WO2018089902A1 - Composés de diaminothiazole, compositions et procédés d'utilisation associés - Google Patents

Composés de diaminothiazole, compositions et procédés d'utilisation associés Download PDF

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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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amino
thiazol
alkyl
methanone
phenyl
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Charles D. Smith
Yan Zhuang
Lynn W. Maines
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Apogee Biotechnology Corp
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Apogee Biotechnology Corp
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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

L'invention concerne des dérivés de diaminothiazole de formule (I), dans laquelle les variables sont telles que définies dans la description, l'invention concerne en outre, des compositions pharmaceutiques contenant de tels composés, et des procédés pour l'utilisation de tels composés et compositions pour le traitement de maladies et de troubles hyperprolifératifs, inflammatoires ou neurologiques.
PCT/US2017/061327 2016-11-13 2017-11-13 Composés de diaminothiazole, compositions et procédés d'utilisation associés Ceased WO2018089902A1 (fr)

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JP2023522250A (ja) * 2020-04-24 2023-05-29 バイエル・アクチエンゲゼルシヤフト 免疫活性化のためのｄｇｋｚｅｔａ阻害剤としての置換アミノチアゾール類
CN116813608A (zh) * 2023-06-08 2023-09-29 英矽智能科技(上海)有限公司 噻唑类化合物及其应用
WO2024235203A1 (fr) * 2023-05-15 2024-11-21 微境生物医药科技(上海)有限公司 COMPOSÉ UTILISÉ COMME INHIBITEUR DE DGKζ
WO2025167814A1 (fr) * 2024-02-06 2025-08-14 微境生物医药科技(上海)有限公司 COMPOSÉ UTILISÉ EN TANT QU'INHIBITEUR DE DGKζ

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Publication number Priority date Publication date Assignee Title
JP2023522250A (ja) * 2020-04-24 2023-05-29 バイエル・アクチエンゲゼルシヤフト 免疫活性化のためのｄｇｋｚｅｔａ阻害剤としての置換アミノチアゾール類
JP7663603B2 (ja) 2020-04-24 2025-04-16 バイエル・アクチエンゲゼルシヤフト 免疫活性化のためのｄｇｋｚｅｔａ阻害剤としての置換アミノチアゾール類
JP2025120943A (ja) * 2020-04-24 2025-08-18 バイエル・アクチエンゲゼルシヤフト 免疫活性化のためのｄｇｋｚｅｔａ阻害剤としての置換アミノチアゾール類
WO2024235203A1 (fr) * 2023-05-15 2024-11-21 微境生物医药科技(上海)有限公司 COMPOSÉ UTILISÉ COMME INHIBITEUR DE DGKζ
CN116813608A (zh) * 2023-06-08 2023-09-29 英矽智能科技(上海)有限公司 噻唑类化合物及其应用
CN116813608B (zh) * 2023-06-08 2024-03-22 英矽智能科技(上海)有限公司 噻唑类化合物及其应用
WO2025167814A1 (fr) * 2024-02-06 2025-08-14 微境生物医药科技(上海)有限公司 COMPOSÉ UTILISÉ EN TANT QU'INHIBITEUR DE DGKζ

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