HSP90 beta selective inhibitors

Abstract

The present disclosure is directed to Hsp90 inhibitors having the Formula (I), subformulae thereof, pharmaceutically acceptable salts, stereoisomer, or tautomer thereof, and methods of use thereof.

Description

Attorney Docket No.: 063626-502001WOHSP90 BETA SELECTIVE INHIBITORSFIELD

[0001] The present disclosure relates to novel Hsp90p selective inhibitors and the use thereof in treating cancer.CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 746,782, filed January 17, 2025, which is hereby incorporated by reference in its entirety and for all purposes.STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH OR DEVELOPMENT

[0003] This invention was made with government support under grants CA222894 and DA052340 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.BACKGROUND

[0004] The molecular chaperone and heat shock protein 90 kDa (Hsp90), regulates cellular homeostasis by assisting in the maturation of nascent polypeptides, the refolding of denatured proteins, and the disaggregation of protein aggregates. Hsp90 modulates the conformation of more than 300 client protein substrates into their biologically active conformation. Many signalling proteins are drivers of cancer progression, initiation, and / or metastasis. As a result, Hsp90 has emerged as a promising target for the development of anti-cancer agents. Further, Hsp90 has also been implicated in DNA Damage Response (DDR) mechanisms. Specifically, inhibition of DDR can occur through Hsp90 inhibition.SUMMARY

[0005] Disclosed herein are compounds that are Hsp90p selective inhibitors, pharmaceutical compositions comprising the compounds, and methods of treating disease and disorders using the compounds and pharmaceutical compositions.

[0006] A first aspect of the present disclosure relates to compounds of Formula (I)Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof,wherein:A is a C5-C6 cycloalkyl or 4- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N and O, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R5;B is a bond or O;X is CH orN;R1is C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, or C2-C4 alkynyl;R2is C1-C3 alkyl or C1-C3 haloalkyl;each R3and R4is independently selected from C1-C3 alkyl or R3and R4are taken together with the intervening carbon to form a C3-C6 cycloalkyl;each R5is independently H, oxo, cyano, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, CH2R6, -OR7, -N(R7)2, -C(O)R8, -C(O)OR8, or -C(O)N(R7)2;R6is hydroxy, cyano, C1-C4 alkoxy, C1-C4 haloalkoxy, orN(R7)2;each R7is independently H, C1-C3 alkyl or C1-C3 haloalkyl; andR8is C1-C3 alkyl;provided (1) when B is a direct bond and A is a monocyclic 6-membered heterocycle N-linked to B, then R2is C1-C3 haloalkyl; and (2) when B is O, A is not linked through a heteroatom.

[0007] In some aspects, A is 4- to 10-membered heterocycloalkyl; B is a bond or O; R1is C1-C4 alkyl; and R2is C1-C3 alkyl or C1-C3 haloalkyl.

[0008] In some aspects, the compound according to Formula l is a subformulae described herein, wherein the substituents are defined according to those of Formula I unless otherwise specified.Attorney Docket No.: 063626-502001WO

[0009] In some aspects, the compound is a compound according towherein p is an integer from 0 to 4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.cts, the compound is a compound according to:wherein p is an integer from 0 to 4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Attorney Docket No.: 063626-502001WO

[0012] some aspects, the compound is a compound according to:acceptable salt, stereoisomer, or tautomer thereof.

[0013] In some aspects, the compound is a compound according to:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein n is an integer selected from 0, 1, or 2.Attorney Docket No.: 063626-502001WO

[0014] some aspects, the compound is a compound according to:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0015] In some aspects, the compound is a compound according to:(Id), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Attorney Docket No.: 063626-502001WO the compound is a compound according to:tautomer thereof, wherein n is 0 1. or 2.

[0018] In some aspects, the compound is a compound according to:(le), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein n is 0, 1, or 2, and wherein R2is C1-C3 haloalkyl.Attorney Docket No.: 063626-502001WO

[0019] In some aspects, the compound is a compound according to:(Ie-3), wherein n is 0, 1, or 2, , and wherein R2is C1-C3 haloalkyl,(Ie-4), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0020] In some aspects, the compound is a compound according to:(Ie-3), wherein n is 0, 1, or 2, , and wherein R2is C1-C3 haloalkyl,(Ie-4), a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Attorney Docket No.: 063626-502001WO

[0021] In some aspects, the compound is a compound according to:tautomer thereof.

[0023] In some aspects, the compound is a compound according to:(Ih), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Attorney Docket No.: 063626-502001WO

[0024] In some aspects, the compound is a compound according to:(li), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Attorney Docket No.: 063626-502001WO

[0026] In some aspects, the compound is a compound according to:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0027] In some aspects, the compound is a compound according to:(Ij), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Attorney Docket No.: 063626-502001WO

[0028] In some aspects, the compound is a compound according to:(Ij-1),pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0029] In another aspect, the compound according to Formula I is a compound of Table 1.Attorney Docket No.: 063626-502001WOAttorney Docket No.: 063626-502001WO>Attorney Docket No.: 063626-502001WOAttorney Docket No.: 063626-502001WO> >Attorney Docket No.: 063626-502001WOAttorney Docket No.: 063626-502001WOAttorney Docket No.: 063626-502001WOAttorney Docket No.: 063626-502001WOAttorney Docket No.: 063626-502001WO

[0030] In another aspect of the present disclosure are compounds of Formula II,or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:A is a C5-C6 cycloalkyl or 4- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N and O, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R5;B is a bond or O;R1is C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, or C2-C4 alkynyl;R2is C1-C3 alkyl or C1-C3 haloalkyl;each R3and R4is independently selected from C1-C3 alkyl or R3and R4are taken together with the intervening carbon to form a C3-C6 cycloalkyl;Attorney Docket No.: 063626-502001WOeach R5is independently H, oxo, cyano, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, CH2R6, -OR7, -N(R7)2, -C(O)R8, -C(O)OR8, or -C(O)N(R7)2;R6is hydroxy, cyano, C1-C4 alkoxy, C1-C4 haloalkoxy, orN(R7)2;each R7is independently H, C1-C3 alkyl or C1-C3 haloalkyl; andR8is C1-C3 alkyl.

[0031] In some embodiments, A is 4- to 10-membered heterocycloalkyl;B is a bond or O;R1is C1-C4 alkyl; andR2is C1-C3 alkyl or C1-C3 haloalkyl.

[0032] In some embodiments, the compound is of Formula Ila(Ila), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0033] In some embodiments, the compound is of Formula lib:(lib), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0034] In some embodiments, the compound is of Formula lie:Attorney Docket No.: 063626-502001WO(lie), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0035] In some embodiments the compound is selected from the group consisting of:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0036] Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0037] Another aspect of the present disclosure relates to compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for therapeutic use.

[0038] Another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a cell.

[0039] Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate,Attorney Docket No.: 063626-502001WOprodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0040] Another aspect of the present disclosure relates to compounds of Formula (II), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for therapeutic use.

[0041] Another aspect of the present disclosure relates to the use of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a cell.

[0042] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0043] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.

[0044] In some aspects, the present disclosure provides a method of inhibiting Hsp90 comprising contacting Hsp90 with a therapeutically effective amount of a compound described herein. In some aspects, the method of inhibiting Hsp90 comprises contacting Hsp90 with a therapeutically effective amount of a compound according to Formula I. In some aspects, the method of inhibiting Hsp90 comprises contacting Hsp90 with a therapeutically effective amount of a compound according to Table 1. In some aspects, the Hsp90 protein is Hsp90p.

[0045] In some aspects, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or the pharmaceutical composition comprising a compound disclosed herein. In some aspects, the disease or disorder is a: cancer, viral disease, anti-inflammatory disease, angiogenesis-related disease, chemotherapy-induced toxicity, or a protein misfolding or aggregation disease. In some aspects, the disease or disorder is a cancer. In some aspects, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. In some aspects, the cancer is a leukemia. In some aspects, the cancer is a cancer of the bladder, blood, bone, brain, breast, cervix, colon / rectum, endometrium, head and neck, kidney, liver, lung, muscle tissue, ovary,Attorney Docket No.: 063626-502001WOpancreas, prostate, skin, spleen, stomach, testicle, thyroid, or uterus. In some aspects, the cancer is of the colon, breast, bladder, prostate, or kidney.

[0046] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.BRIEF DESCRIPTION OF DRAWINGS

[0047] Figure 1 depicts the pharmacokinetic curves for Compound 2 when dosed orally at 10 mg / kg and iv at 1 mg / kg in CD-I mice.

[0048] Figure 2 depicts the pharmacokinetic curve for Compound 5a disclosed in WO2019 / 232223 when dosed orally at 10 mg / kg in nude mice.

[0049] Figure 3 depicts the phototoxicity readouts of Compound 2 (Drug C) or pan Hsp90 inhibitors NVP auy922 (Drug A) or 17DMAG (Drug B) dosed in C57BL / 6J mice for 19 days. Electroretinograph (ERG) readouts measured electrical responses of retinae after exposure to different luminous intensities.

[0050] Figure 4A depicts the oral efficacy of Compound 2 in the A2780 ovarian cancer animal model. Oral dosing of 25mg / kg of Compound 2 once daily for 8 days in nude mice inhibited tumor growth inhibition (TGI) of 56% compared to vehicle control.

[0051] Figure 4B depicts the tolerability of Compound 2 in the A2780 ovarian cancer model, as determined by body weight measurements.

[0052] Figure 5A depicts the single agent efficacy exhibited by Compound 2 in the orthotopic ID8-luciferase enabled ID8 ovarian cancer model. C56B1 / 6 mice were dosed with Compound 2 administered 15 mg / kg BID by oral administration.

[0053] Figure 5B depicts the tolerability of Compound 2 in ID8-luciferase enabled ID8 ovarian cancer model as determined by body weight measurements.DETAILED DESCRIPTIONDefinitions

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless theAttorney Docket No.: 063626-502001WOcontext clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed present disclosure. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0055] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0056] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0057] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. In some cases, the term “about” refers to ±10% of a stated number or value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5 -fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0058] The term “at least” followed by a number is used herein to denote the start of a range beginning with that number (which may be a range having an upper limit or no upper limit, depending on the variable being defined). For example, “at least 1” means 1 or more than 1.

[0059] The term “at most” followed by a number is used herein to denote the end of a range ending with that number (which may be a range having 1 or 0 as its lower limit, or a rangeAttorney Docket No.: 063626-502001WOhaving no lower limit, depending upon the variable being defined). For example, “at most 4” means 4 or less than 4, and “at most 40%” means 40% or less than 40%. When, in this specification, a range is given as “(a first number) to (a second number)” or “(a first number)-(a second number)” this means a range whose lower limit is the first number and whose upper limit is the second number. For example, 25 to 100 mm means a range whose lower limit is 25 mm, and whose upper limit is 100 mm.

[0060] As used herein, the phrases “at least one”, “one or more”, and “and / or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B and C”, “at least one of A, B, or C”, “one or more of A, B, and C”, “one or more of A, B, or C” and “A, B, and / or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together.

[0061] As used herein, “or” may refer to “and”, “or,” or “and / or” and may be used both exclusively and inclusively. For example, the term “A or B” may refer to “A or B”, “A but not B”, “B but not A”, and “A and B”. In some cases, context may dictate a particular meaning.

[0062] As used herein, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps. As also used herein, in any instance or embodiment described herein, “comprising” may be replaced with “consisting essentially of’ and / or “consisting of’ used herein, in any instance or embodiment described.

[0063] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain ( / .< ., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(Ci-Ce) alkyl, (Ci-Ce) alkyl,Attorney Docket No.: 063626-502001WO(Ci-Ce) alkoxy, (Ci-Ce) haloalkyl, (Ci-Ce) haloalkoxy, -O-(C2-Ce) alkenyl, -O-(C2-Ce) alkynyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -OH, -OP(O)(OH)2, -OC(O)(Ci-C6) alkyl, -C(O)(Ci-C6) alkyl, -OC(O)O(Ci-C6) alkyl, -NH2, -NH((CI-C6) alkyl), -N((CI-C6) alkyl)2, -NHC(O)(CI-C6) alkyl, -C(O)NH(CI-C6) alkyl, -S(O)2(Ci-C6) alkyl, -S(O)NH(CI-C6) alkyl, and S(O)N((CI-C6) alkyl)2. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0064] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moi eties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a RM, and formulation into an efficacious therapeutic agent. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0065] As used herein, the term “unsubstituted” means that the specified group bears no substituents.

[0066] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “carbocyclic”, “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, methyl, ethyl, w-propyl, isopropyl, / / -butyl, ec-butyl, isobutyl, tert-butyl, and the like.Attorney Docket No.: 063626-502001WO

[0067] In some embodiments, “carbocyclic” (or “cycloaliphatic” or “carbocycle” or “cycloalkyl”) refers to a C3-C8 hydrocarbon, which may be monocyclic or multicyclic, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. The rings of multiring carbocyclics may exist as fused, bridged and / or joined through one or more spiro union to 1 or 2 aromatic cycloalkyl or heterocyclic rings. Typical, non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, and the like.

[0068] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2J / -pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl)). In some embodiments, an oxidized form of sulfur includes S=O and S(=O)2.

[0069] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0070] The term “halogen” means F, Cl, Br, or I.

[0071] As used herein, “alkyl” refers to optionally substituted, straight and branched chain aliphatic groups having from 1 to 30 carbon atoms. “Ci, C2, C3, C4, C5 or Ce alkyl” or “Ci-Ce alkyl” is intended to include Ci, C2, C3, C4, C5 or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or Ce branched saturated aliphatic hydrocarbon groups. For example, Ci-Ce alkyl is intends to include Ci, C2, C3, C4, C5 and Ce alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Ce for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. The term “heteroalkyl” as used herein contemplates an alkyl with one or more heteroatoms.

[0072] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl,Attorney Docket No.: 063626-502001WOalkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0073] “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-30 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0074] As used herein, the term “alkenyl” includes unsaturated or partially unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-6 for straight chain, C3-6 for branched chain). The term “C2-6” includes alkenyl groups containing two to six carbon atoms. The term “C3-6” includes alkenyl groups containing three to six carbon atoms.

[0075] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.Attorney Docket No.: 063626-502001WO

[0076] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-6 for straight chain, C3-6 for branched chain). The term “C2-6” includes alkynyl groups containing two to six carbon atoms. The term “C3-6” includes alkynyl groups containing three to six carbon atoms.

[0077] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0078] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl.

[0079] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro) system having 3 to 30 carbon atoms (e.g., C3-12, C3-10, C3-8, or C3-6). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic.Attorney Docket No.: 063626-502001WO

[0080] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic or bicyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1.2.3.6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2.5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,4-dioxaspiro[4.5]decanyl, l-oxaspiro[4.5]decanyl, 1 -azaspiro [4.5 ] decany 1 , 3 'H- spiro [cy cl ohexane- 1 , 1' -i sob enzofurran] -y 1 , 7'H-spiro[cyclohexane-l,5'-furo[3,4-b]pyridin]-yl,3'H-spiro[cyclohexane-l,l'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl,4.5.6.7-tetrahydro-lH-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3 ,4]octanyl, 2-oxa-azaspiro[3 ,4]octan-6-yl, 5.6-dihydro-4H-cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., l,3-dihydrobenzo[c]isoxazol-3-yl).

[0081] As used herein, the term “optionally substituted heterocycloalkyl” refers to unsubstituted heterocycloalkyl having designated substituents replacing one or more hydrogen atoms on one or more carbon or heteroatom. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino,Attorney Docket No.: 063626-502001WOarylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0082] Unless otherwise specifically defined, the term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, — H, -halogen. — O — (Ci-e) alkyl, (Ci-e) alkyl, — O — (C2-6) alkenyl, — O — (C2-6) alkynyl, (C2.6) alkenyl, (C2.6) alkynyl, —OH, — OP(O)(OH)2, — OC(O)(Ci-6) alkyl, — C(O)(Ci-6) alkyl, — OC(O)O(Ci-6) alkyl, — NH2, NH((CI-6) alkyl), N((CI-6) alkyl)2, — S(O)2 — (Ci-e) alkyl, — S(O)NH(Ci-e) alkyl, and — S(O)N((Ci-e) alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two or more fused rings, the aryl groups herein defined may have a saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, 10,ll-dihydro-5H-dibenzo[a,d][7]annulenyl, and the like. Furthermore, when containing two or more fused rings, the aryl groups herein defined may have a saturated or partially unsaturated heterocyclic ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, benzo[d][l,3]dioxol-5-yl, 2,3-dihydrobenzo[b][l,4]dioxin-6-yl, benzo[d]isoxazol-3(2H)-on-6-yl, benzo[d]oxazol-2(3H)-on-6-yl, and benzo[d]oxazol-2(3H)-on-5-yl.

[0083] Unless otherwise specifically defined, “heteroaryl” means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, Se, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl,Attorney Docket No.: 063626-502001WOpyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinol inyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][l,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolof l,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[l,2-a]pyrimidinyl, tetrahydro pyrrolo[l,2-a]pyrimidinyl, 3.4-dihydro-2H-112-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, lH-pyrido[3,4-b][l,4] thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo [l,2,3]triazolyl, imidazof 1 ,2-a]pyrimidinyl, [ 1 ,2,4]triazolo[4,3 -b]pyridazinyl, benzofc] [ 1 ,2,5]thiadiazolyl, benzo[c][l,2,5]oxadiazole, l,3-dihydro-2H-benzo[d]imidazol-2-one, 3.4-dihydro-2H-pyrazolo [l,5-b][l,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring, e.g., a 5 -membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring includes 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted with one or more oxo. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-l IH-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, l,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, l,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl,Attorney Docket No.: 063626-502001WO7,8-dihydro-6H-pyrido[3,2-b]pyrrolizine, pyrazolo[l,5-a]pyrimidin-7(4H)-only, 3 ,4-dihydropyrazino[ 1 ,2-a]indol- 1 (2H)-onyl, or benzofc] [ 1 ,2]oxaborol- 1 (3H)-olyl .

[0084] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenyl carbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl).

[0085] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0086] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0087] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an — OH or — O — .Attorney Docket No.: 063626-502001WO

[0088] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0089] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0090] As used herein, the term “cyano” refers to a nitrile radical (e.g., — CN).

[0091] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0092] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,Attorney Docket No.: 063626-502001WOtrifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and tri chloromethoxy.

[0093] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0094] As described herein, isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.” The compounds of Formula I may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0095] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.

[0096] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure,Attorney Docket No.: 063626-502001WOand the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0097] The present disclosure also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with D,2H, or14C). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

[0098] The disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

[0099] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0100] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, aAttorney Docket No.: 063626-502001WOmeglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0101] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l -carboxylic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton presents in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0102] The compound of Formula I forms salts which are also within the scope of this disclosure. Reference to a compound of the Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, when a compound of Formula I contains both a basic moiety and an acidic moiety, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable salts include those generally acceptable in the art of pharmaceutical sciences for administration in a subject, including humans and animals. In general, the pharmaceutically acceptable salts are non-toxic and physiologically acceptable salts. Salts of the compounds according to the disclosure may be formed, for example, by reacting the compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0103] The compounds of Formula I which contain a basic moiety may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,Attorney Docket No.: 063626-502001WOhemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0104] The compounds of Formula I which contain an acidic moiety may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)-ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

[0105] The disclosure encompasses compounds of Formula I, or pharmaceutically acceptable salts thereof, methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and use of these compounds in the treatment of diseases or disorders associated with Hsp90 inhibitory activity.

[0106] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0107] A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.

[0108] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon theAttorney Docket No.: 063626-502001WOsubject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0109] The term “carrier” as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0110] The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.[OHl] It is to be understood that, for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophy lactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0112] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy.

[0113] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying,Attorney Docket No.: 063626-502001WOencapsulating, entrapping, or lyophilising processes Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0114] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0115] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.Attorney Docket No.: 063626-502001WO

[0116] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0117] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0118] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0119] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers.Attorney Docket No.: 063626-502001WO

[0120] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0121] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. Dosages can range from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.

[0122] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0123] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.

[0124] The term “administer”, “administering”, or “administration” as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body.Attorney Docket No.: 063626-502001WO

[0125] The term “prodrug” as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

[0126] “Treating” or “treatment” as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing ( / .< ., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, “treatment” as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms, fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things.

[0127] “Prevention” or “preventing” refers to inhibiting the onset of a disease in a subject or patient which may be at risk and / or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and / or delaying the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and / or predisposed to the disease but has not yet experienced or displayed any of the pathology or symptomatology of the disease. Prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment.

[0128] Any composition or method disclosed herein is applicable to any herein-disclosed composition or method. In other words, any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

[0129] The details of the present disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the present disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise.Attorney Docket No.: 063626-502001WOUnless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this present disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

[0130] It should be understood that all isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

[0131] Compounds of the present disclosure, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure.

[0132] The compounds of the present disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure. In addition, the present disclosure embraces all geometric and positional isomers. For example, if a compound of the present disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the present disclosure. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

[0133] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the present disclosure may be atropisomers (e.g., substituted biaryls) and are considered asAttorney Docket No.: 063626-502001WOpart of this present disclosure. Enantiomers can also be separated by use of a chiral HPLC column.

[0134] It is also possible that the compounds of the present disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure.

[0135] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this present disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula I incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure). Individual stereoisomers of the compounds of the present disclosure may, for example, be substantially free of other stereoisomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

[0136] The compounds of Formula I may form salts which are also within the scope of this present disclosure. Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.

[0137] The present disclosure is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.Attorney Docket No.: 063626-502001WO

[0138] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:A is a C5-C6 cycloalkyl or 4- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N and O, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R5;B is a bond or O;X is CH orN;R1is C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, or C2-C4 alkynyl;R2is C1-C3 alkyl or C1-C3 haloalkyl;each R3and R4is independently selected from C1-C3 alkyl or R3and R4are taken together with the intervening carbon to form a C3-C6 cycloalkyl;each R5is independently H, oxo, cyano, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, CH2R6, -OR7, -N(R7)2, -C(O)R8, -C(O)OR8, or -C(O)N(R7)2;R6is hydroxy, cyano, C1-C4 alkoxy, C1-C4 haloalkoxy, orN(R7)2;each R7is independently H, C1-C3 alkyl or C1-C3 haloalkyl; andR8is C1-C3 alkyl; provided (1) when B is a direct bond and A is a monocyclic 6-membered heterocycle N-linked to B, then R2is C1-C3 haloalkyl; and (2) when B is O, A is not linked through a heteroatom.

[0139] In some embodiments, A is a C5 cycloalkyl. In some embodiments, A is a Ce cycloalkyl.

[0140] In some embodiments, A is a 4-, 5-, 6-, 7-, 8, 9-, or 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N and O. In some embodiments, the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R5.

[0141] In some embodiments, B is a bond. In some embodiments, B is O.Attorney Docket No.: 063626-502001WO

[0142] In some embodiments, R1is C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, or C2-C4 alkynyl. In some embodiments, R1is C1-C4 alkyl. In some embodiments, R1is C1-C4 haloalkyl. In some embodiments, R1is C2-C4 alkenyl. In some embodiments, R1is C2-C4 haloalkenyl. In some embodiments, R1is C2-C4 alkynyl.

[0143] In some embodiments, R2is C1-C3 alkyl or C1-C3 haloalkyl. In some embodiments, R1is C1-C3 alkyl. In some embodiments, R2is C1-C3 haloalkyl.

[0144] In some embodiments, R3and R4is independently selected from C1-C3 alkyl, or R3and R4are taken together with the intervening carbon to form a C3-C6 cycloalkyl. In some embodiments, R3and R4is independently selected from C1-C3 alkyl. In some embodiments, R3and R4are taken together with the intervening carbon to form a C3-C6 cycloalkyl.

[0145] In some embodiments, R5is independently H, oxo, cyano, halogen, C1-C3 alkyl, Ci-C3haloalkyl, hydroxy, CH2R6, -OR7, -N(R7)2, -C(O)R8, -C(O)OR8, or -C(O)N(R7)2. In some embodiments, each R5is independently H. In some embodiments, each R5is independently oxo. In some embodiments, each R5is independently cyano. In some embodiments, each R5is independently halogen. In some embodiments, each R5is independently C1-C3 alkyl. In some embodiments, each R5is independently C1-C3 haloalkyl. In some embodiments, each R5is independently hydroxy. In some embodiments, each R5is independently CH2R6. In some embodiments, each R5is independently -OR7. In some embodiments, each R5is independently -N(R7)2. In some embodiments, eachR5is independently -C(O)R8. In some embodiments, each R5is independently -C(O)OR8. In some embodiments, each R5is independently -C(O)N(R7)2.

[0146] In some embodiments, R6is hydroxy, cyano, C1-C4 alkoxy, C1-C4 haloalkoxy, or N(R7)2. In some embodiments, R6is hydroxy. In some embodiments, R6is cyano. In some embodiments, R6is C1-C4 alkoxy. In some embodiments, R6is C1-C4 haloalkoxy. In some embodiments, R6is N(R7)2.

[0147] In some embodiments, each R7is independently H, C1-C3 alkyl or C1-C3 haloalkyl. In some embodiments, each R7is independently H. In some embodiments, each R7is independently C1-C3 alkyl. In some embodiments, each R7is independently C1-C3 haloalkyl.

[0148] In some embodiments, R8is C1-C3 alkyl; provided (1) when B is a direct bond and A is a monocyclic 6-membered heterocycle N-linked to B, then R2is C1-C3 haloalkyl; and (2) when B is O, A is not linked through a heteroatom.Attorney Docket No.: 063626-502001WO

[0149] In some embodiments, the present disclosure provides a compound selected from acompound of any of Formulae la, la-1, la-2, or la-3pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, wherein p is an integer from 0 to 4.

[0150] In some embodiments, the present disclosure provides a compound selected from aAttorney Docket No.: 063626-502001WOacceptable salt, stereoisomer, or tautomer thereof, wherein n is 1 or 2, and wherein p is an integer from 0 to 4.

[0151] In some embodiments, the present disclosure provides a compound selected from a compound of any of Formulae Ic, Ic-1, Ic-2, or Ic-3 Ic-4, Ic-5, Ic-6, or Ic-7:Attorney Docket No.: 063626-502001WO(Ic-6), orpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0152] In some embodiments, the present disclosure provides a compound selected from acompound of any of Formulae Id or Id-1:

[0153] In some embodiments, the present disclosure provides a compound selected from a compound of any of Formulae le, Ie-1, Ie-2, or Ie-3, or Ie-4, wherein n is 0, 1, or 2, and R2isAttorney Docket No.: 063626-502001WOC1-C3 haloalkyl:(le), or a pharmaceutically acceptable salt,stereoisomer, or tautomer thereof, whereinstereoisomer, or tautomer thereof.Attorney Docket No.: 063626-502001WO

[0154] In some embodiments, the present disclosure provides a compound selected from acompound of Formulapharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0155] In some embodiments, the present disclosure provides a compound selected from acompound of Formulapharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0156] In some embodiments, the present disclosure provides a compound selected from acompound of any of FormulaeAttorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0157] In some embodiments, the present disclosure provides a compound selected from acompound of any of Formulae li, Ii-1, Ii-2, or Ii-3:(li),pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0158] In some embodiments, the present disclosure provides a compound selected from acompound of any of Formulae Ij, Ij-1, Ij-2, or Ij-3:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0159] It should be understood that all isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

[0160] Compounds of the present disclosure, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure.

[0161] The compounds of the present disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure. In addition, the present disclosure embraces all geometric and positional isomers. For example, if a compound of the present disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the present disclosure, each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

[0162] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can beAttorney Docket No.: 063626-502001WOseparated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the present disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this present disclosure. Enantiomers can also be separated by use of a chiral HPLC column.

[0163] It is also possible that the compounds of the present disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure.

[0164] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this present disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula I incorporates a double bond or a fused ring, both the cis- and transforms, as well as mixtures, are embraced within the scope of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure). Individual stereoisomers of the compounds of the present disclosure may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.General Synthetic Methods and Synthesis of Intermediate Compounds

[0165] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also providesAttorney Docket No.: 063626-502001WOdetailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

[0166] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0167] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0168] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’ s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art.Attorney Docket No.: 063626-502001WO

[0169] During the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition. John Wiley & Sons. New York, 1999.

[0170] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0171] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers, however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0172] Methods include but are not limited to those methods described below. Compounds of the present disclosure can be synthesized by following the steps outlined in Scheme 1, which comprise different sequences of assembling intermediates or compounds. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below.

[0173] Compounds of the disclosure can be synthesized according to the following exemplary general schemes.Attorney Docket No.: 063626-502001WOGeneral Scheme 1. Exemplary synthesis of compounds 27-29

[0174] Details of General Scheme 1 include (a) Anhydride, DMAP, DIPEA, DCM, 40 °C, 20 h. (b) Hydrazine monohydrate, EtOH, 60 °C, 4 h, yield: 65%. (c) 2-Acyl dimedone, EtOH, 100 °C, 6 h, yield: 42-84%. (d) Methyl-3-oxohexanotae, K2CO3, DMF, 70 °C, 16 h. (e) Sulfuric acid:Water: Acetic Acid (2:1:7), 130 °C, 12 h, yield: 26-28% (over 2 steps), (f) Ammonium HC1 salt, DIPEA, DMSO, 140 °C, yield: 33-72%.General Synthesis of Acylated Dimedones I2a, I 2b, and I2c

[0175] To a solution of dimedone II (3.57 mmol, 1 equiv.), DMAP (1.07 mmol, 0.3 equiv.), and DIPEA (3.93 mmol, 1.1 equiv.) in DCM (4.0 mL) was added dropwise the appropriate anhydride (3.93 mmol, 1.1 equiv.). The reaction was stirred at 40 °C for 20 h and, upon cooling to room temperature, was quenched with aqueous, IN HC1 (4.0 mL). The aqueous layer was extracted with DCM (3 x 2.0 mL), and the combined organic fractions were washed with water (5.0 mL), then brine (5.0 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.Attorney Docket No.: 063626-502001WOThe crude residue (typically a yellow-, orange-, or red-colored oil) was utilized in the next reaction without further purification or characterization.Table 2. Acylated dimedones I2a-I2cSynthesis of 2, 6-dijluoro-4-hydrazineylbenzonitrile (Benzonitrile 14)NHNH2F CN

[0176] Hydrazine monohydrate (-55% solution) (3.4 g, 63.8 mmol, -2 equiv.) was added dropwise to a solution of 2,4,6-trifluorobenzonitrile 13 (5.0 g, 31.9 mmol, 1 equiv.) in EtOH (50 mL) at 60 °C, and the reaction was stirred at this temperature until the complete consumption of starting material was observed, as determined via TLC (-4 h). Upon cooling to room temperature, the solvent was removed in vacuo, and water (50 mL) was added to the remaining solid matter. The aqueous layer was extracted with ethyl acetate (3 x 50 mL), andAttorney Docket No.: 063626-502001WOthe combined organic fractions were washed with water (100 mL), then brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography (2% MeOH in DCM) to give the product as a colorless solid. 2,6-difluoro-4-hydrazineylbenzonitrile (14). Yield 65%, 6.98 g; 'H NMR (400 MHz, DMSO) 8 8.50 (s, 1H), 6.48 (d, J = 12.6 Hz, 2H), 4.53 (s, 2H).13CNMR(101 MHz, DMSO-de) 6 164.12 (d, J = 250.5 Hz), 158.32 (2, t, J = 14.4 Hz), 112.02, 93.38 (2, d, J = 23.8 Hz), 74.86 (t, J = 20.7 Hz). HRMS (ESI) m / z [M + H] calc’d for C7H6F2N3, 170.0524, found 170.0526.Synthesis of 2, 6-dijluoro-4-( 3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 -tetrahydro- IH-indazol-l-ylfbenzonitrile (Benzonitrile I5a) and 4-(3-(dijluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-2, 6-dijluorobenzonitrile (Benzonitrile I5b)

[0177] 2-Acyl dimedone Ila or 12b (591 pmol, 1 equiv.) was added to a pressure vessel charged with a solution of 2,6-difluoro-4-hydrazineylbenzonitrile 14 (591 pmol, 1 equiv.) in EtOH (1.5 mL). The tube was sealed, and the reaction was stirred at 100 °C for 6 h. Upon cooling to room temperature, the solvent was removed in vacuo, and the remaining matter was resuspended in ethyl acetate (5.0 mL). The organic layer was washed with water (5.0 mL), then brine (5.0 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.

[0178] The residue was purified via column chromatography (5-40% ethyl acetate in hexanes) to give the products as light-yellow or orange-colored solids.

[0179] 2, 6-dijluoro-4-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 -tetrahydro- IH-indazol-l-yl)benzonitrile (I5a). Yield 84%, 156 mg; 1HNMR (400 MHz, Chloroform-d) 67.37-7.30 (m, 2H), 2.90 (s, 2H), 2.49 (s, 3H), 2.40 (s, 2H), 1.13 (s, 6H). 13C NMR (101 MHz, Chloroformdi 193.07, 164.77 (d, J = 6.2 Hz), 162.18 (d, J = 6.2 Hz), 151.69, 149.53, 144.41 (t, J = 12.6 Hz), 118.82, 108.64, 106.28 (d, J = 3.6 Hz), 106.04 (d, J = 3.5 Hz), 90.47 (t, J = 19.5 Hz), 52.04, 37.98, 36.05, 28.41 (2), 13.38. HRMS (ESI) m / z [M + H] calc’d for C17H16F2N3O.Attorney Docket No.: 063626-502001WO

[0180] 4-(3-(difhioromethyl)-6, 6-dimethyl-4-oxo-4,5, 6, 7-tetrahydro-lH-indazol-l-yl)- 2,6-difluorobenzonitrile (I5b). Yield 42%, 88 mg;XHNMR (400 MHz, Chloroform-d) 67.43- 7.37 (m, 2H), 7.07 (t, J = 53.5 Hz, 1H), 2.95 (s, 2H), 2.48 (s, 2H), 1.16 (s, 6H).13CNMR(101 MHz, Chloroform-d) 6 191.34, 164.81 (d, J = 6.0 Hz), 162.20 (d, J = 5.9 Hz), 150.24, 146.55 (t, J = 25.8 Hz), 143.61 (t, J = 12.4 Hz), 118.30 (t, J = 2.3 Hz), 109.99 (d, J = 238.5 Hz), 108.26 (d, J =184.4 Hz), 107.26 (d, J = 3.7 Hz), 107.02 (d, J = 3.8 Hz), 92.05 (t, J = 19.3 Hz), 51.79, 37.59, 36.20, 28.32 (2). HRMS (ESI) m / z [M + H] calc’d for C17H14F4N3O, 352.1068, found 352.1077.Synthesis of 8-fluoro-3-propyl-6-( 3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 -tetrahydro- IH-indazol-l-yl)isoquinolin-

[0181] To a solution of benzonitrile I5a or I5b (569 pmol, 1 equiv.) and potassium carbonate (683 pmol, 1.2 equiv.) in DMF (2.5 mL) was added methyl-3 -oxohexanoate (683 pmol, 1.2 equiv.). The reaction was stirred at 70 °C until the complete consumption of starting material was observed, as determined via TLC (~16 h). Upon cooling to room temperature, the solution was acidified to pH 5 with aqueous, IN HC1, followed by the addition of saturated, aqueous ammonium chloride (10 mL). The aqueous layer was extracted with ethyl acetate (3 x 10 mL).Attorney Docket No.: 063626-502001WO

[0182] The combined organic fractions were washed with water (3 x 20 mL), then brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue (typically an orange-or brown-colored oil) was utilized in the next step without further purification or characterization.

[0183] The crude material from the previous step (-450 mg) was added to a 15 mL pressure vessel and dissolved in 1.4 mL of sulfuric acid (36 N), 0.7 mL of water, and 4.9 mL of acetic acid (H2SO4:H2O:ACOH = 2:1:7). After this time, the vessel was sealed, and the reaction was then stirred at 130 °C for 12 h. Upon cooling to room temperature, the reaction was quenched by pouring the solution into 100 mL of water. The precipitate was collected and dried via vacuum filtration and then redissolved in ethyl acetate (25 mL). The residue was loaded directly onto silica gel and purified via column chromatography (12-100% ethyl acetate in hexanes) to give the products as light-brown solids.

[0184] 8-fluoro-3-propyl-6-(3, 6, 6-trimethyl-4-oxo-4,5, 6, 7 -tetrahydro- IH-indazol-l-yl)isoquinolin- l(2H)-one (I7a). Yield 28%, 109 mg. Subsequent syntheses provided up to 45% yield. 'H NMR(500 MHz, chloroform-d) 8 10.32 (s, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 14.0 Hz, 1H), 6.37-6.29 (s, 1H), 2.91 (s, 2H), 2.61 (t, J = 7.6 Hz, 2H), 2.57 (s, 3H), 2.44 (s, 2H), 1.80 (h, J = 7.4 Hz, 2H), 1.15 (s, 6H), 1.04 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, chloroform-d) 6 193.3, 162.9 (d, J = 265.2 Hz), 161.1 (d, J = 4.5 Hz), 150.8, 149.3, 144.5, 142.8 (d, J = 11.9 Hz), 142.0 (d, J = 2.4 Hz), 117.8, 114.6 (d, J = 4.6 Hz), 112.2 (d, J = 7.2 Hz), 107.5 (d, J = 25.7 Hz), 103.3 (d, J = 3.5 Hz), 52.3, 37.8, 36.0, 35.2, 28.4 (2), 21.4, 13.5, 13.4. HRMS (ESI) m / z [M + Na] calcd for C22H24FN3O2Na, 404.1750, found 404.1765

[0185] 6-(3-(difhioromethyl)-6, 6-dimethyl-4-oxo-4,5, 6, 7 -tetrahydro- IH-indazol-l-yl) -8-fluoro-3- propylisoquinolm-l(2H)-one (I7b). Yield 26%, 104 mg; 'H NMR (400 MHz, Chloroform-d) 6 11.09 (s, 1H), 7.48-7.31 (m, 1H), 7.26 (s, 1H), 7.24-6.97 (m, 1H), 6.36 (s, 1H), 2.91 (d, J = 18.1 Hz, 2H), 2.63 (t, J = 7.7 Hz, 2H), 2.48 (s, 2H), 1.80 (h, J = 7.5 Hz, 2H), 1.12 (d, J = 25.4 Hz, 6H), 1.04 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, Chloroform-d) 6 191.74, 163.04 (d, J = 266.8 Hz), 161.57 (d, J = 3.8 Hz), 149.95, 145.75 (t, J = 25.4 Hz), 145.32, 142.20 (d, J = 1.4 Hz), 141.54 (d, J = 11.8 Hz), 117.48, 115.39 (d, J = 4.2 Hz), 112.92, 109.11 (t, J = 237.8 Hz), 107.72 (d, J = 25.7 Hz), 103.36 (d, J = 2.6 Hz), 52.00, 37.37, 36.12, 35.21, 28.36 (2), 21.47, 13.56.HRMS (ESI) m / z [M + H] calc’d for C22H23F3N3O2, 418.1737, found 418.1735.Attorney Docket No.: 063626-502001WOGeneral Scheme 2. Exemplary synthesis of compounds 1-4

[0186] Details of General Scheme 2 include (a) Anhydride, DMAP, DIPEA, DCM, 40 °C, 20 h. (b) Hydrazine monohydrate, EtOH, 60 °C, 4 h, 63%. (c) / Mketoester, K2CO3, DMF, 70 °C, 16 h. (d) Sulfuric acid:Water: Acetic Acid (2:1:7), 130 °C, 12 h, 20-41% (over 2 steps), (e) Grignard reagent, THF, 110 °C, MW, 1 h. (f) Grignard reagent, THF, 100 °C, 16 h, 30-43%. (g)NaH, DMF, rt, 15 min; then 140 °C, 16 h, 80%. (h) Indazolone, DMEDA, K3PO4, Cui, 1,4-Dioxane, 110 °C, 16 h, 34-61%.General Synthesis of Acylated Dimedones I2a—I2c

[0187] To a solution of dimedone II (3.57 mmol, 1 equiv.), DMAP (1.07 mmol, 0.3 equiv.), and DIPEA (3.93 mmol, 1.1 equiv.) in DCM (4.0 mL) was added dropwise the appropriate anhydride (3.93 mmol, 1.1 equiv.). The reaction was stirred at 40 °C for 20 h and, upon coolingAttorney Docket No.: 063626-502001WOto room temperature, was quenched with aqueous, IN HC1 (4.0 mL). The aqueous layer was extracted with DCM (3 x 2.0 mL), and the combined organic fractions were washed with water (5.0 mL), then brine (5.0 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue (typically a yellow-, orange-, or red-colored oil) was utilized in the next reaction without further purification or characterization.General Synthesis of 19 Intermediates (I9a-I9c)Synthesis of 3 -(difluoromethyl) -6, 6-dimethyl-l, 5, 6, 7-tetrahydro-4H-indazol-4-one<

[0188] Hydrazine monohydrate (-55% solution) (118 mg, 115 pL, 2.36 mmol, 1 equiv.) was added to a solution of 2-acyl dimedones I2a-I2c (1.03 g, 4.71 mmol, 2 equiv.) in EtOH (6.0 mL), and the reaction was stirred at 100 °C until completion of the reaction was observed via TLC (6-12 h). Upon cooling to room temperature, the solvent was removed in vacuo, and the remaining matter was resuspended in ethyl acetate (6.0 mL). The organic layer was washed with water (6.0 mL), then brine (6.0 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography (30% ethyl acetate in hexanes) to give the products as off-white, light-yellow solids.

[0189] 3-(methyl)-6, 6-dimethyl-l, 5, 6, 7-tetrahydro-4H-indazol-4-one

[0190] Using the method above, 3-(methyl)-6, 6-dimethyl-l, 5,6, 7-tetrahydro-4H-indazol-4-one (I9a) was prepared from the intermediate of Example I2a as an off-white, light-yellow solid Yield 85%, 8.3 g; 1H NMR (400 MHz, Chloroform-d) 87.80 (s, 1H), 2.68 (s, 2H), 2.54 (d, J = 1.6 Hz, 3H), 2.34 (d, J = 1.5 Hz, 2H), 1.08 (d, J = 1.8 Hz, 6H). 13C NMR (101 MHz, CDC13) 6 194.72, 154.17, 145.00, 114.61, 53.01, 36.35, 35.60, 28.45 (2), 12.06. HRMS (ESI) m / z [M + H] calc’d for C10H15N2O, 179.1179, found 179.1177.

[0191] 3-(difluoromethyl)-6, 6-dimethyl-l, 5, 6, 7-tetrahydro-4H-indazol-4-one (I9b). Yield 63%, 320 mg; 'H NMR (400 MHz, Chloroform-d) 6 12.77 (s, 1H), 7.15 (t, J = 54.0 Hz, 1H),Attorney Docket No.: 063626-502001WO2.81 (s, 2H), 2.39 (s, 2H), 1.10 (s, 6H).13C NMR (101 MHz, Chloroform-d) 6 192.91, 151.62, 144.10 (t, J = 23.9 Hz), 115.20 (t, J = 3.4 Hz), 109.45 (t, J = 236.8 Hz), 52.43, 35.95, 34.68, 28.25 (2). HRMS (ESI) m / z [M + H] calc’d for C10H13F2N2O, 215.0990, found 215.0998.

[0192] 3-(ethyl)-6,6-dimethyl-l,5,6,7-tetrahydro-4H-indazol-4-one

[0193] Using the method of I9a, 3-(ethyl)-6,6-dimethyl-l,5,6,7-tetrahydro-4H-indazol-4-one (I9c) was prepared from the intermediate of I2c as an off-white, light-yellow solid in Yield 80%, 7.6 g; 1HNMR (400 MHz, Chloroform-d) 6 10.91 (s, 1H), 2.93 (q, J = 7.6 Hz, 2H), 2.66 (s, 2H), 2.33 (s, 2H), 1.25 (t, J = 7.5 Hz, 3H), 1.06 (s, 6H). 13C NMR (101 MHz, CDC13) 6 194.47, 154.37, 150.72, 113.85, 53.06, 36.34, 35.51, 28.42 (2), 19.99, 12.80. HRMS (ESI) m / z [M + H] calc’d for Cl 1H17N2O, 193.1335, found 193.1333.General Synthesis of Intermediates 112 and II 5a / b

[0194] The appropriate / Lketoester (5.50 mmol, 1.2 equiv.) was added to a solution of benzonitrile I10a or I10b (4.59 mmol, 1 equiv.) and potassium carbonate (5.50 mmol, 1.2 equiv.) in DMF (20 mL), and the reaction was stirred at 70 °C until the complete consumption of starting material was observed, as determined via TLC (~16 h). Upon cooling to room temperature, the solution was acidified to pH 5 with aqueous, IN HC1, followed by saturated, aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic fractions were washed with water (5 x 20 mL), then brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was utilized in the next step without further purification or characterization.

[0195] The crude material from the previous step (~2.5 g) was dissolved in a 50 mL pressure vessel and dissolved in 5.0 mL of sulfuric acid (36 N), 2.5 mL of water, and 18 mL of glacial acetic acid (H2SC>4:H2O:AcOH = 2:1:7). After this time, the vessel was sealed, and the reaction was then stirred at 130 °C for 12 h. Upon cooling to room temperature, the mixture was neutralized with aqueous sodium bicarbonate, and the aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organic fractions were washed with water (25 mL), then brine (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residueAttorney Docket No.: 063626-502001WOwas purified via column chromatography (12-100% ethyl acetate in hexanes) to give the products as brown solids.

[0197] Yield 20%, 333 mg;1H NMR (400 MHz, Chloroform-d) 6 11.46 (s, 1H), 6.95-6.85 (m, 1H), 6.78 (ddd, J = 11.4, 9.0, 2.4 Hz, 1H), 6.23 (d, J = 2.2 Hz, 1H), 2.59 (t, J = 7.7 Hz, 2H), 1.77 (h, J = 7.4 Hz, 2H), 1.01 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, Chloroform-d) 6 165.56 (dd, J = 93.9, 13.6 Hz), 162.98 (dd, J = 106.6, 13.5 Hz), 162.22-162.00 (m), 144.81, 142.83 (d, J = 1.8 Hz), 142.71 (d, J = 2.1 Hz), 106.62 (dd, J = 21.2, 4.6 Hz), 103.27 (t, J = 3.3 Hz), 102.18 (dd, J = 26.9, 24.8 Hz). 35.08, 21.50, 13.54. HRMS (ESI) m / z [M + H] calc’d for C12H12F2NO, 224.0881, found 224.0876.

[0198] 6- bromo-8-fluoro-3-propylisoquinolm-l(2H)-one

[0199] Yield 41%, 607 mg;XH NMR (400 MHz, Chloroform-d) 6 11.45 (s, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.16 (dd, J = 10.7, 1.8 Hz, 1H), 6.20 (d, J = 2.2 Hz, 1H), 2.58 (t, J = 7.6 Hz, 2H), 1.76 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, Chloroform-d) 6 162.30 (d, J = 4.0 Hz), 162.22 (d, J = 268.4 Hz), 144.83, 142.25, 127.04 (d, J= 10.9 Hz), 124.25 (d, J = 4.6 Hz), 116.09 (d, J = 24.6 Hz), 112.16 (d, J = 6.4 Hz), 102.83 (d, J = 2.7 Hz), 35.08, 21.45, 13.52. HRMS (ESI) m / z [M + H] calc’d for Ci2Hi2BrFN2O, 284.0081, found 284.0084.

[0200] 6- bromo-3-butyl-8-fluoroisoquinolin-l ( 2H)-oneAttorney Docket No.: 063626-502001WO

[0201] Yield 30%, 410 mg; 'H NMR (400 MHz, Chloroform-d) 6 11.47 (s, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.16-7.11 (m, 1H), 6.23 (d, J = 2.1 Hz, 1H), 2.58 (t, J = 7.7 Hz, 2H), 1.68 (p, J = 7.5 Hz, 2H), 1.38 (dq, J = 14.7, 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, Chloroform-d) 6 162.59 (d, J = 3.9 Hz), 162.06 (d, J = 268.9 Hz), 144.83, 142.18, 127.34 (d, J = 10.9 Hz), 124.31 (d, J = 4.6 Hz), 117.13-115.46 (m), 111.78 (d, J = 6.5 Hz), 103.29 (d, J = 2.6 Hz), 32.80, 30.08, 22.12, 13.70. HRMS (ESI) m / z [M + H] calc’d for Ci3Hi4BrFNO, 298.0237, found 298.0250.General Syntheses of Intermediates I13a / b and II 6a / b

[0202] Selected Intermediates of General Scheme 2 were prepared in accordance with General Procedures A and B:

[0203] General Procedure A: To a solution of isoquinolinone 112 (1 Eq) in THF was added a freshly prepared 1 molar solution of Grignard reagent from the respective alkyl bromide (2 Eq) and subsequently heated to 110 °C via microwave radiation for 15 mins to 1 hour until consumption of all starting material was determined per TLC. The reaction was quenched with water, extracted with EtOAc (3x), the organic phases concentrated in vacuo, and the crude was carried forward without further characterization.

[0204] General Procedure B: 4-Bromotetrahydropyran (3.03 mmol, 1 equiv.) was added dropwise to a solution of magnesium turnings (10 equiv.) in anhydrous THF (4.0 mL), and the reaction was stirred at room temperature for 3 h. After this time, the resulting Grignard reagent was added dropwise to a separate solution of I15a or I15b (0.671 pmol, 0.2 equiv.) in THF (1.0 mL), and the reaction was stirred at 100 °C for 16 h. Upon cooling to room temperature, the excess Grignard reagent was quenched via the slow addition of MeOH (5.0 mL), the solvent was removed in vacuo, and the remaining matter was loaded directly onto silica gel and purified via column chromatography (12-100% ethyl acetate in hexanes) to give the products as lightyellow solids.

[0205] 8-cyclohexyl-6-fluoro-3-propylisoquinolin-l(2H)-onewas prepared using General Procedure A.Attorney Docket No.: 063626-502001WO

[0206] 6-fluoro-3-propyl-8-(tetrahydro-2H-pyran-4-yl)isoquinolin-l(2H)-one (I13b) was prepared using General Procedure A.

[0207] 6- bromo-3-propyl-8-( tetrahydro-2H-pyran-4-yl)isoquinolin-l ( 2H)-onewas prepared using General Procedure B. Yield 30%, 70 mg; 'H NMR (400 MHz, Chloroform-d) 6 12.03 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 6.21 (d, J = 1.6 Hz, 1H), 4.78 (tt, J= 11.7, 3.4 Hz, 1H), 4.21 -4.03 (m, 2H), 3.63 (td, J = 11.5, 2.0 Hz, 2H), 2.63 (t, J = 7.4 Hz, 2H), 1.90 (ddd, J = 12.5, 3.8, 1.9 Hz, 2H), 1.79 (dqd, J = 12.1, 7.7, 4.1 Hz, 4H), 1.01 (t, J = 7.4 Hz, 3H).13C NMR (101 MHz, CDC13) 6 165.38, 151.31, 142.99, 142.33, 127.37, 127.06, 126.88, 119.99, 104.05, 68.80 (2), 37.30, 34.53, 34.16 (2), 21.36, 13.53. HRMS (ESI) m / z [M + H] calc’d for Ci7H2iBrNO2, 350.0750, found 350.0755.

[0208] 6-fluoro-3-propyl-8-(tetrahydro-2H-pyran-4-yl)isoquinolin-l(2H)-oneoik .H (I13b) was prepared using General Procedure B and used in the next step without further purification.

[0209] 6- bromo-3-butyl-8-(tetrahydro-2H-pyran-4-yl)isoquinolin-l(2H)-onewas prepared using General Procedure B. Yield 43%, 105 mg; 'H NMR (400 MHz, Chloroform-d) 6 11.33 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 6.21 (d, J = 1.6 Hz, 1H), 4.76 (tt, J = 11.7, 3.4 Hz, 1H), 4.18- 4.05 (m, 2H), 3.64 (td, J = 11.6, 2.0 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 1.94-1.66 (m, 6H), 1.46-1.35 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, CDCI3) 6 165.02, 151.38, 142.93, 142.29, 127.44,Attorney Docket No.: 063626-502001WO127.12, 126.87, 119.97, 103.92, 68.76 (2), 37.26, 34.14 (2), 32.40, 30.10, 22.02, 13.88. HRMS (ESI) m / z [M + H] calc’d for Ci8H23BrNO2, 364.0907, found 364.0920.

[0210] Compounds 1-4 were prepared in accordance with General Procedures C or D:

[0211] General Procedure C: To a solution of NaH (60% Wt, 2 Eq) in DMF was added indazolone I9a or I9c (2 Eq) dissolved in DMF in a microwave vial. The solution was allowed to stir for 15 min after which a solution of isoquinolinone I13a or I13b (1 Eq) in 2 mL DMF was added. The microwave vial was sealed and heated at 140 °C overnight. The reaction was subsequently quenched with water, the aqueous extract with EtOAc (3x), the organic phases concentrated in vacuo, and the crude purified via column chromatography (0-50% ethyl acetate in hexanes) to give the products as colorless solids.

[0212] General Procedure D: Indazolone I9b (0.12 mmol, 1 equiv.), I16a or I16b (0.12 mmol, 1 equiv.), DMEDA (47 pmol, 0.4 equiv), andKsPCh (0.25 mmol, 2.1 equiv.) were added to a pressure vessel, dissolved in 1,4-di oxane (500 pL), and stirred at room temperature. Following a 10-minute purge with argon gas, copper(I) iodide (23 pmol, 0.2 equiv.) was then added to the solution, which was subsequently purged with argon gas for an additional 10 minutes. The reaction tube was sealed, and the solution was then stirred at 110 °C for 24 h. Upon cooling to room temperature, the mixture was filtered through a pad of Celite, and the filter cake was washed with ethyl acetate (2 x 5.0 mL). The filtrate was concentrated in vacuo, the residue was purified via column chromatography (50% ethyl acetate in hexanes), and then further purified via preparatory TLC (25% ethyl acetate in hexanes) to give the final products as colorless solids.General Synthetic Scheme 3. Synthesis of II 7a, Il 7b, 118 a and II 8b>Attorney Docket No.: 063626-502001WO

[0213] Reaction conditions of General Scheme 3 include (a) Anhydride, DMAP, DIPEA 1,4-Dioxane, 80° C (b) Anhydride, DMAP, DIPEA, DCM, rt, 20 h.

[0214] 7-propionylspiro[3.5]nonane-6, 8-dione(I17a) was synthesized according to the following steps, and as described in General Synthetic Scheme 3.

[0215] To the solution of commercially available spiro[3.5]nonane-6, 8-dione (I17ii) (500 mg, 3.28 mmol, 1 Eq.) dissolved in 15 mL 1,4-Dioxane, propionic anhydride (0.55 mL, 4.26 mmol, 1.3 Eq) was added dropwise, then DIPEA (1.72 ml, 9.84 mmol, 3 Eq), DMAP (39 mg, 0.32 mmol, 0.1 Eq) were added and the reaction was stirred at 80°C for 12 h. After reaction was complete as monitored using TLC, silica gel was added and solvent was evaporated in vacuo and purified using column chromatography using 10% ethyl acetate in hexanes to afford 540 mg of 7-propionylspiro[3.5]nonane-6, 8-dione (I17a) as yellow oil (83% yield).!H NMR (400 MHz, Chloroform- ) 8 3.05 (q, J = 7.2 Hz, 2H), 2.75 (s, 2H), 2.58 (s, 2H), 1.96 - 1.84 (m, 6H), 1.12 (t, J = 7.3 Hz, 3H).

[0216] 6-propionylspiro[2.5]octane-5, 7-dione(I17b) is synthesized with commercially available Spiro[2.5]octane-5, 7-dione (I17i) using the same procedure as I17a.

[0217] General Synthetic Scheme 4.Attorney Docket No.: 063626-502001WO

[0218] Reaction conditions of General Scheme 4 include (a) Hydrazine hydrate, Ethanol, 60° C (b) substituted dimedone, DMSO, 100° C (c) NH4OH, THF, 100° C in a pressure tube, (d) NH4OH, DMSO, 120° C in a pressure tube (e) cone. H2SO4, 100° C (f) aldehyde, solvent (THF or 1,4-Dioxane), cat. PTSA. 120° C in a pressure tube, (g) Amine, DMSO, DIPEA, 130° C (h) Boronate ester, Pd(OAc)2, DPPF, K2CO3, 1,4-Dioxane: H2O (18:2) (i) 10% Pd on carbon:Attorney Docket No.: 063626-502001WOPdCh (1:1), MeOH, H2 gas, 45° C (j) LKetoester, K2CO3, CuBr, 1, 10-Phenanthroline, DMSO, 100° C, (k) cone. H2SO4, water, 100° C, (1) Grignard reagent, THF, 130° C (m) corresponding alcohol, NaH, DMSO, 140° C.

[0219] 7-(2,2-difluoroacetyl)spiro[3.5]nonane-6, 8-dione

[0220] To the solution of commercially available spiro[3.5]nonane-6,8-dione(I17ii) (500 mg, 3.28 mmol, 1 Eq.) dissolved in 15 mL DCM, Difluoroacetic anhydride (741 mg, 4.26 mmol, 1.3 Eq) was added dropwise, then DIPEA (1.72 ml, 9.84 mmol, 3 Eq), DMAP (39 mg, 0.32 mmol, 0.1 Eq) were added and the reaction was stirred at rt for 12 h. After reaction was complete as monitored using TLC, solvent was evaporated in vacuo and 50 ml water was added, acidified to pH -3 and extracted twice with 20 mL ethyl acetate. Combined organic extracts are washed with 20 mL water, dried using sodium sulfate and evaporated to obtain 490mg of I18a as crude orange oil (66% yield). This was utilized in next reactions without further purification.

[0221] synthesized with commercially available Spiro[2.5]octane-5, 7-dione (I17i) using the same procedure as I18a

[0222] 2,6-dichloro-4-hydrazineylbenzonitrile

[0223] In a 250 ml round bottom flask, 2,6-dichloro-4-fluorobenzonitrile (I18c) (1 g, 5.26 mmol, 1 Eq.) was dissolved in 30 ml Ethanol and heated to 60° C, hydrazine monohydrate (-55% solution) (1.1 g, 21 mmol, 4 Eq.) was added dropwise. The reaction was monitoredAttorney Docket No.: 063626-502001WOusing TLC for the consumption of starting material. Upon completion of the reaction (~2 h), reaction was cooled to rt and the solvents and excess hydrazine were evaporated in vacuo to obtain 1 g 119 as white solid. 'H NMR (400 MHz, Chloroform-t / ) 66.87 (s, 2H), 5.76 (s, 1H), 3.74 (s, 2H).

[0224] 2, 6-dichloro-4-(3-ethyl-6, 6-dimethyl-4-oxo-4, 5, 6, 7 -tetrahydro- IH-indazol-l-

[0225] 2,6-dichloro-4-hydrazineylbenzonitrile (119) (0.9 g, 4.45 mmol, 1 Eq.), 5,5- dimethyl-2-propionylcyclohexane-l,3-dione (1 g, 4.86 mmol, 1.1 Eq) were added to a round bottom flask containing 20 ml DMSO which was stirred and heated at 100° C for 6 h. Upon completion, 100 ml water was added to the reaction mixture, and the precipitate was filtered, washed with water and air dried. The dried powder was sonicated with 50 ml hexanes and filtered to obtain 1.5 g of 119 as yellow powder (83% yield). 'HNMR (400 MHz, Chloroform-d) 57.70 (s, 2H), 2.97 (q, J= 7.5 Hz, 2H), 2.89 (s, 2H), 2.45 (s, 2H), 1.31 (t, J= 7.5 Hz, 3H), 1.17 (s, 6H).

[0226] 2, 6-dichloro-4-(3 ’-ethyl-4 ’-oxo-4 7 ’-dihydrospiro [cyclopropane- 1, 6 ’-indazol]-procedure used to synthesize I20a.Attorney Docket No.: 063626-502001WO

[0227] 2, 6-dichloro-4-(3 ’-ethyl-4 ’-oxo-4 7 ’-dihydrospiro [cyclobutane- 1, 6 ’-indazol]-was synthesized using I17a following the procedure used to synthesize I20a. 'H NMR (400 MHz, Chloroform-d) 67.70 (s, 2H), 3.10 (s, 2H), 2.94 (q, J = 7.5 Hz, 2H), 2.69 (s, 2H), 2.04 - 1.82 (m, 4H), 1.34 - 1.09 (m, 5H).

[0228] Intermediates I21a-I21c are synthesized according to I20a. Compounds with physical characterization provided were synthesized.Table 3. Characterization of Intermediates I21a-I21c>Attorney Docket No.: 063626-502001WO

[0229] 4-(3-ethyl-6, 6-dimethyl-4-oxo-4, 5, 6, 7-tetrahydro-lH-indazol-l-yl)-2, 6-

[0230] To a stirred solution of 2,6-difluoro-4-hydrazinylbenzonitrile (72 g, 425.70 mmol) in Ethanol (1080 ml) were added 5, 5-dimethyl-2-propionylcyclohexane-l, 3-dione (116.35, 638.56 mmol) at rt. The resulting reaction mixture was stirred at 100 °C for 7-8 h. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was concentrated under reduced pressure to afford crude solid. To the resulting crude was added Ethanol (200 ml x 2) and it was stirred at rt for 30 min. The resulting solid was filtered off and washed with Ethanol (50 ml x 2 times). The obtained solid was then dried under vacuum to afford 4-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-2,6-difluorobenzonitrile (122) (82 g, 58.48 % yield). LCMS: Mass found; m / z = 330.03 [M+H]+. 'HNMR (400 MHz, DMSC ): 6u 7.38-7.27 (m, 2H), 2.98-2.91 (m, 4H), 2.70 (s, 2H), 1.38-1.26 (m, 3H), 1.16 (s, 6H).Attorney Docket No.: 063626-502001WO

[0231] 2 -amino-6-chloro-4-(3-(difluoromethyl)-6, 6-dimethyl-4-oxo-4,5, 6, 7-tetrahydro-

[0232] Step 1: In a pressure tube, 2,6-dichloro-4-(3-(difluoromethyl)-6,6-dimethyl-4-oxo- 4,5,6,7-tetrahydro-lH-indazol-l-yl)benzonitrile (I21a) (200 mg, 0.52 mmol, lEq) was dissolved in 10 ml DMSO , 2 ml NE OH solution (30% NH3) was then added and the tube was sealed with PTFE screwcap. The reaction was heated to 120° C for 12 h, cooled to rt, diluted with 50ml water and acidified with H2SO4 to pH ~6. The resulting precipitate was extracted using 20 mL ethyl acetate. The organic extract was washed with water and saturated NH4CI solution. The organic extract was then dried in vacuo to obtain 2-amino-6-chloro-4-(3- (difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)benzonitrile as crude which was used in the next step without further purification.

[0233] Step 2: To the crude obtained in step 1 containing 2-amino-6-chloro-4-(3- (difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)benzonitrile was added 3 ml cone. H2SO4 and heated to 100° C for 15 minutes. The reaction mixture was cooled to rt, Water 50 ml was then carefully added to the reaction mixture, resulting precipitate was extracted using 50 ml Ethyl acetate. Organic extract was washed with 25 mL water, dried using sodium sulfate and then evaporated in vacuo with silica gel and flash column chromatography was performed using 50% ethyl acetate in hexanes to obtain 130 mg of 2-amino-6-chloro-4- (3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)benzamide (I23a) (65% overall yield). 'H NMR (400 MHz, Chloroforms / ) 8 7.12 (t, J = 53.5 Hz, 1H), 6.68 (m, 2H), 6.57 (dd, J= 13.4, 2.1 Hz, 1H), 6.47 (s, 2H), 5.69 (s, 1H), 2.89 (s, 2H), 2.47 (s, 2H), 1.15 (s, 6H).

[0234] Intermediates I23b-I23c and I24a-I24c are synthesized according to 123 a. Compounds with physical characterization provided were synthesized.Attorney Docket No.: 063626-502001WOTable 4. Characterization of Intermediates I23b-I23c and I24a-I24cAttorney Docket No.: 063626-502001WO

[0235] 2 -amino-4-(3-ethyl-6, 6-dimethyl-4-oxo-4,5, 6, 7-tetrahydro-lH-indazol-l-yl)-6-

[0236] Step 1: 4-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-2,6- difluorobenzonitrile (122) (1 g, 3 mmol, 1 Eq.) was dissolved in 30 ml THF in a pressure tube, 2 ml NH4OH solution (30% NH3) was then added, and the tube was sealed with PTFE screwcap. The reaction was heated to 100° C for 5 h. The reaction was then cooled to rt, solvents were evaporated in vacuo, water 30 ml was added to the reaction crude, acidified with H2SO4 to pH ~6 and extracted with 50 ml ethyl acetate. The organic extract was then dried over sodium sulfate and evaporated in vitro to afford 0.8 g of 2-amino-4-(3-ethyl-6,6-dimethyl-4- oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-6-fluorobenzonitrile as crude which was used in the next step without further purification.

[0237] Step 2: To 0.8 g of crude 2-amino-4-(3-ethyl-6,6-dimethyl-4-oxo-4, 5,6,7- tetrahydro-lH-indazol-l-yl)-6-fluorobenzonitrile in an round bottom flask was added 3 mL of Cone. H2SO4 and heated to 100° C for 15 minutes. The reaction mixture was cooled to rt, Water 50 ml was then carefully added to the reaction mixture, resulting precipitate was extracted using 50 ml Ethyl acetate. Organic extract was washed with 25 mL water, dried using sodiumAttorney Docket No.: 063626-502001WOsulfate and then evaporated in vacuo with silica gel and flash column chromatography was performed using 50% ethyl acetate in hexanes to obtain 740 mg 2-amino-4-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-6-fluorobenzamide (I25a) as white solid (73% yield).XH NMR (400 MHz, Chloroform^ / ) 8 6.73 (s,lH) 6.67 (dd, J= 2.2, 1.1 Hz, 2H), 6.58 (dd, J= 13.8, 2.1 Hz, 1H), 6.43 (s, 2H), 5.70 (s, 1H), 2.96 (q, J= 7.5 Hz, 2H), 2.87 (s, 2H), 2.42 (s, 2H), 1.31 (t, J= 7.5 Hz, 3H), 1.14 (s, 6H).

[0238] 2 -amino-4-(3-(difluoromethyl)-6, 6-dimethyl-4-oxo-4, 5, 6, 7 -tetrahydro- IH-indazol-was synthesized using I5b in the synthetic procedure described for 125a (55% yield). 'H NMR (400 MHz, Chloroform-d) 6 7.13 (t, J = 53.5 Hz, 1H), 6.70 (m, 2H), 6.58 (dd, J = 13.4, 2.1 Hz, 1H), 6.48 (s, 2H), 5.75 (s, 1H), 2.91 (s, 2H), 2.49 (s, 2H), 1.17 (s, 6H).

[0239] 5 -chlor o-7 -(3 -(difluoromethyl) -6, 6-dimethyl-4-oxo-4,5, 6, 7 -tetrahydro- IH-indazol-

[0240] 2 -amino-6-chloro-4-(3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)benzamide (I23a) (100 mg, 0.26 mmol, 1 Eq.) was solubilized in 3 ml 1,4-Dioxane in a pressure tube, PTSA (5 mg, 0.03 mmol), butyraldehyde (56 mg, 0.78 mmol) were then added and the reaction was heated to 80 °C without the screwcap closed in a ventilated hood. After an hour, the screwcap was closed and the reaction was heated to 110° C for 12h. Upon completion, solvents were evaporated in vacuo, adsorbed on silica gel, purified using flash chromatography using 40% ethyl acetate in hexanes to afford 74 mg 5-chloro-7-(3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-2-Attorney Docket No.: 063626-502001WOpropylquinazolin-4(3H)-one (I26a) as white solid (66% yield). 'H NMR (400 MHz, Chloroforms / ) 6 10.41 (s, 1H), 7.84 (d, J= 2.2 Hz, 1H), 7.66 (d, J= 2.2 Hz, 1H), 7.08 (d, J = 53.6 Hz, 1H), 3.00 (s, 2H), 2.77 - 2.69 (m, 2H), 2.51 (s, 2H), 1.92 (h, J = 7.5 Hz, 2H), 1.17 (s, 6H), 1.10 (t, J = 7.4 Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C21H22C1F2N4O2, 435.1402, found 435.1394.

[0241] Intermediates I26b and I26c, I27a-I27c, and I28a-I28b are synthesized according to I26a using 123, 124, and 125 intermediates. Compounds with physical characterization provided were synthesized.Table 5. Characterization of I26b and I26c, I27a-I27c, and I28a-I28bAttorney Docket No.: 063626-502001WOAttomey Docket No.: 063626-502001WO

[0242] 8 -chlor o-6-( 3-ethyl-6, 6-dimethyl-4-oxo-4, 5, 6, 7 -tetrahydro- lH-indazol-l-yl)-3-

[0243] Step 1: 2,6-dichloro-4-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol- l-yl)benzonitrile (I20a) (500 mg, 1.38 mmol, 1 Eq.), methyl 3 -oxohexanoate (0.59 g,4.14mmol), K2CO3 (0.95 g , 6.9 mmol), CuBr (9 mg, 0.07 mmol), 1,10-Phenanthroline (24 mg, 0.14mmol) were taken In an round bottom flask, 10 mL DMSO was then added, and theAttorney Docket No.: 063626-502001WOreaction mix was stirred and heated to 100°C for 3-5h. TLC was monitored for consumption of starting material. Upon completion, 50 ml water was added and pH was adjusted to ~5, extracted with 30 ml ethyl acetate. The organic extract was washed with water, brine, then dried over sodium sulfate and evaporated to obtain a crude mixture. 5 ml Cone. H2SO4 was then added to the crude mixture and heated to 100° C for 30 mins. The reaction mixture was cooled to rt and 1 ml water was added to the reaction dropwise and then heated to 100° C again for 30 minutes. The reaction mix was cooled again to rt and 50ml water was added and the precipitate was collected via filtration and subjected to flash chromatography using silica gel to obtain 380 mg of 8-chloro-6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (I29a) as beige solid. (71% yield). 'H NMR (400 MHz, Chloroform-tZ) 8 10.50 (s, 1H), 7.61 (d, J= 2.1 Hz, 1H), 7.52 (d, J= 2.1 Hz, 1H), 6.34 (d, J = 1.7 Hz, 1H), 3.00 (q, J= 7.5 Hz, 3H), 2.92 (s, 2H), 2.62 (t, J= 7.6 Hz, 2H), 2.46 (d, J= 2.0 Hz, 2H), 1.83 (h, J= 7.5 Hz, 2H), 1.34 (t, J= 7.5 Hz, 3H), 1.16 (s, 6H), 1.06 (t, J= 7.3 Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C23H27C1N3O2, 412.1789, found 412.1786.

[0244] Intermediates I29b and I29c, I30a-I30c, and 154 are synthesized according to I29a using 120 and 121 intermediates. Compounds with physical characterization provided were synthesized.Table 6a. Characterization of I29b and I29c, I30a-I30cAttorney Docket No.: 063626-502001WOAttorney Docket No.: 063626-502001WO

[0245] 6-(3-ethyl-6, 6-dimethyl-4-oxo-4, 5, 6, 7-tetrahydro-lH-indazol-l-yl)-8-fluoro-3-

[0246] Step 1: To a stirred solution of 24-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro- lH-indazol-l-yl)-2,6-difluorobenzonitrile (I22a) (80 g, 242.90 mmol) in DMF (400 ml) were added K2CO3 (40.28 g, 291.48 mmol) and Ethyl 3 -Oxohexanoate (44.36 g, 291.48 mmol). The resulting reaction mixture was stirred at 60°C for 7-8 h. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was diluted with water and extracted in EtOAc (1000 ml x 3). The combined organic layer was washed with brine solution (1000 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted with 30-50% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 2-(2-cyano-5-(3-ethyl-6,6- dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-fluorophenyl)-3-oxohexanoate (30 g, 29.35% yield).Attomey Docket No.: 063626-502001WO

[0247] Step2: To a stirred solution of crude 2-(2-cyano-5-(3-ethyl-6,6-dimethyl-4-oxo- 4.5.6.7-tetrahydro-lH-indazol-l-yl)-3-fluorophenyl)-3-oxohexanoate (obtained in step 1) (30 g, 64.16 mmol) in AcOH (1500 ml) was added H2SO4 (240 ml). The resulting reaction mixture was stirred at 110 °C for 12 hrs. After completion of the starting material, the reaction mixture was cooled to 0 °C reaction mass pH was adjusted to pH ~8-9 by adding aq. NaHCCh. Product was extracted with EtOAc (1000 ml x 3). The combined organic layer was washed with brine solution (1000 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted in 30-40% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 6-(3-ethyl-6,6-dimethyl-4-oxo- 4.5.6.7-tetrahydro-lH-indazol-l-yl)-8-fluoro-3-propylisoquinolin-l(2H)-one (8 g, 31.52 % yield). LCMS: Mass found; m / z = 396.2 [M+H]+. 'H NMR (400 MHz, DMSC ): On 9.70 (s, 1H), 7.43 (d, J=1.2 Hz, 1H), 7.29-7.26 (m, 1H), 6.33 (s, 1H), 3.02-2.96 (m, .7=22,4 Hz, 2H), 2.92 (s, 2H), 2.61-2.57 (m, J=14.8 Hz, 2H), 2.45 (s, 2H), 1.82-1.77 (m, J=25.9 Hz, 2H), 1.35-1.32 (t, J=14.8 Hz, 3H), 1.16 (s, 6H), 1.07-1.04 (t, J=14.8 Hz, 3H).

[0248] 6-(4-((tert-butyldiphenylsilyl)oxy)-3-ethyl-6, 6-dimethyl-4,5, 6, 7-tetrahydro-lH-

[0249] Step 1 : To a stirred solution of 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-fluoro-3-propylisoquinolin-l(2H)-one (131) (3.5 g, 8.85 mmol) in THF (40 ml) was added LAH (1 M in THF) 017.7 ml, 17.700 mmol) at 0 °C. Reaction mixture was stirred at rt for 3-4 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was quenched with saturated NH4CI solution at 0 °C and extracted in EtOAc (500 ml x 2). The combined organic layer was washed with brine solution (200 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography by using 60-120 mesh silica gel and product eluted in 45-50% EtOAc / Hexanes to afford 6-(3-ethyl-4-hydroxy-Attorney Docket No.: 063626-502001WO6,6-dimethyl-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-fluoro-3-propylisoquinolin-l(2H)-one (132) (3.2 g, 90.96% yield). LCMS: Mass found; m / z = 398.3 [M+H]+.

[0250] Step 2: To a stirred solution of 6-(3-ethyl-4-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-fluoro-3-propylisoquinolin-l(2H)-one (132) (3.2 g, 8.05 mmol) inDMF (30ml)was added Imidazole (1.09 g, 16.10 mmol) and TBDPSC1 (3.30g, 12.07 mmol) at rt. The resulting reaction mixture was stirred at rt for 12 hrs. After completion of the starting material, the reaction mixture was diluted with water and extracted with EtOAc (150 ml x 3). The combined organic layer was washed with brine solution (70 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted in 10-20% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 6-(3-ethyl-4-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-fluoro-3 propylisoquinolin- l(2H)-one (133) (3.0 g, 58.60 % yield). LCMS: Mass found; m / z = 636.6 [M+H]+. 'H NMR (400 MHz, CDC13): 6H 9.5 (s, 1H), 7.85-7.75 (m, 4H), 7.55-7.40 (m, 6H), 7.43 (d, J=1.2 Hz, 1H), 7.29-7.26 (m, 1H), 6.33 (s, 1H), 5.00-5.10 (t, 1H) ,2.80-2.55 (m,5H), 2.49-2.41(m, 1H), 1.85-1.70 (m, 3H), 1.35-1.26 (q, 2H), 1.20-1.00 (m, 17H), 0.82-0.72 (m, 3H).General Synthetic Scheme 5. Synthesis of 137-141

[0251] Reaction conditions of General Scheme 5 include (a) hydrazine hydrate, methanol, 60° C, 2 h (b) 2-acetyl-5,5-dimethylcyclohexane-l, 3-dione, Ethanol, 100° C (c) pent-l-yne,Attorney Docket No.: 063626-502001WOPd(dppf)C12, Cui, DIPEA, DMF, 70-80° C. (d) H2SO4, methanol, 80° C, 48 h (e) Ammonia In methanol, 80° C.

[0253] To a stirred solution of 2,6-dibromo-4-fluorobenzonitrile (136) (50 g, 179.26 mmol) in methanol (500 ml) was added hydrazine hydrate (80% in water) (18.12 ml, 358.53 mmol) at 25 °C. The reaction mixture was stirred for 2-3 hr at reflux temperature. After completion of the starting material, the reaction mixture was cooled to rt and solid precipitate was filtered off, washed with MeOH (100 ml) and dried under vacuum to afford 137 (2,6-Dibromo-4-hydrazineylbenzonitrile) (50.0 g, 78.74 % yield). LCMS: Mass found; m / z = 292.0 [M+H]+. 'H NMR (400 MHz, DMSOofe): 6118.33 (s, 1H), 7.02 (s, 2H), 4.51 (s, 2H).

[0254] 2, 6-dibromo-4-(3-ethyl-6, 6-dimethyl-4-oxo-4, 5, 6, 7 -tetrahydro- IH-indazol-l-

[0255] To a stirred solution of 2,6-Dibromo-4-hydrazineylbenzonitrile (137) (40 g, 137.48 mmol) in Ethanol (800 ml) were added Int-2s (5,5-dimethyl-2-propionylcyclohexane-l,3-dione) (25.05, 137.48 mmol) at rt. The resulting reaction mixture was stirred at 100 °C for 7-8 h. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was concentrated under reduced pressure to afford crude solid. To the resulting crude was added Ethanol (200 ml) and it was stirred at rt for 30 min. The resulting solid was filtered off and washed with Ethanol (50 ml * 2 times). The obtained solid was then dried under vacuum to afford 2,6-dibromo-4-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)benzonitrile (138) (45 g, 72.55 % yield). LCMS: Mass found; m / z = 452.01 [M+H]+. 'H NMR (400 MHz, DMSOofe): 611 8.12 (s, 2H), 3.05 (s, 2H), 2.86-2.80 (m, 2H), 2.35 (s, 2H), 1.23-1.19 (t, J= 14.8 Hz, 2 H), 1.03 (s, 6 H).Attomey Docket No.: 063626-502001WO

[0256] 2 -bromo-4-( 3-ethyl-6, 6-dimethyl-4-oxo-4, 5, 6, 7 -tetrahydro- lH-indazol-l-yl)-6-

[0257] To a stirred solution of 2,6-dibromo-4-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)benzonitrile 138 (40 g, 88.66 mmol) in DMF (400 ml) were added DIPEA (17.15 g, 132.99 mmol), Cui (1.68 g, 8.86 mmol) and Pd(dppf)C12 (6.21 g, 8.86 mmol) at rt. N2 gas was purged to resulting rreaction mixture for 30 min. Int-4 (pent-l-yne) (7.23 g, 106.39 mmol) was added and resulting reaction mixture was stirred at 70 °C for 7-8 h. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was diluted with water and extracted in EtOAc (1000 ml x 3). The combined organic layer was washed with brine solution (1000 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted with 3-5% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 2-bromo-4-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-l-yl)-6-(pent-l-yn-l-yl)benzonitrile (139) (23 g, 59.17% yield). LCMS: Mass found; m / z = 440.11 [M+H]+.!H NMR (400 MHz, DMSOofe): 611 8.06-8.05 (m, J= 3.6 Hz, 1H), 7.81-7.80 (m, J= 4.0 Hz, 1H), 3.02 (s, 2H), 2.85-2.79 (m, J= 24 Hz, 2H), 2.57-2.54 (m, J= 12 Hz, 2H), 2.33 (m, 2H), 1.64-1.59 (m, J= 20 Hz, 2H), 1.22-1.18 (m, J= 3.6 Hz, 3H), 1.07-1.02 (m, 9H).

[0258] l-(8-bromo-l-oxo-3-propyl-lH-isochromen-6-yl)-3-ethyl-6,6-dimethyl-l,5,6,7-tetrahydro-4H-indazol-4-oneAttomey Docket No.: 063626-502001WO

[0259] To a stirred solution of 2-bromo-4-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-l-yl)-6-(pent-l-yn-l-yl)benzonitrile (139) (22 g, 50.18 mmol) in MeOH (220 ml) was added H2SO4 (HO ml). The resulting reaction mixture was stirred at 80 °C for 48 hrs. After completion of the starting material, the reaction mixture was cooled to 0 °C reaction mass pH was adjusted to pH ~7-8 by adding aq. NaHCCh. Product was extracted with EtOAc (700 ml x 2). The combined organic layer was washed with brine solution (300 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted in 20-25% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford l-(8-bromo-l-oxo-3-propyl-lH-isochromen-6-yl)-3-ethyl-6,6- dimethyl-l,5,6,7-tetrahydro-4H-indazol-4-one (140) (5.5 g, 23.96 % yield). LCMS: Mass found; m / z = 457.26 [M+H]+. 'HNMR (400 MHz, DMSOofe): 6117.89 (d, J= 1.6 Hz, 1H), 7.48 (d, J= 1.6 Hz, 1H), 6.29 (s, 1H), 3.00-2.96 (m, 2H), 2.90 (s, 2H), 2.54-2.50 (m, 2H), 2.44 (s, 2H), 1.79-1.73 (m, J= 24 Hz, 2H), 1.34-1.30 (m, J= 14.8 Hz, 3H), 1.15 (s, 6H), 1.04-1.00 (t, J= 7.6 Hz, 3H).

[0260] 8 -bromo-6-( 3-ethyl-6, 6-dimethyl-4-oxo-4, 5, 6, 7 -tetrahydro- lH-indazol-l-yl)-3-

[0261] l-(8-bromo-l -oxo-3-propyl-1H-isochromen-6-yl)-3-ethyl-6, 6-dimethyl-l, 5,6,7-tetrahydro-4H-indazol-4-one (140) (5.5 g, 12.02 mmol) was taken in ammonia in MeOH (7M) (55 ml) at rt. Reaction mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with water and extracted in EtOAc (250 ml x 2). The combined organic layer was washed with brine solution (100 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography by using 60-120 mesh silica gel and product eluted in 30% EtOAc / Hexanes to afford 8-bromo-6-(3- ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (141) (3.0 g, 54.66% yield). LCMS: Mass found; m / z = 457.10 [M+H]+. 'H NMR (400 MHz,Attorney Docket No.: 063626-502001WODMSOofe): 6n 11.40 (s, 1H), 7.82-7.76 (m, J= 24.4 Hz, 2H), 6.50 (s, 1H), 3.02 (s, 2H), 2.86-2.80 (m, J= 22.4 Hz, 2H), 2.45-2.44 (m, 2H), 2.35 (s, 2H), 1.68-1.62 (m, 2H), 1.24-1.19 (m, 3H), 1.03 (s, 6H), 0.93-0.90 (t, J= 2.8 Hz, 3H).OTBDPS

[0262] 4-((tert-butyldiphenylsilyl)oxy)cyclohexan-l-one O (142)

[0263] To a stirred solution of 4-hydroxycyclohexan-l-one (I42i) (8.0 g, 70.08 mmol) in DCM (100 ml) was added Imidazole (9.53 g, 140.17 mmol) and TBDPSC1 (28.89 g, 105.13 mmol) 0 °C under N2 atmosphere. The resulting reaction mixture was stirred at rt for 16 h. After completion of the starting material, the reaction mixture was diluted with water and extracted in EtOAc (200 ml x 3). The combined organic layer was washed with brine solution (250 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by flash chromatography and product was eluted with 2-5% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 4-((tert-butyldiphenylsilyl)oxy)cyclohexan-l-one (142) (6.0 g, 24.28% yield). 'H NMR (400 MHz, DMSC ): 611 7.75-7.69 (m, J= 24 Hz, 5H), 7.49-7.72 (m, 5H), 4.87-4.16 (m, 1H), 2.80-2.72 (m, J= 32 Hz, 2H), 2.02-1.95 (s, 2H), 1.83-1.76 (m, J= 26 Hz, 4H), 1.12 (s, 9H).

[0264] 4-( tert-butyldiphenylsily I) oxy) cyclohex- 1-en-l-yl trifluoromethane sulfonate

[0265] To a stirred solution of 4-((tert-butyldiphenylsilyl)oxy)cyclohexan-l-one (142) (6 g, 17.01 mmol) in THF (60 ml) was added LiHMDS (IM in THF) (25.52 ml, 25.52 mmol) at -78 °C under N2 atmosphere. The resulting reaction mixture was stirred at this temperature for 5 min. N-Phenyl-bis(trifluoromethanesulfonimide) (7.01 g, 25.52 mmol) was added and the resulting reaction mixture was stirred at rt for 16 h. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was diluted with water and extracted with EtOAc (300 ml x 3). The combined organic layer was washed with brine solution (250Attorney Docket No.: 063626-502001WOml), dried over sodium sulphate. The combined organic layer was washed with brine solution (250 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by flash chromatography and product was eluted with 10-15% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 4-((tert-butyldiphenylsilyl)oxy)cyclohex-l-en-l-yl trifluoromethanesulfonate (143) (5.5 g, 63.66%).[HNMR (400 MHz, DMSC ): On 7.68-7.65 (m, J= 12 Hz, 4H), 7.47-7.38 (m, J=36 Hz, 6H), 5.59 (s, 1H), 4.05-4.03 (m, J= 8 Hz, 1H), 2.62-2.58 (m, J= 16 Hz, 1H), 2.25-2.21 (m, J= 16 Hz, 3H), 1.90-1.84 (m, J= 24 Hz, 1H), 1.76-1.70 (m, J= 24 Hz, 1H),1.12 (s, 9H).

[0266] tert-butyldiphenyl( (4-(4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)cyclohex-3-en-

[0267] To a stirred solution of 4-((tert-butyldiphenylsilyl)oxy)cyclohex-l-en-l-yl trifluoromethanesulfonate (143) (5.5 g, 11.34 mmol) in Dioxane (55 ml) was added bis(pinacolato)diboron (1.89 g, 22.69 mmol), KOAc (3.34 g, 34.04 mmol) and sodium bromide (0.58 g, 5.67 mmol) at rt. The resulting reaction mixture was degassed under N2 atmosphere at rt for 10-15 min. PdCh(dppf) (0.41 g, 0.567 mmol) was added and the resulting reaction mixture was stirred at 100 °C for 16 h. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was diluted with water and extracted with EtOAc (400 ml x 3). The combined organic layer was washed with brine solution (250 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to afford tert-butyldiphenyl((4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) cyclohex-3 -en-l-yl)oxy)silane (144) (4.0 g, crude). The resulting crude was taken for next step without further purification.Attorney Docket No.: 063626-502001WO

[0268] 8-(4-((tert-butyldiphenyl silyl)oxy)cyclohex- 1 -en- 1 -yl)-6-(3 -ethyl-6,6-dimethyl-4-oxo-4, 5 , 6,7-tetrahy dro- 1 H-indazol- 1 -y 1 ) -3 -propyli soquinolin- 1 (2H)-one

[0269] To a stirred solution of 8-bromo-6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (141) (2.0 g, 4.38 mmol) in dioxane (20 ml) was added tert-butyldiphenyl((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)oxy)silane (144) (4.05 g, 8.76 mmol), water (2 ml) and Na2CO3 (1.39 g, 13.14 mmol). The resulting reaction mixture was degassed under N2 atmosphere at rt for 10-15 min. PdC12(dppf) (0.160 g, 0.219 mmol) was added and the resulting reaction mixture was stirred at 80 °C for 16 h. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was diluted with water and extracted with EtOAc (250 ml x 2). The combined organic layer was washed with brine solution (200 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The resulting crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted with 50-55% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 8-(4-((tert-butyldiphenylsilyl)oxy)cyclohex-l-en-l-yl)-6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (145) (0.65 g, 21% yield). LCMS: Mass found; m / z = 712.6 [M+H]+. 'H NMR (400 MHz, DMSC ): 611 11.09 (s, 1H), 7.69-7.59 (m, 5H), 7.47-7.40 (m, 6H), 7.20 (s, 1H), 6.44 (s, 1H), 5.26 (s, 1H), 4.16 (s, 1H), 3.93 (s, 2H), 2.99-2.98 (m, J= 4 Hz, 2H), 2.86-2.81 (m, J= 20 Hz, 2H), 2.48-2.46 (m, J= 8 Hz, 2H), 2.44-2.40 (m, J= 16 Hz, 2H), 2.33-2.27 (m, J= 24 Hz, 2H), 1.87-1.86 (m, J= 4 Hz, 2H), 1.68-1.62 (m, J= 24 Hz, 2H), 1.30-1.21 (m, 5H), 1.12-1.07 (m, 22 H), 0.94-0.91 (m, J= 12 Hz, 3H).

[0270] Intermediates 146-150 are synthesized according to the syntheses described for 142- 145 as indicated in Table 6b.Attorney Docket No.: 063626-502001WOTable 6b. Intermediates 146-150Attorney Docket No.: 063626-502001WO

[0271] tert-butyl 4-( 6-(3-ethyl-6, 6-dimethyl-4-oxo-4, 5, 6, 7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-8-yl)-3,6-dihydropyridine-l(2H)-carboxylate

[0272] To a stirred solution of 8-bromo-6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (141) (0.6 g, 1.31 mmol) in 1,4-dioxane (6 ml) was added water (1 ml), PdC12(dppf) (96 mg, 0.131 mmol), Na2CO3 (0.589 g, 5.56 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (0.816 g, 2.62 mmol) at rt. The reaction mixture was stirred for 16 hr at 100° C. After completion of the starting material, the reaction mixture was diluted with water and extracted in EtOAc (100 ml x 3). The combined organic layer was washed with brine solution (100 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by flash chromatography and product was eluted with 15-17% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 0.5 g of 151, 68.06% yield). LCMS: Mass found; m / z = 559.3 [M+H] +.1H NMR (400 MHz, DMSOd6): 5H 11.19 (s, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.48 (d, J=6.0 Hz, 1H), 5.48 (s, 1H), 3.97 (s, 2H), 3.61 (s, 2H), 3.02 (s, 2H), 2.86-2.81 (m, J=22Attorney Docket No.: 063626-502001WOHz, 2H), 2.50-2.45 (m, J=17.2 Hz, 2H), 2.36 (s, 2H), 2.34-2.31 (m, J=2.4 Hz, 2H), 1.69-1.64 (m, J=22.4 Hz, 2H), 1.44 (s, 9H), 1.23-1.99 (m, 3H), 1.08 (s, 2H), 1.04 (s, 6H), 0.99-0.93 (m, J=21.6 Hz, 3H).

[0273] 8-(3, 6-dihydro-2H-pyran-4-yl)-6-(3-ethyl-6, 6-dimethyl-4-oxo-4,5, 6, 7-tetrahydro-

[0274] (I52a) was synthesized using I29a in method (step 1) of Compound 5 (76% yield). 'HNMR (400 MHz, Chloroform- ) 69.35 (s, 1H), 7.55 (d, J= 2.2 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 6.38 - 6.33 (m, 1H), 5.64 (s, 1H), 4.42 - 4.36 (m, 2H), 4.07 (t, J= 5.2 Hz, 2H), 3.00 (q, J= 7.5 Hz, 2H), 2.91 (s, 2H), 2.59 (t, J= 7.5 Hz, 2H), 2.47 (d, J= 13.3 Hz, 4H), 1.77 (h, J= 7.4 Hz, 2H), 1.35 (t, J= 7.5 Hz, 3H), 1.15 (s, 6H), 1.04 (t, J= 7.3 Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C28H34N3O3, 460.2595, found 460.2595.

[0275] 6-(3-(difhioromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-(3,6-dihydro-2H-pyran-4-yl)-3-propylisoquinolin-l(2H)-one(I52b) is synthesized using I30a in the synthesis of Compound 5.Attorney Docket No.: 063626-502001WO

[0276] 8 -chloro-6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-(prop-2-yn- 1 -yl)i soquinolin- 1 (2H)-onesynthesized using the method of I29a."tert-butyl 3-(6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-8-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate (154) is synthesized using I29a and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate according to the synthesis of Compound 5 (see step 1).

[0277] tert-butyl 3-(6-(3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-8-yl)-2,5-dihydro-lH-pyrrole-l-""carboxylatesynthesized using I30a and tert-Butyl 3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate according to the synthesis of Compound 5 (see step 1).Attorney Docket No.: 063626-502001WOPharmaceutical Compositions

[0278] Another aspect of the present disclosure relates to pharmaceutical compositions comprising a compound of Formula I. In some embodiments the pharmaceutical composition comprises a compound described herein.

[0279] In some embodiments, the present disclosure provides a composition comprising a compound provided by this disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of a compound in the compositions of this disclosure is such that it is effective to measurably inhibit Hsp90 in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that it is effective to measurably inhibit Hsp90, in a biological sample or in a patient. In certain embodiments, a composition provided by this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition provided by this disclosure is formulated for oral administration to a patient.

[0280] Compositions provided by this disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions provided by this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0281] For this purpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose orAttorney Docket No.: 063626-502001WOsimilar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0282] Pharmaceutically acceptable compositions provided by this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0283] Alternatively, pharmaceutically acceptable compositions provided by this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0284] Pharmaceutically acceptable compositions provided by this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds provided by this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

[0285] Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended orAttorney Docket No.: 063626-502001WOdissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0286] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0287] Pharmaceutically acceptable compositions provided by this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0288] Preferably, pharmaceutically acceptable compositions provided by this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions provided by this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions provided by this disclosure are administered with food.

[0289] Pharmaceutically acceptable compositions provided by this disclosure can be administered to humans and other animals orally, rectally, parenterally, intraci stemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, as required. In certain embodiments, the compounds provided by this disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0290] In some embodiments, a therapeutically effective amount of a compound of formula (I), may be about 1 mg / kg to about 1000 mg / kg, about 5 mg / kg to about 950 mg / kg, about 10 mg / kg to about 900 mg / kg, about 15 mg / kg to about 850 mg / kg, about 20 mg / kg to about 800 mg / kg, about 25 mg / kg to about 750 mg / kg, about 30 mg / kg to about 700 mg / kg, about 35 mg / kg to about 650 mg / kg, about 40 mg / kg to about 600 mg / kg, about 45 mg / kg to about 550Attorney Docket No.: 063626-502001WOmg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg to about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 80 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg.

[0291] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0292] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0293] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0294] In order to prolong the effect of a compound provided by this disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline orAttorney Docket No.: 063626-502001WOamorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0295] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds provided by this disclosure with suitable nonirritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity and release the active compound.

[0296] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or di calcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0297] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatingsAttorney Docket No.: 063626-502001WOand other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0298] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0299] Dosage forms for topical or transdermal administration of a compound provided by this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0300] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolusAttorney Docket No.: 063626-502001WOand infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.

[0301] The amount of compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0302] A compound of the current disclosure can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the disclosure and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. Exemplary of such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs (CSAIDs), Interleukin- 10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof. A compound of the current disclosure can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient’s status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[0303] Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.Attorney Docket No.: 063626-502001WO

[0304] As used herein, the term “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound of the current disclosure, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0305] The amount of both a provided compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this disclosure should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of a provided compound can be administered.

[0306] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this disclosure may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent.

[0307] The amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0308] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or disorder being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.Attorney Docket No.: 063626-502001WO

[0309] Compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered to subjects by a variety of methods. In any of the uses or methods described herein, administration may be by various routes known to those skilled in the art, including without limitation oral, inhalation, intravenous, intramuscular, topical, subcutaneous, systemic, and / or intraperitoneal administration to a subject in need thereof.

[0310] The amount of the compound of the present disclosure, or pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and / or symptoms of the disease and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein.

[0311] In some embodiments, the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as disclosed herein may be administered by oral administration or parenteral administration (including, but not limited to, subcutaneous, intramuscular, intravenous, intraperitoneal, intracardiac and intraarticular injections).

[0312] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies. For example, useful dosages of a compound of the present invention, or pharmaceutically acceptable salts thereof, can be determined by comparing their in vitro activity, and in vivo activity in animal models.

[0313] Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. In some embodiments, the pharmaceutical composition can further comprise an additional pharmaceutically active agent.Attorney Docket No.: 063626-502001WO

[0314] In one embodiment, the pharmaceutical acceptable carrier further comprises an excipient, diluent, surfactant, or any combination thereof.

[0315] In one embodiment, the pharmaceutical composition further comprises at least one additional therapeutic agent.

[0316] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

[0317] In one embodiment, the composition comprises about 1 mg to about 2000 mg of the compound.

[0318] In one embodiment, the composition is administered to the subject twice daily, once daily, once every other day, or once weekly.Methods of Use

[0319] Another aspect of the present disclosure is directed to methods of inhibiting an Hsp90 chaperone protein in a cell or subject, comprising contacting the cell or subject with an effective amount of a compound according to a compound of the disclosure. In some aspects, the compound is a compound according to Formula I. In some embodiments, the contacting of the cell occurs in vitro. In some embodiments, the contacting of the cell occurs in vivo.

[0320] In some embodiments, the Hsp90 chaperone protein is an Hsp90p isoform. In some embodiments, the Hsp90 chaperone protein is an Hsp90a isoform. In some embodiments, a compound described herein selectively associates, or binds to the Hsp90p isoform. The Hsp90p isoform is constitutively expressed in the cytoplasm, whereas Hsp90a is inducible and expressed in the cytosol upon exposure to cellular stress.

[0321] In some embodiments, the compounds of Formula I inhibit Hsp90. In some embodiments the compounds of Formula I have increased affinity for Hsp90p in comparison to the compounds’ affinity for other isoforms. In some embodiments the compounds of Formula I have increased selectivity for Hsp90p in comparison to the other isoforms. The compounds of Formula I may have >20-fold selectivity for Hsp90 P, >50-fold selectivity for Hsp90 P, > 100-fold selectivity for Hsp90p, >200-fold selectivity for Hsp90p, >300-foldAttorney Docket No.: 063626-502001WOselectivity for Hsp90p or >400-fold selectivity for Hsp90p. In some aspects, the binding affinity for Hsp90 isoforms can be measured using Fluorescence Polarization (FP). In some aspects, selectivity is measured as a half maximal inhibitory concentration (IC50).

[0322] Another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a cell.

[0323] In some embodiments, the subject is a mammal.

[0324] In some embodiments, the mammal is a human.

[0325] In certain embodiments, the method comprises administering an effective amount of the active compound or its salt as described herein, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination or alternation with another bioactive agent or combination of agents, to a patient in need thereof.

[0326] In certain embodiments, the present disclosure provides a method of treating a disease or disorder described herein, in a patient in need thereof.

[0327] In other embodiments, the patient is administered an additional therapeutic agent. In other embodiments, the compound as described herein, and the additional therapeutic agent are administered simultaneously or sequentially.

[0328] In certain embodiments, the application provides a method of preventing a disease or disorder described herein, in a patient in need thereof.

[0329] Administration of the disclosed compounds may also be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.

[0330] In certain embodiments, the application provides a method of preventing a disease or disorder described herein, in a patient in need thereof.

[0331] In certain embodiments, the patient is a human.Attorney Docket No.: 063626-502001WO

[0332] In some embodiments, the disease or disorder is mediated by Hsp90 activity, and may be referred to herein as an “Hsp90 mediated disease or disorder”. In some embodiments, the disease or disorder is mediated by increased Hsp90 activity. In some embodiments, the disease or disorder is mediated by excessive Hsp90 activity.

[0333] In certain embodiments, the Hsp90 mediated disease or disorder is a cancer or a proliferation disease, viral diseases such as hepatitis C (HCV), anti-inflammatory diseases such as rheumatoid arthritis, asthma, MS, Type I diabetes, lupus, psoriasis and inflammatory bowel disease, cystic fibrosis, angiogenesis-related diseases, chemotherapy-induced toxicity, protein misfolding or aggregation diseases (e.g., scrapie / CJD, Huntington’s disease) and Alzheimer’s disease.

[0334] In certain embodiments, the disease or disorder is cancer or a proliferation disease.

[0335] In some embodiments, the cancer is a cancer type or subtype affecting pathways mediated by the Hsp90 protein for proliferation and tumor development.

[0336] In some embodiments, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. In certain embodiments, the cancer is a leukemia. In some embodiments, the cancer is a cancer of the bladder, blood, bone, brain, breast, cervix, colon / rectum, endometrium, head and neck, kidney, liver, lung, muscle tissue, ovary, pancreas, prostate, skin, spleen, stomach, testicle, thyroid or uterus. In certain embodiments, the cancer is of the colon, breast, bladder, prostate, or kidney.

[0337] In some embodiments, the cancer is a cancer sensitive to Hsp90 inhibition, including human breast cancers (e.g., primary breast tumors, node-negative breast cancer, invasive duct adenocarcinomas of the breast, non-endometrioid breast cancers), mantle cell lymphomas, colorectal and endometrial cancers.

[0338] In some embodiments, the cancer is an ErbB2-positive cancer. Cancers which are commonly ErbB2 positive include: breast, prostate, lung, and gastric cancer; chronic myeloid leukemia; androgen receptor dependent prostate cancer; Flt3 -dependent acute myeloid leukemia; melanoma associated with BRAF mutation; multiple myeloma; and gastrointestinal stromal tumors (GIST).Attorney Docket No.: 063626-502001WO

[0339] In certain embodiments, the Hsp90 mediated disorder is a cancer that has metastasized. In certain embodiments the Hsp90 mediated disorder is a cancer that has metastasized to the brain, lungs bone, liver, peritoneum, adrenal gland, skin, or muscle.

[0340] In further embodiments, the disease or disorder is sarcoma of the bones, muscles, tendons, cartilage, nerves, fat, or blood vessels.

[0341] In further embodiments, the disease or disorder is soft tissue sarcoma, bone sarcoma, or osteosarcoma.

[0342] In further embodiments, the disease or disorder is multiple myeloma.

[0343] In other embodiments, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, and other arthritic conditions, neuroinflammation, allergy, pain, neuropathic pain, fever, pulmonary disorders, lung inflammation, adult respiratory distress chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn’s disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, autoimmune disease, graft vs. host reaction and allograft rejections, cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bone cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and / or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), angiogenesis including neoplasia, metastasis, central nervous system disorders, central nervous system disorders having an inflammatory or apoptotic component, peripheral neuropathy, or B-Cell Lymphoma.

[0344] In other embodiments, the pharmaceutical composition comprising a compound as described herein and the additional therapeutic agent are administered simultaneously or sequentially.Attorney Docket No.: 063626-502001WO

[0345] In other embodiments, the disease or disorder is cancer. In further embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, myelomas, solid tumors, hematological cancers or solid cancers.

[0346] In some embodiments, the method is used to treat or prevent a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immunologically-mediated diseases. In other embodiments, the condition is selected from a proliferative disorder.

[0347] In certain embodiments a compound of the present invention is used to treat an abnormal cell proliferation such as a tumor or cancer that has a Hsp90 protein.

[0348] Another aspect of the present invention provides a method of treating or preventing a proliferative disease. The method comprises administering an effective amount of a pharmaceutical composition comprising a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof and optionally a pharmaceutically acceptable carrier to a patient in need thereof.

[0349] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.EXAMPLES

[0350] The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments,Attorney Docket No.: 063626-502001WOmodifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims.

[0351] The compounds of the present disclosure may be prepared by use of known chemical reactions and procedures, and as described above. Nevertheless, the synthesis examples are presented to aid the reader in synthesizing the compounds with specific details provided below in the experimental section to illustrate working examples.

[0352] All variable groups of these methods are as described in the generic description if they are not specifically defined below.

[0353] It is recognized that compounds of the disclosure with each claimed optional functional group may not be prepared by each of the below-listed methods. Within the scope of each method, optional substituents may appear on reagents or intermediates which may act as protecting or otherwise non-participating groups. Utilizing methods well known to those skilled in the art, these groups are introduced and / or removed during the course of the synthetic schemes which provide the compounds of the present disclosure.Acronyms and AbbreviationsAcOH acetic acidACN or MeCN acetonitrileBAEE N-benzoyl-L-arginine ethyl esterBH3 boraneBoc tert-butyl oxy carbonylBOC2O di-tert-butyl dicarbonateBn benzylBu butylz-Bu isobutyl / -Bu tert-butylt-BuOH tert-butanolBSA bovine serum albuminAttorney Docket No.: 063626-502001WOCD3OD, Methanol-cU deuteromethanolCHAPS 3-[(3-cholamidopropyl)dimethylammonio]-l- propanesulfonateCS2CO3 cesium carbonateD2O deuterium oxideDCM dichloromethaneDEA diethanolamineDIPEA diisopropylethylamineDMAP 4-dimethylaminopyridineDMF dimethyl formamideDMSO dimethyl sulfoxideDMSO-t / e deutero-dimethyl sulfoxideDTT dithiothreitolequiv, eq. equivalent(s)Et ethylEt3N triethylamineESI electrospray ionizationEtOAc ethyl acetateH2SO4 sulfuric acidHATU l-[Bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HC1 hydrochloric acidHEPES 4-(2 -hydroxy ethyl)- 1 -piperazineethanesulfonic acid HPLC high-performance liquid chromatographyPrep-HPLC preparative high-performance liquid chromatography K2CO3 potassium carbonateKNO3 potassium nitrateAttorney Docket No.: 063626-502001WOLCMS liquid chromatography mass spectrometry LiAlH4lithium aluminium hydrideMe methylMeOH methanolMel methyl iodideMgSO4magnesium sulfatemin, min. minute(s)MS Mass spectrometryMsCl methanesulfonyl chlorideNaCl sodium chlorideNa2CO3sodium carbonateNaH sodium hydrideNaHCCh sodium bicarbonateNaIO4sodium periodateNaOH sodium hydroxideNa2SO4sodium sulfateNa2S2O4Sodium di thioniteNBS N-bromosuccinimideNH3ammoniaNH4C1 ammonium chlorideNMR Nuclear magnetic resonancePd(dppf)Cl2[1, r-Bis(diphenylphosphino)ferrocene] / ?a / / at / / wm(II) di chloridePd2(dba)3Tris(bibenzylideneacetone)dipalladium(0) PEPPSi-IPr [l,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II) dichloridePh phenylAttorney Docket No.: 063626-502001WOPr propylz-Pr isopropylIP A isopropanolrt room temperatureRT retention timeRuCh Ruthenium(III)chlorideSEM 2-(Trimethylsilyl)ethoxymethylSFC supercritical fluid chromatographySi-Pyridine functionalized silica gel: Silicycle R43030B, 40-63micron particle sizeSOCI2 thionyl chlorideTBAF tetrabutylammonium fluorideTBDPS tertbutyldiphenylsilylTBS tertbutyldimethylsilylTFA trifluoroacetic acidTHF tetrahydrofuranTi(OiPr)4 titanium isopropoxideTLC thin layer chromatographyPrep-TLC preparative thin layer chromatographyTPEN A,A,A',A-tetrakis(2-pyridinylmethyl)-l,2- ethanediamineTs 4-toluenesulfonylTsCl 4-toluenesulfonyl chlorideAnalytical Procedures and MethodsNMR

[0354] The following conditions were used for obtaining proton nuclear magnetic resonance (NMR) spectra: NMR spectra were taken in either 400 MHz or 500 MHz. BrukerAttorney Docket No.: 063626-502001WOinstrument using either DMSO-cU or CDCI3 as solvent and internal standard. The crude NMR data was analyzed by using either ACD Spectrus version 2015-01 by ADC Labs or MestReNova software.

[0355] Chemical shifts are reported in parts per million (ppm) downfield from internal tetramethylsilane (TMS) or from the position of TMS inferred by the deuterated NMR solvent. Apparent multiplicities are reported as: singlet-s, doublet-d, triplet-t, quartet-q, or multiplet-m. Peaks that exhibit broadening are further denoted as br. Integrations are approximate. It should be noted that integration intensities, peak shapes, chemical shifts and coupling constants can be dependent on solvent, concentration, temperature, pH, and other factors. Further, peaks that overlap with or exchange with water or solvent peaks in the NMR spectrum may not provide reliable integration intensities. In some cases, NMR spectra may be obtained using water peak suppression, which may result in overlapping peaks not being visible or having altered shape and / or integration.Synthetic Examples

[0356] All reactions were performed in oven- or flame-dried glassware under an argon atmosphere unless otherwise stated. Commercially available solvents and reagents were utilized during synthesis. Flash column chromatography was performed using silica gel (40-63 pm particle size).1H NMR spectra were recorded on a Bruker instrument at 500 and 400 MHz frequencies, and13C NMR spectra were recorded at 126 and 101 MHz frequencies. Data are recorded as: hp = heptet, h = hextet, p = pentet, q = quartet, t = triplet, d = doublet, s = singlet, bs = broad singlet, m = multiplet, with coupling constant(s) reported in Hz. High-resolution mass spectral data were obtained on a time-of-flight mass spectrometer, and analysis was performed using electrospray ionization. The final products were determined to be >90% pure using an Agilent Technologies Infinity II instrument with a Poroshell 120 EC-C182.7 pm (4.6 x 100 mm) using a solvent gradient of solvent A (H2O with 0.1% trifluoroacetic acid) and solvent B (acetonitrile with 0.1% trifluoroacetic acid). Thin-layer chromatography was performed with TLC silica gel 60F254 plates purchased from Millipore Sigma and visualized by UV light.Attorney Docket No.: 063626-502001WOExample 1: Synthesis of Compounds 1-4

[0357] 8-cyclohexyl-3-propyl-6-( 3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 -tetrahydro- IH-indazol-l-yl)isoquinolin-l(2H)-one (Compound 1). Prepared using General Procedure C. Yield 80%;XH NMR (400 MHz, CDC13) 6 11.52 (s, 1H), 7.49 (d, = 2.2 Hz, 1H), 7.42 (d,J = 2.1 Hz, 1H), 6.36 (s, 1H), 4.63 (t, J= 11.5 Hz, 1H), 2.90 (s, 2H), 2.69 (t, J= 7.5 Hz, 2H), 2.60 (s, 3H), 2.45 (s, 2H), 2.08 (d, J= 11.9 Hz, 2H), 1.93 (d, J= 13.0 Hz, 3H), 1.88-1.78 (m, 3H), 1.67-1.50 (m, 2H), 1.50-1.43 (m, 1H), 1.47-1.25 (m, 1H), 1.15 (s, 6H), 1.06 (t, J= 7.3 Hz, 3H).13C NMR (101 MHz, CDCI3) 6 193.48, 153.94, 150.34, 149.16, 142.77, 141.82, 141.11, 118.77, 117.51, 117.40, 104.73, 77.25, 52.44, 40.03, 37.60, 35.95, 34.76, 34.67, 28.46, 27.29, 26.43, 21.38, 13.50. HRMS (ESI) m / z: [M + H] calc’d for C28H35N3O2446.2802; Found 446.2809.

[0358] 6-(3-ethyl-6, 6-dimethyl-4-oxo-4, 5, 6, 7-tetrahydro-lH-indazol-l-yl)-3-propyl-8- (tetrahydro-2H-pyran-4-yl)isoquinolin-l(2H)-one (Compound 2). Prepared using General Procedure C. Yield 80%; 'H NMR (400 MHz, CDCI3) 6 10.09 (s, 1H), 7.40 (s, 2H), 6.27 (d, J = 2.0 Hz, 1H), 5.23 (s, 1H), 4.79 (tt, J = 11.6, 3.4 Hz, 1H), 4.13-4.02 (m, 2H), 3.63 (td, J = 11.7, 2.1 Hz, 2H), 2.92 (q, J = 7.5 Hz, 2H), 2.80 (s, 2H), 2.54 (t, J = 7.5 Hz, 2H), 2.37 (s, 2H), 1.89 (d, J = 12.7 Hz, 2H), 1.76 (ddd, J = 26.4, 13.3, 7.6 Hz, 3H), 1.26 (t, J = 7.5 Hz, 3H), 1.06 (s, 6H), 0.97 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, CDCI3) 6 193.13, 164.14, 156.01, 151.53, 149.27, 142.33, 141.86, 141.44, 120.34, 118.87, 118.13, 116.91, 104.72, 77.24, 68.76, 53.45, 52.49, 37.67, 37.39, 35.92, 34.82, 34.22, 28.48, 21.38, 21.29, 13.52, 12.88. HRMS (ESI) m / z:[M + H] calc’d for C28H35N3O3462.2751; Found 462.2756.Attorney Docket No.: 063626-502001WO

[0359] 6-(3-(difluoromethyl)-6, 6-dimethyl-4-oxo-4,5, 6, 7-tetrahydro-lH-indazol-l-yl)-3-propyl-8-(tetrahydro-2H-pyran-4-yl)isoquinolin-l(2H)-one (Compound 3). Prepared using General Procedure D. Yield 34%, 19 mg; 'H NMR (400 MHz, Chloroform-d) 6 11.56 (s, 1H), 7.49 (dd, J = 21.5, 2.2 Hz, 2H), 7.14 (t, J = 53.8 Hz, 1H), 6.39 (d, J = 1.8 Hz, 1H), 4.89 (tt, J = 11.8, 3.4 Hz, 1H), 4.15 (dd, J = 10.9, 4.0 Hz, 2H), 3.69 (td, J = 11.7, 2.0 Hz, 2H), 2.91 (s, 2H), 2.67 (t, J = 7.4 Hz, 2H), 2.50 (s, 2H), 2.02-1.93 (m, 2H), 1.91-1.79 (m, 4H), 1.15 (s, 6H), 1.05 (t, J = 7.4 Hz, 3H).13C NMR (101 MHz, Chloroform-d) 6 191.75, 164.79, 151.85, 149.77, 145.50 (t, J = 25.4 Hz), 143.26, 141.98, 140.66, 120.99, 118.84, 118.78, 117.24 (t, J = 2.2 Hz), 109.27 (t, J = 237.7 Hz), 104.79, 68.75 (2), 52.13, 37.50, 37.28, 36.10, 34.65, 34.22 (2), 28.41 (2), 21.34, 13.53. 19 F NMR (376 MHz, CDC13) 6 -116.44. HRMS (ESI) m / z [M + H] calc’d for C27H32F2N3O3, 484.2406, found 484.2402.

[0360] 3-butyl-6-(3-(difluoromethyl)-6, 6-dimethyl-4-oxo-4, 5, 6, 7-tetrahydro-lH-indazol- l-yl)-8-(tetrahydro-2H-pyran-4-yl)isoquinolin-l(2H)-one (Compound 4). Prepared using General Procedure D. Yield 61%, 36 mg; 'H NMR (400 MHz, Chloroform-d) 6 11.64 (s, 1H), 7.49 (dd, J = 20.6, 2.2 Hz, 2H), 7.30-6.98 (m, 1H), 6.39 (d, J = 1.7 Hz, 1H), 4.89 (tt, J = 11.8, 3.4 Hz, 1H), 4.20-4.09 (m, 2H), 3.68 (td, J = 11.5, 1.9 Hz, 2H), 2.91 (s, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.49 (s, 2H), 2.02-1.94 (m, 2H), 1.93-1.81 (m, 2H), 1.81-1.74 (m, 2H), 1.51- 1.38 (m, 2H), 1.15 (s, 6H), 0.97 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, Chloroform-d) 6 191.78, 164.84, 151.84, 149.79, 145.48 (t, J = 25.5 Hz), 143.53, 141.99, 140.64, 120.96, 118.81, 118.76, 117.23 (t, J = 2.1 Hz), 109.28 (t, J = 237.6 Hz), 104.65, 68.75 (2), 52.13, 37.49, 37.27, 36.10, 34.22 (2), 32.42, 30.11, 28.40 (2), 22.04, 13.93. 19 F NMR (376 MHz, CDCI3) 6 -116.43. HRMS (ESI) m / z [M + H] calc’d for C28H34F2N3O3, 498.2563, found 498.2555.Table 7: Additional Compounds Synthesized According to Example 1Attorney Docket No.: 063626-502001WOExample 2. Synthesis of compounds 27-29

[0361] See General Scheme 1.

[0362] DIPEA (0.42 mmol, 6 equiv.) was added to a pressure tube charged with intermediate I7a or I7b (69 pmol, 1 equiv.) and the appropriate ammonium salt (0.21 mmol, 3 equiv.) dissolved in DMSO (600 pL). The vessel was sealed, and the reaction was stirred at 140 °C for 12 h. Upon cooling to room temperature, water (25 mL) was added to the solution, and the aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organic fractions were washed with water (5 x 25 mL), then brine (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography (5% MeOH in DCM) and then further purified via preparatory TLC (3% MeOH in DCM) to give the final products as light-yellow solids.

[0363] 8-(6-oxa-3-azabicyclo [3.1.1 ]heptan-3-yl)-6-(3-(difluoromethyl)-6, 6-dimethyl-4-oxo-4, 5, 6, 7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (Compound 27). Yield 62%, 21 mg; 'H NMR (400 MHz, Chloroform-d) 6 11.01 (s, 1H), 7.34-6.91 (m, 3H), 6.28 (s, 1H), 4.67 (d, J = 5.9 Hz, 2H), 3.97 (d, J = 11.3 Hz, 2H), 3.64 (d, J = 11.4 Hz, 2H), 3.23 (q, J = 6.7 Hz, 1H), 2.90 (s, 2H), 2.72 (d, J = 7.8 Hz, 1H), 2.55 (t, J = 7.4 Hz, 2H), 2.47 (s, 2H), 1.75 (h, J = 7.2 Hz, 2H), 1.14 (s, 6H), 1.00 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, Chloroformdi 191.80, 163.13, 153.71, 149.86, 145.25 (t, J = 25.6 Hz), 143.43, 143.33, 141.20, 117.05 (t, J = 2.3 Hz), 115.38, 112.44, 109.69, 109.43 (t, J = 235.9 Hz), 104.40, 79.42 (2), 53.94 (2), 52.15, 37.23, 36.05, 34.33, 31.38, 28.39 (2), 21.03, 13.44. 19 F NMR (376 MHz, CDC13) 6 -116.36. HRMS (ESI) m / z [M + H] calc’d for C27H31F2N4O3, 497.2359, found 497.2344.Attorney Docket No.: 063626-502001WO

[0364] 8-(6-oxa-3-azabicyclo [3.1.1 ]heptan-3-yl)-3-propyl-6-(3, 6, 6-trimethyl-4-oxo- 4,5,6,7-tetrahydro-lH-indazol-l-yl)isoquinolin-l(2H)-one (Compound 28). Yield 72%, 26 mg; 'H NMR (400 MHz, Chloroform-d) 6 10.44 (s, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.26 (s, 1H), 4.67 (d, J = 6.0 Hz, 2H), 4.00-3.91 (m, 2H), 3.63 (d, J = 11.5 Hz, 2H), 3.22 (dt, J = 7.8, 6.1 Hz, 1H), 2.87 (s, 2H), 2.74 (d, J = 7.9 Hz, 1H), 2.55 (d, J = 12.2 Hz, 5H), 2.42 (s, 2H), 1.74 (h, J = 7.4 Hz, 2H), 1.12 (s, 6H), 1.00 (t, J = 7.4 Hz, 3H).13C NMR (101 MHz, CDC13) 6 193.46, 163.09, 153.57, 150.27, 149.17, 143.36, 142.89, 141.91, 138.23, 133.08, 123.67, 117.40, 116.85, 114.89, 111.99, 109.77, 104.49, 79.54, 78.22, 53.96, 52.41, 49.56, 37.60, 35.94, 34.38, 32.61, 31.37, 28.48 (2), 21.06, 13.49, 13.45. HRMS (ESI) m / z [M + H] calc’d for C27H33N4O3, 461.2547, found 461.2546.

[0365] 6-(3-(difluoromethyl)-6, 6-dimethyl-4-oxo-4,5, 6, 7-tetrahydro-lH-indazol-l-yl)-3-propyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)isoquinolin-l(2H)-one (Compound 29). Yield 33%, 12 mg; 'H NMR (400 MHz, Chloroform-d) 6 10.54 (s, 1H), 7.06 (d, J = 53.8 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.20 (d, J = 1.8 Hz, 1H), 3.98 (s, 4H), 3.67 (t, J = 5.2 Hz, 4H), 2.85 (s, 2H), 2.58 (t, J = 7.5 Hz, 2H), 2.46 (s, 2H), 1.84 (t, J = 5.2 Hz, 4H), 1.78 (q, J = 7.4 Hz, 2H), 1.12 (s, 6H), 1.03 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, Chloroformdi 191.83, 162.79, 153.83, 149.88, 145.09 (t, J = 25.4 Hz), 142.96, 142.66, 140.97, 116.89 (t, J = 2.4 Hz), 111.00, 109.59 (t, J =237.1 Hz), 108.83, 105.10, 104.11, 65.39 (2), 65.03 (2), 52.18, 37.20, 36.52, 35.98, 34.74 (2), 32.74, 28.35 (2), 21.18, 13.62. 19 F NMR (376 MHz, CDCI3) 6 -116.29. HRMS (ESI) m / z [M + H] calc’d for C29H35F2N4O3, 525.2672, found 525.2641.Example 3: Synthesis of Compound 5

[0366] 3 ’ -ethyl- 1 ’-( I -oxo-3-propyl-8-(tetrahydro-2H-pyran-4-yl)-l, 2-dihydroisoquinolin-6-yl)-l 7 ’-dihydrospiro [cyclobutane -1 , 6 ’-indazol]-4 ’(5 ’H)-one(Compound 5)Attorney Docket No.: 063626-502001WO

[0367] Step 1: In a pressure tube, l’-(8-chloro-l-oxo-3-propyl-l,2-dihydroisoquinolin-6-yl)-3’-ethyl-r,7’-dihydrospiro[cyclobutane-l,6’-indazol]-4’(5’H)-one (I29c) (25 mg, 0.06 mmol, 1 Eq), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (25 mg, 0.12 mmol), Pd(0Ac)2 (1.3 mg, 0.006 mmol), DPPF (6.6 mg, 0.012mmol), K2CO3 (33 mg, 0.24mmol) were added followed by addition of 3ml of 1,4-Dioxane and 0.3ml water. The reaction was degassed with nitrogen, sealed with PTFE screwcap and heated to 130° C while stirring for 12h. Upon completion, solvent was evaporated in vacuo, water (20 ml) was added to the residue and extracted with ethyl acetate (25ml X 2). The combined organic extracts was dried on sodium sulfate, adsorbed onto silica gel and flash chromatography was performed using 40% Ethyl acetate in hexanes to afford l’-(8-(3,6-dihydro-2H-pyran-4-yl)-l-oxo-3-propyl- 1 ,2-dihydroisoquinolin-6-yl)-3 ’ -ethyl- 1 ’ ,7’ -dihydrospirofcyclobutane- 1 ,6’ -indazol]-4’(5’H)-one as crude which was used in next step.

[0368] Step 2: Crude l’-(8-(3,6-dihydro-2H-pyran-4-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-6-yl)-3’-ethyl-r,7’-dihydrospiro[cyclobutane-l,6’-indazol]-4’(5’H)-one was solubilized in 5 ml methanol in a round bottom flask, wet (50% moisture)Palladium on carbon (20% w / w,) (5 mg, 0.0047 mmol (8 mol%)) and PdCE (1 mg, 0.006mmol, 10 mol%) were then added, round bottom flask was sealed with a rubber septa, vacuum was applied and then a hydrogen gas was introduced via a balloon. The reaction was warmed to 40°C and stirred for 12h at this temperature. Upon completion, the gas ballon was removed, round bottom flask cooled to rt, reaction mix was filtered through celite, and solvent was removed in vacuo to result in a crude which was dissolved using methanol and loaded on a preparative TLC, purification was then performed using 3% methanol in DCM as mobile phase to afford 17mg of 3’-ethyl-r-(l-oxo-3-propyl-8-(tetrahydro-2H-pyran-4-yl)-l,2-dihydroisoquinolin-6-yl)-r,7’-dihydrospiro[cyclobutane-l,6’-indazol]-4’(5’H)-one (Compound 5) (63% overall yield). 'H NMR (400 MHz, Chloroforms / ) 8 9.76 (s, 1H), 7.51 (q, J= 2.2 Hz, 2H), 6.36 (d, J= 1.9 Hz, 1H), 4.94 - 4.82 (m, 1H), 4.16 (dd, J= 11.3, 4.1 Hz, 2H), 3.78 - 3.68 (m, 2H), 3.11 (s, 2H), 3.00 (q, J= 7.5 Hz, 2H), 2.71 (s, 2H), 2.62 (t, J= 7.5 Hz, 2H), 2.05 - 1.75 (m, 12H), 1.35 (t, J= 7.5 Hz, 3H), 1.06 (t, J= 13 Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C29H36N3O3, 474.2746, found 474.2751.Table 8: Additional Compounds for Synthesis According to Example 3Compounds with physical characterization provided were synthesized.Attorney Docket No.: 063626-502001WO<Attorney Docket No.: 063626-502001WOAttorney Docket No.: 063626-502001WOAttorney Docket No.: 063626-502001WOExample 4: Synthesis of Compound 9(Compound 9)

[0369] 4-(6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-8-yl)tetrahydro-2H-pyran-4-carbonitrileAttorney Docket No.: 063626-502001WO

[0370] Exemplary reaction conditions for the synthesis of Compound 9 include (a) ethyl 3 -oxohexanoate, K2CO3, DMF, 70° C (b) Cone H2SO4: Acetic Acid: Water (7:2: 1), 110° C (c) LAH, THF (d) TBDPSC1, Imidazole, DMF, rt (e) tetrahydro-2H-pyran-4-carbonitrile, KHMDS, Toluene (f) TBAF, THF, rt (g) DMP, DCM, rt.

[0371] Step 1: To a stirred solution of 6-(3-ethyl-4-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-fluoro-3 propylisoquinolin- l(2H)-one (133) (3.0 g, 4.71 mmol) in Toluene (30 ml) was added KHMDS (1 M in THF) (14.15 ml, 14.15 mmol) and tetrahydro-2H-pyran-4-carbonitrile (1.04 g, 9.42 mmol) at rt. The resulting reaction mixture was stirred at 110 °C for 12 hrs. After completion of the starting material, the reaction mixture was diluted with water and extracted with EtOAc (200 ml x 3). The combined organic layer was washed with brine solution (100 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted in 30-40% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 4-(6-(4-((tert-butyldiphenylsilyl)oxy)-3-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-8-yl)tetrahydro-2H-pyran-4-carbonitrile (134) (2.2 g, 64.10 % yield). LCMS: Mass found; m / z = 727.7 [M+H]+.

[0372] Step 2: To a stirred solution of 4-(6-(4-((tert-butyldiphenylsilyl)oxy)-3-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-8-yl)tetrahydro-2H-pyran-4-carbonitrile (134) (0.5 g, 0.68 mmol) in THF (10 ml) was addedAttorney Docket No.: 063626-502001WOTBAF (IM in THF) (4.81 ml, 4.81 mmol) at rt. The resulting reaction mixture was stirred at rt for 12 hrs. After completion of the starting material, the reaction mixture was diluted with saturated solution of ammonium chloride and extracted with EtOAc (100 ml x 3). The combined organic layer was washed with brine solution (50 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted in 35-40% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 4-(6-(3-ethyl-4-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-8-yl)tetrahydro-2H-pyran-4-carbonitrile (135) (0.25 g, 74.43 % yield). LCMS: Mass found; m / z = 489.5 [M+H]+.

[0373] Step 3: To a stirred solution of 4-(6-(3-ethyl-4-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro- IH-indazol- 1 -yl)- 1 -oxo-3 -propyl- 1 ,2-dihydroisoquinolin-8-yl)tetrahydro-2H-pyran-4-carbonitrile (135) (0.25 g, 0.511 mmol) in DCM (10 ml) was added Dess-Martin periodinane (0.43 g, 1.20 mmol) at rt. The resulting reaction mixture was stirred at rt for 12 hrs. After completion of the starting material, the reaction mixture was diluted water and extracted with EtOAc (100 ml x 3). The combined organic layer was washed with brine solution (50 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted in 15-20% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 4-(6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro- IH-indazol- 1 -yl)- 1 -oxo-3 -propyl- 1 ,2-dihydroisoquinolin-8-yl)tetrahydro-2H-pyran-4-carbonitrile (0.035 g, 14.05 % yield). LCMS: Mass found; m / z = 487.2 [M+H]+. 'H NMR (400 MHz, DMSC ): 6H 10.61 (s, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 6.41 (s, 1H), 4.17-4.15 (m, J=7.6 Hz, 4H), 3.04-2.98 (m, . / =22,4 Hz, 2H), 2.91 (s, 2H), 2.84-2.81 (m, J=10.8 Hz, 2H), 2.76-2.72 (m, 2H), 2.47 (s, 2H), 2.13 (s, 2H), 1.88-1.82 (m, 2H), 1.37-1.33 (m, 3H), 1.27 (t, J=14.2Hz, 3H), 1.17 (s, 6H), 1.11-1.07 (t, J=13.6 Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C29H35N4O3, 487.2704, found 487.2730.Table 9: Additional Compounds for Synthesis According to Example 4| Compound | Chemical Structure | Intermediates for use in synthesisAttorney Docket No.: 063626-502001WOExample 5a: Synthesis of Compound 11(Compound 11)

[0374] 4-(6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-8-yl)tetrahydro-2H-pyran-4-carboxamide

[0375] In a 10 ml glass vial, 4-(6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-8-yl)tetrahydro-2H-pyran-4-carbonitrile (lOmg, 0.02mmol) was taken, ethanol 3 ml and 0.3ml DMSO were added and warmed to 50°C to dissolve the solid. Thereafter, 0.15ml of NaOH (2 M solution) and 0.1 ml of 34%H2C>2 solution were added and the reaction was stirred at 40°C overnight. Upon completion, solvents were evaporated, 5 ml water was added and extracted with 5 ml ethyl acetate twice. The organic extracts were combined and washed with brine, dried over sodium sulfate, evaporated and purified using preparative TLC using 80 % ethyl acetate +5% methanol in hexanes to afford 5 mg of 4-(6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-8-yl)tetrahydro-2H-pyran-4-carboxamide (Example 12) as white solid (48% yield). 'H NMR (400 MHz, Chloroform^ / ) 8 10.77 (s, 1H), 7.73 (s, 1H), 7.42 (s, 1H), 6.29 (s, 1H), 5.12 (s, 2H), 4.06 - 3.98 (m, 2H), 2.79 (m, 8H), 2.35 (m, 4H), 1.73 (q, J= 7.4 Hz, 2H), 1.29 (m, 4H), 1.07 (s, 6H), 1.00 (t, J= 7.3 Hz, 3H). HRMS (ESI) m / z [M + Na] calc’d for C29H36N4O4Na, 527.2634, found 527.2679.Attorney Docket No.: 063626-502001WOExample 5b: Synthesis of Compound 13(Compound 13)

[0376] 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-(piperidin-4-y 1 ) -3 -propyli soquinolin- 1 (2H)-one

[0377] Exemplary reaction conditions for the synthesis of Compound 13 include a) boronate ester, Pd(dppf)C12, Na2COs, Dioxane / water,100° C,16 h (b) Pd / C, MeOH, EE 250 psi, 24 h (c) HC1 in dioxane, DCM, rt.

[0378] Step 1 : To a stirred solution of tert-butyl 4-(6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro- IH-indazol- 1 -yl)- 1 -oxo-3 -propyl- 1 ,2-dihydroisoquinolin-8-yl)-3 ,6-dihydropyridine-l(2H)-carboxylate (151) (0.5 g, 0.894 mmol) in Methanol (10 ml) was added Palladium on carbon (50% moisture) (0.1 g, 20% w / w) at rt. The resulting reaction mixture was stirred at rt after applying 250 psi H2 pressure in autoclave. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was filtered through celite pad and resulting mother liquor was concentrated under reduced pressure to afford crude. The crude was purified by flash chromatography and product was eluted with 30-50% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford tertbutyl 4-(6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl- l,2-dihydroisoquinolin-8-yl)piperi dine- 1 -carboxylate (0.3 g, 59.78% yield). LCMS: Mass found; m / z = 561.4 [M+H] +.Attorney Docket No.: 063626-502001WO

[0379] Step 2: To a stirred solution of tert-butyl 4-(6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro- IH-indazol- 1 -yl)- 1 -oxo-3 -propyl- 1 ,2-dihydroisoquinolin-8-yl)piperidine- 1 -carboxylate from previous step (0.3 g, 0.535 mmol) in DCM (10 ml) was added HC1 in Dioxane (4M) (3 ml) at rt. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was diluted with water pH of the reaction mixture adjusted to pH ~7-8. The product was then extracted in EtOAc (100 ml x 3). The combined organic layer was washed with brine solution (1000 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The resulting crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted with 3-5% MeOH / DCM. The pure fractions were concentrated and dried under vacuum to afford 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-(piperidin-4-yl)-3-propylisoquinolin-l(2H)-one (Compound 13) (150 mg, 60.85% yield). LCMS: Mass found; m / z = 461.50 [M+H] +. 1HNMR (400 MHz, DMSOd6): 6H 11.09 (s, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.45 (s, 1H), 6.43 (s, 1H), 4.63-4.58 (m, 1H), 3.32-2.99 (m, 4H), 2.86-2.81 (m, 2H), 2.67-2.62 (m, 2H), 2.49-2.43 (m, 2H), 2.36 (s, 2H), 1.79-1.76 (m, 2H), 1.69-1.60 (m, 2H), 1.53-1.50 (m, 2H), 1.24-1.20 (t, J=16 Hz, 3H), 1.02 (s, 6H), 0.94-0.91 (t, J=12 Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C28H37N4O2, 461.2911, found 461.2895.Example 6: Synthesis of Compound 15

[0380] 8-(l-(2,2-difluoroethyl)piperidin-4-yl)-6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (Compound 15)

[0381] To a stirred solution of 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-(piperidin-4-yl)-3-propylisoquinolin-l(2H)-one (Compound 13) (0.045 g, 0.097 mmol) in DCM (5 ml) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.041 g, 0.195 mmol) and TEA (0.049 g, 0.488 mmol) at rt. The reaction mixture was stirred for 6 h at 50° C. After completion of the starting material, the reaction mixture was diluted with water and extracted in DCM (50 ml x 3). The combined organic layer was washed with brine solutionAttorney Docket No.: 063626-502001WO(30 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by flash chromatography and product was eluted with 10-15% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 8-(l-(2,2-difluoroethyl)piperidin-4-yl)-6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (Compound 15) (0.040 g, 70.23% yield).1H NMR (400 MHz, DMSOd6): 5H 11.14 (s, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.46 (d, J=1.6 Hz, 1H), 6.45 (d, J=1.6 Hz, 1H), 6.33-6.02 (m, 1H), 4.50-4.47 (m, J=11.6 Hz, 1H), 3.05-3.00 (m, 4H), 2.87-2.74 (m, 4H), 2.46-2.41 (m, 2H), 2.36-2.32 (m, 4H), 1.86-1.83 (m, 2H), 1.68-1.61 (m, J=15.2 Hz, 4H), 1.24-1.20 (t, J=15.2 Hz, 3H), 1.03 (s, 6H), 0.94-0.88 (t, J=20 Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C30H39F2N4O2, 525.3036, found 525.3048.Example 7: Synthesis of Compound 16

[0382] 2-(4-(6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-8-yl)piperidin-l-yl)acetonitrile (Compound 16)

[0383] To a stirred solution of 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-(piperidin-4-yl)-3-propylisoquinolin-l(2H)-one (Compound 13) (0.05 g, 0.108 mmol) in DCM (5 ml) was added Bromoacetonitrile (0.026 g, 0.217 mmol) and TEA (0.054 g, 0.542 mmol) at rt. The reaction mixture was stirred for 16 hr at rt. After completion of the starting material, the reaction mixture was diluted with water and extracted in DCM (50 ml x 3). The combined organic layer was washed with brine solution (30 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude was purified by flash chromatography and product was eluted with 25-30% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 2-(4-(6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-l-oxo-3-propyl-l,2-dihydroisoquinolin-8-yl)piperidin-l-yl)acetonitrile (Compound 16) (0.035 g, 65% yield). 'H NMR (400 MHz, DMSOd6): 5H 11.16 (s, 1H), 7.61 (d, J=1.6Hz, 1H), 7.46 (d, J=1.6Hz, 1H), 6.46 (s, 1H), 4.52-4.46 (m, 1H), 3.78 (s, 2H), 3.00 (s, 2H), 2.94-2.87 (m, 2H), 2.85-2.82 (m,Attorney Docket No.: 063626-502001WO2H), 2.47-2.45 (m, 2H), 2.40-2.34 (m, 4H), 1.92-1.89 (m, 2H), 1.69-1.61 (m, 4H), 1.24-1.20 (m, J=1.6 Hz, 3H), 1.03 (s, 6H), 0.98-0.91 (m, J=28 Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C30H38N5O2, 500.3020, found 500.3069.Example 8: Synthesis of Compound 17

[0384] 8-(l-acetylpiperidin-4-yl)-6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (Compound 17)

[0385] To a solution of 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-(piperidin-4-yl)-3-propylisoquinolin-l(2H)-one (Compound 13)(0.015 g, 0.026 mmol, 1 Eq) in 3 ml DCM was added acetic anhydride (10 pl, 0.1 mmol) and stirred at rt for 12h. Upon completion, the solvent was evaporated in vacuo, 10 ml water was added to the reaction crude and extracted with ethyl acetate(10 ml). Organic extract was washed with NaHCO3 solution and dried over sodium sulfate and in vacuo to result in 13 mg 8-(l-acetylpiperidin-4-yl)-6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (Example 17) (81% yield). 'H NMR (400 MHz, Chloroform^ / ) 69.30 (s, 1H), 7.48 - 7.41 (m, 2H), 6.35 (d, J= 1.9 Hz, 1H), 4.85 (dt, J= 15.0, 11.3 Hz, 2H), 3.99 (d, J= 13.3 Hz, 1H), 3.35 (t, J= 12.0 Hz, 1H), 3.00 (q, J= 7.5 Hz, 2H), 2.87 (s, 2H), 2.80 (t, J= 12.1 Hz, 1H), 2.59 (t, J = 7.5 Hz, 2H), 2.46 (s, 2H), 2.17 (s, 3H), 2.10 (dd, J= 29.4, 12.9 Hz, 2H), 1.80 (p, J= 7.4 Hz, 2H), 1.66 (ddd, J= 24.2, 12.2, 4.0 Hz, 2H), 1.35 (t, J= 7.5 Hz, 3H), 1.15 (d, J= 5.0 Hz, 6H), 1.05 (t, J= 13 Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C30H39N4O3, 503.3011, found 503.3017.Example 9: Synthesis of Compounds 19, 21, 47, 48 using Intermediates I52a, I52b, 154, and 155Attorney Docket No.: 063626-502001WO22, , =2 154 R=Ethyl, X=NBoc, n=1 Compound 21 R=Ethyl, X=NH, n=1 155 R=CF2H, X=NBOC, n=1 Compound 48 R=CF2H, X=NH, n=1

[0386] Exemplary reaction conditions for the synthesis of Compounds 19, 21, 47, 48 include (a) m-CPBA, DCM, rt (b) Pd(PBus)2, t-BuOH, reflux, (c) (only when X=NH) HC1 in methanol, rt.Example 10: Synthesis of Compounds 22, 35, and 37

[0387] Exemplary reaction conditions for the synthesis of Compounds 22, 35, and 37 include (a) Imidazole, TBDPSC1, DMF, rt (b) LiHMDS in THF, PhNTf, THF, 16 h (c) B2pin2, KO Ac, Pd(dppf)Cl2, NaBr, dioxane, reflux, 16 h (d) aryl halide, Na2COs, Pd(dppf)Cl2, Dioxane / water (10:1), 80° C (e) TBAF (IM in THF) (f) Pd / C, MeOH, H2.Attorney Docket No.: 063626-502001WO

[0388] 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-(4-hydroxycyclohexyl)-3-propylisoquinolin-l(2H)-one(Compound 22)

[0389] Step 1 : To a stirred solution of 8-(4-((tert-butyldiphenylsilyl)oxy)cyclohex-l-en-l-yl)-6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (145) (0.45 g, 0.986 mmol) in THF (10 ml) was added TBAF (1 M in THF) (3.94 ml, 1.97 mmol) at rt for 16 h. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was diluted with water and extracted with EtOAc (100 ml x 2). The organic layer dried over sodium sulphate and evaporated under reduced pressure to afford as a crude product. It was triturated with ether to afford 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-(4-hydroxycyclohex-l-en-l-yl)-3-propylisoquinolin-l(2H)-one (30 ml) to afford (200 mg-crude). The resulting crude was as such taken for the next step without further purification.

[0390] Step 2: To a stirred solution of 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-IH-indazol- 1 -yl)-8-(4-hy droxy cyclohex- 1 -en- 1 -y 1 )-3 -propylisoquinolin- 1 (2H)-one (from step 1) (0.2 g, 0.422 mmol) in MeOH (10 ml) was added Palladium on carbon (50% moisture) (40 mg, 20% w / w) in autoclave. The reaction mixture was degassed with N2 and further stirred at rt for 16 h with 200 psi H2 pressure. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was filtered through celite pad. The organic layer dried over sodium sulphate and evaporated under reduced pressure to get the crude product. The resulting crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted with 32-35% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-(4-hydroxycyclohexyl)-3-propylisoquinolin-l(2H)-one. It was further purified by Prep HPLC purification using chiral column to afford Compound 22 (55 mg, 20% yield). LCMS: Mass found; m / z = 476.2 [M+H]+. 'H NMR (400 MHz, DMSC ): 611 11.08 (s, 1H),Attorney Docket No.: 063626-502001WO7.54 (d, J= 2 Hz, 1H), 7.50 (d, J= 2 Hz, 1H), 6.42 (d, J= 1.6 Hz, 1H), 4.53-4.47 (m, 1H), 4.36-4.35 (d, J= 3.6 Hz, 1H), 3.93 (s, 1H), 2.98 (s, 2H), 2.87-2.81 (m, 2H), 2.47-2.43 (m, 2H), 2.36 (s, 2H), 1.85-1.77 (m, 4H), 1.69-1.57 (m, 6H), 1.26-1.19 (t, J= 27.6 Hz, 3H), 1.07 (s, 6H), 0.94-0.90 (t, J= 14.4 Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C29H38N3O3, 476.2908, found 476.2941.Table 10: Additional Compounds for Synthesis according to Example 10Attorney Docket No.: 063626-502001WOExample 11. Synthesis of Compound 24

[0391] 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propyl-8-((tetrahydro-2H-pyran-4-yl)oxy)isoquinolin-l(2H)-one (Compound 24) was synthesized as per General Synthetic Scheme 4.

[0392] 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-fluoro-3-propylisoquinolin-l(2H)-one (131) (50 mg, 1 eq, 0.13 mmol) was taken in a 5 mL pressure vial, followed by the addition of 1 mL of DMSO. Then, tetrahydro-2H-pyran-4-ol (17 mg, 1.3 Eq, 0.16 mmol) and sodium hydride (6.1 mg, 5.1 pL, 2 Eq, 0.25 mmol) were added in a vial under an argon atmosphere. The reaction vessel was then sealed and heated to 140 °C for 12 h and cooled, and cold water (25 mL) was added. The aqueous layer was extracted with ethyl acetate (25 mL *3); the organic fractions were combined and washed with brine (25 mL) and dried over sodium sulfate. Purification by column chromatography (SiO2, 5:95 hexane / ethyl acetate) yielded the Compound 24 as a white solid. 1H NMR (400 MHz, CDC13) 6 10.80 (s, 1H), 7.03 - 6.95 (m, 2H), 6.18 (s, 1H), 4.71 (tt, J = 7.1, 3.6 Hz, 1H), 4.07 (ddd, J = 11.1, 7.2, 3.5 Hz, 2H),Attorney Docket No.: 063626-502001WO3.58 (ddd, J = 11.1, 7.0, 3.6 Hz, 2H), 2.91 (q, J = 7.5 Hz, 3H), 2.80 (s, 2H), 2.55 (t, J = 7.4 Hz, 2H), 2.36 (s, 2H), 2.11 - 1.99 (m, 2H), 1.93 (dtd, J = 13.5, 6.9, 3.4 Hz, 2H), 1.72 (h, J = 7.4 Hz, 3H), 1.25 (t, J = 7.5 Hz, 3H), 1.06 (s, 6H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDC13) 6 193.26, 162.80, 159.84, 156.11, 149.53, 144.10, 142.87, 142.36, 117.11, 114.73, 112.17, 107.04, 103.77, 73.62, 64.92, 52.68, 37.98, 36.07, 34.96, 31.67, 28.65, 21.57, 21.36, 13.62, 13.06. HRMS (ESI) m / z [M + H] calc’d for C28H35N3O4, 500.2532, found 500.2519.Example 12. Synthesis of Compound 26

[0393] 7-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-2-propyl-5- (tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (Compound 26)

[0394] 7-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-5-fluoro-2-propylquinazolin-4(3H)-one (I28a) (50 mg, 0.12 mmol, 1 Eq) was dissolved in 10 ml THF in a pressure tube and (tetrahydro-2H-pyran-4-yl)magnesium bromide (0.36mmol) was added as a freshly prepared solution in THF. The pressure tube was closed using screwcap and the reaction was heated to 130 °C for Ih. Reaction was then cooled to rt, reaction dropwise quenched with 5ml water, water was then acidified to pH~5, to this, ethyl acetate 10ml is added and organic layer is separated and washed with 10 ml water. Combined organic extracts are dried over sodium sulfate, adsorbed onto silica gel and flash chromatography followed by preparative TLC was performed using 50% ethyl acetate in hexanes to obtain 12 mg of Compound 26 as white solid powder in 20% yield. 'HNMR (400 MHz, Chloroform-t / ) 611.23 (s, IH), 7.65 (d, J= 2.2 Hz, IH), 7.54 (d, J= 2.2 Hz, IH), 4.55 (tt, J= 9.5, 4.7 Hz, IH), 4.09 (dt, J= 11.2, 3.1 Hz, 2H), 3.60 (td, J= 11.2, 3.4 Hz, 2H), 2.92 (q, J = 7.5 Hz, 2H), 2.88 (s, 2H), 2.69 (dd, J= 8.4, 6.8 Hz, 2H), 2.37 (s, 2H), 1.93 - 1.79 (m, 6H), 1.27 (t, J= 7.5 Hz, 3H), 1.06 (s, 6H), 1.03 (t, = 7.4Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C27H35N4O3, 463.2696, found 463.2703.Attorney Docket No.: 063626-502001WOTable 11 : Additional Compounds for Synthesis according to Example 13Example 13. Synthesis of Compound 31

[0395] 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propyl-8-(2-oxaspiro[3.3]heptan-6-yl)isoquinolin-l(2H)-one (Compound 31)

[0396] Step 1: To a stirred solution of 8-bromo-6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (I41)(0.34 g, 0.745 mmol) in Dioxane (10 ml) was added 4,4,5,5-tetramethyl-2-(2-oxaspiro[3.3]hept-5-en-6-yl)-l,3,2-dioxaborolane (0.5 g, 2.23 mmol), water (1 ml) and Na2CO3 (0.316 g, 2.98 mmol). The resulting reaction mixture was degassed under N2 atmosphere at rt for 10-15 min. PdC12(dppf) (0.027 g, 0.037 mmol) was added and the resulting reaction mixture was stirred at 80 oC for 16 h. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was diluted with water and extracted with EtOAc (100 ml x 3). The combined organic layer was washed with brine solution (100 ml), dried over sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The resulting crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted with 50-60% EtOAc / Hexanes. The pure fractions were concentrated and dried underAttorney Docket No.: 063626-502001WOvacuum to afford 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propyl-8-(2-oxaspiro[3.3]hept-5-en-6-yl)isoquinolin-l(2H)-one (200 mg, 56.87% yield). LCMS: Mass found; m / z = 472.30 [M+H] +. 'H NMR (400 MHz, DMSOd6): 6H 11.21 (s, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 6.80 (s, 1H), 6.45 (d, J=1.2 Hz, 1H), 4.82-4.78 (m, 4H), 3.15 (s, 2H), 3.00 (s, 2H), 2.85-2.83 (m, J=8 Hz, 2H), 2.47-2.45 (m, J=8 Hz, 2H), 2.37 (s, 2H), 1.67-1.65 (m, J=8 Hz 2H), 1.24-1.16 (m, 3H), 1.03 (s, 6H), 0.95-0.91 (m, 3H).

[0397] Step 2: To a stirred solution of 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propyl-8-(2-oxaspiro[3.3]hept-5-en-6-yl)isoquinolin-l(2H)-one (from step 1) (0.2 g, 0.424 mmol) in MeOH (10 ml) was added Palladium on carbon (50% moisture) (40 mg, 20% w / w) (0.5 g, 2.23 mmol) in autoclave. The reaction mixture was degassed with N2 and further stirred at rt for 16 h with 200 psi H2 pressure. The reaction was monitored by TLC. After completion of the starting material, the reaction mixture was filtered through celite pad. The organic layer dried over sodium sulphate and evaporated under reduced pressure to get the crude product. The resulting crude was purified by column chromatography by using 60-120 mesh silica gel and product was eluted with 30-37% EtOAc / Hexanes. The pure fractions were concentrated and dried under vacuum to afford 6-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-3-propyl-8-(2-oxaspiro[3.3]heptan-6-yl)isoquinolin-l(2H)-one (Compound 31) (70 mg, 34.85% yield).XH NMR (400 MHz, DMSOd6): 5H 11.10 (s, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 6.41 (s, 1H), 4.74 (s, 2H), 4.61-4.56 (m, J=17.6 Hz, 1H), 4.48 (s, 2H), 2.99 (s, 2H), 2.88-2.82 (m, J=24 Hz 2H), 2.74-2.69 (m, J=20 Hz 2H), 2.47-2.43 (m, J=16 Hz, 2H), 2.37 (s, 2H), 2.28-2.23 (m, 2H), 1.68-1.62 (m, 2H), 1.24-1.21 (t, 3H), 1.03 (s, 6H), 0.94-0.91 (m, J=12Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C29H36N3O3, 474.2751, found 474.2754.Table 12: Additional Compounds for Synthesis according to Example 13Attorney Docket No.: 063626-502001WOExample 14. Synthesis of Compound 32

[0398] 6-(3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-morpholino-3-propylisoquinolin-l(2H)-one (Compound 32)

[0399] In a pressure tube, 8-chloro-6-(3-(difluoromethyl)-6,6-dimethyl-4-oxo-4, 5,6,7-tetrahydro-lH-indazol-l-yl)-3-propylisoquinolin-l(2H)-one (1130a) (25 mg, 0.09 mmol) was dissolved using 3ml DMSO followed by the addition of morpholine (47 mg, 0.54 mmol). The tube was sealed and the reaction was heated to 130 °C for 12h. Upon completion, 50 ml water was added to the reaction and extracted using ethyl acetate (25mlX2). The organic extracts were combined, washed with brine, dried over sodium sulfate and evaporated to give a crude which was purified using preparative TLC with 50%ethyl acetate, 3% methanol in hexanes as mobile phase to afford 18mg of 6-(3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-8-morpholino-3-propylisoquinolin-l(2H)-one (Compound 32) as yellowish solid (66% yield). 'H NMR (400 MHz, Chloroform^ / ) 8 10.26 (s, 1H), 7.16 (t, J = 53.5 Hz, 1H), 7.15 (d, J= 2.0 Hz, 1H), 7.04 (d, J= 2.1 Hz, 1H), 6.31 (s, 1H), 4.03 (t, J= 4.5 Hz, 4H), 3.26 (s, 4H), 2.92 (s, 2H), 2.64 (t, J= 7.6 Hz, 2H), 2.51 (s, 2H), 1.81 (h, J= 7.4 Hz, 2H), 1.17 (s, 6H), 1.06 (t, J= 7.3 Hz, 3H).13C NMR (101 MHz, CDC13) 6191.76, 162.46, 155.56, 149.82, 145.37 (t, J = 25.4 Hz), 143.46, 143.29, 141.22, 117.13, 116.05, 113.48, 109.76, 109.28 (t, J = 237.7 Hz), 104.27, 67.14 (2), 53.36(2), 52.13, 37.27, 36.04, 34.81, 28.38 (2), 21.21, 13.53. HRMS (ESI) m / z [M + H] calc’d for C26H31F2N4O3, 485.2363, found 485.2359.Attorney Docket No.: 063626-502001WOTable 13: Additional Compounds for Synthesis according to Example 14>Attorney Docket No.: 063626-502001WOExample 15. Synthesis of Compound 33

[0400] 5-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-7-(3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-2-propylquinazolin-4(3H)-one (Compound 33) was synthesized according to General Synthetic Scheme 4.

[0401] In a pressure tube, 7-(3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-5-fluoro-2-propylquinazolin-4(3H)-one (I28b) (25 mg, 0.06 mmol, 1 Eq) was dissolved using 3ml DMSO followed by the addition of 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride (24 mg, 0.18 mmol) and DIPEA (31mg, 0.24mmol). The tube was sealed and the reaction was heated to 130°C for 12h. Upon completion, 50 ml water was added to the reaction and extracted using ethyl acetate (25mlX2). The organic extracts were combined, washed with brine, dried over sodium sulfate and evaporated to give a crude which was purified using preparative TLC with 50%ethyl acetate, 3% methanol in hexanes as mobile phase to afford 10 mg of 5-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-7-(3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indazol-l-yl)-2-propylquinazolin-4(3H)-one (Compound 33) as yellowish solid (34% yield). 'H NMR (400 MHz, Chloroform-t / ) 6 10.60 (s, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.13 (d, J= 2.1 Hz, 1H), 7.07 (t, J= 56 Hz,lH), 4.65 - 4.59 (m, 2H), 3.84 (d, J = 11.5 Hz, 2H), 3.67- 3.59 (m, 2H), 3.24- 3.14 (m, 1H), 2.91 (s, 2H), 2.64 -2.51 (m, 3H), 2.42 (s, 2H), 1.81 (h, J = 7.4 Hz, 2H), 1.08 (s, 6H), 1.00 (t, J = 7.4 Hz, 3H). HRMS (ESI) m / z [M + H] calc’d for C26H30F2N5O3, 498.2304, found 498.2311.Attorney Docket No.: 063626-502001WOExample 16. Synthesis of Compounds 19, 47, 21, and 48S2a R-Ethyl, X-O, n-2 Compound 19 R=Ethyl, X=O, n=2I52b R-CF2H, X-O, n-2 Compound 47 R=CF2H, X=O, n=2154 R-Ethyl, X-NBoc, n-1 Compound 21 R=Ethyl, X=NH, n=1155 R-CF2H, X-NBOC, n-1 Compound 48 R=CF2H, X=NH, n=1

[0402] General methods for synthesizing compounds 19, 47, 21, and 48 as stated in Example 9 and below include (a) m-CPBA, DCM, rt (b) Pd(PBus)2, t-BuOH, reflux, (c) (only when X=NH) HC1 in methanol, rt as described above.Table 14: Methods and Intermediates for the Synthesis of Compounds of Example 16Attorney Docket No.: 063626-502001WOExample 17: Melting Point Data

[0403] Melting point (M.P.) analyses were conducted on various compounds described herein as described below. Lower melting point values can favor higher dissolution rates in biololgical fluids, including gastric and intestinal fluids, leading to higher oral absorption.

[0404] A 50 mL borosilicate glass tube was filled with 25 mL silicon oil. Subsequently, a one end sealed glass capillary was filled with ~2 mg compound and was tied to a traceable thermometer using a thread, making sure the closed end of the capillary aligned with the lower tip thermometer. The thermometer and capillary were submerged in the 50 mL borosilicate glass tube containing silicon oil and the tube was heated with a heat gun to the required temperature. The melting of the compound was observed and the corresponding temperature was recorded three times for the compound and the average M.P. was reported.

[0405] Alternative procedure included measuring melting point of the compounds of the present disclosure using using Thermo Scientific Mel-Temp 1001D Capillary Melting Point Apparatus using standard procedures.Attorney Docket No.: 063626-502001WOExample 18: Biological DataHsp90 Isoform Binding Affinity

[0406] Compounds of the disclosure were evaluated for their binding affinity against the cytosolic Hsp90 Isoforms, as well as selectivity for Hsp90p selectivity. The assay was performed as reported in J. Med. Chem. 2021, 64, 1545-1557 and as described below. The assay was performed in a 96-well format in black, flat-bottom plates (Santa Cruz Biotechnology) with a final volume of 100 pL. Twenty -five microliters of assay buffer (20 mM HEPES, pH 7.3, 50mM KC1, 5mM MgC12, 20mM Na2MoO4, 2mM DTT, O.lmg / mL BGG, and 0.01% NP-40), 25pL of assay buffer containing 6 nM FITC-GDA (fluorescent tracer, stock in DMSO and diluted in assay buffer), and 50 pL of assay buffer containing 10 nM of Hsp90P(Enzo, ADI-SPP-777), Hsp90a(Enzo, ADI-SPP-776), Grp94(Enzo, ADI-SPP-766), or 50 nM Trapl (Enzo, ADI-SPP-848) was added to each well. Compounds were tested in triplicate wells (1% DMSO final concentration). For each plate, wells containing buffer only (background), tracer in buffer only (low polarization control), and protein and tracer in buffer with 1% DMSO (high polarization control) were included. Plates were incubated at 4 °C with rocking for 2h. Polarization values (in mP units) were measured at 37 °C with an excitation filter at 485 nm and an emission filter at 528 nm. Polarization values were correlated to % tracer bound and compound concentrations. The concentration at which the tracer was 50% displaced by the inhibitor was determined using MS Excel and reported with a standard deviation value from average of triplicate data.Table 15. Binding affinity and selectivity dataAttorney Docket No.: 063626-502001WO<Attorney Docket No.: 063626-502001WOAttorney Docket No.: 063626-502001WO><Attorney Docket No.: 063626-502001WO> > > > > << <Selectivity: @>500-fold; 500-fold > $ >150-fold; 150-fold > # > 50-fold; / < 50-foldAttorney Docket No.: 063626-502001WO in vitro Cellular Inhibition Data

[0407] Compounds of the disclosure were screened for growth inhibition activity against cancer cell lines. Inhibition (IC50) data is provided in Table 16.Table 16. Cellular Inhibition of Compounds of the disclosure (IC50 values)<Attorney Docket No.: 063626-502001WOIC5o : + >10; 10 > ++ > 5; 5 > +++ > 1; 0.1<*<l; **<0.1Oral Pharmacokinetics

[0408] CD-I fasted mice were dosed with compounds of the disclosure at 1 mg / kg. Formulations administered were DMSO (10 %) + Tween 20 (5%) + 10 mM PBS, pH 7.4 (85 %). IV administration was conducted in solutions of 0.2 mg / mL. Oral administration was conducted in solutions of 1 mg / mL. The compounds of the disclosure were weighed separately and then to each are added 100 uL DMSO (warmed to dissolve), then 850 uL of 10 mM PBS at pH 7.4 and 50 uL of Tween 20 vortex were added. After dosing, blood samples were collected using micro sampling technique at time points of 0.5, 1, 2, 4, 8 and 24 Hours. Plasma was then analyzed for each compound using LCMS Triple Quad 6500 Plus. A 6 in 1 internal standard mix was used for the analytical method control.Attorney Docket No.: 063626-502001WOTumor Growth inhibition assessed by vivo oral dosing

[0409] Mice were dosed orally at 10 mg / kg of compounds described herein. Maximum serum concentration (Cmax values) were then assessed.

[0410] The mice were treated with daily doses by oral gavage. Tumor volume is then measured by caliper. Body weight were measured every 2 days.Efficacy (CDX model)

[0411] BALB / c nude Female, 6-7 Weeks old mice were implanted with 5xl05A2780 cells in 0.1 mL medium (PBS with Matrigel (1:1)) at the right front flank region. After the mean tumor volume reached 150 mm3, mice were divided in three groups; 1) Vehicle (DMSO (10 %) + Tween 20 (5%) + 10 mM PBS, pH 7.4 (85 %) 2) compound of the disclosure at lOmg / Kg and 3) compound of the disclosure at 25 mg / Kg and dosed daily. Tumor volume was measured three times in a week along with clinical signs of toxicity and body weight. Animals were then euthanized if they reach the humane endpoint of -2000 mm3tumor volume or body weight loss was >15%. Plasma, tumor and eye samples were subsequently collected post-last dose and analyzed for compound concentration.In vivo efficacy in ID8 -luciferase orthotopic mouse model

[0412] In this study, in vivo therapeutic efficacy of Compound 2 was evaluated using the ID8-luc intraperitoneal model in C57BL / 6 mice. Mice were intraperitoneally injected with ID8-luc tumor cells (1 x 10A7 / mouse) to establish ID8-luc ovarian cancer syngeneic model. Day 18 after inoculation, tumor-bearing mice were imaged by IVIS imaging and randomized into groups with 8 mice in each group. The day of grouping is recorded as PG-D(-l), and the treatments were started since the next day of randomization (recorded as PG-D0). Compound 2 was formulated using 10% DMSO + 5% Tween20 +85% PBS and dosed orally twice a day (BID) During the dosing time, mice were examined by fluorescence imaging once a week. The total flux was used to measure tumor load and characterize intraperitoneal tumor growth.In vivo dosing in mice to measure ocular toxicity

[0413] The study enrolled 8 weeks old C57BL / 6 mice that were grouped in 4 groups of 6 mice each (3 males and 3 females). The four groups were 1) Vehicle (10% DMSO, 5% tween 20, PBS 85%) p.o. BID 2) Drug A (NVP AUY922) 25mg / kg IP three times a week (MWF) 3)Attorney Docket No.: 063626-502001WODrug B (17 DMAG) 25mg / kg IP three times a week (MWF) 4) Drug C (Compound 2) 15mg / kg p.o. BID. The dosing volume was 10 ml / kg. Each group was dosed as described for 19 days and then on Day20 Full-Field Electroretinography (ffERG) (photopic and scotopic series) was performed on all groups as follows:

[0414] After overnight dark adaptation (>8 hrs), mice were anesthetized by intraperitoneal injection of zoletil 50 and xylazine under weak red light. Compound tropicamide eye drops (Santen Pharmaceutical Co., Ltd.) were gently dropped onto the eyes to dilate pupils. During the experiments, eyes were kept moist with sterile saline. The dark-adapted ERG responses were stimulated and recorded with Visual electrophysiological examination system (RetiMIER-P, Chongqing Elxi Medical Equipment Co., LTD). Gold wire ring electrodes were placed on the surface of corneas to record ERG responses from both eyes, and needle electrodes were placed in the cheek and tail as reference and ground leads, respectively. In a Ganzfeld dome, eyes were stimulated by LED white light flashes at three different intensities: 0.01 cd s / m2 (scotopic) for evoking rod-dominant responses, followed by 3 cd s / m2 (photopic 1) and 10 cd s / m2 (photopic 2) for evoking mixed rod- and cone-driven responses. ERG responses were band-pass-filtered at 0.1 to 100 Hz, and digitized at 2 kHz. Data recorded were analyzed by a custom-texted program in Matlab. Amplitudes of a-waves were calculated by subtracting the baseline from the peak, whereas amplitudes of b-waves were measured from the baseline (responses without a-waves) or the proceeding troughs (responses with a-waves). Latencies of a-waves and b-waves were calculated by the time from light flashes to a-wave amplitudes emergency and b-wave amplitudes emergency, respectively. And every light flash was repeated 3 times with 1 minute interval on every mouse.Compounds of the present disclosure may exhibit lower compound melting points than compounds of WO2019 / 232223, facilitating dissolution and enabling oral bioavailability

[0415] Morpholino N-linked Hsp90b inhibitors (e.g., Reference Compound 5a) disclosed in WO2019 / 232223 exhibit poor bioavailability to be evaluated in efficacy studies for oral administration.Attorney Docket No.: 063626-502001WOReference Compound 5a

[0416] This lack of bioavailability by oral administration may diminish the development potential of the exemplified compounds as clinical candidates, thereby limiting commercial use. Unexpectedly, certain non-N-linked compounds generically covered by the genus of WO2019 / 232223, exhibit improved properties that impart oral bioavailability, tolerability, and efficacy. Certain compounds of the present disclosure exhibit melting points lower than compounds exemplified in WO2019 / 232223. Lower melting points enable favorable dissolution rates of crystalline compounds, leading to enhanced oral absorption.

[0417] Replacement of N-linked heterocycles exemplified in WO2019 / 232223 with C-linked cyclic structures alone or in combination with replacement of the alkyl R2substituent with fluorinated analogs afford compounds of the present disclosure with unexpectedly reduced melting points (MP) to enable oral administration. By way of example, Compound 2, a representative example herein, exhibits a MP = 212° C corresponding to aa value 83° C below that of the corresponding bioisosteric N-linked Compound 5a (MP = 295° C) of WO2019 / 232223. Compounds 4, 5, 11, 13, 22, 26, 27, 28, 30 and 31 exhibited melting points ranging from 1700C to 2230C, corresponding to values 720C to 1250C lower than the representative Compound 5a of WO2019 / 232223.

[0418] As summarized in Table 17, Figure 1 and Figure 2, (Compound 2 exhibited a ( / max of 1159 ng / mL and an exposure AUC of 5183 ng.h / mL when dosed orally at 10 mg / kg in nude mice. Under the same conditions and at the same dose, Compound 5a from WO2019 / 232223 exhibited a lower Cmax of 342 ng / mL and a lower exposure AUC of 1273 ng.h / mL when dosed orally at 10 mg / kg in CD-I mice (Table B and Figure 2). Thus, Compound 2 of the present disclosure exhibits an AUC 4-fold higher than the closest analog Compound 5a from WO2019 / 232223.Attorney Docket No.: 063626-502001WO

[0419] This improvement in oral bioavailability is not only unexpected compared to WO2019 / 232223, but is unexpected when compared with the publicly known libraries of Hsp90b-selective inhibitors. At the time of the disclosure, there are no known orally bioavailable Hsp90 b-selective compounds in therapeutic development.Table 17. PK Comparison of Compound 2 with Reference Compound 5aThe potent and selective Hsp90b inhibitor Compound 2 does not cause ocular toxicity compared to other nonselective Hsp90 inhibitors

[0420] C57BL / 6J mice were treated with various Hsp90 inhibitors for 19 days. Four groups of six mice (3M, 3F) were treated with Hsp90b selective inhibitor Compound 2, pan Hsp90 inhibitor NVP AUY922, pan Hsp90 inhibitor 17DMAG, or vehicle control. NVP AUY922 and 17DMAG were dosed at 25mg / kg 3 times per week (MWF) by intraperitoneal injection. Compound 2 was dosed at 15mg / kg BID by oral administration.Attorney Docket No.: 063626-502001WO

[0421] Measurement of photosensitivity using electroretinograph (ERG) was conducted on Day 19 to measure the electrical response of retinae after exposure to different luminous intensities. Compound 2 (Drug C) demonstrated no loss of retinal function when compared to vehicle control. However, the pan Hsp90 inhibitors NVP auy922 (Drug A) and 17DMAG (Drug B) demonstrated significant retinal damage as determined by a decrease in retinal function recorded as a-wave and b-wave amplitudes (Figure 3).Efficacy and tolerability after daily oral dosing of improved Hsp90b selective inhibitor Compound 2 in the A2780 ovarian cancer model

[0422] Compound 2 exhibited oral efficacy in an ovarian cancer animal model. Oral dose of 25mg / kg of Compound 2 once daily for 8 days in nude mice inhibited tumor growth inhibition (TGI) of 56% compared to vehicle control (Figure 4A). Compound 2 was well-tolerated, as determined by body weight measurements (Figure 4B).Efficacy and tolerability after daily oral dosing of improved Hsp90b selective inhibitor Compound 2 in the ID8-Luc ovarian cancer model in C56B1 / 6 mice

[0423] Compound 2exhibited single agent efficacy in the orthotopic ID8 -luciferase enabled ID8 ovarian cancer model. C56B1 / 6 mice were dosed with Compound 2administered 15 mg / kg BID by oral administration.

[0424] Compound 2 exhibited significant reduction in tumor burden as measured by bioluminescence (Figure 5A). Compound 2 was well tolerated. There was no change in body weight compared to vehicle control after continuous dosing for 45 days (Figure 5B).

[0425] Discovery of orally bioavailable, efficacious, and well tolerated Hsp90 b-selective inhibitors overcomes the barrier to translate the promise of Hsp90 inhibitors into clinical trials. Unexpected improvement in the melting points over compounds exemplified in WO2019 / 232223 can lead to increased dissolution and improved oral bioavailability, as exemplified by Compound 2 compared to analog Compound 5a exemplified in WO2019 / 232223. Compound 2 has a C-linked heterocyclic ring (tetrahydropyran-4-yl) at substituent A (see generic scope) as opposed to an N-linked morpholinyl ring of Reference Compound 5a of WO2019 / 232223. Compound 5a in WO2019 / 232223 has a higher melting point and poor oral bioavailability compared to Compound 2 of the present disclosure. The improved oral bioavailability of Compound 2 enables oral efficacy in xenograft models ofAttorney Docket No.: 063626-502001WOcancer demonstrating that not only is the drug being absorbed but it is also reaching the intended site of action for anti-tumor activity. Moreover, the high Hsp90b isoform selectivity of Compound 2 was well tolerated (Figure 4B and 5B). Increases in Hsp90b potency and / or selectivity versus the Hsp90a off-target profile of Compound 5a of WO2019 / 232223, together with the pharmaceutical advance enabling efficacy and tolerability by oral administration, provide unexpected properties for developing Hsp90b selective inhibitors.ENUMERATED EMBODIMENTSEnumerated Embodiment 1. A compound of Formula I:or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:A is a Cs-Ce cycloalkyl or 4- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N and O, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R5;B is a bond or O;X is CH orN;R1is C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, or C2-C4 alkynyl;R2is C1-C3 alkyl or C1-C3 haloalkyl;each R3and R4is independently selected from C1-C3 alkyl or R3and R4are taken together with the intervening carbon to form a C3-C6 cycloalkyl;each R5is independently H, oxo, cyano, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, CH2R6, -OR7, -N(R7)2, -C(O)R8, -C(O)OR8, or -C(O)N(R7)2;R6is hydroxy, cyano, C1-C4 alkoxy, C1-C4 haloalkoxy, orN(R7)2;each R7is independently H, C1-C3 alkyl or C1-C3 haloalkyl; andR8is C1-C3 alkyl;Attorney Docket No.: 063626-502001WOprovided (1) when B is a direct bond and A is a monocyclic 6-membered heterocycle N- linked to B, then R2is C1-C3 haloalkyl; and (2) when B is O, A is not linked through a heteroatom.Enumerated Embodiment 2. The compound of Enumerated Embodiment 1, wherein A is 4- to 10-membered heterocycloalkyl;B is a bond or O;R1is C1-C4 alkyl; andR2is C1-C3 alkyl or C1-C3 haloalkyl.Enumerated Embodiment 3. The compound of Enumerated Embodiment 1, wherein the compound is of Formula la:wherein p is an integer from 0 to 4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 4. The compound of Enumerated Embodiment 1, wherein the compound is of Formula la-1:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 5. The compound of Enumerated Embodiment 1, wherein the compound is of Formula la-2:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 6. The compound of Enumerated Embodiment 1, wherein the compound is of Formula la-3:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 7. The compound of Enumerated Embodiment 1, wherein the compound is of Formula lb:wherein p is an integer from 0 to 4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. Enumerated Embodiment 8. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ib-1:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 9. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ib-2:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein n is 1 or 2.Enumerated Embodiment 10. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ib-3:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 11. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ib-4:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 12. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ib-5 :pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 13. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ib-6:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 14. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ib-7:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 15. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ic:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein n is an integer selected from 0, 1, or 2.Enumerated Embodiment 16. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ic-1:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 17. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ic-2:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 18. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ic-3:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 19. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ic-4:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 20. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ic-5:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 21. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ic-6:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 22. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ic-7:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 23. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Id:Attorney Docket No.: 063626-502001WOEnumerated Embodiment 24. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Id-1:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 25. The compound of Enumerated Embodiment 1, wherein the compound is of Formula le:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein n is 0, 1, or 2.Enumerated Embodiment 26. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ie-1:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 27. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ie-2:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 28. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ie-3:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2is C1-C3 haloalkyl. Enumerated Embodiment 29. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ie-4:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 30. The compound of Enumerated Embodiment 1, wherein the compound is of Formula If:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 31. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ig:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 32. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ih:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 33. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ih-1:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 34. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ih-2:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 35. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ih-3:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 36. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ih-4:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 37. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ih-5:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 38. The compound of Enumerated Embodiment 1, wherein the compound is of Formula li:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 39. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ii-1:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 40. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ii-2:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 41. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ii-3 :Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 42. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ij :pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 43. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ij -1 :pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 44. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ij-2:Attorney Docket No.: 063626-502001WOstereoisomer, or tautomer thereof.Enumerated Embodiment 45. The compound of Enumerated Embodiment 1, wherein the compound is of Formula Ij-3:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 46. A compound selected from the group consisting of:Attorney Docket No.: 063626-502001WOAttorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 48. A pharmaceutical composition comprising the compound of any of Enumerated Embodiments 1-47, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.Enumerated Embodiment 49. A compound of Formula II:Attorney Docket No.: 063626-502001WOor a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:A is a C5-C6 cycloalkyl or 4- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N and O, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R5;B is a bond or O;R1is C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, or C2-C4 alkynyl;R2is C1-C3 alkyl or C1-C3 haloalkyl;each R3and R4is independently selected from C1-C3 alkyl or R3and R4are taken together with the intervening carbon to form a C3-C6 cycloalkyl;each R5is independently H, oxo, cyano, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, CH2R6, -OR7, -N(R7)2, -C(O)R8, -C(O)OR8, or -C(O)N(R7)2;R6is hydroxy, cyano, C1-C4 alkoxy, C1-C4 haloalkoxy, orN(R7)2;each R7is independently H, C1-C3 alkyl or C1-C3 haloalkyl; andR8is C1-C3 alkyl.Enumerated Embodiment 50. The compound of Enumerated Embodiment 49, wherein A is 4- to 10-membered heterocycloalkyl;B is a bond or O;R1is C1-C4 alkyl; andR2is C1-C3 alkyl or C1-C3 haloalkyl.Enumerated Embodiment 51. The compound of Enumerated Embodiment 49, wherein the compound is of Formula Ila:Attorney Docket No.: 063626-502001WO(Ila), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 52. The compound of Enumerated Embodiment 49, wherein the compound is of Formula lib :(lib), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 53. The compound of Enumerated Embodiment 49, wherein the compound is of Formula lie:Attorney Docket No.: 063626-502001WO(lie), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Enumerated Embodiment 54. A pharmaceutical composition comprising the compound of any of Enumerated Embodiments 49-53, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.Enumerated Embodiment 55. A method of inhibiting Hsp90 comprising contacting Hsp90 with a therapeutically effective amount of the compound of any of Enumerated Embodiments 1-47 or 49-53.Enumerated Embodiment 56. The method of Enumerated Embodiment 55, wherein the Hsp90 is Hsp90p.Enumerated Embodiment 57. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any of Enumerated Embodiments 1-47 or 49-53, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or the pharmaceutical composition of Enumerated Embodiments 48 or 54.Enumerated Embodiment 58. The method of Enumerated Embodiment 57, wherein the disease or disorder is a: cancer, viral disease, anti-inflammatory disease, angiogenesis-related disease, chemotherapy -induced toxicity, or a protein misfolding or aggregation disease.Attorney Docket No.: 063626-502001WOEnumerated Embodiment 59. The method of Enumerated Embodiment 58, wherein the disease or disorder is a cancer.Enumerated Embodiment 60. The method of Enumerated Embodiment 59, wherein the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.Enumerated Embodiment 61. The method of Enumerated Embodiment 59, wherein the cancer is leukemia.Enumerated Embodiment 62. The method of Enumerated Embodiment 59, wherein the cancer is a cancer of the bladder, blood, bone, brain, breast, cervix, colon / rectum, endometrium, head and neck, kidney, liver, lung, muscle tissue, ovary, pancreas, prostate, skin, spleen, stomach, testicle, thyroid, or uterus.Enumerated Embodiment 63. The method of Enumerated Embodiment 59, wherein the cancer is of the colon, breast, bladder, prostate, or kidney.EQUIVALENTSThe details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.

Claims

1. Attorney Docket No.: 063626-502001WOCLAIMSWhat is claimed is:

1. A compound of Formula I:or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:A is a C5-C6 cycloalkyl or 4- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N and O, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R5;B is a bond or O;X is CH orN;R1is C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, or C2-C4 alkynyl; R2is C1-C3 alkyl or C1-C3 haloalkyl;each R3and R4is independently selected from C1-C3 alkyl or R3and R4are taken together with the intervening carbon to form a C3-C6 cycloalkyl;each R5is independently H, oxo, cyano, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, CH2R6, -OR7, -N(R7)2, -C(O)R8, -C(O)OR8, or -C(O)N(R7)2;R6is hydroxy, cyano, C1-C4 alkoxy, C1-C4 haloalkoxy, orN(R7)2;each R7is independently H, C1-C3 alkyl or C1-C3 haloalkyl; andR8is C1-C3 alkyl;provided (1) when B is a direct bond and A is a monocyclic 6-membered heterocycle N- linked to B, then R2is C1-C3 haloalkyl; and (2) when B is O, A is not linked through a heteroatom.

2. The compound of claim 1, wherein A is 4- to 10-membered heterocycloalkyl;B is a bond or O;R1is C1-C4 alkyl; andR2is C1-C3 alkyl or C1-C3 haloalkyl.Attorney Docket No.: 063626-502001WO3. The compound of claim 1, wherein the compound is of Formula la:wherein p is an integer from 0 to 4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

4. The compound of claim 1, wherein the compound is of Formula la-1 :pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

5. The compound of claim 1, wherein the compound is of Formula la-2:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

6. The compound of claim 1, wherein the compound is of Formula la-3:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

7. The compound of claim 1, wherein the compound is of Formula lb:wherein p is an integer from 0 to 4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

8. The compound of claim 1, wherein the compound is of Formula Ib-1 :pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

9. The compound of claim 1, wherein the compound is of Formula Ib-2:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein n is 1 or 2.

10. The compound of claim 1, wherein the compound is of Formula Ib-3 :pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

11. The compound of claim 1, wherein the compound is of Formula Ib-4:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

12. The compound of claim 1, wherein the compound is of Formula Ib-5 :Attorney Docket No.: 063626-502001WO13. The compound of claim 1, wherein the compound is of Formula Ib-6:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

14. The compound of claim 1, wherein the compound is of Formula Ib-7:

15. The compound of claim 1, wherein the compound is of Formula Ic:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein n is an integer selected from 0, 1, or 2.

16. The compound of claim 1, wherein the compound is of Formula Ic-1 :pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

17. The compound of claim 1, wherein the compound is of Formula Ic-2:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

18. The compound of claim 1, wherein the compound is of Formula Ic-3:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

19. The compound of claim 1, wherein the compound is of Formula Ic-4:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

20. The compound of claim 1, wherein the compound is of Formula Ic-5:stereoisomer, or tautomer thereof.

21. The compound of claim 1, wherein the compound is of Formula Ic-6:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

22. The compound of claim 1, wherein the compound is of Formula Ic-7:stereoisomer, or tautomer thereof.

23. The compound of claim 1, wherein the compound is of Formula Id:

24. The compound of claim 1, wherein the compound is of Formula Id-1 :Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

25. The compound of claim 1, wherein the compound is of Formula le:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein n is 0, 1, or 2.

26. The compound of claim 1, wherein the compound is of Formula Ie-1 :pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

27. The compound of claim 1, wherein the compound is of Formula Ie-2:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

28. The compound of claim 1, wherein the compound is of Formula Ie-3:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2is C1-C3 haloalkyl.

29. The compound of claim 1, wherein the compound is of Formula Ie-4:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

30. The compound of claim 1, wherein the compound is of Formula If:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

31. The compound of claim 1, wherein the compound is of Formula Ig:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

32. The compound of claim 1, wherein the compound is of Formula Ih:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

33. The compound of claim 1, wherein the compound is of Formula Ih- 1 :Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

34. The compound of claim 1, wherein the compound is of Formula Ih-2:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

35. The compound of claim 1, wherein the compound is of Formula Ih-3:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

36. The compound of claim 1, wherein the compound is of Formula Ih-4:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

37. The compound of claim 1, wherein the compound is of Formula Ih-5:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

38. The compound of claim 1, wherein the compound is of Formula li:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

39. The compound of claim 1, wherein the compound is of Formula Ii-1:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

40. The compound of claim 1, wherein the compound is of Formula Ii-2:stereoisomer, or tautomer thereof.

41. The compound of claim 1, wherein the compound is of Formula Ii-3:pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

42. The compound of claim 1, wherein the compound is of Formula Ij :Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

43. The compound of claim 1, wherein the compound is of Formula Ij - 1 :pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

44. The compound of claim 1, wherein the compound is of Formula Ij-2:stereoisomer, or tautomer thereof.

45. The compound of claim 1, wherein the compound is of Formula Ij-3:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

46. A compound selected from the group consisting of:Attorney Docket No.: 063626-502001WOpharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

47. A pharmaceutical composition comprising the compound of any of claims 1-46, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

48. A compound of Formula II:Attorney Docket No.: 063626-502001WOor a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:A is a C5-C6 cycloalkyl or 4- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N and O, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R5;B is a bond or O;R1is C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, or C2-C4 alkynyl; R2is C1-C3 alkyl or C1-C3 haloalkyl;each R3and R4is independently selected from C1-C3 alkyl or R3and R4are taken together with the intervening carbon to form a C3-C6 cycloalkyl;each R5is independently H, oxo, cyano, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, CH2R6, -OR7, -N(R7)2, -C(O)R8, -C(O)OR8, or -C(O)N(R7)2;R6is hydroxy, cyano, C1-C4 alkoxy, C1-C4 haloalkoxy, orN(R7)2;each R7is independently H, C1-C3 alkyl or C1-C3 haloalkyl; andR8is C1-C3 alkyl.

49. The compound of claim 48, wherein A is 4- to 10-membered heterocycloalkyl;B is a bond or O;R1is C1-C4 alkyl; andR2is C1-C3 alkyl or C1-C3 haloalkyl.

50. The compound of claim 48, wherein the compound is of Formula Ila:Attorney Docket No.: 063626-502001WO(Ila), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

51. The compound of claim 48, wherein the compound is of Formula lib :(lib), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

52. The compound of claim 48, wherein the compound is of Formula lie:(lie), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.Attorney Docket No.: 063626-502001WO53. A pharmaceutical composition comprising the compound of any of claims 48-52, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

54. A method of inhibiting Hsp90 comprising contacting Hsp90 with a therapeutically effective amount of the compound of any of claims 1-46 or claims 48-52.

55. The method of claim 54, wherein the Hsp90 is Hsp90p.

56. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any of claims 1-46, or 48-52, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or the pharmaceutical composition of claim 47 or 53.

57. The method of claim 56, wherein the disease or disorder is a: cancer, viral disease, anti-inflammatory disease, angiogenesis-related disease, chemotherapy-induced toxicity, or a protein misfolding or aggregation disease.

58. The method of claim 57, wherein the disease or disorder is a cancer.

59. The method of claim 58, wherein the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

60. The method of claim 58, wherein the cancer is leukemia.

61. The method of claim 58, wherein the cancer is a cancer of the bladder, blood, bone, brain, breast, cervix, colon / rectum, endometrium, head and neck, kidney, liver, lung, muscle tissue, ovary, pancreas, prostate, skin, spleen, stomach, testicle, thyroid, or uterus.

62. The method of claim 58, wherein the cancer is of the colon, breast, bladder, prostate, or kidney.

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