INHIBITORS OF ALPHA-5 BETA-1 INTEGRIN AND USES THEREOF

BACKGROUND

Despite its high prevalence, current therapeutic options for asthma are quite limited. There is a paucity of effective treatments for asthma. Pharmacological modulation of the α5β1 integrin by small molecules presents one route to test the role of the α5β1 integrin in asthma. There is a need in the art for potent, selective α5β1 integrin inhibitors. Disclosed herein, inter alia, are solutions to these and other problems in the art.

BRIEF SUMMARY

In an aspect is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:

X is a bond, —C(R15)(R16)— or —N(R15)—. The symbol m is 1 or 2.

The symbol n is an integer from 1 to 3.

R7and R15are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R9and R11are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R2A, R2B, R2C, R3A, R3B, R3C, R4B, R4B, R4C, R5A, R5B, R5C, R6A, R6B, R6C, R7A, R7B, R7C, R8A, R8B, R8C, R9A, R9B, R9C, R10A, R10B, R10C, R11A, R11B, R11C, R12A, R12B, R12C, R15C, R16C, R20A, R20B, R20C, R21A, R21B, and R21Care independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —OSO3H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl3, —OCBr3, —OCF3, —OCI3, —OCH2Cl, —OCH2Br, —OCH2F, —OCH2I, —OCHCl2, —OCHBr2, —OCHF2, —OCHI2, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R5Aand R5Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R6Aand R6Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R7Aand R7Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R8Aand R8Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9Aand R9Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R10Aand R10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R11Aand R11Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R12Aand R12Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R20Aand R20Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R21Aand R21Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable excipient.

In an aspect is provided a method of treating an inflammatory disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof.

In an aspect is provided a method of treating cancer in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof.

In an aspect is provided a method of inhibiting angiogenesis in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof.

In an aspect is provided a method of modulating (e.g., reducing) the level of activity of α5β1 integrin in a cell, the method including contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof.

DETAILED DESCRIPTION

The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, —CH2CH2CH2CH2—. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds.

In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. A bicyclic or multicyclic cycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings.

In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. A bicyclic or multicyclic cycloalkenyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkenyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkenyl ring of the multiple rings.

In embodiments, the term “heterocycloalkyl” means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system. In embodiments, heterocycloalkyl groups are fully saturated. A bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings.

Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

The term “alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.

In a recited claim or chemical formula description herein, each R substituent or L linker that is described as being “substituted” without reference as to the identity of any chemical moiety that composes the “substituted” group (also referred to herein as an “open substitution” on an R substituent or L linker or an “openly substituted” R substituent or L linker), the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituent groups as defined below.

The first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R1may be substituted with one or more first substituent groups denoted by R1.1, R2may be substituted with one or more first substituent groups denoted by R2.1, R3may be substituted with one or more first substituent groups denoted by R3.1, R4may be substituted with one or more first substituent groups denoted by R4.1, R5may be substituted with one or more first substituent groups denoted by R5.1, and the like up to or exceeding an R100that may be substituted with one or more first substituent groups denoted by R100.1. As a further example, R1Amay be substituted with one or more first substituent groups denoted by R1A.1, R2Amay be substituted with one or more first substituent groups denoted by R2A.1, R3Amay be substituted with one or more first substituent groups denoted by R3A.1, R4Amay be substituted with one or more first substituent groups denoted by R4A.1, R5Amay be substituted with one or more first substituent groups denoted by R5A.1and the like up to or exceeding an R100Amay be substituted with one or more first substituent groups denoted by R100A.1As a further example, L1may be substituted with one or more first substituent groups denoted by RL1.1, L2may be substituted with one or more first substituent groups denoted by RL2.1, L3may be substituted with one or more first substituent groups denoted by RL3.1, L4may be substituted with one or more first substituent groups denoted by RL4.1, L5may be substituted with one or more first substituent groups denoted by RL5.1and the like up to or exceeding an L100which may be substituted with one or more first substituent groups denoted by RL100.1. Thus, each numbered R group or L group (alternatively referred to herein as RWWor LWWwherein “WW” represents the stated superscript number of the subject R group or L group) described herein may be substituted with one or more first substituent groups referred to herein generally as RWW.1or RLWW.1, respectively. In turn, each first substituent group (e.g., R1.1, R2.1, R3.1, R4.1, R5.1. . . R100.1; R1A.1, R2A.1, R3A.1, R4A.1, R5A.1. . . R100A.1; RL1.1, RL2-1, RL3.1, RL4.1, RL5.1. . . RL100.1) may be further substituted with one or more second substituent groups (e.g., R1.2, R2.2, R3.2, R4.2, R5.2. . . R100.2; R1A.2, R2A.2, R3A.2, R4A.2, R5A.2. . . R100A.2; RL1.2, RL2.2, RL3.2, RL4.2, RL5.2. . . RL100.2, respectively). Thus, each first substituent group, which may alternatively be represented herein as RWW.1as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as RWW.2.

Thus, as used herein, RWWrepresents a substituent recited in a claim or chemical formula description herein which is openly substituted. “WW” represents the stated superscript number of the subject R group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). Likewise, LWWis a linker recited in a claim or chemical formula description herein which is openly substituted. Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). As stated above, in embodiments, each RWWmay be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3. Similarly, each LWWlinker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RLWW.1; each first substituent group, RLWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RLWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RLWW.3. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if RWWis phenyl, the said phenyl group is optionally substituted by one or more RWW.1groups as defined herein below, e.g., when RWW.1is RWW.2-substituted or unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more RWW.2, which RWW.2is optionally substituted by one or more RWW. 3. By way of example when the RWWgroup is phenyl substituted by RWW.1, which is methyl, the methyl group may be further substituted to form groups including but not limited to:

Where two different RWWsubstituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl), in embodiments the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group, RWW.2, may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3; and each third substituent group, RWW.3, is unsubstituted. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. In the context of two different RWWsubstituents joined together to form an openly substituted ring, the “WW” symbol in the RWW.1, RWW.2and RWW.3refers to the designated number of one of the two different RWWsubstituents. For example, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW.1is R100A.1, RWW.2is R100A.2, and RWW. 3is R100A.3. Alternatively, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW.1is R100B.1, RWW.2is R100B.2, and RWW. 3is R100B.3. RWW.1, RWW.2and RWW. 3in this paragraph are as defined in the preceding paragraphs.

It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.

As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g., —NH2, —COOH, —N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., —N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., -sulfo-N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).

Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or streptavidin to form an avidin-biotin complex or streptavidin-biotin complex.

The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.

“Analog,” “analogue,” or “derivative” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

The terms “a” or “an”, as used in herein means one or more. In addition, the phrase “substituted with a[n]”, as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20alkyl, or unsubstituted 2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C1-C20alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13substituents are present, each R13substituent may be distinguished as R13.A, R13.B, R13.C, R13.D, etc., wherein each of R13.A, R13.B, R13.C, R13.D, etc. is defined within the scope of the definition of R13and optionally differently.

Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (−)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.

The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.

A polypeptide, or a cell is “recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.

“Co-administer” is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

The terms “treating” or “treatment” refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. For example, the certain methods presented herein successfully treat cancer by decreasing the incidence of cancer and or causing remission of cancer. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. The term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is no prophylactic treatment.

“Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables).

The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In some embodiments contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.

As defined herein, the term “activation,” “activate,” “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.

The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.

As defined herein, the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity or function of the cellular component in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.

The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.

The term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

The term “modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.

“Patient”, “patient in need thereof”, “subject”, or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human.

“Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is an inflammatory disease. In embodiments, the disease is asthma. In embodiments, the disease is a cancer. In embodiments, the disease is angiogenesis.

The term “asthma” refers to any disease or condition characterized by inflammation within the respiratory system, often accompanied with wheezing, airway restriction, shortness of breath, chest tightness, and coughing. In embodiments, asthma is characterized by airway hyperresponsiveness. In embodiments, asthma is airway hyperresponsiveness. Asthma may refer inflammation in the bronchi and bronchioles. Asthma may refer to atopic asthma. Asthma may refer to non-atopic asthma.

As used herein, the term “lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin's disease. Hodgkin's disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

The term “melanoma” is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

As used herein, the terms “metastasis,” “metastatic,” and “metastatic cancer” can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and/or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non-metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.

The terms “cutaneous metastasis” and “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast). In cutaneous metastasis, cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin.

The term “visceral metastasis” refers to secondary malignant cell growths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from a primary cancer site may migrate to the internal organs where they divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs.

The term “drug” is used in accordance with its common meaning and refers to a substance which has a physiological effect (e.g., beneficial effect, is useful for treating a subject) when introduced into or to a subject (e.g., in or on the body of a subject or patient). A drug moiety is a radical of a drug.

Radioactive substances (e.g., radioisotopes) that may be used as imaging and/or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to,18F,32P,33P,45Ti,47Sc,52Fe,59Fe,62Cu,64Cu,67Cu,67Ga,68Ga,77As,86Y,90Y,89Sr,89Zr,94Tc,94Tc,99mTc,99Mo,105Pd,105Rh,111Ag,111In,123I,124I,125I,131I,142Pr,143Pr,149Pm,153Sm,154-1581Gd,161Tb,166Dy,166Ho,169Er,175Lu,177Lu,186Re,188Re,189Re,194Ir,198Au,199Au,211At,211Pb,212Bi,212Pb,213Bi,223Ra and225Ac. Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

As used herein, the term “administering” is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating a disease associated with cells expressing a disease associated cellular component, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.

In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another.

In therapeutic use for the treatment of a disease, compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily. A daily dose range of about 0.01 mg/kg to about 500 mg/kg, or about 0.1 mg/kg to about 200 mg/kg, or about 1 mg/kg to about 100 mg/kg, or about 10 mg/kg to about 50 mg/kg, can be used. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of cancer diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention, should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a protein associated disease, disease associated with a cellular component) means that the disease (e.g., inflammatory disease, asthma, cancer, or angiogenesis) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component). As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease.

The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

The term “electrophilic” as used herein refers to a chemical group that is capable of accepting electron density. An “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.

“Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.

The term “isolated,” when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

The terms “numbered with reference to” or “corresponding to,” when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

Integrins are transmembrane proteins that mediate interactions between adhesion molecules on adjacent cells and/or the extracellular matrix (ECM). Integrins have diverse roles in several biological processes including, for example, cell migration during development and wound healing, cell differentiation, and apoptosis. Integrins typically exist as heterodimers consisting of a subunits (about 120-170 kDa in size) and p subunits (about 90-100 kDa in size).

The terms “α5β1” and “α5β1 integrin” refer to an integrin comprised of an α5 subunit and a β1 subunit and is used according to its common, ordinary meaning. The term “α5β1” refers to proteins of the same or similar names, homologs, isoforms, and functional fragments thereof, so long as such fragments retain α5β1 integrin activity. The term includes any recombinant or naturally-occurring form of α5β1, or an α5β1 preprotein, or variants thereof that maintain α5β1 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype α5β1). In embodiments, α5 has the protein sequence corresponding to RefSeq NP_002196.3. In embodiments, α5 has the protein sequence corresponding to the proteolytically processed mature version of RefSeq NP_002196.3. In embodiments, α5 has the amino acid sequence corresponding to the reference number GI: 938148811. In embodiments, β1 has the protein sequence corresponding to RefSeq NP_002202.2 In embodiments, β1 has the amino acid sequence corresponding to the reference number GI: 19743813.

An “α5β1-inhibitor” as used herein refers to a composition (e.g., a compound, nucleic acid, polynucleotide, peptide, protein, or antibody) capable of reducing the activity of α5β1 integrin when compared to a control compound (e.g., known to have no reduction in α5β1 integrin activity) or the absence of the α5β1-inhibitor compound. An “α5β1-inhibitor compound” refers to a compound (e.g., compounds described herein) that reduce the activity of α5β1 integrin when compared to a control, such as absence of the compound or a compound with known inactivity.

An “α5β1-specific moiety”, “specific,” “specifically”, “specificity”, or the like of a composition (e.g., a compound, nucleic acid, polynucleotide, peptide, protein, or antibody) refers to the composition's ability to discriminate between particular molecular targets to a significantly greater extent than other proteins in the cell (e.g., a compound having specificity towards α5β1 integrin binds to α5β1 integrin whereas the same compound displays little-to-no binding to other integrins such as αvβ1, α8β1, α2β1, αvβ3, αvβ5, or αvβ6). An “α5β1-specific compound” refers to a compound (e.g. compounds described herein) having specificity towards α5β1 integrin.

The terms “α5β1-selective,” “selective,” or “selectivity” or the like of a compound refers to the composition's (e.g., a compound, nucleic acid, polynucleotide, peptide, protein, or antibody) ability to cause a particular action in a particular molecular target (e.g., a compound having selectivity toward α5β1 integrin would inhibit only α5β1). An “α5β1-selective compound” refers to a compound (e.g. compounds described herein) having selectivity towards α5β1 integrin.

In an aspect is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:

X is a bond, —C(R15)(R16)— or —N(R15)—.

The symbol m is 1 or 2.

The symbol n is an integer from 1 to 3.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

It will be understood by one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms. For example, a tautomer of formula (I-2) is

In embodiments, m is 1. In embodiments, m is 2.

In embodiments, X is a bond. In embodiments, X is —C(R15)(R16)—. In embodiments, X is —CH2—. In embodiments, X is —N(R15)—. In embodiments, X is —NH—.

In embodiments, L1is a bond, —NH—, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, L1is a bond, —NH—, —(CH2)z1—NH—, —(CH2)z2—, or —(CH2)z3—N((CH2)z4CH3)—C(O)—, wherein z1, z2, and z3 are independently an integer from 1 to 10; and z4 is an integer from 0 to 9. In embodiments, L1is a bond. In embodiments, L1is —NH—. In embodiments, L1is —(CH2)z1—NH—, wherein z1 is an integer from 1 to 4. In embodiments, L1is —(CH2)z2—, wherein z2 is an integer from 1 to 4. In embodiments, L1is —(CH2)z3—N((CH2)z4CH3)—C(O)—; wherein z3 is an integer from 1 to 4, and z4 is an integer from 0 to 4.

In embodiments, a substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R2Aand R2Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R6(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R6is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R6is substituted, it is substituted with at least one substituent group. In embodiments, when R6is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R6Aand R6Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R6Aand R6Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R6Aand R6Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R6Aand R6Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R6Aand R6Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R5A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R5Ais substituted, it is substituted with at least one substituent group. In embodiments, when R5Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R5Aand R5Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R7Aand R7Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R7Aand R7Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R7Aand R7Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R7Aand R7Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R7Aand R7Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R7C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R7Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R7Cis substituted, it is substituted with at least one substituent group. In embodiments, when R7Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R7and R15substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R7and R15substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R7and R15substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R7and R15substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R7and R15substituents are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, R7and R15are joined to form a substituted or unsubstituted C5-C6cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R7and R15are joined to form an unsubstituted cyclohexyl. In embodiments, R7and R15are joined to form an unsubstituted 6 membered heterocycloalkyl, wherein the heterocycloalkyl includes (i) an oxygen atom, (ii) a nitrogen atom, or (iii) an oxygen atom and a nitrogen atom. In embodiments, R7and R15are joined to form an unsubstituted phenyl.

In embodiments, X is —C(R15)(R16)— and R7is bonded to R15together with the ring carbon atoms to which they are attached to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C4-C8, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 4 to 8 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R7bonded to R15together with the ring carbon atoms to which they are attached form:

The symbol n13 is an integer from 0 to 4.

The symbols m13 and v13 are independently 1 or 2.

The symbol z13 is an integer from 0 to 7.

In embodiments, a substituted ring formed when R13Aand R13Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R13Aand R13Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R13Aand R13Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R13Aand R13Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R13Aand R13Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R8Aand R8Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R8Aand R8Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R8Aand R8Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R8Aand R8Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R8Aand R8Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R9Aand R9Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R9Aand R9Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R9Aand R9Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R9Aand R9Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R9Aand R9Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R10A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R10Ais substituted, it is substituted with at least one substituent group. In embodiments, when R10Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R10Aand R10Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R11Aand R11Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R11Aand R11Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R11Aand R11Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R11Aand R11Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R11Aand R11Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments R11is

In embodiments, a substituted ring formed when R9and R11substituents are joined (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R9and R11substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R9and R11substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R9and R11substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R9and R11substituents are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, R9and R11are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R9and R11are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl containing one nitrogen atom.

In embodiments, R9is bonded to R11together with the ring carbon atoms to which they are attached to form substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 4 to 8 membered, or 5 to 6 membered), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R9bonded to R11together with the ring carbon atoms to which they are attached form:

In embodiments, a substituted ring formed when R12Aand R12Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R12Aand R12Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R12Aand R12Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R12Aand R12Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R12Aand R12Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R20Aand R20Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R20Aand R20Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R20Aand R20Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R20Aand R20Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R20Aand R20Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R21Aand R21Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R21Aand R21Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R21Aand R21Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R21Aand R21Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R21Aand R21Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, when R1is substituted, R1is substituted with one or more first substituent groups denoted by R1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1substituent group is substituted, the R1.1substituent group is substituted with one or more second substituent groups denoted by R1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2substituent group is substituted, the R1.2substituent group is substituted with one or more third substituent groups denoted by R1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1, R1.1, R1.2, and R1.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R1, R1.1, R1.2, and R1.3, respectively.

In embodiments, when R2is substituted, R2is substituted with one or more first substituent groups denoted by R2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.1substituent group is substituted, the R2.1substituent group is substituted with one or more second substituent groups denoted by R2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.2substituent group is substituted, the R2.2substituent group is substituted with one or more third substituent groups denoted by R2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2, R2.1, R2.2, and R2.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2, R2.1, R2.2, and R2.3, respectively.

In embodiments, when R2Ais substituted, R2Ais substituted with one or more first substituent groups denoted by R2A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.1substituent group is substituted, the R2A.1substituent group is substituted with one or more second substituent groups denoted by R2A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.2substituent group is substituted, the R2A.2substituent group is substituted with one or more third substituent groups denoted by R2A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2A, R2A.1, R2A.2, and R2A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2A, R2A.1, R2A.2, and R2A.3, respectively.

In embodiments, when R2Bis substituted, R2Bis substituted with one or more first substituent groups denoted by R2B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.1substituent group is substituted, the R2Bsubstituent group is substituted with one or more second substituent groups denoted by R2B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.2substituent group is substituted, the R2B.2substituent group is substituted with one or more third substituent groups denoted by R2B3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2B, R2B.1, R2B.2, and R2B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2B, R2B.1, R2B.2, and R2B.3, respectively.

In embodiments, when R2Aand R2Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R2A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.1substituent group is substituted, the R2A.1substituent group is substituted with one or more second substituent groups denoted by R2A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2A.2substituent group is substituted, the R2A.2substituent group is substituted with one or more third substituent groups denoted by R2A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2A.1, R2A.2, and R2A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R2A.1, R2A.2, and R2A.3, respectively.

In embodiments, when R2Aand R2Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R2B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.1substituent group is substituted, the R2B.1substituent group is substituted with one or more second substituent groups denoted by R2B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2B.2substituent group is substituted, the R2B.2substituent group is substituted with one or more third substituent groups denoted by R2B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2B.1, R2B.2, and R2B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R2B.1, R2B.2, and R2B.3, respectively.

In embodiments, when R2Cis substituted, R2Cis substituted with one or more first substituent groups denoted by R2C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2C.1substituent group is substituted, the R2C.1substituent group is substituted with one or more second substituent groups denoted by R2C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2C.2substituent group is substituted, the R2C.2substituent group is substituted with one or more third substituent groups denoted by R2C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2C, R2C.1, R2C.2, and R2C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R2C, R2C.1, R2C.2, and R2C.3, respectively.

In embodiments, when R3is substituted, R3is substituted with one or more first substituent groups denoted by R3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.1substituent group is substituted, the R3.1substituent group is substituted with one or more second substituent groups denoted by R3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3.2substituent group is substituted, the R3.2substituent group is substituted with one or more third substituent groups denoted by R3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3, R3.1, R3.2, and R3.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3, R3.1, R3.2, and R3.3, respectively.

In embodiments, when R3Ais substituted, R3Ais substituted with one or more first substituent groups denoted by R3A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.1substituent group is substituted, the R3A.1substituent group is substituted with one or more second substituent groups denoted by R3A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.2substituent group is substituted, the R3A.2substituent group is substituted with one or more third substituent groups denoted by R3A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3A, R3A.1, R3A.2, and R3A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3A, R3A.1, R3A.2, and R3A.3, respectively.

In embodiments, when R3Bis substituted, R3Bis substituted with one or more first substituent groups denoted by R3B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.1substituent group is substituted, the R3B.1substituent group is substituted with one or more second substituent groups denoted by R3B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.2substituent group is substituted, the R3B.2substituent group is substituted with one or more third substituent groups denoted by R3B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3B, R3B.1, R3B.2, and R3B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3B, R3B.1, R3B.2, and R3B.3, respectively.

In embodiments, when R3Aand R3Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R3A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.1substituent group is substituted, the R3A.1substituent group is substituted with one or more second substituent groups denoted by R3A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A.2substituent group is substituted, the R3A.2substituent group is substituted with one or more third substituent groups denoted by R3A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3A.1, R3A.2, and R3A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R3A.1, R3A.2, and R3A.3, respectively.

In embodiments, when R3Aand R3Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R3B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.1substituent group is substituted, the R3B.1substituent group is substituted with one or more second substituent groups denoted by R3B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B.2substituent group is substituted, the R3B.2substituent group is substituted with one or more third substituent groups denoted by R3B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3B.1, R3B.2, and R3B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R3B.1, R3B.2, and R3B.3, respectively.

In embodiments, when R3Cis substituted, R3Cis substituted with one or more first substituent groups denoted by R3C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3C.1substituent group is substituted, the R3C.1substituent group is substituted with one or more second substituent groups denoted by R3C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3C.2substituent group is substituted, the R3C.2substituent group is substituted with one or more third substituent groups denoted by R3C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3C, R3C.1, R3C.2, and R3C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R3C, R3C.1, R3C.2, and R3C.3, respectively.

In embodiments, when R4is substituted, R4is substituted with one or more first substituent groups denoted by R4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.1substituent group is substituted, the R4.1substituent group is substituted with one or more second substituent groups denoted by R4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4.2substituent group is substituted, the R4.2substituent group is substituted with one or more third substituent groups denoted by R4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R4.1, R4.2, and R4.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4, R4.1, R4.2, and R4.3, respectively.

In embodiments, when R4Ais substituted, R4Ais substituted with one or more first substituent groups denoted by R4A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.1substituent group is substituted, the R4A.1substituent group is substituted with one or more second substituent groups denoted by R4A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.2substituent group is substituted, the R4A.2substituent group is substituted with one or more third substituent groups denoted by R4A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4A, R4A.1, R4A.2, and R4A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4B, R4A.1, R4A.2, and R4A.3, respectively.

In embodiments, when R4Bis substituted, R4Bis substituted with one or more first substituent groups denoted by R4B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.1substituent group is substituted, the R4B.1substituent group is substituted with one or more second substituent groups denoted by R4B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.2substituent group is substituted, the R4B.2substituent group is substituted with one or more third substituent groups denoted by R4B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4B, R4B.1, R4B.2, and R4B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4B, R4B.1, R4B.2, and R4B.3, respectively.

In embodiments, when R4Aand R4Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R4A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.1substituent group is substituted, the R4A.1substituent group is substituted with one or more second substituent groups denoted by R4A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A.2substituent group is substituted, the R4A.2substituent group is substituted with one or more third substituent groups denoted by R4A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4A.1, R4A.2, and R4A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R4A.1, R4A.2, and R4A.3, respectively.

In embodiments, when R4Aand R4Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R4B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.1substituent group is substituted, the R4B.1substituent group is substituted with one or more second substituent groups denoted by R4B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B.2substituent group is substituted, the R4B.2substituent group is substituted with one or more third substituent groups denoted by R4B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4B.1, R4B.2, and R4B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R4B.1, R4B.2, and R4B.3, respectively.

In embodiments, when R4Cis substituted, R4Cis substituted with one or more first substituent groups denoted by R4C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4C.1substituent group is substituted, the R4C.1substituent group is substituted with one or more second substituent groups denoted by R4C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4C.2substituent group is substituted, the R4C.2substituent group is substituted with one or more third substituent groups denoted by R4C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4C, R4C.1, R4C.2, and R4C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R4C, R4C.1, R4C.2, and R4C.3, respectively.

In embodiments, when R5is substituted, R5is substituted with one or more first substituent groups denoted by R5.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.1substituent group is substituted, the R5.1substituent group is substituted with one or more second substituent groups denoted by R5.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5.2substituent group is substituted, the R5.2substituent group is substituted with one or more third substituent groups denoted by R5.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5, R5.1, R5.2, and R5.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5, R5.1, R5.2, and R5.3, respectively.

In embodiments, when R5Ais substituted, R5Ais substituted with one or more first substituent groups denoted by R5A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5A.1substituent group is substituted, the R5A.1substituent group is substituted with one or more second substituent groups denoted by R5A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5A.2substituent group is substituted, the R5A.2substituent group is substituted with one or more third substituent groups denoted by R5A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5A, R5A.1, R5A.2, and R5A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5A, R5A.1, R5A.2, and R5A.3, respectively.

In embodiments, when R5Bis substituted, R5Bis substituted with one or more first substituent groups denoted by R5B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B.1substituent group is substituted, the R5B.1substituent group is substituted with one or more second substituent groups denoted by R5B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B.2substituent group is substituted, the R5B.2substituent group is substituted with one or more third substituent groups denoted by R5B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5B, R5B.1, R5B.2, and R5B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R5B, R5B.1, R5B.2, and R5B.3, respectively.

In embodiments, when R5Aand R5Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R5A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5A.1substituent group is substituted, the R5A.1substituent group is substituted with one or more second substituent groups denoted by R5A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5A.2substituent group is substituted, the R5A.2substituent group is substituted with one or more third substituent groups denoted by R5A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5A.1, R5A.2, and R5A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R5A.1, R5A.2, and R5A.3, respectively.

In embodiments, when R5Aand R5Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R5B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B.1substituent group is substituted, the R5B.1substituent group is substituted with one or more second substituent groups denoted by R5B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5B.2substituent group is substituted, the R5B.2substituent group is substituted with one or more third substituent groups denoted by R5B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5B.1, R5B.2, and R5B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R5B.1, R5B.2, and R5B0.3, respectively.

In embodiments, when R5Cis substituted, R5Cis substituted with one or more first substituent groups denoted by R5C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5C.1substituent group is substituted, the R5C.1substituent group is substituted with one or more second substituent groups denoted by R5C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5C.2substituent group is substituted, the R5C.2substituent group is substituted with one or more third substituent groups denoted by R5C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5C, R5C.1, R5C.2, and R5C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R8C, R5C.1, R5C.2, and R5C.3, respectively.

In embodiments, when R6is substituted, R6is substituted with one or more first substituent groups denoted by R6.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6.1substituent group is substituted, the R6.1substituent group is substituted with one or more second substituent groups denoted by R6.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6.2substituent group is substituted, the R6.2substituent group is substituted with one or more third substituent groups denoted by R6.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6, R6.1, R6.2, and R6.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R6, R6.1, R6.2, and R6.3, respectively.

In embodiments, when R6Ais substituted, R6Ais substituted with one or more first substituent groups denoted by R6A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6A.1substituent group is substituted, the R6A.1substituent group is substituted with one or more second substituent groups denoted by R6A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6A.2substituent group is substituted, the R6A.2substituent group is substituted with one or more third substituent groups denoted by R6A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6A, R6A.1, R6A.2, and R6A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R6A, R6A.1, R6A.2, and R6A.3, respectively.

In embodiments, when R6Bis substituted, RBis substituted with one or more first substituent groups denoted by R6B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6B.1substituent group is substituted, the R6B.1substituent group is substituted with one or more second substituent groups denoted by R6.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6B.2substituent group is substituted, the R6B.2substituent group is substituted with one or more third substituent groups denoted by R6B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6B, R6B.1, R6B.2, and R6B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R6B, R6B.1, R6B.2, and R6B.3, respectively.

In embodiments, when R6Aand R6Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R6A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6A.1substituent group is substituted, the R6A.1substituent group is substituted with one or more second substituent groups denoted by R6A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6A.2substituent group is substituted, the R6A.2substituent group is substituted with one or more third substituent groups denoted by R6A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6A.1, R6A.2, and R6A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R6A.1, R6A.2, and R6A.3, respectively.

In embodiments, when R6Aand R6Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R6B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6B.1substituent group is substituted, the R6B.1substituent group is substituted with one or more second substituent groups denoted by R6B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6B.2substituent group is substituted, the R6B.2substituent group is substituted with one or more third substituent groups denoted by R6B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6B.1, R6B.2, and R6B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R6B.1, R6B.2, and R6B.3, respectively.

In embodiments, when R6Cis substituted, R6Cis substituted with one or more first substituent groups denoted by R6C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6C.1substituent group is substituted, the R6C.1substituent group is substituted with one or more second substituent groups denoted by R6C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R6C.2substituent group is substituted, the R6C.2substituent group is substituted with one or more third substituent groups denoted by R6C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R6C, R6C.1, R6C.2, and R6C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R6C, R6C.1, R6C.2, and R6C.3, respectively.

In embodiments, when R7is substituted, R7is substituted with one or more first substituent groups denoted by R7.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.1substituent group is substituted, the R7.1substituent group is substituted with one or more second substituent groups denoted by R7.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.2substituent group is substituted, the R7.2substituent group is substituted with one or more third substituent groups denoted by R7.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7, R7.1, R7.2, and R7.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R7, R7.1, R7.2, and R7.3, respectively.

In embodiments, when R7Ais substituted, R7Ais substituted with one or more first substituent groups denoted by R7A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7A.1substituent group is substituted, the R7A.1substituent group is substituted with one or more second substituent groups denoted by R7A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7A.2substituent group is substituted, the R7A.2substituent group is substituted with one or more third substituent groups denoted by R7A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7A, R7A.1, R7A.2, and R7A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R7A, R7A.1, R7A.2, and R7A.3, respectively.

In embodiments, when R7Bis substituted, R7Bis substituted with one or more first substituent groups denoted by R7B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7B.1substituent group is substituted, the R7B.1substituent group is substituted with one or more second substituent groups denoted by R7B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7B.2substituent group is substituted, the R7B.2substituent group is substituted with one or more third substituent groups denoted by R7B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7B, R7B.1, R7B.2, and R7B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R7B, R7B.1, R7B.2, and R7B.3, respectively.

In embodiments, when R7Aand R7Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R7A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7A.1substituent group is substituted, the R7A.1substituent group is substituted with one or more second substituent groups denoted by R7A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7A.2substituent group is substituted, the R7A.2substituent group is substituted with one or more third substituent groups denoted by R7A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7A.1, R7A.2, and R7A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R7A.1, R7A.2, and R7A.3, respectively.

In embodiments, when R7Aand R7Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R7B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7B.1substituent group is substituted, the R7B.1substituent group is substituted with one or more second substituent groups denoted by R7B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7B.2substituent group is substituted, the R7B.2substituent group is substituted with one or more third substituent groups denoted by R7B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7B.1, R7B.2, and R7B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R7B.1, R7B.2, and R7B.3, respectively.

In embodiments, when R7Cis substituted, R7Cis substituted with one or more first substituent groups denoted by R7C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7C.1substituent group is substituted, the R7C.1substituent group is substituted with one or more second substituent groups denoted by R7C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7C.2substituent group is substituted, the R7C.2substituent group is substituted with one or more third substituent groups denoted by R7C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7C, R7C.1, R7C.2, and R7C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R7C, R7C.1, R7C.2, and R7C.3, respectively.

In embodiments, when R8is substituted, R8is substituted with one or more first substituent groups denoted by R8.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8.1substituent group is substituted, the R8.1substituent group is substituted with one or more second substituent groups denoted by R8.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8.2substituent group is substituted, the R8.2substituent group is substituted with one or more third substituent groups denoted by R8.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R8, R8.1, R8.2, and R8.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R8, R8.1, R8.2, and R8.3, respectively.

In embodiments, when R8Ais substituted, R8Ais substituted with one or more first substituent groups denoted by R8A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8A.1substituent group is substituted, the R8A.1substituent group is substituted with one or more second substituent groups denoted by R8A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8A.2substituent group is substituted, the R8A.2substituent group is substituted with one or more third substituent groups denoted by R8A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R8A, R8A.1, R8A.2, and R8A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R8A, R8A.1, R8A.2, and R8A.3, respectively.

In embodiments, when R8Bis substituted, R8Bis substituted with one or more first substituent groups denoted by R8B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8B.1substituent group is substituted, the R8B.1substituent group is substituted with one or more second substituent groups denoted by R8B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8B.2substituent group is substituted, the R8B.2substituent group is substituted with one or more third substituent groups denoted by R8B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R8B, R8B.1, R8B.2, and R8B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW. 3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R8B, R8B.1, R8B.2, and R8B.3, respectively.

In embodiments, when R8Aand R8Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R8A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8A.1substituent group is substituted, the R8A.1substituent group is substituted with one or more second substituent groups denoted by R8A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8A.2substituent group is substituted, the R8A.2substituent group is substituted with one or more third substituent groups denoted by R8A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R8A.1, R8A.2, and R8A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R8A.1, R8A.2, and R8A.3, respectively.

In embodiments, when R8Aand R8Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R8B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8B.1substituent group is substituted, the R8B.1substituent group is substituted with one or more second substituent groups denoted by R8B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R8B.2substituent group is substituted, the R8B.2substituent group is substituted with one or more third substituent groups denoted by R8B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R8B.1, R8B.2, and R8B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R8B.1, R8B.2, and R8B.3, respectively.

In embodiments, when R8Cis substituted, R8Cis substituted with one or more first substituent groups denoted by R5C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5C.1substituent group is substituted, the R5C.1substituent group is substituted with one or more second substituent groups denoted by R5C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5C.2substituent group is substituted, the R5C.2substituent group is substituted with one or more third substituent groups denoted by R5C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R8C, R8C.1, R8C.2, and R8C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R8C, R8C.1, R8C.2, and R8C.3, respectively.

In embodiments, when R9is substituted, R9is substituted with one or more first substituent groups denoted by R9.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9.1substituent group is substituted, the R9.1substituent group is substituted with one or more second substituent groups denoted by R9.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9.2substituent group is substituted, the R9.2substituent group is substituted with one or more third substituent groups denoted by R9.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R9, R9.1, R9.2, and R9.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R9, R9.1, R9.2, and R9.3, respectively.

In embodiments, when R9Ais substituted, R9Ais substituted with one or more first substituent groups denoted by R9A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9A.1substituent group is substituted, the R9A.1substituent group is substituted with one or more second substituent groups denoted by R9A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9A.2substituent group is substituted, the R9A.2substituent group is substituted with one or more third substituent groups denoted by R9A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R9A, R9A.1, R9A.2, and R9A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R9A, R9A.1, R9A.2, and R9A.3, respectively.

In embodiments, when R9Bis substituted, R9Bis substituted with one or more first substituent groups denoted by R9B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9B.1substituent group is substituted, the R9B.1substituent group is substituted with one or more second substituent groups denoted by R9B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9B.2substituent group is substituted, the R9B.2substituent group is substituted with one or more third substituent groups denoted by R9B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R9B, R9B.1, R9B.2, and R9B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R9B, R9B.1, R9B.2, and R9B.3, respectively.

In embodiments, when R9Aand R9Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R9A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9A.1substituent group is substituted, the R9A.1substituent group is substituted with one or more second substituent groups denoted by R9A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9A.2substituent group is substituted, the R9A.2substituent group is substituted with one or more third substituent groups denoted by R9A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R9A.1, R9A.2, and R9A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R9A.1, R9A.2, and R9A.3, respectively.

In embodiments, when R9Aand R9Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R9B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9B.1substituent group is substituted, the R9B.1substituent group is substituted with one or more second substituent groups denoted by R9B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9B.2substituent group is substituted, the R9B.2substituent group is substituted with one or more third substituent groups denoted by R9B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R9B.1, R9B.2, and R9B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R9B.1, R9B.2, and R9B.3, respectively.

In embodiments, when R9Cis substituted, R9Cis substituted with one or more first substituent groups denoted by R9C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9C.1substituent group is substituted, the R9C.1substituent group is substituted with one or more second substituent groups denoted by R9C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9C.2substituent group is substituted, the R9C.2substituent group is substituted with one or more third substituent groups denoted by R9C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R9C, R9C.1, R9C.2, and R9C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R9C, R9C.1, R9C.2, and R9C.3, respectively.

In embodiments, when R10is substituted, R10is substituted with one or more first substituent groups denoted by R10.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.1substituent group is substituted, the R10.1substituent group is substituted with one or more second substituent groups denoted by R10.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10.2substituent group is substituted, the R10.2substituent group is substituted with one or more third substituent groups denoted by R10.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10, R10.1, R10.2, and R10.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10, R10.1, R10.2, and R10.3, respectively.

In embodiments, when R10Ais substituted, R10Ais substituted with one or more first substituent groups denoted by R10A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.1substituent group is substituted, the R10A.1substituent group is substituted with one or more second substituent groups denoted by R10A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.2substituent group is substituted, the R10A.2substituent group is substituted with one or more third substituent groups denoted by R10A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10A, R10A.1, R10A.2, and R10A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10A, R10A.1, R10A.2, and R10A.3, respectively.

In embodiments, when R10Bis substituted, R10Bis substituted with one or more first substituent groups denoted by R10B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10B.1substituent group is substituted, the R10B.1substituent group is substituted with one or more second substituent groups denoted by R10B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10B.2substituent group is substituted, the R10B.2substituent group is substituted with one or more third substituent groups denoted by R10B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10B, R10B.1, R10B.2, and R10B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10B, R10B.1, R10B.2, and R10B.3, respectively.

In embodiments, when R10Aand R10Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R10A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.1substituent group is substituted, the R10A.1substituent group is substituted with one or more second substituent groups denoted by R10A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10A.2substituent group is substituted, the R10A.2substituent group is substituted with one or more third substituent groups denoted by R10A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10A.1, R10A.2, and R10A.3have values corresponding to the values of RWW.1, RWW.2, and RWW. 3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R10A.1, R10A.2, and R10A.3, respectively.

In embodiments, when R10Aand R10Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R10B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10B.1substituent group is substituted, the R10B.1substituent group is substituted with one or more second substituent groups denoted by R10B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10B.2substituent group is substituted, the R10B.2substituent group is substituted with one or more third substituent groups denoted by R10B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10B.1, R10B.2, and R10B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R10B.1, R10B.2, and R10B.3, respectively.

In embodiments, when R10Cis substituted, R10Cis substituted with one or more first substituent groups denoted by R10C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10C.1substituent group is substituted, the R10C.1substituent group is substituted with one or more second substituent groups denoted by R10C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R10C.2substituent group is substituted, the R10C.2substituent group is substituted with one or more third substituent groups denoted by R10C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R10C, R10C.1, R10C.2, and R10C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R10C, R10C.1, R10C.2, and R10C.3, respectively.

In embodiments, when R11is substituted, R11is substituted with one or more first substituent groups denoted by R11.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11.1substituent group is substituted, the R11.1substituent group is substituted with one or more second substituent groups denoted by R11.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11.2substituent group is substituted, the R11.2substituent group is substituted with one or more third substituent groups denoted by R11.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R11, R11.1, R11.2, and R11.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R11, R11.1, R11.2, and R11.3, respectively.

In embodiments, when R11Ais substituted, R11Ais substituted with one or more first substituent groups denoted by R11A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11A.1substituent group is substituted, the R11A.1substituent group is substituted with one or more second substituent groups denoted by R11A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11A.2substituent group is substituted, the R11A.2substituent group is substituted with one or more third substituent groups denoted by R11A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R11A, R11A.1, R11A.2, and R11A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R11A, R11A.1, R11A.2, and R11A.3, respectively.

In embodiments, when R11Bis substituted, R11Bis substituted with one or more first substituent groups denoted by R11B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11B.1substituent group is substituted, the R11B.1substituent group is substituted with one or more second substituent groups denoted by R11B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11B.2substituent group is substituted, the R11B.2substituent group is substituted with one or more third substituent groups denoted by R11B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R11B, R11B.1, R11B.2, and R11B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R11B, R11B.1, R11B.2, and R11B.3, respectively.

In embodiments, when R11Aand R11Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R11A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11A.1substituent group is substituted, the R11A.1substituent group is substituted with one or more second substituent groups denoted by R11A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11A.2substituent group is substituted, the R11A.2substituent group is substituted with one or more third substituent groups denoted by R11A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R11A.1, R11A.2, and R11A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R11A.1, R11A.2, and R11A.3, respectively.

In embodiments, when R11Aand R11Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R11B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11B.1substituent group is substituted, the R11B.1substituent group is substituted with one or more second substituent groups denoted by R11B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11B.2substituent group is substituted, the R11B.2substituent group is substituted with one or more third substituent groups denoted by R11B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R11B.1, R11B.2, and R11B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R11B.1, R11B.2, and R11B.3, respectively.

In embodiments, when R11Cis substituted, R11Cis substituted with one or more first substituent groups denoted by R11C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11C.1substituent group is substituted, the R11C.1substituent group is substituted with one or more second substituent groups denoted by R11C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11C.2substituent group is substituted, the R11C.2substituent group is substituted with one or more third substituent groups denoted by R11C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R11C, R11C.1, R11C.2, and R11C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R11C, R11C.1, R11C.2, and R11C.3, respectively.

In embodiments, when R9and R11substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R9.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9.1substituent group is substituted, the R9.1substituent group is substituted with one or more second substituent groups denoted by R9.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R9.2substituent group is substituted, the R9.2substituent group is substituted with one or more third substituent groups denoted by R9.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R9.1, R9.2, and R9.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R9.1, R9.2, and R9.3, respectively.

In embodiments, when R9and R11substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R11.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11.1substituent group is substituted, the R11.1substituent group is substituted with one or more second substituent groups denoted by R11.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R11.2substituent group is substituted, the R11.2substituent group is substituted with one or more third substituent groups denoted by R11.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R11.1, R11.2, and R11.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R11.1, R11.2, and R11.3, respectively.

In embodiments, when R12is substituted, R12is substituted with one or more first substituent groups denoted by R12.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12.1substituent group is substituted, the R12.1substituent group is substituted with one or more second substituent groups denoted by R12.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12.2substituent group is substituted, the R12.2substituent group is substituted with one or more third substituent groups denoted by R12.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R12, R12.1, R12.2, and R12.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R12, R12.1, R12.2, and R12.3, respectively.

In embodiments, when R12Ais substituted, R12Ais substituted with one or more first substituent groups denoted by R12A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12A.1substituent group is substituted, the R12A.1substituent group is substituted with one or more second substituent groups denoted by R12A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12A.2substituent group is substituted, the R12A.2substituent group is substituted with one or more third substituent groups denoted by R12A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R12A, R12A.1, R12A.2, and R12A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW. 3correspond to R12A, R12A.1, R12A.2, and R12A.3, respectively.

In embodiments, when R12Bis substituted, R12Bis substituted with one or more first substituent groups denoted by R12B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12B.1substituent group is substituted, the R12B.1substituent group is substituted with one or more second substituent groups denoted by R12B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12B.2substituent group is substituted, the R12B.2substituent group is substituted with one or more third substituent groups denoted by R12B.3. as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R12B, R12B.1, R12B.2, and R12B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R12B, R12B.1, R12B.2, and R12B.3, respectively.

In embodiments, when R12Aand R12Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R12A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12A.1substituent group is substituted, the R12A.1substituent group is substituted with one or more second substituent groups denoted by R12A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12A.2substituent group is substituted, the R12A.2substituent group is substituted with one or more third substituent groups denoted by R12A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R12A.1, R12A.2, and R12A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R12A.1, R12A.2, and R12A.3, respectively.

In embodiments, when R12Aand R12Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R12B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12B.1substituent group is substituted, the R12B.1substituent group is substituted with one or more second substituent groups denoted by R12B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12B.2substituent group is substituted, the R12B.2substituent group is substituted with one or more third substituent groups denoted by R12B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R12B.1, R12B.2, and R12B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R12B.1, R12B.2, and R12B.3, respectively.

In embodiments, when R12Cis substituted, R12Cis substituted with one or more first substituent groups denoted by R12C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12C.1substituent group is substituted, the R12C.1substituent group is substituted with one or more second substituent groups denoted by R12C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12C.2substituent group is substituted, the R12C.2substituent group is substituted with one or more third substituent groups denoted by R12C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R12C, R12C.1, R12C.2, and R12C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R12C, R12C.1, R12C.2, and R12C.3, respectively.

In embodiments, when R13is substituted, R13is substituted with one or more first substituent groups denoted by R13.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13.1substituent group is substituted, the R13.1substituent group is substituted with one or more second substituent groups denoted by R13.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13.2substituent group is substituted, the R13.2substituent group is substituted with one or more third substituent groups denoted by R13.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R13, R13.1, R13.2, and R13.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R13, R13.1, R13.2, and R13.3, respectively.

In embodiments, when R13Ais substituted, R13Ais substituted with one or more first substituent groups denoted by R13A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13A.1substituent group is substituted, the R13A.1substituent group is substituted with one or more second substituent groups denoted by R13A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13A.2substituent group is substituted, the R13A.2substituent group is substituted with one or more third substituent groups denoted by R13A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R13A, R13A.1, R13A.2, and R13A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R13A, R13A.1, R13A.2, and R13A.3, respectively.

In embodiments, when R13Bis substituted, R13Bis substituted with one or more first substituent groups denoted by R13B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13B.1substituent group is substituted, the R13B.1substituent group is substituted with one or more second substituent groups denoted by R13B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13B.2substituent group is substituted, the R13B.2substituent group is substituted with one or more third substituent groups denoted by R13B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R13B, R13B.1, R13B.2, and R13B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R13B, R13B.1, R13B.2, and R13B.3, respectively.

In embodiments, when R13Aand R13Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R13A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13A.1substituent group is substituted, the R13A.1substituent group is substituted with one or more second substituent groups denoted by R13A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13A.2substituent group is substituted, the R13A.2substituent group is substituted with one or more third substituent groups denoted by R13A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R13A.1, R13A.2, and R13A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R13A.1, R13A.2, and R13A.3, respectively.

In embodiments, when R13Aand R13Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R13B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13B.1substituent group is substituted, the R13B.1substituent group is substituted with one or more second substituent groups denoted by R13B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13B.2substituent group is substituted, the R13B.2substituent group is substituted with one or more third substituent groups denoted by R13B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R13B.1, R13B.2, and R13B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R13B.1, R13B.2, and R13B.3, respectively.

In embodiments, when R13Cis substituted, R13Cis substituted with one or more first substituent groups denoted by R13C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13C.1substituent group is substituted, the R13C.1substituent group is substituted with one or more second substituent groups denoted by R13C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R13C.2substituent group is substituted, the R13C.2substituent group is substituted with one or more third substituent groups denoted by R13C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R13C, R13C.1, R13C.2, and R13C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW. 3correspond to R13C, R13C.1, R13C.2, and R13C.3, respectively.

In embodiments, when R15is substituted, R15is substituted with one or more first substituent groups denoted by R15.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R15.1substituent group is substituted, the R15.1substituent group is substituted with one or more second substituent groups denoted by R15.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R15.2substituent group is substituted, the R15.2substituent group is substituted with one or more third substituent groups denoted by R15.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R15, R15.1, R15.2, and R15.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R15, R15.1, R15.2, and R15.3, respectively.

In embodiments, when R15Cis substituted, R15Cis substituted with one or more first substituent groups denoted by R15C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R15C.1substituent group is substituted, the R15C.1substituent group is substituted with one or more second substituent groups denoted by R15C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R15C.2substituent group is substituted, the R15C.2substituent group is substituted with one or more third substituent groups denoted by R15C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R15C, R15C.1, R15C.2, and R15C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R15C, R15C.1, R15C.2, and R15C.3, respectively.

In embodiments, when R7and R15substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R7.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.1substituent group is substituted, the R7.1substituent group is substituted with one or more second substituent groups denoted by R7.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R7.2substituent group is substituted, the R7.2substituent group is substituted with one or more third substituent groups denoted by R7.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R7.1, R7.2, and R7.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R7.1, R7.2, and R7.3, respectively.

In embodiments, when R7and R15substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R15.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R15.1substituent group is substituted, the R15.1substituent group is substituted with one or more second substituent groups denoted by R15.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R15.2substituent group is substituted, the R15.2substituent group is substituted with one or more third substituent groups denoted by R15.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R15.1, R15.2, and R15.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R15.1, R15.2, and R15.3, respectively.

In embodiments, when R16is substituted, R16is substituted with one or more first substituent groups denoted by R16.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R16.1substituent group is substituted, the R16.1substituent group is substituted with one or more second substituent groups denoted by R16.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R16.2substituent group is substituted, the R16.2substituent group is substituted with one or more third substituent groups denoted by R16.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R16, R16.1, R16.2, and R16.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R16, R16.1, R16.2, and R16.3, respectively.

In embodiments, when R16Cis substituted, R16Cis substituted with one or more first substituent groups denoted by R16C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R16C.1substituent group is substituted, the R16C.1substituent group is substituted with one or more second substituent groups denoted by R16C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R16C.2substituent group is substituted, the R16C.2substituent group is substituted with one or more third substituent groups denoted by R16C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R16C, R16C.1, R16C.2, and R16C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R16C, R16C.1, R16C.2, and R16C.3, respectively.

In embodiments, when R20is substituted, R20is substituted with one or more first substituent groups denoted by R20.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20.1substituent group is substituted, the R20.1substituent group is substituted with one or more second substituent groups denoted by R20.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20.2substituent group is substituted, the R20.2substituent group is substituted with one or more third substituent groups denoted by R20.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20, R20.1, R20.2, and R20.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW. 3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R20, R20.1, R20.2, and R20.3, respectively.

In embodiments, when R20Ais substituted, R20Ais substituted with one or more first substituent groups denoted by R20A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20A.1substituent group is substituted, the R20A.1substituent group is substituted with one or more second substituent groups denoted by R20A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20A.2substituent group is substituted, the R20A.2substituent group is substituted with one or more third substituent groups denoted by R20A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20A, R20A.1, R20A.2, and R20A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R20A, R20A.1, R20A.2, and R20A.3, respectively.

In embodiments, when R20Bis substituted, R20Bis substituted with one or more first substituent groups denoted by R20B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20B.1substituent group is substituted, the R20B.1substituent group is substituted with one or more second substituent groups denoted by R20B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20B.2substituent group is substituted, the R20B.2substituent group is substituted with one or more third substituent groups denoted by R20B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20B, R20B.1, R20B.2, and R20B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R20B, R20B.1, R20B.2, and R20B.3, respectively.

In embodiments, when R20Aand R20Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R20A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20A.1substituent group is substituted, the R20A.1substituent group is substituted with one or more second substituent groups denoted by R20A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20A.2substituent group is substituted, the R20A.2substituent group is substituted with one or more third substituent groups denoted by R20A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20A.1, R20A.2, and R20A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R20A.1, R20A.2, and R20A.3, respectively.

In embodiments, when R20Aand R20Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R20B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20B.1substituent group is substituted, the R20B.1substituent group is substituted with one or more second substituent groups denoted by R20B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20B.2substituent group is substituted, the R20B.2substituent group is substituted with one or more third substituent groups denoted by R20B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20B.1, R20B.2, and R20B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R20B.1, R20B.2, and R20B.3, respectively.

In embodiments, when R20Cis substituted, R20Cis substituted with one or more first substituent groups denoted by R20C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20C.1substituent group is substituted, the R20C.1substituent group is substituted with one or more second substituent groups denoted by R20C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R20C.2substituent group is substituted, the R20C.2substituent group is substituted with one or more third substituent groups denoted by R20C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R20C, R20C.1, R20C.2, and R20C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R20C, R20C.1, R20C.2, and R20C.3, respectively.

In embodiments, when R21is substituted, R21is substituted with one or more first substituent groups denoted by R21.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21.1substituent group is substituted, the R21.1substituent group is substituted with one or more second substituent groups denoted by R21.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21.2substituent group is substituted, the R21.2substituent group is substituted with one or more third substituent groups denoted by R21.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R21, R21.1, R21.2, and R21.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW. 3correspond to R21, R21.1, R21.2, and R21.3, respectively.

In embodiments, when R21Ais substituted, R21Ais substituted with one or more first substituent groups denoted by R21A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21A.1substituent group is substituted, the R21A.1substituent group is substituted with one or more second substituent groups denoted by R21A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21A.2substituent group is substituted, the R21A.2substituent group is substituted with one or more third substituent groups denoted by R21A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R21A, R21A.1, R21A.2, and R21A.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R21A, R21A.1, R21A.2, and R21A.3, respectively.

In embodiments, when R21Bis substituted, R21Bis substituted with one or more first substituent groups denoted by R21B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21B.1substituent group is substituted, the R21B.1substituent group is substituted with one or more second substituent groups denoted by R21B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21B.2substituent group is substituted, the R21B.2substituent group is substituted with one or more third substituent groups denoted by R21B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R21B, R21B.1, R21B.2, and R21B.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3correspond to R21B, R21B1, R21B.2, and R21B.3, respectively.

In embodiments, when R21Aand R21Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R21A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21A.1substituent group is substituted, the R21A.1substituent group is substituted with one or more second substituent groups denoted by R21A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21A.2substituent group is substituted, the R21A.2substituent group is substituted with one or more third substituent groups denoted by R21A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R21A.1, R21A.2, and R21A.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R21A.1, R21A.2, and R21A.3, respectively.

In embodiments, when R21Aand R21Bsubstituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R21B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21B.1substituent group is substituted, the R21B.1substituent group is substituted with one or more second substituent groups denoted by R21B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21B.2substituent group is substituted, the R21B.2substituent group is substituted with one or more third substituent groups denoted by R21B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R21B.1, R21B.2, and R21B.3have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3correspond to R21B.1, R21B.2, and R21B.3, respectively.

In embodiments, when R21Cis substituted, R21Cis substituted with one or more first substituent groups denoted by R21C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21C.1substituent group is substituted, the R21C.1substituent group is substituted with one or more second substituent groups denoted by R21C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R21C.2substituent group is substituted, the R21C.2substituent group is substituted with one or more third substituent groups denoted by R21C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R21C, R21C.1, R21C.2, and R21C.3have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW. 3correspond to R21C, R21C.1, R21C.2, and R21C.3, respectively.

In embodiments, when L1is substituted, L1is substituted with one or more first substituent groups denoted by RL1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL1.1substituent group is substituted, the RL1.1substituent group is substituted with one or more second substituent groups denoted by RL1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL1.2substituent group is substituted, the RL1.2substituent group is substituted with one or more third substituent groups denoted by RL1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L1, RL1.1, RL1.2, and RL1.3have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3are L1, RL1.1, RL1.2, and RL1.3, respectively.

In embodiments, the compound is useful as a comparator compound. In embodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables).

In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims).

In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable excipient.

In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound.

IV. Methods of Use

In an aspect is provided a method of treating an inflammatory disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof.

In embodiments, the administering is by inhalation.

In an aspect is provided a method of treating cancer in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof.

In embodiments, the subject is a human.

In an aspect is provided a method of inhibiting angiogenesis in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof.

In embodiments, the subject is a human.

In an aspect is provided a method of modulating (e.g., reducing) the level of activity of α5β1 integrin in a cell, the method including contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof. In embodiments, the level of activity of α5β1 integrin is reduced by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of α5β1 integrin is reduced by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the method is performed in vitro. In embodiments, the method is perform in situ.

Embodiment P1. A compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:

Embodiment P2. The compound of embodiment P1, having the formula:

Embodiment P3. The compound of one of embodiments P1 to P2, wherein R20and R21are independently hydrogen, halogen, or unsubstituted C1-C4alkyl.

Embodiment P4. The compound of one of embodiments P1 to P2, wherein R20and R21are independently hydrogen, —F, or unsubstituted methyl.

Embodiment P5. The compound of embodiment P1, having the formula:

Embodiment P6. The compound of embodiment P1, having the formula:

Embodiment P7. The compound of embodiment P1, having the formula:

Embodiment P8. The compound of embodiment P1, having the formula:

Embodiment P9. The compound of embodiment P1, having the formula:

Embodiment P10. The compound of one of embodiments P1 to P9, wherein A1is C(R4), A3is C(R3), and A4is C(R5).

Embodiment P11. The compound of one of embodiments P1 to P9, wherein A1is N, A3is C(R3), and A4is C(R5).

Embodiment P12. The compound of one of embodiments P1 to P9, wherein A1is C(R4), A3is N, and A4is N.

Embodiment P13. The compound of one of embodiments P1 to P12, wherein m is 1.

Embodiment P14. The compound of one of embodiments P1 to P12, wherein m is 2.

Embodiment P15. The compound of one of embodiments P1 to P14, wherein X is a bond.

Embodiment P16. The compound of one of embodiments P1 to P14, wherein X is —C(R15)(R16)—.

Embodiment P17. The compound of one of embodiments P1 to P14, wherein X is —N(R15)—.

Embodiment P18. The compound of one of embodiments P1 to P17, wherein L1is a bond, —NH—, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

Embodiment P19. The compound of one of embodiments P1 to P17, wherein L1is a bond, —NH—, —(CH2)z1—NH—, —(CH2)z2—, or —(CH2)z3—N((CH2)z4CH3)—C(O)—, wherein z1, z2, and z3 are independently an integer from 1 to 10; and z4 is an integer from 0 to 9.

Embodiment P20. The compound of one of embodiments P1 to P17, wherein L1is a bond.

Embodiment P21. The compound of one of embodiments P1 to P17, wherein L1is —NH—.

Embodiment P22. The compound of one of embodiments P1 to P17, wherein L1is —(CH2)z1—NH—, wherein z1 is an integer from 1 to 4.

Embodiment P23. The compound of one of embodiments P1 to P17, wherein L1is —(CH2)z2—, wherein z2 is an integer from 1 to 4.

Embodiment P24. The compound of one of embodiments P1 to P17, wherein L1is —(CH2)z3—N((CH2)z4CH3)—C(O)—; wherein z3 is an integer from 1 to 4, and z4 is an integer from 0 to 4.

Embodiment P25. The compound of one of embodiments P1 to P24, wherein R1is hydrogen.

Embodiment P27. The compound of embodiment P26, wherein X2is independently —F or —Cl.

Embodiment P29. The compound of embodiment P28, wherein X6is independently —F or —Cl.

Embodiment P30. The compound of one of embodiments P1 to P24, wherein R2and R6are halogen.

Embodiment P31. The compound of one of embodiments P1 to P24, wherein R2and R6are —Cl.

Embodiment P32. The compound of one of embodiments P1 to P24, wherein R2is halogen and R6is unsubstituted C1-C6alkyl.

Embodiment P33. The compound of one of embodiments P1 to P32, wherein R4is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment P34. The compound of one of embodiments P1 to P32, wherein R4is hydrogen.

Embodiment P35. The compound of one of embodiments P1 to P32, wherein R4is substituted or unsubstituted phenyl.

Embodiment P36. The compound of one of embodiments P1 to P32, wherein R4is unsubstituted phenyl.

Embodiment P37. The compound of one of embodiments P1 to P32, wherein R4is halogen, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment P38. The compound of one of embodiments P1 to P37, wherein R3is hydrogen.

Embodiment P39. The compound of one of embodiments P1 to P38, wherein R5is hydrogen.

Embodiment P40. The compound of one of embodiments P1 to P7 and P10 to P39, wherein R7is hydrogen.

Embodiment P41. The compound of one of embodiments P1 to P7 and P10 to P14, wherein R7and R15are joined to form a substituted or unsubstituted C5-C6cycloalkyl, substituted or unsubstituted 5 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment P42. The compound of one of embodiments P1 to P7 and P10 to P14, wherein R7and R15are joined to form an unsubstituted cyclohexyl.

Embodiment P43. The compound of one of embodiments P1 to P7 and P10 to P14, wherein R7and R15are joined to form an unsubstituted 6 membered heterocycloalkyl, wherein the heterocycloalkyl comprises (i) an oxygen atom, (ii) a nitrogen atom, or (iii) an oxygen atom and a nitrogen atom.

Embodiment P44. The compound of one of embodiments P1 to P7 and P10 to P14, wherein R7and R15are joined to form an unsubstituted phenyl.

Embodiment P45. The compound of one of embodiments P1 to P7 and P10 to P14, wherein R7and R15are joined to form an unsubstituted 5 to 6 membered heteroaryl, wherein the heteroaryl comprises one or two nitrogen atoms.

Embodiment P46. The compound of one of embodiments P1, P3 to P5, and P10 to P45, wherein R8is hydrogen.

Embodiment P47. The compound of one of embodiments P1 to P46, wherein R10is hydrogen.

Embodiment P48. The compound of one of embodiments P1 to P5 and P8 to P47, wherein R9is hydrogen.

Embodiment P49. The compound of one of embodiments P1 to P48, wherein R11is hydrogen.

Embodiment P50. The compound of one of embodiments P1 to P48, wherein R11is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.

Embodiment P51. The compound of one of embodiments P1 to P48, wherein R11is substituted or unsubstituted heterocycloalkyl.

Embodiment P52. The compound of one of embodiments P1 to P48, wherein R11is substituted or unsubstituted 5 to 6 membered heterocycloalkyl.

Embodiment P53. The compound of one of embodiments P1 to P48, wherein R11is unsubstituted 5 to 6 membered heterocycloalkyl.

Embodiment P54. The compound of one of embodiments P1 to P48, wherein R11is

Embodiment P55. The compound of one of embodiments P1 to P48, wherein R11is hydrogen, —C(NR11C)NR11AR11B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment P56. The compound of embodiment P55, wherein R11is

Embodiment P57. The compound of embodiment P56, wherein R11is

Embodiment P58. The compound of embodiment P56, wherein R11is

Embodiment P59. The compound of one of embodiments P1 to P5 and P8 to P47, wherein R9and R11are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl.

Embodiment P60. The compound of embodiment P59, wherein R9and R11are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl containing one nitrogen atom.

Embodiment P61. The compound of one of embodiments P1 to P60, wherein R12is hydrogen, —C(NR12C)NR12AR12B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment P62. The compound of one of embodiments P1 to P60, wherein R12is hydrogen.

Embodiment P63. The compound of embodiment P1, having the formula:

Embodiment P64. The compound of embodiment P1, having the formula:

Embodiment P65. The compound of embodiment P1, having the formula:

Embodiment P66. The compound of embodiment P1, having the formula:

Embodiment P67. A pharmaceutical composition comprising the compound of one of embodiments P1 to P66, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable excipient.

Embodiment P68. A method of treating an inflammatory disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P66, or a pharmaceutically acceptable salt or tautomer thereof.

Embodiment P69. The method of embodiment P68, wherein the inflammatory disease is asthma.

Embodiment P71. A method of treating cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P66, or a pharmaceutically acceptable salt or tautomer thereof.

Embodiment P72. A method of inhibiting angiogenesis in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P66, or a pharmaceutically acceptable salt or tautomer thereof.

Embodiment P73. A method of reducing the level of activity of α5β1 integrin in a cell, said method comprising contacting the cell with an effective of a compound of one of embodiments P1 to P66, or a pharmaceutically acceptable salt or tautomer thereof.

EXAMPLES

General information: All evaporations were carried out in vacuo with a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at rt. Thin layer chromatography (TLC) was performed on silica gel plates, spots were visualized by UV light (214 and 254 nm). Purification by column and flash chromatography was carried out using silica gel (200-300 mesh). Solvent systems are reported as mixtures by volume. All NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1H chemical shifts are reported in 8 values in ppm with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br=broad, m=multiplet), coupling constant (Hz), integration.

Route for SU15210-0204-01

1. The Synthesis of 5-(1,4,5,6-tetrahydropyrimidin-2-ylamino)nicotinic acid (0204-2)

A solution of 0007-3 (1.5 g, 6.5 mmol) and 5-aminonicotinic acid (0.9 g, 6.5 mmol) in DMA (10 mL) was stirred at 85° C. for 4 days. Cooled to room temperature and purified by reverse flash to give 0204-2 (180 mg, 13% yield) as a white solid.

A solution of 0204-2 (180 mg, 0.82 mmol) in SOCl2(5 mL) was stirred at reflux for 30 min, then remove the excess SOCl2under reduced pressure. The residue was then added to a solution of int-A (409 mg, 0.82 mmol) and TEA (331 mg, 3.28 mmol) in DMF (5 mL) at 0° C., the solution was then allowed to warm to room temperature and stirred for overnight. Poured the solution into water (50 mL), collected the precipitate by filtration, the solid was dried then purified by prep-HPLC to get 0204-3 (80 mg, 14% yield) as a white solid.

3. The Synthesis of (S)-2-(3,5-dichlorobiphenyl-4-ylcarboxamido)-3-(2-(5-(1,4,5,6-tetrahydropyrimidin-2-ylamino)nicotinamido)acetamido)propanoic acid (SU15210-0204-01)

To a solution of 0204-3 (80 mg, 0.11 mmol) in EA (5 mL) was added Pd/C (16 mg), the solution was stirred under H2at room temperature for overnight. Filter to remove the catalyst, the filtrate was concentrated and purified by prep-HPLC to give SU15210-0204-01 (6 mg, 9% yield) as a white solid.

Route for SU15210-0206-01

1. The Synthesis of methyl 5-nitro-6-oxo-1,6-dihydropyridine-3-carboxylate (0206-2)

A solution of 0206-1 (3.0 g, 16.29 mmol) and added H2SO4(3 mL) in MeOH (20 mL) was stirred at reflux for 16 h. Cooled to room temperature and concentrated to remove the solvent, the residue was recrystallized from ethyl acetate, dried in vacuum to give 206-2 (3.0 g, 93% yield) as a yellow solid.

2. The Synthesis of methyl 5-amino-6-oxo-1,6-dihydropyridine-3-carboxylate (0206-3)

To a solution of 0206-2 (3.0 g, 15.14 mmol) in MeOH (30 mL) was added AcOH (6 mL) and Zn (2.0 g, 30 mmol), the solution was stirred at rt for 0.5 h. When the reaction was completed, concentrated to remove the organic solution, extracted with EA, the organic phase was separated and dried over Na2SO4, concentrated to give 0206-3 (2.0 g, 80%) as a yellow 10 solid.

3. The Synthesis of methyl 5-(3-benzoylthioureido)-6-oxo-1,6-dihydropyridine-3-carboxylate (0206-4)

To a solution of 0206-3 (2.0 g, 11.90 mmol) in acetone (20 mL) was added benzoyl isothiocyanate (1.9 g, 11.90 mmol), the solution was stirred at reflux for 3 h. Concentrated to remove the solvent to give 0206-4 (3.0 g, 77%) as a yellow solid.

4. The Synthesis of methyl 6-oxo-5-thioureido-1,6-dihydropyridine-3-carboxylate (0206-5)

To a solution of 0206-4 (3.0 g, 9.10 mmol) in DMF (30 mL) was added NaOMe (490 mg, 9.10 mmol). The solution was stirred at 70° C. for 1 h. Cooled to room temperature and collected the precipitate by filtration, the solid was washed with ethyl acetate (20 mL) then dried in vacuum to give 0206-5 (1.3 g, 63% yield) as an off-white solid.

A solution of 0206-5 (1.3 g, 5.70 mmol) and CH3I (810 mg, 5.70 mmol) in MeOH (20 mL) was stirred at reflux for 4 h. The solution was then allowed to warm to room temperature. We concentrated the mixture. Water (10 mL) was added, extracted with ethyl acetate (10 mL×3), washed with water (10 mL×3), dried and concentrated. The crude product was purified by pre-HPLC to give 0206-6 (1.2 g, yield: 87%) as a light-yellow solid.

6. The Synthesis of methyl 6-oxo-5-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-1,6-dihydropyridine-3-carboxylate (0206-7)

A solution of 0206-6 (1.2 g, 4.98 mmol) and propane-1,3-diamine (370 mg, 5.0 mmol) in DMA (10 mL) was stirred at 95° C. for 16 h. The solution was then allowed to warm to room temperature. Water (10 mL) was added, extracted with ethyl acetate (10 mL×3), washed with water (10 mL×3), dried and concentrated. The crude product was purified by pre-HPLC to give 0206-7 (200 mg, yield: 16%) as a white solid.

7. The Synthesis of 6-oxo-5-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-1,6-dihydropyridine-3-carboxylic acid (0206-8)

A solution of 0206-7 (200 mg, 0.80 mmol) in H2O (5 mL) and THF (5 mL) was stirred at rt. NaOH (38 mg, 0.96 mmol) was added. The solution was then reacted at 40° C. until finished. Water (10 mL) was added, extracted with ethyl acetate (10 mL×3), washed with water (10 mL×3), dried and concentrated. The crude product was purified by pre-HPLC to give 0206-8 (100 mg, yield: 53%) as a white solid.

9. The Synthesis of (S)-2-(3,5-dichlorobiphenyl-4-ylcarboxamido)-3-(2-(6-oxo-5-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-1,6-dihydropyridine-3-carboxamido)acetamido)propanoic acid (SU15210-0206)

To a solution of 0206-9 (50 mg, 0.07 mmol) in MeOH (5.0 mL) was added Pd/C (10 mg). The mixture was stirred under H2in balloon at room temperature for 16 h. When the reaction completed, filtrated to remove the catalyst, the filtrate was concentrated and purified by prep-HPLC to get SU15210-00206-01 (5 mg, 11% yield) as a white solid.