HK1229329A1

HK1229329A1 - Diaminopyrimidine benzenesulfone derivatives and uses thereof

Info

Publication number: HK1229329A1
Application number: HK17103116.4A
Authority: HK
Inventors: James E. Bradner; Jun Qi; Minoru Tanaka
Original assignee: 达纳-法伯癌症研究所股份有限公司
Priority date: 2014-01-31
Filing date: 2015-02-02
Publication date: 2017-11-17

Description

Diaminopyrimidine phenylsulfone derivatives and uses thereof

RELATED APPLICATIONS

This application claims priority from U.S. provisional patent application u.s.s.n.61/934,635 filed 2014 1/31 as required by 35u.s.c. § 119(e), which is incorporated herein by reference.

Background

Bromodomain-containing proteins (bromodomain-containing proteins) have important biological implications, which are determinants of the composition and epigenetic memory of transcription factor complexes. For example, the bromodomain and extra-terminal (BET) protein families (e.g., bromodomain-containing protein 2(BRD2), bromodomain-containing protein 3(BRD3), bromodomain-containing protein 4(BRD4), and bromodomain testis-specific protein (BRDT)) share a common region structure characterized by two amino-terminal bromodomains and a more divergent carboxy-terminal recruitment domain that exhibit high levels of sequence conservation (filippokopoulos et al, Nature 2010, 468, 1067-. It has been reported that BRD2 and BRD3 bind to histones along actively transcribed genes and may be involved in promoting transcriptional elongation (Leroy et al, mol. It has also been reported that BRD4 or BRD3 can fuse with ribonucleoprotein testis (NUT) in the formation of highly malignant epithelial tumors to form new fusion oncogenes BRD4-NUT or BRD3-NUT (French et al, Cancer Res., 2003, 63, 304-41307; French et al, J.Clin.Oncol.2004, 22, 4135-4139). The data show that BRD-NUT fusion protein promotes carcinogenesis (French et al, Oncogene 2008, 27, 2237-. BRDT is specifically expressed in the testis and ovary. All BET family members have been reported to have some role in the control or execution of the cell cycle and have been shown to remain complexed with chromosomes during cell division, demonstrating their role in maintaining epigenetic memory. In addition, some viruses utilize BET proteins to bind their genome to host Cell chromatin as part of the viral replication process (You et al, Cell 2004, 117, 349-. BRD4 appears to be involved in the recruitment of the pTEF-b complex to the inducible gene, resulting in phosphorylation of the RNA polymerase and increased transcriptional output (Hargreaves et al, Cell 2009, 138, 129-145). In humans, BRD2, BRD3, BRD4 and BRDT exhibit similar gene arrangement, regional structure and some functional properties (Wu et al, j.biol.chem.2007, 282, 13141-.

Summary of The Invention

The present invention provides compounds of formula (II) (e.g., compounds of formula (I)). The compounds described herein are binding agents to transcription factors, such as bromodomain-containing proteins (e.g., BET proteins), and are useful for male contraception and the treatment and/or prevention of a wide range of diseases (e.g., diseases associated with bromodomains, diseases associated with bromodomain activity (e.g., aberrant activity), diseases associated with bromodomain-containing proteins, and diseases associated with bromodomain-containing protein activity (e.g., aberrant activity)). Diseases that can be treated and/or prevented by the methods of the invention include, but are not limited to, proliferative diseases (e.g., cancer, benign tumors, angiogenesis, inflammatory diseases, and autoimmune diseases), cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning. The invention also provides pharmaceutical compositions, kits, methods and uses comprising or using the compounds described herein.

In one aspect, the present invention provides a compound of formula (II):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives and prodrugs thereof, wherein R is ¹、R²、R³、R⁴、R⁵、R⁶、A、L¹、L²、L³、L⁴、R^B1P, q and n are as described herein.

In some embodiments, the compound of formula (II) is formula (I):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives and prodrugs thereof.

Exemplary compounds of formula (II) include, but are not limited to:

Other exemplary compounds of formula (II) include compounds as shown in figures 5, 7, 9 and 10, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives and prodrugs thereof.

The compounds described herein are capable of binding bromodomain-containing proteins. In some embodiments, the compounds described herein bind to a bromodomain (e.g., a bromodomain of a bromodomain-containing protein). The compounds described herein can inhibit the activity of bromodomain-containing proteins. The compounds described herein may also inhibit the function of bromodomains.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound described herein, and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions of the invention comprise a therapeutically or prophylactically effective amount of a compound described herein. The pharmaceutical composition may be for use in treating and/or preventing a disease in a subject in need thereof. The pharmaceutical compositions may also be used to inhibit viral replication, kill viruses, inhibit the activity of bromodomain-containing proteins, inhibit the activity of bromodomains, inhibit the binding of bromodomains of bromodomain-containing proteins to acetylated lysine residues of histones or other proteins, modulate (e.g., inhibit) transcriptional elongation, modulate (e.g., reduce) the level of bromodomain-containing proteins, and/or modulate (e.g., down-regulate or inhibit) the expression (e.g., transcription) of genes regulated by bromodomain-containing proteins in a subject or cell.

In some embodiments, the disease described herein is a disease associated with activity (e.g., aberrant activity (e.g., increased activity)) of a bromodomain-containing protein. In some embodiments, the disease is a disease associated with the function of a bromodomain-containing protein. In some embodiments, the disease is a disease associated with activity (e.g., abnormal activity (e.g., increased activity)) of a bromodomain. In some embodiments, the disease is a disease associated with the function of a bromodomain.

In some embodiments, the disease is a proliferative disease (e.g., cancer, benign tumor, angiogenesis, inflammatory disease, or autoimmune disease), cardiovascular disease, viral infection, fibrotic disease, metabolic disease, endocrine disease, or radiation poisoning.

In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the cell is present in vitro. In some embodiments, the cell is present in vivo.

Other aspects of the invention relate to a method of treating a disease in a subject in need thereof.

In another aspect, the invention provides a method of preventing a disease in a subject in need thereof.

Other aspects of the invention relate to a method of reducing the risk of developing a disease in a subject in need thereof.

Other aspects of the invention relate to a method of inhibiting replication of a virus, such as Human Immunodeficiency Virus (HIV), Human Papilloma Virus (HPV), Hepatitis C Virus (HCV), Herpes Simplex Virus (HSV), ebola virus, and influenza virus.

Other aspects of the invention relate to a method of killing viruses, such as Human Immunodeficiency Virus (HIV), Human Papilloma Virus (HPV), Hepatitis C Virus (HCV), Herpes Simplex Virus (HSV), ebola virus, and influenza virus.

In another aspect, the invention provides a method of inhibiting the activity of a bromodomain-containing protein in a subject or cell. In some embodiments, the activity of the bromodomain-containing protein is an aberrant or undesired activity (e.g., increased activity) of the bromodomain-containing protein. In some embodiments, the activity of the bromodomain-containing protein is selectively inhibited by the method (e.g., when compared to an activity other than a bromodomain-containing protein kinase).

In other aspects, the invention provides a method of inhibiting the activity of a bromodomain in a subject or cell. In some embodiments, the activity of the bromodomain that is inhibited is an aberrant or undesirable activity (e.g., increased activity) of the bromodomain.

In other aspects, the invention provides a method of inhibiting binding of a bromodomain to an acetylated lysine residue of a second protein (e.g., a histone described herein)) in a subject or cell. In some embodiments, the second protein is a protein comprising at least one acetylated lysine residue.

In other aspects, the invention provides a method of modulating expression (e.g., transcription) of a gene regulated by a bromodomain-containing protein in a subject or cell. In some embodiments, the method of modulating gene expression (e.g., transcription) is a method of down-regulating or inhibiting expression (e.g., transcription) of a gene. The methods can result in a decrease in the level of a gene product (e.g., RNA, protein) in the cell.

In other aspects, the invention provides a method of modulating (e.g., inhibiting) transcriptional elongation in a subject or cell.

In other aspects, the invention provides a method of modulating (e.g., reducing) the level of a bromodomain-containing protein in a subject or cell.

The methods of the invention comprise administering to a subject, contacting a cell or virus with an effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount. In some embodiments, the methods of the invention further comprise administering to the subject, contacting the cell or virus with an additional agent in combination with a compound or pharmaceutical composition described herein. In some embodiments, the combination of the agent and the compound or pharmaceutical composition described herein is synergistic.

Other aspects of the invention relate to methods of screening libraries of compounds to identify compounds useful in the methods of the invention.

Other aspects of the invention relate to kits comprising a container containing a compound or pharmaceutical composition described herein. The kits of the invention may comprise a single dose or multiple doses of a compound or pharmaceutical composition described herein. The provided kits may be used in the methods of the invention. In some embodiments, the kit further comprises instructions for using the kit.

In other aspects, the invention provides compounds and pharmaceutical compositions described herein for use in the methods of the invention.

In other aspects, the invention provides the use of compounds and pharmaceutical compositions described herein in the methods of the invention.

This application is related to various issued patents, published patent applications, journal articles and other publications, which are incorporated herein by reference in their entirety. The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the embodiments and claims.

Drawings

FIG. 1 shows the determination of K at BRD4.1 by Isothermal Titration Calorimetry (ITC)) of an exemplary compound of formula (II)_dThe value is obtained. JQ1 (a known BRD inhibitor) was used as a positive control and GW843682 (a PLK inhibitor) was used as a negative control.

FIG. 2 shows a cell cycle analysis of an exemplary compound of formula (II) by flow cytometry. Ruxolitinib, JQ1, GSK461364 and DMSO were used as controls.

FIGS. 3A-3C show that compound TG101209 is a type N BRD4 inhibitor (FIG. 3A) and a type I kinase inhibitor (FIG. 3B). The hinge motif interacts with Asn140 of BRD4 (fig. 3A) and Leu932 of JAK2 (fig. 3B). FIG. 3C: kinase assay data for TG 101209. See, Leukemia,2007,21, 1658; stuart w.j.ember et al, acschem.biol.,2014,9, 1160.

FIG. 4 shows a 3D view of the X-ray cocrystal structure of compound TG101209 with JAK2(PDB:4 JIQ). This result was used to improve selectivity using the guard (gatekeeper) of JAK 2.

Figure 5 shows exemplary Structure Activity Relationship (SAR) results for selective compounds described herein. Substituents for guards (e.g. R)²) The selectivity can be improved.

Figures 6A and 6B show different binding patterns when the compounds described herein bind to BRD4(1) (figure 6A) or JAK2 (figure 6B). These results were used to exploit conformational preference to improve selectivity; the substituents at the R position may improve selectivity. (FIG. 6A: BRD4(1) (PDB: 4076); FIG. 6B: JAK2(PDB:4JI 9).

Figure 7 shows other exemplary SAR results for selective compounds described herein. Bulkier R²(R⁶) May result in improved selectivity. "NT": is not obtained.

FIGS. 8A and 8B show exemplary X-ray cocrystal structures (3D view) of selective compounds with BRD4 (1). The bulky substituents on the phenylsulfonamide ring, such as bromo or phenyl, are taken up to the ZA channel and enhance the inhibitory activity.

Figure 9 shows additional exemplary SAR results for selective compounds described herein. Modification of R ²(R⁶) To exploit conformational preference to improve selectivity. "NT": is not obtained.

Figure 10 shows additional exemplary SAR results for selective compounds described herein. R²(R⁶) And R³(R²) Unmodified.

Definition of

The definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are defined in the periodic Table of the elements, CAS version, Handbook of Chemistry and Physics, 75 th edition, inner cover, and the specific functional groups are generally defined as described herein. Furthermore, the general principles of Organic Chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausaltito, 1999; smith and March, March's Advanced Organic Chemistry, 5 th edition, John Wiley & Sons, Inc., New York, 2001; larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and carrousers, Some model Methods of Organic Synthesis, 3 rd edition, Cambridge University Press, Cambridge, 1987.

The compounds described herein may contain one or more asymmetric centers and may therefore exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al, eneriomers, Racemates and solutions (Wiley Interscience, New York, 1981); wilen et al, Tetrahedron 33:2725 (1977); eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, tablets of solving Agents and Optical solutions, page 268 (E.L. Eliel, eds., Univ.of Notre Dame Press, Notre Dame, IN 1972). The invention also includes the compounds described herein as single isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

When a range of values is recited, each value and subrange within the range is intended to be encompassed. E.g. "C_1-6"is intended to cover C₁、C₂、C₃、C₄、C₅、C₆、C_1-6、C_1-5、C_1-4、C_1-3、C_1-2、C_2-6、C_2-5、C_2-4、C_2-3、C_3-6、C_3-5、C_3-4、C_4-6、C_4-5And C_5-6。

The term "aliphatic" includes saturated and unsaturated, straight-chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which may be optionally substituted with one or more functional groups. As will be understood by those skilled in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term "alkyl" includes straight chain, branched chain and cyclic alkyl groups. Similar rules apply to other general terms such as "alkenyl", "alkynyl", and the like. Furthermore, the terms "alkyl", "alkenyl", "alkynyl", and the like encompass both substituted and unsubstituted groups. In some embodiments, "lower alkyl" is used to denote those alkyl groups having 1 to 6 carbon atoms (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched).

In some embodiments, alkyl, alkenyl, and alkynyl groups used in the present invention contain 1-20 aliphatic carbon atoms. In some other embodiments, alkyl, alkenyl, and alkynyl groups used in the present invention contain 1-10 aliphatic carbon atoms. In still other embodiments, alkyl, alkenyl, and alkynyl groups useful herein contain 1-8 aliphatic carbon atoms. In still other embodiments, alkyl, alkenyl, and alkynyl groups useful herein contain 1-6 aliphatic carbon atoms. In still other embodiments, alkyl, alkenyl, and alkynyl groups useful herein contain 1 to 4 carbon atoms. Thus, exemplary aliphatic groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH ₂-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH₂-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH₂-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH₂Cyclohexyl and the like, which likewise may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, buteneA 1-methyl-2-buten-1-yl group, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

"alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-20 alkyl"). In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C1-10 alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C1-7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C)_1-6Alkyl "). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C) _2-6Alkyl "). C_1-6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5) and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise indicated, an alkyl group is independently in each instance optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halogen, e.g., F). In some embodiments, the alkyl group is unsubstituted C1-10 alkyl (e.g., -CH)₃(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl)A group (n-Bu), an unsubstituted tert-butyl group (tert-Bu or t-Bu), an unsubstituted sec-butyl group (sec-Bu), an unsubstituted isobutyl group (i-Bu)). In some embodiments, the alkyl group is a substituted C1-10 alkyl (e.g., substituted C_1-6Alkyl radicals, e.g., -CF ₃、Bn)。

"alkenyl" means a group of straight or branched hydrocarbon radicals having 2 to 20 carbon atoms, one or more carbon-carbon double bonds and no triple bonds ("C)_2-20Alkenyl "). In some embodiments, alkenyl groups have 2-10 carbon atoms ("C)_2-10Alkenyl "). In some embodiments, alkenyl groups have 2-9 carbon atoms ("C)_2-9Alkenyl "). In some embodiments, alkenyl groups have 2-8 carbon atoms ("C)_2-8Alkenyl "). In some embodiments, alkenyl groups have 2-7 carbon atoms ("C)_2-7Alkenyl "). In some embodiments, alkenyl groups have 2-6 carbon atoms ("C)_2-6Alkenyl "). In some embodiments, alkenyl groups have 2-5 carbon atoms ("C)_2-5Alkenyl "). In some embodiments, alkenyl groups have 2-4 carbon atoms ("C)_2-4Alkenyl "). In some embodiments, alkenyl groups have 2-3 carbon atoms ("C)_2-3Alkenyl "). In some embodiments, alkenyl has 2 carbon atoms ("C)₂Alkenyl "). The one or more carbon-carbon double bonds may be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). C_2-4Examples of the alkenyl group include vinyl (C)₂) 1-propenyl (C)₃) 2-propenyl (C)₃) 1-butenyl (C)₄) 2-butenyl (C)₄) Butadienyl radical (C) ₄) And the like. C_2-6Examples of the alkenyl group include the above-mentioned C_2-4Alkenyl, and pentenyl (C)₅) Pentadienyl (C)₅) Hexenyl (C)₆) And the like. Additional examples of alkenyl groups include heptenyl (C)₇) Octenyl (C)₈) Octrienyl (C)₈) And the like. Unless otherwise specified, an alkenyl group is optionally independently substituted in each instance, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In some embodiments, the alkenyl group is notSubstituted C_2-10An alkenyl group. In some embodiments, the alkenyl is substituted C_2-10An alkenyl group. In some embodiments, the alkenyl group is a substituted C2-10 alkenyl group. In the alkenyl group, a stereochemically unspecified C ═ C double bond (e.g., -CH ═ CHCH₃Or) May be an (E) -or (Z) -double bond.

"alkynyl" refers to a group of straight or branched hydrocarbon radicals having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds and optionally one or more double bonds ("C)_2-20Alkynyl "). In some embodiments, alkynyl groups have 2-10 carbon atoms ("C)_2-10Alkynyl "). In some embodiments, alkynyl groups have 2-9 carbon atoms ("C)_2-9Alkynyl "). In some embodiments, alkynyl groups have 2-8 carbon atoms ("C) _2-8Alkynyl "). In some embodiments, alkynyl groups have 2-7 carbon atoms ("C)_2-7Alkynyl "). In some embodiments, alkynyl groups have 2-6 carbon atoms ("C)_2-6Alkynyl "). In some embodiments, alkynyl groups have 2-5 carbon atoms ("C)_2-5Alkynyl "). In some embodiments, alkynyl groups have 2-4 carbon atoms ("C)_2-4Alkynyl "). In some embodiments, alkynyl groups have 2-3 carbon atoms ("C)_2-3Alkynyl "). In some embodiments, alkynyl has 2 carbon atoms ("C)₂Alkynyl "). The one or more carbon-carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). C_2-4Examples of alkynyl groups include, but are not limited to, ethynyl (C)₂) 1-propynyl (C)₃) 2-propynyl (C)₃) 1-butynyl (C)₄) 2-butynyl (C)₄) And the like. C_2-6Examples of the alkenyl group include the above-mentioned C_2-4Alkynyl and pentynyl (C)₅) Hexynyl (C)₆) And the like. Other examples of alkynyl groups include heptynyl (C)₇) (C) octynyl group₈) And the like. Unless otherwise specified, alkynyl groups are in each case optionally independently substituted, i.e., unsubstituted (an "unsubstituted)Substituted alkynyl ") or substituted with one or more substituents (" substituted alkynyl "). In some embodiments, the alkynyl group is unsubstituted C _2-10Alkynyl. In some embodiments, the alkynyl is substituted C_2-10Alkynyl.

"carbocyclyl" or "carbocyclic" refers to a group of nonaromatic cyclic hydrocarbon radicals having from 3 to 10 ring carbon atoms ("C)_3-10Carbocyclyl ") and no heteroatoms in the non-aromatic ring system. In some embodiments, carbocyclyl has 3 to 8 ring carbon atoms ("C)_3-8Carbocyclyl "). In some embodiments, carbocyclyl has 3-6 ring carbon atoms ("C)_3-6Carbocyclyl "). In some embodiments, carbocyclyl has 3-6 ring carbon atoms ("C)_3-6Carbocyclyl "). In some embodiments, carbocyclyl has 5 to 10 ring carbon atoms ("C)_5-10Carbocyclyl "). Exemplary C_3-6Carbocyclyl includes, but is not limited to, cyclopropyl (C)₃) Cyclopropenyl group (C)₃) Cyclobutyl (C)₄) Cyclobutenyl radical (C)₄) Cyclopentyl (C)₅) Cyclopentenyl group (C)₅) Cyclohexyl (C)₆) Cyclohexenyl (C)₆) Cyclohexadienyl (C)₆) And the like. Exemplary C_3-8Carbocyclyl includes, but is not limited to, C as described above_3-6Carbocyclyl and cycloheptyl (C)₇) Cycloheptenyl (C)₇) Cycloheptadienyl (C)₇) Cycloheptatrienyl (C)₇) Cyclooctyl (C)₈) Cyclooctenyl (C)₈) Bicyclo [2.2.1]Heptyl (C)₇) Bicyclo [2.2.2]Octyl radical (C)₈) And the like. Exemplary C _3-10Carbocyclyl includes, but is not limited to, C as described above_3-8Carbocyclyl and cyclononyl (C)₉) Cyclononenyl (C)₉) Cyclodecyl (C)₁₀) Cyclodecenyl (C)₁₀) octahydro-1H-indenyl (C)₉) Decahydronaphthyl (C)₁₀) Spiro [4.5 ]]Decyl (C)₁₀) And the like. As illustrated by the examples above, in some embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, e.g., a bicyclic system ("bicyclic carbocyclyl") and may be saturated or partially unsaturatedIs saturated. "carbocyclyl" may also include ring systems wherein the carbocycle as defined above is fused to one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocycle and in such cases carbon number still refers to the number of carbons in the carbocyclic ring system. Unless otherwise specified, a carbocyclyl group is optionally independently substituted in each instance, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In some embodiments, the carbocyclyl is unsubstituted C_3-10A carbocyclic group. In some embodiments, the carbocyclyl is substituted C_3-10A carbocyclic group.

In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl ("C") having 3 to 10 ring carbon atoms _3-10Cycloalkyl "). In some embodiments, cycloalkyl groups have from 3 to 8 ring carbon atoms ("C)_3-8Cycloalkyl "). In some embodiments, cycloalkyl groups have 3 to 6 ring carbon atoms ("C)_3-6Cycloalkyl "). In some embodiments, cycloalkyl groups have 5 to 6 ring carbon atoms ("C)_5-6Cycloalkyl "). In some embodiments, cycloalkyl groups have from 5 to 10 ring carbon atoms ("C)_5-10Cycloalkyl "). C_5-6Examples of cycloalkyl include cyclopentyl (C)₅) And cyclohexyl (C)₆)。C_3-6Examples of the cycloalkyl group include the above-mentioned C_5-6Cycloalkyl and cyclopropyl (C)₃) And cyclobutyl (C)₄)。C_3-8Examples of the cycloalkyl group include the above-mentioned C_3-6Cycloalkyl and cycloheptyl (C)₇) And cyclooctyl (C)₈). Unless otherwise specified, a cycloalkyl group is independently in each instance unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In some embodiments, the cycloalkyl is unsubstituted C_3-10A cycloalkyl group. In some embodiments, the cycloalkyl is substituted C_3-10A cycloalkyl group.

"Heterocyclyl" or "heterocyclic" refers to a group of a 3-to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl"). In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, for example a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. The heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. "heterocyclyl" also includes ring systems in which a heterocyclic ring as defined above is fused to one or more carbocyclic groups in which the point of attachment is on the carbocyclic or heterocyclic ring, or ring systems in which a heterocyclic ring as defined above is fused to one or more aryl or heteroaryl groups in which the point of attachment is on the heterocyclic ring, and in which case the number of ring atoms still refers to the number of ring atoms in the heterocyclic ring system. Unless otherwise specified, a heterocyclyl group is optionally independently substituted in each instance, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In some embodiments, the heterocyclyl is an unsubstituted 3-10 membered heterocyclyl. In some embodiments, the heterocyclyl is a substituted 3-10 membered heterocyclyl.

In some embodiments, heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, oxacyclopropane, and thietane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulphonamyl), and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiacyclohexyl (thianyl). Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxacyclohexyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl (azepanyl), oxepanyl (oxepanyl), and thiepanyl (thiepanyl). Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azacyclooctyl (azocanyl), oxocyclooctyl (oxocanyl), and thiacyclooctyl (thiocanyl). And C ₆Exemplary 5-membered heterocyclic groups to which the aryl ring is fused (also referred to herein as 5, 6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl (benzoxazolinonyl), and the like. Exemplary 6-membered heterocyclic groups fused to the aryl ring (also referred to herein as 6, 6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

"aryl" refers to a group of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n +2 aromatic ring system (e.g., having 6, 10, or 14 ring arrays sharing pi electrons) having 6-14 ring carbon atoms and no heteroatoms ("C") in the aromatic ring system_6-14Aryl "). In some embodiments, an aryl group has 6 ring carbon atoms ("C)₆Aryl "; e.g., phenyl (Ph)). In some embodiments, an aryl group has 10 ring carbon atoms ("C)₁₀Aryl "; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C)₁₄Aryl "; for example, an anthracene group). "aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclic or heterocyclic groups in which the groups or points of attachment are on the aryl ring, and in which case the number of carbon atoms still refers to the number of carbon atoms in the aryl ring system. Unless otherwise specified, an aryl group is optionally independently substituted in each instance, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In some embodiments, the aryl group is unsubstituted C _6-14And (4) an aryl group. In some embodiments, the aryl is substituted C_6-14And (4) an aryl group.

"aralkyl" is a subset of alkyl and aryl and refers to an optionally substituted alkyl substituted with an optionally substituted aryl. In some embodiments, the aralkyl group is an optionally substituted benzyl group. In some embodiments, the aralkyl group is benzyl. In some embodiments, the aralkyl group is an optionally substituted phenethyl group. In some embodiments, the aralkyl group is phenethyl.

"heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n +2 aromatic ring system (e.g., having 6 or 10 ring arrays sharing pi electrons) having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one, or both rings. "heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in which case the number of ring atoms still refers to the number of ring atoms in the heteroaryl ring system. "heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in which case the number of ring atoms refers to the number of ring atoms in the fused (aryl/heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment can be on either ring, i.e., on a heteroatom-containing ring (e.g., 2-indolyl) or on a non-heteroatom-containing ring (e.g., 5-indolyl).

In some embodiments, heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, heteroaryl groups are in each case optionally independently substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In some embodiments, the heteroaryl is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl is a substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzoisothiofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6, 6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl (cinnolinyl), quinoxalinyl, phthalazinyl, and quinazolinyl.

"heteroarylalkyl" is a subset of alkyl and heteroaryl and refers to optionally substituted alkyl substituted with optionally substituted heteroaryl.

"unsaturated" or "partially unsaturated" refers to a group that contains at least one double or triple bond. A "partially unsaturated" ring system is further intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl) as defined herein. Likewise, "saturated" refers to groups that do not contain double or triple bonds, i.e., contain only single bonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, which are divalent bridging groups and when prefixed, are further represented, for example, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene and heteroarylene.

Unless explicitly stated otherwise, an atom, moiety or group described herein may be unsubstituted or substituted, as valency permits. The term "optionally substituted" refers to substituted or unsubstituted.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced with an allowable substituent (e.g., a substituent that is substituted to form a stable compound that, for example, does not spontaneously undergo transformations, such as rearrangement, cyclization, elimination, or other reactions). Unless otherwise mentioned, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position is substituted in any given structure, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds (any of the substituents described herein that result in the formation of stable compounds). The present invention includes any and all such combinations to provide stable compounds. For purposes of the present invention, a heteroatom (e.g., nitrogen) can have a hydrogen substituent and/or any suitable substituent described herein that satisfies the valence of the heteroatom and forms a stable group. In some embodiments, the substituent is a carbon atom substituent. In some embodiments, the substituent is a nitrogen atom substituent. In some embodiments, the substituent is an oxygen atom substituent. In some embodiments, the substituent is a sulfur atom substituent.

Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OR^aa、-ON(R^bb)₂、-N(R^bb)₂、-N(R^bb)₃ ⁺X^-、-N(OR^cc)R^bb、-SH、-SR^aa、-SSR^cc、-C(＝O)R^aa、-CO₂H、-CHO、-C(OR^cc)₂、-CO₂R^aa、-OC(＝O)R^aa、-OCO₂R^aa、-C(＝O)N(R^bb)₂、-OC(＝O)N(R^bb)₂、-NR^bbC(＝O)R^aa、-NR^bbCO₂R^aa、-NR^bbC(＝O)N(R^bb)₂、-C(＝NR^bb)R^aa、-C(＝NR^bb)OR^aa、-OC(＝NR^bb)R^aa、-OC(＝NR^bb)OR^aa、-C(＝NR^bb)N(R^bb)₂、-OC(＝NR^bb)N(R^bb)₂、-NR^bbC(＝NR^bb)N(R^bb)₂、-C(＝O)NR^bbSO₂R^aa、-NR^bbSO₂R^aa、-SO₂N(R^bb)₂、-SO₂R^aa、-SO₂OR^aa、-OSO₂R^aa、-S(＝O)R^aa、-OS(＝O)R^aa、-Si(R^aa)₃、-OSi(R^aa)₃、-C(＝S)N(R^bb)₂、-C(＝O)SR^aa、-C(＝S)SR^aa、-SC(＝S)SR^aa、-SC(＝O)SR^aa、-OC(＝O)SR^aa、-SC(＝O)OR^aa、-SC(＝O)R^aa、-P(＝O)₂R^aa、-OP(＝O)₂R^aa、-P(＝O)(R^aa)₂、-OP(＝O)(R^aa)₂、-OP(＝O)(OR^cc)₂、-P(＝O)₂N(R^bb)₂、-OP(＝O)₂N(R^bb)₂、-P(＝O)(NR^bb)₂、-OP(＝O)(NR^bb)₂、-NR^bbP(＝O)(OR^cc)₂、-NR^bbP(＝O)(NR^bb)₂、-P(R^cc)₂、-P(R^cc)₃、-OP(R^cc)₂、-OP(R^cc)₃、-B(R^aa)₂、-B(OR^cc)₂、-BR^aa(OR^cc)、C_1-10Alkyl radical, C_1-10Perhaloalkyl, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Carbocyclyl, 3-14 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddSubstituted by groups; or two geminal hydrogens on a carbon atom are replaced by a group ═ O, ═ S, ═ NN (R)^bb)₂、＝NNR^bbC(＝O)R^aa、＝NNR^bbC(＝O)OR^aa、＝NNR^bbS(＝O)₂R^aa、＝NR^bbOr as NOR^ccSubstitution;

R^aaindependently at each occurrence selected from C_1-10Alkyl radical, C_1-10Perhaloalkyl, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Carbocyclyl, 3-14 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, or two R^AaThe groups taken together form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddSubstituted by groups;

R^bbindependently at each occurrence, selected from hydrogen, -OH, -OR^aa、-N(R^cc)₂、-CN、-C(＝O)R^aa、-C(＝O)N(R^cc)₂、-CO₂R^aa、-SO₂R^aa、-C(＝NR^cc)OR^aa、-C(＝NR^cc)N(R^cc)₂、-SO₂N(R^cc)₂、-SO₂R^cc、-SO₂OR^cc、-SOR^aa、-C(＝S)N(R^cc)₂、-C(＝O)SR^cc、-C(＝S)SR^cc、-P(＝O)₂R^aa、-P(＝O)(R^aa)₂、-P(＝O)₂N(R^cc)₂、-P(＝O)(NR^cc)₂、C_1-10Alkyl radical, C_1-10Perhaloalkyl, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Carbocyclyl, 3-14 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, or two R^bbThe groups taken together form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R ^ddSubstituted by groups;

R^ccindependently selected in each case from hydrogen, C_1-10Alkyl radical, C_1-10Perhaloalkyl, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Carbocyclyl, 3-14 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, or two R^ccThe groups taken together form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddSubstituted by groups;

R^ddindependently at each occurrence selected from halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OR^ee、-ON(R^ff)₂、-N(R^ff)₂、-N(R^ff)₃ ⁺X^-、-N(OR^ee)R^ff、-SH、-SR^ee、-SSR^ee、-C(＝O)R^ee、-CO₂H、-CO₂R^ee、-OC(＝O)R^ee、-OCO₂R^ee、-C(＝O)N(R^ff)₂、-OC(＝O)N(R^ff)₂、-NR^ffC(＝O)R^ee、-NR^ffCO₂R^ee、-NR^ffC(＝O)N(R^ff)₂、-C(＝NR^ff)OR^ee、-OC(＝NR^ff)R^ee、-OC(＝NR^ff)OR^ee、-C(＝NR^ff)N(R^ff)₂、-OC(＝NR^ff)N(R^ff)₂、-NR^ffC(＝NR^ff)N(R^ff)₂、-NR^ffSO₂R^ee、-SO₂N(R^ff)₂、-SO₂R^ee、-SO₂OR^ee、-OSO₂R^ee、-S(＝O)R^ee、-Si(R^ee)₃、-OSi(R^ee)₃、-C(＝S)N(R^ff)₂、-C(＝O)SR^ee、-C(＝S)SR^ee、-SC(＝S)SR^ee、-P(＝O)₂R^ee、-P(＝O)(R^ee)₂、-OP(＝O)(R^ee)₂、-OP(＝O)(OR^ee)₂、C_1-6Alkyl radical, C_1-6Perhaloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Carbocyclyl, 3-10 membered heterocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ggSubstituted by radicals, or two geminal R^ddThe substituents may together form ═ O or ═ S;

R^eeindependently at each occurrence selected from C_1-6Alkyl radical, C_1-6Perhaloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Carbocyclyl, C_6-10Aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, each of which is alkylAlkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5R^ggSubstituted by groups;

R^ffindependently selected in each case from hydrogen, C _1-6Alkyl radical, C_1-6Perhaloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Carbocyclyl, 3-10 membered heterocyclyl, C_6-10Aryl and 5-10 membered heteroaryl, or two R^ffThe groups taken together form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ggSubstituted by groups; and

R^ggindependently at each occurrence is halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OC_1-6Alkyl, -ON (C)_1-6Alkyl radical)₂、-N(C_1-6Alkyl radical)₂、-N(C_1-6Alkyl radical)₃ ⁺X^-、-NH(C_1-6Alkyl radical)₂ ⁺X^-、-NH₂(C_1-6Alkyl radical)⁺X^-、-NH₃ ⁺X^-、-N(OC_1-6Alkyl) (C_1-6Alkyl), -N (OH) (C)_1-6Alkyl), -NH (OH), -SH, -SC_1-6Alkyl, -SS (C)_1-6Alkyl), -C (═ O) (C)_1-6Alkyl), -CO₂H、-CO₂(C_1-6Alkyl), -OC (═ O) (C)_1-6Alkyl), -OCO₂(C_1-6Alkyl), -C (═ O) NH₂、-C(＝O)N(C_1-6Alkyl radical)₂、-OC(＝O)NH(C_1-6Alkyl), -NHC (═ O) (C)_1-6Alkyl), -N (C)_1-6Alkyl) C (═ O) (C)_1-6Alkyl), -NHCO₂(C_1-6Alkyl), -NHC (═ O) N (C)_1-6Alkyl radical)₂、-NHC(＝O)NH(C_1-6Alkyl), -NHC (═ O) NH₂、-C(＝NH)O(C_1-6Alkyl), -OC (═ NH) (C)_1-6Alkyl), -OC (═ NH) OC_1-6Alkyl, -C (═ NH) N (C)_1-6Alkyl radical)₂、-C(＝NH)NH(C_1-6Alkyl), -C (═ NH) NH₂、-OC(＝NH)N(C_1-6Alkyl radical)₂、-OC(NH)NH(C_1-6Alkyl), -OC (NH) NH₂、-NHC(NH)N(C_1-6Alkyl radical)₂、-NHC(＝NH)NH₂、-NHSO₂(C_1-6Alkyl), -SO₂N(C_1-6Alkyl radical)₂、-SO₂NH(C_1-6Alkyl), -SO₂NH₂、-SO₂C_1-6Alkyl, -SO₂OC_1-6Alkyl, -OSO₂C_1-6Alkyl, -SOC_1-6Alkyl, -Si (C)_1-6Alkyl radical)₃、-OSi(C_1-6Alkyl radical)₃、-C(＝S)N(C_1-6Alkyl radical)₂、C(＝S)NH(C_1-6Alkyl), C (═ S) NH₂、-C(＝O)S(C_1-6Alkyl), -C (═ S) SC_1-6Alkyl, -SC (═ S) SC _1-6Alkyl, -P (═ O)₂(C_1-6Alkyl), -P (═ O) (C)_1-6Alkyl radical)₂、-OP(＝O)(C_1-6Alkyl radical)₂、-OP(＝O)(OC_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_1-6Perhaloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Carbocyclyl, C_6-10Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R^ggThe substituents may together form ═ O or ═ S; wherein X^-Are counterions.

"counterions" or "anionic counterions" are negatively charged groups that are bound to cationic quaternary amino groups to maintain electroneutrality. Exemplary counterions include halide ions (e.g., F)^-、Cl^-、Br^-、I^-)、NO₃ ^-、ClO₄ ^-、OH^-、H₂PO₄ ^-、HSO₄ ^-Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), BF₄ ^–、PF₄ ^–、PF₆ ^–、AsF₆ ^–、SbF₆ ^–、B[3,5-(CF₃)₂C₆H₃]₄]^–、BPh₄ ^–、Al(OC(CF₃)₃)₄ ^–Carborane anions (e.g. CB)₁₁H₁₂ ^–Or (HCB)₁₁Me₅Br₆)^–) And carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

"halo" or "halogen" refers to fluoro (fluoro, -F), chloro (chloro, -Cl), bromo (bromo, -Br), or iodo (iodo, -I).

"acyl" means a radical selected from-C (═ O) R^aa、-CHO、-CO₂R^aa、-C(＝O)N(R^bb)₂、-C(＝NR^bb)R^aa、-C(＝NR^bb)OR^aa、-C(＝NR^bb)N(R^bb)₂、-C(＝O)NR^bbSO₂R^aa、-C(＝S)N(R^bb)₂、-C(＝O)SR^aaor-C (═ S) SR^aaWherein R is^aaAnd R^bbAs defined herein.

The nitrogen atoms may be substituted or unsubstituted, as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR ^aa、-N(R^cc)₂、-CN、-C(＝O)R^aa、-C(＝O)N(R^cc)₂、-CO₂R^aa、-SO₂R^aa、-C(＝NR^bb)R^aa、-C(＝NR^cc)OR^aa、-C(＝NR^cc)N(R^cc)₂、-SO₂N(R^cc)₂、-SO₂R^cc、-SO₂OR^cc、-SOR^aa、-C(＝S)N(R^cc)₂、-C(＝O)SR^cc、-C(＝S)SR^cc、-P(＝O)₂R^aa、-P(＝O)(R^aa)₂、-P(＝O)₂N(R^cc)₂、-P(＝O)(NR^cc)₂、C_1-10Alkyl radical, C_1-10Perhaloalkyl, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Carbocyclyl, 3-14 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, or two R attached to a nitrogen atom^ccThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddIs substituted by radicals, and wherein R^aa、R^bb、R^ccAnd R^ddAs defined above.

In some embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include, but are not limited to, -OH, -OR^aa、-N(R^cc)₂、-C(＝O)R^aa、-C(＝O)N(R^cc)₂、-CO₂R^aa、-SO₂R^aa、-C(＝NR^cc)R^aa、-C(＝NR^cc)OR^aa、-C(＝NR^cc)N(R^cc)₂、-SO₂N(R^cc)₂、-SO₂R^cc、-SO₂OR^cc、-SOR^aa、-C(＝S)N(R^cc)₂、-C(＝O)SR^cc、-C(＝S)SR^cc、C_1-10Alkyl (e.g., aralkyl, heteroaralkyl), C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Carbocyclyl, 3-14 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddIs substituted by radicals, and wherein R^aa、R^bb、R^ccAnd R^ddAs defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in protecting groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts, third edition, John Wiley&Sons, 1999, which is hereby incorporated by referenceIncorporated by reference.

For example, a nitrogen protecting group such as an amide group (e.g., -C (═ O) R^aa) Including, but not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, 2-picolinamide (picolinamide), 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenyloxyacetamide, acetoacetamide, (N' -dithiobenzyloxyacylamino) acetamide, 3- (p-hydroxyphenyl) propionamide, 3- (o-nitrophenyl) propionamide, 2-methyl-2- (o-nitrophenyloxy) propionamide, 2-methyl-2- (o-phenylazophenoxy) propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, chloramine, chloracetamide, trifluoroacetamide, phenylacetamide, 3-, O-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o- (benzoyloxymethyl) benzamide.

Nitrogen protecting groups such as carbamate (e.g., -C (═ O) OR^aa) Including, but not limited to, methylcarbamate, ethylcarbamate, 9-fluorenylmethylcarbamate (Fmoc), 9- (2-sulfo) fluorenylmethylcarbamate, 9- (2, 7-dibromo) fluorenylmethylcarbamate, 2, 7-di-tert-butyl- [9- (10, 10-dioxo-10, 10,10, 10-tetrahydrothioxanthyl) ]Methyl carbamate (DBD-Tmoc), 4-methoxybenzoyl methyl carbamate (Phenoc), 2,2, 2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (1-adamantyl) -1-methylethyl carbamate (Adpoc), 1-dimethyl-2-haloethylcarbamate, 1-dimethyl-2, 2-dibromoethylcarbamate (DB-t-BOC), 1-dimethyl-2, 2, 2-Trichloroethylcarbamate (TCBOC), 1-methyl-1- (4-biphenylyl) ethylcarbamate (Bpoc), 1- (3, 5-di-tert-butylphenyl) -1-methylethylcarbamate (t-Bumeoc), 2- (2 '-and 4' -pyridyl) ethylcarbamate (Pyoc), 2- (N, N-dicyclohexylcarboxamido) ethylcarbamate, tert-Butylcarbamate (BOC), 1-adamantylcarbamate (Adoc), vinylcarbamate (Voc), allylic carbamate (c)Carbamates (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamates, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2, 4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2- (p-toluenesulfonyl) ethyl carbamate, methyl ethyl carbamate, p-nitrobenzyl carbamate, p-methoxybenzyl carbamate, p-chlorobenzyl carbamate, p-toluenesulfonyl carbamate, N-methylbenzyl, [2- (1, 3-dithianyl) ]Methyl carbamate (Dmoc), 4-methylthiophencarbamate (Mtpc), 2, 4-dimethylthionylcarbamate (Bmpc), 2-phosphorusEthyl carbamate (Peoc), 2-triphenyl phosphineIsopropyl carbamate (Ppoc), 1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl) benzyl carbamate, 5-benzisoxycarbamateAzolylmethylcarbamate, 2- (trifluoromethyl) -6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3, 5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3, 4-dimethoxy-6-nitrobenzylcarbamate, phenyl (o-nitrophenyl) methylcarbamate, t-pentylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2-dimethoxyacylvinylcarbamate, o- (N, N-dimethylformyl carbamateAmino) benzylcarbamate, 1-dimethyl-3- (N, N-dimethylformamido) propylcarbamate, 1-dimethylpropynyl carbamate, bis (2-pyridyl) methylcarbamate, 2-furylmethyl carbamate, 2-iodoethylcarbamate, isobornyl carbamate, isobutyl carbamate, isonicotinoyl carbamate, p- (p' -methoxyphenylazo) benzylcarbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1- (3, 5-dimethoxyphenyl) ethylcarbamate, methyl-1-iodomethylcarbamate, isobornylcarbamate, methyl-1-iodocarbamate, isobornylcarbamate, methyl-1-methoxycarbamazo-ethyl-carbamate, methyl-2-iodobenzylcarbamate, methyl-, 1-methyl-1- (p-phenylazophenyl) ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1- (4-pyridyl) ethylcarbamate, phenylcarbamate, p- (phenylazo) benzylcarbamate, 2,4, 6-tri-tert-butylphenyl carbamate, 4- (trimethylammonium) benzylcarbamate and 2,4, 6-trimethylbenzylcarbamate.

A nitrogen protecting group such as a sulfonamide group (e.g., -S (═ O)₂R^aa) Including, but not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6, -trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4, 6-trimethoxybenzenesulfonamide (Mtb), 2, 6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5, 6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4, 6-trimethylbenzenesulfonamide (Mts), 2, 6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,5,7, 8-pentamethyl chroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β -trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4 ', 8' -dimethoxynaphthylmethyl) benzenesulfonamide (DNN), benzylsulfonamide, trifluoromethylMBS and benzoylmethyl sulfonamide.

Other nitrogen protecting groups include, but are not limited to, phenothiazinyl- (10) -acyl derivatives, N '-p-toluenesulfonylaminoacyl derivatives, N' -phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4, 5-diphenyl-3-Azolin-2-ones, N-phthalimides, N-dithiosuccinimides (Dts), N-2, 3-diphenylmaleimides, N-2, 5-dimethylpyrroles, N-1,1,4, 4-tetramethyldisilylazacyclopentane adducts (STABASE), 5-substituted 1, 3-dimethyl-1, 3, 5-triazacyclocyclohexan-2-ones, 5-substituted 1, 3-dibenzyl-1, 3, 5-triazacyclocyclohexan-2-ones, 1-substituted 3, 5-dinitro-4-pyridones, N-methylamines, N-allylamines, N- [2- (trimethylsilyl) ethoxy ] ethoxy ]Methylamine (SEM), N-3-acetoxypropylamine, N- (1-isopropyl-4-nitro-2-oxo-3-pyrrolidin-3-yl) amine, quaternary ammonium salt, N-benzylamine, N-bis (4-methoxyphenyl) methylamine, N-5-dibenzocycloheptyltrienylamine, N-triphenylmethylamine (Tr), N- [ (4-methoxyphenyl) diphenylmethyl]Amines (MMTr), N-9-phenylfluorenylamine (PhF), N-2, 7-dichloro-9-fluorenylmethylidene amine, N-ferrocenylmethylamino (Fcm), N-2-pyridylmethylamino N' -oxide, N-1, 1-dimethylthiomethylidene amine, N-benzylidene amine, N-p-methoxybenzylideneamine, N-diphenylmethylidene amine, N- [ (2-pyridyl)Base of]Methylamine, N- (N ', N ' -dimethylaminomethylene) amine, N ' -isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylidene amine, N-5-chlorosalicylideneamine, N- (5-chloro-2-hydroxyphenyl) phenylmethylidene amine, N-cyclohexylidene amine, N- (5, 5-dimethyl-3-oxo-1-cyclohexenyl) amine, N-borane derivatives, N-diphenylboronic acid derivatives, N- [ phenyl (pentacylchrome-or tungsten) acyl ] amines]Amines, N-copper chelates, N-zinc chelates, N-nitramines, N-nitrosamines, amine N-oxides, diphenylphosphinamides (Dpp), dimethylthiophosphonamides (Mpt), diphenylphosphinamides (Ppt), dialkylphosphoramidates, dibenzylphosphoramidates, diphenylphosphinates, benzenesulfinamides, o-nitrobenzenesulfinamides (Nps), 2, 4-dinitrobenzenesulfinamides, pentachlorobenzenesulfinamides, 2-nitro-4-methoxybenzenesulfinamides, triphenylmethylsulfinamides, and 3-nitropyridine sulfinamides (Npys). In certain embodiments, the nitrogen protecting groups described herein are Bn, Boc, Cbz, Fmoc, trifluoroacetyl, or, Triphenylmethyl, acetyl or Ts.

Exemplary oxygen atom substituents include, but are not limited to, -R^aa、-C(＝O)SR^aa、-C(＝O)R^aa、-CO₂R^aa、-C(＝O)N(R^bb)₂、-C(＝NR^bb)R^aa、-C(＝NR^bb)OR^aa、-C(＝NR^bb)N(R^bb)₂、-S(＝O)R^aa、-SO₂R^aa、-Si(R^aa)₃、-P(R^cc)₂、-P(R^cc)₃、-P(＝O)₂R^aa、-P(＝O)(R^aa)₂、-P(＝O)(OR^cc)₂、-P(＝O)₂N(R^bb)₂and-P (═ O) (NR)^bb)₂Wherein R is^aa、R^bbAnd R^ccAs defined herein. In some embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen Protecting Groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts, third edition, John Wiley&Sons, 1999, which is incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, methyl, t-butyloxycarbonyl (BOC or Boc), methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM), Benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy) methyl (p-AOM), Guaiacolmethyl (GUM), t-butoxymethyl, 4-Pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2, 2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl (SEMOR), Tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl group, 4-methoxytetrahydropyranyl group (MTHP), 4-methoxytetrahydrothiopyranyl group, 4-methoxytetrahydrothiopyranyl S, S-dioxide, 1- [ (2-chloro-4-methyl) phenyl group ]-4-methoxypiperidin-4-yl (CTMP), 1, 4-bisAlkyl-2-yl, tetrahydrofuryl, tetrahydrothienyl, 2,3,3a,4,5,6,7,7 a-octahydro-7, 8, 8-trimethyl-4, 7-methanobenzofurans (methanobenzobenzofuran) -2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2, 2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylhydroselenyl) ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2, 4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3, 4-dimethoxybenzyl, o-nitrobenzyl, p-halobenzyl, 2, 6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl, 3-picolyl-2-pyridinemethyl-pyridinecarboxylic acid, N-triphenylmethyl-pyridinecarboxylic acid, p-nitrobenzyl, p-trifluoromethylphenyl, benzylacetate, p-triphenylmethyl-benzylether, p-triphenylmethyl-4-triphenylmethyl-triphenylsilyl, p-diphenylmethyl-4-triphenylmethyl-diphenylmethyl-benzylether, diphenylmethyl-4-triphenylmethyl-phenyl (S), diphenylmethyl-phenyl) acetate, diphenylmethyl-triphenylmethyl-4-triphenylmethyl-diphenylmethyl-4-diphenylmethyl-phenyl-4-phenyl-4-triphenylmethyl-diphenylmethyl-4-triphenylmethyl-phenyl-diphenylmethyl-phenyl-triphenylmethyl-phenyl-4-phenyl-triphenylmethyl-ethyl, diphenylmethyl-triphenylmethyl-phenyl-triphenylmethyl-phenyl-triphenylmethyl-phenyl-triphenylmethyl-phenyl-ethyl, diphenylmethyl-phenyl-ethyl, diphenylmethyl-triphenylmethyl-phenyl-triphenylmethyl-phenyl-triphenylmethyl Phenylacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-pentanoate (levulinate), 4- (ethylenedithio) valerate (levulinyl dithioacetal), pivalate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4, 6-trimethylbenzoate (milonoate), alkylmethylcarbonate, 9-fluorenylmethylcarbonate (Fmoc), alkylethylcarbonate, alkyl 2,2, 2-trichloroethylcarbonate (Troc), 2- (trimethylsilyl) ethylcarbonate (TMSEC), 2- (phenylsulfonyl) ethylcarbonate (Psec), 2- (triphenylphosphorophosphonium) acetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-pentone ester (levulinate), 4- (ethylenedithiol) valerate (levulinyl dithiol)Alkyl) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3, 4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy) ethyl, 4- (methylthiomethoxy) butyrate, 2- (methylthiomethoxymethyl) benzoate, 2, 6-dichloro-4-methylphenoxyacetate, 2, 6-dichloro-4- (1,1,3, 3-tetramethylbutyl) phenoxyacetate, 2, 4-di (1, 1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E) -2-methyl-2-crotonate, o- (methoxyacyl) benzoate, α -dinitrophenyl carbamate, N '-di (N' -benzylsulfamate), TMS, N '-phosphoroamidate, N' -benzylcarbamate, N '-toluenesulfonate, TMS, N' -benzylcarbamate, N '-toluenesulfonate, N' -benzylcarbamate, N '-toluenesulfonate, N' -benzylcarbamate, N '-toluenesulfonate, N' -, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl or benzoyl.

Exemplary sulfur atom substituents include, but are not limited to, -R^aa、-C(＝O)SR^aa、-C(＝O)R^aa、-CO₂R^aa、-C(＝O)N(R^bb)₂、-C(＝NR^bb)R^aa、-C(＝NR^bb)OR^aa、-C(＝NR^bb)N(R^bb)₂、-S(＝O)R^aa、-SO₂R^aa、-Si(R^aa)₃、-P(R^cc)₂、-P(R^cc)₃、-P(＝O)₂R^aa、-P(＝O)(R^aa)₂、-P(＝O)(OR^cc)₂、-P(＝O)₂N(R^bb)₂and-P (═ O) (NR)^bb)₂Wherein R is^aa、R^bbAnd R^ccAs defined herein. In some embodiments, the sulfur atom substituent present at the sulfur atom is a sulfur protecting group (also referred to as a mercapto protecting group). Sulfur protecting groups are well known in the art and include protecting groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts, 3 rd edition, John Wiley&Sons, 1999, which is incorporated herein by reference. In certain embodiments, a sulfur protecting group described herein is acetamidomethyl, t-Bu, 3-nitro-2-pyridylthio (sulfenyl), 2-pyridylthio, or triphenylmethyl.

The present invention is not intended to be limited in any way by the illustrative substituents described above.

Other definitions

The following definitions are more general terms used throughout this application.

As used herein, "leaving group" or "LG" is a term known in the art that refers to a molecular fragment that loses a pair of electrons upon cleavage of a heteroatomic bond (hetrolyticbond), wherein the molecular fragment is an anionic or neutral molecule. See, for example, March Advanced Organic Chemistry 6 th edition (501-502). Is suitably a Examples of leaving groups include, but are not limited to, halides (e.g., chloride, bromide, or iodide), alkoxycarbonyloxy, aryloxycarbonyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N, O-dimethylhydroxyamino, pixyl, haloformates, -NO₂Trialkyl ammonium and aryl iodide salts. In some embodiments, the leaving group is a sulfonate. In some embodiments, the sulfonate ester comprises the formula-OSO₂R^LG1Wherein R is^LG1Selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl. In some embodiments, R^LG1Is substituted or unsubstituted C₁-C₆An alkyl group. In some embodiments, R^LG1Is methyl. In some embodiments, R^LG1is-CF₃. In some embodiments, R^LG1Is a substituted or unsubstituted aryl group. In some embodiments, R^LG1Is a substituted or unsubstituted phenyl group. In some embodiments, R^LG1The method comprises the following steps:

the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, the pharmaceutically acceptable salts described in detail in J.pharmaceutical sciences, 1977, 66, 1-19, by Berge et al, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from the appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino and inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids) or salts formed with organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids) or using other methods known in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentylpropionates, gluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, digluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, laurylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, salts of citric acid, salts of lactic acid, salts of malonic acid, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N ⁺(C_1-4Alkyl radical)₄ ^-And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, when appropriate, salts of non-toxic ammonium, quaternary ammonium and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

The term "solvate" refers to a form of a compound or salt thereof associated with a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

The term "hydrate" refers to a compound that binds to water. In general, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, hydrates of the compounds can be used, for example, with the formula R.xH₂O represents, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrates (x is a number greater than 0 and less than 1), e.g., hemihydrate (R0.5H)₂O)) and polyhydrates (x is a number greater than 1, e.g. dihydrate (R.2H)₂O) and hexahydrate (R.6H)₂O))。

The term "tautomer" or "tautomeric" refers to two or more compounds that are convertible into each other as a result of formal migration of at least one hydrogen atom and at least one change in valence (e.g., single bond to double bond, triple bond to single bond, or vice versa). The exact ratio of tautomers depends on a variety of factors including temperature, solvent and pH. Tautomerization (i.e., the reaction that provides a tautomeric pair) can be catalyzed by either an acid or a base. Exemplary tautomerism includes keto-to-enol, amide-to-imide, lactam-to-lactimide, enamine-to-imide, and enamine-to- (different enamine) tautomerism.

It is also understood that compounds having the same molecular formula but differing in nature or in the order of bonding of their atoms or in the arrangement of their atoms in space are referred to as "isomers". Isomers in which the spatial arrangement of their atoms is different are referred to as "stereoisomers".

Stereoisomers that are not mirror images of each other are referred to as "diastereomers" and those that are not overlapping mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and can be described by the R-and S-ordering rules of Cahn and Prelog, or by the fact that the molecule rotates in the plane of polarized light and is designated dextrorotatory or levorotatory (i.e., the (+) or (-) -isomers, respectively). The chiral compound may exist as a single enantiomer or as a mixture thereof. Mixtures containing equal enantiomers are referred to as "racemic mixtures".

The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause a crystalline form to dominate. Various polymorphs of a compound may be prepared by crystallization under different conditions.

The term "prodrug" refers to a compound that includes derivatives of the compounds described herein that have a cleavable group and become the compounds described herein by solvolysis or under physiological conditions, which is pharmaceutically active in vivo. Examples include, but are not limited to, choline ester derivatives and the like, N-alkyl morpholinyl esters, and the like. Other derivatives of the compounds described herein are active in their acid or acid derivative forms, but generally offer advantages in solubility, histocompatibility or delayed release in mammalian organisms in acid-sensitive forms (see Bundgard, h., Design of produgs, pages 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners in the art, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or by reaction of the parent acid compound with a substituted or unsubstituted amineThe prepared amide, or anhydride, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups on the compounds described herein are particular prodrugs. In some cases, it is desirable to prepare diester-type prodrugs, such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters. C of a Compound described herein ₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl, C₇-C₁₂Substituted aryl and C₇-C₁₂Arylalkyl esters may be preferred.

The term "small molecule" is a molecule of relatively low molecular weight, whether naturally occurring or artificially created (e.g., by chemical synthesis). Typically, the small molecule is an organic compound (i.e., it contains carbon). The small molecules can contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, and heterocycles, etc.). In some embodiments, the small molecule has a molecular weight of at most about 1,000g/mol, at most about 900g/mol, at most about 800g/mol, at most about 700g/mol, at most about 600g/mol, at most about 500g/mol, at most about 400g/mol, at most about 300g/mol, at most about 200g/mol, or at most about 100 g/mol. In some embodiments, the small molecule has a molecular weight of at least about 100g/mol, at least about 200g/mol, at least about 300g/mol, at least about 400g/mol, at least about 500g/mol, at least about 600g/mol, at least about 700g/mol, at least about 800g/mol, or at least about 900g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200g/mol and at most about 500g/mol) are also possible. In some embodiments, the small molecule is a therapeutically active agent, such as a drug (e.g., a molecule approved by the U.S. food and drug administration and provided in the U.S. federal regulations compilation (c.f.r)). The small molecule may also be complexed with one or more atoms and/or metal ions. In this case, the small molecule is also referred to as a "small organometallic molecule". Preferred small molecules are biologically active, which produce a biological effect in an animal, preferably a mammal, more preferably a human. Small molecules include, but are not limited to, radionuclides and imaging agents. In some embodiments, the small molecule is a drug. Preferably, but not necessarily, the medicament is one that has been deemed safe and effective for use in humans or animals by a suitable governmental or regulatory agency. For example, drugs approved for use in humans are listed by the FDA in 21c.f.r. § 330.5, 331 to 361 and 440 to 460, which are incorporated herein by reference; drugs for veterinary use are listed by the FDA in 21c.f.r. § 500 to 589, which are incorporated herein by reference. All listed drugs are considered to be acceptable for use in the present invention.

"protein", "peptide" or "polypeptide" includes polymers of amino acid residues joined together by peptide bonds and refers to proteins, polypeptides and peptides of any size, structure or function. Typically, the protein will be at least 3 amino acids in length. A protein may refer to an individual protein or a collection of proteins. The proteins of the invention preferably contain only natural amino acids, but may alternatively employ unnatural amino acids (i.e., compounds that do not occur in nature but which can be incorporated into polypeptide chains) and/or amino acid analogs known in the art. In addition, one or more amino acids in a protein can be modified, for example, by the addition of a chemical entity, such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation or functionalization, or other modification. The protein may be a single molecule or may be a multi-molecule complex. The protein may be a fragment of a naturally occurring protein or peptide. The protein may be naturally occurring, recombinant, synthetic or any combination of these.

The term "gene" refers to a nucleic acid fragment that expresses a particular protein, including regulatory sequences preceding the coding sequence (5 'non-coding sequences) and regulatory sequences following the coding sequence (3' non-coding sequences). "native gene" refers to a gene that is found in nature as its own regulatory sequence. "chimeric gene" or "chimeric construct" refers to any gene or construct (non-native gene) that comprises regulatory and coding sequences that are not found together in nature. Thus, a chimeric gene or chimeric construct may comprise regulatory sequences and coding sequences that are derived from different sources, or regulatory sequences and coding sequences derived from the same source but arranged differently than found in nature. "endogenous gene" refers to a native gene that is naturally located in the genome of an organism. "foreign" gene refers to a gene that is not normally present in a host organism but is introduced into the host organism by gene transfer. The foreign gene may comprise a native gene inserted into a non-native organism, or a chimeric gene. A "transgene" is a gene that has been introduced into the genome by a transformation method.

The term "histone" refers to a strongly basic protein found in the nucleus of eukaryotic cells, which packages and aligns DNA to building blocks known as nucleosomes. They are the major protein component of chromatin, act as spools around which DNA is wound and exert a gene regulatory role. In some embodiments, the histone is histone H1 (e.g., histone H1F, histone H1H 1). In some embodiments, the histone is histone H2A (e.g., histone H2AF, histone H2a1, histone H2a 2). In some embodiments, the histone is histone H2B (e.g., histone H2BF, histone H2B1, histone H2B 2). In some embodiments, the histone is histone H3 (e.g., histone H3a1, histone H3a2, histone H3 A3). In some embodiments, the histone is histone H4 (e.g., histone H41, histone H44).

The term "bromodomain" refers to a protein domain that recognizes acetylated lysine residues (e.g., those residues at the N-terminal tail of histone protein). In some embodiments, the bromodomain of a BET protein comprises about 110 amino acids and shares a conserved fold, which includes a left-handed bundle of 4 alpha helices connected by different loop regions that interact with chromatin.

The term "bromodomain-containing protein" or "bromodomain protein" refers to a protein or variant thereof, whether wild-type or mutant, natural or synthetic, truncated or intact, having a minimum amino acid sequence sufficient for a functional bromodomain to be able to modulate the molecular recognition of acetyl-lysine at an acetylated lysine residue of a second protein (e.g., a histone protein, e.g., at the tail of a histone protein). Bromodomain-containing proteins include, for example, fusion proteins comprising a bromodomain and additional portions (e.g., reporter portions) having desired functions. Exemplary bromodomains include, but are not limited to, bromodomains described herein.

The terms "composition" and "formulation" are used interchangeably.

"subjects" for which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and/or other non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys). In some embodiments, the animal is a mammal. The animal may be male or female at any developmental stage. The animal may be a transgenic animal or a genetically engineered animal. In some embodiments, the subject is a non-human animal. In some embodiments, the animal is a fish. "patient" refers to a human subject in need of treatment for a disease. The subject may also be a plant. In some embodiments, the plant is a terrestrial plant. In some embodiments, the plant is a non-vascular terrestrial plant. In some embodiments, the plant is a vascular terrestrial plant. In some embodiments, the plant is a seed plant. In some embodiments, the plant is a cultivated plant. In some embodiments, the plant is a dicot. In some embodiments, the plant is a monocot. In some embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal, for example, maize (maize), maize (corn), wheat, rice, oats, barley, rye, or millet. In some embodiments, the plant is a leguminous plant, e.g., a legume plant, e.g., a soybean plant. In some embodiments, the plant is a tree or shrub.

The terms "administering," "administering," or "administering" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing into a subject a compound described herein, or a composition thereof.

The terms "treat," "treating," and "treatment" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of the diseases described herein. In some embodiments, treatment may be administered after the disease has appeared or one or more signs or symptoms have been observed. In other embodiments, the treatment may be administered without signs or symptoms of the disease. For example, treatment can be administered to a susceptible subject prior to the onset of symptoms (e.g., based on history of symptoms and/or based on exposure to pathogens). Treatment may also be continued after the symptoms have disappeared, e.g., to delay or prevent relapse.

The terms "condition," "disease," and "disorder" are used interchangeably.

An "effective amount" of a compound described herein refers to an amount sufficient to elicit the desired biological response (i.e., to treat the condition). As will be appreciated by those skilled in the art, the effective amount of a compound described herein may vary depending on the following factors: the biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject are contemplated. An effective amount includes both therapeutic and prophylactic treatment.

A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in treating a disorder or to delay or minimize one or more symptoms associated with the disorder. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent that alone, or in combination with other therapies, provides a therapeutic benefit for treating the condition. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or eliminates the symptoms, signs, or causes of the disorder, and/or enhances the efficacy of another therapeutic agent. In some embodiments, the therapeutically effective amount is effective for inhibiting the activity of the bromodomain-containing protein. In some embodiments, a therapeutically effective amount is effective for treating a disease described herein. In some embodiments, the therapeutically effective amount is effective for inhibiting the activity of the bromodomain-containing protein and treating the diseases described herein.

A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent the disorder or one or more symptoms associated with the disorder, or prevent the recurrence thereof. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent that alone, or in combination with other drugs, provides a prophylactic benefit in preventing the condition. The term "prophylactically effective amount" can include an amount that increases the overall prophylactic or prophylactic effect of another prophylactic agent. In some embodiments, the prophylactically effective amount is effective for inhibiting the activity of a bromodomain-containing protein. In some embodiments, a prophylactically effective amount is effective for preventing a disease described herein. In some embodiments, the prophylactically effective amount is effective for inhibiting the activity of a bromodomain-containing protein and preventing a disease described herein.

"proliferative disease" refers to a disease caused by abnormal growth or expansion due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases may be associated with: 1) pathological proliferation of normal resting stage cells; 2) pathological migration of cells from their normal location (e.g., metastasis of tumor cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis in proliferative retinopathies and tumor metastases. Exemplary proliferative diseases include cancer (i.e., "malignant tumor"), benign tumor, angiogenesis, inflammatory disease, and autoimmune disease.

The term "angiogenesis" refers to the physiological process of forming new blood vessels from pre-existing blood vessels. Angiogenesis is distinct from angiogenesis (vasculogenesis), which is the de novo formation of endothelial cells from mesodermal cell precursors. After the first blood vessels of the developing embryo are formed by angiogenesis, angiogenesis is primarily responsible for the vast majority of blood vessel growth during normal or abnormal development. Angiogenesis is an important process in growth and development, as well as wound healing and the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant state, resulting in the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis can be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). "pathological angiogenesis" refers to abnormal (e.g., excessive or insufficient) angiogenesis that progresses to and/or is associated with a disease.

The terms "neoplasms" and "tumors" are used interchangeably and refer to abnormal masses of tissue in which the growth of the mass exceeds and is not coordinated with the growth of normal tissue. A neoplasm or tumor may be "benign" or "malignant," depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion and metastasis. "benign tumors" are generally well differentiated, have significantly slower growth than malignant tumors, and remain localized to the site of origin. In addition, benign tumors do not have the ability to infiltrate, invade, or metastasize to distant locations. Exemplary benign tumors include, but are not limited to, lipoma, chondroma, adenoma, acrochordon, senile hemangioma, seborrheic keratosis, lentigo, and sebaceous hyperplasia. In some cases, some "benign" tumors may later cause malignant tumors, which may be due to additional genetic changes in a subpopulation of tumor cells of the tumor, and these tumors are referred to as "pre-malignant neoplasms". An exemplary pre-cancerous tumor is a teratoma. In contrast, "malignant tumors" are generally poorly differentiated (anaplasia) and have significantly rapid growth with progressive infiltration, invasion and destruction of surrounding tissue. In addition, malignant tumors often have the ability to metastasize to distant locations. The terms "metastasis," "metastatic," or "migration" refer to the spread or metastasis of cancer cells from a primary or original tumor to another organ or tissue and is typically determined by: in the organ or tissue where the secondary (metastatic) tumor is located, there is a "secondary tumor" or "secondary cell mass" of the tissue type of the primary or original tumor and not of the organ or tissue where it is located. For example, prostate cancer that has metastasized to bone is referred to as metastatic prostate cancer and includes cancerous prostate cancer cells that grow in tissue.

The term "cancer" refers to a malignant tumor (Stedman's Medical Dictionary, 25 th edition; Hensyl editor; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcoma (angiosarcoma) (e.g., lymphangioangiosarcoma, lymphangioendotheliosarcoma, angiosarcoma); appendiceal carcinoma; benign monoclonal propionibacteria; biliary tract cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, breast medullary carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial cancer; carcinoid tumors; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ependymoma; endothelial sarcoma (e.g., kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, barrett's adenocarcinoma); ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; stomach cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumors (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal carcinoma, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemias, such as Acute Lymphocytic Leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), Acute Myelogenous Leukemia (AML) (e.g., B-cell AML, T-cell AML), Chronic Myelogenous Leukemia (CML) (e.g., B-cell CML, T-cell CML), and Chronic Lymphocytic Leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomas such as Hodgkin's Lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL such as Diffuse Large Cell Lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Mantle Cell Lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, lymph node marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), Hairy Cell Leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary Central Nervous System (CNS) lymphoma, and T-cell NHL, such as precursor T lymphoblastic lymphoma/leukemia, Peripheral T Cell Lymphoma (PTCL) (e.g., Cutaneous T Cell Lymphoma (CTCL) (e.g., mycosis fungoides, sezary syndrome), angioimmunoblastic T cell lymphoma, extranodal natural killer T cell lymphoma, enteropathy-type T cell lymphoma, subcutaneous panniculitis-like T cell lymphoma, and anaplastic large cell lymphoma); a mixed state of one or more of the above leukemias/lymphomas; and Multiple Myeloma (MM)), heavy chain disorders (e.g., alpha chain disorders, gamma chain disorders, mu chain disorders); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblast tumors; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as wilms tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, Small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPDs) (e.g., Polycythemia Vera (PV), Essential Thrombocythemia (ET), Agnogenic Myeloid Metaplasia (AMM), also known as Myelofibrosis (MF), chronic idiopathic myelofibrosis, Chronic Myelogenous Leukemia (CML), Chronic Neutrophilic Leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromatosis (e.g., Neurofibromatosis (NF) type 1 or type 2, schwannomatosis (schwannomatosis)); neuroendocrine tumors (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumors); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma (pancreatic adenocarinoma), Intraductal Papillary Mucinous Neoplasm (IPMN), pancreatic islet cell carcinoma); penile cancer (e.g., paget's disease of the penis and scrotum); pineal tumor; primitive Neuroectodermal Tumors (PNT); a plasmacytoma; paraneoplastic syndromes (paraneoplastic syndromes); intraepithelial tumors; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., Squamous Cell Carcinoma (SCC), Keratoacanthoma (KA), melanoma, Basal Cell Carcinoma (BCC)); small bowel cancer (e.g., appendiceal cancer); soft tissue sarcomas (e.g., Malignant Fibrous Histiocytoma (MFH), liposarcoma, Malignant Peripheral Nerve Sheath Tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancer; small bowel cancer; sweat gland cancer; a synovial tumor; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, Papillary Thyroid Carcinoma (PTC), medullary thyroid carcinoma); cancer of the urethra; vaginal cancer; and vulvar cancer (e.g., paget's disease of the vulva).

The term "inflammatory disease" refers to a disease caused by, or resulting in inflammation. The term "inflammatory disease" may also refer to a dysregulated inflammatory response that results in exaggerated responses by macrophages, granulocytes, and/or T-lymphocytes, resulting in abnormal tissue damage and/or cell death. Inflammatory diseases may be acute or chronic inflammatory disorders and may result from infectious or non-infectious causes. Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthritis, rheumatoid arthritis, inflammatory arthritis, sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., type I), myasthenia gravis, hashimoto's thyroiditis, Graves ' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory skin diseases, common interstitial pneumonia (UIP), asbestosis, silicosis, lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, sclerosing syndrome, sclerosing disease, ulcerative colitis, and other diseases, Bronchiectasis, berylliosis, talosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, intercellular pneumonia, exogenous allergic alveolitis, wegener's granulomatosis and related forms of vasculitis (temporal arteritis and nodular multiple arteritis), inflammatory skin diseases, delayed hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, pollinosis, allergy, acute hypersensitivity reactions, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host versus graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, Bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis (testitis), tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. Inflammatory diseases of the eye include, but are not limited to, inflammation following surgery.

"autoimmune disease" refers to a disease that results from an inappropriate immune response of a subject's body to substances and tissues that are normally present in the body. In other words, the immune system mistreats a portion of the body as a pathogen and attacks its own cells. This can be restricted to specific organs (e.g., in autoimmune thyroiditis) or to specific tissues involved in different locations (e.g., goodpasture's disease, which may affect the basement membrane of the lung and kidney). Treatment of autoimmune diseases is often with immunosuppression, e.g., drugs that reduce the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-related vasculitis (e.g., wegener's granulomatosis, microscopic polyangiitis), uveitis (urveitis), sjogren's syndrome, crohn's disease, reiter's syndrome, ankylosing spondylitis, lyme disease, guillain-barre syndrome, hashimoto's thyroiditis, and cardiomyopathy.

"kinases" are a class of enzymes that transfer phosphate groups from high energy donor molecules (e.g., ATP) to specific substrates (called phosphorylation). Part of a large family of kinase phosphotransferases. One of the largest group of kinases is the protein kinases, which act on specific proteins and modify the activity of specific proteins. Kinases are widely used in cells to transmit signals and control complex processes. A variety of other kinases act on small molecules such as lipids, carbohydrates, amino acids, and nucleotides, whether to signal or provide them to metabolic pathways. Kinases are often named for their substrates. Over 500 different protein kinases have been identified in humans. These exemplary human protein kinases include, but are not limited to, AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1, AKT2, AKT3, ALK1, ALK2, ALK4, ALK7, AMPKa1, ANKRD 1, ANPa, ANPb, ARAF, ARAFps, ARG, AurA, AurAps1, AurBps1, aurrc, AXL, BARK1, BIKE, BLK, BMPR 11, BMPR1Aps1, pr1Aps1, BMPR 11, BMPR 36k 1, 36k 1, 36k 1, CDK 36k 1, CDK 36k 1, CDK 36k 1, CDK 36k 1, 36k 1, 36k 1, 36k 1, 36k 1, 36k 1, 36k 1, 36k, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK1, DRAK1, DYRK 11, DYRK1, EGFR, EphA1, EphB1, Erk1, ErfIKARK 1, ErfHRK 1, ErfKARK 1, FLK 1, FLAK 1, FLAK 1, FLKARK 1, FLAK 1, FLKARK 1, FLAK 363672, FLAK 1, FLK 1, FLAK 1, FLKARK 1, FLK 36, LMR, LOK, LRRK, LTK, LYN, LZK, MAK, MAP2K1, MAP2K2, MAP2K, MAP3K, MAPKAPK, MAPKAKPK, MAPKAPK, MAPKAPPKPs, MARK, MARKps, NIKps, MARKps, NuKps, MYKps, MARKps, MARK, NEKpk, MARK2 Kpk, NEKpk, MARK, NEMLKpt, MARK, NEKpk, NEKpt, MARK, p38b, p38d, p38g, p70S6K, p70S6Kb, p70S6Kps1, p70S6Kps2, PAK 22, PAK2, PASK, PBK, PCTAIRE2, PDGFRa, PDK 2, PEK, TAK 2, PFTATATAIRE 2, PFKg 2, PHKg 361 ps2, PHKg 12, PHKg2, PIK3R 2, PKRYPCK 2, PKRYPRYPRYPRYPRK 2, PKRKP 2, PKRYPRYPRYPRK 2, PKRKP 2, PKRKPROPK 2, PKRK 2, PKRKP 2, PKRYPRK 2, PKRK 2, PKRKP 2, PKRYPK 2, PKR3672, PKRKP 2, PKRK 2, PKR3672, PKRKP 2, PKRKP 2, PKR3672, PKRK 2, PKRKP 2, PKR3672, PKRKP 2, PKRKP 2, PKRKP 2, PKR3672, 2, PKR3672, PKRKP 2, PKR3672, 2, PKRKP 2, PKR3672, PK, skMLCK, SLK, Slob, smMLCK, SNRK, SPEG, SRC, SRM, SRPK2, SSTK, STK33, STLK6ps, STLK-rs, SuRTK106, SYK, TAK, TAO, TBCK, TBK, TEC, TESK, TGFbR, TIE, TLK1, TLK2ps, TNK, Trad, Trb, Trio, KA, TRKB, TRKC, TSSK, TSSKKps, TSSKSKKs, TTSKBK, TTBKYABK, TTK, TTN, TXK, TYK, TYPK, TYK, TYKs, TYKK, TYK, TXK, TYK, TRK, WYK, WZK, WYK, WYSK, VRK, WYK, WYSK, VRK, W.

Detailed description of certain embodiments of the invention

Recently, some compounds have been reported as bromodomain binders, e.g., WO 2012/075383, WO2011/054553, WO 2011/054841, WO 2011/054844, WO 2011/054845, WO 2011/054846, WO2011/054848, WO 2011/143669, and WO 2011/161031. Furthermore, japanese patent application publication JP 2008/156311 discloses benzimidazole derivatives, purportedly BRD2 bromodomain binding agents, which have utility for viral infection and/or proliferation. International PCT publication WO 2009/084693 discloses a series of thienotriazolodiazepinesDerivatives, which are said to inhibit the binding between acetylated histones and bromodomain-containing proteins, are said to be useful as anti-cancer drugs. International PCT publication WO 2011/054843 suggests that compounds that inhibit the binding of bromodomains to their cognate acetylated proteins may have utility in the treatment of a wide range of autoimmune and inflammatory diseases or disorders. However, there is still a need for more effective and safe bromodomain binders.

The present invention provides compounds of formula (II), (e.g., compounds of formula (I)) which are binders of bromodomains and/or bromodomain-containing proteins. The compounds described herein can be used to bind to a binding pocket of a bromodomain (e.g., a bromodomain of a bromodomain-containing protein). Without wishing to be bound by any particular theory, the compounds described herein can bind to the binding pocket of the bromodomain by mimicking the contact between the acetylated lysine residue of a second protein (e.g., a histone) and the binding pocket of the bromodomain. In some embodiments, the compounds described herein bind to the binding pocket of the bromodomain. The compounds described herein may also be inhibitors of bromodomains and/or bromodomain-containing proteins. The invention also provides pharmaceutical compositions, methods, uses and kits useful for inhibiting the activity of bromodomain-containing proteins (e.g., transcription factors). The compounds, pharmaceutical compositions, methods, uses and kits are useful for treating and/or preventing diseases associated with bromodomains, diseases associated with bromodomain-containing proteins, diseases associated with activity (e.g., aberrant activity) of bromodomains, and diseases associated with activity (e.g., aberrant activity) of bromodomain-containing proteins. Exemplary diseases that can be prevented and/or treated with the compounds described herein include proliferative diseases (e.g., cancer, benign tumors, angiogenesis, inflammatory diseases, and autoimmune diseases), autoimmune diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning. The compounds, pharmaceutical compositions, methods, uses and kits may also be used for male contraception and inhibiting viral replication or killing viruses.

Compound (I)

The present invention provides compounds of formula (II):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein:

R¹is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, orSubstituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group attached to a nitrogen atom;

R²is hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^D1、–N(R^D1)₂、–SR^D1、–CN、–SCN、–C(＝NR^D1)R^D1、–C(＝NR^D1)OR^D1、–C(＝NR^D1)N(R^D1)₂、–C(＝O)R^D1、–C(＝O)OR^D1、–C(＝O)N(R^D1)₂、–NO₂、–NR^D1C(＝O)R^D1、–NR^D1C(＝O)OR^D1、–NR^D1C(＝O)N(R^D1)₂、–OC(＝O)R^D1、–OC(＝O)OR^D1or-OC (═ O) N (R)^D1)₂Wherein R is^D1Independently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R ^D1The groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring;

R³and R⁴Each independently is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group; or R³And R⁴The radicals together forming a substituted or unsubstituted heterocycle or substituted or unsubstitutedA substituted heteroaryl ring;

R⁵independently at each occurrence is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁶independently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^B1a、–N(R^B1a)₂、–SR^B1a、–CN、–SCN、–C(＝NR^B1a)R^B1a、–C(＝NR^B1a)OR^B1a、–C(＝NR^B1a)N(R^B1a)₂、–C(＝O)R^B1a、–C(＝O)OR^B1a、–C(＝O)N(R^B1a)₂、–NO₂、–NR^B1aC(＝O)R^B1a、–NR^B1aC(＝O)OR^B1a、–NR^B1aC(＝O)N(R^B1a)₂、–OC(＝O)R^B1a、–OC(＝O)OR^B1aor-OC (═ O) N (R)^B1a)₂；

q is 0, 1, 2, 3 or 4;

a is ═ N-or ═ C (R) ²)–；

R^B1Independently at each occurrence, hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^B1a、-N(R^B1a)₂、-SR^B1a、-CN、-SCN、-C(＝NR^B1a)R^B1a、-C(＝NR^B1a)OR^B1a、-C(＝NR^B1a)N(R^B1a)₂、-C(＝O)R^B1a、-C(＝O)OR^B1a、-C(＝O)N(R^B1a)₂、-NO₂、-NR^B1aC(＝O)R^B1a、-NR^B1aC(＝O)OR^B1a、-NR^B1aC(＝O)N(R^B1a)₂、-OC(＝O)R^B1a、-OC(＝O)OR^B1aor-OC (═ O) N (R)^B1a)₂；

R^B1aIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^B1aThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring;

p is 0 or an integer between 1 and 4, inclusive;

n is 0, 1, 2, 3, 4, 5 or 6;

L¹、L²and L⁴Each independently is a bond,

L³Is composed of

R^a1Is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group; and

R^c1Independently each occurrence is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstitutedSubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^c1a、–N(R^c1a)₂、–SR^c1a、–CN、–C(＝O)R^c1a、–C(＝O)OR^c1a、–C(＝O)N(R^c1a)₂、–NR^c1aC(＝O)R^c1a、–NR^c1aC(＝O)OR^c1a、–NR^c1aC(＝O)N(R^c1a)₂、–OC(＝O)R^c1aor-OC (═ O) N (R)^c1a)₂Wherein R is^c1aIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^c1aThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, the present invention provides compounds of formula (II) and pharmaceutically acceptable salts thereof.

As generally defined herein, L³Is thatAs generally defined herein, R¹Is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group attached to a nitrogen atom.

In some embodiments, R¹Is hydrogen. In some embodiments, R¹Is substituted or unsubstituted C_1-6Alkyl groups, for example, methyl, ethyl, propyl or butyl. In thatIn some embodiments, R¹Is an unsubstituted methyl group. In some embodiments, R¹Is an unsubstituted ethyl group. In some embodiments, R¹Is a branched chain C_1-6Alkyl groups, for example, isopropyl, isobutyl or tert-butyl. In some embodiments, R¹Is unsubstituted tert-butyl. In some embodiments, R¹Is substituted or unsubstituted C_1-6Haloalkyl radicals, e.g., -CF₃、–CH₂CF₃、–CHF₂、–CH₂F、–CF₂CH₃or-CF₂CF₃. In some embodiments, R¹Is a substituted or unsubstituted aralkyl group, for example, benzyl. In some embodiments, R¹Is a substituted or unsubstituted alkoxyalkyl group, e.g., -CH₂OR^1a、–CH₂CH₂OR^1aor-CH₂CH(CH₃)OR^1aWherein R is^1aIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl or substituted or unsubstituted phenyl.

In some embodiments, R¹Is a substituted or unsubstituted alkenyl group, for example, vinyl, allyl, propenyl, or butenyl. In some embodiments, R¹Is a substituted or unsubstituted alkynyl group, for example, propargyl, propynyl or butynyl.

In some embodiments, R ¹Is a substituted or unsubstituted carbocyclyl. In some embodiments, R¹Is a substituted or unsubstituted 3-6 membered carbocyclic group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R¹Is a 3-6 membered carbocyclic group, which is substituted by 1, 2, 3, 4 or 5R^1bIs substituted in which R^1bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^1ba、–N(R^1ba)₂、–SR^1ba、–CN、–SCN、–C(＝NR^1ba)R^1ba、–C(＝NR^1ba)OR^1ba、–C(＝NR^1ba)N(R^1ba)₂、–C(＝O)R^1ba、–C(＝O)OR^1ba、–C(＝O)N(R^1ba)₂、–NO₂、–NR^1baC(＝O)R^1ba、–NR^1baC(＝O)OR^1ba、–NR^1baC(＝O)N(R^1ba)₂、–OC(＝O)R^1ba、–OC(＝O)OR^1baor-OC (═ O) N (R)^1ba)₂And R is^1baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^1baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R¹Is a substituted or unsubstituted heterocyclic group. In some embodiments, R¹Is a substituted or unsubstituted 3-6 membered heterocyclic group, for example, oxetanyl, tetrahydrofuryl, pyranyl, azetidinyl, pyrrolidinyl or piperidinyl. In some embodiments, R¹Is a 3-6 membered heterocyclic group which is substituted with 1, 2, 3, 4 or 5R^1bIs substituted in which R^1bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^1ba、–N(R^1ba)₂、–SR^1ba、–CN、–SCN、–C(＝NR^1ba)R^1ba、–C(＝NR^1ba)OR^1ba、–C(＝NR^1ba)N(R^1ba)₂、–C(＝O)R^1ba、–C(＝O)OR^1ba、–C(＝O)N(R^1ba)₂、–NO₂、–NR^1baC(＝O)R^1ba、–NR^1baC(＝O)OR^1ba、–NR^1baC(＝O)N(R^1ba)₂、–OC(＝O)R^1ba、–OC(＝O)OR^1baor-OC (═ O) N (R)^1ba)₂And R is^1baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R ^1baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R¹Is a substituted or unsubstituted aryl group. In some embodiments, R¹Is a substituted or unsubstituted phenyl group. In some embodiments, R¹Is substituted by 1, 2, 3, 4 or 5R^1bSubstituted phenyl, wherein R^1bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^1ba、–N(R^1ba)₂、–SR^1ba、–CN、–SCN、–C(＝NR^1ba)R^1ba、–C(＝NR^1ba)OR^1ba、–C(＝NR^1ba)N(R^1ba)₂、–C(＝O)R^1ba、–C(＝O)OR^1ba、–C(＝O)N(R^1ba)₂、–NO₂、–NR^1baC(＝O)R^1ba、–NR^1baC(＝O)OR^1ba、–NR^1baC(＝O)N(R^1ba)₂、–OC(＝O)R^1ba、–OC(＝O)OR^1baor-OC (═ O) N (R)^1ba)₂And R is^1baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^1baThe groups are linked together to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R¹Is a substituted or unsubstituted heteroaryl. In some embodiments, R¹Is a substituted or unsubstituted 5-6 membered heteroaryl group, for example, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, R¹Is a 5-6 membered heteroaryl substituted with 1, 2, 3, 4 or 5R^1bIs substituted in which R^1bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^1ba、–N(R^1ba)₂、–SR^1ba、–CN、–SCN、–C(＝NR^1ba)R^1ba、–C(＝NR^1ba)OR^1ba、–C(＝NR^1ba)N(R^1ba)₂、–C(＝O)R^1ba、–C(＝O)OR^1ba、–C(＝O)N(R^1ba)₂、–NO₂、–NR^1baC(＝O)R^1ba、–NR^1baC(＝O)OR^1ba、–NR^1baC(＝O)N(R^1ba)₂、–OC(＝O)R^1ba、–OC(＝O)OR^1baor-OC (═ O) N (R)^1ba)₂And R is^1baIndependently each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstitutedAn alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R ^1baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, -L³–R¹Is of the formula:in some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is that

In some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is thatIn some embodiments, -L³–R¹Is that

As generally defined herein, a is ═ N-or ═ C (R)²)-. As generally defined herein, R²Is hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR ^D1、–N(R^D1)₂、–SR^D1、–CN、–SCN、–C(＝NR^D1)R^D1、–C(＝NR^D1)OR^D1、–C(＝NR^D1)N(R^D1)₂、–C(＝O)R^D1、–C(＝O)OR^D1、–C(＝O)N(R^D1)₂、–NO₂、–NR^D1C(＝O)R^D1、–NR^D1C(＝O)OR^D1、–NR^D1C(＝O)N(R^D1)₂、–OC(＝O)R^D1、–OC(＝O)OR^D1or-OC (═ O) N (R)^D1)₂. As generally defined herein, R^D1Independently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^D1The groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R²Is substituted or unsubstituted C_1-6Alkyl groups, for example, methyl, ethyl, propyl or butyl. In some embodiments, R²Is an unsubstituted methyl group. In some embodiments, R²Is an unsubstituted ethyl group. In some embodiments, R²Is a branched chain C_1-6An alkyl group, a carboxyl group,for example, isopropyl, isobutyl or tert-butyl. In some embodiments, R²Is unsubstituted tert-butyl. In some embodiments, R²Is substituted or unsubstituted C_1-6Haloalkyl radicals, e.g., -CF₃、–CH₂CF₃、–CHF₂、–CH₂F、–CF₂CH₃or-CF₂CF₃. In some embodiments, R ²Is a substituted or unsubstituted aralkyl group, for example, benzyl. In some embodiments, R²Is a substituted or unsubstituted alkoxyalkyl group, e.g., -CH₂OR^2a、–CH₂CH₂OR^2aor-CH₂CH(CH₃)OR^2aWherein R is^2aIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl or substituted or unsubstituted phenyl.

In some embodiments, R²Is a substituted or unsubstituted alkenyl group, for example, vinyl, allyl, propenyl, or butenyl. In some embodiments, R²Is a substituted or unsubstituted alkynyl group, for example, propargyl, propynyl or butynyl.

In some embodiments, R²Is a substituted or unsubstituted carbocyclyl. In some embodiments, R²Is a substituted or unsubstituted 3-6 membered carbocyclic group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R²Is substituted by 1, 2, 3, 4 or 5R^2bSubstituted 3-6 membered carbocyclyl wherein R^2bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR ^2ba、–N(R^2ba)₂、–SR^2ba、–CN、–SCN、–C(＝NR^2ba)R^2ba、–C(＝NR^2ba)OR^2ba、–C(＝NR^2ba)N(R^2ba)₂、–C(＝O)R^2ba、–C(＝O)OR^2ba、–C(＝O)N(R^2ba)₂、–NO₂、–NR^2baC(＝O)R^2ba、–NR^2baC(＝O)OR^2ba、–NR^2baC(＝O)N(R^2ba)₂、–OC(＝O)R^2ba、–OC(＝O)OR^2baor-OC (═ O) N (R)^2ba)₂And R is^2baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^2baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R²Is a substituted or unsubstituted heterocyclic group. In some embodiments, R²Is a substituted or unsubstituted 3-6 membered heterocyclic group, for example, oxetanyl, tetrahydrofuryl, pyranyl, azetidinyl, pyrrolidinyl or piperidinyl. In some embodiments, R²Is substituted by 1, 2, 3, 4 or 5R^2bSubstituted 3-6 membered heterocyclyl, wherein R^2bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR ^2ba、–N(R^2ba)₂、–SR^2ba、–CN、–SCN、–C(＝NR^2ba)R^2ba、–C(＝NR^2ba)OR^2ba、–C(＝NR^2ba)N(R^2ba)₂、–C(＝O)R^2ba、–C(＝O)OR^2ba、–C(＝O)N(R^2ba)₂、–NO₂、–NR^2baC(＝O)R^2ba、–NR^2baC(＝O)OR^2ba、–NR^2baC(＝O)N(R^2ba)₂、–OC(＝O)R^2ba、–OC(＝O)OR^2baor-OC (═ O) N (R)^2ba)₂And R is^2baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^2baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R²Is a substituted or unsubstituted aryl group. In some embodiments, R²Is a substituted or unsubstituted phenyl group. In some embodiments, R²Is Ph. In some embodiments, R²Is substituted by 1, 2, 3, 4 or 5R^2bSubstituted phenyl, wherein R^2bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^2ba、–N(R^2ba)₂、–SR^2ba、–CN、–SCN、–C(＝NR^2ba)R^2ba、–C(＝NR^2ba)OR^2ba、–C(＝NR^2ba)N(R^2ba)₂、–C(＝O)R^2ba、–C(＝O)OR^2ba、–C(＝O)N(R^2ba)₂、–NO₂、–NR^2baC(＝O)R^2ba、–NR^2baC(＝O)OR^2ba、–NR^2baC(＝O)N(R^2ba)₂、–OC(＝O)R^2ba、–OC(＝O)OR^2baor-OC (═ O) N (R) ^2ba)₂And R is^2baIndependently each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstitutedA substituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^2baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R²Is a substituted or unsubstituted heteroaryl. In some embodiments, R²Is a substituted or unsubstituted 5-6 membered heteroaryl group, for example, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, R²Is substituted by 1, 2, 3, 4 or 5R^2bSubstituted 5-6 membered heteroaryl, wherein R^2bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR ^2ba、–N(R^2ba)₂、–SR^2ba、–CN、–SCN、–C(＝NR^2ba)R^2ba、–C(＝NR^2ba)OR^2ba、–C(＝NR^2ba)N(R^2ba)₂、–C(＝O)R^2ba、–C(＝O)OR^2ba、–C(＝O)N(R^2ba)₂、–NO₂、–NR^2baC(＝O)R^2ba、–NR^2baC(＝O)OR^2ba、–NR^2baC(＝O)N(R^2ba)₂、–OC(＝O)R^2ba、–OC(＝O)OR^2baor-OC (═ O) N (R)^2ba)₂And R is^2baIndependently at each occurrence, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroarylA nitrogen protecting group attached to the nitrogen atom, an oxygen protecting group attached to the oxygen atom or a sulfur protecting group attached to the sulfur atom, or two R^2baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R²Is C (═ O) R^D1、–C(＝O)OR^D1or-C (═ O) N (R)^D1)₂. In some embodiments, R²Is C (═ O) R^D1(ii) a And R^D1Is a substituted or unsubstituted alkyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In some embodiments, R²is-C (═ O) OR^D1(ii) a And R^D1Is a substituted or unsubstituted alkyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In some embodiments, R ²is-C (═ O) N (R)^D1)₂(ii) a And in each case R^D1Independently is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to the nitrogen atom, or two R^D1The groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R²is-OR^D1. In some embodiments, R²is-OR^D1(ii) a And R^D1Is hydrogen. In some embodiments, R²is-OR^D1(ii) a And R^D1Is C_1-6Alkyl groups, for example, methyl, ethyl, propyl or butyl. In some embodiments, R²is-OR^D1(ii) a And R^D1Is an unsubstituted methyl group. In some embodiments, R²is-OR^D1(ii) a And R^D1Is an unsubstituted ethyl group. In some embodiments, R²is-OR^D1(ii) a And R^D1Is a branched chain C_1-6Alkyl radicals, e.g. isoPropyl, isobutyl or tert-butyl. In some embodiments, R²is-OR^D1(ii) a And R^D1Is unsubstituted tert-butyl. In some embodiments, R²is-OR^D1(ii) a And R^D1Is substituted or unsubstituted C_1-6Haloalkyl radicals, e.g., -CF₃、–CH₂CF₃、–CHF₂、–CH₂F、–CF₂CH₃or-CF₂CF₃. In some embodiments, R²is-OR ^D1(ii) a And R^D1Is a substituted or unsubstituted aralkyl group, for example, benzyl.

In some embodiments, R²is-N (R)^D1)₂. In some embodiments, R²is-N (R)^D1)₂(ii) a And R^D1Is hydrogen. In some embodiments, R²is-N (R)^D1)₂(ii) a And at least one R^D1Is C_1-6Alkyl groups, for example, methyl, ethyl, propyl or butyl. In some embodiments, R²is-N (R)^D1)₂(ii) a And R^D1Is an unsubstituted methyl group. In some embodiments, R²is-N (R)^D1)₂(ii) a And R^D1Is an unsubstituted ethyl group. In some embodiments, R²is-N (R)^D1)₂(ii) a And at least one R^D1Is a branched chain C_1-6Alkyl groups, for example, isopropyl, isobutyl or tert-butyl. In some embodiments, R²is-N (R)^D1)₂(ii) a And R^D1Is unsubstituted tert-butyl. In some embodiments, R²is-N (R)^D1)₂(ii) a And at least one R^D1Is substituted or unsubstituted C_1-6Haloalkyl radicals, e.g., -CF₃、–CH₂CF₃、–CHF₂、–CH₂F、–CF₂CH₃or-CF₂CF₃. In some embodiments, R²is-N (R)^D1)₂(ii) a And at least one R^D1Is a substituted or unsubstituted aralkyl group, for example, benzyl. At one endIn some embodiments, R²is-NH₂。

In some embodiments, R²is-CN.

In some embodiments, a is ═ N —; and R²Is hydrogen. In some embodiments, a is ═ N —; and R ²Is a halogen. In some embodiments, a is ═ N —; and R²Is substituted or unsubstituted C_1-6Alkyl groups, for example, methyl, ethyl, propyl or butyl. In some embodiments, a is ═ N —; and R²Is an unsubstituted methyl group. In some embodiments, a is ═ N —; and R²Is an unsubstituted ethyl group. In some embodiments, a is ═ N —; and R²Is a branched chain C_1-6Alkyl groups, for example, isopropyl, isobutyl or tert-butyl. In some embodiments, a is ═ N —; and R²Is substituted or unsubstituted C_1-6Haloalkyl radicals, e.g., -CF₃、–CH₂CF₃、–CHF₂、–CH₂F、–CF₂CH₃or-CF₂CF₃. In some embodiments, a is ═ N —; and R²Is a substituted or unsubstituted aralkyl group, for example, benzyl. In some embodiments, a is ═ N —; and R²Is a substituted or unsubstituted alkoxyalkyl group, e.g. -CH₂OR^2a、–CH₂CH₂OR^2aor-CH₂CH(CH₃)OR^2aWherein R is^2aIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl or substituted or unsubstituted phenyl. In some embodiments, a is ═ N —; and R²is-NH₂。

In some embodiments, a is ═ c (h) -; and R²Is hydrogen. In some embodiments, a is ═ c (h) -; and R²Is a halogen. In some embodiments, a is ═ c (h) -; and R ²Is substituted or unsubstituted C_1-6Alkyl groups, for example, methyl, ethyl, propyl or butyl. In some embodiments of the present invention, the substrate is,a is ═ c (h) -; and R²Is an unsubstituted methyl group. In some embodiments, a is ═ c (h) -; and R²Is an unsubstituted ethyl group. In some embodiments, a is ═ c (h) -; and R²Is a branched chain C_1-6Alkyl groups, for example, isopropyl, isobutyl or tert-butyl. In some embodiments, a is ═ c (h) -; and R²Is substituted or unsubstituted C_1-6Haloalkyl radicals, e.g., -CF₃、–CH₂CF₃、–CHF₂、–CH₂F、–CF₂CH₃or-CF₂CF₃. In some embodiments, a is ═ c (h) -; and R²Is a substituted or unsubstituted aralkyl group, for example, benzyl. In some embodiments, a is ═ c (h) -; and R²Is a substituted or unsubstituted alkoxyalkyl group, e.g., -CH₂OR^2a、–CH₂CH₂OR^2aor-CH₂CH(CH₃)OR^2aWherein R is^2aIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl or substituted or unsubstituted phenyl. In some embodiments, a is ═ c (h) -; and R²is-NH₂。

As generally defined herein, R^B1Independently each occurrence is hydrogen, halogen, substituted OR unsubstituted alkyl (e.g., Me), substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR ^B1a、–N(R^B1a)₂、–SR^B1a、–CN、–SCN、–C(＝NR^B1a)R^B1a、–C(＝NR^B1a)OR^B1a、–C(＝NR^B1a)N(R^B1a)₂、–C(＝O)R^B1a、–C(＝O)OR^B1a、–C(＝O)N(R^B1a)₂、–NO₂、–NR^B1aC(＝O)R^B1a、–NR^B1aC(＝O)OR^B1a、–NR^B1aC(＝O)N(R^B1a)₂、–OC(＝O)R^B1a、–OC(＝O)OR^B1aor-OC (═ O) N (R)^B1a)₂Wherein in each case R^B1aIndependently is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^B1aThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring. As generally defined herein, p is 0 or an integer between 1 and 4, inclusive.

In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

In some embodiments, ring B has one of the following configurations:wherein R is^B1Is not hydrogen.

In some embodiments, ring B isIn some embodiments, ring B is not

As generally defined herein, L¹、L²And L⁴Each independently is a bond,As generally defined herein, R ^a1Is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group. As generally defined herein, R^c1Independently at each occurrence, hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^c1a、–N(R^c1a)₂、–SR^c1a、–CN、–C(＝O)R^c1a、–C(＝O)OR^c1a、–C(＝O)N(R^c1a)₂、–NR^c1aC(＝O)R^c1a、–NR^c1aC(＝O)OR^c1a、–NR^c1aC(＝O)N(R^c1a)₂、–OC(＝O)R^c1aor-OC (═ O) N (R)^c1a)₂Wherein R is^c1aIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^c1aThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R^a1Or R^c1Is hydrogen. In some embodiments, R^a1And R^c1Are all hydrogen. In some embodiments, R^a1Or R^c1Is other than hydrogen. In some embodiments, R^a1Or R^c1Are not all hydrogen.

In some embodiments, L is¹Is a bond. In some embodiments, L is¹Is thatIn some embodiments, L is¹Is thatIn some embodiments, L is¹Is thatIn some embodiments, L is¹Is that

In some embodiments, L is²Is a bond. In some embodiments, L is²Is composed ofIn some embodiments, L is²Is composed ofIn some embodiments, L is²Is composed ofIn some embodiments, L is²Is composed of

In some embodiments, L is⁴Is a bond. In some embodiments, L is⁴Is a bond; and n is 0. In some embodiments, L is⁴Is composed ofIn some embodiments，L⁴Is composed ofAnd n is 2, 3, or 4 (e.g., 2). In some embodiments, L is⁴Is composed ofIn some embodiments, L is⁴Is composed ofIn some embodiments, L is⁴Is composed of

In some embodiments, L is¹Not a bond. In some embodiments, L is¹Is not thatIn some embodiments, L is¹Is not thatIn some embodiments, L is¹Is not thatIn some embodiments, L is¹Is not that

In some embodiments, L is²Not a bond. In some embodiments, L is ²Is not thatIn some embodiments, L is²Is not thatIn some embodiments, L is²Is not thatIn some embodiments, L is²Is not that

In some embodiments, L is⁴Not a bond. In some embodiments, L is⁴Is not thatIn some embodiments, L is⁴Is not thatIn some embodiments, L is⁴Is not thatIn some embodiments, L is⁴Is not that

In some embodiments, L is¹Is a bond. In some embodiments, L is¹Is composed ofAnd L²Is composed ofIn some embodiments, L is²Is composed ofAnd L¹Is composed ofIn some embodiments, L is¹Is composed ofAnd L²Is composed ofIn some embodiments, L is¹Is composed ofAnd L²Is composed ofIn some embodiments, L is¹Is composed ofAnd L²Is composed ofIn some embodiments, L is²Is composed ofAnd L¹Is composed ofIn some embodiments, L is¹Is composed ofAnd L²Is composed ofIn some embodiments, L is¹Is composed ofAnd L²Is composed ofIn some embodiments, L is²Is composed ofAnd L¹Is composed ofIn some embodiments, L is¹Is composed ofAnd L²Is composed ofIn some embodiments, L is²Is composed ofAnd L¹Is composed ofIn some embodiments, L is¹Is composed ofAnd L²Is composed ofIn some embodiments, L is²Is composed ofAnd L¹Is composed of

In some embodiments, L is⁴Is composed ofIn some embodiments, L is⁴Is composed ofL¹Is composed ofAnd L²Is composed ofIn some embodiments, L is⁴Is composed ofL²Is composed ofAnd L¹Is composed ofIn some embodiments, L is ⁴Is composed ofL¹Is composed ofAnd L²Is composed ofIn some embodiments, L is⁴Is composed ofL¹Is composed ofAnd L²Is composed ofIn some embodiments, L is⁴Is composed ofL¹Is composed ofAnd L²Is composed ofIn some embodiments, L is⁴Is composed ofL²Is composed ofAnd L¹Is composed ofIn some embodiments, L is⁴Is composed ofL¹Is composed ofAnd L²Is composed ofIn some embodiments, L is⁴Is composed ofL¹Is composed ofAnd L²Is composed ofIn some embodiments, L is⁴Is composed ofL²Is composed ofAnd L¹Is composed ofIn some embodiments, L is⁴Is composed ofL¹Is composed ofAnd L²Is composed ofIn some embodiments, L is⁴Is composed ofL²Is composed ofAnd L¹Is composed ofIn some embodiments, L is⁴Is composed ofL¹Is composed ofAnd L²Is composed ofIn some embodiments, L is⁴Is composed ofL²Is composed ofAnd L¹Is composed of

In some embodiments, R^c1Is halogen, for example, fluorine, chlorine, bromine or iodine.

In some embodiments, R^c1Is substituted or unsubstituted C_1-6Alkyl groups, for example, methyl, ethyl, propyl or butyl. In some embodiments, R^c1Is a branched chain C_1-6Alkyl groups, for example, isopropyl, isobutyl or tert-butyl. In some embodiments, R^c1Is substituted or unsubstituted C_1-6Haloalkyl radicals, e.g., -CF₃、–CH₂CF₃、–CHF₂、–CH₂F、–CF₂CH₃or-CF₂CF₃. In some embodiments, R^c1Is a substituted or unsubstituted aralkyl group, for example, benzyl. In some embodiments, R^c1Is a substituted or unsubstituted alkoxyalkyl group, e.g., -CH₂OR^1aa、–CH₂CH₂OR^1aa、–CH₂CH(CH₃)OR^1aaWherein R is ^1aaIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl or substituted or unsubstituted phenyl.

In some embodiments, R^a1Is substituted or unsubstituted C_1-6Alkyl groups, for example, methyl, ethyl, propyl or butyl. In some embodiments, R^a1Is a branched chain C_1-6Alkyl groups, for example, isopropyl, isobutyl or tert-butyl. In some embodiments, R^a1Is substituted or unsubstituted C_1-6Haloalkyl radicals, e.g., -CF₃、–CH₂CF₃、–CHF₂、–CH₂F、–CF₂CH₃or-CF₂CF₃. In some embodiments, R^a1Is a substituted or unsubstituted aralkyl group, for example, benzyl. In some embodiments, R^a1Is a substituted or unsubstituted alkoxyalkyl group, e.g., -CH₂OR^1aa、–CH₂CH₂OR^1aa、–CH₂CH(CH₃)OR^1aaWherein R is^1aaIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl or substituted or unsubstituted phenyl.

In some embodiments, R^a1Is a substituted or unsubstituted alkenyl group, for example, vinyl, allyl, propenyl, or butenyl. In thatIn some embodiments, R^a1Is a substituted or unsubstituted alkynyl group, for example, propargyl, propynyl or butynyl.

In some embodiments, R^a1Is a substituted or unsubstituted carbocyclyl. In some embodiments, R^a1Is a substituted or unsubstituted 3-6 membered carbocyclic group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R ^a1Is substituted by 1, 2, 3, 4 or 5R^1xSubstituted 3-6 membered carbocyclyl wherein R^1xIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^1y、–N(R^1y)₂、–SR^1y、–CN、–SCN、–C(＝NR^1y)R^1y、–C(＝NR^1y)OR^1y、–C(＝NR^1y)N(R^1y)₂、–C(＝O)R^1y、–C(＝O)OR^1y、–C(＝O)N(R^1y)₂、–NO₂、–NR^1yC(＝O)R^1y、–NR^1yC(＝O)OR^1y、–NR^1yC(＝O)N(R^1y)₂、–OC(＝O)R^1y、–OC(＝O)OR^1yor-OC (═ O) N (R)^1y)₂And R^1yIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^1yThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R^a1Is a substituted or unsubstituted heterocyclic group. In some embodiments, R^a1Is a substituted or unsubstituted 3-6 membered heterocyclic group, for example, oxetanyl, tetrahydrofuryl, pyranyl, azetidinyl, pyrrolidinyl or piperidinyl. In some embodiments, R ^a1Is substituted by 1, 2, 3, 4 or 5R^1xSubstituted 3-6 membered heterocyclyl, wherein R^1xIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^1y、–N(R^1y)₂、–SR^1y、–CN、–SCN、–C(＝NR^1y)R^1y、–C(＝NR^1y)OR^1y、–C(＝NR^1y)N(R^1y)₂、–C(＝O)R^1y、–C(＝O)OR^1y、–C(＝O)N(R^1y)₂、–NO₂、–NR^1yC(＝O)R^1y、–NR^1yC(＝O)OR^1y、–NR^1yC(＝O)N(R^1y)₂、–OC(＝O)R^1y、–OC(＝O)OR^1yor-OC (═ O) N (R)^1y)₂And R is^1yIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^1yThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R^a1Is a substituted or unsubstituted aryl group. In some embodiments, R^a1Is a substituted or unsubstituted phenyl group. In some embodiments, R^a1Is substituted by 1, 2, 3, 4 or 5R^1xSubstituted phenyl, wherein R ^1xIndependently each occurrence is halogen, substituted or unsubstituted alkyl, orSubstituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^1y、–N(R^1y)₂、–SR^1y、–CN、–SCN、–C(＝NR^1y)R^1y、–C(＝NR^1y)OR^1y、–C(＝NR^1y)N(R^1y)₂、–C(＝O)R^1y、–C(＝O)OR^1y、–C(＝O)N(R^1y)₂、–NO₂、–NR^1yC(＝O)R^1y、–NR^1yC(＝O)OR^1y、–NR^1yC(＝O)N(R^1y)₂、–OC(＝O)R^1y、–OC(＝O)OR^1yor-OC (═ O) N (R)^1y)₂And R is^1yIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^1yThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R^a1Is a substituted or unsubstituted heteroaryl. In some embodiments, R^a1Is a substituted or unsubstituted 5-6 membered heteroaryl group, for example, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, R ^a1Or R^c1Is substituted by 1, 2, 3, 4 or 5R^1xSubstituted 5-6 membered heteroaryl, wherein R^1xIndependently each occurrence is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycylAryl, -OR^1y、–N(R^1y)₂、–SR^1y、–CN、–SCN、–C(＝NR^1y)R^1y、–C(＝NR^1y)OR^1y、–C(＝NR^1y)N(R^1y)₂、–C(＝O)R^1y、–C(＝O)OR^1y、–C(＝O)N(R^1y)₂、–NO₂、–NR^1yC(＝O)R^1y、–NR^1yC(＝O)OR^1y、–NR^1yC(＝O)N(R^1y)₂、–OC(＝O)R^1y、–OC(＝O)OR^1yor-OC (═ O) N (R)^1y)₂And R is^1yIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^1yThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

As generally defined herein, R³And R⁴Each independently is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group attached to a nitrogen atom; or wherein R is ³And R⁴The groups together form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring. As generally defined herein, R⁵Is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. As generally defined herein, n is 1, 2, 3, 4, 5, or 6.

In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

In some embodiments, R³Is substituted or unsubstituted C_1-6Alkyl groups, for example, methyl, ethyl, propyl or butyl. In some embodiments, R³Is unsubstituted methyl. In some embodiments, R³Is an unsubstituted ethyl group. In some embodiments, R³Is a branched chain C_1-6Alkyl groups, for example, isopropyl, isobutyl or tert-butyl. In some embodiments, R³Is unsubstituted tert-butyl. In some embodiments, R ³Is substituted or unsubstituted C_1-6Haloalkyl radicals, e.g., -CF₃、–CH₂CF₃、–CHF₂、–CH₂F、–CF₂CH₃or-CF₂CF₃. In some embodiments, R³Is a substituted or unsubstituted aralkyl group, for example, benzyl. In some embodiments, R³Is substituted or unsubstituted alkoxyalkyl, e.g., -CH₂OR^3a、–CH₂CH₂OR^3aor-CH₂CH(CH₃)OR^3aWherein R is^3aIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl or substituted or unsubstituted phenyl.

In some embodiments, R³Is a substituted or unsubstituted alkenyl group, for example, vinyl, allyl, propenyl, or butenyl. In some embodiments, R³Is a substituted or unsubstituted alkynyl group, for example, propargyl, propynyl or butynyl.

In some embodiments, R³Is a substituted or unsubstituted carbocyclyl. In some embodiments, R³Is a substituted or unsubstituted 3-6 membered carbocyclic group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R³Is represented by 1, 2, 3, 4 or 5R^3bSubstituted 3-6 membered carbocyclyl wherein R^3bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR ^3ba、–N(R^3ba)₂、–SR^3ba、–CN、–SCN、–C(＝NR^3ba)R^3ba、–C(＝NR^3ba)OR^3ba、–C(＝NR^3ba)N(R^3ba)₂、–C(＝O)R^3ba、–C(＝O)OR^3ba、–C(＝O)N(R^3ba)₂、–NO₂、–NR^3baC(＝O)R^3ba、–NR^3baC(＝O)OR^3ba、–NR^3baC(＝O)N(R^3ba)₂、–OC(＝O)R^3ba、–OC(＝O)OR^3baor-OC (═ O) N (R)^3ba)₂And R is^3baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^3baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R³Is a substituted or unsubstituted heterocyclic group. In some embodiments, R³Is a substituted or unsubstituted 3-6 membered heterocyclic group, for example, oxetanyl, tetrahydrofuryl, pyranyl, azetidinyl, pyrrolidinyl or piperidinyl. In some embodiments, R³Is represented by 1, 2, 3, 4 or 5R^3bSubstituted 3-6 membered heterocyclyl, wherein R^3bIndependently each occurrence is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitutedSubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR ^3ba、–N(R^3ba)₂、–SR^3ba、–CN、–SCN、–C(＝NR^3ba)R^3ba、–C(＝NR^3ba)OR^3ba、–C(＝NR^3ba)N(R^3ba)₂、–C(＝O)R^3ba、–C(＝O)OR^3ba、–C(＝O)N(R^3ba)₂、–NO₂、–NR^3baC(＝O)R^3ba、–NR^3baC(＝O)OR^3ba、–NR^3baC(＝O)N(R^3ba)₂、–OC(＝O)R^3ba、–OC(＝O)OR^3baor-OC (═ O) N (R)^3ba)₂And R is^3baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^3baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R³Is a substituted or unsubstituted aryl group. In some embodiments, R³Is a substituted or unsubstituted phenyl group. In some embodiments, R³Is substituted by 1, 2, 3, 4 or 5R^3bSubstituted phenyl, wherein R^3bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^3ba、–N(R^3ba)₂、–SR^3ba、–CN、–SCN、–C(＝NR^3ba)R^3ba、–C(＝NR^3ba)OR^3ba、–C(＝NR^3ba)N(R^3ba)₂、–C(＝O)R^3ba、–C(＝O)OR^3ba、–C(＝O)N(R^3ba)₂、–NO₂、–NR^3baC(＝O)R^3ba、–NR^3baC(＝O)OR^3ba、–NR^3baC(＝O)N(R^3ba)₂、–OC(＝O)R^3ba、–OC(＝O)OR^3baor-OC (═ O) N (R)^3ba)₂And R is^3baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R ^3baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R³Is a substituted or unsubstituted heteroaryl. In some embodiments, R³Is a substituted or unsubstituted 5-6 membered heteroaryl group, for example, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, R³Is substituted by 1, 2, 3, 4 or 5R^3bSubstituted 5-6 membered heteroaryl, wherein R^3bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^3ba、–N(R^3ba)₂、–SR^3ba、–CN、–SCN、–C(＝NR^3ba)R^3ba、–C(＝NR^3ba)OR^3ba、–C(＝NR^3ba)N(R^3ba)₂、–C(＝O)R^3ba、–C(＝O)OR^3ba、–C(＝O)N(R^3ba)₂、–NO₂、–NR^3baC(＝O)R^3ba、–NR^3baC(＝O)OR^3ba、–NR^3baC(＝O)N(R^3ba)₂、–OC(＝O)R^3ba、–OC(＝O)OR^3baor-OC (═ O) N (R)^3ba)₂And R is^3baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R ^3baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R⁴Is substituted or unsubstituted C_1-6Alkyl groups, for example, methyl, ethyl, propyl or butyl. In some embodiments, R⁴Is an unsubstituted methyl group. In some embodiments, R⁴Is an unsubstituted ethyl group. In some embodiments, R⁴Is a branched chain C_1-6Alkyl groups, for example, isopropyl, isobutyl or tert-butyl. In some embodiments, R⁴Is unsubstituted tert-butyl. In some embodiments, R⁴Is substituted or unsubstituted C_1-6Haloalkyl radicals, e.g., -CF₃、–CH₂CF₃、–CHF₂、–CH₂F、–CF₂CH₃or-CF₂CF₃. In some embodiments, R⁴Is a substituted or unsubstituted aralkyl group, for example, benzyl. In some embodiments, R⁴Is a substituted or unsubstituted alkoxyalkyl group, e.g., -CH₂OR^4a、–CH₂CH₂OR^4aor-CH₂CH(CH₃)OR^4aWherein R is^4aIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl or substituted or unsubstituted phenyl.

In some embodiments, R⁴Is a substituted or unsubstituted alkenyl group, for example, vinyl, allyl, propenyl, or butenyl. In some embodiments, R⁴Is a substituted or unsubstituted alkynyl group, for example, propargyl, propynyl or butynyl.

In some embodiments, R⁴Is a substituted or unsubstituted carbocyclyl. In some embodiments, R⁴Is a substituted or unsubstituted 3-6 membered carbocyclic group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R⁴Is substituted by 1, 2, 3, 4 or 5R^4bSubstituted 3-6 membered carbocyclyl wherein R^4bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^4ba、–N(R^4ba)₂、–SR^4ba、–CN、–SCN、–C(＝NR^4ba)R^4ba、–C(＝NR^4ba)OR^4ba、–C(＝NR^4ba)N(R^4ba)₂、–C(＝O)R^4ba、–C(＝O)OR^4ba、–C(＝O)N(R^4ba)₂、–NO₂、–NR^4baC(＝O)R^4ba、–NR^4baC(＝O)OR^4ba、–NR^4baC(＝O)N(R^4ba)₂、–OC(＝O)R^4ba、–OC(＝O)OR^4baor-OC (═ O) N (R)^4ba)₂And R is^4baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^4baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R⁴Is a substituted or unsubstituted heterocyclic group. In some embodiments, R⁴Is a substituted or unsubstituted 3-6 membered heterocyclic group, for example, oxetanyl, tetrahydrofuryl, pyranyl, azetidinyl, pyrrolidinyl or piperidinyl. In some embodiments, R⁴Is substituted by 1, 2, 3, 4 or 5R^4bSubstituted 3-6 membered heterocyclyl, wherein in each case R^4bIndependently halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^4ba、–N(R^4ba)₂、–SR^4ba、–CN、–SCN、–C(＝NR^4ba)R^4ba、–C(＝NR^4ba)OR^4ba、–C(＝NR^4ba)N(R^4ba)₂、–C(＝O)R^4ba、–C(＝O)OR^4ba、–C(＝O)N(R^4ba)₂、–NO₂、–NR^4baC(＝O)R^4ba、–NR^4baC(＝O)OR^4ba、–NR^4baC(＝O)N(R^4ba)₂、–OC(＝O)R^4ba、–OC(＝O)OR^4baor-OC (═ O) N (R)^4ba)₂And R is^4baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R ^4baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R⁴Is a substituted or unsubstituted aryl group. In some embodiments, R⁴Is a substituted or unsubstituted phenyl group. In some casesIn embodiments, R⁴Is substituted by 1, 2, 3, 4 or 5R^4bSubstituted phenyl, wherein R^4bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^4ba、–N(R^4ba)₂、–SR^4ba、–CN、–SCN、–C(＝NR^4ba)R^4ba、–C(＝NR^4ba)OR^4ba、–C(＝NR^4ba)N(R^4ba)₂、–C(＝O)R^4ba、–C(＝O)OR^4ba、–C(＝O)N(R^4ba)₂、–NO₂、–NR^4baC(＝O)R^4ba、–NR^4baC(＝O)OR^4ba、–NR^4baC(＝O)N(R^4ba)₂、–OC(＝O)R^4ba、–OC(＝O)OR^4baor-OC (═ O) N (R)^4ba)₂And R is^4baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^4baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R⁴Is a substituted or unsubstituted heteroaryl. In some embodiments, R⁴Is a substituted or unsubstituted 5-6 membered heteroaryl group, for example, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, R⁴Is substituted by 1, 2, 3, 4 or 5R^4bSubstituted 5-6 membered heteroaryl, wherein R^4bIndependently at each occurrence, is halogen, substituted or unsubstituted alkaneA group, a substituted OR unsubstituted alkenyl group, a substituted OR unsubstituted alkynyl group, a substituted OR unsubstituted carbocyclyl group, a substituted OR unsubstituted heterocyclyl group, a substituted OR unsubstituted aryl group, a substituted OR unsubstituted heteroaryl group, -OR^4ba、–N(R^4ba)₂、–SR^4ba、–CN、–SCN、–C(＝NR^4ba)R^4ba、–C(＝NR^4ba)OR^4ba、–C(＝NR^4ba)N(R^4ba)₂、–C(＝O)R^4ba、–C(＝O)OR^4ba、–C(＝O)N(R^4ba)₂、–NO₂、–NR^4baC(＝O)R^4ba、–NR^4baC(＝O)OR^4ba、–NR^4baC(＝O)N(R^4ba)₂、–OC(＝O)R^4ba、–OC(＝O)OR^4baor-OC (═ O) N (R)^4ba)₂And R is^4baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R ^4baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R³And R⁴Together form a substituted or unsubstituted heterocyclic ring (e.g., a substituted or unsubstituted 4-to 7-membered monocyclic heterocyclic ring in which 1, 2, or 3 atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, R³And R⁴Together form one of the following heterocycles:wherein any ring may be substituted by one or more R^zThe radicals being optionally substituted, provided that there are compoundsAllowing the price; and R is^zIndependently at each occurrence, hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^z1、–N(R^z1)₂、–SR^z1、–CN、–SCN、–C(＝NR^z1)R^z1、–C(＝NR^z1)OR^z1、–C(＝NR^z1)N(R^z1)₂、–C(＝O)R^z1、–C(＝O)OR^z1、–C(＝O)N(R^z1)₂、–NO₂、–NR^z1C(＝O)R^z1、–NR^z1C(＝O)OR^z1、–NR^z1C(＝O)N(R^z1)₂、–OC(＝O)R^z1、–OC(＝O)OR^z1or-OC (═ O) N (R)^z1)₂Wherein R is^z1Independently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R ^z1The groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring. In some embodiments, R³And R⁴Are formed togetherWherein R is^zIs hydrogen. In some embodiments, R³And R⁴Together form a substituted or unsubstituted piperazinyl group (e.g.,). In some embodiments, R³And R⁴Together form a substituted or unsubstituted pyrrolidine (e.g.,)。

in some embodiments, R³And R⁴Together form a substituted or unsubstituted heteroaryl ring. In some embodiments, R³And R⁴Together form one of the following heteroaryl rings:wherein any ring may be substituted by one or more R^zThe groups are optionally substituted as far as valency permits; and in each case R^zIndependently hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^z1、–N(R^z1)₂、–SR^z1、–CN、–SCN、–C(＝NR^z1)R^z1、–C(＝NR^z1)OR^z1、–C(＝NR^z1)N(R^z1)₂、–C(＝O)R^z1、–C(＝O)OR^z1、–C(＝O)N(R^z1)₂、–NO₂、–NR^z1C(＝O)R^z1、–NR^z1C(＝O)OR^z1、–NR^z1C(＝O)N(R^z1)₂、–OC(＝O)R^z1、–OC(＝O)OR^z1or-OC (═ O) N (R)^z1)₂Wherein R is^z1Independently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R ^z1The radicals together forming a substituted or unsubstituted heterocyclic ring or ring systemA substituted or unsubstituted heteroaryl ring. In some embodiments, R³And R⁴Are formed togetherWherein R is^zIs hydrogen.

The formula (II) may contain one or more substituents R⁵. When formula (II) contains two or more R⁵When there are two arbitrary R⁵May be the same as or different from each other. In some embodiments, R⁵Is hydrogen. In some embodiments, R⁵Each occurrence is hydrogen. In some embodiments, R⁵At least one occurrence is fluorine. In some embodiments, R⁵Each occurrence is fluorine.

In some embodiments, R⁵Is halogen, for example, fluorine, chlorine, bromine or iodine.

In some embodiments, R⁵Is substituted or unsubstituted C_1-6Alkyl groups, for example, methyl, ethyl, propyl or butyl. In some embodiments, R⁵Is unsubstituted methyl. In some embodiments, R⁵Is an unsubstituted ethyl group. In some embodiments, R⁵Is a branched chain C_1-6Alkyl groups, for example, isopropyl, isobutyl or tert-butyl. In some embodiments, R⁵Is unsubstituted tert-butyl. In some embodiments, R⁵Is substituted or unsubstituted C_1-6Haloalkyl radicals, e.g., -CF₃、–CH₂CF₃、–CHF₂、–CH₂F、–CF₂CH₃or-CF₂CF₃. In some embodiments, R ⁵Is a substituted or unsubstituted aralkyl group, for example, benzyl. In some embodiments, R⁵Is substituted or unsubstituted alkoxyalkyl, e.g., -CH₂OR^5a、–CH₂CH₂OR^5aor-CH₂CH(CH₃)OR^5aWherein R is^5aIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstitutedC of (A)_1-6Haloalkyl or substituted or unsubstituted phenyl.

In some embodiments, R⁵Is a substituted or unsubstituted alkenyl group, for example, vinyl, allyl, propenyl, or butenyl. In some embodiments, R⁵Is a substituted or unsubstituted alkynyl group, for example, propargyl, propynyl or butynyl.

In some embodiments, R⁵Is a substituted or unsubstituted carbocyclyl. In some embodiments, R⁵Is a substituted or unsubstituted 3-6 membered carbocyclic group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R⁵Is represented by 1, 2, 3, 4 or 5R^5bSubstituted 3-6 membered carbocyclyl wherein R^5bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR ^5ba、–N(R^5ba)₂、–SR^5ba、–CN、–SCN、–C(＝NR^5ba)R^5ba、–C(＝NR^5ba)OR^5ba、–C(＝NR^5ba)N(R^5ba)₂、–C(＝O)R^5ba、–C(＝O)OR^5ba、–C(＝O)N(R^5ba)₂、–NO₂、–NR^5baC(＝O)R^5ba、–NR^5baC(＝O)OR^5ba、–NR^5baC(＝O)N(R^5ba)₂、–OC(＝O)R^5ba、–OC(＝O)OR^5baor-OC (═ O) N (R)^5ba)₂And R is^5baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, orTwo R^5baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R⁵Is a substituted or unsubstituted heterocyclic group. In some embodiments, R⁵Is a substituted or unsubstituted 3-6 membered heterocyclic group, for example, oxetanyl, tetrahydrofuryl, pyranyl, azetidinyl, pyrrolidinyl or piperidinyl. In some embodiments, R⁵Is represented by 1, 2, 3, 4 or 5R^5bSubstituted 3-6 membered heterocyclyl, wherein R^5bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR ^5ba、–N(R^5ba)₂、–SR^5ba、–CN、–SCN、–C(＝NR^5ba)R^5ba、–C(＝NR^5ba)OR^5ba、–C(＝NR^5ba)N(R^5ba)₂、–C(＝O)R^5ba、–C(＝O)OR^5ba、–C(＝O)N(R^5ba)₂、–NO₂、–NR^5baC(＝O)R^5ba、–NR^5baC(＝O)OR^5ba、–NR^5baC(＝O)N(R^5ba)₂、–OC(＝O)R^5ba、–OC(＝O)OR^5baor-OC (═ O) N (R)^5ba)₂And R is^5baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^5baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R⁵To substituteOr an unsubstituted aryl group. In some embodiments, R⁵Is a substituted or unsubstituted phenyl group. In some embodiments, R⁵Is represented by 1, 2, 3, 4 or 5R^5bSubstituted phenyl, wherein R^5bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^5ba、–N(R^5ba)₂、–SR^5ba、–CN、–SCN、–C(＝NR^5ba)R^5ba、–C(＝NR^5ba)OR^5ba、–C(＝NR^5ba)N(R^5ba)₂、–C(＝O)R^5ba、–C(＝O)OR^5ba、–C(＝O)N(R^5ba)₂、–NO₂、–NR^5baC(＝O)R^5ba、–NR^5baC(＝O)OR^5ba、–NR^5baC(＝O)N(R^5ba)₂、–OC(＝O)R^5ba、–OC(＝O)OR^5baor-OC (═ O) N (R)^5ba)₂And R is^5baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R ^5baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, R⁵Is a substituted or unsubstituted heteroaryl. In some embodiments, R⁵Is a substituted or unsubstituted 5-6 membered heteroaryl group, for example, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, R⁵Is represented by 1, 2, 3, 4 or 5R^5bSubstitutionThe 5-6 membered heteroaryl of (1), wherein R^5bIndependently at each occurrence, is halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^5ba、–N(R^5ba)₂、–SR^5ba、–CN、–SCN、–C(＝NR^5ba)R^5ba、–C(＝NR^5ba)OR^5ba、–C(＝NR^5ba)N(R^5ba)₂、–C(＝O)R^5ba、–C(＝O)OR^5ba、–C(＝O)N(R^5ba)₂、–NO₂、–NR^5baC(＝O)R^5ba、–NR^5baC(＝O)OR^5ba、–NR^5baC(＝O)N(R^5ba)₂、–OC(＝O)R^5ba、–OC(＝O)OR^5baor-OC (═ O) N (R)^5ba)₂And R is^5baIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R ^5baThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

In some embodiments, n is 2, and at least one L⁵Is hydrogen. In some embodiments, n is 2, and at least two L⁵Is hydrogen. In some embodiments, n is 2, and at least three L⁵Is hydrogen. In some embodiments, n is 2, and all four L are⁵Are all hydrogen. In some embodiments, n is 2, and at least one L⁵Is fluorine. In some embodiments, n is 2, and at least two L⁵Is fluorine. In some embodiments, n is 2, and at least three L⁵Is fluorine. In some embodiments, n is 2, and all four L are⁵Are both fluorine. In some embodiments, n is 2, and at least one L⁵Is substituted or unsubstituted C_1-6An alkyl group. In some embodiments, n is 2, and at least two L⁵Is substituted or unsubstituted C_1-6An alkyl group. In some embodiments, n is 2, and at least three L⁵Is substituted or unsubstituted C_1-6An alkyl group. In some embodiments, n is 2, and all four L are⁵All are substituted or unsubstituted C_1-6An alkyl group. In some embodiments, n is 2, and at least one L⁵Is methyl. In some embodiments, n is 2, and at least two L ⁵Is methyl. In some embodiments, n is 2, and at least three L⁵Is methyl. In some embodiments, n is 2, and all four L are⁵Are all methyl.

The formula (II) may comprise one or more substituents R on the phenyl moiety⁶. When formula (II) contains two or more R⁶When there are two arbitrary R⁶May be the same as or different from each other. In some embodiments, at least one R is⁶Is halogen (e.g., F, Cl, Br, or I). In some embodiments, at least one R is⁶Is Cl or Br. In some embodiments, at least one R is⁶Is a substituted or unsubstituted alkyl group. In some embodiments, at least one R is⁶Is substituted or unsubstituted C_1-6An alkyl group. In some embodiments, at least one R is⁶Is Me. In some embodiments, at least one R is⁶Being substituted methyl (e.g., -CF)₃、–CH₂OH or Bn). In some embodiments, at least one R is⁶Is Et. In some embodiments, at least one R is⁶Is Pr (e.g., n-Pr or i-Pr). In some embodiments, at least one R is⁶Is Bu (e.g., t-Bu, n-Bu or sec-Bu). In some embodiments, at least one R is⁶Is a substituted ethyl group (e.g., perfluoroethyl), a substituted propyl group (e.g., perfluoropropyl), or a substituted butyl group (e.g., perfluorobutyl). In some embodiments, at least one R is ⁶Is substituted or unsubstituted alkenyl (e.g., substitutedOr unsubstituted C_2-6Alkenyl). In some embodiments, at least one R is⁶Is a substituted or unsubstituted alkynyl group (e.g., substituted or unsubstituted C_2-6Alkynyl). In some embodiments, at least one R is⁶Is a substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted 3-to 7-membered monocyclic carbocyclyl containing 0, 1, or 2 double bonds in the carbocyclic ring system). In some embodiments, at least one R is⁶Is a substituted or unsubstituted cyclopropyl, a substituted or unsubstituted cyclobutyl, a substituted or unsubstituted cyclopentyl, or a substituted or unsubstituted cyclohexyl. In some embodiments, at least one R is⁶Is a substituted or unsubstituted heterocyclyl group (e.g., a substituted or unsubstituted 3-to 7-membered monocyclic heterocyclyl group which contains 0, 1 or 2 double bonds in the heterocyclic ring system, wherein 1, 2 or 3 atoms in the heterocyclic ring system are independently nitrogen, oxygen or sulfur). In some embodiments, at least one R is⁶Is a substituted or unsubstituted oxetanyl group, a substituted or unsubstituted tetrahydrofuryl group, a substituted or unsubstituted pyrrolidinyl group, a substituted or unsubstituted tetrahydropyranyl group, a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted morpholinyl group, or a substituted or unsubstituted piperazinyl group. In some embodiments, at least one R is ⁶Is a substituted or unsubstituted aryl group (e.g., a substituted or unsubstituted 6-to 10-membered aryl group). In some embodiments, at least one R is⁶Is Ph. In some embodiments, at least one R is⁶Is substituted phenyl (e.g., phenyl substituted with one or more substituents independently selected from the group consisting of halogen (e.g., F, Cl, Br, and I), substituted and unsubstituted C_1-6Alkyl (e.g., Me and-CF)₃) -O (substituted and unsubstituted C)_1-6Alkyl) (e.g., -OMe, -OCF₃and-OEt) and-CN). In some embodiments, at least one R is⁶Is 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-chlorophenyl, 2-methylphenyl, 2- (trifluoromethyl) -phenyl, 2-fluorophenyl, 2- (methoxy) -phenyl or 4- (methoxy) -phenyl. In some embodiments, at least one R is⁶Is a substituted or unsubstituted naphthyl group. In some embodiments, toAt least one R⁶Is a substituted or unsubstituted heteroaryl. In some embodiments, at least one R is⁶Is a substituted or unsubstituted 5-to 6-membered monocyclic heteroaryl, wherein 1, 2, 3 or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen or sulfur. In some embodiments, at least one R is ⁶Is a substituted or unsubstituted 9-to 10-membered bicyclic heteroaryl, wherein 1, 2, 3 or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen or sulfur. In some embodiments, at least one R is⁶is-OR^B1a(e.g., -OH, -O (substituted or unsubstituted C)_1-6Alkyl) (e.g., -OMe, -OCF₃-OEt, -OPr, -OBu or-OBn) or-O (substituted or unsubstituted phenyl) (e.g., -OPh)). In some embodiments, at least one R is⁶is-SR^B1a(e.g., -SH, -S (substituted or unsubstituted C)_1-6Alkyl) (e.g., -SMe, -Set, -SPr, -SBu, or-SBn), or-S (substituted or unsubstituted phenyl) (e.g., -SPh)). In some embodiments, at least one R is⁶is-N (R)^B1a)₂(e.g., -NH)₂-NH (substituted or unsubstituted C_1-6Alkyl) (e.g., -NHMe) or-N (substituted or unsubstituted C)_1-6Alkyl) - (substituted or unsubstituted C_1-6Alkyl) (e.g., -NMe)₂)). In some embodiments, at least one R is⁶is-CN. In some embodiments, at least one R is⁶is-SCN. In some embodiments, at least one R is⁶is-NO₂. In some embodiments, at least one R is⁶is-C (═ NR)^B1a)R^B1a、–C(＝NR^B1a)OR^B1aor-C (═ NR) ^B1a)N(R^B1a)₂. In some embodiments, at least one R is⁶is-C (═ O) R^B1、–C(＝O)OR^B1a(e.g., -C (═ O) OH or-C (═ O) OMe) or-C (═ O) N (R)^B1a)₂(e.g., -C (═ O) NH₂C (═ O) NHMe or-C (═ O) NHMe 2). In some embodiments, at least one R is⁶is-NR^B1aC(＝O)R^B1a、–NR^B1aC(＝O)OR^B1aor-NR^B1aC(＝O)N(R^B1a)₂. In some embodiments, at least one R is⁶is-OC (═ O) R^B1a、–OC(＝O)OR^B1aor-OC (═ O) N (R)^B1a)₂。

In some embodiments of the present invention, the substrate is,is represented by the formula:optionally wherein R is⁶Is halogen (e.g. Cl or Br), substituted or unsubstituted C_1-6Alkyl (e.g., Me, Et, or t-Bu), substituted or unsubstituted phenyl (e.g., Ph, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-chlorophenyl, 2-methylphenyl, 2- (trifluoromethyl) -phenyl, 2-fluorophenyl, 2- (methoxy) -phenyl, or 4- (methoxy) -phenyl), or-CN. In some embodiments of the present invention, the substrate is,is represented by the formula:in some embodiments of the present invention, the substrate is,is represented by the formula:

in some embodiments, q is 0. In some embodiments, q is other than 0, and in some embodiments, q is 1. In some embodiments, q is 2, 3, or 4.

In some embodiments, the compound of formula (II) is formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

n is 1, 2, 3, 4, 5 or 6; and

R⁵is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, the compound of formula (II) is of formula (la):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In some embodiments, the compound of formula (II) is of formula (la):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, wherein R is a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof³And R⁴Together, the groups form a substituted or unsubstituted heterocyclic ring (e.g., a substituted or unsubstituted 4-to 7-membered monocyclic heterocyclic ring in which 1, 2, or 3 atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur).

In some embodiments, the compound of formula (II) is of formula (la):

In some embodiments, the compound of formula (II) comprises any one of:

other exemplary compounds of formula (II) include compounds as shown in figures 5, 7, 9 and 10, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives and prodrugs thereof, provided that the compound is not TG101348, TG101209 or a pharmaceutically acceptable salt thereof.

In some embodiments of the present invention, the substrate is,is not represented by the formula:in some embodiments of the present invention, the substrate is,is not represented by the formula:in some embodiments, R²Not being unsubstituted C_1-6Alkyl (e.g., Me). In some embodiments, if Is represented by the formula:then R²Not being unsubstituted C_1-6Alkyl (e.g., Me). In some embodiments, ifIs represented by the formula:q is 0, then R²Not being unsubstituted C_1-6Alkyl (e.g., Me). In some embodiments, ifIs represented by the formula:then q is not 0.

In some embodiments, the compound of formula (II) does not include any of the following:

(TG101348 or TG-101348), and pharmaceutically acceptable salts thereof.

In some embodiments, the compounds of formula (II) do not include compounds of the formula:

(TG101209 or TG-101209),

and pharmaceutically acceptable salts thereof.

In some embodiments, the compounds of formula (II) do not include compounds disclosed in any of the following patents: US patent 7,528,143, 7,825,246, 8,133,900, 8,138, 199 or 8,604,042.

In some embodiments, the compounds described herein are compounds of formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives and prodrugs thereof. In some embodiments, the compounds described herein are compounds of formula (II), and pharmaceutically acceptable salts, solvates, and hydrates thereof. In some embodiments, the compounds described herein are compounds of formula (II), and pharmaceutically acceptable salts thereof. In some embodiments, the compounds described herein are compounds of formula (II).

The compounds described herein are binding agents for bromodomain-containing proteins. In some embodiments, the compounds described herein bind to bromodomain-containing proteins. Without wishing to be bound by any particular theory, the compounds described herein bind to the binding pocket of the bromodomain-containing protein. In some embodiments, the compounds described herein bind to the binding pocket of the bromodomain by mimicking the contact between an acetyl-lysine residue of a second protein (e.g., a histone) and the binding pocket of the bromodomain. In some embodiments, the compounds described herein bind to the binding pocket of the bromodomain. In some embodiments, the compounds described herein are covalently bound to a bromodomain-containing protein. In some embodiments, the compounds described herein non-covalently bind to bromodomain-containing proteins. In some embodiments, the compounds described herein reversibly bind to a bromodomain-containing protein. In some embodiments, the compounds described herein non-reversibly bind to bromodomain-containing proteins. In some embodiments, the compounds described herein inhibit the activity of bromodomain-containing proteins. In some embodiments, the compounds described herein inhibit the activity of a bromodomain-containing protein as a result of the compound binding the bromodomain-containing protein. In some embodiments, the compounds described herein inhibit the activity of a bromodomain-containing protein as a result of the compound binding to a bromodomain of the bromodomain-containing protein. In some embodiments, the compounds described herein inhibit the activity of a bromodomain. In some embodiments, the activity of the bromodomain is the activity of the bromodomain binding to an acetylated lysine residue (e.g., an acetylated lysine residue on the histone N-terminal tail). In some embodiments, the compounds described herein specifically bind to bromodomain-containing proteins. In some embodiments, the compounds described herein specifically bind to a bromodomain of a bromodomain-containing protein. In some embodiments, the compounds described herein that specifically bind to a bromodomain-containing protein exhibit a greater affinity for the bromodomain-containing protein than one or more other proteins or one or more other bromodomain-containing proteins. In some embodiments, the compounds described herein non-specifically bind bromodomain-containing proteins. In some embodiments, the compounds described herein non-specifically bind to a bromodomain of a bromodomain-containing protein. In some embodiments, the compounds described herein reduce transcriptional elongation. In some embodiments, the compounds described herein disrupt the subcellular localization of bromodomain-containing proteins. In some embodiments, a compound described herein reduces chromatin binding. In some embodiments, the compounds described herein inhibit binding of a histone H4Kac peptide to a bromodomain of a bromodomain-containing protein. In some embodiments, the compounds described herein form one or more hydrogen bonds with evolutionarily conserved asparagine in the bromodomain of a bromodomain-containing protein. In some embodiments, the asparagine is Asn 40 in BRD4(1) and Asn429 in BRD2 (2). In some embodiments, the bromodomain-containing protein is BRD4 or BRD2 and the asparagine is Asnl40 in BRD4(1) and Asn429 in BRD2 (2). In some embodiments, a compound described herein competitively binds to chromatin in a cellular environment. The compounds described herein may therefore be useful in the treatment of diseases associated with the activity of bromodomain-containing proteins (e.g., proliferative diseases).

Bromodomain-containing proteins that bind to and whose activity is inhibited by the compounds described herein include, but are not limited to, the bromodomain-containing proteins described herein. In some embodiments, the bromodomain-containing protein is bromo and extra terminal protein (BET). In some embodiments, the bromodomain-containing protein is BRD 2. In some embodiments, the bromodomain-containing protein is BRD2 (1). In some embodiments, the bromodomain-containing protein is BRD2 (2). In some embodiments, the bromodomain-containing protein is BRD 3. In some embodiments, the bromodomain-containing protein is BRD3 (1). In some embodiments, the bromodomain-containing protein is BRD3 (2). In some embodiments, the bromodomain-containing protein is BRD 4. In some embodiments, the bromodomain-containing protein is BRD4 (1). In some embodiments, the bromodomain-containing protein is BRD4 (2). In some embodiments, the bromodomain-containing protein is BRDT. In some embodiments, the bromodomain-containing protein is BRDT (1). In some embodiments, the bromodomain-containing protein is BRDT (2). In some embodiments, the bromodomain-containing protein is a TBP (TATA box binding protein) -related factor protein (TAF). In some embodiments, the bromodomain-containing protein is TAF 1. In some embodiments, the bromodomain-containing protein is TAF 1L. In some embodiments, the bromodomain-containing protein is a CREB-binding protein (CBP). In some embodiments, the bromodomain-containing protein is E1A binding protein p300(EP 300).

The binding affinity of the compounds described herein to bromodomain-containing proteins can be determined using methods known in the art (e.g., Isothermal Titration Calorimetry (ITC)) to determine the dissociation constant (Kd) value of the adducts of the compounds described herein and the bromodomain-containing proteins. In some embodiments, the adduct comprises a compound described herein and a bromodomain-containing protein, which are bound (e.g., covalently or non-covalently) to each other. In some embodiments, the adduct has a Kd value of at most about 100 μ M, at most about 30 μ M, at most about 10 μ M, at most about 3 μ M, at most about 1 μ M, at most about 300nM, at most about 100nM, at most about 30nM, at most about 10nM, at most about 3nM, or at most about 1 nM. In some embodiments, the adduct has a Kd value of at least about 1nM, at least about 10nM, at least about 100nM, at least about 1 μ M, at least about 10 μ M, or at least about 100 μ M. Combinations of the above ranges (e.g., up to about 10 μ M and at least about 1nM) are also within the scope of the invention. Other ranges are also possible. In some embodiments, the adduct has a Kd value of at most about 10 μ M. In some embodiments, the adduct has a Kd value of at most about 300 nM. In some embodiments, the adduct has a Kd value of at most about 100 nM.

In some embodiments, the activity of the bromodomain-containing proteins described herein is inhibited by a compound described herein. The inhibition of the activity of a bromodomain-containing protein by a compound described herein can be determined by the half maximal inhibitory concentration (IC50) value of the compound described herein when the compound described herein or a pharmaceutical composition thereof is contacted with the bromodomain-containing protein, directly or indirectly. This IC50 value can be obtained using methods known in the art. In some embodiments, IC50 values are obtained by a competitive binding assay. In some embodiments, IC50 values may be obtained using the methods described herein. In some embodiments, a compound described herein has an IC50 value of at most about 1mM, at most about 300 μ Μ, at most about 100 μ Μ, at most about 30 μ Μ, at most about 10 μ Μ, at most about 3 μ Μ, at most about 1 μ Μ, at most about 300nM, at most about 100nM, at most about 30nM, at most about 10nM, at most about 3nM or at most about 1 nM. In some embodiments, a compound described herein has an IC50 value of at least about 1nM, at least about 3nM, at least about 10nM, at least about 30nM, at least about 100nM, at least about 300nM, at least about 1 μ Μ, at least about 3 μ Μ, at least about 10 μ Μ, at least about 30 μ Μ, at least about 100 μ Μ, at least about 300 μ Μ or at least 1 mM. Combinations of the above ranges (e.g., up to about 300 μ M and at least about 1 μ M) are also within the scope of the invention. Other ranges are also possible. In some embodiments, the compounds described herein have an IC50 value of up to about 300 μ M. In some embodiments, the compounds described herein have an IC50 value of up to about 30 μ M. In some embodiments, the compounds described herein have an IC50 value of up to about 10 μ M.

The compounds described herein selectively inhibit the activity of bromodomain-containing proteins. It will be understood that when a compound, pharmaceutical composition, method, use or kit is referred to as "selectively" inhibiting the activity of a first protein, the compound, pharmaceutical composition, method, use or kit inhibits the activity of the first protein to a greater extent than at least one second protein that is different from the first protein. In some embodiments, the compounds described herein selectively inhibit the activity of a bromodomain-containing protein compared to a different bromodomain-containing protein. In some embodiments, the compounds described herein selectively inhibit the activity of a bromodomain-containing protein as compared to a protein that is not a bromodomain-containing protein. In some embodiments, the compounds described herein selectively inhibit the activity of a bromodomain-containing protein as compared to a kinase (e.g., a kinase described herein). In some embodiments, the compounds described herein selectively inhibit the activity of bromodomain-containing proteins as compared to the following kinases: MPS1(TTK), ERK5(BMK1, MAPK7), polo-like kinases (e.g., polo-like kinase 1, polo-like kinase 2, polo-like kinase 3, polo-like kinase 4), Ack1, Ack2, AbI, DCAMKL1, ABL1, AbI mutants, DCAMKL2, ARK5, BRK, MKNK 5, FGFR 5, TNK 5, PLK 5, ULK 5, PLK 5, PRKD 5, ROS 1, RPS6KA 5, TAOK 5, TNK 5, Bcr-ABL, GAK, cSrc, TPR-Met, Tie 5, MET, FGFR, TRK 5, TrkR-5, TrkX, Bmx-kit, TrkK 5, AuSrc, TPR-5, TPR-Met 5, PKC, RAFR-5, TrkB, TrkS 5, and RAFR/RAFR. In some embodiments, the compounds described herein selectively inhibit the activity of bromodomain-containing proteins compared to MAP kinase. In some embodiments, the compounds described herein selectively inhibit the activity of bromodomain-containing proteins compared to mitotic spindle kinase. In some embodiments, the compounds described herein selectively inhibit the activity of a bromodomain-containing protein compared to polo-like kinase. In some embodiments, a compound described herein selectively inhibits BET proteins. In some embodiments, the compounds described herein selectively inhibit BRD 2. In some embodiments, the compounds described herein selectively inhibit BRD 3. In some embodiments, the compounds described herein selectively inhibit BRD 4. In some embodiments, the compounds described herein selectively inhibit BRDT. In some embodiments, the compounds described herein selectively inhibit TAF proteins (e.g., TAF1 or TAF1L), CBPs, and/or EP 300. In some embodiments, the compounds described herein are non-selective inhibitors of two or more bromodomain-containing proteins. In some embodiments, the compounds described herein are non-selective inhibitors of bromodomain-containing proteins and proteins that are not bromodomain-containing proteins.

The compounds described herein may also selectively bind to the bromodomain of bromodomain-containing proteins. It will be understood that when reference is made to a compound as "selectively" binding to a bromodomain of a bromodomain-containing protein, the compound binds the bromodomain of the bromodomain-containing protein with greater affinity than the non-bromodomain of the bromodomain-containing protein.

The selectivity of a compound described herein for inhibiting the activity of a bromodomain-containing protein over a second protein (e.g., a kinase) that is different from the bromodomain-containing protein can be measured by dividing the IC50 value for the compound described herein for inhibiting the activity of the second protein by the IC50 value for the compound described herein for inhibiting the activity of the bromodomain-containing protein. The selectivity of a compound described herein for a bromodomain-containing protein over a second protein can also be measured by dividing the Kd value of the adduct of a compound described herein and a second protein by the Kd value of the adduct of a compound described herein and a bromodomain-containing protein. In some embodiments, the selectivity is at least about 1-fold, at least about 3-fold, at least about 5-fold, at least about 10-fold, at least about 30-fold, at least about 100-fold, at least about 300-fold, at least about 1,000-fold, at least about 3,000-fold, at least about 10,000-fold, at least about 30,000-fold, or at least about 100,000-fold. In some embodiments, the selectivity is at most about 100,000-fold, at most about 10,000-fold, at most about 1,000-fold, at most about 100-fold, at most about 10-fold, or at most about 1-fold. Combinations of the above ranges (e.g., at least about 2 times and at most about 10,000 times) are also within the scope of the invention. Other ranges are also possible. In some embodiments, the selectivity is at least about 3-fold. In some embodiments, the selectivity is at least about 10-fold. In some embodiments, the selectivity is at least about 100-fold.

Bromodomain-containing proteins are known in the art to be involved in a wide range of diseases. For example, BRD3 and BRD4 are involved in BRD3NUT midline carcinoma and BRD4NUT midline carcinoma (midline carcinoma), respectively, BRDT is involved in spermatogenesis, and CBP is involved in mixed leukemia (MLL). Accordingly, the compounds described herein are useful for the treatment and/or prevention of diseases associated with bromodomain-containing proteins or as male contraceptives.

Pharmaceutical compositions and administration

The present invention provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof), and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions of the present invention comprise a compound of formula (II), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions of the present invention comprise a compound of formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the compounds described herein are provided in an effective amount in a pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount. In some embodiments, the effective amount is an amount effective to treat and/or prevent a disease (e.g., a disease described herein) in a subject in need thereof. In some embodiments, the effective amount is an amount effective to treat a disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective to prevent a disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective to reduce the risk of developing a disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective for contraception in a subject in need thereof. In some embodiments, the effective amount is an amount effective to inhibit viral replication. In some embodiments, the effective amount is an amount effective to kill the virus. In some embodiments, the effective amount is an amount effective to inhibit the activity (e.g., aberrant activity, e.g., increased activity) of the bromodomain-containing protein in the subject or cell. In some embodiments, the effective amount is an amount effective to inhibit the activity (e.g., aberrant activity, e.g., increased activity) of the bromodomain in a subject or cell. In some embodiments, the effective amount is an amount effective to inhibit binding of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., histone) in a subject or cell. In some embodiments, the effective amount is an amount effective to modulate (e.g., inhibit) transcriptional elongation in a subject or cell. In some embodiments, the effective amount is an amount effective to modulate (e.g., down-regulate or inhibit) the expression (e.g., transcription) of a gene regulated by a bromodomain-containing protein in a subject or cell. In some embodiments, the effective amount is an amount effective to modulate (e.g., reduce) the level of a bromodomain-containing protein in a subject or cell.

The effective amount of the compound may vary within the following ranges: from about 0.001mg/kg to about 1000mg/kg, in one or more doses (depending on the mode of administration) administered daily or every several days. In some embodiments, the effective amount per dose varies from about 0.001mg/kg to about 1000mg/kg, from about 0.01mg/kg to about 750mg/kg, from about 0.1mg/kg to about 500mg/kg, from about 1.0mg/kg to about 250mg/kg, and from about 10.0mg/kg to about 150 mg/kg.

In some embodiments, the effective amount is an amount effective to inhibit binding, transcriptional extension, and/or expression (e.g., transcription) of a gene regulated by the bromodomain-containing protein to the following extent of the activity of the bromodomain-containing protein, the activity of the bromodomain, the bromodomain of the bromodomain-containing protein, and acetyl-lysine residues of a second protein (e.g., histone): at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the effective amount is an amount effective to inhibit the activity of the bromodomain-containing protein, the binding of the bromodomain-containing protein to acetyl-lysine residues of a second protein (e.g., histone protein), and/or the expression (e.g., transcription) of a gene regulated by the bromodomain-containing protein to the following extent: at most about 90%, at most about 80%, at most about 70%, at most about 60%, at most about 50%, at most about 40%, at most about 30%, at most about 20%, or at most about 10%. Combinations of the ranges recited herein (e.g., at least about 20% and at most about 50%) are also within the scope of the invention. In some embodiments, the activity of the bromodomain-containing protein, the binding of the bromodomain-containing protein to acetyl-lysine residues of a second protein (e.g., histone) and/or the expression (e.g., transcription) of a gene regulated by the bromodomain-containing protein is inhibited by an effective amount of a compound described herein by a percentage or range of percentages described herein.

In some embodiments, the gene modulated by the bromodomain-containing protein is a gene modulated by bromodomain and extra terminal protein (BET). In some embodiments, the gene modulated by the bromodomain-containing protein is BRD 2. In some embodiments, the gene modulated by the bromodomain-containing protein is BRD2 (1). In some embodiments, the gene modulated by the bromodomain-containing protein is BRD2 (2). In some embodiments, the gene modulated by the bromodomain-containing protein is BRD 3. In some embodiments, the gene modulated by the bromodomain-containing protein is BRD3 (1). In some embodiments, the gene modulated by the bromodomain-containing protein is BRD3 (2). In some embodiments, the gene modulated by the bromodomain-containing protein is BRD 4. In some embodiments, the gene modulated by the bromodomain-containing protein is BRD4 (1). In some embodiments, the gene modulated by the bromodomain-containing protein is BRD4 (2). In some embodiments, the gene modulated by the bromodomain-containing protein is BRDT. In some embodiments, the gene modulated by the bromodomain-containing protein is BRDT (1). In some embodiments, the gene modulated by the bromodomain-containing protein is BRDT (2). In some embodiments, the gene modulated by a bromodomain-containing protein is a gene modulated by TBP (TATA box binding protein) -related factor protein (TAF). In some embodiments, the gene modulated by the bromodomain-containing protein is TAF 1. In some embodiments, the gene modulated by the bromodomain-containing protein is TAF 1L. In some embodiments, the gene modulated by the bromodomain-containing protein is a gene modulated by CREB-binding protein (CBP). In some embodiments, the gene modulated by a bromodomain-containing protein is a gene modulated by E1A binding protein p300(EP 300).

The pharmaceutical compositions described herein may be prepared by any method known in the art of pharmacology. Generally, such a preparation method comprises the steps of: the compounds described herein (i.e., the "active ingredients") are combined with carriers or excipients, and/or one or more other adjuvants, and the product is then, if necessary and/or desired, shaped and/or packaged into the desired single-or multi-dose units.

The pharmaceutical compositions may be prepared, packaged and/or sold in bulk in a single unit dose and/or in multiple single unit doses. A "unit dose" is a discrete amount (discrete amount) of a pharmaceutical composition comprising a predetermined amount of active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to the subject and/or a simple fraction of this dose, for example, one half or one third of this dose.

The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and/or any additional ingredients in the pharmaceutical compositions described herein will vary depending on the identity, size, and/or condition of the subject being treated and further depending on the route of administration of the composition. The composition may comprise from 0.1% to 100% (w/w) of the active ingredient.

Pharmaceutically acceptable excipients used in preparing the provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents and/or oils. Excipients (e.g., cocoa butter and suppository waxes), coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dicalcium phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, sugar powder, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly (vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (cross-linked carboxymethyl cellulose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

Exemplary surfactants and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondlux, cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, waxes, and lecithin), bentonites (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glycerol monostearate and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene (carbopypolymethylene), polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose), Hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate: (20) Polyoxyethylene sorbitan: (60) Polyoxyethylene sorbitan monooleate (A)80) Sorbitan monopalmitate (b) 40) Sorbitan monostearate (C)60) Sorbitan tristearate (C)65) Glycerol monooleate, sorbitan monooleate (C)80) Polyoxyethylene esters (e.g., polyoxyethylene monostearate) ((C))45) Polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxyl stearate and) Sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g.,) Polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether: (A)30) Poly (vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate,f-68, poloxamer P-188, cetrimide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium and/or mixtures thereof.

Exemplary binding agents include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, and the like), natural and synthetic gums (e.g., acacia gum, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mango gum (muciger of isapolhsks), carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly (vinyl-pyrrolidone), magnesium aluminum silicate And larch arabinogalactan (larch arabinogalactan), alginate, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylate, wax, water, ethanol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal preservatives, ethanol preservatives, acidic preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, thioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate, trisodium ethylenediaminetetraacetate, disodium calcium ethylenediaminetetraacetate, dipotassium ethylenediaminetetraacetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethanol.

Exemplary acidic preservatives include vitamin a, vitamin C, vitamin E, beta carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deferoxamine mesylate, cetrimide, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), ethylenediamine, Sodium Lauryl Sulfate (SLS), Sodium Lauryl Ether Sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, sodium metabisulfi,Plus、Methyl p-hydroxybenzoate,115、II、And

exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium glucoheptonate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium pentanoate, valeric acid, calcium hydrogen phosphate, phosphoric acid, calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethanol, and mixtures thereof.

Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond (almonds), almond (apricot kernel), avocado, babassu (babassu), bergamot, blackcurrant seed, borage, juniper, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver oil, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, linseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba oil, kui nut oil (kui nut), hybrid lavender (lavandin), lavender (lavender), lemon, piper cubeba, hawaii nut (macademia nut), mallow, mango kernel, meadowfoam seed (meadowfoam seed), mink, nutmeg, olive, orange, tilapia (orange), safflower, palm kernel, peach kernel, peanut, poppy seed, rosemary, sunflower seed, sesame seed, and so forth, Camellia (sasquana), savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, toona sinensis (tsubaki), rock grass, walnut, and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils such as cottonseed, groundnut, corn, germ, olive, castor, and sesame oils, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions can contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In some embodiments of parenteral administration, the conjugates described herein are mixed with a solubilizing agent, e.g., a solubilizing agentAlcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Among the acceptable carriers and solvents that may be used are water, u.s.p. ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty oils (e.g., oleic acid) can be used in the preparation of injectables.

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

In order to prolong the therapeutic effect of a drug, it is often desirable to slow the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the drug depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oily carrier.

Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ordinary temperatures but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active ingredient.

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

Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmacological arts. They may optionally comprise opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferably, in a specific part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active ingredient may be in microencapsulated form with one or more of the excipients mentioned above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent (e.g., sucrose, lactose or starch). Such dosage forms may contain, as is common practice, other substances in addition to inert diluents, e.g., tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may contain buffering agents. They may optionally comprise opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferably, in a specific part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents that may be used include polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of the compounds described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Typically, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any required preservatives and/or required buffers. Furthermore, the present invention contemplates the use of transdermal patches, which generally have the added advantage of controllably delivering the active ingredient to the body. Such dosage forms may be prepared, for example, by dissolving and/or dispersing the active ingredient in the appropriate medium. Alternatively or additionally, the rate may be controlled by providing a rate controlling membrane and/or dispersing the active ingredient in a polymer matrix and/or gel.

Suitable devices for delivering the intradermal pharmaceutical compositions described herein include short needle devices, such as those described in U.S. Pat. Nos. 4,886,499; 5,190,521, respectively; 5,328,483, respectively; 5,527,288; 4,270,537, respectively; 5,015,235, respectively; 5,141,496, respectively; and 5,417,662. Intradermal compositions may be administered using devices that limit the effective penetration length of the needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof. Alternatively or additionally, conventional syringes may be used for classical mantoux for intradermal administration. A rapid injection device that delivers liquid vaccine to the dermis by a liquid jet syringe and/or by a needle that pierces the stratum corneum and creates a jet that reaches the dermis is suitable. Rapid injection devices are described, for example, in us patent 5,480,381; 5,599,302, respectively; 5,334,144, respectively; 5,993,412, respectively; 5,649,912, respectively; 5,569,189, respectively; 5,704,911, respectively; 5,383,851, respectively; 5,893,397, respectively; 5,466,220, respectively; 5,339,163, respectively; 5,312,335, respectively; 5,503,627, respectively; 5,064,413, respectively; 5,520,639, respectively; 4,596,556, respectively; 4,790,824, respectively; 4,941,880, respectively; 4,940,460, respectively; and PCT publications WO 97/37705 and WO 97/13537. Ballistic powder/particle delivery devices that use compressed gas to accelerate compounds in powder form across the outer layers of the skin into the dermis are suitable.

Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid formulations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions, such as creams, ointments and/or pastes, and/or solutions and/or suspensions. Formulations for topical administration may, for example, contain from about 1% to about 10% (w/w) of the active ingredient, but the concentration of the active ingredient may be up to the solubility limit of the active ingredient in the solvent. Formulations for topical administration may also include one or more additional ingredients as described herein.

The pharmaceutical compositions described herein may be prepared, packaged and/or sold in formulations suitable for pulmonary administration through the oral cavity. Such formulations may include dry particles that contain the active ingredient and which have a diameter in the range of about 0.5 to about 7 nanometers, or about 1 to about 6 nanometers. Such compositions are conveniently administered in the form of a dry powder using a device comprising a dry powder reservoir into which a propellant stream is directed to disperse the powder, and/or using a self-propelled solvent/powder dispensing container, e.g. a device comprising an active ingredient dissolved and/or suspended in a low boiling point propellant in a closed container. Such powders comprise particles wherein at least 98% by weight of the particles have a diameter greater than 0.5 nm and at least 95% by number of the particles have a diameter less than 7 nm. Alternatively, at least 95% by weight of the particles have a diameter greater than 1 nanometer and at least 90% by number of the particles have a diameter less than 6 nanometers. The dry powder composition may include a solid finely divided diluent (e.g. sugar) and is conveniently provided in unit dosage form.

Low boiling propellants typically include liquid propellants having a boiling point of less than 65 ° F at atmospheric pressure. Typically, the propellant may constitute 50-99.9% (w/w) of the composition and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as liquid non-ionic and/or solid anionic surfactants and/or solid diluents (which may be of the same order of particle size as the particles comprising the active ingredient).

The pharmaceutical compositions described herein for pulmonary delivery can provide the active ingredient in the form of droplets of solution and/or suspension. Such formulations may be prepared, packaged and/or sold as aqueous and/or diluted alcohol solutions and/or suspensions, optionally sterile, containing the active ingredient and conveniently administered using any spraying and/or atomising device. Such formulations may also contain one or more additional ingredients including, but not limited to, flavoring agents, such as sodium saccharin, volatile oils, buffering agents, surfactants, and/or preservatives, such as methyl hydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range of about 0.1 to about 200 nanometers.

The formulations for pulmonary delivery described herein are used for intranasal delivery of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle size of about 0.2 to 500 microns. Such formulations are administered by rapid inhalation into the nasal passage from a powder container held near the nostril.

Formulations for nasal administration may, for example, comprise from about at least 0.1% (w/w) to at most 100% (w/w) of the active ingredient, and may comprise one or more additional ingredients as described herein. The pharmaceutical compositions described herein may be prepared, packaged and/or sold in an orally administrable formulation. Such formulations may, for example, be in the form of tablets and/or lozenges prepared using conventional methods and may comprise, for example, 0.1 to 20% (w/w) of the active ingredient, the balance comprising an orally dissolving and/or degrading composition, and optionally one or more additional ingredients described herein. Alternatively, formulations for oral administration may comprise powders and/or aerosolized solutions and/or suspensions containing the active ingredient. Such powdered, aerosolized and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size ranging from about 0.1 to about 200 nanometers, and may further comprise one or more additional ingredients described herein.

The pharmaceutical compositions described herein may be prepared, packaged and/or sold in an ophthalmic delivery formulation. Such formulations may, for example, be in the form of eye drops comprising, for example, a solution and/or suspension of 0.1-1.0% (w/w) of the active ingredient in an aqueous or oily liquid carrier or vehicle. Such drops may also comprise buffers, salts and/or one or more other additional ingredients as described herein. Other useful formulations for ocular administration include those comprising the active ingredient in microcrystalline and/or liposomal formulation. Ear drops and/or eye drops are also intended to be encompassed within the scope of the present invention.

Although the description of the pharmaceutical compositions provided herein primarily refers to pharmaceutical compositions suitable for administration to humans, those skilled in the art will appreciate that such compositions are generally suitable for administration to a variety of animals. It is well known to modify pharmaceutical compositions suitable for administration to humans to render the compositions suitable for administration to various animals, and veterinarians of ordinary skill in the art can design and/or practice such modifications with ordinary experimentation.

The compounds provided herein are generally formulated in dosage unit form for ease of administration and uniformity of dosage. However, it will be understood that the total daily dosage of the compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective amount level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disease; the activity of the particular active ingredient employed; the specific composition employed; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the particular active ingredient employed; the duration of the treatment; drugs used in combination or concomitantly with the specific active ingredient employed; and similar factors well known in the medical arts.

The compounds and compositions provided herein can be administered by any route, including enterally (e.g., oral), parenterally, intravenously, intramuscularly, intraarterially, intramedullary, intrathecally, subcutaneously, intraventricularly, transdermally, intradermally, rectally, intravaginally, intraperitoneally, topically (e.g., by powders, ointments, creams, and/or drops), mucosally, nasally, buccally; by intratracheal instillation, bronchial instillation and/or inhalation; and/or as an oral spray, nasal spray and/or aerosol. Routes of particular concern are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via the blood and/or lymphatic supply, and/or direct administration to the affected site. Generally, the most suitable route of administration will depend on various factors, including the nature of the agent (e.g., stability in the gastrointestinal environment), and/or the condition of the subject (e.g., whether the subject can tolerate oral administration). In some embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

The exact amount of a compound required to achieve an effective amount varies from subject to subject, depending, for example, on the species, age, and general condition of the subject, the severity of the side effect or disorder, the identity of the particular compound, the mode of administration, and the like. The desired dose may be delivered three times daily, twice daily, once every two days, once every three days, once weekly, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, a desired dose can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). An effective amount may be included in a single dose (e.g., a single oral dose) or in multiple doses (e.g., multiple oral doses). In some embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two of the multiple doses comprise different amounts or substantially the same amount of a compound described herein. In some embodiments, when multiple doses are administered to the subject or multiple doses are applied to the tissue or cells, the frequency of administering multiple doses to the subject or multiple doses to the tissue or cells is three doses a day, two doses a day, one dose every other day, one dose every three days, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In some embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is one dose per day. In some embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is two doses a day. In some embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is three doses a day. In some embodiments, when administering multiple doses to a subject or applying multiple doses to a tissue or cell, the time span between the first and last doses of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In some embodiments, the time span between the first and last doses of the plurality of doses is three months, six months, or one year. In some embodiments, the time span between the first and last doses of the plurality is the lifetime of the subject, tissue, or cell. In some embodiments, a dose described herein (e.g., a single dose or multiple doses of any dose) independently includes between 0.1 μ g and 1 μ g, between 0.001mg and 0.01mg, between 0.01mg and 0.1mg, between 0.1mg and 1mg, between 1mg and 3mg, between 3mg and 10mg, between 10mg and 30mg, between 30mg and 100mg, between 100mg and 300mg, between 300mg and 1,000mg, or between 1g and 10g of a compound described herein, inclusive. In some embodiments, a dose described herein independently includes between 1mg and 3mg of a compound described herein, inclusive. In some embodiments, a dose described herein independently includes between 3mg and 10mg of a compound described herein, inclusive. In some embodiments, a dose described herein independently includes between 10mg and 30mg of a compound described herein, inclusive. In some embodiments, the doses described herein independently include between 30mg and 100mg of a compound described herein, inclusive.

In some embodiments, an effective amount of a compound administered one or more times daily to a 70kg adult human may include from about 0.0001mg to about 3000mg, from about 0.0001mg to about 2000mg, from about 0.0001mg to about 1000mg, from about 0.001mg to about 1000mg, from about 0.01mg to about 1000mg, from about 0.1mg to about 1000mg, from about 1mg to about 100mg, from about 10mg to about 1000mg, or from about 100mg to about 1000mg of the compound per unit dosage form.

In some embodiments, the compounds described herein may be delivered at a dosage level sufficient to deliver from about 0.001mg/kg to about 100mg/kg, from about 0.01mg/kg to about 50mg/kg, preferably from about 0.1mg/kg to about 40mg/kg, preferably from about 0.5mg/kg to about 30mg/kg, from about 0.01mg/kg to about 10mg/kg, from about 0.1mg/kg to about 10mg/kg, and more preferably from about 1mg/kg to about 25mg/kg of the subject's body weight once or more times daily to achieve the desired therapeutic and/or prophylactic effect.

It will be understood that the dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. The amount administered to, for example, a child or adolescent can be determined by a physician or one skilled in the art and can be slightly less than or the same as the amount administered to an adult.

It is also understood that a compound or composition described herein can be administered in combination with one or more other agents (e.g., therapeutically and/or prophylactically active agents). Administering a compound or composition in combination with other agents can increase their activity (e.g., potency and/or effectiveness) in treating a disease in a subject in need thereof, preventing a disease in a subject in need thereof, reducing a subject in need thereof from suffering from a disease, inhibiting viral replication, killing a virus, inhibiting activity of a bromodomain-containing protein in a subject or cell, inhibiting activity of a bromodomain in a subject or cell, inhibiting binding of a bromodomain-containing protein and an acetyl-lysine residue of a second protein (e.g., histone) in a subject or cell, modulating (e.g., inhibiting) transcriptional elongation, modulating (e.g., inhibiting) expression (e.g., transcription) of a gene regulated by a bromodomain-containing protein in a subject or cell, or a method of treating a disease in a subject in need thereof, Modulating (e.g., reducing) the level of bromodomain-containing proteins in a subject or cell can increase bioavailability and/or safety, reduce drug resistance, reduce and/or improve their metabolism, inhibit their excretion, and/or improve their distribution in the subject. It will also be appreciated that the applied treatment may achieve the desired effect on the same condition, and/or may achieve different effects. In some embodiments, a pharmaceutical composition described herein comprising a compound described herein and an additional agent exhibits a synergistic effect, whereas a pharmaceutical composition comprising a compound described herein or an additional agent other than both does not exhibit such a synergistic effect.

The compound or composition may be administered concurrently with, before, or after one or more additional agents, which may be used, for example, as a combination therapy. The medicament includes a therapeutically active agent. The medicament also includes a prophylactically active agent. Agents include small organic molecules, such as pharmaceutical compounds (e.g., human or veterinary compounds approved by the U.S. food and drug administration as provided in the federal regulations Compilation (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells. In some embodiments, the additional agent is an agent for treating and/or preventing a disease described herein. Each additional agent may be administered at a dose and/or on a schedule determined by the agent. The additional agents may also be administered together with each other and/or with the compounds or compositions described herein, in a single dose or separately in different doses. The particular combination employed in this regimen will take into account the compatibility of the compounds described herein with additional agents and/or the desired therapeutic and/or prophylactic effect that will be achieved. Generally, it is contemplated that the additional agents when used in combination are at levels not exceeding those when used individually. In some embodiments, the levels used in combination will be lower than they are used individually.

Such additional agents include, but are not limited to, antiproliferative agents, anticancer agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressive agents, antibacterial agents, antiviral agents, cardiovascular agents, lipid-lowering agents, antidiabetic agents, antiallergic agents, contraceptive agents, and pain-relieving agents. In some embodiments, the additional agent is an antiproliferative agent. In some embodiments, the additional agent is an anti-cancer agent. In some embodiments, the additional agent is an anti-leukemic agent. In some embodiments, the additional agent is ABITREXATE (methotrexate), ADE, doxorubicin RDF (doxorubicin hcl), ambochloririn (chlorambucil), arron (nelarabine), ARZERRA (efamumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin hcl), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOFAAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINE (Alopecurania americana), FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA (Invitromab), GLEEVEVEVEC (imatinib mesylate), Hydrab (CVIRE), vincamine butyrate (VIRTAIN), vincristine hydrochloride (mustard), vincristine (FOREBO), Vincristine (VIRTA), VIRTA (VITROBULABITRIBO), VETAB (VITROCTAB), VITROCTAB (VITROMOBULABAMALITRIBO), VITROCA (VITROCA), VITROCE (VITROCTAB), VITROCB, METHOTREXATE LPF (METHOTREXATE), MEXATE-AQ (METHOTREXATE), mitoxantrone hydrochloride, mustagen (nitrogen mustard hydrochloride), myreran (busulfan), NEOSAR (cyclophosphamide), ONCASPAR (peimepirnase), PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), triribo (homoharringtonine), TARABINE PFS (cytarabine), TASIGNA (nilotinib), trenda (bendamustine hydrochloride), trisox (arsenic trioxide), VINCASAR PFS (vincristine sulfate), zydelig (idelalisib), or combinations thereof. In some embodiments, the additional agent is an anti-lymphoma drug. In some embodiments, the additional agent is ABITREXATE (methotrexate), ABVD, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCINRDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR (tositumomab and I131 tositumomab), BICNU (carmustine), BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP-ABV, CVP, CYXAN (cyclophosphamide), DECYCYPOT (cytarabine), DTIC-DOME (EPOCALME), FOLDEHEC (FOLDEN), FOURACH, FOLDEN (FOURACEAX-2), FORCONITAX (FOURACORX), FORCONITAX-2 (FORCONITON), FORCONITON (FORCONITAX 2), FORCONITON (FORCONITON), FORCONITON, FORCAT, BENCIL 2, BENCA, FORCONITON, isotaxx (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), lomustine, MATULANE (procarbazine hydrochloride), METHOTREXATE LPF (METHOTREXATE), MEXATE-AQ (METHOTREXATE), MOPP, MOZOBIL (plerixafof), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (dinil 2), OPPA, R-CHOP, revalid (lenalidomide), rituximab (rituximab), STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), velsa (vinblastine sulfate), VINCASAR PFS (vincristine sulfate), zetimumab), zovovaciz (vinelalin), linidizein (zuelidlyigin), or combinations thereof. In some embodiments, the additional agent is revalimid (lenalidomide), DACOGEN (decitabine), vidaka (azacitidine), cytar-U (cytarabine), IDAMYCIN (idarubicin), CERUBIDINE (daunorubicin), LEUKERAN (chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof. In some embodiments, the additional agent is ABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticulate formulation), AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (disodium pemetrexed), AREDIA (disodium pamidronate), ARIDEX (anastrozole), AROMASTIN (exemestane), AVASTIN (bevacizumab), BECENUM (carmustine), BECEP, BICNU (carmustine), BLENOXANOX (bleomycin), CAF, CAMPAR (irinotecan hydrochloride), CAPRELA (vandetanib), BOPLATIN-TAXOL, CARBRMUMUIS (carmustine), CASOX (DEMOX), CAMPIREMU (CLARIFIX), HORU (CINOX), HOMORPE (CIT), HALCOME (E), HALCOME (CIT-C (CALCIUM), HALCIUM (CALCIUM), CALCIUM, COSMEGEN (Actinomycin D), CYFOS (ifosfamide), CYRAMZA (ramucirumab ), CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), doxorubicin hydrochloride, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITEX (cetuximab), ERIVEGE (IgY), ERIVEGE (etoposide phosphate), EVACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUORLEX (fluorouracil), FOLFLEX (methotrexate), FOLFLEX PFS (FOLEVIRU-IFLOX), FOVARIFU, FORX-FORXIX (FOIREFI), FOIREFI, FORCA-like vaccine (FOIREFI), FOIREFI, FORCU-S (FOIRIFO-S), FOIRIFO-S (FORCA), FORCA, FOIREFI), FOIREFI (FOIRIDX, FOIREFI), FOIRE (FOIRE, FOIREFI), FO, Gemcitabine-cisplatin, Gemcitabine-oxaliplatin, GEMZAR (Gemcitabine hydrochloride), GILOTRIF (Afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab), HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON A (recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruzotinib phosphate), JEVTANA (cabazitaxel), KADCYLA (KaDCYLA), KYPEROLIB (KYLIS (Carbavirgine), LIPOX (Doxox hydrochloride), LULUPOLLUTINN (DELULULAB), GLURINE (DELUPROGLURIN 4), LUPROGLURINA (DELUPROGLINE-4), LUPROLIN-4 (DELUPROLIN-PROLIN-4) LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol acetate), MEKINIST (triametinib), METHAZOLASTONE (temozolomide), METHOTREE LPF (METHOTREXATE), MEXATE-AQ (METHOTREXATE), mitoxantrone hydrochloride, MITOTZYTREX (mitomycin C), MOZOBIL (plerifof), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin C), MYLOSAR (azacitidine), NAVSBILINE (vinorelbine tartrate), NEOSAR (cyclophosphamide), NEXAVAR (mefenanib tosylate), NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), PAD, PARLAT (carboplatin), PARAPAPAPMAPI (carboplatin), PEG-IN (interferon-2 b), pemetrexed (polyethylene glycol), polyethylene glycol-2 b), disodium (prednisone), prednisone (prednisone), prednisolone (prednisone), prednisone (prednisone), cisplatin), prednisone (prednisone), prednisone (prednisone, cisplatin), and cisplatin) PROLIA (dinolizumab), PROVENGE (sipuleucel-t), revalimid (lenalidomide), RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT (sunitinib malate), sylaron (peginterferon alfa-2b), sylvatant (siltuximab), SYNOVIR (thalidomide), TAC, tafillar (dalafinil), TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA (nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), temozolomide (temozolomide), thalomoid (thalidomide), topirar (etoposide), tolerol (sirolimus), TPF, triox (triox), keratinib (tympaninb), vinpocetine (vinpocetine), valcecrolimus (valacil), etoposide (valacil), valceva (valacilin), valacilin (valacil), valacil (valacil), valacilin (valacil), valacil (valaci, VINCASAR PFS (vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVOLIN (calcium folinate), XALKORI (crizotinib), XELODA (capecitabine), XELOX, XGAVA (dinolizumab), XOFIGO (radium dichloride 223), XTANDI (enzalutamide), YERVOY ((YIPPINMA), LTRAP (Abirap), ZELBORAF (Verofenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid), ZYKADIA (ceritinib)), ZYTIGA (abiraterone acetate), or combinations thereof. The additional agent is selected from the group consisting of epigenetic (epigenetics) or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other differentiation promoting drugs. In some embodiments, the compounds or pharmaceutical compositions described herein can be administered in combination with anti-cancer therapies including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.

The invention also includes kits (e.g., pharmaceutical packages). Kits provided can include a pharmaceutical composition or compound described herein, and a container (e.g., a vial, ampoule, bottle, syringe, and/or dispensing package, or other suitable container). In some embodiments, the provided kits may also optionally include a second container comprising a pharmaceutical excipient for diluting or suspending a pharmaceutical composition or compound described herein. In some embodiments, a pharmaceutical composition or compound described herein is provided in a first container and a second container is combined to form a unit dosage form.

Thus, in one aspect, a kit is provided that includes a first container comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the kit is for use in treating and/or preventing a disease described herein in a subject in need thereof. In some embodiments, the kit is for treating a disease described herein in a subject in need thereof. In some embodiments, the kit is for preventing a disease described herein in a subject in need thereof. In some embodiments, the kit is for use in reducing the risk of developing a disease described herein in a subject in need thereof. In some embodiments, the kit is for contraception (e.g., male contraception). In some embodiments, the kit is for inhibiting viral replication. In some embodiments, the kit is for killing a virus. In some embodiments, the kit is for inhibiting activity (e.g., aberrant activity, e.g., increased activity) of a bromodomain-containing protein in a subject or cell. In some embodiments, the kit is for inhibiting the activity (e.g., abnormal activity, e.g., increased activity) of a bromodomain in a subject or cell. In some embodiments, the kit is for inhibiting binding of a bromodomain-containing protein and an acetyl-lysine residue of a second protein (e.g., histone) in a subject or cell. In some embodiments, the kit is for modulating (e.g., inhibiting) transcriptional elongation in a subject or cell. In some embodiments, the kit is for modulating (e.g., down-regulating or inhibiting) expression (e.g., transcription) of a gene regulated by a bromodomain-containing protein in a subject or cell. In some embodiments, the kit is for modulating (e.g., reducing) the level of a bromodomain-containing protein in a subject or cell.

In some embodiments, the kit is used to screen libraries of compounds to identify compounds useful in the methods of the invention.

In some embodiments, the kits of the invention further comprise instructions for using the kit, e.g., instructions for using the kit in the methods of the invention (e.g., instructions for administering a compound or pharmaceutical composition described herein to a subject). Kits of the invention may also include information required by regulatory agencies such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information included in the kit is prescription information. In some embodiments, the kits and instructions provide for treating and/or preventing a disease described herein in a subject in need thereof. In some embodiments, the kits and instructions provide for treating a disease described herein in a subject in need thereof. In some embodiments, the kits and instructions provide for preventing a disease described herein in a subject in need thereof. In some embodiments, the kits and instructions provide for reducing the risk of developing a disease described herein in a subject in need thereof. In some embodiments, the kits and instructions provide for contraception (e.g., male contraception). In some embodiments, the kits and instructions provide for inhibiting viral replication. In some embodiments, the kits and instructions provide for killing a virus. In some embodiments, the kits and instructions provide for inhibiting activity (e.g., aberrant activity, e.g., increased activity) of a bromodomain-containing protein in a subject or cell. In some embodiments, the kits and instructions provide for inhibiting the activity (e.g., abnormal activity, e.g., increased activity) of a bromodomain in a subject or cell. In some embodiments, the kits and instructions provide for inhibiting binding of a bromodomain-containing protein and an acetyl-lysine residue of a second protein (e.g., histone) in a subject or cell. In some embodiments, the kits and instructions provide for modulating (e.g., inhibiting) transcriptional elongation. In some embodiments, the kits and instructions provide for modulating (e.g., down-regulating or inhibiting) expression (e.g., transcription) of a gene regulated by a bromodomain-containing protein in a subject or cell. In some embodiments, the kits and instructions provide for modulating (e.g., reducing) the level of a bromodomain-containing protein in a subject or cell. In some embodiments, the kits and instructions provide for screening libraries of compounds to identify compounds useful in the methods of the invention. The kits of the invention may include one or more additional agents of the invention as separate compositions.

Method of treatment

The present invention provides methods of treating a wide range of diseases, such as diseases associated with bromodomains, diseases associated with activity (e.g., aberrant activity) of bromodomains, diseases associated with bromodomain-containing proteins, and diseases associated with activity (e.g., aberrant activity) of bromodomain-containing proteins. Exemplary diseases include, but are not limited to, proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning. The invention also provides methods of contraception (e.g., male contraception). The invention also provides methods of inhibiting the activity (e.g., aberrant activity, e.g., increased activity) of a bromodomain or bromodomain-containing protein, methods of inhibiting the binding of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., histone), methods of modulating (e.g., inhibiting) transcriptional elongation, and methods of modulating (e.g., down-regulating or inhibiting) the expression (e.g., transcription) of a gene regulated by a bromodomain-containing protein.

Gene regulation is fundamentally controlled by the reversible, non-covalent assembly of macromolecules. Signal transduction by RNA polymerase requires a highly ordered protein complex, spatially regulated by assembly factors that can explain the post-translational modification state of chromatin. Epigenetic readers are structurally diverse proteins, and each epigenetic reader has one or more evolutionarily conserved effector modules that recognize covalent modifications of proteins (e.g., histones) or DNA. the-N-acetylation of lysine residues (Kac) at the tail of histones is associated with open chromatin structure and transcriptional activation. Context-specific molecular recognition of acetyl-lysine is mediated primarily by the bromodomain.

Bromodomain-containing proteins are of biological interest as components of transcription factor complexes (e.g., TBP (TATA box binding protein) -related factor 1(TAF1), CREB-binding protein (CBP or CREBBP), P300/CBP-related factor (PCAF), and Gcn5) and determinants of epigenetic memory. There are 41 human proteins, which contain a total of 57 different bromodomains. Despite the large sequence differences, all bromodomains share a conserved fold, which includes the definitionSubstrate-specific, distinct loop regions (ZA and BC loops) linked 4 α helices (α)_Z、α_A、α_BAnd α_C) The left side of the bundle. The co-crystal structure with the peptide substrate shows that the acetyl-lysine is recognized by the central hydrophobic cavity and anchored with hydrogen bonds of asparagine residues present in most of the bromine-containing domains. Bromine and extra terminal protein (BET) families (e.g., BRD2, BRD3, BRD4, and BRDT) share a common domain structure that includes two N-terminal bromodomains that exhibit high levels of sequence conservation and a more diverse C-terminal recruitment region.

Recent studies have established a convincing theory to target BRD4 in cancer. The function of BRD4 is to promote cell cycle progression, whose knockdown in cultured cancer cell lines promotes G1 phase arrest. BRD4 is an important mediator of transcriptional elongation that serves to recruit the positive transcriptional elongation factor complex (P-TEFb). Cyclin-dependent kinase-9 (the core component of P-TEFb) is a potent target in chronic lymphocytic leukemia, and has recently been linked to c-Myc-dependent transcription. The bromodomain present in BRD4 recruits P-TEFb to the mitotic chromosome, thereby increasing expression of the growth-promoting gene. BRD4 still binds to the transcriptional start site of genes expressed in M/G1 phase, but it was not found to occur at the start site of genes expressed later in the cell cycle. Knock-out of BRD4 in proliferating cells has been shown to result in G1 phase arrest and apoptosis by reducing the expression levels of genes important for mitotic progression and survival.

Importantly, BRD4 has recently been identified as a component of recurrent t (15; 19) chromosomal translocations in the invasive form of human squamous cell carcinoma. This translocation expresses the tandem N-terminal bromodomain of BRD4 as an in-frame association with the nuclear testis protein (NUT), thereby genetically defining the NUT Midline Carcinoma (NMC). Functional studies in patient-derived NMC cell lines have demonstrated an important role for BRD4-NUT oncoprotein in maintaining the characteristic reproductive advantage and differentiation block of this malignancy. Notably, RNA silencing of BRD4-NUT gene expression prevented proliferation and promoted squamous differentiation with significant increases in cytokeratin expression. Bromodomains may also down-regulate Myc and other transcription factors, such as the interleukin 7 receptor (IL 7R). This observation underscores the utility and therapeutic potential of bromodomain-containing protein binders or inhibitors.

In another aspect, the invention provides a method of inhibiting the activity of a bromodomain-containing protein in a subject or cell. In some embodiments, the bromodomain-containing protein is a bromodomain-containing protein described herein (e.g., a BET protein, such as BRD2, BRD3, BRD4, or BRDT). In some embodiments, the activity of a bromodomain-containing protein in a subject or cell is inhibited with the methods of the invention. In some embodiments, the activity of a bromodomain-containing protein in a subject or cell is inhibited by a method of the invention by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the activity of a bromodomain-containing protein in a subject or cell is inhibited by a method of the invention by at most about 90%, at most about 80%, at most about 70%, at most about 60%, at most about 50%, at most about 40%, at most about 30%, at most about 20%, at most about 10%, at most about 3%, or at most about 1%. Combinations of the above ranges (e.g., at least about 10% and at most about 50%) are also within the scope of the invention. Other ranges are also possible. In some embodiments, the activity of a bromodomain-containing protein in a subject or cell is selectively inhibited by the methods of the invention. In some embodiments, the activity of the bromodomain-containing protein in the subject or cell is selectively inhibited by the methods of the invention as compared to the activity of a kinase (e.g., MAP kinase, mitotic spindle kinase, polo-like kinase). In other embodiments, the activity of the bromodomain-containing protein in a subject or cell is non-selectively inhibited by the methods of the invention. In some embodiments, the cytokine level and/or histamine release is reduced by the methods of the invention.

In some embodiments, the activity of the bromodomain-containing protein is an aberrant bromodomain-containing protein activity. In some embodiments, the activity of the bromodomain-containing protein is an increased activity of the bromodomain-containing protein. In some embodiments, the activity of the bromodomain-containing protein is reduced by the methods of the invention.

In some embodiments, the subject is an animal. The animal may be of any sex and may be at any stage of development. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject of the invention is a human. In some embodiments, the subject of the invention is a human male. In some embodiments, the subject of the invention is a female. In some embodiments, the subject is a human diagnosed with a disease described herein. In some embodiments, the subject is a human diagnosed as having a higher than normal risk of a disease described herein. In some embodiments, the subject is a human suspected of having a disease described herein. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a fish. In some embodiments, the subject is a mammal. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a human or non-human mammal. In some embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In some embodiments, the subject is a companion animal, such as a dog or cat. In some embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In some embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In some embodiments, the animal is a genetically engineered animal. In some embodiments, the animal is a transgenic animal (e.g., a transgenic mouse and a transgenic pig).

In some embodiments, the cells of the invention are present in vitro. In some embodiments, the cell is present ex vivo. In some embodiments, the cell is present in vivo.

In another aspect, the invention provides methods of inhibiting the activity of a bromodomain in a subject or cell. In some embodiments, the activity of the bromodomain is an aberrant bromodomain activity. In some embodiments, the activity of the bromodomain is an increased activity of the bromodomain. In some embodiments, the activity of the bromodomain is reduced by the methods of the invention.

Other aspects of the invention relate to methods of inhibiting binding of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone) in a subject or cell. In some embodiments, the second protein is a protein comprising at least one acetyl-lysine residue. In some embodiments, the second protein is not a bromodomain-containing protein. In some embodiments, the second protein is a histone. In some embodiments, the histone is selected from H1, H2A, H2B, H3, H4, and H5. In some embodiments, binding of the bromodomain-containing protein and an acetyl-lysine residue of a second protein (e.g., a histone) is inhibited by the methods of the invention.

In another aspect, the invention provides methods of modulating (e.g., inhibiting) transcriptional elongation. In some embodiments, the transcriptional extension is modulated (e.g., inhibited) by the methods of the invention.

In another aspect, the invention provides methods of modulating expression (e.g., transcription) of a gene regulated by a bromodomain-containing protein (e.g., a gene described herein) in a subject or cell. In some embodiments, the invention provides methods of down-regulating or inhibiting expression (e.g., transcription) of a gene regulated by a bromodomain-containing protein in a subject or cell. Without wishing to be bound by any particular theory, the compounds and pharmaceutical compositions described herein are capable of interfering with the binding of a bromodomain-containing protein to the transcription initiation site of a gene. In some embodiments, the compounds and pharmaceutical compositions described herein interfere with the recognition of acetyl-lysine during gene expression (e.g., transcription). In some embodiments, the compounds and pharmaceutical compositions described herein interfere with acetyl-lysine anchoring during gene expression (e.g., transcription). In some embodiments, expression (e.g., transcription) of a gene regulated by a bromodomain-containing protein in a subject or cell is modulated by the methods of the invention. In some embodiments, expression (e.g., transcription) of a gene regulated by a bromodomain-containing protein in a subject or cell is down-regulated or inhibited by the methods of the invention. In some embodiments, the gene regulated by the bromodomain-containing protein is an oncogene.

Other aspects of the invention relate to methods of treating a disease in a subject in need thereof. In some embodiments, the disease is treated by the methods of the invention.

In some embodiments, the disease is a disease associated with a bromodomain-containing protein. In some embodiments, the disease is a disease associated with the activity of a bromodomain-containing protein. In some embodiments, the disease is a disease associated with aberrant activity (e.g., increased activity) of a bromodomain-containing protein.

In some embodiments, the disease is a disease associated with a bromodomain (e.g., a bromodomain of a bromodomain-containing protein). In some embodiments, the disease is a disease associated with the activity of a bromodomain. In some embodiments, the disease is a disease associated with abnormal activity (e.g., increased activity) of a bromodomain. In some embodiments, the disease is a disease associated with a function (e.g., dysfunction) of a bromodomain.

In some embodiments, the diseases described herein are driven by transcriptional activators. In some embodiments, the transcription activator is Myc. In some embodiments, the disease is associated with NUT rearrangement. In some embodiments, the disease is a disease associated with abnormal Myc function. In some embodiments, the disease is a disease associated with interleukin 7 receptor (IL 7R).

In some embodiments, the disease is a proliferative disease (e.g., a proliferative disease described herein). In some embodiments, the disease is cancer (e.g., a cancer described herein). In some embodiments, the disease is lung cancer. In some embodiments, the disease is multiple myeloma. In some embodiments, the disease is neuroblastoma. In some embodiments, the disease is colon cancer. In some embodiments, the disease is testicular cancer. In some embodiments, the disease is ovarian cancer. In some embodiments, the disease is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer). In some embodiments, the disease is NUT midline carcinoma (e.g., BRD3NUT midline carcinoma or BRD4NUT midline carcinoma). In some embodiments, the disease is leukemia. In some embodiments, the disease is mixed leukemia (MLL). In some embodiments, the disease is Acute Myeloid Leukemia (AML), bi-epi B myelomonocytic leukemia (biphenotypic B myelogenous leukemia) or erythroleukemia. In some embodiments, the disease is selected from burkitt's lymphoma, breast cancer, colon cancer, neuroblastoma, glioblastoma multiforme, chronic lymphocytic leukemia, and squamous cell carcinoma.

In some embodiments, the disease is a benign tumor (e.g., a benign tumor as described herein).

In some embodiments, the disease is an inflammatory disease (e.g., an inflammatory disease as described herein). In some embodiments, the disease is a disease that involves an inflammatory response to bacterial, viral, fungal, parasitic and/or protozoal infection. In some embodiments, the disease is selected from osteoarthritis, acute gout, multiple sclerosis, inflammatory bowel disease (e.g., crohn's disease and ulcerative colitis), neuroinflammation, asthma, chronic obstructive airways disease, pneumonia, myositis, eczema, dermatitis, acne, cellulitis, occlusive disease, thrombosis, alopecia, nephritis, vasculitis, retinitis, uveitis, scleritis, sclerosing cholangitis, hypophysitis, thyroiditis, septic shock, Systemic Inflammatory Response Syndrome (SIRS), toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, burns, pancreatitis (e.g., acute pancreatitis), post-operative syndrome, sarcoidosis, herkhausmer's reaction, encephalitis, myelitis, meningitis, and malaria. In some embodiments, the disease is acute or chronic pancreatitis. In some embodiments, the disease is a burn. In some embodiments, the disease is an inflammatory bowel disease. In some embodiments, the disease is neuroinflammation. In some embodiments, the disease is sepsis or sepsis syndrome. In some embodiments, the disease is Graft Versus Host Disease (GVHD).

In some embodiments, the disease is an autoimmune disease (e.g., an autoimmune disease as described herein). In some embodiments, the disease is rheumatoid arthritis. In some embodiments, the disease is psoriasis, systemic lupus erythematosus, vitiligo, bullous skin disease.

In some embodiments, the disease is a cardiovascular disease. In some embodiments, the disease is atherogenesis or atherosclerosis. In some embodiments, the disease is arterial stent occlusion, heart failure (e.g., congestive heart failure), coronary artery disease, myocarditis, pericarditis, heart valve disease, stenosis, restenosis, in-stent stenosis, angina, myocardial infarction, acute coronary syndrome, coronary bypass graft, cardiopulmonary bypass, endotoxemia, ischemia-reperfusion injury, cerebrovascular ischemia (stroke), renal reperfusion injury, embolism (e.g., pulmonary embolism, renal embolism, hepatic embolism, gastrointestinal tract embolism, or peripheral limb embolism), or myocardial ischemia.

In some embodiments, the disease is a viral infection. In some embodiments, the disease is a DNA virus infection. In some embodiments, the disease is a dsDNA virus infection. In some embodiments, the disease is a ssDNA virus infection. In some embodiments, the disease is an RNA viral infection. In some embodiments, the disease is a dsRNA virus infection. In some embodiments, the disease is (+) ssRNA virus infection. In some embodiments, the disease is a (-) ssRNA virus infection. In some embodiments, the disease is a Retroviral (RT) infection. In some embodiments, the disease is a ssRNA-RT viral infection. In some embodiments, the disease is a dsDNA-RT viral infection. In some embodiments, the disease is a Human Immunodeficiency Virus (HIV) infection. In some embodiments, the disease is Acquired Immune Deficiency Syndrome (AIDS). In some embodiments, the disease is a Human Papilloma Virus (HPV) infection. In some embodiments, the disease is a Hepatitis C Virus (HCV) infection. In some embodiments, the disease is a herpes virus infection (e.g., a Herpes Simplex Virus (HSV) infection). In some embodiments, the disease is an ebola virus infection. In some embodiments, the disease is Severe Acute Respiratory Syndrome (SARS). In some embodiments, the disease is an influenza virus infection. In some embodiments, the disease is an influenza virus infection. In some embodiments, the disease is an influenza a virus infection. In some embodiments, the disease is human influenza (e.g., H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, or H10N7 virus infection). In some embodiments, the disease is avian influenza (e.g., H5N1 or H7N9 virus infection). In some embodiments, the disease is swine influenza (e.g., H1N1, H1N2, H2N1, H3N1, H3N2, or H2N3 virus infection, or influenza c virus infection). In some embodiments, the disease is equine influenza (e.g., H7N7 or H3N8 virus infection). In some embodiments, the disease is canine influenza (e.g., H3N8 virus infection). In some embodiments, the disease is an influenza b virus infection. In some embodiments, the disease is an influenza c virus infection. In some embodiments, the disease is dengue fever, Dengue Hemorrhagic Fever (DHF), Dengue Shock Syndrome (DSS), hepatitis a, hepatitis B, hepatitis d, hepatitis e, hepatitis hex, coxsackie a virus infection, coxsackie B virus infection, fulminant viral hepatitis, viral myocarditis, parainfluenza virus infection, RS virus (RSV) infection (e.g., RSV bronchiolitis, RSV pneumonia, RSV infection and RSV pneumonia especially in infants and children with cardiopulmonary disorders), measles virus infection, vesicular stomatitis virus infection, rabies virus infection, japanese encephalitis, junin virus infection, human cytomegalovirus infection, varicella virus infection, cytomegalovirus infection, murine cytomegalovirus infection, proboscis virus infection (proboscis infection), rosea virus infection, lymphocryptovirus infection, herpes virus infection, hepatitis B virus infection, hepatitis c virus infection, hepatitis d virus infection, hepatitis B virus infection, RSV infection, hepatitis d virus infection, hepatitis B virus infection, and/or a viral infection, Maca virus infection (macavirus infection), equine herpes virus (percavirus) infection, monkey virus (rhadinovirus) infection), poliovirus infection, marburg virus infection, lassa fever virus infection, venezuelan equine encephalitis, rigo fever virus infection, korean hemorrhagic fever virus infection, crimean-congo hemorrhagic fever virus infection, encephalitis, Saint louis encephalitis, gsannous sarnu forest disease, murray valley encephalitis, tick-borne encephalitis, west nile encephalitis, yellow fever, adenovirus infection, pox virus infection, or viral infection in immunocompromised patients.

In some embodiments, the disease is a fibrotic disorder. In some embodiments, the disease is selected from renal fibrosis, post-surgical stenosis, keloid formation, cirrhosis, biliary cirrhosis, and cardiac fibrosis. In some embodiments, the disease is scleroderma. In some embodiments, the disease is idiopathic pulmonary fibrosis.

In some embodiments, the disease is an endocrine disease. In some embodiments, the disease is addison's disease.

In some embodiments, the disease is a metabolic disease. In some embodiments, the disease is diabetes. In some embodiments, the disease is type I diabetes. In some embodiments, the disease is type II diabetes or gestational diabetes. In some embodiments, the disease is obesity. In some embodiments, the disease is fatty liver (NASH or other), cachexia, hypercholesterolemia, or a disorder of lipid metabolism modulated by apolipoprotein a1(APOA 1).

In some embodiments, the disease is radiation poisoning. In some embodiments, the disease is radiation injury.

In some embodiments, the disease is acute rejection of a transplanted organ or multiple organ dysfunction syndrome.

In some embodiments, the disease is alzheimer's disease.

In other aspects, the invention provides methods of preventing a disease described herein in a subject in need thereof. In some embodiments, the disease is prevented by the methods of the invention.

In other aspects, the invention provides methods of reducing the risk of acquiring a disease described herein in a subject in need thereof. In some embodiments, the risk of suffering from a disease described herein is reduced by the methods of the invention.

In other aspects, the invention provides methods of contraception in a subject in need thereof. In some embodiments, the present invention provides methods of male contraception in a male subject in need thereof. In some embodiments, the present invention provides methods of female contraception in a female subject in need thereof.

In other aspects, the invention provides methods of inhibiting spermatogenesis in a subject in need thereof.

Other aspects of the invention relate to methods of inhibiting viral replication. In some embodiments, the viral replication is inhibited by the methods of the invention.

In some embodiments, the virus is a virus of the present invention. In some embodiments, the virus is a virus that causes infection by a virus described herein. In some embodiments, the virus is Human Immunodeficiency Virus (HIV), Human Papilloma Virus (HPV), Hepatitis C Virus (HCV), Herpes Simplex Virus (HSV), ebola virus, or influenza virus.

In some embodiments, the virus of the invention is present in vitro. In some embodiments, the virus of the invention is present ex vivo. In some embodiments, the virus of the invention is present in vivo.

Other aspects of the invention relate to methods of killing viruses. In some embodiments, the virus is killed by the methods of the invention.

Other aspects of the invention relate to methods of inhibiting the interaction between a bromodomain-containing protein and an immunoglobulin (Ig) regulatory element in a subject or cell.

In some embodiments, the methods of the invention comprise administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the methods of the invention comprise administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the methods of the invention comprise administering to a subject in need thereof a prophylactically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the methods of the invention comprise contacting a cell with an effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the methods of the invention comprise contacting a virus with an effective amount of a compound or pharmaceutical composition described herein.

Other aspects of the invention relate to methods of modulating gene expression regulated by bromodomain-containing proteins in a subject or cell.

Other aspects of the invention relate to methods of modulating the level of a bromodomain-containing protein in a subject or cell.

Other aspects of the invention relate to methods of screening libraries of compounds and pharmaceutically acceptable salts thereof to identify compounds or pharmaceutically acceptable salts thereof that are useful in the methods of the invention. In some embodiments, the method of screening a library comprises obtaining at least two different compounds described herein; and performing at least one test using the different compounds described herein. In some embodiments, at least one test can be used to identify compounds useful in the methods of the invention.

Typically, the method of screening a library of compounds comprises at least one test. In some embodiments, the test is performed to detect one or more of the following characteristics: features associated with treating and/or preventing a disease described herein, features associated with inhibiting the activity of a bromodomain-containing protein, features associated with inhibiting the activity of a bromodomain, features associated with inhibiting the binding of a bromodomain to an acetyl-lysine residue of a second protein (e.g., a histone), features associated with modulating (e.g., inhibiting) transcriptional elongation, and/or features associated with modulating (e.g., inhibiting) the expression (e.g., transcription) of a gene regulated by a bromodomain-containing protein. The characteristic can be a desired characteristic (e.g., the disease is being treated, the disease is being prevented, the risk of developing the disease is being reduced, viral replication is being inhibited, the virus is being killed, the activity of the bromodomain-containing protein is being inhibited, the activity of the bromodomain is being inhibited, binding of the acetyl-lysine residue of the bromodomain and a second protein (e.g., histone) is being inhibited, transcriptional elongation is being modulated (e.g., is being inhibited), the bromodomain-containing protein in the subject or cell is being modulated (e.g., reduced) or the expression (e.g., transcription) of a gene regulated by the bromodomain-containing protein is being modulated (e.g., is being inhibited)). The characteristic can be an undesirable characteristic (e.g., the disease has not been treated, the disease has not been prevented, the risk of developing the disease has not been reduced, viral replication has not been inhibited, the virus has not been killed, the activity of the bromodomain-containing protein has not been inhibited, the activity of the bromodomain has not been inhibited, binding of the acetyl-lysine residue of the bromodomain and a second protein (e.g., histone) has not been inhibited, transcriptional elongation has not been modulated (e.g., has not been inhibited), the bromodomain-containing protein in the subject or cell has not been modulated (e.g., has not been reduced), or expression (e.g., transcription) of a gene regulated by the bromodomain-containing protein has not been modulated (e.g., has not been inhibited)). The test may be an immunoassay, such as a double antibody sandwich test, a competitive binding test, a one-step direct test, a two-step test, or a western blot test. The step of performing at least one test may be performed automatically or manually. In some embodiments, the testing comprises (a) contacting a library of compounds with a bromodomain-containing protein; and (b) detecting binding of the library of compounds to the bromodomain-containing protein. In some embodiments, the assay comprises detecting specific binding of a library of compounds and a bromodomain-containing protein. In some embodiments, the assay comprises detecting specific binding of a library of compounds to a bromodomain of a bromodomain-containing protein. In some embodiments, specific binding of the library of compounds detected and the bromodomain-containing protein can be used to identify compounds useful in the methods of the invention. In some embodiments, the step of detecting binding comprises using Differential Scanning Fluorimetry (DSF), Isothermal Titration Calorimetry (ITC), and/or light activated chemiluminescence immunoassay (ALPHA). The step of performing at least one test can be performed in vitro, ex vivo, or in vivo in a cell (e.g., in a cancer cell). In some embodiments, the step of performing at least one test is performed in vitro in a cell (e.g., in a cancer cell). In some embodiments, the testing comprises (a) contacting a library of compounds with a cell; and (b) detecting a decrease in cell proliferation, an increase in cell death, and/or an increase in cell differentiation. In some embodiments, the cell death is apoptotic cell death. In some embodiments, the cell differentiation is identified by detecting an increase in cytokeratin expression. In some embodiments, the step of performing at least one test further comprises detecting a decrease in transcriptional elongation.

In another aspect, the invention provides a compound described herein for use in the methods of the invention.

In other aspects, the invention provides pharmaceutical compositions as described herein, for use in the methods of the invention.

In other aspects, the invention provides the use of a compound described herein in the methods of the invention.

In other aspects, the invention provides the use of a pharmaceutical composition as described herein in the methods of the invention.

Examples

In order that the invention may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are intended to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed as limiting their scope in any way.

Preparation of the Compounds

A variety of established synthetic methods can be used to synthesize the compounds of the invention. In one embodiment, the compounds of the present invention may be prepared using the reaction scheme provided in scheme 1. Intermediates S-1 and S-2 (wherein X¹And X²Each independently halogen) can be contacted under conditions suitable to effect cross-coupling or nucleophilic addition reactions to form compound S-3. Compound S-3 can be contacted with a compound of S-4 under conditions suitable to effect a cross-coupling or nucleophilic addition reaction to form a compound of formula (I). In some embodiments, the cross-coupling conditions include a transition metal catalyst, for example, palladium or nickel. In some embodiments, the cross-coupling conditions include a ligand, e.g., a phosphine ligand, e.g., Xanthphos. In some embodiments, the aromatic addition conditions comprise heating. In some embodiments, the aromatic addition conditions comprise irradiation under microwaves. In some embodiments, the method comprises The coupling steps described in scheme 1 can be performed in an alternative order.

Scheme 1.

When the linking group L²When alkyl, an alternative method of constructing a linkage to compound S-3 is employed (see scheme 2). Organometallic species S-5, wherein M^xIs a metal or nonmetal (e.g., magnesium, lithium, zinc, boron, tin, or silicon) and is used to replace the halogen group X of compound S-3¹To produce a compound of formula (I). In some embodiments, the reaction conditions may include a transition metal catalyst, e.g., palladium, nickel. In some embodiments, the reaction conditions may include a ligand, e.g., a phosphine ligand, e.g., X-phos. Alternatively, the metal species S-6 can be used to couple or replace the halogen group of S-7 (see scheme 3), where X³Is a halogen group (e.g., bromine, iodine). Other assembly sequences for generating formula (I) from various synthetic intermediates are contemplated.

Scheme 2.

Scheme 3.

The compounds of formula (II) can be prepared by using methods analogous to those used for the preparation of compounds of formula (I). Non-limiting examples are shown in examples 1-22.

General procedure for synthesizing 2_228_1, 2_232_1, 3_052_1, 3_054_1, 3_056_1 and 3_058_1

A mixture of 5-methyl-N2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) pyrimidine-2, 4-diamine (1mol equivalent), 3-bromo-N- (tert-butyl) -5-substituted benzenesulfonamide (1.2mol equivalent), tris (dibenzylideneacetone) dipalladium (0) (0.05mol equivalent), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (0.1mol equivalent), cesium carbonate (2mol equivalent) was suspended in 1, 4-dioxane (0.17M) and N, N-dimethylformamide (0.5M) and heated to reflux under a nitrogen atmosphere for 48 hours. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate and washed with brine. The extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-ethyl acetate) to give the title compound.

Example 1 preparation of N, 3-di-tert-butyl-5- ((5-methyl-2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (2-228-1)

The yield was 15%. Light brown powder.¹H NMR (400MHz, chloroform-d) ppm 1.17(s, 9H)1.32(s, 9H)1.91(m, 4H)2.14(s, 3H)2.75-2.97(m, 4H)3.00-3.15(m, 2H)4.14-4.29(m, 2H)6.39(s, 1H)6.68-6.78(m, 1H)6.90(d, J-9.00 Hz, 2H)7.38(d, J-9.00 Hz, 2H)7.48 (broad singlet, 1H)7.63(s, 1H)7.91(s, 1H)8.23(s, 1H). MS (ESI) M/z 581(M + H)⁺。

Example 2.3 preparation of bromo-N- (tert-butyl) -5- ((5-methyl-2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (2-232-1)

The yield was 14%. Light brown powder.¹H NMR (400MHz, chloroform-d) ppm 1.23-1.28(m, 9H)1.87 (broad singlet, 4H)2.13(s, 3H)2.75 (broad singlet, 4H)2.99 (broad singlet, 2H)4.18(t, J ═ 5.67Hz, 2H)4.58-4.68(m, 1H)6.44(s, 1H)6.80-6.86(m, 1H)6.95(d, J ═ 9.00Hz, 2H)7.35-7.43(m, 2H)7.67-7.80(m, 1H)7.92-7.96(m, 1H)7.98(s, 1H)8.15(s, 1H). MS (ESI) M/z 603(M + H)⁺。

Example 3 preparation of N- (tert-butyl) -3-methyl-5- ((5-methyl-2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (3_052_1)

The yield was 28%. Brown amorphous solid.¹H NMR (400MHz, DMSO-d6) ppm 1.12(s, 9H)1.68(dt, J ═ 7.14, 3.28Hz, 4H)2.11(s, 3H)2.34(s, 3H)2.75(t, J ═ 6.06Hz, 2H)3.31 (broad singlet, 4H)3.98(t, J ═ 6.06Hz, 2H)6.78(d, J ═ 9.00Hz, 2H)7.31(s, 1H)7.44-7.54(m, 3H)7.84-7.91(m, 2H)7.91-7.98(m, 1H)8.44(s, 1H)8.75(s, 1H). MS (ESI) M/z 539(M + H)⁺。

Example 4 preparation of N- (tert-butyl) -3-ethyl-5- ((5-methyl-2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (3_054_1)

The yield was 37%. Brown amorphous solid.¹H NMR (400MHz, DMSO-d6) ppm 1.10-1.14(m, 9H)1.17(t, J-7.63 Hz, 3H)1.68(dt, J-6.85, 3.23Hz, 4H)2.12(s, 3H)2.65(d, J-7.43 Hz, 2H)2.75(t, J-6.06 Hz, 2H)3.32(s, 4H)3.98(t, J-5.87 Hz, 2H)6.78(d, J-9.39 Hz, 2H)7.36(s, 1H)7.44-7.54(m, 3H)7.85(s, 1H)7.90(d, J-0.78 Hz, 1H)7.98 (broad, 1H)8.45(s, 1H)8 (s, 1H)7.90(d, J-0.78 Hz, 1H). MS (ESI) M/z 553(M + H)⁺。

Example 5 preparation of N- (tert-butyl) -3-chloro-5- ((5-methyl-2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (3_056_1)

The yield was 25%. Brown amorphous solid.¹H NMR(400MHz，DMSO-d6)ppm 1.14(s，9H)1.68(dt，J＝6.85，3.23Hz，4H)2.12(s，3H)2.75(t，J＝5.87Hz，2H)3.31(s，4H)4.00(t，J＝5.87Hz，2H)6.77-6.87(m，2H)7.43-7.52(m，3H)7.69(s，1H)7.95(s，1H)8.09(s，1H)8.25(t，J＝1.96Hz，1H)8.66(s，1H)8.87(s，1H)。MS(ESI)m/z:559(M+H)⁺。

Example 6 preparation of N- (tert-butyl) -3-cyano-5- ((5-methyl-2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (3_058_1)

The yield was 7%. Brown amorphous solid.¹H NMR (400MHz, DMSO-d6) ppm 1.14(s, 9H)1.68 (broad singlet, 4H)2.13(s, 3H)2.77(t, J ═ 5.87Hz, 2H)3.31(s, 4H)4.02(t, J ═ 5.87Hz, 2H)6.85(d, J ═ 9.00Hz, 2H)7.49(d, J ═ 9.00Hz, 2H)7.76(s, 1H)7.82(s, 1H)7.97(s, 1H)8.37(s, 1H)8.66(s, 1H)8.81(s, 1H)8.95(s, 1H). MS (ESI) M/z 550(M + H)⁺。

Example 7 preparation of N- (tert-butyl) -5- ((5-methyl-2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -3-sulfonamide (3_064_1)

A mixture of 3-bromo-N- (tert-butyl) -5- ((5-methyl-2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (1mol equivalent), phenylboronic acid (1.5mol equivalent), [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.05mol equivalent), potassium carbonate (3mol equivalent), water (10mol equivalent) was suspended in 1, 4-dioxane (0.2M) and heated to reflux under nitrogen for 17 hours. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate and washed with brine. The extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-ethyl acetate) to give the title compound (yield 5%) as a brown amorphous solid.

¹H NMR (400MHz, DMSO-d6) ppm 1.09-1.17(m, 9H)1.68 (broad singlet, 4H)2.14(s, 3H)2.64-2.72(m, 2H)3.32(s, 4H)3.77-3.85(m, 2H)6.45-6.57(m, 2H)7.31-7.68(m, 8H)7.77-7.83(m, 1H)7.90-7.96(m, 1H)8.08-8.14(m, 1H)8.19-8.26(m, 1H)8.59-8.65(m, 1H)8.75-8.81(m, 1H). MS (ESI) M/z 601(M + H)⁺。

Example 8 preparation of 3-bromo-N- (tert-butyl) -5- ((5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (3_106_1)

A mixture of 5-methyl-N2- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidine-2, 4-diamine (1mol equivalent), 3-bromo-N- (tert-butyl) -5-substituted benzenesulfonamide (1.2mol equivalent), tris (dibenzylideneacetone) dipalladium (0) (0.05mol equivalent), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (0.1mol equivalent), cesium carbonate (2mol equivalent) was suspended in 1, 4-dioxane (0.17M) and N, N-dimethylformamide (0.5M) and heated to reflux under a nitrogen atmosphere for 48 hours. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate and washed with brine. The extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-ethyl acetate) to give the title compound (yield 41%) as a grey amorphous solid.

¹H NMR(400MHz，DMSO-d6)ppm 1.14(s，9H)2.11(s，3H)2.21(s，3H)2.40-2.47(m，4H)2.97-3.08(m，4H)6.85(d，J＝9.00Hz，2H)7.45(d，J＝9.00Hz，2H)7.59(s，1H)7.70(s，1H)7.93(s，1H)8.11-8.18(m，1H)8.32(s，1H)8.62(s，1H)8.79(s，1H)。MS(ESI)m/z:588(M+H)⁺。

General procedure for the Synthesis of 3_114_1, 3_188_1, 3_190_1, 3_232_1, 3_238_1, 3_276_1, 4_002_1, 4_006_1, 4_008_1, and 4_020_1

A mixture of 3-bromo-N- (tert-butyl) -5- ((5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (1mol equivalent), substituted phenylboronic acid (1.5mol equivalent), [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.05mol equivalent), potassium carbonate (3mol equivalent), water (10mol equivalent) was suspended in 1, 4-dioxane (0.2M) and heated to reflux under nitrogen for 17 hours. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate and washed with brine. The extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-ethyl acetate) to give the title compound.

Example 9 preparation of N- (tert-butyl) -5- ((5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -3-sulfonamide (3_114_1)

The yield was 41%. A pale yellow amorphous solid.¹H NMR (400MHz, DMSO-d6) ppm 1.10-1.19(m, 9H)2.14(s, 3H)2.17-2.23(m, 3H)2.35-2.43(m, 4H)2.80-2.88(m, 4H)6.49(d, J ═ 8.61Hz, 2H)7.34-7.44(m, 3H)7.44-7.51(m, 2H)7.61(s, 1H)7.66(d, J ═ 7.04Hz, 2H)7.80(d, J ═ 1.57Hz, 1H)7.92(s, 1H)8.10 (broad singlet, 1H)8.21-8.28(m, 1H)8.60(s, 1H)8.71(s, 1H). MS (ESI) M/z 586(M + H) ⁺。

Example 10 preparation of N- (tert-butyl) -3 '-cyano-5- ((5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -3-sulfonamide (3-188-1)

The yield was 50%. Brown amorphous solid.¹H NMR (400MHz, DMSO-d6) ppm 1.15 (broad singlet, 9H)2.14 (broad singlet, 3H)2.28 (broad singlet, 3H)2.53-2.63(m, 4H)2.86 (broad singlet, 4H)6.46(d, J ═ 7.04Hz, 2H)6.86(d, J ═ 8.22Hz, 1H)7.37(d, J ═ 8.22Hz, 2H)7.46(d, J ═ 8.61Hz, 1H)7.58 (broad singlet, 1H)7.67(dd, J ═ 14.87, 7.04Hz, 1H)7.80-8.03(m, 3H)8.10 (broad singlet, 1H)8.37 (broad, 1H)8.67 (broad, 1H)8.78 (broad singlet). MS (ESI) M/z 611(M + H)⁺。

Example 11 preparation of N- (tert-butyl) -4 '-cyano-5- ((5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -3-sulfonamide (3_190_1)

The yield was 48%. Light yellowAn amorphous solid.¹H NMR (400MHz, DMSO-d6) ppm 1.13-1.17(m, 9H)2.14(s, 3H)2.20(s, 3H)2.41(d, J ═ 4.70Hz, 4H)2.83 (broad singlet, 4H)6.42-6.51(m, 2H)7.31-7.39(m, 2H)7.61-7.63(m, 1H)7.79-7.81(m, 1H)7.82(s, 1H)7.84-7.87(m, 1H)7.90(s, 1H)7.93(d, J ═ 3.91Hz, 2H)8.11-8.15(m, 1H)8.40-8.43(m, 1H)8.64-8.69(m, 1H)8.73-8.77(m, 1H). MS (ESI) M/z 611(M + H) ⁺。

Example 12 preparation of N- (tert-butyl) -2 '-chloro-5- ((5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -3-sulfonamide (3_232_1)

The yield was 8%. Brown amorphous solid.¹H NMR(400MHz，DMSO-d6)ppm 1.15(s，9H)2.13(s，3H)2.21(s，3H)2.38-2.47(m，4H)2.87-2.95(m，4H)6.52-6.61(m，2H)7.31-7.52(m，5H)7.53-7.62(m，2H)7.62-7.66(m，1H)7.88-7.93(m，1H)8.05-8.09(m，1H)8.15-8.21(m，1H)8.55-8.62(m，1H)8.65-8.70(m，1H)。MS(ESI)m/z:620(M+H)⁺。

Example 13 preparation of N- (tert-butyl) -2 '-methyl-5- ((5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -3-sulfonamide (3-238-1)

The yield was 15%. Brown amorphous solid.¹H NMR(400MHz，DMSO-d6)ppm 1.10-1.17(m，9H)2.13(s，3H)2.25(s，3H)2.27(s，4H)2.88-2.99(m，4H)6.59(d，J＝8.61Hz，2H)7.26(dd，J＝4.11，1.76Hz，2H)7.30-7.35(m，2H)7.39(d，J＝9.00Hz，2H)7.45(t，J＝1.37Hz，1H)7.61(s，1H)7.91(s，1H)7.94(t，J＝1.76Hz，1H)8.18(s，1H)8.54(s，1H)8.66(s，1H)。MS(ESI)m/z:600(M+H)⁺。

Example 14 preparation of N- (tert-butyl) -2 '-cyano-5- ((5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -3-sulfonamide (3_276_1)

The yield was 17%. Yellow amorphous solid.¹H NMR (400MHz, DMSO-d6) ppm 1.17(s, 9H)2.14(s, 3H)2.21(s, 3H)2.43(d, J ═ 4.70Hz, 4H)2.91 (broad singlet, 4H)6.50-6.61(m, 2H)7.31-7.41(m, 2H)7.67(d, J ═ 3.52Hz, 4H)7.75-7.81(m, 1H)7.93(d, J ═ 0.78Hz, 1H)7.96-8.02(m, 1H)8.18-8.23(m, 1H)8.25-8.31(m, 1H)8.68(s, 2H). MS (ESI) M/z 611(M + H)⁺。

Example 15 preparation of N- (tert-butyl) -5- ((5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) -2'- (trifluoromethyl) - [1,1' -biphenyl ] -3-sulfonamide (4_002_1)

The yield was 54%. Brown amorphous solid.¹H NMR (400MHz, chloroform-d) ppm 1.12(s, 9H)2.01(s, 3H)2.23-2.34(m, 3H)2.46-2.57(m, 4H)3.02-3.10(m, 4H)6.44(s, 1H)6.74(d, J ═ 9.00Hz, 2H)6.86(s, 1H)7.11-7.20(m, 2H)7.28(d, J ═ 8.61Hz, 2H)7.37-7.50(m, 3H)7.60(s, 1H)7.67(d, J ═ 7.83Hz, 1H)7.80(s, 1H)8.34(s, 1H). MS (ESI) M/z 654(M + H)⁺。

Example 16 preparation of N- (tert-butyl) -2 '-fluoro-5- ((5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -3-sulfonamide (4_006_1)

The yield was 81%. Brown amorphous solid.¹H NMR (400MHz, chloroform-d) ppm 1.23(s, 9H)2.09-2.13(m, 3H)2.33-2.40(m, 3H)2.54-2.64(m, 4H)3.06-3.15(m, 4H)6.53(s, 1H)6.77(d, J ═ 9.00Hz, 2H)6.97(s, 1H)7.12-7.22(m, 3H)7.32-7.41(m, 4H)7.76(d, J ═ 1.17Hz, 1H)7.86-7.92(m, 2H)8.33(t, J ═ 1.76Hz, 1H). MS (ESI) M/z 604(M + H)⁺。

Example 17 preparation of N- (tert-butyl) -4 '-methoxy-5- ((5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -3-sulfonamide (4_008_1)

The yield was 73%. Brown amorphous solid.¹H NMR (400MHz, chloroform-d) ppm 1.22(s, 9H)2.11(s, 3H)2.36(s, 3H)2.52-2.64(m, 4H)3.03-3.12(m, 4H)3.83(s, 3H)6.52(s, 1H)6.73(d, J ═ 9.00Hz, 2H)6.77(s, 1H)6.93(d, J ═ 8.61Hz, 2H)7.00(s, 1H)7.36(d, J ═ 9.00Hz, 2H)7.46(d, J ═ 8.61Hz, 2H)7.77(s, 1H)7.88(s, 1H)7.90(s, 1H)8.19(s, 1H). MS (ESI) M/z 616(M + H) ⁺。

Example 18 preparation of N- (tert-butyl) -2 '-methoxy-5- ((5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -3-sulfonamide (4_020_1)

The yield was 34%. Brown amorphous solid.¹H NMR (400MHz, chloroform-d) ppm 1.21-1.26(m, 9H)2.11(s, 3H)2.33-2.41(m, 3H)2.54-2.67(m, 4H)3.07-3.16(m, 4H)3.78(s, 3H)6.49(s, 1H)6.77(d, J ═ 9.00Hz, 2H)6.94-7.04(m, 3H)7.28-7.34(m, 2H)7.34-7.40(m, 3H)7.76-7.81(m, 1H)7.88(s, 2H)8.26(t, J ═ 1.76Hz, 1H). MS (ESI) M/z 616(M + H)⁺。

General procedure for synthesizing 3_264_1 and 4_110_1

Step 1

A mixture of 4-amino-2-chloropyrimidine-5-carbonitrile (1mol equivalent) and 4- (4-methylpiperazino) aniline (1.1mol equivalent) was suspended in acetic acid (0.46M) and heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate and washed with brine. The extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ether to give 4-amino-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidine-5-carbonitrile (60% yield) as a brown solid.

Step 2

A mixture of 4-amino-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidine-5-carbonitrile (1mol equivalent), 3-bromo-N- (tert-butyl) -5-substituted benzenesulfonamide (1.2mol equivalent), tris (dibenzylideneacetone) dipalladium (0) (0.05mol equivalent), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (0.1mol equivalent), cesium carbonate (2mol equivalent) was suspended in 1, 4-dioxane (0.17M) and N, N-dimethylformamide (0.5M) and heated to reflux under a nitrogen atmosphere for 48 hours. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate and washed with brine. The extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-ethyl acetate) to give the title compound.

Example 19 preparation of N- (tert-butyl) -3- ((5-cyano-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (3_264_1)

The yield was 19%. A pale yellow amorphous solid.¹H NMR(400MHz，DMSO-d6)ppm 1.10(s，9H)2.21(s，3H)2.40-2.47(m，4H)3.01-3.11(m，4H)6.85(d，J＝9.00Hz，2H)7.21-7.43(m，3H)7.47-7.65(m，3H)8.29(s，1H)9.32-9.52(m，2H)。MS(ESI)m/z:521(M+H)⁺。

Example 20.3 preparation of 3-bromo-N- (tert-butyl) -5- ((5-cyano-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (4_110_1)

The yield was 69%. A pale yellow amorphous solid.¹H NMR(400MHz，DMSO-d6)ppm 1.12(s，9H)2.21(s，3H)2.36-2.47(m，4H)2.96-3.12(m，4H)6.75-6.94(m，2H)7.25-7.44(m，2H)7.56-7.77(m，2H)7.80-7.96(m，1H)8.04-8.22(m，1H)8.44-8.55(m，1H)9.64-9.97(m，2H)。MS(ESI)m/z:599(M+H)⁺。

General procedure for synthesizing 4_126_1 and 4_128_1

A mixture of 3-bromo-N- (tert-butyl) -5- ((5-cyano-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (1mol equivalent), substituted phenylboronic acid (1.5mol equivalent), [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.05mol equivalent), potassium carbonate (3mol equivalent), water (10mol equivalent) was suspended in 1, 4-dioxane (0.2M) and heated to reflux under nitrogen for 48 hours. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate and washed with brine. The extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-ethyl acetate) to give the title compound.

Example 21 preparation of N- (tert-butyl) -5- ((5-cyano-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -3-sulfonamide (4_126_1)

The yield was 50%. Brown amorphous solid.¹H NMR (400MHz, DMSO-d6) ppm 1.13(s, 9H)2.19(s, 3H)2.37 (broad singlet, 4H)2.75-2.87(m, 4H)6.25-6.42(m, 2H)7.18-7.36(m, 2H)7.38-7.45(m, 1H)7.48(s, 2H)7.53-7.62(m, 1H)7.64-7.73(m, 2H)7.78-7.88(m, 1H)7.90-8.00(m, 1H)8.18(s, 1H)8.50(s, 1H)9.68-9.90(m, 2H). MS (ESI) M/z 597(M + H)⁺。

Example 22 preparation of N- (tert-butyl) -2 '-cyano-5- ((5-cyano-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -3-sulfonamide (4-128-1)

The yield was 23%. Brown amorphous solid.¹H NMR (400MHz, DMSO-d6) ppm 1.07-1.31(m, 9H)2.20(s, 3H)2.41 (broad singlet, 4H)2.90 (broad singlet, 4H)6.46 (broad singlet, 2H)7.16-7.38(m, 2H)7.39-7.56(m, 2H)7.59-7.91(m, 3H)7.92-8.08(m, 2H)8.13 (broad singlet, 1H)8.52(s, 1H)9.68-10.04(m, 2H). MS (ESI) M/z 622(M + H)⁺。

Example 23 Biochemical and cellular testing of Compounds

Acetyl-histone binding assay

The tests were carried out according to the manufacturer's protocol (Perkinelmer, USA) with minor modifications. All reagents were diluted in 50mM HEPES, 150mM NaCl, 0.1% w/v BSA and 0.01% w/v Tween 20, pH 7.5 and allowed to equilibrate to room temperature before addition to the plate. After the Alpha beads were added to the mother liquor, all subsequent steps were performed under low light conditions. mu.L of a 2 × component solution with a final concentration of 80nM BRD4.1, 25. mu.g/ml Ni-coated acceptor beads and 80nM biotinylated H4-tetraacetyl was added to 384-well plates (AlphaPlate-384, Perkinelmer, USA). The biotinylated peptide of BRD4.1 was synthesized internally on a CEM library 9008005 microwave peptide synthesizer (H4-tetraacetyl, biotin-PEG 2-SGRGKacGGKacLGKacGGACRHRK-COOH). Addition to each well was performed with a multichannel pipettor (for optimization experiments) or Biotek EL406 liquid handler. After 1 minute of sedimentation at 1000-rpm, 100nL of the inventive solution added to the mother plate was transferred by a needle using Janus works (Perkinelmer, USA). Streptavidin-coated donor beads (25. mu.g/ml final) were added to the previous 2X, 10. mu.L volume of solution. After this addition, the plate was sealed with foil to block exposure and prevent evaporation. The plate was spun down again at 1000rpm for 1 minute. Next, the plate was incubated with a plate reader at room temperature for 1.5 hours (for temperature equilibration) and the test was read. Measurements were made on an Envision 2104(PerkinElmer, USA) using the manufacturer's protocol.

Cell assay

Compounds of the invention can be evaluated for cellular activity in a BRD 4-dependent cell line to generate cellular IC₅₀The value is obtained.

Cells (e.g., BRD 4-dependent cells) were counted and adjusted to 60,000 cells/mL. Using BiotekEL406, 50 μ Ι _ of cells in culture medium were distributed on Thermo 384-well white plates. Compounds of the invention in DMSO were distributed to the plates immediately after inoculation. For large plate sets, cells were returned to the 37 ℃ incubator when not in use. 100nL of the compound was added to the plate using 384-well needle transfer on Janus works. The stocks were aligned in DMSO stocks in 384-well Greiner compound plates at 10-point four-fold dilution dose responses. After addition of the compound, the plates were incubated in an incubator at 37 ℃ for three days. Cell viability was read using ATPlite from Perkin Elmer. The plates were removed from the incubator and returned to room temperature prior to use. The lyophilized powder was resuspended in lysis buffer and diluted 1:2 with deionized water. 25 μ L of this solution was added to each well using a Biotek liquid handler. The plates were sealed with aluminum sealing tape and then vortexed and spun at 1000g for 1 minute. Plates were incubated at room temperature for 15 minutes and then the signal was read on an Envision Plate reader.

Isothermal titration calorimetry

ITC was obtained using a commercial GE^TM(Northampton, MA) by ITC200 microcalorimeter. All experiments were performed at 25 ℃ with stirring at 1000rpm in ITC buffer (50mM HEPES pH 7.4 at 25 ℃ in 150mM NaCl). The microsyringe was filled with a protein sample solution (225 μ M in ITC buffer). The compound solution (22.5 μ M in ITC buffer) was titrated into the protein solution by syringe. All titrations were performed using: an initial injection volume of 0.2. mu.l was followed by 19 equal injections of 2. mu.l with a duration of 5 seconds (per injection) and an injection interval of 90 seconds. The heat of titration was determined by a separate titration (protein into buffer) and subtracted from the experimental data. The collected data are transmitted to a MicroCal connected to the instrument^TMIn Origin software, the binding enthalpy (. DELTA.H) and binding constant (Ka) were obtained. The collected data are transmitted to a MicroCal connected to the instrument^TMOrigin software to derive binding enthalpy (Δ H) and binding constant (KB) as previously described by Wiseman and coworkers. Thermodynamic parameters were calculated (Δ G ═ Δ H-T Δ S ═ RTlnKB, where Δ G, Δ H, and Δ S are changes in free energy, enthalpy, and binding entropy, respectively). A single binding site model was used.

Cell cycle analysis by flow cytometry

797, MOLM-13 and HL60 cells were placed in T-75 flasks and grown in DMEM (797) or RPMI (MOLM-13 and HL60) containing 10% fetal bovine serum and 1% penicillin/streptomycin. Cells were treated with 1uM (797) or 500nM (MOLM-13 and HL60) compounds or with equal volume of DMSO for 24 hours. 2X 106 cells at 4 ℃ 500x g centrifugal several minutes and PBS washing. The pellet was resuspended in 1mL cold PBS and added dropwise to 9mL 70% ethanol in a 15mL polypropylene centrifuge tube with gentle vortexing. The fixed cells were then frozen at-20 ℃ overnight. The next day, cells were centrifuged at 500x g for 10 minutes at 4 ℃ and washed with 3mL of cold PBS. Cells were resuspended in 500. mu.L of propidium iodide staining solution (0.2mg/mL RNAseA, 0.2mg/mL propidium iodide, 01.% Triton-X in PBS) and incubated at 37 ℃ for 20 min. The samples were then transferred to ice and analyzed on a BD FACS Canto II. Histograms were obtained and cell cycle analysis was performed using ModFit flow cytometry analysis software.

Results

Table 1 shows the percent inhibition of BRD4.1 in vitro at a concentration of 2.5 μ M compound, the compound IC50 value at BRD4.1(M), the EC50 value (M) of the compound in a BRD4 dependent cell line (798, HL60), and the Kd value of the compound at BRD4.1 as measured by ITC. "uM" refers to μ M. "% INHIB" refers to percent inhibition.

Table 1.

Other exemplary results are shown in FIGS. 1-10.

Substituents for guards (e.g. R)²) Can improve the selectivity

IC50 values for compound TG101209 and selected compounds herein were determined against BRD4, cells (797 cells), JAK2 and FLT 3. The IC50 value of BRD4 was determined by ALPHASCREEN. IC50 values for JAK2 and FLT3 were determined by Z' -LYTE ([ ATP ] ═ Km _ app). Exemplary results (IC50 values) are shown in fig. 5. The results show that JAK2 (guard: Met929) is more susceptible to bulky substituents than FLT3 (guard: Phe691) and the effect on BRD4 inhibition is limited.

Greater R²(R⁶) May lead to an increased selectivity

IC50 values for compound TG101209, compound TG101348 and selected compounds herein were determined for BRD4, cells (797 cells) and JAK 2. IC50 values for BRD4 were determined with ALPHASCREEN. IC50 for JAK2 was determined by Z' -LYTE ([ ATP ] ═ Km _ app). Exemplary results (IC50 values) are shown in fig. 7. The results show that a more bulky substituent can lead to improved selectivity.

Modification of R²(R⁶) To exploit conformational preference to improve selectivity

IC50 values for compound TG101209 and selective compounds described herein were determined for BRD4, cells (797 cells), JAK2 and FLT 3. IC50 values for BRD4 were determined by ALPHASCREEN. IC50 values for JAK2 and FLT3 were determined by Z' -LYTE ([ ATP ] ═ Km _ app). Exemplary results (IC50 values) are shown in fig. 9.

Modification of R²(R⁶) And R³(R²)

IC50 values for compound TG101209 and selective compounds described herein were determined for BRD4, cells (797 cells), JAK2 and FLT 3. IC50 values for BRD4 were determined with ALPHASCREEN. IC50 values for JAK2 and FLT3 were determined by Z' -LYTE ([ ATP ] ═ Km _ app). Exemplary results (IC50 values) are shown in fig. 10.

Other embodiments

In the claims, for example, "a," "an," and "the" may mean one or more than one unless the context clearly dictates otherwise. Claims or descriptions that include an "or" between one or more members of a group are deemed to be satisfactory if one, more than one, or all of the members of the group are present, employed, or otherwise relevant to a given product or process, unless the context clearly indicates otherwise. The invention includes embodiments in which only one member of the group is present, employed, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one or all members of the group are present, employed or otherwise relevant in connection with a given product or process.

Furthermore, the present invention includes all variations, combinations, and permutations in which one or more limitations, elements, phrases, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim dependent on another claim may be modified to include one or more of the definitions found in any other claim dependent on the same base claim. When elements are presented as a list, for example, in the form of a markush group, each subset of the elements is also disclosed and any element can be removed from the group. It will be understood that in general, when the invention or aspects of the invention are specified to include a particular element and/or feature, some embodiments of the invention or aspects of the invention consist of, or consist essentially of, such element and/or feature. For the sake of brevity, those embodiments are not specifically mentioned herein with words. It should also be noted that the terms "comprising" and "comprises" are intended to be open-ended and allow for the inclusion of other elements or steps. When ranges are given, endpoints are included. Furthermore, unless otherwise indicated or clearly indicated by context and understanding of one of ordinary skill in the art, values expressed as ranges can take any specific value or subrange within the ranges set forth in the various embodiments of the invention, up to one tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

This application refers to various published patents, published patent applications, periodicals, and other publications, which are incorporated herein by reference in their entirety. In the event of conflict between any of the references cited and the present application, the present specification shall control. Furthermore, any particular embodiment of the invention falling within the prior art may be explicitly excluded from any one or more claims. Since such embodiments are considered to be known to those skilled in the art, they may be excluded even if the exclusion is not explicitly mentioned herein. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the presence of prior art.

Those skilled in the art will understand, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the specific embodiments described herein is not intended to be limited by the foregoing description, but is instead set forth in the following claims. Those skilled in the art will appreciate that various changes and modifications may be made to the disclosure without departing from the spirit or scope of the disclosure, as defined by the claims.

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein:

R¹is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitutedA substituted heteroaryl or a nitrogen protecting group attached to a nitrogen atom;

R²is hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR^D1、–N(R^D1)₂、–SR^D1、–CN、–SCN、–C(＝NR^D1)R^D1、–C(＝NR^D1)OR^D1、–C(＝NR^D1)N(R^D1)₂、–C(＝O)R^D1、–C(＝O)OR^D1、–C(＝O)N(R^D1)₂、–NO₂、–NR^D1C(＝O)R^D1、–NR^D1C(＝O)OR^D1、–NR^D1C(＝O)N(R^D1)₂、–OC(＝O)R^D1、–OC(＝O)OR^D1or-OC (═ O) N (R)^D1)₂Wherein R is^D1Independently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^D1The groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring;

R³And R⁴Each independently is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group; or R³And R⁴The groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring;

R⁵independently each occurrence is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitutedSubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

q is 0, 1, 2, 3 or 4;

a is ═ N-or ═ C (R)²)–；

In each case R^B1Independently hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, -OR ^B1a、–N(R^B1a)₂、–SR^B1a、–CN、–SCN、–C(＝NR^B1a)R^B1a、–C(＝NR^B1a)OR^B1a、–C(＝NR^B1a)N(R^B1a)₂、–C(＝O)R^B1a、–C(＝O)OR^B1a、–C(＝O)N(R^B1a)₂、–NO₂、–NR^B1aC(＝O)R^B1a、–NR^B1aC(＝O)OR^B1a、–NR^B1aC(＝O)N(R^B1a)₂、–OC(＝O)R^B1a、–OC(＝O)OR^B1aor-OC (═ O) N (R)^B1a)₂；

p is 0 or an integer between 1 and 4, inclusive;

n is 0, 1, 2, 3, 4, 5 or 6;

L¹、L²and L⁴Each independently is a bond,Or

L³Is composed ofOr

R^c1independently each occurrence is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted Substituted aryl, substituted OR unsubstituted heteroaryl, -OR^c1a、–N(R^c1a)₂、–SR^c1a、–CN、–C(＝O)R^c1a、–C(＝O)OR^c1a、–C(＝O)N(R^c1a)₂、–NR^c1aC(＝O)R^c1a、–NR^c1aC(＝O)OR^c1a、–NR^c1aC(＝O)N(R^c1a)₂、–OC(＝O)R^c1aor-OC (═ O) N (R)^c1a)₂Wherein R is^c1aIndependently at each occurrence is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R^c1aThe groups together form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

2. The compound of claim 1, wherein the compound is a compound of formula (I):

wherein:

n is 1, 2, 3, 4, 5 or 6; and

3. The compound of claim 1 or 2, wherein the compound is not of the formula:

Or a pharmaceutically acceptable salt thereof.

4. The compound 3 of any one of claims 1-3, wherein the compound is not a compound of the formula:

or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-4, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-4, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-4, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1-4, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof, wherein R³And R⁴The groups together form a substituted or unsubstituted heterocyclic ring.

10. The compound of any one of claims 1-4, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1-4, wherein the compound is of the formula:

Or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 1-4, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

13. The compound of any one of claims 1-4, wherein the compound is of the formula:

14. The compound of any one of claims 1-13, wherein R¹Is substituted or unsubstituted C_1-6An alkyl group.

15. The compound of claim 14, wherein R¹Is C_1-6A haloalkyl group.

16. The compound of claim 14, wherein R¹Is a tert-butyl group.

17. The compound of claim 14, wherein R¹Is ethyl.

18. The compound of claim 14, wherein R¹Is methyl.

19. The compound of any one of claims 1-18, wherein R²Is hydrogen.

20. The compound of any one of claims 1-18, wherein R²Is substituted or unsubstituted C_1-6An alkyl group.

21. The compound of claim 20, wherein R²Is substituted or unsubstituted C_2-6An alkyl group.

22. The compound of claim 20, wherein R²Is methyl.

23. The compound of claim 20, wherein R²Is ethyl.

24. The compound of claim 20, wherein R ²Is substituted or unsubstituted C_1-6A haloalkyl group.

25. The compound of any one of claims 1-18, wherein R²Is a substituted or unsubstituted 4-6 membered heterocyclic group.

26. The compound of any one of claims 1-18, wherein R²Is a substituted or unsubstituted 5-6 membered heteroaryl.

27. The compound of any one of claims 1-18, wherein R²is-OR^D1。

28. The compound of any one of claims 1-18, wherein R²is-N (R)^D1)₂。

29. The compound of claim 28, wherein R²is-NH₂。

30. The compound of any one of claims 1-18, wherein R²is-CN.

31. The compound of any one of claims 1-18, wherein R²Is a substituted or unsubstituted phenyl group.

32. The compound of claim 31, wherein R²Is Ph.

33. The compound of any one of claims 1-9 and 14-32, wherein at least one R⁶Is halogen.

34. The compound of claim 33, wherein at least one R⁶Is Cl or Br.

35. The compound of any one of claims 1-9 and 14-34, wherein at least one R⁶Is substituted or unsubstituted C_1-6An alkyl group.

36. The compound of claim 35, wherein at least one R⁶Me, Et or t-Bu.

37. The compound of any one of claims 1-9 and 14-36, wherein at least one R⁶Is a substituted or unsubstituted phenyl group.

38. The compound of claim 37, wherein at least one R⁶Is Ph, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-chlorophenyl, 2-methylphenyl, 2- (trifluoromethyl) -phenyl, 2-fluorophenyl, 2- (methoxy) -phenyl or 4- (methoxy) -phenyl.

39. The compound of any one of claims 1-9 and 14-38, wherein at least one R⁶is-CN.

40. The compound of any one of claims 1, 3-4, and 14-32, wherein q is 0.

41. The compound of any one of claims 1, 3-4, and 14-39, wherein q is 1.

42. The compound of any one of claims 1-6, 10, and 14-41, wherein L¹Is composed of

43. The compound of any one of claims 1-6, 10, and 14-41, wherein L¹Is composed of

44. The compound of claim 43, wherein L¹Is composed of

45. The compound of any one of claims 1-6, 10, and 14-44, wherein L²Is composed of

46. The compound of claim 45, wherein L²Is composed of

47. The compound of any one of claims 1-6, 10, and 14-44, wherein L²Is composed of

48. The compound of claim 45, wherein L²Is composed of

49. The compound of any one of claims 1-6, 10, and 14-41, wherein L¹Is composed ofAnd L is²Is composed of

50. The compound of any one of claims 1-6, 10, and 14-41, wherein L²Is composed ofAnd L is¹Is composed of

51. The compound of any one of claims 1-6, 10, 14-41, and 45-48, wherein L¹Is composed ofAnd R is^a1Is neither hydrogen nor C_1-6An alkyl group.

52. The compound of any one of claims 1-6, 10, and 14-44A compound of formula (I), wherein L²Is composed ofAnd R is^a1Is not hydrogen.

53. The compound of any one of claims 1-6, 10, and 14-41, wherein L¹And L²Are all made ofAnd at least one R^a1Not being hydrogen or substituted or unsubstituted C_1-6An alkyl group.

54. The compound of any one of claims 1-6, 10, and 14-41, wherein each L¹And L²is-NH-.

55. The compound of any one of claims 1-5 and 14-54, wherein L³Is composed ofOr

56. The compound of claim 55, wherein-L³–R¹Is represented by the formula:

57. the compound of any one of claims 1-8, 10-12, and 14-56, wherein L⁴Is composed ofAnd n is 2, 3 or 4.

58. The compound of any one of claims 1-8, 10-12, and 14-56, wherein L⁴Is a bond; and n is 0.

59. The compound of any one of claims 1-58, wherein ring B isOr

60. The compound of any one of claims 1-5 and 14-59, wherein a is ═ N-.

61. The compound of any one of claims 1-5 and 14-59, wherein a is ═ c (h) -.

62. Claim 1A compound of any one of-8, 10-12, 14-57 and 59-61, wherein n is 2, and R is ⁵Independently in each occurrence hydrogen, halogen or-CF₃。

63. The compound of any one of claims 1-62, wherein R³And R⁴Together form a substituted or unsubstituted 4-to 7-membered monocyclic heterocycle wherein 1, 2 or 3 atoms in the heterocyclic ring system are independently nitrogen, oxygen or sulfur.

64. The compound of claim 63, wherein R³And R⁴Together form a substituted or unsubstituted piperazinyl group.

65. The compound of claim 63, wherein R³And R⁴Together form a substituted or unsubstituted pyrrolidine.

66. The compound of any one of claims 1-13 and 33-65, wherein R¹Is methyl, and R²Is substituted or unsubstituted C_2-6Alkyl or substituted or unsubstituted amino.

67. The compound of any one of claims 1-66, wherein R^B1Is not-OR^B1a。

68. The compound of claim 1, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

69. The compound of claim 1, wherein the compound is a compound shown in figures 5, 7, 9, and 10, or a pharmaceutically acceptable salt thereof; and the compound is not of the formula:

or a pharmaceutically acceptable salt thereof.

70. A pharmaceutical composition comprising a compound of any one of claims 1-69, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

71. A kit comprising a container, a pharmaceutical composition of a compound of any one of claims 1-69, and instructions for use in a patient.

72. The kit of claim 71, further comprising an additional drug or agent.

73. A method of treating a disease associated with aberrant activity of a bromodomain in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-69 or a pharmaceutical composition of claim 70.

74. A method of preventing or reducing the risk of developing a disease associated with a bromodomain-containing protein in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-69 or a pharmaceutical composition of claim 70.

75. A method of preventing or reducing the risk of a disease associated with aberrant activity of a bromodomain in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-69 or a pharmaceutical composition of claim 70.

76. The method of claim 73 or 75, wherein the aberrant activity of a bromodomain is an increased activity of said bromodomain.

77. A method of contraception in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of any one of claims 1-69 or a pharmaceutical composition of claim 70.

78. A method of inhibiting bromodomain-containing protein activity in a subject or a cell, the method comprising administering to the subject or contacting the cell with an effective amount of a compound of any one of claims 1-69 or a pharmaceutical composition of claim 70.

79. A method of inhibiting the activity of a bromodomain in a subject or a cell, the method comprising administering to the subject or contacting the cell with an effective amount of a compound of any one of claims 1-69 or a pharmaceutical composition of claim 70.

80. The method of claim 79, wherein said compound, or a pharmaceutically acceptable salt thereof, selectively inhibits the activity of said bromodomain compared to the activity of a kinase.

81. A method of inhibiting binding of a bromodomain-containing protein to an acetyl-lysine residue of a histone in a subject or cell, the method comprising administering to the subject an effective amount of the compound of any one of claims 1-69 or the pharmaceutical composition of claim 70 or contacting the cell with an effective amount of the compound of any one of claims 1-69 or the pharmaceutical composition of claim 70.

82. A method of modulating transcription of a gene regulated by a bromodomain-containing protein in a subject or cell, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-69 or a pharmaceutical composition of claim 70 or contacting the cell with an effective amount of a compound of any one of claims 1-69 or a pharmaceutical composition of claim 70.

83. A method of inhibiting transcription of a gene regulated by a bromodomain-containing protein in a subject or a cell, the method comprising administering to the subject an effective amount of the compound of any one of claims 1-69 or the pharmaceutical composition of claim 70 or contacting the cell with an effective amount of the compound of any one of claims 1-69 or the pharmaceutical composition of claim 70.

84. The method of any one of claims 74, 78, and 81-83, wherein the bromodomain-containing protein is a Bromo and Extra Terminal (BET) protein.

85. The method of any one of claims 74, 78, and 81-83, wherein the bromodomain-containing protein is bromodomain-containing protein 2(BRD2), bromodomain-containing protein 3(BRD3), or bromodomain-containing protein 4(BRD 4).

86. The method of any one of claims 74, 78, and 81-83, wherein the bromodomain-containing protein is TBP (TATA box binding protein) -associated factor protein (TAF).

87. The method of any one of claims 74, 78, and 81-83, wherein the bromodomain-containing protein is TAF1 or TAF 1L.

88. The method of any one of claims 74, 78 and 81-83, wherein said bromodomain-containing protein is a CREB-binding protein (CBP).

89. The method of any one of claims 74, 78, and 81-83, wherein the bromodomain-containing protein is E1A binding protein p300(EP 300).

90. The method of any one of claims 73-76 and 84-89, wherein the disease is an autoimmune disease, a cardiovascular disease, a viral infection, a fibrotic disease, or a metabolic disease.

91. The method of any one of claims 73-76 and 84-89, wherein the disease is rheumatoid arthritis, sepsis, atherogenesis, atherosclerosis, Human Immunodeficiency Virus (HIV) infection, acquired immunodeficiency syndrome (AIDS), Human Papilloma Virus (HPV) infection, Hepatitis C Virus (HCV) infection, Herpes Simplex Virus (HSV) infection, ebola virus infection, Severe Acute Respiratory Syndrome (SARS), influenza, radiation poisoning, scleroderma, idiopathic pulmonary fibrosis, graft-versus-host disease (GVHD), diabetes, or obesity.

92. The method of claim 91, wherein the disease is atherogenesis.

93. The method of claim 91, wherein the disease is an ebola virus infection.

94. The method of claim 91, wherein the disease is Severe Acute Respiratory Syndrome (SARS).

95. The method of claim 91, wherein the disease is radiation poisoning.

96. The method of claim 91, wherein the disease is idiopathic pulmonary fibrosis.

97. The method of claim 91, wherein the disease is type II diabetes or gestational diabetes.

98. The method of claim 91, wherein the disease is obesity.

99. The method of any one of claims 73-98, wherein the subject is a human.

100. The method of claim 99, wherein the subject is a male.