CDK7 inhibitors and methods of use thereof

Abstract

Compounds having activity as anti-cancer agents are provided. The compounds have the following Structure (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer, thereof, wherein x1, x2, R1, R2, R3, R4, L1, and L2 are as defined herein. This disclosure provides methods associated with preparation and use of such compounds pharmaceutical compositions comprising the same, and methods for treating a CDK7-dependent disease (e.g., cancer).

Description

[0001] CDK7 INHIBITORS AND METHODS OF USE THEREOF

[0002] BACKGROUND

[0003] Technical Field

[0004] The present disclosure is directed to novel compounds having activity as inhibitors of CDK7 and methods for their preparation and use as therapeutic or prophylactic agents, for example for treatment of cancer (e.g., solid tumors and hematological cancers).

[0005] Description of the Related Art

[0006] Cancer is a group of diseases involving abnormal cell growth with a potential to spread to various parts of the body. Hundreds of types of cancers affect humans, and millions of people have been diagnosed and millions more are being diagnosed every year. The most common types of cancers include lung cancer, breast cancers, prostate cancers, colorectal cancers, among others. Treatment for cancers includes surgery, radiation therapy, chemotherapy, immunotherapy, hormone therapy, and stem cell replacement. Treatment options can be invasive and have a variety of undesirable side effects.

[0007] Accordingly, while the scientific community has made progress in this field, there remains a need in the art for improved compounds and methods for treatment of cancer. The present disclosure fulfills this need and provides further related advantages.

[0008] BRIEF SUMMARY

[0009] In brief, embodiments of the present disclosure provide compounds, including pharmaceutically acceptable salts, stereoisomers, hydrates, solvates, or isotopic forms thereof. Methods for use of such compounds for treatment of various diseases or conditions, such as cancers are provided.

[0010] One embodiment provides a compound having the following Structure (I): or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotope thereof, wherein X1, X2, R1, R2, R3, R4, L1, and L2are as defined herein. Another embodiment provides pharmaceutical compositions comprising one or more compounds of Structure (I) and a pharmaceutically acceptable carrier or excipient.

[0011] Other embodiments of the present disclosure provide a method for treatment of a disease (e.g., CDK7-dependent disease), the method comprising administering an effective amount of a compound of Structure (I) or pharmaceutical composition comprising a compound of Structure (I) to a subject in need thereof. These and other aspects of the disclosure will be apparent upon reference to the following detailed description.

[0012] DETAILED DESCRIPTION

[0013] In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details.

[0014] Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is, as "including, but not limited to".

[0015] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size, or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the terms "about" and "approximately" mean ± 20%, ± 10%, ± 5% or ± 1% of the indicated range, value, or structure, unless otherwise indicated. The terms "a" and "an" as used herein refer to "one or more" of the enumerated components. The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives.

[0016] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

[0017] Definitions

[0018] "Amino" refers to the -NH2 radical.

[0019] "Carboxy" or "carboxyl" refers to the -CO2H radical.

[0020] "Cyano" refers to the -CN radical.

[0021] "Hydroxy" or "hydroxyl" refers to the -OH radical.

[0022] "Oxo" refers to the =0 substituent.

[0023] "Nitro" refers to the -NO2 radical.

[0024] "Thiol" refers to the -SH substituent.

[0025] "Thioxo" refers to the =S substituent.

[0026] "Alkyl" refers to a saturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C12 alkyl), preferably one to eight carbon atoms (Ci-Cs alkyl) or one to six carbon atoms (Ci-Ce alkyl), and which is attached to the rest of the molecule by a single bond, c.g, methyl, ethyl, / / -propyl,

[0027] 1 -methylethyl ( / o-propyl), / / -butyl, / / -pentyl, 1,1 -dimethylethyl ( / -butyl), 3 -methylhexyl,

[0028] 2-methylhexyl and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted.

[0029] "Alkenyl" refers to an unsaturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds, having from two to twelve carbon atoms (C2-C12 alkenyl), two to eight carbon atoms (C2- Cs alkenyl) or two to six carbon atoms (C2-C6 alkenyl), or any value within these ranges, and which is attached to the rest of the molecule by a single bond, c.g, ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted.

[0030] "Alkoxy" refers to a radical of the formula -ORa where R is an alkyl radical as defined above containing one to twelve carbon atoms (C1-C12 alkoxy), one to eight carbon atoms (Ci-Cs alkoxy) or one to six carbon atoms (Ci-Ce alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted. "Alkylamino" refers to a radical of the formula -NRaRb where Ra is alkyl as defined above and Rb is H or alkyl as defined above. Unless stated otherwise specifically in the specification, an alkylamino group is optionally substituted.

[0031] "Aromatic ring" refers to a cyclic planar portion of a molecule (z.e., a radical) with a ring of resonance bonds that exhibits increased stability relative to other connective arrangements with the same sets of atoms. Generally, aromatic rings contain a set of covalently bound coplanar atoms and comprises a number of 7t-electrons (for example, alternating double and single bonds) that is even but not a multiple of 4 (z.e., 4n + 2 7t-electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, pyrimidonyl. Unless stated otherwise specifically in the specification, an "aromatic ring" includes all radicals that are optionally substituted.

[0032] "Aryl" refers to a carbocyclic ring system (z.e., a ring system wherein each ring atom is carbon) radical comprising 6 to 18 carbon ring atoms and at least one aromatic ring. For purposes of embodiments of this disclosure, the aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, 5-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar" (such as in "aralkyl") is meant to include aryl radicals that are optionally substituted.

[0033] "Arylalkyl" or "aralkyl" refer to a radical of the formula -RbRf where Rb is an alkylene chain as defined above and Rf is an aryl radical as defined above. Unless stated otherwise specifically in the specification, an arylalkyl group is optionally substituted.

[0034] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic carbocyclic radical, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group is optionally substituted. The term "alkyl-cycloalkyl" refers to a radical of the formula -RbRf where Rb is an alkylene chain as defined above and Rf is a cycloalkyl radical as defined above. This term may also be combined with an indication for the number of carbons for each group. For example, a "Ci-Ce alkyl-Cs-Cs cycloalkyl" is a radical group with a alkylene group having from 1-6 carbons and a cycloalkyl group with 3-8 carbons.

[0035] "Fused" refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the disclosure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or the fused heteroaryl ring is replaced with a nitrogen atom.

[0036] "Halo" or "halogen" refers to bromo (Br), chloro (Cl), fluoro (F) or iodo (I).

[0037] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0038] "Heterocyclyl" or "heterocyclic ring" refers to a stable 3- to 18-membered non-aromatic ring radical having one to twelve ring carbon atoms (e.g., two to twelve) and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic ("spiro-heterocyclyl") and / or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical is optionally oxidized; the nitrogen atom is optionally quaternized; and the heterocyclyl radical is partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1, 2,3,4- tetrahydroquinolinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted.

[0039] The term "alkyl-heterocyclyl" refers to a radical of the formula -RbRf where Rb is an alkylene chain as defined above and Rf is a heterocyclyl radical as defined above. This term may also be combined with an indication for the number of carbons for each group. For example, a "Ci-Ce alkyl-3 -8-membered heterocyclyl " is a radical group with an alkylene group having from 1-6 carbons and a heterocyclyl group with 3-8 atoms.

[0040] "Hydroxy alkyl" or "hydroxylalkyl" refers to an alkyl group comprising at least one hydroxyl substituent. The -OH substituent may be on a primary, secondary, or tertiary carbon. Unless stated otherwise specifically in the specification, a hydroxyalkyl group is optionally substituted.

[0041] "Heteroaryl" refers to a 5- to 18-membered, for example 5- to 6-membered, 5- to 7 membered, 5- to 10-membered ring system radical comprising one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. Heteroaryl radicals may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl,

[0042] 1 -phenyl- 177-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (z.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.

[0043] "Haloalkoxy" refers to a radical of the formula -ORa where Ra is a haloalkyl radical as defined herein containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a haloalkoxy group is optionally substituted.

[0044] "Heterocyclylalkyl" refers to a radical of the formula -RbRe where Rb is an alkylene chain as defined above and Reis a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group is optionally substituted.

[0045] "Heteroarylalkyl" refers to a radical of the formula -RbRf where Rb is an alkylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group is optionally substituted.

[0046] The term "substituted" as used herein means any of the above groups wherein at least one hydrogen atom (e.g, 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent. Examples of non-hydrogen substituents include, but are not limited to amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxylalkyl substituents, each of which may also be optionally substituted with one or more of the above substituents.

[0047] In some embodiments, the optional substituents are selected from the group consisting of amino, carboxyl, cyano, halo, hydroxyl, Ci-6 alkyl, Ci-6 alkylamino, Ci-6 haloalkyl, Ci-6 alkylcarbonyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 alkoxycarbonyl, Ce-Cio aryl and Ce-Cio heteroaryl.

[0048] It is understood that each choice for R1, R2, R3, R4, and L2is optionally substituted as described above unless specifically stated otherwise, and provided that all valences are satisfied by the substitution. Specifically, each choice for R1, R2, R3, R4, and L2is optionally substituted unless specifically stated otherwise, and provided such substitution results in a stable molecule (e.g, groups such as H and halo are not optionally substituted).

[0049] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to affect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and / or cell migration. The specific dose will vary depending on the compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. As used herein, "treatment" or "treating" refer to an approach for obtaining beneficial or desired results with respect to a disease, disorder or medical condition including but not limited to a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" means eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0050] A "therapeutic effect," as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0051] The term "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0052] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0053] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2 -hydroxy ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2- oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, -toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0054] "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0055] The terms "antagonist" and "inhibitor" are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as CDK7. Accordingly, the terms "antagonist" and "inhibitors" are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor.

[0056] The term "agonist" as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0057] As used herein, "agent" or "biologically active agent" refers to a biological, pharmaceutical, or chemical compound or another moiety. Non-limiting examples include a simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound. Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures. In addition, various natural sources can provide compounds for screening, such as plant or animal extracts, and the like.

[0058] An "anti-cancer agent", "anti-tumor agent" or "chemotherapeutic agent" refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents comprises chemotherapeutic agents. "Chemotherapy" means the administration of one or more chemotherapeutic drugs and / or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository.

[0059] "Subject" refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

[0060] "Mammal" includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.

[0061] "Radiation therapy" means exposing a subject, using routine methods and compositions known to the practitioner, to radiation emitters such as alpha-particle emitting radionuclides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters (i.e., beta emitters), conversion electron emitters (e.g., strontium-89 and samarium-153-EDTMP, or high-energy radiation, including without limitation x-rays, gamma rays, and neutrons.

[0062] Prodrugs of the disclosed compounds are included in various embodiments. "Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g, compound of Structure (I)). Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some embodiments, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergam on Press, 1987, both of which are incorporated in full by reference herein. The term "prodrug" includes any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.

[0063] The term "in vivo" refers to an event that takes place in a subject's body.

[0064] Embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of Structure (I) being isotopically labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number (z.e., an "isotopic form" of a compound of Structure (I)). Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,nC,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. These radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action. Certain isotopically labeled compounds of Structure (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (z.e.,3H) and carbon- 14 (z.e.,14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence are preferred in some circumstances.

[0065] Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of Structure (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically labeled reagent in place of the nonlabeled reagent previously employed.

[0066] Certain embodiments are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the embodiments include compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood, or other biological samples.

[0067] "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 reaction mixture, and formulation into an efficacious therapeutic agent.

[0068] Often crystallizations produce a solvate of the compound of the disclosure. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the disclosure with one or more molecules of solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of Structure (I) may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. In some embodiments, the compound of the disclosure is a true solvate, while in other cases, the compound of the disclosure merely retains adventitious water or is a mixture of water plus some adventitious solvent.

[0069] "Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0070] A "pharmaceutical composition" refers to a formulation of a compound of the disclosure and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0071] "Pharmaceutically acceptable carrier, diluent or excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0072] The compounds of the disclosure (z.e., compounds of Structure (I) and embodiments thereof), or their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also included.

[0073] The present disclosure includes all manner of rotamers and conformationally restricted states of a compound of the disclosure.

[0074] A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. Unless otherwise indicated, stereoisomers include racemers, enantiomers and diastereomers. A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. Embodiments thus include tautomers of the disclosed compounds.

[0075] The chemical naming protocol and structure diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, using the ACD / Name Version 9.07 software program and / or ChemDraw Ultra Version 11.0.1 software naming program (CambridgeSoft). For complex chemical names employed herein, a substituent group is typically named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.

[0076] Compounds

[0077] As detailed above, the present disclosure provides compounds showing significant activity as CDK7 inhibitors. Accordingly, one embodiment provides a compound having the following Structure (I): or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof, wherein:

[0078] / '' represents an aromatic ring such that all valences are satisfied;

[0079] X1is C and X2is N; or X1is N and X2is C;

[0080] R1is Ci-Ce alkyl, Ci-Ce haloalkyl, cyano, or Cs-Cs cycloalkyl;

[0081] R2is Cs-Cs cycloalkyl, 3-8-membered heterocyclyl, optionally substituted Ci-Ce alkyl-

[0082] C3-C8 cycloalkyl, or optionally substituted Ci-Ce alkyl-3 -8-membered heterocyclyl;

[0083] R3is halo;

[0084] R4is C3-C8 cycloalkyl, Ce-Cio aryl, 3-8-membered heterocyclyl, or 5-10-membered heteroaryl;

[0085] R5is H or Ci-Ce alkyl;

[0086] L1is -O-, -S-, or -NR5-; and

[0087] L2is a direct bond or Ci-4 alkylene, wherein each alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted.

[0088] Some embodiments provide a compound having the following Structure (la): or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof, wherein:

[0089] R1is Ci-Ce alkyl, Ci-Ce haloalkyl, cyano, or C3-C8 cycloalkyl;

[0090] R2is C3-C8 cycloalkyl, 3-8-membered heterocyclyl, optionally substituted Ci-Ce alkyl- C3-C8 cycloalkyl, or optionally substituted Ci-Ce alkyl-3 -8-membered heterocyclyl;

[0091] R3is halo;

[0092] R4is C3-C8 cycloalkyl, Ce-Cio aryl, 3-8-membered heterocyclyl, or 5-10-membered heteroaryl;

[0093] R5is H or Ci-Ce alkyl;

[0094] L1is -O-, -S-, or -NR5-; and

[0095] L2is a direct bond or Ci-4 alkylene, wherein each alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted.

[0096] Other embodiments provide a compound having the following Structure (lb): or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof, wherein:

[0097] R1is Ci-Ce alkyl, Ci-Ce haloalkyl, cyano, or C3-C8 cycloalkyl;

[0098] R2is C3-C8 cycloalkyl, 3-8-membered heterocyclyl, optionally substituted Ci-Ce alkyl- C3-C8 cycloalkyl, or optionally substituted Ci-Ce alkyl-3 -8-membered heterocyclyl;

[0099] R3is halo; R4is C3-C8 cycloalkyl, Ce-Cio aryl, 3-8-membered heterocyclyl, or 5-10-membered heteroaryl;

[0100] R5is H or Ci-Ce alkyl;

[0101] L1is -O-, -S-, or -NR5-; and

[0102] L2is a direct bond or Ci-4 alkylene, wherein each alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted.

[0103] Another embodiment provides a compound having Structure (la-1):

[0104] (la-1) or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof, wherein:

[0105] R1is Ci-Ce alkyl, Ci-Ce haloalkyl, cyano, or C3-C8 cycloalkyl;

[0106] R2is C3-C8 cycloalkyl, 3-8-membered heterocyclyl, optionally substituted Ci-Ce alkyl- C3-C8 cycloalkyl, or optionally substituted Ci-Ce alkyl-3 -8-membered heterocyclyl;

[0107] R3is halo;

[0108] R4is C3-C8 cycloalkyl, Ce-Cio aryl, 3-8-membered heterocyclyl, or 5-10-membered heteroaryl;

[0109] R5is H or Ci-Ce alkyl;

[0110] L1is -O-, -S-, or -NR5-; and wherein each alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted.

[0111] Another embodiment provides a compound having Structure (Ib-1):

[0112] (Ib-1) or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof, wherein:

[0113] R1is Ci-Ce alkyl, Ci-Ce haloalkyl, cyano, or C3-C8 cycloalkyl; R2is C3-C8 cycloalkyl, 3-8-membered heterocyclyl, optionally substituted Ci-Ce alkyl- C3-C8 cycloalkyl, or optionally substituted Ci-Ce alkyl-3 -8-membered heterocyclyl;

[0114] R3is halo;

[0115] R4is C3-C8 cycloalkyl, Ce-Cio aryl, 3-8-membered heterocyclyl, or 5-10-membered heteroaryl;

[0116] R5is H or Ci-Ce alkyl;

[0117] L1is -O-, -S-, or -NR5-; and wherein each alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted.

[0118] Another embodiment provides a compound having Structure (la-2):

[0119] (la-2) or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof, wherein:

[0120] R1is Ci-Ce alkyl, Ci-Ce haloalkyl, cyano, or C3-C8 cycloalkyl;

[0121] R2is C3-C8 cycloalkyl, 3-8-membered heterocyclyl, optionally substituted Ci-Ce alkyl- C3-C8 cycloalkyl, or optionally substituted Ci-Ce alkyl-3 -8-membered heterocyclyl;

[0122] R3is halo;

[0123] R4is C3-C8 cycloalkyl, Ce-Cio aryl, 3-8-membered heterocyclyl, or 5-10-membered heteroaryl;

[0124] R5is H or Ci-Ce alkyl;

[0125] L1is -O-, -S-, or -NR5-; and wherein each alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted.

[0126] Another embodiment provides a compound having Structure (Ib-2):

[0127] (Ib-1) or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof, wherein:

[0128] R1is Ci-Ce alkyl, Ci-Ce haloalkyl, cyano, or C3-C8 cycloalkyl;

[0129] R2is C3-C8 cycloalkyl, 3-8-membered heterocyclyl, optionally substituted Ci-Ce alkyl- C3-C8 cycloalkyl, or optionally substituted Ci-Ce alkyl-3 -8-membered heterocyclyl;

[0130] R3is halo;

[0131] R4is C3-C8 cycloalkyl, Ce-Cio aryl, 3-8-membered heterocyclyl, or 5-10-membered heteroaryl;

[0132] R5is H or Ci-Ce alkyl;

[0133] L1is -O-, -S-, or -NR5-; and wherein each alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted.

[0134] In some embodiments, compounds of Structure (I), (la), or (lb) are provided wherein L2is C2-4 alkylene. In specific embodiments, L2is ethylene. In yet other embodiments, L2is propylene. In some embodiments, L2is butylene.

[0135] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R1is Ci-Ce alkyl, Ci-Ce haloalkyl, or cyano. In one embodiment, R1is C1-3 alkyl, C1-C3 haloalkyl, or cyano. In yet other embodiments, R1is methyl, ethyl, propyl, isopropyl, CF3, or cyano.

[0136] In other embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R1is C3-C8 cycloalkyl. In one embodiment, R1is C3-6 cycloalkyl. In yet other embodiments, R1is cyclopropyl, cyclobutyl, or cyclopentyl.

[0137] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R2is C3-C8 cycloalkyl. In one embodiment, R2is C3-6 cycloalkyl. In yet other embodiments, R2is cyclopentyl or cyclohexyl.

[0138] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R2is 3-6-membered heterocyclyl. In one embodiment, R2is piperidinyl or tetrahydropyranyl.

[0139] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R2is substituted with one or more substituents.

[0140] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R2has the following structure: wherein:

[0141] R2aand R2bare each independently hydrogen or C1-C4 alkyl; and

[0142] R2Cis hydrogen, C1-C4 alkyl, -OH, or halo.

[0143] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R2has one of the following structures:

[0144] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R3is F, Cl, Br, or I. In one embodiment, R3is F or Cl. In a specific embodiment, R3is F. In a specific embodiment, R3is Cl. In a specific embodiment, R3is Br. In a specific embodiment, R3is I.

[0145] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R4is C3-C8 cycloalkyl. In one embodiment, R4is C3-6 cycloalkyl. In yet other embodiments, R4is cyclopropyl, cyclobutyl, or cyclopentyl.

[0146] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R4is Ce-Cio aryl. In one embodiment, R4is phenyl.

[0147] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R4is 3-8-membered heterocyclyl.

[0148] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R4is 5-10-membered heteroaryl. In certain embodiments, R4is indazolyl, benzoisothiazolyl or benzoisoxazolyl.

[0149] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R4is substituted with one or more substituents. In one embodiment, the one or more substituents are selected from the group consisting of halo, haloalkyl, alkoxy, haloalkoxy, aminyl, heteroaryl, and -NH-C(=O)-phenyl. In some embodiments, the phenyl of the -NH-C(=O)-phenyl substituent is optionally substituted with fluoro or -P(=O)(-CH3)2.

[0150] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R4is substituted with one or more substituents selected from the group consisting of halo, haloalkyl, alkoxy, haloalkoxy, aminyl, heteroaryl, -NH-C(=O)-phenyl, -NH- C(=O)-heteroaryl, -NH-C(=O)-heterocyclyl, -NH-S(0)2-phenyl, -NH-C(=O)-NH-phenyl, and - C(=O)-NH-phenyl .

[0151] In some embodiments, the phenyl of the -NH-C(=O)-phenyl substituent is optionally substituted with alkyl, chloro, fluoro, -P(=O)(-CH3)2, -NH-C(=O)-alkyl (e.g., methyl, ethyl, n- propyl, isopropyl), -NH-S(O)2-CH3, -NH-S(O)2-CH2CH3, -S(O)2-NH-CH3, -S(O)2-NH-CH2CH3, cyano, and -C(=0)-NH2.

[0152] In certain embodiments, the heteroaryl of the -NH-C(=O)-heteroaryl substituent is optionally substituted with alkyl (e.g., methyl, ethyl, n-propyl, isopropyl).

[0153] In some embodiments, the phenyl of the -C(=O)-NH-phenyl substituent is optionally substituted with halo.

[0154] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R4has one of the following structures:

[0155] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib- 2) are provided wherein R4has one of the following structures:

[0156] In some embodiments, compounds of Structure (I), (la), (lb), (la-1), (Ib-1), (la-2) or (Ib-

[0157] 2) are provided wherein L1is -O-. In other embodiments, L1is -S-. In yet other embodiments, L1is -NR5-. In specific embodiments, R5is H. In additional embodiments, R5is Ci-Ce alkyl. In further embodiments, R5is methyl.

[0158] In another embodiment, a compound is selected from any one of the compounds listed in Table 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof. In specific embodiments, compounds of Table 1 are provided wherein the compound is an HC1, TFA, or HCO2H salt form. Representative compounds of Structure (I), (la), (lb), (la- 1), (lb- 1), (la-2) or (Ib-2) applicable, include any one of the compounds listed in Table 1 below, as well as a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof. To this end, representative compounds are identified herein by their respective "Compound Number," which is sometimes abbreviated as "Compound No." or "Cpd. No." or "No."

[0159] Table 1. Representative Compounds t Also obtained as an HC1 salt

[0160] 1Also obtained as a formic acid salt

[0161] Aalso obtained as a trifluoroacetic acid salt

[0162] Pharmaceutical Compositions Other embodiments are directed to pharmaceutical compositions. The pharmaceutical composition comprises anyone (or more) of the foregoing compounds of Structure (I)) and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still more embodiments, the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent. Non-limiting examples of such therapeutic agents are described herein below.

[0163] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. In certain embodiments, a compound of Structure (I) is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound of Structure (I) is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound of Structure (I) is administered topically.

[0164] The compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that are used in some embodiments. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0165] In some embodiments, a compound of the disclosure is administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, to introduce the agent quickly. However, other routes are used as appropriate. A single dose of a compound of the disclosure may also be used for treatment of an acute condition.

[0166] In some embodiments, a compound of the disclosure is administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the disclosure and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the disclosure and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0167] Administration of the compounds of the disclosure may continue as long as necessary. In some embodiments, a compound of the disclosure is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the disclosure is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the disclosure is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[0168] In some embodiments, the compounds of the disclosure are administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the disclosure may be found by routine experimentation considering the instant disclosure.

[0169] In some embodiments, the compounds of Structure (I) are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0170] Provided herein are pharmaceutical compositions comprising a compound of Structure (I) and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which compounds of Structure (I) are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more compounds of Structure (I).

[0171] A pharmaceutical composition, as used herein, refers to a mixture of a compound of Structure (I) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds of Structure (I) provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or medical condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds of Structure (I) are used singly or in combination with one or more therapeutic agents as components of mixtures.

[0172] In one embodiment, one or more compounds of Structure (I) is formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compound of Structure (I) is / are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the compounds of Structure (I) are formulated for other parenteral injections, appropriate formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0173] In another embodiment, compounds of Structure (I) are formulated for oral administration. Compounds of Structure (I) are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compounds of Structure (I) are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0174] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds of Structure (I), optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0175] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, arabic gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and / or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and / or pigments are optionally utilized to characterize different combinations of active compound doses.

[0176] In certain embodiments, therapeutically effective amounts of at least one of the compounds of Structure (I) are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0177] In other embodiments, therapeutically effective amounts of at least one of the compounds of Structure (I) are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the compounds of Structure (I) are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and / or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, suspensions of the active compounds (e.g., compounds of Structure (I)) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions of Structure (I) include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0178] In still other embodiments, the compounds of Structure (I) are administered topically. The compounds of Structure (I) are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0179] In yet other embodiments, the compounds of Structure (I) are formulated for transdermal administration. In specific embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and / or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the compounds of Structure (I) is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the compounds of Structure (I). In specific embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period and means to secure the device to the skin.

[0180] In other embodiments, the compounds of Structure (I) are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. Pharmaceutical compositions of any of compound of Structure (I) are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules, and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator is formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0181] In still other embodiments, the compounds of Structure (I) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

[0182] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable. Pharmaceutical compositions comprising a compound of Structure (I) are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0183] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one compound of Structure (I), as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods of administering and pharmaceutical compositions of Structure (I) include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds of Structure (I) are included within the scope of the compounds presented herein. Additionally, the compounds of Structure (I) encompass un-solvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and / or other therapeutically valuable substances. Accordingly, one embodiment provides a pharmaceutically acceptable salt of any one of the compounds of Structure (I) described herein. In more specific embodiments, the pharmaceutically acceptable salt is an acid addition salt (e.g., a trifluoroacetic acid salt or a hydrochloric acid salt).

[0184] Methods for the preparation of compositions comprising the compounds of Structure (I) include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The form of the pharmaceutical compositions of Structure (I) includes liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

[0185] In some embodiments, pharmaceutical composition comprising at least one compound of Structure (I) illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically, when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[0186] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran.

[0187] Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound of Structure (I). The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0188] Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[0189] Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0190] Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0191] Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.

[0192] Still other useful compositions include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0193] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0194] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds of Structure (I) are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

[0195] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and / or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0196] In some embodiments, the concentration of the compound of Structure (I) provided in the pharmaceutical compositions is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v or v / v.

[0197] In some embodiments, the concentration of the compound of Structure (I) provided in the pharmaceutical compositions is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%,

[0198] 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%,

[0199] 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%,

[0200] 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%,

[0201] 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v. In some embodiments, the concentration of the compound of Structure (I) provided in the pharmaceutical compositions is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w / w, w / v or v / v.

[0202] In some embodiments, the concentration of the compound of Structure (I) provided in the pharmaceutical compositions is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w / w, w / v or v / v.

[0203] In some embodiments, the amount the compound of Structure (I) provided in the pharmaceutical compositions is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

[0204] In some embodiments, the amount of the compound of Structure (I) provided in the pharmaceutical compositions is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g-

[0205] In some embodiments, the amount of the compound of Structure (I) provided in the pharmaceutical compositions is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0206] Kits / Articles of Manufacture

[0207] For use in the therapeutic applications described herein, kits and articles of manufacture are also provided. In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.

[0208] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes one or more compounds of Structure (I), optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0209] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound of Structure (I). Nonlimiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack for example contains metal or plastic foil, such as a blister pack. Or the pack or dispenser device is accompanied by instructions for administration. Or the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0210] Methods of Treatment and Administration

[0211] Embodiments of the present disclosure provide a method for treating CDK7-dependent diseases (e.g., cancer). One embodiment provides a method for treating a CDK7-dependent disease, the method comprising administering an effective amount of a compound of Structure (I) (or pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound of Structure (I) as disclosed in any one of the embodiments herein to a subject in need thereof. Another embodiment provides a method of modulating CDK7 comprising contacting a cell with an effective amount of the compound of Structure (I) or the pharmaceutical composition of the compound of Structure (I) and any of its embodiments.

[0212] In some more specific embodiments, the CDK7-dependent disease is cancer. For example, in some embodiments, the cancer is a breast cancer. In some embodiments, the cancer is triple negative breast cancer (TNBC). In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a sarcoma.

[0213] In some embodiments, the method of administering relates to the treatment of cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers (e.g., Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity, and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Viral-Induced cancer. In some embodiments, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)). In some more specific embodiments, the cancer is neuroblastoma, medulloblastoma, Ewing sarcoma, chordoma or combinations thereof. In some embodiments, the cancer is neuroblastoma. In some other embodiments, the cancer is medulloblastoma. In still other embodiments, the cancer is Ewing sarcoma. In certain embodiments, the cancer is chordoma.

[0214] In some embodiments, the cancer is a gastric cancer. In some embodiments, the cancer is ovarian. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is DIPG. In some embodiments, the cancer is pancreatic. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is AML. In some embodiments, the cancer comprises solid tumors. In some specific embodiments, the cancer is brain cancer. In some embodiments, the cancer comprises a cancer addicted to oncogenic super-enhancers that drive expression of oncogenes such as MYC.

[0215] Further therapeutic agents that can be combined with a compound of the disclosure are found in Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Thirteenth Edition edited by Brunton, Hilal-Dandan and Knollmann or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety.

[0216] The compounds of Structure (I) can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments the one or more compounds of Structure (I) will be co-administered with other agents as described above. When used in combination therapy, the compounds of Structure (I) are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound of Structure (I) and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of Structure (I) and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of Structure (I) can be administered just followed by and any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, a compound of Structure (I) and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.

[0217] The compounds of Structure (I) include novel compounds as inhibitors of cyclin- dependent kinase (CDK7). CDK7 is a unique kinase that can regulate both cell-cycle progression and RNA polymerase-dependent transcription and is member of CDK family kinases including CDK1, 2, 4, 5, 6, 8, and 9 which regulates the cell cycle function and phosphorylation.

[0218] The present disclosure also provides methods for single or combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of Structure (I), or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof. In one aspect, such therapy includes but is not limited to the combination of one or more compounds of Structure (I) with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.

[0219] In various embodiments of the method, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, phosphatidylinositol kinase (PI3K) inhibitor, insulinlike growth factor receptor (IGF1R) inhibitor, Janus kinase (JAK) inhibitor, a Met kinase inhibitor, a SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular-signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitors (such as irinotecan, etoposide, or doxorubicin), taxanes (such as anti -microtubule agents including paclitaxel and docetaxel), anti-metabolite agents (such as 5-FU or such as gemcitabine), alkylating agents (such as cisplatin or such as cyclophosphamide), or a taxane.

[0220] In other embodiments, the additional therapeutic agent is a checkpoint inhibitor.

[0221] A "checkpoint inhibitor" is an agent which acts on surface proteins which are members of either the TNF receptor or B7 superfamilies, including agents which bind to negative costimulatory molecules selected from CTLA-4, PD-1, TIM-3, BTLA, VISTA, LAG-3, and / or their respective ligands, including PD-L1.

[0222] In some embodiments, the additional therapeutic agent is selected from chemotherapeutic drugs, radiation therapy, HD AC inhibitors, PARP inhibitors, or checkpoint inhibitors.

[0223] In some specific embodiments, the additional therapeutic agent is gemcitabine, cisplatin, 5-fluorouracil, nutlin, panobinostat, olaparib, or combinations thereof. In some more specific embodiments, the additional therapeutic agent is Gemcitabine. In some embodiments, the additional therapeutic agent is cisplatin. In some embodiments, the additional therapeutic agent is 5-fluorouracil. In some embodiments, the additional therapeutic agent is nutlin. In some embodiments, the additional therapeutic agent is abraxane. In some embodiments, the additional therapeutic agent is panobinostat. In some embodiments, the additional therapeutic agent is olaparib. In some embodiments, the additional therapeutic agent is radiation. In some embodiments, the additional therapeutic agent is selected from the group consisting of gemcitabine, cisplatin, 5-fluorouracil, nutlin, panobinostat, olaparib, checkpoint inhibitors and combinations thereof.

[0224] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, such as Erlotinib or such as Afatinib. In some embodiments, the additional therapeutic agent is Iressa. In some embodiments, the additional therapeutic agent is a monoclonal antibody such as cetuximab (Erbitux) or panitumumab (Vectibix). In some embodiments the GFR inhibitor is a dual or pan-HER inhibitor. In other embodiments, the additional therapeutic agent is a phosphatidylinositol-3kinase (PI3K) inhibitor, such as GDC0941, MLN1117, BYL719 (Alpelisib) or BKM120 (Buparlisib). GDC0941 refers to 2-(lH- indazol-4-yl)-6-(4-methanesulfonyl-piperazin-l- ylmethyl)-4-morpholin-4-yl-thieno[3,2- d]pyrimidine or a salt thereof (e.g., / v.s-mesylate salt).

[0225] In still different embodiments, the additional therapeutic agent is an insulin-like growth factor receptor (IGF1R) inhibitor. For example, in some embodiments the insulin-like growth factor receptor (IGF1R) inhibitor is NVP-AEW541. In other embodiments, the additional therapeutic agent is IGOSI-906 (Linsitinib), BMS-754807, or in other embodiments the additional therapeutic agent is a neutralizing monoclonal antibody specific to IGF1R such as AMG-479 (ganitumab), CP-751,871 (figitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab), and R-1507 (robatumumab).

[0226] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor. In some embodiments, the additional therapueitc agent is CYT387, GLPG0634, Baricitinib, Lestaurtinib, momelotinib, Pacritinib, Ruxolitinib or TG101348.

[0227] In some other embodiments, the additional therapeutic agent is an MET kinase inhibitor, such as Crizotinib, tivantinib, AMG337, cabozantinib, foretinib. In other embodiments, the additional therapeutic agent is a neutralizing monoclonal antibody to MET such as onartuzumab.

[0228] In more embodiments, the additional therapeutic agent is a SRC family non-receptor tyrosine kinase inhibitor. For example, in some embodiments, the additional therapeutic agent is an inhibitor of the subfamily of SRC family non-receptor tyrosine kinases. Exemplary inhibitors in this respect include Dasatinib. Other examples in this regard include Ponatinib, saracatinib, and bosutinib.

[0229] In yet different embodiments, the additional therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is trametinib, selumetinib, cobimetinib, PD0325901, or RO5126766. In other embodiments, the MEK inhibitor is GSK-1120212, also known as trametinib.

[0230] In yet different embodiments, the additional therapeutic agent is an extracellular-signal- regulated kinase (ERK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is SCH722984 or GDC-0994.

[0231] The exact method for administering the compound of Structure (I) and the additional therapeutic agent will be apparent to one of ordinary skill in the art. In some exemplary embodiments, the compound of Structure (I) and the additional therapeutic agent are coadministered. In other embodiments, the compound of Structure (I) and the additional therapeutic agent are separately administered.

[0232] In some embodiments, the compound of Structure (I) and the additional therapeutic agent are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound of Structure (I) and any of the additional therapeutic agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of Structure (I) and any of the additional therapeutic agents described herein can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, the compound of Structure (I) can be administered just followed by and any of the additional therapeutic agents described herein, or vice versa. In some embodiments of the separate administration protocol, the compound of Structure (I) and any of the additional therapeutic agents described herein are administered a few minutes apart, or a few hours apart, or a few days apart.

[0233] In other embodiments, the additional therapeutic agent is a protein kinase inhibitor, such as Staurosporine or Midostaurin. In other embodiments, the protein kinase inhibitor is Afatinib, Axitinib, Bevacizumab, Bostutinib, Cetuximab, Crizotinib, Dasatinib, Erlotinib, Fostamatinib, Gefitinib, Imatinib, Lapatinib, Lenvatinib, Ibrutinib, Nilotinib, Panitumumab, Pazopanib, Pegaptanib, Ranibizumab, Ruxolitinib, Sorafenib, Sunitinib, SU6656, Trastuzumab, Tofacitinib, Vandetanib, or Vemurafenib.

[0234] In still more embodiments, the additional therapeutic agent is a topoisomerase inhibitor. In some of these embodiments, the topoisomerase inhibitor is Irinotecan. In some more embodiments, the additional therapeutic agent is a taxane. Exemplary taxanes include Taxol and Docetaxel. In addition to the above additional therapeutic agent, other chemotherapeutics are presently known in the art and can be used in combination with the compounds of Structure (I). In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.

[0235] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (Imatinib Mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and Adriamycin as well as a host of chemotherapeutic agents.

[0236] Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, CasodexTM, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5- oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6- azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK.RTM.; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g., paclitaxel (TAXOLTM, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERETM, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0237] Also included as suitable chemotherapeutic cell conditioners are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, (NolvadexTM), raloxifene, aromatase inhibiting 4(5)-imidazoles, 4- hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Where desired, the compounds or pharmaceutical composition of Structure (I) can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-Allylamino-17- demethoxygeldanamycin, Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy), Calyculin, cell-cycle nonspecific antineoplastic agents, Di chloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarb azole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Naf oxi dine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V, Swainsonine, Talaporfin, Tariquidar, Tegafur- uracil, Temodar, Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar. This disclosure further relates to a method for using the compounds of Structure (I) or pharmaceutical compositions provided herein, in combination with radiation therapy for inhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of Structure (I) in this combination therapy can be determined as described herein.

[0238] Radiation therapy can be administered through one of several methods, or a combination of methods, including without limitation external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachytherapy. The term "brachytherapy," as used herein, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term includes exposure to radioactive isotopes (e.g., At-211, 1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present disclosure include both solids and liquids. The radiation source can be a radionuclide, such as 1-125, 1-131, Yb-169, Ir-192 as a solid source, 1-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of 1-125 or 1-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive micro spheres.

[0239] Without being limited by any theory, the compounds of Structure (I) can render abnormal cells more sensitive to treatment with radiation for purposes of killing and / or inhibiting the growth of such cells. Accordingly, this disclosure further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of Structure (I) or a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof, which amount is effective is sensitizing abnormal cells to treatment with radiation. The amount of the compound of Structure (I) in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.

[0240] In some embodiments, the compounds described herein are formulated or administered in conjunction with liquid or solid tissue barriers also known as lubricants. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, seprafilm, interceed, and hyaluronic acid.

[0241] The examples and preparations provided below further illustrate and exemplify the compounds of Structure (I) and methods of preparing such compounds. It is understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. In the following examples, and throughout the specification and claims, molecules with a single stereocenter, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more stereocenters, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers / diastereomers are obtained by methods known to those skilled in the art.

[0242] Methods of Preparation

[0243] Compounds of Structure (I) can be prepared according to methods known in the art and according to methods disclosed herein. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)).

[0244] EXAMPLES

[0245] The following examples are provided for exemplary purposes. Other compounds of Structure (I) exemplified in Tables 1 were prepared according to analogous procedures, routine in the art.

[0246] EXAMPLE 1

[0247] CHARACTERIZATION OF REPRESENTATIVE COMPOUNDS

[0248] Representative compounds of Structure (I) were prepared by procedures like the ones described the Synthetic Examples with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions. The characterization data of the compounds are also summarized herein in Table 2.

[0249] Table 2. Characterization of representative compounds SYNTHETIC EXAMPLE 1

[0250] SYNTHESIS OF 4-FLUORO-N-(3-((6-FLUORO-3-ISOPROPYL-5-(PIPERIDIN-4-YLTHIO)PYRAZOLO[1,5-

[0251] A]PYRIMIDIN-7-YL)AMINO)PHENYL)BENZAMIDE

[0252] Step-1 : Synthesis of tert-butyl 4-((7-((tert-butoxycarbonyl)(3-(4- fluorobenzamido)phenyl)amino)-6-fluoro-3-isopropylpyrazolo[l,5-a]pyrimi din-5- yl)thio)piperidine- 1 -carboxylate

[0253] To a stirred solution of / ?-fluorobenzoic acid (50.4 mg, 1.2 eq., 0.360 mmol) in dimethylformamide (5 mL) was added 7V-ethylbis(isopropyl)amine (116 mg, 3 eq., 0.899 mmol) followed by l,l,3,3-tetramethyl-2-(3H-l,2,3,4-tetraazainden-3-yl)-3-isoureaium hexafluoridophosphate (141 mg, 2 eq., 0.599 mmol). The mixture was stirred for 5 min then added tert-butyl 4-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-6-fluoro-3- isopropylpyrazolo[l,5-a]pyrimidin-5-yl)thio)piperidine-l-carboxylate (180 mg,l eq, 0.3 mmol). The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, it was quenched with ice-cold water (1.5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine solution (3 x 5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography using 30-35% Ethyl acetate in Hexane to get tert-butyl 4-((7-((tert-butoxycarbonyl)(3-(4-fluorobenzamido)phenyl)amino)-6-fluoro-3- isopropylpyrazolo[l,5-a]pyrimidin-5-yl)thio)piperidine-l-carboxylate (120 mg, 55.41% yield) as an off-white salt reaction.

[0254] 'HNMR (400 MHz, DMSO-de): 5 = 10.33 (s, 1H), 8.08 (s, 1H), 8.02-7.98 (m,2H), 7.78 (d, J= 6.8 Hz, 2H), 7.38 - 7.33 (m, 3H), 7.09 (d, J= 8.0 Hz, 1H), 4.13-4.08 (m, 1H), 3.84 (d, J =13.2 Hz ,2H), 3.18 (t, J =6.8 Hz ,1H),3.O9 (s, 2H), 2.11 (d, J= 10.4 Hz, 2H), 1.65 (d, J= 9.6 Hz, 2H),1.40 (s, 9H), 1.37-1.23 (m,14H), 0.86 (t, J=7 Hz ,1H). LCMS: 723.4 (M+H)+.

[0255] Step 2: Synthesis of 4-fluoro-N-(3-((6-fluoro-3-isopropyl-5-(piperidin-4- ylthio)pyrazolo[l,5-a]pyrimidin-7-yl)amino)phenyl)benzamide

[0256] To a stirred solution of tert-butyl 4-(7-{(tert-butyl)[m-(p- fluorobenzylamino)phenyl](oxycarbonylamino)}-6-fluoro-3-isopropyl-l,4,7a-triaza-5- indenylthio)-l -piperidinecarboxylate (0.1 g, 0.138 mmol) in DCM (5 mL) was added trifluoroacetic acid (52.9 pL, 5 eq., 0.692 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, solvent was removed under reduced pressure and triturated with / / -pentane-di ethyl ether (1:1, 3 x 5 mL) then dried under vacuum to afford white solid of 4-fluoro-N-(3-((6-fluoro-3-isopropyl-5-(piperidin-4-ylthio)pyrazolo[l,5- a]pyrimidin-7-yl)amino)phenyl)benzamide-TFA salt (35 mg, 33.7% yield).

[0257] 'HNMR (400 MHz, DMSO-de): 5 = 10.32 (s, 1H), 9.95 (s, 1H), 8.50 (s, 2H), 8.04-8.00 (m, 3H), 7.72 (s, 1H), 7.54 (d, J= 8.4 Hz, 1H), 7.39-7.29 (m, 3H), 6.99 (d, J= 8 Hz, 1H), 4.15- 4.12 (m, 1H) , 3.21 - 3.10 (m, 3H), 2.32-2.28 (m, 2H), 1.88 - 1.80(m, 2H), 1.36 (d, J= 6.8 Hz, 6H).

[0258] LCMS: 523.2 (M+H)+.

[0259] SYNTHETIC EXAMPLE 2

[0260] SYNTHESIS OF N-{M-[6-FLUORO-3-ISOPROPYL-5-(4-PIPERIDYLTHIO)-1, 4, 7A-TRIAZA-7- INDENYLAMINO]PHENYL}P-(DIMETHYLPHOSPHORYL)BENZAMIDE TRIFLUORO ACETIC ACID SALT

[0261] Step 1 : Synthesis of tert-butyl 4-((7-((tert-butoxycarbonyl)(3-(4- iodobenzamido)phenyl)amino)-6-fluoro-3-isopropylpyrazolo[l,5-a]pyrimidin-5- yl)thio)piperidine- 1 -carboxylate

[0262] To a stirred solution of / ?-iodobenzoic acid (238 mg, 1.2 eq., 0.959 mmol) in dimethylformamide (12 mL) was added N-ethylbis(isopropyl)amine (310 mg, 3 eq., 2.4 mmol) followed by l,l,3,3-tetramethyl-2-(3H-l,2,3,4-tetraazainden-3-yl)-3-isoureaium hexafluoridophosphate (376 mg, 2 eq., 1.6 mmol). The reaction mixture was stirred for 5 min then added tert-butyl 4-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-6-fluoro-3- isopropylpyrazolo[l,5-a]pyrimidin-5-yl)thio)piperidine-l-carboxylate (480 mg, 1 eq, 0.799 mmol). The reaction mixture was stirred at room temperature for 16 h. Progress was monitored by TLC and LCMS. After completion of the reaction, it was quenched with ice-cold water (2 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine solution (3 x 5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography using 30-35% Ethyl acetate in Hexane to get tert-butyl 4-(7-{(tert-butyl)[m-(p-iodobenzylamino)phenyl](oxycarbonylamino)}-6-fluoro-3- isopropyl-l,4,7a-triaza-5-indenylthio)-l-piperidinecarboxylate (350 mg, 52.73% yield) as an off white solid.

[0263] 'HNMR (400 MHz, DMSO-de): 5 = 10.36 (s, 1H), 8.08 (s, 1H), 7.90 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 8 Hz, 2H), 7.71 (d, J= 8.4 Hz, 2H), 7.36 (t, J= 8.2 Hz, 1H), 7.09 (d, J= 8 Hz, 1H), 3.20 - 3.14 (m, 1H), 3.09 (s, 1H), 2.11 (d, J= 10.4 Hz, 2H),1.69-1.64(m,2H) , 1.40-1.34(m,24H).

[0264] LCMS: 829.63 (M-H)+.

[0265] Step 2: Synthesis of tert-butyl 4-((7-((tert-butoxycarbonyl)(3-(4-

[0266] (dimethylphosphoryl)benzamido)phenyl)amino)-6-fluoro-3-isopropylpyrazolo[l,5-a]pyrimidin-

[0267] 5-yl)thio)piperidine- 1 -carboxylate

[0268] To a stirred solution of tert-butyl 4-(7-{(tert-butyl)[m-(p- iodobenzylamino)phenyl](oxycarbonylamino)}-6-fluoro-3-isopropyl-l,4,7a-triaza-5- indenylthio)-! -piperidinecarboxylate (0.3 g, 1 eq, 0.361 mmol) in 1,4-di oxane (6 mL) was added tripotassium phosphate (123 mg, 1.6 eq., 0.578 mmol) and dimethylphosphaniumone (83.5 mg, 3 eq., 1.08 mmol). The mixture degassed with N2 gas for 20 minutes. To this solution was added 4,5-Z>zs(diphenylphosphino)-9,9-dimethyl-9H-xanthene (31.3 mg, 0.15 eq., 0.054 mmol) and was added palladium / v.s(acetate) (4.05 mg, 0.05 eq., 0.018 mmol) at room temperature. The reaction mixture stirred at 130 °C for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, it was concentrated to get the crude compound. The crude compound was purified by prep-HPLC using 0.1% Ammonium acetate in acetonitrile to get tertbutyl 4-((7-((tert-butoxycarbonyl)(3-(4-(dimethylphosphoryl)benzamido)phenyl)amino)-6- fluoro-3-isopropylpyrazolo[l,5-a]pyrimidin-5-yl)thio)piperidine-l-carboxylate (0.1 g, 35.46%yield) as a pale yellow solid.

[0269] 'HNMR (400 MHz, DMSO-de): 5 = 10.45(s, 1H), 8.09 (s, 1H), 8.02 (d, J= 8 Hz, 2H), 7.90 (t, J= 9.4 Hz, 2H), 7.80 (s, 2H), 7.37 (t, J= 8.4 Hz, 1H), 7.10 (d, J= 7.6 Hz, 1H), 4.13-4.08 (m, 1H), 3.85 (d, J= 13.6 Hz, 2H), 3.22 - 3.15 (m, 3H), 2.11 (d, J= 10.8 Hz, 2H), 1.70-1.62 (m, 8H), 1.4-1.34 (m, 24H).

[0270] LCMS: 781.78 (M+H)+.

[0271] Step 3: Synthesis of 4-(dimethylphosphoryl)-N-(3-((6-fluoro-3-isopropyl-5-(piperidin-4- ylthio)pyrazolo[l,5-a]pyrimidin-7-yl)amino)phenyl)benzamide:

[0272] To a stirred solution of tert-butyl 4-((7-((tert-butoxycarbonyl)(3-(4- (dimethylphosphoryl)benzamido)phenyl)amino)-6-fluoro-3-isopropylpyrazolo[l,5-a]pyrimidin- 5-yl)thio)piperidine-l-carboxylate (0.1 g, 1 eq, 0.128 mmol) in DCM (3 mL) was added trifluoroacetic acid (49 pL, 5 eq., 0.640 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, it was concentrated under reduced pressure and triturated with zz-pentane-di ethyl ether (1:1, 3 x 5 mL) then dried under vacuum to get white solid of 4-(dimethylphosphoryl)-N-(3-((6-fluoro-3-isopropyl-5-(piperidin-4-ylthio)pyrazolo[l,5- a]pyrimidin-7-yl)amino)phenyl)benzamide-TFA Salt (20 mg, 19.31% yield).

[0273] 'HNMR (400 MHz, DMSO-de): 5 = 10.44 (s, 1H), 9.98 (s, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 8.04 (d, J= 6.4 Hz, 3H), 7.92 (t, J= 9.4 Hz, 2H), 7.75 (s, 1H), 7.56 (d, J= 8 Hz, 1H), 7.33 (t, J= 8.0 Hz, 1H), 7.00 (d, J= 8.0 Hz, 1H), 4.13 (s, 1H), 3.35(s, 2H), 3.20 - 3.15 (m, 3H), 2.31 (d, J= 14 Hz, 2H), 1.88-1.81 (m, 2H), 1.69 (d, J= 13.2 Hz, 6H), 1.36 (d, J= 6.8 Hz, 6H).

[0274] LCMS: 581.3 (M+H)+.

[0275] SYNTHETIC EXAMPLE 3

[0276] SYNTHESIS OF 4-FLUORO-N-(3-((3-ISOPROPYL-5-(PIPERIDIN-3-YLOXY)PYRAZOLO[1,5-

[0277] A]PY IMIDIN-7-YL)AMINO)PHENYL)BENZAMIDE

[0278] Step 3: Synthesis of 3-isopropylpyrazolo[l,5-a]pyrimidine-5,7-diol:

[0279] EtO2C^CO2Et

[0280] To a stirred solution of 4-isopropyl-5-pyrazolylamine (15 g, 1 eq., 120 mmol.) in Ethanol (150 mL) was added sodium ethoxide (20% in ethanol) (93.9 mL, 2 eq., 240 mmol.) and diethyl malonate (23.8 mL, 1.3 eq., 156 mmol.) at room temperature. Reaction mixture was stirred at 90 °C for 16 h. Progress of the reaction was monitored by TLC. After completion of reaction, reaction mixture was cooled and concentrated under reduced pressure to get the crude residue as brown oil. Crude brown oil was dissolved in ice-cold water and acidified up to pH ~ 4-5 using 4N HC1 under cooling to get an off-white solid compound. The resulting solid compound was filtered through Buchner funnel and washed with ice cold water, and dried under reduced pressure to get the crude title compound as 3-isopropylpyrazolo[l,5-a]pyrimidine-5,7-diol (10 g, 43.19%) as an off white solid.

[0281] 'HNMR (400 MHz, DMSO-de): 5 = 12.0 (bs, 1H), 11.37 (s, 1H), 7.78 (s, 1H), 7.68 (s, 1H), 3.07-3.00 (m, 1H), 1.16 (d, J = 6.8 Hz, 6H).

[0282] LCMS: (m / z): 194.1 (M+H)+.

[0283] Step 4: Synthesis of 5,7-dichloro-3-isopropylpyrazolo[l,5-a]pyrimidine:

[0284] To a stirred solution of 3-isopropylpyrazolo[l,5-a]pyrimidine-5,7-diol (5 g,l eq., 25.9 mmol.)was added phosphoryl trichloride (72.6 mL, 30 eq., 776 mmol.) at 0 °C and the reaction mixture was heated at 100 °C for 16 h. Progress of the reaction was monitored on TLC. After completion if reaction, Phosphoryl chloride was concentrated under reduced pressure to get the crude brown residue. Crude residue was quenched with crushed ice, added ice-cold water (100 mL) and extracted with ethyl acetate (4 x 60 mL). Organic layer washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to get the crude compound as brown oil. Purification was done by column chromatography using silica (100-200) mesh and (with gradient elution of 1- 5% EtOAc: n-Hexane) to afford the title compound as 5,7-dichloro- 3-isopropylpyrazolo[l,5-a]pyrimidine (3.5 g, 58.78%) as yellow solid.

[0285] 'HNMR (400 MHz, CDC13): 5 = 8.09 (s, 1H), 6.92 (s, 1H), 3.35-3.28 (m, 1H), 1.36 (d, J = 7.2 Hz, 6H).

[0286] LCMS: (m / z): 230.1 (M)+

[0287] Step 5: Synthesis of 5-chloro-3-isopropyl-N-(3-nitrophenyl)pyrazolo[l,5-a]pyrimidin-7- amine:

[0288] To a stirred solution of 5,7-dichloro-3-isopropylpyrazolo[l,5-a]pyrimidine (3.5 g, 15.2 mmol) in dimethylformamide (50.3 mL, 650 mmol) was added m-nitroaniline (2.1 g, 15.2 mmol) was added dipotassium carbonate (5.26 g, 2.5 eq., 38 mmol) at room temperature. Then reaction mixture was heat 80 °C and stirred overnight. The reaction monitored by TLC. Then add Ice cold water (10 mL) and extract with ethyl acetate (3 x 10 mL) both organic layers are dried over Na2SO4. Concentrate under reduced pressure to get crude of 5-chloro-3-isopropyl-N-(3- nitrophenyl)pyrazolo[l,5-a]pyrimidin-7-amine. Crude compound was purified by using combi- flash with gradient elution of 20 % Ethyl Acetate-Hexane to afford the title compound 5-chloro- 3-isopropyl-7-(m-nitrophenylamino)-l,4,7a-triazaindene as yellow solid (3 g, 59.45% yield).

[0289] JH NMR (400 MHz, CDCL3): 5 = 8.30 (s, 1H), 8.24-8.23 (m, 1H), 8.18-8.15 (m, 1H), 7.95 (s, 1H), 7.73-7.66 (m, 2H), 6.33 (s, 1H), 3.35-3.28 (m, 1H), 1.37 (d, J= 6.8 Hz, 6H).

[0290] LCMS: 332.1 (M+H)+

[0291] Step 6: Synthesis of 2-ter / -butyl (5-chloro-3-isopropylpyrazolo[l,5-a]pyrimidin-7-yl)(3- nitrophenyl)carbamate.

[0292] To a stirred solution of 5-chloro-3-isopropyl-7-(m-nitrophenylamino)-l,4,7a-triazaindene (3 g, 1 eq, 9.04 mmol) in tetrahydrofuran (30 mL) was added ethylbi s(propan-2-yl)amine (4.73 mL, 3 eq., 18.1 mmol) and di-Zc / V-butyl dicarbonate (4.15 mL, 2 eq., 18.1 mmol) at room temperature and then 4-(dimethylamino)pyridin-l-ium (111 mg, 0.1 eq., 0.904mmol) was done. Reaction mixture was stirred at room temperature for 2h. TLC monitored progress of the reaction. After completion of reaction, reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title crude compound 2-tert-butyl (5-chloro-3-isopropylpyrazolo[l,5-a]pyrimidin-7-yl)(3- nitrophenyl)carbamate (2.8 g, 71.7% yield) as yellow gummy solid. It was use for the next step without further purification.

[0293] 1H NMR (400 MHz, CDC13): 5 = 8.22 (t, J= 2 Hz, 1H), 8.14 (d, J = 3.2 Hz, lH),8.01(s, 1H), 7.63 (d, .7= 7.2 Hz, 1H), 7.52 (t, . / =8.2 Hz, 1H),6.71 (s, 1H), 3.37-3.31 (m, 1H), 1.50-1.12 (m, 15H).

[0294] LCMS: (m / z): 376.41 (M+H)+

[0295] Step 7: Synthesis of tert-butyl 3-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3- isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l-carboxylate.

[0296] To a stirred solution of 2-5-chloro-3-isopropyl-l,4,7a-triaza-7-indenyl 2-terLbutyl (5- chloro-3-isopropylpyrazolo[l,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamate (2.5 g,l eq, 5.79 mmol) in toluene (25 mL), tert-butyl 3 -hydroxy- 1 -piperidinecarboxylate (1.75 g, 1.5 eq., 8.68 mmol) , CS2CO3 (5.66 g, 17.4 mmol, 3 eq) and rac -BINAP (721 mg, 1.16mmol, 0.2 eq) were added at room temperature. The reaction mixture was purged with argon for 10 min then added tris(benzylideneacetone)dipalladium (530 mg, 0.579 mmol, 0.1 eq) again purged with argon for 5 min and heated at 95°C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ethyl acetate and pass through a pad of diatomaceous earth (e.g., Celite®). The organic phase was washed with water (2 x 20 mL), brine (20 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude product. It was purified by flash chromatography (using 25% EtOAc / Hexane as a eluent) to afford desired product tert-butyl 3-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3- isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l-carboxylate as a pale-yellow solid (2 g, 57.9 % yield).

[0297] 'HNMR (400 MHz, DMSO-de): 5 = 8.30 (s, 1H), 8.18(d, J= 7.6 Hz, 1H), 8.02 (s, 1H), 7.92-7.83 (m, 1H), 7.68 (t, J= 7.8 Hz, 1H), 6.87 (s, 1H), 5.03 (s, 1H), 4.29 (d, J= 11.6 Hz, 1H), 3.74 (s, 1H), 3.54 (s, 1H), 3.14-3.07 (m, 1H), 2.93 (s, 1H), 1.90 (s, 2H), 1.73 (s, 1H), 1.50-1.47 (m, 1 H), 1.39-1.23 (m, 18 H), 0.90 (s, 6H).

[0298] LCMS: (m / z): 597.60 (M+H)+.

[0299] Step 8: Synthesis of tert-butyl 3-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3- isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l-carboxylate. To a stirred solution of tert-butyl 3-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3- isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l-carboxylate (2 g,l eq, 3.35 mmol) in methanol -water (2: 1, 33 mL) at 0 °C was added iron (1.87 g, 10 eq., 33.5 mmol) followed by ammonium chloride (3.59 g, 20 eq., 67 mmol). The reaction mixture was stirred at 80 °C for 2h. The progress of the reaction was monitored by TLC. After completion of reaction, reaction mixture was cooled to rt and filtered through a pad of diatomaceous earth (e.g., Celite®). The filtrate was diluted with water (40 mL) and extracted with ethyl acetate (3 ^ 30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by flash column by using 35-40% ethyl acetate in Hexane as eluent to afford tert-butyl 3-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5- yl)oxy)piperidine-l -carboxylate (1.4 g, 73.7% yield) as pale brown solid.

[0300] 'HNMR (400 MHz, DMSO-de): 5 = 7.94 (s, 1H), 6.97 (t, J= 8 Hz, 1H), 6.53(s, 1H), 6.49-6.43 (m, 2H), 6.24 (s, 1H), 5.22 (s, 2H), 5.01 (s, 1H), 4.32 (d, J= 12.4 Hz, 1H), 3.76 (d, J = 8 Hz, lH),3.20-3.14 (m, 1H), 3.09-3.04 (m, 1H), 2.87-2.81 (m, 1H), 1.84 (s, 2H), 1.67 (d, J= 4.4 Hz, 1H), 1.48-1.42 (m, 1H), 1.28-1.23 (m, 18H), 0.87 (s, 6H).

[0301] LCMS: (m / z): 567.3(M+H)+.

[0302] Step 9: Synthesis of tert-butyl 3-((7-((tert-butoxycarbonyl)(3-(4- fluorobenzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l- carboxylate:

[0303] To a stirred solution of p-fluorobenzoic acid (59.3 mg, 1.2 eq., 0.424 mmol) in dimethylformamide (5 mL) was added N-ethylbis(isopropyl)amine (137 mg, 3 eq., 1.06 mmol) followed by l,l,3,3-tetramethyl-2-(3H-l,2,3,4-tetraazainden-3-yl)-3-isoureaium hexafluoridophosphate(l-) (166 mg, 2 eq., 0.706 mmol). The mixture was stirred for 5 min then tert-butyl 3 -((7-((3 -aminophenyl)(tert-butoxy carbonyl)amino)-3 -i sopropylpyrazolof 1 , 5 - a]pyrimidin-5-yl)oxy)piperidine-l -carboxylate (0.2 g, 1 eq., 0.353 mmol) was added to it. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the Reaction, the mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography using 30-40% Ethyl acetate in Hexane to afford white solid of tert-butyl 3-((7-((tert-butoxycarbonyl)(3-(4- fluorobenzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l- carboxylate (140 mg, 57.59% yield) .

[0304] 'HNMR (400 MHz, DMSO-de): 5 = 10.35 (s, 1H), 7.98-7.95(m,3H),7.77(s, 1H), 7.70(d, J= 6.8 Hz, 1H), 7.37-7.31 (m, 3H), 7.10 (d, J=7.6 Hz ,1H), 6.42(s, 1H), 4.99 (s, 1H), 4.29 (d, J = 11.6 Hz, 1H), 3.74(d, J= 11.6 Hz, 1H), 3.23(d, = 12 Hz, 1H), 3.12-3.05(m,lH), 2.91- 2.85(m,lH), 1.86 (s, 2H), 1.73-1.64 (m,lH), 1.46-1.44(m,lH), 1.31-1.22(m,18H), 0.85(d, ,1 17.6 z ,6H).

[0305] LCMS: 689.4 (M+H)+

[0306] Step 10: Synthesis of 4-fluoro-N-(3-((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[l,5- a]pyrimidin-7-yl)amino)phenyl)benzamide

[0307] To a stirred solution of tert-butyl 3-(7-{(tert-butyl)[m-(p- fluorobenzylamino)phenyl](oxycarbonylamino)}-3-isopropyl-l,4,7a-triaza-5-indenyloxy)-l- piperidinecarboxylate (140 mg,l eq, 0.203 mmol) in DCM (8 mL) was added trifluoroacetic acid (77.8 pL, 5 eq., 1.02 mmol) at 0°C. Then the reaction mixture was stirred at room temperature for 3 h. Then total solvent was evaporated under reduced pressure and triturated with n-pentane (20 mL) and diethyl ether (20 mL) then dried under vacuum to afford white solid of 4-fluoro-N- (3-((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[l,5-a]pyrimidin-7-yl)amino)phenyl)benzamide- TFA Salt (50 mg, 34.33% yield).

[0308] 'HNMR (400 MHz, DMSO-de): 5 = 10.44 (s, 1H), 9.83 (s, 1H), 8.80 (s, 1H), 8.43 (s, 1H), 8.06-8.03 (m, 2H), 7.96 (s, 1H), 7.89 (s, 1H), 7.66 (d, .7=8 Hz ,1H), 7.46-7.36 (m, 3H), 7.16 (d, =8 Hz ,1H), 5.64 (s, 1H), 5.35 (s, 1H), 3.32 (d, J=12.4 Hz ,2H), 3.10-2.98 (m, 3H), 1.91- 1.83 (m, 3H), 1.68-1.65 (m, 1H), 1.30 (d, J= 6.8 Hz ,6H).

[0309] LCMS: (m / z): 489.3 (M+H)+. SYNTHETIC EXAMPLE 4

[0310] SYNTHESIS OF 4-(DIMETHYLPHOSPHORYL)-N-(3-((3-ISOPROPYL-5-(PIPERIDIN-3-

[0311] YLOX Y)p YRAZOLO [ 1 , 5 -A]p YRIMIDIN-7- YL)AMINO)PHEN YL)BENZ AMIDE

[0312] Step 1 : Synthesis of tert-butyl 3-((7-((tert-butoxycarbonyl)(3-(4- iodobenzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l- carboxylate:

[0313] To a stirred solution of / ?-iodobenzoic acid (263 mg, 1.2 eq., 1.06 mmol) in dimethylformamide (14 mL) was added N-ethylbis(isopropyl)amine (342 mg, 3 eq., 2.65 mmol) followed by l,l,3,3-tetramethyl-2-(3H-l,2,3,4-tetraazainden-3-yl)-3-isoureaium hexafluoridophosphate(l-) (415 mg, 2 eq., 1.76 mmol). The reaction mixture was stirred for 5 min then added tert-butyl 3-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3- isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperi dine- 1 -carboxylate (0.5 g, 0.882 mmol,leq). The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC.

[0314] After completion of the reaction, it was quenched with ice-cold water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine solution (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography using 30-40% Ethyl acetate in Hexane to afford tert-butyl 3- ((7-((tert-butoxycarbonyl)(3-(4-iodobenzamido)phenyl)amino)-3-isopropylpyrazolo[l,5- a]pyrimidin-5-yl)oxy)piperidine-l -carboxylate (0.3 g, 42.68% yield).

[0315] 'HNMR (400 MHz, DMSO-de): 5 = 10.38 (s, 1H), 8.01 (s, 1H), 7.91 (d, J= 8.4 Hz, 2H), 7.86 - 7.70 (m, 4H), 7.35 (t, J= 8.0 Hz, 1H), 7.13 (d, J= 8.0 Hz, 1H), 6.49 (s, 1H), 5.01 (s, 1H), 4.26 (d, J= 11.6 Hz, 1H), 3.72 (s, 1H), 3.17-3.07 (m, 1H), 2.92 (s, 1H), 1.87 (s, 2H), 1.72 (s, 1H), 1.48-1.45 (m, 1H), 1.33-1.23 (m, 18H), 1.17-1.46 (m, 1H), 0.92 (s, 6H)

[0316] Step 2: Synthesis of tert-butyl 3-((7-((tert-butoxycarbonyl)(3-(4- (dimethylphosphoryl)benzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5- yl)oxy)piperidine- 1 -carboxylate:

[0317] To a stirred solution of tert-butyl 3-((7-((tert-butoxycarbonyl)(3-(4- iodobenzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l- carboxylate (0.3 g, 1 eq, 0.377 mmol) in 1,4-dioxane (5mL) was added tripotassium phosphate (128 mg, 1.6 eq., 0.602 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (32.7 mg, 0.15 eq., 0.056 mmol) and degassed with argon for 20 minutes. To this was added dimethylphosphaniumone (87 mg, 3 eq., 1.13mmol) and palladium A / .s(acetate) (4.23 mg, 0.05 eq., 0.018 mmol) at room temperature.

[0318] The mixture was stirred at 130 °C for 3h. The reaction was monitored by TLC and LCMS. After completion of the reaction, it was concentrated to get the crude compound .The crude compound was purified by prep-HPLC using 0.1% NH4OAC in ACN to get tert-butyl 3- {7-[(tert-butyl){m-[p-(dimethylphosphoryl)benzylamino]phenyl}(oxycarbonylamino)]-3- isopropyl-l,4,7a-triaza-5-indenyloxy}-l-piperidinecarboxylate (0.1 g, 35.56% yield) as a white solid.

[0319] 'HNMR (400 MHz, DMSO-de): 5 = 10.46 (s, 1H), 8.01-7.98 (m, 3H), 7.91 - 7.68 (m, 2H),7.81 (s, 1H), 7.72 (d, J= 8.4 Hz, 1H), 7.36 (t, J = 8.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H),6.43 (s, 1H), 4.99 (s, 1H), 4.30 (d, J= 14.4 Hz, 1H), 3.75-3.70 (m, 1H), 3.23 (d, J= 14 Hz, 1H), 3.14- 3.05 (m, 1H), 2.29-2.86 (m, 1H), 1.85 (s, 2H), 1.69 (d, J= 13.6Hz, 6H), 1.46-1.43 (m, 2H),1.33- 1.28 (m, 18H),0.88 (s, 6H).

[0320] LCMS: 747.4 (M+H)+.

[0321] Step 3 : Synthesis of 4-(dimethylphosphoryl)-N-(3-((3-isopropyl-5-(piperidin-3- yloxy)pyrazolo[l,5-a]pyrimidin-7-yl)amino)phenyl)benzamide:

[0322] To a stirred solution of tert-butyl 3-{7-[(tert-butyl){m-[p- (dimethylphosphoryl)benzylamino]phenyl}(oxycarbonylamino)]-3-isopropyl-l,4,7a-triaza-5- indenyloxy}-l -piperidinecarboxylate (0.1 g,l eq, 0.134 mmol) in DCM (5 mL) was added trifluoroacetic acid (51.2 pL, 5 eq., 0.669 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored using TLC and LCMS. After completion of the reaction, it was concentrated under reduced pressure and triturated with w-pentane-diethyl ether (1 : 1, 1 mL x 3) then dried under vacuum to get N-{m-[3-isopropyl-5-(3- piperidyloxy)-l,4,7a-triaza-7-indenylamino]phenyl}p-(dimethylphosphoryl)benzamide-TFA salt (45 mg, 43.38% yield) as a white solid.

[0323] 'HNMR (400 MHz, DMSO-de): 5 = 10.54(s, 1H), 9.85 (s, 1H), 8.73 (s, 1H), 8.40 (s, 1H), 8.08-8.05 (m, 2H), 7.97-7.89 (m, 4H), 7.56 (d, J= 8.4 Hz, 1H), 7.48 (t, J= 8.0 Hz, 1H), 7.20 (d, J= 8.0 Hz, 1H), 5.72 (s, 1H), 5.37 (s, 1H), 3.32 (d, J= 3.2 Hz, 2H), 3.12-3.00 (m, 3H), 6.79 - 6.74 (m, 1H), 6.48 (d, J= 15.2 Hz, 1H), 4.12 (brs, 1H), 3.96 (d, J= 6.0 Hz, 1H), 3.20 - 3.12 (m, 3H), 1.90 (d, J= 12.4 Hz, 3H), 1.74 (d, J= 13.6 Hz, 7H), 1.32 (d, J= 6.8 Hz, 6H).

[0324] LCMS: 547.3 (M+H)+.

[0325] SYNTHETIC EXAMPLE 5

[0326] SYNTHESIS OF (5)-4-FLUORO-N-(3 -((3 -ISOPROPYL-5 -(PIPERIDIN-3 - YLOXY)PYRAZOLO[ 1,5- A]PYRIMIDIN-7-YL)AMINO)PHENYL)BENZAMIDE

[0327] Step 1 : Synthesis of tert-butyl (5)-3-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3- isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l-carboxylate:

[0328] To a stirred mixture of tert-butyl (5-chloro-3-isopropylpyrazolo[l,5-a]pyrimidin-7-yl)(3- nitrophenyl)carbamate (2.8 g,leq,6.48 mmol) in toluene (25 mL), tert-butyl (S)-3 -hydroxy- 1- piperidinecarboxylate (1.96 g, 1.5 eq., 9.72 mmol), CS2CO3 (6.34 g, 19.4 mmol, 3 eq) and rac- BINAP (807 mg, 1.3 mmol, 0.2 eq.) were added at room temperature. The reaction mixture was purged with argon for 10 min then added tris(benzylideneacetone)dipalladium (594 mg, 0.648 mmol, 0.1 eq.) again purged with argon for 5 min and heated at 95 °C for 16 h. The progress of the reaction was done by TLC and LCMS. After completion of reaction, the reaction mixture was diluted with ethyl acetate and pass through a pad of diatomaceous earth (e.g., Celite®). The organic phase was washed with water (2 x 20 mL), brine (20 mL), dried over Na2SO4 and concentrated under vacuum to get the crude product. The crude compound was purified by flash chromatography (using 25% EtOAc / Hexane as a eluent) to get the desired product tert-butyl (S)- 3-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5- yl)oxy)piperidine-l -carboxylate as an pale-yellow solid (2.2g, 56.87 % yield ).

[0329] 'HNMR (400 MHz, DMSO-de): 5 = 8.29 (d, J= 2 Hz, 1H), 8.24(d, J= 2 Hz, 1H), 7.89- 7.78 (m, 1H), 7.73-7.66 (m, 1H), 6.87 (s, 1H), 5.03 (s, 1H), 4.30 (d, J= 9.2 Hz, 1H), 3.74 (s, 1H), 3.14-3.07 (m, 1H), 2.93 (s, 1H), 1.89 (s, 2H), 1.73 (s, 1H), 1.49-1.47 (m, 1 H), 1.33-1.12 (m, 18 H), 1.05-1.00 (m, 1 H), 0.90 (s, 6H)

[0330] LCMS: (m / z): 597.60 (M+H)+

[0331] Step 2: Synthesis of tert-butyl (S)-3-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3- isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l-carboxylate. To a stirred solution of tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)- 3-isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l-carboxylate (2.2 g,l eq, 3.69 mmol) in methanol-water (1 : 1, 33 mL) at 0 °C was added iron (2.06 g, 10 eq., 36.9 mmol), ammonium chloride (3.94 g, 20 eq., 73.7 mmol) and the reaction mixture was stirred at 80 °C for 2h. The progress of the reaction was monitored using TLC and LCMS. After completion of the reaction, it was cooled to rt and filtered through a pad of diatomaceous earth (e.g., Celite®). Filtrate was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by flash column by using 30-40% E / A in Hexane as eluent to afford tert-butyl (5)-3-((7-((3- aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5- yl)oxy)piperidine-l -carboxylate (1.2 g, 57.43% yield) as pale brown solid.

[0332] 'HNMR (400 MHz, DMSO-de): 5 = 7.98 (s, 1H), 6.97 (t, J= 8 Hz, 1H), 6.56 (d, J= 2 Hz, 1H), 6.47 (d, J= 7.6 Hz, 2H), 6.34 (s, 1H), 5.21 (s, 2H), 5.01 (s, 1H), 3.72 (s,lH), 3.14-3.08 (m,lH), 3.07 (s, 1H), 1.87 (s, 2H), 1.73 (d, J= 9.6 Hz, 1H), 1.48-1.45 (m, 1H), 1.33-1.27 (m, 18H), 1.19-1.04 (m, 2H), 0.96 (s, 6H).

[0333] LCMS: (m / z): 567.64 (M+H)+.

[0334] Step 3: Synthesis of tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(3-(4- fluorobenzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l- carboxylate.

[0335] To a stirred solution of / 2-fluorobenzoic acid (59.34 mg, 1.2 eq., 0.424 mmol) in dimethylformamide (5 mL) was added N-ethylbis(isopropyl)amine (137 mg, 3 eq., 1.06 mmol) followed by l,l,3,3-tetramethyl-2-(3H-l,2,3,4-tetraazainden-3-yl)-3-isoureaium hexafluoridophosphate(l-) (166 mg, 2 eq., 0.706 mmol). The reaction mixture was stirred for 5 min then added tert-butyl (5)-3-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3- isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperi dine- 1 -carboxylate (0.2 g,l eq, 0.353 mmol). The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, it was quenched with ice- cold water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography using 30-40% Ethyl acetate in hexane to afford tert-butyl (5)-3-((7-((tert-butoxycarbonyl)(3-(4- fluorobenzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l- carboxylate (130 mg, 53.48% yield) as a white solid.

[0336] 1H NMR (400 MHz, DMSO-de): 5 = 10.35 (s, 1H), 8.01-7.96(m,3H),7.81(s, 1H), 7.68(d, J= 7.2 Hz, 1H), 7.41-7.33 (m, 3H), 7.13 (d, =8 Hz ,1H), 6.41 (s, 1H), 5.01 (s, 1H), 4.37 (d, J= 14.4 Hz, 1H), 3.81-3.79(m,lH),3.22 (d, J= 12.8 Hz, 1H), 3.14-3.07(m,lH), 2.87 (s, 1H), 1.89 (s, 2H), 1.71 (s, 1H), 1.48(d, J= / 0. Hz ,1H), 1.34-1.06(m,18H), 0.87(s,6H).

[0337] LCMS: 689.4 (M+H)+

[0338] Step 4: Synthesis of (5)-4-fluoro-N-(3-((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[l,5- a]pyrimidin-7-yl)amino)phenyl)benzamide

[0339] To a stirred solution of tert-butyl (5)-3-((7-((tert-butoxycarbonyl)(3-(4- fluorobenzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l- carboxylate (130 mg,l eq, 0.189 mmol) in DCM (4 mL) was added trifluoroacetic acid (72.2 pL, 5 eq., 0.944 mmol). The mixture was stirred at room temperature for 3 h. Progress of the reaction was monitored using TLC and LCMS. After completion of the reaction the mixture was concentrated under reduced pressure and triturated with / / -pentane-di ethyl ether (1 : 1, 2 mL) then dried under vacuum to afford white solid of (5)-4-fluoro-N-(3-((3-isopropyl-5-(piperidin-3- yloxy)pyrazolo[l,5-a]pyrimidin-7-yl)amino)phenyl)benzamide-TFA Salt (45 mg, 33.27% yield).

[0340] 'HNMR (400 MHz, DMSO-de): 5 = 10.44 (s, 1H), 9.83 (s, 1H), 8.80 (s, 1H), 8.44 (s, 1H), 8.06-8.03 (m, 2H), 7.96 (s, 1H), 7.89 (s, 1H), 7.66 (d, .7=8 Hz ,1H), 7.43 (t, .7=8 Hz ,1H), 7.34 (t, .7=8.8 Hz ,2H), 7.16 (d, J =8 Hz ,1H),5.64 (s, 1H), 5.35 (s, 1H), 3.29 (d, J =2.8 Hz ,2H), 3.08-2.94 (m, 3H), 1.91-1.82 (m, 3H), 1.68-1.63 (m, 1H), 1.32 (d, J =7.2 Hz ,6H)

[0341] LCMS: (m / z): 489.3 (M+H)+ SYNTHETIC EXAMPLE 6

[0342] SYNTHESIS OF (5 -4-(DIMETHYLPHOSPHORYL)-7V-(3-((3-ISOPROPYL-5-(PIPERIDIN-3-

[0343] YLOX Y)p YRAZOLO [ 1 , 5 -A]p YRIMIDIN-7- YL)AMINO)PHEN YL)BENZ AMIDE

[0344] Step 1 : Synthesis of tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(3-(4- iodobenzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l- carboxylate.

[0345] To a stirred solution of / ?-iodobenzoic acid (263 mg, 1.2 eq., 1.06 mmol) in dimethylformamide (14 mL) was added N-ethylbis(isopropyl)amine (461 pL, 3 eq., 2.65 mmol), l,l,3,3-tetramethyl-3a-(3H-l,2,3,4-tetraazainden-3-yl)-3a-ureaium (415 mg, 2 eq., 1.76 mmol) and was stirred for 5 min. Then tert-butyl (5)-3-{7-[(m-aminophenyl)(tert- butyl)(oxycarbonylamino)]-3-isopropyl-l,4,7a-triaza-5-indenyloxy}-l-piperidinecarboxylate (0.5 g, 0.882 mmol,l eq) was added. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, it was quenched with ice-cold water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine solution (3 x 5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography using 30-40% Ethyl acetate in Hexane to get tert-butyl (S)-3-((7-((tert- butoxycarbonyl)(3-(4-iodobenzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5- yl)oxy)piperidine-l -carboxylate (300 mg, 42.68% yield).

[0346] 'HNMR (400 MHz, DMSO-de): 5 = 10.37 (s, 1H), 8.00 (s, 1H), 7.90(d, J= 8.4 Hz, 2H), 7.78 - 7.74 (m, 2H), 7.71(d, J= 8.4 Hz, 2H), 7.35 (t, J= 8.2 Hz, 1H), 7.12(d, J= 8 Hz, 1H), 6.48(s, 1H), 5.01(s, 1H), 3.72(s, lH),3.52(s, 1H), 3.13 - 3.07 (m,lH), 2.95-2.89 (m, 1H), 1.89 (d, J= 12.8 Hz, 2H), 1.71(s, 1H), 1.48-1.44 (m, 1H), 1.33-1.15 (m, 18H), 1.09(s, 1H), 0.92(s, 6H).

[0347] LCMS: 797.26 (M+H)+ Step 2: Synthesis of tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(3-(4- (dimethylphosphoryl)benzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5- yl)oxy)piperidine- 1 -carboxylate.

[0348] To a stirred solution of tert-butyl (5 -3-((7-((tert-butoxycarbonyl)(3-(4- iodobenzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5-yl)oxy)piperidine-l- carboxylate (0.3 g, 377 pmol,l eq) in 1,4-dioxane (6 mL) was added tripotassium phosphate (128mg, 1.6 eq., 0.602 mmol), dimethylphosphaniumone (87 mg, 3 eq., 1.13 mmol) and degassed with argon for 20 minutes. To this mixture was added 4,5-bis(diphenylphosphino)-9,9- dimethyl-9H-xanthene (32.7 mg, 0.15 eq., 0.056 mmol), palladium A / .s(acetate) (4.23 mg, 0.05 eq., 0.018 mmol) at room temperature and the reaction mixture stirred at 130 °C for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, it was concentrated under reduced pressure to get the crude of tert-butyl (5)-3-((7-((tert- butoxycarbonyl)(3-(4-(dimethylphosphoryl)benzamido)phenyl)amino)-3-isopropylpyrazolo[l,5- a]pyrimidin-5-yl)oxy)piperidine-l-carboxylate. The crude compound was purified by prep- HPLC using 0.1% Ammonium acetate in ACN to get white solid of tert-butyl (S)-3-((7-((tert- butoxycarbonyl)(3-(4-(dimethylphosphoryl)benzamido)phenyl)amino)-3-isopropylpyrazolo[l,5- a]pyrimidin-5-yl)oxy)piperidine-l -carboxylate (0.1 g, 35.56%yield).

[0349] ‘HNMR (400 MHz, DMSO-de): 5 = 10.46 (s, 1H), 8.04-8.01 (m, 3H), 7.93-7.88 (m, 2H),7.81 (s, 1H), 7.77 (d, J= 8.4 Hz, 1H), 7.36(t, J= 8.0 Hz, 1H), 7.14 (d, J= 8.8Hz, 1H), 6.49 (s, 1H) ,5.02 (s, 1H), 4.25 (d, J= 10.8 Hz, 1H), 3.73 (d, J= 7.2 Hz, 1H), 3.48 (d, J= 5.2 Hz, 1H), 3.16-3.07 (m, 1H), 2.92 (s, 1H), 1.89-1.88 (m, 2H), 1.74-1.67 (m, 7H), 1.48-1.45 (m, 1H), 1.33- 1.23 (m, 17H), 0.93 (s, 6H).

[0350] LCMS: 831.33 (M+H)+

[0351] Step 3: Synthesis of (5)-4-(dimethylphosphoryl)-A-(3-((3-isopropyl-5-(piperidin-3- yloxy)pyrazolo[l,5-a]pyrimidin-7-yl)amino)phenyl)benzamide

[0352] To a stirred solution of tert-butyl (5)-3-((7-((tert-butoxycarbonyl)(3-(4- (dimethylphosphoryl)benzamido)phenyl)amino)-3-isopropylpyrazolo[l,5-a]pyrimidin-5- yl)oxy)piperidine-l -carboxylate (0.1 g, 0.134 mmol,l eq) in DCM (5 mL) at 0 °C was trifluoroacetic acid (51.2 pL, 5 eq., 0.669 mmol).

[0353] Then the reaction mixture was stirred at room temperature for 3 h. Progress of the reaction was monitored using TLC. After completion of the reaction the reaction mixture was concentrated under reduced pressure and triturated with v-pentane-di ethyl ether (1 : 1, 3 * 2 mL) then lyophilized to get white solid of (5)-4-(dimethylphosphoryl)-A-(3-((3-isopropyl-5- (piperidin-3-yloxy)pyrazolo[l,5-a]pyrimidin-7-yl)amino)phenyl)benzamide-TFA Salt (40 mg, 38.56% yield).

[0354] 'HNMR (400 MHz, DMSO-de): 5 = 10.54 (s, 1H), 9.85 (s, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 8.06 (t, J= 4.2 Hz, 2H), 7.97-7.91 (m, 4H),7.68 (d, J= 8.0 Hz, 2H), 7.46 (t, J= 8.0 Hz, 1H), 7.18 (d, J= 8.4 Hz, 1H), 5.64 (s, 1H), 5.35 (s, 1H), 3.10-3.00 (m, 3H), 1.92-1.84 (m, 3H), 1.73 (d, J= 13.6 Hz, 7H),1.32 (d, J= 6.8 Hz, 6H).

[0355] LCMS: 547.3 (M+H)+

[0356] BIOLOGICAL EXAMPLE 1

[0357] ACTIVITY OF REPRESENTATIVE COMPOUNDS

[0358] Kinase Gio Assay

[0359] Materials:

[0360] Assay Buffer: 50 mM HEPES, 3 mM MgCh, 3 mM MnCh, 1 mM DTT, 3 pM Na3VO4, pH 7.5

[0361] Enzymes: CDK7 / CycH / MATl (ProQinase #: 0366-0360-4)

[0362] Kinase-Glo™ Assay (Promega #: V6711): ATP: 10 mM, Kinase-Glo™ Reagent

[0363] 384-well white assay plates

[0364] Method:

[0365] A ten-point serial dilution of compound was prepared at 5* concentration in assay buffer with the final assay concentrations starting at 30 pM, 10 pM, 3 pM, 1 pM. . .0 pM. Enzyme and ATP were used at 40 ng and 1 pM, respectively. The assay plate was set up by mixing the components in a total reaction volume of 10 pL per well. The plate was centrifuged gently for 10 seconds and incubated at room temperature (RT) for 60 minutes in the dark. The Kinase-Glo Reagent was added and incubated as recommended. The reaction was quantified by measuring luminescence on the Perkin Elmer Envision plate reader. Data was analyzed using Graphpad Prism 7 software. Table 3 Biological activity for representative compounds - CDK7 activity is a result of the enzymatic assay.

[0366] +++++ indicates an IC50 value up to 1 pM

[0367] ++++ indicates an IC50 value from 1 to up to 5 pM

[0368] +++ indicates an IC50 value from 5 up to 20 pM

[0369] ++ indicates an IC50 value from 20 up to 100 pM + indicates an IC50 value from 100 up to 1000 pM

[0370] BIOLOGICAL EXAMPLE 2

[0371] CELL VIABILITY ASSAY

[0372] Materials:

[0373] Cell Lines (Treated according to ATCC guidelines - A2780, Kasumi-1, MIA PaCa-2, MDA-MB-231)

[0374] Cell Titer Gio (Promega Cat# G7572)

[0375] DMSO 96-well White Tissue Culture Treated Plates (Perkin Elmer Cat# 60005680)

[0376] Methods:

[0377] Cells were seeded in a white 96-well tissue culture treated plate at a density of 1500 cells in 90 pL of media per well and allowed to settle overnight. A ten-point serial dilution of drugs was prepared at 10x concentration in media with the final assay concentrations starting at 30 pM, 10 pM, 3 pM, 1 pM, 0.3 pM, and 0 pM. A dilution of DMSO was included as a control. The assay was set up by adding 10 pL of the corresponding drug to each well in duplicate, followed by a 72-hour incubation at 37 °C, 5% CO2. Cell viability was quantified by adding 90 pL of Cell Titer Gio to each well and incubating at room temperature for 10 minutes. The reaction was quantified by measuring luminescence using the Envision Plate Reader. Data was analyzed using Graphpad Prism 7 software.

[0378] Table 4 Cell viability activity for representative compounds

[0379] +++++ indicates an IC50 value up to 1 pM

[0380] ++++ indicates an IC50 value from 1 to up to 5 pM +++ indicates an IC50 value from 5 up to 20 pM ++ indicates an IC50 value from 20 up to 100 pM + indicates an IC50 value from 100 up to 1000 pM

[0381] All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference, including U.S. Provisional Patent Application No. 63 / 572,067 filed March 29, 2024, in its entirety to the extent not inconsistent with the present description. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications, and publications to provide yet further embodiments.

[0382] From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the disclosure. Accordingly, the disclosure is not limited except as by the appended claims.

Claims

CLAIMS1. A compound having Structure (I):or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof, wherein: represents an aromatic ring such that all valences are satisfied;X1is C and X2is N; or X1is N and X2is C;R1is Ci-Ce alkyl, Ci-Ce haloalkyl, cyano, or C3-C8 cycloalkyl;R2is C3-C8 cycloalkyl, 3-8-membered heterocyclyl, optionally substituted Ci-Ce alkyl- C3-C8 cycloalkyl, or optionally substituted Ci-Ce alkyl-3 -8-membered heterocyclyl;R3is halo;R4is C3-C8 cycloalkyl, Ce-Cio aryl, 3-8-membered heterocyclyl, or 5-10-membered heteroaryl;R5is H or Ci-Ce alkyl;L1is -O-, -S-, or -NR5-; andL2is a direct bond or Ci-4 alkylene, wherein each alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted.

2. The compound of claim 1, having Structure (la):or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof.

3. The compound of claim 1, having Structure (lb):or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof.

4. The compound of claim 1, having Structure (la- 1):(la-1) or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof.

5. The compound of claim 1, having Structure (Ib-1):(Ib-1) or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof.

6. The compound of claim 1, having Structure (la-2):or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof.

7. The compound of claim 1, having Structure (Ib-2):(Ib-2) or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof.

8. The compound of any one of claims 1-3, wherein L2is C2-4 alkylene.

9. The compound of any one of claims 1-8, wherein R1is Ci-Ce alkyl, Ci-Ce haloalkyl, or cyano.

10. The compound of claim 9, wherein R1is C1-3 alkyl, C1-C3 haloalkyl, or cyano.

11. The compound of claim 9, wherein R1is methyl, ethyl, propyl, isopropyl, CF3, or cyano.

12. The compound of any one of claims 1-8, wherein R1is C3-C8 cycloalkyl.

13. The compound of claim 12, wherein R1is C3-6 cycloalkyl.

14. The compound of claim 13, wherein R1is cyclopropyl, cyclobutyl, or cyclopentyl.

15. The compound of any one of claims 1-14, wherein R2is Cs-Cs cycloalkyl.

16. The compound of claim 15, wherein R2is C3-6 cycloalkyl.

17. The compound of claim 16, wherein R2is cyclopentyl or cyclohexyl.

18. The compound of any one of claims 1-14, wherein R2is 3-6-membered heterocyclyl.

19. The compound of claim 18, wherein R2is piperidinyl or tetrahydropyranyl.

20. The compound of any one of claims 1-19, wherein R2is substituted with one or more substituents.

21. The compound of any one of claims 1-14, wherein R2has the following structure:wherein:R2aand R2bare each independently hydrogen or C1-C4 alkyl; andR2Cis hydrogen, C1-C4 alkyl, -OH, or halo.

22. The compound of any one of claims 1-14, wherein R2has one of the following structures:

23. The compound of any one of claims 1-22, wherein R3is F.

24. The compound of any one of claims 1-23, wherein R4is Cs-Cs cycloalkyl.

25. The compound of any one of claims 1-23, wherein R4is Ce-Cio aryl.

26. The compound of claim 25, wherein R4is phenyl.

27. The compound of any one of claims 1-23, wherein R4is 3-8-membered heterocyclyl.

28. The compound of any one of claims 1-23, wherein R4is 5-10-membered heteroaryl.

29. The compound of claim 28, wherein R4is indazolyl, benzoisothiazolyl or benzoisoxazolyl.

30. The compound of any one of claims 1-29, wherein R4is substituted with one or more substituents.

31. The compound of claim 30, wherein the one or more substituents are selected from the group consisting of halo, haloalkyl, alkoxy, haloalkoxy, aminyl, heteroaryl, -NH- C(=O)-phenyl, -NH-C(=O)-heteroaryl, -NH-C(=O)-heterocyclyl, -NH-S(O)2-phenyl, -NH- C(=O)-NH-phenyl, and -C(=O)-NH-phenyl.

32. The compound of any one of claims 1-31, wherein R4has one of the following structures:

33. The compound of any one of claims 1-32, wherein L1is -O-.

34. The compound of any one of claims 1-32, wherein L1is -S-.

35. The compound of any one of claims 1-32, wherein L1is -NR5-.

36. The compound of claim 35, wherein R5is H.

37. The compound of claim 35, wherein R5is Ci-Ce alkyl.

38. The compound of claim 37, wherein R5is methyl.

39. The compound of any one of claims 1-38, wherein the compound has a structure of Table 1 or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or isotope thereof.

40. The compound of claim 39, wherein the compound is an HC1, TFA, or HCO2H salt form.

41. A pharmaceutical composition comprising the compound of any one of claims 1- 52, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient.

42. A method of modulating CDK7, comprising contacting a cell with an effective amount of the compound of any one of claims 1-39 or the pharmaceutical composition of claim 41.

43. A method of treating a CDK7-dependent disease, comprising administering to a subject in need thereof an effective amount of the compound of any one of claims 1-39 or the pharmaceutical composition of claim 41.

44. Use of the compound of any one of claims 1-39 or the pharmaceutical composition of claim 41 in a method of treating a CDK7-dependent disease.

45. The method of claim 43 or use of claim 44, wherein the CDK7-dependent disease is cancer.

46. The method or use of claim 45, wherein the cancer is pancreatic cancer or breast cancer.

47. The method or use of claim 46, wherein the breast cancer is triple negative breast cancer.

48. The method or use of claim 45, wherein the cancer is neuroblastoma, medulloblastoma, Ewing sarcoma, chordoma, or combinations thereof.

49. The method or use of any one of claims 43-48, wherein the method further comprises administering an additional therapeutic agent selected from the group consisting of chemotherapeutic drugs, radiation therapy, HD AC inhibitors, PARP inhibitors, and checkpoint inhibitors.

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