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US20220396549A1 - Small molecule inhibitors of the mcl-1 oncoprotein and uses therof - Google Patents

Small molecule inhibitors of the mcl-1 oncoprotein and uses therof Download PDF

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US20220396549A1
US20220396549A1 US17/114,374 US202017114374A US2022396549A1 US 20220396549 A1 US20220396549 A1 US 20220396549A1 US 202017114374 A US202017114374 A US 202017114374A US 2022396549 A1 US2022396549 A1 US 2022396549A1
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hydroxy
carcinoma
acid
benzoic acid
isobutyl
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Steven Fletcher
Maryanna Lanning
Lijia Chen
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University of Maryland Baltimore
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University of Maryland Baltimore
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    • 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
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
    • 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
    • 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
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C07D261/12—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the invention relates generally to compounds and methods of using the same for treating conditions characterized by the overexpression or unregulated activity of anti-apoptotic B-Cell Lymphoma (Bcl-2) family proteins and more particularly, but not exclusively, to compounds that bind to the protein Myeloid Cell Leukemia-1 (Mcl-1).
  • Bcl-2 anti-apoptotic B-Cell Lymphoma family proteins
  • Mcl-1 Myeloid Cell Leukemia-1
  • the pathway involves protein-protein interactions (PPIs) between pro-apoptotic members of the Bcl-2 family, such as Bim, Bak and Bad, and anti-apoptotic members, such as Bcl-xL and myeloid cell leukemia-1 (Mcl-1).
  • PPIs protein-protein interactions
  • pro-apoptotic members of the Bcl-2 family such as Bim, Bak and Bad
  • anti-apoptotic members such as Bcl-xL and myeloid cell leukemia-1 (Mcl-1).
  • Mcl-1 myeloid cell leukemia-1
  • the anti-apoptotic Bcl-2 proteins capture the BH3 ⁇ -helical domains of their pro-apoptotic counterparts, effectively “neutralizing” their cell killing functions.
  • Evasion of apoptosis is a hallmark of cancer,
  • Mcl-1 overexpression and/or amplification of the Mcl-1 gene immortalizes cells, and has been observed in many human solid tumors, including pancreatic, prostate, cervical, lung and breast cancers, as well as B-cell lymphomas and hematological cancers, including acute myeloid leukemia (AML). While certain BCl- XL /BCl-2 inhibitors perform well in clinical trials, their low affinity for Mcl-1 is a contributing factor to the observed resistance of several tumor cell lines. Moreover, the upregulation of Mcl-1 has been directly linked to the reduced efficacy of several FDA-approved anti-cancer chemotherapies. Accordingly, the pharmacologic inhibition of Mcl-1 is an attractive, complementary, and/or adjuvant strategy towards the execution of cancer cells by re-activating apoptosis.
  • AML acute myeloid leukemia
  • Mcl-1 selectively binds Mcl-1 with high affinity and methods for using such compounds to treat diseases characterized by overexpression or unregulated anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins.
  • the invention includes compounds of formula (I):
  • X 1 may be a substituent selected from the group consisting of H, C, CH, CIT, and CH 3 ;
  • X 4 may be a substituent selected from the group consisting of C, CH, N, and NR 2 , wherein the dashed lines can independently represent a single bond, a double bond, or no bond;
  • A may be a substituent selected from the group consisting of S( ⁇ O), S( ⁇ O) 2 , C( ⁇ O), C( ⁇ O)O, and CH 2 ;
  • L may be a bond or an NR 3 substituent
  • each Z may independently represent a substituent selected from the group consisting of H, halo, cyano, hydroxy, nitro, and optionally substituted acyl sulfonamide, alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkynyl, alkenyl-cycloalkyl, alkynyl-cycloalkyl, carbonyl, carboxaldehyde, carboxyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amino, amido, aryl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, hetero
  • each R 1 , R 2 , R 3 , and R 4 may independently represent a substituent selected from the group consisting of H and optionally substituted alkyl, cycloalkyl, sulfinyl, sulfonyl, and aryl; and R 1 and R 3 may, taken together, comprise an optionally substituted cycloalkyl or heterocycloalkyl ring; and
  • the dashed line between X 1 and X 2 may represent a double bond and the dashed line between X 1 and X 4 may represent a double bond. Accordingly, in some embodiments, X 1 , X 2 , X 3 , and X 4 may represent a portion of an aromatic ring.
  • Y 1 and Y 2 may collectively represent a carboxylic acid bioisostere which may, for example, be an optionally substituted alkyl ester, an acylsulfonamide, a hydroxamic acid, a hydroxamate, a tetrazole, a hydroxyisoxazole, an isoxazol-3-one, or a sulfonamide.
  • the compounds of formula (I) may include one or more of:
  • the compounds of formula (I) may include those compounds wherein R 1 and R 3 each independently represent a substituent selected from the group consisting of optionally substituted alkyl and aryl; and R 1 and R 3 may, taken together, comprise an optionally substituted cycloalkyl or heterocycloalkyl ring.
  • the invention includes compounds of formula (II);
  • each R 21 and R 22 may independently represent a substituent selected from the group consisting of H and optionally substituted alkyl and aryl;
  • a 21 may be a substituent selected from the group consisting of S( ⁇ O), S( ⁇ O) 2 , C( ⁇ O), and CH 2 ;
  • X 21 may be CH or N
  • each Z 21 may independently represent a substituent selected from the group consisting of H, halo, cyano, hydroxy, nitro, and optionally substituted acyl sulfonamide, alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkynyl, alkenyl-cycloalkyl, alkynyl-cycloalkyl, carbonyl, carboxaldehyde, carboxyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, alkoxy, alkoxy carbonyl, acyl, acyloxy, amino, amido, aryl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl,
  • Y 21 may be a substituent selected from the group consisting of —C(O)O—, —CONR 22 —, —CONR 22 —SO 2 —, —CONR 22 O—,
  • R 23 and R 24 each may independently represent a substituent selected from the group consisting of H and optionally substituted alkyl and aryl; and R 23 and R 24 may, taken together, comprise an optionally substituted cycloalkyl or heterocycloalkyl ring;
  • R 25 may be a substituent selected from the group consisting of H and optionally substituted alkyl, aryl, sulfinyl, and sulfonyl;
  • Y 21 and R 22 may collectively represent an optionally substituted acylsulfonamide.
  • Y 21 and R 22 may collectively represent a carboxylic acid bioisostere which may, for example, be an optionally substituted alkyl ester, an acylsulfonamide, a hydroxamic acid, a hydroxamate, a tetrazole, a hydroxyisoxazole, an isoxazol-3-one, or a sulfonamide.
  • the compounds of formula (II) may include one or more of:
  • the compounds of formula (II) may include those compounds wherein R 23 and R 24 each independently represent a substituent selected from the group consisting of optionally substituted alkyl and aryl; and R 23 and R 24 may, taken together, comprise an optionally substituted cycloalkyl or heterocycloalkyl ring.
  • the invention includes one or more compounds of formula (IIIa) or formula (IIIb):
  • each R 31 may independently represent a substituent selected from the group consisting of H and an optionally substituted alkyl and aryl;
  • a 31 may be a bond or a substituent selected from the group consisting of S( ⁇ O), S( ⁇ O) 2 , C( ⁇ O), C( ⁇ O)O, and CH 2 ;
  • X 31 may be a substituent selected from the group consisting of optionally substituted alkyl and aryl;
  • Y 31 may be a substituent selected from the group consisting of —C(O)O—, —CONR 31 —, —CONR 31 —SO 2 —, —CONR 31 O—,
  • Z 31 , Z 32 , Z 33 , and Z 34 each may independently represent a substituent selected from the group consisting of H, halo, cyano, hydroxy, nitro, and optionally substituted acylsulfonamide, alkyl, alkylaryl, alkylhetaryl, alkyl heterocycloalkyl, alkenyl, alkynyl, alkenyl-cycloalkyl, alkynyl-cycloalkyl, carboxaldehyde, carbonyl, carboxyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amino, amido, aryl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl,
  • Y 31 and R 31 may collectively represent an optionally substituted acylsulfonamide.
  • Y 31 and R 31 may collectively represent a carboxylic acid bioisostere which may, for example, be an optionally substituted alkyl ester, an acylsulfonamide, a hydroxamic acid, a hydroxamate, a tetrazole, a hydroxyisoxazole, an isoxazol-3-one, or a sulfonamide.
  • the compound of formula (IIIa) or formula (IIIb) may include one or more of:
  • the invention includes compounds of formula (IV):
  • R 41 may be a substituent selected from the group consisting of H and optionally substituted alkyl, aryl, and cycloalkyl;
  • Z 41 and Z 42 each may independently represent a substituent selected from the group consisting of H, cyano, OR 42 , COOR 42 , CONR 42 OR 42 , CONR 42 R 42 , CON(R 42 )—S(O) 2 R 42 ,
  • each R 42 may independently represent a substituent selected from the group consisting of H and optionally substituted alkyl and aryl;
  • a 41 may be a bond or a substituent selected from the group consisting of S( ⁇ O), S( ⁇ O) 2 , and C( ⁇ O);
  • X 41 may be a substituent selected from the group consisting of optionally substituted alkyl, aryl, cycloalkyl, and heterocycloalkyl;
  • Z 41 and/or Z 42 may represent a carboxylic acid bioisostere which may, for example, be an optionally substituted alkyl ester, an acylsulfonamide, a hydroxamic acid, a hydroxamate, a tetrazole, a hydroxyisoxazole, an isoxazol-3-one, or a sulfonamide.
  • the compound of formula (IV) may include one or more of:
  • the compounds of formula (IV) may include one or more compounds wherein Z 41 and Z 42 each may independently represent a substituent selected from the group consisting of OR 42 and COOR 42 .
  • the compound of the invention is selected from the group consisting of:
  • the invention includes a method of treating a condition alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method including administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • the invention includes a method of treating a condition alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method including administering a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • the invention includes a method of treating a condition alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method including administering a therapeutically effective amount of a compound of formula (IIIa) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • the invention includes a method of treating a condition alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method including administering a therapeutically effective amount of a compound of formula (IIIb) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • the invention includes a method of treating a condition alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method including administering a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • a method of treating a condition alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment including administering a therapeutically effective amount of one or more compounds selected from the group consisting of:
  • the condition alleviated by inhibiting Mcl-1 protein may be selected from the group consisting of: pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyper
  • condition alleviated by inhibiting Mcl-1 protein may be selected from the group consisting of: myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.
  • the invention may include a pharmaceutical composition for treating a condition alleviated by inhibiting Mcl-1 protein activity, the pharmaceutical composition including one or more compounds of formula (I), (II), (IIIa), (IIIb), and (IV), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable carrier medium.
  • the pharmaceutical composition may include one or more of: 4-(N-(4-(4-chloro-3,5-dimethyl phenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
  • FIG. 1 illustrates the binding mode of 3a, as predicted by SILCS. Important residues within the p2 binding pocket are shown in stick representation.
  • FIG. 2 illustrates a 2D NMR HSQC spectra, which shows chemical shift perturbations caused by the direct interaction of compound 3ba with Mcl-1.
  • the spectrum of the control sample is overlaid with the spectrum of Mcl-1 bound to 3ba. Inset is enlargement of boxed region.
  • FIG. 3 illustrates Mcl-1 residues whose chemical shifts are perturbed in the presence of compound 3ba.
  • FIG. 4 illustrates atom GFE contributions for the most LGFE favorable binding conformation of the four compounds.
  • Compound (A) is 3b
  • compound (B) is 3a
  • compound (C) is 3bi
  • compound (D) is 3bl.
  • FIGS. 5 A to 5 D illustrate computational modeling studies of certain compounds described herein with Mcl-1 and Bcl-xL proteins.
  • FIG. 5 A illustrates a difference FragMap between Mcl-1 and Bcl-xL showing the favourable binding patterns for Mcl-1. The atom grid free energy (GFE) contributions to the binding affinity difference are also shown.
  • FIG. 5 B illustrates the experimental structures of Mcl-1 (A, 4HW4) and BCl-x L (B, 1BXL) shows that the binding pocket between helix ⁇ 4 (upper right) and ⁇ 5 (bottom left) is larger for Mcl-1 than Bcl-x L .
  • the predicted binding modes of 3a for Mcl-1 (X) and BCl-x L (Y) differs due to this p2 pocket difference.
  • FIG. 5 C illustrates binding orientations of 3bl to Mcl-1 (A, 4HW4) and Bcl-x L (B, 1BXL) along with the ⁇ FragMaps, The predicted binding modes of 3a for Mcl-1 (X) and Bcl-x L (Y) are also shown.
  • FIG. 5 D illustrates the binding orientations of 3bl to BCl-x L (1BXL) along with the Bcl-x L APOLAR and NEG FragMaps.
  • FIG. 6 illustrates pharmacophore features for the Mcl-1 binding site.
  • the pharmacophore features developed from SILCS FragMaps are used to explore the binding conformation of the tested compounds. Crystal structure of Mcl-1 and the inhibitor Fesik60 from complex (PDBID:4HW3) are shown. Protein atoms occluding the view of the binding pocket were removed to facilitate visualization. Features APOLAR (i.e., F1, F3, F4, and F5), HBDON (i.e., F7), HBACC (i.e., F6), and NEG (i.e., F2) are marked.
  • APOLAR i.e., F1, F3, F4, and F5
  • HBDON i.e., F7
  • HBACC i.e., F6
  • NEG i.e., F2
  • FIG. 7 illustrates a correlation plot of experimental binding affinity (from Ki) vs. predicted LGFE (standard deviations are shown by the error bars) for all the tested compounds of MCL-1. A correlation coefficient of 0.53 and a predictive index of 0.70 were obtained.
  • FIG. 8 illustrates a correlation plot of Bcl-xl experimental binding affinity (from Ki) vs. predicted LGFE (standard deviations are shown by the error bars) for all the compounds tested against Bcl-xL. A correlation coefficient of 0.58 and a predictive index of 0.76 were obtained.
  • FIG. 9 illustrates a correlation plot of experimental binding affinity difference between Mcl-1 and Bcl-xL (from Ki) vs. predicted LGFE difference for all compounds tested against Bcl-x. A correlation coefficient of 0.57 and a predictive index of 0.83 were obtained.
  • FIG. 10 illustrates the relative locations of Asn260 and Arg263 on the tertiary structure of the Mcl-1 protein in addition to the locations of the p2 and p3 pockets.
  • FIG. 11 illustrates the proposed Mcl-1 binding orientations for the tetrahydroquinoline, salicylate, and naphthoate Mcl-1 inhibitors described herein.
  • FIG. 12 illustrates a 2D 1H-15N HSQC spectra of Mcl-1 collected in the absence and presence of ⁇ 2 from Example 4.
  • FIG. 13 illustrates resonance variations that were mapped onto the Mcl-1 crystal structure after calculating the chemical shift perturbations for each amino acid following the 2D 1H-15N HSQC analysis with ⁇ 2 from Example 4.
  • FIG. 14 illustrates the design of a 4-aminobenzoate analog based on the THQ scaffold.
  • FIG. 15 illustrates the predicted binding of 4-aminobenzoate to Mcl-1.
  • FIG. 16 illustrates the predicted binding of 4-aminobenzoate to Mcl-1 after the installation of a hydroxyl group ortho to the carboxylic acid (i.e., converting the 4-aminobenzoate into a 4-aminosalicylate).
  • FIG. 17 illustrates the predicted binding of 5-aminosalicylate to Mcl-1.
  • FIG. 18 illustrates a 2D 1H-15N HSQC spectra of apo-Mcl-1 collected in the absence and presence of 13ak.
  • FIG. 19 illustrates a plot of chemical shift of Mcl-1 protein upon 13ak binding, where black columns are the amino residues that were significantly perturbed (A chemical shift >0.3 ppm).
  • FIG. 20 illustrates NMR chemical shift perturbations of the MCL-1/13ak complex mapped onto MCL-1 crystal coordinates (PDB ID: 4HW3) in PyMOL. Residues experiencing chemical shifts of at least 0.3 ppm are shaded.
  • administer refers to (1) providing, giving, dosing, and/or prescribing by either a health practitioner or his authorized agent or under his or her direction according to the disclosure; and/or (2) putting into, taking or consuming by the mammal, according to the disclosure.
  • co-administration encompass administration of two or more active pharmaceutical ingredients to a subject so that both active pharmaceutical ingredients and/or their metabolites are present in the subject at the same time.
  • Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present. Simultaneous administration in separate compositions and administration in a composition in which both agents are present are preferred.
  • active pharmaceutical ingredient and drug include the Mcl-1 inhibitors described herein and, more specifically, the Mcl-1 inhibitors described by Formulas I, II, IIIa, IIIb, and IV.
  • active pharmaceutical ingredient and drug may also include those compounds described herein that bind Mcl-1 protein and thereby modulate Mcl-1 protein activity.
  • isostere refers to a group or molecule whose chemical and/or physical properties are similar to those of another group or molecule.
  • a “bioisostere” is a type of isostere and refers to a group or molecule whose biological properties are similar to those of another group or molecule.
  • a carboxylic acid may be replaced by one of the following bioisosteres for carboxylic acids, including, without limitation, alkyl esters (COOR), acyl sulfonamides (CONR—SO 2 R), hydroxamic acids (CONR—OH), hydroxamates (CONR—OR), tetrazoles, hydroxyisoxazoles, isoxazol-3-ones, and sulfonamides (SO 2 NR), where each R may independently represent hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • in vivo refers to an event that takes place in a subject's body.
  • in vitro refers to an event that takes places outside of a subject's body.
  • in vitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.
  • an effective amount refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment.
  • a therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells (e.g., the reduction of platelet adhesion and/or cell migration).
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • the terms “treat,” “treatment,” and/or “treating” may refer to the management of a disease, disorder, or pathological condition (e.g., pain, a neurological disorder, diarrhea, coughing, muscular tension, and glaucoma), or symptom thereof with the intent to cure, ameliorate, stabilize, prevent, and/or control the disease, disorder, pathological condition or symptom thereof.
  • control may include the absence of condition progression, as assessed by the response to the methods recited herein, where such response may be complete (e.g., placing the disease in remission) or partial (e.g., lessening or ameliorating any symptoms associated with the condition).
  • the terms “modulate” and “modulation” refer to a change in biological activity for a biological molecule (e.g., a protein, gene, peptide, antibody, and the like), where such change may relate to an increase in biological activity (e.g., increased activity, agonism, activation, expression, upregulation, and/or increased expression) or decrease in biological activity (e.g., decreased activity, antagonism, suppression, deactivation, downregulation, and/or decreased expression) for the biological molecule.
  • the biological molecules modulated by the methods and compounds of the invention to effect treatment may include one or both of the ⁇ -opioid receptor and the ⁇ -opioid receptor.
  • QD means quaque die, once a day, or once daily.
  • BID bis in die, twice a day, or twice daily.
  • TID means bis in die, twice a day, or twice daily.
  • TID means ter in die, three times a day, or three times daily.
  • QID means quater in die, four times a day, or four times daily.
  • pharmaceutically acceptable salt refers to salts derived from a variety of organic and inorganic counter ions known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.
  • Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • cocrystal refers to a molecular complex derived from a number of cocrystal formers known in the art.
  • a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “physiologically compatible” carrier or carrier medium is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients.
  • the use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the invention is contemplated. Additional active pharmaceutical ingredients, such as other drugs, can also be incorporated into the described compositions and methods.
  • a “prodrug” refers to a derivative of a compound described herein, the pharmacologic action of which results from the conversion by chemical or metabolic processes in vivo to the active compound.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxyl or carboxylic acid group of formulas I, II, IIIa, IIIb, and IV.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by one or three letter symbols but also include, for example, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters (e.g., methyl esters and acetoxy methyl esters).
  • Prodrug esters as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of the method of the invention with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methyl carbonates, benzoates and the like.
  • free hydroxyl groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs, sulfonate prodrugs, sulfonate esters and sulfate esters of hydroxyl groups.
  • Free amines can also be derivatized to amides, sulfonamides or phosphonamides. All of the stated prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • any compound that can be converted in vivo to provide the bioactive agent e.g., a compound of formula I, II, IIIa, IIIb, and IV
  • Various forms of prodrugs are well known in the art.
  • pro drugs and prodrug derivatives are described in: (a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., (Academic Press, 1996); (b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); (c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds., (Harwood Academic Publishers, 1991).
  • prodrugs may be designed to improve the penetration of a drug across biological membranes in order to obtain improved drug absorption, to prolong duration of action of a drug (slow release of the parent drug from a prodrug, decreased first-pass metabolism of the drug), to target the drug action (e.g. organ or tumor-targeting, lymphocyte targeting), to modify or improve aqueous solubility of a drug (e.g., i.v. preparations and eyedrops), to improve topical drug delivery (e.g. dermal and ocular drug delivery), to improve the chemical/enzymatic stability of a drug, or to decrease off-target drug effects, and more generally in order to improve the therapeutic efficacy of the compounds utilized in the invention.
  • target the drug action e.g. organ or tumor-targeting, lymphocyte targeting
  • aqueous solubility of a drug e.g., i.v. preparations and eyedrops
  • topical drug delivery e.g. dermal and ocular drug delivery
  • the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by 13 C- or 14 C-enriched carbons are within the scope of this invention.
  • ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.
  • Use of the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary. The variation is typically from 0% to 15%, preferably from 0% to 10%, more preferably from 0% to 5% of the stated number or numerical range.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., (C 1-10 )alkyl or C 1-10 alkyl).
  • a numerical range such as “1 to 10” refers to each integer in the given range—e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” where no numerical range is specifically designated.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl.
  • the alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl) and 3-methylhexyl.
  • an alkyl group is optionally substituted by one or more of substituents which are independently heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —OC(O)N(R a ) 2 , —C(O)N(R a ) 2 , —N(R a )
  • Alkylaryl refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • Alkylhetaryl refers to an -(alkyl)hetaryl radical where hetaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • Alkylheterocycloalkyl refers to an -(alkyl) heterocycyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl respectively.
  • alkene refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., (C 2-10 )alkenyl or C 2-10 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range—e.g., “2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • the alkenyl moiety may be attached to the rest of the molecule by a single bond, such as for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl and penta-1,4-dienyl.
  • ethenyl i.e., vinyl
  • prop-1-enyl i.e., allyl
  • but-1-enyl i.e., pent-1-enyl and penta-1,4-dienyl.
  • an alkenyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR 3 , —OC(O)N(R a ) 2 , —C(O)N(R a ) 2 , —N(R
  • Alkenyl-cycloalkyl refers to an -(alkenyl)cycloalkyl radical where alkenyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., (C 2-10 )alkynyl or C 2-10 alkynyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range—e.g., “2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, acylsulfonamido, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a )
  • Alkynyl-cycloalkyl refers to an -(alkynyl)cycloalkyl radical where alkynyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkynyl and cycloalkyl respectively.
  • “Acylsulfonamide” refers to the group —C( ⁇ O)NR a —S( ⁇ O)R a , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.
  • Carboxaldehyde refers to a —(C ⁇ O)H radical.
  • Carbonyl refers to the group —C( ⁇ O)—. Carbonyl groups may be substituted with the following exemplary substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, acylsulfonamido, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —NR a —OR a —, —C(O)OR a , —OC(O)N(R a ) 2 ,
  • Carboxyl refers to a —(C ⁇ O)OH radical.
  • Cyano refers to a —CN radical.
  • Cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e. (C 3-10 )cycloalkyl or C 3-10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range—e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.
  • a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, acylsulfonamido, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —OC(O)N(R a
  • Cycloalkyl-alkenyl refers to a -(cycloalkyl)alkenyl radical where cycloalkyl and alkenyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.
  • Cycloalkyl-heterocycloalkyl refers to a -(cycloalkyl)heterocycloalkyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heterocycloalkyl, respectively.
  • Cycloalkyl-heteroaryl refers to a -(cycloalkyl)heteroaryl radical where cycloalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.
  • alkoxy refers to the group —O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. “Lower alkoxy” refers to alkoxy groups containing one to six carbons.
  • substituted alkoxy refers to alkoxy wherein the alkyl constituent is substituted (i.e., —O-(substituted alkyl)).
  • the alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, acylsulfonamido, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C
  • alkoxycarbonyl refers to a group of the formula (alkoxy)(C ⁇ O)— attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms.
  • a (C 1-6 )alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
  • Lower alkoxycarbonyl refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.
  • substituted alkoxycarbonyl refers to the group (substituted alkyl)-O—C(O)— wherein the group is attached to the parent structure through the carbonyl functionality.
  • substituents which independently are: alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R
  • “Acyl” refers to the groups (alkyl)-C(O)—, (aryl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C(O)— and (heterocycloalkyl)-C(O)—, wherein the group is attached to the parent structure through the carbonyl functionality. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms.
  • the alkyl, aryl or heteroaryl moiety of the acyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —OC(O)N(R a ) 2 , —C(O)N, —C(O)N
  • “Acyloxy” refers to a R(C ⁇ O)O— radical wherein R is alkyl, aryl, heteroaryl, heteroalkyl or heterocycloalkyl, which are as described herein. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms.
  • R of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —OC(O)N(R a ) 2 , —C(O)N(R a ) 2 , —N(R a )C(O)C(O)C(O)
  • Amino or “amine” refers to a —N(R a ) 2 radical group, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
  • R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
  • R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl
  • —N(R a ) 2 is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • an amino group is optionally substituted by one or more substituents which independently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a ,
  • substituted amino also refers to N-oxides of the groups —NHR d , and NR d R d each as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.
  • “Amide” or “amido” refers to a chemical moiety with formula —C(O)N(R) 2 or —NHC(O)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted.
  • R 2 of —N(R) 2 of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring.
  • an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, amino, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
  • An amide may be an amino acid or a peptide molecule attached to a compound disclosed herein, thereby forming a prodrug.
  • the procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.
  • Aromaatic or “aryl” or “Ar” refers to an aromatic radical with six to ten ring atoms (e.g., C 6 -C 10 aromatic or C 6 -C 10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl).
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.
  • an aryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a
  • alkyl or “arylalkyl” refers to an (aryl)alkyl-radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • Ester refers to a chemical radical of formula —COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
  • R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
  • the procedures and specific groups to make esters are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.
  • an ester group is optionally substituted by one or more substituents which independently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —OC(O)N(R a ) 2 , —C(O)N(R a ) 2 , —N(R )
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
  • Halo “Halo,” “halide,” or, alternatively, “halogen” is intended to mean fluoro, chloro, bromo or iodo.
  • haloalkyl “haloalkenyl,” “haloalkynyl,” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
  • Heteroalkyl refers to optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • a numerical range may be given—e.g., C 1 -C 4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long.
  • a heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, acylsulfonamido, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —OC(O)N(R a ) 2 , —C(O)N(R a ) 2 , —N(R a )C(O)OR
  • Heteroalkylaryl refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.
  • Heteroalkyl heteroaryl refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.
  • Heteroalkylheterocycloalkyl refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl, respectively.
  • Heteroalkylcycloalkyl refers to an -(heteroalkyl)cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.
  • Heteroaryl or “heteroaromatic” or “HetAr” refers to a 5- to 18-membered aromatic radical (e.g., C 5 -C 13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system.
  • a numerical range such as “5 to 18” refers to each integer in the given range—e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical—e.g., a pyridyl group with two points of attachment is a pyridylidene.
  • a N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • the polycyclic heteroaryl group may be fused or non-fused.
  • the heteroatom(s) in the heteroaryl radical are optionally oxidized.
  • heteroaryl may be attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benz
  • a heteroaryl moiety is optionally substituted by one or more substituents which are independently; alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —OC(O)N(R a ) 2 , —C(O)N(R a ) 2 , —C(O)N(R a )
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (—O—) substituents, such as, for example, pyridinyl N-oxides.
  • Heteroarylalkyl refers to a moiety having an aryl moiety, as described herein, connected to an alkylene moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkylene group.
  • Heterocycloalkyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range—e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms.
  • the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
  • the heteroatoms in the heterocycloalkyl radical may be optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heterocycloalkyl radical is partially or fully saturated.
  • the heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s).
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-o-
  • a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —S(O) t R a — (where t is 1 or 2), —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —OC(O)N(R a ) 2 , —C(O)N(R a ) 2 , —C(O)N(R
  • Heterocycloalkyl also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
  • “hydroxamate” refers to the —C(O)NR a OR a moiety, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • Niro refers to the —NO 2 radical.
  • Oxa refers to the —O— radical.
  • Oxo refers to the ⁇ O radical.
  • “Isomers” are different compounds that have the same molecular formula “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space—i.e., having a different stereochemical configuration. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1; 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.
  • stereochemistry at each chiral carbon can be specified by either (R) or (S).
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or ( ⁇ ) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S).
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • Enantiomeric purity refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (R)- or an (S)-isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (S)-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (S)-isomer and 20% (R)-isomer, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%.
  • the enantiomeric purity of a compound can be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle's reagents, or derivatization of a compounds using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.
  • the enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition.
  • Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, el al., Enantiomers, Racemates and Resolutions , Wiley Interscience, New York (1981); E. L. Eliel, Stereochemistry of Carbon Compounds , McGraw-Hill, New York (1962); and E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds , Wiley-Interscience, New York (1994).
  • an enantiomerically enriched preparation of the (S)-enantiomer means a preparation of the compound having greater than 50% by weight of the (S)-enantiomer relative to the (R)-enantiomer, such as at least 75% by weight, or such as at least 80% by weight.
  • the enrichment can be significantly greater than 80% by weight, providing a “substantially enantiomerically enriched” or a “substantially non-racemic” preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, or such as at least 95% by weight.
  • a “substantially enantiomerically enriched” or a “substantially non-racemic” preparation refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, or such as at least 95% by weight.
  • the terms “enantiomerically pure” or “substantially enantiomerically pure” refers to a composition that comprises at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.
  • “Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • “Tautomers” are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization.
  • keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerization is phenol-keto tautomerization.
  • phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
  • a “leaving group or atom” is any group or atom that will, under selected reaction conditions, cleave from the starting material, thus promoting reaction at a specified site.
  • Examples of such groups include halogen atoms and mesyloxy, p-nitrobenzensulphonyloxy and tosyloxy groups.
  • Protecting group is intended to mean a group that selectively blocks one oi more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and the group can then be readily removed or deprotected after the selective reaction is complete.
  • a variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York (1999).
  • Solvate refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent.
  • “Substituted” means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxamate, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups,
  • substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons.
  • optionally substituted means optional substitution with the specified groups, radicals or moieties.
  • “Sulfanyl” refers to groups that include —S-(optionally substituted alkyl), —S-(optionally substituted aryl), —S-(optionally substituted heteroaryl) and —S-(optionally substituted heterocycloalkyl).
  • “Sulfinyl” refers to groups that include —S(O)—H, —S(O)-(optionally substituted alkyl), —S(O)-(optionally substituted amino), —S(O)-(optionally substituted aryl), —S(O)-(optionally substituted heteroaryl) and —S(O)-(optionality substituted heterocycloalkyl).
  • “Sulfonyl” refers to groups that include —S(O 2 )—H, —S(O 2 )-(optionally substituted alkyl), —S(O 2 )-(optionally substituted amino), —S(O 2 )-(optionally substituted aryl), —S(O 2 )-(optionally substituted heteroaryl), and —S(O 2 )-(optionally substituted heterocycloalkyl).
  • “Sulfonamidyl” or “sulfonamido” refers to a —S( ⁇ O) 2 —NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
  • the R groups in —NRR of the —S( ⁇ O) 2 —NRR radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring.
  • a sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
  • “Sulfoxyl” refers to a —S( ⁇ O) 2 OH radical.
  • “Sulfonate” refers to a —S( ⁇ O) 2 —OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). A sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
  • Compounds of the invention also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • Crystalstalline form” and “polymorph” are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
  • the compounds and compositions described herein can be used in methods for treating diseases.
  • the compounds and compositions described herein can be used in methods for treating diseases associated with the upregulation of myeloid cell leukemia-1 (Mcl-1) oncoprotein.
  • the compounds and compositions described herein can be used for the treatment of hyperproliferative disorders, including those hyperproliferative disorders associated with the upregulation of Mcl-1.
  • the compounds and compositions described herein may also be used in treating other disorders as described herein and in the following paragraphs.
  • the hyperproliferative disorder is cancer.
  • the cancer is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia,
  • the hyperproliferative disorder treated by the compounds and compositions described herein includes cells having Mcl-1 protein and/or Mcl-1 related protein expression.
  • the disease treated by the compounds and compositions described herein is selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.
  • the compounds described herein may induce cell cycle arrest and/or apoptosis in cells containing functional Mcl-1 proteins.
  • the compounds described herein may be used for sensitizing cells to additional agent(s), such as inducers of apoptosis and/or cell cycle arrest, and chemoprotection of normal cells through the induction of cell cycle arrest prior to treatment with chemotherapeutic agents.
  • the compounds described herein may be useful for the treatment of disorders, such as those responsive to induction of apoptotic cell death, e.g., disorders characterized by dysregulation of apoptosis.
  • the compounds may be used to treat cancer that is characterized by resistance to cancer therapies (e.g., those cancer cells which are chemoresistant, radiation resistant, hormone resistant, and the like).
  • cancer therapies e.g., those cancer cells which are chemoresistant, radiation resistant, hormone resistant, and the like.
  • the compounds can be used to treat hyperproliferative diseases characterized by expression of functional Mcl-1 and/or Mcl-1 related proteins, which may or may not be resilient to Bcl-x L inhibitors.
  • the invention includes compounds that may be Mcl-1 inhibitors and/or modulators of Mcl-1 protein activity.
  • the compounds described herein may be selective inhibitors of Mcl-1 protein activity as compared to BCl-x L .
  • the compounds described herein may selectively decrease the activity of Mcl-1 protein as compared to BCl-x L protein in a ratio of at least about 1.5 to about 1, or at least about 2 to about 1, or at least about 3 to about 1, or at least about 4 to about 1, or at least about 5 to about 1, or at least about 10 to about 1, or at least about 15 to about 1, or at least about 20 to about 1, or at least about 25 to about 1, or at least about 30 to about 1, or at least about 35 to about 1, or at least about 40 to about 1, or at least about 45 to about 1, or at least about 50 to about 1, or at least about 100 to about 1, or at least about 200 to about 1, or at least about 300 to about 1, or at least about 400 to about 1, or at least about 500 to about 1, or at least about 600 to about 1, or at least about 700 to about 1, or least about 800 to about 1, or at least about 900 to about 1, or at least about 1000 to about 1, or at least about 10000 to about 1, or at least about 100000 to about 1, respectively.
  • the Mcl-1 inhibitor may be a compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, tautomer, or prodrug thereof.
  • the Mcl-1 inhibitor of formula I includes one or more of:
  • the Mcl-1 inhibitor may be a compound of formula II, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, tautomer, or prodrug thereof.
  • the compounds of formula I include the compounds of formula II, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, tautomers, or prodrugs thereof.
  • the Mcl-1 inhibitor of formula II includes one of more of
  • the Mcl-1 inhibitor may be a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, tautomer, or prodrug thereof.
  • the compounds of formula I include the compounds of formula IIIa or IIIb, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, tautomers, or prodrugs thereof.
  • the Mcl-1 inhibitor of formula IIIa or IIIb includes one or more of:
  • the Mcl-1 inhibitor may be a compound of formula IV, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, tautomer, or prodrug thereof.
  • the compounds of formula 1 include the compounds of formula IV, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, tautomers, or prodrugs thereof.
  • the Mcl-1 inhibitor of formula IV may include one or more of:
  • the Mcl-1 inhibitor may be one or more of the compounds set forth in the table below:
  • the Mcl-1 inhibitors described above may be delivered as listed or as a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, tautomer, or prodrug thereof.
  • an active pharmaceutical ingredient or combination of active pharmaceutical ingredients such as any of the foregoing Mcl-1 inhibitors, is provided as a pharmaceutically acceptable composition.
  • the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the invention is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/v/v/v
  • the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%
  • the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the invention is in the range from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12% or about 1% to about 10% w/w, w/v or v/v of the pharmaceutical composition.
  • the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the invention is in the range from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/v or v/v of the pharmaceutical composition.
  • the amount of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g,
  • the amount of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055
  • Each of the active pharmaceutical ingredients according to the invention is effective over a wide dosage range.
  • dosages independently range from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • the clinically-established dosages of the foregoing Mcl-1 inhibitors may also be used if appropriate.
  • the molar ratio of two active pharmaceutical ingredients in the pharmaceutical compositions is in the range from 10:1 to 1:10, preferably from 2.5:1 to 1.2.5, and more preferably about 1:1.
  • the weight ratio of the molar ratio of two active pharmaceutical ingredients in the pharmaceutical compositions is selected from the group consisting of 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9.1, 8.1, 7.1, 6.1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20.
  • the weight ratio of the molar ratio of two active pharmaceutical ingredients in the pharmaceutical compositions is selected from the group consisting of 20:1, 19:1, 18:1, 17.1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, too 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20.
  • the pharmaceutical compositions described herein are for use in the treatment of hyperproliferative disorders associated with the overexpression or upregulation of Mcl-1.
  • the pharmaceutical compositions described herein are for use in the treatment of a cancer associated with overexpression or upregulation of Mcl-1 selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple
  • the pharmaceutical compositions described herein are for use in the treatment of a cancer associated with overexpression or upregulation of Mcl-1 selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.
  • the described methods of treatment may normally include medical follow-up to determine the therapeutic or prophylactic effect brought about in the subject undergoing treatment with the compound(s) and/or composition(s) described herein.
  • compositions and methods for preparing the same are non-limiting pharmaceutical compositions and methods for preparing the same.
  • compositions for Oral Administration are provided.
  • the invention provides a pharmaceutical composition for oral administration containing the active pharmaceutical ingredient or combination of active pharmaceutical ingredients, such as the Mcl-1 inhibitors described herein, and a pharmaceutical excipient suitable for oral administration.
  • the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, and (ii) a pharmaceutical excipient suitable for oral administration.
  • the composition further contains (iii) an effective amount of a third active pharmaceutical ingredient and optionally (iv) an effective amount of a fourth active pharmaceutical ingredient.
  • the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.
  • Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, sachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, a water-in-oil liquid emulsion, powders for reconstitution, powders for oral consumptions, bottles (including powders or liquids in a bottle), orally dissolving films, lozenges, pastes, tubes, gums, and packs.
  • Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient(s) into association with the carrier, which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the invention further encompasses anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds.
  • water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • Each of the active pharmaceutical ingredients can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols, of carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrol
  • suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • talc calcium carbonate
  • microcrystalline cellulose e.g., powdere., powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which disintegrate in the bottle. Too little may be insufficient for disintegration to occur, thus altering the rate and extent of release of the active ingredients from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, sodium stearyl fumarate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, silicified microcrystalline cellulose, or mixtures thereof.
  • a lubricant can optionally be added in an amount of less than about 0.5% or less than about 1% (by weight) of the pharmaceutical composition.
  • the active pharmaceutical ingredient(s) may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, tor example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Surfactants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed
  • a suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10.
  • An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (HLB value).
  • HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts, sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides, and mixtures
  • ionic surfactants include, by way of example, lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatide add, phosphatidylserine, lysophosphatidylcholine, lysphosphatidylethanolamine, lysphosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate
  • Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivative
  • hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl oleate
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters; lower alcohol fatty acids esters, propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.
  • preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use—e.g., compositions for injection.
  • a solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ⁇ -caprolactam
  • solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidine, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included is not particularly limited.
  • the amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art.
  • the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients.
  • very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less.
  • the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.
  • the composition can further include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons.
  • pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, tri isopropanol amine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals and alkaline earth metals.
  • Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenyl sulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycoli
  • a pharmaceutical composition for injection containing an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, such as an Mcl-1 inhibitor, and a pharmaceutical excipient suitable for injection.
  • Aqueous solutions in saline are also conventionally used tor injection.
  • Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and thimerosal.
  • Sterile injectable solutions are prepared by incorporating an active pharmaceutical ingredient or combination of active pharmaceutical ingredients in the required amounts in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • a pharmaceutical composition for transdermal delivery containing an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, such as Mcl-1 inhibitors described herein, and a pharmaceutical excipient suitable for transdermal delivery.
  • compositions of the present invention can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions.
  • DMSO dimethylsulfoxide
  • carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients.
  • a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
  • compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin.
  • suitable solid or gel phase carriers or excipients which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin.
  • humectants e.g., urea
  • glycols e.g., propylene glycol
  • alcohols e.g., ethanol
  • tatty acids e.g, oleic acid
  • surfactants e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.glycerol monolaurate, sulfoxides, terpenes (e.g., menthol)
  • amines amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients in controlled amounts, either with oi without another active pharmaceutical ingredient.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252; 4,992,445 and 5,001,139, the entirety of which are incorporated herein by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • compositions for Inhalation are provided.
  • 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 and the Mcl-1 inhibitors described herein.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • Dry powder inhalers may also be used to provide inhaled delivery of the compositions.
  • compositions of the Mcl-1 inhibitors described herein may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; and Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, N.Y., 1990, each of which is incorporated by reference herein in its entirety.
  • Administration of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients or a pharmaceutical composition thereof can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation.
  • the active pharmaceutical ingredient or combination of active pharmaceutical ingredients can also be administered intraadiposally or intrathecally.
  • Exemplary parenteral administration forms include solutions or suspensions oi active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • kits include an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, either alone or in combination in suitable packaging, and written material that can include instructions tor use, discussion of clinical studies and listing of side effects.
  • kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.
  • the kit may further contain another active pharmaceutical ingredient.
  • an active pharmaceutical ingredient or combination of active pharmaceutical ingredients are provided as separate compositions in separate containers within the kit. In selected embodiments, an active pharmaceutical ingredient or combination of active pharmaceutical ingredients are provided as a single composition within a container in the kit.
  • Suitable packaging and additional articles for use e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like
  • Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in selected embodiments, be marketed directly to the consumer.
  • the invention provides a kit comprising a composition comprising a therapeutically effective amount of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. These compositions are typically pharmaceutical compositions.
  • the kit is for co-administration of the active pharmaceutical ingredient or combination of active pharmaceutical ingredients, either simultaneously or separately.
  • the invention provides a kit comprising (1) a composition comprising a therapeutically effective amount of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and (2) a diagnostic test for determining whether a patient's cancer is a particular subtype of a cancer. Any of the foregoing diagnostic methods may be utilized in the kit.
  • kits described above are preferably for use in the treatment of the diseases and conditions described herein.
  • the kits are for use in the treatment of hyperproliferative disorders.
  • kits described herein are for use in the treatment of cancer.
  • the kits described herein are tor use in the treatment of a cancer selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, chorio
  • a cancer selected from the group
  • an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect—e.g., by dividing such larger doses into several small doses for administration throughout the day.
  • the dosage of the pharmaceutical compositions and active pharmaceutical ingredients may be provided in units of mg/kg of body mass or in mg/m 2 of body surface area.
  • the invention include methods of treating a cancer in a human subject suffering from the cancer in which cancer cells overexpress Mcl-1, the method comprising the steps of administering a therapeutically effective dose of an active pharmaceutical ingredient that is an Mcl-1 inhibitor to the human subject.
  • a pharmaceutical composition or active pharmaceutical ingredient is administered in a single dose.
  • Such administration may be by injection, e.g., intravenous injection, in order to introduce the active pharmaceutical ingredient quickly.
  • routes including the preferred oral route, may be used as appropriate.
  • a single dose of a pharmaceutical composition may also be used for treatment of an acute condition.
  • a pharmaceutical composition or active pharmaceutical ingredient is administered in multiple doses.
  • a pharmaceutical composition is administered in multiple doses. Dosing may be once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be once a month, once every two weeks, once a week, or once every other day. In other embodiments, a pharmaceutical composition is administered about once per day to about 6 times per day. In some embodiments, a pharmaceutical composition is administered once daily, while in other embodiments, a pharmaceutical composition is administered twice daily, and in other embodiments a pharmaceutical composition is administered three times daily.
  • a pharmaceutical composition is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a pharmaceutical composition is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a pharmaceutical composition is administered chronically on an ongoing basis—e.g., tor the treatment of chronic effects. In some embodiments, the administration of a pharmaceutical composition continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • an effective dosage of an active pharmaceutical ingredient disclosed herein is in the range of about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 to about 202 mg.
  • an effective dosage of an active pharmaceutical ingredient disclosed here is in the range of about 1
  • an effective dosage of an active pharmaceutical ingredient disclosed herein is in the range of about 0.01 mg/kg to about 200 mg/kg, or about 0.1 to 100 mg/kg, or about 1 to 50 mg/kg.
  • an active pharmaceutical ingredient is adminstered at a dosage of 10 to 200 mg BID, including 50, 60, 70, 80, 90, 100, 150, or 200 mg BID.
  • an active pharmaceutical ingredient is adminstered at a dosage of 10 to 500 mg BID, including 1, 5, 10, 15, 25, 50, 75, 100, 150, 200, 300, 400, or 500 mg BID.
  • dosage levels below the lower limit of the aforesaid ranges may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect—e.g., by dividing such larger doses into several small doses for administration throughout the day.
  • the dosage actually administered will depend upon the condition being treated, the age, health and weight of the recipient, the type of concurrent treatment, if any, and the frequency of treatment.
  • the effective dosage amount may be determined by one skilled in the art on the basis of routine empirical activity testing to measure the bioactivity of the compound(s) in a bioassay, and thus establish the appropriate dosage to be administered.
  • An effective amount of the combination of the active pharmaceutical ingredient may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • compositions described herein further include controlled-release, sustained release, or extended-release therapeutic dosage forms for administration of the compounds described herein, which involves incorporation of the compounds into a suitable delivery system in the formation of certain compositions.
  • This dosage form controls release of the compound(s) in such a manner that an effective concentration of the compound(s) in the bloodstream may be maintained over an extended period of time, with the concentration in the blood remaining relatively constant, to improve therapeutic results and/or minimize side effects.
  • a controlled-release system would provide minimum peak to trough fluctuations in blood plasma levels of the compound.
  • Example 1 Compound Scaffolds Including the 1-Hydroxy-2-Naphthoate Scaffold
  • Described herein are potent inhibitors of Mcl-1 based on a novel 1-hydroxy-2-naphthoate scaffold.
  • This disclosure includes a 1-hydroxy-2-naphthoic acid core that would provide an alternative platform from which to inhibit Mcl-1, wherein the carboxylic acid was predicted to bind R263, and the distal phenyl ring the p3 pocket. Further engineering to gain access to the p2 pocket was driven by the hydroxyl group and the carboxylic acid whose ortho- and meta-directing effects, respectively, synergize to promote the regioselective 4-chlorosulfonylation of the scaffold, subsequent animation of this readily introduced functional group is expected to facilitate occupancy of the p2 pocket.
  • the subject scaffold design is illustrated in Scheme 1-1, which permits access to Mcl-1 inhibitors in only two synthetic steps from commercially available starting materials.
  • Scheme 1-1 Structure-based design of novel 1-hydroxy-4-sulfamoyl-2-naphthoates (3) as Mcl-1 inhibitors.
  • SILCS FragMaps represent the 3D grid free energy distribution of different types of functional groups around the protein.
  • the FragMaps include contributions from solute-protein interactions, solute desolvation and protein desolvation in the context of protein flexibility.
  • the protein surface is defined based on SILCS exclusion maps.
  • Mcl-1 Bcl-xL LGFE LGFE Mcl-1 Bcl-x L (kcal (kcal Comp. R 1 R 2 K i ( ⁇ M) a K i ( ⁇ M) b Selectivity mol ⁇ 1 ) mol ⁇ 1 ) 3a 4-Br—C 6 H 4 H 2.76 ⁇ 1.26 51.4 ⁇ 31.3 19 ⁇ 39.46 ⁇ 36.20 3b H H 99.0 ⁇ 11.2 NA ⁇ 31.00 3c Bn H 56.3 ⁇ 2.1 NA ⁇ 39.02 3d CH 2 -(2-Cl—C 6 H 4 ) H 50.3 ⁇ 11.8 — — ⁇ 37.09 3e CH 2 -(3-Cl—C 6 H 4 ) H 5.03 ⁇ 2.78 — — ⁇ 38.80 3f CH 2 -(4-Cl—C 6 H 4 ) H 21.0 ⁇ 3.9 338
  • Unsubstituted sulfonamide 3b was the weakest Mcl-1 inhibitor with a K i of 99.0 ⁇ M, which was consistent with the less favorable LGFE score (Table 1-1).
  • Replacement of the NH 2 group with benzylic amines and anilines improved Mcl-1 inhibitory activity in every case, which is attributed to the occupancy of the apolar FragMaps with the apolar FragMap in the p2 pocket yielding more favourable LGFE scores.
  • the FragMaps extend further towards the interior of the protein, suggesting that further hydrophobic extension of benzylic amines would improve activity.
  • chlorobenzylic amine derivatives 3d-3f were more potent than unsubstituted benzylic amine derivative 3c by up to 8-fold.
  • Replacement of the benzyl group in 3c with a cyclohexylmethyl group (3g) also afforded an 8-fold improvement in inhibitory activity with a K i of 7.31 ⁇ M.
  • Mcl-1 Bcl-x L Mcl-1 Bcl-x L LGFE LGFE
  • R 2 R 3 K i ( ⁇ M) a K i ( ⁇ M) a Selectivity b (kcal mol ⁇ 1 ) (kcal mol ⁇ 1 ) 3ba iBu iPr 0.487 ⁇ 6.08 ⁇ 0.81 12 ⁇ 38.81 ⁇ 36.24 3bb H Ph 1.15 ⁇ 0.28 ND — ⁇ 43.68 3bc H 4-Me—C 6 H 4 0.335 ⁇ 0.84 ⁇ 0.05 2.5 ⁇ 43.58 ⁇ 42.87 3bd H 1-Naphthyl 0.082 ⁇ 0.22 ⁇ 0.06 3.7 ⁇ 47.46 ⁇ 48.26 3be H 3-Br—C 6 H 4 0.114 ⁇ 0.30 ⁇ 0.04 3.8 ⁇ 44.65 ⁇ 44.31 3bf H 3,5
  • Mcl-1 Mcl-1 LGFE Comp. X Y K i ( ⁇ M) a (kcal mol ⁇ 1 ) 3ca CO2H OH 0.566 ⁇ ⁇ 42.19 3cb CO 2 Me OH >500 ⁇ 34.23 3cc CO 2 Me OMe >500 ⁇ 35.45 3ed CO 2 H OMe 23.4 ⁇ 2.6 ⁇ 42.41 a K i values determined by Nikolovska-Coleska equation from IC 50 values. Data represent the average of at least two independent assays; errors are standard deviations.
  • NMR HSQC experiments using 15 N-labeled Mcl-1 confirmed the direct interaction of this class of compounds with the protein.
  • the HSQC of compound 3ba shows perturbation of the chemical shifts of Mcl-1 backbone 1 H- 15 N correlations consistent with the predicted binding mode of 3a shown in FIG. 1 .
  • the amino acid residues interacting with the compound are undergoing intermediate chemical exchange so their 1 H- 15 N correlation peaks are broadened or lost.
  • Intermediate exchange was expected based on the binding affinity determined for 3ba, K i of 0.487 ⁇ M. Mapping the residues completely lost due to chemical exchange broadening on the 3D structure of Mcl-1 ( FIG.
  • the predicted conformation of 3a, 3b, 3bi, and 3bl was analyzed inside the Mcl-1 binding site.
  • the carboxylic acid overlaps with the negative FragMap, associated with its interaction with R263 of Mcl-1 and the aromatic rings suitably overlap with hydrophobic FragMaps, binding within the hydrophobic groove.
  • the sulfonamide group is placed outside of the hydrophobic binding pocket corresponding to an H-bond donor FragMap indicating its possible H-bonding interaction with residue H224.
  • the hydroxyl group on the naphthalene ring overlaps with an H-bond acceptor FragMap, possibly making an H-bond to residue T266.
  • the naphthalene group flipped over relative to 3b, maintaining the position of the carboxylic acid while allowing the additional aromatic groups to interact with the hydrophobic binding pocket.
  • the sulfonamide oxygen atoms in this orientation overlap with an acceptor FragMap associated with interactions with residue T266.
  • SILCS Pharm approach was performed using the SILCS Pharm approach.
  • the SILCS Pharm method allows for well-defined pharmacophore features to be identified based on the SILCS FragMaps and used to direct ligand placement. As shown in FIG. 6 a total of seven pharmacophore features were located in the binding pocket. Three out of seven features (F1, F2 and F5) have good overlap with the corresponding functional groups in the crystal structure of Fesik60 bound to Mcl-1 (PDB: 4HW4).
  • hydrophobic pharmacophore feature F5 was derived from the FragMap region, such that without the inclusion of protein flexibility in SILCS such an important feature for this series of compounds would likely not be captured.
  • FIG. 5 shows the ⁇ FragMaps between Mcl-1 and Bcl-x L , and includes the docked orientation of 3a with the atom contributions to the ⁇ LGFE between Mcl-1 and Bcl-x L mapped onto this orientation.
  • the p-bromophenyl group that binds deeply in the p2 pocket between helices ⁇ 4 and ⁇ 5 is in a Mcl-1 positive ⁇ FragMap indicating that region to favour binding to Mcl-1.
  • the sulfonamide oxygen contributes to the binding of 3a to Mcl-1 over Bcl-x L .
  • the NH moiety of the sulfonamide contributes to more favourable binding to Bcl-x L over Mcl-1.
  • the acid moiety in the lower right of the figure is also predicted to favour binding to Bcl-x L over Mcl-1.
  • 3bl further extension of the ligands leads to improved binding affinity, but not improved specificity. This may be explained by different predicted binding orientations of the compound to the two proteins. As seen in FIG. 5 (inset C), 3bl binds with its additional 4-chloro-3,5-dimethylphenyl R 3 group deep in the p2 pocket, and with the R benzyl group occupying the upper region of the p2 pocket. In contrast, the orientation of 3bl bound to Bcl-x L shows the 4-chloro-3,5-dimethylphenyl to still interact with the p2 site, though not as deep as that occurring with Mcl-1.
  • Described herein is a class of Mcl-1 inhibitors that target R263 and the p2 and p3 pockets within the hydrophobic BH3-binding crevice on the surface of the protein.
  • the small molecules, or solutes include benzene, propane, methanol, formamide, acetaldehyde, methylammonium and acetate, as previously used, along with imidazole.
  • Ten such protein-small molecule aqueous systems were generated for each protein with each simulation system differing in the initial positions and orientations of the small molecules and water.
  • the SILCS molecular dynamics (MD) simulations were performed using the GROMACS simulation program with the CHARMM36 force field, CHARMM general force field (CGenFF) and TIP3P water model to describe the protein, small molecules and water, respectively. The simulations were each extended for 40 ns, yielding a total of 400 ns of simulation time for each protein. Additional MD simulation details can be found in Reference.
  • GFE grid free energies
  • exclusion maps were constructed by calculating the 3D probability distributions of all non-hydrogen atoms of the water and solutes together and identifying those voxels with zero occupancies, which defines the exclusion maps.
  • This exclusion map represents regions forbidden to the small molecules and water and may be considered an alternate to more traditional representations of the protein surface.
  • these voxels were assigned a very high energetic penalty (1000 kcal/mol) while the remaining voxels were assigned energies associated with the specific FragMaps.
  • the availability of the GFE FragMaps and the exclusion maps allows for quantitative estimates of binding affinities to be made referred to as ligand grid free energies (LGFE).
  • LGFE scores are not directly equivalent to experimental free energies due to the additive approximation of the LGFE scores (i.e. the individual atom-based GFEs are summed to yield the LGFE), the lack of accounting for the energy cost of connecting the fragments that comprise the full compounds and issues associated with the standard state in the experimental and computational conditions.
  • the specific and generic FragMap types include: (1) aromatic, AROM (benzene carbons), (2) aliphatic, ALIP (propane carbons); (3) dual role hydrogen bond atom, MEOO (methanol oxygens); (4) FORN, (formamide nitrogen); (5) FORO, (formamide oxygen); (6) IMIN, (imidazole acceptor nitrogen); (7) IMLH, (imidazole donor nitrogen); (8) AALO, (acetaldehyde oxygen); (9) positive donor, POS (methylammonium nitrogen); (10) negative acceptor, NEG (acetate oxygens); (11) generic nonpolar, APOLAR (benzene and propane carbons); (12) generic neutral hydrogen-bond donor, FIB DON (formamide and imidazole donor nitrogen); and (13) generic neutral hydrogen-hydrogen acceptor, HBACC (formamide, acetaldehyde oxygens and imidazo
  • the convergence of the FragMaps was examined by calculating the overlap coefficient between two sections of the simulations (trajectories 1-5 and trajectories 6-10), as previously described. All the generic FragMaps show an overlap coefficient of greater than 0.6, indicating satisfactory convergence.
  • the SILCS-Pharm protocol was used in which the FragMaps are used to define the pharmacophore features.
  • the selected pharmacophore was used to direct docking of the studied compounds in the Mcl-1 binding pocket.
  • Generation of 250 conformations of each compound and pharmacophore docking were conducted using MOE.
  • LGFE SILCS ligand grid tree energy scoring.
  • the compounds were locally relaxed and minimized using FragMap-based Monte Cairo (MC) sampling (SILCS-MC) from which the LGFE scores were obtained.
  • the SILCS-MC was conducted for 50000 steps under slow cooling mode and was repeated 20 times for each conformation with different random seeds to get a Boltzmann averaged LGFE value, along with the corresponding standard deviation. The lowest energy LGFE conformation for each compound was chosen for visual presentation and analysis.
  • the SILCS-MC was also performed in the same way using FragMaps of BCl-x L to calculate BCl-x L related LGFEs for the compounds that have available Bcl-x L experimental data. Bcl-x L SILCS-MC calculations were initiated from the Mcl-1 SILCS-PHARM orientations in the context of the Bcl-x L FragMaps and exclusion maps.
  • a His6-MBP tagged recombinant human Mcl-1 residues 172 to 327 was produced in E. coli in either lysogeny broth (LB) or minimal media supplemented with 15 NH 4 Cl to produce unlabeled or 15 N-labeled Mcl-1.
  • the tagged protein was initially purified from the crude cell lysate by immobilized metal affinity chromatography (IMAC) chromatography (GE Healthcare Life Sciences), and after dialysis to remove the imidazole the affinity tag was cleaved using PreScission Protease (GE Healthcare Life Sciences).
  • a Sephacryl S-200 size exclusion column was used as a final purification step before the protein was concentrated with a 10,000 MWCO centrifugal filter concentrator (Millipore), The protein purity was shown to be >98% by Coomassie Brilliant Blue (Bio-Rad) stained SDS-PAGE gel and the final concentration was determined using the Bradford protein assay (Bio-Rad) with bovine serum albumin (BSA) standards (Pierce).
  • BSA bovine serum albumin
  • a 6-aminohexanoic acid linker was conjugated to the N-terminus of the Bak BH3 peptide (GQVGRQLAIIGDDINR), capped with fluorescein (on the amino group of the linker), and the peptide was amidated on the C-terminus to give FITC-Ahx-GQVGRQLAIIGDDINR-CONH 2 , hereafter referred to as “FITC-Bak” (synthesized by Neo BioScience in >95% purity).
  • Fluorescence polarization experiments were conducted using a BMG PHERAstar FS multimode microplate reader equipped with two PMTs for simultaneous measurements of the perpendicular and parallel fluorescence emission.
  • the assays were performed m black polypropylene 384-well microplate (Costar) with a final volume of 20 microliter.
  • the affinity (K D ) of the FITC-Bak peptide was determined by titrating Mcl-1 172-327 into 10 nM FITC-Bak peptide in 20 mM HEPES, pH 6.8, 50 mM NaCl, 3 mM DTT, 0.01% Triton X-100 and 5% DMSO at room temperature while monitoring the perpendicular and parallel fluorescence emission with a 485 nm excitation and 520 nm emission filters.
  • the fluorescence polarization competition assay (FPCA) was performed using 100 nM Mcl-1 172-327 in the same buffer (thus, 15 nM FITC-Bak) with varying concentrations of either unlabeled peptide or experimental.
  • NMR spectra was collected at 25° C. with a Bruker AVANCE 800 NMR spectrometer (800.27 MHz for protons) equipped with pulsed-field gradients, four frequency channels, and triple resonance, z-axis gradient cryogenic probes. A one-second relaxation delay was used, and quadrature detection in the indirect dimensions was obtained with states-TPPI phase cycling; initial delays in the indirect dimensions were set to give zero- and first-order phase corrections of 90° and ⁇ 180°, respectively. Data were processed using the processing program nmrPipe on Linux workstations. All proton chemical shifts are reported with respect to the H 2 O or HDO signal, taken to be 4,658 ppm relative to external TSP (0.0 ppm) at 37° C. The 15 N chemical shifts were indirectly referenced using the zero-point frequency at 37° C. of 0.10132905 for 15 N- 1 H, as previously described.
  • Example 2 Following onto Example 1, additional naphthoate Mcl-1 inhibitors were prepared to probe various aspects of the Mcl-1 binding site. And, unless specified otherwise, the compound numbering in Example 2 is equivalent to the compound numbering in Example 1 Naphthoates 13 and 14 were prepared as shown in scheme 2-1.
  • the potent compound 3bl was evaluated for its ability to inhibit the proliferation of A375 and SK-MEL-5 melanoma cells, both of which express high levels of Mcl-1.
  • the IC 50 for 3bl was 50 ⁇ M and 90 ⁇ M in A375 and SK-MEL-5 cells, respectively (Table 2-1).
  • the poor efficacy in cells may be attributed to the charged carboxylic acid of 3bl.
  • two ester prodrugs were prepared of the potent, but more hydrophilic, inhibitor 3ba, methyl ester 13 and acetoxymethyl ester 14, according to Scheme 3.
  • Example 3 Inhibitors of the Mcl-1 Oncoprotein Based on Carboxy-Substituted Tetrahydroquinolines, Salicylate- and 1-Hydroxy-2-Naphthoate-Based Scaffolds
  • Mcl-1 inhibitors based on a carboxy-substituted tetrahydroquinoline (THQ) scaffold, a salicylate scaffold and a 1-hydroxy-2-naphthoate scaffold that are proposed to bind these sites as well as Asn260 and the p3 pocket ( FIGS. 10 and 11 ).
  • THQs carboxy-substituted tetrahydroquinolines
  • Mcl-1 has emerged as an attractive target to expand the armamentarium in the war on cancer Using structure-based design, 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines were developed as a new chemotype to inhibit the Mcl-1 oncoprotein.
  • the short and facile synthetic chemistry is expected to mediate future compound optimization.
  • the intrinsic apoptosis pathway is activated when a cell undergoes stress, which leads to the homodimerization of the pro-apoptotic Bcl-2 proteins Bak and Bax at the outer mitochondrial membrane, and, in turn, a caspase cascade ensues that results in the formation of apoptosomes.
  • the net result of this process is programmed cell death, or apoptosis.
  • anti-apoptotic members of the Bcl-2 family which include Bcl-xL, Bcl-2 and Mcl-1, are over-expressed, immortalizing the cancer cells.
  • Mcl-1 inhibitors of Bcl-xL and Bcl-2 Whilst inhibitors of Bcl-xL and Bcl-2 have advanced to clinical trials (dual Bcl-xL/Bcl-2: ABT-263 (navitociax); Bcl-2 specific: ABT-199), progress in the development of specific Mcl-1 inhibitors has been less successful and there currently exists no drug to inhibit this protein. Upregulation of Mcl-1 specifically has been associated with the development and progression of several cancers that include acute myeloid leukaemia, melanoma, non-small-cell lung, pancreatic, prostate, and ovarian cancers. Moreover, it is known that cancers dependent on Bcl-xL can exhibit resistance to the Bcl-xL inhibitor ABT-737 (a variant of ABT-263) through upregulation of Mcl-1. Therefore, the development of inhibitors of Mcl-1, either as single agents or as adjuvant therapies, represents an unmet medical need.
  • Mcl-1 directly antagonizes the pro-apoptotic Bcl-2 proteins, which include Bak, Bax and Bim, through capturing their BH3 ⁇ -helical “death” domains, effectively “neutralizing” the cell-killing role of these proteins. More specifically, BH3 domains project four conserved hydrophobic side chains from one face of the ⁇ -helix that recognize sub-pockets on the surface of Mcl-1, which are termed p1 through p4. Additionally, a conserved aspartate residue on the opposite face of the helix recognizes R263.
  • IC 50 data which refers to the concentration of inhibitor that results in 50% displacement of FITC-Bak from Mcl-1, were converted to K i values using the Nikolovska-Coleska equation.
  • the target molecules were assayed for their abilities to disrupt the Mcl-1-Bak-BH3 PP1 in a fluorescence polarization competition (FPC) assay with Mcl-1 and FITC-labeled Bak-BH3 peptide. Further details on the FPC assay can be found in the Supporting Information.
  • FPC fluorescence polarization competition
  • unsubstituted racemic 1,2,3,4-tetrahydroquinoline-3-carboxylic acid ( ⁇ 6) did not show any inhibitory effect (K i >500 uM), which may, for example, be due to an inability to reach into the p2 pocket.
  • the highly labile ester ⁇ 12 did not yield a more potent cellular agent, which may, for instance, suggest that the charged carboxylic acid of ⁇ 2 might not be a limiting factor in the translation of in vitro to cellular activity.
  • Mcl-1 inhibitors based on 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines (THQ) scaffold has been described.
  • the molecule presented a carboxylic acid to engage R263 and form a salt bridge, as well as various hydrophobic groups functionalized the N-positon on the ring, which probe deep into the p2 pocket.
  • a structural activity relationship (SAR) analysis has been performed by varying R groups, as shown in FIG. 14 .
  • the THQ ring was simplified with a 4-aminobenzoate scaffold, as it offers a nitrogen atom that can be bi-functionalized by different R 1 and R 2 groups, as well as further decoration potential on the aromatic ring.
  • compound 2 possessed R 1 as an isobutyl group to mimicking part of the hydrophobic core from THQ, and R 2 as the 3,5-dimethyl-4-chloro-phenoxy benzene sulfonamide group, which has significantly contributed to the most potent THQ compound ⁇ 1.
  • the potency of the molecules were evaluated by using a fluorescent polarization competition assay (FPCA) where the compounds were titrated into the mixture of Mcl-1 and FITC-Bak BH3 peptide to monitor their capability to disrupt the interaction between Mcl-1 and FITC-Bak BH3 peptide.
  • FPCA fluorescent polarization competition assay
  • Mcl-1 binding affinity of 4-aminobenzoate analogs Mcl-1 Compd R K i ( ⁇ M) LC-3-029 8a >500 LC-3-031 8b >500 LC-3-030 8c 16.712 ⁇ 2.284 LC-3-025 8d >500 LC-3-035 8e 2.058 ⁇ 0.118
  • compound 12ad, 12bc and 12cc can be further elaborated with different substituted aromatic groups (R 3 ) by S N Ar mechanism to afford compounds 12ah-12ak, 12bd and 12cd, winch were deprotected using the same saponification followed by TFA debenzylation to generate final molecules 13ah-13ak, 13bd and 13cd.
  • compound 11 can also be directly sulfonylated by 4-phenoxybenzene sulfonylchloride to yield compound (12da), and then deprotected to give compound (13da).
  • Mcl-1 binding affinity of 4-aminosalicylate analogs.
  • Mcl-1 Compd R 1 R 2 K i ( ⁇ M) 4jc117-1 13aa 192.038 ⁇ 37.534 4jc117-3 13ab 13.821 ⁇ 1.325 4jc117-4 13ac 4.109 ⁇ 0.245 LC-5-025 13ad 99.372 ⁇ 9.374 LC-5-012 13ae 16.980 ⁇ 1.504 4jc117-2 13af 61.243 ⁇ 4.490 LC-4-099 13ag 5.766 ⁇ 0.458 LC-4-119 13ah 2.255 ⁇ 0.168 LC-4-100 13ai 2.964 ⁇ 0.286 LC-4-111 13aj 2.738 ⁇ 0.258 4jc117-5 13ak 0.778 ⁇ 0.050
  • Mcl-1 binding affinity of 4-aminosalicylate analogs (continued).
  • Mcl-1 Compd R 1 R 2 K i ( ⁇ M) LC-4-083 13ba 24.749 ⁇ 9.449 LC-4-082 13bb 5.244 ⁇ 0.694 LC-4-104 13bc 1.762 ⁇ 0.208 LC-4-113 13ca 11.395 ⁇ 1.572 LC-4-112 13cb 1.712 ⁇ 0.144 LC-4-118 13cc 0.659 ⁇ 0.040 LC-5-005 13da H 13.722 ⁇ 1.050
  • the 5-aminosalicylate molecule favorably fitted into the Mcl-1 binding pocket and developed polar interaction with R263 and T266 similar to the 4-aminosalicylate analog. Therefore, a library of 5-aminosalicylate analogs was designed and synthesized to validate the in silica model according to Scheme 5-3. Moreover, the hydroxyl group was also deleted, which converted them into 5-aminobenzoate molecules, to assess its contribution in this binding mode.
  • compound 17bd was first O-benzylated to give compound 17bd′ before coupled with 3,5-dimethyl-4-chloro-phenol to afford 17be, and then underwent saponification and TFA debenzylation to yield final compound 18be.
  • Mcl-1 binding affinity of 5-aminobenzoate and 5-aminosalicylate analogs are listed below.
  • the carboxylic acid moiety may be an important factor in facilitating the MCL-1 protein binding. Therefore, it was anticipated that the carboxylic acid moiety on the benzoate and salicylate compounds may also be important for their potency. Also, the improved potency from 4/5-aminobenzoate to 4/5-aminosalicylate scaffold illustrated the contribution from hydroxyl group. Therefore, the function of carboxylic acid in the binding was explored by synthesizing its ester prodrugs as well as bioisosteres, and the hydroxyl group was methylated to test its impact on the compound's activity in Table 5-5.
  • Mcl-1 binding affinity of 4-aminosalicylates esters and bioisosteres are listed below.
  • Mcl-1 Compd X Y R 1 R 2 K i ( ⁇ M) LC-4-099 13ag OH 5.8 ⁇ 0.46 LC-5-106 19 OMe 106.70 ⁇ 31.12 LC-4-131 20 OH >500 LC-4-134 21 OH >500 LC-4-141 22 OH >500 LC-5-050 23 OH >500 LC-5-068 24 H 3.3 ⁇ 0.26 LC-5-061 25 OH 71 ⁇ 5.8 LC-5-069 Toptop 26 H >500 LC-5-112 27 OH 2.94 ⁇ 0.35 LC-5-096 28 OH 1.9 ⁇ 0.22
  • R 1 group 13ak, 13bc, and 13cc
  • the benzyl substitution analog 13cc being the most selective inhibitor
  • the cyclopentyl analog 13bc being an equal potent inhibitor for both proteins.
  • the R 2 group had a slightly greater impact on the selectivity, particularly when R 2 were 2-naphthyl 18bb and 3,5-dimethyl-4-chloro-phenoxyl group (18bd).
  • substituting the R with a benzyl group on the 5-aminosalicylate scaffold (29) decreased the selectivity dramatically to yield a Mcl-1/Bcl-x L dual inhibitor.
  • Mcl-1 Bcl-xL K i (Mcl-1) Compd X Y R 1 R 2 K i ( ⁇ M) K i ( ⁇ M) K i (Bcl-xL) 4jc117-1 13aa OH 192.038 ⁇ 37.534 154.181 ⁇ 27.596 1:0.80 4jc117-3 13ab OH 13.821 ⁇ 1.325 43.130 ⁇ 14.668 1:3.12 4jc117-4 13ac OH 4.109 ⁇ 0.245 10.781 ⁇ 2.553 1:2.63 LC-4-099 13ag OH 5.766 ⁇ 0.458 17.996 ⁇ 4.602 1:3.12 4jc117-5 13ak OH 0.778 ⁇ 0.050 1.629 ⁇ 0.177 1:2.09 LC-4-104 13bc OH 1.762 ⁇ 0.208 1.911 ⁇ 0.
  • Mcl-1 Bcl-xL K i (Mcl-1) Compd X Y R 1 R 2 K i ( ⁇ M) K i ( ⁇ M) K i (Bcl-xL) LC-4-118 13cc OH 0.629 ⁇ 0.040 1.672 ⁇ 0.351 1:2.65 LC-5-112 27 OH 2.94 ⁇ 0.35 7.223 ⁇ 1.072 1:2.45 LC-5-096 28 OH 1.945 ⁇ 0.222 2.336 ⁇ 0.221 1:1.20 LC-5-107 30 OH 1.232 ⁇ 0.152 1.053 ⁇ 0.146 1:0.85 LC-5-131 31 OH 0.80 ⁇ 0.07 1.615 ⁇ 0.176 1:2.02 LC-5-175 32 OH 0.493 ⁇ 0.031 0.835 ⁇ 0.086 1:1.69 LC-5-129 29
  • Mcl-1 Bcl-xL K i (Mcl-1) Compd R 1 L K i ( ⁇ M) K i ( ⁇ M) K i (Bcl-xL) LC-4-118 13cc 0.629 ⁇ 0.040 1.672 ⁇ 0.351 1:2.66 LC-5-188 35 1.445 ⁇ 16.644 2.984 ⁇ 0.406 1:2.06 LC-5-184 36 15.247 ⁇ 1.891 22.713 ⁇ 4.083 1:1.49
  • the moderate cell grow inhibition ability for the two carboxylic acid ester prodrugs 20 and 21 could be attributed to the enzymatic hydrolysis that generated a free acid molecule (13ag) to function as an Mcl-1 inhibitor in the cells.
  • the data also suggested that the acidic salicylate analogs were cell penetrable, which can be due to the formation of an intramolecular hydrogen bond with the ortho position phenol group to mask the negative charge and make the molecule less polar and more cell penetrable.
  • the most potent Mcl-1/Bcl-xL dual inhibitor 32 was less effective in cell growth inhibition than compound 13cc, indicating other survival proteins might also affected with these inhibitors.
  • Example 6 Inhibitors of the Mcl-1 Oncoprotein Based on Carboxy-Substituted Salicylate Scaffolds Salicylate
  • Functionalized salicylates inhibit the Mcl-1 oncoprotein, as determined by the fluorescence polarization competition assay as described herein.
  • Various functionalized salicylates were prepared and tested as provided hereinbelow in Tables 6-1, 6-2, and 6-3.
  • the term “about” means that dimensions, sizes, formulations, parameters, shapes and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art.
  • a dimension, size, formulation, parameter, shape or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such.
  • transitional terms “comprising”, “consisting essentially of” and “consisting of”, when used in the appended claims, in original and amended form, define the claim scope with respect to what unrecited additional claim elements or steps, if any, are excluded from the scope of the claim(s).
  • the term “comprising” is intended to be inclusive or open-ended and does not exclude any additional, unrecited element, method, step or material.

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Abstract

Compounds that inhibit Myeloid Cell Leukemia-1 (Mcl-1) oncoprotein, and methods of using the same, are provided for treating disease.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims the benefit of U S. Provisional Patent Application No. 62/191,045, filed Jul. 10, 2015, and U.S. Provisional Patent Application No. 62/191,673, filed Jul. 13, 2015, each of which is incorporated herein by reference in its entirety.
    • FIELD OF THE INVENTION
  • The invention relates generally to compounds and methods of using the same for treating conditions characterized by the overexpression or unregulated activity of anti-apoptotic B-Cell Lymphoma (Bcl-2) family proteins and more particularly, but not exclusively, to compounds that bind to the protein Myeloid Cell Leukemia-1 (Mcl-1).
    • BACKGROUND OF THE INVENTION
  • The B-Cell Lymphoma-2 (Bcl-2) family of proteins regulates the intrinsic apoptosis pathway that is responsible for programmed cell death. The pathway involves protein-protein interactions (PPIs) between pro-apoptotic members of the Bcl-2 family, such as Bim, Bak and Bad, and anti-apoptotic members, such as Bcl-xL and myeloid cell leukemia-1 (Mcl-1). Through conserved hydrophobic crevices, the anti-apoptotic Bcl-2 proteins capture the BH3 α-helical domains of their pro-apoptotic counterparts, effectively “neutralizing” their cell killing functions. Evasion of apoptosis is a hallmark of cancer, and is also one culprit for the development of resistance to current chemo- and radiotherapies.
  • Mcl-1 overexpression and/or amplification of the Mcl-1 gene immortalizes cells, and has been observed in many human solid tumors, including pancreatic, prostate, cervical, lung and breast cancers, as well as B-cell lymphomas and hematological cancers, including acute myeloid leukemia (AML). While certain BCl-XL/BCl-2 inhibitors perform well in clinical trials, their low affinity for Mcl-1 is a contributing factor to the observed resistance of several tumor cell lines. Moreover, the upregulation of Mcl-1 has been directly linked to the reduced efficacy of several FDA-approved anti-cancer chemotherapies. Accordingly, the pharmacologic inhibition of Mcl-1 is an attractive, complementary, and/or adjuvant strategy towards the execution of cancer cells by re-activating apoptosis.
  • In a similar vein to the inhibition of BCl-xL, the development of synthetic agents capable of disrupting the interaction between Mcl-1 and the BH3 α-helical “death” domains of pro-apoptotic Bcl-2 proteins could “neutralize” Mcl-1 's cell survival role.
  • Provided herein are small molecules that selectively bind Mcl-1 with high affinity and methods for using such compounds to treat diseases characterized by overexpression or unregulated anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins.
    • SUMMARY OF THE INVENTION
  • In an embodiment, the invention includes compounds of formula (I):
  • Figure US20220396549A1-20221215-C00001
  • wherein X1 may be a substituent selected from the group consisting of H, C, CH, CIT, and CH3;
  • X2 may be a substituent selected from the group consisting of C, CH, and CH2, and n=0 or 1;
  • X3 may be a substituent selected from the group consisting of N, CH, and CH2, and m=0 or 1;
  • X4 may be a substituent selected from the group consisting of C, CH, N, and NR2, wherein the dashed lines can independently represent a single bond, a double bond, or no bond;
  • A may be a substituent selected from the group consisting of S(═O), S(═O)2, C(═O), C(═O)O, and CH2;
  • L may be a bond or an NR3 substituent;
  • each Z may independently represent a substituent selected from the group consisting of H, halo, cyano, hydroxy, nitro, and optionally substituted acyl sulfonamide, alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkynyl, alkenyl-cycloalkyl, alkynyl-cycloalkyl, carbonyl, carboxaldehyde, carboxyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amino, amido, aryl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroaryl, heteroaryl alkyl, heterocycloalkyl, hydroxamate, and heterocycloalkyl;
  • Y1 and Y2 each may independently represent a substituent selected from the group consisting of H, OR4, CONR4OR4, CONR4R4, CONR4—SO2R4, COOR4, and optionally substituted alkyl, aryl, and heteroaryl, and q=0 or 1, and t=0 or 1;
  • each R1, R2, R3, and R4 may independently represent a substituent selected from the group consisting of H and optionally substituted alkyl, cycloalkyl, sulfinyl, sulfonyl, and aryl; and R1 and R3 may, taken together, comprise an optionally substituted cycloalkyl or heterocycloalkyl ring; and
  • pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof.
  • In some embodiments, the compounds of formula (I) may include the proviso that if (1) X1, X2, X3, and X4 together form part of a benzene ring, (2) Y1 is OH or O-alkyl and q=1, (3) A is S(═O)2 or C(═O), and (4) L is NR3, then Y2 is COOR4 and t=1.
  • In some embodiments of formula (I), the dashed line between X1 and X2 may represent a double bond and the dashed line between X1 and X4 may represent a double bond. Accordingly, in some embodiments, X1, X2, X3, and X4 may represent a portion of an aromatic ring.
  • In some embodiments of formula (I) Y1 and Y2 may collectively represent a carboxylic acid bioisostere which may, for example, be an optionally substituted alkyl ester, an acylsulfonamide, a hydroxamic acid, a hydroxamate, a tetrazole, a hydroxyisoxazole, an isoxazol-3-one, or a sulfonamide.
  • In some embodiments, the compounds of formula (I) may include one or more of:
    • 4-(N-(4-(4-chloro-3,5-dimethyl phenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-cyclopentylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-benzylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-chlorophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(3-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(2-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(p-tolyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-isopropyl phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(3-cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-2-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-4-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-3-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-((4-phenylpiperazin-1-yl)sulfonyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(naphthalen-1-yl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(naphthalen-2-yl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-methoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(2-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-nitrophenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(n-(2-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(3-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(cyclohexylmethyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoate,
    • methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoate,
    • 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoic acid,
    • 1-hydroxy-4-(piperidin-1-ylsulfonyl)-2-naphthoic acid,
    • 4-(N-(4-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(2,4-dibromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(naphthalen-1-yloxy)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N,N-dimethylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-phenoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-(3-bromophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(p-tolyloxy)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-(2,4-dichlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-((4-benzylpiperazin-1-yl)sulfonyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-phenylsulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-sulfamoyl-2-naphthoic acid,
    • 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • methyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate,
    • acetoxymethyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate,
    • 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-phenoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(p-tolylthio)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(isobutoxycarbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(4-phenoxybenzyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • phenyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide,
    • methyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • acetoxymethyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • 1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-([1,1′-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(p-tolyloxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(quinolin-8-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((5-(dimethylamino)naphthalen-1-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • (±)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-([1,1′-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • 4-(N-isobutylphenylsulfonamido)benzoic acid,
    • 4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
    • 4-(4-bromo-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-(p-tolyloxy)phenylsulfonamido)benzoic acid,
    • 4-(4-(3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-(2,4-dichlorophenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(4-phenoxyphenylsulfonamido)benzoic acid,
    • 3-(N-isobutylphenylsulfonamido)benzoic acid,
    • 3-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 5-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • methyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(phenylsulfonyl)benzamide,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(methylsulfonyl)benzamide,
    • 4-(N-isobutyl-4-phenoxyphenylsulfonamido)-2-((4-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)benzyl)oxy)benzoic acid,
    • 4-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
    • 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 4-(N-cyclopentyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-cyclopentylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-cyclopentylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 3-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 3-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
    • phenyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • acetoxymethyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • N-(4-cyano-3-hydroxyphenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
    • 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
    • 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-fluoro-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoic acid,
    • 4-(N-benzyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-benzylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
    • 3-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • N-(4-(2H-tetrazol-5-yl)phenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
    • N,2-dihydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzamide,
    • N-isobutyl-N-(4-(3-oxo-2,3-dihydroisoxazol-5-yl)phenyl)-4-phenoxybenzenesulfonamide,
    • 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
    • 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof.
  • In some embodiments, the compounds of formula (I) may include those compounds wherein R1 and R3 each independently represent a substituent selected from the group consisting of optionally substituted alkyl and aryl; and R1 and R3 may, taken together, comprise an optionally substituted cycloalkyl or heterocycloalkyl ring.
  • In an embodiment, the invention includes compounds of formula (II);
  • Figure US20220396549A1-20221215-C00002
  • wherein each R21 and R22 may independently represent a substituent selected from the group consisting of H and optionally substituted alkyl and aryl;
  • A21 may be a substituent selected from the group consisting of S(═O), S(═O)2, C(═O), and CH2;
  • X21 may be CH or N;
  • each Z21 may independently represent a substituent selected from the group consisting of H, halo, cyano, hydroxy, nitro, and optionally substituted acyl sulfonamide, alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkynyl, alkenyl-cycloalkyl, alkynyl-cycloalkyl, carbonyl, carboxaldehyde, carboxyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, alkoxy, alkoxy carbonyl, acyl, acyloxy, amino, amido, aryl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxamate, sulfanyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, and sulfonate;
  • Y21 may be a substituent selected from the group consisting of —C(O)O—, —CONR22—, —CONR22—SO2—, —CONR22O—,
  • Figure US20220396549A1-20221215-C00003
  • R23 and R24 each may independently represent a substituent selected from the group consisting of H and optionally substituted alkyl and aryl; and R23 and R24 may, taken together, comprise an optionally substituted cycloalkyl or heterocycloalkyl ring;
  • R25 may be a substituent selected from the group consisting of H and optionally substituted alkyl, aryl, sulfinyl, and sulfonyl; and
  • pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof.
  • In some embodiments, Y21 and R22 may collectively represent an optionally substituted acylsulfonamide.
  • In some embodiments of formula (II) Y21 and R22 may collectively represent a carboxylic acid bioisostere which may, for example, be an optionally substituted alkyl ester, an acylsulfonamide, a hydroxamic acid, a hydroxamate, a tetrazole, a hydroxyisoxazole, an isoxazol-3-one, or a sulfonamide.
  • In some embodiments, the compounds of formula (II) may include one or more of:
    • 4-(N-(4-(4-chloro-3,5-dimethyl phenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-isobutylsulfamoyl)-1-hydroxyl-naphthoic acid,
    • 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-cyclopentylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-benzylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-chlorophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(3-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(2-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(p-tolyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-isopropylphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(3-cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-2-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-4-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-3-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-((4-phenylpiperazin-1-yl)sulfonyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(naphthalen-1-yl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(naphthalen-2-yl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-methoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(2-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-nitrophenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(2-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(3-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(cyclohexylmethyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoate,
    • methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoate,
    • 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoic acid,
    • 1-hydroxy-4-(piperidin-1-ylsulfonyl)-2-naphthoic acid,
    • 4-(N-(4-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(2,4-dibromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(naphthalen-1-yloxy)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N,N-dimethylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-phenoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-(3-bromophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(p-tolyloxy)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-(2,4-dichlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-((4-benzylpiperazin-1-yl)sulfonyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-phenylsulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-sulfamoyl-2-naphthoic acid,
    • 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • methyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate,
    • acetoxymethyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof.
  • In some embodiments, the compounds of formula (II) may include those compounds wherein R23 and R24 each independently represent a substituent selected from the group consisting of optionally substituted alkyl and aryl; and R23 and R24 may, taken together, comprise an optionally substituted cycloalkyl or heterocycloalkyl ring.
  • In an embodiment, the invention includes one or more compounds of formula (IIIa) or formula (IIIb):
  • Figure US20220396549A1-20221215-C00004
  • wherein each R31 may independently represent a substituent selected from the group consisting of H and an optionally substituted alkyl and aryl;
  • A31 may be a bond or a substituent selected from the group consisting of S(═O), S(═O)2, C(═O), C(═O)O, and CH2;
  • X31 may be a substituent selected from the group consisting of optionally substituted alkyl and aryl;
  • Y31 may be a substituent selected from the group consisting of —C(O)O—, —CONR31—, —CONR31—SO2—, —CONR31O—,
  • Figure US20220396549A1-20221215-C00005
  • Z31, Z32, Z33, and Z34 each may independently represent a substituent selected from the group consisting of H, halo, cyano, hydroxy, nitro, and optionally substituted acylsulfonamide, alkyl, alkylaryl, alkylhetaryl, alkyl heterocycloalkyl, alkenyl, alkynyl, alkenyl-cycloalkyl, alkynyl-cycloalkyl, carboxaldehyde, carbonyl, carboxyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amino, amido, aryl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkyl heteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxamate, sulfanyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, and sulfonate; and
  • pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prod mgs thereof.
  • In some embodiments, Y31 and R31 may collectively represent an optionally substituted acylsulfonamide.
  • In some embodiments of formula (IIIa) and formula (IIIb) Y31 and R31 may collectively represent a carboxylic acid bioisostere which may, for example, be an optionally substituted alkyl ester, an acylsulfonamide, a hydroxamic acid, a hydroxamate, a tetrazole, a hydroxyisoxazole, an isoxazol-3-one, or a sulfonamide.
  • In some embodiments, the compound of formula (IIIa) or formula (IIIb) may include one or more of:
    • 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-phenoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(p-tolylthio)phenyl)sulfony)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid,
    • 1-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
      • 1-(isobutoxycarbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(4-phenoxybenzyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • phenyl 1-((4-(4-chloro-3,5-dimethyl phenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide,
    • methyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • acetoxymethyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • 1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-([1,1′-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(p-tolyloxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(quinolin-8-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((5-(dimethylamino)naphthalen-1-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • (±)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-[1,1′-biphenyl]-ylsulfonyl)-tetrahydroquinoline-S-carboxylicacid,
    • (±)-1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • 4-(N-isobutylphenylsulfonamido)benzoic acid, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof.
  • In an embodiment, the invention includes compounds of formula (IV):
  • Figure US20220396549A1-20221215-C00006
  • wherein R41 may be a substituent selected from the group consisting of H and optionally substituted alkyl, aryl, and cycloalkyl;
  • Z41 and Z42 each may independently represent a substituent selected from the group consisting of H, cyano, OR42, COOR42, CONR42OR42, CONR42R42, CON(R42)—S(O)2R42,
  • Figure US20220396549A1-20221215-C00007
  • and optionally substituted alkyl and aryl;
  • each R42 may independently represent a substituent selected from the group consisting of H and optionally substituted alkyl and aryl;
  • A41 may be a bond or a substituent selected from the group consisting of S(═O), S(═O)2, and C(═O);
  • X41 may be a substituent selected from the group consisting of optionally substituted alkyl, aryl, cycloalkyl, and heterocycloalkyl; and
  • pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof.
  • In some embodiments of formula (IV) Z41 and/or Z42 may represent a carboxylic acid bioisostere which may, for example, be an optionally substituted alkyl ester, an acylsulfonamide, a hydroxamic acid, a hydroxamate, a tetrazole, a hydroxyisoxazole, an isoxazol-3-one, or a sulfonamide.
  • In some embodiments, the compound of formula (IV) may include one or more of:
    • 4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl phenylsulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
    • 4-(4-bromo-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-(p-tolyloxy)phenylsulfonamido)benzoic acid,
    • 4-(4-(3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-(2,4-dichlorophenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(4-phenoxyphenylsulfonamido)benzoic acid,
    • 3-(N-isobutylphenylsulfonamido)benzoic acid,
    • 3-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 5-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • methyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(phenylsulfonyl)benzamide,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(methylsulfonyl)benzamide,
    • 4-(N-isobutyl-4-phenoxyphenylsulfonamido)-2-((4-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)benzyl)oxy)benzoic acid,
    • 4-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
    • 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 4-(N-cyclopentyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-cyclopentylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-cyclopentylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 3-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 3-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
    • phenyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • acetoxymethyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • N-(4-cyano-3-hydroxyphenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
    • 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
    • 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-fluoro-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoic acid,
    • 4-(N-benzyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-benzylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
    • 3-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • N-(4-(2H-tetrazol-5-yl)phenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
    • N,2-dihydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzamide,
    • N-isobutyl-N-(4-(3-oxo-2,3-dihydroisoxazol-5-yl)phenyl)-4-phenoxybenzenesulfonamide,
    • 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
    • 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof.
  • In some embodiments, the compounds of formula (IV) may include one or more compounds wherein Z41 and Z42 each may independently represent a substituent selected from the group consisting of OR42 and COOR42.
  • In an embodiment, the compound of the invention is selected from the group consisting of:
  • Figure US20220396549A1-20221215-C00008
    Figure US20220396549A1-20221215-C00009
  • and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof.
  • In an embodiment, the invention includes a method of treating a condition alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method including administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • In an embodiment, the invention includes a method of treating a condition alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method including administering a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • In an embodiment, the invention includes a method of treating a condition alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method including administering a therapeutically effective amount of a compound of formula (IIIa) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • In an embodiment, the invention includes a method of treating a condition alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method including administering a therapeutically effective amount of a compound of formula (IIIb) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • In an embodiment, the invention includes a method of treating a condition alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method including administering a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • A method of treating a condition alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method including administering a therapeutically effective amount of one or more compounds selected from the group consisting of:
    • 4-(N-(4-(4-chloro-3,5-dimethyl phenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-cyclopentylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxyl-naphthoic acid,
    • 4-(N-benzylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-chlorophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(3-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(2-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(p-tolyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-isopropylphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(3-cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-2-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-4-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-3-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-((4-phenylpiperazin-1-yl)sulfonyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(naphthalen-1-yl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(naphthalen-2-yl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-methoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(2-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-nitrophenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(2-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(3-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(cyclohexylmethyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoate,
    • methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoate,
    • 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoic acid,
    • 1-hydroxy-4-(piperidin-1-ylsulfonyl)-2-naphthoic acid,
    • 4-(N-(4-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(2,4-dibromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(naphthalen-1-yloxy)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N,N-dimethylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-phenoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-(3-bromophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(p-tolyloxy)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-(2,4-dichlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid, 4-((4-benzylpiperazin-1-yl)sulfonyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-phenylsulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-sulfamoyl-2-naphthoic acid,
    • 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • methyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate,
    • acetoxymethyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate,
    • 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-phenoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(p-tolylthio)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(isobutoxycarbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(4-phenoxybenzyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • phenyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide,
    • methyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • acetoxymethyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • 1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-([1,1′-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(p-tolyloxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(quinolin-8-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((5-(dimethylamino)naphthalen-1-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • (±)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-([1,1′-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • 4-(N-isobutylphenylsulfonamido)benzoic acid,
    • 4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
    • 4-(4-bromo-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-(p-tolyloxy)phenylsulfonamido)benzoic acid,
    • 4-(4-(3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-(2,4-dichlorophenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(4-phenoxyphenylsulfonamido)benzoic acid,
    • 3-(N-isobutylphenylsulfonamido)benzoic acid,
    • 3-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 5-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • methyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(phenylsulfonyl)benzamide,
    • 4-(N-benzyl-4-phenoxy phenyl sulfonamido)-2-hydroxy-N-(methylsulfonyl)benzamide,
    • 4-(N-isobutyl-4-phenoxyphenylsulfonamido)-2-((4-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)benzyl)oxy)benzoic acid,
    • 4-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
    • 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutyl phenyl sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 4-(N-cyclopentyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-cyclopentylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-cyclopentylphenylsulfonamido)-2-hydroxy benzoic acid,
    • 3-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 3-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
    • phenyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • acetoxymethyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • N-(4-cyano-3-hydroxyphenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
    • 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
    • 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-fluoro-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoic acid,
    • 4-(N-benzyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-benzylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
    • 3-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • N-(4-(2H-tetrazol-5-yl)phenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
    • N,2-dihydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzamide,
    • N-isobutyl-N-(4-(3-oxo-2,3-dihydroisoxazol-5-yl)phenyl)-4-phenoxybenzenesulfonamide,
    • 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
    • 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, and combinations thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • In some embodiments, the condition alleviated by inhibiting Mcl-1 protein may be selected from the group consisting of: pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma.
  • In some embodiments, the condition alleviated by inhibiting Mcl-1 protein may be selected from the group consisting of: myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.
  • In an embodiment, the invention may include a pharmaceutical composition for treating a condition alleviated by inhibiting Mcl-1 protein activity, the pharmaceutical composition including one or more compounds of formula (I), (II), (IIIa), (IIIb), and (IV), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable carrier medium.
  • In some embodiments, the pharmaceutical composition may include one or more of: 4-(N-(4-(4-chloro-3,5-dimethyl phenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-isobutylsulfamoyl)-1-hydroxyl-naphthoic acid,
    • 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-cyclopentylsulfamoyl)-1-hydroxyl-naphthoic acid,
    • 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-benzylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-chlorophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(3-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(2-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(p-tolyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-isopropylphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(3-cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-2-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-4-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-3-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-((4-phenylpiperazin-1-yl)sulfonyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(naphthalen-1-yl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(naphthalen-2-yl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-methoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(2-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-nitrophenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(2-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(3-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(cyclohexylmethyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoate,
    • methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoate,
    • 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoic acid,
    • 1-hydroxy-4-(piperidin-1-ylsulfonyl)-2-naphthoic acid,
    • 4-(N-(4-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(2,4-dibromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(naphthalen-1-yloxy)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N,N-dimethylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-phenoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-(3-bromophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(p-tolyloxy)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-(2,4-dichlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-((4-benzylpiperazin-1-yl)sulfonyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-phenylsulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-sulfamoyl-2-naphthoic acid,
    • 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • methyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate,
    • acetoxymethyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate,
    • 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-phenoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic
    • acid,
    • 1-((4-(p-tolylthio)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(isobutoxycarbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(4-phenoxybenzyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
      • phenyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide,
    • methyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • acetoxymethyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • 1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-([1,1′-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(p-tolyloxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(quinolin-8-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((5-(dimethylamino)naphthalen-1-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • (±)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-([1,1′-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • 4-(N-isobutylphenylsulfonamido)benzoic acid,
    • 4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
    • 4-(4-bromo-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-(p-tolyloxy)phenylsulfonamido)benzoic acid,
    • 4-(4-(3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-(2,4-dichlorophenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(4-phenoxyphenylsulfonamido)benzoic acid,
    • 3-(N-isobutylphenylsulfonamido)benzoic acid,
    • 3-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 5-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • methyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(phenylsulfonyl)benzamide,
    • 4-(N-benzyl-4-phenoxy phenyl sulfonamido)-2-hydroxy-N-(methylsulfonyl)benzamide,
    • 4-(N-isobutyl-4-phenoxyphenylsulfonamido)-2-((4-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)benzyl)oxy)benzoic acid,
    • 4-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
    • 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 4-(N-cyclopentyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-cyclopentylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-cyclopentylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 3-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 3-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
    • phenyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • acetoxymethyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • N-(4-cyano-3-hydroxyphenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
    • 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
    • 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-fluoro-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoic acid,
    • 4-(N-benzyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-benzylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
    • 3-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • N-(4-(2H-tetrazol-5-yl)phenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
    • N,2-dihydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzamide,
    • N-isobutyl-N-(4-(3-oxo-2,3-dihydroisoxazol-5-yl)phenyl)-4-phenoxybenzenesulfonamide,
    • 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
    • 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, and combinations thereof.
    BRIEF DESCRIPTION OF THE DRAWINGS
  • The foregoing summary, as well as the following detailed description of embodiments of the invention, will be better understood when read in conjunction with the appended drawings and figures.
  • In the drawings:
  • FIG. 1 illustrates the binding mode of 3a, as predicted by SILCS. Important residues within the p2 binding pocket are shown in stick representation.
  • FIG. 2 illustrates a 2D NMR HSQC spectra, which shows chemical shift perturbations caused by the direct interaction of compound 3ba with Mcl-1. The spectrum of the control sample is overlaid with the spectrum of Mcl-1 bound to 3ba. Inset is enlargement of boxed region.
  • FIG. 3 illustrates Mcl-1 residues whose chemical shifts are perturbed in the presence of compound 3ba.
  • FIG. 4 illustrates atom GFE contributions for the most LGFE favorable binding conformation of the four compounds. Compound (A) is 3b, compound (B) is 3a; compound (C) is 3bi; and compound (D) is 3bl.
  • FIGS. 5A to 5D illustrate computational modeling studies of certain compounds described herein with Mcl-1 and Bcl-xL proteins. FIG. 5A illustrates a difference FragMap between Mcl-1 and Bcl-xL showing the favourable binding patterns for Mcl-1. The atom grid free energy (GFE) contributions to the binding affinity difference are also shown. FIG. 5B illustrates the experimental structures of Mcl-1 (A, 4HW4) and BCl-xL (B, 1BXL) shows that the binding pocket between helix α4 (upper right) and α5 (bottom left) is larger for Mcl-1 than Bcl-xL. The predicted binding modes of 3a for Mcl-1 (X) and BCl-xL (Y) differs due to this p2 pocket difference. The 4-bromophenyl ring of 3a binds deeply to the opened pocket for Mcl-1 while it binds on the protein surface for Bcl-xL. FIG. 5C illustrates binding orientations of 3bl to Mcl-1 (A, 4HW4) and Bcl-xL (B, 1BXL) along with the ΔFragMaps, The predicted binding modes of 3a for Mcl-1 (X) and Bcl-xL (Y) are also shown. FIG. 5D illustrates the binding orientations of 3bl to BCl-xL (1BXL) along with the Bcl-xL APOLAR and NEG FragMaps.
  • FIG. 6 illustrates pharmacophore features for the Mcl-1 binding site. The pharmacophore features developed from SILCS FragMaps are used to explore the binding conformation of the tested compounds. Crystal structure of Mcl-1 and the inhibitor Fesik60 from complex (PDBID:4HW3) are shown. Protein atoms occluding the view of the binding pocket were removed to facilitate visualization. Features APOLAR (i.e., F1, F3, F4, and F5), HBDON (i.e., F7), HBACC (i.e., F6), and NEG (i.e., F2) are marked.
  • FIG. 7 illustrates a correlation plot of experimental binding affinity (from Ki) vs. predicted LGFE (standard deviations are shown by the error bars) for all the tested compounds of MCL-1. A correlation coefficient of 0.53 and a predictive index of 0.70 were obtained.
  • FIG. 8 illustrates a correlation plot of Bcl-xl experimental binding affinity (from Ki) vs. predicted LGFE (standard deviations are shown by the error bars) for all the compounds tested against Bcl-xL. A correlation coefficient of 0.58 and a predictive index of 0.76 were obtained.
  • FIG. 9 illustrates a correlation plot of experimental binding affinity difference between Mcl-1 and Bcl-xL (from Ki) vs. predicted LGFE difference for all compounds tested against Bcl-x. A correlation coefficient of 0.57 and a predictive index of 0.83 were obtained.
  • FIG. 10 illustrates the relative locations of Asn260 and Arg263 on the tertiary structure of the Mcl-1 protein in addition to the locations of the p2 and p3 pockets.
  • FIG. 11 illustrates the proposed Mcl-1 binding orientations for the tetrahydroquinoline, salicylate, and naphthoate Mcl-1 inhibitors described herein.
  • FIG. 12 illustrates a 2D 1H-15N HSQC spectra of Mcl-1 collected in the absence and presence of ±−2 from Example 4.
  • FIG. 13 illustrates resonance variations that were mapped onto the Mcl-1 crystal structure after calculating the chemical shift perturbations for each amino acid following the 2D 1H-15N HSQC analysis with ±−2 from Example 4.
  • FIG. 14 illustrates the design of a 4-aminobenzoate analog based on the THQ scaffold.
  • FIG. 15 illustrates the predicted binding of 4-aminobenzoate to Mcl-1.
  • FIG. 16 illustrates the predicted binding of 4-aminobenzoate to Mcl-1 after the installation of a hydroxyl group ortho to the carboxylic acid (i.e., converting the 4-aminobenzoate into a 4-aminosalicylate).
  • FIG. 17 illustrates the predicted binding of 5-aminosalicylate to Mcl-1.
  • FIG. 18 illustrates a 2D 1H-15N HSQC spectra of apo-Mcl-1 collected in the absence and presence of 13ak.
  • FIG. 19 illustrates a plot of chemical shift of Mcl-1 protein upon 13ak binding, where black columns are the amino residues that were significantly perturbed (A chemical shift >0.3 ppm).
  • FIG. 20 illustrates NMR chemical shift perturbations of the MCL-1/13ak complex mapped onto MCL-1 crystal coordinates (PDB ID: 4HW3) in PyMOL. Residues experiencing chemical shifts of at least 0.3 ppm are shaded.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entireties.
    • Definitions
  • As used herein, the terms “administer,” “administration” or “administering” refer to (1) providing, giving, dosing, and/or prescribing by either a health practitioner or his authorized agent or under his or her direction according to the disclosure; and/or (2) putting into, taking or consuming by the mammal, according to the disclosure.
  • The terms “co-administration,” “co-administering,” “administered in combination with,” “administering in combination with,” “simultaneous,” and “concurrent,” as used herein, encompass administration of two or more active pharmaceutical ingredients to a subject so that both active pharmaceutical ingredients and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present. Simultaneous administration in separate compositions and administration in a composition in which both agents are present are preferred.
  • The terms “active pharmaceutical ingredient” and “drug” include the Mcl-1 inhibitors described herein and, more specifically, the Mcl-1 inhibitors described by Formulas I, II, IIIa, IIIb, and IV. The terms “active pharmaceutical ingredient” and “drug” may also include those compounds described herein that bind Mcl-1 protein and thereby modulate Mcl-1 protein activity.
  • The term “isostere” refers to a group or molecule whose chemical and/or physical properties are similar to those of another group or molecule. A “bioisostere” is a type of isostere and refers to a group or molecule whose biological properties are similar to those of another group or molecule. For example, for the Mcl-1 inhibitors described herein, a carboxylic acid may be replaced by one of the following bioisosteres for carboxylic acids, including, without limitation, alkyl esters (COOR), acyl sulfonamides (CONR—SO2R), hydroxamic acids (CONR—OH), hydroxamates (CONR—OR), tetrazoles, hydroxyisoxazoles, isoxazol-3-ones, and sulfonamides (SO2NR), where each R may independently represent hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • The term “in vivo” refers to an event that takes place in a subject's body.
  • The term “in vitro” refers to an event that takes places outside of a subject's body. In vitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.
  • The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells (e.g., the reduction of platelet adhesion and/or cell migration). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.
  • A “therapeutic effect” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • As used herein, the terms “treat,” “treatment,” and/or “treating” may refer to the management of a disease, disorder, or pathological condition (e.g., pain, a neurological disorder, diarrhea, coughing, muscular tension, and glaucoma), or symptom thereof with the intent to cure, ameliorate, stabilize, prevent, and/or control the disease, disorder, pathological condition or symptom thereof. Regarding control of the disease, disorder, or pathological condition more specifically, “control” may include the absence of condition progression, as assessed by the response to the methods recited herein, where such response may be complete (e.g., placing the disease in remission) or partial (e.g., lessening or ameliorating any symptoms associated with the condition).
  • As used herein, the terms “modulate” and “modulation” refer to a change in biological activity for a biological molecule (e.g., a protein, gene, peptide, antibody, and the like), where such change may relate to an increase in biological activity (e.g., increased activity, agonism, activation, expression, upregulation, and/or increased expression) or decrease in biological activity (e.g., decreased activity, antagonism, suppression, deactivation, downregulation, and/or decreased expression) for the biological molecule. In some embodiments, the biological molecules modulated by the methods and compounds of the invention to effect treatment may include one or both of the δ-opioid receptor and the μ-opioid receptor.
  • The terms “QD,” “qd,” or “q.d.” mean quaque die, once a day, or once daily. The terms “BID,” “bid,” or “b.i.d.” mean bis in die, twice a day, or twice daily. The terms “TID,” “tid,” or “t.i.d.” mean ter in die, three times a day, or three times daily. The terms “QID,” “qid,” or “q.i.d.” mean quater in die, four times a day, or four times daily.
  • The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. The term “cocrystal” refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike a salt, a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “physiologically compatible” carrier or carrier medium is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the invention is contemplated. Additional active pharmaceutical ingredients, such as other drugs, can also be incorporated into the described compositions and methods.
  • A “prodrug” refers to a derivative of a compound described herein, the pharmacologic action of which results from the conversion by chemical or metabolic processes in vivo to the active compound. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxyl or carboxylic acid group of formulas I, II, IIIa, IIIb, and IV. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by one or three letter symbols but also include, for example, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters (e.g., methyl esters and acetoxy methyl esters). Prodrug esters as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of the method of the invention with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methyl carbonates, benzoates and the like. As further examples, free hydroxyl groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs, sulfonate prodrugs, sulfonate esters and sulfate esters of hydroxyl groups. Free amines can also be derivatized to amides, sulfonamides or phosphonamides. All of the stated prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities. Moreover, any compound that can be converted in vivo to provide the bioactive agent (e.g., a compound of formula I, II, IIIa, IIIb, and IV) is a prodrug within the scope of the invention. Various forms of prodrugs are well known in the art. A comprehensive description of pro drugs and prodrug derivatives are described in: (a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., (Academic Press, 1996); (b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); (c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds., (Harwood Academic Publishers, 1991). In general, prodrugs may be designed to improve the penetration of a drug across biological membranes in order to obtain improved drug absorption, to prolong duration of action of a drug (slow release of the parent drug from a prodrug, decreased first-pass metabolism of the drug), to target the drug action (e.g. organ or tumor-targeting, lymphocyte targeting), to modify or improve aqueous solubility of a drug (e.g., i.v. preparations and eyedrops), to improve topical drug delivery (e.g. dermal and ocular drug delivery), to improve the chemical/enzymatic stability of a drug, or to decrease off-target drug effects, and more generally in order to improve the therapeutic efficacy of the compounds utilized in the invention.
  • Unless otherwise stated, the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by 13C- or 14C-enriched carbons, are within the scope of this invention.
  • When ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. Use of the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary. The variation is typically from 0% to 15%, preferably from 0% to 10%, more preferably from 0% to 5% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) includes those embodiments such as, for example, an embodiment of any composition of matter, method or process that “consist of” or “consist essentially of” the described features.
  • “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., (C1-10)alkyl or C1-10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range—e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” where no numerical range is specifically designated. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl. The alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl) and 3-methylhexyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of substituents which are independently heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2 where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • “Alkylhetaryl” refers to an -(alkyl)hetaryl radical where hetaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • “Alkylheterocycloalkyl” refers to an -(alkyl) heterocycyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl respectively.
  • An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
  • “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., (C2-10)alkenyl or C2-10 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range—e.g., “2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkenyl moiety may be attached to the rest of the molecule by a single bond, such as for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl and penta-1,4-dienyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)OR3, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Alkenyl-cycloalkyl” refers to an -(alkenyl)cycloalkyl radical where alkenyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.
  • “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., (C2-10)alkynyl or C2-10 alkynyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range—e.g., “2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, acylsulfonamido, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Alkynyl-cycloalkyl” refers to an -(alkynyl)cycloalkyl radical where alkynyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkynyl and cycloalkyl respectively.
  • “Acylsulfonamide” refers to the group —C(═O)NRa—S(═O)Ra, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.
  • “Carboxaldehyde” refers to a —(C═O)H radical.
  • “Carbonyl” refers to the group —C(═O)—. Carbonyl groups may be substituted with the following exemplary substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, acylsulfonamido, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —NRa—ORa—, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Carboxyl” refers to a —(C═O)OH radical.
  • “Cyano” refers to a —CN radical.
  • “Cycloalkyl” refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e. (C3-10)cycloalkyl or C3-10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range—e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, acylsulfonamido, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Cycloalkyl-alkenyl” refers to a -(cycloalkyl)alkenyl radical where cycloalkyl and alkenyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.
  • “Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl)heterocycloalkyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heterocycloalkyl, respectively.
  • “Cycloalkyl-heteroaryl” refers to a -(cycloalkyl)heteroaryl radical where cycloalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.
  • The term “alkoxy” refers to the group —O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. “Lower alkoxy” refers to alkoxy groups containing one to six carbons.
  • The term “substituted alkoxy” refers to alkoxy wherein the alkyl constituent is substituted (i.e., —O-(substituted alkyl)). Unless stated otherwise specifically in the specification, the alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, acylsulfonamido, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroaryl alkyl.
  • The term “alkoxycarbonyl” refers to a group of the formula (alkoxy)(C═O)— attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a (C1-6)alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker. “Lower alkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.
  • The term “substituted alkoxycarbonyl” refers to the group (substituted alkyl)-O—C(O)— wherein the group is attached to the parent structure through the carbonyl functionality. Unless stated otherwise specifically in the specification, the alkyl moiety of an alkoxycarbonyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORn, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Acyl” refers to the groups (alkyl)-C(O)—, (aryl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C(O)— and (heterocycloalkyl)-C(O)—, wherein the group is attached to the parent structure through the carbonyl functionality. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the alkyl, aryl or heteroaryl moiety of the acyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Rn)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Acyloxy” refers to a R(C═O)O— radical wherein R is alkyl, aryl, heteroaryl, heteroalkyl or heterocycloalkyl, which are as described herein. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the R of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Amino” or “amine” refers to a —N(Ra)2 radical group, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. When a —N(Ra)2 group has two Ra substituents other than hydrogen, they can be combined with the nitrogen atom to form a 4-, 5-, 6- or 7-membered ring. For example, —N(Ra)2 is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • The term “substituted amino” also refers to N-oxides of the groups —NHRd, and NRdRd each as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.
  • “Amide” or “amido” refers to a chemical moiety with formula —C(O)N(R)2 or —NHC(O)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted. The R2 of —N(R)2 of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring. Unless stated otherwise specifically in the specification, an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, amino, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide may be an amino acid or a peptide molecule attached to a compound disclosed herein, thereby forming a prodrug. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.
  • “Aromatic” or “aryl” or “Ar” refers to an aromatic radical with six to ten ring atoms (e.g., C6-C10 aromatic or C6-C10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • “Ester” refers to a chemical radical of formula —COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The procedures and specific groups to make esters are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which independently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
  • “Halo,” “halide,” or, alternatively, “halogen” is intended to mean fluoro, chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl,” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
  • “Heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl” refer to optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range may be given—e.g., C1-C4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long. A heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, acylsulfonamido, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclyl alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Heteroalkylaryl” refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.
  • “Heteroalkyl heteroaryl” refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.
  • “Heteroalkylheterocycloalkyl” refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl, respectively.
  • “Heteroalkylcycloalkyl” refers to an -(heteroalkyl)cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.
  • “Heteroaryl” or “heteroaromatic” or “HetAr” refers to a 5- to 18-membered aromatic radical (e.g., C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range—e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. Bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical—e.g., a pyridyl group with two points of attachment is a pyridylidene. A N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. The heteroatom(s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-d]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, isoxazol-3-one, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which are independently; alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (—O—) substituents, such as, for example, pyridinyl N-oxides.
  • “Heteroarylalkyl” refers to a moiety having an aryl moiety, as described herein, connected to an alkylene moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkylene group.
  • “Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range—e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —S(O)tRa— (where t is 1 or 2), —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Heterocycloalkyl” also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
  • “hydroxamate” refers to the —C(O)NRaORa moiety, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • “Nitro” refers to the —NO2 radical.
  • “Oxa” refers to the —O— radical.
  • “Oxo” refers to the ═O radical.
  • “Isomers” are different compounds that have the same molecular formula “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space—i.e., having a different stereochemical configuration. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1; 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either (R) or (S). Resolved compounds whose absolute configuration is unknown can be designated (+) or (−) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S). The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or 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 that the compounds include both E and Z geometric isomers.
  • “Enantiomeric purity” as used herein refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (R)- or an (S)-isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (S)-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (S)-isomer and 20% (R)-isomer, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%. The enantiomeric purity of a compound can be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle's reagents, or derivatization of a compounds using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.
  • In preferred embodiments, the enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition. Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, el al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, New York (1962); and E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley-Interscience, New York (1994).
  • The terms “enantiomerically enriched” and “non-racemic,” as used herein, refer to compositions in which the percent by weight of one enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (e.g., greater than 1:1 by weight). For example, an enantiomerically enriched preparation of the (S)-enantiomer, means a preparation of the compound having greater than 50% by weight of the (S)-enantiomer relative to the (R)-enantiomer, such as at least 75% by weight, or such as at least 80% by weight. In some embodiments, the enrichment can be significantly greater than 80% by weight, providing a “substantially enantiomerically enriched” or a “substantially non-racemic” preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, or such as at least 95% by weight. The terms “enantiomerically pure” or “substantially enantiomerically pure” refers to a composition that comprises at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.
  • “Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • “Tautomers” are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
  • A “leaving group or atom” is any group or atom that will, under selected reaction conditions, cleave from the starting material, thus promoting reaction at a specified site.
  • Examples of such groups, unless otherwise specified, include halogen atoms and mesyloxy, p-nitrobenzensulphonyloxy and tosyloxy groups.
  • “Protecting group” is intended to mean a group that selectively blocks one oi more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and the group can then be readily removed or deprotected after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York (1999).
  • “Solvate” refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent.
  • “Substituted” means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxamate, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons. The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.
  • “Sulfanyl” refers to groups that include —S-(optionally substituted alkyl), —S-(optionally substituted aryl), —S-(optionally substituted heteroaryl) and —S-(optionally substituted heterocycloalkyl).
  • “Sulfinyl” refers to groups that include —S(O)—H, —S(O)-(optionally substituted alkyl), —S(O)-(optionally substituted amino), —S(O)-(optionally substituted aryl), —S(O)-(optionally substituted heteroaryl) and —S(O)-(optionality substituted heterocycloalkyl).
  • “Sulfonyl” refers to groups that include —S(O2)—H, —S(O2)-(optionally substituted alkyl), —S(O2)-(optionally substituted amino), —S(O2)-(optionally substituted aryl), —S(O2)-(optionally substituted heteroaryl), and —S(O2)-(optionally substituted heterocycloalkyl).
  • “Sulfonamidyl” or “sulfonamido” refers to a —S(═O)2—NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The R groups in —NRR of the —S(═O)2—NRR radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring. A sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
  • “Sulfoxyl” refers to a —S(═O)2OH radical.
  • “Sulfonate” refers to a —S(═O)2—OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). A sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
  • Compounds of the invention also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. “Crystalline form” and “polymorph” are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
    • Methods of Treating Cancers and Other Diseases
  • The compounds and compositions described herein can be used in methods for treating diseases. In some embodiments, the compounds and compositions described herein can be used in methods for treating diseases associated with the upregulation of myeloid cell leukemia-1 (Mcl-1) oncoprotein. In some embodiments, the compounds and compositions described herein can be used for the treatment of hyperproliferative disorders, including those hyperproliferative disorders associated with the upregulation of Mcl-1. The compounds and compositions described herein may also be used in treating other disorders as described herein and in the following paragraphs.
  • In some embodiments, the hyperproliferative disorder is cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma, and the like.
  • In some embodiments, the hyperproliferative disorder treated by the compounds and compositions described herein includes cells having Mcl-1 protein and/or Mcl-1 related protein expression. In some embodiments, the disease treated by the compounds and compositions described herein is selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.
  • In some embodiments, the compounds described herein may induce cell cycle arrest and/or apoptosis in cells containing functional Mcl-1 proteins. The compounds described herein may be used for sensitizing cells to additional agent(s), such as inducers of apoptosis and/or cell cycle arrest, and chemoprotection of normal cells through the induction of cell cycle arrest prior to treatment with chemotherapeutic agents.
  • In some embodiments, the compounds described herein may be useful for the treatment of disorders, such as those responsive to induction of apoptotic cell death, e.g., disorders characterized by dysregulation of apoptosis. In some embodiments, the compounds may be used to treat cancer that is characterized by resistance to cancer therapies (e.g., those cancer cells which are chemoresistant, radiation resistant, hormone resistant, and the like). In other embodiments, the compounds can be used to treat hyperproliferative diseases characterized by expression of functional Mcl-1 and/or Mcl-1 related proteins, which may or may not be resilient to Bcl-xL inhibitors.
  • Efficacy of the compounds and combinations of compounds described herein in treating the indicated diseases or disorders can be tested using various models known in the art, and described herein, which provide guidance for treatment of human disease.
    • MCL-1 Inhibitors
  • In an embodiment, the invention includes compounds that may be Mcl-1 inhibitors and/or modulators of Mcl-1 protein activity. In some embodiments, the compounds described herein may be selective inhibitors of Mcl-1 protein activity as compared to BCl-xL.
  • In some embodiments, the compounds described herein may selectively decrease the activity of Mcl-1 protein as compared to BCl-xL protein in a ratio of at least about 1.5 to about 1, or at least about 2 to about 1, or at least about 3 to about 1, or at least about 4 to about 1, or at least about 5 to about 1, or at least about 10 to about 1, or at least about 15 to about 1, or at least about 20 to about 1, or at least about 25 to about 1, or at least about 30 to about 1, or at least about 35 to about 1, or at least about 40 to about 1, or at least about 45 to about 1, or at least about 50 to about 1, or at least about 100 to about 1, or at least about 200 to about 1, or at least about 300 to about 1, or at least about 400 to about 1, or at least about 500 to about 1, or at least about 600 to about 1, or at least about 700 to about 1, or least about 800 to about 1, or at least about 900 to about 1, or at least about 1000 to about 1, or at least about 10000 to about 1, or at least about 100000 to about 1, respectively.
  • In an embodiment, the Mcl-1 inhibitor may be a compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, tautomer, or prodrug thereof. In some embodiments, the Mcl-1 inhibitor of formula I includes one or more of:
    • 4-(N-(4-(4-chloro-3,5-dimethyl phenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-cyclopentylsulfamoyl)-1-hydroxyl-naphthoic acid,
    • 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-benzylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-chlorophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(3-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(2-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(p-tolyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-isopropylphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(3-cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-2-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-4-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-3-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-((4-phenylpiperazin-1-yl)sulfonyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(naphthalen-1-yl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(naphthalen-2-yl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-methoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(2-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-nitrophenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(2-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(3-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(cyclohexylmethyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoate,
    • methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoate,
    • 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoic acid,
    • 1-hydroxy-4-(piperidin-1-ylsulfonyl)-2-naphthoic acid,
    • 4-(N-(4-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(2,4-dibromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(naphthalen-1-yloxy)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N,N-dimethylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-phenoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-(3-bromophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(p-tolyloxy)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-(2,4-dichlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-((4-benzyl piperazin-1-yl)sulfonyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-phenylsulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-sulfamoyl-2-naphthoic acid,
    • 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • methyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate,
    • acetoxymethyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate,
    • 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-b-carboxylic acid,
    • 1-((4-phenoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(p-tolylthio)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(isobutoxycarbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(4-phenoxybenzyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • phenyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide,
    • methyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • acetoxymethyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • 1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-([1,1′-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(p-tolyloxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(quinolin-8-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((5-(dimethylamino)naphthalen-1-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
      • (±)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-([1,1′-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • 4-(N-isobutylphenylsulfonamido)benzoic acid,
    • 4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
    • 4-(4-bromo-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-(p-tolyloxy)phenylsulfonamido)benzoic acid,
    • 4-(4-(3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-(2,4-dichlorophenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(4-phenoxyphenylsulfonamido)benzoic acid,
    • 3-(N-isobutylphenylsulfonamido)benzoic acid,
    • 3-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 5-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • methyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(phenylsulfonyl)benzamide,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(methylsulfonyl)benzamide,
    • 4-(N-isobutyl-4-phenoxyphenylsulfonamido)-2-((4-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)benzyl)oxy)benzoic acid,
    • 4-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
    • 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 4-(N-cyclopentyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-cyclopentylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-cyclopentylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 3-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 3-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
    • phenyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • acetoxymethyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • N-(4-cyano-3-hydroxyphenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
    • 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
    • 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-fluoro-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoic acid,
    • 4-(N-benzyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-benzylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
    • 3-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • N-(4-(2H-tetrazol-5-yl)phenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
    • N,2-dihydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzamide,
    • N-isobutyl-N-(4-(3-oxo-2,3-dihydroisoxazol-5-yl)phenyl)-4-phenoxybenzenesulfonamide,
    • 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid, and
    • 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide.
  • In an embodiment, the Mcl-1 inhibitor may be a compound of formula II, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, tautomer, or prodrug thereof. In some embodiments, the compounds of formula I include the compounds of formula II, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, tautomers, or prodrugs thereof.
  • In some embodiments, the Mcl-1 inhibitor of formula II includes one of more of
    • 4-(N-(4-(4-chloro-3,5-dimethyl phenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-cyclopentylsulfamoyl)-1-hydroxyl-naphthoic acid,
    • 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxyl-naphthoic acid,
    • 4-(N-benzylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-chlorophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(3-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(2-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(p-tolyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-isopropylphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(3-cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-2-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-4-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-([1,1′-biphenyl]-3-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-((4-phenylpiperazin-1-yl)sulfonyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(naphthalen-1-yl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(naphthalen-2-yl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-methoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(2-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-nitrophenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(2-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(3-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(cyclohexylmethyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoate,
    • methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoate,
    • 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoic acid,
    • 1-hydroxy-4-(piperidin-1-ylsulfonyl)-2-naphthoic acid,
    • 4-(N-(4-chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(2,4-dibromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(naphthalen-1-yloxy)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N,N-dimethylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-phenoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-(3-bromophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-(4-(p-tolyloxy)phenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-(2,4-dichlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-((4-benzylpiperazin-1-yl)sulfonyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(4-chlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 4-(N-(4-(3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-(N-phenylsulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid,
    • 1-hydroxy-4-sulfamoyl-2-naphthoic acid,
    • 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid,
    • 4-(N-(4-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid,
    • methyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate, and
    • acetoxymethyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate.
  • In an embodiment, the Mcl-1 inhibitor may be a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, tautomer, or prodrug thereof. In some embodiments, the compounds of formula I include the compounds of formula IIIa or IIIb, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, tautomers, or prodrugs thereof. In some embodiments, the Mcl-1 inhibitor of formula IIIa or IIIb includes one or more of:
    • 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid,
    • 1-((4-phenoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(p-tolylthio)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid,
    • 1-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(isobutoxycarbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(4-phenoxybenzyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • phenyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide,
    • methyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • acetoxymethyl 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate,
    • 1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-([1,1′-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(p-tolyloxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-(quinolin-8-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((5-(dimethylamino)naphthalen-1-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • 1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid,
    • (±)-1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-bromophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-([1,1′-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-((4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid,
    • (±)-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid, and
    • 4-(N-isobutylphenylsulfonamido)benzoic acid.
  • In an embodiment, the Mcl-1 inhibitor may be a compound of formula IV, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, tautomer, or prodrug thereof. In some embodiments, the compounds of formula 1 include the compounds of formula IV, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, tautomers, or prodrugs thereof.
  • In some embodiments, the Mcl-1 inhibitor of formula IV may include one or more of:
    • 4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
    • 4-(4-bromo-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-(p-tolyloxy)phenylsulfonamido)benzoic acid,
    • 4-(4-(3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-(2,4-dichlorophenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(4-phenoxyphenylsulfonamido)benzoic acid,
    • 3-(N-isobutylphenylsulfonamido)benzoic acid,
    • 3-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 5-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • methyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(phenylsulfonyl)benzamide,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(methylsulfonyl)benzamide,
    • 4-(N-isobutyl-4-phenoxyphenylsulfonamido)-2-((4-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)benzyl)oxy)benzoic acid,
    • 4-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
    • 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 2-hydroxy-4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 4-(N-cyclopentyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-cyclopentylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-(4-chloro-3,5-dimethylphenoxy)-N-cyclopentylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 3-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
    • 3-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
    • phenyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • acetoxymethyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
    • N-(4-cyano-3-hydroxyphenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
    • 4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
    • 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
    • 3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(4-fluoro-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
    • 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoic acid,
    • 4-(N-benzyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-benzylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
    • 4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
    • 3-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutylphenylsulfonamido)benzoic acid,
    • 2-hydroxy-5-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
    • N-(4-(2H-tetrazol-5-yl)phenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
    • N,2-dihydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzamide,
    • N-isobutyl-N-(4-(3-oxo-2,3-dihydroisoxazol-5-yl)phenyl)-4-phenoxybenzenesulfonamide,
    • 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid, and
    • 5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide.
  • In an embodiment, the Mcl-1 inhibitor may be one or more of the compounds set forth in the table below:
  • Naphthoate Analogs
    Identifier Compound Name Structure
    JY-5-371 4-(N-(4-(4-chloro-3,5- dimethyl phenoxy)phenyl)sulfamoyl)- 1-hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00010
    JY-5-377 4-(N-(4-(4-chloro-3,5- dimethyl phenoxy)phenyl)-N- isobutylsulfamoyl)- 1-hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00011
    JY-5-379 4-(N-(4-(4-chloro-3,5- dimethylphenoxy)phenyl)- N-cyclopentylsulfamoyl)- 1- hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00012
    JY-5-380 4-(N-benzyl-N-(4-(4- chloro-3,5- dimethylphenoxy)phenyl) sulfamoyl)-1-hydroxy-2- naphthoic acid
    Figure US20220396549A1-20221215-C00013
    5jc65 4-(N-benzylsulfamoyl)- 1-hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00014
    5jc67 4-(N-(4- chlorophenyl)sulfamoyl)- 1-hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00015
    5jc71 4-(N-(3- chlorobenzyl)sulfamoyl)-1- hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00016
    5jc73-1 1-hydroxy-4-(N-(4- (trifluoromethyl) phenyl)sulfamoyl)-2- naphthoic acid
    Figure US20220396549A1-20221215-C00017
    5jc73-2 4-(N-(2- chlorobenzyl)sulfamoyl)- 1-hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00018
    5jc74-l 1-hydroxy-4-(N-(p- tolyl)sulfamoyl)-2- naphthoic acid
    Figure US20220396549A1-20221215-C00019
    574-2 1-hydroxy-4-(N-(4- isopropylphenyl) sulfamoyl)-2-naphthoic acid
    Figure US20220396549A1-20221215-C00020
    5jc75-2 4-(N-(3- cyanophenyl)sulfamoyl)- 1-hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00021
    LC-4-002 4-(N-([1,1′-biphenyl]-2- yl)sulfamoyl)-1-hydroxy- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00022
    LC-3-191 4-(N-([1,1′-biphenyl]-4- yl)sulfamoyl)- 1-hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00023
    LC-3-192 4-(N-([1,1′-biphenyl]-3- yl)sulfamoyl)-1-hydroxy- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00024
    EW-2-051 1-hydroxy-4-((4- phenylpiperazin-1- yl)sulfonyl)-2-naphthoic acid
    Figure US20220396549A1-20221215-C00025
    EW-2-056 1-hydroxy-4-(N- (naphthalen-1-yl) sulfamoyl)-2-naphthoic acid
    Figure US20220396549A1-20221215-C00026
    EW-2-057 1-hydroxy-4-(N- (naphthalen-2-yl) sulfamoyl)-2-naphthoic acid
    Figure US20220396549A1-20221215-C00027
    TA-1-018 4-(N-(4- cyanophenyl)sulfamoyl)-1- hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00028
    MEL-3-018 1-hydroxy-4-(N-(4- methoxyphenyl) sulfamoyl)-2-naphthoic acid
    Figure US20220396549A1-20221215-C00029
    TA-1-017 1-hydroxy-4-(N-(2- (trifluoromethyl)phenyl) sulfamoyl)-2-naphthoic acid
    Figure US20220396549A1-20221215-C00030
    MEL-3-005 1-hydroxy-4-(N-(4- nitrophenyl)sulfamoyl)-2- naphthoic acid
    Figure US20220396549A1-20221215-C00031
    TA-1-019 4-(N-(2- bromophenyl)sulfamoyl)- 1-hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00032
    TA-1-020 4-(N-(3- bromophenyl)sulfamoyl)- 1-hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00033
    MEL-3-006 4-(N-(cyclohexylmethyl) sulfamoyl)-1-hydroxy- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00034
    MEL-3-009-A methyl 4-(N-(4- bromophenyl)-N- isobutylsulfamoyl)-1- methoxy- 2-naphthoate
    Figure US20220396549A1-20221215-C00035
    MEL-3-009-B methyl 4-(N-(4- bromophenyl)-N- isobutylsulfamoyl)-1- hydroxy-2-naphthoate
    Figure US20220396549A1-20221215-C00036
    MEL-3-010 4-(N-(4-bromophenyl)-N- isobutylsulfamoyl)-1- methoxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00037
    SF-5-263 1-hydroxy-4-(piperidin-1- ylsulfonyl)- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00038
    SF-5-264 4-(N-(4- chlorobenzyl)sulfamoyl)-1- hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00039
    SF-5-290 4-(N-(2,4- dibromophenyl)sulfamoyl)- 1-hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00040
    SF-5-293 1-hydroxy-4-(N-(4- isopropoxyphenyl) sulfamoyl)-2-naphthoic acid
    Figure US20220396549A1-20221215-C00041
    SF-5-300 1-hydroxy-4-(N-(4- (naphthalen-1- yloxy)phenyl)sulfamoyl)- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00042
    SF-5-295 4-(N,N- dimethylsulfamoyl)-1- hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00043
    SF-5-299 1-hydroxy-4-(N-(4- phenoxyphenyl) sulfamoyl)-2-naphthoic acid
    Figure US20220396549A1-20221215-C00044
    SF-5-303 4-(N-(4-(3- bromophenoxy)phenyl) sulfamoyl)-1-hydroxy- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00045
    SF-5-301 1-hydroxy-4-(N-(4-(p- tolyloxy) phenyl)sulfamoyl)-2- naphthoic acid
    Figure US20220396549A1-20221215-C00046
    SF-5-302 4-(N-(4-(2,4- dichlorophenoxy) phenyl)sulfamoyl)-1- hydroxy- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00047
    SF-5-307 4-((4-benzylpiperazin-1-yl) sulfonyl)-1-hydroxy- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00048
    SF-5-304 4-(N-(4-(4-chlorophenoxy) phenyl)sulfamoyl)-1- hydroxy-2-naphthoic acid
    Figure US20220396549A1-20221215-C00049
    SF-5-306 4-(N-(4-(3,5- dimethylphenoxy) phenyl)sulfamoyl)-1- hydroxy- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00050
    SF-5-311 1-hydroxy-4-(N- phenylsulfamoyl)-2- naphthoic acid
    Figure US20220396549A1-20221215-C00051
    SF-5-308 4-(N-(4-bromophenyl)-N- isobutylsulfamoyl)-1- hydroxy- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00052
    SF-5-294 1-hydroxy-4-sulfamoyl- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00053
    MEL-2-116 1-hydroxy-4-(N-isobutyl- N- (4- isopropoxyphenyl) sulfamoyl)- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00054
    SF-5-180 4-(N-(4-bromophenyl) sulfamoyl)-1-hydroxy- 2-naphthoic acid
    Figure US20220396549A1-20221215-C00055
    MEL-3-118 methyl 1-hydroxy-4-(N- isobutyl- N-(4-isopropoxyphenyl) sulfamoyl)-2-naphthoate
    Figure US20220396549A1-20221215-C00056
    MEL-3-128 acetoxymethyl 1-hydroxy- 4-(N isobutyl-N-(4- isopropoxyphenyl) sulfamoyl)-2-naphthoate
    Figure US20220396549A1-20221215-C00057
    Tetrahydroquinoline Analogs
    SF-5-118 1-(phenylsulfonyl)- 1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00058
    LC-3-004 1-((4- bromophenyl)sulfonyl)- 1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00059
    LC-4-013 1-((4- phenoxyphenyl)sulfonyl)- 1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00060
    LC-3-006 1-(naphthalen-2- ylsulfonyl)-1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00061
    LC-4-159 1-((4-(3,5- dimethylphenoxy)phenyl) sulfonyl)-1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00062
    LC-4-160 1-((4-(p- tolylthio)phenyl)sulfonyl)- 1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00063
    LC-3-182 1- ((benzyloxy)carbonyl)- 1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00064
    LC-3-177 1-(isobutoxycarbonyl)- 1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00065
    LC-3-178 1-(tert-butoxycarbonyl)- 1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00066
    LC-4-180 1-(4-phenoxybenzyl)- 1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00067
    LC-3-014 1-(3-(4-chloro-3,5- dimethylphenoxy)propyl)- 1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00068
    LC-3-122 phenyl 1-((4-(4-chloro- 3,5- dimethylphenoxy)phenyl) sulfonyl)-1,2,3,4- tetrahydroquinoline-6- carboxylate
    Figure US20220396549A1-20221215-C00069
    LC-3-119 1-((4-(4-chloro-3,5- dimethylphenoxy)phenyl) sulfonyl)-1,2,3,4- tetrahydroquinoline-6- carboxamide
    Figure US20220396549A1-20221215-C00070
    LC-3-121 methyl 1-((4-(4-chloro- 3,5- dimethylphenoxy)phenyl) sulfonyl)-1,2,3,4- tetrahydroquinoline-6- carboxylate
    Figure US20220396549A1-20221215-C00071
    LC-3-128 acetoxymethyl 1-((4-(4- chloro-3,5- dimethylphenoxy)phenyl) sulfonyl)-1,2,3,4- tetrahydroquinoline-6- carboxylate
    Figure US20220396549A1-20221215-C00072
    LC-3-010 1-((4- fluorophenyl)sulfonyl)- 1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00073
    LC-3-002 1-([1,1′-biphenyl]-4- ylsulfonyl)-1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00074
    LC-4-158 1-((4-(p- tolyloxy)phenyl)sulfonyl)- 1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00075
    LC-4-172 1-(quinolin-8- ylsulfonyl)-1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00076
    LC-4-165 1-((5- (dimethylamino)naphth- alen-1-yl)sulfonyl)- 1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00077
    LC-3-012 1-((4-(4-chloro-3,5- dimethylphenoxy)phenyl) sulfonyl)-1,2,3,4- tetrahydroquinoline-6- carboxylic acid
    Figure US20220396549A1-20221215-C00078
    SF-5-103 (±)-1-(phenylsulfonyl)- 1,2,3,4- tetrahydroquinoline-3- carboxylic acid
    Figure US20220396549A1-20221215-C00079
    SF-5-135 (±)-1-((4- bromophenyl)sulfonyl)- 1,2,3,4- tetrahydroquinoline-3- carboxylic acid
    Figure US20220396549A1-20221215-C00080
    SF-5-136 (±)-1-((4- fluorophenyl)sulfonyl)- 1,2,3,4- tetrahydroquinoline-3- carboxylic acid
    Figure US20220396549A1-20221215-C00081
    SF-5-133 (±)-1-([1,1′-biphenyl]-4- ylsulfonyl)-1,2,3,4- tetrahydroquinoline-3- carboxylic acid
    Figure US20220396549A1-20221215-C00082
    SF-5-134 (±)-1-(naphthalen-2- ylsulfonyl)-1,2,3,4- tetrahydroquinoline-3- carboxylic acid
    Figure US20220396549A1-20221215-C00083
    SF-5-141/ LC-3-115 (±)-1-((4-(4-chloro-3,5- dimethylphenoxy)phenyl) sulfonyl)-1,2,3,4- tetrahydroquinoline-3- carboxylic acid
    Figure US20220396549A1-20221215-C00084
    LC-3-016 (±)-1-(3-(4-chloro-3,5- dimethylphenoxy)propyl)- 1,2,3,4- tetrahydroquinoline-3- carboxylic acid
    Figure US20220396549A1-20221215-C00085
    Salicylate/Aminobenzoate Analogs
    LC-3-029 4-(N- isobutylphenylsulfonami- do)benzoic acid
    Figure US20220396549A1-20221215-C00086
    LC-3-030 4-(N-isobutyl-[1,1′- biphenyl]-4- ylsulfonamido)benzoic acid
    Figure US20220396549A1-20221215-C00087
    LC-3-031 4-(N- isobutylnaphthalene-2- sulfonamido)benzoic acid
    Figure US20220396549A1-20221215-C00088
    4jc117-1 2-hydroxy-4-(N- isobutylphenylsulfonami- ido)benzoic acid
    Figure US20220396549A1-20221215-C00089
    4jc117-2 2-hydroxy-4-(N- isobutyl-4- methylphenylsulfonami- do)benzoic acid
    Figure US20220396549A1-20221215-C00090
    LC-5-012 4-(4-bromo-N- isobutylphenylsulfonami- do)-2-hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00091
    LC-4-119 2-hydroxy-4-(N- isobutyl-4-(p- tolyloxy)phenylsulfon- amido)benzoic acid
    Figure US20220396549A1-20221215-C00092
    LC-4-100 4-(4-(3,5- dimethylphenoxy)-N- isobutylphenylsulfonami- do)-2-hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00093
    LC-4-111 4-(4-(2,4- dichlorophenoxy)-N- isobutylphenylsulfonami- do)-2-hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00094
    LC-5-005 2-hydroxy-4-(4- phenoxyphenylsulfon- amido)benzoic acid
    Figure US20220396549A1-20221215-C00095
    4jc177-1 3-(N- isobutylphenylsulfonami- do)benzoic acid
    Figure US20220396549A1-20221215-C00096
    4jc177-2 3-(N-isobutyl-4- methylphenylsulfonami- do)benzoic acid
    Figure US20220396549A1-20221215-C00097
    JY-5-299 2-hydroxy-5-(N- isobutylnaphthalene-2- sulfonamido)benzoic acid
    Figure US20220396549A1-20221215-C00098
    JY-5-304 5-(4-(4-chloro-3,5- dimethylphenoxy)-N- isobutylphenylsulfonami- do)-2-hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00099
    LC-4-131 methyl 2-hydroxy-4-(N- isobutyl-4- phenoxyphenylsulfon- amido)benzoate
    Figure US20220396549A1-20221215-C00100
    LC-5-096 4-(N-benzyl-4- phenoxyphenylsulfon- amido)-2-hydroxy-N- (phenylsulfonyl)benzamide
    Figure US20220396549A1-20221215-C00101
    LC-5-112 4-(N-benzyl-4- phenoxyphenylsulfon- amido)-2-hydroxy-N- (methylsulfonyl)benzamide
    Figure US20220396549A1-20221215-C00102
    LC-5-111 4-(N-isobutyl-4- phenoxyphenylsulfon- amido)-2-((4-(((3-nitro- 4-(((tetrahydro-2H- pyran-4- yl)methyl)amino)phenyl) sulfonyl)carbamoyl) benzyl)oxy)benzoic acid
    Figure US20220396549A1-20221215-C00103
    LC-3-025 4-(4-fluoro-N- isobutylphenylsulfonami- do)benzoic acid
    Figure US20220396549A1-20221215-C00104
    LC-3-035 4-(4-(4-chloro-3,5- dimethylphenoxy)-N- isobutylphenylsulfonami- do)benzoic acid
    Figure US20220396549A1-20221215-C00105
    4jc117-3 2-hydroxy-4-(N- isobutylnaphthalene-2- sulfonamido)benzoic acid
    Figure US20220396549A1-20221215-C00106
    4jc117-4 2-hydroxy-4-(N- isobutyl-[1,1′-biphenyl]- 4- ylsulfonamido)benzoic acid
    Figure US20220396549A1-20221215-C00107
    LC-4-082 4-(N-cyclopentyl-[1,1′- biphenyl]-4- ylsulfonamido)-2- hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00108
    LC-4-083 4-(N- cyclopentylnaphthalene- 2-sulfonamido)-2- hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00109
    LC-4-104 4-(4-(4-chloro-3,5- dimethylphenoxy)-N- cyclopentylphenylsulfon- amido)-2- hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00110
    4jc177-3 3-(N- isobutylnaphthalene-2- sulfonamido)benzoic acid
    Figure US20220396549A1-20221215-C00111
    4jc177-4 3 (N-isobutyl-[1,1′- biphenyl]-4- ylsulfonamido)benzoic acid
    Figure US20220396549A1-20221215-C00112
    4jc177-5 3-(4-(4-chloro-3,5- dimethylphenoxy)-N- isobutylphenylsulfonami- do)benzoic acid
    Figure US20220396549A1-20221215-C00113
    LC-4-134 phenyl 2-hydroxy-4-(N- isobutyl-4- phenoxyphenylsulfon- amido)benzoate
    Figure US20220396549A1-20221215-C00114
    LC-4-141 acetoxymethyl 2- hydroxy-4-(N-isobutyl- 4- phenoxyphenylsulfon- amido)benzoate
    Figure US20220396549A1-20221215-C00115
    LC-5-050 N-(4-cyano-3- hydroxyphenyl)-N- isobutyl-4- phenoxybenzenesulfon- amide
    Figure US20220396549A1-20221215-C00116
    LC-5-107 4-(N-benzyl-4- phenoxyphenylsulfon- amido)-2-hydroxy-N-((3- nitro-4-(((tetrahydro- 2H-pyran-4- yl)methyl)amino)phenyl) sulfonyl)benzamide
    Figure US20220396549A1-20221215-C00117
    LC-5-131 4-(N-benzyl-4-(4- chloro-3,5- dimethylphenoxy)phenyl- sulfonamido)-2- hydroxy-N-((3-nitro-4- (((tetrahydro-2H-pyran- 4- yl)methyl)amino)phenyl) sulfonyl)benzamide
    Figure US20220396549A1-20221215-C00118
    4jc117-5 3-(4-(4-chloro-3,5- dimethylphenoxy)-N- isobutylphenylsulfonami- do)-2-hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00119
    LC-5-025 4-(4-fluoro-N- isobutylphenylsulfonami- do)-2-hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00120
    LC-4-099 2-hydroxy-4-(N- isobutyl-4- phenoxyphenylsulfon- amido)benzoic acid
    Figure US20220396549A1-20221215-C00121
    LC-4-112 4-(N-benzyl-[1,1′- biphenyl]-4- ylsulfonamido)-2- hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00122
    LC-4-113 4-(N- benzylnaphthalene-2- sulfonamido)-2- hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00123
    LC-4-118 4-(N-benzyl-4-(4- chloro-3,5- dimethylphenoxy)phenyl- sulfonamido)-2- hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00124
    4jc177-6 3-(4-fluoro-N- isobutylphenylsulfon- amido)benzoic acid
    Figure US20220396549A1-20221215-C00125
    JY-5-296 2-hydroxy-5-(N- isobutylphenylsulfonami- do)benzoic acid
    Figure US20220396549A1-20221215-C00126
    JY-5-300 2-hydroxy-5-(N- isobutyl-[1,1′-biphenyl]- 4- ylsulfonamido)benzoic acid
    Figure US20220396549A1-20221215-C00127
    LC-5-068 N-(4-(2H-tetrazol-5- yl)phenyl)-N-isobutyl- 4- phenoxybenzenesulfon- amide
    Figure US20220396549A1-20221215-C00128
    LC-5-062 N,2-dihydroxy-4-(N- isobutyl-4- phenoxyphenylsulfon- amido)benzamide
    Figure US20220396549A1-20221215-C00129
    LC-5-069 N-isobutyl-N-(4-(3- oxo-2,3- dihydroisoxazol-5- yl)phenyl)-4- phenoxybenzenesulfon- amide
    Figure US20220396549A1-20221215-C00130
    LC-5-129 5-(N-benzyl-4-(4- chloro-3,5- dimethylphenoxy)phenyl- sulfonamido)-2- hydroxybenzoic acid
    Figure US20220396549A1-20221215-C00131
    LC-5-132 5-(N-benzyl-4-(4- chloro-3,5- dimethylphenoxy)phenyl- sulfonamido)-2- hydroxy-N-((3-nitro-4- (((tetrahydro-2H-pyran- 4- yl)methyl)amino)phenyl) sulfonyl)benzamide
    Figure US20220396549A1-20221215-C00132
  • In some embodiments, the Mcl-1 inhibitors described above may be delivered as listed or as a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, tautomer, or prodrug thereof.
    • Pharmaceutical Compositions
  • In an embodiment, an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, such as any of the foregoing Mcl-1 inhibitors, is provided as a pharmaceutically acceptable composition.
  • In some embodiments, the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the invention, such as any of the foregoing Mcl-1 inhibitors, is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/v of the pharmaceutical composition.
  • In some embodiments, the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the invention, such as any of the foregoing Mcl-1 inhibitors, is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, v/v, or v/v of the pharmaceutical composition.
  • In some embodiments, the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the invention, such as any of the foregoing Mcl-1 inhibitors, is in the range from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12% or about 1% to about 10% w/w, w/v or v/v of the pharmaceutical composition.
  • In some embodiments, the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the invention, such as any of the foregoing Mcl-1 inhibitors, is in the range from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/v or v/v of the pharmaceutical composition.
  • In some embodiments, the amount of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the invention, such as any of the foregoing Mcl-1 inhibitors, is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.
  • In some embodiments, the amount of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the invention, such as any of the foregoing Mcl-1 inhibitors, is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.
  • Each of the active pharmaceutical ingredients according to the invention is effective over a wide dosage range. For example, in the treatment of adult humans, dosages independently range from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. The clinically-established dosages of the foregoing Mcl-1 inhibitors may also be used if appropriate.
  • In an embodiment, the molar ratio of two active pharmaceutical ingredients in the pharmaceutical compositions is in the range from 10:1 to 1:10, preferably from 2.5:1 to 1.2.5, and more preferably about 1:1. In an embodiment, the weight ratio of the molar ratio of two active pharmaceutical ingredients in the pharmaceutical compositions is selected from the group consisting of 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9.1, 8.1, 7.1, 6.1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20. In an embodiment, the weight ratio of the molar ratio of two active pharmaceutical ingredients in the pharmaceutical compositions is selected from the group consisting of 20:1, 19:1, 18:1, 17.1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, too 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20.
  • In an embodiment, the pharmaceutical compositions described herein, such as any of the foregoing Mcl-1 inhibitors, are for use in the treatment of hyperproliferative disorders associated with the overexpression or upregulation of Mcl-1. In a some embodiments, the pharmaceutical compositions described herein are for use in the treatment of a cancer associated with overexpression or upregulation of Mcl-1 selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin s disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma.
  • In a some embodiments, the pharmaceutical compositions described herein are for use in the treatment of a cancer associated with overexpression or upregulation of Mcl-1 selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.
  • Furthermore, the described methods of treatment may normally include medical follow-up to determine the therapeutic or prophylactic effect brought about in the subject undergoing treatment with the compound(s) and/or composition(s) described herein.
  • Described below are non-limiting pharmaceutical compositions and methods for preparing the same.
    • Pharmaceutical Compositions for Oral Administration
  • In an embodiment, the invention provides a pharmaceutical composition for oral administration containing the active pharmaceutical ingredient or combination of active pharmaceutical ingredients, such as the Mcl-1 inhibitors described herein, and a pharmaceutical excipient suitable for oral administration.
  • In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, and (ii) a pharmaceutical excipient suitable for oral administration. In selected embodiments, the composition further contains (iii) an effective amount of a third active pharmaceutical ingredient and optionally (iv) an effective amount of a fourth active pharmaceutical ingredient.
  • In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, sachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, a water-in-oil liquid emulsion, powders for reconstitution, powders for oral consumptions, bottles (including powders or liquids in a bottle), orally dissolving films, lozenges, pastes, tubes, gums, and packs. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient(s) into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • The invention further encompasses anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • Each of the active pharmaceutical ingredients can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions tor an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols, of carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which disintegrate in the bottle. Too little may be insufficient for disintegration to occur, thus altering the rate and extent of release of the active ingredients from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, sodium stearyl fumarate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, silicified microcrystalline cellulose, or mixtures thereof. A lubricant can optionally be added in an amount of less than about 0.5% or less than about 1% (by weight) of the pharmaceutical composition.
  • When aqueous suspensions and/or elixirs are desired for oral administration, the active pharmaceutical ingredient(s) may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, tor example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Surfactants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed
  • A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (HLB value).
  • Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts, sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides, and mixtures thereof.
  • Within the aforementioned group, ionic surfactants include, by way of example, lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatide add, phosphatidylserine, lysophosphatidylcholine, lysphosphatidylethanolamine, lysphosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.
  • Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
  • Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters; lower alcohol fatty acids esters, propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • In an embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use—e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethyl acetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl tri ethyl citrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, .epsilon.-caprolactone and isomers thereof, 5-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.
  • Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidine, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. It desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.
  • The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, tri isopropanol amine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals and alkaline earth metals. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenyl sulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid.
    • Pharmaceutical Compositions for Injection
  • In some embodiments, a pharmaceutical composition is provided for injection containing an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, such as an Mcl-1 inhibitor, and a pharmaceutical excipient suitable for injection.
  • The forms in which the compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Aqueous solutions in saline are also conventionally used tor injection. Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and thimerosal.
  • Sterile injectable solutions are prepared by incorporating an active pharmaceutical ingredient or combination of active pharmaceutical ingredients in the required amounts in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
    • Pharmaceutical Compositions for Topical Delivery
  • In some embodiments, a pharmaceutical composition is provided for transdermal delivery containing an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, such as Mcl-1 inhibitors described herein, and a pharmaceutical excipient suitable for transdermal delivery.
  • Compositions of the present invention can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
  • The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), tatty acids (e g, oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients in controlled amounts, either with oi without another active pharmaceutical ingredient.
  • The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252; 4,992,445 and 5,001,139, the entirety of which are incorporated herein by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
    • Pharmaceutical Compositions for Inhalation
  • 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 and the Mcl-1 inhibitors described herein. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. Dry powder inhalers may also be used to provide inhaled delivery of the compositions.
    • Other Pharmaceutical Compositions
  • Pharmaceutical compositions of the Mcl-1 inhibitors described herein may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; and Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, N.Y., 1990, each of which is incorporated by reference herein in its entirety.
  • Administration of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients or a pharmaceutical composition thereof can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. The active pharmaceutical ingredient or combination of active pharmaceutical ingredients can also be administered intraadiposally or intrathecally.
  • Exemplary parenteral administration forms include solutions or suspensions oi active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • The invention also provides kits. The kits include an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, either alone or in combination in suitable packaging, and written material that can include instructions tor use, discussion of clinical studies and listing of side effects. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may further contain another active pharmaceutical ingredient. In selected embodiments, an active pharmaceutical ingredient or combination of active pharmaceutical ingredients are provided as separate compositions in separate containers within the kit. In selected embodiments, an active pharmaceutical ingredient or combination of active pharmaceutical ingredients are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in selected embodiments, be marketed directly to the consumer.
  • In some embodiments, the invention provides a kit comprising a composition comprising a therapeutically effective amount of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. These compositions are typically pharmaceutical compositions. The kit is for co-administration of the active pharmaceutical ingredient or combination of active pharmaceutical ingredients, either simultaneously or separately.
  • In some embodiments, the invention provides a kit comprising (1) a composition comprising a therapeutically effective amount of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and (2) a diagnostic test for determining whether a patient's cancer is a particular subtype of a cancer. Any of the foregoing diagnostic methods may be utilized in the kit.
  • The kits described above are preferably for use in the treatment of the diseases and conditions described herein. In a particular embodiment, the kits are for use in the treatment of hyperproliferative disorders.
  • In a particular embodiment, the kits described herein are for use in the treatment of cancer. In some embodiments, the kits described herein are tor use in the treatment of a cancer selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma. In particular embodiments, the kits described herein are for use in the treatment of a cancer selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.
    • Dosages and Dosing Regimens
  • The amounts of the pharmaceutical compositions administered using the methods herein, such as the dosages of Mcl-1 inhibitors, will be dependent on the human or mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the active pharmaceutical ingredients and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect—e.g., by dividing such larger doses into several small doses for administration throughout the day. The dosage of the pharmaceutical compositions and active pharmaceutical ingredients may be provided in units of mg/kg of body mass or in mg/m2 of body surface area.
  • In some embodiments, the invention include methods of treating a cancer in a human subject suffering from the cancer in which cancer cells overexpress Mcl-1, the method comprising the steps of administering a therapeutically effective dose of an active pharmaceutical ingredient that is an Mcl-1 inhibitor to the human subject.
  • In some embodiments, a pharmaceutical composition or active pharmaceutical ingredient is administered in a single dose. Such administration may be by injection, e.g., intravenous injection, in order to introduce the active pharmaceutical ingredient quickly. However, other routes, including the preferred oral route, may be used as appropriate. A single dose of a pharmaceutical composition may also be used for treatment of an acute condition.
  • In some embodiments, a pharmaceutical composition or active pharmaceutical ingredient is administered in multiple doses. In an embodiment, a pharmaceutical composition is administered in multiple doses. Dosing may be once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be once a month, once every two weeks, once a week, or once every other day. In other embodiments, a pharmaceutical composition is administered about once per day to about 6 times per day. In some embodiments, a pharmaceutical composition is administered once daily, while in other embodiments, a pharmaceutical composition is administered twice daily, and in other embodiments a pharmaceutical composition is administered three times daily.
  • Administration of the active pharmaceutical ingredients may continue as long as necessary. In selected embodiments, a pharmaceutical composition is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a pharmaceutical composition is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a pharmaceutical composition is administered chronically on an ongoing basis—e.g., tor the treatment of chronic effects. In some embodiments, the administration of a pharmaceutical composition continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • In some embodiments, an effective dosage of an active pharmaceutical ingredient disclosed herein is in the range of about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 to about 202 mg. In some embodiments, an effective dosage of an active pharmaceutical ingredient disclosed herein is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg.
  • In some embodiments, an effective dosage of an active pharmaceutical ingredient disclosed herein is in the range of about 0.01 mg/kg to about 200 mg/kg, or about 0.1 to 100 mg/kg, or about 1 to 50 mg/kg.
  • In some embodiments, an active pharmaceutical ingredient is adminstered at a dosage of 10 to 200 mg BID, including 50, 60, 70, 80, 90, 100, 150, or 200 mg BID. In some embodiments, an active pharmaceutical ingredient is adminstered at a dosage of 10 to 500 mg BID, including 1, 5, 10, 15, 25, 50, 75, 100, 150, 200, 300, 400, or 500 mg BID.
  • In some instances, dosage levels below the lower limit of the aforesaid ranges may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect—e.g., by dividing such larger doses into several small doses for administration throughout the day. Of course, as those skilled in the art will appreciate, the dosage actually administered will depend upon the condition being treated, the age, health and weight of the recipient, the type of concurrent treatment, if any, and the frequency of treatment. Moreover, the effective dosage amount may be determined by one skilled in the art on the basis of routine empirical activity testing to measure the bioactivity of the compound(s) in a bioassay, and thus establish the appropriate dosage to be administered.
  • An effective amount of the combination of the active pharmaceutical ingredient may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • In some embodiments, the compositions described herein further include controlled-release, sustained release, or extended-release therapeutic dosage forms for administration of the compounds described herein, which involves incorporation of the compounds into a suitable delivery system in the formation of certain compositions. This dosage form controls release of the compound(s) in such a manner that an effective concentration of the compound(s) in the bloodstream may be maintained over an extended period of time, with the concentration in the blood remaining relatively constant, to improve therapeutic results and/or minimize side effects.
  • Additionally, a controlled-release system would provide minimum peak to trough fluctuations in blood plasma levels of the compound.
  • The following examples describe the invention in further detail. These examples are provided for illustrative purposes only, and should in no way be considered as limiting the invention.
    • EXAMPLES Example 1: Compound Scaffolds Including the 1-Hydroxy-2-Naphthoate Scaffold
  • Described herein are potent inhibitors of Mcl-1 based on a novel 1-hydroxy-2-naphthoate scaffold. This disclosure includes a 1-hydroxy-2-naphthoic acid core that would provide an alternative platform from which to inhibit Mcl-1, wherein the carboxylic acid was predicted to bind R263, and the distal phenyl ring the p3 pocket. Further engineering to gain access to the p2 pocket was driven by the hydroxyl group and the carboxylic acid whose ortho- and meta-directing effects, respectively, synergize to promote the regioselective 4-chlorosulfonylation of the scaffold, subsequent animation of this readily introduced functional group is expected to facilitate occupancy of the p2 pocket. The subject scaffold design is illustrated in Scheme 1-1, which permits access to Mcl-1 inhibitors in only two synthetic steps from commercially available starting materials.
  • Figure US20220396549A1-20221215-C00133
  • Scheme 1-1: Structure-based design of novel 1-hydroxy-4-sulfamoyl-2-naphthoates (3) as Mcl-1 inhibitors.
  • To facilitate ligand design, the Site Identification by Ligand Competitive Saturation (SILCS) method was used. SILCS FragMaps represent the 3D grid free energy distribution of different types of functional groups around the protein. The FragMaps include contributions from solute-protein interactions, solute desolvation and protein desolvation in the context of protein flexibility. In addition, to assure that all regions accessible to solute atoms can be occupied by the studied ligands, the protein surface is defined based on SILCS exclusion maps.
    • Results and Discussion
  • Molecular modeling and SILCS functional group affinity mapping (FragMaps) of the Mcl-1 binding site indicated that the carboxylic acid of designed molecule 3a (FIG. 1C) would occupy an energetically favorable region, associated with a salt bridge interaction with R263 of the Mcl-1 binding site, while the ring of the naphthyl core would bind in the p3 pocket demarcated by a favorable non-polar FragMap. The aniline was directed into the hydrophobic p2 pocket, which is also demarcated by a nonpolar FragMap. With the molecular modeling data in hand, compound 3a was then synthesized according to Scheme 1-2.
  • Briefly, commercially available 1-hydroxy-2-naphthoic acid (4) was regioselectively 4-chlorosulfonylated to yield 5, which was isolated by pouring over ice and used without further purification. Sulfonyl chloride 5 was next reacted with 4-bromoaniline to furnish the target molecule 3a in excellent overall yield (83%). Evaluation of 3a in a fluorescence polarization competition assay (FPCA) indicated that it disrupted the Mcl-1-Bak-BH3 PP1 with an IC50 of 10.9 μM, corresponding to a Ki of 2.76 μM. Given the ability of 3a to inhibit Mcl-1, a structure-activity relationship (SAR) study was developed, the results of which are presented in the tables below. The target molecules in Table 1-1 were all prepared according to the concise synthetic route depicted in Scheme 1-2, those in Table 1-2 were synthesized using anilines prepared as described in Scheme 1-3, whilst those in Table 1-3 were generated by following the synthetic route in Scheme 1-4.
  • Figure US20220396549A1-20221215-C00134
  • TABLE 1-1
    Experimental and computational Mcl-1 and Bcl-xL inhibitory profiles of first generation inhibitors.
    Mcl-1 Bcl-xL
    LGFE LGFE
    Mcl-1 Bcl-xL (kcal (kcal
    Comp. R1 R2 Ki (μM)a Ki (μM)b Selectivity mol−1) mol−1)
    3a 4-Br—C6H4 H 2.76 ± 1.26 51.4 ± 31.3 19 −39.46 −36.20
    3b H H 99.0 ± 11.2 NA −31.00
    3c Bn H 56.3 ± 2.1  NA −39.02
    3d CH2-(2-Cl—C6H4) H 50.3 ± 11.8 — — −37.09
    3e CH2-(3-Cl—C6H4) H 5.03 ± 2.78 — — −38.80
    3f CH2-(4-Cl—C6H4) H 21.0 ± 3.9  338 ± 203 16 −41.13 −38.60
    3g CH2-C6H11 H 7.31 ± 1.42 77.6 ± 14.3 11 −42.01 −40.99
    3h Me Me 25.7 ± 4.86 NA −35.73
    3i —CH2CH2CH2CH2CH2— 2.95 ± 0.43 — −42.58
    3j —CH2CH2N(Ph)CH2CH2— 4.54 ± 3.86 — −44.80
    3k —CH2CH2N(Bn)CH2CH2— 3.41 ± 0.37 — −34.40
    3l Ph H 106 ± 26  NA −37.18
    3m 2-Br—C6H4 H 6.84 ± 2.23 — −36.80
    3n 3-Br—C6H4 H 5.64 ± 1.76 — −38.98
    3o 2,4-di-Br—C6H3 H 0.420 ± 0.163 2.31 ± 1.35 5.5 −39.00 −37.67
    3p 1-Naphthyl H 11.2 ± 2.0  110 ± 45  10 −39.78 −38.34
    3q 2-Naphthyl H 4.58 ± 1.56 68.5 ± 36.3 15 −38.84 −37.24
    3r 2-Ph—C6H4 H 8.50 ± 1.34 — −42.88
    3s 3-Ph—C6H4 H 1.88 ± 0.62 −41.08
    3t 4-Ph—C6H4 H 1.54 ± 0.46 — −43.70
    3u 2-CF3—C6H4 H 4.05 ± 2.11 19.3 ± 9.0  4.8 −41.75 −40.68
    3v 4-Cl—C6H4 H 1.91 ± 0.26 — −39.51
    3w 4-CF3—C6H4 H 2.50 ± 0.65 — −43.43
    3x 4-Me—C6H4 H 34.3 ± 1.0  — −38.82
    3y 4-(iPr)—C6H4 H 3.86 ± 1.53 — −41.58
    3z 4-OMe—C6H4 H 11.9 ± 2.5  71.9 ± 21.0 6 −38.27 −36.46
    3aa 4-(OiPr)—C6H4 H 54.0 ± 4.6  NA −40.81
    3ab 4-CN—C6H4 H 22.2 ± 1.6  — −36.95
    3ac 4-NO2—C6H4 H 4.49 ± 1.20 23.3 ± 2.5  5.2 −39.27 −38.47
    3ad 3-CN—C6H4 H 26.9 ± 0.6  −36.40
    aKi values determined by Nikolovska-Coleska equation from IC50 values. Data represent the average of at least two independent assays; errors are standard deviations.
    bSelectivity is defined as the Ki (Bcl-xL) divided by the Ki (Mcl-1).
    NA, no activity.
  • Unsubstituted sulfonamide 3b was the weakest Mcl-1 inhibitor with a Ki of 99.0 μM, which was consistent with the less favorable LGFE score (Table 1-1). Replacement of the NH2 group with benzylic amines and anilines improved Mcl-1 inhibitory activity in every case, which is attributed to the occupancy of the apolar FragMaps with the apolar FragMap in the p2 pocket yielding more favourable LGFE scores. In addition, the FragMaps extend further towards the interior of the protein, suggesting that further hydrophobic extension of benzylic amines would improve activity. Indeed, chlorobenzylic amine derivatives 3d-3f were more potent than unsubstituted benzylic amine derivative 3c by up to 8-fold. Replacement of the benzyl group in 3c with a cyclohexylmethyl group (3g) also afforded an 8-fold improvement in inhibitory activity with a Ki of 7.31 μM. Piperidine derivative 3i achieved good inhibition (Ki=2.95 μM), as did the neutral and the basic piperazines 3j and 3k, respectively, indicating a positively-charged group here is not detrimental to binding. Substitution of the aniline ring in 3l with bromine atoms afforded between 10 to 54-fold improvement in activity, with the most profound effect observed with para-substituted derivative 3a (Ki=2.76 μM, cf. 83.8 μM for 3l). Introduction of an additional bromine atom into the ortho position of 3a to afford 2,4-dibromo derivative 3o led to an even more potent inhibitor with a Ki of 420 nM. Concomitantly, this change led to an erosion in selectivity of more than ten-fold for Mcl-1 over Bcl-xL. Naphthalene derivatives 3p and 3q were also more active than unsubstituted 3l. Functionalization of the aniline ring in 3l with additional phenyl rings to afford biphenyls 3r-3t resulted in improved inhibition in each case, again with para-substituted derivative 3u the most potent of the series (Ki=1.54 μM). For the remainder of the compounds in Table 1-1, substitution of the aniline ring in 3l with hydrophobic and polar groups resulted in enhanced activities in all instances with the greatest improvements observed with hydrophobic groups in the para position.
  • Motivated by the improved activity of extended hydrophobic substituents on the sulfonamide phenyl ring (e.g. 3o and 3s) along with the extended apolar FragMap in the p2 pocket (FIG. 1B), we chose to expand our library of para-substituted anilines by introduction of various aryloxy groups into the para position. Requisite anilines were synthesized according to Scheme 1-3, and then coupled to sulfonyl chloride 5 according to Scheme 1-2. As shown in Table 1-2, compounds 3ba-3bi afforded potent inhibition of Mcl-1 with the tightest binder delivering a Ki of 79 nM. This ˜1000-fold enhancement in inhibitory activity relative to unsubstituted aniline 31 is associated with the increased overlap of the nonpolar groups with the second apolar FragMaps in the p2 pocket, as quantified by the systematically more favourable LGFE scores (Table 1-2).
  • TABLE 1-2
    Experimental and computational Mcl-1 and Bcl-xL inhibitory profiles of
    second generation inhibitors.
    Figure US20220396549A1-20221215-C00135
    Mcl-1 Bcl-xL
    Mcl-1 Bcl-xL LGFE LGFE
    Comp. R2 R3 Ki (μM)a Ki (μM)a Selectivityb (kcal mol−1) (kcal mol−1)
    3ba iBu iPr 0.487 ± 6.08 ± 0.81 12 −38.81 −36.24
    3bb H Ph 1.15 ± 0.28 ND — −43.68
    3bc H 4-Me—C6H4 0.335 ± 0.84 ± 0.05 2.5 −43.58 −42.87
    3bd H 1-Naphthyl 0.082 ± 0.22 ± 0.06 3.7 −47.46 −48.26
    3be H 3-Br—C6H4 0.114 ± 0.30 ± 0.04 3.8 −44.65 −44.31
    3bf H 3,5-di-Me—C6H3 0.284 ± 0.39 ± 0.10 1.4 −46.21 −45.53
    3bg H 2,4-di-Cl—C6H3 0.079 ± 0.19 ± 0.02 2.4 −46.79 −46.47
    3bh H 4-Cl—C6H4 0.173 ± ND — −45.94
    3bi H 4-Cl-3,5-di-Me—C6H2 0.117 ± 0.060 0.48 ± 0.05 4.1 −47.29 −46.68
    3bj iBu 4-Cl-3,5-di-Me—C6H2 0.080 ± 0.019 0.17 ± 0.06 2.1 −48.23 −47.38
    3bk Cp 4-Cl-3,5-di-Me—C6H2 0.033 ± 0.025 0.29 ± 0.05 8.8 −40.05 −38.93
    3bl Bn 4-Cl-3,5-di-Me—C6H2 0.031 ± 0.017 0.34 ± 0.13 11 −51.93 −50.94
    aKi values determined by Nikolovska-Coleska equation from IC50 values. Data represent the average of at least two
    independent assays; errors are standard deviations.
    bSelectivity is defined as the Ki (Bcl-xL) divided by the Ki (Mcl-1).
    ND. not determined.
  • Simultaneously, these modifications also greatly increased affinity of the compounds to Bcl-xL. The sulfonamide NH group in 3bi offers an additional position from which further inhibitory activity might be acquired. Indeed, alkylation of this nitrogen atom with cyclopentyl (3bk) and benzyl (3bl) resulted in our most potent inhibitors yet with Kis of 33 nM and 31 nM, respectively. These alkylations also led to a recovery of selectivity for Mcl-1 over Bcl-xL of up to eleven-fold.
  • Figure US20220396549A1-20221215-C00136
  • Finally, the importance of the carboxylic acid and hydroxyl groups of the inhibitor scaffold was ascertained. Towards this goal, the compounds shown in Scheme 1-4 were synthesized. As seen in Table 1-3, the carboxylic acid is important to activity, which is consistent with its likelihood of binding R263. Methylation of the hydroxyl group to deliver compound 3cd resulted in around a 40-fold reduction in activity indicating its importance, too.
  • TABLE 1-3
    Investigation into the significance of the inhibitor’s carboxylic acid and
    hydroxyl group towards the inhibition of Mcl-1.
    Figure US20220396549A1-20221215-C00137
    Mcl-1 Mcl-1 LGFE
    Comp. X Y Ki (μM)a (kcal mol−1)
    3ca CO2H OH 0.566 ± −42.19
    3cb CO2Me OH >500 −34.23
    3cc CO2Me OMe >500 −35.45
    3ed CO2H OMe 23.4 ± 2.6  −42.41
    aKi values determined by Nikolovska-Coleska equation from IC50 values. Data represent the average of at least two independent assays; errors are standard deviations.
  • Although SILCS predicted the methoxy derivative 3cd (LGFE=−42.41 kcal/mol) to bind with slightly greater affinity than its hydroxy counterpart 3ca (LGFE=−42.19 kcal/mol), the observed disparity may be explained by an anticipated greater acidity for the latter through a six-membered intramolecular hydrogen bond between the hydroxyl and the carboxylate that affords a stronger salt bridge with R263.
  • Figure US20220396549A1-20221215-C00138
  • NMR HSQC experiments using 15N-labeled Mcl-1 (recombinant human Mcl-1 residues 172 to 327) confirmed the direct interaction of this class of compounds with the protein. Specifically, the HSQC of compound 3ba (FIG. 2 ) shows perturbation of the chemical shifts of Mcl-1 backbone 1H-15N correlations consistent with the predicted binding mode of 3a shown in FIG. 1 . Under the NMR experimental conditions the amino acid residues interacting with the compound are undergoing intermediate chemical exchange so their 1H-15N correlation peaks are broadened or lost. Intermediate exchange was expected based on the binding affinity determined for 3ba, Ki of 0.487 μM. Mapping the residues completely lost due to chemical exchange broadening on the 3D structure of Mcl-1 (FIG. 3 ) supports the model shown in FIG. 1 . The majority of the changes occur in residues near the compound including R263 and N260, residues in the p2 pocket (V249, M250, and F270), and in the p3 pocket (A227 and M231).
  • Comprehensive SILCS SAR analysis of Mcl-1 binding: Additional SILCS based modeling was undertaken to predict the bound orientation of the active ligands, to better understand the contributions of the different regions of the ligands to binding to Mcl-1 as well as to differential binding of the compounds to Mcl-1 versus Bcl-xL. This information would be of utility in designing ligands with improved potency and selectivity for Mcl-1 Thus, subsequent modeling involved docking of each studied compound using the SILCS-Pharm approach as described in FIG. 6 . The docked orientation of each compound was then subjected to SILCS MC sampling to allow the molecules to sample to local region as defined by the FragMaps and the exclusion maps from which the LGFE scores were calculated. Comparison of the LGFE values for all the tested compounds with the experimental affinities converted to free energies (ΔG=−RTlnKi, where R is the Boltzmann constant and T is the temperature) for Mcl-1 yields a correlation of R2=0.53 and a high predictive index of 0.70, (FIG. 7 ). Thus, the LGFE scores correlate with the Mcl-1 experimental data, indicating the quality of the bound orientations from the SILCS-Pharm-SILCS-MC protocol.
  • Given the predictive capabilities of the LGFE scores, further analysis was undertaken to use the SILCS modeling to further interpret the experimental SAR data. This analysis focused on four compounds: 3b, 3a, 3bi and 3bl. These compounds differ in the number of phenyl rings attached to the sulfonamide moiety going from 0 to 3 rings, in that order, with the binding affinities varying from 99 μM down to 31 nM. For these compounds a correlation of R2=0.99 between the LGFE and experimental G values is obtained.
  • The predicted conformation of 3a, 3b, 3bi, and 3bl was analyzed inside the Mcl-1 binding site. For all four compounds, the carboxylic acid overlaps with the negative FragMap, associated with its interaction with R263 of Mcl-1 and the aromatic rings suitably overlap with hydrophobic FragMaps, binding within the hydrophobic groove. For 3b, the sulfonamide group is placed outside of the hydrophobic binding pocket corresponding to an H-bond donor FragMap indicating its possible H-bonding interaction with residue H224. The hydroxyl group on the naphthalene ring overlaps with an H-bond acceptor FragMap, possibly making an H-bond to residue T266. For the other three compounds, the naphthalene group flipped over relative to 3b, maintaining the position of the carboxylic acid while allowing the additional aromatic groups to interact with the hydrophobic binding pocket. Notably the sulfonamide oxygen atoms in this orientation overlap with an acceptor FragMap associated with interactions with residue T266.
  • Additional analysis of the contribution of individual atoms and functional groups on the compounds to binding was performed by analyzing the atom-based GFE contributions of the individual atoms to the overall LGFEs. Presented in FIG. 4 are the GFE contributions for the most favorable binding conformations of the four compounds. For all compounds, the naphthyl and acid moieties make favorable contributions to binding. With 3b, significant favourable contributions occur with both the sulfonamide and hydroxyl moieties. In the remaining three compounds with the naphthyl moiety flipped, the sulfonamide and hydroxyl moieties make favourable contributions to binding though the magnitude is generally less than that of 3b. For example, while some of the sulfonamide oxygens make more favourable contributions with the larger compounds, the amide NH makes a very unfavourable contribution. However, the less favourable interactions of the hydroxyl and sulfonamide moieties are overcome by favorable contributions from the additional aromatic groups, which lead to the improved binding of the larger inhibitors. Interestingly, the quite favourable contributions from the second phenyl ring coming off the sulfonamide at the R2 position was counter-balanced by decreased contributions from the aromatics group at the R1 position upon going from 3bi to 3bl. This is consistent with the experimental free energy of binding changing by only −0.8 kcal/mol versus 3bi while differences going from 3b to 3a and 3a to 3bi are −2.1 and −1.9 kcal/mol, respectively. This atomic detailed interpretation of the experimental SAR data is anticipated to facilitate further improvements in the compounds.
  • SILCS Captures the Binding Specificity of Compounds for Mcl-1 Over Bcl-xL
  • A long-standing challenge in targeting the anti-apoptotic Bcl-2 proteins is achieving family member specificity, particularly Mcl-1 specificity, although selective ligands are beginning to emerge.
  • Compound posing was performed using the SILCS Pharm approach. The SILCS Pharm method allows for well-defined pharmacophore features to be identified based on the SILCS FragMaps and used to direct ligand placement. As shown in FIG. 6 a total of seven pharmacophore features were located in the binding pocket. Three out of seven features (F1, F2 and F5) have good overlap with the corresponding functional groups in the crystal structure of Fesik60 bound to Mcl-1 (PDB: 4HW4). Notably, hydrophobic pharmacophore feature F5 was derived from the FragMap region, such that without the inclusion of protein flexibility in SILCS such an important feature for this series of compounds would likely not be captured. Based on the seven pharmacophore features, five pharmacophore models were developed. All five included two important features that overlap with Fesik60 (F1 and F2), one feature from the remaining five features (F3-F6) as another important feature, with the remaining features being marked as supplementary features. Docking of 250 conformations of the tested compounds in a partial matching mode was then performed against the pharmacophore models. In the partial matching mode all important features must to be matched by each ligand and supplementary features may be matched. In this matching mode, compounds that cannot match the important features are rejected. The best conformation based on RMS difference for each model was then subjected to the SILCS-MC approach, with the compound conformation with the most favorable LGFE selected for additional analysis.
  • To investigate the binding specificity of compounds for Mcl-1 versus Bcl-xL, SILCS simulations and GFE FragMap generation followed by LGFE scoring were also done for BCl-xL (Table 1-5).
  • TABLE 1-5
    Experimental binding data ΔG and LGFE (kcal/mol) scores for all tested
    compounds for Mcl-1 and Bcl-xL.
    Figure US20220396549A1-20221215-C00139
    Mcl-1 Exp Mcl-1 Bcl-xL Bcl-xL
    Name R1 R2 Δ G GFE Exp Δ G LGFE
    1; 3a 4-Br—C6H4 H −7.58 −39.46 −5.85 −36.20
    3b; SF-5-294 H H −5.46 −31.00
    3c; SF-5-311 Bn H −5.79 −39.02
    3d; 5JC73-2 CH2—(2-Cl—C6H5) H −5.86 −37.09
    3e; 5JC71 CH2—(3-Cl—C6H5) H −7.22 −38.80
    3f; SF-5-264 CH2—(4-Cl—C6H5) H −6.38 −41.13 −4.73 −38.60
    3g; MEL-3-006 CH2—C6H11 H −7.00 −42.01 −5.60 −40.99
    3h; SF-5-295 Me Me −6.26 −35.73
    3i; SF-5-263 —CH2CH2CH2CH2CH2— −7.54 −42.58
    3j; EW-2-051 —CH2CH2N(Ph)CH2CH2— −7.29 −44.80
    3k; SF-5-307 —CH2CH2N(Bn)CH2CH2— −7.45 −34.40
    3l; SF-5-311 Ph H −5.42 −37.18
    3m; TA-1-019 2-Br—C6H5 H −7.04 −36.80
    3n; TA-1-020 3-Br—C6H5 H −7.16 −38.98
    3o; SF-5-290 2,4-di-Br—C6H4 H −8.69 −39.00 −7.68 −37.67
    3p; EW-2-056 1-Naphthyl H −6.75 −39.78 −5.40 −38.34
    3q; EW-2-057 2-Naphthyl H −7.28 −38.84 −5.68 −37.24
    3r; LC-4-002 2-Ph—C6H4 H −6.91 −42.88
    3s; LC-3-192 3-Ph—C6H4 H −7.81 −41.08
    3t; LC-3-192 4-Ph—C6H4 H −7.93 −43.70
    3u; TA-1-017 2-CF3—C6H4 H −7.35 −41.75 −6.43 −40.68
    3v; 5JC67 4-Cl—C6H4 H −7.80 −39.51
    3w; 5JC73-1 4-CF3—C6H4 H −7.64 −43.43
    3x; 5JC74-1 4-Me—C6H4 H −6.09 −38.82
    3y; 5JC74-2 4-(iPr)—C6H4 H −7.38 −41.58
    3z; MEL-3-018 4-OMe—C6H4 H −6.71 −38.27 −5.65 −36.46
    3aa; SF-5-293 4-(OiPr)—C6H4 H −5.82 −40.81
    3ab; TA-1-018 4-CN—C6H4 H −6.35 −36.95
    3ac; MEL-3-005 4-NO2—C6H4 H −7.29 −39.27 −6.31 −38.47
    3ad; 5JC75-2 3-CN—C6H4 H −6.23 −36.40
    Figure US20220396549A1-20221215-C00140
    Mcl-1 Exp Mcl-1 Bcl-xL Bcl-xL
    Compound R2 R3 Δ G GFE Exp Δ G LGFE
    3ba; MEL-2-116 iBu iPr −8.61 −38.81 −7.11 −36.24
    3bb; SF-5-299 H Ph −8.10 −43.68
    3bc; SF-5-301 H 4-Me—C6H4 −8.83 −43.58 −8.28 −42.87
    3bd; SF-5-300 H 1-Naphthyl −9.66 −47.46 −9.08 −48.26
    3be; SF-5-303 H 3-Br—C6H4 −9.47 −44.65 −8.89 −44.31
    3bf; SF-5-306 H 3,5-di-Me—C6H3 −8.93 −46.21 −8.74 −45.53
    3bg; SF-5-302 H 2,4-di-Cl—C6H3 −9.68 −46.79 −9.16 −46.47
    3bh; SF-5-304 H 4-Cl—C6H4 −9.22 −45.94
    3bi; JY-5-371 H 4-Cl-3,5-di-Me—C6H2 −9.45 −47.29 −8.61 −46.68
    3bj; JY-5-377 iBu 4-Cl-3,5-di-Me—C6H2 −9.68 −48.23 −9.23 −47.38
    3bk; JY-5-379 Cp 4-Cl-3,5-di-Me—C6H2  −10.20 −40.05 −8.91 −38.93
    3bl; JY-5-380 Bn 4-Cl-3,5-di-Me—C6H2  −10.24 −51.93 −8.82 −50.94
    Figure US20220396549A1-20221215-C00141
    Mcl-1 Exp Mcl-1
    Compound X Y Δ G GFE
    3ca CO2H OH −8.52 −42.19
    3cb CO2Me OH >−4.50  −34.23
    3cc CO2Me OMe >−4.50  −35.45
    3cd CO2H OMe −6.31 −42.41
  • A correlation of R2=0.58 and a high predictive index of 0.76 was found between the LGFE and experimental binding data for Bcl-xL (FIG. 8 ). Difference FragMaps, ΔFragMaps, were then calculated as GFEBcl-xl-GFE Mcl-1 such that positive ΔFragMaps favour Mcl-1 over Bcl-xL. The ΔFragMaps may then be used to qualitatively understand the contributions driving specificity as well as quantitatively obtain difference LGFE scores (ΔLGFE). Correlation analysis between the ΔLGFE scores and the experimental differences in the binding affinities for Mcl-1 and Bcl-xL yielded an R2=0.57 and predictive index of 0.83 (FIG. 9 ), indicating the quality of the SILCS ΔFragMaps in modeling the relative affinities for Mcl-1 versus Bcl-xL. Additional analysis was therefore undertaken on 3a as this compound showed the largest specificity for Mcl-1 over Bcl-xL. FIG. 5 (inset A) shows the ΔFragMaps between Mcl-1 and Bcl-xL, and includes the docked orientation of 3a with the atom contributions to the ΔLGFE between Mcl-1 and Bcl-xL mapped onto this orientation. The p-bromophenyl group that binds deeply in the p2 pocket between helices α4 and α5 is in a Mcl-1 positive ΔFragMap indicating that region to favour binding to Mcl-1. Similarly, the sulfonamide oxygen contributes to the binding of 3a to Mcl-1 over Bcl-xL. Alternatively, the NH moiety of the sulfonamide contributes to more favourable binding to Bcl-xL over Mcl-1. The acid moiety in the lower right of the figure is also predicted to favour binding to Bcl-xL over Mcl-1. Summing over the different ΔFragMap classes showed the overall ΔLGFE score of 3.0 kcal/mol favouring binding to Mel-1 to have favourable contributions from the hydrophobic and neutral acceptor terms, 4.4 and 1.6 kcal/mol, respectively, while the neutral donor, negatively charged acceptor and hydroxyl groups favour BCl-xL binding, with values of −1.8, −0.7 and −0.5 kcal/mol, respectively. Similar trends are observed for the other compounds for which a selectivity of Mcl-1 over BCl-xL was found, as shown in Table 1-6.
  • TABLE 1-6
    FragMap type contributions to the ΔLGFE scores between Mcl-1 and Bcl- xL using the
    most favorable binding conformations, where positive values favor binding to Mcl-1.
    Exp. No. of
    ΔG heavy Hydroxyl Neutral Neutral Charged
    Comp. diff. atoms ΔLGFE Hydrophobic group Acceptor Donor Acceptor
    1; 3a 1.73 25 3.01 4.37 −0.53 1.58 −1.75 −0.66
    3f; SF-5-264 1.65 26 2.39 0.95 −0.17 −0.44 −2.29 4.34
    3g; MEL-3-006 1.40 25 1.56 3.03 0.80 0.54 −3.71 0.90
    3o; SF-5-290 1.01 26 2.00 5.35 −0.98 0.35 −4.09 1.37
    3p; EW-2-056 1.35 28 2.77 2.30 −0.89 −0.36 0.01 1.72
    3q; EW-2-057 1.60 28 1.85 4.50 0.82 0.11 −4.46 0.89
    3u; TA-1-017 0.92 28 1.79 −0.56 0.70 2.41 −1.73 0.96
    3z; MEL-3-018 1.06 26 2.27 0.72 −0.25 1.81 −1.39 1.38
    3ac; MEL-3-005 0.98 27 0.88 2.94 −0.55 −0.09 −1.40 −0.02
    3ba; MEL-2-116 1.50 32 3.11 0.49 −0.14 0.43 0.00 2.33
    3bc; SF-5-301 0.55 32 0.70 0.32 0.93 −0.42 −0.37 0.24
    3bd; SF-5-300 0.58 35 −0.58 −0.96 −0.15 −0.23 0.04 0.72
    3bc; SF-5-303 0.58 32 0.43 0.44 −0.20 0.50 −0.18 −0.14
    3bf; SF-5-306 0.19 33 0.42 −0.20 −0.20 0.50 −0.27 0.58
    3bg; SF-5-302 0.52 33 0.77 1.37 −0.21 0.20 −0.27 −0.32
    3bi; JY-5-371 0.84 34 1.21 5.59 −0.43 −0.18 −1.01 −2.75
    3bj; JY-5-377 0.45 38 0.64 3.32 0.27 −0.58 0.00 −2.36
    3bk; JY-5-379 1.29 39 2.16 1.70 0.10 −2.31 0.00 2.67
    3bl; JY-5-380 1.42 41 1.34 1.17 0.00 −0.85 0.00 1.02
  • Indeed, given that all the tested compounds favoured Mcl-1 binding over Bcl-xL, these results indicate that the exploitation of the binding pocket inherently favours Mcl-1 binding, as previously discussed by Fesik. Without being limited to any one theory of the invention, the docked orientation of 3a in the two proteins indicates that this pocket is not being exploited with Bcl-xL. This is consistent with the fact that Mcl-1 shows more opening at the p2 pocket as compared to Bcl-xL as illustrated in FIG. 5 (inset B), disallowing access of 3a deep into the hydrophobic pocket in the p2 site of Bcl-xL.
  • However, further extension of the ligands (e.g. 3bl) leads to improved binding affinity, but not improved specificity. This may be explained by different predicted binding orientations of the compound to the two proteins. As seen in FIG. 5 (inset C), 3bl binds with its additional 4-chloro-3,5-dimethylphenyl R3 group deep in the p2 pocket, and with the R benzyl group occupying the upper region of the p2 pocket. In contrast, the orientation of 3bl bound to Bcl-xL shows the 4-chloro-3,5-dimethylphenyl to still interact with the p2 site, though not as deep as that occurring with Mcl-1. This leads to a shift in the location of the naphthyl ring as well as the R2 phenyl group into the p3 site where they can exploit the hydrophobic character of that sub-pocket as well as interactions with R263, as indicated by the apolar and neg FragMaps in FIG. 5 (inset D), respectively. Thus, the significant increase in the size of 3bl leads to increased affinity with respect to both Mcl-1 and Bcl-xL with that larger size predicted to change the binding orientation with Bcl-xL such that increased specificity for Mcl-1 is not gained over 3a
    • Conclusions
  • Described herein is a class of Mcl-1 inhibitors that target R263 and the p2 and p3 pockets within the hydrophobic BH3-binding crevice on the surface of the protein. SILCS analysis of this region of the BH3 binding site supported this strategy, with the use of the SILCS exclusion maps indicated significant additional opening of the p2 pocket that could be exploited in ligand design. Accordingly, a series of compounds were synthesized and subjected to experimental evaluation using a FP assay with binding of 3ba to targeted pocket of Mcl-1 verified using NMR. From this strategy, 3bl was identified with a Ki=31 nM for Mcl-1 with a specificity of 11-fold over Bcl-xL.
  • The two-step synthesis then allowed the rapid synthesis and testing of over 40 analogs. This yielded compounds with affinities spanning over a 10,000 fold range. Detailed SILCS analysis of all of these compounds identified the moieties leading to improved affinity. These results suggest that fine tuning of interactions with the p2 pocket via appropriate modifications of the R3 ring (Table 1-2) as well as of the R1 ring will likely lead to improved affinity. Additional SILCS analysis on the differential binding of selected compounds to Mcl-1 versus Bcl-xL indicates that fine tuning of the R3 ring occupying the p2 pocket may also improve specificity. Further modifications that may contribute to improved specificity include alkylation of the NH moiety of the sulfonamide moiety and additions of both hydrogen bond acceptor (e.g. OMe) or hydrophobic (e.g. Cl) functional groups to the naphthyl ring as indicated by the differential Fragmaps in the top, central region of FIG. 7A.
  • Experimental
  • Computational
  • Molecular modeling studies were initiated with the crystal structure of the Mcl-1-BH3 peptide complex (PDB ID: 4HW4), following removal of the 16mer BH3 peptide, and with the Bcl-xL-Bak complex structure (PDB ID: 1BXL), following removal of the Bak peptide. For both proteins, the Reduce software was used to choose optimal Asn, Gin, and His side-chain orientations and determine the optimal protonation states of His residues. The protein was immersed in a box of an aqueous solution containing eight small probe molecules at approximately 0.25 M each with water at ˜55 M. The size of the simulation box was chosen so as to have the protein extrema separated from the edges by a minimum of 8 Å based on non-hydrogen atoms. The small molecules, or solutes, include benzene, propane, methanol, formamide, acetaldehyde, methylammonium and acetate, as previously used, along with imidazole. Ten such protein-small molecule aqueous systems were generated for each protein with each simulation system differing in the initial positions and orientations of the small molecules and water. The SILCS molecular dynamics (MD) simulations were performed using the GROMACS simulation program with the CHARMM36 force field, CHARMM general force field (CGenFF) and TIP3P water model to describe the protein, small molecules and water, respectively. The simulations were each extended for 40 ns, yielding a total of 400 ns of simulation time for each protein. Additional MD simulation details can be found in Reference.
  • From the simulation, 3D probability distributions of selected atoms from the small molecules were constructed to form the FragMaps, yielding a total of ten different FragMaps. The final FragMaps are converted to free energies, termed grid free energies (GFE), by normalizing the distributions with respect to the distributions of the solutes in an aqueous solution in the absence of the proteins followed by Boltzmann transformation to yield the GFE values. As the GFE FragMaps are normalized with respect to the fragment probabilities in solution, they contain both favorable regions as well as unfavorable regions. The unfavorable regions typically range from 0 to 3 kcal/mol, with the upper limit based on sampling issues. In addition to the FragMaps, exclusion maps were constructed by calculating the 3D probability distributions of all non-hydrogen atoms of the water and solutes together and identifying those voxels with zero occupancies, which defines the exclusion maps. This exclusion map represents regions forbidden to the small molecules and water and may be considered an alternate to more traditional representations of the protein surface. For quantitative analysis, these voxels were assigned a very high energetic penalty (1000 kcal/mol) while the remaining voxels were assigned energies associated with the specific FragMaps. The availability of the GFE FragMaps and the exclusion maps allows for quantitative estimates of binding affinities to be made referred to as ligand grid free energies (LGFE). These are a simple summation of the GFE energy contribution of all the atoms in each ligand that are classified with respect to the FragMap types followed by normalization of the summed energies by the number of classified ligands atoms and subsequent multiplication by the total number of non-hydrogen atoms, yielding the final LGFE values. Note that the LGFE scores are not directly equivalent to experimental free energies due to the additive approximation of the LGFE scores (i.e. the individual atom-based GFEs are summed to yield the LGFE), the lack of accounting for the energy cost of connecting the fragments that comprise the full compounds and issues associated with the standard state in the experimental and computational conditions.
  • In the present study the specific FragMaps were used for calculation of GFE and LGFE scores, while generic FragMaps are used for visualization. The specific and generic FragMap types that were used include: (1) aromatic, AROM (benzene carbons), (2) aliphatic, ALIP (propane carbons); (3) dual role hydrogen bond atom, MEOO (methanol oxygens); (4) FORN, (formamide nitrogen); (5) FORO, (formamide oxygen); (6) IMIN, (imidazole acceptor nitrogen); (7) IMLH, (imidazole donor nitrogen); (8) AALO, (acetaldehyde oxygen); (9) positive donor, POS (methylammonium nitrogen); (10) negative acceptor, NEG (acetate oxygens); (11) generic nonpolar, APOLAR (benzene and propane carbons); (12) generic neutral hydrogen-bond donor, FIB DON (formamide and imidazole donor nitrogen); and (13) generic neutral hydrogen-hydrogen acceptor, HBACC (formamide, acetaldehyde oxygens and imidazole acceptor nitrogen). The convergence of the FragMaps was examined by calculating the overlap coefficient between two sections of the simulations (trajectories 1-5 and trajectories 6-10), as previously described. All the generic FragMaps show an overlap coefficient of greater than 0.6, indicating satisfactory convergence.
  • To identify the binding modes of the tested compounds with Mcl-1, the SILCS-Pharm protocol was used in which the FragMaps are used to define the pharmacophore features. The selected pharmacophore was used to direct docking of the studied compounds in the Mcl-1 binding pocket. Generation of 250 conformations of each compound and pharmacophore docking were conducted using MOE. For each compound, the best conformation, based on the smallest RMSD with the pharmacophore was retained for SILCS ligand grid tree energy (LGFE) scoring. The compounds were locally relaxed and minimized using FragMap-based Monte Cairo (MC) sampling (SILCS-MC) from which the LGFE scores were obtained. The SILCS-MC was conducted for 50000 steps under slow cooling mode and was repeated 20 times for each conformation with different random seeds to get a Boltzmann averaged LGFE value, along with the corresponding standard deviation. The lowest energy LGFE conformation for each compound was chosen for visual presentation and analysis. The SILCS-MC was also performed in the same way using FragMaps of BCl-xL to calculate BCl-xL related LGFEs for the compounds that have available Bcl-xL experimental data. Bcl-xL SILCS-MC calculations were initiated from the Mcl-1 SILCS-PHARM orientations in the context of the Bcl-xL FragMaps and exclusion maps.
  • Chemistry
  • General. Unless otherwise stated, all reactions were performed under an inert atmosphere (N2). Reagents and solvents were ACS grade, and purchased from Sigma-Aldrich, Alfa Aesar, Oakwood and TCI America. Anhydrous solvents were used as provided without further purification. Reactions were monitored by thin-layer chromatography (TLC), visualizing with a UV lamp and/or KMnO4 stain. Flash column chromatography was performed with silica gel 60 Å (70-230 mesh, Merck). 1H and 13C NMR spectra were recorded on a Varian INOVA 400 MHz NMR spectrometer at 25° C. Chemical shifts are reported in parts per million (ppm). Data for 1H NMR are reported as follows: chemical shift (6 ppm) (multiplicity, coupling constant (Hz), integration), where multiplicities are: s=singlet, d=doublet, t=triplet, sep=septet, m=multiplet. The residual solvent peak was used as an internal reference: CDCl3 (δH 7.26; δC 77.21) and d6-DMSO (δH 2.50; δC 39.51). Mass spectra were obtained on an Electrospray TOF (ESI-TOF) mass spectrometer (Bruker AmaZon X). All final molecules were deemed to be >95% pure by reversed-phased HPLC using a Waters 1525 analytical/preparative HPLC fitted with a C18 reversed-phase column (Atlantis T3: 4.6 mm×150 mm) according to the following conditions with solvents (A) H2O/0.1% TFA, (B) CH3CN—H2O, 9:1 with 0.1% TFA at 1 ml min-1: (I) a gradient of 100% A to 100% B over 22 min; (II) a gradient of 50% A to 100% B over 22 mm; (III) a gradient of 25% A to 100% B over 22 min; (IV) an isocratic gradient of 100% B over 22 min. Data are presented as retention time (tR (min)), purity (%), condition (I or II).
  • 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5). 1-Hydroxy-2-naphthoic acid (4; 5 g, 26.6 mmol) was added portionwise with stirring over the course of 1 h to chlorosulfonic acid (25 mL) at −10° C. Once the addition was complete, TLC of the reaction mixture confirmed all starting material had been consumed (acetone/EtOAc, 1:1). The reaction mixture was carefully poured over ice. The resulting pinkish-grey solid was collected by vacuum filtration, washing several times with ice-cold water. After the product was allowed to dry on the filter tor 1 h, it was transferred to a vacuum oven where it was dried further at 50° C. for 16 h.
  • General Procedure A: Animation with Anilines. 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5; 1 eq) was suspended in anhydrous acetone (0.2 M), and then the requisite aniline (1.2 eq) and pyridine (3 eq) were added under an inert (N2) atmosphere. The reaction mixture was stirred at 50° C. for 3 h, by which time TLC (acetone/EtOAc, 1:1) indicated that the reaction was complete. The reaction was concentrated to dryness and then suspended in a 1.1 mixture of EtOAc and 1 M and was vigorously stirred for 5 min. The mixture was transferred to a separatory funnel, then partitioned between EtOAc and 1 M HCl. The organic layer was washed three times with 1 M HCl, dried over Na2SO4, filtered, concentrated to deliver a residue that was purified by column chromatography over silica gel using an eluent of CH2Cl2/MeOH/AcOH 92:7:1 to provide the title compound.
  • General Procedure B: Animation with Primary Aliphatic Amines. 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5; 1 eq) was suspended in anhydrous acetone (0.2 M). The requisite benzylic amine (1.2 eq) and DIPEA (2.5 eq) were added under an inert (N2) atmosphere at room temperature (RT). The reaction was stirred at RT for 16 h. 1 LC (acetone/EtOAc, 1:1) indicated that reaction was complete. The reaction was concentrated to dryness and then suspended in a 1:1 mixture of EtOAc and 1 M and was vigorously stirred for 5 min. The mixture was transferred to a separatory funnel, then partitioned between EtOAc and 1 M HCl. The organic layer was washed three times with 1 M HCl, dried over Na2SO4, filtered, concentrated to deliver a residue that was purified by column chromatography over silica gel using an eluent of CH2Cl2/MeOH/AcOH 92:7:1 to provide the title compound.
  • General Procedure C: Animation with Secondary Aliphatic Amines. 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5; 1 eq) was suspended in anhydrous acetone (0.2 M), and then the requisite secondary amine (3 eq) was added under an inert (N2) atmosphere at room temperature. After 1 h, TLC (acetone/EtOAc, 1:1) indicated that the reaction was complete. The reaction was concentrated to dryness and then suspended in a 1:1 mixture of EtOAc and 1 M and was vigorously stirred for 5 min. The mixture was transferred to a separatory funnel, then partitioned between EtOAc and 1 M HCl. The organic layer was washed three times with 1 M HCl, dried over Na2SO4, filtered, concentrated to deliver a residue that was purified by column chromatography over silica gel using an eluent of CH2Cl2/MeOH/AcOH 92:7:1 to provide the title compound.
  • General Procedure D: Nucleophilic aromatic substitution (SNAr). 4-Fluoronitrobenzene (1 eq) and the requisite phenol (1 eq) were dissolved in anhydrous DMSO (0.3 M). K2CO3 (2 eq) was added, and then the reaction was stirred at 120° C. for 16 h. The next day, TLC (Hex/EtOAc, 9:1) indicated the reaction was complete. The reaction was quenched with water and ice, which resulted in precipitation. The precipitate was collected by vacuum filtration and then dried overnight in a vacuum oven at 50° C. to furnish compounds 7 that were sufficiently pure to be advanced to the next step.
  • General Procedure E: Reduction of Nitro Group with SnCl2.2H2O. The appropriate nitroarene 7 was dissolved in EtOAc (0.1 M), and then SnCl2.2H2O (5 eq) was added. The reaction mixture was stirred tor 50° C. for 16 h, by which time TLC confirmed reaction completion. The reaction mixture was partitioned between EtOAc and sat, NaHCO3. The organic layer was collected and the aqueous layer was extracted two times with EtOAc. The organics were combined, washed with sat. NaHCO3, brine, dried with Na2SO4, filtered and concentrated. No further purification was required.
  • General Procedure F: Reductive Amination. The aniline (1 eq) was dissolved in 1,2-dichloroethane (0.1 M) and the required aldehyde (1 eq) was added, followed by NaBH(OAc)3 (2 eq). The reaction mixture stirred for 16 h at room temperature. TLC (Hex/EtOAc, 1:1) indicated that the reaction was complete. The reaction mixture was diluted with CH2Cl2 and then partitioned with sat. NaHCO3. The aqueous layer was extracted with further CH2Cl2 (×2), and then the organic layers were combined, washed with brine, dried (Na2SO4) filtered and concentrated. The crude material was purified by flash column chromatography over silica gel using an eluent of Hex/EtOAc, 1:1 to provide the title compound.
  • 4-(N-(4-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3a). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-bromoaniline according to General Procedure A on a 1 mmol scale to yield the title compound as an off-white solid (300 mg, 71%): δH (400 MHz, d6-DMSO) 10.47 (s, 1H, SO2NH), 8.48-8.45 (m, 2H, Ar), 8.32 (d, 1H, Ar, J=8.0 Hz), 7.67 (t, 1H, Ar, J=7.4 Hz), 7.49 (t, 1H, Ar, J=7.4 Hz), 7.31 (d, 2H, Ph, J=8.4 Hz), 6.93 (d, 2H, Ph, J=8.8 Hz); δC (100 MHz, d6-DMSO) 171.0, 138.0, 133.8, 132.2, 131.5, 130.0, 128.0, 125.4, 125.2, 124.5, 120.7, 117.5, 115.3, 107.3, 95.9; Calcd (M+): 421.0, Found: 420.0 ([M−H]−); tR=8.1 min (100%, III).
  • 1-Hydroxy-4-sulfamoyl-2-naphthoic acid (3b). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5; 287 mg, 1 eq) was suspended in dioxane (5 mL) at 0° C., then NH4OH (1 mL) was added dropwise. After 1 h, TLC confirmed the reaction was complete. The reaction mixture was concentrated to dryness, then partitioned between EtOAc (50 mL) and 1 M HCl (25 mL). The aqueous layer was extracted with further EtOAc (50 mL), then the organic layers were washed with brine, dried (Na2SO4), filtered and concentration to afford the title compound light orange solid (160 mg, 60%): δH (400 MHz, d6-DMSO) 8.43-8.40 (m, 2H, Ar), 8.34 (d, 1H, Ar, J=8.4 Hz), 7.60 (t, 1H, Ar, J=7.4 Hz), 7.46 (t, 1H, Ar, J=8.0 Hz), 7.13 (s, 2H, SO2NH2); δC (100 MHz, d6-DMSO) 171.3, 170.6, 131.5, 130.6, 128.9, 128.4, 125.3, 125.0, 124.6, 122.6, 107.9; Calcd (M+): 267.0, Found: 266.0 ([M−H]−).
  • 4-(N-Benzylsulfamoyl)-1-hydroxy-2-naphthoic acid (3c). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to benzylamine according to General Procedure B on a 1 mmol scale to yield the title compound as a dark yellow solid (232 mg, 65%); δH (400 MHz, d6-DMSO) 8.45 (d, J=8.0, 1 H, Ar), 8.43 (s, 1H, Ar), 8.36 (d, J=8.0, 1H, Ar), 7.95 (t, J=6.4, 1H, NH), 7.62 (t, J=8.0, 1H, Ar), 7.48 (t, J=8.0, 1H, Ar), 7.22-7.10 (m, 5H, Ar), 3.89 (d, J=6.4, 2H, CH2) δC (100 MHz, d6-DMSO) 171.2, 138.6, 132.9, 131.7, 129.3, 128.4, 127.8, 127.3, 125.1, 125.0, 124.8, 46.2; Calcd (M+): 357.1, Found: 356.0 ([M−H]−); =115 min (98.9%, II).
  • 4-(N-(2-Chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic add (3d). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 2-chlorobenzylamine according to General Procedure B on a 1 mmol scale to yield the title compound as a light purple solid (274 mg, 70%); δH (400 MHz, d6-DMSO) 8.45-8.33 (m, 2H, Ar), 8.35 (d, J=7.6, 1 H, Ar), 7.99 (t, J=6.0, 1H, NH), 7.61 (t, J=7.6, 1 H, Ar), 7.46 (t, J=7.6, 1 H, Ar), 7.40-7.37 (m, 1H, Ar), 7.32-7.29 (m, 1H, Ar) 7.22-7.17 (m, 2H, Ar), 3.98 (d, J=6.0, 2 H, CH2), δC (100 MHz, d6-DMSO) 171.0, 135.7, 133.1, 132.2, 131.7, 129.9, 129.3, 129.1, 128.6, 127.2, 125.1, 125.0, 124.7, 107.8, 43.6; Calcd (M+): 391.0, Found: 414.1 ([M+Na]−); tR=10.2 min (97.2%, II).
  • 4-(N-(3-Chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3e). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 3-chlorobenzylamine according to General Procedure B on a 1 mmol scale to yield the title compound as a dark purple solid (286 mg, 73%): δH (400 MHz, d6-DMSO) 8.43-8.39 (m, 2H, Ar), 8.35 (d, J=7.6, 1 H, Ar), 8.04 (t, J=6.4, 1 H, NH), 7.63 (t, J=7.6, 1 H, Ar), 7.47 (t, J=7.6, 1 H, Ar), 7.21-7.15 (m, 3H, Ar) 7.13-7.09 (m, 1H, Ar), 3.91 (d, J=6.4, 2 H, CHS); δC (100 MHz, d6-DMSO) 171.2, 141.2, 133.1, 132.8, 131.6, 130.1, 129.4, 128.3, 127.6, 127.1, 126.4, 125.1, 125.0, 124.9, 107.6, 45.5; Calcd (M+): 391.0, Found: 414.1 ([M+Na]−); tR=21.5 min (98.8%, I).
  • 4-(N-(4-Chlorobenzyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3f) 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-chlorobenzylamine according to General Procedure Bon a 1 mmol scale to yield the title compound as a light brown solid (294 mg, 75%); δH (400 MHz, d6-DMSO) 8.56 (d, 1H, Ar, J=8.4 Hz), 8.46 (t, 1H, SO2NH, J=5.8 Hz), 8.39 (d, 1H, Ar, J=8.8 Hz), 8.32 (s, 1H, Ar), 7.84 (t, 1H, Ar, J=7.6 Hz), 7.71 (t, 1H, Ar, J=7.4 Hz), 7.11, 7.06 (ABq, 4H, Ar, JAB=8.8 Hz), 3.97 (d, 1H, Ar, J=6.4 Hz); δC (100 MHz, CDCl3) 177.1, 169.4, 141.6, 136.7, 136.1, 136.0, 134.6, 134.4, 134.2, 132.3, 131.9, 130.6, 130.1, 129.1, 109.8, 50.3; Calcd (M+): 391.0, Found: 392.0 ([M+H]+); tR=12.8 min (100%, II).
  • 4-(N-(Cyclohexylmethyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3g). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to cyclohexylmethylamine according to General Procedure B on a 1 mmol scale to yield the title compound as a brown solid (218 mg, 60%): δH (400 MHz, d6-DMSO) 8.61 (d, 1H, Ar, J=8.8 Hz), 8.42-8.39 (m, 3H, Ar), 7.86-7.81 (m, 2H, Ar, SO2NH), 7.71 (m, 1H, Ar, J=7.4 Hz), 2.56 (t, 1H, CHCH 2, J=5.8 Hz), 1.55-1.45 (m, 5H, cyclohexyl), 1.30-1.18 (m, 1H, CHCH2), 1.05-0.90 (m, 3H, cyclohexyl), 0.62-0.74 (m, 2H, cyclohexyl); δC (100 MHz, d6-DMSO) 172.1, 164.1, 131.2, 130.8, 129.1, 126.8, 125.8, 125.2, 125.1, 124.0, 104.5, 48.6, 37.2, 30.1, 25.9, 25.3; Calcd (M+): 363.1, Found: 386.3 ([M+Na]+); tR=13.7 min (98.2%, II).
  • 4-(N,N-Dimethylsulfamoyl)-1-hydroxy-2-naphthoic acid (3h), 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to dimethylamine hydrochloride according to General Procedure B on a 1 mmol scale to yield the title compound as a dark purple solid (170 mg, 58%): δH (400 MHz, d6-DMSO) 8.58 (d, 1H, Ar, J=8.4 Hz), 8.43 (d, 1H, Ar, J=8.0 Hz), 8.40 (s, 1H, Ar), 7.86 (t, 1H, Ar, J=7.8 Hz), 7.71 (t, 1H, Ar, J=7.4 Hz), 2.70 (s, 6H, N(CH3)2); δC (100 MHz, d6-DMSO) 172.2, 165.3, 132.3, 131.5, 127.3, 127.2, 125.7, 125.5, 124.5, 121.7, 105.6, 37.4; Calcd (M+): 295.1, Found: 296.2 ([M+H]+); tR=20.5 min (98.3%, I).
  • 1-Hydroxy-4-(piperidin-1-ylsulfonyl)-2-naphthoic acid (3i). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to piperidine according to General Procedure C on a 0.8 mmol scale to yield the title compound as a light brown solid (265 mg, 79%): δH (400 MHz, d6-DMSO) 8.58 (d, 1H, Ar, J=8.4 Hz), 8.43 (d, 1H, Ar, J=8.8 Hz), 8.40 (s, 1H, Ar), 7.88 (t, 1H, Ar, J=7.8 Hz), 7.73 (t, 1H, Ar, J=7.6 Hz), 3.05-3.03 (m, 4H, CH2NCH2), 1.50-1.32 (m, 6H, piperidinyl); δC (100 MHz, d6-DMSO) 172.3, 164.7, 132.1, 131.5, 131.2, 127.4, 125.5, 125.4, 124.5, 122.9, 105.4, 46.2, 25.4, 23.3; Calcd (M+): 335.1, Found: 336.2 ([M+H]+); tR=16.5 min (95.1%, II).
  • 1-Hydroxy-4-((4-phenylpiperazin-1-yl)sulfonyl)-2-naphthoic add (3j). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 1-phenylpiperizine according to General Procedure C on a 0.8 mmol scale to yield the title compound as a brown-orange solid (264 mg, 64%): δH (400 MHz, d6-DMSO) 8.70 (d, 1H, Ar, J=8.8 Hz), 8.46-8.43 (m, 2H, Ar), 7.88 (t, 1H, Ar, J=8.0 Hz), 7.73 (t, 1H, Ar, J=7.4 Hz), 7.17 (t, 2H, Ph, J=7.8 Hz), 6.86 (d, 2H, Ph, J=8.0 Hz), 3.19-3.12 (m, 8H, piperazinyl); δC (100 MHz, d6-DMSO) 171.9, 165.0, 150.4, 131.8, 131.5, 131.3, 129.0, 127.0, 125.3, 125.1, 124.2, 121.3, 119.8, 116.2, 105.3, 48.3, 45.2; Calcd (M+): 412.1, Found: 413.3 ([M+H]+); tR=19.4 min (100%, II).
  • 4-((4-Benzylpiperazin-1-yl)sulfonyl)-1-hydroxy-2-naphthoic avid (3k). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to N-benzylpiperazine according to General Procedure C on a 1 mmol scale to yield the title compound as a light yellow solid (303 mg, 71%); δH (400 MHz, d6-DMSO) 8.41-8.37 (m, 3H, Ar), 7.62 (t, 1H, Ar, J=7.6 Hz), 7.47 (t, 1H, Ar, J=7.6 Hz), 7.43-7.36 (m, 5H, Ph), 4.22 (br s, 2H, CH 2Ph), 3.70-2.80 (m, 8H, piperazinyl); δC (100 MHz, d6-DMSO) 173.4, 170.4, 158.7, 135.3, 132.6, 131.3, 131.0, 129.9, 129.2, 129.1, 125.6, 125.5, 124.9, 124.8, 107.9; Calcd (M+): 426.1, Found: 427.2 ([M+H]+); tR=6.5 min (95.3%, II).
  • 1-Hydroxy-4-(N-phenylsulfamoyl)-2-naphthoic add (3l). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to aniline according to General Procedure A on a 1 mmol scale to yield the title compound as a cream solid (275 mg, 80%): δH (400 MHz, d6-DMSO) 10.58 (s, 1H, SO2NH), 8.66 (d, 1H, Ar, J=8.4 Hz), 8.47 (s, 1H, Ar), 8.38 (d, 1H, Ar, J=8.8 Hz), 7.87 (t, 1H, Ar, J=8.0 Hz), 7.71 (t, 1H, Ar, J=7.8 Hz), 7.15 (t, 2H, Ph, J=7.8 Hz), 6.99 (d, 2H, Ph, J=8.0 Hz), 6.92 (t, 1H, Ph, J=7.0 Hz); δC (100 MHz, d6-DMSO) 172.2, 164.9, 137.9, 131.6, 131.3, 130.9, 129.5, 127.4, 125.3, 125.0, 124.7, 124.6, 124.1, 119.7, 105.2; Calcd (M+): 343.1, Found: 344.1 ([M+H]+); tR=3.9 min (100%, II).
  • 4-(N-2-bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3m). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 2-bromoaniline according to General Procedure A on a 1 mmol scale to yield the title compound as a pink solid (287 mg, 68%): δH (400 MHz, d6-DMSO) 10.07 (s, 1H, SO2NH), 8.60 (d, 1H, Ar, J=8.4 Hz), 8.41 (d, 1H, Ar, J=8.4 Hz), 7.78 (t, 1H, Ar, J=7.4 Hz), 7.69 (t, 1H, Ar, J=7.4 Hz), 7.48 (d, 1H, Ar, J=7.6 Hz), 7.23 (t, 1H, Ar, J=7.4 Hz), 7.15 (d, 1H, Ar, J=8.0 Hz), 7.09 (t, 1H, Ar, J=7.4 Hz); δC (100 MHz, d6-DMSO) 172.2, 165.2, 135.4, 133.5, 131.7, 131.1, 130.2, 128.9, 128.8, 128.7, 128.6, 127.2, 125.8, 125.6, 124.4, 120.9, 105.3; Calcd (M+): Calcd (M+): 421.0, Found: 420.2 ([M−H]−); tR=12.0 min (98.6%, II).
  • 4-(N-(3-Bromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3n). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 3-bromoaniline according to General Procedure A on a 1 mmol scale to yield the title compound as a light pink solid (300 mg, 71%): δH (400 MHz, d6-DMSO) 11.86 (s, 1H, SO2NH), 8.61 (d, 1H, Ar, J=8.8 Hz), 8.51 (s, 1H, Ar), 8.38 (d, 1H, Ar, J=8.4 Hz), 7.87 (t, 1H, Ar, J=7.4 Hz), 7.69 (t, 1H, Ar, J=7.4 Hz), 7.18 (s, 1H, Ar), 7.14-7.00 (m, 3H, Ar); δC (100 MHz, d6-DMSO) 172.1, 165.5, 139.7, 131.6, 131.5, 131.4, 131.2, 127.4, 126.5, 125.6, 125.5, 124.7, 123.5, 122.2, 121.4, 117.8, 105.4; Gated (M+): 421.0, Found: 420.2 ([M−H]−); tR=12.3 min (98.5%, II).
  • 4-(N-(2,4-Dibromophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3o). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 2,4-dibromoaniline according to General Procedure A on a 1 mmol scale to yield the title compound as a dark beige solid (291 mg, 58%): δH (400 MHz, d6-DMSO) 10.15 (s, 1H, SO2NH), 8.56 (d, 1H, Ar, J=8.4 Hz), 8.41 (d, 1H, Ar, J=8.4 Hz), 8.30 (s, 1H, Ar), 7.80-7.75 (m, 2H, Ar), 7.69 (t, 1H, Ar, J=7.4 Hz), 7.50 (dd, 1H, Ar, J=8.8, 1.6 Hz), 7.09 (d, 1H, Ar, J=8.4 Hz); δC (100 MHz, d6-DMSO) 172.2, 165.3, 135.4, 135.1, 131.8, 131.6, 131.2, 130.3, 129.8, 127.3, 125.6, 125.5, 125.4, 124.5, 121.8, 120.0, 105.3; Calcd (M+): 498.9, Found: 498.1 ([M−H]−); tR=18.2 min (97.0%, II).
  • 1-Hydroxy-4-(N-(naphthalen-1-yl)sulfamoyl)-2-naphthoic acid (3p). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 1-naphthylamine according to General Procedure A on a 1 mmol scale to yield the title compound as a dark purple solid (283 mg, 72%): δH (400 MHz, d6-DMSO) 10.46 (s, 1H, SO2NH), 8.74 (d, 1H, Ar, J=8.8 Hz), 8.38 (d, 1H, Ar, J=8.8 Hz), 8.26 (s, 1H, Ar), 7.96 (d, 1H, Ar, J=8.8 Hz), 7.85-7.83 (m, 2H, Ar), 7.73-7.68 (m, 2H, Ar), 7.41 (t, 1H, Ar, J=7.6 Hz), 7.34 (t, 1H, Ar, J=7.8 Hz), 7.28 (t, 1H, Ar, J=7.4 Hz), 7.12 (d, 1H, Ar, J=8.0 Hz); δC (100 MHz, d6-DMSO) 171.8, 164.6, 134.7, 133.8, 132.2, 131.3, 130.9, 130.0, 129.4, 128.5, 128.0, 126.9, 126.7, 126.2, 125.9, 125.6, 125.0, 124.9, 124.1, 123.0, 104.8; Calcd (M+): 393.1, Found: 416.2 ([M+Na]+); tR=9.7 min (100%, II).
  • 1-Hydroxy-4-(N-(naphthalen-2-yl)sulfamoyl)-2-naphthoic add (3q). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 2-naphthylamine according to General Procedure A on a 1 mmol scale to yield the title compound as a grey-purple solid (303 mg, 77%): δH (400 MHz, d6-DMSO) 10.83 (s, 1H, SO2NH), 8.72 (d, 1H, Ar, J=7.6 Hz), 8.57 (s, 1H, Ar), 8.35 (d, 1H, Ar, J=8.4 Hz), 7.87 (t, 1H, Ar, J=8.0 Hz), 7.72-7.65 (m, 4H, Ar), 7.47 (s, 1H, Ar), 7.38 (t, 1H, J=7.0 Hz), 7.32 (t, 1H, Ar, J=7.0 Hz), 7.22 (d, 1H, Ar, J=8.8 Hz); δC (100 MHz, d6-DMSO) 171.8, 164.9, 135.3, 133.2, 131.2, 131.0, 130.9, 129.8, 129.1, 127.5, 127.0, 126.9, 126.8, 125.2, 124.9, 124.6, 124.3, 123.7, 119.7, 115.0, 105.0; Calcd (M+): 393.1, Found: 392.2 ([M−H]−); tR=12.7 min (94.5%, II).
  • 4-(N-([1,1′-Biphenyl]-2-yl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3r). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 2-aminobiphenyl according to General Procedure A on a 1 mmol scale to yield the title compound as a beige solid (252 mg, 60%): δH (400 MHz, d6-DMSO) 9.60 (s, 1H), 8.33-8.28 (m, 2H), 8.07 (s, 1H), 7.62-7.58 (m, 2H), 7.23 (t, J=4.8 Hz, 2H), 7.11 (t, J=4.8 Hz, 1H), 7.03-7.00 (m, 6H). δC (100 MHz, d6-DMSO) 172.3, 164.9, 139.9, 138.6, 133.5, 131.4, 131.3, 130.9, 129.5, 129.1, 128.5, 127.8, 127.7, 126.9, 126.8, 126.4, 125.5, 125.4, 124.3, 105.1; Calcd (M+): 419.1, Found: 442.2 ([M+Na]+); tR=14.6 min (98.7%, II).
  • 4-(N-([1,1′-Biphenyl]-3-yl)sulfamoyl)-1-hydroxy-2-naphthoic add (3s). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 3-aminobiphenyl according to General Procedure A on a 1 mmol scale to yield the title compound as a dark brown solid (239 mg, 58%): δH (400 MHz, d6-DMSO) 10.45 (s, 1H), 8.61 (s, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.32 (d, J=8.8 Hz, 1H), 7.68 (t, J=8 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.40 (m, 4H), 7.34 (m, 1H), 7.28 (s, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 6.95 (d, J=8 Hz, 1H). δC (100 MHz, d6-DMSO) 171.1, 141.3, 140.2, 139.2, 134.1, 131.6, 130.1, 129.9, 129.4, 128.0, 126.9, 125.4, 125.2, 124.6, 121.5, 117.7, 116.6, 107.1; Calcd (M+): 419.1, Found: 418.3 ([M−H]−); tR=13.9 min (100%, II).
  • 4-(N-([1,1′-Biphenyl]-4-yl)sulfamoyl)-1-hydroxy-2-naphthoic avid (3t). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-aminobiphenyl according to General Procedure A on a 1 mmol scale to yield the title compound as a brown solid (260 mg, 62%): δH (400 MHz, d6-DMSO) 10.37 (s, 1H), 8.54 (s, 1H), 8.47 (d, J=8 Hz, 1H), 8.31 (d, J=7.6 Hz, 1H), 7.62 (t, J=8 Hz, 1H), 7.51 (d, J=8 Hz, 2H), 7.44 (d, J=8.4 Hz, 3H), 7.35 (t, J=8 Hz, 2H), 7.25 (t, 1=7.6 Hz, 1H), 7.05 (d, J=7.6 Hz, 2H). δC (100 MHz, d6-DMSO) 172.5, 170.8, 139.9, 138.2, 134.8, 134.3, 131.6, 129.6, 129.2, 128.7, 127.6, 127.3, 126.6, 125.3, 124.8, 124.5, 118.8, 116.3, 107.9; Calcd (M+): 419.5, Found: 418.3 ([M−H]−); tR=13.9 min (98.3%, II).
  • 1-Hydroxy-4-(N-(2-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid (3u). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 2-trifluoromethylaniline according to General Procedure A on a 1 mmol scale to yield the title compound as a dark pink solid (222 mg, 54%): δH (400 MHz, d6-DMSO) 10.06 (s, 1H, SO2NH), 8.62 (d, 1H, Ar, J=8.0 Hz), 8.44 (d, 1H, Ar, J=8.8 Hz), 8.32 (s, 1H, Ar), 7.80 (t, 1H, Ar, J=7.4 Hz), 7.71-7.66 (m, 2H, Ar), 7.52 (t, 1H, Ar, J=7.2 Hz), 7.41 (t, 1H, Ar, J=7.0 Hz), 6.99 (d, 1H, Ar, J=7.6 Hz); δC (100 MHz, d6-DMSO) 172.1, 166.2, 134.5, 133.8, 133.7, 131.5, 131.0, 130.7, 130.6, 129.5, 127.8, 127.4, 126.9, 126.2 (q, 2JCF=40 Hz), 125.5 (q, 1JCF=108 Hz), 125.5, 124.6, 105.6; Calcd (M+): 411.0, Found: 410.2 ([M−H]−); tR=10.7 min (96.7%, II).
  • 4-(N-(4-Chlorophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3v). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-chloroaniline according to General Procedure A on a 1 mmol scale to yield the title compound as a light brown solid (189 mg, 50%): δH (400 MHz, d6-DMSO) 10.74 (s, 1H, NH), 8.62 (d, J=8.8, 1H, Ar), 8.46 (s, 1H, Ar), 8.39 (d, J=8.8, 1H, Ar), 7.86 (t, J=8.8, 1H, Ar), 7.71 (t, J=8.8, 1 H, Ar), 7.22 (d, J=8.4, 2H, Ar), 7.00 (d, J=8.4, 2H, Ar) δC (100 MHz, d6-DMSO) 172.2, 165.0, 136.9, 131.7, 131.2, 131.1, 129.5, 128.1, 127.4, 125.4, 124.9, 124.6, 124.2, 121.1, 105.3; Calcd (M+): 377.0, Found: 376.2 ([M−H]−), tR=12.2 min (95.7%, II).
  • 1-Hydroxy-4-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)-2-naphthoic acid (3w). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-trifluoromethylaniline according to General Procedure A on a 1 mmol scale to yield the title compound as a light pink solid (218 mg, 53%): δH (400 MHz, d6-DMSO) 11.13 (s, 1H, NH), 8.60 (d, J 8.8, 1 H, Ar), 8.57 (s, 1H, Ar), 8.39 (d, J=8.8, 1 H, Ar), 7.85 (t, J=8.8, 1 H, Ar), 7.68 (t, J=8.8, 1 H, Ar), 7.55 (d, J=8.8, 2H, Ar), 7.19 (d, J=8.8, 2 H, Ar); δC (100 MHz, d6-DMSO) 172.0, 165.7, 141.8, 131.7, 131.5, 131.2, 127.4, 127.0, 125.9, 125.7, 124.8, 124.7, 123.6, 118.2, 105.5; Calcd (M+): 411.0, Found: 434.2 ([M+Na]+); tR=15.6 min (95.4%, II).
  • 1-Hydroxy-4-(N-(p-tolyl)sulfamoyl)-2-naphthoic acid (3x), 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to p-toluidine according to General Procedure A on a 1 mmol scale to yield the title compound as a beige solid (225 mg, 63%): δH (400 MHz, d6-DMSO) 10.39 (s, 1H, NH), 8.65 (d, J=8.8, 1 H, Ar), 8.43 (s, 1H, Ar), 8.38 (d, J=8.8, 1 H, Ar), 7.86 (t, J=8.8, 1 H, Ar), 7.70 (t, J=8.8, 1 H, Ar), 6.95 (d, J=8.0, 2 H, Ar), 6.87 (d, J=8.0, 2 H, Ar), 2.11 (s, 3H, CH3); δC (100 MHz, d6-DMSO) 172.2, 165.0, 135.2, 133.4, 131.5, 131.4, 131.0, 129.9, 127.3, 125.4, 125.1, 124.5, 120.2, 105.3, 20.6; Calcd (M+). 357.1, Found: 380.2 ([M+Na]+); tR=9.0 min (95.5%, II).
  • 1-Hydroxy-4-(N-(4-isopropylphenyl)sulfamoyl)-2-naphthoic acid (3y). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to p-isopropylaniline according to General Procedure A on a 1 mmol scale to yield the title compound as a beige solid (235 mg, 61%); δH (400 MHz, d6-DMSO) 10.42 (s, 1H, NH), 8.63 (d, J=8.4, 1H, Ar), 8.46 (s, 1H, Ar), 8.39 (d, J 8.4, 1H, Ar), 7.84 (t, J=8.4, 1H, Ar), 7.70 (t, J=8.4, 1H, Ar), 7.02 (d, J=8.4, 2H, Ar), 6.90 (d, J=8.0, 2 H, Ar), 2.71 (sept, J=7.2, 1 H, CH), 1.06 (d, J=7.2, 6H, 2×CH3); δC (100 MHz, d6-DMSO) 172.2, 164.8, 144.3, 135.5, 131.5, 131.4, 130.8, 127.3, 125.3, 125.1, 124.5, 120.0, 105.2, 33.1, 24.2; Calcd (M+): 385.1, Found: 408.3 ([M+Na]+); tR=15.3 min (95.9%, II).
  • 1-Hydroxy-4-(N-(4-methoxyphenyl)sulfamoyl)-2-naphthoic acid (3z). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to p-anisidine according to General Procedure A on a 1 mmol scale to yield the title compound as a light brown solid (281 mg, 75%): δH (400 MHz, d6-DMSO) 1018 (s, 1H, SO2NH), 8.64 (d, 1H, Ar, J=8.8 Hz), 8.38 (d, 1H, Ar, J=8.4 Hz), 8.36 (s, 1H, Ar), 7.86 (t, 1H, Ar, J=7.4 Hz), 7.71 (t, 2H, Ar J=7.6 Hz), 6.85 (d, 2H, Ar, J=9.2 Hz), 6.71 (d, 2H, Ar, J=8.8 Hz), 3.59 (s, 3H, OMe); δC (100 MHz, d6-DMSO): 172.24, 164.74, 156.76, 131.48-131.44, 130.74, 130.27, 127.32, 125.29, 125.19, 124.82, 124.51, 123.33, 114.72, 105.19, 55.51; Calcd (M+): 373.1, Found: 372.3 ([M−H−); tR=8.7 min (99.6%, III).
  • 1-Hydroxy-4-(N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid (3aa). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-isopropoxyaniline according to General Procedure A on a 1 mmol scale to yield the title compound as a white solid (289 mg, 72%): δH (400 MHz, d6-DMSO) 10.15 (s, 1H, SO2NH), 8.63 (d, 1H, Ar, J=8.8 Hz), 8.39 (d, 1H, Ar, J=8.0 Hz), 8.35 (s, 1H, Ar), 7.85 (t, 1H, Ar, J=7.4 Hz), 7.71 (t, 1H, Ar, J=7.8 Hz), 6.83 (d, 2H, Ar, J=9.6 Hz), 6.69 (d, 2H, Ar, J=8.8 Hz), 4.41 (hep, 1H, CH(CH3)2, J=5.8 Hz), 1.14 (d, 6H, CH(CH 3)2, J=5.2 HZ); 6C (100 MHZ, d6-DMSO) 172.2, 164.7, 155.0, 131.5, 131.4, 130.7, 130.1, 127.3, 125.3, 125.2, 124.9, 124.5, 123.4, 116.5, 105.2, 69.7, 22.1; Calcd (M+): 401.1, Found: 402.0 ([M+H]+); tR=10.2 min (98.6%, II).
  • 4-(N-(4-Cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3ab). Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-aminobenzonitrile according to General Procedure A on a 1 mmol scale to yield the title compound as a light pink solid (254 mg, 69%): δH (400 MHz, d6-DMSO) 11.32 (s, 1H, SO2NH), 8.60-8.57 (m, 2H, Ar), 8.39 (d, 1H, Ar, J=8.8 Hz), 7.87 (t, 1H, Ar, J=7.4 Hz), 7.69 (t, 1H, Ar, J=7.8 Hz), 7.63 (d, 2H, Ar, J=8.4 Hz), 7.15 (d, 2H, Ar, J=8.8 Hz); δC (100 MHz, d6-DMSO) 172.0, 166.1, 142.5, 134.1, 131.8, 131.7, 131.1, 127.3, 125.8, 124.8, 124.6, 122.9, 119.1, 118.1, 105.9, 105.3; Calcd (M+): 368.1, Found: 367.1 ([M−H]−); tR=5.5 min (98.3%, II).
  • 1-Hydroxy-4-(N-(4-nitrophenyl)sulfamoyl)-2-naphthoic add (3ae). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-nitroaniline according to General Procedure A on a 2 mmol scale to yield the title compound as a dark yellow solid (249 mg, 64%): δH (400 MHz, d6-DMSO) 11.54 (s, 1H, SO2NH), 8.61-8.58 (m, 2H, Ar), 8.38 (d, 1H, Ar, J=8.0 Hz), 8.07 (d, 2H, Ar, J=8.4 Hz), 7.86 (t, 1H, Ar, J=7.6 Hz), 7.68 (t, 1H, Ar, J=7.6 Hz), 7.20 (d, 2H, Ar, J=9.2 Hz); δC (100 MHz, d6-DMSO) 171.5, 166.2, 144.1, 142.2, 131.8, 131.3, 130.8, 126.9, 125.6, 125.5, 124.5, 124.1, 121.9, 117.2, 105.4; Gated (M+): 388.0, Found: 387.3 ([M−H]−); tR=4.8 min (97.4%, 1).
  • 4-(N-(3-Cyanophenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3ad) 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 3-aminobenzonitrile according to General Procedure A on a 1 mmol scale to yield the title compound as a reddish-purple solid (188 mg, 61%): δH (400 MHz, d6-DMSO) 10.71 (s, 1H, NH), 8.54 (s, 1H, Ar), 8.40 (d, J=8.4, 1 H, Ar), 8.32 (d, J=8.4, 1 H, Ar), 7.63 (t, J=8.4, 1H, Ar), 7.44 (t, J=8.4, 1 H, Ar), 7.39-7.27 (m, 4H, Ar) δC (100 MHz, d6-DMSO) 173.3, 170.5, 139.9, 134.7, 131.5, 130.9, 129.7, 129.0, 126.5, 125.5, 124.9, 124.2, 122.7, 120.7, 118.8, 114.8, 112.1, 107.8; Calcd (M+): 368.1, Found: 367.1 ([M−H]−); tR=7.4 min (97.2%, II).
  • 1-Hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid (3ba). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-isopropoxyaniline (8a) according to General Procedure A on a 1 mmol scale to yield the title compound as a beige solid (350 mg, 69%): δH (400 MHz, d6-DMSO) 8.32 (d, 1H, Ar, J=8.4 Hz), 8.30 (s, 1H, Ar), 8.10 (1H, Ar, J=7.6 Hz), 7.49-8.39 (m, 2H, Ar), 6.96 (d, 2H, Ph, J=8.8 Hz), 6.77 (d, 2H, Ph, J=8.8 Hz), 7.06 (t, 1H, Ar, J=7.4 Hz), 4.56-4.50 (m, 1H, OCH), 3.25 (d, 2H, CH 2CH, J=6.8 Hz) 1.39-1.34 (m, 1H, CH2CH) 1.22 (d, 6H, OCH(CH3)2, J=6.4 Hz), 0.73 (d, 6H, CH2CH(CH 3)2, J=6.8 HZ); δC (100 MHz, d6-DMSO) 172.4, 170.8, 156.9, 134.7, 132.3, 131.9, 130.2, 128.9, 128.6, 125.1, 125.0 124.6, 115.9, 115.4, 108.0, 69.7, 57.5, 26.7, 22.2, 20.1; Calcd (M+): 457.2, Found: 456.2 ([M−H]−); tR=16.7 min (99.5%, III).
  • 1-Hydroxy-4-(N-(4-phenoxyphenyl)sulfamoyl)-2-naphthoic acid (3bb). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-phenoxyaniline (8b) according to General Procedure A on a 1 mmol scale to yield the title compound as a beige solid (340 mg, 78%): δH (400 MHz, d6-DMSO) 10.41 (s, 1H, SO2NH), 8.63 (d, 1H, Ar, J=8.8 Hz), 8.40-8.38 (m, 2H, Ar), 7.85 (t, 1H, Ar, J=7.6 Hz), 7.71 (t, 1H, Ar, J=7.6 Hz), 7.31 (t, 2H, Ar, J=8.0 Hz), 7.06 (t, 1H, Ar, J=7.4 Hz), 6.96 (d, 2H, Ar, J=8.8 Hz), 6.84-6.81 (m, 4H, Ar); δC (100 MHz, d6-DMSO) 172.2, 165.1, 158.2, 157.4, 133.5, 131.5, 131.0, 130.4, 127.3, 125.4, 125.1, 124.6, 123.5, 122.8, 120.2, 118.3, 116.0, 114.9, 105.3; Calcd (M+): 435.1, Found; 436.0 ([M+H]−); tR=14.4 min (100%, II).
  • 1-Hydroxy-4-(N-(4-(p-tolyloxy)phenyl)sulfamoyl)-2-naphthoic acid (3bc). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-(p-tolyloxy)aniline (8c) according to General Procedure A on a 1 mmol scale to yield the title compound as a beige solid (342 mg, 76%); δH (400 MHz, d6-DMSO) 10.37 (s, 1H, SO2NH), 8.63 (d, 1H, Ar, J=8.8 Hz), 8.41-8.39 (m, 2H, Ar), 7.85 (t, 1H, Ar, J=7.4 Hz), 7.71 (t, 1H, Ar, J=7.8 Hz), 7.11 (d, 2H, Ar, J=8.8 Hz), 6.94 (d, 2H, Ar, J=8.4 Hz), 6.78 (d, 2H, Ar, J=8.8 Hz), 6.74 (d, 1H, Ar, J=8.0 Hz), 2.24 (s, 3H, CH3); δC (100 MHz, d6-DMSO) 172.2, 164.5, 154.9, 153.9, 133.0, 132.7, 131.5, 130.9, 130.7, 127.3, 125.3, 125.1, 124.6, 122.8, 119.6, 118.6, 105.2, 20.6; Calcd (M+): 449.1, Found; 472.3 ([M+Na]+); tR=9.3 min (100%, III).
  • 1-Hydroxy-4-(N-(4-(naphthalen-1-yloxy)phenylfsulfamoyl)-2-naphthoic acid (3bd). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-(naphthalen-1-yloxy)aniline (8d) according to General Procedure A on a 1 mmol scale to yield the title compound as a light purple solid (351 mg, 70%); δH (400 MHz, d6-DMSO) 10.42 (s, 1H, SO2NH), 8.63 (d, 1H, Ar, J=8.8 Hz), 8.42-8.39 (m, 2H, Ar), 7.99 (d, 1H, Ar, J=8.8 Hz), 7.94 (d, 1H, Ar, J=8.0 Hz), 7.86 (t, 1H, Ar, J=7.4 Hz), 7.72 (t, 1H, Ar, J=7.8 Hz), 7.66 (d, 1H, Ar, J=8.8 Hz), 7.55 (t, 1H, Ar, J=7.4 Hz), 7.49 (t, 1H, Ar, J=7.0 Hz), 7.38 (t, 1H, Ar, J=7.8 Hz), 6.98, 6.88 (ABq, 4H, Ar, JAB=8.4 Hz), 6.73 (d, 1H, Ar, J=8.0 Hz); δC (100 MHz, d6-DMSO) 172.2, 165.2, 153.9, 153.0, 147.4, 134.9, 133.5, 131.4, 131.3, 131.0, 128.3, 127.3, 127.2, 126.6, 126.5, 125.5, 125.1, 124.6, 124.3, 123.5, 122.8, 121.7, 119.8, 113.1, 105.3; Calcd (M+): 485.1, Found; 508.3 ([M+Na]+); tR=11.2 min (100%, III).
  • 4-(N-(4-(3-Bromophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3be). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-(3-bromophenoxy)aniline (8e) according to General Procedure A on a 1 mmol scale to yield the title compound as a beige solid (334 mg, 65%). δH (400 MHz, d6-DMSO) 10.45 (s, 1H, SO2NH), 8.62 (d, 1H, Ar, J=8.8 Hz), 8.43 (s, 1H, Ar), 8.40 (d, 1H, Ar, J=8.8 Hz), 7.86 (t, 1H, Ar, J=7.4 Hz), 7.71 (t, 1H, Ar, J=7.4 Hz), 7.26-7.25 (m, 2H, Ar), 7.01-6.99 (m, 3H, Ar), 6.90 (d, 2H, Ar, J=8.4 Hz), 6.83-6.80 (m, 1H, Ar); δC (100 MHz, d6-DMSO) 172.2, 165.2, 158.7, 152.2, 134.2, 132.1, 131.4, 131.0, 127.3, 126.2, 125.6, 125.1, 124.6, 122.6, 122.5, 120.9, 120.8, 117.0, 115.9, 112.5, 105.3; Calcd (M+): 513.0, Found: 513.9 ([M+H]+), tR=10.7 min (99.6%, III).
  • 4-(N-(4-(3,5-Dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic add (3bf). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-(3,5-dimethylphenoxy)aniline (8f) according to General Procedure A on a 1 mmol scale to yield the title compound as a cream solid (306 mg, 66%); 8H (400 MHz, d6-DMSO) 10.40 (s, 1H, SO2NH), 8.62 (d, 1H, Ar, J=8.8 Hz), 8.41-8.39 (m, 3H, Ar), 7.85 (t, 1H, Ar, J=7.4 Hz), 7.71 (t, 1H, Ar, J=7.4 Hz), 6.95, 6.79 (ABq, 4H, Ar, JAB=9.0 Hz), 6.70 (s, 1H, Ar), 6.43 (s, 2H, Ar), 2.18 (s, 6H, 2×CH3); δC (100 MHz, d6-DMSO) 172.2, 157.4, 153.4, 139.7, 133.3, 131.6, 131.4, 130.9, 129.9, 127.4, 127.3, 125.5, 125.1, 124.6, 124.5, 122.7, 120.1, 116.1, 105.3, 21.3; Calcd (M+): 463.1, Found: 463.91 ([M+H]+); tR=19.8 min (98.9%, II).
  • 4-(N-(4-(2,4-Dichlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic add (3bg). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-(2,4-dichlorophenoxy)aniline (8g) according to General Procedure A on a 1 mmol scale to yield the title compound as a beige solid (297 mg, 66%): δH (400 MHz, d6-DMSO) 10.46 (s, 1H, SO2NH), 8.62 (d, 1H, Ar, J=8.8 Hz), 8.41-8.39 (m, 2H, Ar), 7.85 (t, 1H, Ar, J=7.4 Hz), 7.73-7.70 (m, 2H, Ar), 7.34 (dd, 1H, Ar, J=8.8, 2.4 Hz), 6.97 (d, 2H, Ar, J=8.8 Hz), 6.88-6.82 (m, 3H, Ar); δC (100 MHz, d6-DMSO) 172.1, 165.3, 151.6, 148.8, 133.9, 131.4, 131.0, 130.5, 129.1, 127.4, 127.3, 125.5, 125.0, 124.2, 124.1, 122.6, 121.6, 119.3, 105.3; Calcd (M+): 503.0, Found: 503.9 ([M+H]+); tR=12.3 min (100%, III).
  • 4-(N-(4-(4-Chlorophenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3bh). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-(4-chlorophenoxy)aniline (8h) according to General Procedure A on a 1 mmol scale to yield the title compound as a beige solid (291 mg, 62%): δH (400 MHz, d6-DMSO) 10.45 (s, 1H, SO2NH), 8.63 (d, 1H, Ar, J=8.8 Hz), 8.41-8.39 (m, 2H, Ar), 7.86 (t, 1H, Ar, J=7.4 Hz), 7.72 (t, 1H, Ar, J=7.4 Hz), 7.35 (d, 1H, Ar, J=9.2 Hz), 6.98 (d, 1H, Ar, J=8.4 Hz), 6.85 (app t, 4H, Ar, J=8.6 Hz); δC (100 MHz, d6-DMSO) 172.2, 165.0, 156.4, 152.8, 133.9, 131.5, 131.4, 130.9, 130.2, 127.4, 127.2, 125.4, 125.1, 124.6, 124.5, 122.7, 120.4, 119.9, 105.2, Calcd (M+): 469.0, Found: 469.91 ([M+H]+); tR=19.5 min (98.8%, II).
  • 4-(N-(4-(4-Chloro-3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3bi). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-(4-chloro-3,5-dimethylphenoxy)aniline (8i) according to General Procedure A on a 1 mmol scale to yield the title compound as an off-white solid (374 mg, 75%): δH (400 MHz, d6-DMSO, TMS) δH 10.41 (s, 1H, NH), 8.61 (d, 1H, Ar—H, J=8.8 Hz), 8.42 (s, 1H, Ar—H), 8.39 (d, 1H, Ar—H, J=8.4 Hz), 7.84 (t, 1H, Ar—H, J=7.6 Hz), 7.69 (t, 1H, Ar—H, J=7.6 Hz), 6.96 (d, 2H, Ar—H, J=8.8 Hz), 6.82 (d, 2H, Ar—H, J=8.8 Hz), 6.70 (s, 2H, Ar—H), 2.24 (s, 6H, Ar—CH3). δC (100 MHz, d6-DMSO) 172.2, 164.8, 155.2, 153.2, 137.6, 133.4, 131.5, 130.8, 128.2, 127.3, 125.3, 125.1, 124.7, 124.5, 122.5, 119.9, 118.6, 105.2, 20.7; Calcd (M+): 497.1, Found: 496.2 ([M−H]−); tR=4.0 min (95.0%, IV).
  • 4-(N-(4-(4-Chloro-3,5-dimethylphenoxy)phenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid (3bj). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylaniline (9a) according to General Procedure A on a 1 mmol scale to yield the title compound as a cream solid (399 mg, 72%): δH (400 MHz, d6-DMSO, TMS) δH 8.37 (d, 1H, Ar—H, J=8 Hz), 8.27 (s, 1H, Ar—H), 8.14 (d, 1H, Ar—H, J=8 Hz), 7.62 (t, 1H, Ar—H, J=7.4 Hz), 7.56 (t, 1H, Ar—H, J=7.4 Hz), 7.06 (d, 2H, Ar—H, J=8.8 Hz), 6.86 (s, 2H, Ar—H), 6.85 (d, 2H, Ar—H, J=8.8 Hz), 3.32 (d, 2H, NCH2, J=7.2 Hz), 2.31 (s, 6H, Ar—CH3), 1.42 (m, 1H, CH2CH(CH3)2), 0.78 (d, 6H, CH(CH3)2, J=6.4 Hz) δC (100 MHz, d6-DMSO) 156.3, 154.3, 137.9, 134.2, 132.9, 132.2, 130.6, 130.2, 128.9, 126.7, 126.1, 125.2, 124.7, 119.7, 118.7, 57.3, 26.8, 20.7, 20.2; Calcd (M+): 553.1, Found: 552.2 ([M−H]−); tR=8.0 mm (96.8%, IV).
  • 4-(N-(4-(4-Chloro-3,5-dimethylphenoxy)phenyl)-N-cyclopentylsulfamoyl)-1-hydroxy-2-naphthoic acid (3bk). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylaniline (9b) according to General Procedure A on a 1 mmol scale to yield the title compound as a white solid (396 mg, 70%). δH (400 MHz, d6-DMSO, TMS) δH 8.44 (app. t, 2H, Ar—H, J=7.2 Hz), 8.27 (s, 1H, Ar—H), 7.90 (t, 1H, Ar—H, J=7.8 Hz), 7.74 (t, 1H, Ar—H, J=7.6 Hz), 6.94 (d, 2H, Ar—H, J=8.8 Hz), 6.88 (d, 4H, Ar—H, J=8.4 Hz), 4.54 (m, 1H, NCH(CH2)2, J=8.2 Hz), 2.30 (s, 6H, Ar—CH3), 1.80-1.68 (m, 2H, (CHCH2CH2)), 1.50-1.17 (m, 6H, 3(CHCH2CH2)) δC (100 MHz, d6-DMSO) 172.2, 165, 157.3, 153.9, 138, 134, 131.6, 131.5, 130.2, 129.2, 127.3, 125.4, 125.2, 124.6, 124.4, 119.9, 118.3, 105.3, 59.9, 30.3, 22.4, 20.7; Calcd (M+): 565.1, Found: 564.3 ([M−H]−); tR=8.5 min (95.4%, IV).
  • 4-(N-Benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid (3bl). 4-Chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-(4-chloro-3,5-dimethylphenoxy)-V-isobutyl aniline (9c) according to General Procedure A on a 1 mmol scale to yield the title compound as a white solid (423 mg, 72%): δH (400 MHz, d6-DMSO, TMS) δH 8.43 (d, 1H, Ar—H, J=8 Hz), 8.39 (s, 1H, Ar—H), 8.26 (d, 1H, Ar—H, J=8 Hz), 7.73 (m, 2H, Ar—H, J=7.2 Hz), 7.24-7.17 (m, 5H, Ph), 7.02 (d, 2H, Ar—H, J=8.8 Hz), 6.77 (m, 3H, Ar—H), 4.78 (s, 2H, NCH2), 2.28 (s, 6H, (Ar—CH3)2) δC (100 MHz, d6-DMSO) 172.2, 165.2, 156.3, 154.2, 137.9, 136.5, 133.6, 132, 131.9, 131.2, 130.9, 128.9, 128.6, 127.8, 127.2, 125.5, 125.4, 124.5, 123.1, 119.6, 118.5, 105.5, 53.8, 20.7; Calcd (M+): 587.1, Found: 586.2 ([M−H]−); tR=5.7 min (95.9%, IV).
  • 4-(N-(4-Bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid (3ca) 4-chlorosulfonyl-1-hydroxy-2-naphthoic acid (5) was coupled to 4-bromo-V-isobutylaniline (8j) according to General Procedure A on a 6 mmol scale to yield the title compound as a light pink solid (393 mg, 68%): δH (400 MHz, d6-DMSO, TMS) 5H 8.41-8.39 (m, 1H, Ar), 8.29 (s, 1H, Ar), 8.15-8.13 (m, 1H, Ar), 7.68-7.65 (m, 2H, Ar), 7.48 (d, 2H, Ph, J=8.8 Hz), 7.07 (d, 2H, Ph, J=8.4 Hz), 3.36 (d, 2H, NCH 2, J=7.2 Hz), 1.44-1.37 (m, 1H, CH2CH), 0.77 (d, 6H, CH(CH 3)2, J=6 Hz) δC (100 MHz, d6-DMSO) 172.0, 165.8, 138.5, 132.4, 132.1, 131.9, 131.1, 130.8, 127.1, 125.7, 125.2, 124.5, 122.8, 120.9, 105.6, 57.1, 26.9, 19.9; Calcd (M+): 477.0, Found: 476.0 ([M−H]−); tR=16.3 min (99.5%, III).
  • Methyl 4-(N-(4-bromphenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoate (3cb) and Methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoic (3cc). Compound 3ca (752 mg, 1.3 mmol, 1 eq) was treated with Mel (2.2 eq) and K2CO, (3 eq) in DMF (13 mL) at RT. After 16 h, the reaction was incomplete, yielding two products. Water (150 mL) was added to the reaction mixture, which was subsequently extracted with EtOAc (30 mL×3). The EtOAc extractions were combined, washed with water (100 mL×3), brine, dried (Na2SO4), filtered and concentrated. The residue was adsorbed onto silica gel and purified by flash column chromatography, eluting with a gradient of EtOAc in hexanes to deliver first 3cc (395 mg, 60%) and second 3cb (211 mg, 33%) as cream-coloured solids. 3cb: δH (400 MHz, d6-DMSO) 12.28 (s, 1H, OH), 8.40 (d, 2H, Ar, J=8.4 Hz), 8.27 (s, 1H, Ar), 8.11 (d, 2H, Ar, J=8.4 Hz), 7.70-7.45 (m, 2H, Ar), 7.46 (d, 2H, Ar, J=8.4 Hz), 7.05 (d, 2H, Ar, J=8.4 Hz), 3.96 (s, 3H, CO2CH3), 3.34 (d, 1H, CH 2CH(CH3)2), J=7.6 Hz), 1.38 (hep, 1H, CH(CH3)2, J=6.9 Hz), 0.75 (d, 6H, CH(CH 3)2, J=6.0 Hz); δC (100 MHz, d6-DMSO) 174.3, 168.2, 143.1, 137.2, 136.5, 136.3, 135.7, 135.6, 132.5, 130.0, 129.9, 129.3, 129.2, 125.9, 109.8, 61.9, 58.4, 31.6, 24.7; Calcd (M+): 491.0, Found 514.0 ([M+Na]+); tR=9.5 min (95.1%, IV). 3cc: δH (400 MHz, d6-DMSO) 8.37 (d, 1H, Ar, J=7.6 Hz), 8.31 (s, 1H, Ar), 8.15 (d, 1H, Ar, J=8.8 Hz), 7.75 (t, 1H, Ar, J=7.6 Hz), 7.67 (t, 1H, Ar, J=7.4 Hz), 7.50 (d, 211, Ar, J=8.4 Hz), 7.08 (d, 2H, Ar, J=8.4 Hz), 4.05 (s, 3H, CH3), 3.93 (s, 3H, CH3), 3.39 (d, 1H, CH 2CH(CH3)2, J=6.8 Hz), 1.43 (hep, 1H, CH(CH3)2, J=6.7 Hz), 0.79 (d, 6H, CH(CH 3)2, J=5.2 Hz); δC (100 MHz, d6-DMSO) 165.1, 162.1, 138.2, 132.5, 132.2, 131.3, 130.9, 130.7, 129.3, 128.8, 128.3, 125.3, 124.7, 121.2, 117.1, 64.2, 57.2, 53.2, 26.9, 19.9; Calcd (M+): 505.1, Found: 528.1 ([M+Na]+).
  • 4-(N-(4-Bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoic acid (3cd). Compound 3cc was saponified using LiOH.H2O (3eq) in a mixture of THF/H2O/MeOH (3:1:1) on a 0.2 mmol scale to deliver the title compound as a white solid (79 mg, 80%): δH (400 MHz, d6-DMSO) 13.5 (brs, 1H, CO2H), 8.36 (d, 1H, Ar, J=8.4 Hz), 8.32 (s, 1H, Ar), 8.15 (d, 1H, Ar, J=8.0 Hz), 7.73 (t, 1H, Ar, J=7.8 Hz), 7.65 (t, 1H, Ar, J=7.6 Hz), 7.49 (d, 2H, Ar, J=8.4 Hz), 7.07 (d, 2H, Ar, J=8.4 Hz), 4.06 (s, 3H, OMe), 3.40 (d, 2H, CH 2CH(CH3)2), J=6.8 Hz), 1.43 (hep, 1H, CH(CH3)2, J=6.8 Hz), 0.80 (d, 6H, CH(CH 3)2, J=6.4 Hz); δC (100 MHz, d6-DMSO) 166.0, 161.6, 137.9, 132.5, 132.1, 130.8, 130.6, 130.0, 129.0, 128.2, 127.8, 124.9, 124.3, 120.8, 117.9, 63.6, 56.8, 26.5, 19.6; Calcd (M+): 491.0, Found: 490.0 ([M−H]−); tR=15.3 min (98.5%, III).
  • Biology
  • General. All chemical reagents were ACS grade or higher unless otherwise indicated. All buffers were passed through Chelex-100 (Bio-Rad, Hercules, Calif.) to remove trace metals. The D2O, d6-DMSO, 15NH4Cl, and 13C-labeled glucose were purchased from Cambridge Isotope Laboratories, Inc. (Andover, Mass.).
  • Protein Production
  • A His6-MBP tagged recombinant human Mcl-1 residues 172 to 327 was produced in E. coli in either lysogeny broth (LB) or minimal media supplemented with 15NH4Cl to produce unlabeled or 15N-labeled Mcl-1. The tagged protein was initially purified from the crude cell lysate by immobilized metal affinity chromatography (IMAC) chromatography (GE Healthcare Life Sciences), and after dialysis to remove the imidazole the affinity tag was cleaved using PreScission Protease (GE Healthcare Life Sciences). A Sephacryl S-200 size exclusion column was used as a final purification step before the protein was concentrated with a 10,000 MWCO centrifugal filter concentrator (Millipore), The protein purity was shown to be >98% by Coomassie Brilliant Blue (Bio-Rad) stained SDS-PAGE gel and the final concentration was determined using the Bradford protein assay (Bio-Rad) with bovine serum albumin (BSA) standards (Pierce).
  • Peptide
  • A 6-aminohexanoic acid linker was conjugated to the N-terminus of the Bak BH3 peptide (GQVGRQLAIIGDDINR), capped with fluorescein (on the amino group of the linker), and the peptide was amidated on the C-terminus to give FITC-Ahx-GQVGRQLAIIGDDINR-CONH2, hereafter referred to as “FITC-Bak” (synthesized by Neo BioScience in >95% purity).
  • Fluorescence Polarization Experiments
  • Fluorescence polarization experiments were conducted using a BMG PHERAstar FS multimode microplate reader equipped with two PMTs for simultaneous measurements of the perpendicular and parallel fluorescence emission. The assays were performed m black polypropylene 384-well microplate (Costar) with a final volume of 20 microliter. Initially the affinity (KD) of the FITC-Bak peptide was determined by titrating Mcl-1172-327 into 10 nM FITC-Bak peptide in 20 mM HEPES, pH 6.8, 50 mM NaCl, 3 mM DTT, 0.01% Triton X-100 and 5% DMSO at room temperature while monitoring the perpendicular and parallel fluorescence emission with a 485 nm excitation and 520 nm emission filters. The fluorescence polarization competition assay (FPCA) was performed using 100 nM Mcl-1172-327 in the same buffer (thus, 15 nM FITC-Bak) with varying concentrations of either unlabeled peptide or experimental. Regression analysis was carried out using Origin (OriginLab, Northampton, Mass.) to fit the data to the Hill equation (1) to determine the initial binding affinity (KD) and the IC50 in the FPCA. For the fluorescence polarization competition titrations, an equation derived by Nikolovska-Coleska et al. was used to calculate the Ki from the IC50 data. The affinity of FITC-Bak for Mcl-1172-327 was determined to be 33.8±0.50 nM in the assay conditions used.
  • Nuclear Magnetic Resonance Spectroscopy
  • NMR spectra was collected at 25° C. with a Bruker AVANCE 800 NMR spectrometer (800.27 MHz for protons) equipped with pulsed-field gradients, four frequency channels, and triple resonance, z-axis gradient cryogenic probes. A one-second relaxation delay was used, and quadrature detection in the indirect dimensions was obtained with states-TPPI phase cycling; initial delays in the indirect dimensions were set to give zero- and first-order phase corrections of 90° and −180°, respectively. Data were processed using the processing program nmrPipe on Linux workstations. All proton chemical shifts are reported with respect to the H2O or HDO signal, taken to be 4,658 ppm relative to external TSP (0.0 ppm) at 37° C. The 15N chemical shifts were indirectly referenced using the zero-point frequency at 37° C. of 0.10132905 for 15N-1H, as previously described.
  • Uniformly 15N-labeled Mcl-1 was used to collect two-dimensional 1H, 15N-fast HSQC (heteronuclear single quantum coherence) spectra of Mcl-1 with and without compound to detect changes in the backbone 15N and 1H resonances of Mcl-1 due to the direct interaction with the compound. All compounds used for NMR were initially suspended in 100% d6-DMSO. The NMR samples contained 131 μM 15N-labeled Mcl-1, 182 μM compound, 20 mM HEPES, pH 6.8, 50 mM NaCl, 3 mM DTT, 20% D2O, and 5% D6-DMSO.
    • Example 2: Synthesis of 1-hydroxy-4-sulfamoyl-2-naphthoates and Cell Growth Inhibitory Activities of the Same
  • Following onto Example 1, additional naphthoate Mcl-1 inhibitors were prepared to probe various aspects of the Mcl-1 binding site. And, unless specified otherwise, the compound numbering in Example 2 is equivalent to the compound numbering in Example 1 Naphthoates 13 and 14 were prepared as shown in scheme 2-1.
  • Figure US20220396549A1-20221215-C00142
  • TABLE 2-1
    Inhibition of cell proliferation by select compounds,
    as determined by a cell titer blue assay.
    IC50 (μM)
    Compound A375 SK-MEL-5
     3a ~300 ~300
     3bl 50 90
     3ba 150 ~300
    13 ~300 ~300
    14 15 15
  • A long-standing challenge in targeting the anti-apoptotic Bcl-2 proteins is achieving family member specificity, particularly Mcl-1 specificity, although selective ligands are beginning to emerge.
  • To investigate the cellular activity of selected Mcl-1 inhibitors, the potent compound 3bl was evaluated for its ability to inhibit the proliferation of A375 and SK-MEL-5 melanoma cells, both of which express high levels of Mcl-1. Unfortunately, the IC50 for 3bl was 50 μM and 90 μM in A375 and SK-MEL-5 cells, respectively (Table 2-1). Without being limited to any one theory, the poor efficacy in cells may be attributed to the charged carboxylic acid of 3bl. To test this hypothesis, two ester prodrugs were prepared of the potent, but more hydrophilic, inhibitor 3ba, methyl ester 13 and acetoxymethyl ester 14, according to Scheme 3. As expected, both prodrugs 13 and 14 demonstrated no binding affinity to Mcl-1 in vitro, Naphthoate derivative 3ba exhibited worse activity than 3bl in cells, consistent with its weaker affinity to Mcl-1. However, the acetoxymethyl ester 14 displayed an IC50 of 15 μM in both A375 and SK-MEL-5 cells, presumably due to improved cell penetration and then intracellular hydrolysis to the active metabolite 3ba (Table 2-1). It is postulated that the lack of cellular activity for methyl ester 13 may be due to limited hydrolysis to 3ba. These results suggest a path forward with respect to rationally improving the cell penetration capabilities of this class of compounds based on a prodrug strategy.
    • Example 3: Inhibitors of the Mcl-1 Oncoprotein Based on Carboxy-Substituted Tetrahydroquinolines, Salicylate- and 1-Hydroxy-2-Naphthoate-Based Scaffolds
  • Indoles, benzothiophenes and benzofurans appropriately functionalized with a carboxylic acid and a flexible hydrophobic group may be potent inhibitors of the Mcl-1 oncoprotein through recognition of Arg263 and occupancy of the p2 pocket, respectively. Three families are provided herein as Mcl-1 inhibitors based on a carboxy-substituted tetrahydroquinoline (THQ) scaffold, a salicylate scaffold and a 1-hydroxy-2-naphthoate scaffold that are proposed to bind these sites as well as Asn260 and the p3 pocket (FIGS. 10 and 11 ).
  • Several of the carboxy-substituted tetrahydroquinolines (THQs) described herein are shown to inhibit the Mcl-1 oncoprotein, as determined by a fluorescence polarization competition assay (Table 3-1).
  • TABLE 3-1
    Mcl-1 and Bcl-xL inhibitory activity for various THQ compounds.
    Figure US20220396549A1-20221215-C00143
    Code Ki (μM)
    Number R1 Bcl-xL Mcl-1
    SF-5-135
    Figure US20220396549A1-20221215-C00144
         		ND >1000
    SF-5-133
    Figure US20220396549A1-20221215-C00145
         		ND 12
    SF-5-134
    Figure US20220396549A1-20221215-C00146
         		ND 30
    SF-5-136
    Figure US20220396549A1-20221215-C00147
         		ND >1000
    SF-5-141
    Figure US20220396549A1-20221215-C00148
         		ND 0.286
    Figure US20220396549A1-20221215-C00149
    Code Ki (μM)
    Number R2 Bcl-xL Mcl-1
    LC-3-004
    Figure US20220396549A1-20221215-C00150
         		ND 203
    LC-3-002
    Figure US20220396549A1-20221215-C00151
         		ND 14
    LC-3-006
    Figure US20220396549A1-20221215-C00152
         		ND 22
    LC-3-010
    Figure US20220396549A1-20221215-C00153
         		ND >1000
    LC-3-012
    Figure US20220396549A1-20221215-C00154
         		ND 0.332
    • Example 4: Structure-Based Design of 3-Carboxy-Substituted 1,2,3,4-Tetrahydroquinolines
  • Mcl-1 has emerged as an attractive target to expand the armamentarium in the war on cancer Using structure-based design, 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines were developed as a new chemotype to inhibit the Mcl-1 oncoprotein. The most potent compound inhibited Mcl-1 with a Ki of 120 nM, as determined by a fluorescence polarization competition assay. Direct binding was confirmed by 2D 1H-15N HSQC NMR spectroscopy with 15N-Mcl-1, which indicated interactions with R263 and T266, and occupation of the p2 pocket are likely responsible for the potent binding affinity. The short and facile synthetic chemistry is expected to mediate future compound optimization.
  • The intrinsic apoptosis pathway is activated when a cell undergoes stress, which leads to the homodimerization of the pro-apoptotic Bcl-2 proteins Bak and Bax at the outer mitochondrial membrane, and, in turn, a caspase cascade ensues that results in the formation of apoptosomes. The net result of this process is programmed cell death, or apoptosis. In many human cancers, anti-apoptotic members of the Bcl-2 family, which include Bcl-xL, Bcl-2 and Mcl-1, are over-expressed, immortalizing the cancer cells. Whilst inhibitors of Bcl-xL and Bcl-2 have advanced to clinical trials (dual Bcl-xL/Bcl-2: ABT-263 (navitociax); Bcl-2 specific: ABT-199), progress in the development of specific Mcl-1 inhibitors has been less successful and there currently exists no drug to inhibit this protein. Upregulation of Mcl-1 specifically has been associated with the development and progression of several cancers that include acute myeloid leukaemia, melanoma, non-small-cell lung, pancreatic, prostate, and ovarian cancers. Moreover, it is known that cancers dependent on Bcl-xL can exhibit resistance to the Bcl-xL inhibitor ABT-737 (a variant of ABT-263) through upregulation of Mcl-1. Therefore, the development of inhibitors of Mcl-1, either as single agents or as adjuvant therapies, represents an unmet medical need.
  • By virtue of a hydrophobic groove on its surface, Mcl-1 directly antagonizes the pro-apoptotic Bcl-2 proteins, which include Bak, Bax and Bim, through capturing their BH3 α-helical “death” domains, effectively “neutralizing” the cell-killing role of these proteins. More specifically, BH3 domains project four conserved hydrophobic side chains from one face of the α-helix that recognize sub-pockets on the surface of Mcl-1, which are termed p1 through p4. Additionally, a conserved aspartate residue on the opposite face of the helix recognizes R263. α-helix mimetics have been developed of the BH3 “death” domains to inhibit Mcl-1, as well as the family members Bcl-2 and Bcl-xL. Similarly, a complementary strategy to inhibit Mcl-1 through a more traditional small-molecule approach has begun to emerge. However, the discovery of clinical candidates remains elusive, and so new Mcl-1 inhibitors fashioned from novel scaffolds are essential. Furthermore, synthetic routes to access these inhibitors should be as short and simple as possible to expedite compound synthesis and keep costs to a minimum. In light of these considerations, we present our progress on the discovery of novel Mcl-1 inhibitors based on a simple and synthetically-accessible THQ scaffold.
  • As depicted in Scheme 4-1, quinoline-3-carboxylic acid 3 was esterified with thionyl chloride in methanol to yield ester 4. Reduction of the pyridine ring of 4 with pyridine-borane complex in glacial acetic acid then delivered racemic THQ 5 whose methyl ester was saponified to yield ±−6. Alternatively, sulphonylation of ±−5 furnished compounds ±−7, which were also saponified with lithium hydroxide to afford the 3-carboxy target compounds ±−8 Further elaboration of the phenylsulfonyl group in ±−7c was accomplished by an SNAr reaction with 4-chloro-3,5-dimethylphenol followed by ester hydrolysis to afford compound ±−2, as shown in Scheme 4-2. In addition, the phenylsulfonyl moiety in ±−2 was replaced with a more flexible propylene group through a reductive amination-saponification sequence to yield ±−11.
  • Figure US20220396549A1-20221215-C00155
  • Figure US20220396549A1-20221215-C00156
  • TABLE 4-1
    Fluorescence polarization competition assay with Mcl-1 and FITC-labeled
    Bak-BH3 peptide (“FITC-Bak”).
    Figure US20220396549A1-20221215-C00157
    Compd R1 R2 Ki (μM)
    ±-8  - -H - -H >500
    ±-8a - -H
    Figure US20220396549A1-20221215-C00158
         		193 ± 24 
    ±-8b - -H
    Figure US20220396549A1-20221215-C00159
         		117 ± 19 
    ±-8c - -H
    Figure US20220396549A1-20221215-C00160
         		176 ± 115
    ±-8d - -H
    Figure US20220396549A1-20221215-C00161
         		>500
    ±-8e - -H
    Figure US20220396549A1-20221215-C00162
         		59.0 ± 6.0 
    ±-9  - -Me
    Figure US20220396549A1-20221215-C00163
         		>500
    ±-2  - -H
    Figure US20220396549A1-20221215-C00164
         		0.120 ± 0.053
    ±-11 - -H
    Figure US20220396549A1-20221215-C00165
         		7.77 ± 1.39
  • In Table 4-1, the IC50 data, which refers to the concentration of inhibitor that results in 50% displacement of FITC-Bak from Mcl-1, were converted to Ki values using the Nikolovska-Coleska equation.
  • The target molecules were assayed for their abilities to disrupt the Mcl-1-Bak-BH3 PP1 in a fluorescence polarization competition (FPC) assay with Mcl-1 and FITC-labeled Bak-BH3 peptide. Further details on the FPC assay can be found in the Supporting Information. As expected, unsubstituted racemic 1,2,3,4-tetrahydroquinoline-3-carboxylic acid (±−6) did not show any inhibitory effect (Ki>500 uM), which may, for example, be due to an inability to reach into the p2 pocket. Substitution of the THQ nitrogen with a phenylsulfonyl group (±−8) resulted in the discovery of a weak inhibitor of Mcl-1 (Ki=193 uM), whose activity was further enhanced by the addition of a bulky, hydrophobic bromine atom in the para position of the phenyl ring (±−8b: Ki=117 uM). However, there appears to be a geometrical constraint on the nature of the para hydrophobic group, since a phenyl ring here was not tolerated ((±−8d: Ki>500 uM). On the other hand, a 2-naphthylsulfonyl group (±−8e) afforded a two-fold increase in affinity to Mcl-1 over ±−8b indicating that large groups can be accommodated in the pocket binding the sulfonyl substituent. Gratifyingly, the originally designed molecule ±−2 exhibited the most potent binding of the series with a Ki of 120 nM. We surmise this dramatic improvement in binding affinity is due to efficient and deep occupation of the p2 pocket by the 4-chloro-3,5-di methyl phenyl moiety that is facilitated by the ether oxygen providing increased structural flexibility not available to biphenyl ±−8d. A similarly impressive enhancement in the Ki value of about three orders of magnitude exists for ±−8a as compared to ±−2. Compound ±−11 was a weaker inhibitor titan ±−2 by over an order of magnitude, demonstrating the positive contribution made by the phenylsulfonyl group likely achieving favourable interactions at the top of the p2 pocket. Finally, the methyl ester of ±−2, i.e., compound ±−9, had no appreciable affinity to Mcl-1 indicating the significance of the carboxylic acid, which presumably binds R263 as proposed.
  • Confirmation of the direct binding of ±−2 to Mcl-1 was afforded by heteronuclear NMR studies. 2D 1H-15N HSQC spectra of Mcl-1 were collected in the absence and presence of ±−2 (FIG. 12 ). An overlay of the two spectra revealed significant chemical shift changes and negligible peak broadening, characteristics of a fast exchange regime, and consistent with the nanomolar affinity observed in the FPC assay. Chemical shift perturbations were calculated for each amino acid and the resonance variation was mapped onto the Mcl-1 crystal structure, 3WIX in FIG. 13 . Residues that experienced significant chemical shifts in the presence of ±−2 are shown in red and cluster around the p2 pocket, in support of the docking model presented above. More particularly, considerable shifts were observed among residues predicted to bind the carboxylate anion (R263 and T266) and 4-chloro-3,5-dimethylphenyl moiety (M250 and F270). On the other hand, the NMR data argues against a model in which H224 participates in π-π ring stacking with the benzene ring of the THQ.
  • The activity of ±−2 on the viability of human A375 melanoma cells that demonstrate increased expression of Mcl-1 was investigated next. A modest GI50 of 50 uM for ±−2 was observed (Table 4-2), which is more than two orders of magnitude less potent than the in vitro FP data. The moderate cellular activity of ±−2 may, for instance, be due to limited cell penetration owing to the charged carboxylic acid. Thus, the acetoxymethyl ester ±−12 (R1=CH2OCOCH3) was prepared as a neutral prodrug of ±−2. Like methyl ester ±−9, ±−12 was inactive in the FPC assay (Ki>500 uM), consistent with the requirement of the carboxylic acid function to engage R263. Surprisingly, however, the highly labile ester ±−12 did not yield a more potent cellular agent, which may, for instance, suggest that the charged carboxylic acid of ±−2 might not be a limiting factor in the translation of in vitro to cellular activity.
  • TABLE 4-2
    Biological activity of select compounds.
    Compd Ki (μM)a GI50 (μM)b
     ±-2 0.120 ± 0.053 50
    ±-12 >500 73
    aIn vitro activity determined as described in Table 1.
    bViability of A375 cells as determined by a CellTiter-Blue ® assay.
  • In conclusion, a new chemotype to inhibit Mcl-1 has been discovered based on a THQ core. Compound ±−2 has a Ki of 120 nM. The direct interaction of ±−2 with Mcl-1 was confirmed with 2D 1H-15N HSQC NMR data. Unlike the binding modes of the BH3 peptides with Mcl-1 in which all four hydrophobic pockets are bound, GOLD docking studies indicated that, whilst ±−2 interacts with the p2 pocket, no significant interactions with the p3 or p4 pockets were observed, which was largely substantiated by the HSQC NMR data. Thus, future analogs of ±−2 will focus on targeting the p3 and p4 pockets in addition to further exploration of the p2 pocket. Furthermore, docking studies suggested that the S-enantiomer is likely a stronger binder than its R counterpart, and so both enantiomers of ±−2 will be synthesized and evaluated to interrogate the impact of the chiral centre.
    • Example 5: Simplifying THQ Scaffold with the 4-Aminobenzoate Moiety
  • A class of Mcl-1 inhibitors based on 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines (THQ) scaffold has been described. The molecule presented a carboxylic acid to engage R263 and form a salt bridge, as well as various hydrophobic groups functionalized the N-positon on the ring, which probe deep into the p2 pocket. A structural activity relationship (SAR) analysis has been performed by varying R groups, as shown in FIG. 14 .
  • Due to the rigid nature of the THQ scaffold, it was synthetically challenging to systematically investigate the SAR regarding varying functional groups on the benzene ring, as well as installing additional moieties on the piperidine ring. Therefore, the THQ ring was simplified with a 4-aminobenzoate scaffold, as it offers a nitrogen atom that can be bi-functionalized by different R1 and R2 groups, as well as further decoration potential on the aromatic ring. For example, compound 2 possessed R1 as an isobutyl group to mimicking part of the hydrophobic core from THQ, and R2 as the 3,5-dimethyl-4-chloro-phenoxy benzene sulfonamide group, which has significantly contributed to the most potent THQ compound ±1.
  • To verify the design of the molecule, a GOLD docking experiment was run to test the possibility of compound 2 to bind to the Mcl-1 protein. As shown in FIG. 15 , compound 2 was successfully docked into the p2 binding pocket of Mcl-1 protein. Key interactions were observed between the ligand and the protein including: the polar interaction between carboxylic acid and R263, the hydrophobic interaction between 3,5-dimethyl-4-chlorophenol and the deep portion of p2 hydrophobic binding site, and also the hydrophobic interaction between isobutyl group and the subtle hydrophobic pocket formed by A227, F228, M231 and F270.
  • To further validate the design of 4-aminobenzoates, a concise SAR library was synthesized according to general procedure shown in scheme 5-1. 4-nitrobenzoic acid 3 was esterified with sulfuric acid and methanol to yield ester 4. The nitro group of compound 4 was reduced with tin chloride dihydrate to deliver compound 5, which further underwent reductive amination with isobutyraldehyde to afford compound 6. Compound 6 was coupled to different aromatic sulfonyl chlorides to generate compounds library 7a-7d, which were saponified using lithium hydroxide to yield 4-aminobenzoate compounds 8a-8d. Additionally, compound 7d can be further elaborated with 3,5-dimethyl-4-chloro-phenol by SNAr reaction, followed by saponification to give compound 8e.
  • Figure US20220396549A1-20221215-C00166
    Figure US20220396549A1-20221215-C00167
  • The potency of the molecules were evaluated by using a fluorescent polarization competition assay (FPCA) where the compounds were titrated into the mixture of Mcl-1 and FITC-Bak BH3 peptide to monitor their capability to disrupt the interaction between Mcl-1 and FITC-Bak BH3 peptide.
  • The inhibition constant for Mcl-1 (Ki) of each compound was shown in table 5-1 The biphenyl analog 8c was a moderate inhibitor with Ki=16.71 μM while the naphthyl analog 8b became a much weaker binder. The data indicated the significant influence on Ki when using geometrically different rigid hydrophobic moieties. Therefore, if the binding pattern of these compounds were similar to the predicted mode from GOLD docking result, it can be inferred that the pocket accommodating R group can be a relatively small pocket, and hence the geometric shape of R moieties can play an important role to generate the best fit. Similar with what we found in the THQ library, further extension of the R group with the 3,5-dimethyl-4-chloro phenoxy group 8e rendered a more than 10-fold stronger binder comparing to 8c.
  • TABLE 5-1
    Mcl-1 binding affinity of 4-aminobenzoate analogs
    Figure US20220396549A1-20221215-C00168
    Mcl-1
    Compd R Ki (μM)
    LC-3-029 8a
    Figure US20220396549A1-20221215-C00169
         		>500
    LC-3-031 8b
    Figure US20220396549A1-20221215-C00170
         		>500
    LC-3-030 8c
    Figure US20220396549A1-20221215-C00171
         		16.712 ± 2.284 
    LC-3-025 8d
    Figure US20220396549A1-20221215-C00172
         		>500
    LC-3-035 8e
    Figure US20220396549A1-20221215-C00173
         		2.058 ± 0.118
  • With further investigation of the docking result demonstrated in FIG. 15 , it is suspected that installing additional polar function groups onto the ortho position of carboxylic acid could potentially form favorable polar interactions with either R263 or T266 depending on the direction of the benzene ring. A GOLD docking experiment was done to show the possible binding pattern after installing a hydroxyl group ortho to the carboxylic acid, which converted the 4-aminobenzoate into a 4-aminosalicylate scaffold (FIG. 16 ). In this particular conformation, the hydroxyl group successfully recognized the R263, and also turned the carboxylic acid to a position where it was close enough to H-bond with T266.
  • To test this hypothesis, a library of analogs was designed and synthesized analogbased on the 4-aminosalicylate scaffold according to scheme 5-2,4-aminosalicylate was esterified under sulfuric acid and methanol condition to yield compound 10, which was further O-benzylated by reacting with benzyl bromide to afford compound 11. Reductive aminated compound 11 with different aldehydes and ketones (R1) afforded compounds set 12a-12c. Sulfonylation of 12a-12c with various R2—SO2Cl delivered compounds 12aa-12ag, 12ba-12bc, and 12ca-12cc. These compounds were further deprotected by saponification and TFA debenzylation to yield analogs of 13aa-13ag, 13ba, 13bb, and 13ca, 13cc. Alternatively, compound 12ad, 12bc and 12cc can be further elaborated with different substituted aromatic groups (R3) by SNAr mechanism to afford compounds 12ah-12ak, 12bd and 12cd, winch were deprotected using the same saponification followed by TFA debenzylation to generate final molecules 13ah-13ak, 13bd and 13cd. Additionally, compound 11 can also be directly sulfonylated by 4-phenoxybenzene sulfonylchloride to yield compound (12da), and then deprotected to give compound (13da).
  • Figure US20220396549A1-20221215-C00174
    Figure US20220396549A1-20221215-C00175
    Figure US20220396549A1-20221215-C00176
  • Using the same FPCA experiment, the potencies of the analogs were determined and their structure activity relationships were examined in Tables 5-2 and 5-3. Excitingly, all of 4-aminosalicylate analogs in Table 5-2 exhibited stronger Mcl-1 binding affinities compared to their corresponding 4-aminobenzoates derivatives in Table 5-1, demonstrating the significant contribution from the OH group to the Mcl-1 binding.
  • With this expanded library shown in Table 5-2 compared to Table 5-1, it is clearer to see the increased hydrophobicity of R2 substitution yielded stronger inhibitors, as illustrated by the decreasing KiS from the phenyl 13aa, 4-fluorphenyl 13ad, 4-methylphenyl 13af, 4-bromophenyl 13ae, 2-naphthenyl 13ab to 4-biphenyl Bac compounds with almost 50-fold improvement in binding affinity. Further expanding the R2 moiety from the para position of the benzene sulfonamide with an oxygen linker rendered a group of tighter binders 13ag-13ak. The subtle structural changes on the phenoxy group were reflected well by their corresponding Ki, indicating the sensitivity of the binding region on the protein. Again, the most potent analog 13ak presented the key moiety of 3,5-dimethyl-4-chloro-phenoxy group, contributing to its Ki=778 nM.
  • Various R1 substitutions were also made to further investigate the hydrophobic interactions between the N-substitutions and the Mcl-1 protein as shown in Table 5-3. When vertically comparing the analogs in Table 5-3, it is noticeable the consistent trend in Ki from naphthyl, p-biphenyl to 3,5-dimethyl-4-chloro-phenoxy benzene group. On the other hand, when horizontally comparing the analogs in Table 5-3 with their corresponding derivatives in Table 5-2, the alterations of R1 group have a significant impact on the potencies of these molecules. Completely deleting the hydrophobicity turned the compound 13da into a much weaker binder, indicating the importance of hydrophobic group on R1 position. Comparing the Ki among compounds where R1=isobutyl (tBu), cyclopentyl (Cp) and Benzyl (Bn), it is apparent that R1=Cp rendered the least potent binders (13ab, 13ac, 13ak), R1=tBu gave the moderate potent binders 13ba-13bc, and R1=Bn contributed to the most potent binders 13 ca-13cc.
  • TABLE 5-2
    Mcl-1 binding affinity of 4-aminosalicylate analogs.
    Figure US20220396549A1-20221215-C00177
    Mcl-1
    Compd R1 R2 Ki (μM)
    4jc117-1 13aa
    Figure US20220396549A1-20221215-C00178
    Figure US20220396549A1-20221215-C00179
         		192.038 ± 37.534 
    4jc117-3 13ab
    Figure US20220396549A1-20221215-C00180
    Figure US20220396549A1-20221215-C00181
         		13.821 ± 1.325 
    4jc117-4 13ac
    Figure US20220396549A1-20221215-C00182
    Figure US20220396549A1-20221215-C00183
         		4.109 ± 0.245
    LC-5-025 13ad
    Figure US20220396549A1-20221215-C00184
    Figure US20220396549A1-20221215-C00185
         		99.372 ± 9.374 
    LC-5-012 13ae
    Figure US20220396549A1-20221215-C00186
    Figure US20220396549A1-20221215-C00187
         		16.980 ± 1.504 
    4jc117-2 13af
    Figure US20220396549A1-20221215-C00188
    Figure US20220396549A1-20221215-C00189
         		61.243 ± 4.490 
    LC-4-099 13ag
    Figure US20220396549A1-20221215-C00190
    Figure US20220396549A1-20221215-C00191
         		5.766 ± 0.458
    LC-4-119 13ah
    Figure US20220396549A1-20221215-C00192
    Figure US20220396549A1-20221215-C00193
         		2.255 ± 0.168
    LC-4-100 13ai
    Figure US20220396549A1-20221215-C00194
    Figure US20220396549A1-20221215-C00195
         		2.964 ± 0.286
    LC-4-111 13aj
    Figure US20220396549A1-20221215-C00196
    Figure US20220396549A1-20221215-C00197
         		2.738 ± 0.258
    4jc117-5 13ak
    Figure US20220396549A1-20221215-C00198
    Figure US20220396549A1-20221215-C00199
         		0.778 ± 0.050
  • TABLE 5-3
    Mcl-1 binding affinity of 4-aminosalicylate analogs (continued).
    Figure US20220396549A1-20221215-C00200
    Mcl-1
    Compd R1 R2 Ki (μM)
    LC-4-083 13ba
    Figure US20220396549A1-20221215-C00201
    Figure US20220396549A1-20221215-C00202
         		24.749 ± 9.449 
    LC-4-082 13bb
    Figure US20220396549A1-20221215-C00203
    Figure US20220396549A1-20221215-C00204
         		5.244 ± 0.694
    LC-4-104 13bc
    Figure US20220396549A1-20221215-C00205
    Figure US20220396549A1-20221215-C00206
         		1.762 ± 0.208
    LC-4-113 13ca
    Figure US20220396549A1-20221215-C00207
    Figure US20220396549A1-20221215-C00208
         		11.395 ± 1.572 
    LC-4-112 13cb
    Figure US20220396549A1-20221215-C00209
    Figure US20220396549A1-20221215-C00210
         		1.712 ± 0.144
    LC-4-118 13cc
    Figure US20220396549A1-20221215-C00211
    Figure US20220396549A1-20221215-C00212
         		0.659 ± 0.040
    LC-5-005 13da H
    Figure US20220396549A1-20221215-C00213
         		13.722 ± 1.050 
  • Next, the relative position of carboxylic acid and hydroxyl group was further adjusted to investigate their impact on Mcl-1 binding affinity. Based on the predicted binding mode from FIG. 16 , it seems legitimate to switch the position of carboxylic acid and hydroxyl group yet still maintaining the same polar contact with R263 and T266, which rendered a new scaffold: 5-aminosalicylate. Another GOLD docking experiment was then conducted with the result shown in FIG. 17 .
  • The 5-aminosalicylate molecule favorably fitted into the Mcl-1 binding pocket and developed polar interaction with R263 and T266 similar to the 4-aminosalicylate analog. Therefore, a library of 5-aminosalicylate analogs was designed and synthesized to validate the in silica model according to Scheme 5-3. Moreover, the hydroxyl group was also deleted, which converted them into 5-aminobenzoate molecules, to assess its contribution in this binding mode.
  • Figure US20220396549A1-20221215-C00214
    Figure US20220396549A1-20221215-C00215
    Figure US20220396549A1-20221215-C00216
  • Esterification of 5-aminobenzoic acid 14a and 5-aminosalicylic acid 14b afforded compounds 15a and 15b. Reductive amination with isobutyraldehyde formed compounds 16a and 16b, which were further furnished by different R-sulfonyl chlorides to yield 17aa-17ad, and 17ba-17bc. The compounds were then subjected to saponification to yield final molecules 18aa-18ad, and 18ba-18bc. Also, compound 17ad was further elaborated on the fluorine by SNAr with 3,5-dimethyl-4-chloro-phenol, followed by basic hydrolysis to afford compound 18ae. In the case of 5-aminosalicylate, compound 17bd was first O-benzylated to give compound 17bd′ before coupled with 3,5-dimethyl-4-chloro-phenol to afford 17be, and then underwent saponification and TFA debenzylation to yield final compound 18be.
  • The SAR analysis of both 5-aminobenzoate and 5-aminosalicylate derivatives were reported in Table 5-4. Comparing the left column of 5-aminobenzoates with the right column of 5-aminosalicylates, the pronounced differences of their Kis demonstrate the compelling effect generated from hydroxyl group. Interestingly, in both classes, the 2-naphthyl analogs (18ab, 18bb) exhibited stronger binding affinity compared to 4-biphenyl analogs (18ac, 18bc), which was in a sharp contrast to the relationships in 4-aminobenzoate and 4-aminosalicylate scaffold. This may, for instance, be explained possibly by the change of binding direction potentially caused a collision of the 4-biphenyl moiety with the Mcl-1 hydrophobic pocket, while it guided the 2-naphthyl group to a favorable direction towards the pocket. The most potent compounds (18af and 18bd), which exhibited the Ki=1.45 μM and 586 nM, respectively, again carried the 3,5-dimethyl-4-chloro-phenoxy group.
  • TABLE 5-4
    Mcl-1 binding affinity of 5-aminobenzoate and 5-aminosalicylate analogs.
    Figure US20220396549A1-20221215-C00217
    Mcl-1
    Compd X R Ki (μM)
    4jc177-1 18aa H
    Figure US20220396549A1-20221215-C00218
         		>500
    4jc177-3 18ab H
    Figure US20220396549A1-20221215-C00219
         		61.659 ± 4.730 
    4jc177-4 18ac H
    Figure US20220396549A1-20221215-C00220
         		>500
    4jc177-6 18ad H
    Figure US20220396549A1-20221215-C00221
         		>500
    4jc177-2 18ae H
    Figure US20220396549A1-20221215-C00222
         		154.766 ± 14.670 
    4jc177-5 18af H
    Figure US20220396549A1-20221215-C00223
         		1.454 ± 0.890
    JY-5-296 18ba OH
    Figure US20220396549A1-20221215-C00224
         		46.468 ± 9.816 
    jy-5-299 18bb OH
    Figure US20220396549A1-20221215-C00225
         		7.509 ± 0.840
    JY-5-300 18bc OH
    Figure US20220396549A1-20221215-C00226
         		8.704 ± 2.049
    JY-5-304 18bd OH
    Figure US20220396549A1-20221215-C00227
         		0.586 ± 0.041
  • The carboxylic acid moiety may be an important factor in facilitating the MCL-1 protein binding. Therefore, it was anticipated that the carboxylic acid moiety on the benzoate and salicylate compounds may also be important for their potency. Also, the improved potency from 4/5-aminobenzoate to 4/5-aminosalicylate scaffold illustrated the contribution from hydroxyl group. Therefore, the function of carboxylic acid in the binding was explored by synthesizing its ester prodrugs as well as bioisosteres, and the hydroxyl group was methylated to test its impact on the compound's activity in Table 5-5. Apparently, substitution of the hydroxyl group (13ag) with methoxyl group (19) dramatically diminished the Mcl-1 binding affinity, suggesting that the H-bond donating effect from the hydroxyl group was more responsible for the polar interaction with Mcl-1 protein rather than H-bond accepting effect. Conversion of anionic carboxylic acid 13ag into neutral esters 20-22 negatively impacted their binding affinity, confirming its dominance in the formation of protein-ligand complex. On the contrary, bioisosteric replacement of carboxylic acid with different ionizable moieties yielded analogs with a wide range of potencies. Two of the most competent binders were the tetrazole analog 24 and the acyl sulfonamide analogs 27 and 28. Neither of salicylic nitrile 23 nor 3-hydroxyisoxazole 26 exhibited desirable potencies, while hydroxamic acid analog 25 turned out to be a moderate binder. These data indicated that the recognition of these different anionic moieties was associated with their conformational shapes, which is determined by the pointing direction acidic proton, as well as the distance between the proton and R263.
  • TABLE 5-5
    Mcl-1 binding affinity of 4-aminosalicylates esters and bioisosteres.
    Figure US20220396549A1-20221215-C00228
    Mcl-1
    Compd X Y R1 R2 Ki (μM)
    LC-4-099 13ag OH
    Figure US20220396549A1-20221215-C00229
    Figure US20220396549A1-20221215-C00230
    Figure US20220396549A1-20221215-C00231
         		 5.8 ± 0.46
    LC-5-106 19 OMe
    Figure US20220396549A1-20221215-C00232
    Figure US20220396549A1-20221215-C00233
    Figure US20220396549A1-20221215-C00234
         		106.70 ± 31.12 
    LC-4-131 20 OH
    Figure US20220396549A1-20221215-C00235
    Figure US20220396549A1-20221215-C00236
    Figure US20220396549A1-20221215-C00237
         		>500
    LC-4-134 21 OH
    Figure US20220396549A1-20221215-C00238
    Figure US20220396549A1-20221215-C00239
    Figure US20220396549A1-20221215-C00240
         		>500
    LC-4-141 22 OH
    Figure US20220396549A1-20221215-C00241
    Figure US20220396549A1-20221215-C00242
    Figure US20220396549A1-20221215-C00243
         		>500
    LC-5-050 23 OH
    Figure US20220396549A1-20221215-C00244
    Figure US20220396549A1-20221215-C00245
    Figure US20220396549A1-20221215-C00246
         		>500
    LC-5-068 24 H
    Figure US20220396549A1-20221215-C00247
    Figure US20220396549A1-20221215-C00248
    Figure US20220396549A1-20221215-C00249
         		 3.3 ± 0.26
    LC-5-061 25 OH
    Figure US20220396549A1-20221215-C00250
    Figure US20220396549A1-20221215-C00251
    Figure US20220396549A1-20221215-C00252
         		 71 ± 5.8
    LC-5-069 Toptop 26 H
    Figure US20220396549A1-20221215-C00253
    Figure US20220396549A1-20221215-C00254
    Figure US20220396549A1-20221215-C00255
         		>500
    LC-5-112 27 OH
    Figure US20220396549A1-20221215-C00256
    Figure US20220396549A1-20221215-C00257
    Figure US20220396549A1-20221215-C00258
         		2.94 ± 0.35
    LC-5-096 28 OH
    Figure US20220396549A1-20221215-C00259
    Figure US20220396549A1-20221215-C00260
    Figure US20220396549A1-20221215-C00261
         		 1.9 ± 0.22
  • To further validate the Mcl-1 binding pattern of the molecules discussed above, one representative compound 13ak was examined by HSQC-NMR studies with Mcl-1 and the result was shown in FIGS. 18, 19, and 20 . The 2D 1H-15N HSQC spectra of Mcl-1 was collected with 13ak and without 13ak. It clearly showed that R263 and T266 were both perturbed upon the binding of the compound. Moreover, the majority of hydrophobic residues in the p2 binding pocket, which was formed by Mcl-1 protein helixes α2 to α6, were heavily perturbed as showing in red (A chemical shift >0.3 ppm). In the meantime, the rest of residues located far from the p2 pocket were not interfere as showing gray, further confirming the proposed binding pattern in FIG. 16 .
  • The selectivity of 4-aminosalicylate and 5-aminosalicylate analogs is shown in Table 5-6. Most compounds exhibited weak to moderate selectivity against Bcl-xL, indicating their dual Mcl-1/Bcl-xL inhibition profile. Generally, the compounds' binding affinity for Bcl-xL increased along with the development of stronger potency for Mcl-1 inhibition. Comparing the 4-aminosalicylate analogs, changing R2 group (13aa, 13ab, 13ac, 13ag and 13ak) had little effects on selectivity. Substitution of R1 group (13ak, 13bc, and 13cc) exhibited a very subtle response on the selectivity as well, with the benzyl substitution analog 13cc being the most selective inhibitor and the cyclopentyl analog 13bc being an equal potent inhibitor for both proteins. For the 5-aminosalicylate analogs, the R2 group had a slightly greater impact on the selectivity, particularly when R2 were 2-naphthyl 18bb and 3,5-dimethyl-4-chloro-phenoxyl group (18bd). Contrastingly, substituting the R with a benzyl group on the 5-aminosalicylate scaffold (29) decreased the selectivity dramatically to yield a Mcl-1/Bcl-xL dual inhibitor.
  • Table 5-6
    The selectivity of Mcl-1 against Bcl-xL for 4-aminosalicylate and 5-
    aminosalicylate analogs.
    Figure US20220396549A1-20221215-C00262
    Mcl-1 Bcl-xL Ki (Mcl-1):
    Compd X Y R1 R2 Ki (μM) Ki (μM) Ki (Bcl-xL)
    4jc117-1 13aa OH
    Figure US20220396549A1-20221215-C00263
    Figure US20220396549A1-20221215-C00264
    Figure US20220396549A1-20221215-C00265
         		192.038 ± 37.534  154.181 ± 27.596  1:0.80
    4jc117-3 13ab OH
    Figure US20220396549A1-20221215-C00266
    Figure US20220396549A1-20221215-C00267
    Figure US20220396549A1-20221215-C00268
         		13.821 ± 1.325  43.130 ± 14.668 1:3.12
    4jc117-4 13ac OH
    Figure US20220396549A1-20221215-C00269
    Figure US20220396549A1-20221215-C00270
    Figure US20220396549A1-20221215-C00271
         		4.109 ± 0.245 10.781 ± 2.553  1:2.63
    LC-4-099 13ag OH
    Figure US20220396549A1-20221215-C00272
    Figure US20220396549A1-20221215-C00273
    Figure US20220396549A1-20221215-C00274
         		5.766 ± 0.458 17.996 ± 4.602  1:3.12
    4jc117-5 13ak OH
    Figure US20220396549A1-20221215-C00275
    Figure US20220396549A1-20221215-C00276
    Figure US20220396549A1-20221215-C00277
         		0.778 ± 0.050 1.629 ± 0.177 1:2.09
    LC-4-104 13bc OH
    Figure US20220396549A1-20221215-C00278
    Figure US20220396549A1-20221215-C00279
    Figure US20220396549A1-20221215-C00280
         		1.762 ± 0.208 1.911 ± 0.117 1:1.08
    LC-4-118 13cc OH
    Figure US20220396549A1-20221215-C00281
    Figure US20220396549A1-20221215-C00282
    Figure US20220396549A1-20221215-C00283
         		0.629 ± 0.040 1.672 ± 0.351 1:2.65
    jy-5-296 18ba
    Figure US20220396549A1-20221215-C00284
         		OH
    Figure US20220396549A1-20221215-C00285
    Figure US20220396549A1-20221215-C00286
         		46.468 ± 9.816  49.331 ± 5.026  1:1.06
    jy-5-299 18bb
    Figure US20220396549A1-20221215-C00287
         		OH
    Figure US20220396549A1-20221215-C00288
    Figure US20220396549A1-20221215-C00289
         		7.509 ± 0.840 44.636 ± 5.929  1:5.94
    JY-5-300 18bc
    Figure US20220396549A1-20221215-C00290
         		OH
    Figure US20220396549A1-20221215-C00291
    Figure US20220396549A1-20221215-C00292
         		8.704 ± 2.049 13.851 ± 3.364  1:1.59
    JY-5-304 18bd
    Figure US20220396549A1-20221215-C00293
         		OH
    Figure US20220396549A1-20221215-C00294
    Figure US20220396549A1-20221215-C00295
         		0.586 ± 0.041 2.905 ± 0.191 1:4.96
    LC-5-129 29
    Figure US20220396549A1-20221215-C00296
         		OH
    Figure US20220396549A1-20221215-C00297
    Figure US20220396549A1-20221215-C00298
         		1.40 ± 0.47 1.816 ± 0.234 1:1.30
  • Additionally, a new hybrid molecule that fuses a Bcl-2 p4 moiety with a Mcl-1 p2 binding moiety through an acyl sulfonamide bond was developed.
  • In order to explore the SAR of this hybrid molecule, a library of analogs have been designed and synthesized in Table 5-7. First of all, various acyl sulfonamides were installed to compare their activity on both Mcl-1 and BCl-xL (27, 28, 30, 31 and 32). Expansion of moiety size on the Y-position can completely revert the analog's selectivity profile, from selective against Bcl-xL (27), to dual Mcl-1/Bcl-xL inhibitor (28) and selective against Mcl-1 (29). During this process, the potency for both Mcl-1 and Bcl-xL was also increased from compound 27 to 30. Therefore, further optimization on the R2 group with 3,5-dimethyl-4-phenol was expected to afford a more potent compound 31, with Ki (Mcl-1)=800 nM and a slightly increased selectivity against Bcl-xL. The identical Mcl-1/Bcl-xL inhibition profile between acyl sulfonamide compound 31 and carboxylic acid compound 13cc again demonstrated the bioisosteric character of acyl sulfonamide group. Further extending the Bcl-2 p4 moiety through an additional benzene sulfonamide linker generated the most potent dual Mcl-1/Bcl-xL inhibitor 32, with Ki (Mcl-1)=493 nM and Ki (Bcl-xL)=835 nM. This suggested that the length of p4 moiety can be further optimized to improve the potency of these molecules. Also, the corresponding hybrid compound for 5-aminosalicylate compound was also synthesized (33) and exhibited very similar potency compared to its carboxylic acid analog 29. Finally, the different merging location was tested by synthesizing compound 34, which the Bcl-2 p4 moiety was merged onto the hydroxyl group position, similar to the merging position of Tanaka's molecule. However, this method of merging lessened the compound's Mcl-1 and Bcl-xL binding affinity compared to compound 13cc, suggesting that the carboxylic acid is the optimal position for this hybridization strategy.
  • TABLE 5-7
    The selectivity of Mcl-1 over Bcl-xL when substituting carboxylic acid
    with various acyl sulfonamides.
    Figure US20220396549A1-20221215-C00299
    Mcl-1 Bcl-xL Ki (Mcl-1):
    Compd X Y R1 R2 Ki (μM) Ki (μM) Ki (Bcl-xL)
    LC-4-118 13cc OH
    Figure US20220396549A1-20221215-C00300
    Figure US20220396549A1-20221215-C00301
    Figure US20220396549A1-20221215-C00302
         		0.629 ± 0.040 1.672 ± 0.351 1:2.65
    LC-5-112 27 OH
    Figure US20220396549A1-20221215-C00303
    Figure US20220396549A1-20221215-C00304
    Figure US20220396549A1-20221215-C00305
         		2.94 ± 0.35 7.223 ± 1.072 1:2.45
    LC-5-096 28 OH
    Figure US20220396549A1-20221215-C00306
    Figure US20220396549A1-20221215-C00307
    Figure US20220396549A1-20221215-C00308
         		1.945 ± 0.222 2.336 ± 0.221 1:1.20
    LC-5-107 30 OH
    Figure US20220396549A1-20221215-C00309
    Figure US20220396549A1-20221215-C00310
    Figure US20220396549A1-20221215-C00311
         		1.232 ± 0.152 1.053 ± 0.146 1:0.85
    LC-5-131 31 OH
    Figure US20220396549A1-20221215-C00312
    Figure US20220396549A1-20221215-C00313
    Figure US20220396549A1-20221215-C00314
         		0.80 ± 0.07 1.615 ± 0.176 1:2.02
    LC-5-175 32 OH
    Figure US20220396549A1-20221215-C00315
    Figure US20220396549A1-20221215-C00316
    Figure US20220396549A1-20221215-C00317
         		0.493 ± 0.031 0.835 ± 0.086 1:1.69
    LC-5-129 29
    Figure US20220396549A1-20221215-C00318
         		OH
    Figure US20220396549A1-20221215-C00319
    Figure US20220396549A1-20221215-C00320
         		1.40 ± 0.47 1.816 ± 0.234 1:1.30
    LC-5-132 33
    Figure US20220396549A1-20221215-C00321
         		OH
    Figure US20220396549A1-20221215-C00322
    Figure US20220396549A1-20221215-C00323
         		1.01 ± 0.08 1.535 ± 0.226 1:1.52
    LC-5-111 34
    Figure US20220396549A1-20221215-C00324
    Figure US20220396549A1-20221215-C00325
    Figure US20220396549A1-20221215-C00326
    Figure US20220396549A1-20221215-C00327
         		8.55 ± 1.53 3.195 ± 1.883 1:0.37
  • TABLE 5-8
    Selectivity of Mcl-1 against Bcl-xL when varying the linker.
    Figure US20220396549A1-20221215-C00328
    Mcl-1 Bcl-xL Ki (Mcl-1):
    Compd R1 L Ki (μM) Ki (μM) Ki (Bcl-xL)
    LC-4-118 13cc
    Figure US20220396549A1-20221215-C00329
    Figure US20220396549A1-20221215-C00330
         		0.629 ± 0.040 1.672 ± 0.351 1:2.66
    LC-5-188 35
    Figure US20220396549A1-20221215-C00331
    Figure US20220396549A1-20221215-C00332
         		 1.445 ± 16.644 2.984 ± 0.406 1:2.06
    LC-5-184 36
    Figure US20220396549A1-20221215-C00333
    Figure US20220396549A1-20221215-C00334
         		15.247 ± 1.891  22.713 ± 4.083  1:1.49
  • The impact of using a different linker group was also evaluated by replacing the sulfonamide group with a C-3 alkyl linker (35). Similar to the Mcl-1 inhibition resulting from the THQ scaffold, a sulfonamide linker increased the binding affinity for Mcl-1 from the C-3 alkyl linker. It also improved the compound's BCl-xL binding affinity at the same time. Again, a hydrophobic R1 group was desirable for the potency as compared to a hydrogen atom (36).
  • TABLE 5-9
    Cell viability of HL-60 cell line after treating with inhibitors for 24 hrs.
    Figure US20220396549A1-20221215-C00335
    HL-60 HL-60
    Mcl-1 Bcl-xL IC50 (μM) IC50 (μM)
    Compd X Y R1 R2 Ki (μM) Ki (μM) 0.5% FBS 10% FBS
    LC-4-099 13ag OH
    Figure US20220396549A1-20221215-C00336
    Figure US20220396549A1-20221215-C00337
    Figure US20220396549A1-20221215-C00338
         		5.766 ± 0.458 17.996 ± 4.602  18.51 >120
    LC-4-131 20 OH
    Figure US20220396549A1-20221215-C00339
    Figure US20220396549A1-20221215-C00340
    Figure US20220396549A1-20221215-C00341
         		>500 N.A 68.07 76.42
    LC-4-141 21 OH
    Figure US20220396549A1-20221215-C00342
    Figure US20220396549A1-20221215-C00343
    Figure US20220396549A1-20221215-C00344
         		>500 N.A 46.42 > 120
    LC-4-118 13cc OH
    Figure US20220396549A1-20221215-C00345
    Figure US20220396549A1-20221215-C00346
    Figure US20220396549A1-20221215-C00347
         		0.629 ± 0.040 1.672 ± 0.351 <7.5 53.2
    LC-5-188 36 OH
    Figure US20220396549A1-20221215-C00348
    Figure US20220396549A1-20221215-C00349
    Figure US20220396549A1-20221215-C00350
         		 1.445 ± 16.644 2.984 ± 0.406 7.359 88.01
    JY-5-304 18bd
    Figure US20220396549A1-20221215-C00351
         		OH
    Figure US20220396549A1-20221215-C00352
    Figure US20220396549A1-20221215-C00353
         		0.586 ± 0.041 2.905 ± 0.191 9.817 >120
    LC-5-131 31 OH
    Figure US20220396549A1-20221215-C00354
    Figure US20220396549A1-20221215-C00355
    Figure US20220396549A1-20221215-C00356
         		0.80 ± 0.07 1.615 ± 0.176 9.965 >120
    LC-5-175 32 OH
    Figure US20220396549A1-20221215-C00357
    Figure US20220396549A1-20221215-C00358
    Figure US20220396549A1-20221215-C00359
         		0.493 ± 0.031 0.835 ± 0.086 16.74 >120
  • Next, the most potent compounds were evaluated for their ability to kill human acute promyelocytic leukemia cell line HL-60, which has been reported to be more sensitive to Mcl-1 blockade than Bcl-2/Bcl-xL blockade, and most sensitive when a broad range of Bcl-2 pro-apoptotic proteins were inhibited including Bcl-2, Bcl-xL and Mcl-1. All the carboxylic acid and acyl sulfonamide compounds showed dose dependent cell growth inhibition with IC50 ranging from less than 7.5 μM to 18.51 μM in the 0.5% fetal bovine serum environment. They all showed heavy serum binding when 10% of FBS was added to the culture environment, with a 10-fold or more drop in IC50. The moderate cell grow inhibition ability for the two carboxylic acid ester prodrugs 20 and 21 could be attributed to the enzymatic hydrolysis that generated a free acid molecule (13ag) to function as an Mcl-1 inhibitor in the cells. The data also suggested that the acidic salicylate analogs were cell penetrable, which can be due to the formation of an intramolecular hydrogen bond with the ortho position phenol group to mask the negative charge and make the molecule less polar and more cell penetrable. Interestingly, the most potent Mcl-1/Bcl-xL dual inhibitor 32 was less effective in cell growth inhibition than compound 13cc, indicating other survival proteins might also affected with these inhibitors.
    • Example 6: Inhibitors of the Mcl-1 Oncoprotein Based on Carboxy-Substituted Salicylate Scaffolds Salicylate
  • Functionalized salicylates inhibit the Mcl-1 oncoprotein, as determined by the fluorescence polarization competition assay as described herein. Various functionalized salicylates were prepared and tested as provided hereinbelow in Tables 6-1, 6-2, and 6-3.
  • Table 6-1. Exemplary functionalized salicylate analogs with their associated Mcl-1 and BCl-xL inhibitory activities,
  • TABLE 6-2
    Exemplary functionalized salicylate analogs with their associated
    Mcl-1 and Bcl-XL inhibitory activities.
    Figure US20220396549A1-20221215-C00360
    Ki (μM)
    Compd R2 R1 Mcl-1 Bcl-xL
    LC-3-029
    Figure US20220396549A1-20221215-C00361
    Figure US20220396549A1-20221215-C00362
         		ND ND
    LC-3-031
    Figure US20220396549A1-20221215-C00363
    Figure US20220396549A1-20221215-C00364
         		ND ND
    LC-3-036
    Figure US20220396549A1-20221215-C00365
    Figure US20220396549A1-20221215-C00366
         		ND ND
    LC-3-025
    Figure US20220396549A1-20221215-C00367
    Figure US20220396549A1-20221215-C00368
         		ND ND
    LC-3-030
    Figure US20220396549A1-20221215-C00369
    Figure US20220396549A1-20221215-C00370
         		0.361 ± 0.058 ND
    4jc-117-1
    Figure US20220396549A1-20221215-C00371
    Figure US20220396549A1-20221215-C00372
         		NA NA
    4jc-112-3
    Figure US20220396549A1-20221215-C00373
    Figure US20220396549A1-20221215-C00374
         		60.300 ± 24.434 ND
    4jc-117-4
    Figure US20220396549A1-20221215-C00375
    Figure US20220396549A1-20221215-C00376
         		7.672 ± 0.263 ND
    Figure US20220396549A1-20221215-C00377
    Figure US20220396549A1-20221215-C00378
         		ND ND
    4jc-112-5
    Figure US20220396549A1-20221215-C00379
    Figure US20220396549A1-20221215-C00380
         		0.025 ± 0.012 0.05 ± 0.40
  • TABLE 6-3
    Exemplary functionalized salicylate analogs with their associated
    Mcl-1 and Bcl-xL inhibitory activities.
    Figure US20220396549A1-20221215-C00381
    Ki (μM)
    Compd R2 R1 Mcl-1 Bcl-xL
    4jc-117-2
    Figure US20220396549A1-20221215-C00382
    Figure US20220396549A1-20221215-C00383
         		301.875 ± 31.626  ND
    LC-4-099
    Figure US20220396549A1-20221215-C00384
    Figure US20220396549A1-20221215-C00385
         		ND ND
    LC-4-111
    Figure US20220396549A1-20221215-C00386
    Figure US20220396549A1-20221215-C00387
         		ND ND
    LC-4-119
    Figure US20220396549A1-20221215-C00388
    Figure US20220396549A1-20221215-C00389
         		ND ND
    LC-4-100
    Figure US20220396549A1-20221215-C00390
    Figure US20220396549A1-20221215-C00391
         		ND ND
    LC-4-104
    Figure US20220396549A1-20221215-C00392
    Figure US20220396549A1-20221215-C00393
         		ND ND
    LC-4-118
    Figure US20220396549A1-20221215-C00394
    Figure US20220396549A1-20221215-C00395
         		ND ND
  • A number of patent and non-patent publications are cited herein in order to describe the state of the art to which this invention pertains. The entire disclosure of each of these publications is incorporated by reference herein.
  • While certain embodiments of the present invention have been described and/or exemplified above, various other embodiments will be apparent to those skilled in the art from the foregoing disclosure. The present invention is, therefore, not limited to the particular embodiments described and/or exemplified, but is capable of considerable variation and modification without departure from the scope and spirit of the appended claims.
  • Moreover, as used herein, the term “about” means that dimensions, sizes, formulations, parameters, shapes and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, a dimension, size, formulation, parameter, shape or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such.
  • It is noted that embodiments of very different sizes, shapes and dimensions may employ the described arrangements.
  • Furthermore, the transitional terms “comprising”, “consisting essentially of” and “consisting of”, when used in the appended claims, in original and amended form, define the claim scope with respect to what unrecited additional claim elements or steps, if any, are excluded from the scope of the claim(s). The term “comprising” is intended to be inclusive or open-ended and does not exclude any additional, unrecited element, method, step or material. The term “consisting of” excludes any element, step or material other than those specified in the claim and, in the latter instance, impurities ordinary associated with the specified material(s). The term “consisting essentially of” limits the scope of a claim to the specified elements, steps or material(s) and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. All compounds, compositions, formulations, and methods described herein that embody the present invention can, in alternate embodiments, be more specifically defined by any of the transitional terms “comprising,” “consisting essentially of,” and “consisting of”.
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Claims (18)

1.-8. (canceled)
9. A compound of formula (IV):
Figure US20220396549A1-20221215-C00396
wherein R41 is a substituent selected from the group consisting of H and optionally substituted alkyl, aryl, and cycloalkyl;
Z41 and Z42 each can independently represent a substituent selected from the group consisting of H, cyano, OR42, COOR42, CONR42OR42, CONR42R42, CON(R42)—S(O)2R42,
Figure US20220396549A1-20221215-C00397
and optionally substituted alkyl and aryl;
each R42 can independently represent a substituent selected from the group consisting of H and optionally substituted alkyl and aryl;
A41 is a bond or a substituent selected from the group consisting of S(═O), S(═O)2, and C(═O);
X41 is a substituent selected from the group consisting of optionally substituted alkyl, aryl, cycloalkyl, and heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
10. The compound of claim 9, wherein the compound is selected from the group consisting of 4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
2-hydroxy-4-(N-isobutylphenylsulfonamido)benzoic acid,
2-hydroxy-4-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
4-(4-bromo-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
2-hydroxy-4-(N-isobutyl-4-(p-tolyloxy)phenylsulfonamido)benzoic acid,
4-(4-(3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
4-(4-(2,4-dichlorophenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
2-hydroxy-4-(4-phenoxyphenylsulfonamido)benzoic acid,
3-(N-isobutylphenylsulfonamido)benzoic acid,
3-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
2-hydroxy-5-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
5-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
methyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(phenylsulfonyl)benzamide,
4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(methylsulfonyl)benzamide,
4-(N-isobutyl-4-phenoxyphenylsulfonamido)-2-((4-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)benzyl)oxy)benzoic acid,
4-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
4-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
2-hydroxy-4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
2-hydroxy-4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
4-(N-cyclopentyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
4-(N-cyclopentylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
4-(4-(4-chloro-3,5-dimethylphenoxy)-N-cyclopentylphenylsulfonamido)-2-hydroxybenzoic acid,
3-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
3-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
phenyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
acetoxymethyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
N-(4-cyano-3-hydroxyphenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
4-(4-fluoro-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoic acid,
4-(N-benzyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
4-(N-benzylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
3-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
2-hydroxy-5-(N-isobutylphenylsulfonamido)benzoic acid,
2-hydroxy-5-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
N-(4-(2H-tetrazol-5-yl)phenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
N,2-dihydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzamide,
N-isobutyl-N-(4-(3-oxo-2,3-dihydroisoxazol-5-yl)phenyl)-4-phenoxybenzenesulfonamide,
5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
11. The compound of claim 9, wherein Z41 and Z42 each can independently represent a substituent selected from the group consisting of OR42 and COOR42.
12. A compound of the formula:
Figure US20220396549A1-20221215-C00398
or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
13. A method of treating a condition by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method comprising administering a therapeutically effective amount of a compound of claim 9 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
14.-16. (canceled)
17. A method of treating a condition by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method comprising administering a therapeutically effective amount of one or more compounds selected from the group consisting of:
4-(N-isobutylphenylsulfonamido)benzoic acid,
4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
2-hydroxy-4-(N-isobutylphenylsulfonamido)benzoic acid,
2-hydroxy-4-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
4-(4-bromo-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
2-hydroxy-4-(N-isobutyl-4-(p-tolyloxy)phenylsulfonamido)benzoic acid,
4-(4-(3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
4-(4-(2,4-dichlorophenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
2-hydroxy-4-(4-phenoxyphenylsulfonamido)benzoic acid,
3-(N-isobutylphenylsulfonamido)benzoic acid,
3-(N-isobutyl-4-methylphenylsulfonamido)benzoic acid,
2-hydroxy-5-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
5-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
methyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(phenylsulfonyl)benzamide,
4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-(methylsulfonyl)benzamide,
4-(N-isobutyl-4-phenoxyphenylsulfonamido)-2-((4-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)benzyl)oxy)benzoic acid,
4-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
4-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
2-hydroxy-4-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
2-hydroxy-4-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
4-(N-cyclopentyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
4-(N-cyclopentylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
4-(4-(4-chloro-3,5-dimethylphenoxy)-N-cyclopentylphenylsulfonamido)-2-hydroxybenzoic acid,
3-(N-isobutylnaphthalene-2-sulfonamido)benzoic acid,
3-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)benzoic acid,
phenyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
acetoxymethyl 2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoate,
N-(4-cyano-3-hydroxyphenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
4-(N-benzyl-4-phenoxyphenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
3-(4-(4-chloro-3,5-dimethylphenoxy)-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
4-(4-fluoro-N-isobutylphenylsulfonamido)-2-hydroxybenzoic acid,
2-hydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzoic acid,
4-(N-benzyl-[1,1′-biphenyl]-4-ylsulfonamido)-2-hydroxybenzoic acid,
4-(N-benzylnaphthalene-2-sulfonamido)-2-hydroxybenzoic acid,
4-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
3-(4-fluoro-N-isobutylphenylsulfonamido)benzoic acid,
2-hydroxy-5-(N-isobutylphenylsulfonamido)benzoic acid,
2-hydroxy-5-(N-isobutyl-[1,1′-biphenyl]-4-ylsulfonamido)benzoic acid,
N-(4-(2H-tetrazol-5-yl)phenyl)-N-isobutyl-4-phenoxybenzenesulfonamide,
N,2-dihydroxy-4-(N-isobutyl-4-phenoxyphenylsulfonamido)benzamide,
N-isobutyl-N-(4-(3-oxo-2,3-dihydroisoxazol-5-yl)phenyl)-4-phenoxybenzenesulfonamide,
5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxybenzoic acid,
5-(N-benzyl-4-(4-chloro-3,5-dimethylphenoxy)phenylsulfonamido)-2-hydroxy-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
18. A method of treating a condition by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method comprising administering a therapeutically effective amount of a compound of formula:
Figure US20220396549A1-20221215-C00399
or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
19. The method of claim 18, wherein the condition is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma.
20. The method of claim 18, wherein the condition is selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.
21. A pharmaceutical composition for treating a condition alleviated by inhibiting Mcl-1 protein activity, the pharmaceutical composition comprising one or more compounds according to claim 12, and a pharmaceutically acceptable carrier.
22. The method of claim 13, wherein the condition is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma.
23. The method of claim 13, wherein the condition is selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.
24. A pharmaceutical composition for treating a condition alleviated by inhibiting Mcl-1 protein activity, the pharmaceutical composition comprising one or more compounds according to claim 9, and a pharmaceutically acceptable carrier.
25. The method of claim 17, wherein the condition is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma.
26. The method of claim 17, wherein the condition is selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.
27. A pharmaceutical composition for treating a condition alleviated by inhibiting Mcl-1 protein activity, the pharmaceutical composition comprising one or more compounds according to claim 10, and a pharmaceutically acceptable carrier.
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