an optionally substituted heteroaryl.
67. The compound of claim 43, wherein R4 is an optionally substituted aryl.
68. The compound of claim 43, wherein R4 is an optionally substituted
heterocyclylalkyl.
69. The compound of claim 43, wherein R5 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
70. The compound of claim 43, wherein R5 is hydrogen.
71. The compound of claim 43 , wherein R5 is methyl.
72. The compound of claim 43, wherein R5 is fluorine.
73. The compound of claim 43, wherein R5 is an optionally substituted heteroaryl.
74. The compound of claim 43, wherein R5 is an optionally substituted aryl.
75. The compound of claim 43 , wherein R5 is an optionally substituted
heterocyclylalkyl.
76. The compound of claim 43, wherein R6 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, and halo.
77. The compound of claim 43, wherein R6 is hydrogen.
78. The compound of claim 43, wherein R6 is methyl.
79. The compound of claim 43, wherein R6 is fluorine.
80. The compound of claim 43, wherein R6 is an optionally substituted heteroaryl.
81. The compound of claim 43 , wherein R6 is an optionally substituted aryl.
B4002959vl - 181 -
82. The compound of claim 43, wherein R6 is an optionally substituted
heterocyclylalkyl.
83. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure imgf000183_0001
B4002959vl - 182 -
Figure imgf000184_0001
Figure imgf000184_0002
Figure imgf000184_0003
B4002959vl - 183-
Figure imgf000185_0001
Figure imgf000185_0002
B4002959vl - 184-
Figure imgf000186_0001
Figure imgf000186_0002
B4002959vl - 185-
Figure imgf000187_0001
87. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
B4002959vl - 186 -
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000189_0002
B4002959vl - 188-
Figure imgf000190_0001
Figure imgf000190_0002
B4002959vl - 189-
Figure imgf000191_0001
90. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
B4002959vl - 190 -
Figure imgf000192_0001
Figure imgf000192_0002
B4002959vl - 191 -
92. The compound of any one of claims 1-89, wherein the compound is an inhibitor of casein kinase 1 (CK1), CKlyl, CKly2, or CKly3.
93. The compound of claim 92, wherein the compound has an IC50 of less than 5000 nM for CK1, CKlyl, CKly2, or CKly3.
94. The compound of claim 93, wherein the compound has an IC50 of less than 1000 nM for CK1, CKlyl, CKly2, or CKly3.
95. The compound of claim 94, wherein the compound has an IC50 of less than 500 nM for CK1, CKlyl, CKly2, or CKly3.
96. The compound of any one of claims 1-89, wherein the compound is an inhibitor of casein kinase 2 (CK2).
97. The compound of claim 96, wherein the compound has an IC50 of less than 5000 nM for CK2.
98. The compound of claim 97, wherein the compound has an IC50 of less than 1000 nM for CK2.
99. The compound of claim 98, wherein the compound has an IC50 of less than 500 nM for CK2.
100. The compound of any one of claims 1-89, wherein the compound is an inhibitor of Pim-1, Pim-2, or Pim-3.
101. The compound of claim 100, wherein the compound has an IC50 of less than 5000 nM for Pim-1, Pim-2, or Pim-3.
102. The compound of claim 101, wherein the compound has an IC50 of less than 1000 nM for Pim-1, Pim-2, or Pim-3.
103. The compound of claim 102, wherein the compound has an IC50 of less than 500 nM for Pim-1, Pim-2, or Pim-3.
104. The compound of any one of claims 1-89, wherein the compound is an inhibitor of the Wnt pathway.
105. The compound of any one of claims 1-89, wherein the compound is an inhibitor of the TGF pathway.
B4002959vl - 192 -
106. The compound of any one of claims 1-89, wherein the compound is an inhibitor of the JAK/STAT pathway.
107. The compound of any one of claims 1-89, wherein the compound is an inhibitor of the mTOR pathway.
108. The compound of any one of claims 1-89, wherein the compound is a modulator of Pgp degradation, drug efflux, or drug resistance.
109. A pharmaceutical composition, comprising a compound of any one of claims 1-108 and a pharmaceutically acceptable excipient.
110. A method of inhibiting CKl activity, comprising contacting casein kinase 1 (CKl), CKlyl, CKly2, or CKly3 with a compound of any one of claims 1-108, or a
pharmaceutical composition of claim 109.
111. A method of inhibiting casein kinase 2 (CK2) activity, comprising contacting CK2 with a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
112. A method for treating or preventing a condition associated with aberrant casein kinase 1 (CKl), CKlyl, CKly2, or CKly3 activity, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1- 108, or a pharmaceutical composition of claim 109.
113. A method for treating or preventing a condition associated with aberrant casein kinase 2 (CK2) activity, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
114. A method of treating cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
115. The method of claim 114, wherein the cancer is a cancer of the hematopoietic system, immune system, endocrine system, pulmonary system, gastrointestinal system, musculoskeletal system, reproductive system, central nervous system or urologic system.
116. The method of claim 114, wherein the cancer is located in the mammal's myeloid tissues, lymphoid tissues, pancreatic tissues, thyroid tissues, lung tissues, colon tissues,
B4002959vl - 193 - rectal tissues, anal tissues, liver tissues, skin, bone, ovarian tissues, uterine tissues, cervical tissues, breast, prostate, testicular tissues, brain, brainstem, meningeal tissues, kidney or bladder.
117. The method of claim 114, wherein the cancer is breast cancer, colon cancer, multiple myeloma, prostate cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, multiple myeloma, renal cell carcinoma, malignant melanoma, pancreatic cancer, lung cancer, colorectal carcinoma, brain cancer, head and neck cancer, bladder cancer, thyroid cancer, ovarian cancer, cervical cancer or myelodysplastic syndrome.
118. A method of treating Alzheimer's disease, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1- 108, or a pharmaceutical composition of claim 109.
119. A method of treating a Wnt-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
120. A method of treating a TGFP-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
121. A method of treating a JAK/STAT-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
122. A method of treating an mTOR-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
123. A method of treating or preventing a disease or condition selected from the group consisting of inflammation, inflammatory disease, neurological conditions and
neurodegeneration, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
124. The method of claim 123, wherein the disease or condition is an inflammatory disease selected from the group consisting of osteoarthritis and rheumatoid arthritis.
B4002959vl - 194 -
125. A method of treating or preventing a bone -related disease or facilitating bone restoration, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
126. The method of claim 125, wherein the bone-related disease is osteoporosis.
127. A method of treating or preventing a condition selected from the group consisting of hypoglycemia, metabolic syndrome and diabetes, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
128. A method of increasing the rate of apoptosis in cancerous cells in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
129. A method of treating or preventing aberrant embryonic development, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
130. A method of inhibiting Pirn activity, comprising contacting Pim-1, Pim-2 or Pim-3 with a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
131. A method for treating or preventing a condition associated with aberrant Pirn activity, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
132. A method of modulating Pgp degradation and/or drug efflux activity, comprising contacting a cell with an effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
133. A method for treating a malignancy based upon modulation of Pgp, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109.
134. A method for treating a malignancy based upon modulation of Pgp, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-108, or a pharmaceutical composition of claim 109, in
B4002959vl - 195 - conjunction with another drug, compound, or material, to abrogate resistance to the drug, compound, or material.
B4002959vl - 196 -
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