Aminopyrimidine Kinase Inhibitors

Information

  • Patent Application
  • 20120270892
  • Publication Number
    20120270892
  • Date Filed
    April 20, 2012
    12 years ago
  • Date Published
    October 25, 2012
    12 years ago
Abstract
Disclosed are compounds, pharmaceutical compositions containing those compounds, and uses of the compounds and compositions as modulators of casein kinase 1 (e.g., CK1γ), casein kinase 2 (CK2), Pim-1, Pim-2, Pim-3, the TGFβ 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., CK1γ), casein kinase 2 (CK2), Pim-1, Pim-2, Pim-3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, and/or the mTOR pathway.
Description
BACKGROUND OF THE INVENTION

Casein kinase 1 (CK1) is a family of evolutionarily conserved serine/threonine kinases including seven known members in vertebrates (CK1α, -β, -γ1, -γ2, -γ3, -δ and -ε). The CK1s 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 CK1s, 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 CK1α, β, γ1-3, 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 CK1δ 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.


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)-1, 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-1−/−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, including the positive regulation of transcription of nuclear factor kappa-B (NF-κB)-responsive genes, which have implications in both inflammation and oncology. Therefore, Pim kinases are attractive targets for both therapeutic areas.


Further, Pim 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 Pim 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:




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wherein independently for each occurrence:


W is C(R1)2, C(R1)2C(R1)2, C(R1)2C(R1)2C(R1)2, or S(O)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;


wherein the compound is not




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An embodiment relates to a compound of formula 2 or a pharmaceutically acceptable salt thereof:




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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.


An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:




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An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:




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An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:




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An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:




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An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:




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An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:




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An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:




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An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:




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An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:




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An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment the compound has an IC50 of less than 5000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment the compound has an IC50 of less than 1000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment the compound has an IC50 of less than 500 nM for CK1, CK1γ1, CK1γ2, or CK1γ3.


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 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 TGFβ 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 CK1 activity, comprising contacting CK1, CK1γ1, CK1γ2, or CK1γ3 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 CK1, CK1γ1, CK1γ2, or CK1γ3 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.


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 TGFβ-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.


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 Pim-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 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.


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, 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 polycycles. 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 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, —Cl, —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 —SO2. “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:




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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 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:




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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:




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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:




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wherein X50 is a bond or represents an oxygen or a sulfur, and R55 and R56 represents a hydrogen, an alkyl, an alkenyl, —(CH2)m—R61 or 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 —O(C═O)NRR′, where R and R′ are independently H, aliphatic groups, aryl groups or heteroaryl groups.


The term “oxo” refers to a carbonyl oxygen (═O).


The terms “oxime” and “oxime ether” are art-recognized and refer to moieties that may be represented by the general formula:




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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 —(CH2)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, —O—(CH2)m—R61, where m and R61 are described above.


The term “sulfonate” is art recognized and refers to a moiety that may be represented by the general formula:




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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:




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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:




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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:




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in 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:




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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:




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in which R58 is defined above.


The term “phosphoryl” is art-recognized and may in general be represented by the formula:




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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:




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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:




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wherein Q51, R50, R51 and R59 are as defined above.


The term “phosphonamidite” is art-recognized and may be represented in the general formulas:




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wherein Q51, R50, R51 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 nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-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, p-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 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 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 (—NRC(═O)R) or a urethane (—NRC(═O)OR), for example, as: a methyl amide (—NHC(═O)CH3); a benzyloxy amide (—NHC(═O)OCH2C6H5NHCbz); as a t-butoxy amide (—NHC(═O)OC(CH3)3, —NHBoc); a 2-biphenyl-2-propoxy amide (—NHC(═O)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. 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-1,4-dioate, hexyne-1,6-dioate, benzoate, 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 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 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 (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyl-oxymethyl, N—(C1-C6)alkoxycarbonylamino-methyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanoyl, arylactyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl wherein said α-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, —P(O)(OH)2, —P(O)(O(C1-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(O)OH or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (C1-C4)alkyl, (C2-C12)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, 1-(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—(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)-alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(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 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,




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wherein independently for each occurrence:


W is C(R1)2, C(R1)2C(R1)2, C(R1)2C(R1)2C(R1)2, or S(O)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;


wherein the compound is not




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In one embodiment, R1 is hydrogen.


In one embodiment, R1 is methyl.


In one embodiment, W is S(O)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.


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,




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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.


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.


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.


In one embodiment, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:




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In one embodiment, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:




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In one embodiment, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:




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In one embodiment, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:




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In one embodiment, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:




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In one embodiment, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:




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In one embodiment, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:




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In one embodiment, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:




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In one embodiment, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:




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Any one of the aforementioned compounds may exist as the E-geometric isomer, the Z-geometric isomer, or mixtures thereof. For example, in one embodiment,




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in the aforementioned structures represents the E-isomer of the particular compound. In another embodiment,




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represents the Z-isomer of the particular compound. In yet another embodiment,




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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 CK1γ1, CK1γ2, or CK1γ3.


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.


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 TGFβ pathway.


In some embodiments, the compound has an IC50 of less than 5000 nM for CK1γ1, CK1γ2, or CK1γ3.


In some embodiments, the compound has an IC50 of less than 1000 nM for CK1γ1, CK1γ2, or CK1γ3.


In some embodiments, the compound has an IC50 of less than 500 nM for CK1γ1, CK1γ2, or CK1γ3.


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.


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.










Structure
ID
MW
Name







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A1 
203.997
6-bromo-4- fluoropicolinaldehyde







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A2 
186.006
6-bromopicolinaldehyde







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A3 
200.033
6-bromo-4- methylpicolinaldehyde







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A4 
216.032
6-bromo-3- methoxypicolinaldehyde







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A5 
254.004
6-bromo-4- (trifluoromethyl) picolinaldehyde







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A6 
236.065
3-bromoisoquinoline- 1-carbaldehyde







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A7 
186.006
2-bromonicotinaldehyde







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A8 
236.065
2-bromoquinoline- 3-carbaldehyde







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A9 
186.006
6-bromonicotinaldehyde







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A10
211.016
2-bromo-5- formylnicotinonitrile







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A11
258.069
ethyl 2-bromo- 5-formylnicotinate







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A12
186.006
2- bromoisonicotinaldehyde







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A13
254.004
2-bromo-6- (trifluoromethyl) isonicotinaldehyde







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A14
203.997
2-bromo-5- fluoroisonicotinaldehyde







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A15
201.021
6-amino-2- bromonicotinaldehyde







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A16
185.018
2-bromobenzaldehyde







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A17
185.018
3-bromobenzaldehyde
















TABLE 2







Reactant B Prophetic Examples.










Structure
ID
MW
Name







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B1 
257.926
(2,4-bis (trifluoromethyl) phenyl)boronic acid







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B2 
181.982
(2,4- dimethoxyphenyl) boronic acid







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B3 
205.927
(2- (trifluoromethoxy) phenyl)boronic acid







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B4 
179.966
2-borono-4- methylbenzoic acid







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B5 
165.939
benzo[d][1,3] dioxol-5- ylboronic acid







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B6 
255.077
(3- (benzylcarbamoyl) phenyl)boronic acid







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B7 
164.997
(3- (dimethylamino) phenyl)boronic acid







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B8 
178.981
(3- acetamidophenyl) boronic acid







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B9 
214.025
(4- phenoxyphenyl) boronic acid







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B10
160.966
(1H-indol-5- yl)boronic acid







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B11
172.976
isoquinolin-5- ylboronic acid







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B12
127.957
thiophen-3- ylboronic acid







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B13
178.016
benzo[b] thiophen- 3-ylboronic acid







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B14
169.994
(5- acetylthiophen- 2-yl)boronic acid







embedded image


B15
111.892
furan-2- ylboronic acid







embedded image


B16
161.95 
benzofuran-2- ylboronic acid







embedded image


B17
111.892
furan-3- ylboronic acid







embedded image


B18
110.907
(1H-pyrrol-2- yl)boronic acid







embedded image


B19
172.976
isoquinolin-4- ylboronic acid







embedded image


B20
172.976
quinolin-4- ylboronic acid







embedded image


B21
140.908
(3-fluoropyridin- 4-yl)boronic acid







embedded image


B22
158.899
(2,6- difluoropyridin- 4-yl)boronic acid







embedded image


B23
165.985
(6- (dimethylamino) pyridin- 3-yl)boronic acid







embedded image


B24
166.973
(2- (dimethylamino) pyrimidin-5- yl)boronic acid







embedded image


B25
140.933
(3,5- dimethylisoxazol- 4-yl)boronic acid







embedded image


B26
111.895
(1H-pyrazol-4- yl)boronic acid







embedded image


B27
111.895
(1H-pyrazol- 5-yl)boronic acid









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.










Mol.
Reactant












No.
Chemical Name
Formula
Weight
A
B















1
(Z)-5-((2-(4-((((6-(2,4-bis(trifluoromethyl)phenyl)-4-
C28H23F7N6O2S
640.575
A1
B1



fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


2
(Z)-5-((2-(4-((((6-(2,4-
C28H24F6N6O2S
622.585
A2
B1



bis(trifluoromethyl)phenyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


3
(Z)-5-((2-(4-((((6-(2,4-bis(trifluoromethyl)phenyl)-4-
C29H26F6N6O2S
636.611
A3
B1



methylpyridin-2-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


4
(Z)-5-((2-(4-((((6-(2,4-bis(trifluoromethyl)phenyl)-3-
C29H26F6N6O3S
652.611
A4
B1



methoxypyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


5
(Z)-5-((2-(4-((((6-(2,4-bis(trifluoromethyl)phenyl)-4-
C29H23F9N6O2S
690.583
A5
B1



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


6
(Z)-5-((2-(4-((((3-(2,4-
C32H26F6N6O2S
672.643
A6
B1



bis(trifluoromethyl)phenyl)isoquinolin-1-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


7
(Z)-5-((2-(4-((((2-(2,4-
C28H24F6N6O2S
622.585
A7
B1



bis(trifluoromethyl)phenyl)pyridin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


8
(Z)-5-((2-(4-((((2-(2,4-
C32H26F6N6O2S
672.643
A8
B1



bis(trifluoromethyl)phenyl)quinolin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


9
(Z)-5-((2-(4-((((6-(2,4-
C28H24F6N6O2S
622.585
A9
B1



bis(trifluoromethyl)phenyl)pyridin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


10
(Z)-2-(2,4-bis(trifluoromethyl)phenyl)-5-((((1-(4-
C29H23F6N7O2S
647.594
A10
B1



((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-



yl)methyl)amino)methyl)nicotinonitrile


11
(Z)-ethyl 2-(2,4-bis(trifluoromethyl)phenyl)-5-((((1-
C31H28F6N6O4S
694.647
A11
B1



(4-((2,4-dioxothiazolidin-5-



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)nicotinate


12
(Z)-5-((2-(4-((((2-(2,4-
C28H24F6N6O2S
622.585
A12
B1



bis(trifluoromethyl)phenyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


13
(Z)-5-((2-(4-((((2-(2,4-bis(trifluoromethyl)phenyl)-6-
C29H23F9N6O2S
690.583
A13
B1



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


14
(Z)-5-((2-(4-((((2-(2,4-bis(trifluoromethyl)phenyl)-5-
C28H23F7N6O2S
640.575
A14
B1



fluoropyridin-4-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


15
(Z)-5-((2-(4-((((6-amino-2-(2,4-
C28H25F6N7O2S
637.599
A15
B1



bis(trifluoromethyl)phenyl)pyridin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


16
(Z)-5-((2-(4-((((6-(2,4-dimethoxyphenyl)-4-
C28H29FN6O4S
564.631
A1
B2



fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


17
(Z)-5-((2-(4-((((6-(2,4-dimethoxyphenyl)pyridin-2-
C28H30N6O4S
546.641
A2
B2



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


18
(Z)-5-((2-(4-((((6-(2,4-dimethoxyphenyl)-4-
C29H32N6O4S
560.667
A3
B2



methylpyridin-2-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


19
(Z)-5-((2-(4-((((6-(2,4-dimethoxyphenyl)-3-
C29H32N6O5S
576.667
A4
B2



methoxypyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


20
(Z)-5-((2-(4-((((6-(2,4-dimethoxyphenyl)-4-
C29H29F3N6O4S
614.639
A5
B2



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


21
(Z)-5-((2-(4-((((3-(2,4-dimethoxyphenyl)isoquinolin-
C32H32N6O4S
596.699
A6
B2



1-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


22
(Z)-5-((2-(4-((((2-(2,4-dimethoxyphenyl)pyridin-3-
C28H30N6O4S
546.641
A7
B2



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


23
(Z)-5-((2-(4-((((2-(2,4-dimethoxyphenyl)quinolin-3-
C32H32N6O4S
596.699
A8
B2



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


24
(Z)-5-((2-(4-((((6-(2,4-dimethoxyphenyl)pyridin-3-
C28H30N6O4S
546.641
A9
B2



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


25
(Z)-2-(2,4-dimethoxyphenyl)-5-((((1-(4-((2,4-
C29H29N7O4S
571.65
A10
B2



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-



yl)methyl)amino)methyl)nicotinonitrile


26
(Z)-ethyl 2-(2,4-dimethoxyphenyl)-5-((((1-(4-((2,4-
C31H34N6O6S
618.703
A11
B2



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-yl)methyl)amino)methyl)nicotinate


27
(Z)-5-((2-(4-((((2-(2,4-dimethoxyphenyl)pyridin-4-
C28H30N6O4S
546.641
A12
B2



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


28
(Z)-5-((2-(4-((((2-(2,4-dimethoxyphenyl)-6-
C29H29F3N6O4S
614.639
A13
B2



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


29
(Z)-5-((2-(4-((((2-(2,4-dimethoxyphenyl)-5-
C28H29FN6O4S
564.631
A14
B2



fluoropyridin-4-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


30
(Z)-5-((2-(4-((((6-amino-2-(2,4-
C28H31N7O4S
561.655
A15
B2



dimethoxyphenyl)pyridin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


31
(Z)-5-((2-(4-((((4-fluoro-6-(2-
C27H24F4N6O3S
588.576
A1
B3



(trifluoromethoxy)phenyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


32
(Z)-5-((2-(4-((((6-(2-
C27H25F3N6O3S
570.586
A2
B3



(trifluoromethoxy)phenyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


33
(Z)-5-((2-(4-((((4-methyl-6-(2-
C28H27F3N6O3S
584.613
A3
B3



(trifluoromethoxy)phenyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


34
(Z)-5-((2-(4-((((3-methoxy-6-(2-
C28H27F3N6O4S
600.612
A4
B3



(trifluoromethoxy)phenyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


35
(Z)-5-((2-(4-((((6-(2-(trifluoromethoxy)phenyl)-4-
C28H24F6N6O3S
638.584
A5
B3



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


36
(Z)-5-((2-(4-((((3-(2-
C31H27F3N6O3S
620.645
A6
B3



(trifluoromethoxy)phenyl)isoquinolin-1-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


37
(Z)-5-((2-(4-((((2-(2-
C27H25F3N6O3S
570.586
A7
B3



(trifluoromethoxy)phenyl)pyridin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


38
(Z)-5-((2-(4-((((2-(2-
C31H27F3N6O3S
620.645
A8
B3



(trifluoromethoxy)phenyl)quinolin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


39
(Z)-5-((2-(4-((((6-(2-
C27H25F3N6O3S
570.586
A9
B3



(trifluoromethoxy)phenyl)pyridin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


40
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C28H24F3N7O3S
595.595
A10
B3



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(2-



(trifluoromethoxy)phenyl)nicotinonitrile


41
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C30H29F3N6O5S
642.649
A11
B3



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(2-



(trifluoromethoxy)phenyl)nicotinate


42
(Z)-5-((2-(4-((((2-(2-
C27H25F3N6O3S
570.586
A12
B3



(trifluoromethoxy)phenyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


43
(Z)-5-((2-(4-((((2-(2-(trifluoromethoxy)phenyl)-6-
C28H24F6N6O3S
638.584
A13
B3



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


44
(Z)-5-((2-(4-((((5-fluoro-2-(2-
C27H24F4N6O3S
588.576
A14
B3



(trifluoromethoxy)phenyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


45
(Z)-5-((2-(4-((((6-amino-2-(2-
C27H26F3N7O3S
585.601
A15
B3



(trifluoromethoxy)phenyl)pyridin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


46
(Z)-2-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C28H27FN6O4S
562.615
A1
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-4-fluoropyridin-2-yl)-4-



methylbenzoic acid


47
(Z)-2-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C28H28N6O4S
544.625
A2
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-yl)-4-



methylbenzoic acid


48
(Z)-2-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C29H30N6O4S
558.651
A3
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-4-methylpyridin-2-yl)-4-



methylbenzoic acid


49
(Z)-2-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C29H30N6O5S
574.651
A4
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-5-methoxypyridin-2-yl)-4-



methylbenzoic acid


50
(Z)-2-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C29H27F3N6O4S
612.623
A5
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-4-(trifluoromethyl)pyridin-



2-yl)-4-methylbenzoic acid


51
(Z)-2-(1-((((1-(4-((2,4-dioxothiazolidin-5-
C32H30N6O4S
594.683
A6
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)isoquinolin-3-yl)-4-



methylbenzoic acid


52
(Z)-2-(3-((((1-(4-((2,4-dioxothiazolidin-5-
C28H28N6O4S
544.625
A7
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-yl)-4-



methylbenzoic acid


53
(Z)-2-(3-((((1-(4-((2,4-dioxothiazolidin-5-
C32H30N6O4S
594.683
A8
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)quinolin-2-yl)-4-



methylbenzoic acid


54
(Z)-2-(5-((((1-(4-((2,4-dioxothiazolidin-5-
C28H28N6O4S
544.625
A9
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-yl)-4-



methylbenzoic acid


55
(Z)-2-(3-cyano-5-((((1-(4-((2,4-dioxothiazolidin-5-
C29H27N7O4S
569.634
A10
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-yl)-4-



methylbenzoic acid


56
(Z)-2-(5-((((1-(4-((2,4-dioxothiazolidin-5-
C31H32N6O6S
616.687
A11
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-3-(ethoxycarbonyl)pyridin-



2-yl)-4-methylbenzoic acid


57
(Z)-2-(4-((((1-(4-((2,4-dioxothiazolidin-5-
C28H28N6O4S
544.625
A12
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-yl)-4-



methylbenzoic acid


58
(Z)-2-(4-((((1-(4-((2,4-dioxothiazolidin-5-
C29H27F3N6O4S
612.623
A13
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-6-(trifluoromethyl)pyridin-



2-yl)-4-methylbenzoic acid


59
(Z)-2-(4-((((1-(4-((2,4-dioxothiazolidin-5-
C28H27FN6O4S
562.615
A14
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-5-fluoropyridin-2-yl)-4-



methylbenzoic acid


60
(Z)-2-(6-amino-3-((((1-(4-((2,4-dioxothiazolidin-5-
C28H29N7O4S
559.639
A15
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-yl)-4-



methylbenzoic acid


61
(Z)-5-((2-(4-((((6-(benzo[d][1,3]dioxol-5-yl)-4-
C27H25FN6O4S
548.589
A1
B5



fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


62
(Z)-5-((2-(4-((((6-(benzo[d][1,3]dioxol-5-yl)pyridin-
C27H26N6O4S
530.598
A2
B5



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


63
(Z)-5-((2-(4-((((6-(benzo[d][1,3]dioxol-5-yl)-4-
C28H28N6O4S
544.625
A3
B5



methylpyridin-2-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


64
(Z)-5-((2-(4-((((6-(benzo[d][1,3]dioxol-5-yl)-3-
C28H28N6O5S
560.624
A4
B5



methoxypyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


65
(Z)-5-((2-(4-((((6-(benzo[d][1,3]dioxol-5-yl)-4-
C28H25F3N6O4S
598.596
A5
B5



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


66
(Z)-5-((2-(4-((((3-(benzo[d][1,3]dioxol-5-
C31H28N6O4S
580.657
A6
B5



yl)isoquinolin-1-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


67
(Z)-5-((2-(4-((((2-(benzo[d][1,3]dioxol-5-yl)pyridin-
C27H26N6O4S
530.598
A7
B5



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


68
(Z)-5-((2-(4-((((2-(benzo[d][1,3]dioxol-5-
C31H28N6O4S
580.657
A8
B5



yl)quinolin-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


69
(Z)-5-((2-(4-((((6-(benzo[d][1,3]dioxol-5-yl)pyridin-
C27H26N6O4S
530.598
A9
B5



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


70
(Z)-2-(benzo[d][1,3]dioxol-5-yl)-5-((((1-(4-((2,4-
C28H25N7O4S
555.608
A10
B5



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-



yl)methyl)amino)methyl)nicotinonitrile


71
(Z)-ethyl 2-(benzo[d][1,3]dioxol-5-yl)-5-((((1-(4-
C30H30N6O6S
602.661
A11
B5



((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-yl)methyl)amino)methyl)nicotinate


72
(Z)-5-((2-(4-((((2-(benzo[d][1,3]dioxol-5-yl)pyridin-
C27H26N6O4S
530.598
A12
B5



4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


73
(Z)-5-((2-(4-((((2-(benzo[d][1,3]dioxol-5-yl)-6-
C28H25F3N6O4S
598.596
A13
B5



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


74
(Z)-5-((2-(4-((((2-(benzo[d][1,3]dioxol-5-yl)-5-
C27H25FN6O4S
548.589
A14
B5



fluoropyridin-4-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


75
(Z)-5-((2-(4-((((6-amino-2-(benzo[d][1,3]dioxol-5-
C27H27N7O4S
545.613
A15
B5



yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


76
(Z)-N-benzyl-3-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C34H32FN7O3S
637.726
A1
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-4-fluoropyridin-2-



yl)benzamide


77
(Z)-N-benzyl-3-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C34H33N7O3S
619.736
A2
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-yl)benzamide


78
(Z)-N-benzyl-3-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C35H35N7O3S
633.763
A3
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-4-methylpyridin-2-



yl)benzamide


79
(Z)-N-benzyl-3-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C35H35N7O4S
649.762
A4
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-5-methoxypyridin-2-



yl)benzamide


80
(Z)-N-benzyl-3-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C35H32F3N7O3S
687.734
A5
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-4-(trifluoromethyl)pyridin-



2-yl)benzamide


81
(Z)-N-benzyl-3-(1-((((1-(4-((2,4-dioxothiazolidin-5-
C38H35N7O3S
669.795
A6
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)isoquinolin-3-yl)benzamide


82
(Z)-N-benzyl-3-(3-((((1-(4-((2,4-dioxothiazolidin-5-
C34H33N7O3S
619.736
A7
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-yl)benzamide


83
(Z)-N-benzyl-3-(3-((((1-(4-((2,4-dioxothiazolidin-5-
C38H35N7O3S
669.795
A8
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)quinolin-2-yl)benzamide


84
(Z)-N-benzyl-3-(5-((((1-(4-((2,4-dioxothiazolidin-5-
C34H33N7O3S
619.736
A9
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-yl)benzamide


85
(Z)-N-benzyl-3-(3-cyano-5-((((1-(4-((2,4-
C35H32N8O3S
644.745
A10
B6



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-yl)methyl)amino)methyl)pyridin-2-



yl)benzamide


86
(Z)-ethyl 2-(3-(benzylcarbamoyl)phenyl)-5-((((1-(4-
C37H37N7O5S
691.799
A11
B6



((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-yl)methyl)amino)methyl)nicotinate


87
(Z)-N-benzyl-3-(4-((((1-(4-((2,4-dioxothiazolidin-5-
C34H33N7O3S
619.736
A12
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-yl)benzamide


88
(Z)-N-benzyl-3-(4-((((1-(4-((2,4-dioxothiazolidin-5-
C35H32F3N7O3S
687.734
A13
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-6-(trifluoromethyl)pyridin-



2-yl)benzamide


89
(Z)-N-benzyl-3-(4-((((1-(4-((2,4-dioxothiazolidin-5-
C34H32FN7O3S
637.726
A14
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-5-fluoropyridin-2-



yl)benzamide


90
(Z)-3-(6-amino-3-((((1-(4-((2,4-dioxothiazolidin-5-
C34H34N8O3S
634.751
A15
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-yl)-N-



benzylbenzamide


91
(Z)-5-((2-(4-((((6-(3-(dimethylamino)phenyl)-4-
C28H30FN7O2S
547.647
A1
B7



fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


92
(Z)-5-((2-(4-((((6-(3-(dimethylamino)phenyl)pyridin-
C28H31N7O2S
529.656
A2
B7



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


93
(Z)-5-((2-(4-((((6-(3-(dimethylamino)phenyl)-4-
C29H33N7O2S
543.683
A3
B7



methylpyridin-2-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


94
(Z)-5-((2-(4-((((6-(3-(dimethylamino)phenyl)-3-
C29H33N7O3S
559.682
A4
B7



methoxypyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


95
(Z)-5-((2-(4-((((6-(3-(dimethylamino)phenyl)-4-
C29H30F3N7O2S
597.654
A5
B7



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


96
(Z)-5-((2-(4-((((3-(3-
C32H33N7O2S
579.715
A6
B7



(dimethylamino)phenyl)isoquinolin-1-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


97
(Z)-5-((2-(4-((((2-(3-(dimethylamino)phenyl)pyridin-
C28H31N7O2S
529.656
A7
B7



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


98
(Z)-5-((2-(4-((((2-(3-
C32H33N7O2S
579.715
A8
B7



(dimethylamino)phenyl)quinolin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


99
(Z)-5-((2-(4-((((6-(3-(dimethylamino)phenyl)pyridin-
C28H31N7O2S
529.656
A9
B7



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


100
(Z)-2-(3-(dimethylamino)phenyl)-5-((((1-(4-((2,4-
C29H30N8O2S
554.666
A10
B7



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-



yl)methyl)amino)methyl)nicotinonitrile


101
(Z)-ethyl 2-(3-(dimethylamino)phenyl)-5-((((1-(4-
C31H35N7O4S
601.719
A11
B7



((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-yl)methyl)amino)methyl)nicotinate


102
(Z)-5-((2-(4-((((2-(3-(dimethylamino)phenyl)pyridin-
C28H31N7O2S
529.656
A12
B7



4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


103
(Z)-5-((2-(4-((((2-(3-(dimethylamino)phenyl)-6-
C29H30F3N7O2S
597.654
A13
B7



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


104
(Z)-5-((2-(4-((((2-(3-(dimethylamino)phenyl)-5-
C28H30FN7O2S
547.647
A14
B7



fluoropyridin-4-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


105
(Z)-5-((2-(4-((((6-amino-2-(3-
C28H32N8O2S
544.671
A15
B7



(dimethylamino)phenyl)pyridin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


106
(Z)-N-(3-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C28H28FN7O3S
561.63
A1
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-4-fluoropyridin-2-



yl)phenyl)acetamide


107
(Z)-N-(3-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C28H29N7O3S
543.64
A2
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-



yl)phenyl)acetamide


108
(Z)-N-(3-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C29H31N7O3S
557.667
A3
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-4-methylpyridin-2-



yl)phenyl)acetamide


109
(Z)-N-(3-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C29H31N7O4S
573.666
A4
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-5-methoxypyridin-2-



yl)phenyl)acetamide


110
(Z)-N-(3-(6-((((1-(4-((2,4-dioxothiazolidin-5-
C29H28F3N7O3S
611.638
A5
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-4-(trifluoromethyl)pyridin-



2-yl)phenyl)acetamide


111
(Z)-N-(3-(1-((((1-(4-((2,4-dioxothiazolidin-5-
C32H31N7O3S
593.699
A6
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)isoquinolin-3-



yl)phenyl)acetamide


112
(Z)-N-(3-(3-((((1-(4-((2,4-dioxothiazolidin-5-
C28H29N7O3S
543.64
A7
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-



yl)phenyl)acetamide


113
(Z)-N-(3-(3-((((1-(4-((2,4-dioxothiazolidin-5-
C32H31N7O3S
593.699
A8
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)quinolin-2-



yl)phenyl)acetamide


114
(Z)-N-(3-(5-((((1-(4-((2,4-dioxothiazolidin-5-
C28H29N7O3S
543.64
A9
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-



yl)phenyl)acetamide


115
(Z)-N-(3-(3-cyano-5-((((1-(4-((2,4-dioxothiazolidin-
C29H28N8O3S
568.649
A10
B8



5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-



yl)phenyl)acetamide


116
(Z)-ethyl 2-(3-acetamidophenyl)-5-((((1-(4-((2,4-
C31H33N7O5S
615.703
A11
B8



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-yl)methyl)amino)methyl)nicotinate


117
(Z)-N-(3-(4-((((1-(4-((2,4-dioxothiazolidin-5-
C28H29N7O3S
543.64
A12
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-



yl)phenyl)acetamide


118
(Z)-N-(3-(4-((((1-(4-((2,4-dioxothiazolidin-5-
C29H28F3N7O3S
611.638
A13
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-6-(trifluoromethyl)pyridin-



2-yl)phenyl)acetamide


119
(Z)-N-(3-(4-((((1-(4-((2,4-dioxothiazolidin-5-
C28H28FN7O3S
561.63
A14
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-5-fluoropyridin-2-



yl)phenyl)acetamide


120
(Z)-N-(3-(6-amino-3-((((1-(4-((2,4-dioxothiazolidin-
C28H30N8O3S
558.655
A15
B8



5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)pyridin-2-



yl)phenyl)acetamide


121
(Z)-5-((2-(4-((((4-fluoro-6-(4-
C32H29FN6O3S
596.674
A1
B9



phenoxyphenyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


122
(Z)-5-((2-(4-((((6-(4-phenoxyphenyl)pyridin-2-
C32H30N6O3S
578.684
A2
B9



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


123
(Z)-5-((2-(4-((((4-methyl-6-(4-
C33H32N6O3S
592.711
A3
B9



phenoxyphenyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


124
(Z)-5-((2-(4-((((3-methoxy-6-(4-
C33H32N6O4S
608.71
A4
B9



phenoxyphenyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


125
(Z)-5-((2-(4-((((6-(4-phenoxyphenyl)-4-
C33H29F3N6O3S
646.682
A5
B9



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


126
(Z)-5-((2-(4-((((3-(4-phenoxyphenyl)isoquinolin-1-
C36H32N6O3S
628.743
A6
B9



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


127
(Z)-5-((2-(4-((((2-(4-phenoxyphenyl)pyridin-3-
C32H30N6O3S
578.684
A7
B9



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


128
(Z)-5-((2-(4-((((2-(4-phenoxyphenyl)quinolin-3-
C36H32N6O3S
628.743
A8
B9



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


129
(Z)-5-((2-(4-((((6-(4-phenoxyphenyl)pyridin-3-
C32H30N6O3S
578.684
A9
B9



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


130
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C33H29N7O3S
603.693
A10
B9



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(4-



phenoxyphenyl)nicotinonitrile


131
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C35H34N6O5S
650.747
A11
B9



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(4-



phenoxyphenyl)nicotinate


132
(Z)-5-((2-(4-((((2-(4-phenoxyphenyl)pyridin-4-
C32H30N6O3S
578.684
A12
B9



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


133
(Z)-5-((2-(4-((((2-(4-phenoxyphenyl)-6-
C33H29F3N6O3S
646.682
A13
B9



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


134
(Z)-5-((2-(4-((((5-fluoro-2-(4-
C32H29FN6O3S
596.674
A14
B9



phenoxyphenyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


135
(Z)-5-((2-(4-((((6-amino-2-(4-
C32H31N7O3S
593.699
A15
B9



phenoxyphenyl)pyridin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


136
(Z)-5-((2-(4-((((4-fluoro-6-(1H-indol-5-yl)pyridin-2-
C28H26FN7O2S
543.615
A1
B10



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


137
(Z)-5-((2-(4-((((6-(1H-indol-5-yl)pyridin-2-
C28H27N7O2S
525.625
A2
B10



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


138
(Z)-5-((2-(4-((((6-(1H-indol-5-yl)-4-methylpyridin-2-
C29H29N7O2S
539.651
A3
B10



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


139
(Z)-5-((2-(4-((((6-(1H-indol-5-yl)-3-methoxypyridin-
C29H29N7O3S
555.651
A4
B10



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


140
(Z)-5-((2-(4-((((6-(1H-indol-5-yl)-4-
C29H26F3N7O2S
593.623
A5
B10



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


141
(Z)-5-((2-(4-((((3-(1H-indol-5-yl)isoquinolin-1-
C32H29N7O2S
575.683
A6
B10



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


142
(Z)-5-((2-(4-((((2-(1H-indol-5-yl)pyridin-3-
C28H27N7O2S
525.625
A7
B10



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


143
(Z)-5-((2-(4-((((2-(1H-indol-5-yl)quinolin-3-
C32H29N7O2S
575.683
A8
B10



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


144
(Z)-5-((2-(4-((((6-(1H-indol-5-yl)pyridin-3-
C28H27N7O2S
525.625
A9
B10



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


145
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C29H26N8O2S
550.634
A10
B10



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(1H-indol-5-



yl)nicotinonitrile


146
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C31H31N7O4S
597.687
A11
B10



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(1H-indol-5-yl)nicotinate


147
(Z)-5-((2-(4-((((2-(1H-indol-5-yl)pyridin-4-
C28H27N7O2S
525.625
A12
B10



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


148
(Z)-5-((2-(4-((((2-(1H-indol-5-yl)-6-
C29H26F3N7O2S
593.623
A13
B10



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


149
(Z)-5-((2-(4-((((5-fluoro-2-(1H-indol-5-yl)pyridin-4-
C28H26FN7O2S
543.615
A14
B10



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


150
(Z)-5-((2-(4-((((6-amino-2-(1H-indol-5-yl)pyridin-3-
C28H28N8O2S
540.639
A15
B10



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


151
(Z)-5-((2-(4-((((4-fluoro-6-(isoquinolin-5-yl)pyridin-
C29H26FN7O2S
555.626
A1
B11



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


152
(Z)-5-((2-(4-((((6-(isoquinolin-5-yl)pyridin-2-
C29H27N7O2S
537.635
A2
B11



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


153
(Z)-5-((2-(4-((((6-(isoquinolin-5-yl)-4-
C30H29N7O2S
551.662
A3
B11



methylpyridin-2-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


154
(Z)-5-((2-(4-((((6-(isoquinolin-5-yl)-3-
C30H29N7O3S
567.661
A4
B11



methoxypyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


155
(Z)-5-((2-(4-((((6-(isoquinolin-5-yl)-4-
C30H26F3N7O2S
605.633
A5
B11



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


156
(Z)-5-((2-(4-((([3,5′-biisoquinolin]-1-
C33H29N7O2S
587.694
A6
B11



ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


157
(Z)-5-((2-(4-((((2-(isoquinolin-5-yl)pyridin-3-
C29H27N7O2S
537.635
A7
B11



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


158
(Z)-5-((2-(4-((((2-(isoquinolin-5-yl)quinolin-3-
C33H29N7O2S
587.694
A8
B11



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


159
(Z)-5-((2-(4-((((6-(isoquinolin-5-yl)pyridin-3-
C29H27N7O2S
537.635
A9
B11



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


160
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C30H26N8O2S
562.645
A10
B11



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(isoquinolin-5-



yl)nicotinonitrile


161
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C32H31N7O4S
609.698
A11
B11



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(isoquinolin-5-



yl)nicotinate


162
(Z)-5-((2-(4-((((2-(isoquinolin-5-yl)pyridin-4-
C29H27N7O2S
537.635
A12
B11



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


163
(Z)-5-((2-(4-((((2-(isoquinolin-5-yl)-6-
C30H26F3N7O2S
605.633
A13
B11



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


164
(Z)-5-((2-(4-((((5-fluoro-2-(isoquinolin-5-yl)pyridin-
C29H26FN7O2S
555.626
A14
B11



4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


165
(Z)-5-((2-(4-((((6-amino-2-(isoquinolin-5-yl)pyridin-
C29H28N8O2S
552.65
A15
B11



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


166
(Z)-5-((2-(4-((((4-fluoro-6-(thiophen-3-yl)pyridin-2-
C24H23FN6O2S2
510.607
A1
B12



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


167
(Z)-5-((2-(4-((((6-(thiophen-3-yl)pyridin-2-
C24H24N6O2S2
492.616
A2
B12



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


168
(Z)-5-((2-(4-((((4-methyl-6-(thiophen-3-yl)pyridin-2-
C25H26N6O2S2
506.643
A3
B12



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


169
(Z)-5-((2-(4-((((3-methoxy-6-(thiophen-3-yl)pyridin-
C25H26N6O3S2
522.642
A4
B12



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


170
(Z)-5-((2-(4-((((6-(thiophen-3-yl)-4-
C25H23F3N6O2S2
560.614
A5
B12



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


171
(Z)-5-((2-(4-((((3-(thiophen-3-yl)isoquinolin-1-
C28H26N6O2S2
542.675
A6
B12



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


172
(Z)-5-((2-(4-((((2-(thiophen-3-yl)pyridin-3-
C24H24N6O2S2
492.616
A7
B12



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


173
(Z)-5-((2-(4-((((2-(thiophen-3-yl)quinolin-3-
C28H26N6O2S2
542.675
A8
B12



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


174
(Z)-5-((2-(4-((((6-(thiophen-3-yl)pyridin-3-
C24H24N6O2S2
492.616
A9
B12



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


175
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C25H23N7O2S2
517.626
A10
B12



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(thiophen-3-



yl)nicotinonitrile


176
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C27H28N6O4S2
564.679
A11
B12



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(thiophen-3-yl)nicotinate


177
(Z)-5-((2-(4-((((2-(thiophen-3-yl)pyridin-4-
C24H24N6O2S2
492.616
A12
B12



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


178
(Z)-5-((2-(4-((((2-(thiophen-3-yl)-6-
C25H23F3N6O2S2
560.614
A13
B12



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


179
(Z)-5-((2-(4-((((5-fluoro-2-(thiophen-3-yl)pyridin-4-
C24H23FN6O2S2
510.607
A14
B12



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


180
(Z)-5-((2-(4-((((6-amino-2-(thiophen-3-yl)pyridin-3-
C24H25N7O2S2
507.631
A15
B12



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


181
(Z)-5-((2-(4-((((6-(benzo[b]thiophen-3-yl)-4-
C28H25FN6O2S2
560.666
A1
B13



fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


182
(Z)-5-((2-(4-((((6-(benzo[b]thiophen-3-yl)pyridin-2-
C28H26N6O2S2
542.675
A2
B13



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


183
(Z)-5-((2-(4-((((6-(benzo[b]thiophen-3-yl)-4-
C29H28N6O2S2
556.702
A3
B13



methylpyridin-2-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


184
(Z)-5-((2-(4-((((6-(benzo[b]thiophen-3-yl)-3-
C29H28N6O3S2
572.701
A4
B13



methoxypyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


185
(Z)-5-((2-(4-((((6-(benzo[b]thiophen-3-yl)-4-
C29H25F3N6O2S2
610.673
A5
B13



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


186
(Z)-5-((2-(4-((((3-(benzo[b]thiophen-3-
C32H28N6O2S2
592.734
A6
B13



yl)isoquinolin-1-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


187
(Z)-5-((2-(4-((((2-(benzo[b]thiophen-3-yl)pyridin-3-
C28H26N6O2S2
542.675
A7
B13



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


188
(Z)-5-((2-(4-((((2-(benzo[b]thiophen-3-yl)quinolin-3-
C32H28N6O2S2
592.734
A8
B13



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


189
(Z)-5-((2-(4-((((6-(benzo[b]thiophen-3-yl)pyridin-3-
C28H26N6O2S2
542.675
A9
B13



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


190
(Z)-2-(benzo[b]thiophen-3-yl)-5-((((1-(4-((2,4-
C29H25N7O2S2
567.685
A10
B13



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-



yl)methyl)amino)methyl)nicotinonitrile


191
(Z)-ethyl 2-(benzo[b]thiophen-3-yl)-5-((((1-(4-((2,4-
C31H30N6O4S2
614.738
A11
B13



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-yl)methyl)amino)methyl)nicotinate


192
(Z)-5-((2-(4-((((2-(benzo[b]thiophen-3-yl)pyridin-4-
C28H26N6O2S2
542.675
A12
B13



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


193
(Z)-5-((2-(4-((((2-(benzo[b]thiophen-3-yl)-6-
C29H25F3N6O2S2
610.673
A13
B13



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


194
(Z)-5-((2-(4-((((2-(benzo[b]thiophen-3-yl)-5-
C28H25FN6O2S2
560.666
A14
B13



fluoropyridin-4-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


195
(Z)-5-((2-(4-((((6-amino-2-(benzo[b]thiophen-3-
C28H27N7O2S2
557.69
A15
B13



yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


196
(Z)-5-((2-(4-((((6-(5-acetylthiophen-2-yl)-4-
C26H25FN6O3S2
552.644
A1
B14



fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


197
(Z)-5-((2-(4-((((6-(5-acetylthiophen-2-yl)pyridin-2-
C26H26N6O3S2
534.653
A2
B14



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


198
(Z)-5-((2-(4-((((6-(5-acetylthiophen-2-yl)-4-
C27H28N6O3S2
548.68
A3
B14



methylpyridin-2-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


199
(Z)-5-((2-(4-((((6-(5-acetylthiophen-2-yl)-3-
C27H28N6O4S2
564.679
A4
B14



methoxypyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


200
(Z)-5-((2-(4-((((6-(5-acetylthiophen-2-yl)-4-
C27H25F3N6O3S2
602.651
A5
B14



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


201
(Z)-5-((2-(4-((((3-(5-acetylthiophen-2-yl)isoquinolin-
C30H28N6O3S2
584.712
A6
B14



1-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


202
(Z)-5-((2-(4-((((2-(5-acetylthiophen-2-yl)pyridin-3-
C26H26N6O3S2
534.653
A7
B14



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


203
(Z)-5-((2-(4-((((2-(5-acetylthiophen-2-yl)quinolin-3-
C30H28N6O3S2
584.712
A8
B14



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


204
(Z)-5-((2-(4-((((6-(5-acetylthiophen-2-yl)pyridin-3-
C26H26N6O3S2
534.653
A9
B14



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


205
(Z)-2-(5-acetylthiophen-2-yl)-5-((((1-(4-((2,4-
C27H25N7O3S2
559.663
A10
B14



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-



yl)methyl)amino)methyl)nicotinonitrile


206
(Z)-ethyl 2-(5-acetylthiophen-2-yl)-5-((((1-(4-((2,4-
C29H30N6O5S2
606.716
A11
B14



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-yl)methyl)amino)methyl)nicotinate


207
(Z)-5-((2-(4-((((2-(5-acetylthiophen-2-yl)pyridin-4-
C26H26N6O3S2
534.653
A12
B14



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


208
(Z)-5-((2-(4-((((2-(5-acetylthiophen-2-yl)-6-
C27H25F3N6O3S2
602.651
A13
B14



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


209
(Z)-5-((2-(4-((((2-(5-acetylthiophen-2-yl)-5-
C26H25FN6O3S2
552.644
A14
B14



fluoropyridin-4-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


210
(Z)-5-((2-(4-((((2-(5-acetylthiophen-2-yl)-6-
C26H27N7O3S2
549.668
A15
B14



aminopyridin-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


211
(Z)-5-((2-(4-((((4-fluoro-6-(furan-2-yl)pyridin-2-
C24H23FN6O3S
494.541
A1
B15



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


212
(Z)-5-((2-(4-((((6-(furan-2-yl)pyridin-2-
C24H24N6O3S
476.551
A2
B15



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


213
(Z)-5-((2-(4-((((6-(furan-2-yl)-4-methylpyridin-2-
C25H26N6O3S
490.577
A3
B15



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


214
(Z)-5-((2-(4-((((6-(furan-2-yl)-3-methoxypyridin-2-
C25H26N6O4S
506.577
A4
B15



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


215
(Z)-5-((2-(4-((((6-(furan-2-yl)-4-
C25H23F3N6O3S
544.549
A5
B15



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


216
(Z)-5-((2-(4-((((3-(furan-2-yl)isoquinolin-1-
C28H26N6O3S
526.609
A6
B15



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


217
(Z)-5-((2-(4-((((2-(furan-2-yl)pyridin-3-
C24H24N6O3S
476.551
A7
B15



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


218
(Z)-5-((2-(4-((((2-(furan-2-yl)quinolin-3-
C28H26N6O3S
526.609
A8
B15



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


219
(Z)-5-((2-(4-((((6-(furan-2-yl)pyridin-3-
C24H24N6O3S
476.551
A9
B15



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


220
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C25H23N7O3S
501.56
A10
B15



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(furan-2-



yl)nicotinonitrile


221
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C27H28N6O5S
548.613
A11
B15



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(furan-2-yl)nicotinate


222
(Z)-5-((2-(4-((((2-(furan-2-yl)pyridin-4-
C24H24N6O3S
476.551
A12
B15



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


223
(Z)-5-((2-(4-((((2-(furan-2-yl)-6-
C25H23F3N6O3S
544.549
A13
B15



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


224
(Z)-5-((2-(4-((((5-fluoro-2-(furan-2-yl)pyridin-4-
C24H23FN6O3S
494.541
A14
B15



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


225
(Z)-5-((2-(4-((((6-amino-2-(furan-2-yl)pyridin-3-
C24H25N7O3S
491.565
A15
B15



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


226
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)-4-fluoropyridin-
C28H25FN6O3S
544.6
A1
B16



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


227
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)pyridin-2-
C28H26N6O3S
526.609
A2
B16



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


228
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)-4-
C29H28N6O3S
540.636
A3
B16



methylpyridin-2-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


229
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)-3-
C29H28N6O4S
556.635
A4
B16



methoxypyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


230
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)-4-
C29H25F3N6O3S
594.607
A5
B16



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


231
(Z)-5-((2-(4-((((3-(benzofuran-2-yl)isoquinolin-1-
C32H28N6O3S
576.668
A6
B16



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


232
(Z)-5-((2-(4-((((2-(benzofuran-2-yl)pyridin-3-
C28H26N6O3S
526.609
A7
B16



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


233
(Z)-5-((2-(4-((((2-(benzofuran-2-yl)quinolin-3-
C32H28N6O3S
576.668
A8
B16



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


234
(Z)-5-((2-(4-((((6-(benzofuran-2-yl)pyridin-3-
C28H26N6O3S
526.609
A9
B16



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


235
(Z)-2-(benzofuran-2-yl)-5-((((1-(4-((2,4-
C29H25N7O3S
551.619
A10
B16



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-



yl)methyl)amino)methyl)nicotinonitrile


236
(Z)-ethyl 2-(benzofuran-2-yl)-5-((((1-(4-((2,4-
C31H30N6O5S
598.672
A11
B16



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-yl)methyl)amino)methyl)nicotinate


237
(Z)-5-((2-(4-((((2-(benzofuran-2-yl)pyridin-4-
C28H26N6O3S
526.609
A12
B16



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


238
(Z)-5-((2-(4-((((2-(benzofuran-2-yl)-6-
C29H25F3N6O3S
594.607
A13
B16



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


239
(Z)-5-((2-(4-((((2-(benzofuran-2-yl)-5-fluoropyridin-
C28H25FN6O3S
544.6
A14
B16



4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


240
(Z)-5-((2-(4-((((6-amino-2-(benzofuran-2-yl)pyridin-
C28H27N7O3S
541.624
A15
B16



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


241
(Z)-5-((2-(4-((((4-fluoro-6-(furan-3-yl)pyridin-2-
C24H23FN6O3S
494.541
A1
B17



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


242
(Z)-5-((2-(4-((((6-(furan-3-yl)pyridin-2-
C24H24N6O3S
476.551
A2
B17



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


243
(Z)-5-((2-(4-((((6-(furan-3-yl)-4-methylpyridin-2-
C25H26N6O3S
490.577
A3
B17



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


244
(Z)-5-((2-(4-((((6-(furan-3-yl)-3-methoxypyridin-2-
C25H26N6O4S
506.577
A4
B17



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


245
(Z)-5-((2-(4-((((6-(furan-3-yl)-4-
C25H23F3N6O3S
544.549
A5
B17



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


246
(Z)-5-((2-(4-((((3-(furan-3-yl)isoquinolin-1-
C28H26N6O3S
526.609
A6
B17



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


247
(Z)-5-((2-(4-((((2-(furan-3-yl)pyridin-3-
C24H24N6O3S
476.551
A7
B17



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


248
(Z)-5-((2-(4-((((2-(furan-3-yl)quinolin-3-
C28H26N6O3S
526.609
A8
B17



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


249
(Z)-5-((2-(4-((((6-(furan-3-yl)pyridin-3-
C24H24N6O3S
476.551
A9
B17



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


250
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C25H23N7O3S
501.56
A10
B17



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(furan-3-



yl)nicotinonitrile


251
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C27H28N6O5S
548.613
A11
B17



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(furan-3-yl)nicotinate


252
(Z)-5-((2-(4-((((2-(furan-3-yl)pyridin-4-
C24H24N6O3S
476.551
A12
B17



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


253
(Z)-5-((2-(4-((((2-(furan-3-yl)-6-
C25H23F3N6O3S
544.549
A13
B17



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


254
(Z)-5-((2-(4-((((5-fluoro-2-(furan-3-yl)pyridin-4-
C24H23FN6O3S
494.541
A14
B17



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


255
(Z)-5-((2-(4-((((6-amino-2-(furan-3-yl)pyridin-3-
C24H25N7O3S
491.565
A15
B17



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


256
(Z)-5-((2-(4-((((4-fluoro-6-(1H-pyrrol-2-yl)pyridin-
C24H24FN7O2S
493.556
A1
B18



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


257
(Z)-5-((2-(4-((((6-(1H-pyrrol-2-yl)pyridin-2-
C24H25N7O2S
475.566
A2
B18



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


258
(Z)-5-((2-(4-((((4-methyl-6-(1H-pyrrol-2-yl)pyridin-
C25H27N7O2S
489.593
A3
B18



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


259
(Z)-5-((2-(4-((((3-methoxy-6-(1H-pyrrol-2-
C25H27N7O3S
505.592
A4
B18



yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


260
(Z)-5-((2-(4-((((6-(1H-pyrrol-2-yl)-4-
C25H24F3N7O2S
543.564
A5
B18



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


261
(Z)-5-((2-(4-((((3-(1H-pyrrol-2-yl)isoquinolin-1-
C28H27N7O2S
525.625
A6
B18



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


262
(Z)-5-((2-(4-((((2-(1H-pyrrol-2-yl)pyridin-3-
C24H25N7O2S
475.566
A7
B18



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


263
(Z)-5-((2-(4-((((2-(1H-pyrrol-2-yl)quinolin-3-
C28H27N7O2S
525.625
A8
B18



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


264
(Z)-5-((2-(4-((((6-(1H-pyrrol-2-yl)pyridin-3-
C24H25N7O2S
475.566
A9
B18



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


265
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C25H24N8O2S
500.575
A10
B18



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(1H-pyrrol-2-



yl)nicotinonitrile


266
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C27H29N7O4S
547.629
A11
B18



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(1H-pyrrol-2-



yl)nicotinate


267
(Z)-5-((2-(4-((((2-(1H-pyrrol-2-yl)pyridin-4-
C24H25N7O2S
475.566
A12
B18



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


268
(Z)-5-((2-(4-((((2-(1H-pyrrol-2-yl)-6-
C25H24F3N7O2S
543.564
A13
B18



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


269
(Z)-5-((2-(4-((((5-fluoro-2-(1H-pyrrol-2-yl)pyridin-
C24H24FN7O2S
493.556
A14
B18



4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


270
(Z)-5-((2-(4-((((6-amino-2-(1H-pyrrol-2-yl)pyridin-
C24H26N8O2S
490.581
A15
B18



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


271
(Z)-5-((2-(4-((((4-fluoro-6-(isoquinolin-4-yl)pyridin-
C29H26FN7O2S
555.626
A1
B19



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


272
(Z)-5-((2-(4-((((6-(isoquinolin-4-yl)pyridin-2-
C29H27N7O2S
537.635
A2
B19



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


273
(Z)-5-((2-(4-((((6-(isoquinolin-4-yl)-4-
C30H29N7O2S
551.662
A3
B19



methylpyridin-2-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


274
(Z)-5-((2-(4-((((6-(isoquinolin-4-yl)-3-
C30H29N7O3S
567.661
A4
B19



methoxypyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


275
(Z)-5-((2-(4-((((6-(isoquinolin-4-yl)-4-
C30H26F3N7O2S
605.633
A5
B19



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


276
(Z)-5-((2-(4-((([3,4′-biisoquinolin]-1-
C33H29N7O2S
587.694
A6
B19



ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


277
(Z)-5-((2-(4-((((2-(isoquinolin-4-yl)pyridin-3-
C29H27N7O2S
537.635
A7
B19



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


278
(Z)-5-((2-(4-((((2-(isoquinolin-4-yl)quinolin-3-
C33H29N7O2S
587.694
A8
B19



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


279
(Z)-5-((2-(4-((((6-(isoquinolin-4-yl)pyridin-3-
C29H27N7O2S
537.635
A9
B19



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


280
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C30H26N8O2S
562.645
A10
B19



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(isoquinolin-4-



yl)nicotinonitrile


281
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C32H31N7O4S
609.698
A11
B19



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(isoquinolin-4-



yl)nicotinate


282
(Z)-5-((2-(4-((((2-(isoquinolin-4-yl)pyridin-4-
C29H27N7O2S
537.635
A12
B19



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


283
(Z)-5-((2-(4-((((2-(isoquinolin-4-yl)-6-
C30H26F3N7O2S
605.633
A13
B19



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


284
(Z)-5-((2-(4-((((5-fluoro-2-(isoquinolin-4-yl)pyridin-
C29H26FN7O2S
555.626
A14
B19



4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


285
(Z)-5-((2-(4-((((6-amino-2-(isoquinolin-4-yl)pyridin-
C29H28N8O2S
552.65
A15
B19



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


286
(Z)-5-((2-(4-((((4-fluoro-6-(quinolin-4-yl)pyridin-2-
C29H26FN7O2S
555.626
A1
B20



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


287
(Z)-5-((2-(4-((((6-(quinolin-4-yl)pyridin-2-
C29H27N7O2S
537.635
A2
B20



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


288
(Z)-5-((2-(4-((((4-methyl-6-(quinolin-4-yl)pyridin-2-
C30H29N7O2S
551.662
A3
B20



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


289
(Z)-5-((2-(4-((((3-methoxy-6-(quinolin-4-yl)pyridin-
C30H29N7O3S
567.661
A4
B20



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


290
(Z)-5-((2-(4-((((6-(quinolin-4-yl)-4-
C30H26F3N7O2S
605.633
A5
B20



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


291
(Z)-5-((2-(4-((((3-(quinolin-4-yl)isoquinolin-1-
C33H29N7O2S
587.694
A6
B20



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


292
(Z)-5-((2-(4-((((2-(quinolin-4-yl)pyridin-3-
C29H27N7O2S
537.635
A7
B20



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


293
(Z)-5-((2-(4-((([2,4′-biquinolin]-3-
C33H29N7O2S
587.694
A8
B20



ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


294
(Z)-5-((2-(4-((((6-(quinolin-4-yl)pyridin-3-
C29H27N7O2S
537.635
A9
B20



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


295
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C30H26N8O2S
562.645
A10
B20



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(quinolin-4-



yl)nicotinonitrile


296
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C32H31N7O4S
609.698
A11
B20



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(quinolin-4-yl)nicotinate


297
(Z)-5-((2-(4-((((2-(quinolin-4-yl)pyridin-4-
C29H27N7O2S
537.635
A12
B20



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


298
(Z)-5-((2-(4-((((2-(quinolin-4-yl)-6-
C30H26F3N7O2S
605.633
A13
B20



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


299
(Z)-5-((2-(4-((((5-fluoro-2-(quinolin-4-yl)pyridin-4-
C29H26FN7O2S
555.626
A14
B20



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


300
(Z)-5-((2-(4-((((6-amino-2-(quinolin-4-yl)pyridin-3-
C29H28N8O2S
552.65
A15
B20



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


301
(Z)-5-((2-(4-((((3′,4-difluoro-[2,4′-bipyridin]-6-
C25H23F2N7O2S
523.558
A1
B21



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


302
(Z)-5-((2-(4-((((3′-fluoro-[2,4′-bipyridin]-6-
C25H24FN7O2S
505.567
A2
B21



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


303
(Z)-5-((2-(4-((((3′-fluoro-4-methyl-[2,4′-bipyridin]-6-
C26H26FN7O2S
519.594
A3
B21



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


304
(Z)-5-((2-(4-((((3′-fluoro-5-methoxy-[2,4′-bipyridin]-
C26H26FN7O3S
535.593
A4
B21



6-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


305
(Z)-5-((2-(4-((((3′-fluoro-4-(trifluoromethyl)-[2,4′-
C26H23F4N7O2S
573.565
A5
B21



bipyridin]-6-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


306
(Z)-5-((2-(4-((((3-(3-fluoropyridin-4-yl)isoquinolin-
C29H26FN7O2S
555.626
A6
B21



1-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


307
(Z)-5-((2-(4-((((3′-fluoro-[2,4′-bipyridin]-3-
C25H24FN7O2S
505.567
A7
B21



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


308
(Z)-5-((2-(4-((((2-(3-fluoropyridin-4-yl)quinolin-3-
C29H26FN7O2S
555.626
A8
B21



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


309
(Z)-5-((2-(4-((((3′-fluoro-[2,4′-bipyridin]-5-
C25H24FN7O2S
505.567
A9
B21



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


310
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C26H23FN8O2S
530.577
A10
B21



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-3′-fluoro-[2,4′-bipyridine]-



3-carbonitrile


311
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C28H28FN7O4S
577.63
A11
B21



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-3′-fluoro-[2,4′-bipyridine]-



3-carboxylate


312
(Z)-5-((2-(4-((((3′-fluoro-[2,4′-bipyridin]-4-
C25H24FN7O2S
505.567
A12
B21



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


313
(Z)-5-((2-(4-((((3′-fluoro-6-(trifluoromethyl)-[2,4′-
C26H23F4N7O2S
573.565
A13
B21



bipyridin]-4-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


314
(Z)-5-((2-(4-((((3′,5-difluoro-[2,4′-bipyridin]-4-
C25H23F2N7O2S
523.558
A14
B21



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


315
(Z)-5-((2-(4-((((6-amino-3′-fluoro-[2,4′-bipyridin]-3-
C25H25FN8O2S
520.582
A15
B21



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


316
(Z)-5-((2-(4-((((2′,4,6′-trifluoro-[2,4′-bipyridin]-6-
C25H22F3N7O2S
541.548
A1
B22



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


317
(Z)-5-((2-(4-((((2′,6′-difluoro-[2,4′-bipyridin]-6-
C25H23F2N7O2S
523.558
A2
B22



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


318
(Z)-5-((2-(4-((((2′,6′-difluoro-4-methyl-[2,4′-
C26H25F2N7O2S
537.584
A3
B22



bipyridin]-6-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


319
(Z)-5-((2-(4-((((2′,6′-difluoro-5-methoxy-[2,4′-
C26H25F2N7O3S
553.584
A4
B22



bipyridin]-6-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


320
(Z)-5-((2-(4-((((2′,6′-difluoro-4-(trifluoromethyl)-
C26H22F5N7O2S
591.556
A5
B22



[2,4′-bipyridin]-6-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


321
(Z)-5-((2-(4-((((3-(2,6-difluoropyridin-4-
C29H25F2N7O2S
573.616
A6
B22



yl)isoquinolin-1-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


322
(Z)-5-((2-(4-((((2′,6′-difluoro-[2,4′-bipyridin]-3-
C25H23F2N7O2S
523.558
A7
B22



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


323
(Z)-5-((2-(4-((((2-(2,6-difluoropyridin-4-yl)quinolin-
C29H25F2N7O2S
573.616
A8
B22



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


324
(Z)-5-((2-(4-((((2′,6′-difluoro-[2,4′-bipyridin]-5-
C25H23F2N7O2S
523.558
A9
B22



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


325
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C26H22F2N8O2S
548.567
A10
B22



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2′,6′-difluoro-[2,4′-



bipyridine]-3-carbonitrile


326
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C28H27F2N7O4S
595.62
A11
B22



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2′,6′-difluoro-[2,4′-



bipyridine]-3-carboxylate


327
(Z)-5-((2-(4-((((2′,6′-difluoro-[2,4′-bipyridin]-4-
C25H23F2N7O2S
523.558
A12
B22



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


328
(Z)-5-((2-(4-((((2′,6′-difluoro-6-(trifluoromethyl)-
C26H22F5N7O2S
591.556
A13
B22



[2,4′-bipyridin]-4-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


329
(Z)-5-((2-(4-((((2′,5,6′-trifluoro-[2,4′-bipyridin]-4-
C25H22F3N7O2S
541.548
A14
B22



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


330
(Z)-5-((2-(4-((((6-amino-2′,6′-difluoro-[2,4′-
C25H24F2N8O2S
538.572
A15
B22



bipyridin]-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


331
(Z)-5-((2-(4-((((6′-(dimethylamino)-4-fluoro-[2,3′-
C27H29FN8O2S
548.635
A1
B23



bipyridin]-6-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


332
(Z)-5-((2-(4-((((6′-(dimethylamino)-[2,3′-bipyridin]-
C27H30N8O2S
530.645
A2
B23



6-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


333
(Z)-5-((2-(4-((((6′-(dimethylamino)-4-methyl-[2,3′-
C28H32N8O2S
544.671
A3
B23



bipyridin]-6-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


334
(Z)-5-((2-(4-((((6′-(dimethylamino)-5-methoxy-[2,3′-
C28H32N8O3S
560.67
A4
B23



bipyridin]-6-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


335
(Z)-5-((2-(4-((((6′-(dimethylamino)-4-
C28H29F3N8O2S
598.642
A5
B23



(trifluoromethyl)-[2,3′-bipyridin]-6-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


336
(Z)-5-((2-(4-((((3-(6-(dimethylamino)pyridin-3-
C31H32N8O2S
580.703
A6
B23



yl)isoquinolin-1-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


337
(Z)-5-((2-(4-((((6′-(dimethylamino)-[2,3′-bipyridin]-
C27H30N8O2S
530.645
A7
B23



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


338
(Z)-5-((2-(4-((((2-(6-(dimethylamino)pyridin-3-
C31H32N8O2S
580.703
A8
B23



yl)quinolin-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


339
(Z)-5-((2-(4-((((6′-(dimethylamino)-[2,3′-bipyridin]-
C27H30N8O2S
530.645
A9
B23



5-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


340
(Z)-6′-(dimethylamino)-5-((((1-(4-((2,4-
C28H29N9O2S
555.654
A10
B23



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-yl)methyl)amino)methyl)-[2,3′-



bipyridine]-3-carbonitrile


341
(Z)-ethyl 6′-(dimethylamino)-5-((((1-(4-((2,4-
C30H34N8O4S
602.707
A11
B23



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-yl)methyl)amino)methyl)-[2,3′-



bipyridine]-3-carboxylate


342
(Z)-5-((2-(4-((((6′-(dimethylamino)-[2,3′-bipyridin]-
C27H30N8O2S
530.645
A12
B23



4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


343
(Z)-5-((2-(4-((((6′-(dimethylamino)-6-
C28H29F3N8O2S
598.642
A13
B23



(trifluoromethyl)-[2,3′-bipyridin]-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


344
(Z)-5-((2-(4-((((6′-(dimethylamino)-5-fluoro-[2,3′-
C27H29FN8O2S
548.635
A14
B23



bipyridin]-4-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


345
(Z)-5-((2-(4-((((6-amino-6′-(dimethylamino)-[2,3′-
C27H31N9O2S
545.659
A15
B23



bipyridin]-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


346
(Z)-5-((2-(4-((((6-(2-(dimethylamino)pyrimidin-5-
C26H28FN9O2S
549.623
A1
B24



yl)-4-fluoropyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


347
(Z)-5-((2-(4-((((6-(2-(dimethylamino)pyrimidin-5-
C26H29N9O2S
531.633
A2
B24



yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


348
(Z)-5-((2-(4-((((6-(2-(dimethylamino)pyrimidin-5-
C27H31N9O2S
545.659
A3
B24



yl)-4-methylpyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


349
(Z)-5-((2-(4-((((6-(2-(dimethylamino)pyrimidin-5-
C27H31N9O3S
561.659
A4
B24



yl)-3-methoxypyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


350
(Z)-5-((2-(4-((((6-(2-(dimethylamino)pyrimidin-5-
C27H28F3N9O2S
599.631
A5
B24



yl)-4-(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


351
(Z)-5-((2-(4-((((3-(2-(dimethylamino)pyrimidin-5-
C30H31N9O2S
581.691
A6
B24



yl)isoquinolin-1-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


352
(Z)-5-((2-(4-((((2-(2-(dimethylamino)pyrimidin-5-
C26H29N9O2S
531.633
A7
B24



yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


353
(Z)-5-((2-(4-((((2-(2-(dimethylamino)pyrimidin-5-
C30H31N9O2S
581.691
A8
B24



yl)quinolin-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


354
(Z)-5-((2-(4-((((6-(2-(dimethylamino)pyrimidin-5-
C26H29N9O2S
531.633
A9
B24



yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


355
(Z)-2-(2-(dimethylamino)pyrimidin-5-yl)-5-((((1-(4-
C27H28N10O2S
556.642
A10
B24



((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-



yl)methyl)amino)methyl)nicotinonitrile


356
(Z)-ethyl 2-(2-(dimethylamino)pyrimidin-5-yl)-5-
C29H33N9O4S
603.695
A11
B24



((((1-(4-((2,4-dioxothiazolidin-5-



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)nicotinate


357
(Z)-5-((2-(4-((((2-(2-(dimethylamino)pyrimidin-5-
C26H29N9O2S
531.633
A12
B24



yl)pyridin-4-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


358
(Z)-5-((2-(4-((((2-(2-(dimethylamino)pyrimidin-5-
C27H28F3N9O2S
599.631
A13
B24



yl)-6-(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


359
(Z)-5-((2-(4-((((2-(2-(dimethylamino)pyrimidin-5-
C26H28FN9O2S
549.623
A14
B24



yl)-5-fluoropyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


360
(Z)-5-((2-(4-((((6-amino-2-(2-
C26H30N10O2S
546.647
A15
B24



(dimethylamino)pyrimidin-5-yl)pyridin-3-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


361
(Z)-5-((2-(4-((((6-(3,5-dimethylisoxazol-4-yl)-4-
C25H26FN7O3S
523.582
A1
B25



fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


362
(Z)-5-((2-(4-((((6-(3,5-dimethylisoxazol-4-
C25H27N7O3S
505.592
A2
B25



yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


363
(Z)-5-((2-(4-((((6-(3,5-dimethylisoxazol-4-yl)-4-
C26H29N7O3S
519.619
A3
B25



methylpyridin-2-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


364
(Z)-5-((2-(4-((((6-(3,5-dimethylisoxazol-4-yl)-3-
C26H29N7O4S
535.618
A4
B25



methoxypyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


365
(Z)-5-((2-(4-((((6-(3,5-dimethylisoxazol-4-yl)-4-
C26H26F3N7O3S
573.59
A5
B25



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


366
(Z)-5-((2-(4-((((3-(3,5-dimethylisoxazol-4-
C29H29N7O3S
555.651
A6
B25



yl)isoquinolin-1-yl)methyl)amino)methyl)piperidin-



1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-



dione


367
(Z)-5-((2-(4-((((2-(3,5-dimethylisoxazol-4-
C25H27N7O3S
505.592
A7
B25



yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


368
(Z)-5-((2-(4-((((2-(3,5-dimethylisoxazol-4-
C29H29N7O3S
555.651
A8
B25



yl)quinolin-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


369
(Z)-5-((2-(4-((((6-(3,5-dimethylisoxazol-4-
C25H27N7O3S
505.592
A9
B25



yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


370
(Z)-2-(3,5-dimethylisoxazol-4-yl)-5-((((1-(4-((2,4-
C26H26N8O3S
530.601
A10
B25



dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-



yl)methyl)amino)methyl)nicotinonitrile


371
(Z)-ethyl 2-(3,5-dimethylisoxazol-4-yl)-5-((((1-(4-
C28H31N7O5S
577.655
A11
B25



((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-



yl)piperidin-4-yl)methyl)amino)methyl)nicotinate


372
(Z)-5-((2-(4-((((2-(3,5-dimethylisoxazol-4-
C25H27N7O3S
505.592
A12
B25



yl)pyridin-4-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


373
(Z)-5-((2-(4-((((2-(3,5-dimethylisoxazol-4-yl)-6-
C26H26F3N7O3S
573.59
A13
B25



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


374
(Z)-5-((2-(4-((((2-(3,5-dimethylisoxazol-4-yl)-5-
C25H26FN7O3S
523.582
A14
B25



fluoropyridin-4-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


375
(Z)-5-((2-(4-((((6-amino-2-(3,5-dimethylisoxazol-4-
C25H28N8O3S
520.607
A15
B25



yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


376
(Z)-5-((2-(4-((((4-fluoro-6-(1H-pyrazol-4-yl)pyridin-
C23H23FN8O2S
494.545
A1
B26



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


377
(Z)-5-((2-(4-((((6-(1H-pyrazol-4-yl)pyridin-2-
C23H24N8O2S
476.554
A2
B26



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


378
(Z)-5-((2-(4-((((4-methyl-6-(1H-pyrazol-4-
C24H26N8O2S
490.581
A3
B26



yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


379
(Z)-5-((2-(4-((((3-methoxy-6-(1H-pyrazol-4-
C24H26N8O3S
506.58
A4
B26



yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


380
(Z)-5-((2-(4-((((6-(1H-pyrazol-4-yl)-4-
C24H23F3N8O2S
544.552
A5
B26



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


381
(Z)-5-((2-(4-((((3-(1H-pyrazol-4-yl)isoquinolin-1-
C27H26N8O2S
526.613
A6
B26



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


382
(Z)-5-((2-(4-((((2-(1H-pyrazol-4-yl)pyridin-3-
C23H24N8O2S
476.554
A7
B26



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


383
(Z)-5-((2-(4-((((2-(1H-pyrazol-4-yl)quinolin-3-
C27H26N8O2S
526.613
A8
B26



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


384
(Z)-5-((2-(4-((((6-(1H-pyrazol-4-yl)pyridin-3-
C23H24N8O2S
476.554
A9
B26



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


385
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C24H23N9O2S
501.564
A10
B26



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(1H-pyrazol-4-



yl)nicotinonitrile


386
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C26H28N8O4S
548.617
A11
B26



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(1H-pyrazol-4-



yl)nicotinate


387
(Z)-5-((2-(4-((((2-(1H-pyrazol-4-yl)pyridin-4-
C23H24N8O2S
476.554
A12
B26



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


388
(Z)-5-((2-(4-((((2-(1H-pyrazol-4-yl)-6-
C24H23F3N8O2S
544.552
A13
B26



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


389
(Z)-5-((2-(4-((((5-fluoro-2-(1H-pyrazol-4-yl)pyridin-
C23H23FN8O2S
494.545
A14
B26



4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


390
(Z)-5-((2-(4-((((6-amino-2-(1H-pyrazol-4-yl)pyridin-
C23H25N9O2S
491.569
A15
B26



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


391
(Z)-5-((2-(4-((((4-fluoro-6-(1H-pyrazol-5-yl)pyridin-
C23H23FN8O2S
494.545
A1
B27



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


392
(Z)-5-((2-(4-((((6-(1H-pyrazol-5-yl)pyridin-2-
C23H24N8O2S
476.554
A2
B27



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


393
(Z)-5-((2-(4-((((4-methyl-6-(1H-pyrazol-5-
C24H26N8O2S
490.581
A3
B27



yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


394
(Z)-5-((2-(4-((((3-methoxy-6-(1H-pyrazol-5-
C24H26N8O3S
506.58
A4
B27



yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


395
(Z)-5-((2-(4-((((6-(1H-pyrazol-5-yl)-4-
C24H23F3N8O2S
544.552
A5
B27



(trifluoromethyl)pyridin-2-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


396
(Z)-5-((2-(4-((((3-(1H-pyrazol-5-yl)isoquinolin-1-
C27H26N8O2S
526.613
A6
B27



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


397
(Z)-5-((2-(4-((((2-(1H-pyrazol-5-yl)pyridin-3-
C23H24N8O2S
476.554
A7
B27



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


398
(Z)-5-((2-(4-((((2-(1H-pyrazol-5-yl)quinolin-3-
C27H26N8O2S
526.613
A8
B27



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


399
(Z)-5-((2-(4-((((6-(1H-pyrazol-5-yl)pyridin-3-
C23H24N8O2S
476.554
A9
B27



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


400
(Z)-5-((((1-(4-((2,4-dioxothiazolidin-5-
C24H23N9O2S
501.564
A10
B27



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(1H-pyrazol-5-



yl)nicotinonitrile


401
(Z)-ethyl 5-((((1-(4-((2,4-dioxothiazolidin-5-
C26H28N8O4S
548.617
A11
B27



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-2-(1H-pyrazol-5-



yl)nicotinate


402
(Z)-5-((2-(4-((((2-(1H-pyrazol-5-yl)pyridin-4-
C23H24N8O2S
476.554
A12
B27



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


403
(Z)-5-((2-(4-((((2-(1H-pyrazol-5-yl)-6-
C24H23F3N8O2S
544.552
A13
B27



(trifluoromethyl)pyridin-4-



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


404
(Z)-5-((2-(4-((((5-fluoro-2-(1H-pyrazol-5-yl)pyridin-
C23H23FN8O2S
494.545
A14
B27



4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


405
(Z)-5-((2-(4-((((6-amino-2-(1H-pyrazol-5-yl)pyridin-
C23H25N9O2S
491.569
A15
B27



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


406
(Z)-5-((2-(4-((((2′,4′-bis(trifluoromethyl)-[1,1′-
C29H25F6N5O2S
621.597
A16
B1



biphenyl]-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


407
(Z)-5-((2-(4-((((2′,4′-bis(trifluoromethyl)-[1,1′-
C29H25F6N5O2S
621.597
A17
B1



biphenyl]-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


408
(Z)-5-((2-(4-((((2′,4′-dimethoxy-[1,1′-biphenyl]-2-
C29H31N5O4S
545.653
A16
B2



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


409
(Z)-5-((2-(4-((((2′,4′-dimethoxy-[1,1′-biphenyl]-3-
C29H31N5O4S
545.653
A17
B2



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


410
(Z)-5-((2-(4-((((2′-(trifluoromethoxy)-[1,1′-
C28H26F3N5O3S
569.598
A16
B3



biphenyl]-2-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


411
(Z)-5-((2-(4-((((2′-(trifluoromethoxy)-[1,1′-
C28H26F3N5O3S
569.598
A17
B3



biphenyl]-3-yl)methyl)amino)methyl)piperidin-1-



yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione


412
(Z)-2′-((((1-(4-((2,4-dioxothiazolidin-5-
C29H29N5O4S
543.637
A16
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-5-methyl-[1,1′-biphenyl]-



2-carboxylic acid


413
(Z)-3′-((((1-(4-((2,4-dioxothiazolidin-5-
C29H29N5O4S
543.637
A17
B4



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-5-methyl-[1,1′-biphenyl]-



2-carboxylic acid


414
(Z)-5-((2-(4-(((2-(benzo[d][1,3]dioxol-5-
C28H27N5O4S
529.61
A16
B5



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


415
(Z)-5-((2-(4-(((3-(benzo[d][1,3]dioxol-5-
C28H27N5O4S
529.61
A17
B5



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


416
(Z)-N-benzyl-2′-((((1-(4-((2,4-dioxothiazolidin-5-
C35H34N6O3S
618.748
A16
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-[1,1′-biphenyl]-3-



carboxamide


417
(Z)-N-benzyl-3′-((((1-(4-((2,4-dioxothiazolidin-5-
C35H34N6O3S
618.748
A17
B6



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-[1,1′-biphenyl]-3-



carboxamide


418
(Z)-5-((2-(4-((((3′-(dimethylamino)-[1,1′-biphenyl]-
C29H32N6O2S
528.668
A16
B7



2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


419
(Z)-5-((2-(4-((((3′-(dimethylamino)-[1,1′-biphenyl]-
C29H32N6O2S
528.668
A17
B7



3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-



4-yl)methylene)thiazolidine-2,4-dione


420
(Z)-N-(2′-((((1-(4-((2,4-dioxothiazolidin-5-
C29H30N6O3S
542.652
A16
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-[1,1′-biphenyl]-3-



yl)acetamide


421
(Z)-N-(3′-((((1-(4-((2,4-dioxothiazolidin-5-
C29H30N6O3S
542.652
A17
B8



ylidene)methyl)pyrimidin-2-yl)piperidin-4-



yl)methyl)amino)methyl)-[1,1′-biphenyl]-3-



yl)acetamide


422
(Z)-5-((2-(4-((((4′-phenoxy-[1,1′-biphenyl]-2-
C33H31N5O3S
577.696
A16
B9



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


423
(Z)-5-((2-(4-((((4′-phenoxy-[1,1′-biphenyl]-3-
C33H31N5O3S
577.696
A17
B9



yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


424
(Z)-5-((2-(4-(((2-(1H-indol-5-
C29H28N6O2S
524.637
A16
B10



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


425
(Z)-5-((2-(4-(((3-(1H-indol-5-
C29H28N6O2S
524.637
A17
B10



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


426
(Z)-5-((2-(4-(((2-(isoquinolin-5-
C30H28N6O2S
536.647
A16
B11



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


427
(Z)-5-((2-(4-(((3-(isoquinolin-5-
C30H28N6O2S
536.647
A17
B11



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


428
(Z)-5-((2-(4-(((2-(thiophen-3-
C25H25N5O2S2
491.628
A16
B12



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


429
(Z)-5-((2-(4-(((3-(thiophen-3-
C25H25N5O2S2
491.628
A17
B12



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


430
(Z)-5-((2-(4-(((2-(benzo[b]thiophen-3-
C29H27N5O2S2
541.687
A16
B13



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


431
(Z)-5-((2-(4-(((3-(benzo[b]thiophen-3-
C29H27N5O2S2
541.687
A17
B13



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


432
(Z)-5-((2-(4-(((2-(5-acetylthiophen-2-
C27H27N5O3S2
533.665
A16
B14



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


433
(Z)-5-((2-(4-(((3-(5-acetylthiophen-2-
C27H27N5O3S2
533.665
A17
B14



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


434
(Z)-5-((2-(4-(((2-(furan-2-
C25H25N5O3S
475.563
A16
B15



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


435
(Z)-5-((2-(4-(((3-(furan-2-
C25H25N5O3S
475.563
A17
B15



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


436
(Z)-5-((2-(4-(((2-(benzofuran-2-
C29H27N5O3S
525.621
A16
B16



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


437
(Z)-5-((2-(4-(((3-(benzofuran-2-
C29H27N5O3S
525.621
A17
B16



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


438
(Z)-5-((2-(4-(((2-(furan-3-
C25H25N5O3S
475.563
A16
B17



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


439
(Z)-5-((2-(4-(((3-(furan-3-
C25H25N5O3S
475.563
A17
B17



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


440
(Z)-5-((2-(4-(((2-(1H-pyrrol-2-
C25H26N6O2S
474.578
A16
B18



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


441
(Z)-5-((2-(4-(((3-(1H-pyrrol-2-
C25H26N6O2S
474.578
A17
B18



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


442
(Z)-5-((2-(4-(((2-(isoquinolin-4-
C30H28N6O2S
536.647
A16
B19



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


443
(Z)-5-((2-(4-(((3-(isoquinolin-4-
C30H28N6O2S
536.647
A17
B19



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


444
(Z)-5-((2-(4-(((2-(quinolin-4-
C30H28N6O2S
536.647
A16
B20



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


445
(Z)-5-((2-(4-(((3-(quinolin-4-
C30H28N6O2S
536.647
A17
B20



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


446
(Z)-5-((2-(4-(((2-(3-fluoropyridin-4-
C26H25FN6O2S
504.579
A16
B21



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


447
(Z)-5-((2-(4-(((3-(3-fluoropyridin-4-
C26H25FN6O2S
504.579
A17
B21



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


448
(Z)-5-((2-(4-(((2-(2,6-difluoropyridin-4-
C26H24F2N6O2S
522.57
A16
B22



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


449
(Z)-5-((2-(4-(((3-(2,6-difluoropyridin-4-
C26H24F2N6O2S
522.57
A17
B22



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


450
(Z)-5-((2-(4-(((2-(6-(dimethylamino)pyridin-3-
C28H31N7O2S
529.656
A16
B23



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


451
(Z)-5-((2-(4-(((3-(6-(dimethylamino)pyridin-3-
C28H31N7O2S
529.656
A17
B23



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


452
(Z)-5-((2-(4-(((2-(2-(dimethylamino)pyrimidin-5-
C27H30N8O2S
530.645
A16
B24



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


453
(Z)-5-((2-(4-(((3-(2-(dimethylamino)pyrimidin-5-
C27H30N8O2S
530.645
A17
B24



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


454
(Z)-5-((2-(4-(((2-(3,5-dimethylisoxazol-4-
C26H28N6O3S
504.604
A16
B25



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


455
(Z)-5-((2-(4-(((3-(3,5-dimethylisoxazol-4-
C26H28N6O3S
504.604
A17
B25



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


456
(Z)-5-((2-(4-(((2-(1H-pyrazol-4-
C24H25N7O2S
475.566
A16
B26



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


457
(Z)-5-((2-(4-(((3-(1H-pyrazol-4-
C24H25N7O2S
475.566
A17
B26



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


458
(Z)-5-((2-(4-(((2-(1H-pyrazol-5-
C24H25N7O2S
475.566
A16
B27



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione


459
(Z)-5-((2-(4-(((3-(1H-pyrazol-5-
C24H25N7O2S
475.566
A17
B27



yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-



yl)methylene)thiazolidine-2,4-dione









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(═O)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(═O)CH3, —OAc).


For example, an aldehyde or ketone group may be protected as an acetal or ketal, respectively, in which the carbonyl group (C(═O)) 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(═O)R) or a urethane (—NRC(═O)OR), for example, as: a methyl amide (—NHC(═O)CH3); a benzyloxy amide (—NHC(═O)OCH2C6H5NHCbz); as a t-butoxy amide (—NHC(═O)OC(CH3)3, —NHBoc); a 2-biphenyl-2-propoxy amide (—NHC(═O)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(═O)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.


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, 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 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.


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 CK1 and subtypes thereof, CK2, the Wnt pathway, and/or the TGFβ 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 CK1 (e.g., CK1γ), CK2, the Wnt pathway, and/or the TGFβ 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 CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway. Bone-related diseases and conditions, including osteoporosis and bone formation, also can be treated by administration of modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway. Bone restoration can be facilitated by administration of modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway. Additional conditions that can be treated by administration of modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway include hypoglycemia, metabolic syndrome and diabetes. Modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway are also useful for influencing apoptosis (e.g., increasing the rate of apoptosis in cancerous cells). Modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway are also useful in treatment or prevention of aberrant embryonic development.


Based at least on the fact that increased CK1γ 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 CK1γ. 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 Pim-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, 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 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 include: Huntington's Diseases, Spinalbulbar Muscular Atrophy (SBMA or Kennedy's Disease), Dentatorubropallidoluysian Atrophy (DRPLA), Spinocerebellar Ataxia 1 (SCAT), Spinocerebellar Ataxia 2 (SCA2), Machado-Joseph Disease (MJD; SCA3), Spinocerebellar Ataxia 6 (SCA6), Spinocerebellar Ataxia 7 (SCAT), and Spinocerebellar Ataxia 12 (SCA12).


Any other disease in which the Wnt pathway, TGFβ pathway, JAK/STAT pathway, the mTOR pathway, Pgp modulation, CK1, CK1γ, 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.


Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the CK1, CK1γ, CK2, Piml-3, Wnt pathway, TGFβ 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.


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



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(E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1)

1,1-dimethoxy-N,N-dimethylmethanamine (100 g, 839 mmol, 1.02 equiv.) and 1,1-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)-1,1-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



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Sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2)

A solution of thiourea (64.7 g, 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)-1,1-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-(dimethoxymethyl)pyrimidine-2-thiolate (2) was used directly in the next step without further purification. LC-MS m/z 209 (M+1). Reference: WO 2006/0097341A1 (incorporated by reference), pg 67.


Example 3



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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 (2×150 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+1). Reference: WO 2006/0097341A1 (incorporated by reference), pg 67.


Example 4



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2-(methylthio)pyrimidine-4-carbaldehyde (4)

4-(dimethoxymethyl)-2-(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 3 hours. 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 (3×150 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+1). Reference: WO 2006/009734 A1 (incorporated by reference), pg 67.


Example 5



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(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 μL, 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 (1×20 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+1).


Example 6



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(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, 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-(methylsulfonyl)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+1).


Example 7



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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 μL, 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).


Example 8



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Displacement/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 μL 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).


Example 9



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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 NaHCO3 (2 mL). The aqueous layer was back extracted with DCE (2×2 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



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(Z)-5-((2-(4-((((5-phenylpyridin-2-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 11



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(Z)-5-((2-(4-((((8-(trifluoromethyl)quinolin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)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+1).


Example 12



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(Z)-5-((2-(4-((((6-(4-methoxyphenyl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 13



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(Z)-5-((2-(4-((((5-(furan-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 14



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(Z)-5-((2-(4-((((5-methylpyridin-2-yl)methyl)amino)methyl)piperidin-1-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+1).




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Example 15

(Z)-5-((2-(4-(((quinolin-2-ylmethyl)amino)methyl)piperidin-1-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+1).


Example 16



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(Z)-5-((2-(((1-((6-(thiophen-3-yl)pyridin-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-(thiophen-3-yl)picolinaldehyde (38.8 mg, 46.8 mg theoretical, 83%). LC-MS m/z 493.6 (M+1).


Example 17



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(Z)-5-((2-(((1-((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+1).


Example 18



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(Z)-5-((2-(((1-((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+1).


Example 19



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(Z)-5-((2-(((1-(pyridin-3-ylmethyl)piperidin-4-yl)methyl)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+1).




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Example 20

(Z)-5-((2-(4-((((2-(1H-pyrazol-5-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-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)-1H-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+1).


Example 21



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(Z)-5-((2-(4-((((2-(furan-3-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 22



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(Z)-5-((2-(4-((((2-(thiophen-3-yl)pyridin-4-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 23



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(Z)-5-((2-(4-((((2-(furan-3-yl)pyridin-4-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 24



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(Z)-5-((2-(4-((((2,3-dihydrobenzofuran-5-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)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+1).


Example 25



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(Z)-5-((2-(4-(((4-fluorobenzyl)amino)methyl)piperidin-1-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+1).


Example 26



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(Z)-5-((2-(4-(((3-chlorobenzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 3-chlorobenzaldehyde (13.8 mg, 32.0 mg theoretical, 43.2%). LC-MS m/z 444.9 (M+1).


Example 27



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(Z)-5-((2-(4-((((2-(furan-2-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 28



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(Z)-5-((2-(4-(((3-(thiophen-2-yl)benzyl)amino)methyl)piperidin-1-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+1).


Example 29



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(Z)-5-((2-(4-((((2-(5-(trifluoromethyl)thiophen-2-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 245-(trifluoromethyl)thiophen-2-yl)nicotinaldehyde (19.9 mg, 26.9 mg theoretical, 74%). LC-MS m/z 561.6 (M+1).


Example 30



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(Z)-5-((2-(4-((((2-(furan-2-yl)pyridin-4-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 31



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(Z)-5-((2-(4-((methyl((6-(thiophen-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)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+1).


Example 32



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(Z)-5-((2-(4-((((6-fluoronaphthalen-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)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+1).


Example 33



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(Z)-5-((2-(4-((((3-fluoro-6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 34



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(Z)-5-((2-(4-((((2-(thiophen-3-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 35



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(Z)-5-((2-(4-((((2-(2-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 36



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(Z)-5-((2-(4-((((2-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 37



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(Z)-5-((2-(4-((((2-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-(4-(trifluoromethyl)phenyl)nicotinaldehyde (9.1 mg, 26.6 mg theoretical, 34.2%). LC-MS m/z 555.5 (M+1).


Example 38



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(Z)-5-((2-(4-((((2-(benzofuran-2-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)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+1).


Example 39



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(Z)-5-((2-(4-((((6-(furan-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 40



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(Z)-5-((2-(4-((((6-(2-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)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+1).


Example 41



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(Z)-5-((2-(4-((((6-(3-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 42



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(Z)-5-((2-(4-((((6-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 43



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(Z)-5-((2-(4-((((6-(benzofuran-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 44



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(Z)-5-((2-(4-(β2-(furan-2-yl)benzyl)amino)methyl)piperidin-1-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+1).




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(Z)-5-((2-(4-((((6-(furan-2-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 46



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(Z)-5-((2-(4-((((3-(thiophen-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)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+1).


Example 47



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(Z)-5-((2-(4-((((2-(5-(trifluoromethyl)thiophen-2-yl)pyridin-4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 245-(trifluoromethyl)thiophen-2-yl)isonicotinaldehyde (3.0 mg, 26.9 mg theoretical, 11%). LC-MS m/z 561 (M+1).


Example 48



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(Z)-5-((2-(4-((((2-(methylthio)pyrimidin-4-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 49



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(Z)-5-((2-(4-((((2-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 50



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(Z)-5-((2-(4-((((2-(trifluoromethyl)quinolin-4-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 51



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(Z)-5-((2-(4-((((5-(thiophen-3-yl)furan-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 5-(thiophen-3-yl)furan-2-carbaldehyde (12.0 mg, 23.1 mg theoretical, 52%). LC-MS m/z 482 (M+1).


Example 52



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(Z)-5-((2-(4-((([3,3′-bithiophen]-5-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 3,3′-bithiophene]-5-carbaldehyde (3.5 mg, 23.8 mg theoretical, 14%). LC-MS m/z 498 (M+1).


Example 53



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(Z)-5-((2-(4-(((4-fluoro-2-(furan-2-yl)benzyl)amino)methyl)piperidin-1-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+1).


Example 54



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(Z)-5-((2-(4-(((2,4-difluorobenzyl)amino)methyl)piperidin-1-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+1).


Example 55



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(Z)-5-((2-(4-((((5-(3,5-bis(trifluoromethyl)phenyl)furan-2-yl)methyl)amino)methyl)piperidin-1-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%). LC-MS m/z 612 (M+1).


Example 56



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(Z)-5-((2-(4-((([2,2′-bifuran]-5-ylmethyl)amino)methyl)piperidin-1-yl)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+1).




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(Z)-5-((2-(4-((((4-(furan-2-yl)thiophen-2-yl)methyl)amino)methyl)piperidin-1-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+1).




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Example 58

(Z)-5-((2-(4-(((furan-3-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and furan-3-carbaldehyde (2.0 mg, 19.1 mg theoretical, 10%). LC-MS m/z 400 (M+1).


Example 59



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(Z)-5-((2-(4-(((furan-2-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and furan-2-carbaldehyde (7.4 mg, 19.1 mg theoretical, 38%). LC-MS m/z 400 (M+1).




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Example 60

(Z)-5-((2-(4-(((2,3,4-trifluorobenzyl)amino)methyl)piperidin-1-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+1).


Example 61



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(Z)-5-((2-(4-((((5-(2,4-dichlorophenyl)furan-2-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 62



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(Z)-5-((2-(4-((((5-(2-chlorophenyl)furan-2-yl)methyl)amino)methyl)piperidin-1-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, 36.7 mg theoretical, 46.8%). LC-MS m/z 511.5 (M+1).


Example 63



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(Z)-5-((2-(4-((((5-(2-(trifluoromethyl)phenyl)furan-2-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 64



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(Z)-5-((2-(4-((((5-(3-(trifluoromethyl)phenyl)furan-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-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+1).


Example 65



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(Z)-5-((2-(4-(((thiophen-3-ylmethyl)amino)methyl)piperidin-1-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+1).


Example 66



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(Z)-5-((2-(4-(((1-(6-(thiophen-3-yl)pyridin-2-yl)ethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 1-(6-(thiophen-3-yl)pyridin-2-yl)ethanone (3 mg, 37.4 mg theoretical, 8.6%). LC-MS m/z 507 (M+1).


Example 67



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(Z)-5-((2-(4-((((3-fluoro-6-(furan-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 3-fluoro-6-(furan-2-yl)picolinaldehyde (13.6 mg, 23.7 mg theoretical, 57%). LC-MS m/z 495 (M+1).


Example 68



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(Z)-5-((2-(4-(((2-fluoro-5-(thiophen-3-yl)benzyl)amino)methyl)piperidin-1-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+1).


Example 69



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(Z)-5-((2-(4-(((2-fluoro-6-(thiophen-3-yl)benzyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-fluoro-6-(thiophen-3-yl)benzaldehyde (8.9 mg, 24.4 mg theoretical, 36%). LC-MS m/z 510 (M+1).




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Example 70

(Z)-5-((2-(4-(((benzofuran-5-ylmethyl)amino)methyl)piperidin-1-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+1).


Example 71



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(Z)-5-((2-(4-(((benzo[b]thiophen-5-ylmethyl)amino)methyl)piperidin-1-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+1).




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(Z)-5-β6-(4-((((6-fluoroquinolin-2-yl)methyl)amino)methyl)piperidin-1-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+1).




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Example 73

(Z)-5-((2-(4-((((1-methyl-1H-benzo[d]imidazol-5-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 1-methyl-1H-benzo[d]imidazole-5-carbaldehyde (5.6 mg, 22.5 mg theoretical, 25%). LC-MS m/z 464 (M+1).




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Example 74

(Z)-5-((2-(4-((((1H-indol-5-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 1H-indole-5-carbaldehyde (5.2 mg, 24.5 mg theoretical, 24%). LC-MS m/z 449 (M+1).




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Example 75

(Z)-5-((2-(4-((((6-fluoroquinolin-2-yl)methyl)amino)methyl)-4-methylpiperidin-1-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+1).




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(Z)-5-((2-(4-((((2-(2-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-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+1).


Example 77



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(Z)-5-((2-(4-(((6-fluoroquinolin-2-yl)methyl)amino)piperidin-1-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+1).




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Example 78

(Z)-5-((2-(4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)piperidin-1-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+1).




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(Z)-5-((2-(7-((2-(pyridin-2-yl)ethyl)amino)-3,4-dihydroisoquinolin-2(1H)-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+1).


Example 80



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(Z)-5-((2-(5-((2-(pyridin-2-yl)ethyl)amino)-3,4-dihydroisoquinolin-2(1H)-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+1).


Example 81



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(Z)-5-((2-(4-(((2-methylquinolin-4-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 2-methylquinoline-4-carbaldehyde (5.1 mg, 34.1 mg theoretical, 15%). LC-MS m/z 461.5 (M+1).


Example 82



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(Z)-5-((2-(4-((phenethylamino)methyl)piperidin-1-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+1).


Example 83



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(Z)-5-((2-(4-(2-(((6-(thiophen-2-yl)pyridin-2-yl)methyl)amino)ethyl)piperidin-1-yl)pyrimidin-4-yl)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+1).


Example 84



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(Z)-5-((2-(4-(((1,2,3,4-tetrahydronaphthalen-2-yl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and 3,4-dihydronaphthalen-2(1H)-one (2.0 mg, 32.4 mg theoretical, 6%). LC-MS m/z 450 (M+1).


Example 85



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(Z)-5-((2-((1R,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+1).


Example 86



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(Z)-5-((2-((1R,5S)-8-((((6-(thiophen-3-yl)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+1).




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(Z)-5-((2-((1R,5S)-8-(((quinolin-2-ylmethyl)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 quinoline-2-carbaldehyde (1.4 mg, 32.6 mg theoretical, 4.3%). LC-MS m/z 487.5 (M+1).




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(Z)-5-((2-(2-((4-fluoro-2-(furan-2-yl)benzyl)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 4-fluoro-2-(furan-2-yl)benzaldehyde (9.1 mg, 34.8 mg theoretical, 26.1%). LC-MS m/z 520.5 (M+1).


Example 89



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(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+1).


Example 90



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(Z)-5-((6-methoxy-2-(4-((((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Example 153), the general reductive amination procedure and 6-(thiophen-3-yl)picolinaldehyde (34.3 mg, 65 mg theoretical, 52.8%). LC-MS m/z 523 (M+1).


Example 91



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(Z)-5-((6-methoxy-2-(4-((((2-methylquinolin-4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using (Z)-5-((2-(4-(aminomethyl)piperidin-1-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+1).


Example 92



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(Z)-5-((2-(4-((((6-fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using (Z)-5-((2-(4-(aminomethyl)piperidin-1-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+1).




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(Z)-5-((6-methoxy-2-(4-((((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using (Z)-5-((2-(4-(aminomethyl)piperidin-1-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+1).


Example 94



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(Z)-5-((2-(4-((((5-(pyrrolidin-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-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-1-carboxylate followed by the general de-protection procedure (29.3 mg, 39.8 mg theoretical, 73.6%). LC-MS m/z 480.6 (M+1).


Example 95



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(Z)-5-((2-(4-((((2-(1H-pyrrol-2-yl)pyridin-3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and tert-butyl 2-(3-formylpyridin-2-yl)-1H-pyrrole-1-carboxylate followed by the general de-protection procedure (16.5 mg, 17.1 mg theoretical, 96%). LC-MS m/z 476.6 (M+1).


Example 96



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(Z)-5-((2-(4-((methylamino)methyl)piperidin-1-yl)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+1).


Example 97



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(Z)-5-((2-(4-(((thiophen-2-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination 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+1).


Example 98



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(Z)-5-((2-(4-(((2-aminobenzyl)amino)methyl)piperidin-1-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+1).


Example 99



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(Z)-5-((2-(4-((((4-aminopyridin-3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination 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+1).




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Example 100

(Z)-5-((2-(4-((((3-aminopyridin-4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination 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+1).




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(Z)-5-((2-(4-(aminomethyl)-4-methylpiperidin-1-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+1).




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(Z)-5-((6-(4-(aminomethyl)piperidin-1-yl)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+1).


Example 103



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(Z)-5-((2-((1R,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((1R,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+1).




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Example 104

(Z)-5-((2-(4-(2-aminoethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione, 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+1).


Example 105



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(Z)-5-((2-(4-(2-aminoacetyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure and tert-butyl (2-oxo-2-(piperazin-1-yl)ethyl)carbamate followed by the general de-protection procedure (3.9 mg, 26.5 mg theoretical, 15%). LC-MS m/z 348 (M+1).


Example 106



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(Z)-5-((2-(2-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 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+1).


Example 107



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(Z)-5-((2-(5-chlorospiro[indoline-3,4′-piperidin]-1′-yl)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+1).


Example 108



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(Z)-5-((2-(4-(4-aminophenyl)piperidin-1-yl)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+1).


Example 109



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(Z)-5-((2-(4-(2-aminophenyl)piperidin-1-yl)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+1).


Example 110



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(Z)-5-((2-(4-(2-aminophenyl)piperidin-1-yl)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+1).


Example 111
Synthesized Sulfonamide Analogs
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. NaHCO3 and the aqueous layer was extracted with DCE (2×2 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



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(Z)—N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)-1-methyl-1H-indole-5-sulfonamide was prepared using General Procedure for the Preparation of Sulfonamides and 1-methyl-1H-indole-5-sulfonyl chloride (13.2 mg, 36.9 mg theoretical, 35.8%). LC-MS m/z 513.6 (M+1).


Example 113



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(Z)—N-((1-(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+1).


Example 114



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(Z)—N-((1-(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+1).


Example 115



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(Z)-5-chloro-N-((1-(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+1).


Example 116



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(Z)—N-((1-(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 mg theoretical, 26%). LC-MS m/z 475 (M+1).


Example 117



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(Z)—N-((1-(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+1).


Example 118
General Boronic Acid Coupling Procedures



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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 Na2CO3 (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 NaHCO3 (1 mL). The aqueous layer was extracted with EtOAc (3×1 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 119



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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+1).


Example 120



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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+1).




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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+1).


Example 122



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6-(3-(trifluoromethyl)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+1).


Example 123



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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+1).


Example 124



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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+1).


Example 125



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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 Na2CO3 (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 NaHCO3 (1 mL). The aqueous layer was extracted with EtOAc (3×1 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 126



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2-(furan-3-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and furan-3-ylboronic acid (40 mg, 93.2 mg theoretical, 42.9%). LC-MS m/z 174.2 (M+1).


Example 127



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2-(furan-2-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and furan-2-ylboronic acid (38 mg, 93.2 mg theoretical, 40.8%). LC-MS m/z 174.2 (M+1).




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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+1).




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Example 129

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+1).


Example 130



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2-(1H-pyrazol-5-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (1H-pyrazol-5-yl)boronic acid (60 mg, 93.2 mg theoretical, 64.4%). LC-MS m/z 174.2 (M+1).


Example 131



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tert-butyl 2-(3-formylpyridin-2-yl)-1H-pyrrole-1-carboxylate was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (66 mg, 146.5 mg theoretical, 45.1%). LC-MS m/z 273.3 (M+1).




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Example 132

2-(2-(trifluoromethyl)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+1).


Example 133



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2-(3-(trifluoromethyl)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+1).


Example 134



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2-(4-(trifluoromethyl)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+1).




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Example 135

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+1).


Example 136



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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 Na2CO3 (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 NaHCO3 (1 mL). The aqueous layer was extracted with EtOAc (3×1 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 1



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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+1).


Example 138



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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+1).


Example 139



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tert-butyl 2-(4-formylpyridin-2-yl)-1H-pyrrole-1-carboxylate was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (56 mg, 146.5 mg theoretical, 38.2%). LC-MS m/z 273.3 (M+1).


Example 140



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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+1).


Example 141



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2-(5-(trifluoromethyl)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+1).


Example 142



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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 Na2CO3 (0.368 mL, 0.735 mmol, 1.5 equiv.) and Pd(Ph3P)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 NaHCO3 (1 mL). The aqueous layer was extracted with EtOAc (3×1 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 143



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3-fluoro-6-(thiophen-3-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromo-3-fluoropicolinaldehyde and thiophen-3-ylboronic acid (80.5 mg, 101.5 mg theoretical, 79.3%). LC-MS m/z 208.2 (M+1).


Example 144



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2-(3-(trifluoromethoxy)phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure with 2-bromonicotinaldehyde and (3-(trifluoromethoxy)phenyl)boronic acid (101 mg, 144 mg theoretical, 70.1%). LC-MS m/z 268 (M+1).




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Example 145

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+1).


Example 146



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[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+1).


Example 147



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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+1).


Example 148



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[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+1).




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Example 149

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+1).




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Example 150

3-fluoro-6-(furan-2-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure with 6-bromo-3-fluoropicolinaldehyde and furan-2-ylboronic acid (41 mg, 94 mg theoretical, 43.6%). LC-MS m/z 192 (M+1).




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Example 151

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+1).


Example 152



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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+1).


Example 153
Preparation of Methoxyaminopyrimidine Intermediate

(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared as follows.




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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), K2CO3 (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 H2O (25 mL) and the water layer was extracted with EtOAc (2×20 mL). The combined organic layer was dried over Na2SO4 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.




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Methyl 2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-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 μL, 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 NaHCO3 (10 mL). The organic layer was dried over Na2SO4 and dried under reduced pressure to provide the crude product. Purification using the Biotage (SiO2, 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%).




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tert-Butyl((1-(4-formyl-6-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)carbamate

A 50 mL 2-neck round-bottomed flask was charged with the methyl ester intermediate (150 mg, 0.39 mmol, 1 equiv.), CH2Cl2 (2 mL, 0.195 M), and then DIBAL-H 1 M in CH2Cl2 (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 concentrated under reduced pressure and the residue was partitioned between CH2Cl2 (20 mL) and saturated NaHCO3 (20 mL). The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure to provide the crude product, which was used in the next step without further purification.




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(Z)-tert-Butyl((1-(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 μL, 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 (SiO2, 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+1).




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(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-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 μmol, 1 equiv.), CH2Cl2 (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 μL) to provide (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-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+1).




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Example 154
(Z)-5-((6-methoxy-2-(4-((((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione

(4.1 mg, 5.9 mg theoretical, 69%) LC-MS m/z 480 (M+1), 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-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione.




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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 Na2CO3 (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 NaHCO3 (1 mL). The aqueous layer was extracted with EtOAc (3×1 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.


Example 155



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(Z)-5-((6-methoxy-2-(4-((((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione

(292 mg, 360 mg theoretical, 81%) LC-MS m/z 334 (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-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Example 153):




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Example 156



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(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-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-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Example 153).




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Example 157



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(Z)—N-(1-(4-((2,4-dioxothiazolidin-5-ylidene)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+1).


Step 1.



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A 30 mL RB-vial was charged with furan-2-carbonitrile (25 mg, 0.269 mmol), methanol (300 μL, 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.



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A 2-dram RB-vial was charged with the crude material from step 1, methyl furan-2-carbimidate (37 mg, 296 μmol) and then treated with MeOH (Volume: 1.5 mL), (Z)-5-((2-(4-aminopiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (22.6 mg, 74 μmol), and 2 mL of DMSO was added providing a homogeneous solution. After 2 h at RT, DIPEA was added (250 μl). After 24 h at RT, the reaction was purified using RP-HPLC with TFA as the modifier to provide (Z)—N-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)furan-2-carboximidamide.




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(Z)-5-((2-(4-(furan-2-yl(imino)methyl)piperazin-1-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+1).


Step 1.



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A 30 mL RB-vial was charged with furan-2-carbonitrile (25 mg, 0.269 mmol), methanol (300 μL, 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.



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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-1-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 HCl in dioxane. After 30 minutes the final product (M+1=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.



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The crude material from Step 2, furan-2-yl(piperazin-1-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 reaction was then purified by RP-HPLC using TFA as the modifier to provide (Z)-5-((2-(4-(furan-2-yl(imino)methyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione.


Example 159



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(Z)—N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)furan-2-carboximidamide was prepared using the following procedure (4.7 mg, 31.4 mg theoretical, 15%). LC-MS m/z 413.1 (M+1).


Step 1.



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A 30 mL RB-vial was charged with furan-2-carbonitrile (25 mg, 0.269 mmol), methanol (300 μL, 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.



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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, 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-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)furan-2-carboximidamide.


Example 160



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(Z)-5-((6-(4-(aminomethyl)piperidin-1-yl)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+1).




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Step 1: Synthesis of methyl 6-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-2-chloropyrimidine-4-carboxylate



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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 μL, 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 3 h15. LC-MS showed mostly the desired product (2.77 min, M+1=385) and a small amount of the other regioisomer (3.28 min, M+1-isobutene=329). The solvent was evaporated and the residue was purified by biotage (SiO2, 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+1).


Step 2: Synthesis of methyl 6-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)pyrimidine-4-carboxylate



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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 6 h under 1 atm H2. The catalyst was filtered and the solvent was evaporated to give the crude desired product (150 mg, 110% crude yield) which was used directly in the next step. LC-MS m/z 351 (M+1).


Step 3: Synthesis of tert-butyl((1-(6-formylpyrimidin-4-yl)piperidin-4-yl)methyl)carbamate



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A 25 mL round-bottomed flask was charged with methyl 6-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)pyrimidine-4-carboxylate (150 mg, 0.43 mmol, 1 equiv.) and CH2Cl2 (2 mL). The reaction mixture was cooled to −78° C. DIBAL-H 1 M in CH2Cl2 (0.64 mL, 0.64 mmol, 1.5 equiv.) was added in 3 minutes at −78° C. The reaction was stirred for 4 h at −78° C. LC-MS showed some starting material. Another portion of DIBAL-H 1 M in CH2Cl2 (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 CH2Cl2 (10 mL) and 1 N NaOH (6 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL). The organic layer was dried over Na2SO4. 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+H2O) and 351 (M+1+MeOH).


Step 4: (Z)-tert-butyl((1-(6-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate



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An 8 mL round-bottomed vial was charged with tert-butyl((1-(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 μL, 0.48 mmol, 2 equiv.). Piperidine (1.04 mg, 23 L of a solution of 52 L 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% NH4Cl (5 mL). The organic layer was dried over Na2SO4. Evaporation of solvent gave the crude (Z)-tert-butyl((1-(6-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate (79.8 mg, 78%). LC-MS: M+1=420.




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Example 161

(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)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+1).


Example 162
Cell Proliferation Inhibition













TABLE 4









Incubation


Human cancer
Cell line
Medium
Positive drug
time







Prostate cancer
LNCaP
RPMI 1640
Cisplatin
72 h


Leukemia
KU812
RPMI 1640


Pancreas cancer
Panc-1
DMEM









All cells were cultured in the media supplemented with 10% FBS in the temperature of 37° C., 5% CO2 and 95% humidity. All culture media were purchased from GIBCO.


Reagents:
CellTiter 96® Aqueous MTS Reagent Powder

(Cat. No.: G1112, 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; CO2 Water Jacketed Incubator, Thermo (USA). Reverse microscope, Chongguang XDS-1B, Chongqing Guangdian Corp. (Chongqing, P.R.China).


Cytotoxicity and IC50 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 1.11×105 cells/mL for LNCaP cells, 2.22×105 cells/mL for KU812 cells, 5.56×104 cells/mL for Panc-1 cells.

  • 3. Add 90 μL cell suspensions to 96-well plate, the final cell densities are 1×104 cells/well for LNCaP cells, 2×104 cells/well for KU812 cells, and 4×103 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 μL 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 μL of the mixture into each well of the 96 well assay plate containing 100 μL culture medium. (The final reaction volume is 120 μL).

  • 8. Incubate the plate for 1-4 hours at 37° C. in a humidified, 5% CO2 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.









TABLE 5







IC50 values (μM)












Compound
LNCaP
KU812
Panc-1
















10903
4.050
NA
21.20



10904
24.20
NA
9.943e+007



10905
10.76
NA
68.46



10906
6.416
NA
27.57



10907
6.523
NA
8.164



10909
10.70
NA
13.64



10910
6.222
NA
7.441



10913
6.710
NA
10.88



10914
6.574
NA
7.498



10915
10.37
NA
8.998



11086
NA
259.8
153.9



11087
NA
1.776
11.05



11088
NA
2.225
12.16



11089
NA
11.86
8.908



11090
NA
15.26
18.92



11091
NA
6.622
16.80



11092
NA
7.284
56.35



11093
NA
4.041
13.76



11094
NA
41.30
NA



11100
NA
4.300e+007
12.96



11101
NA
13.97
9.555



11102
NA
10.59
162.9



11103
NA
6.538
11.35



11104
NA
22.48
151.24



11105
NA
3.462
7.333



11106
NA
3.383e+012
29.56



11193
NA
>30
11.9



11196
NA
16.2
>30



11198
NA
12
22.2



11204
NA
3.4
>30



11205
NA
14.2
6



11206
NA
15
>30



11207
NA
12.9
>30



11209
NA
15.5
>30



11210
NA
10.1
25.1



11211
NA
6.2
>30



11212
NA
20
>30



11213
NA
>30
>30



11214
NA
6.6
>30



11215
NA
7.7
>30



11216
NA
5.3
>30



11217
NA
>30
>30



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



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








Positive
Incubation


Human cancer
Cell line
Medium
drug
time







Multiple
MV4-11
IMDM
Cisplatin
72 hours


Myeloma
RPMI-8226
RPMI-1640



NCI-H929
RPMI-1640 +




0.05 mM 2-




mercaptoethanol









All cells were cultured in media supplemented with 10% FBS except for which are marked specially, in the temperature of 37° C., 5% CO2 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.: G11 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:

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 HCl.
  • f. Filter-sterilize the MTS solution through a 0.2 μm 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 μL 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 μL 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.



Equipment:

SpectraMAX plus microplate spectrophotometer Model 3011, Molecular Devices Corp. (California, USA); CO2 water jacketed incubator, Therma (USA). Reverse microscope, Chongguang XDS-1B, 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 2.22×105 or 1.11×105 or 5.56×104 cells/mL with respective medium.

  • 3. 90 μL cell suspensions were added to 96-well plates (triplicates for each cell concentration), the final cell densities were 2×104 or 1×104 or 5×103 cells/well. The density of 5×103 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 μL 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 μL of the mixture was introduced into each well of the 96-well assay plate containing 100 μL culture medium. (The final reaction volume was 120 μL).

  • 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.









TABLE 7







IC50 values (μM)












Compound
MV4-11
RPMI 8226
NCI-H929
















10903
4.990
NA
12.09



10904
7.176
NA
3.871



10905
4.478
NA
6.975



10906
4.036
NA
14.94



10907
7.452
NA
13.09



10909
8.415
NA
11.83



10910
11.37
NA
9.746



10913
9.954
NA
NA



10914
11.75
NA
41.02



10915
7.072
NA
28.94



11086
NA
 1.31e+006
7.131



11087
NA
17.78
2.748



11088
NA
11.70
9.976



11089
NA
9.030
12.67



11090
NA
6.033e+007
12.44



11091
NA
10.46
18.69



11092
NA
16.16
11.75



11093
NA
78.70
5.537



11094
NA
3.229
29.77



11100
NA
58.46
3.508e+010



11101
NA
12.78
15.67



11102
NA
20.23
14.63



11103
NA
28.83
12.84



11104
NA
21.90
21.58



11105
NA
11.71
10.62



11106
NA
18.59
6.319



11193
NA
>30
28.1



11196
NA
19.4
254.



11198
NA
8.2
3.5



11204
NA
7.4
10.1



11205
NA
3.4
3



11206
NA
>30
29



11207
NA
11.8
11.5



11209
NA
23.2
16.9



11210
NA
11.3
11.5



11211
NA
23.3
27.7



11212
NA
7.7
>30



11213
NA
>30
>30



11214
NA
11.1
7.8



11215
NA
12.7
12.7



11216
NA
11.2
8.1



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



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)

















Pim-
Pim-
Pim-


Compound
CK1γ2(h)
CK1(y)
CK2(h)
1(h)
2(h)
3(h)
















11193
85
91
92
33
31
30


11196
94
108
101
71
72
93


11198
85
45
76
8
13
6


11204
106
97
102
26
73
61


11205
95
107
108
56
55
38


11206
100
102
101
65
104
43


11207
88
105
106
53
66
54


11209
70
98
95
70
73
48


11210
89
109
100
108
106
102


11211
68
72
93
16
56
42


11212
76
89
94
17
35
24





IC50 (nM) for compound 11198 (with ATP concentration = Km of enzyme): Pim-1(h), 25; Pim-2(h), 15; Pim-3(h), 6.






Example 165









TABLE 9







Percent Activity of Enzyme When Treated with 300


nM of Compound (ATP Concentration = Km of Enzyme)

















Pim-
Pim-
Pim-


Compound
CK1γ2(h)
CK1(y)
CK2(h)
1(h)
2(h)
3(h)
















10903
69
76
79
18
14
17


10904
63
31
92
2
4
3


10905
77
61
55
18
21
10


10906
47
56
73
7
11
12


10907
10
78
63
53
44
100


10909
45
70
50
10
12
5


10910
96
81
54
18
21
5


10913
23
80
81
75
63
96


10914
23
76
76
66
57
91


10915
28
82
78
74
72
96


10917
84
97
109
75
69
63


11019
73
86
14
39
10
10


11020
96
98
12
48
20
11


11021
102
96
11
42
25
11


11022
94
103
8
34
21
9


11086
81
41
62
8
10
4


11087
35
−3
41
7
−1
0


11088
39
39
79
8
10
10


11089
55
61
68
9
11
9


11090
80
81
78
17
24
9


11091
78
88
75
32
21
11


11092
52
58
73
12
12
7


11093
32
12
83
14
44
11


11094
95
95
79
30
29
12


11213
103
112
79
60
66
43


11214
23
34
70
3
16
10


11215
17
46
88
18
16
38


11216
58
18
52
3
1
3


11217
94
100
75
46
35
19


11220
82
111
62
59
58
39


11221
83
113
91
91
75
78


11222
52
62
74
5
19
12


11223
34
69
90
22
30
43


11224
102
89
81
44
51
27


11225
112
88
84
37
47
25


11226
83
82
85
22
31
22


11227
80
84
71
31
38
22


11232
128
102
107
90
109
76


11234
47
67
91
22
32
47


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


11667
−1
22
73
17
8
10









Example 166









TABLE 10







IC50 (nM) of Compound When ATP


Concentration = Km of Enzyme

















Pim-
Pim-
Pim-


Compound
CK1γ2(h)
CK1(y)
CK2(h)
1(h)
2(h)
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









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.

Claims
  • 1. A compound of formula 1 or a pharmaceutically acceptable salt thereof,
  • 2. The compound of claim 1, wherein R1 is hydrogen.
  • 3. (canceled)
  • 4. (canceled)
  • 5. The compound of claim 1, wherein W is CH2.
  • 6-42. (canceled)
  • 43. A compound of formula 2 or a pharmaceutically acceptable salt thereof,
  • 44. The compound of claim 43, wherein R1 is hydrogen.
  • 45-82. (canceled)
  • 83. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • 84. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • 85. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • 86. The compound of claim 1, or a pharmaceutically acceptable salt thereof selected from the groan consisting of:
  • 87. The compound of claim 1, or a pharmaceutically y acceptable salt thereof, selected from the group consisting of:
  • 88. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • 89. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • 90-108. (canceled)
  • 109. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
  • 110. (canceled)
  • 111. (canceled)
  • 112. A method for treating or preventing a condition associated with aberrant casein kinase 1 (CK1), CK1γ1, CK1γ2, or CK1γ3 activity, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any claim 1.
  • 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 claim 1.
  • 114. A method of treating cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.
  • 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, 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 claim 1.
  • 119-122. (canceled)
  • 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 claim 1.
  • 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.
  • 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 claim 1.
  • 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 claim 1.
  • 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 claim 1.
  • 129-134. (canceled)
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 Apr. 22, 2011; and U.S. Provisional Patent Application No. 61/555,617, filed Nov. 4, 2011.

Provisional Applications (2)
Number Date Country
61478302 Apr 2011 US
61555617 Nov 2011 US