Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

• the present invention provides novel macrocyclic compounds having tumor vascular remodeling effects and anti-CAF (Cancer Associated Fibroblast) activity.
• the compounds can be used for, e.g., treating cancer or inhibiting tumor growth in a subject.
• Halichondrins such as Halichondrin B
• Halichondrin B are anticancer agents originally isolated from the marine sponge Halichondria okadai (See, e.g., D. Uemura et al.“Norhalichondrin A: An Antitumor Polyether Macrolide from a Marine Sponge” J. Am. Chem. Soc., 107, 4796 (1985)), and subsequently found in Axinella sp., Phakellia carteri, and Lissodendoryx sp. A total synthesis of Halichondrin B was published in 1992 (See, e.g., Y.
• Halichondrin B has demonstrated in vitro inhibition of tubulin polymerization, microtubule assembly, beta 5-tubulin crosslinking, GTP and vinblastine binding to tubulin, and tubulin- dependent GTP hydrolysis, and has shown in vitro and in vivo anti-cancer properties (See, e.g., Y. Hirata et al.“Halichondrins-antitumor polyether macrolides from a marine sponge” Pure Appl. Chem., 58, 701 (1986); Fodstad et al.“Comparative antitumor activities of halichondrins and vinblastine against human tumor xenografts” J. of Experimental
• HalavenTM Eribulin mesylate
• CAFs Cancer associated fibroblasts
• invasive breast cancer See, e.g., M. Yamashita et al.“Role of stromal myofibroblasts in invasive breast cancer: stromal expression of alpha-smooth muscle actin correlates with worse clinical outcome” Breast Cancer 19, 170, 2012
• esophageal adenocarcinoma See, e.g., T. J. Underwood et al.“Cancer-associated fibroblasts predict poor outcome and promote periostin-dependent invasion in esophageal
• CAFs correlate to resistance in a variety of tumors, such as, for example, breast cancer (See, e.g., P. Farmer et al.“A stroma-related gene signature predicts resistance to neoadjuvant
• tumor vascular remodeling effects and anti-CAF activity result in the improvement of the cancer microenvironment, which assists tumor treatment.
• Blood vessels are essential for the growth of tumors. Reconstructed blood vessels in tumors can deliver anti-cancer agents to the tumors, in addition to alleviating hypoxia.
• eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to the elimination of inner tumor hypoxia. Because abnormal tumor microenvironments enhance both drug resistance and metastasis, the apparent ability of eribulin to reverse these aggressive characteristics may contribute to its clinical benefits (See, e.g., Y. Funahashi el al.
• Halichondrins as well as analogs and derivatives thereof, are useful therapeutic agents.
• Examples of halichondrins, analogs, and derivatives thereof, as well as methods of using the same, and methods of synthesizing the same, can be found in, e.g., U.S. Publication No. 2017/0137437, published May 18, 2017; International Publication No. WO 2016/003975, published January 7, 2016; U.S. Publication No. 2018/0230164, published August 16, 2018; International Publication No. WO 2016/176560, published November 3, 2016; U.S.
• the present invention relates to macrocyclic compounds (e.g., compounds of Formulae (I), (II), (III), and (IV)), and pharmaceutically acceptable salts thereof, and isotopically labeled derivatives thereof, and pharmaceutical compositions thereof.
• the compounds have tumor vascular remodeling effects and anti-CAF activity.
• the invention also provides methods of using the compounds provided herein, e.g., for treating a proliferative disease in a subject.
• the invention includes methods of using compounds provided herein for treating a subject with cancer, methods for reversibly or irreversibly inhibiting mitosis in a cell, and methods for inhibiting tumor growth in vitro, in vivo, or in a subject.
• the present invention provides kits comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
• the present invention provides compounds of Formula (I):
• R N1 and R N2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group, optionally wherein R N1 and R N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
• R P1 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group
• R x is hydrogen or -OR Xa ;
• R Y is hydrogen or -OR Ya ;
• R Xa and R Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group, optionally wherein R Xa and R Ya are joined together with the intervening atoms to form optionally substituted heterocyclyl;
• n 1 or 2.
• the present invention provides compounds of Formula (II):
• R N1 and R N2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group, optionally wherein R N1 and R N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
• R P1 and R p2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
• R x is hydrogen or -OR Xa ;
• R Y is hydrogen or -OR Ya ;
• R Xa and R Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group, optionally wherein R Xa and R Ya are joined together with the intervening atoms to form optionally substituted heterocyclyl;
• R° is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group
• R P1 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group
• R x is hydrogen or -OR Xa ;
• R Y is hydrogen or -OR Ya ;
• R Xa and R Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group, optionally wherein R Xa and R Ya are joined together with the intervening atoms to form optionally substituted heterocyclyl;
• n 1 or 2.
• the compound of Formula (III) is not the following:
• R° is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group
• R P1 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group
• R x is hydrogen or -OR Xa ;
• R Y is hydrogen or -OR Ya ;
• R Xa and R Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group, optionally wherein R Xa and R Ya are joined together with the intervening atoms to form optionally substituted heterocyclyl.
• the invention features a compound which is Compound (1):
• Compound (1) is excluded from the invention. In certain embodiments, Compound (1) and all pharmaceutically acceptable salts thereof and isotopically labeled derivatives thereof are excluded from the invention.
• the invention provides pharmaceutical compositions comprising a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof.
• the pharmaceutical compositions may comprise one or more
• compositions may further comprise one or more additional therapeutic agents in combination, alternation, or other kind of synchronized therapy, to achieve the desired goal of treatment.
• the invention also features methods of making compounds provided herein, or intermediates thereto.
• the synthetic intermediates are also provided herein as part of the invention.
• the compounds provided herein have an advantageous effect on tumor vascular remodeling and has anti-CAF activity, as demonstrated in the Figures and Examples. Accordingly, the compounds provided herein have potential use in the treatment of proliferative diseases.
• the compounds can be used to treat cancer (e.g ., squamous cell carcinoma of the head and neck (SCCHN), breast cancer, esophageal cancer, uterine cancer, ovarian cancer, colorectal cancer, endometrial cancer, gastric cancer, lung cancer, small bowel cancer, bladder cancer, sweat gland cancer, sarcomas, rare cancers).
• cancer e.g squamous cell carcinoma of the head and neck (SCCHN)
• breast cancer e.g squamous cell carcinoma of the head and neck (SCCHN)
• esophageal cancer uterine cancer
• ovarian cancer colorectal cancer
• endometrial cancer gastric cancer
• lung cancer small bowel cancer
• bladder cancer e.g sarcomas
• the present invention provides methods for treating cancer or inhibiting tumor growth in a subject with a compound provided herein, or a pharmaceutically acceptable salt, or isotopically labeled derivative thereof.
• the present invention provides methods for inhibiting any tumor growth or cancer that will respond to a compound with tumor vascular remodeling effects and/or anti-CAF activity, in a subject, typically a human, with a compound provided herein, or a pharmaceutically acceptable salt, or isotopically labeled derivative thereof.
• a compound provided herein, or a pharmaceutically acceptable salt, or isotopically labeled derivative thereof, or a composition thereof, may be administered in combination with any other active agent that provides beneficial results for the patient.
• a compound provided herein is used in combination, alternation, or other synchronized therapy with an immunotherapy.
• the immunotherapy is an anti-EGFR (epidermal growth factor receptor) antibody, an anti-HER2 (human epidermal growth factor receptor) antibody, an anti-PD-l antibody, or an anti-PD-Ll antibody, as described in more detail below.
• a method is provided to treat squamous cell carcinoma of the head and neck (SCCHN) in a subject, typically a human, in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, or isotopically labeled derivative thereof, or a composition thereof, in combination with an anti-EGFR (epidermal growth factor receptor) mAb therapy.
• the anti-EGFR (epidermal growth factor receptor) mAb is cetuximab.
• a method to treat breast cancer in a subject comprising administering to said subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, or isotopically labeled derivative thereof, or a composition thereof, in combination with an HER2 (human epidermal growth factor receptor) mAb therapy.
• the HER2 (human epidermal growth factor receptor) mAb is trastuzumab.
• the compound may be used to treat breast cancer in combination with traditional chemotherapy, such as adriamycin, cyclophosphamide, taxol, etc., or an anti-estrogen such as a selective estrogen modulator (SERM), a selective estrogen degrader (SERD), a partial or total estrogen inhibitor (such as fulvestrant) or a CDK 4/6 inhibitor such as palbociclib (Pfizer).
• traditional chemotherapy such as adriamycin, cyclophosphamide, taxol, etc.
• an anti-estrogen such as a selective estrogen modulator (SERM), a selective estrogen degrader (SERD), a partial or total estrogen inhibitor (such as fulvestrant) or a CDK 4/6 inhibitor such as palbociclib (Pfizer).
• SERM selective estrogen modulator
• SELD selective estrogen degrader
• Pfizer a partial or total estrogen inhibitor
• CDK 4/6 inhibitor such as palbociclib
• kits described herein may include a single dose or multiple doses of the compound or pharmaceutical composition thereof.
• a kit of the invention may include instructions for using the provided therapeutic dosage forms (e.g ., instructions for using the compound or pharmaceutical composition included in the kit).
• the present invention thus includes at least the following features:
• a method for treatment that includes administering an effective amount to a subject such as a human of a compound provided herein, or a
• the pharmaceutically acceptable salt or isotopically labeled derivative which may be optionally be in the form of a hydrate, solvate, stereoisomer, or polymorph, to treat a proliferative disease.
• the proliferative disease is cancer.
• the cancer is head and neck cancer (e.g., squamous cell carcinoma of the head and neck (SCCHN), adenoid cystic carcinoma), breast cancer, esophageal cancer (e.g., esophageal adenocarcinoma), uterine cancer (e.g., uterine sarcoma), ovarian cancer, colorectal cancer, or sarcoma (e.g., synovial sarcoma, angiosarcoma, soft tissue sarcoma, fibrosarcoma, uterine sarcoma, intimal sarcoma).
• SCCHN head and neck cancer
• esophageal cancer e.g., esophageal adenocarcinoma
• uterine cancer e.g., uterine sarcoma
• ovarian cancer colorectal cancer
• sarcoma e.g., synovial sarcoma, angio
• the cancer is bladder cancer (e.g., urothelial carcinoma), gastric cancer, small bowel cancer (e.g., small bowel adenocarcinoma), endometrial cancer, lung cancer (e.g., non-small cell lung cancer), or sweat gland cancer (e.g., sweat gland carcinoma).
• the cancer is a rare cancer;
• a method for treatment that includes administering an effective amount to a subject such as a human of a compound provided herein, or a
• pharmaceutically acceptable salt or isotopically labeled derivative thereof which may be optionally be in the form of a hydrate, solvate, stereoisomer, or polymorph, for use in treating a medical disorder that responds to vascular remodeling effects and/or anti-CAF activity (e.g., a proliferative disease such as cancer or a tumor);
• the proliferative disease is cancer.
• the cancer is squamous cell carcinoma of the head and neck (SCCHN), breast cancer, esophageal cancer, uterine cancer, ovarian cancer, colorectal cancer, endometrial cancer, or a sarcoma;
• a medical disorder that responds to vascular remodeling effects and/or anti-CAF activity e.g., a proliferative disease such as a cancer or tumor
• a medical disorder that responds to vascular remodeling effects and/or anti-CAF activity e.g., a proliferative disease such as a cancer or tumor
• a process for manufacturing a medicament intended for the therapeutic use for treating or preventing a disorder such as a proliferative disease (e.g., cancer or tumor) that responds to vascular remodeling effects and/or anti-CAF activity characterized in that a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, which may be optionally be in the form of a hydrate, solvate, stereoisomer, or polymorph described above, or an embodiment of the active compound, is used in the manufacture;
• a disorder described herein e.g., proliferative disease
• a disorder described herein e.g., proliferative disease
• Figure 1 shows antitumor effects of Compound (1) in FaDu subcutaneous xenograft model (head and neck cancer) in mice as monotherapy as described in Pharmacological Test Example 4.
• Figure 2 shows antitumor activity of Compound (1) against OSC-19 subcutaneous xenograft model (head and neck cancer) in mice as monotherapy as described in
• Figure 3 shows antitumor activity of Compound (1) against HCC-1806
• subcutaneous xenograft (breast cancer) model in mice as monotherapy as described in Pharmacological Test Example 6.
• Figure 4 shows antitumor effects of Compound (1) in FaDu subcutaneous xenograft model in combination with cetuximab in mice as described in Pharmacological Test Example 7.
• Figure 5 shows antitumor activity of Compound (1) in KPL-4 subcutaneous xenograft model (breast cancer) in combination with trastuzumab in mice as described in Pharmacological Test Example 8.
• Figure 6A-6B show anti-tumor effect of Compound (1) in HSC-2 orthotopic transplantation mouse model.
• Figure 6A Nude mice were implanted with luciferase- transduced HSC-2 (1 x 10 6 cells/spot) in tongue. The amount of luciferase-transduced HSC-2 was analyzed using In Vivo Imaging System (IVIS). Data show the bioluminescence levels in tongue in each mouse.
• Figure 6B Representative bioluminescence image of 16 mice.
• CDDP, CTX, CDDP+CTX were used for as comparators, which are currently used in treatment of SCCHN cancer patient treatment.
• CDDP cisplatin
• CTX cetuximab.
• Figure 7A-7B show survival advantage of Compound (1) in combination with cetuximab in HSC-2 orthotopic transplantation mouse model.
• Figure 8A-8B show anti-tumor effect of Compound (1) in combination with radiation therapy in FaDu mouse xenograft model.
• Figure 8A Nude mice were
• mice subcutaneously implanted with luciferase-transduced FaDu (5 x 10 6 cells/spot) in the right thighs.
• luciferase-transduced FaDu 5 x 10 6 cells/spot
• Figure 9 shows anti-tumor activities of Compound (1) in combination with anti- mPD-l antibody.
• CT26 s.c. syngeneic mouse model colon carcinoma
• Figure 10A shows a cell-free tubulin polymerization assay.
• Compound (1) has inhibitory activity on tubulin polymerization.
• Figure 10B shows a microtubule dynamics assay.
• Compound (1) also has inhibitory activity on microtubule dynamics.
• Figure 11 shows that Compound (1) is a potent antiproliferative agent in esophageal cancer (OE21, OE33, and TE-8) and uterine cancer (MES-SA, MES-SA/Dx5-Rxl) cell lines.
• Figure 12 shows that Compound (1) has potent anti-tumor activity in subcutaneous xenograft models of breast and ovarian cancer (KPL-4 and COLO-704, respectively) as a monotherapy.
• Figure 13 shows the effect of Compound (1) on tumor microenvironments. As shown, Compound (1) increases microvessel density. * P ⁇ 0.05, ** P ⁇ 0.01, ****P ⁇ 0.0001 versus non-treat (Dunnett multiple comparison test).
• Figure 14 shows the effect of Compound (1) on tumor microenvironments. As shown, Compound (1) reduces a-SMA positive CAFs.
• Figure 15 shows that Compound (1) decreases ECM proteins from CAFs in FaDu subcutaneous xenograft model. FaDu xenograft tumors were collected on Day 6 after single administration of Compound (1) 180 pg/kg + cetuximab on Day 1.
• CTX cetuximab
• Figure 17 shows antitumor effects in the soft tissue sarcoma xenograft models in mice as monotherapy.
• MES-SA human uterine sarcoma
• HT-1080 human fibrosarcoma
• CTG-2041 human angiosarcoma
• Figure 18 shows antitumor effects in endometrial cancer xenograft models in mice as monotherapy. HEC-108 and AN3CA (endometrial cancer) are shown.
• Figures 19A-19H show that Compound (1) reduced TGF-P-induced a-SMA expression in an in vitro CAF-inducing system.
• Figure 19 A BJ cells (normal human lung fibroblasts) were co-cultured with FaDu cells for three days in the absence (vehicle) or presence of A83-01, a potent selective TGF-P-R inhibitor, and the expression of a-SMA was analysed by immunofluorescence staining (red color). Samples were also stained with anti- pan-human cytokeratin (green color) for cancer cell staining and DAPI (blue color) for nuclear staining.
• Figures 19B-19F BJ cells were treated with Compound (1) (0.15 nmol/F in immunofluorescence staining data and indicated concentrations in western blot analysis data) and TGF-b for 2 days.
• Figures 19B-19E Samples were stained with the indicated antibody (red color) and DAPI (blue color) for nuclear staining.
• Figure 19F Western blot images and quantification of the images. The graph shows ratios of the results of treatment groups to the non-treated group.
• Figures 19G and 19F BJ cells were pretreated with defactinib (1 pmol/F) and TGF-b for 2 days.
• the lens magnification used was x4 ( Figures 19A, 19B, 19C, 19G, and 19H) or x40 ( Figures 19D and 19E).
• FIGS 20A and 20B Quantification of immunofluorescence images of BJ cells treated with TGF-b (1 ng/mF) and the indicated concentrations of Compound (1) for a-SMA ( Figure 20A ), Phospho-S6-ribosomal protein (Ser235/236) ( Figure 20B).
• Figure 20C Quantification of Compound (1) for a-SMA ( Figure 20A ), Phospho-S6-ribosomal protein (Ser235/236) ( Figure 20B).
• Figure 20C Quantification of immunofluorescence images of BJ cells treated with TGF-b (1 ng/mF) and the indicated concentrations of Compound (1) for a-SMA ( Figure 20A ), Phospho-S6-ribosomal protein (Ser235/236) ( Figure 20B).
• Figure 20C Quantification of immunofluorescence images of BJ cells treated with TGF-b (1 ng/mF) and the indicated concentrations of Compound (1) for a-SMA ( Figure 20A ), Phospho-
• FIG. 20D Immunofluorescence analysis of BJ cells treated with TGF-b in the absence or presence of dactolisib, a phosphatidylinositol 3 kinase inhibitor.
• Figure 20D Immunofluorescence analysis of phosphorylated Smad2/3 in BJ cells pretreated with Compound (1) (72 hours) after 30 minutes of stimulation with TGF-b. Acetylated-a-tubulin was co-stained to confirm the activity of Compound (1).
• Figure 20E Western blot analysis of Smad2/3 in BJ cells treated with TGF-b and the indicated concentrations of Compound (1). The lens magnification used was x4 ( Figure 20C) or x40 ( Figure 20D).
• Figure 21 A Immunofluorescence staining of a-SMA (red color) and pan-cytokeratin (green color) in TIG3 co-cultured with FaDu in the absence or presence of A83-01, an FAK inhibitor.
• Figures 21 B and 21C Quantification of immunofluorescence images of TIG3 cells treated with TGF-b and the indicated concentrations of Compound (1) for a-SMA ( Figure 21 B), Phospho-S6-ribosomal protein (Ser235/236) ( Figure 21C).
• Figure 21 D and 21 E Quantification of immunofluorescence images of TIG3 cells treated with TGF-b and the indicated concentrations of Compound (1) for a-SMA ( Figure 21 B), Phospho-S6-ribosomal protein (Ser235/236)
• Figure 22 Antitumor effect of Compound (1) in an HS-SY-II (human synovial sarcoma) xenograft model in mice as a monotherapy.
• FIG. 23 Antitumor effect of Compound (1) in an HuTu 80 (human duodenal cell) xenograft model in mice as a monotherapy.
• Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
• the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
• Isomers 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 isomers can be prepared by asymmetric syntheses.
• HPLC high pressure liquid chromatography
• the invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of 12 C with 13 C or 14 C are within the scope of the disclosure.
• Such compounds are useful, for example, as analytical tools or probes in biological assays.
• aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
• heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
• alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“CH O alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-s alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci- 6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”).
• an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“Ci -3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“Ci -2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
• Ci -6 alkyl groups include methyl (Ci), ethyl (C 2 ), propyl (C 3 ) (e.g., n- propyl, .so-propyl), butyl (C 4 ) (e.g., H-butyl, ie/7-butyl, .scc-butyl, .so-butyl), pentyl (C 5 ) ⁇ e.g., «-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C 6 ) (e.g., «-hexyl).
• alkyl groups include «-heptyl (C 7 ), «- octyl (Cs), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an“unsubstituted alkyl”) or substituted (a“substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
• substituents e.g., halogen, such as F
• the alkyl group is an unsubstituted C HO alkyl (such as unsubstituted Ci -6 alkyl, e.g., -CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted «-propyl ( «-Pr), unsubstituted Ao-propyl (/-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted «-butyl ( «-Bu), unsubstituted / ⁇ ?
• C HO alkyl such as unsubstituted Ci -6 alkyl, e.g., -CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted «-propyl ( «-Pr), unsub
• the alkyl group is a substituted Ci-io alkyl (such as substituted Ci -6 alkyl, e.g., -CF 3 , Bn).
• haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
• the haloalkyl moiety has 1 to 8 carbon atoms (“Ci-s haloalkyl”).
• the haloalkyl moiety has 1 to 6 carbon atoms (“Ci- 6 haloalkyl”).
• the haloalkyl moiety has 1 to 4 carbon atoms (“Ci- 4 haloalkyl”).
• the haloalkyl moiety has 1 to 3 carbon atoms (“Ci -3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“Ci -2 haloalkyl”). Examples of haloalkyl groups include -CHF 2 , -CH 2 F, -CF 3 , -CH 2 CF , -CF 2 CF , -CF 2 CF 2 CF , -CCl 3 , -CFCh, -CF 2 Cl, and the like.
• heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within ( i.e ., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
• a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-io alkyl”).
• a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain
• heteroCi- 9 alkyl a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-s alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi- 7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi- 6 alkyl”).
• a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroCi- 5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroCi- 4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi- 3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi- 2 alkyl”).
• a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an“unsubstituted heteroalkyl”) or substituted (a“substituted heteroalkyl”) with one or more substituents. In certain
• the heteroalkyl group is an unsubstituted heteroCi-io alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-io alkyl.
• alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds ( e.g .,
• an alkenyl group has 2 to 9 carbon atoms (“C 2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2-7 alkenyl”).
• an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5 alkenyl”). In some
• an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In some
• an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In some
• an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
• the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in l-butenyl).
• Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), l-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
• C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an“unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
• heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
• a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-i o alkenyl”).
• a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2- s alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkenyl”).
• a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-4 alkenyl”).
• a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an“unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.
• the heteroalkenyl group is an unsubstituted heteroC 2-i o alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-i o alkenyl.
• the term“alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds ( e.g ., 1, 2, 3, or 4 triple bonds) (“C 2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-
• an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”). In some
• an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In some
• an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
• the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in l-butynyl).
• Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), l-propynyl (C 3 ), 2- propynyl (C 3 ), l-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
• C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an“unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C 2-10 alkynyl.
• heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within ( i.e ., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
• a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-i o alkynyl”).
• a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-
• a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). In some
• a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroC 2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkynyl”).
• a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an“unsubstituted heteroalkynyl”) or substituted (a“substituted
• heteroalkynyl with one or more substituents.
• the heteroalkynyl group is an unsubstituted heteroC 2-i o alkynyl.
• the heteroalkynyl group is a substituted heteroC 2-i o alkynyl.
• carbocyclyl or“carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
• a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”).
• a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”).
• a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclyl”).
• a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
• Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (Co), cyclohexenyl (Co), cyclohexadienyl (Co), and the like.
• Exemplary C 3-8 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.l]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (Cs), and the like.
• Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C 9 ), decahydronaphthalenyl (C 10 ),
• the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
• “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
• each instance of a carbocyclyl group is independently unsubstituted (an“unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents.
• the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl.
• the carbocyclyl group is a substituted C 3-14 carbocyclyl.
• “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
• a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
• C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
• Examples of C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (Cs).
• each instance of a cycloalkyl group is independently unsubstituted (an“unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents.
• the cycloalkyl group is an unsubstituted C 3-14 cycloalkyl.
• the cycloalkyl group is a substituted C 3-14 cycloalkyl.
• heterocyclyl or“heterocyclic” refers to a radical of a 3- to l4-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”).
• the point of attachment can be a carbon or nitrogen atom, as valency permits.
• a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds.
• Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
• each instance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents.
• the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
• a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”).
• a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
• a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
• the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
• Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
• Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
• Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
• Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
• Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
• Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
• Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
• Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl.
• Exemplary 7- membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
• heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
• Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-l,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl,
• aryl refers to a radical of a monocyclic or polycyclic (e.g ., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-i4 aryl”).
• aromatic ring system e.g., having 6, 10, or 14 p electrons shared in a cyclic array
• an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
• an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as l-naphthyl and 2-naphthyl).
• an aryl group has 14 ring carbon atoms (“Ci 4 aryl”; e.g., anthracyl).“Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
• each instance of an aryl group is independently unsubstituted (an“unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents.
• the aryl group is an unsubstituted C 6-i4 aryl.
• the aryl group is a substituted C 6-i4 aryl.
• heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g ., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”).
• the point of attachment can be a carbon or nitrogen atom, as valency permits.
• Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.“Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
• Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
• Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
• the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
• a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
• a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
• a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
• the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
• each instance of a heteroaryl group is independently unsubstituted (an“unsubstituted heteroaryl”) or substituted (a“substituted heteroaryl”) with one or more substituents.
• the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
• the heteroaryl group is a substituted 5-14 membered heteroaryl.
• Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
• Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
• Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
• 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
• Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
• Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
• 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
• Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
• Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
• Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
• Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
• alkylene is the divalent moiety of alkyl
• alkenylene is the divalent moiety of alkenyl
• alkynylene is the divalent moiety of alkynyl
• heteroalkylene is the divalent moiety of heteroalkyl
• heteroalkenylene is the divalent moiety of heteroalkenyl
• heteroalkynylene is the divalent moiety of heteroalkynyl
• carbocyclylene is the divalent moiety of carbocyclyl
• heterocyclylene is the divalent moiety of heterocyclyl
• arylene is the divalent moiety of aryl
• heteroarylene is the divalent moiety of heteroaryl.
• a group is optionally substituted unless expressly provided otherwise.
• the term “optionally substituted” refers to being substituted or unsubstituted.
• alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
• “Optionally substituted” refers to a group which may be substituted or unsubstituted ( e.g .,“substituted” or“unsubstituted” alkyl, “substituted” or“unsubstituted” alkenyl,“substituted” or“unsubstituted” alkynyl, “substituted” or“unsubstituted” heteroalkyl,“substituted” or“unsubstituted” heteroalkenyl, “substituted” or“unsubstitute
• the term“substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
• a“substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
• substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
• the present invention contemplates any and all such combinations in order to arrive at a stable compound.
• heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
• the invention is not intended to be limited in any manner by the exemplary substituents described herein.
• R aa is, independently, selected from Ci-io alkyl, Ci-io perhaloalkyl, C 2-i o alkenyl, C 2-i o alkynyl, heteroCi-10 alkyl, heteroC 2-i o alkenyl, heteroC 2-i o alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl,
• each instance of R cc is, independently, selected from hydrogen, CM O alkyl, Ci-io perhaloalkyl, C 2-i o alkenyl, C 2-i o alkynyl, heteroCi-10 alkyl, heteroC 2-i o alkenyl, heteroC 2-i o alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-i4 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
• each instance of R ee is, independently, selected from Ci -6 alkyl, Ci -6 perhaloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, heteroCi-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-i o carbocyclyl, C 6-i o aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
• each instance of R ff is, independently, selected from hydrogen, Ci -6 alkyl, Ci -6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroCi- 6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-i o carbocyclyl, 3-10 membered heterocyclyl, C 6-i o aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
• halo or“halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).
• hydroxyl refers to the group -OH.
• amino refers to the group -NH 2 .
• substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the“substituted amino” is a monosubstituted amino or a
• trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(R bb ) 3 and -N(R bb ) 3 + X _ , wherein R bb and X- are as defined herein.
• sulfonyl refers to a group selected from -S0 2 N(R bb ) 2 , -S0 2 R aa , and - S0 2 OR aa , wherein R aa and R bb are as defined herein.
• R X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl,
• heteroaryloxy aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R X1 groups taken together form a 5- to 6-membered heterocyclic ring.
• acyl groups include aldehydes (-CHO), carboxylic acids (-C0 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
• Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g ., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, al
• sil refers to the group -Si(R aa ) 3 , wherein R aa is as defined herein.
• Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
• Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR ⁇ , -N(R CC ) 2 , -CN,
• the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an“amino protecting group”).
• heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc and R dd are as defined herein.
• Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
• Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-/-butyl-[9-( 10, 10-dioxo- 10, 10, 10, 10-tctrahydrothioxanthyl)] methyl carbamate (DBD- Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l- methylethyl
• TBOC 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-/-butylphenyl)-l- methylethyl carbamate (i-Bumeoc), 2-(2'- and 4'-pyridyl)cthyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, /-butyl carbamate (BOC or Boc), l-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), l-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carba
• Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide
• nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)- acyl derivative, N ' - p - 1 o 1 u c n c s u 1 fo n y 1 a m i n o acyl derivative, N'-phcnylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3- oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substitute
• diphenylthiophosphinamide Ppt
• dialkyl phosphoramidates dibenzyl phosphoramidate, diphenyl phosphoramidate
• benzenesulfenamide o-nitrobenzenesulfenamide
• Nps 2,4- dinitrobenzenesulfenamide
• pentachlorobenzenesulfenamide 2-nitro-4- methoxybenzenesulfenamide
• triphenylmethylsulfenamide triphenylmethylsulfenamide
• 3-nitropyridinesulfenamide Npys
• a nitrogen protecting group is benzyl (Bn), tert- butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).
• Bn benzyl
• BOC tert- butyloxycarbonyl
• Cbz carbobenzyloxy
• Fmoc 9-flurenylmethyloxycarbony
• the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an“hydroxyl protecting group”).
• Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
• oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), i-butylthiomethyl,
• DEIPS diethylisopropylsilyl
• TDMS dimethylthexylsilyl
• TDPS t- butyldiphenylsilyl
• tribenzylsilyl tri-p-xylylsilyl, triphenylsilyl
• DPMS diphenylmethylsilyl
• TMPS /-butyl mcthoxyphcnylsilyl
• formate benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroe
• an oxygen protecting group is silyl.
• an oxygen protecting group is /-huty ldipheny 1 si 1 y 1 (TBDPS), t- butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate,
• methoxymethyl (MOM), l-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2- trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), /-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).
• MTM tetrahydropyranyl
• THF tetrahydrofuranyl
• PMP p- methoxyphenyl
• Tr methoxytrityl
• the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a“thiol protecting group”).
• a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine- sulfenyl, or triphenylmethyl.
• A“counterion” or“anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
• An anionic counterion may be monovalent ( i.e ., including one formal negative charge).
• An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
• Exemplary counterions include halide ions (e.g ., F , CE, Br , E), NO3 , Cl0 4 , OH , H 2 P0 4 , HCO3T HS0 4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, lO-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-l -sulfonic acid- 2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF 4 -, PF 4 , PF 6 , As
• Exemplary counterions which may be multivalent include C0 3 2- , HP0 4 2_ , P0 4 3- , B 4 0 7 2_ , S0 4 2- , S 2 0 3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
• carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
• carboranes e.g., tartrate, citrate, fumarate, maleate,
• phrase“at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
• salt refers to any and all salts, and encompasses pharmaceutically acceptable salts.
• pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe
• Pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
• Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
• Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
• organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
• Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C I-4 alkyl) 4 _ salts.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
• Compounds described herein are also provided, and can be administered, as a free base.
• composition and“formulation” are used interchangeably.
• A“subject” to which administration is contemplated refers to a human (i.e ., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
• the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
• primate e.g., cynomolgus monkey or rhesus monkey
• commercially relevant mammal e.g., cattle, pig, horse, sheep, goat, cat, or dog
• bird e.g., commercially relevant bird, such
• the non-human animal is a fish, reptile, or amphibian.
• the non-human animal may be a male or female at any stage of development.
• the non-human animal may be a transgenic animal or genetically engineered animal.
• the term“patient” refers to a human subject in need of treatment of a disease.
• administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
• treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
• treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed.
• treatment may be administered in the absence of signs or symptoms of the disease.
• treatment may be administered to a susceptible subject prior to the onset of symptoms. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
• an“effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response.
• An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. Alternatively, in a separate method or use, the invention may be used, where indicated and effective, as a prophylactic treatment. In certain
• an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses.
• A“therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
• a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
• the term“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
• a therapeutically effective amount is an amount sufficient for treating in any disease or condition described.
• “inhibition”,“inhibiting”,“inhibit” and“inhibitor”, and the like refer to the ability of a compound to reduce, slow, halt, or prevent the activity of a biological process (e.g., tumor growth).
• the inhibition is about 45% to 50%.
• the inhibition is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99.9%, or 100%.
• the present invention is described in detail below with reference to embodiments and the like of the present invention.
• the invention provides compounds (e.g., compounds of Formulae (I), (II), (III), and (IV)), and pharmaceutically acceptable salts or isotopically labeled derivatives thereof, and pharmaceutical compositions thereof.
• the invention also provides methods of treating proliferative diseases (e.g., inhibiting tumor growth and/or treating cancer) in a subject comprising administering an effective amount to the subject of a compound or composition provided herein.
• the compound or composition may be administered as a monotherapy or in combination with another therapy, as described herein.
• the present invention provides methods of preparing compounds of Formulae (I), (II), (III), and (IV), and synthetic intermediates useful to that end.
• the present invention provides compounds of Formula (I):
• R N1 and R N2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group, optionally wherein R N1 and R N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
• R P1 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group
• R x is hydrogen or -OR Xa ;
• R Y is hydrogen or -OR Ya ;
• R Xa and R Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group, optionally wherein R Xa and R Ya are joined together with the intervening atoms to form optionally substituted heterocyclyl;
• n 1 or 2.
• the compound of Formula (I) is not Compound (1), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof. In certain embodiments, Compound (1) and all pharmaceutically acceptable salts and isotopically labeled derivatives thereof are excluded from the invention.
• the compound of Formula (I) is of one of the following formulae:
• the compound of Formula (I) is of one of the following formulae:
• the compound of Formula (I) is selected from the group consisting of:
• the present invention provides compounds of Formula (II):
• R N1 and R N2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group, optionally wherein R N1 and R N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
• R P1 and R p2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting gi R x is hydrogen or -OR Xa ;
• R Y is hydrogen or -OR Ya ;
• R Xa and R Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group, optionally wherein R Xa and R Ya are joined together with the intervening atoms to form optionally substituted heterocyclyl;
• m 0 or 1.
• the compound of Formula (II) is of one of the following formulae:
• the compound of Formula (II) is of one of the following formulae:
• the compound of Formula (II) is selected from the group consisting of:
• the present invention provides compounds of Formula (III):
• R° is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group
• R P1 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group
• R x is hydrogen or -OR Xa ;
• R Y is hydrogen or -OR Ya ;
• R Xa and R Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group, optionally wherein R Xa and R Ya are joined together with the intervening atoms to form optionally substituted heterocyclyl;
• n 1 or 2.
• the compound of Formula (III) is not (D-6), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof. In certain embodiments (D-6), and all pharmaceutically acceptable salts and isotopically labeled derivatives thereof, are excluded from the invention.
• the compound of Formula (III) is of one of the following formulae:
• the compound of Formula (III) is of one of the following formulae:
• the compound of Formula (III) is selected from the group consisting of:
• R° is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group
• R P1 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group
• R x is hydrogen or -OR Xa ;
• R Y is hydrogen or -OR Ya ;
• R Xa and R Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group, optionally wherein R Xa and R Ya are joined together with the intervening atoms to form optionally substituted heterocyclyl; and
• m 0 or 1.
• the compound of Formula (IV) is of one of the following formulae:
• the compound of Formula (IV) is selected from the group consisting of:
• the compounds provided herein may be optionally be in the form of a hydrate, solvate or polymorph, optionally in a pharmaceutically acceptable carrier or excipient.
• the present invention also provides stereoisomers of any one of the compounds described herein.
• Compounds provided herein may exist as a crystal polymorph, and the compound of the present invention may be in any of single crystal forms or a mixture of two or more crystal forms.
• Compounds provided herein can be in an amorphous form, or can be an anhydride or a solvate, such as a hydrate.
• the present invention includes isotopically labeled derivatives of compounds provided herein, and pharmaceutically acceptable salts thereof.
• the isotopically labeled compound is equivalent to compounds provided herein, except that one or more atom(s) are replaced by atom(s) having an atomic mass or a mass number different from those usually found in nature.
• Examples of an isotope that can be incorporated into the compound of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, bromine and chlorine, such as 3 ⁇ 4, 3 H, n C, 13 C, 14 C, 18 F, 35 S, 123 I, and 125 I.
• the isotopically labeled compound such as a compound into which a radioactive isotope of, for example, 3 H and/or 14 C is incorporated, is useful for a tissue distribution assay for a medicine and/or a matrix.
• the isotopes 3 H and 14 C are regarded to be useful because these isotopes can be easily prepared and detected.
• the isotopes n C and 18 F are useful in PET (positron emission tomography).
• the isotope 125 I is regarded to be useful in SPECT (single photon emission computed tomography), and can be useful in brain imaging.
• the isotopically labeled compound can be similarly prepared by using a readily available isotopically labeled reagent instead of a non-isotopically labeled reagent and by performing processes disclosed in schemes and/or examples described below.
• Compounds provided herein can be used as a chemical probe for capturing a target protein of a biologically active low molecular weight compound.
• the compound of the present invention can be transformed into an affinity chromatography probe, a photoaffinity probe or the like by introducing a labeling group, a linker or the like into a moiety other than a structural moiety indispensable to activity expression of the compound by a method described in J. Mass Spectrum. Soc. Jpn. Vol. 51, No. 5, 2003, p. 492-498, WO 2007/139149, or the like.
• Examples of the labeling group, the linker or the like used in such a chemical probe include groups belonging to the following groups (1) to (5).
• Protein labeling groups such as photoaffinity labeling groups (such as a benzoyl group, a benzophenone group, an azide group, a carbonyl azide group, a diaziridine group, an enone group, a diazo group and a nitro group), and chemical affinity groups (such as a ketone group in which an alpha carbon atom is substituted by a halogen atom, a carbamoyl group, an ester group, an alkylthio group, a Michael acceptor of a,P-unsaturated ketone, ester, or the like, and an oxirane group); (2) cleavable linkers such as S-S, O-Si-O, a monosaccharide (such as a glucose group or a galactose group) and a disaccharide (such as lacto)
• a probe prepared by introducing, into the compound of the present invention, a labeling group or the like selected from the above-described groups (1) to (5) by the method described in any of the aforementioned literatures or the like can be used as a chemical probe for identifying a marker protein useful for research of a novel potential drug target.
• a“salt” used herein include salts with inorganic acids, salts with organic acids, and salts with acidic amino acids, and in particular, pharmaceutically acceptable salts are preferred.
• a salt of the compound of the present invention embraces an anhydride of a pharmaceutically acceptable salt thereof and a solvate, such as a hydrate, of the pharmaceutically acceptable salt.
• a salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
• a salt with an organic acid include salts with acetic acid, succinic acid, famaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
• Preferable examples of a salt with an acidic amino acid include salts with aspartic acid and glutamic acid and the like.
• the salt and the hydrate can be converted to a free body of the compound by a conventional method.
• R N1 and R N2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group, optionally wherein R N1 and R N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl.
• R N1 is hydrogen.
• R N1 is optionally substituted alkyl.
• R N1 is optionally substituted acyl. In certain embodiments, R N1 is a nitrogen protecting group. In certain embodiments, R N1 is an ester protecting group. In certain embodiments, R N1 is an alloc protecting group.“Alloc” is of the following formula: . In certain embodiments, R N2 is hydrogen. In certain embodiments, R N2 is optionally substituted alkyl. In certain embodiments, R N2 is optionally substituted acyl. In certain embodiments, R N2 is a nitrogen protecting group. In certain embodiments, R N2 is an ester protecting group. In certain embodiments, R N2 is an alloc protecting group.
• R N1 and R N2 are both hydrogen. In certain embodiments, R N1 is hydrogen; and R N2 is a nitrogen protecting group. In certain embodiments, R N1 is hydrogen; and R N2 is alloc. In certain embodiments, R N1 and R N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R N1 and R N2 are joined together with the intervening atoms to form optionally substituted heteroaryl.
• R P1 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R P1 is hydrogen. In certain embodiments, R P1 is optionally substituted alkyl. In certain embodiments, R P1 is optionally substituted acyl. In certain embodiments, R P1 is an oxygen protecting group. In certain embodiments, R P1 is silyl (e.g., trialkylsilyl). In certain embodiments, R P1 is tert- butyldimethylsilyl (TBS or TBDMS).
• n is 1 or 2. In certain embodiments, n is 1. In certain embodiments, n is 2.
• m is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1. [00142] As generally defined herein, R x is hydrogen or -OR Xa . In certain embodiments, R x is hydrogen. In certain embodiments, R x -OR Xa . In certain embodiments, R x is -OH.
• R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R Xa is hydrogen. In certain embodiments, R Xa is optionally substituted alkyl. In certain embodiments, R Xa is optionally substituted acyl. In certain embodiments, R Xa is an oxygen protecting group.
• R Y is hydrogen or -OR Ya . In certain embodiments, R Y is hydrogen. In certain embodiments, R Y is -OR Ya . In certain embodiments, R Y is -OH.
• R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.
• R Ya is hydrogen.
• R Ya is optionally substituted alkyl.
• R Ya is optionally substituted acyl.
• R Ya is an oxygen protecting group.
• R Xa and R Ya are joined together with the intervening atoms to form optionally substituted heterocyclyl (e.g ., optionally substituted 5-membered heterocyclyl).
• R x and R Y are hydrogen. In certain embodiments, R x is - OR Xa ; and R Y is -OR Ya . In certain embodiments, R x and R Y are -OH. In certain embodiments,
• R x is hydrogen; and R Y is -OR Ya . In certain embodiments, R x is hydrogen; and R Y is -OH.
• R p2 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R p2 is hydrogen. In certain embodiments, R p2 is optionally substituted alkyl. In certain embodiments, R p2 is optionally substituted acyl. In certain embodiments, R p2 is an oxygen protecting group. In certain embodiments, R p2 is silyl (e.g., trialkylsilyl). In certain embodiments, R p2 is tert- butyldimethylsilyl (TBS or TBDMS).
• R° is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R° is optionally substituted alkyl. In certain embodiments, R° is optionally substituted Ci -6 alkyl. In certain embodiments, R° is unsubstituted Ci -6 alkyl. In certain embodiments, R° is optionally substituted Ci -3 alkyl. In certain embodiments, R° is unsubstituted Ci -3 alkyl. In certain embodiments, R° is methyl, ethyl, «-propyl, Ao-propyl, «-butyl, iso-butyl, sec-butyl, or tert- butyl. In certain embodiments, R° is methyl. In certain embodiments, R° is optionally substituted acyl. In certain embodiments, R° is an oxygen protecting group.
• the present invention provides pharmaceutical compositions comprising a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient.
• a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient.
• the compound described herein, or pharmaceutically acceptable salt or isotopically labeled derivative thereof is provided in an effective amount in the
• composition e.g ., a therapeutically effective amount.
• compositions described herein can be prepared by any method known in the art of pharmacology.
• preparatory methods include bringing a compound provided herein (i.e ., the“active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
• a pharmaceutical composition of the invention could be prepared according to the known method such as a method described in the general rules for preparations of the Japanese Pharmacopoeia, l6 th edition, the United States Pharmacopoeia, and the European Pharmacopoeia, 9 th edition.
• a pharmaceutical composition of the invention could be administered to patients appropriately depending on the dosage form.
• compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
• A“unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
• the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.
• compositions described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
• the composition may comprise between 0.1% and 100% (w/w) active ingredient.
• compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
• the compound provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment.
• the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
• the compounds of the present invention and compositions thereof provided herein can be administered by any route, including enteral (e.g ., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
• enteral e.g ., oral
• parenteral intravenous, intramuscular, intra-arterial, intramedullary
• intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
• topical as by powders, ointments, creams, and/or drops
• Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
• intravenous administration e.g., systemic intravenous injection
• regional administration via blood and/or lymph supply e.g., via blood and/or lymph supply
• direct administration e.g., direct administration to an affected site.
• the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
• any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
• the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell may be, in non-limiting examples, three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks, or even slow dose controlled delivery over a selected period of time using a drug delivery device.
• the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day.
• the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments,
• the duration between the first dose and last dose of the multiple doses is about or at least one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell.
• the duration between the first dose and last dose of the multiple doses is about or at least three months, six months, or one year.
• the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
• a dose e.g ., a single dose, or any dose of multiple doses
• a dose described herein includes independently between 0.001 mg/kg and 0.01 mg/kg, between 0.01 mg/kg and 0.1 mg/kg, between 0.1 mg/kg and 1 mg/kg, inclusive of a compound provided herein. Examples are dosage forms with at least about 0.05, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 5, 20, 25, or 50 mg of active compound, or its salt in a dosage form.
• a dose (e.g., a single dose, or any of multiple doses) described herein includes independently between 1.0 pg/m 2 and 1.0 mg/m 2 , inclusive, of a compound provided herein (e.g., Compound (1) or a pharmaceutically acceptable salt thereof).
• a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 1.0 pg/m 2 and 100.0 pg/m 2 , between 1.0 pg/m 2 and 50 pg/m 2 , between 10 pg/m 2 and 50 pg/m 2 , or between 10 pg/m 2 and 30 pg/m 2 , inclusive, of a compound provided herein (e.g., Compound (1) or a pharmaceutically acceptable salt thereof).
• a compound provided herein e.g., Compound (1) or a pharmaceutically acceptable salt thereof.
• Examples are dosage forms with approximately 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40 mg of a compound provided herein (e.g., Compound (1) or a pharmaceutically acceptable salt thereof).
• a compound provided herein e.g., Compound (1) or a pharmaceutically acceptable salt thereof.
• a compound provided herein e.g., Compound (1) or a pharmaceutically acceptable salt thereof
• a compound provided herein e.g., Compound (1) or a
• a compound provided herein e.g., Compound (1) or a pharmaceutically acceptable salt thereof
• a compound provided herein is dosed approximately twice a month.
• a compound provided herein e.g., Compound (1) or a pharmaceutically acceptable salt thereof
• a compound provided herein e.g., Compound (1) or a pharmaceutically acceptable salt thereof
• a compound provided herein e.g., Compound (1) or a
• a compound provided herein e.g., Compound (1) or a pharmaceutically acceptable salt thereof
• the number of cycles will be decided by a physician.
• Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
• the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
• kits e.g., pharmaceutical packs.
• the kits provided may comprise a pharmaceutical composition or compound provided herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
• a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
• provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a
• kits described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
• compounds of Formulae (I), (II), (III), and (IV) have significant tumor vascular remodeling effects and anti-CAF activity, and therefore, have potential use for the treatment of proliferative diseases (e.g ., treatment of cancer and/or the inhibition of tumor growth).
• a method of treating a proliferative disease in a subject comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.
• the present invention also provides a compound described herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, for use in treating a proliferative disease in a subject.
• the present invention also provides the use of a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a
• proliferative diseases are described herein.
• a method of treating cancer in a subject comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a
• the present invention also provides a compound described herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, for use in treating cancer in a subject.
• the present invention also provides the use of a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treating cancer.
• Also provided herein is a method of inhibiting tumor growth in a subject, the method comprising administering to the subject a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof. Also provided herein is a compound described herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, for use in inhibiting tumor growth in a subject. The present invention also provides the use of a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for inhibiting tumor growth. [00167] A“proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology,
• a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location ( e.g ., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix
• proliferative diseases include cancers (i.e .,“malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
• angiogenesis refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development.
• Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer.
• Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF).“Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and/or is associated with a disease.
• neoplasm and“tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue.
• a neoplasm or tumor may be“benign” or“malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis.
• A“benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin.
• a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites.
• Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias.
• certain“benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as“pre-malignant neoplasms.”
• An exemplary pre-malignant neoplasm is a teratoma.
• a“malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.
• the term“metastasis,”“metastatic,” or“metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or“secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located.
• the disease to be treated is cancer.
• cancer refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues.
• the cancer is head and neck cancer (e.g ., squamous cell carcinoma of the head and neck (SCCHN), adenoid cystic carcinoma).
• SCCHN head and neck cancer
• adenoid cystic carcinoma e.g ., squamous cell carcinoma of the head and neck (SCCHN), adenoid cystic carcinoma.
• the cancer is oral cancer (e.g., buccal cavity cancer, lip cancer, tongue cancer, mouth cancer, pharynx cancer, hypopharynx cancer (e.g.,
• throat cancer e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer
• salivary gland cancer e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer
• the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma, esophageal adenocarcinoma, Barrett’s adenocarcinoma, esophageal leiomyo s arcoma) .
• esophageal cancer e.g., esophageal squamous cell carcinoma, esophageal adenocarcinoma, Barrett’s adenocarcinoma, esophageal leiomyo s arcoma
• the cancer is gastrointestinal cancer (e.g., anal cancer, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), gall bladder cancer, gastric cancer (e.g., stomach cancer (e.g., stomach adenocarcinoma)), gastrointestinal stromal tumor (GIST), small bowel cancer (e.g., appendix cancer, small bowel carcinoma, e.g., small bowel adenocarcinoma), small intestine cancer, large bowel cancer, large intestine cancer).
• gastrointestinal cancer e.g., anal cancer, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), gall bladder cancer, gastric cancer (e.g., stomach cancer (e.g., stomach adenocarcinoma)), gastrointestinal stromal tumor (GIST), small bowel cancer (e.g., appendix cancer, small bowel carcinoma, e
• the cancer is cardiovascular cancer (e.g., primary cardiac tumors, angiosarcoma (e.g., lymphangio sarcoma, lymphangioendothelio sarcoma, hemangiosarcoma), endothelio sarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma), cardiac myxoma, cardiac rhabdomyoma).
• angiosarcoma e.g., lymphangio sarcoma, lymphangioendothelio sarcoma, hemangiosarcoma
• endothelio sarcoma e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma
• cardiac myxoma e.g., cardiac rhabdomyoma
• the cancer is lung cancer (e.g., bronchus cancer (e.g., bronchogenic carcinoma, bronchial adenoma), alveolar carcinoma, mesothelioma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, chondromatous hamartoma, papillary adenocarcinoma).
• lung cancer e.g., bronchus cancer (e.g., bronchogenic carcinoma, bronchial adenoma), alveolar carcinoma, mesothelioma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, chondromatous hamartoma, papillary adenocarcinoma).
• SCLC small cell lung cancer
• NSCLC non-small cell lung cancer
• lung adenocarcinoma chondromatous hamartoma
• the cancer is a genitourinary cancer (e.g., bladder cancer (e.g., urothelial carcinoma), urethral cancer, kidney cancer (e.g., nephroblastoma a.k.a.
• bladder cancer e.g., urothelial carcinoma
• urethral cancer e.g., nephroblastoma a.k.a.
• Wilms tumor, renal cell carcinoma), testicular cancer (e.g., seminoma, testicular embryonal carcinoma), germ cell cancer, prostate cancer (e.g., prostate adenocarcinoma), penile cancer (e.g., Paget’s disease of the penis and scrotum)).
• testicular cancer e.g., seminoma, testicular embryonal carcinoma
• germ cell cancer e.g., prostate cancer
• prostate cancer e.g., prostate adenocarcinoma
• penile cancer e.g., Paget’s disease of the penis and scrotum
• the cancer is a gynecological cancer (e.g., breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, triple negative breast cancer, HER-2 positive breast cancer, HER2-negative breast cancer), endometrial cancer (e.g., uterine cancer (e.g., uterine sarcoma, choriocarcinoma), endometrial carcinoma), cervical cancer (e.g., cervical adenocarcinoma), ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), germ cell cancer, vulvar cancer (e.g., Paget’s disease of the vulva) vaginal cancer, fallopian tube cancer).
• breast cancer e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, me
• the cancer is a hematopoietic cancer (e.g., leukemia (e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, G-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, G-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, G-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, G-cell CLL)); lymphoma (e.g., Hodgkin lymphoma (HL) (e.g., B-cell HL, G-cell HL)), non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma)), f
• ALL acute lymphocy
• angioimmunoblastic G-cell lymphoma extranodal natural killer G-cell lymphoma, enteropathy type G-cell lymphoma, subcutaneous panniculitis-like G-cell lymphoma, anaplastic large cell lymphoma
• heavy chain disease e.g ., alpha chain disease, gamma chain disease, mu chain disease
• MPD myeloproliferative disorder
• PV polycythemia vera
• ET essential thrombocytosis
• AAM agnogenic myeloid metaplasia
• the cancer is leukemia.
• the cancer is acute lymphoblastic leukemia (ALL).
• the cancer is early T-cell precursor (ETP)-acute lymphoblastic leukemia (ALL).
• the cancer is liver cancer (e.g., hepatocellular cancer (HCC) (e.g., hepatocellular carcinoma, hepatoblastoma, hepatocellular adenoma), malignant hepatoma, hemangiomas, biliary cancer (e.g., cholangiocarcinoma)).
• HCC hepatocellular cancer
• hepatoblastoma hepatocellular carcinoma
• hepatocellular adenoma hepatocellular adenoma
• malignant hepatoma hemangiomas
• biliary cancer e.g., cholangiocarcinoma
• the cancer is musculoskeletal cancer (e.g., bone cancer (e.g., osteosarcoma, osteoid osteoma, malignant fibrous histiocytoma, Ewing’s sarcoma, chordoma, malignant giant cell tumor chordoma, chondrosarcoma osteochondroma, benign chondroma, chondroblastoma chondromyxofibroma, myelodysplastic syndrome (MDS)), muscle cancer (e.g., rhabdomyosarcoma, rhabdomyoma), connective tissue cancer, synovioma).
• bone cancer e.g., osteosarcoma, osteoid osteoma, malignant fibrous histiocytoma, Ewing’s sarcoma, chordoma, malignant giant cell tumor chordoma, chondrosarcoma osteochondroma, benign chondroma, chondroblastoma chondromyxo
• the cancer is a nervous system cancer (e.g., brain cancer (e.g., astrocytoma, medulloblastoma, glioma (e.g., astrocytoma, oligodendroglioma), glioblastomas, glioblastoma multiform, medulloblastoma, ependymoma, germinoma (i.e., pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors,
• brain cancer e.g., astrocytoma, medulloblastoma, glioma (e.g., astrocytoma, oligodendroglioma), glioblastomas, glioblastoma multiform, medulloblastoma, ependymoma, germinoma (i.e., pinealoma
• the disease to be treated is a brain tumor.
• the disease is pleomorphic xenoanthrocytoma (PXA).
• the disease is pediatric pleomorphic xenoanthrocytoma (PXA).
• the cancer is selected from endocrine/exocrine cancers (e.g., thyroid cancer (e.g., papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma), pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors, ductal adenocarcinoma, insulinoma, glucagonoma, vipoma), adrenal gland cancer, neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP- NET), carcinoid tumor), sebaceous gland carcinoma, sweat gland carcinoma).
• the cancer is sweat gland cancer (e.g., sweat gland cancer (
• the cancer is skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC), dermatofribroma).
• SCC squamous cell carcinoma
• KA keratoacanthoma
• BCC basal cell carcinoma
• dermatofribroma dermatofribroma
• the cancer is a soft tissue cancer (e.g., intraepithelial neoplasms, epithelial carcinomas, epithelial sarcomas, adenocarcinomas, adenomas, fibrosarcomas, fibromas, liposarcomas, lipomas, myxomas, teratomas).
• a soft tissue cancer e.g., intraepithelial neoplasms, epithelial carcinomas, epithelial sarcomas, adenocarcinomas, adenomas, fibrosarcomas, fibromas, liposarcomas, lipomas, myxomas, teratomas.
• the cancer is a rare cancer.
• the term“rare cancer” refers to cancers that occur in a relatively small number of patients. Rare cancers include, but are not limited to, sarcomas (e.g., soft tissue sarcoma, liposarcoma, uterine sarcoma,
• sarcoma leiomyosarcoma, myxofibrosarcoma, osteosarcoma, angiosarcoma, Ewing’s sarcoma, synovial sarcoma, rhabdomyosarcoma, intimal sarcoma), malignant lymphomas, thymic cancer (e.g., thymomas), mesothelioma, gastrointestinal stromal tumors (GISTs), neuroendocrine cancer, eye cancer, brain tumors, bone soft tissue tumors, skin cancer, and germ cell tumors.
• thymic cancer e.g., thymomas
• mesothelioma mesothelioma
• GISTs gastrointestinal stromal tumors
• neuroendocrine cancer eye cancer, brain tumors, bone soft tissue tumors, skin cancer, and germ cell tumors.
• the cancer is head and neck cancer (e.g., squamous cell carcinoma of the head and neck, adenoid cystic carcinoma, oral cancer, throat cancer, salivary gland cancer, tongue cancer).
• the cancer is breast cancer (e.g., HER2-positive breast cancer, HER2-negative breast cancer, triple negative breast cancer).
• the cancer is colorectal cancer (e.g., colon carcinoma).
• the cancer is esophageal cancer (e.g., esophageal adenocarcinoma).
• the cancer is uterine cancer (e.g., uterine sarcoma). In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is a sarcoma (e.g., uterine sarcoma, fibrosarcoma, angiosarcoma, synovial sarcoma, soft tissue sarcoma, intimal sarcoma). In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer). In certain embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma). In certain embodiments, the cancer is endometrial cancer.
• a sarcoma e.g., uterine sarcoma, fibrosarcoma, angiosarcoma, synovial sarcoma, soft tissue sarcoma, intimal sarcoma
• the cancer is gastric cancer.
• the cancer is
• the cancer is small bowel cancer (e.g ., small bowel carcinoma, e.g., small bowel adenocarcinoma).
• the cancer is sweat gland cancer (e.g., sweat gland carcinoma).
• the cancer is a rare cancer.
• compounds provided herein can be administered in combination with other therapeutic agents or treatment modalities.
• the compound is administered in combination with an anti-cancer agent.
• Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents.
• biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon a, interferon g), vaccines, hematopoietic growth factors, monoclonal serotherapy, immuno stimulants and/or
• immunodulatory agents e.g., IL-l, 2, 4, 6, or 12
• immune cell growth factors e.g., GM- CSF
• antibodies e.g., Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexxar
• chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2- DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine
• anti-estrogens e.g. tamoxifen, raloxifene, and megestrol
• LHRH agonists
• alkylsulphonates e.g. busulfan and treosulfan
• triazenes e.g. dacarbazine, temozolomide
• platinum containing compounds e.g. cisplatin, carboplatin, oxaliplatin
• vinca alkaloids e.g. vincristine, vinblastine, vindesine, and vinorelbine
• taxoids e.g.
• paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel
• paclitaxel docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor- activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-l (paclitaxel bound to the erbB2-recognizing peptide EC-l), and glucose-conjugated paclitaxel, e.g., 2 '-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins ( e.g .
• DHFR inhibitors e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate
• IMP dehydrogenase inhibitors e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR
• ribonuclotide reductase inhibitors e.g. hydroxyurea and deferoxamine
• uracil analogs e.g. 5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine
• cytosine analogs e.g. cytarabine (ara C)
• cytosine arabinoside e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate
• IMP dehydrogenase inhibitors e.g. mycophenolic acid, ti
• fludarabine purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. l-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g.
• purine analogs e.g. mercaptopurine and Thioguanine
• Vitamin D3 analogs e.g. EB 1089, CB 1093, and KH 1060
• isoprenylation inhibitors e.g. lovastatin
• dopaminergic neurotoxins e.g
• daunorubicin doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone
• MDR inhibitors e.g. verapamil
• Ca 2+ ATPase inhibitors e.g.
• thapsigargin imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTINTM, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib
• TASIGNA® semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab
• CAMPATH® gemtuzumab ozogamicin
• MYLOTARG® gemtuzumab ozogamicin
• TORISEL® temsirolimus
• ENMD-2076 PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors
• a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof is used in combination with radiation therapy (RT).
• RT radiation therapy
• the compound is administered in combination with surgery.
• the compound is administered in combination with an immunotherapy.
• a compound of the present invention can be administered in combination with another therapeutic agent, such as anti-EGFR therapy, anti-HER2 therapy, anti-PD-l therapy, anti-PD-Ll therapy, or irradiation therapy.
• another therapeutic agent such as anti-EGFR therapy, anti-HER2 therapy, anti-PD-l therapy, anti-PD-Ll therapy, or irradiation therapy.
• a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof is administered in combination with an anti-EGFR therapy (e.g ., anti-EGFR monoclonal antibody (mAb), such as cetuximab).
• an anti-EGFR therapy e.g ., anti-EGFR monoclonal antibody (mAb), such as cetuximab.
• mAb monoclonal antibody
• mAb monoclonal antibody
• a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof is administered in combination with an anti-HER2 therapy (e.g., anti-HER2 monoclonal antibody (mAb), such as trastuzumab).
• an anti-HER2 therapy e.g., anti-HER2 monoclonal antibody (mAb), such as trastuzumab.
• mAb monoclonal antibody
• mAb monoclonal antibody
• HER2 human epidermal growth factor receptor
• the anti-HER2 mAb is trastuzumab.
• a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a pharmaceutical composition thereof is administered in combination with an anti-PD-l or anti-PD-Ll therapy (e.g., anti- PD-l or anti-PD-Ll monoclonal antibody).
• an anti-PD-l or anti-PD-Ll therapy e.g., anti- PD-l or anti-PD-Ll monoclonal antibody.
• a method of treating colorectal cancer in a subject in need thereof comprising administering to said subject a compound provided herein, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof, or a composition thereof, in combination with an anti-PD-l or anti-PD-Ll therapy (e.g mAb therapy).
• the compound according to the present invention can be produced by the methods described in Examples below. However, these examples are only for illustrative purposes, and the compound according to the present invention is not limited to the specific examples mentioned below in any way.
• the silica gel for purification by using silica gel column chromatography was Hi-FlashTM Column (Silica Gel, 30 pm 60 A or 40 pm 60 A, Yamazen Corporation), the silica gel for purification by using NH silica gel column chromatography was Chromatorex NH silica gel (Fuji Silysia Chemical LTD).
• Analytical thin layer chromatography (TLC) was performed with TLC silica gel 60 E 254 , layer thickness 0.25mm (Merck KGaA) or Chromatorex TLC NH silica gel F 254 , layer thickness 0.25mm (Fuji Silysia Chemical LTD). TLC plates were visualized by staining with p-anisaldehyde stain, phosphomolybdic acid stain or Hanessian’s Stain.
• NMR spectra were recorded on a JEOL ECZ500R (500 MHz), JEOL ECZ400S (400 MHz), Varian Inova 500 (500 MHz), Varian Mercury 400 (400 MHz) or Bruker Avance (600MHz) spectrometer. Chemical shifts are reported in parts per million (ppm).
• 'H NMR spectra (CDCI 3 , C f ,D f ,, and/or CD 3 OD)
• the residual solvent peak was used as the internal reference (7.27 ppm in CDCI 3 ; 7.16 ppm in C 6 D 6 ; 3.31 ppm in CD 3 OD).
• High performance liquid chromatography was carried out with Shimadzu LC-10AD on a UV spectrophotometric detector (200 nm, Shimadzu SPD-10A).
• AIBN 2,2'-azobis(isobutyronitrile); Alloc: allyloxycarbonyl; 9-BBN: 9-borabicyclo[3.3.l]nonane; Bu 3 SnH: tri-normal-butyltin hydride; (+)-CSA: (lS)-(+)-lO-Camphorsulfonic acid;
• DMAP 4-dimethylaminopyridine;
• DCM dichloromethane;
• DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone; DIBAL:
• MeOH methanol
• MPM p a ra - m c t h o x y b c n zy I
• PPh 3 triphenylphosphine
• t-BuOH tertiary- butyl alcohol
• tBuLi tertiary- butyl lithium
• TBME methyl tertiary- butyl ether
• TBAF tetrabutylammonium fluoride
• TBS le l i a ry -huty Idi methyl si 1 y I
• THF tetrahydrofuran
• TMS trimethylsilyl
• Ts pa ra - 1 o I u c n c s u I fo n y I .
• reaction mixture was stirred at -78 °C. After 90 min, the reaction was quenched with MeOH (4.37 mL) carefully at -78 °C, then removed the cooling bath. Saturated potassium sodium tartrate tetrahydrate solution (300 mL) was added to the reaction mixture, continued stirring for 2 hr at room temperature. The reaction mixture was poured into a separatory funnel, then the layers were separated. The aqueous layer was extracted with EtOAc (300 mL). The combined organic extracts were washed with brine (300 mL), dried over Na 2 S0 4 , filtered, concentrated under reduced pressure. The crude lactol was used for the next reaction without purification.
• the reaction mixture was stirred at -10 °C for 15 min, then at room temperature for 1 hr.
• the reaction mixture was quenched with sat.NaHCCL aq at 0 °C and diluted with DCM, then the layers were separated.
• the aqueous layer was extracted with DCM.
• the combined organic extracts were washed with brine.
• the combined organic layer was dried over MgS0 4 , filtered and concentrated under reduced pressure.
• reaction mixture was stirred at 20 °C for 2 hr.
• the reaction mixture was diluted with EtOAc and quenched with sat.NH 4 Cl aq, then the layers were separated.
• the aqueous layer was extracted with EtOAc.
• the combined organic extracts were washed with brine, dried over MgS0 4 , filtered and concentrated under reduced pressure.
• reaction mixture was quenched with sat.Na 2 S0 3 aq and the layers were separated.
• the aqueous layer was extracted with DCM.
• the combined organic extracts were washed with brine.
• the combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
• reaction mixture was stirred at 4 °C for 20 hr.
• the reaction mixture was diluted with EtOAc and quenched with sat.NaHCCE aq, then the layers were separated.
• the aqueous layer was extracted with EtOAc.
• the combined organic extracts were washed with brine, dried over MgS0 4 , filtered and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 0% to 35%
• Imidazole hydrochloride 155 mg, 1.48 mmol was dissolved in DMF (2.9 mL) to give a 0.5 M imidazole hydrochloride solution in DMF. 1.0 mL of this solution was mixed with 1.0 mL of TBAF (1.0 M, THF solution) to give a premixed solution of 0.5 M TBAF and 0.25 M imidazole hydrochloride in THF-DMF (1:1).
• Natural Halichondrin compounds and modified compounds thereof are known in the literature (See, e.g., D. Uemura el al.“Norhalichondrin A: An Antitumor Polyether Macrolide from a Marine Sponge” 7. Am. Chem. Soc., 107, 4796 (1985); Marc Litaudon et al.
• Antitumor Polyether Macrolides New and Hemisynthetic Halichondrins from the New Zealand Deep-Water Sponge Lissodendoryx sp.” 7. Org. Chem., 1997, 62, 1868-1871).
• Dr. Uemura et.al. isolated 12.5 mg of Halichondrin B, 35.0 mg of Norhalichondrin A and 17.2 mg of Homohalichondrin A from as much as 600 kg of Halichondria okadai Kadota (See, e.g., D. Uemura et al.
• Halichondrin B shows the strongest anti-tumor activities against B-16 melanoma cells in vitro and is highly active against L-1210 Leukemia in vivo (See, e.g., D. Uemura et al.“Norhalichondrin A: An Antitumor Polyether Macrolide from a Marine Sponge” 7. Am. Chem. Soc., 107, 4796 (1985)).
• Halichondrin C is also active in various in vivo models but unstable in aqueous solution in comparison with Halichondrin B.
• Norhalichondrin B is much weaker than Halichondrin B not only in vitro but also in vivo See, e.g., D. Uemura et al.“Norhalichondrin A: An Antitumor Polyether Macrolide from a Marine Sponge” 7. Am. Chem. Soc., 107, 4796 (1985)). The following pharmacological tests use Halichondrin B (Hali-B) as reference compounds as needed. Pharmacological Test Example 1. FaDu growth inhibition assay
• FaDu cells were maintained in an RPMI-1640 (Wako Pure Chemical Industries, Ltd., 187-02021) medium containing 10% fetal bovine serum (FBS: Nichirei, 12D168), and penicillin and streptomycin in a 5% C0 2 incubator (37 °C).
• Dulbecco’s Modified Eagle’s medium (Wako Pure Chemical Industries, Ltd., 044-29765) medium containing 10% fetal bovine serum (FBS: Nichirei, 12D168), and penicillin and streptomycin in a 5% C0 2 incubator (37 °C).
• FBS fetal bovine serum
• penicillin and streptomycin in a 5% C0 2 incubator (37 °C).
• cell viability was determined by CellTiter-Glo ® Luminescent Cell Viability Assay (Promega) with EnVision 2103 Multilabel Reader (Perkin-Elmer, Wellesley, MA). Value of the wells containing cells without adding the test compounds was defined as 100% and the value of the wells containing no cells was defined as 0%. The concentration of the test compound necessary for inhibiting the cell growth by 50% (i.e., an IC 50 value) was calculated, and shown in Table 2.
• HCC1954 the growth inhibitory activity of test compounds in a human breast cancer cell line HCC1954 was measured.
• HCC1954 cells were maintained in an RPMI-1640 medium modified to contain 2 mM L- glutamine, 10 mM HEPES, 1 mM sodium pyruvate, 4500 mg/L glucose, and 1500 mg/L sodium bicarbonate (ATCC 30-2001) containing 10% fetal bovine serum (FBS: Nichirei, 12D168), and penicillin and streptomycin in a 5% C0 2 incubator (37 °C).
• FBS fetal bovine serum
• penicillin and streptomycin penicillin and streptomycin in a 5% C0 2 incubator (37 °C).
• a human squamous cell carcinoma of the head and neck (SCCHN) cell line FaDu which had been cultured in an RPMI-1640 medium containing 10% FBS, and penicillin and streptomycin, was adjusted to a concentration of 4.8 x 10 7 cells/mL with Hanks' Balanced Salt Solution to prepare a cell suspension.
• the cell suspension was inoculated in a volume of 100 pL into a subcutaneous part of a right flank of nude mice, 7 weeks of ages (CAnN.Cg- Foxnlnu/CrlCrlj, female, Charles River Laboratories Japan Inc.).
• Tumor volume (mm 3 ) Longest diameter (mm) x Shortest diameter (mm) x Shortest diameter (mm)/2
• Relative tumor volume (RTV) Tumor volume (day X) / Tumor volume (the first day)
• Tumor Regression (%) (1 - minimum RTV) xlOO
• mice On the basis of the volumes of tumors obtained on the first day of administration, the mice were grouped such that averages of the tumor volumes were substantially equal among the groups. Each test compound was dissolved in DMSO and a solution was stored at the freezer before use. Immediately before the administration, the stock solution was diluted in saline with 100 pM of hydroxypropyl-P-cyclodextrin. Each evaluation sample was intravenously administered at a maximum tolerable dose (MTD). Incidentally, the experiment was conducted on groups each consisting of 4 mice. Tumor regression (%) of each test compound was shown in Table 4. Table 4
• SCHN head and neck
• the cell suspension was inoculated in a volume of 100 pFinto a subcutaneous part of a right flank of nude mice, 5 weeks of ages (CAnN.Cg-Foxnlnu/CrlCrlj, female, Charles River Faboratories Japan, Inc.).
• the cell suspension was inoculated in a volume of 100 pFinto a subcutaneous part of a right flank of nude mice, 5 weeks of ages (CAnN.Cg-Foxnlnu/CrlCrlj, female, Charles River Faboratories Japan, Inc.).
• the shortest diameter and the longest diameter of a tumor in each mouse were measured by using an electronic digital caliper (DigimaticTM caliper, Mitutoyo Corporation), so as to calculate the volume of the tumor in accordance with the following calculation formulae:
• Tumor volume (mm 3 ) Fongest diameter (mm) x Shortest diameter (mm) x Shortest diameter (mm)/2
• Relative tumor volume (RTV) Tumor volume (day X) / Tumor volume (the first day)
• Tumor Regression (%) (1 - minimum RTV) xlOO
• mice On the basis of the volumes of tumors obtained on the first day of administration, the mice were grouped such that averages of the tumor volumes were substantially equal among the groups. The experiment was conducted on groups each consisting of 6 mice. Test compound was dissolved in saline and intravenously administered at doses from 0.06 mg/kg to 0.18 mg/kg once a week for 2 weeks (Q7Dx2 schedule). Tumor regression (%) of each test dose is shown in Table 5. Table 5
• the cell suspension was inoculated in a volume of 100 pLinto a subcutaneous part of a right flank of nude mice, 5 weeks of ages (CAnN.Cg-Foxnlnu/CrlCrlj, female, Charles River Laboratories Japan, Inc.). Twelve days after cell inoculation, the shortest diameter and the longest diameter of a tumor in each mouse were measured by using an electronic digital caliper (DigimaticTM caliper, Mitutoyo
• Tumor volume (mm 3 ) Longest diameter (mm) x Shortest diameter (mm) x Shortest diameter (mm)/2
• Relative tumor volume (RTV) Tumor volume (day X) / Tumor volume (the first day)
• Tumor Regression (%) (1 - minimum RTV) xlOO
• mice On the basis of the volumes of tumors obtained on the first day of administration, the mice were grouped such that averages of the tumor volumes were substantially equal among the groups. The experiment was conducted on groups each consisting of 6 mice. Test compound was dissolved in saline and intravenously administered at 0.18 mg/kg once a week for 2 weeks (Q7Dx2 schedule). Tumor regression (%) for Compound (1) is shown in
• a human squamous cell carcinoma of the head and neck (SCCHN) cell line FaDu which had been cultured in an RPMI-1640 medium containing 10% FBS, and penicillin and streptomycin, was adjusted to a concentration of 5 x 10 7 cells/mL with Hanks' Balanced Salt Solution to prepare a cell suspension.
• the cell suspension was inoculated in a volume of 100 pL into a subcutaneous part of a right flank of nude mice, 7 weeks of ages (CAnN.Cg- Foxnlnu/CrlCrlj, female, Charles River Laboratories Japan Inc.).
• Tumor volume (mm 3 ) Longest diameter (mm) x Shortest diameter (mm) x Shortest diameter (mm)/2
• Relative tumor volume Tumor volume (day X) / Tumor volume (the first day)
• Tumor Regression on day 35 (%) (1- RTV on day 35) xlOO
• mice On the basis of the volumes of tumors obtained on the first day of administration, the mice were grouped such that averages of the tumor volumes were substantially equal among the groups. Each test compound was dissolved in DMSO and a solution was stored at the freezer before use. Immediately before the administration, the stock solution was diluted in saline with 100 mM of hydroxypropyl-P-cyclodextrin. Each test compound and was intravenously administered at doses from 1/4 MTD to 1/2 MTD in combination with cetuximab (Erbitux, Merck Serono Co., Ltd.). Incidentally, the experiment was conducted on groups each consisting of 4 mice. Tumor regression on day 35 (%) of each test compound are shown in Table 7. Table 7
• a human HER-2 positive breast cancer cell line KPL-4 which had been cultured in an RPMI-1640 medium containing 10% FBS, and penicillin and streptomycin, was adjusted to a concentration of 1 x 10 8 cells/mL with Hank’s Balanced Salt Solution to prepare a cell suspension.
• the cell suspension was inoculated in a volume of 100 pL into a subcutaneous part of a right flank of nude mice, 7 weeks of ages (CAnN.Cg-Foxnlnu/CrlCrlj, female, Charles River Laboratories Japan, Inc.).
• Tumor volume (mm 3 ) Longest diameter (mm) x Shortest diameter (mm) x Shortest diameter (mm)/2
• Relative tumor volume (RTV) Tumor volume (day X) / Tumor volume (the first day)
• Tumor Regression (%) (1 - minimum RTV) xlOO
• mice On the basis of the volumes of tumors obtained on the first day of administration, the mice were grouped such that averages of the tumor volumes were substantially equal among the groups. The experiment was conducted on groups each consisting of 6 mice. Each test compound was dissolved in DMSO and a solution was stored at the freezer before use.
• test compound (1) was intravenously administered at 0.09 mg/kg or 0.18 mg/kg in combination with trastuzumab (Herceptin, Genentech, Inc.). Tumor regression for Compound (1) is shown in
• Test compound Dose (mg/kg) Trastuzumab Tumor Regression
• a human squamous cell carcinoma of the head and neck (SCCHN) cell line FaDu which had been cultured in an RPMI-1640 medium containing 10% FBS, and penicillin and streptomycin, was adjusted to a concentration of 5 xlO 7 cells/mL with PBS to prepare a cell suspension.
• the cell suspension was inoculated in a volume of 100 pL into a subcutaneous part of a right flank of nude mice, 7 weeks of ages (CAnN.Cg-Foxnlnu/CrlCrlj, female, Charles River Laboratories Japan, Inc.).
• Sections were deparaffinized, conditioned and the antigens were retrieved with CC1 (Ventana Medical Systems). Slides were blocked with Blocker A and Blocker B (Endogenous biotin blocking kit, Roche Diagnostics). Rat anti mouse IgG CD31 antibody (Dianova GmbH) was applied at 2 pg/mL. Sections were incubated with the antibody for 6 hr, followed by 32 minutes incubation with biotinylated anti-rat IgG antibody (Jackson ImmunoResearch Laboratories) at 2.2 pg/mL.
• the detection was performed with Strep tavidin-HRP D for 16 min, followed by incubation with DAB D and DAB H 2 0 2 D (DABMap kit, Ventana Medical Systems, Inc) for 8 min. Slides were counterstained with Hematoxylin II (Roche Diagnostics) for 16 min, followed by incubation with Bluing reagent for 4 min. Sections were dehydrated in graded ethanols, defatted in xylene replacement and covered with DPX (Merck KGaA).
• Increase rate of blood vessel number (%) ((blood vessel number of the test compound dosing group— blood vessel number of the control group) / blood vessel number of the control group) xlOO
• a human squamous cell carcinoma of the head and neck (SCCHN) cell line FaDu which had been cultured in an RPMI-1640 medium containing 10% FBS, and penicillin and streptomycin, was adjusted to a concentration of 5xl0 7 cells/mL with PBS to prepare a cell suspension.
• the cell suspension was inoculated in a volume of 100 pL
• Mouse anti-a-SMA monoclonal antibody conjugated with alkaline phosphatase (clone 1A4, Sigma) was applied at 5 pg/mL. Sections were incubated with the antibody for 6 hr. The detection was performed with RedMap kit (Ventana Medical Systems, Inc). Sections were dehydrated in graded ethanols, defatted in xylene replacement and covered with DPX (Merck KGaA). The serial tumor slices were deparaffinized and stained with Mayer’s hematoxylin (Muto Pure Chemicals) for 1 min. Sections were dehydrated in graded ethanols, defatted in xylene replacement and covered with DPX (Merck KGaA).
• Luciferase-transduced HSC-2-Luc cells were established by retrovirus -mediated gene transfer.
• the DNA fragment encoding firefly luciferase was obtained from pGL3- enhancer plasmid (GenBank#:U47297), and subcloned into the retroviral vector pCX4pur (GenBank#: AB086386).
• helper-free recombinant retroviruses were produced by transfecting the above retroviral expression vector together with pGP and pE-Ampho plasmids (Takara Bio; Shiga, Japan), into 293T cells (ATCC; Manassas, USA).
• HSC-2 cells were infected with the recombinant retroviruses, and were cultured for two weeks in the presence of puromycin (2 pg/mL). The infected cells were selected from a polyclonal proliferative population of the culture.
• the tumor volume was analyzed using bioluminescence signal from HSC-2- Luc cells.
• bioluminescence imaging 0.1 mL of 15 mg/mL D-luciferin (Promega, Madison, WI) was injected intraperitoneally into nude mice under 1% to 2% inhaled isoflurane anesthesia. The bioluminescence signal was monitored using the IVIS

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