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WO2018089902A1 - Diaminothiazole compounds, compositions and methods of use - Google Patents

Diaminothiazole compounds, compositions and methods of use Download PDF

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Publication number
WO2018089902A1
WO2018089902A1 PCT/US2017/061327 US2017061327W WO2018089902A1 WO 2018089902 A1 WO2018089902 A1 WO 2018089902A1 US 2017061327 W US2017061327 W US 2017061327W WO 2018089902 A1 WO2018089902 A1 WO 2018089902A1
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Prior art keywords
amino
thiazol
alkyl
methanone
phenyl
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PCT/US2017/061327
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French (fr)
Inventor
Charles D. Smith
Yan Zhuang
Lynn W. Maines
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Apogee Biotechnology Corporation
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Publication of WO2018089902A1 publication Critical patent/WO2018089902A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present disclosure relates to diaminothiazole compounds and pharmaceutical compositions thereof which are useful, for example, for the treatment of inflammatory, hyperproliferative or neurologic diseases.
  • the disclosure also provided methods utilizing those compositions for the treatment of inflammatory, hyperproliferative or neurologic diseases.
  • Glycogen Synthase kinase 3 (GSK3)
  • Glycogen synthase kinase-3s are constitutively active protein kinases that regulate vital cellular functions such as proliferation and apoptosis, as well as inflammation.
  • GSK3s regulate signaling through NFKB, and therefore mediate responses to inflammatory cytokines, including TNFa, IL- 1 p and IL-6. Consequently, excessive GSK3 activity has been implicated in several hyperproliferative and inflammatory diseases including cancer. Inhibiting GSK3s initially focused on suppressing neuroinflammation in neurologic diseases such as Alzheimer's disease; however, interest in evaluating GSK3 inhibitors as anticancer drugs is growing.
  • GSK3 plays an important role in pancreatic cancer development and progression, dedifferentiation, proliferation, survival, and invasion. Importantly, inhibition of GSK3 sensitizes pancreatic cancer cells to killing by radiation and other drugs including gemcitabine. Therefore, inhibition of GSK3 is a new approach to cancer treatment.
  • GSK3 plays an important role in Inflammatory Bowel Diseases (IBD).
  • IBD Inflammatory Bowel Diseases
  • CD Crohn's Disease
  • mice treated intraperitoneally with GSK3 inhibitors had significantly reduced colitis, associated with increased CREB activity and decreased NFkB activity.
  • GSK3 inhibitors also protect intestinal crypt cells and increase mouse survival following lethal radiation, further demonstrating Gl protection through suppression of GSK3 activity.
  • CDK9 cyclin-dependent kinase 9
  • P-TEFb positive transcription elongation factor b
  • CDK9 is elevated and provides oncogenic transcription profiles in several cancers due, at least in part, to its requirement for transcriptional activation of MYC-targeted genes.
  • CDK9 also promotes the expression of inflammatory cytokine genes and COX-2, and the extravasation of leukocytes into sites of inflammation.
  • CDK9 signals through NFKB, p38 MAPK, JNK and ERK.
  • pNFKB is required for CDK9 binding to P-TEFb, and so crosstalk between the GSK3 and CDK9 pathways is critical for inflammatory responses.
  • gene expression by CDK9 is mediated by STAT3, a second proinflammatory transcription factor that is essential for cytokine signaling, including IL-6. Because pancreatic cancer growth is enhanced by its highly inflamed environment, and because CDK9 is overexpressed in inflamed pancreatic islet cells and pancreatic tumors, CDK9 inhibitors may be particularly effect in this cancer.
  • flavopiridol a pan-CDK inhibitor, but with approximately 10-fold higher potency for CDK9 than other CDKs
  • Suppression of CDK9 by flavopiridol attenuates inflammation in the collagen-induced arthritis model, protects against ConA-induced murine hepatitis, and protects cartilage from the catabolic effects of I L- 1 , TNFa and LPS or mechanical injury.
  • flavopiridol or CDK9 siRNA inhibits IL-6/STAT3 signaling in the liver.
  • roscovitine another potent but non-selective CDK inhibitor
  • CDK9 expression is elevated in serum, peripheral blood mononuclear cells (PBMCs) and artery wall sections from atherosclerotic patients compared with controls, and so CDK9 may be both a target and biomarker for coronary artery disease.
  • PBMCs peripheral blood mononuclear cells
  • the cytoskeleton of eukaryotic cells is involved in the regulation of a number of cellular processes, including motility, secretion and proliferation.
  • Cellular microtubules are in a dynamic state, demonstrating continuous polymerization and depolymerization at their ends. This dynamic cycling is required for the maintenance of normal microtubule structure and function, and therefore is strictly controlled in a healthy cell.
  • microtubules are the molecular targets of several currently utilized anticancer drugs.
  • Clinically useful compounds which induce microtubule depolymerization include vinblastine, vincristine and colchicine. These compounds bind to unpolymerized tubulin, blocking its assembly into microtubules. This ultimately leads to elimination of microtubules in both the mitotic spindle and the cytosol, and consequently to prevention of cell division.
  • Tubulin-targeted drugs are commonly used in the chemotherapy of acute lymphocytic leukemias, neuroblastoma, Wilms' tumor, rhabdomyosarcoma, Hogkin's disease, non-Hodgkin's lymphoma, small-cell lung, breast and testicular carcinoma.
  • paclitaxel increases microtubule assembly by reducing tubulin loss at the minus end of the microtubule.
  • paclitaxel alters microtubule structure in the mitotic spindle and promotes microtubule polymerization and bundling in the cytosol. This results in inhibition of microtubule treadmilling and loss of mitotic spindle function.
  • Taxol has activity against certain solid tumors, including ovarian and breast; however, the clinical efficacy of this compound may be restricted by the acquisition of tumor resistance.
  • Sphingolipid metabolism has been shown to play critical roles in several diseases. Ceramide is produced by the hydrolysis of sphingomyelin in response to several growth stimulatory (e.g. growth factors and oncoproteins) and inflammatory (e.g. cytokines and radiation) signals. Ceramide induces apoptosis in tumor cells. Additionally, ceramide is hydrolyzed by ceramidases to produce sphingosine, which is phosphorylated by sphingosine kinases (SK1 and SK2) to produce sphingosine 1-phosphate (S1 P). Studies in many cancer cell lines indicate that S1 P induces proliferation and protects against ceramide-induced apoptosis.
  • growth stimulatory e.g. growth factors and oncoproteins
  • inflammatory e.g. cytokines and radiation
  • S1 P sphingosine 1-phosphate
  • ceramide/S1 P rheostat a critical balance, i.e. a ceramide/S1 P rheostat, has been hypothesized to determine the fate of tumor cells.
  • Sphingolipids also regulate the sensitivities of tumor cells to anticancer drugs.
  • ceramide increases apoptosis induced by paclitaxel, etoposide and gemcitabine. Therefore, inhibition of SK is expected to increase tumor chemosensitivity by elevating ceramide levels in the cells.
  • SKs regulate deleterious inflammation from cytokines such as TNFa and IL-6. Because activation of SK activity generates the S1 P that drives inflammatory responses, SKs are also new targets for developing anti-inflammatory drugs.
  • the present disclosure encompasses the compounds of formula (I), shown below, pharmaceutical compositions containing such compounds, and methods employing such compounds or compositions in the treatment or prevention of a hyperproliferative disease, an inflammatory disease, an angiogenic disease or a neurologic disease.
  • the disclosure provides compounds of formula I :
  • R 1A and R 1 B are each independently selected from H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci-C 4 alkenyl, optionally substituted Ci-C 4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -C(0)R 1C , -C(S)R 1C , -S(0)i- 2 R 1C , -C(0)0R 1C , -C(0)NR 1 D R 1C , -C(0)SR 1 C , -C(S)0R 1C , -C(S)NR 1 D R 1C , -C(S)SR 1 C , -C(NR 1 D )NR 1 D R 1 C and -S(0)i- 2 NR 1 D R 1C , in which
  • each R 1C is independently selected from H, C1-C4 alkyl, Ci-C alkenyl, Ci-C alkynyl, C1-C3 fluoroalkyl, Ci-C 3 hydroxyalkyl and (Ci-C 3 alkoxy)Ci-C 3 alkyl, and
  • each R 1 D is independently selected from H, Ci-C alkyl, Ci-C alkenyl, Ci-C alkynyl, Ci-C 3 fluoroalkyl, Ci-C 3 hydroxyalkyl, (Ci-C 3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl) , -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl); the ring system denoted by "A” is phenyl or a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N , O and S;
  • R 2 is selected from H, C1-C3 fluoroalkyl, halogen, nitro, -CN, -NR 2A R 2B , -C(0)R 2A , -S(0)i- 2 R 2A , -C(0)R 2A , -C(0)NR 2B R 2A , -C(S)NR 2B R 2A ,-C(0)OR 2A , -C(0)SR 2A , -C(S)OR 2A , -C(S)SR 2A , -S(0)i- 2 OR 2A and -S(0)i.
  • each R 2A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl
  • each R 2B is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl), with the proviso that when
  • each R 3A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl
  • each R 3B is independently selected from H, optionally substituted C1-C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl); m is 0, 1 , 2, 3 or 4;
  • the ring system denoted by "B” is phenyl or a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O and S;
  • each R 4 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF 5 , -N 3 , -C(0)R 4A , -SR 4A , -S(0)i_ 2 R 4A , -OR 4A , -NR 4B R 4A , -C(0)R 4A , -C(0)NR 4B R 4A , -NR 4B C(0)R 4A , -C(S)NR 4B R 4A , -NR 4B C(S)R 4A , -C(0)OR 4A , -OC(0)R 4A , -C(0)SR 4A , -SC(0)R 4A , -C(S)OR 4A , -OC(S)R 4A , -C(S)
  • each R 4A is independently selected from H, optionally substituted C 1 -C4 alkyl, optionally substituted C 1 -C4 alkenyl, optionally substituted C 1 -C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl
  • each R 4B is independently selected from H, optionally substituted C 1 -C4 alkyl; optionally substituted C 1 -C4 alkenyl, optionally substituted C 1 -C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl) ; and n is 0, 1 , 2, 3,
  • each alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene is straight-chain or branched;
  • each optionally substituted alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene is unsubstituted or substituted with 1 -5 substituents independently selected from halogen, nitro, -CN, -SF 5 , -N 3 , -C(0)R5, -SR 5 , -S(0)i_ 2 R 5 , -OR 5 , -NR 6 R 5 , -C(0)NR 6 R 5 , -NR 6 C(0)R 5 , -C(S)NR 6 R 5 , -NR 6 C(S)R 5 , -C(0)OR 5 , -OC(0)R 5 , -C(0)SR 5 , -SC(0)R 5 , -C(S)OR 5 , -OC(S)R 5 , -C(S)SR 5 , -SC(S)R 5 , -S(0)i_ 2 OR 5 , -OS(0)i- 2 R 5 , -
  • each R 5 is independently selected from H, C 1 -C3 alkyl, C 1 -C3 fluoroalkyl, C 1 -C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl;
  • each R 6 is independently selected from H, C 1 -C3 alkyl, C 1 -C3 fluoroalkyl, C 1 -C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i -2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl).
  • the compound is not
  • compositions comprising a compound or salt of formula I and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent.
  • the disclosure also provides methods for the treatment or prevention of hyperproliferative disease, inflammatory disease, angiogenic disease or neurologic disease.
  • the disclosure also provides methods for inhibiting GSK3s, SKs and/or microtubule dynamics in a cell comprising contacting the cell with an inhibitory effective amount of a compound according to the preceding aspects.
  • the disclosure provides methods for treating a disease selected from a hyperproliferative disease, an inflammatory disease, an angiogenic disease or a neurologic disease comprising providing to a patient in need of such treatment a therapeutically effective amount of a compound or a pharmaceutical composition according to any of the preceding aspects.
  • Figure 1 shows dose-response curves for inhibition of GSK3a, GSK3P and CDK9 by compound 32.
  • Figure 2 shows depolymerization of cancer cell microtubules by compound 91.
  • Hep3B liver cancer cells were treated with the indicated concentrations of compound 91 for 18 hours. The cells were then fixed and stained with anti-tubulin antibodies, and images were recorded by microscopy.
  • Figure 3 shows toxicology parameters following 7 day treatment with 50 mg/kg of compound 17, 32, 57, 60, 62 or 67.
  • the parameters of blood urea nitrogen (BUN), alanine aminotransferase (ALT), white blood cell count (WBC), red blood cell count (RBC), Platelets, hemoglobin (Hgb), Kidney Weight and Heart Weight are shown in Panels A-H, respectively.
  • Figure 4 shows toxicology parameters following 7 day treatment with 100 or 200 mg/kg of compound 91 or 32.
  • the parameters of Creatinine, ALT, WBC, RBC, Platelets, Glucose, Liver Weight and Heart Weight are shown in Panels A-H, respectively.
  • Figure 5 shows inhibition of melanoma tumor growth by compound 32.
  • C57BL/6 mice were injected subcutaneously with B16 melanoma cells suspended in PBS. After tumor volume of at least 100 mm 3 , animals were treated 5 times per week by oral gavage of either 0.1 ml Vehicle (open squares) or 5 mg/kg of compound 32 (gray squares). Whole body weight and tumor volume measurement was performed for 1 1 days. * p ⁇ 0.05. Inset: Averaged body weight of mice from each group during course of study.
  • Figure 6 shows inhibition of pancreatic tumor growth by compound 32.
  • C57BL/6 mice were injected subcutaneously with PAN02 pancreatic cancer cells suspended in PBS/growth matrix. After tumor volume of at least 100 mm 3 , animals were treated 5 times per week by oral gavage of either 0.1 ml Vehicle (open squares) or 5 mg/kg of compound 32 (gray squares). Whole body weight and tumor volume measurement was performed for 22 days. ** p ⁇ 0.01. Inset: Averaged body weight of mice from each group during course of study.
  • Figure 7 shows inhibition of pancreatic tumor growth by compound 91 . C57BL/6 mice were injected subcutaneously with PAN02 pancreatic cancer cells suspended in PBS/growth matrix.
  • tumor size is expressed as normalized tumor volume, which is tumor volume at Day 3 to 31 divided by tumor volume at Day 1 for each individual mouse. ** p ⁇ 0.01 .
  • Figure 8 shows effects of compounds on Disease Activity Index (DAI) in the DSS- IBD model.
  • Male C57BL/6 mice were treated for 6 days as follows: normal drinking water and daily oral administration of Vehicle (Sham); 2% DSS in the drinking water and daily oral administration of Vehicle (V/DSS); 2% DSS in the drinking water and daily oral administration of 50 mg/kg compound 27, 57, 9 or 32.
  • Figure 9 shows effects of compounds on neutrophil infiltration into the colon in the acute DSS-IBD model.
  • Figure 10 shows effects of Compound 32 on colon cytokine levels in the DSS-IBD model.
  • Figure 1 1 shows effects of compound 32 in the TNBS-colitis model.
  • the disclosure also provides a variety of subgenera of compounds in which the regiochemistry of the structural formula (I), the ring system denoted by "A”, R2, R3, m, the ring system denoted by “B”, R4 and n are optionally independently selected from the groups (1 a) et seq. , (2a) et seq., (3a) et seq.
  • R 1A and R 1 B are each independently selected from H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci-C 4 alkenyl, optionally substituted C1-C4 alkynyl, Ci-C 3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -C(0)R 1C , -C(S)R 1C , -S(0)i- 2 R 1C , -C(0)0R 1C , -C(0)NR 1 D R 1C , -C(0)SR 1C , -C(S)0R 1C , -C(S)NR 1 D R 1C , -C(S)SR 1C , -C(NR 1 D )NR 1 D R 1C and -S(0)i- 2 NR 1 D R 1C , in which each R 1C is independently selected from H, C1-C4 alkyl
  • R 1A is selected from one of the following groups:
  • R 1A is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, Ci-C 3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -C(0)R 1C , -C(S)R 1C , -S(0)i- 2 R 1C , -C(0)0R 1C , -C(0)NR 1 D R 1C , -C(0)SR 1C , -C(S)0R 1C , -C(S)NR 1 D R 1C , -C(S)SR 1C , -C(NR 1 D )NR 1 D R 1C or -S(0)i- 2 NR 1 D R 1C , (1 b) R 1A is H, optionally substituted C 1 -C4 alkyl, optionally substituted C 1 -C
  • R 1A is not H.
  • R 1A is -(C1-C4 alkyl).
  • R 1A is -(C1-C4 alkyl), -C(0)-(Ci-C 4 alkyl), or -C(0)-(Ci-C 4 alkenyl).
  • each "optionally substituted" alkyl, alkenyl and alkynyl of R 1A is unsubstituted or fluorinated.
  • each "optionally substituted" alkyl, alkenyl and alkynyl of R 1A is unsubstituted.
  • R 1A is not an alkenyl or an alkynyl.
  • R 1B is selected from one of the following groups:
  • R 1B is H, optionally substituted C 1 -C4 alkyl, optionally substituted C 1 -C4 alkenyl, optionally substituted C 1 -C4 alkynyl, Ci-C 3 fluoroalkyl, C 1 -C3 hydroxyalkyl, (C 1 -C3 alkoxy)Ci-C 3 alkyl, -C(0)R 1C , -C(S)R 1C , -S(0)i- 2 R 1C , -C(0)0R 1C , -C(0)NR 1D R 1C , -C(0)SR 1C , -C(S)0R 1C , -C(S)NR 1D R 1C , -C(S)SR 1C , -C(NR 1 D )NR 1D R 1C or
  • R 1B is H, optionally substituted C 1 -C4 alkyl, optionally substituted C 1 -C4 alkenyl, optionally substituted C 1 -C4 alkynyl, Ci-C 3 fluoroalkyl, C 1 -C3 hydroxyalkyl, (C 1 -C3 alkoxy)Ci-C 3 alkyl, -C(0)R 1C and -S(0)i. 2 R 1c
  • R 1B is C 1 -C4 alkyl.
  • R 1B is -C(0)R 1C , in which R 1C is H, optionally substituted C 1 -C4 alkyl, optionally substituted C 1 -C4 alkenyl, optionally substituted C 1 -C4 alkynyl, C 1 -C3 fluoroalkyl, C1-C3 hydroxyalkyl or (C1-C3 alkoxy)Ci-C 3 alkyl.
  • each "optionally substituted” alkyl, alkenyl and alkynyl of R 1B is unsubstituted or fluorinated.
  • each "optionally substituted" alkyl, alkenyl and alkynyl of R 1B is unsubstituted.
  • R 1 B is not an alkenyl or an alkynyl.
  • R 1C is selected from one of the following groups:
  • R 1C is independently selected from H, Ci-C 4 alkyl, Ci-C 4 alkenyl, Ci-C 4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl,
  • each R 1C is independently selected from H, C1-C4 alkyl, Ci-C 3 fluoroalkyl, Ci-C 3 hydroxyalkyl and (Ci-C 3 alkoxy)Ci-C 3 alkyl.
  • each R 1C is independently selected from H and Ci-C alkyl.
  • R 1C is not an alkenyl or an alkynyl.
  • R 1 D is selected from one of the following groups:
  • each R 1 D is independently selected from H, Ci-C alkyl, Ci-C alkenyl, Ci-C alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl).
  • each R 1 D is independently selected from H, C1-C4 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl.
  • each R 1 D is independently selected from H and C1-C4 alkyl.
  • R 1 D is not an alkenyl or an alkynyl.
  • the -NR 1A R 1 B is selected from one of the following groups:
  • R 1 B is -N(Ci-C 4 alkyl)(Ci-C 4 alkyl).
  • R 1 B is -NHC(0)CH 2 CH 3 .
  • the ring system denoted by “A” is phenyl or a 5- or 6- membered heteroaryl having one or two heteroatoms independently selected from N, O and S.
  • the ring system denoted by “A” is selected from one of the following groups:
  • the ring system denoted by "A” is a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O and S, e.g., pyridyl, such as pyrid-2- yl, pyrid-3-yl, or pyrid-4-yl.
  • the ring system denoted by "A” is a 5- or 6-membered heteroaryl having one heteroatom independently selected from N, O and S, e.g., pyridyl, such as pyrid-2- yl, pyrid-3-yl, or pyrid-4-yl.
  • R 2 is selected from H, C1-C3 fluoroalkyl, halogen, nitro, -CN, -NR 2A R 2B , -C(0)R 2A , -S(0)i- 2 R 2A , -C(0)R 2A , -C(0)NR 2B R 2A , -C(S)NR 2B R 2A ,-C(0)OR 2A , -C(0)SR 2A , -C(S)OR 2A , -C(S)SR 2A , -S(0)i_ 2 OR 2A and -S(0)i_ 2 NR 2B R 2A , in which each R 2A is independently selected from H, optionally substituted Ci-C 4 alkyi, optionally substituted Ci-C 4 alkenyl, optionally substituted Ci-C 4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)C
  • R 2 is selected from H, Ci-C 3 fluoroalkyl, halogen, nitro, -CN, -NR 2A R 2B , -C(0)R 2A , -S(0)i- 2 R 2A , -C(0)R 2A , -C(0)NR 2B R 2A , -C(S)NR 2B R 2A ,-C(0)OR 2A , -C(0)SR 2A , -C(S)OR 2A , -C(S)SR 2A , -S(0)i- 2 OR 2A and -S(0)i_ 2 NR 2B R 2A
  • R 2 is Ci-C 3 fluoroalkyl, halogen, -NR 2A R 2B , nitro, or -CN.
  • R 2 is -CN.
  • R 2 is halogen, e.g., chloro or fluoro.
  • R 2 is nitro.
  • R 2 is -C(0)R 2A , -S(0)i- 2 R 2A , -C(0)R 2A , -C(0)NR 2B R 2A , -C(S)NR 2B R 2A , -C(0)OR 2A , -C(0)SR 2A , -C(S)OR 2A , -C(S)SR 2A , -S(0)i_ 2 OR 2A or -S(0)i_ 2 NR 2B R 2A
  • R 2 is selected from Ci-C 3 fluoroalkyl, halogen, nitro, -CN, -C(0)R 2A , -S(0)i- 2 R 2A , -C(0)R 2A , -C(0)NR 2B R 2A , -C(S)NR 2B R 2A ,-C(0)OR 2A , -C(0)SR 2A , -C(S)OR 2A , -C(S)SR 2A , -S(0)i- 2 OR 2A and -S(0)i_ 2 NR 2B R 2A
  • R 2 is Ci-C 3 fluoroalkyl, halogen, nitro, or -CN.
  • each "optionally substituted" alkyl, alkenyl and alkynyl of R 2 is unsubstituted or fluorinated.
  • each "optionally substituted" alkyl, alkenyl and alkynyl of R 2 is unsubstituted.
  • R 2 is not an alkenyl or an alkynyl.
  • each R 2A is independently selected from H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci-C 4 alkenyl, optionally substituted Ci-C 4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl.
  • each R 2A is selected from one of the groups below:
  • each R 2A is independently selected from H, optionally substituted C 1 -C4 alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, Ci-C 3 fluoroalkyl, Ci-C 3 hydroxyalkyl and (Ci-C 3 alkoxy)Ci-C 3 alkyl.
  • each R 2A is independently selected from H, Ci-C alkyl, Ci-C 3 fluoroalkyl, Ci-C 3 hydroxyalkyl and (Ci-C 3 alkoxy)Ci-C 3 alkyl.
  • each R 2A is independently selected from H and Ci-C alkyl.
  • each "optionally substituted” alkyl, alkenyl and alkynyl of R 2A is unsubstituted or fluorinated.
  • each "optionally substituted” alkyl, alkenyl and alkynyl of R 2A is unsubstituted.
  • R 2A is not an alkenyl or an alkynyl.
  • each R 2B is independently selected from H, optionally substituted Ci-C alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl).
  • each R 2B is selected from one of the groups below:
  • each R 2A is independently selected from H, optionally substituted Ci-C alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, Ci-C 3 fluoroalkyl, Ci-C 3 hydroxyalkyl, (Ci-C 3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl).
  • each R 2B is independently selected from H, Ci-C alkyl, Ci-C 3 fluoroalkyl, Ci-C 3 hydroxyalkyl, (Ci-C 3 alkoxy)Ci-C 3 alkyl, -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl).
  • each R 2B is independently selected from H and C1-C4 alkyl.
  • each "optionally substituted” alkyl, alkenyl and alkynyl of R 2B is unsubstituted or fluorinated.
  • each "optionally substituted” alkyl, alkenyl and alkynyl of R 2B is unsubstituted.
  • R 2B is not an alkenyl or an alkynyl.
  • the R 2 substituent can be disposed on the ring system denoted by "A" in a variety of regiochemical relationships with respect to the thienylcarbonyl.
  • the regiochemistry of the R 2 substituent is selected from one of the following:
  • the ring system denoted by "A” is a six-membered ring, and wherein the R 2 is disposed in a 1 ,4 relationship with respect to the thienylcarbonyl.
  • the R 2 is disposed in a 1 ,3 relationship with respect to the thienylcarbonyl.
  • the R 2 is disposed in a 1 ,2 relationship with respect to the thienylcarbonyl.
  • each R 3 is independently selected from optionally substituted Ci-C 4 alkyl, optionally substituted Ci-C 4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF 5 , -N 3 , -C(0)R 3A , -SR 3A , -S(0)i_ 2 R 3A , -OR 3A , -NR 3B R 3A , -C(0)R 3A , -C(0)NR 3B R 3A , -NR 3B C(0)R 3A , -C(S)NR 3B R 3A ,
  • each R 3A is independently selected from H, optionally substituted Ci-C alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (Ci-C 3 alkoxy)Ci-C 3 alkyl
  • each R 3B is independently selected from H, optionally substituted Ci-C alkyl; optionally substituted Ci-C alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl).
  • each R 3 substituent is selected from one of the following groups: (1 1 a) each R 3 is independently selected from optionally substituted Ci-C 4 alkyl, optionally substituted Ci-C 4 alkenyl, optionally substituted Ci-C 4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF 5 , -N 3 , -C(0)R 3A , -SR 3A , -S(0)i_ 2 R 3A , -OR 3A , -NR 3B R 3A , -C(0)R 3A , -C(0)NR 3B R 3A , -NR 3B C(0)R 3A , -C(S)NR 3B R 3A , -NR 3B C(S)R 3A , -C(0)OR 3A , -OC(0)R 3A , -C(0)SR 3A , -SC(0)R 3A ,
  • each R 3 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF 5 , -N 3 , -C(0)R 3A , -SR 3A , -S(0)i_ 2 R 3A , -OR 3A , -NR 3B R 3A , -C(0)R 3A , -C(0)NR 3B R 3A , -NR 3B C(0)R 3A , -C(S)NR 3B R 3A , -NR 3B C(S)R 3A , -C(0)OR 3A , -OC(0)R 3A , -C(0)SR 3A , -SC(0)R 3A , -C(S)OR 3A , -OC(S)R 3A , -C(S)OR 3A
  • each R 3 is independently selected from optionally substituted Ci-C alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, Ci-C 3 fluoroalkyl, halogen, nitro, -CN, -SF 5 , -N 3 , -C(0)R 3A , -SR 3A , -S(0)i_ 2 R 3A , -OR 3A , -NR 3B R 3A or -C(0)R 3A .
  • each R 3 is independently Ci-C alkyl, Ci-C alkenyl, Ci-C alkynyl, Ci-C 3 fluoroalkyl, halogen, nitro, -CN, -C(0)R 3A , -S(0)i_ 2 R 3A , or -OR 3A , in which each R 3A is independently H, Ci-C alkyl, Ci-C alkenyl, Ci-C alkynyl, Ci-C 3 fluoroalkyl, Ci-C 3 hydroxyalkyl or (Ci-C 3 alkoxy)Ci-C 3 alkyl.
  • each "optionally substituted" alkyl, alkenyl and alkynyl of R 3 is unsubstituted or fluorinated.
  • each "optionally substituted" alkyl, alkenyl and alkynyl of R 3 is unsubstituted.
  • R 3 is not an alkenyl or an alkynyl.
  • each R 3A is independently selected from H, optionally substituted Ci-C alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, Ci-C 3 fluoroalkyl, Ci-C 3 hydroxyalkyl and (Ci-C 3 alkoxy)Ci-C 3 alkyl.
  • each R 3A substituent is selected from one of the following groups:
  • each R 3A is independently selected from H, optionally substituted C 1 -C4 alkyl, optionally substituted C 1 -C4 alkenyl, optionally substituted C 1 -C4 alkynyl, C 1 -C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl.
  • each R 3A is independently selected from H, optionally substituted C 1 -C4 alkyl, C 1 -C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl.
  • each R 3A is H, C1-C4 alkyl or C1-C4 fluoroalkyl.
  • each R 3A is H or C 1 -C4 alkyl.
  • each R 3A is H.
  • each "optionally substituted" alkyl, alkenyl and alkynyl of R 3A is unsubstituted or fluorinated.
  • each "optionally substituted" alkyl, alkenyl and alkynyl of R 3A is unsubstituted.
  • R 3A is not an alkenyl or an alkynyl.
  • each R 3B is independently selected from H, optionally substituted C 1 -C4 alkyl; optionally substituted C 1 -C4 alkenyl, optionally substituted C 1 -C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl).
  • each R 3B substituent is selected from one of the following groups:
  • each R 3B is independently selected from H, optionally substituted C 1 -C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl) , -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl) .
  • each R 3B is independently selected from H, optionally substituted C 1 -C4 alkyl; C 1 -C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl) , -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl) .
  • each R 3B is H, -C(0)-(Ci-C 4 alkyl) , -C(0)-(Ci-C 4 fluoroalkyl), C1-C4 alkyl or C1-C4 fluoroalkyl.
  • each R 3B is H. [0061] In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 13a-13d above), each "optionally substituted" alkyl, alkenyl and alkynyl of R 3B is unsubstituted or fluorinated. For example, in certain such embodiments each "optionally substituted” alkyl, alkenyl and alkynyl of R 3B is unsubstituted. In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 13a-13d above), R 3B is not an alkenyl or an alkynyl.
  • the ring system denoted by “B” is phenyl or a 5- or 6- membered heteroaryl having one or two heteroatoms independently selected from N, O and S.
  • the ring system denoted by “B” is selected from one of the following groups:
  • the ring system denoted by "B” is a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O and S.
  • the ring system denoted by "B” is a 5- or 6-membered heteroaryl having one heteroatoms independently selected from N, O and S.
  • each R 4 is independently selected from optionally substituted Ci-C 4 alkyl, optionally substituted Ci-C 4 alkenyl, optionally substituted Ci-C 4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF 5 , -N 3 , -C(0)R 4A , -SR 4A , -S(0)i_ 2 R 4A , -OR 4A , -NR 4B R 4A , -C(0)R 4A , -C(0)NR 4B R 4A , -NR 4B C(0)R 4A , -C(S)NR 4B R 4A ,
  • each R 4A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl
  • each R 4B is independently selected from H, optionally substituted C1-C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl).
  • each R 4A is independently selected from H, optionally substituted C1
  • each R 4 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF 5 , -N 3 , -C(0)R 4A , -SR 4A , -S(0)i_ 2 R 4A , -OR 4A , -NR 4B R 4A , -C(0)R 4A , -C(0)NR 4B R 4A , -NR 4B C(0)R 4A , -C(S)NR 4B R 4A , -NR 4B C(S)R 4A , -C(0)OR 4A , -OC(0)R 4A , -C(0)SR 4A , -SC(0)R 4A , -C(S)OR 4A , -OC(S)R 4A , -C(S)
  • each R 4 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF 5 , -N 3 , -C(0)R 4A , -SR 4A , -S(0)i_ 2 R 4A , -OR 4A , -NR 4B R 4A , -C(0)R 4A , -C(0)NR 4B R 4A , -NR 4B C(0)R 4A , -C(S)NR 4B R 4A , -NR 4B C(S)R 4A , -C(0)OR 4A , -OC(0)R 4A , -C(0)SR 4A , -SC(0)R 4A , -C(S)OR 4A , -OC(S)R 4A , -C(S)
  • each R 4 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF 5 , -N 3 , -C(0)R 4A , -SR 4A , -S(0)i_ 2 R 4A , -OR 4A , -NR 4B R 4A or -C(0)R 4A .
  • each R 4 is independently C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -C(0)R 4A , -S(0)i_ 2 R 4A , or -OR 4A , in which each R 4A is independently H, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl or (C1-C3 alkoxy)Ci-C 3 alkyl.
  • each R 4 is independently halogen (e.g., chloro or fluoro).
  • each R 4 is independently C1-C4 alkyl.
  • each R 4 is independently nitro.
  • each R 4 is independently C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, or C1-C3 fluoroalkyl.
  • each R 4 is independently -OR 4A , in which R 4A is independently H, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl or (C1-C3 alkoxy)Ci-C 3 alkyl.
  • each "optionally substituted” alkyl, alkenyl and alkynyl of R 4 is unsubstituted or fluorinated.
  • each "optionally substituted” alkyl, alkenyl and alkynyl of R 4 is unsubstituted.
  • R 4 is not an alkenyl or an alkynyl.
  • each R 4A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl.
  • each R 4A substituent is selected from one of the following groups:
  • each R 4A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl.
  • each R 4A is independently selected from H, optionally substituted C1-C4 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C 3 alkyl.
  • each R 4A is H, C1-C4 alkyl or C1-C4 fluoroalkyl.
  • each R 4A is H or C1-C4 alkyl.
  • each R 4A is H.
  • each "optionally substituted” alkyl, alkenyl and alkynyl of R 4A is unsubstituted or fluorinated.
  • each "optionally substituted” alkyl, alkenyl and alkynyl of R 4A is unsubstituted.
  • R 4A is not an alkenyl or an alkynyl.
  • each R 4B is independently selected from H, optionally substituted C 1 -C4 alkyl; optionally substituted C 1 -C4 alkenyl, optionally substituted C 1 -C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl).
  • each R 4B substituent is selected from one of the following groups:
  • each R 4B is independently selected from H, optionally substituted C 1 -C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl).
  • each R 4B is independently selected from H, optionally substituted C 1 -C4 alkyl; C 1 -C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C 3 alkyl, -S(0)i- 2 (Ci-C 3 alkyl), -C(0)(Ci-C 3 alkyl) and -C(0)0(Ci-C 3 alkyl).
  • each R 4B is H, -C(0)-(Ci-C 4 alkyl), -C(0)-(Ci-C 4 fluoroalkyl), C1-C4 alkyl or C1-C4 fluoroalkyl.
  • each R 4B is H.
  • each "optionally substituted” alkyl, alkenyl and alkynyl of R 4B is unsubstituted or fluorinated.
  • each "optionally substituted” alkyl, alkenyl and alkynyl of R 4B is unsubstituted.
  • R 4B is not an alkenyl or an alkynyl.
  • n can be 0, 1 , 2, 3, 4 or 5.
  • the person of ordinary skill in the art will appreciate that this numberwill be limited by the number of substitutable atoms in the ring system denoted by "B".
  • the value of n is selected from one of the following:
  • n 0, 1 , 2, 3, 4 or 5.
  • n 0, 1 or 2.
  • n 1 or 2.
  • n is O.
  • Various particular embodiments nos. 1 -640 of compounds of the disclosure include compounds of any one of the formulae (I), each as defined in each of the following rows (or a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof), in which each entry is a group number as defined above (e.g., 13d refers to each R 3 being H).
  • Group numbers separated by slashes indicate that the entry includes all such limitations. When two or more group numbers defining the same substituent are separated by a slash, it indicates that any such substituent definitions can apply.
  • group numbers defining different substituents are separated by a slash, it indicates that all such substituent definitions apply.
  • 7f/8b/9b indicates that the (7f) definition of R 2 , the (8b) definition of R 2A , and the (9b) definition of R 2B all apply.
  • the R 2 substituent can be disposed on the ring system denoted by "A" in a variety of regiochemical relationships with respect to the thienylcarbonyl.
  • the regiochemistry of the R 2 substituent is selected from one of the following:
  • the ring system denoted by "A” is a six-membered ring, and wherein the R 2 is disposed in a 1 ,4 relationship with respect to the thienylcarbonyl.
  • the R 2 is disposed in a 1 ,3 relationship with respect to the thienylcarbonyl.
  • the R 2 is disposed in a 1 ,2 relationship with respect to the thienylcarbonyl.
  • the compound has one of the structural formulae below:
  • each and every "optionally substituted" alkyl, alkylene, alkenyl is unsubstituted or fluorinated.
  • each and every "optionally substituted" alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene is unsubstituted.
  • none of the R 1A , R 1 B , R 1C , R 1 D , R 2A , R 2B , R 3 , R 3A , R 3B , R 4 , R 4A and R 4B substituents is an alkynyl.
  • none of the R 1A , R 1 B , R 1 C , R 1 D , R 2A , R 2B , R 3 , R 3A , R 3B , R 4 , R 4A and R 4B substituents is an alkenyl or an alkynyl.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, which are well known to those in the art. Additionally, enantiomers can be characterized by the manner in which a solution of the compound rotates a plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-) isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the compounds of the disclosure may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • These compounds can be, for example, racemates, chiral non-racemic or diastereomers
  • Such compounds can therefore be produced as individual stereoisomers (e.g., in the case of a single asymmetric center, (R)- or (S)-stereoisomers) or as mixtures thereof.
  • the single enantiomers i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates.
  • Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPLC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereomers via chromatography, and removing the resolving agent to generate the original compound in enantiomerically enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of a compound. Unless otherwise indicated, the specification and claims is intended to include both individual enantiomers as well as mixtures, racemic or otherwise, thereof.
  • Certain compounds of this disclosure may exhibit the phenomena of tautomerism and/or structural isomerism.
  • certain compounds described herein may adopt an E or a Z configuration about a carbon-carbon double bond or they may be a mixture of E and Z.
  • the disclosure encompasses any tautomeric or structural isomeric form and mixtures thereof. Accordingly, when the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include the cis, trans, Z- and E- configurations. Likewise, all tautomeric forms are also intended to be included.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • Such compounds are useful, for example, as analytical tools or probes in biologic assays.
  • the disclosure also provides pharmaceutically-acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salt refers to those salts that retain the biological effectiveness of the parent compound.
  • Such salts include: (1) acid addition salt which is obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid, or malonic acid and the like, preferably hydrochloric acid or (L)-malic acid; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g.
  • salts of the compounds of the present disclosure include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, perchloric, and nitric or salts of organic acids such as formic, citric, malic (e.g., (D)- or (L)-), maleic, fumaric, tartaric, succinic, malonic acetic, lactic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic.
  • inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, perchloric, and nitric or salts of organic acids
  • malic e.g., (D)- or (L)-
  • maleic fumaric, tartaric
  • succinic malonic acetic
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, ehanolammonium, diethanolammonium, triethanolammonium, tromethammonium, N-methyl glucammonium, and ammonium.
  • pharmaceutically acceptable salts include, but are not limited to sodium, potassium, calcium, aluminum, lithium, ehanolammonium, diethanolammonium, triethanolammonium, tromethammonium, N-methyl glucammonium, and ammonium.
  • pharmaceutically acceptable salts include, but are not limited to sodium, potassium, calcium, aluminum, lithium, ehanolammonium, diethanolammonium, triethanolammonium, tromethammonium, N-methyl glucammonium, and ammonium.
  • solvate means a physical association of a compound as described here with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution- phase and isolatable solvates. Exemplary solvates include ehanolates, methanolates, and the like.
  • “Hydrate” is a solvate in which the solvent molecule(s) is/are H 2 0.
  • the compounds of the disclosure can be prepared by one skilled in the art based only on knowledge of the compound's chemical structure, based on the description provided herein.
  • the chemistry for the preparation of the compounds of this disclosure is known to those skilled in the art based on the description provided herein. In fact, there may be more than one process to prepare particular compounds of the disclosure. Specific examples of methods of preparation can be found herein and in the art.
  • the symbol "-" in general represents a bond between two atoms in the chain.
  • CH3-0-CH2-CH(Ri)-CH 3 represents a 2-substituted-1-methoxypropane compound.
  • the symbol "-" represents the point of attachment of the substituent to a compound.
  • -C(0)-(Ci-C 4 alkyl) indicates an acyl group attached to the rest of the compound via the carbonyl.
  • R m optionally substituted with 1 , 2 or 3 R q groups indicates that R m is substituted with 1 , 2, or 3 R q groups where the R q groups can be the same or different.
  • halogen or halo indicate fluorine, chlorine, bromine, or iodine. In certain embodiments of the compound as otherwise described herein, each "halogen” or “halo” is fluorine or chlorine.
  • heteroatom means nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
  • alkyl refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert- butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, and the like.
  • C1-C4 alkyl indicates that the alkyl group has 1-4 carbon atoms.
  • alkenyl refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight chain and branched chain groups having at least one carbon-carbon double bond.
  • Ci-C 4 alkenyl indicates that the alkenyl group has 1-4 carbon atoms.
  • An alkyenyl need not be attached to the rest of the molecule through a double-bonded carbon; buten-1-yl, buten-2-yl, buten-3-yl and buten-4-yl are all considered to be a C 4 alkenyl.
  • alkynyl refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight chain and branched chain groups having at least one carbon-carbon triple bond.
  • C1-C4 alkynyl indicates that the alkynyl group has 1-4 carbon atoms.
  • An alkynyl need not be attached to the rest of the molecule through a triple-bonded carbon; butyn-1-yl, butyn-3-yl and butyn-4-yl are all considered to be a C 4 alkynyl.
  • alkoxy represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge.
  • alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.
  • heteroaryl refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include, for example, pyridinyl, furanyl, thienyl, pyrazinyl, pyrimidyl, pyridazinyl, imidazolyl, thiazolyl, isoxazolyl, oxazolyl, isothiazolyl, pyrrolyl and pyrazolyl.
  • GSK3, SK and/or tubulin-related disorder As used herein, "GSK3, SK and/or tubulin-related disorder”, “GSK3, SK and/or tubulin-driven disorder”, and “abnormal GSK3, SK and/or tubulin activity” all refer to a condition characterized by inappropriate, i.e., under or, more commonly, over, GSK3, SK and/or tubulin activity. Inappropriate catalytic activity can arise as the result of either: (1) GSK3 and/or SK expression in cells that normally do not express GSK3 or SK, (2) increased GSK3 and/or SK catalytic activity leading to unwanted cellular process, such as, without limitation, cell proliferation, gene regulation, resistance to apoptosis, and/or differentiation.
  • Such changes in GSK3, SK and/or tubulin expression may occur by increased expression of GSK3, SK and/or tubulin and/or mutation of GSK3, SK and/or tubulin such that its activity is enhanced, (3) decreased GSK3, SK and/or tubulin activity leading to unwanted reductions in cellular processes.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts.
  • modulation refers to the alteration of the activity of GSK3, SK and/or tubulin and/or other proteins.
  • modulating refers to the activation or, preferably, inhibition of GSK3, SK and/or tubulin activity, depending on the concentration of the compound or salt to which GSK3, SK and/or tubulin is exposed.
  • catalytic activity refers to the rate of phosphorylation of a protein under the influence of GSK3, or sphingosine under the influence of a SK.
  • contacting refers to bringing a compound of this disclosure and GSK3, SK and/or tubulin together in such a manner that the compound can affect the activity of GSK3, SK and/or tubulin, either directly, i.e., by interacting with GSK3, SK and/or tubulin itself, or indirectly, i.e., by altering the intracellular localization of GSK3, SK and/or tubulin.
  • Such "contacting” can be accomplished in vitro, i.e. in a test tube, a Petri dish or the like. In a test tube, contacting may involve only a compound and GSK3, SK and/or tubulin or it may involve whole cells.
  • Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment.
  • the ability of a particular compound to affect a GSK3, SK and/or tubulin-related disorder can be determined before the use of the compounds in vivo with more complex living organisms is attempted.
  • multiple methods exist, and are well-known to those skilled in the art, to allow contact of the compounds with GSK3, SK and/or tubulin including, but not limited to, direct cell microinjection and numerous techniques for promoting the movement of compounds across a biological membrane.
  • in vitro refers to procedures performed in an artificial environment, such as for example, without limitation, in a test tube or cell culture system.
  • an isolated GSK3 or SK enzyme may be contacted with a modulator in an in vitro environment.
  • an isolated cell may be contacted with a modulator in an in vitro environment.
  • in vivo refers to procedures performed within a living organism such as, without limitation, a human, mouse, rat, rabbit, bovine, equine, porcine, canine, feline, or primate.
  • IC 5 o or “50% inhibitory concentration” as used herein refers to the concentration of a compound that reduces a biological process by 50%. These processes can include, but are not limited to, enzymatic reactions, i.e. inhibition of GSK3 or SK catalytic activity, or cellular properties, i.e. cell proliferation or apoptosis.
  • administer refers to the delivery of a compound or salt of the present disclosure or of a pharmaceutical composition containing a compound or salt of this disclosure to an organism for the purpose of prevention or treatment of an GSK3, SK and/or tubulin-related disorder.
  • the terms “prevent”, “preventing” and “prevention” refer to a method for barring an organism from acquiring a GSK3, SK and/or tubulin-related disorder.
  • the terms “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a GSK3, SK and/or tubulin-mediated disorder and/or its attendant symptoms.
  • the term "organism” refers to any living entity comprised of at least one cell.
  • a living organism can be as simple as, for example, a single eukaryotic cell or as complex as a mammal.
  • the organism is a mammal.
  • the mammal is a human being.
  • a "pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • a "physiologically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. Typically, this includes those properties and/or substances that are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.
  • a therapeutically effective amount refers to that amount of the compound being administered that is effective to reduce or lessen at least one symptom of the disease being treated or to reduce or delay onset of one or more clinical markers or symptoms of the disease.
  • a therapeutically effective amount refers to that amount that has the effect of: (1) reducing the size of the tumor, (2) inhibiting, i.e. slowing to some extent, preferably stopping, tumor metastasis, (3) inhibiting, i.e. slowing to some extent, preferably stopping, tumor growth, and/or (4) relieving to some extent, preferably eliminating, one or more symptoms associated with the cancer.
  • the compounds of this disclosure may also act as a prodrug.
  • prodrug refers to an agent which is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be a compound of the present disclosure which is administered as an ester (the "prodrug"), carbamate or urea.
  • the compounds of this disclosure may also be metabolized by enzymes in the body of the organism, such as a human being, to generate a metabolite that can modulate the activity of GSK3, SK and/or tubulin. Such metabolites are within the scope of the present disclosure.
  • compositions described herein generally comprise a combination of a compound, salt, hydrate or solvate as described herein and a pharmaceutically acceptable carrier, diluent, or excipient.
  • Such compositions are substantially free of non-pharmaceutically acceptable components, i.e. , contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application.
  • the composition if the compound is dissolved or suspended in water, the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient.
  • the pharmaceutical compositions described herein are solid pharmaceutical compositions (e.g. , tablet, capsules, etc.).
  • compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g. , by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral.
  • topical including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g. , by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal
  • ocular oral or parenteral.
  • Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g. , intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • compositions can contain, as the active ingredient, one or more of the compounds described herein above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound in preparing a formulation, can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • the active compound in preparing a formulation, can be prepared as a spray-dried dispersion, which is a single-phase, amorphous molecular dispension of the drug in a polymer matrix, prepared by dissolving the drug and polymer in an organic solvent and then spray- drying the solution.
  • suitable polymers include vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, polyethylene-polypropylene glycol and hypromellose acetate succinate.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg, more usually about 10 to about 200 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein.
  • a solid preformulation composition containing a homogeneous mixture of a compound described herein.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of a compound described herein.
  • the tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 1 1 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound , the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g. , hydrophobicity), and the route of administration.
  • the compounds described herein can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • One or more additional pharmaceutical agents for treatment methods such as, for example, anti-inflammatory agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g. , IL2, GM-CSF, etc.), and/or tyrosine kinase inhibitors can be used in combination with the compounds and pharmaceutical compositions described herein for treatment of GSK3, SK and/or tubulin related disorders or conditions (as noted above) or for enhancing the effectiveness of the treatment of a disease state or condition, such as cancer.
  • the agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • Therapeutic agents that constitute the standard of care for a particular cancer type or inflammatory disease are expected to benefit when combined with GSK3, SK and/or tubulin inhibitors of the present disclosure.
  • the tumor is sensitive to the cytotoxic effects of the chemotherapeutic agent that will be enhanced by addition of GSK3, SK and/or tubulin inhibitors to the combination treatment.
  • a person of skill in the art will know how to select such chemotherapeutic agent based on the clinical characteristics and known sensitivity of each tumor to different antineoplastic agents.
  • Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoure
  • Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.
  • antimetabolites including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TaxolTM), docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide.
  • certain natural products and their derivatives for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins
  • vinblastine vincristine, vindesine
  • bleomycin dactinomycin
  • cytotoxic agents include navelbene, CPT-1 1 , anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.
  • cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cis-platin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; signal transduction inhibitors; and haematopoietic growth factors.
  • anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4,4-1 BB and PD-1 , or antibodies to cytokines (IL-10, TGF- ⁇ , etc.).
  • trastuzumab Herceptin
  • costimulatory molecules such as CTLA-4,4-1 BB and PD-1
  • cytokines IL-10, TGF- ⁇ , etc.
  • anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2, CCR4 and CCR6.
  • anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.
  • Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • the disclosure also provides methods for treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of a hyperproliferative disease, an inflammatory disease, an angiogenic disease, a neurologic disease or a psychiatric disorder, which includes administration of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment or prevention.
  • a disease or condition selected from the group consisting of a hyperproliferative disease, an inflammatory disease, an angiogenic disease, a neurologic disease or a psychiatric disorder, which includes administration of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment or prevention.
  • One preferred hyperproliferative disease which the compounds of the disclosure are useful in treating or preventing is cancer, including as non-limiting examples thereof solid tumors such as head and neck cancers, lung cancers, gastrointestinal tract cancers, breast cancers, gynecologic cancers, testicular cancers, urinary tract cancers, neurological cancers, endocrine cancers, skin cancers, sarcomas, mediastinal cancers, retroperitoneal cancers, cardiovascular cancers, mastocytosis, carcinosarcomas, cylindroma, dental cancers, esthesioneuroblastoma, urachal cancer, Merkel cell carcinoma and paragangliomas, and hematopoietic cancers such as Hodgkin lymphoma, non-Hodgkin lymphoma, chronic leukemias, acute leukemias, myeloproliferative cancers, plasma cell dyscrasias, and myelodysplasia syndromes.
  • solid tumors such as head and neck cancers
  • inflammatory diseases such as inter alia inflammatory bowel disease, arthritis, atherosclerosis, asthma, allergy, inflammatory kidney disease, circulatory shock, multiple sclerosis, chronic obstructive pulmonary disease, skin inflammation, periodontal disease, psoriasis and T cell-mediated diseases of immunity, including allergic encephalomyelitis, allergic neuritis, transplant allograft rejection, graft versus host disease, myocarditis, thyroiditis, nephritis, systemic lupus erthematosus, and insulin-dependent diabetes mellitus.
  • inflammatory diseases such as inter alia inflammatory bowel disease, arthritis, atherosclerosis, asthma, allergy, inflammatory kidney disease, circulatory shock, multiple sclerosis, chronic obstructive pulmonary disease, skin inflammation, periodontal disease, psoriasis and T cell-mediated diseases of immunity, including allergic encephalomyelitis, allergic neuritis, transplant allograft rejection, graft versus host disease, myocardit
  • angiogenic diseases such as diabetic retinopathy, arthritis, psoriasis, Kaposi's sarcoma, hemangiomas, myocardial angiogenesis, atherscelortic plaque neovascularization, and ocular angiogenic diseases such as choroidal neovascularization, retinopathy of prematurity (retrolental fibroplasias), macular degeneration, corneal graft rejection, rubeosis, neuroscular glacoma and Oster Webber syndrome.
  • angiogenic diseases such as diabetic retinopathy, arthritis, psoriasis, Kaposi's sarcoma, hemangiomas, myocardial angiogenesis, atherscelortic plaque neovascularization, and ocular angiogenic diseases such as choroidal neovascularization, retinopathy of prematurity (retrolental fibroplasias), macular degeneration, corneal graft rejection, rub
  • GSK3 and SK whose catalytic activity is modulated by representative compounds and compositions of this disclosure, are key enzymes involved in signaling pathways that are abnormally activated in a variety of diseases.
  • the following discussion outlines the roles of GSK3, SK and/or microtubules in hyperproliferative, inflammatory, angiogenic diseases and neurologic diseases, and consequently provides examples of uses of the compounds and compositions of this disclosure.
  • the use of these compounds and compositions for the prevention and/or treatment of additional diseases in which GSK3, SK and/or microtubules are abnormally active are also within the scope of the present disclosure.
  • the present disclosure relates to compounds, pharmaceutical compositions and methods useful for the treatment and/or prevention of hyperproliferative diseases. More specifically, the disclosure relates to compounds and pharmaceutical compositions that inhibit the activity of GSK3, SK and/or tubulin for the treatment and/or prevention of hyperproliferative diseases, such as cancer, psoriasis, mesangial cell proliferative disorders, atherosclerosis and restenosis.
  • hyperproliferative diseases such as cancer, psoriasis, mesangial cell proliferative disorders, atherosclerosis and restenosis.
  • hyperproliferative diseases such as cancer, psoriasis, mesangial cell proliferative disorders, atherosclerosis and restenosis.
  • hyperproliferative diseases such as cancer, psoriasis, mesangial cell proliferative disorders, atherosclerosis and restenosis.
  • the following discussion demonstrates the role of GSKs, SKs and/or microtubules
  • Cellular hyperproliferation is a characteristic of a variety of diseases, including, without limitation, cancer, psoriasis, mesangial cell proliferative disorders, atherosclerosis and restenosis. Therefore, the compounds, pharmaceutical compositions and methods of this disclosure will be useful for the prevention and/or treatment of cancer, including solid tumors, hematopoietic cancers and tumor metastases.
  • Such cancers may include, without limitation, solid tumors such as head and neck cancers, lung cancers, gastrointestinal tract cancers, breast cancers, gynecologic cancers, testicular cancers, urinary tract cancers, neurological cancers, endocrine cancers, skin cancers, sarcomas, mediastinal cancers, retroperitoneal cancers, cardiovascular cancers, mastocytosis, carcinosarcomas, cylindroma, dental cancers, esthesioneuroblastoma, urachal cancer, Merkel cell carcinoma and paragangliomas.
  • solid tumors such as head and neck cancers, lung cancers, gastrointestinal tract cancers, breast cancers, gynecologic cancers, testicular cancers, urinary tract cancers, neurological cancers, endocrine cancers, skin cancers, sarcomas, mediastinal cancers, retroperitoneal cancers, cardiovascular cancers, mastocytosis, carcinosarcomas, cylindrom
  • cancers may include, without limitation, hematopoietic cancers such as Hodgkin lymphoma, non-Hodgkin lymphoma, chronic leukemias, acute leukemias, myeloproliferative cancers, plasma cell dyscrasias, and myelodysplasia syndromes.
  • hematopoietic cancers such as Hodgkin lymphoma, non-Hodgkin lymphoma, chronic leukemias, acute leukemias, myeloproliferative cancers, plasma cell dyscrasias, and myelodysplasia syndromes.
  • Psoriasis is a common chronic disfiguring skin disease that is characterized by well-demarcated, red, hardened and scaly plaques that may be limited or widespread. While the disease is rarely fatal, it has serious detrimental effects on the quality of life of the patient, and this is further complicated by the lack of effective therapies. There is therefore a large unmet need for effective and safe drugs for this condition.
  • Psoriasis is characterized by local keratinocyte hyperproliferation, T cell-mediated inflammation and by localized angiogenesis. Abnormal activation of GSK3, SK and/or tubulin has been implicated in all of these processes. Therefore, GSK3, SK and/or tubulin inhibitors are expected to be of use in the therapy of psoriasis.
  • Mesangial cell hyperproliferative disorders refer to disorders brought about by the abnormal hyperproliferation of mesangial cells in the kidney.
  • Mesangial hyperproliferative disorders include various human renal diseases such as glomerulonephritis, diabetic nephropathy, and malignant nephrosclerosis, as well as such disorders such as thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies.
  • the GSK3, SK and/or tubulin inhibitory compounds, pharmaceutical compositions and methods of this disclosure are expected to be of use in the therapy of these mesangial cell hyperproliferative disorders.
  • atherosclerosis and restenosis are characterized by hyperproliferation of vascular smooth muscle cells at the sites of the lesions.
  • the GSK3, SK and/or tubulin inhibitory compounds, pharmaceutical compositions and methods of this disclosure are expected to be of use in the therapy of these vascular disorders.
  • the present disclosure also relates to compounds, pharmaceutical compositions and methods useful for the treatment and/or prevention of inflammatory diseases. More specifically, the disclosure relates to compounds and pharmaceutical compositions that inhibit the activity of GSK3, SK and/or tubulin for the treatment and/or prevention of inflammatory diseases, such as inflammatory bowel disease, arthritis, atherosclerosis, asthma, allergy, inflammatory kidney disease, circulatory shock, multiple sclerosis, chronic obstructive pulmonary disease, skin inflammation, periodontal disease, psoriasis and T cell-mediated diseases of immunity, including allergic encephalomyelitis, allergic neuritis, transplant allograft rejection, graft versus host disease, myocarditis, thyroiditis, nephritis, systemic lupus erthematosus, and insulin-dependent diabetes mellitus.
  • inflammatory diseases such as inflammatory bowel disease, arthritis, atherosclerosis, asthma, allergy, inflammatory kidney disease, circulatory shock, multiple sclerosis, chronic obstructive pulmonary disease
  • I BD Inflammatory bowel disease
  • Crohn's disease and ulcerative colitis are the best-known forms of IBD.
  • the GSK3 and/or SK inhibitory compounds pharmaceutical compositions and methods of this disclosure are expected to be of use in the therapy of IBDs.
  • Rheumatoid arthritis is a chronic, systemic disease that is characterized by synovial hyperplasia, massive cellular infiltration, erosion of the cartilage and bone, and an abnormal immune response.
  • the early phase of rheumatic inflammation is characterized by leukocyte infiltration into tissues, especially by neutrophils. In the case of RA, this occurs primarily in joints where leukocyte infiltration results in synovitis and synovium thickening producing the typical symptoms of warmth, redness, swelling and pain.
  • the inflammatory cytokines TNFa, IL-1 ⁇ and IL-8 act as critical mediators of this infiltration, and these cytokines are present in the synovial fluid of patients with RA.
  • Inflammation is involved in a variety of skin disorders, including psoriasis, atopic dermatitis, contact sensitivity and acne. Since the inflammatory responses typically involve aberrant activation of signaling pathways detailed above, it is likely that the compounds, pharmaceutical compositions and methods of this disclosure will also be useful for the treatment of these skin diseases.
  • the present disclosure also relates to compounds, pharmaceutical compositions and methods useful for the treatment and/or prevention of diseases that involve undesired angiogenesis. More specifically, the disclosure relates to the use of chemical compounds and compositions that inhibit the activity of GSK3, SK and/or tubulin for the treatment and/or prevention of angiogenic diseases, such as diabetic retinopathy, arthritis, cancer, psoriasis, Kaposi's sarcoma, hemangiomas, myocardial angiogenesis, atherscelortic plaque neovascularization, and ocular angiogenic diseases such as choroidal neovascularization, retinopathy of prematurity (retrolental fibroplasias), macular degeneration, corneal graft rejection, rubeosis, neuroscular glacoma and Oster Webber syndrome.
  • angiogenic diseases such as diabetic retinopathy, arthritis, cancer, psoriasis, Kaposi's sarcoma, hemangio
  • Angiogenesis refers to the state in the body in which various growth factors or other stimuli promote the formation of new blood vessels. As discussed below, this process is critical to the pathology of a variety of diseases. In each case, excessive angiogenesis allows the progression of the disease and/or the produces undesired effects in the patient. Since conserved biochemical mechanisms regulate the proliferation of vascular endothelial cells that form these new blood vessels, i.e. neovascularization, identification of methods to inhibit these mechanisms are expected to have utility for the treatment and/or prevention of a variety of diseases.
  • GSK3 has been demonstrated to promote every major pathological process, including amyloid ⁇ peptide production and tau phosphorylation which lead to the two hallmark pathologies of Alzheimer's disease, amyloid plaques and neurofibrillary tangles, respectively.
  • long-term treatment with several different GSK3 inhibitors had remarkably strong effects in protecting mice from developing hind limb paralysis in the mouse multiple sclerosis model, and even initiating treatment with GSK3 inhibitors only after disease onset reversed the clinical symptoms of the disease in mouse models.
  • GSK3 inhibitors have been shown to prolong motor neuron survival and suppress disease progression in amyotrophic lateral sclerosis.
  • GSK3 inhibitors may counteract neuronal loss in Parkinson's disease was first raised by the finding that GSK3 inhibitors reduced apoptosis induced by molecules modeling Parkinson's neurotoxicity. Subsequent studies have further strengthened the potential therapeutic benefits of GSK3 inhibitors in several models of Parkinson's disease. Also in regards to neuronal protection, growing evidence has also demonstrated that GSK3 inhibitors are effective in mouse models of Huntington's disease, stroke, and traumatic brain injury. Additionally, SKs play important roles in pathologic neuroinflammation involved in many neurologic diseases.
  • GSK3 and/or SK inhibitors may contribute to therapies for psychiatric disorders. Patients with bipolar disorder are already being effectively treated with lithium, which is a GSK3 inhibitor. Although the therapeutic mechanism of action of lithium remains to be definitively determined, substantial evidence indicates that inhibition of GSK3 is an important component of lithium's mood stabilizing capacity. Growing evidence also exists that GSK3 and/or SK inhibitors, working through mechanisms, at least in part, involved with brain derived neurotrophic factors, contribute to therapies for schizophrenia, anxiety and depression.
  • Representative compounds of the disclosure include those in Table 1 . Certain of these compounds do not fall within the scope of certain embodiments as described above, but are provided nonetheless for comparative purposes. IC50 values are provided in units of ⁇ for murine pancreatic cancer cells of the cell line PAN02. Table 1. Representative compounds of the disclosure.
  • the dried crude product is typically recrystallized from EtOAc : Hexane (1 :3) , which provides a yield of approximately 50% of the corresponding 4-amino-2-phenylamino-thiazol-5-yl)-phenyl- methanone. Specific examples follow.
  • Example 1 The methods described in Example 1 were used to prepare a library of substituted 4-amino-2-phenylamino-thiazol-5-yl)-phenyl-methanones. Data provided below include the melting point (mp) of the compound, mass spectral (MS) data for the compound, and/or NMR spectral data for the compound.
  • mp melting point
  • MS mass spectral
  • Compound 8 [4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-fluoro-phenyl)- methanone. mp: 217-219 °C (acetone).
  • Compound 43 [4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]-(4- dimethylamino-phenyl)-methanone. mp: 300-302 °C (methanol).
  • Compound 48 4-[4-Amino-5-(4-bromo-benzoyl)-thiazol-2-ylamino]-benzonitrile. mp: 293-295 °C (acetone).
  • Compound 60 [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-nitro- phenyl)-methanone. mp: 207-209 °C (acetone).

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Abstract

The disclosure relates to diaminothiazole derivatives of formula (I) where the variables are as defined herein, pharmaceutical compositions containing such compounds, and methods for the use of such compounds and compositions for the treatment of hyperproliferative, inflammatory or neurologic diseases and disorders.

Description

DIAMINOTHIAZOLE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority of United States Provisional Patent Application no. 62/421 ,328, filed November 13, 2016, which is hereby incorporated herein by reference in its entirety.
BACKGROUND OF THE DISCLOSURE
Field of the Disclosure
[0002] The present disclosure relates to diaminothiazole compounds and pharmaceutical compositions thereof which are useful, for example, for the treatment of inflammatory, hyperproliferative or neurologic diseases. The disclosure also provided methods utilizing those compositions for the treatment of inflammatory, hyperproliferative or neurologic diseases.
Technical Background
[0003] Glycogen Synthase kinase 3 (GSK3)
[0004] Glycogen synthase kinase-3s (GSK3a and GSK3P) are constitutively active protein kinases that regulate vital cellular functions such as proliferation and apoptosis, as well as inflammation. In addition to driving proliferation through c-Myc, GSK3s regulate signaling through NFKB, and therefore mediate responses to inflammatory cytokines, including TNFa, IL- 1 p and IL-6. Consequently, excessive GSK3 activity has been implicated in several hyperproliferative and inflammatory diseases including cancer. Inhibiting GSK3s initially focused on suppressing neuroinflammation in neurologic diseases such as Alzheimer's disease; however, interest in evaluating GSK3 inhibitors as anticancer drugs is growing. GSK3 plays an important role in pancreatic cancer development and progression, dedifferentiation, proliferation, survival, and invasion. Importantly, inhibition of GSK3 sensitizes pancreatic cancer cells to killing by radiation and other drugs including gemcitabine. Therefore, inhibition of GSK3 is a new approach to cancer treatment.
[0005] Interest in evaluating GSK3 inhibitors as anticancer and anti-inflammatory drugs is growing. For example, GSK3 plays an important role in Inflammatory Bowel Diseases (IBD). Using the chronic TNBS model for Crohn's Disease (CD) in mice, it was demonstrated that active, nonphosphorylated GSK3P was highest in colonic lamina propria mononuclear cells during times of the most intense intestinal inflammation, while the phosphorylated, inactive form was expressed before inflammation and during spontaneous resolution of inflammation. Furthermore, it was demonstrated that during resolution of the chronic colitis, IL-13 signaling via IL-13Rc(i inactivates GSK3p, leading to decreased IL-23/IL-17 and increased IL-10 production. Correlations were noted between inhibition of GSK3P and lower NFKB levels and higher CREB levels. In a mouse model of Dextran Sulfate Sodium (DSS)-induced ulcerative colitis (UC), carbon monoxide (CO) attenuated colitis by reducing GSK3P signaling, resulting in significant reductions in TNFa and iNOS, as well as a concurrent increase in IL-10. In vitro studies with U937 and MLN cells also showed that CO decreased TNFa and iNOS expression by inhibiting GSK3P activity, resulting in inhibition of NFkB activity. In another study using the DSS model of UC, mice treated intraperitoneally with GSK3 inhibitors had significantly reduced colitis, associated with increased CREB activity and decreased NFkB activity. Accompanying in vitro work showed that inhibition of GSK3 in murine or human intestinal immune cells significantly reduced the pro-inflammatory phenotype. Interestingly, GSK3 inhibitors also protect intestinal crypt cells and increase mouse survival following lethal radiation, further demonstrating Gl protection through suppression of GSK3 activity.
[0006] Cvclin-dependent kinase 9 (cdk9)
[0007] Another enzyme receiving increasing attention as a target for anticancer drugs is cyclin-dependent kinase (CDK) 9. In contrast with most CDKs which regulate the cell cycle, CDK9, in conjunction with cyclin T1 , T2a or T2b, forms the catalytic core of the positive transcription elongation factor b (P-TEFb), and thus regulates RNA production. CDK9 is elevated and provides oncogenic transcription profiles in several cancers due, at least in part, to its requirement for transcriptional activation of MYC-targeted genes. CDK9 also promotes the expression of inflammatory cytokine genes and COX-2, and the extravasation of leukocytes into sites of inflammation. Mechanistically, CDK9 signals through NFKB, p38 MAPK, JNK and ERK. Interestingly, pNFKB is required for CDK9 binding to P-TEFb, and so crosstalk between the GSK3 and CDK9 pathways is critical for inflammatory responses. In parallel, gene expression by CDK9 is mediated by STAT3, a second proinflammatory transcription factor that is essential for cytokine signaling, including IL-6. Because pancreatic cancer growth is enhanced by its highly inflamed environment, and because CDK9 is overexpressed in inflamed pancreatic islet cells and pancreatic tumors, CDK9 inhibitors may be particularly effect in this cancer. Suppression of CDK9 by flavopiridol (a pan-CDK inhibitor, but with approximately 10-fold higher potency for CDK9 than other CDKs) attenuates inflammation in the collagen-induced arthritis model, protects against ConA-induced murine hepatitis, and protects cartilage from the catabolic effects of I L- 1 , TNFa and LPS or mechanical injury. Additionally, flavopiridol or CDK9 siRNA inhibits IL-6/STAT3 signaling in the liver. Similarly, roscovitine (another potent but non-selective CDK inhibitor) inhibits leukocyte invasion into the endothelium through a CDK9/CDK5/NFKB-dependent pathway, as well as glomerulonephritis in a model of graft-vs-host disease. CDK9 expression is elevated in serum, peripheral blood mononuclear cells (PBMCs) and artery wall sections from atherosclerotic patients compared with controls, and so CDK9 may be both a target and biomarker for coronary artery disease.
[0008] Tubulin
[0009] The cytoskeleton of eukaryotic cells is involved in the regulation of a number of cellular processes, including motility, secretion and proliferation. Cellular microtubules are in a dynamic state, demonstrating continuous polymerization and depolymerization at their ends. This dynamic cycling is required for the maintenance of normal microtubule structure and function, and therefore is strictly controlled in a healthy cell.
[0010] Because of their involvement in mitotic spindle function, microtubules are the molecular targets of several currently utilized anticancer drugs. Clinically useful compounds which induce microtubule depolymerization include vinblastine, vincristine and colchicine. These compounds bind to unpolymerized tubulin, blocking its assembly into microtubules. This ultimately leads to elimination of microtubules in both the mitotic spindle and the cytosol, and consequently to prevention of cell division. Tubulin-targeted drugs are commonly used in the chemotherapy of acute lymphocytic leukemias, neuroblastoma, Wilms' tumor, rhabdomyosarcoma, Hogkin's disease, non-Hodgkin's lymphoma, small-cell lung, breast and testicular carcinoma.
[0011] In contrast with microtubule-destabilizing compounds, paclitaxel increases microtubule assembly by reducing tubulin loss at the minus end of the microtubule. In intact cells, paclitaxel alters microtubule structure in the mitotic spindle and promotes microtubule polymerization and bundling in the cytosol. This results in inhibition of microtubule treadmilling and loss of mitotic spindle function. Taxol has activity against certain solid tumors, including ovarian and breast; however, the clinical efficacy of this compound may be restricted by the acquisition of tumor resistance.
[0012] Sphingosine Kinases
[0013] Sphingolipid metabolism has been shown to play critical roles in several diseases. Ceramide is produced by the hydrolysis of sphingomyelin in response to several growth stimulatory (e.g. growth factors and oncoproteins) and inflammatory (e.g. cytokines and radiation) signals. Ceramide induces apoptosis in tumor cells. Additionally, ceramide is hydrolyzed by ceramidases to produce sphingosine, which is phosphorylated by sphingosine kinases (SK1 and SK2) to produce sphingosine 1-phosphate (S1 P). Studies in many cancer cell lines indicate that S1 P induces proliferation and protects against ceramide-induced apoptosis. Therefore, a critical balance, i.e. a ceramide/S1 P rheostat, has been hypothesized to determine the fate of tumor cells. Sphingolipids also regulate the sensitivities of tumor cells to anticancer drugs. For example, ceramide increases apoptosis induced by paclitaxel, etoposide and gemcitabine. Therefore, inhibition of SK is expected to increase tumor chemosensitivity by elevating ceramide levels in the cells. In addition to their direct effects on tumor cells, SKs regulate deleterious inflammation from cytokines such as TNFa and IL-6. Because activation of SK activity generates the S1 P that drives inflammatory responses, SKs are also new targets for developing anti-inflammatory drugs.
SUMMARY OF THE DISCLOSURE
[0014] The present disclosure encompasses the compounds of formula (I), shown below, pharmaceutical compositions containing such compounds, and methods employing such compounds or compositions in the treatment or prevention of a hyperproliferative disease, an inflammatory disease, an angiogenic disease or a neurologic disease.
[0015] In one aspect, the disclosure provides compounds of formula I :
Figure imgf000005_0001
and pharmaceutically acceptable salts thereof, wherein:
R1A and R1 B are each independently selected from H, optionally substituted Ci-C4 alkyl, optionally substituted Ci-C4 alkenyl, optionally substituted Ci-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3alkyl, -C(0)R1C, -C(S)R1C, -S(0)i-2R1C, -C(0)0R1C, -C(0)NR1 DR1C, -C(0)SR1 C, -C(S)0R1C, -C(S)NR1 DR1C, -C(S)SR1 C, -C(NR1 D)NR1 DR1 C and -S(0)i-2NR1 DR1C, in which
each R1C is independently selected from H, C1-C4 alkyl, Ci-C alkenyl, Ci-C alkynyl, C1-C3 fluoroalkyl, Ci-C3 hydroxyalkyl and (Ci-C3 alkoxy)Ci-C3 alkyl, and
each R1 D is independently selected from H, Ci-C alkyl, Ci-C alkenyl, Ci-C alkynyl, Ci-C3 fluoroalkyl, Ci-C3 hydroxyalkyl, (Ci-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl) , -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl); the ring system denoted by "A" is phenyl or a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N , O and S;
R2 is selected from H, C1-C3 fluoroalkyl, halogen, nitro, -CN, -NR2AR2B, -C(0)R2A, -S(0)i-2R2A, -C(0)R2A, -C(0)NR2BR2A, -C(S)NR2BR2A,-C(0)OR2A, -C(0)SR2A, -C(S)OR2A, -C(S)SR2A, -S(0)i-2OR2A and -S(0)i.2NR2BR2A, in which each R2A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl, and each R2B is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl), with the proviso that when the ring system denoted by "A" is phenyl, R2 is not H; each R3 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R3A, -SR3A, -S(0)i_2R3A, -OR3A, -NR3BR3A, -C(0)R3A, -C(0)NR3BR3A, -NR3BC(0)R3A, -C(S)NR3BR3A, -NR3BC(S)R3A, -C(0)OR3A, -OC(0)R3A, -C(0)SR3A, -SC(0)R3A, -C(S)OR3A, -OC(S)R3A, -C(S)SR3A, -SC(S)R3A, -S(0)i_2OR3A, -OS(0)i_2R3A, -S(0)i_2NR3BR3A, -NR3BS(0)i-2R3A, -OC(0)OR3A, -OC(0)NR3BR3A, -NR3BC(0)OR3A, -NR3BC(0)NR3BR3A, -SC(0)OR3A, -OC(0)SR3A, -SC(0)SR3A, -SC(0)NR3BR3A, -NR3BC(0)SR3A, -OC(S)OR3A, -OC(S)NR3BR3A, -NR3BC(S)OR3A, -NR3BC(S)NR3BR3A, -SC(S)OR3A, -OC(S)SR3A, -SC(S)SR3A, -SC(S)NR3BR3A, -NR3BC(S)SR3A, -NR3BC(NR3B)NR3BR3A and -NR3BS(0)i.2NR3BR3A, in which
each R3A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl, and each R3B is independently selected from H, optionally substituted C1-C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl); m is 0, 1 , 2, 3 or 4;
the ring system denoted by "B" is phenyl or a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O and S;
each R4 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R4A, -SR4A, -S(0)i_2R4A, -OR4A, -NR4BR4A, -C(0)R4A, -C(0)NR4BR4A, -NR4BC(0)R4A, -C(S)NR4BR4A, -NR4BC(S)R4A, -C(0)OR4A, -OC(0)R4A, -C(0)SR4A, -SC(0)R4A, -C(S)OR4A, -OC(S)R4A, -C(S)SR4A, -SC(S)R4A, -S(0)i_2OR4A, -OS(0)i_2R4A, -S(0)i_2NR4BR4A, -NR4BS(0)i-2R4A, -OC(0)OR4A, -OC(0)NR4BR4A, -NR4BC(0)OR4A, -NR4BC(0)NR4BR4A, -SC(0)OR4A, -OC(0)SR4A, -SC(0)SR4A, -SC(0)NR4BR4A, -NR4BC(0)SR4A, -OC(S)OR4A, -OC(S)NR4BR4A, -NR4BC(S)OR4A, -NR4BC(S)NR4BR4A, -SC(S)OR4A, -OC(S)SR4A, -SC(S)SR4A, -SC(S)NR4BR4A, -NR4BC(S)SR4A, -NR4BC(NR4B)NR4BR4A and -NR4BS(0)i.2NR4BR4A, in which
each R4A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl, and each R4B is independently selected from H, optionally substituted C1-C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl) ; and n is 0, 1 , 2, 3, 4 or 5;
wherein
each alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene is straight-chain or branched;
each optionally substituted alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene is unsubstituted or substituted with 1 -5 substituents independently selected from halogen, nitro, -CN, -SF5, -N3, -C(0)R5, -SR5, -S(0)i_2R5, -OR5, -NR6R5, -C(0)NR6R5, -NR6C(0)R5, -C(S)NR6R5, -NR6C(S)R5, -C(0)OR5, -OC(0)R5, -C(0)SR5, -SC(0)R5, -C(S)OR5, -OC(S)R5, -C(S)SR5, -SC(S)R5, -S(0)i_2OR5, -OS(0)i-2R5, -S(0)i-2NR6R5, -NR6S(0)i_2R5, -OC(0)OR5, -OC(0)NR6R5, -NR6C(0)OR5, -NR6C(0)NR6R5, -SC(0)OR5, -OC(0)SR5, SC(0)SR5, -SC(0)NR6R5, -NR6C(0)SR5, -OC(S)OR5, -OC(S)NR6R5, -NR6C(S)OR5, -NR6C(S)NR6R5, -SC(S)OR5, -OC(S)SR5, -SC(S)SR5, -SC(S)NR6R5, -NR6C(S)SR5, -NR6C(NR6)NR6R5 and -NR6S(0)i.2NR6R5, in which
each R5 is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl; and
each R6 is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl).
[0016] In certain embodiments of the disclosure, the compound is not
(4-amino-2-((4-methoxyphenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-chlorophenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
4-((4-amino-5-(4-chlorobenzoyl)thiazol-2-yl)amino)benzonitrile;
(4-amino-2-(p-tolylamino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-(trifluoromethyl)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone; methyl 4-((4-amino-5-(4-chlorobenzoyl)thiazol-2-yl)amino)benzoate; (4-amino-2-((4-(dimethylamino)phenyl)amino)thiazol-5-yl)(4- chlorophenyl)methanone;
(4-amino-2-((4-(benzyloxy)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methano (4-amino-2-((3-nitrophenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanon
(4-amino-2-((4-(cyclohexylmethyl)phenyl)amino)thiazol-5-yl)(4- chlorophenyl)methanone;
(4-amino-2-((3-(trifluoromethyl)phenyl)amino)thiazol-5-yl)(4-chlorophen
(4-amino-2-((4-(methylthio)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)m
(4-amino-2-((4-(trifluoromethoxy)phenyl)amino)thiazol-5-yl)(4- chlorophenyl)methanone;
4-(4-amino-2-((4-methoxyphenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-chlorophenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-cyanophenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-(p-tolylamino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(trifluoromethyl)phenyl)amino)thiazole-5-carbonyl)benzon methyl 4-((4-amino-5-(4-cyanobenzoyl)thiazol-2-yl)amino)benzoate;
4-(4-amino-2-((4-(dimethylamino)phenyl)amino)thiazole-5-carbonyl)benzonitrile; 4-(4-amino-2-((4-(benzyloxy)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((3-nitrophenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(cyclohexylmethyl)phenyl)amino)thiazole-5-carbonyl)benzonitrile; 4-(4-amino-2-((3-(trifluoromethyl)phenyl)amino)thiazole-5-carbonyl)benzonitrile; 4-(4-amino-2-((4-(methylthio)phenyl)amino)thiazole-5-carbonyl)benzonitrile; or 4-(4-amino-2-((4-(trifluoromethoxy)phenyl)amino)thiazole-5-carbonyl)benzonitrile.
[0017] The disclosure also provides pharmaceutical compositions comprising a compound or salt of formula I and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent.
[0018] The disclosure also provides methods for the treatment or prevention of hyperproliferative disease, inflammatory disease, angiogenic disease or neurologic disease.
[0019] The disclosure also provides methods for inhibiting GSK3s, SKs and/or microtubule dynamics in a cell comprising contacting the cell with an inhibitory effective amount of a compound according to the preceding aspects.
[0020] In another aspect, the disclosure provides methods for treating a disease selected from a hyperproliferative disease, an inflammatory disease, an angiogenic disease or a neurologic disease comprising providing to a patient in need of such treatment a therapeutically effective amount of a compound or a pharmaceutical composition according to any of the preceding aspects.
[0021] Additional aspects and specific preferred embodiments of the disclosure will become evident from the following more detailed description of certain preferred embodiments and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 shows dose-response curves for inhibition of GSK3a, GSK3P and CDK9 by compound 32. In vitro kinase assays were conducted using the indicated concentrations of compound 32 and GSK3a (circles), GSK3P (squares) or CDK9 (triangles). Values indicate the mean ± standard deviation for the remaining enzyme activity (n=2).
[0023] Figure 2 shows depolymerization of cancer cell microtubules by compound 91. Hep3B liver cancer cells were treated with the indicated concentrations of compound 91 for 18 hours. The cells were then fixed and stained with anti-tubulin antibodies, and images were recorded by microscopy.
[0024] Figure 3 shows toxicology parameters following 7 day treatment with 50 mg/kg of compound 17, 32, 57, 60, 62 or 67. The parameters of blood urea nitrogen (BUN), alanine aminotransferase (ALT), white blood cell count (WBC), red blood cell count (RBC), Platelets, hemoglobin (Hgb), Kidney Weight and Heart Weight are shown in Panels A-H, respectively.
[0025] Figure 4 shows toxicology parameters following 7 day treatment with 100 or 200 mg/kg of compound 91 or 32. The parameters of Creatinine, ALT, WBC, RBC, Platelets, Glucose, Liver Weight and Heart Weight are shown in Panels A-H, respectively.
[0026] Figure 5 shows inhibition of melanoma tumor growth by compound 32. C57BL/6 mice were injected subcutaneously with B16 melanoma cells suspended in PBS. After tumor volume of at least 100 mm3, animals were treated 5 times per week by oral gavage of either 0.1 ml Vehicle (open squares) or 5 mg/kg of compound 32 (gray squares). Whole body weight and tumor volume measurement was performed for 1 1 days. * p < 0.05. Inset: Averaged body weight of mice from each group during course of study.
[0027] Figure 6 shows inhibition of pancreatic tumor growth by compound 32. C57BL/6 mice were injected subcutaneously with PAN02 pancreatic cancer cells suspended in PBS/growth matrix. After tumor volume of at least 100 mm3, animals were treated 5 times per week by oral gavage of either 0.1 ml Vehicle (open squares) or 5 mg/kg of compound 32 (gray squares). Whole body weight and tumor volume measurement was performed for 22 days. ** p<0.01. Inset: Averaged body weight of mice from each group during course of study. [0028] Figure 7 shows inhibition of pancreatic tumor growth by compound 91 . C57BL/6 mice were injected subcutaneously with PAN02 pancreatic cancer cells suspended in PBS/growth matrix. After tumor volume reached at least 100 mm3, animals were treated 5 times per week by oral gavage of either 0.1 ml Vehicle (open squares) or 2 mg/kg of compound 91 (black squares) . Tumor size is expressed as normalized tumor volume, which is tumor volume at Day 3 to 31 divided by tumor volume at Day 1 for each individual mouse. ** p<0.01 .
[0029] Figure 8 shows effects of compounds on Disease Activity Index (DAI) in the DSS- IBD model. Male C57BL/6 mice were treated for 6 days as follows: normal drinking water and daily oral administration of Vehicle (Sham); 2% DSS in the drinking water and daily oral administration of Vehicle (V/DSS); 2% DSS in the drinking water and daily oral administration of 50 mg/kg compound 27, 57, 9 or 32. The DAI was calculated on Days 4-6 (n=4-5/group) . Values represent the mean ± SEM .
[0030] Figure 9 shows effects of compounds on neutrophil infiltration into the colon in the acute DSS-IBD model. Myeloperoxidase (MPO) activity from the colons of the animals described in Figure 9 was measured (n=4-5/group). Values represent the mean ± SEM .
[0031] Figure 10 shows effects of Compound 32 on colon cytokine levels in the DSS-IBD model. The levels of TNFa, IL-6, ΙΙ_- 1 β and IL- 10 from homogenates of colons harvested at Day 6 were measured (n=4-5/group). Values represent the mean ± SEM. **p<0.01 for compound 32 vs. vehicle.
[0032] Figure 1 1 shows effects of compound 32 in the TNBS-colitis model. Panel A. The Macro Score was calculated on Day 10 (n = 4-5/group) . Panel B. The levels of TNFa were measured (n=4-5/group). Values represent the mean ± SEM . *p<0.05 compound 32 vs. Vehicle.
[0033] Figure 12 shows effects of compound 32 in a model of radiation-induced intestinal damage. Mice were treated with vehicle or compound 32 and then irradiated as described . Panel A. The villi length was calculated on Days 1 and 3 after radiation (n= 34-67 villi length readings across 3-5 mice/group). Panel B. The levels of TNFa were measured (n=4-5/group) . Values represent the mean ± SEM . *** p<0.001 compound 32- vs. Vehicle-treated group of same time point, *p<0.05 compound 32- vs. Vehicle-treated group of same time point.
DETAILED DESCRIPTION
[0034] All patents and publications referred to herein are hereby incorporated by reference for all purposes. [0035] Unless the substituents for a particular formula are expressly defined for that formula, they are understood to carry the definitions set forth in connection with the preceding formula to which the particular formula makes reference.
[0036] As noted above, the disclosure provides compounds of formula I:
Figure imgf000011_0001
and pharmaceutically acceptable salts thereof, wherein the variables are as described below.
[0037] The disclosure also provides a variety of subgenera of compounds in which the regiochemistry of the structural formula (I), the ring system denoted by "A", R2, R3, m, the ring system denoted by "B", R4 and n are optionally independently selected from the groups (1 a) et seq. , (2a) et seq., (3a) et seq. , (4a) et seq., (5a) et seq., (6a) et seq., (7a) et seq., (8a) et seq., (9a) et seq., (10a) et seq., (1 1 a) et seq., (12a) et seq., (13a) et seq., (14a) et seq., (15a) et seq., (16a) et seq., (17a) et seq., (18a) et seq., (19a) et seq., and (20a) et seq. defined hereinbelow (e.g. , wherein the compound is of structural formula (I) as defined in any combination of the embodiments below).
[0038] As described above, R1A and R1 B are each independently selected from H, optionally substituted Ci-C4 alkyl, optionally substituted Ci-C4 alkenyl, optionally substituted C1-C4 alkynyl, Ci-C3fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3alkyl, -C(0)R1C, -C(S)R1C, -S(0)i-2R1C, -C(0)0R1C, -C(0)NR1 DR1C, -C(0)SR1C, -C(S)0R1C, -C(S)NR1 DR1C, -C(S)SR1C, -C(NR1 D)NR1 DR1C and -S(0)i-2NR1 DR1C, in which each R1C is independently selected from H, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl, and each R1 D is independently selected from H, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(d-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl).
[0039] In certain embodiments of the compounds as otherwise described herein, R1A is selected from one of the following groups:
(1 a) R1A is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, Ci-C3fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3alkyl, -C(0)R1C, -C(S)R1C, -S(0)i-2R1C, -C(0)0R1C, -C(0)NR1 DR1C, -C(0)SR1C, -C(S)0R1C, -C(S)NR1 DR1C, -C(S)SR1C, -C(NR1 D)NR1 DR1C or -S(0)i-2NR1 DR1C, (1 b) R1A is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, Ci-C3fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3alkyl, -C(0)R1C and -S(0)i.2R1c
(1 c) R1A is H.
(1 d) R1A is not H.
(1 e) R1A is -(C1-C4 alkyl).
(1f) R1A is -(C1-C4 alkyl), -C(0)-(Ci-C4 alkyl), or -C(0)-(Ci-C4 alkenyl).
[0040] In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 1 a-1f above), each "optionally substituted" alkyl, alkenyl and alkynyl of R1A is unsubstituted or fluorinated. For example, in certain such embodiments each "optionally substituted" alkyl, alkenyl and alkynyl of R1A is unsubstituted. In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 1 a-1f above), R1A is not an alkenyl or an alkynyl.
[0041] In certain embodiments of the compounds as otherwise described herein, R1B is selected from one of the following groups:
(2a) R1B is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, Ci-C3fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3alkyl, -C(0)R1C, -C(S)R1C, -S(0)i-2R1C, -C(0)0R1C, -C(0)NR1DR1C, -C(0)SR1C, -C(S)0R1C, -C(S)NR1DR1C, -C(S)SR1C, -C(NR1 D)NR1DR1C or
Figure imgf000012_0001
(2b) R1B is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, Ci-C3fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3alkyl, -C(0)R1C and -S(0)i.2R1c
(2c) R1B is H.
(2d) R1B is C1-C4 alkyl.
(2e) R1B is -C(0)R1C, in which R1C is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl or (C1-C3 alkoxy)Ci-C3 alkyl.
[0042] In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 2a-2e above), each "optionally substituted" alkyl, alkenyl and alkynyl of R1B is unsubstituted or fluorinated. For example, in certain such embodiments each "optionally substituted" alkyl, alkenyl and alkynyl of R1B is unsubstituted. In certain embodiments of the compounds as otherwise described herein(e.g. , with respect to any of groups 2a-2e above), R1 B is not an alkenyl or an alkynyl.
[0043] In certain embodiments of the compounds as otherwise described herein, R1C is selected from one of the following groups:
(3a) R1C is independently selected from H, Ci-C4 alkyl, Ci-C4 alkenyl, Ci-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl,
(3b) each R1C is independently selected from H, C1-C4 alkyl, Ci-C3 fluoroalkyl, Ci-C3 hydroxyalkyl and (Ci-C3 alkoxy)Ci-C3 alkyl.
(3c) each R1C is independently selected from H and Ci-C alkyl.
[0044] In certain embodiments of the compounds as otherwise described herein (e.g. , with respect to any of groups 3a-3c above) , R1C is not an alkenyl or an alkynyl.
[0045] In certain embodiments of the compounds as otherwise described herein, R1 D is selected from one of the following groups:
(4a) each R1 D is independently selected from H, Ci-C alkyl, Ci-C alkenyl, Ci-C alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl).
(4b) each R1 D is independently selected from H, C1-C4 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl.
(4c) each R1 D is independently selected from H and C1-C4 alkyl.
[0046] In certain embodiments of the compounds as otherwise described herein (e.g. , with respect to any of groups 4a-4c above) , R1 D is not an alkenyl or an alkynyl.
[0047] In certain embodiments of the compounds as otherwise described herein, the -NR1AR1 B is selected from one of the following groups:
(5a) -NR1AR1 B is -N(Ci-C4 alkyl)(Ci-C4 alkyl).
Figure imgf000013_0001
(5c) -NR1AR1 B is -N(CH3)2, -NHC(0)CH3, -NHC(0)CH=CH2 or -NHC(0)CH2CH3.
(5d) -NR1AR1 B is -NHC(0)CH3.
(5e) -NR1AR1 B is -NHC(0)CH=CH2.
(5f) -NR1AR1 B is -NHC(0)CH2CH3.
[0048] As described above, the ring system denoted by "A" is phenyl or a 5- or 6- membered heteroaryl having one or two heteroatoms independently selected from N, O and S. In certain embodiments of the compounds as otherwise described herein, the ring system denoted by "A" is selected from one of the following groups:
(6a) the ring system denoted by "A" is phenyl.
(6b) the ring system denoted by "A" is a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O and S, e.g., pyridyl, such as pyrid-2- yl, pyrid-3-yl, or pyrid-4-yl.
(6c) the ring system denoted by "A" is a 5- or 6-membered heteroaryl having one heteroatom independently selected from N, O and S, e.g., pyridyl, such as pyrid-2- yl, pyrid-3-yl, or pyrid-4-yl.
[0049] As described above, R2 is selected from H, C1-C3 fluoroalkyl, halogen, nitro, -CN, -NR2AR2B, -C(0)R2A, -S(0)i-2R2A, -C(0)R2A, -C(0)NR2BR2A, -C(S)NR2BR2A,-C(0)OR2A, -C(0)SR2A, -C(S)OR2A, -C(S)SR2A, -S(0)i_2OR2A and -S(0)i_2NR2BR2A, in which each R2A is independently selected from H, optionally substituted Ci-C4 alkyi, optionally substituted Ci-C4 alkenyl, optionally substituted Ci-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyi, and each R2B is independently selected from H, optionally substituted C1-C4 alkyi, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, Ci-C3 fluoroalkyl, Ci-C3 hydroxyalkyl, (Ci-C3 alkoxy)Ci-C3 alkyi, -S(0)i-2(Ci-C3 alkyi), -C(0)(Ci-C3 alkyi) and -C(0)0(Ci-C3 alkyi), with the proviso that when the ring system denoted by "A" is phenyl, R2 is not H. In certain embodiments of the compounds as otherwise described herein, R2 is selected from one of the following groups:
(7a) R2 is selected from H, Ci-C3 fluoroalkyl, halogen, nitro, -CN, -NR2AR2B, -C(0)R2A, -S(0)i-2R2A, -C(0)R2A, -C(0)NR2BR2A, -C(S)NR2BR2A,-C(0)OR2A, -C(0)SR2A, -C(S)OR2A, -C(S)SR2A, -S(0)i-2OR2A and -S(0)i_2NR2BR2A
(7b) R2 is Ci-C3 fluoroalkyl, halogen, -NR2AR2B, nitro, or -CN.
(7c) R2 is -CN.
(7d) R2 is halogen, e.g., chloro or fluoro.
(7e) R2 is nitro.
(7f) R2 is -C(0)R2A, -S(0)i-2R2A, -C(0)R2A, -C(0)NR2BR2A, -C(S)NR2BR2A, -C(0)OR2A, -C(0)SR2A, -C(S)OR2A, -C(S)SR2A, -S(0)i_2OR2A or -S(0)i_2NR2BR2A
(7g) R2 is selected from Ci-C3 fluoroalkyl, halogen, nitro, -CN, -C(0)R2A, -S(0)i-2R2A, -C(0)R2A, -C(0)NR2BR2A, -C(S)NR2BR2A,-C(0)OR2A, -C(0)SR2A, -C(S)OR2A, -C(S)SR2A, -S(0)i-2OR2A and -S(0)i_2NR2BR2A
(7h) R2 is Ci-C3 fluoroalkyl, halogen, nitro, or -CN. [0050] In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 7a-7h above), each "optionally substituted" alkyl, alkenyl and alkynyl of R2 is unsubstituted or fluorinated. For example, in certain such embodiments each "optionally substituted" alkyl, alkenyl and alkynyl of R2 is unsubstituted. In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 7a-7h above), R2 is not an alkenyl or an alkynyl.
[0051] As described above, each R2A is independently selected from H, optionally substituted Ci-C4 alkyl, optionally substituted Ci-C4 alkenyl, optionally substituted Ci-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl. In certain embodiments of the compounds as otherwise described herein, each R2A is selected from one of the groups below:
(8a) each R2A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, Ci-C3 fluoroalkyl, Ci-C3 hydroxyalkyl and (Ci-C3 alkoxy)Ci-C3 alkyl.
(8b) each R2A is independently selected from H, Ci-C alkyl, Ci-C3 fluoroalkyl, Ci-C3 hydroxyalkyl and (Ci-C3 alkoxy)Ci-C3 alkyl.
(8c) each R2A is independently selected from H and Ci-C alkyl.
[0052] In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 8a-8c above), each "optionally substituted" alkyl, alkenyl and alkynyl of R2A is unsubstituted or fluorinated. For example, in certain such embodiments each "optionally substituted" alkyl, alkenyl and alkynyl of R2A is unsubstituted. In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 8a-8c above), R2A is not an alkenyl or an alkynyl.
[0053] As described above, each R2B is independently selected from H, optionally substituted Ci-C alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl). In certain embodiments of the compounds as otherwise described herein, each R2B is selected from one of the groups below:
(9a) each R2A is independently selected from H, optionally substituted Ci-C alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, Ci-C3 fluoroalkyl, Ci-C3 hydroxyalkyl, (Ci-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl).
(9b) each R2B is independently selected from H, Ci-C alkyl, Ci-C3 fluoroalkyl, Ci-C3 hydroxyalkyl, (Ci-C3 alkoxy)Ci-C3 alkyl, -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl). (9c) each R2B is independently selected from H and C1-C4 alkyl.
[0054] In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 9a-9c above), each "optionally substituted" alkyl, alkenyl and alkynyl of R2B is unsubstituted or fluorinated. For example, in certain such embodiments each "optionally substituted" alkyl, alkenyl and alkynyl of R2B is unsubstituted. In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 9a-9c above), R2B is not an alkenyl or an alkynyl.
[0055] The R2 substituent can be disposed on the ring system denoted by "A" in a variety of regiochemical relationships with respect to the thienylcarbonyl. In certain embodiments of the compounds as otherwise described herein, including each of the compounds of the table above, the regiochemistry of the R2 substituent is selected from one of the following:
(10a) the ring system denoted by "A" is a six-membered ring, and wherein the R2 is disposed in a 1 ,4 relationship with respect to the thienylcarbonyl.
(10b) the R2 is disposed in a 1 ,3 relationship with respect to the thienylcarbonyl.
(10c) the R2 is disposed in a 1 ,2 relationship with respect to the thienylcarbonyl.
[0056] In addition to the R2 substituent, the ring system denoted by "A" can bear 0, 1 , 2, 3 or 4 R3 substituents. As described above, each R3 is independently selected from optionally substituted Ci-C4 alkyl, optionally substituted Ci-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R3A, -SR3A, -S(0)i_2R3A, -OR3A, -NR3BR3A, -C(0)R3A, -C(0)NR3BR3A, -NR3BC(0)R3A, -C(S)NR3BR3A,
-NR3BC(S)R3A, -C(0)OR3A, -OC(0)R3A, -C(0)SR3A, -SC(0)R3A, -C(S)OR3A, -OC(S)R3A, -C(S)SR3A, -SC(S)R3A, -S(0)i_2OR3A, -OS(0)i_2R3A, -S(0)i_2NR3BR3A, -NR3BS(0)i-2R3A, -OC(0)OR3A, -OC(0)NR3BR3A, -NR3BC(0)OR3A, -NR3BC(0)NR3BR3A, -SC(0)OR3A, -OC(0)SR3A, -SC(0)SR3A, -SC(0)NR3BR3A, -NR3BC(0)SR3A, -OC(S)OR3A, -OC(S)NR3BR3A, -NR3BC(S)OR3A, -NR3BC(S)NR3BR3A, -SC(S)OR3A, -OC(S)SR3A, -SC(S)SR3A, -SC(S)NR3BR3A, -NR3BC(S)SR3A, -NR3BC(NR3B)NR3BR3A and -NR3BS(0)i.2NR3BR3A, in which each R3A is independently selected from H, optionally substituted Ci-C alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (Ci-C3 alkoxy)Ci-C3 alkyl, and each R3B is independently selected from H, optionally substituted Ci-C alkyl; optionally substituted Ci-C alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl). In certain embodiments of the compounds as otherwise described herein, each R3 substituent is selected from one of the following groups: (1 1 a) each R3 is independently selected from optionally substituted Ci-C4 alkyl, optionally substituted Ci-C4 alkenyl, optionally substituted Ci-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R3A, -SR3A, -S(0)i_2R3A, -OR3A, -NR3BR3A, -C(0)R3A, -C(0)NR3BR3A, -NR3BC(0)R3A, -C(S)NR3BR3A, -NR3BC(S)R3A, -C(0)OR3A, -OC(0)R3A, -C(0)SR3A, -SC(0)R3A, -C(S)OR3A, -OC(S)R3A, -C(S)SR3A, -SC(S)R3A, -S(0)i_2OR3A, -OS(0)i_2R3A, -S(0)i_2NR3BR3A, -NR3BS(0)i-2R3A, -OC(0)OR3A, -OC(0)NR3BR3A, -NR3BC(0)OR3A, -NR3BC(0)NR3BR3A, -SC(0)OR3A, -OC(0)SR3A, -SC(0)SR3A, -SC(0)NR3BR3A, -NR3BC(0)SR3A, -OC(S)OR3A, -OC(S)NR3BR3A, -NR3BC(S)OR3A, -NR3BC(S)NR3BR3A, -SC(S)OR3A, -OC(S)SR3A, -SC(S)SR3A, -SC(S)NR3BR3A, -NR3BC(S)SR3A, -NR3BC(NR3B)NR3BR3A and -NR3BS(0)i.2NR3BR3A.
(1 1 b) each R3 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R3A, -SR3A, -S(0)i_2R3A, -OR3A, -NR3BR3A, -C(0)R3A, -C(0)NR3BR3A, -NR3BC(0)R3A, -C(S)NR3BR3A, -NR3BC(S)R3A, -C(0)OR3A, -OC(0)R3A, -C(0)SR3A, -SC(0)R3A, -C(S)OR3A, -OC(S)R3A, -C(S)SR3A, -SC(S)R3A, -S(0)i_2OR3A, -OS(0)i_2R3A, -S(0)i_2NR3BR3A
Figure imgf000017_0001
(1 1 c) each R3 is independently selected from optionally substituted Ci-C alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, Ci-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R3A, -SR3A, -S(0)i_2R3A, -OR3A, -NR3BR3A or -C(0)R3A.
(1 1 d) each R3 is independently Ci-C alkyl, Ci-C alkenyl, Ci-C alkynyl, Ci-C3 fluoroalkyl, halogen, nitro, -CN, -C(0)R3A, -S(0)i_2R3A, or -OR3A, in which each R3A is independently H, Ci-C alkyl, Ci-C alkenyl, Ci-C alkynyl, Ci-C3 fluoroalkyl, Ci-C3 hydroxyalkyl or (Ci-C3 alkoxy)Ci-C3 alkyl.
[0057] In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 1 1 a-1 1 d above), each "optionally substituted" alkyl, alkenyl and alkynyl of R3 is unsubstituted or fluorinated. For example, in certain such embodiments each "optionally substituted" alkyl, alkenyl and alkynyl of R3 is unsubstituted. In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 1 1 a-11 d above), R3 is not an alkenyl or an alkynyl.
[0058] As described above, each R3A is independently selected from H, optionally substituted Ci-C alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C alkynyl, Ci-C3 fluoroalkyl, Ci-C3 hydroxyalkyl and (Ci-C3 alkoxy)Ci-C3 alkyl. In certain embodiments of the compounds as otherwise described herein, each R3A substituent is selected from one of the following groups:
(12a) each R3A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl.
(12b) each R3A is independently selected from H, optionally substituted C1-C4 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl.
(12c) each R3A is H, C1-C4 alkyl or C1-C4 fluoroalkyl.
(12d) each R3A is H or C1-C4 alkyl.
(12e) each R3A is H.
[0059] In certain embodiments of the compounds as otherwise described herein (e.g. , with respect to any of groups 12a-12e above) , each "optionally substituted" alkyl, alkenyl and alkynyl of R3A is unsubstituted or fluorinated. For example, in certain such embodiments each "optionally substituted" alkyl, alkenyl and alkynyl of R3A is unsubstituted. In certain embodiments of the compounds as otherwise described herein (e.g. , with respect to any of groups 12a- 12e above) , R3A is not an alkenyl or an alkynyl.
[0060] As described above, each R3B is independently selected from H, optionally substituted C1-C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl). In certain embodiments of the compounds as otherwise described herein, each R3B substituent is selected from one of the following groups:
(13a) each R3B is independently selected from H, optionally substituted C1-C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl) , -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl) .
(13b) each R3B is independently selected from H, optionally substituted C1-C4 alkyl; C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl) , -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl) .
(13c) each R3B is H, -C(0)-(Ci-C4 alkyl) , -C(0)-(Ci-C4 fluoroalkyl), C1-C4 alkyl or C1-C4 fluoroalkyl.
(13d) each R3B is H. [0061] In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 13a-13d above), each "optionally substituted" alkyl, alkenyl and alkynyl of R3B is unsubstituted or fluorinated. For example, in certain such embodiments each "optionally substituted" alkyl, alkenyl and alkynyl of R3B is unsubstituted. In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 13a-13d above), R3B is not an alkenyl or an alkynyl.
[0062] As described above the number of R3 substituents on the ring system denoted by "A", m, can be 0, 1 , 2, 3 or 4. Of course, the person of ordinary skill in the art will appreciate that this numberwill be limited by the number of substitutable atoms in the ring system denoted by "A". In certain embodiments of the compounds as otherwise described herein, the value of m is selected from one of the following:
(14a) m is 0, 1 , 2, 3 or 4.
(14b) m is 0, 1 or 2.
(14c) m is 1 or 2.
(14d) m is O.
[0063] As described above, the ring system denoted by "B" is phenyl or a 5- or 6- membered heteroaryl having one or two heteroatoms independently selected from N, O and S. In certain embodiments of the compounds as otherwise described herein, the ring system denoted by "B" is selected from one of the following groups:
(15a) the ring system denoted by "B" is phenyl.
(15b) the ring system denoted by "B" is a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O and S.
(15c) the ring system denoted by "B" is a 5- or 6-membered heteroaryl having one heteroatoms independently selected from N, O and S.
[0064] As described above, the ring system denoted by "B" can bear 0, 1 , 2, 3, 4 or 5 R4 substituents. As described above, each R4 is independently selected from optionally substituted Ci-C4 alkyl, optionally substituted Ci-C4 alkenyl, optionally substituted Ci-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R4A, -SR4A, -S(0)i_2R4A, -OR4A, -NR4BR4A, -C(0)R4A, -C(0)NR4BR4A, -NR4BC(0)R4A, -C(S)NR4BR4A,
-NR4BC(S)R4A, -C(0)OR4A, -OC(0)R4A, -C(0)SR4A, -SC(0)R4A, -C(S)OR4A, -OC(S)R4A, -C(S)SR4A, -SC(S)R4A, -S(0)i_2OR4A, -OS(0)i_2R4A, -S(0)i_2NR4BR4A, -NR4BS(0)i-2R4A, -OC(0)OR4A, -OC(0)NR4BR4A, -NR4BC(0)OR4A, -NR4BC(0)NR4BR4A, -SC(0)OR4A, -OC(0)SR4A, -SC(0)SR4A, -SC(0)NR4BR4A, -NR4BC(0)SR4A, -OC(S)OR4A, -OC(S)NR4BR4A, -NR4BC(S)OR4A, -NR4BC(S)NR4BR4A, -SC(S)OR4A, -OC(S)SR4A, -SC(S)SR4A, -SC(S)NR4BR4A, -NR4BC(S)SR4A, -NR4BC(NR4B)NR4BR4A and -NR4BS(0)i.2NR4BR4A, in which each R4A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl, and each R4B is independently selected from H, optionally substituted C1-C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl). In certain embodiments of the compounds as otherwise described herein, each R4 substituent is selected from one of the following groups:
(16a) each R4 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R4A, -SR4A, -S(0)i_2R4A, -OR4A, -NR4BR4A, -C(0)R4A, -C(0)NR4BR4A, -NR4BC(0)R4A, -C(S)NR4BR4A, -NR4BC(S)R4A, -C(0)OR4A, -OC(0)R4A, -C(0)SR4A, -SC(0)R4A, -C(S)OR4A, -OC(S)R4A, -C(S)SR4A, -SC(S)R4A, -S(0)i_2OR4A, -OS(0)i_2R4A, -S(0)i_2NR4BR4A, -NR4BS(0)i-2R4A, -OC(0)OR4A, -OC(0)NR4BR4A, -NR4BC(0)OR4A, -NR4BC(0)NR4BR4A, -SC(0)OR4A, -OC(0)SR4A, -SC(0)SR4A, -SC(0)NR4BR4A, -NR4BC(0)SR4A, -OC(S)OR4A, -OC(S)NR4BR4A, -NR4BC(S)OR4A, -NR4BC(S)NR4BR4A, -SC(S)OR4A, -OC(S)SR4A, -SC(S)SR4A, -SC(S)NR4BR4A, -NR4BC(S)SR4A, -NR4BC(NR4B)NR4BR4A and -NR4BS(0)i.2NR4BR4A.
(16b) each R4 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R4A, -SR4A, -S(0)i_2R4A, -OR4A, -NR4BR4A, -C(0)R4A, -C(0)NR4BR4A, -NR4BC(0)R4A, -C(S)NR4BR4A, -NR4BC(S)R4A, -C(0)OR4A, -OC(0)R4A, -C(0)SR4A, -SC(0)R4A, -C(S)OR4A, -OC(S)R4A, -C(S)SR4A, -SC(S)R4A, -S(0)i_2OR4A, -OS(0)i_2R4A, -S(0)i_2NR4BR4A
Figure imgf000020_0001
(16c) each R4 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R4A, -SR4A, -S(0)i_2R4A, -OR4A, -NR4BR4A or -C(0)R4A.
(16d) each R4 is independently C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -C(0)R4A, -S(0)i_2R4A, or -OR4A, in which each R4A is independently H, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl or (C1-C3 alkoxy)Ci-C3 alkyl.
(16e) each R4 is independently halogen (e.g., chloro or fluoro).
(16f) each R4 is independently C1-C4 alkyl.
(16g) each R4 is independently nitro.
(16h) each R4 is independently C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, or C1-C3 fluoroalkyl.
(16i) each R4 is independently -OR4A, in which R4A is independently H, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl or (C1-C3 alkoxy)Ci-C3 alkyl.
[0065] In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 16a-16i above), each "optionally substituted" alkyl, alkenyl and alkynyl of R4 is unsubstituted or fluorinated. For example, in certain such embodiments each "optionally substituted" alkyl, alkenyl and alkynyl of R4 is unsubstituted. In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 16a-16i above), R4 is not an alkenyl or an alkynyl.
[0066] As described above, each R4A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl. In certain embodiments of the compounds as otherwise described herein, each R4A substituent is selected from one of the following groups:
(17a) each R4A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl.
(17b) each R4A is independently selected from H, optionally substituted C1-C4 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl.
(17c) each R4A is H, C1-C4 alkyl or C1-C4 fluoroalkyl.
(17d) each R4A is H or C1-C4 alkyl.
(17e) each R4A is H.
[0067] In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 17a-17e above), each "optionally substituted" alkyl, alkenyl and alkynyl of R4A is unsubstituted or fluorinated. For example, in certain such embodiments each "optionally substituted" alkyl, alkenyl and alkynyl of R4A is unsubstituted. In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 17a-17e above), R4A is not an alkenyl or an alkynyl.
[0068] As described above, each R4B is independently selected from H, optionally substituted C1-C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl). In certain embodiments of the compounds as otherwise described herein, each R4B substituent is selected from one of the following groups:
(18a) each R4B is independently selected from H, optionally substituted C1-C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl).
(18b) each R4B is independently selected from H, optionally substituted C1-C4 alkyl; C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl).
(18c) each R4B is H, -C(0)-(Ci-C4 alkyl), -C(0)-(Ci-C4 fluoroalkyl), C1-C4 alkyl or C1-C4 fluoroalkyl.
(18d) each R4B is H.
[0069] In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 18a-18d above), each "optionally substituted" alkyl, alkenyl and alkynyl of R4B is unsubstituted or fluorinated. For example, in certain such embodiments each "optionally substituted" alkyl, alkenyl and alkynyl of R4B is unsubstituted. In certain embodiments of the compounds as otherwise described herein (e.g., with respect to any of groups 18a-18d above), R4B is not an alkenyl or an alkynyl.
[0070] As described above the number of R4 substituents on the ring system denoted by "B", n, can be 0, 1 , 2, 3, 4 or 5. Of course, the person of ordinary skill in the art will appreciate that this numberwill be limited by the number of substitutable atoms in the ring system denoted by "B". In certain embodiments of the compounds as otherwise described herein, the value of n is selected from one of the following:
(19a) n is 0, 1 , 2, 3, 4 or 5.
(19b) n is 0, 1 or 2.
(19c) n is 1 or 2.
(19d) n is O. [0071] Various particular embodiments nos. 1 -640 of compounds of the disclosure include compounds of any one of the formulae (I), each as defined in each of the following rows (or a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof), in which each entry is a group number as defined above (e.g., 13d refers to each R3 being H). Group numbers separated by slashes indicate that the entry includes all such limitations. When two or more group numbers defining the same substituent are separated by a slash, it indicates that any such substituent definitions can apply. For example, "5a/5b/5c" indicates that the substituent can be any of -N(d-C4 alkyl)(Ci-C4 alkyl) (i.e., as defined in group 5a), - NH2 (i.e., as defined in group 5b), or -N(CH3)2, -NHC(0)CH3, -NHC(0)CH=CH2 or - NHC(0)CH2CH3 (i.e., as defined in group 5c). When two or more group numbers defining different substituents are separated by a slash, it indicates that all such substituent definitions apply. For example, "7f/8b/9b" indicates that the (7f) definition of R2, the (8b) definition of R2A, and the (9b) definition of R2B all apply.
Figure imgf000023_0001
1A/R1B "A" ring R2 R3 m "B" ring R4 n
1a,2a 6a 7b/8b/9b 11a 14a 15a 16a 19b
1a,2a 6a 7b/8b/9b 11a 14a 15a 16d 19a
1a,2a 6a 7b/8b/9b 11a 14a 15a 16d 19b
1a,2a 6a 7b/8b/9b 11a 14a 15b 16a 19a
1a,2a 6a 7b/8b/9b 11a 14a 15b 16a 19b
1a,2a 6a 7b/8b/9b 11a 14a 15b 16d 19a
1a,2a 6a 7b/8b/9b 11a 14a 15b 16d 19b
1a,2a 6a 7b/8b/9b 11a 14b 15a 16a 19a
1a,2a 6a 7b/8b/9b 11a 14b 15a 16a 19b
1a,2a 6a 7b/8b/9b 11a 14b 15a 16d 19a
1a,2a 6a 7b/8b/9b 11a 14b 15a 16d 19b
1a,2a 6a 7b/8b/9b 11a 14b 15b 16a 19a
1a,2a 6a 7b/8b/9b 11a 14b 15b 16a 19b
1a,2a 6a 7b/8b/9b 11a 14b 15b 16d 19a
1a,2a 6a 7b/8b/9b 11a 14b 15b 16d 19b
1a,2a 6a 7b/8b/9b 11 d 14a 15a 16a 19a
1a,2a 6a 7b/8b/9b 11 d 14a 15a 16a 19b
1a,2a 6a 7b/8b/9b 11 d 14a 15a 16d 19a
1a,2a 6a 7b/8b/9b 11 d 14a 15a 16d 19b
1a,2a 6a 7b/8b/9b 11 d 14a 15b 16a 19a
1a,2a 6a 7b/8b/9b 11 d 14a 15b 16a 19b
1a,2a 6a 7b/8b/9b 11 d 14a 15b 16d 19a
1a,2a 6a 7b/8b/9b 11 d 14a 15b 16d 19b
1a,2a 6a 7b/8b/9b 11 d 14b 15a 16a 19a
1a,2a 6a 7b/8b/9b 11 d 14b 15a 16a 19b
1a,2a 6a 7b/8b/9b 11 d 14b 15a 16d 19a
1a,2a 6a 7b/8b/9b 11 d 14b 15a 16d 19b
1a,2a 6a 7b/8b/9b 11 d 14b 15b 16a 19a
1a,2a 6a 7b/8b/9b 11 d 14b 15b 16a 19b
1a,2a 6a 7b/8b/9b 11 d 14b 15b 16d 19a
1a,2a 6a 7b/8b/9b 11 d 14b 15b 16d 19b
1a,2a 6b 7a 11a 14a 15a 16a 19a
1a,2a 6b 7a 11a 14a 15a 16a 19b
1a,2a 6b 7a 11a 14a 15a 16d 19a
1a,2a 6b 7a 11a 14a 15a 16d 19b
1a,2a 6b 7a 11a 14a 15b 16a 19a
1a,2a 6b 7a 11a 14a 15b 16a 19b
1a,2a 6b 7a 11a 14a 15b 16d 19a
1a,2a 6b 7a 11a 14a 15b 16d 19b
1a,2a 6b 7a 11a 14b 15a 16a 19a
1a,2a 6b 7a 11a 14b 15a 16a 19b
1a,2a 6b 7a 11a 14b 15a 16d 19a
1a,2a 6b 7a 11a 14b 15a 16d 19b
1a,2a 6b 7a 11a 14b 15b 16a 19a
1a,2a 6b 7a 11a 14b 15b 16a 19b
1a,2a 6b 7a 11a 14b 15b 16d 19a
1a,2a 6b 7a 11a 14b 15b 16d 19b
1a,2a 6b 7a 11 d 14a 15a 16a 19a
1a,2a 6b 7a 11 d 14a 15a 16a 19b
1a,2a 6b 7a 11 d 14a 15a 16d 19a
1a,2a 6b 7a 11 d 14a 15a 16d 19b
1a,2a 6b 7a 11 d 14a 15b 16a 19a No. R1A/R1B "A" ring R2 R3 m "B" ring R4 n
86 1a,2a 6b 7a 11 d 14a 15b 16a 19b
87 1a,2a 6b 7a 11 d 14a 15b 16d 19a
88 1a,2a 6b 7a 11 d 14a 15b 16d 19b
89 1a,2a 6b 7a 11 d 14b 15a 16a 19a
90 1a,2a 6b 7a 11 d 14b 15a 16a 19b
91 1a,2a 6b 7a 11 d 14b 15a 16d 19a
92 1a,2a 6b 7a 11 d 14b 15a 16d 19b
93 1a,2a 6b 7a 11 d 14b 15b 16a 19a
94 1a,2a 6b 7a 11 d 14b 15b 16a 19b
95 1a,2a 6b 7a 11 d 14b 15b 16d 19a
96 1a,2a 6b 7a 11 d 14b 15b 16d 19b
97 1a,2a 6b 7b/8b/9b 11a 14a 15a 16a 19a
98 1a,2a 6b 7b/8b/9b 11a 14a 15a 16a 19b
99 1a,2a 6b 7b/8b/9b 11a 14a 15a 16d 19a
100 1a,2a 6b 7b/8b/9b 11a 14a 15a 16d 19b
101 1a,2a 6b 7b/8b/9b 11a 14a 15b 16a 19a
102 1a,2a 6b 7b/8b/9b 11a 14a 15b 16a 19b
103 1a,2a 6b 7b/8b/9b 11a 14a 15b 16d 19a
104 1a,2a 6b 7b/8b/9b 11a 14a 15b 16d 19b
105 1a,2a 6b 7b/8b/9b 11a 14b 15a 16a 19a
106 1a,2a 6b 7b/8b/9b 11a 14b 15a 16a 19b
107 1a,2a 6b 7b/8b/9b 11a 14b 15a 16d 19a
108 1a,2a 6b 7b/8b/9b 11a 14b 15a 16d 19b
109 1a,2a 6b 7b/8b/9b 11a 14b 15b 16a 19a
110 1a,2a 6b 7b/8b/9b 11a 14b 15b 16a 19b
111 1a,2a 6b 7b/8b/9b 11a 14b 15b 16d 19a
112 1a,2a 6b 7b/8b/9b 11a 14b 15b 16d 19b
113 1a,2a 6b 7b/8b/9b 11 d 14a 15a 16a 19a
114 1a,2a 6b 7b/8b/9b 11 d 14a 15a 16a 19b
115 1a,2a 6b 7b/8b/9b 11 d 14a 15a 16d 19a
116 1a,2a 6b 7b/8b/9b 11 d 14a 15a 16d 19b
117 1a,2a 6b 7b/8b/9b 11 d 14a 15b 16a 19a
118 1a,2a 6b 7b/8b/9b 11 d 14a 15b 16a 19b
119 1a,2a 6b 7b/8b/9b 11 d 14a 15b 16d 19a
120 1a,2a 6b 7b/8b/9b 11 d 14a 15b 16d 19b
121 1a,2a 6b 7b/8b/9b 11 d 14b 15a 16a 19a
122 1a,2a 6b 7b/8b/9b 11 d 14b 15a 16a 19b
123 1a,2a 6b 7b/8b/9b 11 d 14b 15a 16d 19a
124 1a,2a 6b 7b/8b/9b 11 d 14b 15a 16d 19b
125 1a,2a 6b 7b/8b/9b 11 d 14b 15b 16a 19a
126 1a,2a 6b 7b/8b/9b 11 d 14b 15b 16a 19b
127 1a,2a 6b 7b/8b/9b 11 d 14b 15b 16d 19a
128 1a,2a 6b 7b/8b/9b 11 d 14b 15b 16d 19b
129 1b,2b 6a 7a 11a 14a 15a 16a 19a
130 1b,2b 6a 7a 11a 14a 15a 16a 19b
131 1b,2b 6a 7a 11a 14a 15a 16d 19a
132 1b,2b 6a 7a 11a 14a 15a 16d 19b
133 1b,2b 6a 7a 11a 14a 15b 16a 19a
134 1b,2b 6a 7a 11a 14a 15b 16a 19b
135 1b,2b 6a 7a 11a 14a 15b 16d 19a
136 1b,2b 6a 7a 11a 14a 15b 16d 19b
137 1b,2b 6a 7a 11a 14b 15a 16a 19a No. R1A/R1B "A" ring R2 R3 m "B" ring R4 n
138 1b,2b 6a 7a 11a 14b 15a 16a 19b
139 1b,2b 6a 7a 11a 14b 15a 16d 19a
140 1b,2b 6a 7a 11a 14b 15a 16d 19b
141 1b,2b 6a 7a 11a 14b 15b 16a 19a
142 1b,2b 6a 7a 11a 14b 15b 16a 19b
143 1b,2b 6a 7a 11a 14b 15b 16d 19a
144 1b,2b 6a 7a 11a 14b 15b 16d 19b
145 1b,2b 6a 7a 11 d 14a 15a 16a 19a
146 1b,2b 6a 7a 11 d 14a 15a 16a 19b
147 1b,2b 6a 7a 11 d 14a 15a 16d 19a
148 1b,2b 6a 7a 11 d 14a 15a 16d 19b
149 1b,2b 6a 7a 11 d 14a 15b 16a 19a
150 1b,2b 6a 7a 11 d 14a 15b 16a 19b
151 1b,2b 6a 7a 11 d 14a 15b 16d 19a
152 1b,2b 6a 7a 11 d 14a 15b 16d 19b
153 1b,2b 6a 7a 11 d 14b 15a 16a 19a
154 1b,2b 6a 7a 11 d 14b 15a 16a 19b
155 1b,2b 6a 7a 11 d 14b 15a 16d 19a
156 1b,2b 6a 7a 11 d 14b 15a 16d 19b
157 1b,2b 6a 7a 11 d 14b 15b 16a 19a
158 1b,2b 6a 7a 11 d 14b 15b 16a 19b
159 1b,2b 6a 7a 11 d 14b 15b 16d 19a
160 1b,2b 6a 7a 11 d 14b 15b 16d 19b
161 1b,2b 6a 7b/8b/9b 11a 14a 15a 16a 19a
162 1b,2b 6a 7b/8b/9b 11a 14a 15a 16a 19b
163 1b,2b 6a 7b/8b/9b 11a 14a 15a 16d 19a
164 1b,2b 6a 7b/8b/9b 11a 14a 15a 16d 19b
165 1b,2b 6a 7b/8b/9b 11a 14a 15b 16a 19a
166 1b,2b 6a 7b/8b/9b 11a 14a 15b 16a 19b
167 1b,2b 6a 7b/8b/9b 11a 14a 15b 16d 19a
168 1b,2b 6a 7b/8b/9b 11a 14a 15b 16d 19b
169 1b,2b 6a 7b/8b/9b 11a 14b 15a 16a 19a
170 1b,2b 6a 7b/8b/9b 11a 14b 15a 16a 19b
171 1b,2b 6a 7b/8b/9b 11a 14b 15a 16d 19a
172 1b,2b 6a 7b/8b/9b 11a 14b 15a 16d 19b
173 1b,2b 6a 7b/8b/9b 11a 14b 15b 16a 19a
174 1b,2b 6a 7b/8b/9b 11a 14b 15b 16a 19b
175 1b,2b 6a 7b/8b/9b 11a 14b 15b 16d 19a
176 1b,2b 6a 7b/8b/9b 11a 14b 15b 16d 19b
177 1b,2b 6a 7b/8b/9b 11 d 14a 15a 16a 19a
178 1b,2b 6a 7b/8b/9b 11 d 14a 15a 16a 19b
179 1b,2b 6a 7b/8b/9b 11 d 14a 15a 16d 19a
180 1b,2b 6a 7b/8b/9b 11 d 14a 15a 16d 19b
181 1b,2b 6a 7b/8b/9b 11 d 14a 15b 16a 19a
182 1b,2b 6a 7b/8b/9b 11 d 14a 15b 16a 19b
183 1b,2b 6a 7b/8b/9b 11 d 14a 15b 16d 19a
184 1b,2b 6a 7b/8b/9b 11 d 14a 15b 16d 19b
185 1b,2b 6a 7b/8b/9b 11 d 14b 15a 16a 19a
186 1b,2b 6a 7b/8b/9b 11 d 14b 15a 16a 19b
187 1b,2b 6a 7b/8b/9b 11 d 14b 15a 16d 19a
188 1b,2b 6a 7b/8b/9b 11 d 14b 15a 16d 19b
189 1b,2b 6a 7b/8b/9b 11 d 14b 15b 16a 19a No. R1A/R1B "A" ring R2 R3 m "B" ring R4 n
190 1b,2b 6a 7b/8b/9b 11 d 14b 15b 16a 19b
191 1b,2b 6a 7b/8b/9b 11 d 14b 15b 16d 19a
192 1b,2b 6a 7b/8b/9b 11 d 14b 15b 16d 19b
193 1b,2b 6b 7a 11a 14a 15a 16a 19a
194 1b,2b 6b 7a 11a 14a 15a 16a 19b
195 1b,2b 6b 7a 11a 14a 15a 16d 19a
196 1b,2b 6b 7a 11a 14a 15a 16d 19b
197 1b,2b 6b 7a 11a 14a 15b 16a 19a
198 1b,2b 6b 7a 11a 14a 15b 16a 19b
199 1b,2b 6b 7a 11a 14a 15b 16d 19a
200 1b,2b 6b 7a 11a 14a 15b 16d 19b
201 1b,2b 6b 7a 11a 14b 15a 16a 19a
202 1b,2b 6b 7a 11a 14b 15a 16a 19b
203 1b,2b 6b 7a 11a 14b 15a 16d 19a
204 1b,2b 6b 7a 11a 14b 15a 16d 19b
205 1b,2b 6b 7a 11a 14b 15b 16a 19a
206 1b,2b 6b 7a 11a 14b 15b 16a 19b
207 1b,2b 6b 7a 11a 14b 15b 16d 19a
208 1b,2b 6b 7a 11a 14b 15b 16d 19b
209 1b,2b 6b 7a 11 d 14a 15a 16a 19a
210 1b,2b 6b 7a 11 d 14a 15a 16a 19b
211 1b,2b 6b 7a 11 d 14a 15a 16d 19a
212 1b,2b 6b 7a 11 d 14a 15a 16d 19b
213 1b,2b 6b 7a 11 d 14a 15b 16a 19a
214 1b,2b 6b 7a 11 d 14a 15b 16a 19b
215 1b,2b 6b 7a 11 d 14a 15b 16d 19a
216 1b,2b 6b 7a 11 d 14a 15b 16d 19b
217 1b,2b 6b 7a 11 d 14b 15a 16a 19a
218 1b,2b 6b 7a 11 d 14b 15a 16a 19b
219 1b,2b 6b 7a 11 d 14b 15a 16d 19a
220 1b,2b 6b 7a 11 d 14b 15a 16d 19b
221 1b,2b 6b 7a 11 d 14b 15b 16a 19a
222 1b,2b 6b 7a 11 d 14b 15b 16a 19b
223 1b,2b 6b 7a 11 d 14b 15b 16d 19a
224 1b,2b 6b 7a 11 d 14b 15b 16d 19b
225 1b,2b 6b 7b/8b/9b 11a 14a 15a 16a 19a
226 1b,2b 6b 7b/8b/9b 11a 14a 15a 16a 19b
227 1b,2b 6b 7b/8b/9b 11a 14a 15a 16d 19a
228 1b,2b 6b 7b/8b/9b 11a 14a 15a 16d 19b
229 1b,2b 6b 7b/8b/9b 11a 14a 15b 16a 19a
230 1b,2b 6b 7b/8b/9b 11a 14a 15b 16a 19b
231 1b,2b 6b 7b/8b/9b 11a 14a 15b 16d 19a
232 1b,2b 6b 7b/8b/9b 11a 14a 15b 16d 19b
233 1b,2b 6b 7b/8b/9b 11a 14b 15a 16a 19a
234 1b,2b 6b 7b/8b/9b 11a 14b 15a 16a 19b
235 1b,2b 6b 7b/8b/9b 11a 14b 15a 16d 19a
236 1b,2b 6b 7b/8b/9b 11a 14b 15a 16d 19b
237 1b,2b 6b 7b/8b/9b 11a 14b 15b 16a 19a
238 1b,2b 6b 7b/8b/9b 11a 14b 15b 16a 19b
239 1b,2b 6b 7b/8b/9b 11a 14b 15b 16d 19a
240 1b,2b 6b 7b/8b/9b 11a 14b 15b 16d 19b
241 1b,2b 6b 7b/8b/9b 11 d 14a 15a 16a 19a No. R1A/R1B "A" ring R2 R3 m "B" ring R4 n
242 1b,2b 6b 7b/8b/9b 11 d 14a 15a 16a 19b
243 1b,2b 6b 7b/8b/9b 11 d 14a 15a 16d 19a
244 1b,2b 6b 7b/8b/9b 11 d 14a 15a 16d 19b
245 1b,2b 6b 7b/8b/9b 11 d 14a 15b 16a 19a
246 1b,2b 6b 7b/8b/9b 11 d 14a 15b 16a 19b
247 1b,2b 6b 7b/8b/9b 11 d 14a 15b 16d 19a
248 1b,2b 6b 7b/8b/9b 11 d 14a 15b 16d 19b
249 1b,2b 6b 7b/8b/9b 11 d 14b 15a 16a 19a
250 1b,2b 6b 7b/8b/9b 11 d 14b 15a 16a 19b
251 1b,2b 6b 7b/8b/9b 11 d 14b 15a 16d 19a
252 1b,2b 6b 7b/8b/9b 11 d 14b 15a 16d 19b
253 1b,2b 6b 7b/8b/9b 11 d 14b 15b 16a 19a
254 1b,2b 6b 7b/8b/9b 11 d 14b 15b 16a 19b
255 1b,2b 6b 7b/8b/9b 11 d 14b 15b 16d 19a
256 1b,2b 6b 7b/8b/9b 11 d 14b 15b 16d 19b
257 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19a
258 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19b
259 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19a
260 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19b
261 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19a
262 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19b
263 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19a
264 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19b
265 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19a
266 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19b
267 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19a
268 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19b
269 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19a
270 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19b
271 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19a
272 1c/1f,2c/2d/2e 6a 7b/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19b
273 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19a
274 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19b
275 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19a
276 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19b
277 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19a
278 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19b
279 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19a
280 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19b
281 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19a
282 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19b
283 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19a
284 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19b
285 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19a
286 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19b
287 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19a
288 1c/1f,2c/2d/2e 6a 7b/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19b
289 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19a
290 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19b
291 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19a
292 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19b
293 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19a No. R1A/R1B "A" ring R2 R3 m "B" ring R4 n
294 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19b
295 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19a
296 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19b
297 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19a
298 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19b
299 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19a
300 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19b
301 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19a
302 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19b
303 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19a
304 1c/1f,2c/2d/2e 6a 7f/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19b
305 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19a
306 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19b
307 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19a
308 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19b
309 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19a
310 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19b
311 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19a
312 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19b
313 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19a
314 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19b
315 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19a
316 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19b
317 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19a
318 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19b
319 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19a
320 1c/1f,2c/2d/2e 6a 7f/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19b
321 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19a
322 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19b
323 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19a
324 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19b
325 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19a
326 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19b
327 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19a
328 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19b
329 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19a
330 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19b
331 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19a
332 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19b
333 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19a
334 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19b
335 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19a
336 1c/1f,2c/2d/2e 6b 7b/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19b
337 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19a
338 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19b
339 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19a
340 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19b
341 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19a
342 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19b
343 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19a
344 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19b
345 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19a No. R1A/R1B "A" ring R2 R3 m "B" ring R4 n
346 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19b
347 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19a
348 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19b
349 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19a
350 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19b
351 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19a
352 1c/1f,2c/2d/2e 6b 7b/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19b
353 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19a
354 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19b
355 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19a
356 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19b
357 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19a
358 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19b
359 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19a
360 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19b
361 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19a
362 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19b
363 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19a
364 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19b
365 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19a
366 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19b
367 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19a
368 1c/1f,2c/2d/2e 6b 7f/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19b
369 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19a
370 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19b
371 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19a
372 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19b
373 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19a
374 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19b
375 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19a
376 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19b
377 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19a
378 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19b
379 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19a
380 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19b
381 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19a
382 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19b
383 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19a
384 1c/1f,2c/2d/2e 6b 7f/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19b
385 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19a
386 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19b
387 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19a
388 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19b
389 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19a
390 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19b
391 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19a
392 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19b
393 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19a
394 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19b
395 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19a
396 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19b
397 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19a No. R1A/R1B "A" ring R2 R3 m "B" ring R4 n
398 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19b
399 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19a
400 5a/5b/5c 6a 7b/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19b
401 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19a
402 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19b
403 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19a
404 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19b
405 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19a
406 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19b
407 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19a
408 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19b
409 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19a
410 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19b
411 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19a
412 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19b
413 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19a
414 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19b
415 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19a
416 5a/5b/5c 6a 7b/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19b
417 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19a
418 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19b
419 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19a
420 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19b
421 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19a
422 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19b
423 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19a
424 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19b
425 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19a
426 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19b
427 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19a
428 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19b
429 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19a
430 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19b
431 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19a
432 5a/5b/5c 6a 7f/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19b
433 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19a
434 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19b
435 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19a
436 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19b
437 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19a
438 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19b
439 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19a
440 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19b
441 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19a
442 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19b
443 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19a
444 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19b
445 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19a
446 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19b
447 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19a
448 5a/5b/5c 6a 7f/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19b
449 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19a No. R1A/R1B "A" ring R2 R3 m "B" ring R4 n
450 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19b
451 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19a
452 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19b
453 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19a
454 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19b
455 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19a
456 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19b
457 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19a
458 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19b
459 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19a
460 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19b
461 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19a
462 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19b
463 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19a
464 5a/5b/5c 6b 7b/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19b
465 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19a
466 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19b
467 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19a
468 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19b
469 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19a
470 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19b
471 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19a
472 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19b
473 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19a
474 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19b
475 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19a
476 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19b
477 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19a
478 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19b
479 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19a
480 5a/5b/5c 6b 7b/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19b
481 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19a
482 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14a 15a 16b/17b/18b 19b
483 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19a
484 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14a 15a 16c/17c/18c 19b
485 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19a
486 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14a 15b 16b/17b/18b 19b
487 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19a
488 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14a 15b 16c/17c/18c 19b
489 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19a
490 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14b 15a 16b/17b/18b 19b
491 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19a
492 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14b 15a 16c/17c/18c 19b
493 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19a
494 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14b 15b 16b/17b/18b 19b
495 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19a
496 5a/5b/5c 6b 7f/8b/9b 11b/12b/13b 14b 15b 16c/17c/18c 19b
497 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19a
498 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14a 15a 16b/17b/18b 19b
499 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19a
500 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14a 15a 16c/17c/18c 19b
501 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19a No. R1A/R1B "A" ring R2 R3 m "B" ring R4 n
502 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14a 15b 16b/17b/18b 19b
503 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19a
504 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14a 15b 16c/17c/18c 19b
505 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19a
506 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14b 15a 16b/17b/18b 19b
507 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19a
508 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14b 15a 16c/17c/18c 19b
509 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19a
510 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14b 15b 16b/17b/18b 19b
511 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19a
512 5a/5b/5c 6b 7f/8b/9b 11c/12c/13c 14b 15b 16c/17c/18c 19b
513 1a,2a 6a 7g 11a 14a 15a 16a 19a
514 1a,2a 6a 7g 11a 14a 15a 16a 19b
515 1a,2a 6a 7g 11a 14a 15a 16d 19a
516 1a,2a 6a 7g 11a 14a 15a 16d 19b
517 1a,2a 6a 7g 11a 14a 15b 16a 19a
518 1a,2a 6a 7g 11a 14a 15b 16a 19b
519 1a,2a 6a 7g 11a 14a 15b 16d 19a
520 1a,2a 6a 7g 11a 14a 15b 16d 19b
521 1a,2a 6a 7g 11a 14b 15a 16a 19a
522 1a,2a 6a 7g 11a 14b 15a 16a 19b
523 1a,2a 6a 7g 11a 14b 15a 16d 19a
524 1a,2a 6a 7g 11a 14b 15a 16d 19b
525 1a,2a 6a 7g 11a 14b 15b 16a 19a
526 1a,2a 6a 7g 11a 14b 15b 16a 19b
527 1a,2a 6a 7g 11a 14b 15b 16d 19a
528 1a,2a 6a 7g 11a 14b 15b 16d 19b
529 1a,2a 6a 7g 11 d 14a 15a 16a 19a
530 1a,2a 6a 7g 11 d 14a 15a 16a 19b
531 1a,2a 6a 7g 11 d 14a 15a 16d 19a
532 1a,2a 6a 7g 11 d 14a 15a 16d 19b
533 1a,2a 6a 7g 11 d 14a 15b 16a 19a
534 1a,2a 6a 7g 11 d 14a 15b 16a 19b
535 1a,2a 6a 7g 11 d 14a 15b 16d 19a
536 1a,2a 6a 7g 11 d 14a 15b 16d 19b
537 1a,2a 6a 7g 11 d 14b 15a 16a 19a
538 1a,2a 6a 7g 11 d 14b 15a 16a 19b
539 1a,2a 6a 7g 11 d 14b 15a 16d 19a
540 1a,2a 6a 7g 11 d 14b 15a 16d 19b
541 1a,2a 6a 7g 11 d 14b 15b 16a 19a
542 1a,2a 6a 7g 11 d 14b 15b 16a 19b
543 1a,2a 6a 7g 11 d 14b 15b 16d 19a
544 1a,2a 6a 7g 11 d 14b 15b 16d 19b
545 1a,2a 6b 7g 11a 14a 15a 16a 19a
546 1a,2a 6b 7g 11a 14a 15a 16a 19b
547 1a,2a 6b 7g 11a 14a 15a 16d 19a
548 1a,2a 6b 7g 11a 14a 15a 16d 19b
549 1a,2a 6b 7g 11a 14a 15b 16a 19a
550 1a,2a 6b 7g 11a 14a 15b 16a 19b
551 1a,2a 6b 7g 11a 14a 15b 16d 19a
552 1a,2a 6b 7g 11a 14a 15b 16d 19b
553 1a,2a 6b 7g 11a 14b 15a 16a 19a No. R1A/R1B "A" ring R2 R3 m "B" ring R4 n
554 1a,2a 6b 7g 11a 14b 15a 16a 19b
555 1a,2a 6b 7g 11a 14b 15a 16d 19a
556 1a,2a 6b 7g 11a 14b 15a 16d 19b
557 1a,2a 6b 7g 11a 14b 15b 16a 19a
558 1a,2a 6b 7g 11a 14b 15b 16a 19b
559 1a,2a 6b 7g 11a 14b 15b 16d 19a
560 1a,2a 6b 7g 11a 14b 15b 16d 19b
561 1a,2a 6b 7g 11 d 14a 15a 16a 19a
562 1a,2a 6b 7g 11 d 14a 15a 16a 19b
563 1a,2a 6b 7g 11 d 14a 15a 16d 19a
564 1a,2a 6b 7g 11 d 14a 15a 16d 19b
565 1a,2a 6b 7g 11 d 14a 15b 16a 19a
566 1a,2a 6b 7g 11 d 14a 15b 16a 19b
567 1a,2a 6b 7g 11 d 14a 15b 16d 19a
568 1a,2a 6b 7g 11 d 14a 15b 16d 19b
569 1a,2a 6b 7g 11 d 14b 15a 16a 19a
570 1a,2a 6b 7g 11 d 14b 15a 16a 19b
571 1a,2a 6b 7g 11 d 14b 15a 16d 19a
572 1a,2a 6b 7g 11 d 14b 15a 16d 19b
573 1a,2a 6b 7g 11 d 14b 15b 16a 19a
574 1a,2a 6b 7g 11 d 14b 15b 16a 19b
575 1a,2a 6b 7g 11 d 14b 15b 16d 19a
576 1a,2a 6b 7g 11 d 14b 15b 16d 19b
577 1b,2b 6a 7g 11a 14a 15a 16a 19a
578 1b,2b 6a 7g 11a 14a 15a 16a 19b
579 1b,2b 6a 7g 11a 14a 15a 16d 19a
580 1b,2b 6a 7g 11a 14a 15a 16d 19b
581 1b,2b 6a 7g 11a 14a 15b 16a 19a
582 1b,2b 6a 7g 11a 14a 15b 16a 19b
583 1b,2b 6a 7g 11a 14a 15b 16d 19a
584 1b,2b 6a 7g 11a 14a 15b 16d 19b
585 1b,2b 6a 7g 11a 14b 15a 16a 19a
586 1b,2b 6a 7g 11a 14b 15a 16a 19b
587 1b,2b 6a 7g 11a 14b 15a 16d 19a
588 1b,2b 6a 7g 11a 14b 15a 16d 19b
589 1b,2b 6a 7g 11a 14b 15b 16a 19a
590 1b,2b 6a 7g 11a 14b 15b 16a 19b
591 1b,2b 6a 7g 11a 14b 15b 16d 19a
592 1b,2b 6a 7g 11a 14b 15b 16d 19b
593 1b,2b 6a 7g 11 d 14a 15a 16a 19a
594 1b,2b 6a 7g 11 d 14a 15a 16a 19b
595 1b,2b 6a 7g 11 d 14a 15a 16d 19a
596 1b,2b 6a 7g 11 d 14a 15a 16d 19b
597 1b,2b 6a 7g 11 d 14a 15b 16a 19a
598 1b,2b 6a 7g 11 d 14a 15b 16a 19b
599 1b,2b 6a 7g 11 d 14a 15b 16d 19a
600 1b,2b 6a 7g 11 d 14a 15b 16d 19b
601 1b,2b 6a 7g 11 d 14b 15a 16a 19a
602 1b,2b 6a 7g 11 d 14b 15a 16a 19b
603 1b,2b 6a 7g 11 d 14b 15a 16d 19a
604 1b,2b 6a 7g 11 d 14b 15a 16d 19b
605 1b,2b 6a 7g 11 d 14b 15b 16a 19a No. R1A/R1B "A" ring R2 R3 m "B" ring R4 n
606 1b,2b 6a 7g 11 d 14b 15b 16a 19b
607 1b,2b 6a 7g 11 d 14b 15b 16d 19a
608 1b,2b 6a 7g 11 d 14b 15b 16d 19b
609 1b,2b 6b 7g 11a 14a 15a 16a 19a
610 1b,2b 6b 7g 11a 14a 15a 16a 19b
611 1b,2b 6b 7g 11a 14a 15a 16d 19a
612 1b,2b 6b 7g 11a 14a 15a 16d 19b
613 1b,2b 6b 7g 11a 14a 15b 16a 19a
614 1b,2b 6b 7g 11a 14a 15b 16a 19b
615 1b,2b 6b 7g 11a 14a 15b 16d 19a
616 1b,2b 6b 7g 11a 14a 15b 16d 19b
617 1b,2b 6b 7g 11a 14b 15a 16a 19a
618 1b,2b 6b 7g 11a 14b 15a 16a 19b
619 1b,2b 6b 7g 11a 14b 15a 16d 19a
620 1b,2b 6b 7g 11a 14b 15a 16d 19b
621 1b,2b 6b 7g 11a 14b 15b 16a 19a
622 1b,2b 6b 7g 11a 14b 15b 16a 19b
623 1b,2b 6b 7g 11a 14b 15b 16d 19a
624 1b,2b 6b 7g 11a 14b 15b 16d 19b
625 1b,2b 6b 7g 11 d 14a 15a 16a 19a
626 1b,2b 6b 7g 11 d 14a 15a 16a 19b
627 1b,2b 6b 7g 11 d 14a 15a 16d 19a
628 1b,2b 6b 7g 11 d 14a 15a 16d 19b
629 1b,2b 6b 7g 11 d 14a 15b 16a 19a
630 1b,2b 6b 7g 11 d 14a 15b 16a 19b
631 1b,2b 6b 7g 11 d 14a 15b 16d 19a
632 1b,2b 6b 7g 11 d 14a 15b 16d 19b
633 1b,2b 6b 7g 11 d 14b 15a 16a 19a
634 1b,2b 6b 7g 11 d 14b 15a 16a 19b
635 1b,2b 6b 7g 11 d 14b 15a 16d 19a
636 1b,2b 6b 7g 11 d 14b 15a 16d 19b
637 1b,2b 6b 7g 11 d 14b 15b 16a 19a
638 1b,2b 6b 7g 11 d 14b 15b 16a 19b
639 1b,2b 6b 7g 11 d 14b 15b 16d 19a
640 1b,2b 6b 7g 11 d 14b 15b 16d 19b
[0072] As noted above, the R2 substituent can be disposed on the ring system denoted by "A" in a variety of regiochemical relationships with respect to the thienylcarbonyl. In certain embodiments of the compounds as otherwise described herein, including each of the compounds of the table above, the regiochemistry of the R2 substituent is selected from one of the following:
(10a) the ring system denoted by "A" is a six-membered ring, and wherein the R2 is disposed in a 1 ,4 relationship with respect to the thienylcarbonyl.
(10b) the R2 is disposed in a 1 ,3 relationship with respect to the thienylcarbonyl.
(1 Oc) the R2 is disposed in a 1 ,2 relationship with respect to the thienylcarbonyl. [0073] In certain embodiments of the compounds as otherwise described herein, including applicable compounds of the table above, the compound has one of the structural formulae below:
Figure imgf000036_0001
Figure imgf000037_0001
[0074] In certain embodiments of the compounds as otherwise described herein, including the compounds of embodiments 1 -640 of the table above, each and every "optionally substituted" alkyl, alkylene, alkenyl is unsubstituted or fluorinated. For example, in certain such embodiments, each and every "optionally substituted" alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene is unsubstituted.
[0075] In certain embodiments of the compounds as otherwise described herein, including the compounds of embodiments 1 -640 of the table above, none of the R1A, R1 B, R1C, R1 D, R2A, R2B, R3, R3A, R3B, R4, R4A and R4B substituents is an alkynyl. In certain embodiments of the compounds as otherwise described herein, including the compounds of embodiments 1 -640 of the table above, none of the R1A, R1 B, R1 C, R1 D, R2A, R2B, R3, R3A, R3B, R4, R4A and R4B substituents is an alkenyl or an alkynyl.
[0076] Certain particular compounds according to the disclosure are provided in more detail below with respect to the Examples.
[0077] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, a carbon atom that is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, which are well known to those in the art. Additionally, enantiomers can be characterized by the manner in which a solution of the compound rotates a plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-) isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
[0078] In certain situations, the compounds of the disclosure may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates, chiral non-racemic or diastereomers Such compounds can therefore be produced as individual stereoisomers (e.g., in the case of a single asymmetric center, (R)- or (S)-stereoisomers) or as mixtures thereof. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPLC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereomers via chromatography, and removing the resolving agent to generate the original compound in enantiomerically enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of a compound. Unless otherwise indicated, the specification and claims is intended to include both individual enantiomers as well as mixtures, racemic or otherwise, thereof.
[0079] Certain compounds of this disclosure may exhibit the phenomena of tautomerism and/or structural isomerism. For example, certain compounds described herein may adopt an E or a Z configuration about a carbon-carbon double bond or they may be a mixture of E and Z. The disclosure encompasses any tautomeric or structural isomeric form and mixtures thereof. Accordingly, when the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include the cis, trans, Z- and E- configurations. Likewise, all tautomeric forms are also intended to be included.
[0080] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biologic assays.
[0081] The disclosure also provides pharmaceutically-acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salt" refers to those salts that retain the biological effectiveness of the parent compound. Such salts include: (1) acid addition salt which is obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid, or malonic acid and the like, preferably hydrochloric acid or (L)-malic acid; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Accordingly, pharmaceutically acceptable salts of the compounds of the present disclosure include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, perchloric, and nitric or salts of organic acids such as formic, citric, malic (e.g., (D)- or (L)-), maleic, fumaric, tartaric, succinic, malonic acetic, lactic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, ehanolammonium, diethanolammonium, triethanolammonium, tromethammonium, N-methyl glucammonium, and ammonium. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable salts. The disclosure also encompasses prodrugs of the compounds of the present disclosure. Those skilled in the art will recognize various synthetic methodologies, which may be employed to prepare pharmaceutically acceptable salts and prodrugs of the compounds encompassed by the present disclosure.
[0082] The disclosure also provides solvates and hydrates of the compounds and salts described herein. The term "solvate" means a physical association of a compound as described here with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution- phase and isolatable solvates. Exemplary solvates include ehanolates, methanolates, and the like. "Hydrate" is a solvate in which the solvent molecule(s) is/are H20.
[0083] The compounds of the disclosure can be prepared by one skilled in the art based only on knowledge of the compound's chemical structure, based on the description provided herein. The chemistry for the preparation of the compounds of this disclosure is known to those skilled in the art based on the description provided herein. In fact, there may be more than one process to prepare particular compounds of the disclosure. Specific examples of methods of preparation can be found herein and in the art.
Definitions
[0084] The definitions and explanations below are for the terms as used throughout this entire document, including both the specification and the claims.
[0085] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" includes a mixture of two or more compounds. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.
[0086] The symbol "-" in general represents a bond between two atoms in the chain. Thus CH3-0-CH2-CH(Ri)-CH3 represents a 2-substituted-1-methoxypropane compound. In addition, the symbol "-" represents the point of attachment of the substituent to a compound. Thus for example -C(0)-(Ci-C4 alkyl) indicates an acyl group attached to the rest of the compound via the carbonyl.
[0087] Where multiple substituents are indicated as being attached to a structure, it is to be understood that the substituents can be the same or different. Thus for example "Rm optionally substituted with 1 , 2 or 3 Rq groups" indicates that Rm is substituted with 1 , 2, or 3 Rq groups where the Rq groups can be the same or different.
[0088] The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substituent is independent of the other.
[0089] As used herein, the terms "halogen" or "halo" indicate fluorine, chlorine, bromine, or iodine. In certain embodiments of the compound as otherwise described herein, each "halogen" or "halo" is fluorine or chlorine.
[0090] The term "heteroatom" means nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
[0091] The term "alkyl", as used herein alone or as part of a larger moiety, refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert- butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, and the like. "C1-C4 alkyl" indicates that the alkyl group has 1-4 carbon atoms.
[0092] The term "alkenyl", as used herein alone or as part of a larger moiety, refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight chain and branched chain groups having at least one carbon-carbon double bond. "Ci-C4 alkenyl" indicates that the alkenyl group has 1-4 carbon atoms. An alkyenyl need not be attached to the rest of the molecule through a double-bonded carbon; buten-1-yl, buten-2-yl, buten-3-yl and buten-4-yl are all considered to be a C4 alkenyl.
[0093] The term "alkynyl", as used herein alone or as part of a larger moiety, refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight chain and branched chain groups having at least one carbon-carbon triple bond. "C1-C4 alkynyl" indicates that the alkynyl group has 1-4 carbon atoms. An alkynyl need not be attached to the rest of the molecule through a triple-bonded carbon; butyn-1-yl, butyn-3-yl and butyn-4-yl are all considered to be a C4 alkynyl.
[0094] The term "alkoxy", as used herein alone or as part of a larger moiety, represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.
[0095] The term "heteroaryl", as used herein alone or as part of a larger moiety, refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, pyridinyl, furanyl, thienyl, pyrazinyl, pyrimidyl, pyridazinyl, imidazolyl, thiazolyl, isoxazolyl, oxazolyl, isothiazolyl, pyrrolyl and pyrazolyl.
[0096] As used herein, "GSK3, SK and/or tubulin-related disorder", "GSK3, SK and/or tubulin-driven disorder", and "abnormal GSK3, SK and/or tubulin activity" all refer to a condition characterized by inappropriate, i.e., under or, more commonly, over, GSK3, SK and/or tubulin activity. Inappropriate catalytic activity can arise as the result of either: (1) GSK3 and/or SK expression in cells that normally do not express GSK3 or SK, (2) increased GSK3 and/or SK catalytic activity leading to unwanted cellular process, such as, without limitation, cell proliferation, gene regulation, resistance to apoptosis, and/or differentiation. Such changes in GSK3, SK and/or tubulin expression may occur by increased expression of GSK3, SK and/or tubulin and/or mutation of GSK3, SK and/or tubulin such that its activity is enhanced, (3) decreased GSK3, SK and/or tubulin activity leading to unwanted reductions in cellular processes. Some examples of GSK3, SK and/or tubulin-related disorders, without limitation, are described elsewhere in this application.
[0097] The term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts.
[0098] The term "modulation" or "modulating" refers to the alteration of the activity of GSK3, SK and/or tubulin and/or other proteins. In particular, modulating refers to the activation or, preferably, inhibition of GSK3, SK and/or tubulin activity, depending on the concentration of the compound or salt to which GSK3, SK and/or tubulin is exposed. [0099] The term "catalytic activity" as used herein refers to the rate of phosphorylation of a protein under the influence of GSK3, or sphingosine under the influence of a SK.
[00100] The term "contacting" as used herein refers to bringing a compound of this disclosure and GSK3, SK and/or tubulin together in such a manner that the compound can affect the activity of GSK3, SK and/or tubulin, either directly, i.e., by interacting with GSK3, SK and/or tubulin itself, or indirectly, i.e., by altering the intracellular localization of GSK3, SK and/or tubulin. Such "contacting" can be accomplished in vitro, i.e. in a test tube, a Petri dish or the like. In a test tube, contacting may involve only a compound and GSK3, SK and/or tubulin or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment. In this context, the ability of a particular compound to affect a GSK3, SK and/or tubulin-related disorder can be determined before the use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, multiple methods exist, and are well-known to those skilled in the art, to allow contact of the compounds with GSK3, SK and/or tubulin including, but not limited to, direct cell microinjection and numerous techniques for promoting the movement of compounds across a biological membrane.
[00101] The term "in vitro" as used herein refers to procedures performed in an artificial environment, such as for example, without limitation, in a test tube or cell culture system. The skilled artisan will understand that, for example, an isolated GSK3 or SK enzyme may be contacted with a modulator in an in vitro environment. Alternatively, an isolated cell may be contacted with a modulator in an in vitro environment.
[00102] The term "in vivo" as used herein refers to procedures performed within a living organism such as, without limitation, a human, mouse, rat, rabbit, bovine, equine, porcine, canine, feline, or primate.
[00103] The term "IC5o" or "50% inhibitory concentration" as used herein refers to the concentration of a compound that reduces a biological process by 50%. These processes can include, but are not limited to, enzymatic reactions, i.e. inhibition of GSK3 or SK catalytic activity, or cellular properties, i.e. cell proliferation or apoptosis.
[00104] As used herein, "administer" or "administration" refers to the delivery of a compound or salt of the present disclosure or of a pharmaceutical composition containing a compound or salt of this disclosure to an organism for the purpose of prevention or treatment of an GSK3, SK and/or tubulin-related disorder.
[00105] As used herein, the terms "prevent", "preventing" and "prevention" refer to a method for barring an organism from acquiring a GSK3, SK and/or tubulin-related disorder. [00106] As used herein, the terms "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a GSK3, SK and/or tubulin-mediated disorder and/or its attendant symptoms.
[00107] The term "organism" refers to any living entity comprised of at least one cell. A living organism can be as simple as, for example, a single eukaryotic cell or as complex as a mammal. In a preferred aspect of this disclosure, the organism is a mammal. In a particularly preferred aspect of this disclosure, the mammal is a human being.
[00108] A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
[00109] As used herein, the term a "physiologically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. Typically, this includes those properties and/or substances that are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
[00110] An "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Example, without limitations, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.
[00111] The term "therapeutically effective amount" as used herein refers to that amount of the compound being administered that is effective to reduce or lessen at least one symptom of the disease being treated or to reduce or delay onset of one or more clinical markers or symptoms of the disease. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount that has the effect of: (1) reducing the size of the tumor, (2) inhibiting, i.e. slowing to some extent, preferably stopping, tumor metastasis, (3) inhibiting, i.e. slowing to some extent, preferably stopping, tumor growth, and/or (4) relieving to some extent, preferably eliminating, one or more symptoms associated with the cancer.
[00112] The compounds of this disclosure may also act as a prodrug. The term "prodrug" refers to an agent which is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present disclosure which is administered as an ester (the "prodrug"), carbamate or urea.
[00113] The compounds of this disclosure may also be metabolized by enzymes in the body of the organism, such as a human being, to generate a metabolite that can modulate the activity of GSK3, SK and/or tubulin. Such metabolites are within the scope of the present disclosure.
Pharmaceutical Formulations and Dosage Forms
[00114] The pharmaceutical compositions described herein generally comprise a combination of a compound, salt, hydrate or solvate as described herein and a pharmaceutically acceptable carrier, diluent, or excipient. Such compositions are substantially free of non-pharmaceutically acceptable components, i.e. , contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application. In some embodiments of this aspect, if the compound is dissolved or suspended in water, the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient. In other embodiments, the pharmaceutical compositions described herein are solid pharmaceutical compositions (e.g. , tablet, capsules, etc.).
[00115] These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g. , by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g. , intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. [00116] Also, pharmaceutical compositions can contain, as the active ingredient, one or more of the compounds described herein above in combination with one or more pharmaceutically acceptable carriers. In making the compositions described herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
[00117] In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
[00118] In preparing a formulation, the active compound can be prepared as a spray-dried dispersion, which is a single-phase, amorphous molecular dispension of the drug in a polymer matrix, prepared by dissolving the drug and polymer in an organic solvent and then spray- drying the solution. Some examples of suitable polymers include vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, polyethylene-polypropylene glycol and hypromellose acetate succinate.
[00119] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
[00120] The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg, more usually about 10 to about 200 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
[00121] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
[00122] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of a compound described herein.
[00123] The tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
[00124] The liquid forms in which the compounds and compositions can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
[00125] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
[00126] The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
[00127] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 1 1 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
[00128] The therapeutic dosage of the compounds can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound , the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g. , hydrophobicity), and the route of administration. For example, the compounds described herein can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. Combination Therapy
[00129] One or more additional pharmaceutical agents for treatment methods such as, for example, anti-inflammatory agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g. , IL2, GM-CSF, etc.), and/or tyrosine kinase inhibitors can be used in combination with the compounds and pharmaceutical compositions described herein for treatment of GSK3, SK and/or tubulin related disorders or conditions (as noted above) or for enhancing the effectiveness of the treatment of a disease state or condition, such as cancer. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
[00130] Therapeutic agents that constitute the standard of care for a particular cancer type or inflammatory disease are expected to benefit when combined with GSK3, SK and/or tubulin inhibitors of the present disclosure. For example, for the case of tumors, is it preferable that the tumor is sensitive to the cytotoxic effects of the chemotherapeutic agent that will be enhanced by addition of GSK3, SK and/or tubulin inhibitors to the combination treatment. A person of skill in the art will know how to select such chemotherapeutic agent based on the clinical characteristics and known sensitivity of each tumor to different antineoplastic agents.
[00131] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
[00132] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.
[00133] Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide. [00134] Other cytotoxic agents include navelbene, CPT-1 1 , anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.
[00135] Also suitable are cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cis-platin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; signal transduction inhibitors; and haematopoietic growth factors.
[00136] Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4,4-1 BB and PD-1 , or antibodies to cytokines (IL-10, TGF-β, etc.).
[00137] Other anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2, CCR4 and CCR6.
[00138] Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.
[00139] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
[00140] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature.
Indications
[00141] The disclosure also provides methods for treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of a hyperproliferative disease, an inflammatory disease, an angiogenic disease, a neurologic disease or a psychiatric disorder, which includes administration of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment or prevention.
[00142] One preferred hyperproliferative disease which the compounds of the disclosure are useful in treating or preventing is cancer, including as non-limiting examples thereof solid tumors such as head and neck cancers, lung cancers, gastrointestinal tract cancers, breast cancers, gynecologic cancers, testicular cancers, urinary tract cancers, neurological cancers, endocrine cancers, skin cancers, sarcomas, mediastinal cancers, retroperitoneal cancers, cardiovascular cancers, mastocytosis, carcinosarcomas, cylindroma, dental cancers, esthesioneuroblastoma, urachal cancer, Merkel cell carcinoma and paragangliomas, and hematopoietic cancers such as Hodgkin lymphoma, non-Hodgkin lymphoma, chronic leukemias, acute leukemias, myeloproliferative cancers, plasma cell dyscrasias, and myelodysplasia syndromes. The foregoing list is by way of example, and is not intended to be exhaustive or limiting.
[00143] Other preferred diseases which can be treated or prevented with the compounds of the disclosure include inflammatory diseases, such as inter alia inflammatory bowel disease, arthritis, atherosclerosis, asthma, allergy, inflammatory kidney disease, circulatory shock, multiple sclerosis, chronic obstructive pulmonary disease, skin inflammation, periodontal disease, psoriasis and T cell-mediated diseases of immunity, including allergic encephalomyelitis, allergic neuritis, transplant allograft rejection, graft versus host disease, myocarditis, thyroiditis, nephritis, systemic lupus erthematosus, and insulin-dependent diabetes mellitus.
[00144] Other preferred diseases which can be treated or prevented with the compounds of the disclosure include angiogenic diseases, such as diabetic retinopathy, arthritis, psoriasis, Kaposi's sarcoma, hemangiomas, myocardial angiogenesis, atherscelortic plaque neovascularization, and ocular angiogenic diseases such as choroidal neovascularization, retinopathy of prematurity (retrolental fibroplasias), macular degeneration, corneal graft rejection, rubeosis, neuroscular glacoma and Oster Webber syndrome.
[00145] Other preferred diseases which can be treated or prevented with the compounds of the disclosure include neurologic and psychiatric diseases, such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinsons disease, Huntington's disease, stroke, traumatic brain injury, bipolar disorder, schizophrenia, anxiety and depression. GSK3 and SK, whose catalytic activity is modulated by representative compounds and compositions of this disclosure, are key enzymes involved in signaling pathways that are abnormally activated in a variety of diseases. The following discussion outlines the roles of GSK3, SK and/or microtubules in hyperproliferative, inflammatory, angiogenic diseases and neurologic diseases, and consequently provides examples of uses of the compounds and compositions of this disclosure. The use of these compounds and compositions for the prevention and/or treatment of additional diseases in which GSK3, SK and/or microtubules are abnormally active are also within the scope of the present disclosure.
Hyperproliferative Diseases
[00146] The present disclosure relates to compounds, pharmaceutical compositions and methods useful for the treatment and/or prevention of hyperproliferative diseases. More specifically, the disclosure relates to compounds and pharmaceutical compositions that inhibit the activity of GSK3, SK and/or tubulin for the treatment and/or prevention of hyperproliferative diseases, such as cancer, psoriasis, mesangial cell proliferative disorders, atherosclerosis and restenosis. The following discussion demonstrates the role of GSKs, SKs and/or microtubules in several of these hyperproliferative diseases. Since the same processes are involved in the above listed diseases, the compounds, pharmaceutical compositions and methods of this disclosure will be useful for the treatment and/or prevention of a variety of diseases.
[00147] Cellular hyperproliferation is a characteristic of a variety of diseases, including, without limitation, cancer, psoriasis, mesangial cell proliferative disorders, atherosclerosis and restenosis. Therefore, the compounds, pharmaceutical compositions and methods of this disclosure will be useful for the prevention and/or treatment of cancer, including solid tumors, hematopoietic cancers and tumor metastases. Such cancers may include, without limitation, solid tumors such as head and neck cancers, lung cancers, gastrointestinal tract cancers, breast cancers, gynecologic cancers, testicular cancers, urinary tract cancers, neurological cancers, endocrine cancers, skin cancers, sarcomas, mediastinal cancers, retroperitoneal cancers, cardiovascular cancers, mastocytosis, carcinosarcomas, cylindroma, dental cancers, esthesioneuroblastoma, urachal cancer, Merkel cell carcinoma and paragangliomas. Additionally, such cancers may include, without limitation, hematopoietic cancers such as Hodgkin lymphoma, non-Hodgkin lymphoma, chronic leukemias, acute leukemias, myeloproliferative cancers, plasma cell dyscrasias, and myelodysplasia syndromes.
[00148] Psoriasis is a common chronic disfiguring skin disease that is characterized by well-demarcated, red, hardened and scaly plaques that may be limited or widespread. While the disease is rarely fatal, it has serious detrimental effects on the quality of life of the patient, and this is further complicated by the lack of effective therapies. There is therefore a large unmet need for effective and safe drugs for this condition. Psoriasis is characterized by local keratinocyte hyperproliferation, T cell-mediated inflammation and by localized angiogenesis. Abnormal activation of GSK3, SK and/or tubulin has been implicated in all of these processes. Therefore, GSK3, SK and/or tubulin inhibitors are expected to be of use in the therapy of psoriasis.
[00149] Mesangial cell hyperproliferative disorders refer to disorders brought about by the abnormal hyperproliferation of mesangial cells in the kidney. Mesangial hyperproliferative disorders include various human renal diseases such as glomerulonephritis, diabetic nephropathy, and malignant nephrosclerosis, as well as such disorders such as thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies. As the hyperproliferation of mesangial cells is induced by growth factors whose action is dependent on increased signaling through GSK3, SK and/or tubulin, the GSK3, SK and/or tubulin inhibitory compounds, pharmaceutical compositions and methods of this disclosure are expected to be of use in the therapy of these mesangial cell hyperproliferative disorders. [00150] In addition to inflammatory processes discussed below, atherosclerosis and restenosis are characterized by hyperproliferation of vascular smooth muscle cells at the sites of the lesions. As the hyperproliferation of vascular smooth muscle cells is induced by growth factors whose action is dependent of increased signaling through GSK3, SK and/or tubulin , the GSK3, SK and/or tubulin inhibitory compounds, pharmaceutical compositions and methods of this disclosure are expected to be of use in the therapy of these vascular disorders.
Inflammatory Diseases
[00151] The present disclosure also relates to compounds, pharmaceutical compositions and methods useful for the treatment and/or prevention of inflammatory diseases. More specifically, the disclosure relates to compounds and pharmaceutical compositions that inhibit the activity of GSK3, SK and/or tubulin for the treatment and/or prevention of inflammatory diseases, such as inflammatory bowel disease, arthritis, atherosclerosis, asthma, allergy, inflammatory kidney disease, circulatory shock, multiple sclerosis, chronic obstructive pulmonary disease, skin inflammation, periodontal disease, psoriasis and T cell-mediated diseases of immunity, including allergic encephalomyelitis, allergic neuritis, transplant allograft rejection, graft versus host disease, myocarditis, thyroiditis, nephritis, systemic lupus erthematosus, and insulin-dependent diabetes mellitus. The following discussion demonstrates the role of GSK3 and/or SK in several of these inflammatory diseases. Since the same processes are involved in the above listed diseases, the compounds, pharmaceutical compositions and methods of this disclosure will be useful for the treatment and/or prevention of a variety of diseases.
[00152] Inflammatory bowel disease (I BD) encompasses a group of disorders characterized by pathological inflammation of the lower intestine. Crohn's disease and ulcerative colitis are the best-known forms of IBD. As the processes involved in IBDs are induced by cytokines and growth factors whose action is dependent on increased signaling through GSK3 and/or SK, the GSK3 and/or SK inhibitory compounds, pharmaceutical compositions and methods of this disclosure are expected to be of use in the therapy of IBDs.
[00153] Rheumatoid arthritis (RA) is a chronic, systemic disease that is characterized by synovial hyperplasia, massive cellular infiltration, erosion of the cartilage and bone, and an abnormal immune response. The early phase of rheumatic inflammation is characterized by leukocyte infiltration into tissues, especially by neutrophils. In the case of RA, this occurs primarily in joints where leukocyte infiltration results in synovitis and synovium thickening producing the typical symptoms of warmth, redness, swelling and pain. As the disease progresses, the aberrant collection of cells invade and destroy the cartilage and bone within the joint leading to deformities and chronic pain. The inflammatory cytokines TNFa, IL-1 β and IL-8 act as critical mediators of this infiltration, and these cytokines are present in the synovial fluid of patients with RA.
[00154] Inflammation is involved in a variety of skin disorders, including psoriasis, atopic dermatitis, contact sensitivity and acne. Since the inflammatory responses typically involve aberrant activation of signaling pathways detailed above, it is likely that the compounds, pharmaceutical compositions and methods of this disclosure will also be useful for the treatment of these skin diseases.
Angiogenic Diseases
[00155] The present disclosure also relates to compounds, pharmaceutical compositions and methods useful for the treatment and/or prevention of diseases that involve undesired angiogenesis. More specifically, the disclosure relates to the use of chemical compounds and compositions that inhibit the activity of GSK3, SK and/or tubulin for the treatment and/or prevention of angiogenic diseases, such as diabetic retinopathy, arthritis, cancer, psoriasis, Kaposi's sarcoma, hemangiomas, myocardial angiogenesis, atherscelortic plaque neovascularization, and ocular angiogenic diseases such as choroidal neovascularization, retinopathy of prematurity (retrolental fibroplasias), macular degeneration, corneal graft rejection, rubeosis, neuroscular glacoma and Oster Webber syndrome. The following discussion demonstrates the role of GSK3, SK and/or tubulin in several of these angiogenic diseases. Since the same processes are involved in the above listed diseases, the compounds, pharmaceutical compositions and methods of this disclosure will be useful for the treatment and/or prevention of a variety of diseases.
[00156] Angiogenesis refers to the state in the body in which various growth factors or other stimuli promote the formation of new blood vessels. As discussed below, this process is critical to the pathology of a variety of diseases. In each case, excessive angiogenesis allows the progression of the disease and/or the produces undesired effects in the patient. Since conserved biochemical mechanisms regulate the proliferation of vascular endothelial cells that form these new blood vessels, i.e. neovascularization, identification of methods to inhibit these mechanisms are expected to have utility for the treatment and/or prevention of a variety of diseases.
Neurologic Diseases
[00157] In Alzheimer's disease, GSK3 has been demonstrated to promote every major pathological process, including amyloid β peptide production and tau phosphorylation which lead to the two hallmark pathologies of Alzheimer's disease, amyloid plaques and neurofibrillary tangles, respectively. In addition, long-term treatment with several different GSK3 inhibitors had remarkably strong effects in protecting mice from developing hind limb paralysis in the mouse multiple sclerosis model, and even initiating treatment with GSK3 inhibitors only after disease onset reversed the clinical symptoms of the disease in mouse models. Along these lines, GSK3 inhibitors have been shown to prolong motor neuron survival and suppress disease progression in amyotrophic lateral sclerosis.
[00158] The relation that GSK3 inhibitors may counteract neuronal loss in Parkinson's disease was first raised by the finding that GSK3 inhibitors reduced apoptosis induced by molecules modeling Parkinson's neurotoxicity. Subsequent studies have further strengthened the potential therapeutic benefits of GSK3 inhibitors in several models of Parkinson's disease. Also in regards to neuronal protection, growing evidence has also demonstrated that GSK3 inhibitors are effective in mouse models of Huntington's disease, stroke, and traumatic brain injury. Additionally, SKs play important roles in pathologic neuroinflammation involved in many neurologic diseases.
[00159] There is growing evidence that GSK3 and/or SK inhibitors may contribute to therapies for psychiatric disorders. Patients with bipolar disorder are already being effectively treated with lithium, which is a GSK3 inhibitor. Although the therapeutic mechanism of action of lithium remains to be definitively determined, substantial evidence indicates that inhibition of GSK3 is an important component of lithium's mood stabilizing capacity. Growing evidence also exists that GSK3 and/or SK inhibitors, working through mechanisms, at least in part, involved with brain derived neurotrophic factors, contribute to therapies for schizophrenia, anxiety and depression.
EXAMPLES
[00160] The present disclosure may be better understood with reference to the following examples. These examples are intended to be representative of specific embodiments of the disclosure, and are not intended as limiting the scope of the disclosure.
[00161] Representative compounds of the disclosure include those in Table 1 . Certain of these compounds do not fall within the scope of certain embodiments as described above, but are provided nonetheless for comparative purposes. IC50 values are provided in units of μΜ for murine pancreatic cancer cells of the cell line PAN02. Table 1. Representative compounds of the disclosure.
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
General Chemistry Methods
[00162] Unless otherwise noted, all reagents and solvents were purchased from commercial sources and used without further purification. The 1 H NMR spectra were obtained using a Bruker 400 MHz, Varian 400 MHz or 500 MHz spectrometer. All 1 H NMR spectra are reported in δ units ppm and are referenced to tetramethylsilane (TMS) if conducted in CDCI3 or to the central line of the quintet at 2.49 ppm for samples in DMSO-d6. Coupling constants (J values) are reported in Hz. Column chromatography was typically performed on silica gel (Merck, grade 60, 230-400 mesh) or utilizing a CombiFlash Sg 100c separation system (ISCO) with Luknova disposable silica gel columns (ISCO).
Example 1. General Synthesis of Substituted 4-amino-2-phenylamino-thiazol-5-yl)- phenyl-methanones.
Figure imgf000065_0001
[00163] At 0 °C, a mixture of a phenyl-isothiocyanate (1 mmol) and cyanamide (1 mmol) in tetrahydrofuran (4 mL) is treated with sodium methoxide (1 mmol) for 30 min. A phenacyl bromide (1 .0 mmol) is then added, and the suspension is stirred for approximately 12 h. The solvent is removed, and the semisolid residue is typically triturated with water to give the crude product, which is filtered and dried in a vacuum oven (typically at 50 °C for 2 h) . The dried crude product is typically recrystallized from EtOAc : Hexane (1 :3) , which provides a yield of approximately 50% of the corresponding 4-amino-2-phenylamino-thiazol-5-yl)-phenyl- methanone. Specific examples follow.
Example 2. Synthesis of Substituted 4-amino-2-phenylamino-thiazol-5-yl)-phenyl- methanones.
[00164] The methods described in Example 1 were used to prepare a library of substituted 4-amino-2-phenylamino-thiazol-5-yl)-phenyl-methanones. Data provided below include the melting point (mp) of the compound, mass spectral (MS) data for the compound, and/or NMR spectral data for the compound.
[00165] Compound 1 : (4-Amino-2-phenylamino-thiazol-5-yl)-phenyl-methanone. mp: 186- 188 °C (acetone). 1 H NMR (500 MHz, Acetone-d6) δ 9.715 (s, 1 H, NH), 7.732-7.748 (d, J= 8 Hz, 2H), 7.644-7.660 (d, J= 8 Hz, 2H), 7.448-7.500 (m, 3H), 7.356-7.388 (t, J = 8Hz, 2H), 7.098-7.127 (t, J = 7.5 Hz, 1 H) ; MS m/z (rel intensity) 296.00 (M+, 100), 297.00(35), 298.00 (15). [00166] Compound 2: (4-Amino-2-phenylamino-thiazol-5-yl)-(4-chloro-phenyl)-methanone. mp: 203-205 °C (acetone). 1 H NMR (500 MHz, Acetone-de) δ 9.785 (s, 1 H, NH), 7.769-7.786 (d, J= 8.5Hz, 2H), 7.662-7.678 (d, J= 8Hz, 2H), 7.51 1 -7.527 (d, J=8.0 Hz, 2H),7.382-7.414 (t, J=8.0 Hz, 2H), 7.129-7.159 (t, J = 7.5 Hz, 1 H); MS m/z (rel intensity) 330.03 (M+, 100), 331 .02 (30), 332.02 (50).
[00167] Compound 3: (4-Amino-2-phenylamino-thiazol-5-yl)-(4-bromo-phenyl)- methanone. mp: 210-212 °C (acetone). 1 H NMR (500 MHz, Acetone-de) δ 9.786 (s, 1 H, NH), 7.670-7.723 (m, 5H), 7.390-7.417 (m, 3H), 7.137-7.152 (t, J = 12 Hz, 1 H); MS m/z (rel intensity) 373.86 (M+, 98), 374.86 (45), 375.88 (98).
[00168] Compound 4: (4-Amino-2-phenylamino-thiazol-5-yl)-(4-nitro-phenyl)-methanone. mp: 219-221 °C (acetone). 1 H NMR (500 MHz, Acetone-de) δ 9.855 (s, 1 H, NH), 8.351 -8.366 (d, J= 7.5Hz, 2H), 7.987-8.002 (d, J= 7.5Hz, 2H), 7.669-7.680 (m, 2H), 7.398-7.452 (t, J=7.0 Hz, 2H), 7.154-7.179 (t, J = 6.0 Hz, 1 H); MS m/z (rel intensity) 340.99 (M+, 100), 341 .98 (35), 342.98 (15).
[00169] Compound 5: 4-(4-Amino-2-phenylamino-thiazole-5-carbonyl)-benzonitrile. mp: 240-242 °C (acetone). 1 H NMR (500 MHz, DMSO-de) δ 10.926 (s, 1 H, NH), 8.189-8.459 (s(br), 2H, NH2), 7.942-7.958 (d, J = 8 Hz, 2H), 7.810-7.826 (d, J = 8 Hz, 2H), 7.598-7.614 (d, J= 8 Hz, 2H), 7.361 -7.393 (t, J = 8 Hz, 2H), 7.101-7.130 (t, J = 7.25 Hz, 1 H); MS m/z (rel intensity) 320.99 (M+, 100), 321 .99 (18).
[00170] Compound 6: (4-Amino-2-phenylamino-thiazol-5-yl)-(3,4-dimethoxy-phenyl)- methanone. mp: 218-220 °C (acetone). 1 H NMR (500 MHz, Acetone-de) δ 9.741 (s, 1 H, NH), 7.679-7.695 (d, J = 8 Hz, 2H), 7.405-7.412 (m, 2H), 7.376-7.392 (d, J = 8 Hz, 2H), 7.1 12-7.141 (t, J = 7 Hz, 1 H), 7.013-7.029 (d, J = 8 Hz, 1 H); 3.883-3.888 (s,s, 6H, 20CH3); MS m/z (rel intensity) 355.86 (M+, 100), 356.84 (45), 357.84 (15).
[00171] Compound 7: [4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-phenyl-methanone. mp: 217-218 °C (acetone). 1 H NMR (500 MHz, Acetone-de) δ 9.809 (s, 1 H, NH), 7.721 -7.772 (m, 4H), 7.472-7.518 (m, 3H), 7.384-7.415 (m, 2H); MS m/z (rel intensity) 329.93 (M+, 100), 330.88 (80), 331 .87 (90).
[00172] Compound 8: [4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-fluoro-phenyl)- methanone. mp: 217-219 °C (acetone). 1 H NMR (500 MHz, DMSO-de) δ 10.894 (s, 1 H, NH), 8.226 (s(br), 2H, NH2), 7.735-7.762 (t, J = 8.5 Hz, 2H), 7.658-7.675 (d, J = 8.5 Hz, 2H), 7.407- 7.424 (d, J= 8.5 Hz, 2H), 7.290-7.324 (t, J = 8.5 Hz, 2H); MS m/z (rel intensity) 347.85 (M+, 100), 348.85 (15). [00173] Compound 9: [4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-chloro-phenyl)- methanone. mp: 242-244 °C (acetone). 1 H NMR (500 MHz, Acetone-d6) δ 9.89 (s, 1 H, NH), 7.77-7.79 (d, J = 10 Hz, 2H), 7.23-7.43 (d, J = 10 Hz, 2H), 7.52-7.54 (d, J = 10 Hz, 2H), 7.41 - 7.51 (d, J = 10 Hz, 2H); MS m/z (rel intensity) 363.83 (M+, 100), 364.81 (40), 365.82 (70).
[00174] Compound 10: [4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-bromo-phenyl)- methanone. mp: 240-242 °C (acetone). 1 H NMR (500 MHz, Acetone-d6) δ 9.877 (s, 1 H, NH), 7.672-7.745 (m, 6H), 7.396-7.414 (d, J = 9 Hz, 2H); MS m/z (rel intensity) 407.74 (M+, 98), 408.73 (60), 409.73 (M+, 100), 410.72 (45).
[00175] Compound 11. [4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-nitro-phenyl)- methanone. mp: 262-263 °C (acetone). 1 H NMR (500 MHz, Acetone-d6) δ 9.948 (s, 1 H, NH), 8.347-8.365 (d, J = 9 Hz, 2H), 7.982-8.000 (d, J = 9 Hz, 2H), 7.726-7.744 (d, J = 9 Hz, 2H), 7.402-7.420 (d, J = 9 Hz, 2H); MS m/z (rel intensity) 374.78 (M+, 100), 375.77 (40), 376.77 (60).
[00176] Compound 12. 4-[4-Amino-2-(4-chloro-phenylamino)-thiazole-5-carbonyl]- benzonitrile. mp: 273-274 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 9.948 (s, 1 H, NH), 8.179-8.369 (s(br), 2H, NH2), 7.948-7.964 (d, J = 8 Hz, 2H), 7.813-7.829 (d, J = 8 Hz, 2H), 7.651 -7.669 (d, J= 9 Hz, 2H), 7.415-7.433 (d, J = 9 Hz, 2H); MS m/z (rel intensity) 354.86 (M+, 40), 355.84 (10).
[00177] Compound 13: [4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(3,4-dimethoxy- phenyl)-methanone. mp: 243-245 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 9.801 (s, 1 H, NH), 7.739-7.756 (d, J = 8.5 Hz, 2H), 7.378-7.414 (m, 4H), 7.017-7.034 (d, J = 8.5 Hz, 1 H), 3.893 (s, 3H, OCH3), 3.888 (s, 3H, OCH3); MS m/z (rel intensity) 389.70 (M+, 100), 390.69 (50), 391 .68 (60).
[00178] Compound 14: [4-Amino-2-(4-fluoro-phenylamino)-thiazol-5-yl]-phenyl- methanone. mp: 200-202 °C (acetone). 1 H NMR (500 MHz, Acetone-d6) δ 9.693 (s, 1 H, NH), 7.746-7.761 (d, J = 7.5 Hz, 2H), 7.696-7.719 (m, 2H), 7.462-7.507 (m, 3H), 7.153-7.182 (m, 2H), 2.808 (s, 2H, NH2); MS m/z (rel intensity) 313.97 (M+, 100), 314.90 (75), 315.90 (35).
[00179] Compound 15: [4-Amino-2-(4-fluoro-phenylamino)-thiazol-5-yl]-(4-chloro-phenyl)- methanone. mp: 230-232 °C (acetone). 1 H NMR (500 MHz, Acetone-d6) δ 9.75 (s, 1 H, NH), 7.763-7.777 (d, J = 7 Hz, 2H), 7.700-7.723 (m, 2H), 7.51 1 -7.525 (d, J = 7 Hz, 2H), 7.162-7.188 (m, 2H), 2.804 (s, 2H, NH2); MS m/z (rel intensity) 347.89 (M+, 100), 348.87 (35), 349.87 (50).
[00180] Compound 16: [4-Amino-2-(4-fluoro-phenylamino)-thiazol-5-yl]-(4-bromo-phenyl)- methanone. mp: 241 -243 °C (acetone). 1 H NMR (500 MHz, Acetone-d6) δ 9.30 (s, 1 H, NH), 7.666-7.723 (m, 6H), 7.159-7.188 (t, J = 7.5 Hz, 2H), 2.769 (s, 2H, NH2); MS m/z (rel intensity) 391 .69 (M+, 100), 392.67 (45), 393.61 (98).
[00181] Compound 17: [4-Amino-2-(4-fluoro-phenylamino)-thiazol-5-yl]-(4-nitro-phenyl)- methanone. mp: 254-256 °C (acetone). 1 H NMR (500 MHz, Acetone-d6) δ 9.975 (s, 1 H, NH), 8.348-8.366 (d, J = 9 Hz, 2H), 7.982-7.999 (d, J = 8.5 Hz, 2H), 7.727-7.744 (d, J = 8.5 Hz, 2H), 7.403-7.420 (d, J = 8.5 Hz, 2H); MS m/z (rel intensity) 358.93 (M+, 100), 359.93 (30).
[00182] Compound 18: 4-[4-Amino-2-(4-fluoro-phenylamino)-thiazole-5-carbonyl]- benzonitrile. mp: 257-259 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 9.948 (s, 1 H, NH), 8.169-8.409 (s(br), 2H, NH2), 7.940-7.957 (d, J = 8.5 Hz, 2H), 7.802-7.819 (d, J = 8.5 Hz, 2H), 7.597-7.512 (m, 2H), 7.203-7.239 (t, J = 8.5 Hz, 2H); MS m/z (rel intensity) 338.94 (M+, 100), 339.93 (25).
[00183] Compound 19: [4-Amino-2-(4-fluoro-phenylamino)-thiazol-5-yl]-(3,4-dimethoxy- phenyl)-methanone. mp: 263-265 °C (acetone). 1 H NMR (500 MHz, Acetone-d6) δ 8.163 (s, 1 H, NH), 7.712-7.735 (m, 2H), 7.373-7.402 (m, 2H), 7.153-7.182 (t, J = 7 Hz, 2H), 7.01 1 - 7.025 (d, J = 7 Hz, 1 H), 4.306-4.323 (s(br), 2H, NH2), 3.890 (s, 3H, OCH3), 3.885 (s, 3H, OCHs); MS m/z (rel intensity) 373.89 (M+, 100), 374.88 (30).
[00184] Compound 20. (4-Amino-2-p-tolylamino-thiazol-5-yl)-phenyl-methanone. mp: 150- 152 °C (methanol). 1 H NMR (500 MHz, Acetone-d6) δ 9.62 (s, 1 H, NH), 7.41 -7.757 (d, J = 8 Hz, 2H), 7.47-7.530 (m, 5H), 7.200-7.216 (d, J = 8 Hz, 2H), 2.795 (s, 2H, NH2) 2.324 (s, 3H, CH3); MS m/z (rel intensity) 309.92 (M+, 100), 310.92 (45), 31 1 .91 (15).
[00185] Compound 21 : (4-Amino-2-p-tolylamino-thiazol-5-yl)-(4-fluoro-phenyl)- methanone. mp: 186-188 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 9.948 (s, 1 H, NH), 8.063-8.379 (s(br), 2H, NH2), 7.715-7.744 (t, J = 7 Hz, 2H), 7.464-7.480 (d, J = 8 Hz, 2H), 7.277-7.312 (t, J = 8 Hz, 2H), 7.169-7.186 (d, J = 8.5 Hz, 2H), 2.281 (s, 3H, CH3); MS m/z (rel intensity) 327.98 (M+, 100), 328.94 (50).
[00186] Compound 22: (4-Amino-2-m-tolylamino-thiazol-5-yl)-(3-chloro-phenyl)- methanone. mp: 202-204 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.738 (s, 1 H, NH), 8.258 (s (br), 2H, NH2), 7.672 (s, 1 H, Ar-H), 7.629-7.644 (d, J = 7.5 Hz, 1 H), 7.567-7.584 (d, J = 8.5 Hz, 1 H), 7.503-7.534 (t, J = 7.5 Hz, 1 H), 7.437-7.453 (d, J = 8 Hz, 1 H), 7.405 (s, 1 H), 7.239-7.271 (t, J = 8 Hz, 1 H), 6.922-6.937(d, J = 7.5 Hz, 1 H), 2.317 (s, 3H, CH3); MS m/z (rel intensity) 343.94 (M+, 100), 344.94 (20), 345.94 (30).
[00187] Compound 23: (4-Amino-2-p-tolylamino-thiazol-5-yl)-(3-chloro-phenyl)- methanone. mp: 206-208 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.727 (s, 1 H, NH), 8.263 (s (br), 2H, NH2), 7.663 (s, 1 H, Ar-H), 7.615-7.633 (d, J = 9 Hz, 1 H), 7.559-7.577 (d, J = 9 Hz, 1 H), 7.512-7.28 (d, J = 8 Hz, 1 H), 7.480-7.497 (d, J = 8.5 Hz, 2H), 7.174-7.190 (d, J = 8 Hz, 2H), 2.286 (s, 3H, CH3); MS m/z (rel intensity) 343.82 (M+, 100), 344.81 (35), 345.81 (55).
[00188] Compound 24: (4-Amino-2-m-tolylamino-thiazol-5-yl)-(4-chloro-phenyl)- methanone. mp: 183-185 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.733 (s, 1 H, NH), 8.227 (s (br), 2H, NH2), 7.690-7.707 (d, J = 8.5 Hz, 2H), 7.539-7.556 (d, J = 8.5 Hz, 2H), 7.728- 7.445 (d, J = 8.5 Hz, 1 H), 7.393 (s, 1 H), 7.238-7.270 (t, J = 8 Hz, 1 H), 6.922-6.937 (d, J = 7.5 Hz, 1 H), 2.316 (s, 3H, CH3); MS m/z (rel intensity) 343.89 (M+, 100), 344.88 (25), 345.88 (35).
[00189] Compound 25: (4-Amino-2-p-tolylamino-thiazol-5-yl)-(4-chloro-phenyl)- methanone. mp: 202-204 °C (methanol). 1 H NMR (500 MHz, Acetone-de) δ 9.70 (s, 1 H, NH), 7.756-7.773 (d, J = 8 Hz, 2H), 7.504-7.530 (m, 4H), 7.206-7.222 (d, J = 8 Hz, 2H), 2.795 (s, 2H, NH2), 2.328 (s, 3H, CH3); MS m/z (rel intensity) 343.93 (M+, 100), 344.87 (65), 345.87 (75).
[00190] Compound 26: (4-Amino-2-p-tolylamino-thiazol-5-yl)-(3,4-dichloro-phenyl)- methanone. mp: 177-179 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.770 (s, 1 H, NH), 8.274 (s (br), 2H, NH2), 7.860 (s, 1 H, Ar-H), 7.745-7.762 (d, J = 8.5 Hz, 1 H), 7.640-7.657 (d, J = 8.5 Hz, 1 H), 7.481 -7.498 (d, J = 8.5 Hz, 2H), 7.176-7.193 (d, J = 8.5 Hz, 2H), 2.288 (s, 3H, CH3); MS m/z (rel intensity) 377.86 (M+, 100), 378.88 (40), 379.84 (85).
[00191] Compound 27: (4-Amino-2-p-tolylamino-thiazol-5-yl)-(4-bromo-phenyl)- methanone. mp: 196-98 °C (methanol). 1 H NMR (600 MHz, Acetone-de) δ 9.70 (s, 1 H, NH), 7.66-7.70 (d, d, J = 8.4 Hz, 4H), 7.513-7.527 (d, J = 8.4 Hz, 2H), 7.206-7.220 (d, J = 8.4 Hz, 2H), 2.328 (s, 3H, CH3); MS m/z (rel intensity) 387.81 (M+, 98), 388.81 (95), 389.81 (M+, 100),
390.79 (45).
[00192] Compound 28: (4-Amino-2-p-tolylamino-thiazol-5-yl)-(4-nitro-phenyl)-methanone. mp: 124-126 °C (acetone). 1 H NMR (500 MHz, Acetone-de) δ 9.748 (s, 1 H, NH), 8.337-8.351 (d, J = 7 Hz, 2H), 7.967-7.984 (d, J = 7 Hz, 2H), 7.510-7.527 (d, J = 8.5 Hz, 2H), 7.213-7.230 (d, J = 8.5 Hz, 2H), 2.330 (s, 3H, CH3); MS m/z (rel intensity) 354.85 (M+, 100), 355.84 (30).
[00193] Compound 29: 3-(4-Amino-2-m-tolylamino-thiazole-5-carbonyl)-benzonitrile. mp: 96-98 °C (methanol). 1 H NMR (500 MHz, DMSO-de) δ 10.773 (s, 1 H, NH), 8.300 (s (br), 2H, NH2), 8.072 (s, 1 H, Ar-H), 7.963-7.992 (t, J = 7.5 Hz, 2H), 7.688-7.719 (d, J = 7.5 Hz, 1 H), 7.435-7.452 (d, J = 8.5 Hz, 1 H), 7.404 (s, 1 H), 7.242-7.274 (t, J = 8 Hz, 1 H), 6.927-6.942 (d, J = 7.5 Hz, 1 H), 2.318 (s, 3H, CH3); MS m/z (rel intensity) 334.80 (M+, 100), 335.80 (40),
336.80 (5). [00194] Compound 30: 3-(4-Amino-2-p-tolylamino-thiazole-5-carbonyl)-benzonitrile. Yield: 55%; mp: 229-231 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.76 (s, 1 H, NH), 8.26-8.31 (s (br), 2H, NH2), 8.06 (s, 1 H, Ar-H), 7.96-7.97 (m, 2H), 7.68-7.71 (t, J = 7.5 Hz, 1 H), 7.48-7.49 (d, J = 5 Hz, 2H), 7.18-7.19 (d, J = 5 Hz, 2H), 2.29 (s, 3H, CH3); MS m/z (rel intensity) 334.83 (M+, 100), 335.82 (30), 336.96 (15).
[00195] Compound 31 : 4-(4-Amino-2-m-tolylamino-thiazole-5-carbonyl)-benzonitrile. mp: 203-205 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.791 (s, 1 H, NH), 8.316 (s (br), 2H, NH2), 7.947-7.963 (d, J = 8 Hz, 2H), 7.814-7.830 (d, J = 8 Hz, 2H), 7.423-7.439 (d, J = 8 Hz, 1 H), 7.388 (s, 1 H, Ar-H), 7.242-7.273 (t, J = 8 Hz, 1 H), 6.932-6.947 (d, J = 7.5 Hz, 1 H), 2.316 (s, 3H, CH3); MS m/z (rel intensity) 335.01 (M+, 100), 336.01 (25).
[00196] Compound 33. (4-Amino-2-p-tolylamino-thiazol-5-yl)-pyridin-2-yl-methanone. mp: 206-208 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.663 (s, 1 H, NH), 8.950 (m, 2H, NH2), 8.678-8.668 (d, J= 5 Hz, 1 H), 8.150-8.134 (d, J = 8 Hz, 2H), 8.321 -8.001 (t, J = 5 Hz, 1 H), 7.576-7.560 (d, J = 8 Hz, 2H), 7.196-7.180 (d, J = 8 Hz, 2H), 2.295 (s, 3H, CH3); MS m/z (rel intensity) 31 1 .02 (M+ +1 , 100), 312.02 (20), 313.02(5).
[00197] Compound 34. (4-Amino-2-p-tolylamino-thiazol-5-yl)-pyridin-3-yl-methanone. mp: 238-240 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.773 (s, 1 H, NH), 8.837 (s, 1 H), 8.683-8.674 (d, J = 4.5 Hz, 1 H), 8.303 (m, 2H, NH2), 7.521 -7.475 (m, 3H), 7.195-7.178 (d, J = 8.5 Hz, 2H), 2.286 (s, 3H, CH3); MS m/z (rel intensity) 31 1 .02 (M+ +1 , 100), 312.02 (80), 313.02(30).
[00198] Compound 35: (4-Amino-2-p-tolylamino-thiazol-5-yl)-pyridin-4-yl-methanone. mp: 291 -293 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.802 (s, 1 H, NH), 8.714-8.702 (d, J = 6 Hz, 2H), 8.303 (m, 2H, NH2), 7.580-7.568 (d, J = 6 Hz, 2H), 7.485-7.468 (d, J = 8.5 Hz, 2H), 7.195-7.178. (d, J = 8.5 Hz, 2H), 2.286 (s, 3H, CH3); MS m/z (rel intensity) 31 1 .03 (M+ + 1 , 100), 312.03 (90), 313.03(30).
[00199] Compound 36: (4-Amino-2-p-tolylamino-thiazol-5-yl)-(3,4-dimethoxy-phenyl)- methanone. mp: 220-222 °C (acetone). 1 H NMR (500 MHz, Acetone-d6) δ 9.594 (s, 1 H, NH), 7.537-7.551 (d, J = 7 Hz, 2H), 7.376-7.399 (m, 2H), 7.203-7.216 (d, J = 7 Hz, 2H), 7.007-7.020 (d, J = 7 Hz, 1 H), 3.888 (s, 3H, OCH3), 3.883 (s, 3H, OCH3), 2.772 (s, 2H, NH2), 2.327 (s, 3H, CH3); MS m/z (rel intensity) 369.96 (M+, 100), 370.94 (50), 371 .94 (15).
[00200] Compound 37: 4-[4-Amino-2-(3,4-dimethyl-phenylamino)-thiazole-5-carbonyl]- benzonitrile. mp: 217-219 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.707 (s, 1 H, NH), 8.312 (s(br), 2H, NH2), 7.937-7.953 (d, J = 8 Hz, 2H), 7.798-7.814 (d, J = 8 Hz, 2H), 7.325- 7.341 (d, J = 8 Hz, 1 H), 7.304 (s, 1 H), 7.121 -7.137 (d, J = 8 Hz, 1 H), 2.222 (s, 3H, CH3), 2.197 (s, 3H, CH3); MS m/z (rel intensity) 348.97 (M+, 100), 349.97 (25), 350.97 (10). [00201] Compound 38: 3-[4-Amino-2-(3,4-dimethyl-phenylamino)-thiazole-5-carbonyl]- benzonitrile. mp: 172-174 °C (methanol).1H NMR (500 MHz, DMSO-d6) δ 10.692 (s, 1H, NH), 8.296 (s(br), 2H, NH2), 8.055(s, 1H), 7.952-7.977 (t, J = 6.3 Hz, 2H), 7.677-7.709 (t, J = 8 Hz, 1H), 7.325-7.341 (d, J = 8 Hz, 1H), 7.319 (s, 1H), 7.120-7.136 (d, J = 8 Hz, 1H), 2.224 (s, 3H, CH3), 2.196 (s, 3H, CH3); MS m/z (rel intensity) 348.97 (M+, 100), 349.97 (30), 350.96 (15).
[00202] Compound 39: [4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]-(3-chloro- phenyl)-methanone. mp: 252-254 °C (methanol).1H NMR (500 MHz, DMSO-d6) 011.150 (s, 1H, NH), 8.299 (s, 2H, NH2), 7.861-7.847 (d, J = 7 Hz, 2H), 7.726-7.712 (d, J = 7 Hz, 2H), 7.694 (s, 1H), 7.660-7.646 (d, J= 7 Hz, 1H), 7.600-7.586 (d, J= 7 Hz, 1H), 7.546-7.520 (t, J = 6.5 Hz, 1H); MS m/z (rel intensity) 397.89 (M+ , 100), 398.89(25), 399.89(50).
[00203] Compound 40.3-[4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazole-5-carbonyl]- benzonitrile. mp: 218-220 °C (methanol).1 H NMR (500 MHz, DMSO-d6) δ 11.186 (s, 1 H, NH), 8.339 (s (br), 2H, NH2), 8.102 (s, 1H, Ar-H), 7.988-8.015 (t, J = 7 Hz, 2H), 7.854-7.871 (d, J = 8.5 Hz, 2H), 7.722-7.738 (d, J = 8 Hz, 2H), 7.707 (m, 1 H); MS m/z (rel intensity) 388.88 (M+, 100), 389.86 (55).
[00204] Compound 41: 4-[4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazole-5-carbonyl]- benzonitrile. mp: 247-249 °C (methanol). 1H NMR (500 MHz, DMSO-d6) δ 11.201 (s, 1H, NH), 8.358 (s(br), 2H, NH2), 7.969-7.986 (d, J = 8.5 Hz, 2H), 7.837-7.862 (m, 4H), 7.419-7.756 (d, J= 8.5 Hz, 2H); MS m/z (rel intensity) 388.87 (M+, 100), 389.85 (70).
[00205] Compound 42: 4-[4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazole-5-carbonyl]- benzoic acid, mp: 300-302 °C (methanol). 1H NMR (500 MHz, DMSO-d6) δ 11.167 (s, 1H, NH), 8.316 (s(br), 2H, NH2), 8.047-8.033 (d, J = 7 Hz, 2H), 7.861-7.847 (d, J = 7 Hz, 2H), 7.797-7.783 (d, J= 7 Hz, 2H), 7.726-7.712 (d, J = 7 Hz, 2H); MS m/z (rel intensity) 407.88 (M+ , 100), 408.88(20), 409.87 (5).
[00206] Compound 43: [4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]-(4- dimethylamino-phenyl)-methanone. mp: 300-302 °C (methanol). 1H NMR (500 MHz, DMSO- de) δ 11.024 (s, 1H, NH), 8.068 (s(br), 2H, NH2), 7.872-7.854 (d, J = 9 Hz, 2H), 7.722-7.704 (d, J = 9 Hz, 2H), 7.660-7.642 (d, J = 9 Hz, 2H), 6.764-6.746 (d, J = 9 Hz, 2H), 3.002 (s, 6H, N(CH3)2); MS m/z (rel intensity) 406.90 (M+ , 100), 407.89(25), 408.89 (5).
[00207] Compound 44: [4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]-pyridin-3- yl-methanone. mp: 226-228 °C (methanol). 1H NMR (500 MHz, DMSO-d6) δ 11.201 (s, 1H, NH), 8.882 (s, 1H), 8.717-8.706 (d, J = 5.5 Hz, 1H), 8.351 (s(br), 2H, NH2), 8.076-8.065 (d, J = 5.5 Hz, 1H), 7.874-7.860 (d, J = 7 Hz, 2H), 7.741-7.727 (d, J = 7 Hz, 2H), 7.550-7.537 (m, 1H); MS m/z (rel intensity) 364.96 (M+ , 100), 365.96(30), 366.95 (10). [00208] Compound 45: [4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]-pyridin-4- yl-methanone. mp: >300 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 1 1 .225 (s, 1 H, NH), 8.746-8.736 (d, J = 5 Hz, 2H), 8.389 (s(br), 2H, NH2), 7.870-7.856 (d, J = 7 Hz, 2H), 7.742- 7.728 (d, J = 7 Hz, 2H), 7.617-7.607 (d, J = 5 Hz, 2H); MS m/z (rel intensity) 364.96 (M+ , 100), 365.95(40), 366.94 (10).
[00209] Compound 46: 4-[4-Amino-5-(4-fluoro-benzoyl)-thiazol-2-ylamino]-benzonitrile. mp: 292-294 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 10.048 (s, 1 H, NH), 8.238 (s(br), 2H, NH2), 7.839-7.857 (d, J= 9 Hz, 2H), 7.802-7.820 (d, J = 9 Hz, 2H), 7.753-7.778 (q, J= 8 Hz, 2H), 7.308-7.340 (t, J= 8 Hz, 2H); MS m/z (rel intensity) 338.96 (M+, 100), 339.95 (35).
[00210] Compound 47: 4-[4-Amino-5-(4-chloro-benzoyl)-thiazol-2-ylamino]-benzonitrile. mp: 293-295 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 10.048 (s, 1 H, NH), 8.273 (s(br), 2H, NH2), 7.840-7.858 (d, J = 9 Hz, 2H), 7.805-7.823 (d, J = 9 Hz, 2H), 7.709-7.726 (d, J= 8.5 Hz, 2H), 7.556-7.573 (d, J = 8.5 Hz, 2H); MS m/z (rel intensity) 354.90 (M+, 90), 355.89 (35).
[00211] Compound 48: 4-[4-Amino-5-(4-bromo-benzoyl)-thiazol-2-ylamino]-benzonitrile. mp: 293-295 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 10.048 (s, 1 H, NH), 8.276 (s(br), 2H, NH2), 7.805-7.857 (m, 4H), 7.798-7.715 (d, J = 8.5 Hz, 2H), 7.636-7.653 (d, J= 8.5 Hz, 2H); MS m/z (rel intensity) 398.75 (M+, 98), 399.74 (35), 400.75 (100), 401 .74 (20).
[00212] Compound 49: 4-[4-Amino-5-(4-cyano-benzoyl)-thiazol-2-ylamino]-benzonitrile. mp: > 300 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 9.948 (s, 1 H, NH), 8.356 (s(br), 2H, NH2), 7.962-7.979 (d, J = 8.5 Hz, 2H), 7.809-7.856 (m, 6H); MS m/z (rel intensity) 345.89 (M+, 100), 346.89 (20).
[00213] Compound 50: 4-[4-Amino-2-(4-hydroxymethyl-phenylamino)-thiazole-5- carbonyl]-benzonitrile. mp: 238-240 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.833 (s, 1 H, NH), 8.358 (s(br), 2H, NH2), 7.943-7.960 (t, J = 8.5 Hz, 2H), 7.807-7.824 (d, J = 8.5 Hz, 2H), 7.530-7.547 (d, J = 8.5 Hz, 2H), 7.324-7.307 (d, J = 8.5 Hz, 2H), 5.1 19-5.141 (t, J = 5.5 Hz, 1 H, OH), 4.463-4.474 (d, J = 5.5 Hz, 2H); MS m/z (rel intensity) 350.97 (M+, 100), 351 .97 (25), 352.96 (5).
[00214] Compound 51 : 4-[4-Amino-5-(4-cyano-benzoyl)-thiazol-2-ylamino]-benzoic acid ethyl ester, mp: 238-240 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 1 1 .198 (s, 1 H, NH), 8.353 (s(br), 2H, NH2), 7.984 (s, 1 H), 7.965-7.980 (m, 3H), 7.837-7.854 (t, J = 7.5 Hz, 2H), 7.771 -7.88 (d, J = 7.5 Hz, 2H), 4.283-4.326 (q, J = 7.5 Hz , 2H), 1 .310-1 .339 (t, J = 7.5 Hz, 3H); MS m/z (rel intensity) 392.95 (M+, 100), 393.95 (30), 394.95 (15).
[00215] Compound 52: 4-[4-Amino-5-(4-chloro-benzoyl)-thiazol-2-ylamino]-benzoic acid, mp: >300 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 1 1 .144 (s, 1 H, NH), 8.286 (m, 2H, NH2), 7.949-7.935 (d, J = 7 Hz, 2H), 7.780-7.766 (d, J = 7 Hz, 2H), 7.737-7.723 (d, J = 7 Hz, 2H), 7.580-7.566 (d, J = 7 Hz, 2H); MS m/z (rel intensity) 373.92 (M+ , 50), 374.92 (10).
[00216] Compound 53: 4-[4-Amino-5-(4-cyano-benzoyl)-thiazol-2-ylamino]-benzoic acid, mp: 262-264 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 1 1.108 (s, 1 H, COOH), 8.365 (m, 2H, NH2), 7.986-7.969 (d, J = 8.5 Hz, 2H), 7.947-7.930 (d, J = 8.5 Hz, 2H), 7.855-7.838 (d, J = 8.5 Hz, 2H), 7.74-7.757 (d, J = 8.5 Hz, 2H); MS m/z (rel intensity) 364.94 (M+ +1 , 100), 365.93 (25).
[00217] Compound 54: [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-phenyl- methanone. mp: 155-157 °C (methanol). 1 H NMR (500 MHz, Acetone-d6) δ 9.493 (s, 1 H, NH), 7.732-7.748 (d, J = 8 Hz, 2H), 7.473-7.530 (m, 5H), 6.960-6.979 (m, 2H), 3.820 (s, 3H, OCH3); MS m/z (rel intensity) 326.03 (M+, 100), 326.99 (60), 327.98 (25).
[00218] Compound 55: [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-fluoro- phenyl)-methanone. mp: 186-187 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 9.948 (s, 1 H, NH), 8.063-8.309 (s(br), 2H, NH2), 7.699-7.727 (t, J = 7 Hz, 2H), 7.463-7.479 (d, J = 8 Hz, 2H), 7.267-7.302 (t, J = 8 Hz, 2H), 6.940-6.958 (d, J = 9 Hz, 2H), 3.751 (s, 3H, OCH3); MS m/z (rel intensity) 343.81 (M+, 100), 344.81 (17).
[00219] Compound 56: [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(3-chloro- phenyl)-methanone. mp: 184-186 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.651 (s, 1 H, NH), 8.255 (s, 2H, NH2), 7.649 (s, 1 H), 7.620-7.608 (d, J = 6 Hz, 1 H), 7.571 -7.557 (d, J = 7 Hz, 1 H), 7.522 (s, 1 H), 7.509-7.486. (m, 2H), 6.968-6.953 (d, J = 7.5 Hz, 2H), 3.762 (s, 3H, OCH3); MS m/z (rel intensity) 359.86 (M+ , 100), 360.83(80), 361 .83(90).
[00220] Compound 57: [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-chloro- phenyl)-methanone. mp: 187-89 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1 H, NH), 8.24-8.26 (s (br), 2H, NH2), 7.672-7.655 (d, J = 8.5 Hz, 2H), 7.518-7.536 (d, J = 9 Hz, 2H), 7.441-7.459 (d, J = 9 Hz, 2H), 6.941 -6.959 (d, J = 9 Hz, 2H), 3.76 (s, 3H, OCH3); MS m/z (rel intensity) 359.73 (M+, 100), 369.72 (45), 361 .72 (60).
[00221] Compound 58: [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(3,4-dichloro- phenyl)-methanone. mp: 197-199 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.696 (s, 1 H, NH), 8.2765 (s(br), 2H, NH2), 7.8507 (s, 1 H), 7.757-7.743 (d, J = 7 Hz, 1 H), 7.643-7.629 (d, J = 7 Hz, 1 H), 7.508-7.495 (d, J= 6.5 Hz, 2H), 6.970-6.955 (d, J = 7.5 Hz, 2H), 3.763 (s, 3H, OCH3); MS m/z (rel intensity) 393.85 (M+ , 70), 394.85(20), 395. 85(50).
[00222] Compound 59: [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-bromo- phenyl)-methanone. mp: 172-74 °C (acetone). 1 H NMR (600 MHz, Acetone-d6) δ 9.552 (s, 1 H, NH), 7.645-7.691 (m, 4H), 7.520-7.540 (d, J = 10 Hz, 2H), 6.971 -6.991 (d, J = 10 Hz, 2H), 3.825 (s, 3H, OCH3); MS m/z (rel intensity) 403.73 (M+, 98), 404.73 (85), 405.74(M+, 100), 406.72 (60).
[00223] Compound 60: [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-nitro- phenyl)-methanone. mp: 207-209 °C (acetone). 1 H NMR (500 MHz, Acetone-d6) δ 9.638 (s, 1 H, NH), 8.326-8.344 (d, J = 9 Hz, 2H)), 7.949-7.967 (d, J = 9 Hz, 2H), 7.514-7.532 (d, J = 9 Hz, 2H), 6.970-6.988 (d, J = 9 Hz, 2H), 3.825 (s, 3H, OCH3); MS m/z (rel intensity) 370.93 (M+, 100), 369.93 (35), 371 .93 (30).
[00224] Compound 61 : 3-[4-Amino-2-(4-methoxy-phenylamino)-thiazole-5-carbonyl]- benzonitrile. mp: 184-186 °C (methanol). 1 H NMR (500 MHz, Acetone-d6) δ 10.682 (s, 1 H, NH), 8.263 (s(br), 2H, NH2), 8.040 (s, 1 H), 7.948-7.964 (d, J = 8 Hz, 2H), 7.672-7.704 (t, J = 8 Hz, 1 H), 7.478-7.494 (d, J = 8 Hz, 2H), 6.948-6.966 (d, J = 8 Hz, 2H), 3.757 (s, 3H, OCH3); MS m/z (rel intensity) 350.91 (M+, 100), 351 .89 (60), 352.89 (25).
[00225] Compound 62: 4-[4-Amino-2-(4-methoxy-phenylamino)-thiazole-5-carbonyl]- benzonitrile. mp: 263-265 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 9.948 (s, 1 H, NH), 8.173-8.189 (s(br), 2H, NH2), 7.922-7.938 (d, J = 8 Hz, 2H), 7.779-7.795 (d, J = 8 Hz, 2H), 7.471 -7.455 (d, J = 8 Hz, 2H), 6.942-6.958 (d, J = 8 Hz, 2H), 3.751 (s, 3H, OCH3); MS m/z (rel intensity) 350.91 (M+, 100), 351 .91 (25).
[00226] Compound 63: 4-[4-Amino-2-(4-methoxy-phenylamino)-thiazole-5-carbonyl]- benzoic acid, mp: 289-291 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.679 (s, 1 H, NH), 8.145 (s(br), 2H, NH2), 8.025-8.01 1 (d, J = 7 Hz, 2H), 7.754-7.740 (d, J = 7 Hz, 2H), 7.495-7.481 (d, J= 7 Hz, 2H), 6.964-6.950 (d, J = 7 Hz, 2H), 3.759 (s, 3H, OCH3); MS m/z (rel intensity) 369.96 (M+ , 15), 370.94(5).
[00227] Compound 64: [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-pyridin-3-yl- methanone. mp: 226-228 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.693 (s, 1 H, NH), 8.825 (s, 1 H), 8.674-8.664 (d, J = 5 Hz, 1 H), 8.303 (m, 2H, NH2), 8.021 -8.005 (d, J = 8 Hz, 1 H), 7.512-7.472 (m, 3H), 6.967-6.949. (d, J = 9 Hz, 2H), 3.755 (s, 3H, OCH3).
[00228] Compound 65: [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-pyridin-4-yl- methanone. mp: 262-264 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.725 (s, 1 H, NH), 8.703-8.692 (d, J = 4.5 Hz, 2H), 8.303 (m, 2H, NH2), 7.564-7.552 (d, J = 6 Hz, 2H), 7.483- 7.466 (d, J = 8.5 Hz, 2H), 6.967-6.950 (d, J = 8.5 Hz, 2H), 3.755 (s, 3H, OCH3); MS m/z (rel intensity) 326.99 (M+ +1 , 100), 327.99 (40), 328.99(10).
[00229] Compound 66: [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4- dimethylamino-phenyl)-methanone. mp: 201 -203 °C (methanol). 1 H NMR (500 MHz, DMSO- de) δ 10.468 (s, 1 H, NH), 8.032 (s(br), 2H, NH2), 7.609-7.592 (d, J = 7.5 Hz, 2H), 7.502-7.485 (d, J = 7.5 Hz, 2H), 6.960-6.942 (d, J = 9 Hz, 2H), 6.738-6.720 (d, J = 9 Hz, 2H), 3.756 (s, 3H, OCH3), 2.982 (s, 6H, N(CH3)2); MS m/z (rel intensity) 369.03 (M+ , 100), 370.03(40), 371 .02 (10).
[00230] Compound 67. [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(3,4-dimethoxy- phenyl)-methanone. mp: 189-191 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 8.04-8.08 (s (br), 2H, NH2), 7.481 -7.499 (d, J = 9 Hz, 2H), 7.27-7.29 (m, 2H), 7.012-7.029 (d, J = 5 Hz, 1 H), 6.94-6.96 (d, J = 5 Hz, 2H), 3.82 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.75 (s, 3H, OCH3); MS m/z (rel intensity) 385.87 (M+, 100), 386.87 (30), 387.86 (15).
[00231] Compound 68: [4-Amino-2-(4-trifluoromethoxy-phenylamino)-thiazol-5-yl]-(3- chloro-phenyl)-methanone. mp: 227-229 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.985 (s, 1 H, NH), 8.289 (s, 2H, NH2), 7.762-7.748 (d, J = 7 Hz, 2H), 7.689 (s, 1 H), 7.660- 7.645 (d, J = 7.5 Hz, 1 H), 7.601 -7.586 (d, J= 7.5 Hz, 1 H), 7.548-7.522 (t, J= 6.5 Hz, 1 H), 7.397- 7.383 (d, J = 7 Hz, 2H), 3.749 (s, 3H, OCH3), 3.048 (s, 6H, N(CH3)2); MS m/z (rel intensity) 413.76 (M+ , 100), 414.76(25), 415.76(35).
[00232] Compound 69: 4-[4-Amino-2-(4-trifluoromethoxy-phenylamino)-thiazole-5- carbonyl]-benzonitrile. mp: 245-247 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 1 1 .022 (s, 1 H, NH), 8.340 (s(br), 2H, NH2), 7.966-7.952 (d, J = 7 Hz, 2H), 7.834-7.820 (d, J = 7 Hz, 2H), 7.744-7.729 (d, J= 7.5 Hz, 2H), 7.386-7.371 (d, J = 7.5 Hz, 2H); MS m/z (rel intensity) 404.88 (M+ , 100), 405.88(20), 406.88 (5).
[00233] Compound 70: 4-[4-Amino-2-(4-trifluoromethoxy-phenylamino)-thiazole-5- carbonyl]-benzoic acid, mp: >300 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.998 (s, 1 H, NH), 8.302 (s(br), 2H, NH2), 8.049-8.035 (d, J = 7 Hz, 2H), 7.793-7.779 (d, J = 7 Hz, 2H), 7.760-7.745 (d, J= 7.5 Hz, 2H), 7.396-7.381 (d, J = 7.5 Hz, 2H); MS m/z (rel intensity) 423.89 (M+ , 100), 424.89(30), 425.88 (15).
[00234] Compound 71 : [4-Amino-2-(4-trifluoromethoxy-phenylamino)-thiazol-5-yl]-(4- dimethylamino-phenyl)-methanone. mp: 285-289 °C (methanol). 1 H NMR (500 MHz, DMSO- d6) δ 10.834 (s, 1 H, NH), 8.055 (s(br), 2H, NH2), 7.763-7.745 (d, J = 9 Hz, 2H), 7.646-7.629 (d, J = 8.5 Hz, 2H), 7.382-7.365 (d, J = 8.5 Hz, 2H), 6.758-6.740 (d, J = 9 Hz, 2H), 2.997 (s, 6H, N(CH3)2); MS m/z (rel intensity) 422.84 (M+ , 100), 423.83(25), 424.83 (10).
[00235] Compound 72: [4-Amino-2-(4-trifluoromethoxy-phenylamino)-thiazol-5-yl]-pyridin- 3-yl-methanone. mp: 213-215 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 1 1 .017 (s, 1 H, NH), 8.867 (s, 1 H), 8.705-8.694 (d, J = 5.5 Hz, 1 H), 8.301 (s(br), 2H, NH2), 8.063-8.050 (d, J = 6.5 Hz, 1 H), 7.760-7.745 (d, J = 7.5 Hz, 2H), 7.540-7.519 (m, 1 H), 7.400-7.385 (d, J = 7.5 Hz, 2H); MS m/z (rel intensity) 380.96 (M+ , 100), 381 .96(30), 382.94 (15). [00236] Compound 73: [4-Amino-2-(4-trifluoromethoxy-phenylamino)-thiazol-5-yl]-pyridin- 4-yl-methanone. mp: 284-286 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 1 1.048 (s, 1 H, NH), 8.732-8.720 (d, J = 6 Hz, 2H), 8.372-8.362 (s(br), 2H, NH2), 7.753-7.735 (d, J = 9 Hz, 2H), 7.600-7.588 (d, J = 6 Hz, 2H), 7.399-7.381 (d, J = 9 Hz, 2H); MS m/z (rel intensity) 380.96 (M+ , 100), 381.95(70), 382.94 (20).
[00237] Compound 74: 4-[4-Amino-5-(4-chloro-benzoyl)-thiazol-2-ylamino]- benzenesulfonamide. mp: 284-286 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 10.350 (s, 1 H, NH), 8.248 (s(br), 2H, NH2), 7.799 (s, 4H), 7.707-7.724 (d, J = 8.5 Hz, 2H), 7.554-7.571 (d, J= 8.5 Hz, 2H), 7.275 (s, 2H, SONH2); MS m/z (rel intensity) 408.76 (M+, 100), 409.75 (35), 410.75 (45).
[00238] Compound 75: 4-[4-Amino-5-(4-cyano-benzoyl)-thiazol-2-ylamino]- benzenesulfonamide. mp: 287-289 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 1 1.150 (s, 1 H, NH), 8.337 (s(br), 2H, NH2), 7.960-7.977 (d, J = 8.5 Hz, 2H), 7.830-7.847 (d, J= 8.5 Hz, 2H), 7.800 (s, 4H), 7.283 (s, 2H, SONH2); MS m/z (rel intensity) 399.70 (M+, 35), 400.71 (8).
[00239] Compound 76. 3-[4-Amino-2-(4-tert-butyl-phenylamino)-thiazole-5-carbonyl]- benzonitrile. mp: 216-218 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.793 (s, 1 H, NH), 8.278 (s(br), 2H, NH2), 8.061 (s, 1 H), 7.959-7.985 (t, J = 6.5 Hz, 2H), 7.684-7.715 (t, J = 8 Hz, 1 H), 7.491-7.508 (d, J= 8.5 Hz, 2H), 7.381-7.398 (d, J = 8.5 Hz, 2H), 1.283 (s, 9H, C(CH3)3); MS m/z (rel intensity) 376.91 (M+, 100), 377.89 (50), 378.88 (25).
[00240] Compound 77: 4-[4-Amino-2-(4-tert-butyl-phenylamino)-thiazole-5-carbonyl]- benzonitrile. mp: 271-273 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 10.840 (s, 1 H, NH), 8.298 (s(br), 2H, NH2), 7.948-7.964 (d, J = 8 Hz, 2H), 7.805-7.821 (d, J = 8 Hz, 2H), 7.477- 7.493 (d, J= 8 Hz, 2H), 7.381-7.397 (d, J = 8 Hz, 2H), 1.278 (s, 9H, C(CH3)3); MS m/z (rel intensity) 376.84 (M+, 98), 377.83 (35), 378. 80 (20).
Example 3. General Synthesis of N-acylated 4-amino-2-phenylamino-thiazol-5-yl)- henyl-methanones.
Figure imgf000076_0001
[00241] A 4-amino-2-phenylamino-thiazol-5-yl)-phenyl-methanone (0.5 mmol) is dissolved in 5 mL of anhydrous THF. An acyl-halide, for example acetyl chloride (CH3COCI; 1 M, 1 mL, 1 .0 mmol), and pyridine (0.1 mL, 1 .0 mmol) are added, and the reaction is incubated at room temperature for approximately 6 hours with stirring. When complete, the reaction mixture is mixed with 10 mL of EtOAc and washed with 10 mL of brine. After drying the organic layer using Na2S04, the reaction mixture is filtered and concentrated. The concentrated reaction mixture is then purified by recrystallization, for example from (hexane:EtOAc = 2: 1 ), to obtain the targeted N-acylated 4-amino-2-phenylamino-thiazol-5-yl)-phenyl-methanone. Specific examples follow.
Example 4. Synthesis of N-acylated 4-amino-2-phenylamino-thiazol-5-yl)-phenyl- methanones.
[00242] The methods described in Example 3 were used to prepare a library of substituted N-acylated 4-amino-2-phenylamino-thiazol-5-yl)-phenyl-methanones. Data provided below include the melting point (mp) of the compound, mass spectral (MS) data for the compound, and NMR spectral data for the compound.
[00243] Compound 78: N-[5-(3-Cyano-benzoyl)-2-p-tolylamino-thiazol-4-yl]-acetamide. mp: 264-266 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 8.1 1 (s, 1 H) , 8.02-8.05 (t, J = 7.5 Hz, 2H ), 7.98 (s, 2H) , 7.75-7.78 (t, J = 7.5 Hz, 1 H), 7.38 (s, 4H), 2.40 (s, 3H, CH3) , 1 .96 (s, 3H, CH3); MS m/z (rel intensity) 376.75 (M+, 100) , 377.74 (30), 378.74 (20).
[00244] Compound 79: N-[5-(4-Cyano-benzoyl)-2-p-tolylamino-thiazol-4-yl]-acetamide. mp: 270-272 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 8.01 -8.03 (d (br), J = 10 Hz, 4H), 7.38 (s, 4H), 2.40 (s, 3H, CH3), 1 .95 (s, 3H, CH3) ; MS m/z (rel intensity) 376.92 (M+, 85) , 377.90 (40).
[00245] Compound 80: N-[5-(3-Cyano-benzoyl)-2-p-tolylamino-thiazol-4-yl]-propionamide. mp: 235-237 °C (methanol) . 1 H NMR (500 MHz, DMSO-d6) δ 8.1 15 (s, 1 H) , 8.033-8.048 (d , J = 7.5 Hz, 2H), 7.982 (s, 2H), 7.754-7.785 (t, J = 7.5 Hz, 1 H), 7.372 (s, 4H), 2.400 (s, 3H, CH3), 2.149-2.192 (q, J = 7.3 Hz, 2H, CH2), 0.950-0.979 (t, J = 7.3 Hz, 3H, CH3) .
[00246] Compound 81 : N-[5-(4-Cyano-benzoyl)-2-p-tolylamino-thiazol-4-yl]-propionamide. mp: 248-250 °C (methanol) . 1 H NMR (500 MHz, DMSO-d6) δ 8.035 (s, 1 H) , 8.010-8.022 (d , J = 6 Hz, 2H), 7.873-7.887 (d, J = 7 Hz, 2H) , 7.377 (s, 3H) , 2.406 (s, 3H, CH3), 2.57-2.193 (q, J = 6 Hz, 2H, CH2), 0.954-0.978 (t, J = 6 Hz, 3H, CH3).
[00247] Compound 82: N-[5-(3-Cyano-benzoyl)-2-p-tolylamino-thiazol-4-yl]-acrylamide. mp: 220-222 °C (methanol). 1 H NMR (500 MHz, Acetone-d6) δ 8.133 (s, 1 H, NH), 8.046-8.061 (d, J = 7.5 Hz, 2H, H-Ar), 7.996 (s, 2H), 7.763-7.794 (t, J = 8 Hz, 1 H, H-Ar) , 6.361 -7.405 (m, 3H), 6.392-6.425 (d, J = 16.5Hz, 1 H, HC=), 5.933-5.987 (q, J = 17 Hz, 1 H, HC=), 5.846-5.867 (d, J = 10.5 Hz, 1 H, HC=) , 2.415 (s, 3H, CH3); MS m/z (rel intensity) 388.87 (M+, 75) , 389.88 (10).
[00248] Compound 83: N-[5-(4-Cyano-benzoyl)-2-p-tolylamino-thiazol-4-yl]-acrylamide. mp: 214-216 °C (methanol). 1 H NMR (500 MHz, Acetone-d6) δ 9.1 15 (s, 1 H, NH) , 8.164 (s(br) , 2H, NH2) , 8.025-8.042 (d, J = 8.5 Hz, 3H, NH, H-Ar), 7.880-7.967 (d, J = 8.5 Hz, 2H, H-Ar) , 7.356-7.402 (t, J = 8 Hz, 4H, H-Ar), 6.383-6.416 (d, J = 16 Hz, 1 H, HC=) , 5.930-5.984 (q, J = 17 Hz, 1 H, HC=), 5.841 -5.866 (d, J = 12 Hz, 1 H, HC=), 2.413 (s, 3H, CH3); MS m/z (rel intensity) 388.87 (M+ , 45), 389.87 (10) .
Example 5. General Synthesis of N-substituted 4-amino-2-phenylamino-thiazol-5-yl)- phenyl-methanones
Figure imgf000078_0001
[00249] To a stirred solution of a phenyl-isothiocyanate (2 mmol) in acetone (10 ml) at room temperature a substituted guanidine, for example tetramethylguanidine (2 mmol), is added . The mixture is stirred at room temperature for approximately 30 min, and then a phenacyl bromide (2 mmol) is added and the mixture is stirred at room temperature for approximately 12 hours. After completion of the reaction, the solvent is evaporated and the residue is recrystallized, for example from hexane/AcOEt (2: 1 ), to give an N~substituted 4-amino-2- phenylamino-thiazol-5-yl)-phenyl-methanone.
Example 6. Synthesis of N-substituted 4-amino-2-phenylamino-thiazol-5-yl)-phenyl- methanones.
[00250] The methods described in Example 5 were used to prepare a library of substituted N-substituted 4-amino-2-phenylamino-thiazol-5-yl)-phenyl-methanones. Data provided below include the melting point (mp) of the compound, mass spectral (MS) data for the compound, and NMR spectral data for the compound.
[00251] Compound 84: (4-Bromo-phenyl)-[4-dimethylamino-2-(4-fluoro-phenylamino)- thiazol-5-yl]-methanone. mp: 238-240 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 10.678 (s, 1 H, NH), 7.659-7.676 (d, J = 8.5 Hz, 2H) , 7.571 -7.614 (m, 4H), 7.189-7.224 (t, J = 8.5 Hz, 2H), 3.028 (s, 6H , 2CH3): MS m/z (rel intensity) 419.80 (M+, 100), 420.80 (25) , 421 .79 (95), 422.79 (25). [00252] Compound 85: (4-Dimethylamino-2-p-tolylamino-thiazol-5-yl)-phenyl-methanone. mp: 195-197 °C (methanol).1H NMR (500 MHz, DMSO-d6) δ 10.531 (s, 1H, NH), 7.638-7.624 (d, J = 8 Hz, 2H), 7.524-7.495 (t, J = 6.5 Hz, 1H), 7.467-7.424 (m, 4H), 7.167-7.151. (d, J = 8 Hz, 2H), 3.022 (s, 6H,N(CH3)2), 2.264 (s, 3H, CH3); MS m/z (rel intensity) 338.01 (M+ +1 , 100), 339.01 (30), 340.00(10).
[00253] Compound 86: (4-Chloro-phenyl)-(4-dimethylamino-2-p-tolylamino-thiazol-5-yl)- methanone. mp: 205-207 °C (acetone). 1H NMR (500 MHz, Acetone-d6) δ 9.475 (s, 1H, NH), 7.723-7.740 (d, J = 8.5 Hz, 2H), 7.473-7.619 (m, 4H), 7.188-7.205 (d, J = 8.5 Hz, 2H), 3.102 (s, 6H, 2CH3), 2.317 (s, 3H, CH3); MS m/z (rel intensity) 371.85 (M+, 100), 372.84 (55), 373.84 (75).
[00254] Compound 87: (4-Chloro-phenyl)-(4-dimethylamino-2-m-tolylamino-thiazol-5-yl)- methanone. mp: 174-176 °C (methanol).1H NMR (500 MHz, DMSO-d6) δ 10.598 (s, 1H, NH), 7.648-7.665 (d, J = 8.5 Hz, 2H), 7.516-7.533 (d, J = 8.5 Hz, 2H), 7.382-7.395 (m, 2H), 7.224- 7.256 (t, J = 8 Hz, 1H), 6.887-6.901 (d, J = 7 Hz, 1H), 3.031 (s, 6H, N(CH3)2), 2.300 (s, 3H, CH3); MS m/z (rel intensity) 371.91 (M+, 100), 372.091 (40), 373.90 (60).
[00255] Compound 88: (3-Chloro-phenyl)-(4-dimethylamino-2-m-tolylamino-thiazol-5-yl)- methanone. mp: 167-169 °C (methanol).1H NMR (500 MHz, DMSO-d6) δ 10.586 (s, 1H, NH), 7.609 (s, 1H), 7.574-7.590 (d, J = 8 Hz, 2H), 7.473-7.505 (t, J = 8 Hz, 1H), 7.426-7.443 (d, J = 8.5 Hz, 2H), 7.159-7.176 (d, J = 8.5 Hz, 2H), 3.044 (s, 6H, N(CH3)2), 2.269 (s, 3H, CH3); MS m/z (rel intensity) 371.89 (M+, 100), 372.88 (35), 373.88 (60).
[00256] Compound 89: (4-Bromo-phenyl)-(4-dimethylamino-2-p-tolylamino-thiazol-5-yl)- methanone. mp: 217-219 °C (acetone). 1H NMR (500 MHz, Acetone-d6) δ 9.451 (s, 1H, NH), 7.646-7.656 (m, 4H), 7.494-7.511 (d, J = 8.5 Hz, 2H), 7.188-7.205 (d, J = 8.5 Hz, 2H), 3.103 (s, 6H, 2CH3), 2.317 (s, 3H, CH3); MS m/z (rel intensity) 415.80 (M+, 98), 416.80 (25), 417.79 (100), 418.79 (25).
[00257] Compound 90: (4-Dimethylamino-2-p-tolylamino-thiazol-5-yl)-(4-nitro-phenyl)- methanone. mp: 210-212 °C (acetone). 1H NMR (500 MHz, Acetone-d6) δ 9.512 (s, 1H, NH), 8.304-8.322 (d, J = 9 Hz, 2H), 7.922-7.940 (d, J = 9 Hz, 2H), 7.795-7.512 (d, J = 8.5 Hz, 2H), 7.194-7.211 (d, J = 8.5 Hz, 2H), 3.132 (s, 6H, 2CH3), 2.318 (s, 3H, CH3); MS m/z (rel intensity) 382.96 (M+, 100), 383.95(25), 384.96 (18).
[00258] Compound 91: 3-(4-Dimethylamino-2-p-tolylamino-thiazole-5-carbonyl)- benzonitrile. mp 163-165 C 1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H, NH), 8.01 (s, 1H, Ar-H), 7.96-7.98 (d, J = 5 Hz, 1H), 7.92-7.94 (d, J = 5 Hz, 1H), 7.66-7.69 (t, J = 7.5 Hz, 1H), 7.43-7.45 (d, J = 5 Hz, 2H), 7.16-7.18 (d, J = 5 Hz, 2H), 3.04 (s, 6H, N(CH3)2), 2.27 (s, 3H, CH3); MS m/z (rel intensity) 362.95 (M+, 100), 363.93 (30), 364.93 (15). [00259] Compound 92: 3-(4-Dimethylamino-2-m-tolylamino-thiazole-5-carbonyl)- benzonitrile. mp: 145-147 °C (methanol).1H NMR (500 MHz, DMSO-d6) δ 10.647 (s, 1H, NH), 8.027 (s, 1H), 7.971-7.989 (d, J = 8 Hz, 1H), 7.933-7.949 (d, J = 8 Hz, 1H), 7.666-7.698 (t, J = 8 Hz, 1H), 7.370-7.401 (m, 2H), 7.230-7.262 (t, J = 8 Hz, 1H), 6.896-6.911 (d, J = 7.5 Hz, 1H), 3.045 (s, 6H, N(CH3)2), 2.303 (s, 3H, CH3); MS m/z (rel intensity) 362.89 (M+, 100), 363.88 (55), 364.88 (20).
[00260] Compound 93: 4-(4-Dimethylamino-2-m-tolylamino-thiazole-5-carbonyl)- benzonitrile. mp: 161-163 °C (methanol).1H NMR (500 MHz, DMSO-d6) δ 10.660 (s, 1H, NH), 7.925-7.941 (d, J = 8 Hz, 2H), 7.766-7.782 (d, J = 8 Hz, 2H), 7.379-7.393 (m, 2H), 7.228-7.260 (t, J = 8 Hz, 1H), 6.897-6.912 (d, J = 7.5 Hz, 1H), 3.042 (s, 6H, N(CH3)2), 2.300 (s, 3H, CH3); MS m/z (rel intensity) 363.00 (M+, 100), 364.00 (35), 365.00 (15).
[00261] Compound 94: 4-(4-Dimethylamino-2-p-tolylamino-thiazole-5-carbonyl)- benzonitrile. mp: 215-217 °C (acetone). 1H NMR (500 MHz, DMSO-d6) δ 10.250 (s, 1H, NH), 7.911-7.927 (d, J = 8 Hz, 2H), 7.749-7.765 (d, J = 8 Hz, 2H), 7.414-7.430 (d, J= 8 Hz, 2H), 7.158-7.174 (d, J = 8 Hz, 2H), 3.030 (s, 6H, N(CH3)2), 2.265 (s, 3H, CH3); MS m/z (rel intensity) 362.94 (M+, 100), 363.94 (25), 364.94 (10).
[00262] Compound 95: (4-Dimethylamino-2-p-tolylamino-thiazol-5-yl)-pyridin-2-yl- methanone. mp: 162-164 °C (methanol).1H NMR (500 MHz, DMSO-d6) δ 10.536 (s, 1H, NH), 8.650-8.640 (d, J = 5 Hz, 1H), 8.046-8.031 (d, J = 7.5 Hz, 1H), 7.992-7.958 (m, 1H), 7.558- 7.541. (m, 1H), 7.516-7.500 (d, J = 8 Hz, 2H), 7.178-7.162 (d, J = 8 Hz, 2H), 3.170 (s, 6H,N(CH3)2), 2.276 (s, 3H, CH3); MS m/z (rel intensity) 339.03 (M+ +1, 100), 340.03 (30), 341.03(15).
[00263] Compound 96: (4-Dimethylamino-2-p-tolylamino-thiazol-5-yl)-pyridin-3-yl- methanone. mp: 189-191 °C (methanol).1H NMR (500 MHz, DMSO-d6) δ 10.637 (s, 1H, NH), 8.785 (s, 1H), 8.890-8.680 (d, J = 5 Hz, 1H), 7.987-7.972 (d, J = 7.5 Hz, 1H), 7.505-7.480 (m, 1H), 7.446-7.430. (d, J = 8 Hz, 2H), 7.180-7.164 (d, J = 8 Hz, 2H), 3.035 (s, 6H,N(CH3)2), 2.270 (s, 3H, CH3); MS m/z (rel intensity) 339.00 (M+ +1 , 100), 340.00 (20), 341.00(8).
[00264] Compound 97: (4-Dimethylamino-2-p-tolylamino-thiazol-5-yl)-pyridin-4-yl- methanone. mp: 193-195 °C (methanol).1H NMR (500 MHz, DMSO-d6) δ 10.663 (s, 1H, NH), 8.697-8.685 (d, J = 6 Hz, 2H), 7.527-7.515 (d, J = 6 Hz, 2H), 7.436-7.420 (d, J = 8 Hz, 2H), 7.179-7.163. (d, J = 8 Hz, 2H), 3.065 (s, 6H,N(CH3)2), 2.269 (s, 3H, CH3); MS m/z (rel intensity) 338.99 (M+ +1 , 100), 339.99 (40), 340.99(10).
[00265] Compound 98: 4-[4-Dimethylamino-2-(3,4-dimethyl-phenylamino)-thiazole-5- carbonyl]-benzonitrile. mp: 199-201 °C (methanol). 1H NMR (500 MHz, DMSO-d6) δ 10.577 (s, 1H, NH), 7.917-7.933(d, J = 8 Hz, 2H), 7.752-7.768 (d, J = 8 Hz, 2H), 7.311 (s, 1H), 7.269- 7.285 (d, J = 8 Hz, 1 H), 7.105-7.121 (d, J = 8 Hz, 1 H), 3.033 (s, 6H,N(CH3)2), 2.208 (s, 3H, CH3), 2.182 (s, 3H, CH3); MS m/z (rel intensity) 376.86 (M+, 100), 377.85 (35), 378.85 (15).
[00266] Compound 99: 3-[4-Dimethylamino-2-(3,4-dimethyl-phenylamino)-thiazole-5- carbonyl]-benzonitrile. mp: 172-177 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.704 (s, 1 H, NH), 8.01 1 (s, 1 H), 7.964-7.979 (d, J = 7.5 Hz, 1 H), 7.920-7.935 (d, J = 7.5 Hz, 1 H), 7.657-7.688 (t, J = 8 Hz, 1 H), 7.321 (s, 1 H), 7.279-7.295 (d, J = 8 Hz, 1 H), 7.106-7.122 (d, J = 8 Hz, 1 H), 3.037 (s, 6H,N(CH3)2), 2.210 (s, 3H, CH3), 2.193 (s, 3H, CH3); MS m/z (rel intensity) 376.96 (M+, 100), 377.95 (35), 378.95 (15).
[00267] Compound 100: 4-[4-Dimethylamino-2-(4-trifluoromethyl-phenylamino)-thiazole-5- carbonyl]-benzoic acid, mp: 238-240 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) 5 1 1 .018 (s, 1 H, NH), 8.030-8.016 (d, J = 7 Hz, 2H), 7.822-7.808 (d, J = 7 Hz, 2H), 7.749-7.735 (d, J = 7 Hz, 2H), 7.720-7.706 (d, J = 7 Hz, 2H), 3.045 (s, 6H, N(CH3)2); MS m/z (rel intensity) 435.90 (M+ , 100), 436.90(30), 437.90 (10).
[00268] Compound 101 : 3-[4-Dimethylamino-2-(4-trifluoromethyl-phenylamino)-thiazole-5- carbonyl]-benzonitrile. mp: 184-186 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 1 1 .051 (s, 1 H, NH), 8.062(s, 1 H), 8.016-8.000 (d, J = 8 Hz, 1 H), 7.974-7.958 (d, J = 8 Hz, 1 H), 7.833- 7.816 (d, J = 8.5 Hz, 2H), 7.734-7.717 (d, J = 8.5 Hz, 2H), 7.701 -7.686 (d, J = 7.5 Hz, 1 H), 3.062 (s, 6H,N(CH3)2); MS m/z (rel intensity) 416.89 (M+, 100), 417.89 (30), 418.89(10).
[00269] Compound 102: [4-Dimethylamino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]- pyridin-3-yl-methanone. mp: 216-218 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 1 1 .081 (s, 1 H, NH), 8.826 (s, 1 H), 8.722-8.71 1 (d, J = 5.5 Hz, 1 H), 8.029-8.016 (d, J = 6.5 Hz, 1 H), 7.834-7.820 (d, J = 7 Hz, 2H), 7.736-7.722 (d, J = 7 Hz, 2H), 7.533 (m, 1 H), 3.063 (s, 6H, N(CH3)2); MS m/z (rel intensity) 392.96 (M+ , 100), 393.95(30), 394.95 (10).
[00270] Compound 103: [4-Dimethylamino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]- pyridin-4-yl-methanone. mp: 254-256 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 1 1 .073 (s, 1 H, NH), 8.728-8.718 (d, J = 5 Hz, 2H), 7.830-7.816 (d, J = 7 Hz, 2H), 7.734-7.720 (d, J = 7 Hz, 2H), 7.567-7.557 (d, J = 5 Hz, 2H), 3.094 (s, 6H, N(CH3)2); MS m/z (rel intensity) 392.96 (M+ , 100), 393.96(80), 394.95 (30).
[00271] Compound 104: 4-[4-Dimethylamino-2-(4-hydroxymethyl-phenylamino)-thiazole- 5-carbonyl]-benzonitrile. mp: 1 16-1 18 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.684 (s, 1 H, NH), 8.021 (s, 1 H), 7.970-7.984 (t, J = 8 Hz, 1 H), 7.928-7.944 (d, J = 8 Hz, 1 H), 7.663- 7.695 (t, J = 8 Hz, 1 H), 7.502-7.518 (d, J = 8 Hz, 2H), 7.295-7.313 (d, J = 8 Hz, 2H), 5.090- 5.1 13 (t, J = 5.5 Hz, 1 H, OH), 4.447-4.458 (d, J = 5.5 Hz, 2H), 3.043 (s, 6H, N(CH3)2); MS m/z (rel intensity) 378.93 (M+, 100), 379.93 (40), 380.92 (15). [00272] Compound 105: 4-[5-(3-Cyano-benzoyl)-4-dimethylamino-thiazol-2-ylamino]- benzoic acid ethyl ester, mp: 206-208 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 1 1 .040 (s, 1 H, NH), 8.059 (s, 1 H), 8.009-8.014 (d, J = 7.5 Hz, 1 H), 7.954-7.971 (d,s, J = 8.5 Hz, 3H), 7.744-7.761 (t, J = 8.5 Hz, 2H), 7.684-7.715 (t, J = 7.5 Hz, 1 H), 4.272-4.314 (t, J = 7.25 Hz, 1 H, OH), 3.062 (s, 6H, N(CH3)2), 1 .305-1.334 (t, J = 7.25 Hz, 3H); MS m/z (rel intensity) 420.84 (M+, 100), 321 .84 (30), 422.84 (10).
[00273] Compound 106: 4-[5-(3-Cyano-benzoyl)-4-dimethylamino-thiazol-2-ylamino]- benzoic acid, mp: >300 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.895 (s, 1 H, NH), 8.016 (s, 1 H), 7.972-7.956 (d, J = 8 Hz, 1 H), 7.943-7.927 (d, J = 8 Hz, 1 H), 7.837-7.20 (d, J= 8.5 Hz, 2H), 7.686-7.655 (t, J = 7.5 Hz, 1 H), 7.458 - 7.442 (d, J=8 Hz, 2H), 3.044 (s, 6H, N(CH3)2); MS m/z (rel intensity) 392.84 (M+ , 100), 393.84(30), 394.84(10).
[00274] Compound 107: (3-Chloro-phenyl)-[4-dimethylamino-2-(4-methoxy-phenylamino)- thiazol-5-yl]-methanone. mp: 154-156 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.516 (s, 1 H, NH), 7.593(s, 1 H), 7.580-7.563 (d, J = 8.5 Hz, 2H), 7.497-7.481 (d, J = 8 Hz, 1 H), 7.461 -7.443 (d, J = 9 Hz, 2H), 6.954-6.936 (d, J = 9 Hz, 2H), 3.740 (s, 3H, OCH3), 3.040 (s, 6H,N(CH3)2); MS m/z (rel intensity) 387.95 (M+, 100), 388.95 (28), 389.94(45).
[00275] Compound 108: (4-Chloro-phenyl)-[4-dimethylamino-2-(4-methoxy-phenylamino)- thiazol-5-yl]-methanone. mp: 225-227 °C (acetone). 1 H NMR (500 MHz, DMSO-d6) δ 10.500 (s, 1 H, NH), 7.618-7.635 (d, J = 8.5 Hz, 2H), 7.497-7.514 (d, J = 8.5 Hz, 2H), 7.434-7.452 (d, J= 9 Hz, 2H), 6.930-6.948 (d, J = 9 Hz, 2H), 3.736 (s, 3H, OCH3), 3.018 (s, 6H, N(CH3)2); MS m/z (rel intensity) 387.86 (M+, 100), 388.86 (25 ), 389. 85 (45).
[00276] Compound 109: (3,4-Dichloro-phenyl)-[4-dimethylamino-2-(4-methoxy- phenylamino)-thiazol-5-yl]-methanone. mp: 180-182 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.562 (s, 1 H, NH), 7.803 (s, 1 H), 7.734-7.720 (d, J = 7 Hz, 1 H), 7.603-7.589 (d, J = 7 Hz, 1 H), 7.466-7.451 (d, J= 7.5 Hz, 2H), 6.962-6.947 (d, J = 7.5 Hz, 2H), 3.749 (s, 3H, OCH3), 3.048 (s, 6H, N(CH3)2); MS m/z (rel intensity) 421.86 (M+ , 100), 422.87(35), 423. 85(85).
[00277] Compound 110: (4-Bromo-phenyl)-[4-dimethylamino-2-(4-methoxy-phenylamino)- thiazol-5-yl]-methanone. mp: 224-226 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.505 (s, 1 H, NH), 7.661 -7.644 (d, J = 8.5 Hz, 2H), 7.568-7.551 (d, J = 8.5 Hz, 2H), 7.453-7.435 (d, J = 9 Hz, 2H), 6.953-6.935 (d, J = 9 Hz, 2H), 3.740 (s, 3H, OCH3), 3.023 (s, 6H,N(CH3)2); MS m/z (rel intensity) 433.66 (M+, 98), 431 .66 (M+, 100), 434.66 (35), 432.67(40).
[00278] Compound 111 : 4-[4-Dimethylamino-2-(4-methoxy-phenylamino)-thiazole-5- carbonyl]-benzonitrile. mp 232-34 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1 H, NH), 7.90-7.92 (d, J = 10 Hz, 2H), 7.73-7.75 (d, J = 10 Hz, 2H), 7.43-7.45 (d, J = 10 Hz, 2H), 6.93- 6.95 (d, J = 10 Hz, 2H), 3.74(s, 3H, OCH3), 3.03 (s, 6H, N(CH3)2); MS m/z (rel intensity) 378.94 (M+, 100), 379.93 (38), 380.92 (15).
[00279] Compound 112: 3-[4-Dimethylamino-2-(4-methoxy-phenylamino)-thiazole-5- carbonyl]-benzonitrile. 1 H NMR (500 MHz, DMSO-d6) δ 10.562 (s, 1 H, NH), 8.000 (s, 1 H), 7.975-7.959 (d, J = 8 Hz, 1 H), 7.926-7.910 (d, J = 8 Hz, 1 H), 7.683-7.652 (t, J = 7.5 Hz, 1 H), 7.463-7.445 (d, J = 9 Hz, 2H), 6.957-6.943 (d, J = 7 Hz, 2H), 3.741 (s, 3H, OCH3), 3.033 (s, 6H, N(CH3)2); MS m/z (rel intensity) 378.87 (M+, 100), 379.87 (45), 380.87(15).
[00280] Compound 113: 4-[4-Dimethylamino-2-(4-methoxy-phenylamino)-thiazole-5- carbonyl]-benzoic acid, mp: 156-158 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.523 (s, 1 H, NH), 8.009-7.995 (d, J = 7 Hz, 2H), 7.710-7.696 (d, J = 7 Hz, 2H), 7.460-7.445 (d, J= 7.5 Hz, 2H), 6.954-6.939 (d, J = 7.5 Hz, 2H), 3.748 (s, 3H, OCH3), 3.046 (s, 6H, N(CH3)2); MS m/z (rel intensity) 397.80 (M+ , 100), 398.98(50), 399.80 (20).
[00281] Compound 114: (3-Chloro-phenyl)-[4-dimethylamino-2-(4-trifluoromethoxy- phenylamino)-thiazol-5-yl]-methanone. mp: 184-186 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.842 (s, 1 H, NH), 7.731 -7.727 (d, J = 7 Hz, 2H), 7.643 (s, 1 H), 7.622-7.597 (m, 2H), 7.527-7.501 (t, J= 6.5 Hz, 1 H), 7.386-7.372 (d, J = 7 Hz, 2H), 3.063 (s, 6H, N(CH3)2); MS m/z (rel intensity) 441 .78 (M+ , 100), 442.76(30), 443. 76(45).
[00282] Compound 115: 4-[4-Dimethylamino-2-(4-trifluoromethoxy-phenylamino)-thiazole- 5-carbonyl]-benzoic acid, mp: 216-218 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.852 (s, 1 H, NH), 8.032-8.018 (d, J = 7 Hz, 2H), 7.745-7.732 (d, J = 7.5 Hz, 2H), 7.729- 7.714 (d, J= 7.5 Hz, 2H), 7.385-7.371 (d, J = 7 Hz, 2H), 3.046 (s, 6H, N(CH3)2); MS m/z (rel intensity) 451 .87 (M+ , 100), 452.87(30), 453.87 (10).
[00283] Compound 116: 4-[4-Dimethylamino-2-(4-trifluoromethoxy-phenylamino)-thiazole- 5-carbonyl]-benzonitrile. mp: 215-217 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.879 (s, 1 H, NH), 7.945-7.931 (d, J = 7 Hz, 2H), 7.787-7.773 (d, J = 7 Hz, 2H), 7.715-7.701 (d, J = 7 Hz, 2H), 7.374-7.360 (d, J = 7 Hz, 2H), 3.042 (s, 6H, N(CH3)2); MS m/z (rel intensity) 432.90 (M+ , 100), 433.90(30), 434.90 (10).
[00284] Compound 117: [4-Dimethylamino-2-(4-trifluoromethoxy-phenylamino)-thiazol-5- yl]-pyridin-3-yl-methanone. mp: 180-182 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.881 (s, 1 H, NH), 8.813 (s, 1 H), 8.712-8.701 (d, J = 5.5 Hz, 1 H), 8.014-8.001 (d, J = 6.5 Hz, 1 H), 7.734-7.718 (d, J = 8 Hz, 2H), 7.500 (m, 1 H), 7.388-7.373 (d, J = 7.5 Hz, 2H), 3.053 (s, 6H, N(CH3)2); MS m/z (rel intensity) 408.94 (M+ , 100), 409.93(30), 410.93 (10).
[00285] Compound 118: [2-Dimethylamino-5-(4-trifluoromethoxy-phenylamino)-4H-pyrrol- 3-yl]-pyridin-4-yl-methanone. mp: 236-238 °C (methanol). 1 H NMR (500 MHz, DMSO-d6) δ 10.904 (s, 1 H, NH), 8.719-8.709 (d, J = 5 Hz, 2H), 7.725-7.710 (d, J = 7.5 Hz, 2H), 7.553- 7.543 (d, J = 5 Hz, 2H), 7.388-7.373 (d, J = 7.5 Hz, 2H), 3.084 (s, 6H, N(CH3)2); MS m/z (rel intensity) 408.93 (M+ , 100), 409.94(60), 410.94 (10).
Example 7. Cytotoxicity profiles of representative compounds of this disclosure.
[00286] Each compound was evaluated for cytotoxicity toward PAN02 mouse pancreatic cancer cells. For these studies, the cells were treated with varying concentrations of a test compound for 72 h. The number of surviving cancer cells was then determined using the sulforhodamine B binding assay (Skehan et al., 1990, J Natl Cancer Inst 82: 1 107), and the concentration of compound that inhibited proliferation by 50% (the IC50) was calculated. The cytotoxicities of the compounds of this disclosure are summarized in Table 2, with IC50s ranging from 0.04 to >100 μΜ. As the data show, many of the compounds of this disclosure are antiproliferative at low concentrations; whereas, other compounds are not cytotoxic toward these cancer cells at concentrations up to at least 100 μΜ. Overall, the data demonstrate that many of these compounds are able to prevent cell proliferation, making them useful for the prevention and/or treatment of hyperproliferative diseases, such as cancer.
Table 2. Biological activities of compounds. The indicated compounds were tested for cytotoxicity toward PAN02 cells and the IC50s were calculated. Compounds were also tested for their abilities to inhibit GSK3P, CDK9, SK1 or SK2 at 10 μΜ using in vitro kinase assays performed by Thermo Fisher Scientific Inc. Compounds were also tested for their effects on microtubule morphology in Hep3B cells by immunostaining with anti-tubulin antibodies. In that assay, a score of "-" indicates that the compound had no morphologic effect on microtubule structure; a score of "+" indicates that the compound causes substantial loss of microtubule structure; and a score of "++" indicated that the compound causes complete loss of microtubule structure at the tested concentration. ND = Not Determined.
Figure imgf000084_0001
GSK3p CDK9 SK1 SK2
Microtubule
PAN02 Inhibition inhibition inhibition inhibition
depolymerization ICso (μΜ) (% at 10 (% at 10 (% at 10 (% at 10
(10 μΜ) μΜ) μΜ) μΜ) μΜ)
8.1 85 65 -2 1 -
7.0 85 36 6 2 -
2.6 85 57 -23 -2 -
2.2 83 75 -16 -6 ++
5.4 90 92 -10 5 -
15.6 98 99 7 33 -
>100 81 39 -2 1 -
>100 75 37 5 3 -
0.2 75 44 9 -7 +
8.9 66 44 15 1 -
24.8 97 97 1 1 22 -
1.4 98 99 12 34 +
5.1 84 81 10 -10 -
14 87 98 1 1 12 ND
2.3 ND 96 9 17 ND
21 90 92 1 1 3 ND
0.2 90 85 1 21 +
15.3 49 38 16 2 ND
0.22 76 54 -6 6 -
0.4 90 95 10 7 +
14 91 99 1 1 14 ND
0.24 91 90 2 21 ++
81 22 92 5 8 ND
0.7 82 86 -10 -1 1 -
36 98 86 10 8 ND
21 99 98 20 5 ND
>100 97 81 2 -9 ND
0.21 92 96 9 13 +
2.6 85 89 17 14 ND
0.8 89 95 0 30 ND
>10 ND 43 -3 -12 ND
5.1 70 76 6 12 -
5.6 67 52 4 23 - GSK3p CDK9 SK1 SK2
Microtubule
PAN02 Inhibition inhibition inhibition inhibition
depolymerization ICso (μΜ) (% at 10 (% at 10 (% at 10 (% at 10
(10 μΜ) μΜ) μΜ) μΜ) μΜ)
>10 98 91 -79 -15 ND
>10 26 -7 3 -17 ND
>10 99 96 -8 10 ND
>100 ND ND ND ND ND
>100 64 54 1 1 -5 -
6.7 73 61 1 1 3 +
5.4 60 43 3 -15 -
3.4 98 22 -13 -15 -
>100 98 87 -12 -12 ND
>100 26 50 -3 -2 ND
>10 99 97 -9 3 ND
14 96 57 -74 -28 ND
0.48 94 97 17 12 +
0.22 93 96 -8 0 ++
5 92 94 2 5 ND
0.06 10 6 9 -1 ++
0.30 40 27 -2 -1 ND
0.05 79 76 10 16 ++
0.05 93 94 13 8 ++
38 96 94 13 10 ND
0.22 82 59 -20 9 ++
>10 98 93 -9 -1 ND
3 100 98 5 -9 ND
>10 98 96 9 1 ND
>10 95 95 14 28 ND
0.06 97 96 12 1 ++
>10 ND 72 -4 2 ND
>10 70 63 -17 1 ND
>10 98 92 -41 -5 ND
>10 40 5 5 -13 ND
>10 99 96 0 8 ND
>10 ND ND ND ND ND
14.6 98 99 31 38 - GSK3p CDK9 SK1 SK2
Microtubule
PAN02 Inhibition inhibition inhibition inhibition
No. depolymerization ICso (μΜ) (% at 10 (% at 10 (% at 10 (% at 10
(10 μΜ) μΜ) μΜ) μΜ) μΜ)
75 42.6 97 97 3 6 +
76 5.9 76 77 2 51 ND
77 7.9 71 56 7 45 ++
78 2 41 31 8 -12 ++
79 1.14 10 14 16 1 ++
80 0.3 15 7 6 2 ND
81 0.76 22 12 1 1 -5 ND
82 0.47 54 75 23 27 -
83 0.06 50 62 31 62 ++
84 5.1 18 0 1 1 -1 +
85 2 13 5 33 10 ND
86 0.8 16 6 44 3 ++
87 >100 17 1 1 2 16 ND
88 >10 7 8 21 1 1 ND
89 1.9 1 1 5 21 0 +
90 2.5 7 0 13 -2 +
91 0.21 16 -5 18 13 ++
92 >100 13 1 -2 -1 ND
93 96 9 10 15 -16 ND
94 2.8 12 -7 13 6 -
95 >10 5 14 15 -4 ND
96 >10 6 13 15 -1 ND
97 >100 6 7 1 1 0 ND
98 50 1 1 3 0 2 ND
99 0.2 8 ND 1 1 24 ND
100 >10 1 1 4 -24 -25 ND
101 >10 3 -10 19 17 ND
102 >10 15 -9 6 13 ND
103 >100 ND ND ND ND ND
104 10 32 13 18 3 ND
105 100 4 3 -3 2 ND
106 >10 ND ND 5 -13 ND
107 0.19 15 1 21 12 ND GSK3p CDK9 SK1 SK2
Microtubule
PAN02 Inhibition inhibition inhibition inhibition
No. depolymerization ICso (μΜ) (% at 10 (% at 10 (% at 10 (% at 10
(10 μΜ) μΜ) μΜ) μΜ) μΜ)
108 1 .2 9 -2 13 5 +
109 2 6 17 -2 9 ND
110 3 6 10 22 -2 ND
111 6.5 1 1 -7 8 12 -
112 0.35 ND ND ND ND ND
113 >10 16 -1 -14 0 ND
114 >10 8 9 0 -9 ND
115 >10 -3 -1 1 -49 ND
116 >10 10 2 19 12 ND
117 >10 -5 13 3 ND
118 >10 8 3 6 -15 ND
Example 8. Compounds of this disclosure are active against a variety of cancers.
[00287] To determine if representative compounds have anticancer activity toward a variety of cancers, the cytotoxic potencies of compounds 32 and 91 towards a panel of varied human and mouse tumor cell lines, representing several major tumor types, were determined. Cells were treated with varying concentrations of either compound 32 or 91 for 72 hours, and cell viability was then determined using sulforhodamine B staining and compared to vehicle- (DMSO) treated cells. The data are described in Table 3, wherein values are the mean + standard deviation for at least three experiments. Overall, the data demonstrate that the compounds of this disclosure have anticancer activity against a wide variety of cancers.
[00288] Table 3. Anticancer activity of Compounds 32 and 91 towards various cancer cell lines. The indicated cell lines were incubated with a range of concentrations of either compound 32 or compound 91 and the IC50s were calculated as indicated above.
Figure imgf000088_0001
Human
SK-N-MC 0.06 ± 0.003 0.17 ±0.03
Neuroblastoma
Example 9. Inhibition of protein kinases by compounds of this disclosure.
[00289] Protein kinases are important regulators of a variety of cell activities, including proliferation. Consequently, compounds that inhibit certain protein kinases are potentially useful for the prevention and/or treatment of many diseases. However, a common problem with attempts to develop protein kinase inhibitors is the frequent lack of selectivity toward the target kinase since the majority of inhibitors interact with nucleotide-binding domains that are highly conserved among kinases. Therefore, compounds with a selectivity toward specific kinases are preferred as potential drug candidates. To determine if compound of this disclosure are non-selective kinase inhibitors, the abilities of representative compounds of this disclosure, specifically compound 32 and compound 91 , to inhibit the activities of a diverse panel of purified kinases were determined. For these analyses, compound 32 was tested at 3 μΜ and compound 91 was tested at 1 μΜ for inhibition of >400 kinases using the "SelectScreen" kinase profiling service from Thermo Fisher Scientific Inc. The kinases and the effects of compound 32 and compound 91 are shown in Table 4. The data indicate high specificity of Compound 32 for CDK9, GSK3 alpha and GSK3 beta in that none of the other 400 diverse kinases tested were significantly inhibited by this compound. Compound 91 did not significantly inhibit any of the kinases tested at the concentration of 1 μΜ .
[00290] Compound 32 and compound 91 were tested for inhibition of the indicated kinases at 3 and 1 μΜ , respectively. Kinases that were inhibited by 0-20%, 21 -65% and 66-100% are grouped. The abbreviations represent the standard abbreviation for the kinases, and in some cases indicate specific sites of mutations, i.e. substitution of the indicated amino acid for the native amino acid in the kinase. In some cases, different binding proteins or different substrate proteins are also indicated.
Table 4. Effects of compound 32 or compound 91 on kinase activity
Figure imgf000089_0001
PI4KB (PI4K beta), PLK2, PLK3, SLK,
STK16 (PKL12), TA0K1 , TNIK
I ABL1 , ABL1 E255K, ABL1 G250E, ABL1 ABL1 , ABL1 E255K, ABL1 H396P, ABL1 M351 T, ABL1 Q252H, ABL1 F317I, ABL1 G250E, ABL1 Y253F, ABL2 (Arg), ACVR1 (ALK2), T315I, ABL1 Y253F, ABL2 ACVR1 (ALK2) R206H, ACVR1 B (ALK4), (Arg), ACVR1 B (ALK4), ACVR2A, ACVR2B, ACVRL1 (ALK1), ADRBK1 (GRK2), ADRBK2 ADRBK1 (GRK2), ADRBK2 (GRK3), AKT1 (GRK3), AKT1 (PKB alpha), (PKB alpha), AKT2 (PKB beta), AKT3 AKT2 (PKB beta), AKT3 (PKB (PKB gamma), ALK, ALK C1 156Y, ALK gamma), ALK, AMPK
F1 174L, ALK L1 196M, ALK R1275Q, (A1/B2/G3), AMPK (A2/B1/G2), AMPK (A1/B1/G2), AMPK (A1/B1/G3), AMPK (A2/B1/G3), AMPK AMPK (A1/B2/G 1), AMPK (A2/B2/G 1), (A2/B2/G3), AMPK A1/B1/G1 , AMPK (A2/B2/G2), AMPK A1/B1/G1 , AMPK A2/B1/G 1 , AURKA AMPK A2/B1/G1 , AURKA (Aurora A), (Aurora A), AURKB (Aurora B), AURKB (Aurora B), AURKC (Aurora C), AURKC (Aurora C), AXL, BLK, AXL, AXL R499C, BLK, BMPR1A (ALK3), BMX, BRAF, BRAF V599E, BMPR1 B (ALK6), BMPR2, BMX, BRAF, BRSK1 (SAD1), BTK, CAMK1 D BRAF V599E, BRSK1 (SAD1), BRSK2, (CaMKI delta), CAMK1 G BTK, CAMK1 (CaMK1), CAMK1 D (CaMKI (CAMKI gamma), CAMK2A delta), CAMK2A (CaMKII alpha), CAMK2B (CaMKII alpha), CAMK2B (CaMKII beta), CAMK2D (CaMKII delta), (CaMKII beta), CAMK2D CAMK2G (CaMKII gamma), CAMK4 (CaMKII delta), CAMK4
(CaMKIV), CAMKK1 (CAMKKA), CASK, (CaMKIV), CDC42 BPA
CDC42 BPA (MRCKA), CDC42 BPB (MRCKA), CDC42 BPB
(MRCKB), CDC7/DBF4, CDK1/cyclin A2, (MRCKB), CDC42 BPG
CDK1/cyclin B, CDK1 1 (Inactive), CDK14 (MRCKG), CDK1/cyclin B, (PFTK1)/cyclin Y, CDK16 (PCTK1)/cyclin CDK17/cyclin Y, CDK18/cyclin Y, CDK2/cyclin A, CDK3/cyclin E1 , CDK5 Y, CDK2/cyclin A, CDK5/p25, (Inactive), CDK5/p25, CDK5/p35, CDK5/p35, CDKL5, CHEK1 CDK7/cyclin H/MNAT1 , CDK8/cyclin C, (CHK1), CHEK2 (CHK2), CLK1 , CHEK1 (CHK1), CHEK2 (CHK2), CHUK CLK2, CLK3, CSF1 R (FMS), (IKK alpha), CLK1 , CLK2, CLK3, CSK, CSK, CSNK1A1 (CK1 alpha 1), CSNK1A1 (CK1 alpha 1), CSNK1 D (CK1 CSNK1A1 L, CSNK1 D (CK1 delta), CSNK1 G1 (CK1 gamma 1), delta), CSNK1 E (CK1 epsilon), CSNK1 G3 (CK1 gamma 3), CSNK2A1 CSNK1 G1 (CK1 gamma 1), (CK2 alpha 1), CSNK2A2 (CK2 alpha 2), CSNK1 G2 (CK1 gamma 2), DAPK1 , DAPK2, DAPK3 (ZIPK), CSNK1 G3 (CK1 gamma 3), DCAMKL2 (DCK2), DDR1 , DDR2, DDR2 CSNK2A1 (CK2 alpha 1), N456S, DDR2 T654M, DMPK, DNA-PK, CSNK2A2 (CK2 alpha 2), DYRK1A, DYRK1 B, DYRK2, DYRK3, DAPK3 (ZIPK), DCAMKL1 DYRK4, EEF2K, EGFR (ErbB1), EGFR (DCLK1), DCAMKL2 (DCK2), (ErbB1) d746-750, EGFR (ErbB1) L858R, DNA-PK, DYRK1A, DYRK1 B, EGFR (ErbB1) L861 Q, EGFR (ErbB1) DYRK3, DYRK4, EEF2K, EGFR T790M, EGFR (ErbB1) T790M L858R, (ErbB1), EGFR (ErbB1) L858R, EIF2AK2 (PKR), EPHA1 , EPHA2, EPHA3, EGFR (ErbB1) L861 Q, EGFR EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, (ErbB1) T790M, EGFR (ErbB1) EPHB1 , EPHB2, EPHB3, EPHB4, ERBB2 T790M L858R, EPHA1 , EPHA2, (HER2), ERBB4 (HER4), FER, FES (FPS), EPHA4, EPHA5, EPHA8, FGFR1 , FGFR1 V561 M, FGFR2, FGFR3, EPHB1 , EPHB2, EPHB3, FGFR3 G697C, FGFR3 K650E, FGFR3 EPHB4, ERBB2 (HER2), K650M, FGFR4, FGR, FLT1 (VEGFR1), ERBB4 (HER4), FER, FES FLT3, FLT3 D835Y, FLT3 ITD, FLT4 (FPS), FGFR1 , FGFR2, (VEGFR3), FRAP1 (mTOR), FRK (PTK5), FGFR3, FGFR3 K650E, FYN, FYN A, GRK1 , GRK4, GRK5, GRK6, FGFR4, FGR, FLT1 (VEGFR1), GRK7, GSG2 (Haspin), HCK, HIPK1 FLT3, FLT3 D835Y, FLT4 (Myak), HIPK2, HIPK3 (YAK1), HIPK4, (VEGFR3), FRAP1 (mTOR), IGF1 R, IKBKB (IKK beta), IKBKE (IKK FRK (PTK5), FYN, GRK4, epsilon), INSR, INSRR (IRR), IRAKI , GRK5, GRK6, GRK7, GSK3A IRAK4, ITK, JAK1 , JAK2, JAK2 JH1 JH2, (GSK3 alpha), GSK3B (GSK3 JAK2 JH1 JH2 V617F, JAK3, KDR beta), HCK, HIPK1 (Myak), (VEGFR2), KIT, KIT A829P, KIT D816H, HIPK2, HIPK3 (YAK1), HIPK4, KIT D816V, KIT D820E, KIT N822K, KIT IGF1 R, IKBKB (IKK beta), T670E, KIT T670I, KIT V559D T670I, KIT IKBKE (IKK epsilon), INSR, V654A, KIT Y823D, LATS1 , LATS2, LCK, INSRR (IRR), IRAK4, ITK, LIMK1 , LIMK2, LTK (TYK1), LYN A, LYN JAK1 , JAK2, JAK2 JH1 JH2, B, MAP2K1 (MEK1), MAP2K1 (MEK1) JAK2 JH1 JH2 V617F, JAK3, S218D S222D, MAP2K2 (MEK2), MAP2K3 KDR (VEGFR2), KIT, KIT (MEK3), MAP2K6 (MKK6), MAP2K6 T670I, KIT V559D, KIT V559D (MKK6) S207E T21 1 E, MAP3K10 (MLK2), V654A, KIT V560G, KSR2, MAP3K1 1 (MLK3), MAP3K14 (NIK), LCK, LTK (TYK1), LYN A, LYN MAP3K2 (MEKK2), MAP3K3 (MEKK3), B, MAP2K1 (MEK1), MAP2K2 MAP3K5 (ASK1), M AP3 K7/M AP3K71 P 1 (MEK2), MAP2K6 (MKK6), (TAK1 -TAB1), MAP3K9 (MLK1), MAP4K1 MAP3K19 (YSK4), MAP3K8 (HPK1), MAP4K2 (GCK), MAP4K3 (GLK), (COT), MAP3K9 (MLK1), MAP4K5 (KHS1), MAPK1 (ERK2), MAP4K2 (GCK), MAP4K4 MAPK10 (JNK3), MAPK1 1 (p38 beta), (HGK), MAP4K5 (KHS1), MAPK12 (p38 gamma), MAPK13 (p38 MAPK1 (ERK2), MAPK10 delta), MAPK14 (p38 alpha), MAPK3 (JNK3), MAPK1 1 (p38 beta), (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK12 (p38 gamma), MAPKAPK2, MAPKAPK3, MAPKAPK5 MAPK13 (p38 delta), MAPK14 (PRAK), MARK1 (MARK), MARK2, (p38 alpha), MAPK3 (ERK1), MARK3, MARK4, MATK (HYL), MELK, MAPK7 (ERK5), MAPK8 MERTK (cMER), MERTK (cMER) A708S, (JNK1), MAPK9 (JNK2), MET (cMet), MET D1228H, MET M 1250T, MAPKAPK2, MAPKAPK3, MINK1 , MKNK1 (MNK1), MKNK2 (MNK2), MAPKAPK5 (PRAK), MARK1 MLCK (MLCK2), MST1 R (RON), MST4, (MARK), MARK2, MARK3, MYLK (MLCK), MYLK2 (skMLCK), MY03B MARK4, MATK (HYL), MELK, (MY03 beta), NEK1 , NEK2, NEK4, NEK6, MERTK (cMER), MET (cMet), NEK7, NEK9, NLK, NTRK1 (TRKA), MET M 1250T, MINK1 , MKNK1 NTRK2 (TRKB), NTRK3 (TRKC), NUAK1 (MNK1), MST1 R (RON), MST4, (ARK5), NUAK2, PAK1 , PAK2 (PAK65), MUSK, MYLK2 (SkMLCK), PAK3, PAK4, PAK6, PAK7 (KIAA1264), NEK1 , NEK2, NEK4, NEK6, PASK, PDGFRA (PDGFR alpha), NEK7, NEK9, NIM 1 K, NTRK1 PDGFRA D842V, PDGFRA T674I, (TRKA), NTRK2 (TRKB), PDGFRA V561 D, PDGFRB (PDGFR beta), NTRK3 (TRKC), PAK1 , PAK2 PDK1 , PHKG 1 , PHKG2, PI4KA (PI4K (PAK65), PAK3, PAK4, PAK6, alpha), PIK3C2A (PI3K-C2 alpha), PAK7 (KIAA1264), PASK, PIK3C2B (PI3K-C2 beta), PIK3C3 PDGFRA (PDGFR alpha), (hVPS34), PIK3CA/PIK3R1 (p1 10 PDGFRA D842V, PDGFRA alpha/p85 alpha), PIK3CB/PIK3R1 (p1 10 T674I, PDGFRA V561 D, beta/p85 alpha), PIK3CD/PIK3R1 (p1 10 PDGFRB (PDGFR beta), PDK1 , delta/p85 alpha), PIK3CG (p1 10 gamma), PEAK1 , PHKG 1 , PHKG2, PIM 1 , PIM 1 , PIM2, PKN1 (PRK1), PKN2 (PRK2), PIM2, PIM3, PKN 1 (PRK1), PLK1 , PLK4, PRKACA (PKA), PRKACB PLK1 , PLK2, PLK3, PRKACA (PRKAC beta), PRKACG (PRKAC (PKA), PRKCA (PKC alpha), gamma), PRKCA (PKC alpha), PRKCB1 PRKCB1 (PKC beta I),
(PKC beta I), PRKCB2 (PKC beta II), PRKCB2 (PKC beta II), PRKCD PRKCD (PKC delta), PRKCE (PKC (PKC delta), PRKCE (PKC epsilon), PRKCG (PKC gamma), PRKCH epsilon), PRKCG (PKC (PKC eta), PRKCI (PKC iota), PRKCN gamma), PRKCH (PKC eta), (PKD3), PRKCQ (PKC theta), PRKCZ PRKCI (PKC iota), PRKCN (PKC zeta), PRKD1 (PKC mu), PRKD2 (PKD3), PRKCQ (PKC theta), (PKD2), PRKG1, PRKG2 (PKG2), PRKX, PRKCZ (PKC zeta), PRKD1 PTK2 (FAK), PTK2B (FAK2), PTK6 (Brk), (PKC mu), PRKD2 (PKD2), RAF1 (cRAF) Y340D Y341D, RET, RET PRKG1, PRKG2 (PKG2), G691S, RET M918T, RET V804L, RET PRKX, PTK2 (FAK), PTK2B V804M, RET Y791F, RIPK2, RIPK3, (FAK2), PTK6 (Brk), RAF1 ROCK1, ROCK2, ROS1, RPS6KA1 (cRAF) Y340D Y341D, RET, (RSK1), RPS6KA2 (RSK3), RPS6KA3 RET S891A, RET V804L, RET (RSK2), RPS6KA4 (MSK2), RPS6KA5 Y791F, ROCK1, ROCK2, (MSK1), RPS6KA6 (RSK4), RPS6KB1 ROS1, RPS6KA1 (RSK1), (p70S6K), SGK (SGK1), SGK2, SGKL RPS6KA2 (RSK3), RPS6KA3 (SGK3), SIK1, SIK3, SNF1LK2, SPHK1, (RSK2), RPS6KA4 (MSK2), SPHK2, SRC, SRC N1, SRMS (Srm), RPS6KA5 (MSK1), RPS6KA6 SRPK1, SRPK2, STK17A (DRAK1), (RSK4), RPS6KB1 (p70S6K), STK17B (DRAK2), STK22B (TSSK2), RPS6KB2 (p70S6Kb), SBK1, STK22D (TSSK1), STK23 (MSSK1), SGK(SGK1), SGK2, SGKL STK24 (MST3), STK25 (YSK1), STK3 (SGK3), SNF1LK2, SRC, SRC (MST2), STK32B (YANK2), STK32C N1, SRMS (Srm), SRPK1, (YANK3), STK33, STK38 (NDR), STK38L SRPK2, STK22B (TSSK2), (NDR2), STK39 (STLK3), STK4 (MST1), STK22D (TSSK1), STK23 SYK, TAOK2 (TA01), TAOK3 (JIK), TBK1, (MSSK1), STK24 (MST3), TEC, TEK (Tie2), TEK (TIE2) R849W, TEK STK25 (YSK1), STK3 (MST2), (TIE2) Y1108F, TESK2, TGFBR1 (ALK5), STK4 (MST1), SYK, TAOK2 TGFBR2, TLK1 , TLK2, TNK2 (ACK), TTK, (TA01), TBK1, TEK (TIE2) TXK, TYK2, TYR03 (RSE), ULK1, ULK2, Y897S, TEK (Tie2), TNK1, TXK, ULK3, WEE1 , WNK2, WNK3, YES1 , ZAK, TYK2, TYR03 (RSE), YES1, ZAP70 ZAP70
Example 10. Inhibition of GSK3 and CDK9
[00291] Compound 32 was tested for its potency for inhibition of GSK3a, GSK3P and CDK9, and the results are shown in Figure 1. The data indicate that the IC50s for compound 32 for GSK3a, GSK3P and CDK9 are 0.35, 0.6 and 0.32 μΜ, respectively. Therefore, the potency for inhibition of cancer cell proliferation is closely related to the potency for inhibition of these target kinases. Many compounds of this invention were tested for their effects on GSK3P and CDK9 activity at a concentration of 10 μΜ. As demonstrated in Table 2, compounds had a wide range of inhibitory activity toward these kinases, with many examples of highly inhibitory compounds being identified.
Example 11. Inhibition of cell cycle progression.
[00292] The effects of compound 32 and compound 91 on cancer cell cycle progression were examined. PAN02 cells were treated with 0 or 3 μΜ compound 32 and Hep3B cells were treated with 0 or 350 nM compound 91 for 18 hrs. The cells were then stained with propidium iodide and the DNA content of the cells was measured by flow cytometry. As indicated in Table 5 both compounds caused the arrest of the cancer cells in the G2/M phase of the cell cycle. Treatment with compound 32 also drove a high percentage of the cells into apoptosis, as indicated by the increase in percentage of cells with sub-G 1 levels of DNA. Therefore, the compounds of this disclosure suppress cancer cell transition from G2/M into telophase, and certain of the compounds also induce apoptosis in the cancer cells.
Table 5. Effects of compounds 32 and 91 of the cell cycle distribution of cancer cells. PAN02 cells were treated with 0 or 3 μΜ compound 32 and Hep3B cells were treated with 0 or 350 nM compound 91 for 18 hours and then analyzed by flow cytometry after staining of DNA with propidium iodide.
Figure imgf000093_0001
Example 12. Inhibition of SK activity.
[00293] Many compounds of this invention were tested for their effects on SK1 and SK2 activity at a concentration of 10 μΜ . As demonstrated in Table 2, compounds had a wide range of inhibitory activity toward these kinases, with examples of SK1 -selective, SK2- selective and SK1 /SK2-dual inhibitory compounds being identified.
Example 13. Depolymerization of cellular microtubules.
[00294] Microtubule are polymers composed of tubulin and other proteins that are critical for several cellular processes, including cell proliferation. Because microtubule dynamics, ie. shortening and lengthening in cells, is essential for the proper function of the mitotic spindle, disruption of microtubule action due to drug binding to tubulin is an established mode of action of certain anticancer drugs. To determine if certain compounds of this disclosure affect microtubule structure, Hep3B cancer cells were treated with 10 μΜ of a compound and then microtubules were visualized by staining with anti-tubulin antibodies and fluorescent secondary antibodies. The images were then recorded using microscopy. As indicated in Table 2, certain of these compounds caused marked loss of microtubule structure in these cancer cells. As an example, the effects of compound 91 on microtubule structure in the liver cancer cells is provided in Figure 2. In the control cells, the microtubule network (indicated by the black lines) is extensive and fills the cytoplasm of the cell. Treatment with 200, 500 or 10,000 nM compound 91 caused progressive losses of the assembled microtubule network and pronounced vacuolization of the cells. This response demonstrates that compound 91 acts as a strong microtubule depolymerizing agent, and this is consistent with the arrest of the cancer cells in the G2/M phase of the cell cycle as reported in the previous example.
Example 14. In vivo toxicity of compounds of this disclosure.
[00295] Toxicology studies were conducted with representative compounds of this disclosure. In these experiments, male C57BL/6 mice were divided into experimental groups of 4. Compounds 17, 32, 57, 60, 62 and 67 were individually dissolved in a vehicle comprised of 50% PEG 400, 35% propanediol, 5% ethanol, 5% Tween-80 and 5% saline, and administered by oral gavage at a dose of 50 mg/kg body weight in a volume of 0.1 ml each day for 7 days. Mice were dosed in the morning of Day 7 and sacrificed approximately 5 hours of this final dose. Blood was drawn to evaluate the hematologic parameters of red blood cell count (RBC), white blood cell count (WBC), platelet and hemoglobin (Hgb) levels, as well as levels of blood urea nitrogen (BUN) and alanine aminotransferase (ALT) to assess potential kidney and liver toxicity, respectively. Weights for the liver, kidney, spleen and heart were also measured. As shown in Figure 3, there were generally no significant toxic effects across the 8 parameters assessed (BUN, ALT, WBC, RBC, Platelets, Hgb, Kidney Weight and Heart Weight). Liver and spleen weights were also unchanged by compound treatment.
[00296] An additional toxicology study was conducted in a similar manner with higher doses (100 and 200 mg/kg/day for 7 days) of compounds 91 and 32. As shown in Figure 4, there were no significant toxic effects of either compound across the 8 parameters (creatinine, ALT, WBC, RBC, platelets, glucose, liver weight and heart weight) . Kidney weights were also unchanged in all groups.
Example 15. Antitumor activity of representative compounds of this disclosure.
[00297] The antitumor activity of the representative compounds was evaluated using a syngeneic mouse model in which murine melanoma B16 or murine pancreatic cancer Pan02 cells were grown subcutaneously in immune competent C57BL/6 mice. In one case, C57BL/6 mice, 6-8 weeks old, were injected subcutaneously in the right flank with 10,000 murine melanoma B16 cells suspended in phosphate buffered saline. Tumors were monitored daily until they reached a volume of at least 100 mm3, at which point mice were randomized into Vehicle or compound 32 treatment groups. Compound 32 was dissolved in vehicle (50% PEG400, 35% propanediol, 5% Tween-80, 5% ethanol and 5% saline), and administered by oral gavage 5 times per week at a dose of 5 mg/kg/day. Tumor volume and animal body weight were recorded three times per week. Tumor volume is determined by the formula (L2 x W) x 0.523, wherein L and W are the longer and shorter lengths of the tumor mass, respectively. As indicated in Figure 5, tumor growth in mice treated with compound 32 was significantly lower (>70% decreased at Day 1 1 ) than tumor growth in vehicle-treated mice. The insert in Figure 5 depicts the body weight of the mice during the experiment, and demonstrates that no significance difference was observed, indicating the lack of toxicity from compound 32.
[00298] In another case, C57BL/6 mice, 6-8 weeks old, were injected subcutaneously in the right flank with 1 ,000,000 murine pancreatic cancer PAN02 cells suspended in 1 : 1 mixture of phosphate buffered saline and Reduced Growth Factor Basement Membrane Matrix. Tumors were monitored daily until they reached a volume of at least 100 mm3, at which point mice were randomized into Vehicle or compound 32 treatment groups. Compound 32 was dissolved in vehicle (50% PEG400, 35% propanediol, 5% Tween-80, 5% ethanol and 5% saline), and administered by oral gavage 5 times per week at a dose of 5 mg/kg/day. Tumor volume and animal body weight were recorded three times per week. Tumor volume was determined by the formula (L2 x W) x 0.523, wherein L and W are the longer and shorter lengths of the tumor mass, respectively. As indicated in Figure 6, tumor growth in mice treated with compound 32 was significantly lower (>70% decreased at Day 24) than tumor growth in vehicle-treated mice. The insert in Figure 6 depicts the body weight of the mice during the experiment, and demonstrates that no significance difference was observed, indicating the lack of toxicity from compound 32.
[00299] In another case, C57BL/6 mice, 6-8 weeks old, were injected subcutaneously in the right flank with 1 ,000,000 murine pancreatic cancer PAN02 cells suspended in 1 : 1 mixture of phosphate buffered saline and Reduced Growth Factor Basement Membrane Matrix. Tumors were monitored daily until they reached a volume of at least 100 mm3, at which point mice were randomized into Vehicle or compound 91 treatment groups. Compound 91 was dissolved in vehicle (50% PEG400, 35% propanediol, 5% Tween-80, 5% ethanol and 5% saline) and administered by oral gavage 5 times per week at a dose of 2 mg/kg/day. Tumor volumes and animal weights were recorded three times per week. Tumor size is expressed as normalized tumor volume, which is tumor volume at the indicated Day divided by tumor volume at Day 1 for each individual mouse. As indicated in Figure 7, tumor growth in animals treated with compound 91 was significantly lower (60% decreased at Day 31 ) than tumor growth in control animals. Body weight was monitored, and no significance difference was observed, indicating a lack of toxicity from compound 91 .
[00300] Additional compounds of this disclosure were tested for their ability to inhibit the growth of B16 melanoma or PAN02 pancreatic tumors in mice. The results are summarized in Table 6. [00301] Table 6. In vivo effects of representative compounds in the disclosure on tumor growth. The indicated compounds were tested for efficacy against tumors of PAN02 pancreatic cancer cells or B16 melanoma cells as described in the previous Examples. In all cases, the compound was administered 5 days per week by oral gavage in the same vehicle as detailed above. The dose of the compounds varied from 5 to 50 mg/kg/day. In vivo activity is rated as: None, Weak, Moderate, Good, Very Good or Excellent which represents a suppression of tumor growth by approximately 0-10%, 10-20% , 20-40%, 40-60%, 60-80% or 80- 100%, respectively.
Figure imgf000096_0001
Example 16. In vivo effects of compounds of this disclosure in the Dextran Sulfate Sodium (DSS) acute model of ulcerative colitis.
[00302] Representative Compounds were tested for efficacy in the DSS model of inflammatory bowel disease (IBD). In these experiments, C57BL/6 mice were provided standard rodent diet and water ad libitum. After their acclimation, the animals were randomly divided into experimental groups of 4 or 5. The mice were given either normal drinking water or 2% DSS (40,000 molecular weight) in water, and treated orally with a compound at a dose of 0 or 50 mg/kg/day for 6 days. The compounds were individually dissolved in a vehicle comprised of 50% PEG400, 35% propanediol, 5% ethanol, 5% Tween-80, and 5% saline, and given once daily by oral gavage in a volume of 0.1 ml per dose. The body weight of each animal was measured each day, and the Disease Activity Index (DAI) was calculated for each animal on Days 4-6 according to the following parameters:
Figure imgf000097_0001
[00303] On Day 6, the mice were sacrificed by cervical dislocation and the entire colon was removed and measured to the nearest 0.1 cm. Portions of the colons were then sectioned for biochemical analyses of inflammation markers.
[00304] The DAI monitors weight loss, stool consistency and blood in the stool, and serves as a clinical measure of disease severity. Animals receiving normal drinking water and vehicle as a control had very low DAIs throughout the experiment (Figure 8). Exposure of mice to DSS in their drinking water markedly induced I BD symptoms, including weight loss and production of loose, bloody stools. The intensity of the disease progressively increased from Day 4 to the time the mice were sacrificed on Day 6. Mice receiving DSS and vehicle treatment experienced progressive disease, with DAI values reaching between 2 and 3 on Day 6, representing moderate colitis. Animals receiving treatment with compound 32 or compound 57 demonstrated reduced DAI , most dramatically on Day 6, compared with the Vehicle/DSS controls, demonstrating an anti-inflammatory action of the compounds in this model.
[00305] Myeloperoxidase (MPO) activity, which is a measurement of neutrophil influx into the tissue, was assayed in the colons of the mice from the DSS studies. As indicated in Figure 9, MPO activity was highly elevated in the Vehicle/DSS animals compared to water controls (Sham) . The increase in MPO activity was attenuated in mice receiving daily doses of compound 9 or compound 32, demonstrating an anti-inflammatory action of the compound in this model.
[00306] Several cytokines involved in inflammation, including IL- 10, which suppresses inflammation, and the pro-inflammatory cytokines, TNFa, IL- 1 B and IL-6, in colon samples from mice in the DSS model of colitis were also measured. Figure 10 demonstrates that DSS/Vehicle-treatment altered the levels of all of the indicated cytokines in the colon. Importantly, the increase of the pro-inflammatory cytokine IL-6 induced by DSS treatment was significantly attenuated in mice treated with compound 32. Inversely, levels of the antiinflammatory cytokine, IL-10, markedly decreased in the DSS/Vehicle mice compared with the Sham group, and this suppression was completely overcome by treatment of the mice with compound 32. These data further demonstrate an anti-inflammatory action of the compound in this model
Example 17. Effects of compound 32 in the Trinitrobenzene Sulfonic Acid (TNBS) colitis model, representative of Crohn's disease.
[00307] Representative compounds have been examined in the TNBS model of I BD, which is an immunologically-based colitis model representative of Crohn's disease. In these experiments, C57BL/6 mice were provided standard rodent diet and water ad libitum. After their acclimation, the animals were randomly divided into experimental groups of 4 or 5. Mice receive an enema of either ethanol or TNBS in ethanol on Day 0, and were treated once daily from Days 6-9 with compound 32 dissolved in a vehicle (50% PEG400, 35% propanediol, 5% ethanol, 5% Tween-80, and 5% saline) by oral gavage. Mice were sacrificed on Day 10, and colons were harvested for measurement of the Macroscopic Score. The Macroscopic Score is calculated by assessing the number of sites of inflammatory damage, the size of the inflammatory sites and the severity of the inflammatory sites in the distal 3 cm of the colon. Following scoring, portions of the colons were sectioned for biochemical analyses of inflammation markers.
[00308] As shown in Figure 1 1 A, mice receiving TNBS/Vehicle treatment exhibited macroscopic scores that averaged between 4 and 5 on Day 10, representing moderate colitis. Treatment of the mice with TNBS/compound 32 reduced the intensity of the inflammatory damage to a level of approximately 1 , representative of very mild colitis. The levels of the proinflammatory cytokine TNFa in homogenates of colon samples from the mice were measured. Figure 1 1 B indicates that TNBS/Vehicle treatment strongly increased the amount of TNFa in the colon, compared with EtOH-treated controls. This elevation of TNFa by TNBS was significantly attenuated in mice treated with TNBS/compound 32, demonstrating an antiinflammatory action of the compound in this model.
Example 18. Effects of compound 32 on radiation-induced intestinal damage.
[00309] Representative compounds have been examined for their ability to protect the gastrointestinal tract from damage induced by exposure of mice to ionizing radiation. In these experiments, C57BL/6 mice were provided standard rodent diet and water ad libitum. After their acclimation, mice were randomly divided into experimental groups of 4 or 5. Mice were dosed with either vehicle (50% PEG400, 35% propanediol, 5% ethanol, 5% Tween-80, and 5% saline) or 50 mg of compound 32/kg body weight by oral gavage. Mice were then exposed to 9 Gy of ionizing radiation at a dose rate of approximately 70 cGy per minute. A non- irradiated (sham) group was also studied as a control to radiation damage. Mice were sacrificed at either 1 or 3 days following radiation, and the ilium of the small intestine was harvested for analysis. Each ilium was fixed in 10% neutral buffered formalin, sectioned and stained with hematoxylin and eosin for microscopic evaluations of villi length as a quantitative measure of radiation damage. Radiation damage is manifested as a decrease in villi height at Day 3. As shown in Figure 12A, villi heights in irradiated mice were unchanged as compared to Sham irradiated mice 1 day after irradiation. At 3 days after radiation treatment, there was a marked reduction in villi height in radiation/Vehicle-treated mice as compared to non- irradiated (Sham) animals. Mice dosed with compound 32 before radiation treatment had significantly longer villi than the radiation/Vehicle-treated mice. This demonstrates a protective effect of compound 32 against histologic radiation damage. To determine if radiation damage is associated with increased inflammation in the gastrointestinal tract, the ilium samples were analyzed for their content of TNFa, a known mediator of radiation-induced toxicity. As shown in Figure 12B, levels of TNFa in the ilium were unchanged at Day 1 across all treatment groups, but were markedly elevated in samples from the radiation/Vehicle- treatment group compared to non-irradiation (Sham) animals at Day 3. The ileums of compound 32-treated mice had significantly lower levels of TNFa than did the radiation/Vehicle-treated mice at Day 3, demonstrating an anti-inflammatory action of the compound in this model.
[00310] The present disclosure is illustrated by way of the foregoing description and examples. The foregoing description is intended as a non-limiting illustration, since many variations will become apparent to those skilled in the art in view thereof. It is intended that all such variations within the scope and spirit of the appended claims be embraced thereby. Each referenced document herein is incorporated by reference in its entirety for all purposes.
[00311] Changes can be made in the composition, operation and arrangement of the method of the present disclosure described herein without departing from the concept and scope of the disclosure as defined in the following claims.

Claims

We claim:
1. A compound having the formula
Figure imgf000100_0001
optionally in the form of a pharmaceutically acceptable salt or N-oxide, or a solvate or hydrate, wherein:
R1A and R1B are each independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3alkyl, -C(0)R1C, -C(S)R1C, -S(0)i-2R1C, -C(0)0R1C, -C(0)NR1DR1C, -C(0)SR1C, -C(S)0R1C, -C(S)NR1DR1C, -C(S)SR1C, -C(NR1 D)NR1DR1C and -S(0)i-2NR1DR1C, in which
each R1C is independently selected from H, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl, and
each R1D is independently selected from H, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl,C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl); the ring system denoted by "A" is phenyl or a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O and S;
R2 is selected from H, C1-C3 fluoroalkyl, halogen, nitro, -CN, -C(0)R2A, -S(0)i-2R2A, -C(0)R2A, -C(0)NR2BR2A, -C(S)NR2BR2A,-C(0)OR2A, -C(0)SR2A, -C(S)OR2A, -C(S)SR2A, -S(0)i-2OR2A and -S(0)i_2NR2BR2A, in which
each R2A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl, and each R2B is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl), with the proviso that when the ring system denoted by "A" is phenyl, R2 is not H; each R3 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R3A, -SR3A, -S(0)i_2R3A, -OR3A, -NR3BR3A, -C(0)R3A, -C(0)NR3BR3A, -NR3BC(0)R3A, -C(S)NR3BR3A, -NR3BC(S)R3A, -C(0)OR3A, -OC(0)R3A, -C(0)SR3A, -SC(0)R3A, -C(S)OR3A, -OC(S)R3A, -C(S)SR3A, -SC(S)R3A, -S(0)i_2OR3A, -OS(0)i_2R3A, -S(0)i_2NR3BR3A, -NR3BS(0)i-2R3A, -OC(0)OR3A, -OC(0)NR3BR3A, -NR3BC(0)OR3A, -NR3BC(0)NR3BR3A, -SC(0)OR3A, -OC(0)SR3A, -SC(0)SR3A, -SC(0)NR3BR3A, -NR3BC(0)SR3A, -OC(S)OR3A, -OC(S)NR3BR3A, -NR3BC(S)OR3A, -NR3BC(S)NR3BR3A, -SC(S)OR3A, -OC(S)SR3A, -SC(S)SR3A, -SC(S)NR3BR3A, -NR3BC(S)SR3A, -NR3BC(NR3B)NR3BR3A and -NR3BS(0)i.2NR3BR3A, in which
each R3A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyi, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl, and each R3B is independently selected from H, optionally substituted C1-C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyi, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl); m is 0, 1 , 2, 3 or 4;
the ring system denoted by "B" is phenyl or a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O and S;
each R4 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyi, halogen, nitro, -CN, -SF5, -N3, -C(0)R4A, -SR4A, -S(0)i_2R4A, -OR4A, -NR4BR4A, -C(0)R4A, -C(0)NR4BR4A, -NR4BC(0)R4A, -C(S)NR4BR4A, -NR4BC(S)R4A, -C(0)OR4A, -OC(0)R4A, -C(0)SR4A, -SC(0)R4A, -C(S)OR4A, -OC(S)R4A, -C(S)SR4A, -SC(S)R4A, -S(0)i_2OR4A, -OS(0)i_2R4A, -S(0)i_2NR4BR4A, -NR4BS(0)i-2R4A, -OC(0)OR4A, -OC(0)NR4BR4A, -NR4BC(0)OR4A, -NR4BC(0)NR4BR4A, -SC(0)OR4A, -OC(0)SR4A, -SC(0)SR4A, -SC(0)NR4BR4A, -NR4BC(0)SR4A, -OC(S)OR4A, -OC(S)NR4BR4A, -NR4BC(S)OR4A, -NR4BC(S)NR4BR4A, -SC(S)OR4A, -OC(S)SR4A, -SC(S)SR4A, -SC(S)NR4BR4A, -NR4BC(S)SR4A, -NR4BC(NR4B)NR4BR4A and -NR4BS(0)i.2NR4BR4A, in which
each R4A is independently selected from H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyi, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl, and each R4B is independently selected from H, optionally substituted C1-C4 alkyl; optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyi, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl); and n is 0, 1 , 2, 3, 4 or 5; wherein
each alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene is straight-chain or branched;
each optionally substituted alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene is unsubstituted or substituted with 1 -5 substituents independently selected from halogen, nitro, -CN, -SF5, -N3, -C(0)R5, -SR5, -S(0)i_2R5, -OR5, -NR6R5, -C(0)NR6R5, -NR6C(0)R5, -C(S)NR6R5, -NR6C(S)R5, -C(0)OR5, -OC(0)R5, -C(0)SR5, -SC(0)R5, -C(S)OR5, -OC(S)R5, -C(S)SR5, -SC(S)R5, -S(0)i_2OR5, -OS(0)i-2R5, -S(0)i-2NR6R5, -NR6S(0)i_2R5, -OC(0)OR5, -OC(0)NR6R5, -NR6C(0)OR5, -NR6C(0)NR6R5, -SC(0)OR5, -OC(0)SR5, SC(0)SR5, -SC(0)NR6R5, -NR6C(0)SR5, -OC(S)OR5, -OC(S)NR6R5, -NR6C(S)OR5, -NR6C(S)NR6R5, -SC(S)OR5, -OC(S)SR5, -SC(S)SR5, -SC(S)NR6R5, -NR6C(S)SR5, -NR6C(NR6)NR6R5 and -NR6S(0)i.2NR6R5, in which
each R5 is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl and (C1-C3 alkoxy)Ci-C3 alkyl; and
each R6 is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)Ci-C3 alkyl, -S(0)i-2(Ci-C3 alkyl), -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl);
wherein the compound is not
(4-amino-2-((4-methoxyphenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-chlorophenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
4-((4-amino-5-(4-chlorobenzoyl)thiazol-2-yl)amino)benzonitrile;
(4-amino-2-(p-tolylamino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-(trifluoromethyl)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone; methyl 4-((4-amino-5-(4-chlorobenzoyl)thiazol-2-yl)amino)benzoate;
(4-amino-2-((4-(dimethylamino)phenyl)amino)thiazol-5-yl)(4- chlorophenyl)methanone;
(4-amino-2-((4-(benzyloxy)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((3-nitrophenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-(cyclohexylmethyl)phenyl)amino)thiazol-5-yl)(4- chlorophenyl)methanone;
(4-amino-2-((3-(trifluoromethyl)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-(methylthio)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-(trifluoromethoxy)phenyl)amino)thiazol-5-yl)(4- chlorophenyl)methanone;
4-(4-amino-2-((4-methoxyphenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-chlorophenyl)amino)thiazole-5-carbonyl)benzonitrile; 4-(4-amino-2-((4-cyanophenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-(p-tolylamino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(trifluoromethyl)phenyl)amino)thiazole-5-carbonyl)benzon methyl 4-((4-amino-5-(4-cyanobenzoyl)thiazol-2-yl)amino)benzoate;
4-(4-amino-2-((4-(dimethylamino)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(benzyloxy)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((3-nitrophenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(cyclohexylmethyl)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((3-(trifluoromethyl)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(methylthio)phenyl)amino)thiazole-5-carbonyl)benzonitrile; or
4-(4-amino-2-((4-(trifluoromethoxy)phenyl)amino)thiazole-5-carbonyl)benzonitrile.
2. The compound according to claim 1 , wherein R1A and R1 B are each independently selected from H, optionally substituted Ci-C4 alkyl, optionally substituted Ci-C4 alkenyl, optionally substituted Ci-C4 alkynyl, Ci-C3fluoroalkyl, C1-C3 hydroxyalkyi, (C1-C3 alkoxy)Ci-C3alkyl, -C(0)R1C and -S(0)i.2R1c.
3. The compound according to claim 1 or claim 2, wherein each R1C is independently selected from H, C1-C4 alkyl, Ci-C3 fluoroalkyi, Ci-C3 hydroxyalkyi and (Ci-C3 alkoxy)Ci-C3 alkyl.
4. The compound according to claim 1 or claim 2, wherein each R1C is independently selected from H and C1-C4 alkyl.
5. The compound according to any of claims 1 -4, wherein each R1 D is independently selected from H, C1-C4 alkyl, Ci-C3 fluoroalkyi, Ci-C3 hydroxyalkyi and (Ci-C3 alkoxy)Ci-C3 alkyl.
6. The compound according to any of claims 1 -4, wherein each R1 D is independently selected from H and C1-C4 alkyl.
7. The compound according to claim 1 , wherein R1A is H.
8. The compound according to claim 1 , wherein R1A is not H.
9. The compound according to claim 1 , wherein R1A is -(C1-C4 alkyl), -C(0)-(Ci-C4 alkyl), or -C(0)-(Ci-C4 alkenyl).
10. The compound according to any of claims 1 -9, wherein R1 B is H.
1 1 . The compound according to any of claims 1 -9, wherein R1 B is Ci-C4 alkyl.
12. The compound according to any of claims 1 -9, wherein R1 B is -C(0)R1C, in which R1C is H, optionally substituted Ci-C4 alkyl, optionally substituted Ci-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyi, C1-C3 hydroxyalkyl or (C1-C3 alkoxy)Ci-C3 alkyl.
13. The compound according to claim 1 , wherein the -NR1AR1 B is -N(Ci-C4 alkyl)(Ci-C4 alkyl).
14. The compound according to claim 1 , wherein the -NR1AR1 B is -NH2.
15. The compound according to claim 1 , wherein the -NR1AR1 B is -N(CH3)2, -NHC(0)CH3, -NHC(0)CH=CH2 or -NHC(0)CH2CH3.
16. The compound according to any of claims 1 -15, wherein the ring system denoted by "A" is phenyl.
17. The compound according to any of claims 1 -15, wherein the ring system denoted by "A" is a 5- or 6-membered heteroaryl having one or two heteroatoms selected from N, O and S.
18. The compound according to any of claims 1 -15, wherein the ring system denoted by "A" is a 5- or 6-membered heteroaryl having one heteroatom selected from N, O and S.
19. The compound according to any of claims 1 -15, wherein the ring system denoted by "A" is pyridyl.
20. The compound according to any of claims 17-19, wherein R2 is H.
21 . The compound according to any of claims 1 -20, wherein R2 is C1-C3 fluoroalkyi, halogen, -NR2AR2B, nitro, or -CN.
22. The compound according to any of claims 1 -18, wherein R2 is -CN.
23. The compound according to any of claims 1 -18, wherein R2 is halogen, e.g., chloro or fluoro.
24. The compound according to any of claims 1-18, wherein R2 is nitro.
25. The compound according to any of claims 1-18, wherein R2 is -C(0)R2A, -S(0)i-2R2A, -C(0)R2A, -C(0)NR2BR2A, -C(S)NR2BR2A,-C(0)OR2A, -C(0)SR2A, -C(S)OR2A, -C(S)SR2A, -S(0)i-2OR2A or -S(0)i-2NR2BR2A.
26. The compound according to any of claims 1-18, wherein R2 is selected from C1-C3 fluoroalkyi, halogen, nitro, -CN, -C(0)R2A, -S(0)i_2R2A, -C(0)R2A, -C(0)NR2BR2A, -C(S)NR2BR2A,-C(0)OR2A, -C(0)SR2A, -C(S)OR2A, -C(S)SR2A, -S(0)i_2OR2A and
Figure imgf000105_0001
27. The compound according to any of claims 1-18, wherein R2 is C1-C3 fluoroalkyi, halogen, nitro, or -CN.
28. The compound according to any of claims 1-27, wherein each R2A is independently selected from H, Ci-C4 alkyl, C1-C3 fluoroalkyi, C1-C3 hydroxyalkyi and (Ci-C3 alkoxy)Ci-C3 alkyl.
29. The compound according to any of claims 1-27, wherein each R2A is selected from H and C1-C4 alkyl.
30. The compound according to any of claims 1-29, wherein each R2B is independently selected from H, C1-C4 alkyl, Ci-C3 fluoroalkyi, Ci-C3 hydroxyalkyi, (Ci-C3 alkoxy)Ci-C3 alkyl, -C(0)(Ci-C3 alkyl) and -C(0)0(Ci-C3 alkyl).
31. The compound according to any of claims 1-29, wherein each R2B is independently selected from H and C1-C4 alkyl.
32. The compound according to any of claims 1-31 , wherein the ring system denoted by "A" is a six-membered ring, and wherein the R2 is disposed in a 1 ,4 relationship with respect to the thienylcarbonyl.
33. The compound according to any of claims 1-31 , wherein the R2 is disposed in a 1 ,3 relationship with respect to the thienylcarbonyl.
34. The compound according to any of claims 1-31 , wherein the R2 is disposed in a 1 ,2 relationship with respect to the thienylcarbonyl. The compound according to any of claims 1-14 and 21-31, having the structural formula
Figure imgf000106_0001
The compound according to any of claims 1-14 and 21-31, having the structural formula
Figure imgf000106_0002
The compound accordin to any of claims 1-14 and 21-31, having the structural formula
Figure imgf000106_0003
The compound according to any of claims 1-14 and 20-34, having the structural formula
Figure imgf000106_0004
The compound according to any of claims 1-14 and 20-34, having the structural formula
Figure imgf000107_0001
The compound according to any of claims 1-14 and 20-34, having the structural formula
Figure imgf000107_0002
41. The compound according to any of claims 1-40, wherein each R3 is independently selected from optionally substituted Ci-C4 alkyl, optionally substituted Ci-C4 alkenyl, optionally substituted Ci-C4 alkynyl, C1-C3 fluoroalkyi, halogen, nitro, -CN, -SF5, -N3, -C(0)R3A, -SR3A, -S(0)i-2R3A, -OR3A, -NR3BR3A, -C(0)R3A, -C(0)NR3BR3A, -NR3BC(0)R3A, -C(S)NR3BR3A, -NR3BC(S)R3A, -C(0)OR3A, -OC(0)R3A, -C(0)SR3A, -SC(0)R3A, -C(S)OR3A, -OC(S)R3A, -C(S)SR3A, -SC(S)R3A, -S(0)i_2OR3A, -OS(0)i_2R3A, -S(0)i_2NR3BR3A and
Figure imgf000107_0003
42. The compound according to any of claims 1-40, wherein each R3 is independently selected from optionally substituted C1-C4 alkyl, optionally substituted Ci-C alkenyl, optionally substituted Ci-C4 alkynyl, C1-C3 fluoroalkyi, halogen, nitro, -CN, -SF5, -N3, -C(0)R3A, -SR3A, -S(0)i-2R3A, -OR3A, -NR3BR3A or -C(0)R3A.
43. The compound according to any of claims 1-42, wherein each R3A is independently selected from H, optionally substituted Ci-C alkyl, C1-C3 fluoroalkyi, Ci-C3 hydroxyalkyi and (C1-C3 alkoxy)Ci-C3 alkyl.
44. The compound according to any of claims 1-42, wherein each R3A is H, Ci-C alkyl or Ci- C fluoroalkyi.
45. The compound according to any of claims 1-44, wherein each R3B is H, -C(0)-(Ci-C alkyl), -C(0)-(Ci-C4 fluoroalkyi), C1-C4 alkyl or C1-C4 fluoroalkyi.
46. The compound according to any of claims 1-40, wherein each R3 is independently Ci-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -C(0)R3A, -S(0)i-2R3A, or -OR3A, in which each R3A is independently H, C1-C4 alkyl, C1-C4 alkenyl, Ci-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl or (C1-C3 alkoxy)Ci-C3 alkyl.
47. The compound according to any of claims 1 -46, wherein m is 0, 1 or 2.
48. The compound according to any of claims 1 -46, wherein m is 1 or 2.
49. The compound according to any of claims 1-46, wherein m is 0.
50. The compound according to any of claims 1-49, wherein the ring system denoted by "B" is phenyl.
51. The compound according to any of claims 1-49, wherein the ring system denoted by "B" is a 5- or 6-membered heteroaryl having one or two heteroatoms selected from N, O and S.
52. The compound according to any of claims 1-49, wherein the ring system denoted by "B" is a 5- or 6-membered heteroaryl having one heteroatom selected from N, O and S.
53. The compound according to any of claims 1-52, wherein each R4 is independently selected from optionally substituted Ci-C4 alkyl, optionally substituted Ci-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R4A, -SR4A, -S(0)i-2R4A, -OR4A, -NR4BR4A, -C(0)R4A, -C(0)NR4BR4A, -NR4BC(0)R4A, -C(S)NR4BR4A, -NR4BC(S)R4A, -C(0)OR4A, -OC(0)R4A, -C(0)SR4A, -SC(0)R4A, -C(S)OR4A, -OC(S)R4A, -C(S)SR4A, -SC(S)R4A, -S(0)i_2OR4A, -OS(0)i_2R4A, -S(0)i_2NR4BR4A and
Figure imgf000108_0001
54. The compound according to any of claims 1-52, wherein each R4 is independently selected from optionally substituted Ci-C4 alkyl, optionally substituted Ci-C4 alkenyl, optionally substituted C1-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -SF5, -N3, -C(0)R4A, -SR4A, -S(0)i-2R4A, -OR4A, -NR4BR4A or -C(0)R4A.
55. The compound according to any of claims 1-52, wherein each R4 is independently Ci-C4 alkyl, Ci-C4 alkenyl, Ci-C4 alkynyl, C1-C3 fluoroalkyl, halogen, nitro, -CN, -C(0)R4A, -S(0)i-2R4A, or -OR4A, in which each R4A is independently H, C1-C4 alkyl, C1-C4 alkenyl, Ci-C4 alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl or (C1-C3 alkoxy)Ci-C3 alkyl.
56. The compound according to any of claims 1 -52, wherein each R4 is independently halogen (e.g., chloro or fluoro).
57. The compound according to any of claims 1-52, wherein each R4 is independently Ci-C alkyl.
58. The compound according to any of claims 1-52, wherein each R4 is independently nitro.
59. The compound according to any of claims 1-52, wherein each R4 is independently Ci-C alkyl, Ci-C alkenyl, Ci-C alkynyl, or C1-C3 fluoroalkyl.
60. The compound according to any of claims 1-52, wherein each R4 is independently -OR4A, in which R4A is independently H, Ci-C alkyl, Ci-C alkenyl, Ci-C alkynyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl or (C1-C3 alkoxy)Ci-C3 alkyl.
61. The compound according to any of claims 1-55, wherein each R4A is H, Ci-C alkyl or Ci- C fluoroalkyl.
62. The compound according to any of claims 1-54, wherein each R4B is H, -C(0)-(Ci-C alkyl), -C(0)-(Ci-C4 fluoroalkyl), Ci-C4 alkyl or Ci-C4 fluoroalkyl.
63. The compound according to any of claims 1-62, wherein n is 1 or 2.
64. The compound according to any of claims 1-62, wherein n is 0.
65. The compound according to any of claims 1 -64, wherein each optionally substituted alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene is unsubstituted or substituted with 1-5 substituents independently selected from halogen, nitro, -CN, -SF5, -N3, -C(0)R5, -SR5, -S(0)i-2Rs, -OR5, -NR6R5, -C(0)NR6R5, -NR6C(0)R5, -C(S)NR6R5, -NR6C(S)R5, -C(0)OR5, -OC(0)R5, -C(0)SR5, -SC(0)R5, -C(S)OR5, -OC(S)R5, -C(S)SR5, -SC(S)R5, -S(0)i_2OR5, -OS(0)i-2Rs, -S(0)i-2NR6R5, and -NR6S(0)i.2R5.
66. The compound according to any of claims 1 -64, wherein each optionally substituted alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene is unsubstituted or substituted with 1-5 substituents independently selected from halogen, nitro, -CN, -SF5, -N3, -C(0)R5, -SR5, -S(0)i-2R5, -OR5 and -NR6R5.
67. The compound according to any of claims 1 -64, wherein each optionally substituted alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene is unsubstituted.
68. The compound according to any of claims 1 -64, wherein each optionally substituted alkyl, alkenyl, alkynyl, alkylene, alkenylene or alkynylene is an optionally substituted alkyl or alkylene.
69. The compound according to any of claims 1 -68 wherein each R5 is independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl.
70. The compound according to any of claims 1-69, wherein each R6 is independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl.
71. A compound according to any of claims 1-70, in the form of an N-oxide.
72. A compound according to claim 1 , wherein the compound is
(4-Amino-2-phenylamino-thiazol-5-yl)-phenyl-methanone;
(4-Amino-2-phenylamino-thiazol-5-yl)-(4-chloro-phenyl)-methanone;
(4-Amino-2-phenylamino-thiazol-5-yl)-(4-bromo-phenyl)-methanone;
(4-Amino-2-phenylamino-thiazol-5-yl)-(4-nitro-phenyl)-methanone;
4-(4-Amino-2-phenylamino-thiazole-5-carbonyl)-benzonitrile;
(4-Amino-2-phenylamino-thiazol-5-yl)-(3,4-dimethoxy-phenyl)-methanone;
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-phenyl-methanone;
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-fluoro-phenyl)-methanone;
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-chloro-phenyl)-methanone;
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-bromo-phenyl)-methanone;
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(4-nitro-phenyl)-methanone;
4-[4-Amino-2-(4-chloro-phenylamino)-thiazole-5-carbonyl]-benzonitrile;
[4-Amino-2-(4-chloro-phenylamino)-thiazol-5-yl]-(3,4-dimethoxyphenyl)-methanone;
[4-Amino-2-(4-fluoro-phenylamino)-thiazol-5-yl]-phenyl-methanone;
[4-Amino-2-(4-fluoro-phenylamino)-thiazol-5-yl]-(4-chloro-phenyl)-methanone;
[4-Amino-2-(4-fluoro-phenylamino)-thiazol-5-yl]-(4-bromo-phenyl)-methanone;
[4-Amino-2-(4-fluoro-phenylamino)-thiazol-5-yl]-(4-nitro-phenyl)-methanone;
4-[4-Amino-2-(4-fluoro-phenylamino)-thiazole-5-carbonyl]-benzonitrile; [4-Amino-2-(4-fluoro-phenylamino)-thiazol-5-yl]-(3,4-dimethoxy^henyl)-methanone;
(4-Amino-2-p-tolylamino-thiazol-5-yl)-phenyl-methanone;
(4-Amino-2-p-tolylamino-thiazol-5-yl)-(4-fluoro-phenyl)-methanone;
(4-Amino-2-m-tolylamino-thiazol-5-yl)-(3-chloro-phenyl)-methanone;
(4-Amino-2-p-tolylamino-thiazol-5-yl)-(3-chloro-phenyl)-methanone;
(4-Amino-2-m-tolylamino-thiazol-5-yl)-(4-chloro-phenyl)-methanone;
(4-Amino-2-p-tolylamino-thiazol-5-yl)-(4-chloro-phenyl)-methanone;
(4-Amino-2-p-tolylamino-thiazol-5-yl)-(3,4-dichloro-phenyl)-methanone;
(4-Amino-2-p-tolylamino-thiazol-5-yl)-(4-bromo-phenyl)-methanone
(4-Amino-2-p-tolylamino-thiazol-5-yl)-(4-nitro-phenyl)-methanone;
3-(4-Amino-2-m-tolylamino-thiazole-5-carbonyl)-benzonitrile;
3- (4-Amino-2-p-tolylamino-thiazole-5-carbonyl)-benzonitrile;
4- (4-Amino-2-m-tolylamino-thiazole-5-carbonyl)-benzonitrile;
4-(4-Amino-2-p-tolylamino-thiazole-5-carbonyl)-benzonitrile;
(4-Amino-2-p-tolylamino-thiazol-5-yl)-pyridin-2-yl-methanone;
(4-Amino-2-p-tolylamino-thiazol-5-yl)-pyridin-3-yl-methanone;
(4-Amino-2-p-tolylamino-thiazol-5-yl)-pyridin-4-yl-methanone;
(4-Amino-2-p-tolylamino-thiazol-5-yl)-(3,4-dimethoxy-phenyl)-methanone;
4-[4-Amino-2-(3,4-dimethyl-phenylamino)-thiazole-5-carbonyl]-benzonitrile;
3-[4-Amino-2-(3,4-dimethyl-phenylamino)-thiazole-5-carbonyl]-benzonitrile;
[4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]-(3-chloro-phenyl)-methanone;
3- [4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazole-5-carbonyl]-benzonitrile;
4- [4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazole-5-carbonyl]-benzonitrile;
4-[4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazole-5-carbonyl]-benzoic acid;
[4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]-(4-dimethylamino-phenyl)- methanone;
[4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]-pyridin-3-yl-methanone;
[4-Amino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]-pyridin-4-yl-methanone;
4-[4-Amino-5-(4-fluoro-benzoyl)-thiazol-2-ylamino]-benzonitrile;
4-[4-Amino-5-(4-chloro-benzoyl)-thiazol-2-ylamino]-benzonitrile;
4-[4-Amino-5-(4-bromo-benzoyl)-thiazol-2-ylamino]-benzonitrile;
4-[4-Amino-5-(4-cyano-benzoyl)-thiazol-2-ylamino]-benzonitrile;
4-[4-Amino-2-(4-hydroxymethyl-phenylamino)-thiazole-5-carbonyl]-benzonitrile;
4-[4-Amino-5-(4-cyano-benzoyl)-thiazol-2-ylamino]-benzoic acid ethyl ester;
4-[4-Amino-5-(4-chloro-benzoyl)-thiazol-2-ylamino]-benzoic acid;
4-[4-Amino-5-(4-cyano-benzoyl)-thiazol-2-ylamino]-benzoic acid;
[4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-phenyl-methanone; [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-fluoro-phenyl)-methanone;
[4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(3-chloro-phenyl)-methanone;
[4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-chloro-phenyl)-methanone;
[4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(3,4-dichloro^henyl)-methanone;
[4-Amino-2-(4-methoxy^henylamino)-thiazol-5-yl]-(4-bromo-phenyl)-methanone;
[4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(4-nitro-phenyl)-methanone;
3- [4-Amino-2-(4-methoxy-phenylamino)-thiazole-5-carbonyl]-benzonitrile;
4- [4-Amino-2-(4-methoxy-phenylamino)-thiazole-5-carbonyl]-benzonitrile;
4-[4-Amino-2-(4-methoxy-phenylamino)-thiazole-5-carbonyl]-benzoic acid;
[4-Amino-2-(4-methoxy^henylamino)-thiazol-5-yl]-pyridin-3-yl-methanone;
[4-Amino-2-(4-methoxy^henylamino)-thiazol-5-yl]-pyridin-4-yl-methanone;
[4-Amino-2-(4-methoxy^henylamino)-thiazol-5-yl]-(4-dimethylamino-phenyl)-methan [4-Amino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-(3,4-dimethoxy^henyl)-methanone;
[4-Amino-2-(4-trifluoromethoxy-phenylamino)-thiazol-5-yl]-(3-chloro-phenyl)-methano 4-[4-Amino-2-(4-trifluoromethoxy-phenylamino)-thiazole-5-carbonyl]-benzonitrile; 4-[4-Amino-2-(4-trifluoromethoxy-phenylamino)-thiazole-5-carbonyl]-benzoic acid;
[4-Amino-2-(4-trifluoromethoxy-phenylamino)-thiazol-5-yl]-(4-dimethylamino-pheny ^ methanone;
[4-Amino-2-(4-trifluoromethoxy-phenylamino)-thiazol-5-yl]-pyridin-3-yl-methanone;
[4-Amino-2-(4-trifluoromethoxy-phenylamino)-thiazol-5-yl]-pyridin-4-yl-methanone; 4-[4-Amino-5-(4-chloro-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide;
4-[4-Amino-5-(4-cyano-benzoyl)-thiazol-2-ylamino]-benzenesulfonamide;
3- [4-Amino-2-(4-tert-butyl-phenylamino)-thiazole-5-carbonyl]-benzonitrile;
4- [4-Amino-2-(4-tert-butyl-phenylamino)-thiazole-5-carbonyl]-benzonitrile;
N-[5-(3-Cyano-benzoyl)-2-p-tolylamino-thiazol-4-yl]-acetamide;
N-[5-(4-Cyano-benzoyl)-2-p-tolylamino-thiazol-4-yl]-acetamide;
N-[5-(3-Cyano-benzoyl)-2-p-tolylamino-thiazol-4-yl]-propionamide;
N-[5-(4-Cyano-benzoyl)-2-p-tolylamino-thiazol-4-yl]-propionamide;
N-[5-(3-Cyano-benzoyl)-2-p-tolylamino-thiazol-4-yl]-acrylamide;
N-[5-(4-Cyano-benzoyl)-2-p-tolylamino-thiazol-4-yl]-acrylamide;
(4-Bromo-phenyl)-[4-dimethylamino-2-(4-fluoro^henylamino)-thiazol-5-yl]-methanone; (4-Dimethylamino-2-p-tolylamino-thiazol-5-yl)-phenyl-methanone;
(4-Chloro-phenyl)-(4-dimethylamino-2-p-tolylamino-thiazol-5-yl)-methanone;
(4-Chloro-phenyl)-(4-dimethylamino-2-m-tolylamino-thiazol-5-yl)-methanone;
(3-Chloro-phenyl)-(4-dimethylamino-2-m-tolylamino-thiazol-5-yl)-methanone;
(4-Bromo-phenyl)-(4-dimethylamino-2^-tolylamino-thiazol-5-yl)-methanone;
(4-Dimethylamino-2-p-tolylamino-thiazol-5-yl)-(4-nitro-phenyl)-methanone; 3-(4-Dimethylamino-2-p-tolylamino-thiazole-5-carbonyl)-benzonitrile;
3- (4-Dimethylamino-2-m-tolylamino-thiazole-5-carbonyl)-benzonitrile;
4- (4-Dimethylamino-2-m-tolylamino-thiazole-5-carbonyl)-benzonitrile;
4-(4-Dimethylamino-2-p-tolylamino-thiazole-5-carbonyl)-benzonitrile;
(4-Dimethylamino-2-p-tolylamino-thiazol-5-yl)-pyridin-2-yl-methanone^
(4-Dimethylamino-2-p-tolylamino-thiazol-5-yl)-pyridin-3-yl-methanone;
(4-Dimethylamino-2-p-tolylamino-thiazol-5-yl)-pyridin-4-yl-methanone;
4-[4-Dimethylamino-2-(3,4-dimethyl-phenylamino)-thiazole-5-carbonyl]-ben
3- [4-Dimethylamino-2-(3,4-dimethyl-phenylamino)-thiazole-5-carbonyl]-ben
4- [4-Dimethylamino-2-(4-trifluoromethyl-phenylamino)-thiazole-5-carbonyl]-^ acid;
3- [4-Dimethylamino-2-(4-trifluoromethyl-phenylamino)-thiazole-5-carbonyl]-^
[4-Dimethylamino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]-pyri
[4-Dimethylamino-2-(4-trifluoromethyl-phenylamino)-thiazol-5-yl]-pyri
4- [4-Dimethylamino-2-(4-hydroxymethyl-phenylamino)-thia^
4-[5-(3-Cyano-benzoyl)-4-dimethylamino-thiazol-2-ylamino]-benzoic acid ethyl ester; 4-[4-Amino-5-(3-cyano-benzoyl)-thiazol-2-ylamino]-benzoic acid;
(3-Chloro-phenyl)-[4-dimethylamino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-methano (4-Chloro-phenyl)-[4-dimethylamino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-methano (3,4-Dichloro-phenyl)-[4-dimethylamino-2-(4-methoxy-phenylamino)-thiazol-5-yl]- methanone;
(4-Bromo-phenyl)-[4-dimethylamino-2-(4-methoxy-phenylamino)-thiazol-5-yl]-methan 4-[4-Dimethylamino-2-(4-methoxy-phenylamino)-thiazole-5-carbonyl]-benzonitrile;
3- [4-Dimethylamino-2-(4-methoxy-phenylamino)-thiazole-5-carbonyl]-benzonitrile;
4- [4-Dimethylamino-2-(4-methoxy-phenylamino)-thiazole-5-carbonyl]-benzoic acid; (3-Chloro-phenyl)-[4-dimethylamino-2-(4-trifluoromethoxy-phenylamino)-thiazol-5-yl]- methanone;
4-[4-Dimethylamino-2-(4-trifluoromethoxy-phenylamino)-thiazole-5-carbonyl]-benzoic acid;
4-[4-Dimethylamino-2-(4-trifluoromethoxy-phenylamino)-thiazole-5-carbonyl]-benzon [4-Dimethylamino-2-(4-trifluoromethoxy-phenylamino)-thiazol-5-yl]-pyridin-3-yl- methanone; or
[4-Dimethylamino-2-(4-trifluoromethoxy-phenylamino)-thiazol-5-yl]-pyridin-4-yl- methanone.
73. A compound according to any of claims 1 -72, in the form of a pharmaceutically acceptable salt.
74. A compound according any of claims 1-72, in the form of a base compound.
75. A compound according to any of claims 1-74, in the form of a solvate or hydrate.
76. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier, excipient or diluent, and a compound according to any of claims 1-75 or a compound selected from the group consisting of
(4-amino-2-((4-methoxyphenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-chlorophenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
4-((4-amino-5-(4-chlorobenzoyl)thiazol-2-yl)amino)benzonitrile;
(4-amino-2-(p-tolylamino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-(trifluoromethyl)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone; methyl 4-((4-amino-5-(4-chlorobenzoyl)thiazol-2-yl)amino)benzoate;
(4-amino-2-((4-(dimethylamino)phenyl)amino)thiazol-5-yl)(4- chlorophenyl)methanone;
(4-amino-2-((4-(benzyloxy)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone; (4-amino-2-((3-nitrophenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-(cyclohexylmethyl)phenyl)amino)thiazol-5-yl)(4- chlorophenyl)methanone;
(4-amino-2-((3-(trifluoromethyl)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone; (4-amino-2-((4-(methylthio)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone; (4-amino-2-((4-(trifluoromethoxy)phenyl)amino)thiazol-5-yl)(4- chlorophenyl)methanone;
4-(4-amino-2-((4-methoxyphenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-chlorophenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-cyanophenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-(p-tolylamino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(trifluoromethyl)phenyl)amino)thiazole-5-carbonyl)benzonitrile; methyl 4-((4-amino-5-(4-cyanobenzoyl)thiazol-2-yl)amino)benzoate;
4-(4-amino-2-((4-(dimethylamino)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(benzyloxy)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((3-nitrophenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(cyclohexylmethyl)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((3-(trifluoromethyl)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(methylthio)phenyl)amino)thiazole-5-carbonyl)benzonitrile; and
4-(4-amino-2-((4-(trifluoromethoxy)phenyl)amino)thiazole-5-carbonyl)benzonitrile, optionally in the form of a pharmaceutically acceptable salt or N-oxide, or a solvate or hydrate.
77. A pharmaceutical composition according to claim 76, wherein the pharmaceutical composition is in the form of a tablet, a capsule, a caplet or an injectable mixture.
78. A method of treating or preventing a disorder selected from hyperproliferative disorders, inflammatory disorders, neurologic disorders and psychiatric disorders in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any of claims 1-75 or a compound selected from the group consisting of
(4-amino-2-((4-methoxyphenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-chlorophenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
4-((4-amino-5-(4-chlorobenzoyl)thiazol-2-yl)amino)benzonitrile;
(4-amino-2-(p-tolylamino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-(trifluoromethyl)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone; methyl 4-((4-amino-5-(4-chlorobenzoyl)thiazol-2-yl)amino)benzoate;
(4-amino-2-((4-(dimethylamino)phenyl)amino)thiazol-5-yl)(4- chlorophenyl)methanone;
(4-amino-2-((4-(benzyloxy)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone; (4-amino-2-((3-nitrophenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone;
(4-amino-2-((4-(cyclohexylmethyl)phenyl)amino)thiazol-5-yl)(4- chlorophenyl)methanone;
(4-amino-2-((3-(trifluoromethyl)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone; (4-amino-2-((4-(methylthio)phenyl)amino)thiazol-5-yl)(4-chlorophenyl)methanone; (4-amino-2-((4-(trifluoromethoxy)phenyl)amino)thiazol-5-yl)(4- chlorophenyl)methanone;
4-(4-amino-2-((4-methoxyphenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-chlorophenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-cyanophenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-(p-tolylamino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(trifluoromethyl)phenyl)amino)thiazole-5-carbonyl)benzonitrile; methyl 4-((4-amino-5-(4-cyanobenzoyl)thiazol-2-yl)amino)benzoate;
4-(4-amino-2-((4-(dimethylamino)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(benzyloxy)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((3-nitrophenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(cyclohexylmethyl)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((3-(trifluoromethyl)phenyl)amino)thiazole-5-carbonyl)benzonitrile;
4-(4-amino-2-((4-(methylthio)phenyl)amino)thiazole-5-carbonyl)benzonitrile; and 4-(4-amino-2-((4-(trifluoromethoxy)phenyl)amino)thiazole-5-carbonyl)benzon optionally in the form of a pharmaceutically acceptable salt or N-oxide, or a solvate or hydrate.
79. The method according to claim 78, wherein the disorder is selected from the group consisting of cancer, atherosclerosis, restenosis, mesangial cell proliferative disorders, and psoriasis.
80. The method according to claim 78, wherein the disorder is selected from the group consisting of head and neck cancers, lung cancers, gastrointestinal tract cancers, breast cancers, gynecologic cancers, testicular cancers, urinary tract cancers, neurological cancers, endocrine cancers, skin cancers, sarcomas, mediastinal cancers, retroperitoneal cancers, cardiovascular cancers, mastocytosis, carcinosarcomas, cylindroma, dental cancers, esthesioneuroblastoma, urachal cancer, Merkel cell carcinoma, paragangliomas, Hodgkin lymphoma, non-Hodgkin lymphoma, chronic leukemias, acute leukemias, myeloproliferative cancers, plasma cell dyscrasias, and myelodysplasia syndromes.
81 . The method according to claim 78, wherein the disorder is a mesangial cell proliferative disorder selected from the group consisting of glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies.
82. The method according to claim 78, wherein the disorder is an inflammatory disorder selected from the group consisting of inflammatory bowel disease, arthritis, atherosclerosis, asthma, allergy, inflammatory kidney disease, circulatory shock, multiple sclerosis, chronic obstructive pulmonary disease, skin inflammation, periodontal disease, psoriasis and T cell-mediated diseases of immunity.
83. The method according to claim 78, wherein the disorder is an inflammatory bowel disease selected from the group consisting of ulcerative colitis, Crohn's Disease and indeterminate colitis.
84. The method according to claim 78, wherein the disorder is a T cell-mediated disease of immunity selected from the group consisting of allergic encephalomyelitis, allergic neuritis, transplant allograft rejection, graft versus host disease, myocarditis, thyroiditis, nephritis, systemic lupus erthematosus, and insulin-dependent diabetes mellitus.
85. The method according to claim 78, wherein the disorder is an arthritic disorder selected from the group consisting of rheumatoid arthritis, osteoarthritis, Caplan's Syndrome, Felty's Syndrome, Sjogren's Syndrome, ankylosing spondylitis, Still's Disease, Chondrocalcinosis, gout, rheumatic fever, Reiter's Disease and Wissler's Syndrome.
86. The method according to claim 78, wherein the disorder is an inflammatory kidney disease selected from the group consisting of glomerulonephritis, glomerular injury, nephrotic syndrome, interstitial nephritis, lupus nephritis, Goodpasture's disease, Wegener's granulomatosis, renal vasculitis, IgA nephropathy and idiopathic glomerular disease.
87. The method according to claim 78, wherein the disorder is a skin inflammation disorder selected from the group consisting of psoriasis, atopic dermatitis, contact sensitivity and acne.
88. The method according to claim 78, wherein the neurologic or psychiatric disorder is selected from the group consisting of Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinsons disease, Huntington's disease, stroke, traumatic brain injury, bipolar disorder, schizophrenia, anxiety and depression.
89. A method of inhibiting GSK3 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any of claims 1 - 75, a pharmaceutical composition according to any of claims 76-77, or using a method according to any of claims 78-88.
90. A method of treating a disorder resulting from abnormal activation of GSK3 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any of claims 1 -75, a pharmaceutical composition according to any of claims 76-77, or using a method according to any of claims 78-88.
91 . A method of inhibiting SK in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any of claims 1 - 75, a pharmaceutical composition according to any of claims 76-77, or using a method according to any of claims 78-88.
92. A method of treating a disorder resulting from abnormal activation of SK in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any of claims 1 -75, a pharmaceutical composition according to any of claims 76-77, or using a method according to any of claims 78-88.
93. A method of inhibiting CDK9 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any of claims 1 - 75, a pharmaceutical composition according to any of claims 76-77, or using a method according to any of claims 78-88.
94. A method of treating a disorder resulting from abnormal activation of CDK9 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any of claims 1 -75, a pharmaceutical composition according to any of claims 76-77, or using a method according to any of claims 78-88.
95. A method of inhibiting microtubules in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any of claims 1 - 75, a pharmaceutical composition according to any of claims 76-77, or using a method according to any of claims 78-88.
96. A method of treating a disorder resulting from abnormal activation of microtubules in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any of claims 1 -75, a pharmaceutical composition according to any of claims 76-77, or using a method according to any of claims 78-88.
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