WO2017044575A1 - Benzhydryl sulfonamides contraints utilisés en tant qu'agents anticancéreux et neuroprotecteurs - Google Patents

Benzhydryl sulfonamides contraints utilisés en tant qu'agents anticancéreux et neuroprotecteurs Download PDF

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WO2017044575A1
WO2017044575A1 PCT/US2016/050696 US2016050696W WO2017044575A1 WO 2017044575 A1 WO2017044575 A1 WO 2017044575A1 US 2016050696 W US2016050696 W US 2016050696W WO 2017044575 A1 WO2017044575 A1 WO 2017044575A1
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alkyl
hydrogen
compound
compound according
haloalkyl
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Michael Ohlmeyer
David KASTRINSKY
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Icahn School Of Medicine At Mount Sinai
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes 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 in position 9
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
    • C07D335/12—Thioxanthenes
    • C07D335/14—Thioxanthenes 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 in position 9
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings

Definitions

  • the invention relates to the use of chemical modulators of PP2A, comprising constrained benzhydryl sulfonamides to treat diseases such as cancer, neurodegenerative disease and other disorders.
  • the FOXO (Forkhead transcription factors, Class O) proteins are a group of transcription factors involved in control of a variety of physiological, metabolic and developmental pathways. They are downstream effectors in a number of signaling pathways including insulin and growth factor signaling; they are also regulated by oxidative stress and nutrient deprivation. Cellular processes affected by FOXO activity include cell cycle control, differentiation, proliferation and apoptosis. Disregulation of FOXO mediated processes has been implicated in a number of pathologies including tumorigenesis, inflammation, diabetes and neurodegenerative conditions amongst others. Activity of FOXO transcription factors are controlled in part by their sub-cellular localization, in particular their localization to the nucleus from the cytosol, and their subsequent transcriptional activation.
  • FOXO proteins designated FOXOl, FOX03a, FOX04 and FOX06 are present in human cells and their activity is controlled by a variety of mechanisms including stability (proteolytic cleavage), sub-cellular localization and transcriptional activation. Activity of the first three members of the family is controlled by cytosolic-nuclear translocation.
  • FOXOl regulates expression of a number of genes that play critical roles in cell cycle and apoptosis.
  • a pivotal regulatory mechanism of FOXO is reversible
  • phosphorylation catalyzed by kinases and phosphatases.
  • Phosphorylation of FOXOl is associated with 14-3-3 binding and cytosolic localization, whereas dephosphorylated FOXOl translocates to the nucleus and is transcriptionally active.
  • Protein phosphatase 2A is one of the four major serine threonine phosphatases and is implicated in the negative control of cell growth and division.
  • Protein phosphatase 2A holoenzymes are heterotrimeric proteins composed of a structural subunit A, a catalytic subunit C, and a regulatory subunit B.
  • the PP2A heterotrimeric protein phosphatase is a ubiquitous and conserved phosphatase with broad substrate specificity and diverse cellular functions.
  • proteins of oncogenic signaling cascades such as Raf, MEK, and AKT.
  • PP2 A interacts directly with FOXOl and dephosphorylates FOXOl . Inhibition of PP2 A phosphatases rescues FOXOl -mediated cell death by regulating the level of the pro- apoptotic protein BIM. In addition, PP2 A directly regulates FOX03a subcellular localization and transcriptional activation. Without wishing to be held to any particular theory, it may be that the compounds described herein promote apoptosis by acting on FOXO transcription factors via activation of PP2A.
  • Myc proteins target proliferative and apoptotic pathways vital for progression in cancer and they are overexpressed and deregulated in many human cancers.
  • the control of Myc abundance through protein degradation has attracted considerable interest and Ser-62 phosphorylation by a number of kinases has been shown to stabilize the protein.
  • PP2A is responsible for Ser-62 dephosphorylation which primes the protein for ubiquitylation and degredation, thus PP2A functions as a negative regulator of Myc.
  • Prostate cancer is the second leading cause of cancer death in men in America, behind lung cancer. According to the American Cancer Society, approximately 1 man in 36 will die of prostate cancer. Male hormones, specifically testosterone, fuel the growth of prostate cancer. By reducing the amount and activity of testosterone, the growth of advanced prostate cancer is slowed. Endocrine therapy, known as androgen ablation, is the first line of treatment for metastatic prostate cancer. Androgen deprivation therapy for metastatic prostate cancer results in tumor regression and symptomatic improvement in the majority of patients. However, metastatic prostate cancer inevitably progresses despite castrate levels of serum testosterone. Several new therapies have been approved for patients with castration-resistant prostate cancer (CRPC); however, none are curative and tumors ultimately develop resistance. To combat CRPC new approaches and novel therapies are required.
  • CRPC castration-resistant prostate cancer
  • Breast cancer can affect both men and women. Breast cancer is the most prevalent cancer in women, after skin cancers, with about 1 in every 8 women expected to develop invasive breast cancer at some point. One subset of breast cancer expresses the androgen receptor (AR), which has been implicated as a therapeutic target in that subset. About 10- 20% of breast cancers— more than one out of every 10— are found to be triple-negative. "Triple negative breast cancer” refers to a breast cancer that does not contain estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2 (HER2). This means that the growth of the cancer is not supported by the hormones estrogen and progesterone, nor by the presence of too many HER2 receptors.
  • HER2 human epidermal growth factor receptor 2
  • triple-negative breast cancer does not respond to hormonal therapy (such as tamoxifen or aromatase inhibitors) or therapies that target HER2 receptors, such as Herceptin (chemical name: trastuzumab). While these tumors are often treatable, the chemotherapy is not targeted, and response durations are short. For doctors and researchers, there is intense interest in finding new medications that can treat breast cancer.
  • hormonal therapy such as tamoxifen or aromatase inhibitors
  • Herceptin chemical name: trastuzumab
  • the compounds described herein exhibit anti-proliferative effects and are useful as monotherapy in cancer treatment. Additionally, they can be used in combination with other drugs to restore sensitivity to chemotherapy where resistance has developed.
  • a genus of heterocyclic constrained tricyclic arylsulfonamide derivatives has now been found that induce FOXOl transcription factor translocation to the nucleus by modulating PP2A.
  • the compounds described herein exhibit anti-proliferative effects, and are useful in the treatment of a variety of disorders, including as a monotherapy in cancer treatment, or used in combination with other drugs to restore sensitivity to chemotherapy where resistance has developed.
  • R D is selected from hydrogen and (Ci-C6)alkyl
  • R B is selected from hydrogen and (Ci-C )alkyl
  • T is a benzene ring or a five- or six-membered heteroaromatic ring
  • U is a benzene ring or a five- or six-membered heteroaromatic ring
  • X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, (Ci- C 6 )haloalkylthio, - R*R 2 , -OR 1 , -C(0)R 1 , -OC(0)R 1 , -C(0) R 1 R 2 , -C(0)OR 1 , -SR. 1 , -
  • R 1 and R 2 are independently selected in each instance from the group consisting of hydrogen and (Ci-Ce)alkyl;
  • R A is -D-(CR 15 R 16 ) formulate- HS0 2 R 17 ;
  • D is chosen from -O- and - R 14 -;
  • R 14 is H or (Ci-C 3 )alkyl
  • R 15 and R 16 in each occurrence are chosen independently from H, OH, cyano, amino, (Ci-C )alkylamino, (Ci-C )dialkylamino, (Ci-C )alkyl, (Ci-C )haloalkyl, (Ci- C )haloalkoxy, and (Ci-C )alkoxy, or, taken together, two of R 14 , R 15 and R 16 may form a three to seven membered carbocycle or heterocycle wherein said three to seven membered carbocycle or heterocycle may be additionally substituted with one or two substituents chosen from OH, oxo, F, cyano, amino, (Ci-C )alkylamino, (Ci-C )dialkylamino, (Ci- C )alkyl, (Ci-C )haloalkyl, (Ci-C )haloalkoxy, and (Ci-C )alkoxy; or, taken
  • n is an integer from 2 to 4.
  • R 17 is chosen from phenyl and monocyclic heteroaryl, said phenyl and monocyclic heteroaryl optionally substituted with one or two substituents chosen from OH, halogen, cyano, nitro, (Ci-C )alkylamino, (Ci-C )dialkylamino, (Ci-C )acylamino, (Ci- C 3 )alkylsulfonyl, (Ci-C 3 )alkylthio, (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, (Ci-C 3 )haloalkoxy, and (Ci-C 3 )alkoxy.
  • substituents chosen from OH, halogen, cyano, nitro, (Ci-C )alkylamino, (Ci-C )dialkylamino, (Ci-C )acylamino, (Ci- C 3 )alkylsulfony
  • the invention relates to methods and uses of the above-described compounds in medicine, particularly for the treatment of a disease chosen from (a) cancer; (b) diabetes; (c) autoimmune disease; (d) age onset proteotoxic disease; (e) mood disorder; (f) acne vulgaris; (g) solid organ transplant rejection; (h) graft vs. host disease; i) cardiac hypertrophy; j) viral infection; and (k) parasitic infection.
  • a disease chosen from (a) cancer; (b) diabetes; (c) autoimmune disease; (d) age onset proteotoxic disease; (e) mood disorder; (f) acne vulgaris; (g) solid organ transplant rejection; (h) graft vs. host disease; i) cardiac hypertrophy; j) viral infection; and (k) parasitic infection.
  • a disease chosen from (a) cancer; (b) diabetes; (c) autoimmune disease; (d) age onset proteotoxic disease; (e) mood disorder; (f) acne vulgaris; (g)
  • the invention relates to a method for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer.
  • the method includes
  • the invention in a fourth aspect, relates to a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of PP2A influenced signaling cascades such as the PI3K-AKT, MAP kinase and mTOR pathways.
  • These methods include administering to a patient a therapeutically effective amount of a compound described herein.
  • the invention in a fifth aspect, relates to a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway.
  • These methods include administering to a patient a therapeutically effective amount of a compound described herein.
  • the invention relates to pharmaceutical compositions comprising the compounds described herein. DETAILED DESCRIPTION OF THE INVENTION
  • the invention relates to compounds of formula (II):
  • the invention relates to compounds of formula III:
  • the invention relates to compounds of formula IV:
  • the invention relates to compounds of formula IVa
  • the compound may be of formula I, II, III, IV, IVa or IVb, unless otherwise indicated.
  • R D is hydrogen. In other embodiments, R D is (Ci-C6)alkyl. In still other embodiments, R D is methyl.
  • R B is hydrogen. In other embodiments, R B is (Ci-C3)alkyl.
  • T is a benzene ring. In other embodiments, T is a five- membered heteroaromatic ring. In still other embodiments, T is a six-membered
  • U is a benzene ring. In other embodiments, U is a five- membered heteroaromatic ring. In still other embodiments, U is a six-membered
  • T and U are each independently selected from the group consisting of a benzene ring, furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiadiazole, thiazine, thiazole, thiophene, triazine, and triazole.
  • T and U are each independently selected from a benzene ring, pyridine, pyrimidine, pyridazine, thiophene, thiazole, oxazole, imidazole, pyrrole, and furan.
  • one of T and U is a benzene ring
  • the other of T and U is selected from a benzene ring, pyridine, pyrimidine, and thiophene.
  • T and U are each independently selected from a benzene ring and pyridine.
  • at least one of T and U is a benzene ring.
  • T and U are both benzene rings.
  • R A is -D-(CR 15 R 16 ) n - HS0 2 R 17 .
  • D is -0-. In other embodiments, D is - R 14 -. In some embodiments, D is - H-. In still other embodiments, D is -N(Ci-C3)alkyl-.
  • R is H. In other embodiments, R is (Ci-C3)alkyl. [0035] In some embodiments, R 15 is chosen from H, OH, cyano, amino, (Ci-C3)alkylamino, (Ci-C 3 )dialkylamino, (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, (Ci-C 3 )haloalkoxy, and (Ci- C 3 )alkoxy.
  • R 16 is chosen from H, OH, cyano, amino, (Ci-C 3 )alkylamino, (Ci-C 3 )dialkylamino, (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, (Ci-C 3 )haloalkoxy, and (Ci- C 3 )alkoxy.
  • two of R 14 , R 15 and R 16 may form a three to seven membered carbocycle. In other embodiments, taken together, two of R 14 , R 15 and R 16 may form a three to seven membered heterocycle.
  • the three to seven membered carbocycle or heterocycle may be additionally substituted with one or two substituents chosen from OH, oxo, F, cyano, amino, (Ci-C 3 )alkylamino, (Ci- C 3 )dialkylamino, (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, (Ci-C 3 )haloalkoxy, and (Ci-C 3 )alkoxy.
  • R 14 and R 15 together with the nitrogen to which they are attached, form a three to seven membered heterocycle.
  • the three to seven membered heterocycle may be additionally substituted with one or two substituents chosen from OH, oxo, F, cyano, amino, (Ci-C 3 )alkylamino, (Ci-C 3 )dialkylamino, (Ci- C 3 )alkyl, (Ci-C 3 )haloalkyl, (Ci-C 3 )haloalkoxy, and (Ci-C 3 )alkoxy.
  • D is R 14 , and R 14 and R 15 , together with the nitrogen to which they are attached, form piperidine. In some of these embodiments, the piperidine is unsubstituted.
  • n 4.
  • R 17 is phenyl. In other embodiments, R 17 is monocyclic heteroaryl. In some embodiments, R 17 is phenyl optionally substituted with one or two substituents chosen from OH, halogen, cyano, nitro, (Ci-C3)alkylamino, (Ci- C3)dialkylamino, (Ci-C3)acylamino, (Ci-C3)alkylsulfonyl, (Ci-C3)alkylthio, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (Ci-C3)haloalkoxy, and (Ci-C3)alkoxy.
  • substituents chosen from OH, halogen, cyano, nitro, (Ci-C3)alkylamino, (Ci- C3)dialkylamino, (Ci-C3)acylamino, (Ci-C3)alkylsulfonyl, (Ci-C3)alkylthio,
  • R 17 is monocyclic heteroaryl optionally substituted with one or two substituents chosen from OH, halogen, cyano, nitro, (Ci-C3)alkylamino, (Ci-C3)dialkylamino, (Ci-C3)acylamino, (Ci- C3)alkylsulfonyl, (Ci-C 3 )alkylthio, (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, (Ci-C 3 )haloalkoxy, and (Ci-C 3 )alkoxy.
  • substituents chosen from OH, halogen, cyano, nitro, (Ci-C3)alkylamino, (Ci-C3)dialkylamino, (Ci-C3)acylamino, (Ci- C3)alkylsulfonyl, (Ci-C 3 )alkylthio, (Ci-C 3 )alkyl, (C
  • X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci- C 6 )haloalkoxy, (Ci-C 6 )haloalkylthio, - R3 ⁇ 4 2 , -OR 1 , -C(0)R 1 , -OC(0)R 1 , -C(0) R 1 R 2 , - C(0)OR 1 , -SR 1 , -SO2R 1 , and -SOi R ! R 2 .
  • zero, one or two of X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from halogen, (Ci-Ce)alkyl, and (Ci-Ce)haloalkyl, and the remainder are hydrogen.
  • zero, one or two of X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from (Ci-C3)alkyl, chloro, fluoro, and (Ci-C3)fluoroalkyl, and the remainder are hydrogen.
  • R 1 is hydrogen. In other embodiments, R 1 is (Ci-C6)alkyl. In some embodiments, R 2 is hydrogen. In other embodiments, R 2 is (Ci-C6)alkyl.
  • the compound is of formula II:
  • Q is a direct bond (when Q is -(CH 2 )t- and t is zero). In other embodiments, Q is -CH 2 - (when Q is -(CH 2 )t- and t is one). In still other embodiments, Q is -(CH 2 ) 2 - (when Q is -(CH 2 )t- and t is two). In some embodiments, Q is -0-. In other embodiments, Q is -S- (when Q is -(S0 2 ) p - and p is zero). In other embodiments, Q is - S(O)- (when Q is -(S0 2 ) p - and p is one). In other embodiments, Q is -S(0) 2 - (when Q is - (S0 2 ) p - and p is two). In still other embodiments, Q is - R Q -.
  • R Q is hydrogen. In other embodiments, R Q is optionally substituted (C 1 -C6)alkyl. In still other embodiments, R Q is optionally substituted (C 3 - C 7 )cycloalkyl. In yet other embodiments, R Q is optionally substituted aryl. In further embodiments, R Q is optionally substituted heteroaryl.
  • the optional substituents available for the(Ci-Ce)alkyl, (C 3 -C 7 )cycloalkyl, aryl or heteroaryl may be one or more of hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci-C4)dialkylamino, (Ci-C 4 )acylamino, (Ci-C 4 )alkylsulfonyl, (Ci-C 4 )alkylthio, (Ci-C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (Ci-C 4 )haloalkyl, (Ci-C 4 )haloalkoxy, and (Ci-C 4 )alkoxy.
  • R Q is (Ci- C 6 )alkyl optionally substituted with one or more of hydroxy, fluoro, or (C -C 7 )cycloalkyl. In other embodiments, R Q is (Ci-C )alkyl optionally substituted with one or more of hydroxy or fluoro. In yet other embodiments, R Q is (C -C 7 )cycloalkyl optionally substituted with one or more of hydroxy, methyl, or fluoro. In still other embodiments, R Q is aryl optionally substituted with one or more of hydroxy, methoxy, halogen, (Ci-C )haloalkyl, nitro, amino, or methyl.
  • R Q is phenyl optionally substituted with one or more of hydroxy, chloro, fluoro, methoxy, nitro, amino, trifluoromethyl, or methyl.
  • R Q is heteroaryl optionally substituted with one or more of hydroxy, methoxy, halogen, (Ci-C )haloalkyl, nitro, amino, or methyl.
  • R Q is a nitrogen-containing heteroaryl optionally substituted with one or two methyl groups.
  • R Q is -SO2R 3 .
  • R Q is - S0 2 R R 4 .
  • R 3 and R 4 are independently selected in each instance from hydrogen, (Ci-Ce)alkyl, aryl, and arylalkyl.
  • the aryl or the aryl of the arylalkyl may be optionally substituted with hydroxy, halogen, cyano, nitro, amino, (Ci- C 4 )alkylamino, (Ci-C 4 )dialkylamino, (Ci-C 4 )acylamino, (Ci-C 4 )alkylsulfonyl, (Ci- C 4 )alkylthio, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, (Ci-C 4 )haloalkoxy, or (Ci-C 4 )alkoxy.
  • R 4 is selected from hydrogen and methyl.
  • R 3 is selected from hydrogen, (Ci-C6)alkyl, (Ci-Ce)haloalkyl, aryl, and arylalkyl.
  • the aryl or the aryl of the arylalkyl is optionally substituted with one or more of hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci-C4)dialkylamino, (Ci-C 4 )acylamino, (Ci-C 4 )alkylsulfonyl, (Ci-C 4 )alkylthio, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, (Ci-C4)haloalkoxy, and (Ci-C4)alkoxy.
  • R 5 is selected from hydrogen, optionally substituted (Ci- C4)alkyl, or optionally substituted aryl.
  • the optional substituents are selected from (Ci-C )alkyl, OR 1 , H2, HMe, N(Me) 2 , and heterocycle.
  • R 5 is selected from optionally substituted (Ci-C4)alkyl or optionally substituted aryl, and the optional substituents are selected from one or more of OH, OMe, H2, NHMe, N(Me) 2 , or heterocycle.
  • R Q is -SO2R 3 and R 3 is selected from hydrogen, (Ci-Ce)alkyl, and aryl.
  • the aryl may be substituted with hydroxy, halogen, cyano, amino, or (Ci-C4)alkoxy.
  • R Q is S0 2 NR R 4 ; R 3 is selected from hydrogen, (Ci-C )alkyl, and optionally substituted aryl; and R 4 is hydrogen or methyl.
  • Y is hydroxyl. In other embodiments, Y is hydrogen.
  • Ar is an optionally substituted aromatic ring. In other embodiments, Ar is an optionally substituted heteroaromatic ring. In still other
  • Ar is phenyl substituted with Z 1 and Z 2 .
  • Z 1 is selected from hydrogen, halogen, nitro, cyano, azide, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, -NR3 ⁇ 4 2 , -NR 1 C(0)R 2 , -NR 1 C(0)OR 6 , - OR 1 , -C(0)R 1 , -OC(0)R 1 , -C(0)NR 1 R 2 , -C(0)OR 1 , -SR 1 , -SO2R 1 , and -S0 2 NR 1 R 2 .
  • Z 2 is selected from hydrogen, halogen, nitro, cyano, azide, (Ci- C 6 )alkyl, (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, -NR3 ⁇ 4 2 , -NR 1 C(0)R 2 , -OR 1 , -C(0)R 1 , - OC(0)R 1 , -C(0) R 1 R 2 , -C(0)OR 1 , -SR 1 , -SO2R 1 , and
  • Z 2 is selected from hydrogen, halogen, nitro, cyano, azide, (Ci- C 6 )alkyl, (Ci-C 6 )haloalkyl, (Ci-C 6 )haloalkoxy, -NR3 ⁇ 4 2 , -NR 1 C(0)R 2 , -OR 1 , -C(0)R 1 , - OC(0)R 1 , -C(0) R 1 R 2 , -C
  • Z 1 and Z 2 are independently selected in each instance from hydrogen, halogen, (Ci-C 6 )haloalkyl, - R 1 C(0)OR 6 , (Ci-Ce)alkoxy, and (Ci-C 6 )haloalkoxy.
  • Z 1 is hydrogen and Z 2 is selected from hydrogen, halogen, (Ci-Ce)haloalkyl, - R 1 C(0)OR 6 , (Ci-Ce)alkoxy, and (Ci-Ce)haloalkoxy.
  • Z 1 is hydrogen and Z 2 is hydrogen, fluoro, chloro, trifluoromethyl, HBoc, methoxy, or trifluoromethoxy.
  • Z 2 is para to the attachment of the phenyl ring to the sulfonyl.
  • R 1 , R 2 , R 3 , R 4 , and R 5 may not be hydrogen.
  • R Q when Q is R Q , R Q is -SO2R 3 , and R 3 is hydrogen, the resulting moiety will be unstable. The circumstances under which a hydrogen atom would be inappropriate will be clear to the person of skill in the art.
  • D is H and T and U are phenyl, and the compound is of formula III:
  • R is hydrogen.
  • Y is OH.
  • Q is -(CH 2 )t-.
  • t is 1.
  • zero, one or two of X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from halogen, (Ci- C 6 )alkyl, and (Ci-Ce)haloalkyl, and the remainder are hydrogen.
  • X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from (Ci- C )alkyl, chloro, fluoro, and fluoro(Ci-C )alkyl, and the remainder are hydrogen.
  • Ar is phenyl substituted with Z 1 and Z 2 .
  • Z 1 and Z 2 are independently selected in each instance from the group consisting of hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci-Ce)haloalkoxy, - R ⁇ 2 , - ⁇ CCC R 2 , - R 1 C(0)OR 6 , -OR 1 , -C(0)R 1 , -0C(0)R 1 , -C(0) R 1 R 2 , -C(0)0R 1 , -SR 1 , - SO2R 1 , and
  • Z 1 and Z 2 are independently selected in each instance from hydrogen, halogen, (Ci-C6)haloalkyl, - R 1 C(0)OR 6 , (Ci-C6)alkoxy, and (Ci-C6)haloalkoxy.
  • Z 1 is hydrogen and Z 2 is selected from hydrogen, halogen, (Ci-C 6 )haloalkyl, - R 1 C(0)OR 6 , (Ci-Ce)alkoxy, and (Ci- C6)haloalkoxy.
  • Z 1 is hydrogen and Z 2 is hydrogen, fluoro, chloro, trifluoromethyl, HBoc, methoxy, or trifluoromethoxy.
  • Z 2 is para to the attachment of the phenyl ring to the sulfonyl.
  • R B is hydrogen; Y is OH; Q is -(CH 2 )-; and Ar is phenyl substituted with Z 1 and Z 2 .
  • Z 1 is hydrogen and Z 2 is selected from hydrogen, halogen, (Ci-Ce)haloalkyl, - R 1 C(0)OR 6 , (Ci- C 6 )alkoxy, or (Ci-Ce)haloalkoxy.
  • Z 1 is hydrogen and Z 2 is hydrogen, fluoro, chloro, trifluoromethyl, NHBoc, methoxy, or trifluoromethoxy, and is para to the attachment of the phenyl ring to the sulfonyl.
  • Z 1 is hydrogen and Z 2 is trifluoromethoxy.
  • the relative configurations are such that the amine and the tricycle are both trans to the alcohol (Y), as shown above in Formula IV.
  • Y the alcohol
  • compounds can be either single enantiomers IVa or IVb or a mixture of the two. If a mixture, the mixture will most commonly be racemic, but it need not be. Substantially pure single enantiomers of biologically active compounds such as those described herein often exhibit advantages over their racemic mixture.
  • the invention relates to:
  • T and U are each independently selected from the group consisting of a benzene ring and pyridine.
  • Z 1 and Z 2 are independently selected in each instance from hydrogen, halogen, (Ci-C6)haloalkyl, - R ⁇ C OR 6 , (Ci-Ce)alkoxy, and (Ci-C 6 )haloalkoxy.
  • substituents chosen from OH, oxo, F, cyano, amino, (Ci-C3)alkylamino, (Ci-C3)dialkylamino, (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, (Ci- C 3 )halo
  • Optically active (R)- and (S)- isomers may be prepared using homo-chiral synthons or homo-chiral reagents, or optically resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both (£)- and ⁇ )- geometric isomers. Likewise, all tautomeric forms are intended to be included.
  • enantiomerically pure compounds used herein are a modified version of the denotations taken from Maehr J. Chem. Ed. 62, 1 14-120 (1985): simple lines provide no information about stereochemistry and convey only connectivity; solid and broken wedges are used to denote the absolute configuration of a chiral element; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but not necessarily denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration.
  • simple lines provide no information about stereochemistry and convey only connectivity
  • solid and broken wedges are used to denote the absolute configuration of a chiral element
  • solid and broken bold lines are geometric descriptors indicating the relative configuration shown but not necessarily denoting racemic character
  • wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration.
  • a “pure” or “substantially pure” enantiomer is intended to mean that the enantiomer is at least 95% of the configuration shown and 5% or less of other enantiomers.
  • a “pure” or “substantially pure” diastereomer is intended to mean that the diastereomer is at least 95% of the relative configuration shown and 5% or less of other diastereomers.
  • the convention of Chemical Abstracts is used.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric,
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, ⁇ , ⁇ '-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.
  • composition comprising a compound disclosed above, or a pharmaceutically acceptable salt form thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
  • the most suitable route may depend upon the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula I or a pharmaceutically acceptable salt thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a compound of formula I or a pharmaceutically acceptable salt thereof
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
  • Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.
  • formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use.
  • a sterile liquid carrier for example saline, phosphate-buffered saline (PBS) or the like.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include 2 H, H, 1 C, 14 C, 15 N, 5 S, 18 F, and 6 C1, respectively.
  • Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention.
  • Tritiated, i.e. H, and carbon- 14, i.e., 14 C, radioisotopes are particularly preferred for their ease in preparation and detectability.
  • Radiolabeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
  • the compounds provided herein can be used for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I.
  • the cancer is characterized by
  • the cancer can be selected from the group consisting of: ovarian, pancreatic, renal cell, breast, prostate, lung, hepatocellular carcinoma, glioma, leukemia, lymphoma, colorectal cancers, and sarcomas.
  • the method further comprises administering one or more additional cancer chemotherapeutic agents.
  • the one or more additional cancer chemotherapeutic agents are EGFR inhibitors.
  • the cancer is chemotherapy resistant cancer.
  • the method further comprises administering one or more cancer
  • the one or more cancer chemotherapeutic agents are EGFR inhibitors.
  • administration of a compound of formula I can restore sensitivity to one or more chemotherapeutic agents in a patient wherein the patient has developed a resistance to the one or more chemotherapeutic agents.
  • cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following:
  • cardiac cancers including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma;
  • sarcoma e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma
  • myxoma rhabdomyoma
  • fibroma fibroma; lipoma and teratoma; lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma;
  • bronchogenic carcinoma e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma
  • alveolar and bronchiolar carcinoma bronchial adenoma
  • sarcoma sarcoma
  • cancers of the esophagus e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma
  • cancers of the stomach e.g., carcinoma, lymphoma, and leiomyosarcoma
  • cancers of the pancreas e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma
  • cancers of the small bowel e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma
  • cancers of the large bowel e.g., adenocarcinoma, tubular adenoma, villous ade
  • cancers of the kidney e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia
  • cancers of the bladder and urethra e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma
  • cancers of the prostate e.g., adenocarcinoma, and sarcoma
  • cancer of the testis e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma
  • testis e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,
  • liver cancers including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma;
  • hepatoma e.g., hepatocellular carcinoma
  • cholangiocarcinoma e.g., hepatocellular carcinoma
  • hepatoblastoma hepatoblastoma
  • angiosarcoma hepatocellular adenoma
  • hemangioma hemangioma
  • bone cancers including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;
  • osteogenic sarcoma osteosarcoma
  • fibrosarcoma malignant fibrous histiocytoma
  • chondrosarcoma chondrosarcoma
  • Ewing's sarcoma malignant lymphoma (reticulum cell sarcoma)
  • multiple myeloma malignant giant cell tumor chordoma
  • nervous system cancers including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma;
  • gynecological cancers including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa thecal cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma,
  • intraepithelial carcinoma adenocarcinoma, fibrosarcoma, and melanoma
  • cancers of the vagina e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma
  • cancers of the fallopian tubes e.g., carcinoma
  • hematologic cancers including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin's lymphoma, non Hodgkin's lymphoma
  • skin cancers including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and
  • adrenal gland cancers including, for example, neuroblastoma.
  • Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue.
  • the compounds described herein can also be administered in combination with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery.
  • a method of treating cancer comprising administering an effective amount of a compound according to formula I to a patient, wherein a therapeutically effective amount of one or more additional cancer
  • chemotherapeutic agents are administered to the patient.
  • a method for treating diabetes in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula I.
  • a method for treating an autoimmune disease in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula I.
  • the autoimmune disease can be, for example, inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • Immune responses are constantly and tightly regulated and one important cellular component in maintaining self tolerance (i.e., prevention of autoimmunity) and tolerance of benign commensal gut flora are regulatory T cells (Treg).
  • Treg can be subdivided into multiple phenotypes, but the most common are CD4+CD25+ T cells that express the transcription factor Foxp3.
  • Foxp3 is a direct transcriptional target of FOXO proteins, particularly FOXOl and FOX03.
  • FOXO proteins particularly FOXOl and FOX03.
  • Acute immune mediated rejection and chronic immune mediated rejection are key obstacles to successful solid organ transplantation. It is believed that these forms of rejection can be prevented/overcome by amplifying Treg number and or function.
  • Allo-HCT allogeneic hematopoietic cell transplants
  • T cells may be collected from a subject and differentiated ex vivo to Tregs as described by Taylor et al. [Blood 99, 3493-3499 (2002)].
  • aspects of the invention include methods for treatment of autoimmune disease characterized by deficiency in Treg function comprising administering a therapeutically useful amount of compound of Formula I.
  • the method can also include extraction of naive T-cells from a patient, differentiation of T-cells to Tregs ex vivo by treatment with a compound of Formula I, optionally supplemented with an HDACi, followed by
  • the compounds can be administered to a patient to treat an autoimmune disorder, for example, Addison's disease, Amyotrophic Lateral Sclerosis, celiac disease, Crohn's disease, diabetes, eosinophilic fasciitis, Guillain-Barre syndrome (GBS), Graves' disease, Lupus erythematosus, Miller-Fisher syndrome, psoriasis, rheumatoid arthritis, ulcerative colitis, and vasculitis.
  • an autoimmune disorder for example, Addison's disease, Amyotrophic Lateral Sclerosis, celiac disease, Crohn's disease, diabetes, eosinophilic fasciitis, Guillain-Barre syndrome (GBS), Graves' disease, Lupus erythematosus, Miller-Fisher syndrome, psoriasis, rheumatoid arthritis, ulcerative colitis, and vasculitis.
  • the compound provided herein can be used for treating a disease or disorder in a patient wherein the disease or disorder involves excessive or unregulated cellular proliferation, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I). Also provided herein is a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the pi3K-AKT-FOXO signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I.
  • a method for treating a disease in a patient wherein the disease is characterized by proteotoxicity, including age onset proteotoxicity leading to neurodegeneration comprising administering to the patient a therapeutically effective amount of a compound of formula I.
  • Hyperphosphorylated Tau has been implicated as the pathogenic protein in several neurodegenerative diseases and furthermore PP2A has been shown to be an important phosphatase in reversing aberrant
  • Hyperphosphorylated alpha- Synuclein is a second exemplar of a toxic protein, and again PP2A has been shown to reverse its aberrantly phosphorylated state; see for example Kang-Woo Lee et al, Enhanced Phosphatase Activity Attenuates alpha- Synucleinopathy in a Mouse Model in
  • the disease is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and Pick's disease.
  • the compounds provided herein may further be used in a method for treating a mood disorder in a patient by administering to the patient a therapeutically effective amount of a compound of formula I.
  • the mood disorder is stress- induced depression.
  • Also provided herein is a method for treating acne vulgaris in a patient by administering to the patient a therapeutically effective amount of a compound of formula I.
  • cardiac hypertrophy is associated with a disease selected from hypertension, myocardial infarction, and valvular heart disease.
  • the compounds provided herein may further be used in a method for treating a viral infection in a patient by administering to the patient a therapeutically effective amount of a compound of formula I.
  • viruses that may cause viral infections to be treated include, but are not limited to: a polyomavirus, such as John Cunningham Virus (JCV), Simian virus 40 (SV40), or BK Virus (BKV); influenza, Human Immunodeficiency Virus type 1 (HIV-1), Human Papilloma Virus (HPV), adenovirus, Epstein-Barr Virus (EBV), Hepatitis C Virus (HCV), Molluscum contagiosum virus (MCV); Human T- lymphotropic virus type 1 HTLV-1), Herpes Simplex Virus type 1 (HSV-1),
  • a polyomavirus such as John Cunningham Virus (JCV), Simian virus 40 (SV40), or BK Virus (BKV)
  • influenza Human Immunodeficiency Virus type 1
  • CMV cytomegalovirus
  • hepatitis B virus hepatitis B virus
  • Bovine papillomavirus BPV-1
  • human T-cell lymphotropic virus type 1 Japanese encephalitis virus
  • RSV respiratory syncytial virus
  • West Nile virus West Nile virus
  • a method for treating a parasitic infection in a patient by administering to the patient a therapeutically effective amount of a compound of formula I.
  • parasites that may cause parasitic infections to be treated include, but are not limited to, Plasmodium and Theileria.
  • PP2A enzymes are involved in the regulation of cell transcription, cell cycle, and viral transformation.
  • Many viruses including cytomegalovirus, parainfluenza, DNA tumor viruses, and HIV-1, utilize different approaches to exploit PPA2 in order to modify, control, or inactivate cellular activities of the host [Garcia et al, Microbes and Infection, 2, 2000, 401-407]. Therefore, the compounds provided herein may further be used in a method for treating a viral infection in a patient by administering to the patient a therapeutically effective amount of a compound of formula (I).
  • viruses that may cause viral infections to be treated include, but are not limited to: a polyomavirus, such as John Cunningham Virus (JCV), Simian virus 40 (SV40), or BK Virus (BKV); influenza, Human Immunodeficiency Virus type 1 (HIV-1), Human Papilloma Virus (HPV), adenovirus, Epstein-Barr Virus (EBV), Hepatitis C Virus (HCV), Molluscum contagiosum virus (MCV); Human T-lymphotropic virus type 1 HTLV-1), Herpes Simplex Virus type 1 (HSV-1), cytomegalovirus (CMV), hepatitis B virus, Bovine papillomavirus (BPV-1), human T-cell lymphotropic virus type 1, Japanese encephalitis virus, respiratory syncytial virus (RSV), and West Nile virus.
  • a polyomavirus such as John Cunningham Virus (JCV), Simian virus 40 (SV40), or B
  • Serine/Threonine phosphatases including PP2A are involved in modulation of synaptic plasticity (D. G. Winder and J. D. Sweatt, Nature Reviews Neuroscience, vol 2, July 2001, pages 461 - 474). Persistently decreased PP2A activity is associated with maintenance of Long Term Potentiation (LTP) of synapses, thus treatment PP2A activators such as those described here may reverse synaptic LTP.
  • Psychostimulant drugs of abuse such as cocaine and methamphetamine are associated with deleterious synaptic LTP (L. Mao et al, Neuron 67, September 9, 2010 and A. Stipanovich et al, Nature vol 453, 2008, pages 879 - 884), which may underlie the pathology of addiction and relapse therefore PP2A activators described here may be useful as treatments for psychostimulant abuse.
  • MO or MMO N-methylmorpholine oxide
  • a "patient,” as used herein, includes both humans and other animals, particularly mammals. Thus the methods are applicable to both human therapy and veterinary applications.
  • the patient is a mammal, for example, a primate.
  • the patient is a human.
  • Treatment can involve administering a compound described herein to a patient diagnosed with a disease, and may involve administering the compound to a patient who does not have active symptoms. Conversely, treatment may involve administering the compositions to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • administer refers to the act of introducing the dosage form into the system of subject in need of treatment.
  • administration and its variants are each understood to include concurrent and/or sequential introduction of the dosage form and the other active agents.
  • Administration of any of the described dosage forms includes parallel administration, co-administration or sequential administration.
  • the therapies are administered at approximately the same time, e.g., within about a few seconds to a few hours of one another.
  • a "therapeutically effective" amount of the compounds described herein is typically one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. A therapeutic benefit is achieved with the amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • the term "modulate" with respect to a FOXO transcription factor protein refers to activation of the FOXO transcription factor protein and its biological activities associated with the FOXO pathway. Modulation of FOXO transcription factor proteins includes up-regulation (i.e., agonizing, activation or stimulation).
  • the mode of action of a FOXO modulator can be direct, e.g., through binding to the FOXO transcription factor protein as a ligand. The modulation can also be indirect, e.g., through binding to and/or modifying another molecule which otherwise binds to and activates the FOXO transcription factor protein.
  • Ci to C20 hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl,
  • Aromatic hydrocarbons include benzene (phenyl), naphthalene (naphthyl), anthracene, etc.
  • alkyl (or alkylene) is intended to include linear or branched saturated hydrocarbon structures and combinations thereof.
  • Alkyl refers to alkyl groups from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
  • Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cy-propyl, cy-butyl, cy-pentyl, norbornyl and the like.
  • carbocycle is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state.
  • C3-C10 carbocycle refers to both non-aromatic and aromatic systems, including such systems as cyclopropane, benzene and cyclohexene;
  • C8-C12 carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.
  • Carbocycle if not otherwise limited, refers to monocycles, bicycles and polycycles.
  • Heterocycle means an aliphatic or aromatic carbocycle residue in which from one to four carbons is replaced by a heteroatom selected from the group consisting of N, O, and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • a heterocycle may be non-aromatic (heteroaliphatic) or aromatic (heteroaryl). Examples of heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline,
  • tetrahydroisoquinoline benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
  • heterocyclyl residues include piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl,
  • oxazolidinyl isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl,
  • Alkoxy or alkoxyl refers to groups of from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms of a straight or branched configuration attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purpose of this application, alkoxy and lower alkoxy include methylenedioxy and ethylenedioxy.
  • halogen means fluorine, chlorine, bromine or iodine atoms. In one embodiment, halogen may be a fluorine or chlorine atom.
  • acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • Examples include acetyl, benzoyl, propionyl, isobutyryl and the like.
  • Lower-acyl refers to groups containing one to four carbons.
  • the double bonded oxygen when referred to as a substituent itself is called "oxo".
  • substituted refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical.
  • Oxo is also included among the substituents referred to in "optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl).
  • 1, 2, or 3 hydrogen atoms are replaced with a specified radical.
  • more than three hydrogen atoms can be replaced by fluorine; indeed, all available hydrogen atoms could be replaced by fluorine.
  • substituents are halogen, haloalkyl, alkyl, acyl, hydroxyalkyl, hydroxy, alkoxy, haloalkoxy, aminocarbonyl oxaalkyl, carboxy, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,
  • Preparation of compounds can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W.Greene and P.G.M.Wuts [John Wiley & Sons, New York, 1999], in Protecting Group Chemistry, 1 st Ed., Oxford University Press, 2000; and in March 's Advanced Organic chemistry: Reactions, Mechanisms, and Structure, 5 th Ed., Wiley-Interscience Publication, 2001.
  • N-sulfonylated 2,6-diaminocyclanol 100 may be alkylated or reductively aminated to roduce the desired product:
  • N,N-dibenzylcyclohex-2-enamine A solution of dibenzylamine (5.00 g, 25.3 mmol) in DMF (20.0 mL) was cooled to 0 °C, treated with sodium hydride (60% wt.
  • N-( re/-(lS,2S,3R)-3-(dibenzylamino)-2-hydroxycyclohexyl)-4- (trifluoromethoxy)benzenesulfonamide A solution of re/-(lR,2S,6R)-2-amino-6- (dibenzylamino)cyclohexanol (0.200 g, 0.644 mmol) in DMF (2.0 mL) was cooled to 0 °C, treated with Et N (89.0 ⁇ L, 0.644 mmol), and 4-trifluoromethoxybenzenesulfonyl chloride (109.0 ⁇ L, 0.644 mmol).
  • the mixture was warmed to 25 °C, and stirred for 2 h.
  • the mixture was partitioned between saturated aqueous NaCl (50 mL), and CH2CI2 (100 mL).
  • the organic layer was washed with saturated aqueous NaCl (3 x 50 mL), dried (Na 2 S04), and concentrated in vacuo.
  • the residue was dissolved in a minimal amount of CH2CI2 and purified by flash chromatography (S1O2, 0-35% ethyl acetate-hexanes) to afford the title compound as a yellow solid (0.322 g, 93%).
  • N-(re/-(lS,2S,3R)-3-amino-2-hydroxycyclohexyl)-4- (trifluoromethoxy)benzenesulfonamide A solution of N-(re/-(l S,2S,3R)-3- (dibenzylamino)-2-hydroxycyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide (0.500 g, 0.935 mmol) in MeOH (5.0 mL) in a pressure vessel was treated with 20% Pd(OH) 2 /C (0.180 g) and ammonium formate (0.236 g, 3.74 mmol). The vessel was closed and heated to 60 °C for 14 h.
  • N-(re/-(lS,2S,3R)-3-(benzhydrylamino)-2-hydroxycyclohexyl)-4- (trifluoromethoxy)benzenesulfonamide A solution of N-(re/-(l S,2S,3R)-3-amino-2- hydroxycyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide (0.050 g, 0.141 mmol) in acetonitrile (0.75 mL) was treated with sodium iodide (0.021 g, 0.141 mmol),
  • Reductive amination conditions encompass reacting the ketone with Intermediate 1 in a solvent such as methanol, THF or DMF with a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride with optional addition of 1 to 10% acetic acid as a catalyst. Examples are shown below.
  • Y be hydrogen
  • the foregoing hydroxy cycloaliphatics may be accessed via radical mediated deoxgenation processes as described in, for example, W. Hartwig in "Modern Methods For The Radical Deoxgenation of Alcohols", Tetrahedron Vol. 39, No. 16, page 2609 (1983).
  • This type of transformation as applied to compounds of the present invention is shown below:
  • arylsulfonamide(ii) for example 4-trifluoromethoxybenzene sulfonamide in the presence of a chiral palladium catalyst to give enantiomerically enriched allylarylsulfonamides of type (iii).
  • Protecting groups, Pg include but are not limited to, benzyl(Bn) and substituted benzyl groups or alkoxycarbonyl groups such as Boc or Cbz.
  • the protected allylic sulfonamides (iii) may be epoxidized in a non-diastereoselective fashion to give a diasteromeric mixture of epoxides, (iv), which are separated by chromatographic techniques; or alternatively steroselective expoxidation will give access to one
  • Epoxidation reagents include peroxoic acids such as mCPBA, dioxiranes such as dimethyldioxirane, oxaziridines such as 3-phenyl-2-tosyl-l,2- oxaziridine or hydroperoxides such as t-butylhydroperoxide with transition metal ion catalysis.
  • peroxoic acids such as mCPBA
  • dioxiranes such as dimethyldioxirane
  • oxaziridines such as 3-phenyl-2-tosyl-l,2- oxaziridine
  • hydroperoxides such as t-butylhydroperoxide with transition metal ion catalysis.
  • Either isomer of compound (iv) is converted to intermediates of general formula 100 by treatment with a protected ammonia equivalent such as dibenzylamine, optionally in the presence of an added base and with heating.
  • Protecting groups are removed by, for example hydrogenolysis, or
  • N-benzyl-4-(trifluoromethoxy)benzenesulfonamide (0.200 g, 0.603 mmol) was reacted with tert-butyl (3,6-dihydro-2H-pyran-3-yl) carbonate (0.289 g, 1.45 mmol) in presence of (R,R)-DACH for 10 days to afford (R)-N-benzyl-N-(3,6-dihydro-2H-pyran-3-yl)-4- (trifluoromethoxy)benzenesulfonamide (0.228 g, 92%).
  • dibenzylamine in the presence of a base such as NaNH 2 in toluene with heating for 50 - 100°C for between 1 and 24 hours.
  • Deprotection of the benzyl group is carried out by hydrogenolysis with a catalyst such as palladium on carbon or palladium hydroxide, to give the intermediate amine, N-((3,S',4 ) S',5R)-5-amino-4-hydroxytetrahydro-2H-pyran-3-yl)-4- (trifluoromethoxy)benzenesulfonamide.
  • N-((lS,2S,3R)-3-(benzhydrylamino)-2-hydroxycyclohexyl)-4- (trifluoromethoxy)benzenesulfonamide A solution of N-((l S,2S,3R)-3-amino-2- hydroxycyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide (0.050 g, 0.141 mmol) in acetonitrile (0.75 mL) was treated with sodium iodide (0.021 g, 0.141 mmol),
  • Example 13 (S)-N-(l-(9H-fluoren-9-yl)piperidin-3-yl)-4- (trifluoromethoxy)benzenesulfonamide.
  • a solution of (S)-l-(9H-fluoren-9-yl)piperidin- 3-amine (0.062 g, 0.235 mmol) in CH2CI2 (2.0 mL) was cooled to 0 °C, treated with Et 3 N (33.0 ⁇ L, 0.235 mmol), and 4-trifluoromethoxybenzenesulfonyl chloride (40.0 ⁇ L, 0.235 mmol). The mixture was warmed to 25 °C, and stirred for 2 h.
  • Example 14 (R)-N-(l-(9H-fluoren-9-yl)piperidin-3-yl)-4- (trifluoromethoxy)benzenesulfonamide.
  • a solution of (R)-l-(9H-fluoren-9-yl)piperidin- 3-amine (0.106 g, 0.400 mmol) in CH 2 C1 2 (2.0 mL) was cooled to 0 °C, treated with Et 3 N (55.4 ⁇ L, 0.400 mmol), and 4-trifluoromethoxybenzenesulfonyl chloride (67.9 ⁇ L, 0.400 mmol). The mixture was warmed to 25 °C, and stirred for 2 h.
  • Example 11 (S)-N-(l-(10,ll-dihydro-5H-dibenzo[a,d][7]annulen-5- yl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide.
  • Example 12 (R)-N-(l-(10,ll-dihydro-5H-dibenzo[a,d] [7]annulen-5- yl)piperidin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide.
  • Example 16 (R)-N-(l-benzhydrylpiperidin-3-yl)-4- (trifluoromethoxy)benzenesulfonamide.
  • a solution of (R)-l-benzhydrylpiperidin-3- amine (0.100 g, 0.375 mmol) in CH2CI2 (1.0 mL) was cooled to 0 °C, treated with Et 3 N (52.0 ⁇ L, 0.375 mmol), and 4-trifluoromethoxybenzenesulfonyl chloride (52.0 ⁇ L, 0.375 mmol). The mixture was warmed to 25 °C, and stirred for 2 h.
  • Example 10 N-(3-((9H-fluoren-9-yl)amino)-2-hydroxypropyl)-4- (trifluoromethoxy)benzenesulfonamide.
  • a solution of l-((9H-fluoren-9-yl)amino)-3- aminopropan-2-ol (0.100 g, 0.393 mmol) in DMF (1.0 mL) was cooled to 0 °C, treated with Et 3 N (54.4 ⁇ L, 0.393 mmol), and 4-trifluoromethoxybenzenesulfonyl chloride (66.7 ⁇ L, 0.393 mmol). The mixture was warmed to 25 °C and stirred for 2 h.
  • Example 9 N-(3-((10,ll-dihydro-5H-dibenzo[a,d] [7]annulen-5-yl)amino)- 2-hydroxypropyl)-4-(trifluoromethoxy)benzenesulfonamide.
  • Example 19 N-((lS,2S,3R)-3-((6,ll-dihydrodibenzo[6,e]oxepin-ll- yl)amino)-2-hydroxycyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide .
  • Example 17 N-((lS,2S,3R)-3-((bis(4-fluorophenyl)methyl)amino)-2- hydroxycyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide.
  • Compounds of the present invention in which the bridging group of a tricyclic moiety is an amide may be prepared using the methods described above by alkylation reactions.
  • the requisite 1 l-chlorodibenzoazepin-6-ones as alkylating agents are known, and may be prepared by the methods in Pestellini et al, Eur. J. Med. Chem 23 (1988) 473-476.
  • PP2A modulators are prepared by alkylation with the requisite amine intermediates (described above) by heating in a solvent such as DMF, acetonitrile or methylene chloride in the presence of a tertiary amine base such as triethylamine or Hunigs base with optional heating from room temerature to 100°C.
  • Final products are isolated by dilution into methylene chloride or ethyl acetate, washing organic layer with brine, drying, then concentration and chromatography on silica gel. The syntheses are shown in Scheme 2 above.
  • the MTT solution was subsequently replaced with 300 ⁇ _, of n-propyl alcohol and re-aliquoted to a 96 well plate.
  • Spectrophotometric analysis of each solution was performed using a 96 well plate reader at 600 nm in triplicate. Results are shown in Table 1 :
  • Protocol for clonogenic assay follows Sangodkar et al, J Clin Invest
  • Cell culture and staining For both A5491uc and HI 650 cells, 500 cells are seeded into each well of a 6-well plate and allowed to attach for 24 hours before drug treatment. The following day, cells are treated with either the appropriate dose of drug or an equivalent volume of DMSO (two replicates are treated for each condition). For each condition, depleted media is replaced with fresh media containing the equivalent drug dose four days after initial treatment. Cells are harvested either 7 (A5491uc) or 8 (HI 650) days after initial treatment. Briefly, medium is aspirated from each well and the cells are washed twice with ice-cold PBS, then plates are allowed to dry at room temperature for 4 hours.
  • Colonies are fixed for one hour in a fixing solution consisting of 10% methanol and 10% glacial acetic acid in distilled water, then stained overnight in 1% (w/v) crystal violet dissolved in methanol. The next day, staining solution is aspirated from the wells and plates are washed gently with distilled water to remove excess stain before colony counting. Colonies are imaged on a ChemiDoc XRS+ (Bio-Rad) and images are exported as 8-bit TIFF files. Colonies are counted using the Colony Counter plugin in ImageJ, with colony size defined as between 4 and 400 square pixels, and minimum circularity set at 0.6.
  • Results (number of colonies) for A5491uc cells and results (number of colonies) for H1650 cells may be analyzed separately.
  • subcutaneous xenograft of lung cancer cell line H441 is generated.
  • Cells (5 ⁇ 10 6 ) are injected into the right flank of 6- to 8-week-old male BALB/c nu/nu mice (Charles River, Wilmington, MA).
  • Tumor volume is assessed twice a week by caliper measurement.
  • Mice are randomized to treatment groups based on initial tumor volume average of 100mm 3 per group.
  • Mice are dosed by oral gavage with, for example, 15 mg/kg QD, 15 mg/kg BID, 50 mg/kg QD, or 50 mg/kg BID.
  • Mouse tumors are measured twice a week for the duration of the study.
  • mice body weights are recorded weekly and percentage of mice body weights during treatment is calculated as: weight at each time point/initial weight xlOO. Animals are observed for signs of toxicity (mucous diarrhea, abdominal stiffness and weight loss). Mice undergo treatment for 30 days and are sacrificed 2 hours after the last dose. Tumors are then excised and cut for both formalin-fixation and snap frozen in liquid nitrogen.
  • R B is selected from hydrogen and (Ci-C3)alkyl
  • T is a benzene ring or a five- or six-membered heteroaromatic ring
  • U is a benzene ring or a five- or six-membered heteroaromatic ring
  • X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, (Ci- C 6 )haloalkylthio, - R3 ⁇ 4 2 , -OR 1 , -C(0)R ⁇ -OC(0)R 1 , -C(0) R 1 R 2 , -C(0)OR 1 , -SR. 1 , - SO2R 1 , and -SOi R ! R 2 ;
  • R 1 and R 2 are independently selected in each instance from the group consisting of hydrogen and (Ci-Ce)alkyl;
  • R A is -D-(CR 15 R 16 ) formulate- HS0 2 R 17 ;
  • D is chosen from -O- and - R 14 -;
  • R 14 is H or (Ci-C 3 )alkyl
  • R 15 and R 16 in each occurrence are chosen independently from H, OH, cyano, amino, (Ci-C 3 )alkylamino, (Ci-C 3 )dialkylamino, (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, (Ci-C 3 )haloalkoxy, and (Ci-C 3 )alkoxy, or, taken together, two of R 14 , R 15 and R 16 may form a three to seven membered carbocycle or heterocycle wherein said three to seven membered carbocycle or heterocycle may be additionally substituted with one or two substituents chosen from OH, oxo, F, cyano, amino, (Ci-C 3 )alkylamino, (Ci-C 3 )dialkylamino, (Ci-C 3 )alkyl, (Ci- C 3 )haloalkyl, (Ci-C 3 )haloalkoxy, and (Ci
  • n is an integer from 2 to 4.
  • R 17 is chosen from phenyl and monocyclic heteroaryl, said phenyl and monocyclic heteroaryl optionally substituted with one or two substituents chosen from OH, halogen, cyano, nitro, (Ci-C 3 )alkylamino, (Ci-C 3 )dialkylamino, (Ci-C 3 )acylamino, (Ci- C 3 )alkylsulfonyl, (Ci-C 3 )alkylthio, (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, (Ci-C 3 )haloalkoxy, and (Ci-C 3 )alkoxy.
  • substituents chosen from OH, halogen, cyano, nitro, (Ci-C 3 )alkylamino, (Ci-C 3 )dialkylamino, (Ci-C 3 )acylamino, (Ci- C 3 )alky
  • Q is selected from -(CH 2 -, -0-, S(0) p -, and - R Q -;
  • p is zero, 1 or 2;
  • t is zero, 1 or 2;
  • R 3 and R 4 are independently selected in each instance from hydrogen, (Ci-Ce)alkyl, aryl, and arylalkyl, wherein said aryl or the aryl of the arylalkyl is optionally substituted with hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci-C4)dialkylamino, (Ci- C 4 )acylamino, (Ci-C 4 )alkylsulfonyl, (Ci-C 4 )alkylthio, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, (Ci- C4)haloalkoxy, or (Ci-C4)alkoxy;
  • R 5 is selected from hydrogen, optionally substituted (Ci-C4)alkyl, or optionally substituted aryl, wherein said optional substituents are selected from the group consisting of (Ci-C 3 )alkyl, OR 1 , H 2 , HMe, N(Me) 2 , and heterocycle;
  • Y is hydrogen or hydroxyl
  • Ar is an optionally substituted aromatic or heteroaromatic ring.
  • R 3 is selected in each instance from hydrogen, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, aryl, and arylalkyl, wherein said aryl or the aryl of the arylalkyl is optionally substituted with one or more of hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci- C4)dialkylamino, (Ci-C4)acylamino, (Ci-C4)alkylsulfonyl, (Ci-C4)alkylthio, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, and (Ci-C4)alkoxy;
  • R 4 is selected in each instance from hydrogen and methyl
  • R 5 is selected from optionally substituted (Ci-C4)alkyl or optionally substituted aryl, wherein said optional substituents are selected from one or more of OH, OMe, H 2 ,
  • HMe HMe, N(Me) 2 , or heterocycle.
  • R Q is selected from hydrogen; (Ci-C3)alkyl optionally substituted with one or more of hydroxy or fluoro; (C3-C7)cycloalkyl optionally substituted with one or more of hydroxy, methyl, or fluoro; phenyl optionally substituted with one or more of hydroxy, chloro, fluoro, methoxy, nitro, amino, trifluoromethyl, or methyl; or a nitrogen-containing heteroaryl optionally substituted with one or two methyl groups.
  • R 5 is selected from methyl, optionally substituted with OR 1 , NH 2 , NHMe, N(Me) 2 , and heterocycle.
  • R 5 is selected from the group consisting of phenyl and (Ci-C4)alkyl, each of which may be substituted with OR 1 .
  • R Q is -S0 2 R 3
  • R 3 is selected from the group consisting of (Ci-Ce)alkyl, and aryl; wherein said aryl is optionally substituted with hydroxy, halogen, cyano, amino, or (Ci-C4)alkoxy.
  • R 3 is selected from the group consisting of hydrogen, (Ci-C 3 )alkyl, and optionally substituted aryl; and R 4 is hydrogen or methyl.
  • Z 1 and Z 2 are independently selected in each instance from the group consisting of hydrogen, halogen, nitro, cyano, azide, (Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, - R3 ⁇ 4 2 , - ⁇ CCC R 2 , -OR 1 , -C(0)R 1 , -0C(0)R 1 , -C(0) R 1 R 2 , -C(0)0R 1 , -SR 1 , - SO2R 1 , and -SOi R ! R 2 .
  • Z 1 and Z 2 are independently selected in each instance from hydrogen, halogen, (Ci- Ce)haloalkyl, (Ci-C6)alkoxy, and (Ci-C6)haloalkoxy.
  • Z 1 and Z 2 are independently selected in each instance from the group consisting of hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, - R3 ⁇ 4 2 , - ⁇ CCC R 2 , -OR 1 , -C(0)R ⁇ -0C(0)R 1 , -C(0) R 1 R 2 , -C(0)0R 1 , -SR 1 , - SO2R 1 , and -SOi R ! R 2 .
  • Z 1 and Z 2 are independently selected in each instance from hydrogen, halogen, (Ci- Ce)haloalkyl, (Ci-C6)alkoxy, and (Ci-C6)haloalkoxy.
  • R B is hydrogen
  • Y is OH
  • Ar is phenyl substituted with Z 1 and Z 2 .
  • cancer selected from the group consisting of: ovarian, pancreatic, renal cell, breast, prostate, lung, hepatocellular carcinoma, glioma, leukemia, lymphoma, colorectal cancers, and sarcomas.
  • [74] The method of [73] above, or according to other embodiments of the invention, wherein said viral infection is caused by a virus selected from the group consisting of influenza, HIV-1, HPV, adenovirus, BKV, EBV, JCV, HCV, MCV, polyomavirus, SV40, HTLV-1, HSV-1, CMV, hepatitis B, BPV-1, human T-cell lymphotropic virus type 1, Japanese encephalitis virus, RSV, and West Nile virus.
  • a virus selected from the group consisting of influenza, HIV-1, HPV, adenovirus, BKV, EBV, JCV, HCV, MCV, polyomavirus, SV40, HTLV-1, HSV-1, CMV, hepatitis B, BPV-1, human T-cell lymphotropic virus type 1, Japanese encephalitis virus, RSV, and West Nile virus.
  • a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway comprising administering to the patient a therapeutically effective amount of a compound of one of [1] to [65] above, or according to other embodiments of the invention,.
  • a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway comprising administering to the patient a therapeutically effective amount of a compound of one of [1] to [65] above, or according to other embodiments of the invention,.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of one of [1] to [65] above, or according to other embodiments of the invention.
  • R D is selected from hydrogen and (Ci-C6)alkyl
  • R B is selected from hydrogen and (Ci-C3)alkyl
  • T is a benzene ring or a five- or six-membered heteroaromatic ring
  • U is a benzene ring or a five- or six-membered heteroaromatic ring
  • X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, (Ci- C 6 )haloalkylthio, - R3 ⁇ 4 2 , -OR 1 , -C(0)R ⁇ -OC(0)R 1 , -C(0) R 1 R 2 , -C(0)OR 1 , -SR 1 , - SO2R 1 , and -SOi R!R 2 ;
  • R 1 and R 2 are independently selected in each instance from the group consisting of hydrogen and (Ci-Ce)alkyl;
  • R A is -D-(CR 15 R 16 ) formulate- HS0 2 R 17 ;
  • D is chosen from -O- and - R 14 -;
  • R 14 is H or (Ci-C 3 )alkyl
  • R 15 and R 16 in each occurrence are chosen independently from H, OH, cyano, amino, (Ci-C )alkylamino, (Ci-C )dialkylamino, (Ci-C )alkyl, (Ci-C )haloalkyl, (Ci-C )haloalkoxy, and (Ci-C )alkoxy, or, taken together, two of R 14 , R 15 and R 16 may form a three to seven membered carbocycle or heterocycle wherein said three to seven membered carbocycle or heterocycle may be additionally substituted with one or two substituents chosen from OH, oxo, F, cyano, amino, (Ci-C )alkylamino, (Ci-C )dialkylamino, (Ci-C )alkyl, (Ci- C )haloalkyl, (Ci-C )haloalkoxy, and (Ci-C )alkoxy; or, taken
  • n is an integer from 2 to 4.
  • R 17 is chosen from phenyl and monocyclic heteroaryl, said phenyl and monocyclic heteroaryl optionally substituted with one or two substituents chosen from OH, halogen, cyano, nitro, (Ci-C )alkylamino, (Ci-C )dialkylamino, (Ci-C )acylamino, (Ci- C 3 )alkylsulfonyl, (Ci-C 3 )alkylthio, (Ci-C 3 )alkyl, (Ci-C 3 )haloalkyl, (Ci-C 3 )haloalkoxy, and (Ci-C 3 )alkoxy.
  • substituents chosen from OH, halogen, cyano, nitro, (Ci-C )alkylamino, (Ci-C )dialkylamino, (Ci-C )acylamino, (Ci- C 3 )alkylsulfony
  • Q is selected from -(CH 2 ) t -, -0-, S(0) p -, and - R Q -;
  • p is zero, 1 or 2;
  • t is zero, 1 or 2;
  • R 3 and R 4 are independently selected in each instance from hydrogen, (Ci-Ce)alkyl, aryl, and arylalkyl, wherein said aryl or the aryl of the arylalkyl is optionally substituted with hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci-C4)dialkylamino, (Ci- C 4 )acylamino, (Ci-C 4 )alkylsulfonyl, (Ci-C 4 )alkylthio, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, (Ci- C4)haloalkoxy, or (Ci-C4)alkoxy;
  • R 5 is selected from hydrogen, optionally substituted (Ci-C4)alkyl, or optionally substituted aryl, wherein said optional substituents are selected from the group consisting of (Ci-C 3 )alkyl, OR 1 , H 2 , HMe, N(Me) 2 , and heterocycle;
  • Y is hydrogen or hydroxyl
  • Ar is an optionally substituted aromatic or heteroaromatic ring.
  • R 3 is selected in each instance from hydrogen, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, aryl, and arylalkyl, wherein said aryl or the aryl of the arylalkyl is optionally substituted with one or more of hydroxy, halogen, cyano, nitro, amino, (Ci-C4)alkylamino, (Ci- C4)dialkylamino, (Ci-C4)acylamino, (Ci-C4)alkylsulfonyl, (Ci-C4)alkylthio, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, and (Ci-C4)alkoxy;
  • R 4 is selected in each instance from hydrogen and methyl
  • R 5 is selected from optionally substituted (Ci-C4)alkyl or optionally substituted aryl, wherein said optional substituents are selected from one or more of OH, OMe, H 2 ,
  • HMe HMe, N(Me) 2 , or heterocycle.
  • R Q is selected from hydrogen; (Ci-C3)alkyl optionally substituted with one or more of hydroxy or fluoro; (C3-C7)cycloalkyl optionally substituted with one or more of hydroxy, methyl, or fluoro; phenyl optionally substituted with one or more of hydroxy, chloro, fluoro, methoxy, nitro, amino, trifluoromethyl, or methyl; or a nitrogen- containing heteroaryl optionally substituted with one or two methyl groups.
  • R 5 is selected from the group consisting of phenyl and (Ci-C4)alkyl, each of which may be substituted with OR 1 .
  • R Q is -S0 2 R 3
  • R 3 is selected from the group consisting of (Ci- C 6 )alkyl, and aryl; wherein said aryl is optionally substituted with hydroxy, halogen, cyano, amino, or (Ci-C4)alkoxy.
  • R 3 is selected from the group consisting of hydrogen, (Ci-C 3 )alkyl, and optionally substituted aryl; and R 4 is hydrogen or methyl.
  • Z 1 and Z 2 are independently selected in each instance from the group consisting of hydrogen, halogen, nitro, cyano, azide, (Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, -NR3 ⁇ 4 2 , - ⁇ CCC R 2 , - R ! CCC OR 6 , -OR 1 , -C(0)R 1 , -0C(0)R 1 , -C(0) R 1 R 2 , - C(0)OR 1 , -SR 1 , -SO2R 1 , and -SCh ⁇ R 2 .
  • Z 1 and Z 2 are independently selected in each instance from the group consisting of hydrogen, halogen, nitro, cyano, azide, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)haloalkoxy, -NR3 ⁇ 4 2 , - ⁇ CCC R 2 , - R ! CCC OR 6 , -OR 1 , -C(0)R 1 , -0C(0)R 1 , -C(0) R 1 R 2 , - C(0)OR 1 , -SR 1 , -SO2R 1 , and -SOi R ! R 2 ; and
  • R 6 is (Ci-Cs)hydrocarbon.
  • R B is hydrogen
  • Y is OH
  • Ar is phenyl substituted with Z 1 and Z 2 .
  • Z 1 is hydrogen
  • Z 2 is selected from hydrogen, fluoro, chloro, trifluoromethyl, -NHBoc, methoxy, and trifluoromethoxy and is para to the attachment of the phenyl ring to the sulfonyl.
  • R 14 and R 15 together with the nitrogen to which they are attached, form a three to seven membered heterocycle, wherein said three to seven membered heterocycle may be additionally substituted with one or two substituents chosen from OH, oxo, F, cyano, amino, (Ci-C3)alkylamino, (Ci-C3)dialkylamino, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (Ci- C3)haloalkoxy, and (Ci-C3)alkoxy.
  • substituents chosen from OH, oxo, F, cyano, amino, (Ci-C3)alkylamino, (Ci-C3)dialkylamino, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (Ci- C3)haloalkoxy, and (Ci-C3)alkoxy.
  • the method comprising administering to the patient a therapeutically effective amount of a compound of any of [101] to [169] above, or according to other embodiments of the invention.
  • cancer selected from the group consisting of: ovarian, pancreatic, renal cell, breast, prostate, lung, hepatocellular carcinoma, glioma, leukemia, lymphoma, colorectal cancers, and sarcomas.
  • polyomavirus SV40, HTLV-1, HSV-1, CMV, hepatitis B, BPV-1, human T-cell
  • lymphotropic virus type 1 Japanese encephalitis virus, RSV, and West Nile virus.
  • a method for restoring sensitivity to one or more chemotherapeutic agents in the treatment of cancer comprising administering an effective amount of a compound of any of [101] to [169] above, or according to other embodiments of the invention.
  • a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of the PI3K-AKT-FOXO signaling pathway comprising administering to the patient a therapeutically effective amount of a compound of any of [101] to [169] above, or according to other embodiments of the invention.
  • a method for treating a disease or disorder in a patient where the disease or disorder involves the dysregulation of a Myc dependent signaling pathway comprising administering to the patient a therapeutically effective amount of a compound of any of [101] to [169] above, or according to other embodiments of the invention.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any of [101] to [169] above, or according to other embodiments of the invention.

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  • Organic Chemistry (AREA)
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  • Biomedical Technology (AREA)
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Abstract

La présente invention concerne un genre de dérivés arylsulfonamide de composés hétérocycliques tricycliques contraints. Les composés sont du genre suivant : Les composés induisent une translocation du facteur de transcription FOXO1 vers le noyau par modulation de PP2A et, en conséquence, présentent des effets antiprolifératifs. Ils sont utiles pour le traitement de toute une variété de troubles, y compris en tant que thérapie dans le traitement du cancer, ou sont utilisés en association avec d'autres médicaments pour rétablir la sensibilité à la chimiothérapie quand une résistance s'est développée.
PCT/US2016/050696 2015-09-09 2016-09-08 Benzhydryl sulfonamides contraints utilisés en tant qu'agents anticancéreux et neuroprotecteurs WO2017044575A1 (fr)

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US9937186B2 (en) 2014-03-11 2018-04-10 Icahn School Of Medicine At Mount Sinai Sulfonamides derived from tricyclyl-2-aminocycloalkanols as anticancer agents
US9937180B2 (en) 2014-03-11 2018-04-10 Icahn School Of Medicine At Mount Sinai Constrained tricyclic sulfonamides
US10221158B2 (en) 2015-09-09 2019-03-05 Icahn School Of Medicine At Mount Sinai Heterocyclic constrained tricyclic sulfonamides as anti-cancer agents
US10759790B2 (en) 2015-09-09 2020-09-01 Ichan School Of Medicine At Mount Sinai Heterocyclic constrained tricyclic sulfonamides as anti-cancer agents
WO2021170913A1 (fr) * 2020-02-28 2021-09-02 Rappta Therapeutics Oy Modulateurs tricycliques de pp2a
WO2022167867A1 (fr) * 2021-02-08 2022-08-11 Rappta Therapeutics Oy Modulateurs cycliques substitués de protéine phosphatase 2a (pp2a) et leurs procédés d'utilisation
WO2023023594A1 (fr) * 2021-08-18 2023-02-23 Atux Iskay Llc Dérivés de 2-diarylméthyle-4-aminotétrahydropyrane et composés apparentés utilisés en tant qu'agents anticancéreux, anti-inflammatoires, antifibrotiques et neuroprotecteurs
EP4121031A4 (fr) * 2020-03-20 2024-03-27 Atux Iskay LLC 3-diarylméthylènes et leurs utilisations
WO2024040045A3 (fr) * 2022-08-15 2024-04-11 Atux Iskay Llc 2-diarylméthyl-4-aminotétrahydropyrane sulfonimidamides comme agents anticancéreux, anti-inflammatoires, antifibrotiques et neuroprotecteurs

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9937186B2 (en) 2014-03-11 2018-04-10 Icahn School Of Medicine At Mount Sinai Sulfonamides derived from tricyclyl-2-aminocycloalkanols as anticancer agents
US9937180B2 (en) 2014-03-11 2018-04-10 Icahn School Of Medicine At Mount Sinai Constrained tricyclic sulfonamides
US10221158B2 (en) 2015-09-09 2019-03-05 Icahn School Of Medicine At Mount Sinai Heterocyclic constrained tricyclic sulfonamides as anti-cancer agents
US10759790B2 (en) 2015-09-09 2020-09-01 Ichan School Of Medicine At Mount Sinai Heterocyclic constrained tricyclic sulfonamides as anti-cancer agents
WO2021170913A1 (fr) * 2020-02-28 2021-09-02 Rappta Therapeutics Oy Modulateurs tricycliques de pp2a
EP4121031A4 (fr) * 2020-03-20 2024-03-27 Atux Iskay LLC 3-diarylméthylènes et leurs utilisations
WO2022167867A1 (fr) * 2021-02-08 2022-08-11 Rappta Therapeutics Oy Modulateurs cycliques substitués de protéine phosphatase 2a (pp2a) et leurs procédés d'utilisation
WO2023023594A1 (fr) * 2021-08-18 2023-02-23 Atux Iskay Llc Dérivés de 2-diarylméthyle-4-aminotétrahydropyrane et composés apparentés utilisés en tant qu'agents anticancéreux, anti-inflammatoires, antifibrotiques et neuroprotecteurs
WO2024040045A3 (fr) * 2022-08-15 2024-04-11 Atux Iskay Llc 2-diarylméthyl-4-aminotétrahydropyrane sulfonimidamides comme agents anticancéreux, anti-inflammatoires, antifibrotiques et neuroprotecteurs

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