GLUE DEGRADERS AND METHODS OF USE THEREOF

Described herein are glue degrader compounds, their various targets, their preparation, pharmaceutical compositions comprising them, and their use in the treatment or prevention of conditions, diseases, and disorders mediated by various target proteins.

FIELD OF THE DISCLOSURE

Described herein are glue degrader compounds, their various targets, their preparation, pharmaceutical compositions comprising them, and their use in the treatment of conditions, diseases, and disorders mediated by various target proteins.

BACKGROUND OF THE DISCLOSURE

The Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases comprise over 500 different proteins and are categorized into multiple classes defined by the structural element of their E3 functional activity.

Cereblon (CRBN) interacts with damaged DNA binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4 where it functions as a substrate receptor in which the proteins recognized by CRBN might be ubiquitinated and degraded by proteasomes.

Proteasome-mediated degradation of unneeded or damaged proteins plays a very important role in maintaining regular function of a cell, such as cell survival, proliferation and growth. A new role for CRBN has been identified; i.e., the binding of immunomodulatory drugs (IMiDs), e.g., thalidomide, to CRBN has now been associated with teratogenicity and also the cytotoxicity of IMiDs, including lenalidomide, which are widely used to treat multiple myeloma patients. CRBN is likely a key player in the binding, ubiquitination, and degradation of factors involved in maintaining function of myeloma cells.

Glue degrader compounds that bind to and alter the specificity of a cereblon complex have been shown to induce proteasome-mediated degradation of selected proteins. These molecules can been used to modulate protein expression and may be useful as biochemicals or therapeutics for the treatment of diseases or disorders. There is a need for glue degrader compounds for targeting proteins for degradation. The present application addresses the need for glue degrader molecules that are directed to a variety of protein targets.

SUMMARY OF THE DISCLOSURE

A first aspect of the present disclosure relates to compounds or a pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof that bind to and alter the specificity of a cereblon complex to induce ubiquitination and degradation of a complex-associated protein.

In another aspect, the disclosure relates to compounds that comprises, (i) a tris-tryptophan Pocket Binder moiety that binds to the tris-tryptophan pocket of Cereblon E3 ligase; and (ii) a target affinity moiety attached covalently to the tris-tryptophan Pocket Binder moiety that interacts with the surface of the Cereblon E3 ligase altering its surface and causing the ligase to have affinity for a Target Protein.

Another aspect of the present disclosure relates to compounds of Formula (I)

In another aspect, the present disclosure relates to compounds of Formula (I)

In one aspect of the disclosure, the hydrogens in the compound of Formula (I) are present in their normal isotopic abundances. In a preferred aspect of the disclosure, the hydrogens are isotopically enriched in deuterium (D), and in a particularly preferred aspect of the invention the hydrogen at position Rxis enriched in D, as discussed in more detail concerning isotopes and isotopic enrichment below.

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is useful in the treatment or prevention of a cereblon-mediated disorder, disease, or condition. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

In another aspect, the disclosure relates to a method of modulating cereblon in a biological sample comprising contacting the sample with a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof

Another aspect of the present disclosure relates to a method of inhibiting cereblon in a biological sample comprising contacting the sample with a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure relates to a method of modulating a target protein in a biological sample comprising contacting the sample with a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the present disclosure relates to a method of inhibiting target protein in a biological sample comprising contacting the sample with a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the present disclosure relates to a method of binding to and altering the specificity of a cereblon complex to induce the ubiquitination and degradation of a complex-associated protein selected from the group listed in TABLE 1 in a biological sample, comprising contacting the sample with a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure relates to a method of treating or preventing a cereblon-mediated disorder, disease, or condition in a subject comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the present disclosure relates to a method of treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder in a subject in need thereof.

Another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for treating or preventing cancer.

In another aspect, the disclosure relates to a method of degrading a target protein in a biological sample comprising contacting a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the target protein is selected from the group listed in TABLE 1.

Another aspect of the present disclosure relates to a method of treating or preventing a target protein-mediated disorder, disease, or condition in a subject comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure relates to a method of treating or preventing a cancer in a subject comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for treating or preventing a cereblon-mediated disorder, disease, or condition in a subject in need thereof.

In another aspect, the disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment or prevention of a cereblon-mediated disorder, disease, or condition in a subject in need thereof.

Another aspect of the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment or prevention of cancer.

In another aspect, the disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for treating or preventing a target protein-mediated disorder, disease, or condition in a subject.

Another aspect of the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment or prevention of a target protein-mediated disorder, disease, or condition in a subject.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure relates to compounds and compositions that are capable of modulating or inhibiting a Target Protein by binding to and altering the specificity of a cereblon complex to induce ubiquitination and degradation of a complex-associated protein. The disclosure features methods of treating, preventing, or ameliorating a cereblon-mediated disorder, disease, or condition by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The methods of the present disclosure can be used in the treatment of a variety of a cereblon-mediated disorder, disease, or condition diseases and disorders by modulating the Target Protein levels. Modulation of protein levels through degradation provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, infectious diseases or disorders, and other cereblon-mediated disorders, diseases, or conditions.

In a first aspect of the disclosure, the compounds of Formula (I) are described:

The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

Definition of Terms and Conventions Used

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification and appended claims, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, (C1-10)alkyl means an alkyl group or radical having 1 to 10 carbon atoms. In general, for groups comprising two or more subgroups, the last named group is the radical attachment point, for example, “alkylaryl” means a monovalent radical of the formula alkyl-aryl-, while “arylalkyl” means a monovalent radical of the formula aryl-alkyl-. Furthermore, the use of a term designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the respective divalent radical and vice versa. Unless otherwise specified, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups. The articles “a” and “an” refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

The term “and/or” means either “and” or “or” unless indicated otherwise.

The term “optionally substituted” means that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups.

The term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

The term “unsubstituted” means that the specified group bears no substituents.

Unless otherwise specifically defined, “aryl” means a cyclic, aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group are optionally joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group is optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, —H, -halogen, —CN, —O—C1-6alkyl, C1-6alkyl, —O—C2-C6alkenyl, —O—C2-6alkynyl, C2-6alkenyl, C2-6alkynyl, —OH, —OP(O)(OH)2, —OC(O)C1-6alkyl, —C(O)C1-6alkyl, —OC(O)O(C1-6alkyl), NH2, NH(C1-6alkyl), N(C1-6alkyl)2, —S(O)2—C1-6alkyl, —S(O)NH(C1-6alkyl), and S(O)N(C1-6alkyl)2. The substituents are themselves optionally substituted. Furthermore, when containing two fused rings, the aryl groups optionally have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

“Alkoxy” means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, e.g., —O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” means a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted and may be straight or branched.

“Alkynyl” means a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted.

“Alkylene” or “alkylenyl” means a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C1-6alkylene. An alkylene may further be a C1-4alkylene. Typical alkylene groups include, but are not limited to, —CH2—, —CH(CH3)—, —C(CH3)2—, —CH2CH2—, —CH2CH(CH3)—, —CH2C(CH3)2—, —CH2CH2CH2—, —CH2CH2CH2CH—, and the like.

“Cycloalkyl” or “carbocyclyl” means a monocyclic or polycyclic saturated or partially unsaturated carbon ring containing 3-18 carbon atoms wherein there is not delocalized n electrons (aromaticity) shared among the ring carbon. Examples of cycloalkyl groups include, without limitations, cyclopropenyl, cyclopropyl cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof. A C3-8cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkyl group can be fused (e.g., decalin) or bridged (e.g., norbomane).

“Heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-9alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-7alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-5alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10alkyl.

“Heterocyclyl” means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, or sulfur (O, N, or S) and wherein there is not delocalized n electrons (aromaticity) shared among the ring carbon or heteroatoms. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, dithiolanyl, and homotropanyl.

“Hydroxyalkyl” means an alkyl group substituted with one or more —OH groups. Examples of hydroxyalkyl groups include HO—CH2—, HO—CH2CH2—, and CH2—CH(OH)—.

“Haloalkyl” means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

“Haloalkoxy” means an alkoxy group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

“Cyano” means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C≡N.

“Amino” means a substituent containing at least one nitrogen atom (e.g., NH2).

“Alkylamino” means an amino or NH2group where one of the hydrogens is replaced with an alkyl group, e.g., —NH(alkyl). Examples of alkylamino groups include, but are not limited to, methylamino (e.g., —NH(CH3)), ethylamino, propylamino, iso-propylamino, n-butylamino, sec-butylamino, tert-butylamino, etc.

“Dialkylamino” means an amino or NH2group where both of the hydrogens are replaced with alkyl groups, e.g., —N(alkyl)2. The alkyl groups on the amino group are the same or different alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino (e.g., —N(CH3)2), diethylamino, dipropylamino, diiso-propylamino, di-n-butylamino, di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino, methyl(butylamino), etc.

“Spirocarbocyclyl” means a carbocyclyl bicyclic ring system with both rings connected through a single atom. The rings can be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. A C3-12spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.

“Spiroheterocycloalkyl” or “spiroheterocyclyl” means a spirocarbocyclyl wherein at least one of the rings is a heterocycle one or more of the carbon atoms can be substituted with a heteroatom (e.g., one or more of the carbon atoms can be substituted with a heteroatom in at least one of the rings). One or both of the rings in a spiroheterocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.

“Prodrug” or “prodrug derivative” mean a covalently-bonded derivative or carrier of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s). In general, such prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood, and generally include esters and amide analogs of the parent compounds. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: “Design and Applications of Prodrugs”; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in their entireties.

“Pharmaceutically acceptable prodrug” as used herein means a prodrug of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.

“Salt” means an ionic form of the parent compound or the product of the reaction between the parent compound with a suitable acid or base to make the acid salt or base salt of the parent compound. Salts of the compounds of the present disclosure can be synthesized from the parent compounds which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid parent compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.

“Pharmaceutically acceptable salt” means a salt of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use. The term includes pharmaceutically-acceptable acid addition salts and pharmaceutically-acceptable base addition salts. As the compounds of the present disclosure are useful in both free base and salt form, in practice, the use of the salt form amounts to use of the base form. Lists of suitable salts are found in, e.g., S. M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19, which is hereby incorporated by reference in its entirety.

“Solvate” means a complex of variable stoichiometry formed by a solute, for example, a compound of Formula (I)) and solvent, for example, water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. In general, such solvents selected for the purpose of the disclosure do not interfere with the biological activity of the solute. Solvates encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

The compounds of the present disclosure as discussed below include the free base or acid thereof, their salts, solvates, and prodrugs and may include oxidized sulfur atoms or quaternized nitrogen atoms in their structure, although not explicitly stated or shown, particularly the pharmaceutically acceptable forms thereof. Such forms, particularly the pharmaceutically acceptable forms, are intended to be embraced by the appended claims.

C. Isomer Terms and Conventions

“Isomers” means compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms in space. The term includes stereoisomers and geometric isomers.

“Stereoisomer” or “optical isomer” mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.

“Enantiomers” means a pair of stereoisomers that are non-superimposable mirror images of each other.

“Diastereoisomers” or “diastereomers” mean optical isomers which are not mirror images of each other.

“Racemic mixture” or “racemate” mean a mixture containing equal parts of individual enantiomers.

“Non-racemic mixture” means a mixture containing unequal parts of individual enantiomers.

“Geometrical isomer” means a stable isomer which results from restricted freedom of rotation about double bonds (e.g., cis-2-butene and trans-2-butene) or in a cyclic structure (e.g., cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane). Because carbon-carbon double (olefinic) bonds, C═N double bonds, cyclic structures, and the like may be present in the compounds of the disclosure, the disclosure contemplates each of the various stable geometric isomers and mixtures thereof resulting from the arrangement of substituents around these double bonds and in these cyclic structures. The substituents and the isomers are designated using the cis/trans convention or using the E or Z system, wherein the term “E” means higher order substituents on opposite sides of the double bond, and the term “Z” means higher order substituents on the same side of the double bond. A thorough discussion of E and Z isomerism is provided in J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons, 1992, which is hereby incorporated by reference in its entirety. Several of the following examples represent single E isomers, single Z isomers, and mixtures of E/Z isomers. Determination of the E and Z isomers can be done by analytical methods such as x-ray crystallography,1H NMR, and13C NMR.

Some of the compounds of the disclosure can exist in more than one tautomeric form. As mentioned above, the compounds of the disclosure include all such tautomers.

It is well-known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the disclosure from this disclosure and the knowledge of the prior art.

Thus, although the racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is inactive, it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S-isomer). Furthermore, the pharmacological activities of enantiomers may have distinct biological activity. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos. 5,114,946 and 4,818,541.

Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way, the patient undergoing treatment would be exposed to a lower total dose of the drug and to a lower dose of an enantiomer that is possibly toxic or an inhibitor of the other enantiomer.

Preparation of pure enantiomers or mixtures of desired enantiomeric excess (ee) or enantiomeric purity are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof. These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T. E. Beesley and R. P. W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc., 2000. Furthermore, there are equally well-known methods for the quantitation of enantiomeric excess or purity, for example, GC, HPLC, CE, or NMR, and assignment of absolute configuration and conformation, for example, CD ORD, X-ray crystallography, or NMR.

In general, all tautomeric forms and isomeric forms and mixtures, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, of a chemical structure or compound is intended, unless the specific stereochemistry or isomeric form is specifically indicated in the compound name or structure.

D. Pharmaceutical Administration and Treatment Terms and Conventions

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or nonhuman primate, such as a monkey, chimpanzee, baboon or, rhesus. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

An “effective amount” or “therapeutically effective amount” when used in connection with a compound means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

The terms “pharmaceutically effective amount” or “therapeutically effective amount” means an amount of a compound according to the disclosure which, when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue, system, or patient that is sought by a researcher or clinician. The amount of a compound of according to the disclosure which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the disclosure, and the age, body weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.

As used herein, the term “pharmaceutical composition” refers to a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

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

A subject is “in need of” a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably, a human).

As used herein, the term “treat”, “treating”, or “treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.

As used herein, the term “prevent”, “preventing”, or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

“Disorder” means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

“Administer”, “administering”, or “administration” means to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

“Prodrug” means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

“Compounds of the present disclosure”, “Compounds of Formula (I)”, “compounds of the disclosure”, and equivalent expressions (unless specifically identified otherwise) refer to compounds of Formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (Iaa), (Iab), (Iac), (Iad), (Iae), (Iaf), (Iag), (Iah), (Iai), (Iaj), (Iak), (Ial), and (Iam) as herein described including the tautomers, the prodrugs, salts particularly the pharmaceutically acceptable salts, and the solvates and hydrates thereof, where the context so permits thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labelled compounds (including deuterium substitutions), as well as inherently formed moieties (e.g., polymorphs, solvates and/or hydrates). For purposes of this disclosure, solvates and hydrates are generally considered compositions. In general and preferably, the compounds of the disclosure and the formulas designating the compounds of the disclosure are understood to only include the stable compounds thereof and exclude unstable compounds, even if an unstable compound might be considered to be literally embraced by the compound formula. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.

“Stable compound” or “stable structure” means 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 or diagnostic agent. For example, a compound which would have a “dangling valency” or is a carbanion is not a compound contemplated by the disclosure.

Provided compounds are binders of CRBN and are therefore useful for treating one or more disorders associated with activity of CRBN or mutants thereof. Thus, in certain embodiments, the present disclosure provides a method for treating a CRBN-mediated disorder comprising the step of administering to a patient in need thereof a compound of the disclosure, or pharmaceutically acceptable composition thereof.

As used herein, the term “CRBN-mediated” disorders, diseases, and/or conditions means any disease, condition, or disorder in which CRBN or a mutant thereof is known to play a role. Accordingly, another embodiment relates to treating tor preventing one or more diseases in which CRBN, or a mutant thereof, is known to play a role. Such CRBN-mediated disorders include but are not limited respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders.

In a specific embodiment, the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield.

D. Specific Embodiments and Methods for Testing Compounds of Formula (I)

The present disclosure relates compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for the treatment or prevention of diseases and disorders associated with modulation of protein levels through the binding to and altering of the specificity of a cereblon complex to induce proteasome-mediated degradation of the selected proteins. The disclosure further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for the treatment or prevention of diseases and disorders associated with reducing or decreasing protein levels through the binding to and altering of the specificity of a cereblon complex to induce proteasome-mediated degradation of the selected proteins.

In one embodiment, the compounds of Formula (I) have a formula selected from:

In some embodiments of the formulae above, Rd1is —CH2OC(O)R15, —CH2OP(O)OHOR15, or CH2OP(O)(R15)2. In another embodiment, Rd1is H, —CH2OC(O)R15, or —CH2OP(O)OHOR15. In yet another embodiment, Rd1is H, —CH2OC(O)R15, or —CH2OP(O)(R15)2. In another embodiment, Rd1is H, —CH2OP(O)OHOR15, or —CH2OP(O)(R15)2. In yet another embodiment, Rd1is H or —CH2OC(O)R15. In another embodiment, Rd1is H or —CH2OP(O)OHOR15. In yet another embodiment, Rd1is H or —CH2OP(O)(R15)2. In another embodiment, Rd1is H.

In some embodiments of the formulae above, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In another embodiment, Rd3is

In some embodiments of the formulae above, A1is a 5- or 6-membered heterocyclyl optionally comprising 1-3 additional heteroatoms selected from O, N, and S or 5-membered heteroaryl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S and substituted with one to two R1d. In another embodiment, A1is a 5- or 6-membered heterocyclyl optionally comprising 1-3 additional heteroatoms selected from O, N, and S or 5-membered heteroaryl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S. In yet another embodiment, A1is a 5-membered heterocyclyl optionally comprising 1-3 additional heteroatoms selected from O, N, and S or 5-membered heteroaryl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S and substituted with one to three R1d. In another embodiment, A1is a 5-membered heterocyclyl optionally comprising 1-3 additional heteroatoms selected from O, N, and S or 5-membered heteroaryl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S. In yet another embodiment, A1is a 6-membered heterocyclyl optionally comprising 1-3 additional heteroatoms selected from O, N, and S or 5-membered heteroaryl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S and substituted with one to three R1d. In another embodiment, A1is a 6-membered heterocyclyl optionally comprising 1-3 additional heteroatoms selected from O, N, and S or 5-membered heteroaryl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S.

In another embodiment, A1is a 5- or 6-membered heterocyclyl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S and substituted with one to two R1d. In another embodiment, A1is a 5- or 6-membered heterocyclyl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S. In yet another embodiment, A1is a 5-membered heterocyclyl optionally comprising 1-3 additional heteroatoms selected from N, NRlk, O, and S and substituted with one to three R1d. In another embodiment, A1is a 5-membered heterocyclyl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S. In yet another embodiment, A1is a 6-membered heterocyclyl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S and substituted with one to three R1d. In another embodiment, A1is a 6-membered heterocyclyl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S.

In another embodiment, A1is a 5-membered heteroaryl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S and substituted with one to three R1d. In another embodiment, A1is a 5-membered heteroaryl optionally comprising 1-3 additional heteroatoms selected from N, NR1k, O, and S.

In some embodiments of the formulae above, A2is a C5-7carbocyclyl or 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, NR1k, O, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to three R1d.

In some embodiments of the formulae above, X1is NR4. In another embodiment, X1is S.

In some embodiments of the formulae above, X2is CR1aor N. In another embodiment, X2is CR1a.

In yet another embodiment, X2is N.

In some embodiments of the formulae above, X2ais CR1aor N. In another embodiment, X2ais CR1a. In yet another embodiment, X2ais N.

In some embodiments of the formulae above, each X3is independently CR1dor N; wherein no more than two X3are N.

In some embodiments of the formulae above, each X3′is independently CR1d, CR1cor N, wherein no more than two X3are N and wherein at least one X3′is CR1c. In another embodiment, each X3′is independently CR1dor CR1c, wherein at least one X3′is CR1c. In another embodiment, each X3′is independently CR1cor N, wherein no more than two X3are N.

In some embodiments of the formulae above, each X4is independently CR1dor N, wherein at least one X4is N and wherein no more than two X4are N.

In some embodiments of the formulae above, each X5is independently CR1aor N; wherein no more than two X5are N.

In some embodiments of the formulae above, X6is NR1kor O. In another embodiment, X6is NR1kor S. In yet another embodiment, X6is O or S. In another embodiment, X6is NR1k. In yet another embodiment, X6is O. In another embodiment, X6is S.

In some embodiments of the formulae above, X7is NR4or O. In another embodiment, X7is N NR4or S. In yet another embodiment, X7is O or S. In another embodiment, X7is NR4. In yet another embodiment, X7is O. In another embodiment, X7is S.

In some embodiments of the formulae above, R1d, R1i, and R1jon the benzoxazole ring are not all simultaneously H. In another embodiment, R1dand R1hare H and R1iis not H. In another embodiment, R1iand R1iare H and R1dis not H. In another embodiment, R1dand R1iare H and R1iis not H. In another embodiment, R1dis H and R1iand R1jare not H. In another embodiment, R1iis H and R1dand R1jare not H. In another embodiment, R1jis H and R1dand R1iare not H.

In some embodiments of the formulae above, R3is H or C1-3alkyl. In another embodiment, R3is C1-6alkyl. In yet another embodiment, R3is H or C2-6alkyl. In another embodiment, R3is H or C3-6alkyl. In yet another embodiment, R3is H, methyl, ethyl, n-propyl, or i-propyl. In another embodiment, R3is H, ethyl, n-propyl, or i-propyl. In yet another embodiment, R3is H, n-propyl, or i-propyl. In another embodiment, R3is H, methyl, or ethyl. In yet another embodiment, R3is H or methyl. In another embodiment, R3is H.

In some embodiments of the formulae above, R4is H or C1-3alkyl. In another embodiment, R4is C1-6alkyl. In yet another embodiment, R4is H or C2-6alkyl. In another embodiment, R4is H or C3-6alkyl.

In some embodiments of the formulae above, each R5is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-3haloalkoxy, halogen, —OH, —C(O)H, —C(O)(C1-6alkyl), —C(O)(C6-10aryl), —C(O)(5- or 6-membered heteroaryl), —C(O)(C3-7carbocyclyl), —C(O)(5- to 7-membered heterocyclyl), —(CH2)0-3C(O)OC1-6alkyl, —C(O)NH2, —C(O)NH(C1-6alkyl), —C(O)N(C1-6alkyl)2, —NHC(O)R9, —N(R9)C(O)(R9), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —NHC(O)O(R9), —N(R9)C(O)O(R9), —NHS(O)2R9, —NR9S(O)2R9, —S(O)qNHR9, —S(O)qN(R9)2, —S(O)qR9, C1-6hydroxyalkyl, —O(CH2)1-3CN, —(CH2)0-6—C3-7carbocyclyl, CN, —O(CH2)0-3(C6-C10)aryl, adamantyl, —O(CH2)0-3-5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, —(CH2)0-6-5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, —(CH2)0-6—C6-10aryl, and —(CH2)0-6-5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three R6, and the carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one to four R8; or two R5when on adjacent atoms, together with the atoms to which they are attached form a C3-7carbocyclyl or a 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to three R6; or two R5when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S; or two R5when on the same atom, together with the atom to which they are attached form a C3-7spirocarbocyclyl or a 5- to 7-membered spiroheterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four R10; or two R5when on the same carbon atom form ═(O);

In another embodiment, each R5is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-3haloalkoxy, halogen, —OH, —C(O)H, —C(O)(C1-6alkyl), —C(O)(C6-10aryl), —C(O)(5- or 6-membered heteroaryl), —C(O)(C3-7carbocyclyl), —C(O)(5- to 7-membered heterocyclyl)-(CH2)0-3C(O)OC1-6alkyl, —C(O)NH2, —C(O)NH(C1-6alkyl), —C(O)N(C1-6alkyl)2, —NHC(O)R9, —N(R9)C(O)(R9), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —NHC(O)O(R9), —N(R9)C(O)O(R9), —NHS(O)2R9, —NR9S(O)2R9, —S(O)qNHR9, —S(O)qN(R9)2, —S(O)qR9, C1-6hydroxyalkyl, —O(CH2)1-3CN, CN, —O(CH2)0-6—C3-7carbocyclyl, —O(CH2)0-6-5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, —O(CH2)0-3(C6-C10)aryl, adamantyl, —O(CH2)0-3-5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, —(CH2)0-6—C3-7carbocyclyl, —(CH2)0-6-5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, —(CH2)0-6—C6-10aryl, and —(CH2)0-6-5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three R6, and the carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one to four R8; or two R5when on adjacent atoms, together with the atoms to which they are attached form a C3-7carbocyclyl or a 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to three R6; or two R5when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S; or two R5when on the same atom, together with the atom to which they are attached form a C3-7spirocarbocyclyl or a 5- to 7-membered spiroheterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four R10; or two R5when on the same carbon atom form ═(O).

In another embodiment, two R5when on adjacent atoms, together with the atoms to which they are attached form a C3-7carbocyclyl or a 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to three R6; or two R5when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S; or two R5when on the same atom, together with the atom to which they are attached form a C3-7spirocarbocyclyl or a 5- to 7-membered spiroheterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four R10; or two R5when on the same carbon atom form ═(O).

In another embodiment, two R5when on adjacent atoms, together with the atoms to which they are attached form a C3-7carbocyclyl or a 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to three R6. In yet another embodiment, two R5when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, two R5when on the same atom, together with the atom to which they are attached form a C3-7spirocarbocyclyl or a 5- to 7-membered spiroheterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four R10. In yet another embodiment, two R5when on the same carbon atom form ═(O).

In another embodiment, each R5is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-3haloalkoxy, halogen, —OH, —C(O)H, —C(O)(C1-6alkyl), —C(O)(C6-10aryl), —C(O)(5- or 6-membered heteroaryl), —C(O)(C3-7carbocyclyl), —C(O)(5- to 7-membered heterocyclyl)-(CH2)0-3C(O)OC1-6alkyl, —C(O)NH2, —C(O)NH(C1-6alkyl), —C(O)N(C1-6alkyl)2, —NHC(O)R9, —N(R9)C(O)(R9), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —NHC(O)O(R9), —N(R9)C(O)O(R9), —NHS(O)2R9, —NR9S(O)2R9, —S(O)qNHR9, —S(O)qN(R9)2, —S(O)qR9, C1-6hydroxyalkyl, —O(CH2)1-3CN, wherein the alkyl is optionally substituted with one to three R6, and the carbocyclyl, heterocyclyl, aryl and heteroaryl ire optionally substituted with one to four R8; or two R5when on adjacent atoms, together with the atoms to which they are attached form a C3-7carbocyclyl or a 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to three R6; or two R5when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S; or two R5when on the same atom, together with the atom to which they are attached form a C3-7spirocarbocyclyl or a 5- to 7-membered spiroheterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four R10; or two R5when on the same carbon atom form ═(O).

In another embodiment, each R5is independently —O(CH2)0-6—C3-7carbocyclyl, —O(CH2)0-6-5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, —O(CH2)0-3(C6-C10)aryl, adamantyl, —O(CH2)0-3-5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, —(CH2)0-6—C3-7carbocyclyl, —(CH2)0-6-5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, —(CH2)0-6—C6-10aryl, and —(CH2)0-6-5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one to four R8; or two R5when on adjacent atoms, together with the atoms to which they are attached form a C3-7carbocyclyl or a 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to three R6; or two R5when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S; or two R5when on the same atom, together with the atom to which they are attached form a C3-7spirocarbocyclyl or a 5- to 7-membered spiroheterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four R10; or two R5when on the same carbon atom form ═(O).

In some embodiments of the formulae above, R6is —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, C6-10aryl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R7. In another embodiment, R6is —NH2, —NH(C1-6alkyl), or —N(C1-6alkyl)2. In another embodiment, R6is C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R7. In yet another embodiment, R6is —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2phenyl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R7. In another embodiment, R6is —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, C6-10aryl, or a 5-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R7.

In yet another embodiment, R6is —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, C6-10aryl, or a 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R7. In another embodiment, R6is —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, phenyl, or a 5-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl are optionally substituted with one to three R7.

In another embodiment, R6is —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, phenyl, or a 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl are optionally substituted with one to three R7. In yet another embodiment, R6is —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, or C6-10aryl optionally substituted with one to three R7. In another embodiment, R6is —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S optionally substituted with one to three R7. In another embodiment, R6is —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, or phenyl optionally substituted with one to three R7. In yet another embodiment, R6is —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, 5-membered heteroaryl optionally substituted with one to three R7. In another embodiment, R6is —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, 6-membered heteroaryl optionally substituted with one to three R7.

In some embodiments of the formulae above, R9is C1-4alkyl, C1-4haloalkyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, C6-10aryl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R11. In another embodiment, R9is C1-6alkyl, C1-6haloalkyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, phenyl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl are optionally substituted with one to three R11. In another embodiment, R9is C1-6alkyl, or C1-6haloalkyl. In yet another embodiment, R9is 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, C6-10aryl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R11. In another embodiment, R9is C1-6alkyl, C1-6haloalkyl, C6-10aryl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R9. In yet another embodiment, R9is C1-6alkyl, C1-6haloalkyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the heteroaryl is optionally substituted with one to three R11. In another embodiment, R9is C1-6alkyl, C1-6haloalkyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, or a 5- or 6-membered heteroaryl, wherein the heteroaryl is optionally substituted with one to three R11.

In another embodiment, R9is C1-6alkyl, C1-6haloalkyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, phenyl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl are optionally substituted with one to three R11. In yet another embodiment, R9is C1-6alkyl, C1-6haloalkyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, phenyl, or a 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R11. In another embodiment, R9is C1-6alkyl, C1-6haloalkyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, phenyl, or a 5-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl are optionally substituted with one to three R11. In yet another embodiment, R9is C1-6alkyl, C1-6haloalkyl, 5- or 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, phenyl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl are optionally substituted with one to three R11. In another embodiment, R9is C1-6alkyl, C1-6haloalkyl, 6- or 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, phenyl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl are optionally substituted with one to three R11. In yet another embodiment, R9is C1-6alkyl, C1-6haloalkyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S, phenyl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R11. In another embodiment, R9is C1-6alkyl, C1-6haloalkyl, or 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, R9is C1-6alkyl, C1-6haloalkyl, or phenyl optionally substituted with one to three R11. In another embodiment, R9is C1-6alkyl, C1-6haloalkyl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the heteroaryl is optionally substituted with one to three R11.

In some embodiments of the formulae above, each R1is C1-6alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, or halogen; or two R10, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R10is C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-3haloalkoxy, or halogen. In yet another embodiment, each R10is C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or C1-6haloalkoxy; or two R10, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R10is C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, or halogen; or two R10, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R10is C1-6alkyl, C1-6alkoxy, C1-6haloalkoxy, or halogen; or two R10, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.

In another embodiment, each R10is C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or halogen; or two R10, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R10is C1-6alkyl, C1-6haloalkyl, or halogen; or two R10, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R10is C1-6alkoxy, C1-6haloalkoxy, or halogen; or two R10, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R10is C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or halogen; or two R10, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.

In another embodiment, each R10is C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or halogen; or two R10, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R10is C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or halogen; or two R10, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R10is C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or halogen; or two R10, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or a 5-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R10is C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or halogen; or two R10, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or a 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, two R10, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, two R10, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, two R10, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl. In another embodiment, two R10, when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S.

In some embodiments of the formulae above, each R11is independently C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12. In another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), or —N(C1-6alkyl)C(O)(C1-6alkyl); or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6. 10 aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12. In yet another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12. In another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-4haloalkoxy, —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12.

In another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12. In yet another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12. In another embodiment, each R11is independently C1-6alkyl, C1-6alkoxy, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12.

In another embodiment, each R11is independently C1-6haloalkyl, C1-6alkoxy, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12. In yet another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12. In another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12.

In another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen. In yet another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-4haloalkoxy, or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12. In another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12. In yet another embodiment, each R11is independently C1-6alkoxy, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R12.

In another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl are optionally substituted with one to three R12. In yet another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or a 5-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl are optionally substituted with one to three R12. In another embodiment, each R11is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-4haloalkoxy, —NHC(O)(C1-6alkyl), —N(C1-6alkyl)C(O)(C1-6alkyl), or halogen; or two R11, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or a 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl are optionally substituted with one to three R12. In yet another embodiment, two R11, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl are optionally substituted with one to three R12. In another embodiment, two R11, when on adjacent atoms, together with the atoms to which they are attached form a phenyl optionally substituted with one to three R12. In another embodiment, two R11, when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S and optionally substituted with one to three R12.

In some embodiments of the formulae above, each R12is independently C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy. In another embodiment, each R12is independently C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy. In yet another embodiment, each R12is independently C1-6alkyl, C1-6haloalkyl, or C1-3haloalkoxy. In another embodiment, each R12is independently C1-6alkyl, C1-6alkoxy, or C1-3haloalkoxy.

In yet another embodiment, each R12is independently C1-6haloalkyl, C1-6alkoxy, or C1-3haloalkoxy. In another embodiment, each R12is independently C1-6alkyl or C1-6haloalkyl. In yet another embodiment, each R12is independently C1-6alkyl or C1-6alkoxy. In another embodiment, each R12is independently C1-6alkyl or C1-3haloalkoxy. In yet another embodiment, each R12is independently C1-6haloalkyl or C1-6alkoxy. In another embodiment, each R12is independently C1-6haloalkyl or C1-3haloalkoxy. In yet another embodiment, each R12is independently C1-6alkoxy, or C1-3haloalkoxy. In another embodiment, each R12is independently C1-6alkyl. In yet another embodiment, each R12is independently C1-6haloalkyl. In another embodiment, each R12is independently C1-3haloalkoxy. In yet another embodiment, each R12is independently C1-6alkoxy.

In some embodiments of the formulae above, R13is independently at each occurrence C1-4alkyl, C1-4haloalkyl, C6-10aryl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to two C1-6alkoxy and the aryl and heteroaryl are optionally substituted with one to three R14. In another embodiment, R13is independently at each occurrence C1-6alkyl or C1-6haloalkyl, wherein the alkyl is optionally substituted with one to two C1-6alkoxy. In yet another embodiment, R13is independently at each occurrence C6-10aryl or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with one to three R14. In another embodiment, R13is independently at each occurrence C1-6alkyl, C1-6haloalkyl, phenyl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to two C1-6alkoxy and the phenyl and heteroaryl are optionally substituted with one to three R14. In yet another embodiment, R13is independently at each occurrence C1-6alkyl, C6-10aryl, or a 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to two C1-6alkoxy and the aryl and heteroaryl are optionally substituted with one to three R14.

In another embodiment, R13is independently at each occurrence C1-6alkyl, C1-6haloalkyl, C6-10aryl, or a 5-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to two C1-6alkoxy and the aryl and heteroaryl are optionally substituted with one to three R14. In yet another embodiment, R13is independently at each occurrence C1-6alkyl, C1-6haloalkyl, phenyl, or a 5-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to two C1-6alkoxy and the phenyl and heteroaryl are optionally substituted with one to three R14. In another embodiment, R13is independently at each occurrence C1-6alkyl, C1-6haloalkyl, C6-10aryl, or a 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to two C1-6alkoxy and the aryl and heteroaryl are optionally substituted with one to three R14. In yet another embodiment, R13is independently at each occurrence C1-6alkyl, C1-6haloalkyl, phenyl, or a 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to two C1-6alkoxy and the phenyl and heteroaryl are optionally substituted with one to three R14.

In some embodiments of the formulae above, R15is H or C1-3alkyl. In another embodiment, R15is C1-6alkyl. In yet another embodiment, R11is H or C2-6alkyl. In another embodiment, R11is H or C3-6alkyl. In yet another embodiment, R15is H, methyl, ethyl, n-propyl, or i-propyl. In another embodiment, R15is H, ethyl, n-propyl, or i-propyl. In yet another embodiment, R15is H, n-propyl, or i-propyl. In another embodiment, R15is H, methyl, or ethyl. In yet another embodiment, R15is H or methyl. In another embodiment, R15is H.

In some embodiments of the formulae above, q is 0 or 1. In another embodiment, q is 1 or 2. In another embodiment, q is 0 or 2. In another embodiment, q is 0. In another embodiment, q is 1. In another embodiment, q is 2.

In some embodiments of the formulae above, Rd1is H.

In some embodiments of the formulae above, Rd1is H and Rd2is H.

In some embodiments of the formulae above, Rd1is H andis a double bond.

In some embodiments of the formulae above, Rd1is H andis a single bond.

In some embodiments of the formulae above, Rd2is H andis a double bond.

In some embodiments of the formulae above, Rd2is H andis a single bond.

In some embodiments of the formulae above, Rd1is H, Rd2is H, andis a double bond.

In some embodiments of the formulae above, Rd1is H, Rd2is H, andis a single bond.

the Targeting Ligand is a group that is capable of binding to a Target Protein, e.g., a Target protein disclosed herein in Table 1;

the Linker is a absent or a group that covalently links the Targeting Ligand to the Targeting Ligase Binder; and

Examples of Linkers and Target Ligands and synthesis thereof is provided in related U.S. Provisional Application entitled “BIFUNCTIONAL DEGRADERS AND THEIR METHODS OF USE” filed on Sep. 16, 2019, and assigned U.S. Ser. No. 62/901,161 (Novartis Docket No. PAT058639-US-PSP) which is incorporated herein in its entirety.

Embodiment 1: A compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, capable of binding to and altering the specificity of a cereblon complex to induce ubiquitination and degradation of a complex-associated protein.

Embodiment 2: The compound of Embodiment 1, wherein the compound comprises, (i) a tris-tryptophan Pocket Binder moiety that binds to the tris-tryptophan pocket of Cereblon E3 ligase; and (ii) a target affinity moiety attached covalently to the tris-tryptophan Pocket Binder moiety that interacts with the surface of the Cereblon E3 ligase altering its surface and causing the ligase to have affinity for a Target Protein.

Embodiment 3: The compound of Embodiment 1 or 2, wherein the compound has a Formula (I):

Embodiment 4: The compound of Embodiment 3, wherein Rd1is H.

Embodiment 6: The compound of any one of Embodiments 1-5, wherein Rd2is H.

Embodiment 7: The compound of any one of Embodiments 1-6, wherein Rd1and Rd2are each independently H.

Embodiment 8: The compound of any one of Embodiments 1-7, wherein R1dis H.

Embodiment 9: The compound of any one of Embodiments 1-8, wherein Rd3is

Embodiment 10: The compound of any one of Embodiments 1-9, wherein Rd3is

Embodiment 11: The compound of any one of Embodiments 1-10, wherein the compound has a formula selected from:

Embodiment 12: The compound of any one of the Embodiments 1-11, wherein the compound is selected from:1-(benzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(6-ethynylbenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(5-methylbenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(5-iodobenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(6-iodobenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; phenyl (3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzofuran-5-yl)carbamate;1-(6-chloropyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(7-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(7-(1-(4-(tert-butyl)benzoyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; and1-(6-(1-benzylpiperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

Embodiment 13: A pharmaceutical composition comprising a compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

Embodiment 14: The pharmaceutical composition of Embodiment 13 further comprising at least one additional pharmaceutical agent.

Embodiment 15: The pharmaceutical composition of Embodiment 13 or Embodiment 14 for use in the treatment or prevention of a cereblon-mediated disorder, disease, or condition.

Embodiment 16: The pharmaceutical composition of Embodiment 13 or Embodiment 14 for use in the treatment or prevention of a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder.

Embodiment 17: A method of modulating cereblon in a biological sample comprising contacting the sample with a compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt thereof.

Embodiment 18: A method of binding to and altering the specificity of a cereblon complex to induce the ubiquitination and degradation of a complex-associated protein selected from the group listed in TABLE 1 in a biological sample, comprising contacting the sample with a compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 19: A method of treating or preventing a cereblon-mediated disorder, disease, or condition in a subject comprising administering to the subject a compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 20: The method of Embodiment 19, wherein the disorder, disease, or condition is a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder.

Embodiment 21: The method of Embodiment 20, wherein the disorder, disease, or condition is a proliferative disorder.

Embodiment 22: The method of Embodiment 21, wherein the proliferative disorder is cancer.

Embodiment 23: The method of Embodiment 20, wherein the disorder, disease, or condition is a neurological disorder.

Embodiment 24: A method of treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt thereof.

Embodiment 25: The method of Embodiment 24, wherein the disorder or disease is a proliferative disorder.

Embodiment 26: The method of Embodiment 25, wherein the proliferative disorder is cancer.

Embodiment 27: The method of Embodiment 24, wherein the disorder or disease is a neurological disorder.

Embodiment 28: Use of a compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder in a subject in need thereof.

Embodiment 29: Use of a compound of Embodiments 1-12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for treating or preventing cancer.

Embodiment 30: A method of degrading a target protein in a biological sample comprising contacting the compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the target protein is selected from the group listed in TABLE 1.

Embodiment 31: A method of treating or preventing a target protein-mediated disorder, disease, or condition in a subject comprising administering to the subject the compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 32: The method of Embodiment 31, wherein the disorder, disease, or condition is a proliferative disorder.

Embodiment 33: The method of Embodiment 32, wherein the proliferative disorder is cancer.

Embodiment 34: The method of Embodiment 31, wherein the disorder, disease, or condition is a neurological disorder.

Embodiment 35: A compound selected from:

Embodiment 35A: A compound selected from:

Embodiment 36: A pharmaceutical composition comprising a compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

Embodiment 37: The pharmaceutical composition of Embodiment 36 further comprising at least one additional pharmaceutical agent.

Embodiment 38: The pharmaceutical composition of Embodiment 36 or Embodiment 37 for use in the treatment or prevention of a cereblon-mediated disorder, disease, or condition.

Embodiment 39: The pharmaceutical composition of Embodiment 36 or Embodiment 37 for use in the treatment or prevention of a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder.

Embodiment 40: A method of inhibiting cereblon in a biological sample comprising contacting the sample with a compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt thereof.

Embodiment 41: A method of binding to and altering the specificity of a cereblon complex to induce the ubiquitination and degradation of a complex-associated protein selected from the group listed in TABLE 1 in a biological sample, comprising contacting the sample with a compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 42: A method of treating or preventing a cereblon-mediated disorder, disease, or condition in a subject comprising administering to the subject a compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 43: The method of Embodiment 42, wherein the disorder, disease, or condition is a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder.

Embodiment 44: The method of Embodiment 43, wherein the disorder, disease, or condition is a proliferative disorder.

Embodiment 45: The method of Embodiment 44, wherein the proliferative disorder is cancer.

Embodiment 46: The method of Embodiment 43, wherein the disorder, disease, or condition is a neurological disorder.

Embodiment 47: A method of treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt thereof.

Embodiment 48: The method of Embodiment 47, wherein the disorder or disease is a proliferative disorder.

Embodiment 49: The method of Embodiment 48, wherein the proliferative disorder is cancer.

Embodiment 50: The method of Embodiment 47, wherein the disorder or disease is a neurological disorder.

Embodiment 51: Use of a compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder in a subject in need thereof.

Embodiment 52: Use of a compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for treating or preventing cancer.

Embodiment 53: A method of degrading a target protein in a biological sample comprising contacting a compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the target protein is selected from the group listed in TABLE 1.

Embodiment 54: A method of treating or preventing a target protein-mediated disorder, disease, or condition in a subject comprising administering to the subject a compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 55: The method of Embodiment 54, wherein the disorder, disease, or condition is a proliferative disorder.

Embodiment 56: The method of Embodiment 55, wherein the proliferative disorder is cancer.

Embodiment 57: The method of Embodiment 54, wherein the disorder, disease, or condition is a neurological disorder.

Embodiment 58: A method of treating or preventing a cancer in a subject comprising administering to the subject a compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 59: A compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment or prevention of a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder in a subject in need thereof.

Embodiment 60: A compound of Embodiments 1-12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment or prevention of cancer.

Embodiment 61: Use of a compound of Embodiments 1-12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for treating or preventing a target protein-mediated disorder, disease, or condition in a subject.

Embodiment 62: A compound of Embodiments 1-12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment or prevention of a target protein-mediated disorder, disease, or condition in a subject.

Embodiment 63: A compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment or prevention of a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder in a subject in need thereof.

Embodiment 64: A compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment or prevention of cancer.

Embodiment 65: Use of a compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for treating or preventing a target protein-mediated disorder, disease, or condition in a subject.

Embodiment 66: A compound of Embodiment 35 or Embodiment 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment or prevention of a target protein-mediated disorder, disease, or condition in a subject.

Embodiment 67: A method of treating or preventing a cancer in a subject comprising administering to the subject a compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 68: A compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, capable of binding to and altering the specificity of a cereblon complex to induce ubiquitination and degradation of a complex-associated protein.

Embodiment 69: The compound according to Embodiment 68, wherein the compound comprises, (i) a tris-tryptophan Pocket Binder moiety that binds to the tris-tryptophan pocket of Cereblon E3 ligase; and (ii) a target affinity moiety attached covalently to the tris-tryptophan Pocket Binder moiety that interacts with the surface of the Cereblon E3 ligase altering its surface and causing the ligase to have affinity for a Target Protein.

Embodiment 70: The compound according to Embodiment 68 or 69, wherein the compound has a Formula (I):

Embodiment 71: The compound according to Embodiment 70, wherein Rd1is H.

Embodiment 72: The compound according to Embodiment 70, wherein Rd1is —CH2OC(O)R15, —CH2OP(O)OHOR15, or —CH2OP(O)(R15)2.

Embodiment 73: The compound according to any one of Embodiments 70-72, wherein Rd2is H.

Embodiment 74: The compound according to any one of Embodiments 70-73, wherein Rd1and Rd2are each independently H.

Embodiment 75: The compound according to any one of Embodiments 70-74, wherein R1dis H.

Embodiment 76: The compound according to any one of Embodiments 70-75, wherein Rd3is

Embodiment 77: The compound according to any one of Embodiments 70-76, wherein Rd3is

Embodiment 78: The compound according to any one of Embodiments 70-77, wherein the compound has a formula selected from:

Embodiment 79: The compound according to any one of Embodiments 68-78, wherein the compound is selected from:1-(benzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(6-ethynylbenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(6-ethynylbenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(5-iodobenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(6-iodobenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;phenyl (3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzofuran-5-yl)carbamate;1-(6-chloropyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(7-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(7-(1-(4-(tert-butyl)benzoyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(6-(1-benzylpiperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(6-(3-(dimethylamino)prop-1-yn-1-yl)benzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;N-benzyl-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzofuran-6-carboxamide;1-(6-methylbenzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(5-chlorobenzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(6-(4-methylphenethoxy)benzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;1-(6-(1-benzylpiperidin-4-yl)quinolin-3-yl)pyrimidine-2,4(1H,3H)-dione;1-(7-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione; and1-(7-bromoimidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;

Embodiment 80: A pharmaceutical composition comprising a compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

Embodiment 81: The pharmaceutical composition according to Embodiment 80 further comprising at least one additional pharmaceutical agent.

Embodiment 82: The pharmaceutical composition according to Embodiment 80 or Embodiment 81 14 for use in the treatment or prevention of a cereblon-mediated disorder, disease, or condition.

Embodiment 83: The pharmaceutical composition of Embodiment 80 or Embodiment 81 for use in the treatment or prevention of a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder.

Embodiment 84: A method of modulating cereblon in a biological sample comprising contacting the sample with a compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 85: A method of binding to and altering the specificity of a cereblon complex to induce the ubiquitination and degradation of a complex-associated protein selected from the group listed in TABLE 1 in a biological sample, comprising contacting the sample with a compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 86: A method of treating or preventing a cereblon-mediated disorder, disease, or condition in a subject comprising administering to the subject a compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 87: The method according to Embodiment 86, wherein the disorder, disease, or condition is a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder.

Embodiment 88: The method according to Embodiment 87, wherein the disorder, disease, or condition is a proliferative disorder.

Embodiment 89: The method according to Embodiment 88, wherein the proliferative disorder is cancer.

Embodiment 90: The method according to Embodiment 87, wherein the disorder, disease, or condition is a neurological disorder.

Embodiment 91: A method of treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 92: The method according to Embodiment 91, wherein the disorder or disease is a proliferative disorder.

Embodiment 93: The method according to Embodiment 92, wherein the proliferative disorder is cancer.

Embodiment 94: The method according to Embodiment 91, wherein the disorder or disease is a neurological disorder.

Embodiment 95: Use of a compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder in a subject in need thereof.

Embodiment 96: Use of a compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for treating or preventing cancer.

Embodiment 97: A method of degrading a target protein in a biological sample comprising contacting the target protein with a compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the target protein is selected from the group listed in TABLE 1.

Embodiment 98: A method of treating or preventing a target protein-mediated disorder, disease, or condition in a subject comprising administering to the subject a compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 99: The method according to Embodiment 98, wherein the disorder, disease, or condition is a proliferative disorder.

Embodiment 100: The method according to Embodiment 99, wherein the proliferative disorder is cancer.

Embodiment 101: The method according to Embodiment 98, wherein the disorder, disease, or condition is a neurological disorder.

Embodiment 102: A method of treating or preventing a cancer in a subject comprising administering to the subject a compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 103: A compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment or prevention of a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder in a subject in need thereof.

Embodiment 104: A compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment or prevention of cancer.

Embodiment 105: Use of a compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for treating or preventing a target protein-mediated disorder, disease, or condition in a subject.

Embodiment 106: A compound according to any one of Embodiments 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment or prevention of a target protein-mediated disorder, disease, or condition in a subject.

In one embodiment, the Target Protein comprises a beta-hairpin.

In one embodiment, the Target Protein is a beta-turn containing protein. In another embodiment, the beta-turn containing protein is a protein selected from the group listed in Table 1.

In one embodiment, the target protein is selected from the group consisting of:

In another embodiment of the disclosure, the compounds of the present disclosure are enantiomers. In some embodiments the compounds are the (S)-enantiomer. In other embodiments, the compounds are the (R)-enantiomer. In yet other embodiments, the compounds of the present disclosure may be (+) or (−) enantiomers.

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

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

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

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

All stereoisomers (for example, geometric isomers, optical isomers, and the like) of the present compounds (including those of the salts, solvates, esters, and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.) Individual stereoisomers of the compounds of the disclosure may, for example, be substantially free of other isomers, or is admixed, for example, as racemates or with all other, or other selected, stereoisomers.

The chiral centers of the compounds of the disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

The use of the terms “salt”, “solvate”, “ester,” “prodrug”, and the like, is intended to equally apply to the salt, solvate, ester, and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrugs of the inventive compounds.

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

The compounds and intermediates may be isolated and used as the compound per se. Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and, such as2H,3H,11C,13C,14C,15N,18F,31P32P, respectively. The disclosure includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as3H,13C, and14C, are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F,11C or labeled compound may be particularly desirable for PET or SPECT studies.

Further, substitution with heavier isotopes, particularly deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent) or an improvement in therapeutic index. For example, substitution with deuterium may modulate undesirable side effects of the undeuterated compound, such as competitive CYP450 inhibition, time dependent CYP450 inactivation, etc. It is understood that deuterium in this context is regarded as a substituent in compounds of the present disclosure. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this disclosure is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Isotopically-labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by carrying out the procedures disclosed in the schemes or in the examples and preparations described below using an appropriate isotopically-labeled reagent in place of the non-isotopically labeled reagent.

Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, d6-DMSO.

In some embodiments, the degradation of a target protein is measured by EC50.

Potency of can be determined by EC50value. A compound with a lower EC50value, as determined under substantially similar degradation conditions, is a more potent degrader relative to a compound with a higher EC50value. In some embodiments, the substantially similar conditions comprise determining degradation of protein levels in cells expressing the specific protein, or a fragment of any thereof.

The disclosure is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

E. Methods of Using Compounds of Formula (I)

Compounds and compositions described herein are generally useful for the modulation of CRBN. Another aspect of the disclosure relates to a method of modulating a target protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the target protein is a target protein selected from one of the target proteins listed in Table 1.

In another aspect, the disclosure relates to a method of inhibiting a target protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the target protein is a target protein selected from one of the target proteins listed in Table 1.

Another aspect of the disclosure relates to a method of modulating or inhibiting a target protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the target protein is a target protein selected from one of the target proteins listed in Table 1.

In another aspect, the disclosure relates to a method of treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder mediated by a target protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the disorder is mediated by a target protein listed in Table 1.

Another aspect of the disclosure relates to a method of treating or preventing a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the disclosure relates to a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (Iaa), (Iab), (Iac), (Iad), (Iae), (Iaf), (Iag), (Iah), (Iai), (Iaj), (Iak), (Ial), or (Iam), or Compounds I-1 to I-18, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in inhibiting a target protein in a subject in need thereof. In one embodiment, the target protein is a target protein selected from one of the target proteins listed in Table 1.

In another aspect, the disclosure relates to a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (Iaa), (Iab), (Iac), (Iad), (Iae), (Iaf), (Iag), (Iah), (Iai), (Iaj), (Iak), (Ial), or (Iam), or Compounds I-1 to I-18, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in inhibiting a target protein in a subject in need thereof. In one embodiment, the target protein is a target protein selected from one of the target proteins listed in Table 1.

Another aspect of the disclosure relates to the use of a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (Iaa), (Iab), (Iac), (Iad), (Iae), (Iaf), (Iag), (Iah), (Iai), (Iaj), (Iak), (Ial), or (Iam), or Compounds I-1 to I-18, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating a Target Protein-mediated disorder, disease, or condition in a subject in need thereof. In one embodiment, the Target Protein-mediated disorder, disease, or condition is selected from a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder. In one aspect, the proliferative disorder is a cancer.

The disclosed compounds of the disclosure can be administered in effective amounts to treat a disorder and/or prevent the development thereof in subjects.

Compounds of the application can be administered in therapeutically effective amounts in a combinational therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, e.g., non-drug therapies. For example, synergistic effects can occur with other anti-proliferative, anti-cancer, immunomodulatory or anti-inflammatory substances. Where the compounds of the application are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.

F. Combination Therapy

Combination therapy includes the administration of the subject compounds in further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent, an antiproliferative agent, anticancer agent, immunomodulatory agent, an anti-inflammatory agent, a neurological treatment agent, an anti-viral agent, an anti-fungal agent, anti-parasitic agent, an antibiotic, or a general anti-infective agent) and non-drug therapies (such as, but not limited to, surgery or radiation treatment). For instance, the compounds of the application can be used in combination with other pharmaceutically active compounds, preferably compounds that are able to enhance the effect of the compounds of the application. The compounds of the application can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy or treatment modality. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.

In another embodiment, the additional therapeutic agent is selected from the group consisting of: an antiproliferative agent, anticancer agent, immunomodulatory agent, an anti-inflammatory agent, a neurological treatment agent, an anti-viral agent, an anti-fungal agent, anti-parasitic agent, an antibiotic, and a general anti-infective agent.

In another embodiment, the additional therapeutic agent is selected from the group consisting of: a second a target protein inhibitor.

G. Administration, Pharmaceutical Compositions, and Dosing of Compounds of Formula (I)

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

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

Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564, which is hereby incorporated by reference in its entirety.

In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

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

In one embodiment, the disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present disclosure. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.

The kit of the disclosure may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the disclosure typically comprises directions for administration.

The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored.

EXAMPLES

Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.

Those skilled in the art will recognize if a stereocenter exists in the compounds of the present disclosure. Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.

Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker Avance spectrometer or Varian Oxford 400 MHz spectrometer unless otherwise noted. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26) or other solvent as indicated in NMR spectral data. A small amount of the dry sample (2-5 mg) is dissolved in an appropriate deuterated solvent (1 mL). The chemical names were generated using ChemBioDraw Ultra v14 from CambridgeSoft.

To a solution of benzofuran (1-1a, 0.466 mL, 4.23 mmol) in DCM (10 mL), bromine (0.434 mL, 8.47 mmol) was added then stirred at room temperature for 15 minutes. The reaction was quenched with aqueous sodium thiosulfate then extracted with DCM. The organic phases were combined, dried over Na2SO4, filtered, then concentrated to dryness. The crude residue was dissolved into 10 mL THF and then a solution of KOH (237 mg, 4.23 mmol) in 2 mL MeOH was added. The resultant mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with H2O and extracted with EtOAc (3×10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated to dryness. Silica gel chromatography (heptane) affords the desired product 1-2a as an oil (500 mg, 60% yield).1H NMR (400 MHz, chloroform-d) δ 7.67 (s, 1H), 7.59-7.55 (m, 1H), 7.54-7.48 (m, 1H), 7.36 (dqd, J=8.5, 7.3, 1.3 Hz, 2H).

Preparation of 3-(4-Methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1-4a)

To a microwave vial containing 1-2a (70.0 mg, 0.355 mmol), 1-4a (108 mg, 0.462 mmol), CuI (33.8 mg, 0.178 mmol), and K3PO4(151 mg, 0.711 mmol) was added dioxane (2.5 mL). (+/−)-trans Cyclohexyl diamine (0.021 mL, 0.178 mmol) was then added and nitrogen gas was bubbled through the resulting mixture for 5 minutes. The vial was sealed and heated in the microwave at 150° C. for 1 hr (Biotage microwave). The reaction mixture was filtered through Celite® filter aid and the pad was washed with MeOH. The filtrate was concentrated to dryness and the resulting residue was purified by silica gel chromatography, eluting with 2% MeOH/DCM, to afford 1-5a (90 mg, 72% yield). MS [M+H]+=351.2.

Preparation of 3-Bromo-5-nitrobenzofuran (3-1a)

3-2a was prepared according to the procedure described for 1-5a in Example 1 starting from 3-1a (2 g, 8.26 mmol) and 1-4a (2.5 g, 10.75 mmol). The crude material was purified by silica gel chromatography, eluting with 50% EtOAc/hexane, to afford 3-2a (1.75 g, 55% yield). MS [M+H]+=396.1.

To a stirred solution of 3-2a (1.50 g, 3.79 mmol) in THF (20 mL) was added a solution of NH4Cl (aq) (2.43 g, 53.5 mmol). Zn (1.49 g, 22.8 mmol) was then added portion-wise at room temperature and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then filtered through a Celite® pad. The filtrate was diluted with water then extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness to afford crude 3-3a (1.48 g, 4.0 mmol). The crude material was carried onto the next step without purification. MS [M+H]+=366.0.

To a solution of 3-3a (150 mg, 0.41 mmol) in DCM (5 mL) was added Et3N (0.11 mL, 0.82 mmol). Phenyl chloroformate (0.1 mL, 0.73 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated to dryness and the crude material was purified by silica gel chromatography, eluting with 35% EtOAc/heptane, to afford 3-4a as a yellow solid (80 mg, 40% yield). MS [M+H]+=484.2.

TFA (2 mL) was added to 3-3a (220 mg, 0.60 mmol). TfOH (1 mL) was then added at 0° C. over 5 minutes and the resulting mixture was then stirred at 0° C. for 2 hours. The reaction mixture was concentrated to dryness. The crude residue was slowly neutralized with sat. aq. NaHCO3solution then extracted with EtOAc (3×). The combined organic phases were then washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography, eluting with 3% MeOH/DCM, to afford 4-1a as a brown solid (90 mg, 61% yield). MS [M+H]+=246.0.

To a solution of 5-1a (2.50 g, 15.0 mmol) in DMF at room temperature was added ethyl bromoacetate (5-1, 2.0 mL, 18.0 mmol) followed by K2CO3(6.20 g, 44.9 mmol). The resulting mixture was then heated at 110° C. for 1 hour. The reaction mixture was poured into ice water and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness to afford 5-2a (2.50 g, 71%). The obtained product was carried onto the next step without purification.

To a solution of 5-2a (2.50 g, 10.6 mmol) in EtOH (20 mL) was added KOH (1.19 g, 21.3 mmol) at room temperature and the resulting mixture was then heated at 85° C. for 2 hours. The reaction mixture was then cooled to room temperature and concentrated to dryness. The obtained residue was acidified with 6N HCl. The resulting suspension was filtered and the solid was washed with water (2×) and then dried under vacuum filtration to afford 5-3a (1.40 g, 63%). The material was carried onto the next step without purification.

To a solution of 5-3a (1.4 g 6.8 mmol) in quinoline (20 mL) was added Cu2O (0.10 g, 0.68 mmol) and the resulting mixture was then heated at 200° C. for 2 hours. The reaction mixture was then cooled to room temperature and filtered through Celite® filter aid. The filtrate was diluted with water and extracted with EtOAc (2×100 mL). The combined organic phases were washed with 6N HCl (2×50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography, eluting with 3% EtOAc/hexanes, to afford 5-4a (0.72 g, 65% yield).

To a degassed solution of I-5 (120 mg, 0.34 mmol) in DMF (5 mL) was added Pd(PPh3)4(27 mg, 0.20 mmol) and NEt3(0.240 mL, 1.68 mmol) and the resulting mixture was degassed for 5 minutes with nitrogen gas. CuI (6.4 mg, 0.034 mmol) and ethynyltrimethylsilane (0.24 mL, 1.68 mmol) were then added and the reaction mixture was then heated at 80° C. for 16 hours under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography, eluting with 60-65% EtOAc/hexane, to afford 6-1a (80 mg, 73% yield). MS [M+H]+=327.1

To a vial containing 7-3a (366 mg, 0.861 mmol), 1-4a (255 mg, 1.09 mmol), K3PO4(350 mg, 1.65 mmol), and CuI (32.7 mg, 0.172 mmol) and under an atmosphere nitrogen was added dioxane (6 mL). Rac-trans-cyclohexane-1,2-diamine (19.7 mg, 0.172 mmol) was then added via micropipette and the resulting mixture was sealed (pressure relief cap) and heated at 95° C. overnight. The reaction mixture was cooled to room temperature and filtered through Celite® filter aid, washing the pad with EtOAc (3×15 mL). The filtrate was washed with water (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The resulting brown residue was dissolved in MeCN (10 mL) and NIS (60 mg, 0.267 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (15 mL) and then quenched with 50% aq. sodium thiosulfate solution (5 mL) and water (5 mL). The phases were separated and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness affording a brown oil. The residue was then purified by silica gel chromatography, eluting with 0-6% MeOH/DCM, to afford 7-4a as a brown solid (240 mg, 52% yield). MS [M+H]+=532.2

To 7-4a (240 mg, 0.451 mmol) was added 20% TfOH in TFA (5 mL) and the resulting mixture was heated at 60° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove TFA. The resulting red residue was dissolved in water (5 mL) and then stirred at room temperature for 5 minutes. The mixture was filtered with water washes (2×5 mL). The aqueous phase was then neutralized with solid NaHCO3to ˜pH 7. THF (10 mL) was added to the aqueous mixture followed by the addition of Boc-anhydride (245 μL, 1.054 mmol) and TBAI (33.4 mg, 0.090 mmol). The reaction mixture was stirred at room temperature for 1 hour and then diluted with EtOAc (15 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×15 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated to dryness. The resulting solid was purified by silica gel chromatography, eluting with 1% Et3N/EtOAc, to afford 7-5a as an off-white solid (105 mg, 58% yield).1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 7.18 (dd, J=7.3, 1.6 Hz, 1H), 6.43 (bs, 1H), 4.05 (bs, 2H), 3.80 (t, J=6.7 Hz, 2H), 3.57 (t, J=5.5 Hz, 2H), 2.83 (t, J=6.6 Hz, 2H), 2.54 (bs, 2H), 1.44 (s, 9H). MS [M+H]+=412.1.

To a room temperature suspension of 7-5a (90 mg, 0.219 mmol) in EtOAc (1.5 mL) was added HCl (4N in dioxane) (1.5 mL, 6.00 mmol) and the resulting mixture was then stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness to provide 7-6a as an off-white solid (90 mg, 100% yield), which was carried onto the next step without purification. MS [M+H]+=312.1.

To a stirred solution of 7-4a (3.90 g, 7.34 mmol) in DCM (10 mL) was added 4N HCl in dioxane (5.0 mL) at 0° C. and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to afford the 8-1a as a yellow solid (3.20 g, 93% yield), which was carried onto the next step without purification. MS [M+H]+=432.2.

To a stirred solution of 8-1a (250 mg, 0.70 mmol) in DMF (5.0 mL) was added DIPEA (0.38 mL, 2.13 mmol), 4-(tert-butyl)benzoic acid (139 mg, 0.78 mmol), and HATU (404.0 mg, 1.06 mmol) and the resulting mixture was then stirred at room temperature overnight. Water was added and the mixture was extracted with DCM. The organic phase was separated, dried over Na2SO4, and concentrated to dryness to afford a light brown solid. The obtained solid was purified by silica gel chromatography, eluting with 5% MeOH/DCM, to afford 8-2a as an off-white solid (200 mg, 47% yield). MS [M+H]+=592.0.

Intermediate 9-1a was synthesized according to the procedure described for the synthesis of 7-4a in Example 7, Step 2 starting from 6-bromoimidazo[1,2-a]pyridine (369 mg, 1.97 mmol) to provide 9-1a as a brown amorphous solid (204 mg, 0.34 mmol). MS [M+H]+=532.3.

To a room temperature solution of 9-1a (74 mg, 0.18 mmol) in THF, was added Pd/C (25 mg, 0.023 mmol) and the resulting mixture was purged with hydrogen gas for 5 minutes and stirred under an atmosphere of hydrogen using a gas balloon overnight. The reaction mixture was then purged with nitrogen gas and filtered through Celite® filter aid, washing the pad with DCM (60 mL). The filtrate was concentrated to dryness and the resulting residue was dissolved in DCM (1.5 mL). TFA (300 μL, 3.89 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes and then concentrated to dryness. The resulting residue was stored under high vacuum for 1 hour and dissolved in DMF (1.5 mL). DIPEA (117 μL, 0.668 mmol) was added followed by addition of BnBr (22 μL, 0.187 mmol). The reaction mixture was stirred at room temperature for 20 minutes and then quenched with 1N HCl (3 mL) and filtered. The aqueous mixture was washed with EtOAc (2×5 mL) and DCM (2×5 mL), neutralized to a pH of 7 with solid NaHCO3, and then extracted with EtOAc (4×10 mL). The combined organic phases were then dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography, eluting with 0-20% IPA/DCM, to afford the desired product I-10 as a cream-colored solid (26 mg, 32% yield, broad peak at 20% IPA/DCM).1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.10 (s, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.38-7.24 (m, 6H), 3.78 (t, J=6.7 Hz, 2H), 3.58-3.42 (m, 2H), 3.07-2.78 (m, 4H), 1.86-1.64 (m, 5H). MS [M+H]+=404.2.

Nitrogen gas was bubbled through a stirred suspension of 10-2a (0.796 g, 2.86 mmol), 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1-4a, 1 g, 4.29 mmol), CuI (136 mg, 0.715 mmol), and K3PO4(1.52 g, 7.15 mmol) in dioxane (14.3 mL). (+/−)-trans-1,2-Diaminocyclohexane (86 μL, 0.715 mmol) was then added and the resulting mixture was sparged with nitrogen for a further 5 minutes before it as capped and heated at 90° C. for ˜18 hours. The reaction mixture was then allowed to cool to room temperature and diluted with water (100 mL). 28% NH4OH (aq) (5 mL) was added and the resulting mixture was extracted with EtOAc (2×100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo to afford a brown oily residue. The crude material was pre-adsorbed onto silica gel and purified by silica gel flash chromatography, eluting with 0-5% MeOH/DCM, to afford a brown solid. The solid was sonicated in DCM (10 mL) and the resulting suspension was left to slurry at room temperature for 2 hours. The resulting solid was removed by vacuum filtration and washed with small amounts of DCM. The filtrate was concentrated in vacuo to afford 10-3a as a pale brown foam (1.04 g, 71% yield at 75% purity).1H NMR (400 MHz, DMSO-d6) δ 9.00 (dd, J=1.8, 0.8 Hz, 1H), 8.11 (s, 1H), 7.62 (dd, J=9.6, 0.9 Hz, 1H), 7.32 (dd, J=9.5, 1.8 Hz, 1H), 7.27-7.21 (m, 2H), 6.89-6.85 (m, 2H), 4.82 (s, 2H), 3.81 (t, J=6.7 Hz, 2H), 3.72 (s, 3H), 2.96 (t, J=6.8 Hz, 2H). MS [M+H]+=385.1.

I-5 (150 mg, 0.42 mmol, Example 5) was dissolved in DMF (3 mL) and the resulting mixture was degassed with argon gas for 10 min. CuI (8.0 mg, 0.042 mmol), Pd(PPh)2Cl2(15 mg, 0.021 mmol), Et3N (0.58 mL, 4.2 mmol) and N-Boc propargyl amine (71.9 mg, 0.46 mmol) were then added and the resulting mixture was degassed with argon for 5 min and then heated at 90° C. for 18 h. The reaction mixture was then concentrated to dryness under high vacuum and EtOAc was added to the resulting solid mass. The crude material was purified via silica gel chromatography, eluting with 70-80% EtOAc/hexane, to afford 11-1 as a white solid (96 mg, 90% purity, 59% yield). MS [M+H]+=384.2.

To a stirred solution of 11-1 in dioxane (5 mL) at 0° C. was added HCl (4N in dioxane, 1 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The crude product was washed with MeCN, EtOAc, and CHCl3to afford 11-2 as a solid (50 mg, 94% purity, 66% yield) which was carried onto the next step without further purification. MS [M+H]+=284.1.

To a stirred solution of benzofuran-6-carboxylic acid (12-1, 4 g, 24.7 mmol) in DMF (50 mL) was added MeI (2.3 mL, 37.0 mmol) followed by K2CO3(6.8 g, 49.3 mmol) under an atmosphere of nitrogen at 0° C. and the resulting mixture was allowed to stir and warm up to room temperature over 16 h. The reaction mixture was then diluted with EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated to dryness to afford crude 12-2, which was taken onto the next step without further purification.1H NMR (300 MHz, DMSO-d6): δ 8.21 (d, J=1.8 Hz, 1H), 8.1 (bs, 1H), 7.87 (dd, J=8.1, 1.8 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.07-7.06 (m, 1H), 3.85 (s, 3H).

12-4 was prepared according to the procedure described for 1-5a in Example 1 starting from 12-3 (1.3 g, 5.1 mmol) and 1-4a (1.6 g, 6.6 mmol). The crude material was purified by silica gel chromatography eluting with 50% EtOAc/hexane to afford 12-4 as a yellow oil (0.9 g, 43% yield). MS [M+H]+=409.1.

To a solution of 12-4 (0.5 g, 1.2 mmol) in dioxane (5 mL) was added concentrated HCl (5 mL) at 0° C. and the resulting mixture was then stirred at 50° C. for 40 h (monitored by TLC). The reaction mixture was then concentrated to dryness. The crude material was purified by silica gel chromatography eluting with 4-5% MeOH/DCM to afford 12-5 (0.42 g, 40% purity by LC-MS), which was taken onto next step without further purification. MS [M+H]+=394.9.

To a stirred solution of 12-5 (0.1 g, 40% purity) in DMF (5 mL) were added benzyl amine (0.03 mL, 0.3 mmol) and HATU (0.14 g, 0.38 mmol) followed by DIPEA (0.22 mL, 1.26 mmol) at rt and the resulting mixture was stirred at rt for 16 h. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was purified by silica gel chromatography eluting with 60% EtOAc/heptane, to afford 12-6 (0.14 g, ca. 29% purity by LC-MS), which was taken onto next step without further purification. MS [M+H]+=484.2.

A solution of 3-chloropropanoyl isocyanate (13-2, 0.45 g, 3.4 mmol; see Bioorg. Med. Chem. 2009, 17, 3873-3878) in THF (2 mL) was added dropwise to a solution of 6-methylbenzo[d]isoxazol-3-amine (13-1, 0.25 g, 1.7 mmol) in THF (Volume: 8.4 ml) at rt and the resulting mixture was stirred at rt for 15 min. The reaction mixture was then diluted with EtOAc and quenched with water. The phases were separated and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to provide crude 3-chloro-N-((6-methylbenzo[d]isoxazol-3-yl)carbamoyl)propanamide (13-3) as a white solid which was used in the next step without further purification. MS [M+H]+=282.2.

Potassium tert-butoxide (284 mg, 2.53 mmol) was added to a solution of crude 3-chloro-N-((6-methylbenzo[d]isoxazol-3-yl)carbamoyl)propanamide (13-3, 475 mg, 1.687 mmol) in DMF (17 mL) at rt and the resulting mixture was stirred at rt for 5 min. The reaction mixture was then diluted with EtOAc and quenched with ˜1.5 mL of 2N aqueous HCl solution. Water was added and the phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with water and brine and then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was dissolved in DMSO and purified by reverse-phase HPLC (MeCN/H2O with 0.1% TFA modifier) to provide the trifluoroacetate salt of 1-(6-methylbenzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (I-13, 5.5 mg, 15 umol, 1% yield). MS m/z [M+H]*=246.2.1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.66-7.55 (m, 2H), 7.48 (dd, J=8.7, 1.7 Hz, 1H), 4.05 (t, J=6.6 Hz, 2H), 2.79 (t, J=6.6 Hz, 2H), 2.42 (s, 3H).

A solution of 3-chloropropanoyl isocyanate (13-2, 0.40 g, 3.0 mmol; see Bioorg. Med. Chem. 2009, 17, 3873-3878) in THF (2 mL) was added dropwise to a solution of 5-chlorobenzo[d]isoxazol-3-amine (14-1, 0.25 g, 1.7 mmol) in THF (Volume: 7.4 ml) at rt and the resulting mixture was stirred at rt for 15 min. The reaction mixture was then diluted with EtOAc and quenched with water. The phases were separated and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give crude 3-chloro-N-((5-chlorobenzo[d]isoxazol-3-yl)carbamoyl)propanamide (14-2) as a white solid, which was used in the next step without further purification. MS [M+H]+=302.1.

Potassium tert-butoxide (250 mg, 2.23 mmol) was added to a solution of crude 3-chloro-N-((5-chlorobenzo[d]isoxazol-3-yl)carbamoyl)propanamide (14-2, 448 mg, 1.48 mmol) in DMF (14 mL) at rt and the resulting mixture was stirred at rt for 5 min. The reaction mixture was then diluted with EtOAc and quenched with ˜1.5 mL of 2N aqueous HCl solution. Water was added and the phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with water and brine, and then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was dissolved in DMSO and purified by reverse-phase HPLC (MeCN/H2O with 0.1% TFA modifier) to provide the trifluoroacetate salt of 1-(5-chlorobenzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (I-14, 16 mg, 39 umol, 3% yield). MS [M+H]+266.2.1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.92 (dd, J=2.1, 0.7 Hz, 1H), 7.85-7.77 (m, 1H), 7.70 (ddd, J=9.0, 2.2, 0.6 Hz, 1H), 4.07 (t, J=6.6 Hz, 2H), 2.79 (t, J=6.6 Hz, 2H).

KOtBu (200 mg, 1.782 mmol) was weighed in a vial and then dry DMF (8 mL) was added followed by N-hydroxyacetamide (129 mg, 1,718 mmol) and the resulting mixture was stirred at room temperature for 30 min. A solution of 15-3 (277 mg, 1.085 mmol) in DMF (3 mL) was then added to the suspension all at once. The reaction mixture was then heated at 50° C. overnight (75% conversion) and was then quenched with sat. aq. NH4Cl solution (10 mL) and diluted with water (5 mL). The mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (2×10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to dryness. The resulting colorless oil was purified by silica gel chromatography, eluting with 0-45% EtOAc/heptane, to afford 154 as a white solid (156 rug, 54% yield). MS [M+H]+=269.2.

To a solution of tert-butyl 4-(3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)quinolin-6-yl)piperidine-1-carboxylate (16-6, 562 mg, 1.33 mmol) in THF (10 mL) was added a 4M HCl solution in dioxane (3.0 mL, 13 mmol) and the resulting mixture was stirred for 3 h at 60° C. The solvents were removed under reduced pressure. Water was then added and the resulting aqueous mixture was lyophilized to dryness to provide product 16-7, which was used in the next step without further purification. MS [M+H]+=323.3.

Biological Assays and Data

The activity of a compound according to the present disclosure can be assessed by the following in vitro methods.

Example 18: Prolabel Quantification of IKZF1, GSPT1, or SALL4 protein levels in GripTite™ 293 MSR Cell line

The Prolabel system from DiscoverX was used to develop high-throughput and quantitative assays to measure changes in IKZF1, GSPT1, and SALL4 protein levels in response to compounds. The prolabel tag is derived from the alpha fragment of beta galactosidase and has the following protein sequence: mssnslavvlgrrdwenpgvtglnrlaahppfaswrnseeartdrpsqqlrsinge (SEQ ID NO. 1). The complementary fragment of beta-galactosidase (from DiscoverX), is added to the prolabel tag to form an active beta galactosidase enzyme whose activity can be precisely measured. In this way, the levels of a fusion protein with the prolabel tag can be quantified in cell lysates.

Lentiviral vectors, based on the Invitrogen pLenti6.2/V5 DEST backbone, were constructed that placed the prolabel tag upstream of IKZF1, GSPT1, or SALL4 and expressed the fusion protein from a CMV promoter.

To ensure moderate and consistent expression of the prolabel fusion proteins across all cells in the population, stable cell lines were constructed from cells expressing a single copy of the construct. Lentivirus packaged with the constructs was made using the Virapower kit from Invitrogen. Strongly adherent 293GT cell, GripTite 293 MSR cells from Thermo Fisher Scientific (Catalog number: R79507), were infected with the virus at low multiplicity of infection and selected by 5 μg/mL blasticidin for 2 weeks.

The levels of prolabel tagged fusion proteins in compound treated cell lines were measured as follows:

Day 1, Cells were diluted to 1.0×106cells/mL in normal growth medium. 17.5 μL of cells were plated in each well of a solid white 384 well plate. Plates were incubated overnight in a 37° C. tissue culture incubator.

Day 2, Serial dilutions of compounds were made in 384 well plates from 10 mM stocks. 15 μL of DMSO was added to each well of a 384 well plate. In the first column, 15 μL of stock compound was added. The solution was mixed and 15 μL was transferred to the next column. This was repeated until 20 two-fold dilutions were prepared. 2.5 μL of the diluted compounds were transferred into 60 μL of cell culture medium in another 384 well plate, and mixed well. 2.5 μL of this mixture was added to the plated cells. The final DMSO concentration was 0.5% and the highest concentration of compound was 50 μM. Plates were incubated overnight (e.g., about 14 h, 18 h, or 24 h) in a 37° C. tissue culture incubator.

Day 3, Plates were removed from the incubator and allowed to equilibrate at room temperature for 30 minutes. Prolabel substrate (DiscoverX PathHunter Prolabel Detection Kit, User manual: 93-0180) was added as described by the manufacturers protocols. Plates were incubated at room temperature for three hours and luminescence was read using an Envision reader (Perkin Elmer) Data was analyzed and visualized using the Spotfire software package.

Table 2 shows Ikaros (IKZF1) degradation activity of representative compounds in the disclosure in Pro-label assays in GripTite™ 293 MSR Cell line, (EC50, and % degradation at 10 μM).

Table 3 shows G1 to S phase transition 1 protein (GSPT1) degradation activity of representative compounds of the disclosure in Pro-label assays in GripTite™ 293 MSR Cell line, (EC50, and % degradation at 10 μM).

Table 4 shows Spalt Like Transcription Factor 4 (SALL4) degradation activity of representative compounds of the disclosure in Pro-label assays in GripTite™ 293 MSR Cell line, (EC50, and % degradation at 101 μM).