HK1244282B

HK1244282B - Substituted pyrrolopyrdines as inhibitors of bromodomain

Info

Publication number: HK1244282B
Application number: HK18103833.5A
Authority: HK
Inventors: Brian K. Albrecht; Steven F. BELLON; Daniel J. Burdick; Alexandre Cote; Terry CRAWFORD; Les A. DAKIN; Michael Charles Hewitt; Vickie Hsiao-Wei Tsui; Yves Leblanc; Steven R. Magnuson; Christopher G. Nasveschuk; F. Anthony Romero; Yong Tang; Alexander M. Taylor; Shumei Wang
Original assignee: 基因泰克公司; 星座制药股份有限公司
Priority date: 2014-11-10
Filing date: 2015-11-10
Publication date: 2023-08-25

Description

Substituted pyrrolopyridines as bromodomain inhibitors

Cross Reference to Related Applications

This patent application claims the benefit of priority from U.S. application 62/077,703 filed on month 11 and 10 of 2014, which is incorporated herein by reference.

Technical Field

The present invention relates to compounds useful as bromodomain (bromodomain) inhibitors.

Background

Chromatin is a complex combination of DNA and proteins that make up a chromosome. It has been found in the nucleus of eukaryotic cells and is divided into heterochromatin (aggregates) and euchromatin (stretches) forms. The major components of chromatin are DNA and proteins. Histones are the major protein component of chromatin, acting as a spool around which DNA is wound. Chromatin functions to pack DNA into a smaller volume to fit cells, strengthen DNA to allow mitosis and meiosis, and act as a mechanism to control expression and DNA replication. Chromatin structure is controlled by a series of post-translational modifications to histones, particularly histones H3 and H4, and is mostly within the "histone tail" that extends beyond the core nucleosome structure. The histone tail tends to be free of protein-protein interactions and is also the portion of the histone protein most susceptible to post-translational modifications. These modifications include acetylation, methylation, phosphorylation, ubiquitination, SUMO. These epigenetic markers are written and cleared by specific enzymes that place tags on specific residues within the histone tails, thereby forming an epigenetic code that is subsequently interpreted by the cell to allow gene-specific regulation of the chromatin and thus transcription.

For all classes of proteins, histones are the most sensitive proteins to post-translational modifications. Histone modifications are dynamic in that they can be added or removed in response to specific stimuli, and these modifications direct structural changes in chromatin and changes in gene transcription. Different classes of enzymes, histone Acetyltransferases (HAT) and Histone Deacetylases (HDAC), acetylate or deacetylate specific histone lysine residues (Struhl k., genes dev.,1989,12,5,599-606).

Bromodomains of about 110 amino acids in length are found in a large number of chromatin-associated proteins and have been identified in about 70 human proteins, often in proximity to other protein motifs (Jeanmougin f., et al, trends biochem. Sci.,1997,22,5,151-153; and Tamkun j.w., et al, cell,1992,7,3,561-572). The interaction between bromodomains and modified histones may be an important mechanism under chromatin structure alteration and gene regulation. Bromodomain-containing proteins have been implicated in disease processes including cancer, inflammation, and viral replication. See, e.g., prinjha et al, trends pharm. Sci.,33 (3): 146-153 (2012) and Muller et al, expert rev.,13 (29): 1-20 (9/2011).

Cell type specificity and proper tissue functionality require tight control of different transcription programs that are closely influenced by the environment. This alteration in transcriptional homeostasis is directly associated with a variety of disease states, particularly cancer, immune inflammation, neurological disorders, and metabolic diseases. Bromodomains are located in core chromatin modification complexes that function to control different disease-associated transcription pathways. It is highlighted by mutations in the bromodomain-containing protein that are associated with cancer and immune and nervous system dysfunction. Furthermore, recent findings have demonstrated that small molecule inhibition of the bromodomain of BRD4 may have clinical utility in a variety of human diseases ranging from autoimmunity to cardiac hypertrophy. This is possible because intrinsic mechanisms exist in transcriptional regulation. Thus, selective inhibition of bromodomains across this family would create various opportunities as novel therapeutic agents for human dysfunction.

There is a need for treatment of cancer, immunological disorders and other bromodomain-associated diseases.

Disclosure of Invention

One aspect includes a compound of formula (I) or a salt thereof:

wherein:

R ¹ is methyl, ethyl, C _3–12 Alkyl radical, C _2–12 Alkenyl radical, C _2–12 Alkynyl, carbocyclyl or heterocyclyl, wherein R ¹ Any methyl groups of (a) being substituted by one or more radicals R ^m Substituted in which R ¹ By one or more radicals R ⁿ Is substituted and wherein R ¹ Any of C _3–12 Alkyl radical, C _2-12 Alkenyl radical, C _2–12 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more groups R ^a Substitution;

R ² is H, C _1–12 Alkyl radical, C _2–12 Alkenyl radical, C _2–12 Alkynyl or C _3–8 Cycloalkyl, wherein R ² Each C of _1–12 Alkyl radical, C _2–12 Alkenyl radical, C _2–12 Alkynyl or C _3–8 Cycloalkyl is optionally substituted by one or more radicals R ^b Substitution;

q is a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic group is optionally substituted with one or more groups R ^c Substitution;

each R ^a Independently selected from oxo, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl, heterocyclyl, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^v ) ₂ 、-CN、-C(O)-N(R ^v ) ₂ 、-S(O)-N(R ^v ) ₂ 、-S(O) ₂ -N(R ^v ) ₂ 、-O-R ^v 、-S-R ^v 、-O-C(O)-R ^v 、-O-C(O)-O-R ^v 、-C(O)-R ^v 、-C(O)-O-R ^v 、-S(O)-R ^v 、-S(O) ₂ -R ^v 、-O-C(O)-N(R ^v ) ₂ 、-N(R ^v )-C(O)-OR ^v 、-N(R ^v )-C(O)-N(R ^v ) ₂ 、-N(R ^v )-C(O)-R ^v 、-N(R ^v )-S(O)-R ^v 、-N(R ^v )-S(O) ₂ -R ^v 、-N(R ^v )-S(O)-N(R ^v ) ₂ and-N (R) ^v )-S(O) ₂ -N(R ^v ) ₂ ；

Each R ^b Independently selected from oxo, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl, heterocyclyl, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^w ) ₂ 、-CN、-C(O)-N(R ^w ) ₂ 、-S(O)-N(R ^w ) ₂ 、-S(O) ₂ -N(R ^w ) ₂ 、-O-R ^w 、-S-R ^w 、-O-C(O)-R ^w 、-O-C(O)-O-R ^w 、-C(O)-R ^w 、-C(O)-O-R ^w 、-S(O)-R ^w 、-S(O) ₂ -R ^w 、-O-C(O)-N(R ^w ) ₂ 、-N(R ^w )-C(O)-OR ^w 、-N(R ^w )-C(O)-N(R ^w ) ₂ 、-N(R ^w )-C(O)-R ^w 、-N(R ^w )-S(O)-R ^w 、-N(R ^w )-S(O) ₂ -R ^w 、-N(R ^w )-S(O)-N(R ^w ) ₂ and-N (R) ^w )-S(O) ₂ -N(R ^w ) ₂ Wherein any C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -NO ₂ 、-N(R ^w ) ₂ 、-CN、-C(O)-N(R ^w ) ₂ 、-S(O)-N(R ^w ) ₂ 、-S(O) ₂ -N(R ^w ) ₂ 、-O-R ^w 、-S-R ^w 、-O-C(O)-R ^w 、-C(O)-R ^w 、-C(O)-O-R ^w 、-S(O)-R ^w 、-S(O) ₂ -R ^w 、-C(O)-N(R ^w ) ₂ 、-N(R ^w )-C(O)-R ^w 、-N(R ^w )-S(O)-R ^w 、-N(R ^w )-S(O) ₂ -R ^w And C _1–6 Radical substitution of alkyl, said C _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen;

each R ^c Independently selected from oxo, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl, heterocyclyl, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^u ) ₂ 、-CN、-C(O)-N(R ^u ) ₂ 、-S(O)-N(R ^u ) ₂ 、-S(O) ₂ -N(R ^u ) ₂ 、-O-R ^u 、-S-R ^u 、-O-C(O)-R ^u 、-O-C(O)-O-R ^u 、-C(O)-R ^u 、-C(O)-O-R ^u 、-S(O)-R ^u 、-S(O) ₂ -R ^u 、-O-C(O)-N(R ^u ) ₂ 、-N(R ^u )-C(O)-OR ^u 、-N(R ^u )-C(O)-N(R ^u ) ₂ 、-N(R ^u )-C(O)-R ^u 、-N(R ^u )-S(O)-R ^u 、-N(R ^u )-S(O) ₂ -R ^u 、-N(R ^u )-S(O)-N(R ^u ) ₂ and-N (R) ^u )-S(O) ₂ -N(R ^u ) ₂ Wherein any C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -NO ₂ 、-N(R ^u ) ₂ 、-CN、-C(O)-N(R ^u ) ₂ 、-S(O)-N(R ^u ) ₂ 、-S(O) ₂ -N(R ^u ) ₂ 、-O-R ^u 、-S-R ^u 、-O-C(O)-R ^u 、-C(O)-R ^u 、-C(O)-O-R ^u 、-S(O)-R ^u 、-S(O) ₂ -R ^u 、-N(R ^u )-C(O)-R ^u 、-N(R ^u )-S(O)-R ^u 、-N(R ^u )-S(O) ₂ -R ^u And C _1–6 Radical substitution of alkyl, said C _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen;

each R ^m Independently selected from oxo, carbocyclyl, heterocyclyl, -F, -NO ₂ 、-CN、-C(O)-N(R ^v ) ₂ 、-S(O)-N(R ^v ) ₂ 、-S(O) ₂ -N(R ^v ) ₂ 、-C(O)-R ^v 、-C(O)-O-R ^v 、-S(O)-R ^v and-S (O) ₂ -R ^v Wherein the carbocyclic group is optionally substituted by one or more-O-R ^v Substitution;

each R ⁿ Independently selected from oxo, carbocyclyl, heterocyclyl, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^v ) ₂ 、-CN、-C(O)-N(R ^v ) ₂ 、-S(O)-N(R ^v ) ₂ 、-S(O) ₂ -N(R ^v ) ₂ 、-O-R ^v 、-S-R ^v 、-O-C(O)-R ^v 、-O-C(O)-O-R ^v 、-C(O)-R ^v 、-C(O)-O-R ^v 、-S(O)-R ^v 、-S(O) ₂ -R ^v 、-O-C(O)-N(R ^v ) ₂ 、-N(R ^v )-C(O)-OR ^v 、-N(R ^v )-C(O)-N(R ^v ) ₂ 、-N(R ^v )-C(O)-R ^v 、-N(R ^v )-S(O)-R ^v 、-N(R ^v )-S(O) ₂ -R ^v 、-N(R ^v )-S(O)-N(R ^v ) ₂ and-N (R) ^v )-S(O) ₂ -N(R ^v ) ₂ ；

Each R ^u Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, carbocyclyl and heterocyclyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -N (R) ^ua ) ₂ Hydroxy, carbocyclyl, heterocyclyl and C ₁ -C ₆ Radical substitution of alkyl, said C ₁ -C ₆ Alkyl is optionally substituted by one orA plurality of substituents independently selected from oxo and halogen; or two R ^u Together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one or more substituents independently selected from oxo, halogen, C _1-3 Radical substitution of alkyl and heteroaryl, wherein C _1-3 Alkyl is optionally substituted with one or more substituents independently selected from oxo, hydroxy, -N (R) ^ua ) ₂ And halo and heteroaryl optionally substituted with one or more-N (R) ^ua ) ₂ Substitution;

each R ^v Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, carbocyclyl and heterocyclyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -N (R) ^va ) ₂ Hydroxy, carbocyclyl, heterocyclyl and C ₁ -C ₆ Radical substitution of alkyl, said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen; or two R ^v Together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one or more substituents independently selected from oxo, halogen and C _1–3 Radical substitution of alkyl, said C _1–3 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen;

each R ^w Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, carbocyclyl and heterocyclyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -N (R) ^wa ) ₂ Hydroxy and C ₁ -C ₆ Radical substitution of alkyl, said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen; or two R ^w Together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one or more substituents independently selected from oxo, halogen and C _1–3 Radical substitution of alkyl radicals, saidC _1–3 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen;

each R ^ua Independently selected from hydrogen and C _1–6 An alkyl group;

each R ^va Independently selected from hydrogen and C _1–6 An alkyl group; and

each R ^wa Independently selected from hydrogen and C _1–6 An alkyl group.

Another aspect includes a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

Another aspect includes a method for treating a bromodomain-mediated disorder in an animal comprising administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect includes a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy.

Another aspect includes a compound of formula (I) or a pharmaceutically acceptable salt thereof for prophylactic or therapeutic treatment of bromodomain-mediated disorders.

Another aspect includes the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a bromodomain-mediated disorder in an animal (e.g., a mammal such as a human).

Another aspect includes compounds useful for studying bromodomains.

Another aspect includes the synthetic intermediates and synthetic methods disclosed herein that are useful for preparing compounds of formula (I) or salts thereof.

Detailed Description

Compounds and Definitions

Definitions and terms are described in more detail below. Chemical elements are identified according to the periodic Table of the elements of the CAS version 75 th edition of the Handbook of Chemistry and Physics.

Unless otherwise indicated, compounds of formula I include enantiomeric, diastereomeric and geometric (or conformational) isomeric forms of a given structure. For example, R and S configurations, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers for each asymmetric center are includedAs well as enantiomeric, diastereomeric and geometric (or conformational) mixtures. Unless otherwise indicated, all tautomeric forms of the structures depicted herein are included. In addition, unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of formula I are included wherein one or more hydrogens are independently replaced or enriched by deuterium or tritium ¹³ C-or ¹⁴ C carbon independently replaces or is enriched in one or more carbons ¹⁵ N nitrogen independently replaces or enriches one or more of the nitrogens, consisting of ³³ S、 ³⁴ S or ³⁶ S sulfur independently replaces or is enriched in one or more sulfur, or consists of ¹⁷ O or ¹⁸ O oxygen independently replaces or enriches one or more oxygens. Such compounds are useful, for example, as analytical tools, probes in bioassays, or as therapeutics.

Where a particular enantiomer is described, it may, in certain embodiments, be provided substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched". As used herein, "optically enriched" means that a mixture of enantiomers consists of a significantly greater proportion of one enantiomer and can be described by enantiomeric excess (ee%). In certain embodiments, a mixture of enantiomers consists of at least about 90% by weight (about 90% ee) of a given enantiomer. In other embodiments, a mixture of enantiomers is composed of at least about 95%, 98%, or 99% by weight of a given enantiomer (about 95%, 98%, or 99% ee). Enantiomers and diastereomers may be separated from the racemic mixture by any method known to those skilled in the art, including recrystallization from a solvent in which one stereoisomer is more soluble than the other; chiral High Performance Liquid Chromatography (HPLC); supercritical Fluid Chromatography (SFC); chiral salts are formed and recrystallized, then isolated by any of the above methods, or prepared by asymmetric synthesis and optionally further enriched. See, e.g., jacques et al, eneriomers, racemates and solutions (Wiley Interscience, new York, 1981); wilen et al, tetrahedron 33:2725 (1977); eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); wilen, S.H.tables of solving Agents and Optical solutions p.268 (E.L.Eliel, ed., univ.of Notre Dame Press, notre Dame, IN 1972).

The term "heteroatom" means any atom independently selected from an atom other than carbon or hydrogen, for example, one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; and quaternized form of any nitrogen).

The terms "halo" and "halogen" as used herein refer to an atom selected from the group consisting of fluoro (fluoro, -F), chloro (chloro, -Cl), bromo (bromo, -Br), and iodo (iodo, -I).

The term "oxo" means = O or (= O) ₂ 。

The term "unsaturated" as used herein means that the moiety has one or more units of unsaturation.

The term "carbocyclyl" used alone or as part of a larger moiety refers to a saturated, partially unsaturated, or aromatic ring system having from 3 to 20 carbon atoms. In one embodiment, carbocyclyl includes 3 to 12 carbon atoms (C) ₃ -C ₁₂ ). In another embodiment, carbocyclyl includes C ₃ -C ₈ 、C ₃ -C ₁₀ Or C ₅ -C ₁₀ . In other embodiments, carbocyclyl, as a monocyclic ring, includes C ₃ -C ₈ 、C ₃ -C ₆ Or C ₅ -C ₆ . In another embodiment, carbocyclyl, as bicyclic, includes C ₇ -C ₁₂ . In another embodiment, carbocyclyl, as a spiro system, includes C ₅ -C ₁₂ . Examples of monocyclic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, deuterated cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl and cyclododecyl; bicyclic carbocyclic radicals having from 7 to 12 ring atoms include [4,3]、[4,4]、[4,5]、[5,5]、[5,6]Or [6,6]Ring systems, e.g. bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane, naphthalene and bicyclo [3.2.2]Nonane; and spiro carbocyclyl includes spiro [2.2]Pentane, spiro [2.3]Hexane, spiro [2.4 ]]Heptane, spiro [2.5 ]]Octane and spiro [4.5 ]]Decane. The term carbocyclyl includes aromatic ring systems as defined herein. The term carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated mono-, bi-, or spiro-carbocycles).

The term "alkyl" as used herein refers to a saturated straight or branched chain monovalent hydrocarbon group. In one embodiment, the alkyl group has 1 to 18 carbon atoms (C) ₁ -C ₁₈ ). In other embodiments, alkyl is C ₀ -C ₆ 、C ₀ -C ₅ 、C ₀ -C ₃ 、C ₁ -C ₁₂ 、C ₁ -C ₁₀ 、C ₁ -C ₈ 、C ₁ -C ₆ 、C ₁ -C ₅ 、C ₁ -C ₄ Or C ₁ -C ₃ 。C ₀ Alkyl refers to a bond. Examples of alkyl groups include methyl (Me, -CH) ₃ ) Ethyl (Et, -CH) ₂ CH ₃ ) 1-propyl (n-Pr, n-propyl, -CH) ₂ CH ₂ CH ₃ ) 2-propyl (i-Pr, isopropyl, -CH (CH) ₃ ) ₂ ) 1-butyl (n-Bu, n-butyl, -CH) ₂ CH ₂ CH ₂ CH ₃ ) 2-methyl-1-propyl (i-Bu, isobutyl, -CH) ₂ CH(CH ₃ ) ₂ ) 2-butyl (s-Bu, sec-butyl, -CH (CH) ₃ )CH ₂ CH ₃ ) 2-methyl-2-propyl (t-Bu, tert-butyl, -C (CH) ₃ ) ₃ ) 1-pentyl (n-pentyl, -CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentyl (-CH (CH) ₂ CH ₃ ) ₂ ) 2-methyl-2-butyl (-C (CH) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butyl (-CH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-1-butyl (-CH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-1-butyl (-CH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) 1-hexyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-hexyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ) 3-hexyl (-CH (CH) ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ) 2-methyl-2-pentyl (-C (CH)) ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) 3-methyl-2-pentyl (-CH (CH) ₃ )CH(CH ₃ )CH ₂ CH ₃ ) 4-methyl-2-pentyl (-CH (CH) ₃ )CH ₂ CH(CH ₃ ) ₂ ) 3-methyl-3-pentyl (-C (CH) ₃ )(CH ₂ CH ₃ ) ₂ ) 2-methyl-3-pentyl (-CH (CH) ₂ CH ₃ )CH(CH ₃ ) ₂ ) 2,3-dimethyl-2-butyl (-C (CH) ₃ ) ₂ CH(CH ₃ ) ₂ ) 3,3-dimethyl-2-butyl (-CH (CH) ₃ )C(CH ₃ ) ₃ Heptyl, octyl, nonyl, decyl, undecyl, and dodecyl.

The term "alkenyl" as used herein denotes a straight or branched chain monovalent hydrocarbon group having at least one carbon-carbon double bond. Alkenyl groups include radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In one example, the alkenyl group has 2 to 18 carbon atoms (C) ₂ -C ₁₈ ). In other examples, alkenyl is C ₂ -C ₁₂ 、C ₂ -C ₁₀ 、C ₂ -C ₈ 、C ₂ -C ₆ Or C ₂ -C ₃ . Examples include, but are not limited to, ethenyl or vinyl (-CH = CH) ₂ ) Prop-1-enyl (-CH = CHCH) ₃ ) Prop-2-enyl (-CH) ₂ CH＝CH ₂ ) 2-methylprop-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-1,3-dienyl.

The term "alkynyl" as used herein refers to a straight or branched chain monovalent hydrocarbon radical having at least one carbon-carbon triple bond. In one example, alkynyl has 2 to 18 carbon atoms (C) ₂ -C ₁₈ ). In other examples, alkenyl is C ₂ -C ₁₂ 、C ₂ -C ₁₀ 、C ₂ -C ₈ 、C ₂ -C ₆ Or C ₂ -C ₃ . Examples include, but are not limited to, ethynyl (-C ≡ CH), prop-1-ynyl (-C ≡ CCH) ₃ ) Prop-2-ynyl (propargyl, -CH) ₂ C.ident.CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.

The term "alkoxy" refers to a straight OR branched chain monovalent radical represented by the formula-OR, where R is alkyl, alkenyl, alkynyl, OR carbocyclyl. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and cyclopropoxy.

The term "haloalkyl" as used herein refers to an alkyl group as defined herein substituted with one or more (e.g. 1,2,3 or 4) halo groups.

The term "aryl", alone or as part of a larger moiety, as used in "arylalkyl", "arylalkoxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic carbon ring system, including fused rings, wherein at least one ring in the system is aromatic. The term "aryl" is used interchangeably with the term "aromatic ring". In one embodiment, aryl includes groups having 6 to 18 carbon atoms. In another embodiment, aryl includes groups having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, phenanthryl, naphthonaphthyl (naphthyacenyl), 1,2,3,4-tetrahydronaphthyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like, which may be substituted with one or more substituents described herein or independently. A particular aryl group is phenyl. In another embodiment, aryl includes an aromatic ring fused to one or more carbocyclic rings, such as indanyl or tetrahydronaphthyl, and the like, wherein the radical or point of attachment is on the aromatic ring.

The term "heteroaryl", used alone or as part of a larger moiety, e.g., "heteroarylalkyl" or "heteroarylalkoxy", refers to a monocyclic, bicyclic, or tricyclic ring system having from 5 to 14 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes a 4-6 membered monocyclic aromatic group in which one or more ring atoms is independently optionally substituted nitrogen, sulfur, or oxygen. In another embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups in which one or more ring atoms is independently optionally substituted nitrogen, sulfur, or oxygen. Exemplary heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo [1,5-b ] pyridazinyl, imidazo [1,2-a ] pyrimidinyl, purinyl, benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 4234 xzft 4234-5-yl, 1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, and N2-triazolyl oxides. The term "heteroaryl" also includes groups in which a heteroaryl is fused to one or more aryl, carbocyclyl, or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and pyrido [2,3-b ] -1,4-oxazin-3 (4H) -one. Heteroaryl groups can be monocyclic, bicyclic, or tricyclic.

The term "heterocyclyl" as used herein refers to a "carbocyclyl" as defined herein, wherein one or more (e.g., 1,2,3 or 4) carbon atoms have been replaced with a heteroatom (e.g., O, N or S). In some embodiments, heterocyclyl refers to saturated ring systems, such as 3-to 12-membered saturated heterocyclyl ring systems. In some embodiments, heterocyclyl refers to a heteroaryl ring system, such as a 5-to 14-membered heteroaryl ring system. The heterocyclyl group may be optionally substituted by one or more substituents independently selected from those defined herein. The term heterocyclyl also includes C ₃ -C ₈ A heterocycloalkyl group, a heterocyclic alkyl group,which are saturated or partially unsaturated mono-, bi-or spiro-ring systems containing 3 to 8 carbons and one or more (1, 2,3 or 4) heteroatoms.

In one example, heterocyclyl includes 3-12 ring atoms and includes monocyclic, bicyclic, tricyclic, and spiro ring systems, wherein the ring atoms are carbon and 1-5 ring atoms are heteroatoms selected from nitrogen, sulfur, or oxygen, optionally substituted independently with one or more groups. In one example, heterocyclyl includes 1 to 4 heteroatoms. In another example, heterocyclyl includes 3 to 7 membered monocyclic rings having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, heterocyclyl includes 4 to 6 membered monocyclic rings having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, heterocyclyl includes 3-membered monocyclic rings. In another example, heterocyclyl includes a 4-membered monocyclic ring. In another example, heterocyclyl includes 5-6 membered monocyclic rings. In one example, heterocyclyl includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO) ₂ ) And any nitrogen heteroatom may optionally be quaternized (e.g., [ NR ] ₄ ] ⁺ Cl ^- 、[NR ₄ ] ⁺ OH ^- ). <xnotran> , (aziridinyl), (thiiranyl), (azetidinyl), (oxetanyl), (thietanyl), 5363 zxft 5363- , 3242 zxft 3242- , , -1H- , , , , , , , , , , 4736 zxft 4736- - , , , , , (oxazinanyl), (thiazinanyl), (thioxanyl), , , (azepanyl), (oxepanyl), (thiepanyl), </xnotran>An oxazepinyl group, an oxazepinyl groupzepanyl), diazepanyl, 1,4-diazepanyl, diazaRadical, sulfur heteroA group, a thiazepine group, a tetrahydrothiopyranyl group, an oxazolidinyl group, a thiazolidinyl group, an isothiazolidinyl group, a1,1-dioxoisothiazolidinone group, an oxazolidinonyl group, an imidazolidinonyl group, a4,5,6,7-tetrahydro [2H ] group]Indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo [ d]Imidazolyl, 1,6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl (dioxanyl), 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidonyl, pyrimidinedione, pyrimidine-2,4-dione, piperazinonyl, piperazinedionyl, pyrazolylimidazolinyl, 3-azabicyclo [ 3.1.0.3]Hexane radical, 3,6-diazabicyclo [3.1.1]Heptylalkyl, 6-azabicyclo [3.1.1]Heptylalkyl, 3-azabicyclo [3.1.1]Heptenyl, 3-azabicyclo [4.1.0]Heptylalkyl, azabicyclo [2.2.2]Hexane radical, 2-azabicyclo [3.2.1 ]]Octyl, 8-azabicyclo [3.2.1 ]]Octyl, 2-azabicyclo [2.2.2 ]]Octyl, 8-azabicyclo [2.2.2 ]]Octyl, 7-oxabicyclo [2.2.1 ]]Heptylalkyl, azaspiro [3.5]Nonanyl, azaspiro [2.5 ]]Nonanyl, azaspiro [4.5 ]]Decyl, 1-azaspiro [4.5 ]]Decan-2-onyl, azaspiro [5.5 ]]Undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocycles containing a sulfur or oxygen atom and 1 to 3 nitrogen atoms are thiazolyl (including thiazol-2-yl and thiazol-2-yl N-oxides), thiadiazolyl (including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl), oxazolyl (e.g. oxazol-2-yl) and oxadiazolyl(such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl). Exemplary 5-membered ring heterocyclic groups containing 2 to 4 nitrogen atoms include imidazolyl groups, such as imidazol-2-yl; triazolyl such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl. Exemplary benzofused 5-membered heterocyclic groups are benzoxazol-2-yl, benzothiazol-2-yl, and benzimidazol-2-yl. Exemplary 6-membered heterocyclic groups contain 1 to 3 nitrogen atoms and optionally contain a sulfur or oxygen atom, for example, pyridyl groups such as pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; pyrimidinyl, such as pyrimidin-2-yl and pyrimidin-4-yl; triazinyl groups such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, especially pyridazin-3-yl, and pyrazinyl. Pyridine N-oxides and pyridazine N-oxides and pyridyl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazinyl and 1,3,4-triazin-2-yl are other exemplary heterocyclic groups.

The term "partially unsaturated" as used herein refers to a cyclic moiety that includes at least one double or triple bond between ring atoms, but which cyclic moiety is not aromatic.

The term "inhibitor" as used herein refers to a compound that binds to and inhibits bromodomains with a measurable affinity and activity. In certain embodiments, the IC of the inhibitor ₅₀ Or a binding constant of less than 50 μ M, less than about 1 μ M, less than about 500nM, less than about 100nM, or less than about 10nM.

The terms "measurable affinity" and "measurably inhibit" as used herein refer to a measurable decrease in the activity of a bromodomain between: (i) A sample comprising a compound of formula I or a composition thereof and such bromodomains; and (ii) an equivalent sample comprising such bromodomains without the compound or composition thereof.

"pharmaceutically acceptable salts" include both acid and base addition salts. It is to be understood that when compounds or examples herein are shown as specific salts, the corresponding free base is contemplated, as well as other salts of the corresponding free base (including pharmaceutically acceptable salts of the corresponding free base).

"pharmaceutically acceptable acid addition salts" refers to those salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carbocyclic and sulfonic organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like, which retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable.

"pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. In particular, the base addition salts are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine (procaine), hydrabamine (hydrabamine), choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Specific organic non-toxic bases are isopropylamine, diethylamine, alkylol amine, tromethamine, dicyclohexylamine, choline and caffeine.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions through recombination of some of the bonding electrons.

"solvate" refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of the solvent include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

By "therapeutically effective amount" is meant an amount of a compound of the invention that (i) treats a particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and/or to alleviate one or more symptoms associated with cancer to some extent. For cancer treatment, efficacy can be measured, for example, by assessing time to disease progression (TTP) and/or determining Response Rate (RR). In the case of an immune disorder, a therapeutically effective amount is an amount sufficient to alleviate or alleviate symptoms of an allergic disorder, autoimmune and/or inflammatory disease, or symptoms of an acute inflammatory response (e.g., asthma). In some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly reduce the activity or number of resistant or drug-resistant-persistent cancer cells.

"Treatment" (and variations such as "treat" or "treating") refers to a clinical intervention that attempts to alter the natural process of the subject individual or cell, and can be prophylactic or performed during clinical pathology. The desired therapeutic effect includes one or more of the following: preventing the occurrence or recurrence of disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, stabilizing (i.e., not worsening) the disease state, preventing metastasis, reducing the rate of disease progression, ameliorating or alleviating the disease state, prolonging survival compared to expected survival when not receiving treatment, and remission or improving prognosis. In certain embodiments, the compounds of formula I are used to delay the development of a disease or disorder or to slow the progression of a disease or disorder. Those in need of treatment include those already with the disorder or condition as well as those predisposed to the disorder or condition, (e.g., by gene mutation or abnormal expression of a gene or protein) or those for which the disorder or condition is to be prevented.

As used herein, "a" or "an" means one or more, unless expressly specified otherwise. As used herein, "another" means at least a second or more.

Example values

One embodiment provides a compound of formula I or a salt thereof, wherein:

R ¹ is methyl, ethyl, C _3–12 Alkyl radical, C _2–12 Alkenyl radical, C _2–12 Alkynyl, carbocyclyl or heterocyclyl, wherein R ¹ Any methyl groups of (a) being substituted by one or more radicals R ^m Is substituted in which R ¹ Any ethyl groups of (a) are substituted by one or more radicals R ⁿ Is substituted, and wherein R ¹ Any of C _3–12 Alkyl radical, C _2-12 Alkenyl radical, C _2–12 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more groups R ^a Substitution;

each R ^c Independently selected from oxo, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl, heterocyclyl, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^u ) ₂ 、-CN、-C(O)-N(R ^u ) ₂ 、-S(O)-N(R ^u ) ₂ 、-S(O) ₂ -N(R ^u ) ₂ 、-O-R ^u 、-S-R ^u 、-O-C(O)-R ^u 、-O-C(O)-O-R ^u 、-C(O)-R ^u 、-C(O)-O-R ^u 、-S(O)-R ^u 、-S(O) ₂ -R ^u 、-O-C(O)-N(R ^u ) ₂ 、-N(R ^u )-C(O)-OR ^u 、-N(R ^u )-C(O)-N(R ^u ) ₂ 、-N(R ^u )-C(O)-R ^u 、-N(R ^u )-S(O)-R ^u 、-N(R ^u )-S(O) ₂ -R ^u 、-N(R ^u )-S(O)-N(R ^u ) ₂ and-N (R) ^u )-S(O) ₂ -N(R ^u ) ₂ Wherein any C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -NO ₂ 、-N(R ^u ) ₂ 、-CN、-C(O)-N(R ^u ) ₂ 、-S(O)-N(R ^u ) ₂ 、-S(O) ₂ -N(R ^u ) ₂ 、-O-R ^u 、-S-R ^u 、-O-C(O)-R ^u 、-C(O)-R ^u 、-C(O)-O-R ^u 、-S(O)-R ^u 、-S(O) ₂ -R ^u 、-N(R ^u )-C(O)-R ^u 、-N(R ^u )-S(O)-R ^u 、-N(R ^u )-S(O) ₂ -R ^u And C _1–6 Radical substitution of alkyl radicalsC is _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen;

Each R ^u Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, carbocyclyl and heterocyclyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -N (R) ^ua ) ₂ Hydroxy, carbocyclyl, heterocyclyl and C ₁ -C ₆ Alkyl radical substitution, said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen; or two R ^u Together with the nitrogen to which they are attached form a heterocyclic group,optionally substituted by one or more groups independently selected from oxo, halogen, C _1-3 Alkyl and heteroaryl, wherein C _1-3 Alkyl is optionally substituted with one or more substituents independently selected from oxo, hydroxy, -N (R) ^ua ) ₂ And halo and heteroaryl optionally substituted with one or more-N (R) ^ua ) ₂ Substitution;

each R ^v Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, carbocyclyl and heterocyclyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -N (R) ^va ) ₂ Hydroxy, carbocyclyl, heterocyclyl and C ₁ -C ₆ Radical substitution of alkyl, said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen; or two R ^v Together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one or more substituents independently selected from oxo, halogen and C _1-3 Radical substitution of alkyl, said C _1-3 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen;

each R ^w Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, carbocyclyl and heterocyclyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -N (R) ^wa ) ₂ Hydroxy and C ₁ -C ₆ Radical substitution of alkyl, said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen; or two R ^w Together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one or more substituents independently selected from oxo, halogen and C _1–3 Alkyl radical substitution, said C _1–3 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen;

each R ^ua Independently selected from hydrogen and C _1–6 An alkyl group;

each R ^wa Independently selected from hydrogen and C _1–6 An alkyl group.

One embodiment provides a compound of formula (I) or a salt thereof, wherein

each R ^c Independently selected from oxo, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl, heterocyclyl, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^u ) ₂ 、-CN、-C(O)-N(R ^u ) ₂ 、-S(O)-N(R ^u ) ₂ 、-S(O) ₂ -N(R ^u ) ₂ 、-O-R ^u 、-S-R ^u 、-O-C(O)-R ^u 、-O-C(O)-O-R ^u 、-C(O)-R ^u 、-C(O)-O-R ^u 、-S(O)-R ^u 、-S(O) ₂ -R ^u 、-O-C(O)-N(R ^u ) ₂ 、-N(R ^u )-C(O)-OR ^u 、-N(R ^u )-C(O)-N(R ^u ) ₂ 、-N(R ^u )-C(O)-R ^u 、-N(R ^u )-S(O)-R ^u 、-N(R ^u )-S(O) ₂ -R ^u 、-N(R ^u )-S(O)-N(R ^u ) ₂ and-N (R) ^u )-S(O) ₂ -N(R ^u ) ₂ Wherein any C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -NO ₂ 、-N(R ^u ) ₂ 、-CN、-C(O)-N(R ^u ) ₂ 、-S(O)-N(R ^u ) ₂ 、-S(O) ₂ -N(R ^u ) ₂ 、-O-R ^u 、-S-R ^u 、-O-C(O)-R ^u 、-C(O)-R ^u 、-C(O)-O-R ^u 、-S(O)-R ^u 、-S(O) ₂ -R ^u 、-C(O)-N(R ^u ) ₂ 、-N(R ^u )-C(O)-R ^u 、-N(R ^u )-S(O)-R ^u 、-N(R ^u )-S(O) ₂ -R ^u And C _1–6 Radical substitution of alkyl, said C _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen;

each R ^m Independently selected from oxo,Carbocyclyl, heterocyclyl, -F, -NO ₂ 、-CN、-C(O)-N(R ^v ) ₂ 、-S(O)-N(R ^v ) ₂ 、-S(O) ₂ -N(R ^v ) ₂ 、-C(O)-R ^v 、-C(O)-O-R ^v 、-S(O)-R ^v and-S (O) ₂ -R ^v ；

Each R ^u Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, carbocyclyl and heterocyclyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -N (R) ^ua ) ₂ Hydroxy, carbocyclyl, heterocyclyl and C ₁ -C ₆ Radical substitution of alkyl, said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen; or two R ^u Together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one or more substituents independently selected from oxo, halogen and C _1-3 Radical substitution of alkyl, said C _1-3 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen;

each one of whichR ^v Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, carbocyclyl and heterocyclyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -N (R) ^va ) ₂ Hydroxy, carbocyclyl, heterocyclyl and C ₁ -C ₆ Alkyl radical substitution, said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen; or two R ^v Together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one or more substituents independently selected from oxo, halogen and C _1-3 Alkyl radical substitution, said C _1-3 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen;

each R ^w Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, carbocyclyl and heterocyclyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -N (R) ^wa ) ₂ Hydroxy and C ₁ -C ₆ Alkyl radical substitution, said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen; or two R ^w Together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one or more substituents independently selected from oxo, halogen and C _1–3 Radical substitution of alkyl, said C _1–3 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen;

each R ^ua Independently selected from hydrogen and C _1–6 An alkyl group;

each R ^wa Independently selected from hydrogen and C _1–6 An alkyl group.

With respect to the embodiments of formula (I) above, the following exemplary values are provided. It is to be understood that two or more embodiments provided herein may be combined.

In certain embodiments, R ¹ Is methyl, which is substituted by one or more radicals R ^m And (4) substitution.

In certain embodiments, R ¹ Is ethyl, which is substituted by one or more radicals R ⁿ And (4) substitution.

In certain embodiments, R ¹ Is C _3–12 Alkyl radical, C _2-12 Alkenyl radical, C _2–12 Alkynyl, carbocyclyl or heterocyclyl, wherein R ¹ Any of C _3–12 Alkyl radical, C _2-12 Alkenyl radical, C _2–12 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more groups R ^a And (4) substitution.

In certain embodiments, R ¹ Is C _3–6 Alkyl or C _3–6 Alkenyl, each of which is C _3–6 Alkyl and C _3–6 Alkenyl is optionally substituted with one or more substituents independently selected from carbocyclyl, heterocyclyl, -F, -Cl, -Br, -I, -N (R) ^v ) ₂ 、-CN、-C(O)-N(R ^v ) ₂ 、-O-R ^v 、-O-C(O)-R ^v 、-C(O)-R ^v and-C (O) -O-R ^v Is substituted with a group (b).

In certain embodiments, R ¹ Is C _3–6 Alkyl or C _3–6 Alkenyl, wherein each C _3–6 Alkyl and C _3–6 Alkenyl is optionally substituted with one or more substituents independently selected from carbocyclyl, -F, -Cl, -O-R ^v 、-O-C(O)-R ^v 、-C(O)-R ^v and-C (O) -O-R ^v Is substituted with a group (b).

In certain embodiments, R ¹ Is C _3–6 Alkyl or C _3–6 Alkenyl, each of which is C _3–6 Alkyl and C _3–6 Alkenyl is optionally substituted by one or more independently selected from C _3–6 Cycloalkyl groups.

In certain embodiments, R ¹ Is butyl, 2-cyclopropylethyl, cyclopentylmethyl, 2-penten-1-yl, cyclohexylmethyl, cyclobutylmethyl, 2-cyclohexylethyl, pentyl, 2-methylpropyl, 2-butene-1-yl, butyl, 2-furylmethyl, 3-methylbut-1-yl, 2-propenyl, 3-methyl-2-buten-1-yl, 3-buten-1-yl, 2-methoxyethyl, 3-methoxypropyl or 4-methoxybenzyl.

In certain embodiments, R ² Is H.

In certain embodiments, R ² Is C _1–12 Alkyl optionally substituted by one or more radicals R ^b And (4) substitution.

In certain embodiments, R ² Is methyl.

In certain embodiments, R ² Is H or C _1–12 Alkyl optionally substituted by one or more radicals R ^b And (4) substitution.

In certain embodiments, R ² Is H or C _1–6 Alkyl optionally substituted by one or more radicals R ^b And (4) substitution.

In certain embodiments, R ² Is H or C _1–6 An alkyl group.

In certain embodiments, R ² Is H or C _1–4 An alkyl group.

In certain embodiments, R ² Is H or methyl.

In certain embodiments, Q is carbocyclyl or heterocyclyl, wherein carbocyclyl or heterocyclyl is optionally substituted with one or more groups R ^c And (4) substitution.

In certain embodiments, Q is carbocyclyl, optionally substituted with one or more groups R ^c And (4) substitution.

In certain embodiments, Q is heterocyclyl, optionally substituted with one or more groups R ^c And (4) substitution.

In certain embodiments, Q is C ₃ -C ₈ Cycloalkyl optionally substituted by one or more radicals R ^c And (4) substitution.

In certain embodiments, Q is aryl, optionally substituted with one or more groups R ^c And (4) substitution.

In certain embodiments, Q is phenyl, optionally substituted with one or more groups R ^c And (4) substitution.

In certain embodiments, Q is:

wherein:

the ring A is optionally substituted with one or more groups R ^g Substituted, or ring A optionally fused with a carbocyclic or heterocyclic group to form a polycyclic group, optionally substituted with one or more groups R ^g Substitution;

R ^e is hydrogen, -F, -Cl, -Br, -I, -CN, -O-R ^x 、C _1–6 Alkyl radical, C _2–6 Alkenyl or C _2–6 Alkynyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl or C _2–6 Alkynyl is optionally substituted by one or more groups independently selected from oxo, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^x ) ₂ 、-CN、-C(O)-N(R ^x ) ₂ 、-S(O)-N(R ^x ) ₂ 、-S(O) ₂ -N(R ^x ) ₂ 、-O-R ^x 、-S-R ^x 、-O-C(O)-R ^x 、-O-C(O)-O-R ^x 、-C(O)-R ^x 、-C(O)-O-R ^x 、-S(O)-R ^x 、-S(O) ₂ -R ^x 、-O-C(O)-N(R ^x ) ₂ 、-N(R ^x )-C(O)-OR ^x 、-N(R ^x )-C(O)-N(R ^x ) ₂ -N(R ^x )-C(O)-R ^x 、-N(R ^x )-S(O)-R ^x 、-N(R ^x )-S(O) ₂ -R ^x 、-N(R ^x )-S(O)-N(R ^x ) ₂ and-N (R) ^x )-S(O) ₂ -N(R ^x ) ₂ Substituted with a group of (1);

R ^f is hydrogen, -F, -Cl, -Br, -I, -CN, -O-R ^y 、C _1–6 Alkyl radical, C _2–6 Alkenyl or C _2–6 Alkynyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl or C _2–6 Alkynyl is optionally substituted with one or more substituents independently selected from oxo, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^y ) ₂ 、-CN、-C(O)-N(R ^y ) ₂ 、-S(O)-N(R ^y ) ₂ 、-S(O) ₂ -N(R ^y ) ₂ 、-O-R ^y 、-S-R ^y 、-O-C(O)-R ^y 、-O-C(O)-O-R ^y 、-C(O)-R ^y 、-C(O)-O-R ^y 、-S(O)-R ^y 、-S(O) ₂ -R ^y 、-O-C(O)-N(R ^y ) ₂ 、-N(R ^y )-C(O)-OR ^y 、-N(R ^y )-C(O)-N(R ^y ) ₂ 、-N(R ^y )-C(O)-R ^y 、-N(R ^y )-S(O)-R ^y 、-N(R ^y )-S(O) ₂ -R ^y 、-N(R ^y )-S(O)-N(R ^y ) ₂ and-N (R) ^y )-S(O) ₂ -N(R ^y ) ₂ Substituted with a group of (a);

each R ^g Independently selected from oxo, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl, heterocyclyl, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^z ) ₂ 、-CN、-C(O)-N(R ^z ) ₂ 、-S(O)-N(R ^z ) ₂ 、-S(O) ₂ -N(R ^z ) ₂ 、-O-R ^z 、-S-R ^z 、-O-C(O)-R ^z 、-O-C(O)-O-R ^z 、-C(O)-R ^z 、-C(O)-O-R ^z 、-S(O)-R ^z 、-S(O) ₂ -R ^z 、-O-C(O)-N(R ^z ) ₂ 、-N(R ^z )-C(O)-OR ^z 、-N(R ^z )-C(O)-N(R ^z ) ₂ 、-N(R ^z )-C(O)-R ^z 、-N(R ^z )-S(O)-R ^z 、-N(R ^z )-S(O) ₂ -R ^z 、-N(R ^z )-S(O)-N(R ^z ) ₂ and-N (R) ^z )-S(O) ₂ -N(R ^z ) ₂ Wherein any C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -NO ₂ 、-N(R ^z ) ₂ 、-CN、-C(O)-N(R ^z ) ₂ 、-S(O)-N(R ^z ) ₂ 、-S(O) ₂ -N(R ^z ) ₂ 、-O-R ^z 、-S-R ^z 、-O-C(O)-R ^z 、-C(O)-R ^z 、-C(O)-O-R ^z 、-S(O)-R ^z 、-S(O) ₂ -R ^z 、-C(O)-N(R ^z ) ₂ 、-N(R ^z )-C(O)-R ^z 、-N(R ^z )-S(O)-R ^z 、-N(R ^z )-S(O) ₂ -R ^z 、C _1–6 Alkyl (optionally substituted with one or more groups independently selected from oxo and halogen) and heterocyclyl (optionally substituted with one or more groups independently selected from oxo, halogen and C) _1–6 Alkyl group substituted) groups;

each R ^x Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl and C _2–6 Alkynyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl or C _2-6 Alkynyl is optionally substituted with one or more substituents independently selected from oxo, halo, amino, hydroxy and C ₁ -C ₆ Radical substitution of alkyl;

each R ^y Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl and C _2–6 Alkynyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl or C _2-6 Alkynyl is optionally substituted with one or more substituents independently selected from oxo, halogen, amino, hydroxy and C ₁ -C ₆ Alkyl group substitution; and

each R ^z Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, carbocyclyl and heterocyclyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halogen, cyano, amino, hydroxy, C ₁ Alkoxy, carbocyclyl and C ₁ -C ₆ Radical substitution of alkyl, said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen; or two R ^z Together with the nitrogen to which they are attached form a heterocyclic group, optionally substituted with one or more substituents independently selected from oxo, halogen and C _1–3 Alkyl radical substitution, said C _1–3 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen.

In certain embodiments, R ^e Is hydrogen.

In certain embodiments, R ^f Is hydrogen.

In certain embodiments, ring a is optionally substituted with one or more groups R ^g And (4) substitution.

In certain embodiments, Q is C ₃ -C ₈ Heterocycloalkyl, optionally substituted by one or more radicals R ^c And (4) substitution.

In certain embodiments, Q is heteroaryl, optionally substituted with one or more groups R ^c And (4) substitution.

In certain embodiments, Q is phenyl, optionally substituted with one or more groups R ^c Substituted, wherein each R ^c Independently selected from C _1-6 Alkyl, heterocyclyl, -F, -Cl, -CN, -C (O) -N (R) ^u ) ₂ and-O-R ^u Wherein any C _1–6 Alkyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -NO ₂ 、-N(R ^u ) ₂ 、-CN、-C(O)-N(R ^u ) ₂ 、-S(O)-N(R ^u ) ₂ 、-S(O) ₂ -N(R ^u ) ₂ 、-O-R ^u 、-S-R ^u 、-O-C(O)-R ^u 、-C(O)-R ^u 、-C(O)-O-R ^u 、-S(O)-R ^u 、-S(O) ₂ -R ^u 、-C(O)-N(R ^u ) ₂ 、-N(R ^u )-C(O)-R ^u 、-N(R ^u )-S(O)-R ^u 、-N(R ^u )-S(O) ₂ -R ^u And C _1–6 Radical substitution of alkyl, said C _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen.

In certain embodiments, Q is phenyl, optionally substituted with one or more groups R ^c Is substituted, each of whichR is ^c Is independently selected from C _1–6 Alkyl, heterocyclyl, -F, -Cl, -CN, -C (O) -N (R) ^u ) ₂ and-O-R ^u Wherein any C _1–6 Alkyl or heterocyclyl is optionally substituted by one or more groups independently selected from-O-R ^u And C _1–6 Alkyl radical substitution, said C _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen.

In certain embodiments, Q is phenyl, optionally substituted with a group-C (O) -N (R) ^u ) ₂ Substituted and optionally substituted by one or more radicals R ^c And (4) substitution.

In certain embodiments, Q is phenyl, which is substituted with a group-C (O) -N (R) ^u ) ₂ Substituted and optionally substituted by one or more radicals R ^c Substituted, wherein each R ^c Independently selected from C _1–6 Alkyl, heterocyclyl, -F, -Cl, -CN, -C (O) -N (R) ^u ) ₂ and-O-R ^u Wherein any C _1–6 Alkyl or heterocyclyl is optionally substituted by one or more groups independently selected from-O-R ^u And C _1–6 Alkyl radical substitution, said C _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halo.

In certain embodiments, Q is phenyl, optionally substituted with one or more groups R ^c Substituted and selected from dimethylaminocarbonyl, aminocarbonyl, cyclohexylaminocarbonyl, isopropylaminocarbonyl, tetrahydrofurylaminocarbonyl, N- (2,2-difluoroethyl) -aminocarbonyl, cyclobutylaminocarbonyl, cyclopropylmethylaminocarbonyl, methylaminocarbonyl, pyrrolidin-1-ylcarbonyl, morpholinocarbonyl, ethylaminocarbonyl, 2-methylpropyl) aminocarbonyl, 2- (dimethylamino) ethylaminocarbonyl, 2-hydroxyethylaminocarbonyl, 1-propylaminocarbonyl, 6-acetyl-2,6-diazaspiro [3.3] diazaspiro]The groups-C (O) -N (R) of heptan-2-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl and azetidine-1-carbonyl ^u ) ₂ And (4) substitution.

In certain embodiments, Q is selected from: 3- (N, N-dimethylaminocarbonyl) phenyl, 4-aminocarbonyl-3-fluoroPhenyl, 3-aminocarbonyl-5-fluorophenyl, 4-tert-butylphenyl, 3- (N-cyclohexylaminocarbonyl) phenyl, 4- (N-cyclohexylaminocarbonyl) phenyl, 3- (N-isopropylaminocarbonyl) phenyl, 3-cyano-6-methoxyphenyl, 3-aminocarbonyl-2-fluorophenyl, 3-aminocarbonyl-6-fluorophenyl, phenyl, 3- (N-cyclohexylaminocarbonyl) -6-methoxyphenyl, 3- (N-tetrahydrofurylaminocarbonyl) -6-methoxyphenyl, 3- (N- (2,2-difluoroethyl) aminocarbonyl) -6-methoxyphenyl, 3- (N-cyclobutylaminocarbonyl) -6-methoxyphenyl, 3- (N- (cyclopropylmethyl) aminocarbonyl) -6-methoxyphenyl, 4-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepine-2-keto-7-yl, 3- (N, N-dimethylaminocarbonyl) -5-fluorophenyl, 4- (N-methylaminocarbonyl) phenyl, 3- (pyrrolidin-1-ylcarbonyl) phenyl, 3-aminocarbonylphenyl, 4- (methylsulfonylamino) phenyl, 4- (morpholinocarbonyl) phenyl, 3- (N, N-dimethylaminocarbonyl) -6-fluorophenyl, 3- (N, N-dimethylaminocarbonyl) -2-fluorophenyl, 3- (N, N-dimethylaminocarbonyl) -6-methoxyphenyl, 3- (N-ethylaminocarbonyl) -6-methoxyphenyl, 2-methoxy-5- (N-methylaminocarbonyl) phenyl, 2-methoxy-5- (pyrrolidin-1-ylcarbonyl) phenyl, 2-methoxy-5- (N- (2-methylpropyl) aminocarbonyl) phenyl, 2-methoxy-5- (N- (2- (dimethylamino) ethyl) aminocarbonyl) phenyl, 3- (N- (2-hydroxyethyl) aminocarbonyl) -6-methoxyphenyl, 2-methoxy-5- (N-propylamino-1-ylcarbonyl) phenyl, 3- (6-acetyl-2,6-diazaspiro [3.3]]Heptane-2-ylcarbonyl) -6-methoxyphenyl, 4- (1-hydroxy-1-methylethyl) -2-methoxyphenyl, 4- (1-hydroxy-1-methylethyl) phenyl, 4- (4-methylpiperazin-1-ylcarbonyl) phenyl, 4- (N, N-dimethylaminocarbonyl) phenyl, 3- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl, 3- (N-methylaminocarbonyl) phenyl, 4- (hydroxymethyl) phenyl, 3-chloro-4- (N, N-dimethylaminocarbonyl) phenyl, 3-chloro-4- (aminocarbonyl) phenyl, and 3- (azetidine-1-carbonyl) -6-methoxyphenyl.

In certain embodiments, Q is:

wherein:

the ring A is optionally substituted with one or more groups R ^g Substituted, or ring A optionally fused with carbocyclyl or heterocyclyl to form a polycyclyl group, optionally substituted with one or more groups R ^g Substitution;

R ^e is hydrogen, -F, -Cl, -Br, -I, -CN, -O-R ^x 、C _1–6 Alkyl radical, C _2–6 Alkenyl or C _2–6 Alkynyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl or C _2–6 Alkynyl is optionally substituted by one or more groups independently selected from oxo, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^x ) ₂ 、-CN、-C(O)-N(R ^x ) ₂ 、-S(O)-N(R ^x ) ₂ 、-S(O) ₂ -N(R ^x ) ₂ 、-O-R ^x 、-S-R ^x 、-O-C(O)-R ^x 、-C(O)-R ^x 、-C(O)-O-R ^x 、-S(O)-R ^x 、-S(O) ₂ -R ^x 、-N(R ^x )-C(O)-R ^x 、-N(R ^x )-S(O)-R ^x and-N (R) ^x )-S(O) ₂ -R ^x Substituted with a group of (1);

R ^f is hydrogen, -F, -Cl, -Br, -I, -CN, -O-R ^y 、C _1–6 Alkyl radical, C _2–6 Alkenyl or C _2–6 Alkynyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl or C _2–6 Alkynyl is optionally substituted by one or more groups independently selected from oxo, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^y ) ₂ 、-CN、-C(O)-N(R ^y ) ₂ 、-S(O)-N(R ^y ) ₂ 、-S(O) ₂ -N(R ^y ) ₂ 、-O-R ^y 、-S-R ^y 、-O-C(O)-R ^y 、-C(O)-R ^y 、-C(O)-O-R ^y 、-S(O)-R ^y 、-S(O) ₂ -R ^y 、-N(R ^y )-C(O)-R ^y 、-N(R ^y )-S(O)-R ^y and-N (R) ^y )-S(O) ₂ -R ^y Substituted with a group of (1);

each R ^g Independently selected from oxo, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl, heterocyclyl, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^z ) ₂ 、-CN、-C(O)-N(R ^z ) ₂ 、-S(O)-N(R ^z ) ₂ 、-S(O) ₂ -N(R ^z ) ₂ 、-O-R ^z 、-S-R ^z 、-O-C(O)-R ^z 、-O-C(O)-O-R ^z 、-C(O)-R ^z 、-C(O)-O-R ^z 、-S(O)-R ^z 、-S(O) ₂ -R ^z 、-O-C(O)-N(R ^z ) ₂ 、-N(R ^z )-C(O)-OR ^z 、-N(R ^z )-C(O)-N(R ^z ) ₂ 、-N(R ^z )-C(O)-R ^z 、-N(R ^z )-S(O)-R ^z 、-N(R ^z )-S(O) ₂ -R ^z 、-N(R ^z )-S(O)-N(R ^z ) ₂ and-N (R) ^z )-S(O) ₂ -N(R ^z ) ₂ Wherein any C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -NO ₂ 、-N(R ^z ) ₂ 、-CN、-C(O)-N(R ^z ) ₂ 、-S(O)-N(R ^z ) ₂ 、-S(O) ₂ -N(R ^z ) ₂ 、-O-R ^z 、-S-R ^z 、-O-C(O)-R ^z 、-C(O)-R ^z 、-C(O)-O-R ^z 、-S(O)-R ^z 、-S(O) ₂ -R ^z 、-N(R ^z )-C(O)-R ^z 、-N(R ^z )-S(O)-R ^z 、-N(R ^z )-S(O) ₂ -R ^z And C _1–6 Radical substitution of alkyl and heteroaryl, wherein C _1-3 Alkyl is optionally substituted with one or more substituents independently selected from oxo, hydroxy, -N (R) ^ua ) ₂ And halo and heteroaryl optionally substituted with one or more-N (R) ^ua ) ₂ Substitution;

each R ^x Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl and C _2–6 Alkynyl radical, whichEach of C ₁ – ₆ Alkyl radical, C _2–6 Alkenyl or C _2-6 Alkynyl is optionally substituted with one or more substituents independently selected from oxo, halo, amino, hydroxy and C ₁ -C ₆ Radical substitution of alkyl;

each R ^y Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl and C _2–6 Alkynyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl or C _2-6 Alkynyl is optionally substituted with one or more substituents independently selected from oxo, halo, amino, hydroxy and C ₁ -C ₆ Radical substitution of alkyl; and

each R ^z Independently selected from hydrogen, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, carbocyclyl and heterocyclyl, wherein each C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, carbocyclyl, or heterocyclyl are optionally substituted with one or more substituents independently selected from oxo, halo, amino, hydroxy, heterocyclyl, carbocyclyl, and C ₁ -C ₆ Alkyl radical substitution, said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen; or two R ^z Together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with one or more substituents independently selected from oxo, halogen and C _1–3 Alkyl radical substitution, said C _1–3 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen.

In certain embodiments, R ^e Is hydrogen.

In certain embodiments, R ^f Is hydrogen.

In certain embodiments, R ^c Independently selected from oxo, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl, heterocyclyl, -F, -Cl, -N (R) ^u ) ₂ 、-CN、-C(O)-N(R ^u ) ₂ 、-O-R ^u and-N (R) ^u )-S(O) ₂ -R ^u Wherein any C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -NO ₂ 、-N(R ^u ) ₂ 、-CN、-C(O)-N(R ^u ) ₂ 、-S(O)-N(R ^u ) ₂ 、-S(O) ₂ -N(R ^u ) ₂ 、-O-R ^u 、-S-R ^u 、-O-C(O)-R ^u 、-C(O)-R ^u 、-C(O)-O-R ^u 、-S(O)-R ^u 、-S(O) ₂ -R ^u 、-N(R ^u )-C(O)-R ^u 、-N(R ^u )-S(O)-R ^u 、-N(R ^u )-S(O) ₂ -R ^u And C _1–6 Radical substitution of alkyl, said C _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen.

In certain embodiments, R ^c Independently selected from oxo, C _1–6 Alkyl, heterocyclyl, -F, -Cl, -CN, -C (O) -N (R) ^u ) ₂ 、-O-R ^u and-N (R) ^u )-S(O) ₂ -R ^u Wherein any C _1–6 Alkyl or heterocyclyl is optionally substituted by one or more substituents independently selected from oxo, halogen, -NO ₂ 、-N(R ^u ) ₂ 、-CN、-C(O)-N(R ^u ) ₂ 、-S(O)-N(R ^u ) ₂ 、-S(O) ₂ -N(R ^u ) ₂ 、-O-R ^u 、-S-R ^u 、-O-C(O)-R ^u 、-C(O)-R ^u 、-C(O)-O-R ^u 、-S(O)-R ^u 、-S(O) ₂ -R ^u 、-N(R ^u )-C(O)-R ^u 、-N(R ^u )-S(O)-R ^u 、-N(R ^u )-S(O) ₂ -R ^u And C _1–6 Alkyl radical substitution, said C _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen.

In certain embodiments, R ^c Independently selected from oxo, C _1–6 Alkyl, heterocyclyl, -F, -Cl, -CN, -C (O) -N (R) ^u ) ₂ 、-O-R ^u and-N (R) ^u )-S(O) ₂ -R ^u Wherein any C _1–6 Alkyl or heterocyclyl is optionally substituted by one or more groups independently selected from-O-R ^u And C _1–6 Radical substitution of alkyl, said C _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen.

In certain embodiments, Q is replaced by a-C (O) -N (R) ^u ) ₂ Substituted with radicals and optionally substituted with one or more radicals independently selected from C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl, heterocyclyl, -F, -Cl, -N (R) ^u ) ₂ 、-CN、-C(O)-N(R ^u ) ₂ 、-O-R ^u and-N (R) ^u )-S(O) ₂ -R ^u R of (A) to (B) ^c Is substituted by radicals, any C of which _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -NO ₂ 、-N(R ^u ) ₂ 、-CN、-C(O)-N(R ^u ) ₂ 、-S(O)-N(R ^u ) ₂ 、-S(O) ₂ -N(R ^u ) ₂ 、-O-R ^u 、-S-R ^u 、-O-C(O)-R ^u 、-C(O)-R ^u 、-C(O)-O-R ^u 、-S(O)-R ^u 、-S(O) ₂ -R ^u 、-N(R ^u )-C(O)-R ^u 、-N(R ^u )-S(O)-R ^u 、-N(R ^u )-S(O) ₂ -R ^u And C _1–6 Radical substitution of alkyl, said C _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen.

In certain embodiments, Q is phenyl, which is substituted with a group-C (O) -N (R) ^u ) ₂ Substituted and optionally substituted by one or more radicals R ^c Substituted, wherein each R ^c Independently selected from C _1–6 Alkyl, heterocyclyl, -F, -Cl, -CN, -C (O) -N (R) ^u ) ₂ and-O-R ^u Wherein any C _1–6 Alkyl or heterocyclyl groups optionally substituted by one or more substituentsIs selected from-O-R ^u And C _1–6 Radical substitution of alkyl, said C _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen.

In certain embodiments, Q is selected from:

in certain embodiments, the compound is selected from:

3- (6-allyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethylbenzamide;

3- (6-butyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethylbenzamide;

n, N-dimethyl-3- [6- (3-methylbut-2-enyl) -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] benzamide;

3- [6- (2-cyclopropylethyl) -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N, N-dimethylbenzamide;

3- [6- (cyclopentylmethyl) -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N, N-dimethylbenzamide;

3- [6- [ (4-methoxyphenyl) methyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N, N-dimethylbenzamide;

n, N-dimethyl-3- [ 7-oxo-6- [ (E) -pent-2-enyl ] -1H-pyrrolo [2,3-c ] pyridin-4-yl ] benzamide;

3- (6-but-3-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethylbenzamide;

3- [6- (cyclohexylmethyl) -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N, N-dimethylbenzamide;

3- (6-isopentyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethylbenzamide;

3- [6- (cyclobutylmethyl) -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N, N-dimethylbenzamide;

3- [6- (2-cyclohexylethyl) -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N, N-dimethylbenzamide;

n, N-dimethyl-3- (7-oxo-6-pentyl-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide;

3- [6- (2-methoxyethyl) -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N, N-dimethylbenzamide;

3- [6- (3-methoxypropyl) -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N, N-dimethylbenzamide;

3- (6-isobutyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethylbenzamide;

3- [6- (cyclopropylmethyl) -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N, N-dimethylbenzamide;

6-but-3-enyl-4- [3- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -5-fluoro-N, N-dimethylbenzamide;

4- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -2-fluorobenzamide;

6-but-2-enyl-4- [4- (4-methylpiperazine-1-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

3- (6-but-2-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -5-fluorobenzamide;

6-but-2-enyl-4- (4-tert-butylphenyl) -1H-pyrrolo [2,3-c ] pyridin-7-one;

4- (6-but-2-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N-methylbenzamide;

3- (6-but-2-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N-methylbenzamide;

3- (6-but-2-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N-cyclopropylbenzamide;

6-but-2-enyl-4- [3- (pyrrolidine-1-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

4- (6-but-2-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N-cyclopropylbenzamide;

6-but-2-enyl-4- [4- (hydroxymethyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

3- (6-but-2-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide;

6-but-2-enyl-4- (4-isopropylphenyl) -1H-pyrrolo [2,3-c ] pyridin-7-one;

3- (6-but-2-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethylbenzamide;

6-but-2-enyl-4- [4- (pyrrolidine-1-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

n- [4- (6-but-2-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide;

3- (6-but-2-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N-isopropylbenzamide;

4- (6-but-2-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethylbenzamide;

6-but-2-enyl-4- [4- (morpholine-4-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

3- (6-but-2-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-methoxy-benzonitrile;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -2-fluorobenzamide;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -4-fluorobenzamide;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -4-fluoro-N, N-dimethylbenzamide;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -2-fluoro-N, N-dimethylbenzamide;

4- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -2-chloro-N, N-dimethylbenzamide;

4- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -2-chlorobenzamide;

6- (2-furylmethyl) -4-phenyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

3- (6-butyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-methoxy-benzonitrile;

3- [6- (2-cyclopropylethyl) -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -4-methoxy-benzonitrile;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N-cyclopropyl-4-methoxybenzamide;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -4-methoxy-N, N-dimethylbenzamide;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -4-methoxy-N-tetrahydrofuran-3-ylbenzamide;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N-ethyl-4-methoxybenzamide;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -4-methoxy-N-methylbenzamide;

6- [ (E) -but-2-enyl ] -4- [ 2-methoxy-5- (pyrrolidine-1-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N- (2,2-difluoroethyl) -4-methoxybenzamide;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N-isobutyl-4-methoxybenzamide;

4- [5- (azetidine-1-carbonyl) -2-methoxy-phenyl ] -6- [ (E) -but-2-enyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N- [2- (dimethylamino) ethyl ] -4-methoxybenzamide;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N- (2-hydroxyethyl) -4-methoxybenzamide;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -4-methoxy-N-propylbenzamide;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N-cyclobutyl-4-methoxybenzamide;

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N- (cyclopropylmethyl) -4-methoxybenzamide;

4- [5- (6-acetyl-2,6-diazaspiro [3.3] heptane-2-carbonyl) -2-methoxy-phenyl ] -6- [ (E) -but-2-enyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

4- [5- (6-acetyl-2,6-diazaspiro [3.3] heptane-2-carbonyl) -2-methoxy-phenyl ] -6-butyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [4- (1-hydroxy-1-methyl-ethyl) -2-methoxy-phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-butyl-4- [4- (1-hydroxy-1-methyl-ethyl) -2-methoxy-phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [4- (1-hydroxy-1-methyl-ethyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-butyl-4- (4- (2-hydroxypropan-2-yl) phenyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one;

6- (2-cyclopropylethyl) -4- [4- (1-hydroxy-1-methyl-ethyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

3- (6- (2-cyclopropylethyl) -2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethylbenzamide;

3- (6-butyl-2-methyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethylbenzamide;

3- (6-butyl-2-methyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-methoxy-N, N-dimethylbenzamide;

3- [6- (2-cyclopropylethyl) -2-methyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -4-methoxy-N, N-dimethylbenzamide; and

7- [6- [ (E) -but-2-enyl ] group]-7-oxo-1H-pyrrolo [2,3-c]Pyridin-4-yl]-4-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepine-a 2-ketone;

and salts thereof.

In certain embodiments, the compound is selected from:

6-but-3-enyl-4- [3,4-difluoro-5- (morpholine-4-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-but-3-enyl-4- [ 3-fluoro-5- (3-methylmorpholine-4-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

3- (6-but-3-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -5- (morpholine-4-carbonyl) benzonitrile

6- [ (E) -but-2-enyl ] -4- [ 3-chloro-4- (morpholine-4-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [ 3-chloro-4- (pyrrolidine-1-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-but-3-enyl-4- [ 3-fluoro-5- (morpholine-4-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-but-3-enyl-4- [ 4-fluoro-3- (morpholine-4-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-but-3-enyl-4- [3- (difluoromethoxy) -5- (morpholine-4-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-but-3-enyl-4- [6- (morpholine-4-carbonyl) -1H-benzoimidazol-4-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

7- (6-but-3-enyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethyl-3H-benzimidazole-5-carboxamide;

6-but-3-enyl-4- [7- (morpholine-4-carbonyl) -3H-benzoimidazol-5-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-but-3-enyl-4- [ 3-methyl-7- (morpholine-4-carbonyl) benzimidazol-5-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-but-3-enyl-4- [ 3-ethyl-7- (morpholine-4-carbonyl) benzimidazol-5-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-but-3-enyl-4- [ 1-methyl-7- (morpholine-4-carbonyl) benzimidazol-5-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-but-3-enyl-4- [ 1-methyl-6- (morpholine-4-carbonyl) benzimidazol-4-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-but-3-enyl-4- [ 4-chloro-3- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -2-methyl-4- [4- (morpholine-4-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -2-methyl-4- [4- (pyrrolidine-1-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one

6- [ (E) -but-2-enyl ] -4- [ 3-chloro-4- (pyrrolidine-1-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [2,3-difluoro-4- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [ 3-methoxy-4- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [ 3-chloro-4- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6-but-3-enyl-4- [ 3-fluoro-5- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6-but-3-enyl-4- [ 4-fluoro-3- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [ 5-chloro-6- (morpholine-4-carbonyl) -3-pyridyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [ 3-chloro-4- (4-methylpiperazine-1-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -2-methyl-4- [ 3-methyl-4- (morpholine-4-carbonyl) phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6-allyl-4- [ 3-chloro-4- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6-allyl-4- [2,5-dimethoxy-4- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [ 3-methoxy-5- (morpholine-4-carbonyl) -2-pyridyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [ 4-chloro-5- (morpholine-4-carbonyl) -2-pyridinyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -2-methyl-4- [2- (morpholine-4-carbonyl) pyrimidin-5-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

5- [6- [ (E) -but-2-enyl ] -2-methyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -2- (morpholine-4-carbonyl) benzonitrile;

6- [ (E) -but-2-enyl ] -4- [4- (1-hydroxy-1-methyl-ethyl) -2-methoxy-phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one

6- [ (E) -but-2-enyl ] -4- [2,5-dimethoxy-4- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

3- [6- [ (E) -but-2-enyl ] -2-methyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -4-methoxy-N- (pyrazin-2-ylmethyl) benzamide

6-but-2-enyl-4- [ 3-methoxy-5- (4-methylpiperazine-1-carbonyl) -2-pyridyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [ 6-chloro-5- (morpholine-4-carbonyl) -2-pyridyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

1- [4- [6- [ (E) -but-2-enyl ] -2-methyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -2-chloro-benzoyl ] piperidine-4-carboxylic acid;

1- [4- [6- [ (E) -but-2-enyl ] -2-methyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -2-chloro-benzoyl ] piperidine-4-carboxamide;

6- [ (E) -but-2-enyl ] -4- [ 3-isopropoxy-4- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [3- (cyclopropylmethoxy) -4- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [ 3-chloro-4- (piperazine-1-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

4- [4- [3- (3-aminopyrazol-1-yl) azetidine-1-carbonyl ] -3-chloro-phenyl ] -6- [ (E) -but-2-enyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

4- [4- [3- (3-aminopyrazol-1-yl) azetidine-1-carbonyl ] phenyl ] -6- [ (E) -but-2-enyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [4- (1-hydroxy-1-methyl-ethyl) -2,5-dimethoxy-phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

3- [6- [ (E) -but-2-enyl ] -2-methyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -4-methoxy-N- (pyrimidin-5-ylmethyl) benzamide;

6-butyl-4- [2,5-dimethoxy-4- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6-butyl-4- [ 3-methoxy-5- (4-methylpiperazine-1-carbonyl) -2-pyridyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one; and

6-butyl-4- [ 3-methoxy-5- (morpholine-4-carbonyl) -2-pyridyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one

And salts thereof.

In certain embodiments, the compound is selected from:

and salts thereof.

In certain embodiments, the present invention provides compound 1000 and salts thereof as described in examples 124 and 126. The invention also provides methods for evaluating the ability of a compound to inhibit TAF1-BD2 by monitoring engagement of compound 1000 with the TAF1-BD2 target, as described in example 126.

In certain embodiments, the present invention provides compound 1001 as described in examples 125 and 126 and salts thereof. The invention also provides a method of assessing the ability of a compound to inhibit CECR2 by monitoring engagement of compound 1001 with a CECR2 target, as described in example 126.

Use, formulation and administration

Pharmaceutical composition

Another aspect includes a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the composition further comprises a pharmaceutically acceptable carrier, adjuvant or vehicle. In another embodiment, the composition further comprises an amount of a compound effective to measurably inhibit a bromodomain. In certain embodiments, the composition is formulated for administration to a patient in need thereof.

The term "patient" or "individual" as used herein refers to an animal, such as a mammal, such as a human. In one embodiment, the patient or individual is a human.

The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool fat.

Compositions comprising a compound of formula I or a salt thereof may be administered orally, parenterally, by inhalation spray, topically, transdermally, rectally, nasally, buccally, sublingually, vaginally, intraperitoneally, intrapulmonary, intradermally, epidural, or via an implanted depot. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

In one embodiment, the composition comprising a compound of formula I or a salt thereof is formulated as a solid dosage form for oral administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, a solid oral dosage form comprising a compound of formula (I) or a salt thereof further comprises one or more of the following: (ii) a pharmaceutically inert excipient or carrier such as sodium citrate or dicalcium phosphate, and (ii) a filler or bulking agent such as starch, lactose, sucrose, glucose, mannitol, or silicic acid, (iii) a binder such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, or acacia, (iv) a humectant such as glycerol, (v) a disintegrating agent such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, or sodium carbonate, (vi) a solution blocking agent such as paraffin, (vii) an absorption accelerator such as a quaternary ammonium salt, (viii) a wetting agent such as cetyl alcohol or glycerol monostearate, (ix) an absorbent such as kaolin or bentonite, and (x) a lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycol, or sodium lauryl sulfate. In certain embodiments, the solid oral dosage form is formulated as a capsule, tablet, or pill. In certain embodiments, the solid oral dosage form further comprises a buffering agent. In certain embodiments, such compositions for solid oral dosage forms may be formulated as fillers in soft and hard-filled gelatin capsules containing one or more excipients such as lactose or milk sugar, polyethylene glycol, and the like.

In certain embodiments, tablets, dragees, capsules, pills, and granules of a composition comprising a compound of formula I or a salt thereof optionally comprise a coating or shell, such as an enteric coating. They may optionally contain opacifying agents and may also have a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions include polymeric substances and waxes, which may also be used 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.

In another embodiment, the composition comprises a microencapsulated compound of formula (I) or salt thereof, and optionally, further comprises one or more excipients.

In another embodiment, the composition comprises a liquid dosage formulation for oral administration containing a compound of formula I or a salt thereof, and optionally further comprises one or more of a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup, and elixir. In certain embodiments, the liquid dosage form optionally further comprises one or more of the following: inert diluents (such as water or other solvents), solubilizing agents and emulsifiers (such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols or fatty acid esters of sorbitan), and mixtures thereof. In certain embodiments, the liquid oral compositions optionally further comprise one or more adjuvants such as wetting agents, suspending agents, sweetening, flavoring, and perfuming agents.

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

For example, injectable formulations can be sterilized by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injection medium prior to use.

In order to prolong the effect of the compounds of formula (I), it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials that are poorly water soluble. The rate of absorption of the compound depends on its rate of dissolution, which in turn may depend on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injection depot forms can be made by forming microencapsule matrices of the compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

In certain embodiments, compositions for rectal or vaginal administration are formulated as suppositories, which can be prepared by mixing a compound of formula (I) or a salt thereof with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax, for example those which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound of formula (I).

Exemplary dosage forms for topical or transdermal administration of a compound of formula (I) include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. A compound of formula (I) or a salt thereof is mixed under sterile conditions with a pharmaceutically acceptable carrier and optionally a preservative or buffer. Further formulation examples include ophthalmic preparations, ear drops, eye drops, transdermal patches. Transdermal dosage forms may be prepared by dissolving or dispersing a compound of formula (I) or a salt thereof in a medium, such as ethanol or dimethylsulfoxide. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Nasal aerosol or inhalation formulations of the compounds of formula (I) or salts thereof may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional co-solvents or dispersants.

In certain embodiments, the pharmaceutical composition may be administered with or without food. In certain embodiments, the pharmaceutical composition is not administered with food. In certain embodiments, the pharmaceutical compositions of the present invention are administered with food.

The specific dose and treatment regimen for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the attending physician, and the severity of the particular disease being treated. The amount of a compound of formula I or salt thereof provided in the composition will also depend on the particular compound in the composition.

In one embodiment, a therapeutically effective amount of a compound of the invention administered parenterally per dose will be in the range of about 0.01-100mg/kg, alternatively about 0.1-20mg/kg, of patient body weight per day, with a typical initial range of compounds used being 0.3-15 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain from about 5 to about 100mg of a compound of the invention.

Exemplary tablet oral dosage forms comprise about 2mg, 5mg, 25mg, 50mg,100 mg, 250mg or 500mg of a compound of formula (I) or a salt thereof, and further comprise about 5-30mg of anhydrous lactose, about 5-40mg of croscarmellose sodium (sodium croscarmellose), about 5-30mg of polyvinylpyrrolidone (PVP) K30, and about 1-10mg of magnesium stearate. The process of formulating the tablets involves mixing the powdered ingredients together and further mixing with the PVP solution. The resulting composition may be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment. An example of an aerosol formulation may be prepared by dissolving about 2-500mg of a compound of formula I or a salt thereof in a suitable buffer, for example a phosphate buffer, and, if desired, adding a tonicity agent, for example a salt such as sodium chloride. The solution may be filtered, for example, using a 0.2 micron filter to remove impurities and contaminants.

Use of compounds and pharmaceutical compositions

Another aspect includes the use of a compound of formula (I) or a salt thereof for inhibiting a bromodomain (in vitro or in vivo).

Another embodiment includes a method for treating a bromodomain-mediated disorder in an animal comprising administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt thereof. Bromodomain-mediated disorders include, but are not limited to, those described herein.

Another embodiment includes a method of increasing the efficacy of a cancer treatment comprising a cytotoxic agent in an animal comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment includes a method of delaying or preventing the development of cancer resistance to a cytotoxic agent in an animal comprising administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment includes a method of increasing the duration of response to a cancer treatment in an animal comprising administering to an animal undergoing a cancer treatment a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the duration of response to the cancer treatment when the compound of formula (I), or a pharmaceutically acceptable salt thereof, is increased relative to the duration of response to the cancer treatment in the absence of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

Another embodiment includes a method of treating cancer in an individual comprising administering to the individual (a) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) a cytotoxic agent. In one embodiment, the cytotoxic agent is selected from the group consisting of antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-a inhibitors, fatty acid biosynthesis inhibitors, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and cancer metabolism inhibitors. In one embodiment, the cytotoxic agent is a taxane. In one embodiment, the taxane is paclitaxel or docetaxel. In one embodiment, the cytotoxic agent is a platinum agent. In one embodiment, the cytotoxic agent is an EGFR antagonist. In one embodiment, the EGFR antagonist is N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine or a pharmaceutically acceptable salt thereof (e.g., erlotinib). In one embodiment, the cytotoxic agent is a RAF inhibitor. In one embodiment, the RAF inhibitor is a BRAF or CRAF inhibitor. In one embodiment, the RAF inhibitor is vemurafenib. In one embodiment, the cytotoxic agent is a PI3K inhibitor.

In certain embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, the treatment may be administered without symptoms. For example, treatment may be administered to susceptible individuals prior to the onset of symptoms (e.g., in view of the history of symptoms and/or in view of genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, for example to prevent or delay their recurrence.

Bromodomain-mediated disorders

A "bromodomain-mediated disorder" is characterized by the involvement of one or more bromodomains (e.g., BRD 4) in initiation, manifestation of one or more symptoms or disease markers, severity or progression of the disorder. Bromodomains include, but are not limited to, ASH1L, ATAD2, ATAD2B, BAZ1A, BAZ B, BAZ2A, BAZ B, BPTF, BRD1, BRD2, BRD3, BRD4, BRD7, BRD8, BRD9, BRDT, BRPF1, BRPF3, BRWD1, BRWD3, CECR2, CREBBP (aka, CBP), EP300, GCN5L2, KIAA2026, MLL4, PBRM, PCAF, PHIP, SMARCA2, SMARCA4, SP100, zmsp 110, SP140, SP L, TAF1, TAF1L, TRIM, TRIM28, TRIM33, TRIM66, ynd8, and ynd11.

<xnotran> , , , , ( , , , , , ), T- , , , , , , , , , , , , , () , (chronic myelogenous leukemia), , , , , B , ( ), , , , , , , , , , , , , , , , , , , , , , , , , , , , , ( ), , , , , , , , , T- B- , </xnotran> Medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and wilms' tumor.

In certain embodiments, the cancer is lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and/or melanoma. In certain embodiments, the cancer is lung cancer. In certain embodiments, the lung cancer is NSCLC. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is melanoma.

Bromodomain-mediated disorders also include inflammatory diseases, inflammatory disorders, and autoimmune diseases, including but not limited to: addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, behcet's disease, bullous skin disease, chronic Obstructive Pulmonary Disease (COPD), crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, septicemia, systemic lupus erythematosus, takayasu's arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and wegener's granulomatosis.

Bromodomain-mediated disorders also include AIDS; chronic kidney diseases including, but not limited to, diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, igA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal disease, polycystic kidney disease, and tubulointerstitial nephritis; acute kidney injury or disease or condition, including but not limited to ischemia reperfusion induced, cardiac and major surgery induced, percutaneous coronary intervention induced, contrast agent induced, sepsis induced, pneumonia induced and drug toxicity induced; obesity; dyslipidemia; hypercholesterolemia; alzheimer's disease; metabolic syndrome; hepatic steatosis; type II diabetes; insulin resistance; and diabetic retinopathy.

Bromodomain inhibitors may also be useful in providing male contraception.

Combined administration of compounds and other drugs

The compounds of formula (I) or salts thereof may be used in therapy, alone or in combination with other drugs. For example, the second agent of a pharmaceutical combination formulation or dosage regimen may have complementary activities to the compound of formula (I) such that they do not adversely affect each other. The compounds may be administered together in a single pharmaceutical composition or separately. In one embodiment, the compounds or pharmaceutically acceptable salts thereof may be administered in combination with cytotoxic agents to treat proliferative diseases and cancer.

The term "co-administration" refers to the simultaneous administration, or any separate sequential administration, of a compound of formula (I) or a salt thereof, with another active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation therapy. If not administered simultaneously, the compounds are administered within a time period that is close to each other. Furthermore, it does not matter even if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

In general, any agent active in the disease or condition being treated may be administered in combination. Examples of such drugs may be found in Cancer Principles and Practice of Oncology,6, of v.t. devita and s.hellman (editors) ^th edition(February 15，2001)，Lippincott Williams&Found in Wilkins Publishers. One of ordinary skill in the art will be able to discern which drug combinations will be useful based on the specific characteristics of the drugs and diseases involved.

In one embodiment, the method of treatment comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with at least one cytotoxic agent. The term "cell" as used hereinBy "toxin agent" is meant a substance that inhibits or prevents cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (e.g., at) ²¹¹ 、I ¹³¹ 、I ¹²⁵ 、Y ⁹⁰ 、Re ¹⁸⁶ 、Re ¹⁸⁸ 、Sm ¹⁵³ 、Bi ²¹² 、P ³² 、Pb ²¹² And radioactive isotopes of Lu); a chemotherapeutic agent; a growth inhibitor; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.

Exemplary cytotoxic agents may be selected from the group consisting of antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-a inhibitors; inhibitors of fatty acid biosynthesis; inhibitors of cell cycle signaling; HDAC inhibitors, proteasome inhibitors; and cancer metabolism inhibitors.

"chemotherapeutic agents" include chemical compounds useful for the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (erlotinib) ((ll.), (ll.))Genentech/OSI pharm.), bortezomib (bortezomib) (bortezomib)Millennium pharm.), abstinence sulfur (disulphiram), epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol (radicol), lactate dehydrogenase A (LDH-A), fulvestrant (fulvestrant) ((fulvestrant)AstraZeneca) sunitinib (sunitinb) ((sunitinib))Pfizer/Sugen), letrozole (letrozole), (L-Toxole)Novartis), imatinib mesylate (imatinib mesylate), (I) and (II) a pharmaceutically acceptable salt thereofNovartis)、finasunate(Novartis), oxaliplatin (oxaliplatin) ((oxaliplatin)Sanofi), 5-FU (5-fluorouracil), leucovorin (leucovorin), rapamycin (Rapamycin) (Sirolimus),wyeth), lapatinib (Lapatinib) ((Lapatinib)GSK572016 (Glaxo Smith Kline), lonafamib (Lonafamib) (SCH 66336), sorafenib (sorafenib) (GSK 572016) (Sorafamib)Bayer Labs), gefitinib (gefitinib) (AstraZeneca), AG1478, alkylating agents such as thiotepa andcyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzotepa (benzodopa), carboquone (carboquone), metotepipa (meturedopa), and uredepa (uredpa); ethyleneimine and methylmelamine including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethyleneamineThiophosphoramide and trimethylolmelamine; polyacetogenin (especially bullatacin and bullatacin); camptothecin (including topotecan and irinotecan); bryostatin; sponge statin (callystatin); CC-1065 (including its synthetic analogs of adozelesin, cartezisin and bizelesin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5 α -reductases, including finasteride (finasteride) and dutasteride); vorinostat (vorinostat), romidepsin (romidepsin), panobinostat (panobinostat), valproic acid, moxystatin dolastatin (mocetinostat); aldesleukin (aldesleukin), talc duocarmycin (including synthetic analogs, KW-2189 and CB1-TM 1); shogaol (eleutherobin); coprinus atrata base (pancratistatin); sarcandra glabra alcohol (sarcodictyin); spongistatin (spongistatin); nitrogen mustards such as chlorambucil (chlorambucil), chlorophosphamide (chlorophosphamide), estramustine (estramustine), ifosfamide, mechlorethamine (mechlorethamine), mechlorethamine hydrochloride, melphalan (melphalan), neomustard (novembichin), benzene mustard cholesterol (pherenesterone), prednimustine, qu Linan (trofosfamide), uracil mustard (uracil musard); nitrosoureas such as carmustine (carmustine), chlorouretocin (chlorozotocin), fotemustine (fotemustine), lomustine (lomustine), nimustine (nimustine) and ranimustine (ranirnustine); antibiotics such as enediyne antibiotics (e.g., calicheamicins, especially calicheamicin γ 1I and calicheamicin ω 1I (Angew chem. Intl. Ed. Engl.1994 33Acids (azaserine), bleomycin (bleomycin), actinomycins (cactinomycin), carubicin (carabicin), carminomycin (caminomycin), carzinophilin (carzinophilin) tryptomycin (chromomycins), actinomycin (dactinomycin), daunorubicin (daunorubicin), ditolubicin (detorubicin), 6-diazo-5-oxo-L-norleucine,(doxorubicin)), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrroline-doxorubicin and deoxydoxorubicin), epirubicin (epirubicin), esorubicin (esorubicin), idarubicin (idarubicin), marijumycin (marcellomomycin), mitomycins (mitomycins) such as mitomycin C, mycophenolic acid (mycophenolic acid), nogomycin (nogalamycin), olivomycin (olivomycin), pelomycin (pelomycin), peplomycin, pofiromycin (porfiromycin), puromycin (puromycin), ferricin (quelamemycin), rodobicin (rodorubicin), streptomycin (streptanigrin), streptozocin (streptazocin), tubercidin (tubicin), ubenicillin (ubulin), zorubicin (zorubicin), zosin (zorubicin), zorubicin (zostaphylin), zotocin (zostaphylinicin), zostaphylin (zostaphylin); antimetabolites such as methotrexate (methotrexate) and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine (fludarabine), 6-mercaptopurine, thiamiprine (thiamirhine), thioguanine; pyrimidine analogs such as ancitabine (ancitabine), azacitidine (azacitidine), 6-azauridine, carmofur (carmofur), cytarabine (cytarabine), dideoxyuridine, doxifluridine, enocitabine (enocitabine), floxuridine; androgens such as testosterone carprofonate (calusterone), dromostanolone propionate (dromostanolone propionate), epitioandrostanol (epitiostanol), meindrotane (mepitinolone), testolactone (testolactone); anti-adrenal agents such as aminoglutethimide (aminoglutethimide), mitotane (mitotane), trostane (trilostane); folic acid replenishers such as leucovorin; acetoglufosinate (aceglatone); alanyl phosphoramide glycoside (aldophosphamide glycoside); aminolevulinic acid methyl esterAn acid; eniluracil (eniluracil); amsacrine (amsacrine); bestrabuucil; bisantrene (bisantrene), edatrexate (edatraxate); desphosphamide (defofamine); colchicine (demecolcine); diazaquinone (diaziqutone); efluoromithine (elfosmithine); ammonium etitanium acetate; epothilone (epothilone); etoglut (etoglucid); gallium nitrate; a hydroxyurea; lentinan (lentinan); lonidamine (lonidainine); maytansinoids (maytansinoids) such as maytansine (maytansine) and ansamitocins (ansamitocins); mitoguazone (mitoguzone); mitoxantrone (mitoxantrone); mopidanol (mopidamnol); nitrarine (nitrarine); pentostatin (pentostatin); methionine mustard (phenamett); pirarubicin (pirarubicin); losoxantrone (losoxantrone); podophyllinic acid (podophyllic acid); 2-ethyl hydrazide; procarbazine (procarbazine);polysaccharide complex (JHS Natural Products, eugene, oreg.); razoxane (rizoxane); lisoproxil (rhizoxin); azofurans (sizofurans); germanium spiroamines (spirogyranium); tenuazonic acid (tenuazonic acid); triimine quinone (triaziquone); 2,2', 2' -trichlorotriethylamine; trichothecenes (trichothecenes), in particular T-2 toxin, myxomycin A (veracurin A), bacillocin A (roridin A) and serpentinine (anguidine); urethane (urethan); vindesine (vindesine); dacarbazine (dacarbazine); mannomustine (mannomustine); dibromomannitol (mitobronitol); dibromodulcitol (mitolactol); pipobromane (pipobroman); a polycytidysine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes (taxoids), such as TAXOL (paclitaxel; bristol-Myers Squibb Oncology, princeton, N.J.),(Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical excipients, schaumberg, ill.) and(docetaxel, docetaxel; sanofi-Aventis); zeocin (chlorenbucil);(gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin (cispin) and carboplatin (carboplatin); vinblastine (vinblastine); etoposide (VP-16); ifosfamide; mitoxantrone; vincristine (vincristine);(vinorelbine); norfloxacin (novantrone); teniposide (teniposide); edatrexate (edatrexate); daunomycin (daunomycin); aminopterin (aminopterin); capecitabine (capecitabine)Ibandronate (ibandronate); CPT-11; topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

Chemotherapeutic agents also include: (i) Anti-hormonal agents such as anti-estrogens and Selective Estrogen Receptor Modulators (SERMs) including, for example, tamoxifen (including tamoxifen) for modulating or inhibiting the effects of hormones on tumorsTamoxifen citrate), raloxifene (raloxifene), droloxifene (droloxifene), idoxifene (iodoxyfene), 4-hydroxytamoxifene, trioxifene (trioxifene), raloxifene (keoxifene), LY117018, onapristone (onapristone), and(toremifene citrate); (ii) Aromatase inhibitors which inhibit aromatase which regulates estrogen production in the adrenal gland, e.g. 4 (5) -imidazole, aminoglutethimide,(megestrol acetate) acetate,(exemestane (Pfizer);, formestane (formestanine), fadrozole (fadrozole),(Fu Luo (vorozole)), (vi: (vorozole)), (vi),(letrozole; novartis) and(anastrozole; astraZeneca); (iii) Anti-androgens such as flutamide (flutamide), nilutamide (nilutamide), bicalutamide (bicalutamide), leuprolide (leuprolide), and goserelin (goserelin); buserelin (buserelin), triptorelin (tripterelin), medroxyprogesterone acetate, diethylstilbestrol, bimelin (premarin), fluoxymesterone, retro-retinoic acid, fenretinide (fenretinide), and troxacitabine (troxacitabine) (1,3-dioxolane nucleoside analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) Antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in abnormal cell proliferation, such as PKC- α, ralf, and H-Ras; (vii) Ribozymes such as VEGF expression inhibitors (e.g.,) And an inhibitor of HER2 expression; (viii) Vaccines such as gene therapy vaccines, for example,andrIL-2; topoisomerase I inhibitors such asrmRH; (ix) pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab (bevacizumab), (b) and (c)Genentech); cetuximab (cetuximab), (b), (c) and (d)Imclone); palindrome (panitumumab) (panitumumab)Amgen), rituximab (rituximab), (b)Genentech/Biogen Idec), pertuzumab (pertuzumab) ((ii) and2c4, genentech), trastuzumab (trastuzumab) ((R)Genentech), tositumomab (tositumomab) (Bexxar, corixia) and antibody drug conjugates gemtuzumab ozoga Mi Xing (gemtuzumab ozogamicin) ((s)Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: aprezumab, aselizumab, atlizumab,Bapineuzumab (bapineuzumab), bevacizumab maytansine (bivatuzumab mertansine), canazumab maytansine (cantuzumab mertansine), cetirizumab (cedelizumab), pegylated Cetuzumab (certolizumab pegol), cidfutuzumab, cidtuzumab, daclizumab (daclizumab), ekulizumab (eculizumab), efalizumab (efalizumab), epatuzumab (epratuzumab) Ullizumab (erlizumab), uvlizumab (felvivumab), artuzumab ozogamicin (fontolizumab), getuzumab ozogamicin (Gituzumab ozogamicin), ovzumicin (inotuzumab ozogamicin), ipilimumab (ipilimumab), ra Bei Zhu mab (labetuzumab), lintuzumab (lintuzumab), matuzumab (matuzumab), MEIPUTAZUzumab (mepolizumab) Movizumab (motavizumab), motovizumab, natalizumab (natalizumab), nimotuzumab (nimotuzumab), nolovizumab, numavizumab, ocrelizumab (ocrelizumab), omazumab (omalizumab), palivizumab (palivizumab), paclobuzumab (paclobuzumab), pecuzumab, pertuzumab (pertuzumab), pecfusituzumab (pexuzumab), pexelizumab (pexelizumab) ralivizumab, ranibizumab (ranibizumab), relivizumab, rayleigh mab (relizumab), resyvizumab, luo Weizhu mab (rovelizumab), lu Lizhu mab (ruplizumab), sibutrumab (sibutrumab), siburizumab (siplizumab), matuzumab (sotuzumab), tacurizumab (tacurizumab), tacitatuzumab tetanit (tacatuzumab), tacurizumab (taducizumab), tallizumab (talizumab), tefilzumab (tefibumab), toslizumab (tocilizumab), toslizumab (toralizumab), west Mo Bai interleukin mab (tucotuzumab celluelin), tucusituzumab, umalizumab, wu Zhu mab (urtoxazumab), ultkb (usekinumab), vislizumab (visilizumab), and anti-interleukin-12 (ABT-874/J695, wyeth Research and Abbott Laboratories), anti-interleukin-12 is a recombinant proprietary sequence genetically modified to recognize interleukin-12 p40 protein, full-length IgG, and ₁ lambda antibodies.

Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity,and alternatively referred to as an "EGFR antagonist". Examples of such drugs include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB 8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. patent nos. 4,943, 533, mendelsohn et al) and variants thereof, such as chimeric 225 (C225 or cetuximab;) And modified human 225 (H225) (see, WO 96/40210, imclone Systems Inc.); IMC-11F8, fully human, EGFR-targeting antibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in U.S. patent No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or parlimumab (see WO98/50433, abgenix/Amgen); EMD 55900 (Straglitoto et al, eur. J. Cancer 32A 636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody that competes against EGFR for binding to EGFR with EGF and TGF- α (EMD/Merck); human EGFR antibody, huMax-EGFR (GenMab); fully human antibodies designated E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described in US 6,235,883; MDX-447 (Metarex Inc); and mAb 806 or humanized mAb 806 (Johns et al, j.biol.chem.279 (29): 30375-30384 (2004)). anti-EGFR antibodies can be conjugated to cytotoxic agents to produce immunoconjugates (see, e.g., EP659,439A2, merck Patent GmbH). EGFR antagonists include small molecules such as U.S. patent nos.: 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498 and the following PCT publications: the compounds described in WO98/14451, WO98/50038, WO99/09016 and WO 99/24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib,Genentech/OSI Pharmaceuticals)；PD 183805 (CI 1033, 2-propenamide, N- [4- [ (3-chloro-4-fluorophenyl) amino group]-7- [3- (4-morpholinyl) propoxy]-6-quinazolinyl]Dihydrochloride, pfizer inc.); ZD1839, gefitinib4- (3 '-chloro-4' -fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline, astraZeneca); ZM 105180 ((6-amino-4- (3-methylphenyl-amino) -quinazoline, zeneca); BIBX-1382 (N8- (3-chloro-4-fluoro-phenyl) -N2- (1-methyl-piperidin-4-yl) -pyrimido [5,4-d]Pyrimidine-2,8-diamine, boehringer Ingelheim); PKI-166 ((R) -4- [4- [ (1-phenylethyl) amino)]-1H-pyrrolo [2,3-d]Pyrimidin-6-yl]-phenol); (R) -6- (4-hydroxyphenyl) -4- [ (1-phenylethyl) amino group]-7H-pyrrolo [2,3-d]Pyrimidines); CL-387785 (N- [4- [ (3-bromophenyl) amino)]-6-quinazolinyl]-2-butynylamide); EKB-569 (N- [4- [ (3-chloro-4-fluorophenyl) amino group]-3-cyano-7-ethoxy-6-quinolinyl]-4- (dimethylamino) -2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (lapatinib) ((R))GSK572016 or N- [ 3-chloro-4- [ (3-fluorophenyl) methoxy]Phenyl radical]-6[5[ [ [ [2 methylsulfonyl) ethyl]Amino group]Methyl radical]-2-furyl group]-4-quinazolinamines).

Chemotherapeutic agents also include "tyrosine kinase inhibitors," including the EGFR-targeting drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitors such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors such as EKB-569 (available from Wyeth) that preferentially binds EGFR but inhibits HER2 and EGFR overexpressing cells; lapatinib (GSK 572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; raf-1 inhibitors such as antisense drugs available from ISIS Pharmaceuticals, ISIS-5132, which inhibit Raf-1 signaling; non-HER-targeted TK inhibitionAgents such as imatinib mesylate (b: (b))Available from Glaxo SmithKline); multitarget tyrosine kinase inhibitors such as sunitinib (sunitinib) ((r))Available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK 787/ZK222584, available from Novartis/Schering AG); CI-1040, an inhibitor of MAPK extracellular regulated kinase I (available from Pharmacia); quinazolines, such as PD 153035,4- (3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4- (phenylamino) -7H-pyrrolo [2,3-d]A pyrimidine; curcumin (diferuloylmethane, 4,5-bis (4-fluoroanilino) phthalimide); tyrofostine (tyrphostin) containing nitrothiophene moieties; PD-0183805 (Wamer-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acids); quinoxalines (U.S. patent No. 5,804,396); trypostin (U.S. Pat. No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); affinitac (ISIS 3521; imatinib mesylatePKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); semaxanib (Semaxanib) (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus,) (ii) a Or as described in any of the following patent publications: U.S. Pat. No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, inc); WO 1996/33978 (Zeneca);WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Chemotherapeutic agents also include dexamethasone (dexamethasone), interferon, colchicine (colchicine), chlorphenamine (methaprine), cyclosporine (cyclosporine), amphotericin (amphotericin), metronidazole (metronidazole), alemtuzumab, alitretinoin (alitretinin), allopurinol (allopurinol), amifostine (amifostine), arsenic trioxide, asparaginase, live bacillus calmette (BCG live), bevacizumab (bevacizumab), bexarotene (bexarotene), cladribine (cladribine), clofarabine (clofarabine), alfa bexabepoetin (darbevacizin alfa), dineladin (denin), dexrazine (dexrazine), adoxabexathin (epoetin) erlotinib (eletininib), filgrastim (filgrastim), histrelin acetate (histrelin acetate), ibritumomab (ibritumomab), interferon alpha-2 a, interferon alpha-2 b, lenalidomide (lenalidomide), levamisole (levamisole), mesna (mesna), methoxsalen (methoxsalen), nandrolone (nandrolone), nelarabine (nelarabine), noflumumab (noflumumab), omprex (oprekin), palifermin (palifermin), pamidronate (pamidronate), pegyase (pegademase), pemetrexed (pegaspart), pegavase (pegaspongase), pegafiltr (pegafiltem), pemetrexed (pemetrexed), pemetrexed (pegentin), and poriferin (porifer), pemetrexed (pemetrexed), pemetrexed (pegemid), and pemphigenium (porifer) Quinacrine (quinacrine), labyrinase (rasburicase), sargrastim (sargramostim), temozolomide (temozolomide), VM-26, 6-TG, toremifene (toremifene), tretinoin (tretinoin), ATRA, valrubicin (valrubicin), zoledronate (zoledronate), and zoledronate (zoledronate acid), and pharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, hydrocortisone pivalate, triamcinolone acetonide, mometasone, amcinolone acetonide, budesonide, desonide, fluocinolone acetonide, betamethasone, sodium betamethasone phosphate, dexamethasone phosphateSodium, fluocortolone (fluocortolone), hydrocortisone 17-butyrate, hydrocortisone 17-valerate, alclomethasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednisone propionate, clobetasone 17-butyrate, clobetasone 17-propionate, fluocortolone hexanoate, fluocortolone pivalate and fluprednidene acetate (fluprednidene acetate); selective anti-inflammatory immune peptides (imsaids) such as phenylalanine-glutamic acid-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); antirheumatic drugs such as azathioprine (azathioprine), cyclosporine (cyclosporine) (cyclosporin a), D-penicillamine, gold salts, hydroxychloroquine, leflunomidomeinocycline, sulfasalazine (sulfasalazine); tumor necrosis factor alpha (TNF α) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (adalimumab) (Humira), certolizumab (Cimzia), golimumab (golimumab) (simoni); interleukin 1 (IL-1) blockers such as anakinra (Kineret); t cell co-stimulation blockers such as abenacept (Orencia); interleukin 6 (IL-6) blockers such as tosubuzumabInterleukin 13 (IL-13) blocking agents such as robuzumab; interferon alpha (IFN) blockers such as Luo Dali mab (rotalizumab); β 7 integrin blockers such as rhuMAb β 7; igE channel blockers such as anti-M1 prime; secretion of homotrimeric LTa3 and membrane-bound heterotrimeric LTa1/β 2 blockers such as anti-lymphotoxin alpha (LTa); radioisotope (e.g., at) ²¹¹ 、I ¹³¹ 、I ¹²⁵ 、Y ⁹⁰ 、Re ¹⁸⁶ 、Re ¹⁸⁸ 、Sm ¹⁵³ 、Bi ²¹² 、P ³² 、Pb ²¹² And radioactive isotopes of Lu); various test agents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH ₃ Or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin (quercetin), resveratrol (resveratrol), piceatannol, epigallocatechin (EGCG)Catechin gallate, theaflavin (theaflavin), flavanol (flavanol), procyanidin (procyanidin), betulinic acid (betulinic acid), and derivatives thereof; autophagy inhibitors such as chloroquine (chloroquine); delta-9-tetrahydrocannabinol (dronabinol),) (ii) a Beta-lapachone (beta-lapachone); lapachol (lapachol); colchicine; betulinic acid; acetyl camptothecin, scolecetin (scolecectin), and 9-aminocamptothecin); podophyllotoxin (podophylotoxin); tegafur (tegafur)BexaroteneBisphosphonates such as clodronate (e.g.,or) Etidronate (etidronate)NE-58095 zoledronic acid/zoledronic acid saltAlendronate (alendronate)Pamidronate (pamidronate)Tiludronate (tirudronate)Or risedronate (risedronate)And epidermal growth factor receptor (EGF-R); vaccines such asA vaccine; perifosine (perifosine), COX-2 inhibitors (e.g., celecoxib (celecoxib) or etoricoxib (etoricoxib)), proteasome inhibitors (e.g., PS 341); CCI-779; tipifamob (tipifamob) (R11577); sorafenib (oraafenib), ABT510; bcl-2 inhibitors such as sodium orlimerson (oblimersen sodium)Pixantrone (pixantrone); farnesyl transferase inhibitors such as lonafamib (SCH 6636, SARASAR) ^TM ) (ii) a And pharmaceutically acceptable salts, acids or derivatives of any of the above; and combinations of two or more of the above, such as CHOP, an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone; and FOLFOX, an oxaliplatin (ELOXATIN) ^TM ) Abbreviation for treatment regimen combining 5-FU and folinic acid.

Chemotherapeutic agents also include nonsteroidal anti-inflammatory drugs having analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of cyclooxygenase enzymes. Specific examples of NSAIDs include aspirin (aspirin), propionic acid derivatives such as ibuprofen (ibuprofofen), fenoprofen (fenoprofen), tyroprofen (ketoprofen), flurbiprofen (flurbiprofen), oxaprozin (oxazin) and naproxen (naproxen), acetic acid derivatives such as indomethacin (indomethacin), sulindac (sulindac), etodolac (etodolac), diclofenac (diclofenac), enolic acid derivatives such as piroxicam (piroxicam), meloxicam (meloxicam), tenoxicam (tenoxicam), droxicam (droxicam), lornoxicam (lornoxicam) and isoxicam (isoxicam), fenamic acid (fenamic acid) derivatives such as mefenamic acid (mefenamic acid), meclofenamic acid (meclofenamic acid), fenamic acid (fenamic acid), fenamic acid (valdecoxib), etoricoxib (norfloxacin (valdecoxib), and norfloxacin (loxacin (etoricoxib), etoricoxib (loxacin), and fenamic acid (loxb), and fenamic acid (loxb)). NSAIDs may be useful for symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory joint diseases, ankylosing spondylitis, psoriatic arthritis, reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, post-operative pain, mild to moderate pain due to inflammation and tissue injury, fever, ileus and renal colic.

Chemotherapeutic agents also include therapeutic agents for alzheimer's disease such as donepezil hydrochloride (donepezil hydrochloride) and rivastigmine (rivastigmine); therapeutic agents for Parkinson's Disease such as L-DOPA/carbidopa (cardopa), entacapone (entacapone), ropinirole (roprole), pramipexole (pramipexole), bromocriptine (bromocriptine), pergolide (pergolide), trihexyphenidyl (trihexyphenidyl), and amantadine (amantadine); drugs for treating Multiple Sclerosis (MS) such as interferon-beta (e.g.,and) Glatiramer acetate and mitoxantrone; therapeutic agents for asthma, such as salbutamol (albuterol) and montelukast sodium (montelukast sodium); drugs for treating schizophrenia, such as repropelle (zyprexa), risperidone (risperdal), quetiapine (seroquel), and haloperidol (haloperidol); anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus (tacrolimus), rapamycin, mycophenolate mofetil (mycophenolate mofetil), interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; nerve factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, antispasmodics, ion channel blockers, riluzole (riluzole), and anti-parkinsonism agents; drugs for treating cardiovascular diseases such as beta-blockersACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; drugs for treating liver diseases such as corticosteroids, cholestyramine (cholestyramine), interferon, and antiviral agents; drugs for treating hematological disorders, such as corticosteroids, antileukemic agents, and growth factors; and drugs such as gamma globulin for the treatment of immunodeficiency disorders.

In addition, the chemotherapeutic agent includes pharmaceutically acceptable salts, acids, or derivatives of any of the chemotherapeutic agents described herein, as well as combinations of two or more thereof.

For the treatment of inflammatory or autoimmune diseases, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: methotrexate, tofacitinib, 6-mercaptopurine, azathioprine, sulfasalazine, mesalamine, olsalazine chloroquine/hydroxychloroquine, penicillamine, aurothiomalate (intramuscular and oral), azathioprine, colchicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (albuterol, terbutaline, salmeterol), xanthines (theophylline, aminophylline), cromolinate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporine, FK506, rapamycin, mycophenolate, leflunomide, NSAIDs (e.g. ibuprofen), corticosteroids (e.g. prednisolone), phosphodiesterase inhibitors, adenosine (adensonsine) agonists, antithrombotic agents, inhibitors of adrenergic drugs, drugs that interfere with signaling by cytokines such as TNF or IL-1 (e.g. NIK, K inhibitors or inhibitors of proinflammatory signaling), inhibitors of TNF-1-transferase, inhibitors of TNF-1-6-transferase, TNF-I, soluble inhibitors of intracellular signaling, e.g. TNF-8-I, inhibitors of TNF-1-I, TNF-8-I, inhibitors of intracellular signaling, TNF-1-I, inhibitors of intracellular signaling, e, TNF-8-I, inhibitors of intracellular signaling, e, and inhibitors of TNF-4-I, e, e.g. TNF-1-5, and inhibitors of soluble receptor, e, celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, adalimumab, certolizumab, tosubuzumab, abatacept, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sulfur sodium malate, aspirin, triamcinolone acetonide, propoxyphene naphthalene sulfonate/apap, folate, naproxone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone hydrochloride, hydrocodone/apap bitartrate, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol hydrochloride, salsalate, sulindac, cyanocobalamin/fa/pyridoxine acetaminophen, alendronate sodium, prednisolone, cortisone, betamethasone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine chondroitin/chondroitin, amitriptyline hydrochloride, sulfadiazine oxycodone hydrochloride/acetaminophen, olopatadine hydrochloride, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1TRAP, MRA, CTLA4-IG, IL-18BP, anti-IL-12, anti-IL 1S, BIRB-796, SCI0-469, VX-702, AMG-548, VX-740, roflumilast, IC-485, CDC-801, S1P1 agonists such as FTY720, PKC family inhibitors such as robusta (Ruboxistaurin) or AEB-pram. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with methotrexate or leflunomide. In the case of moderate or severe rheumatoid arthritis, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with cyclosporin and an anti-TNF antibody as described above. The compound of formula (I) or a pharmaceutically acceptable salt thereof may also be administered in combination with: budesonide; an epidermal growth factor; a corticosteroid; cyclosporine, sulfasalazine; an aminosalicylate; 6-mercaptopurine; azathioprine; metronidazole; a lipoxygenase inhibitor; mesalazine; oxalazine; balsalazide (balsalazide); an antioxidant; a thromboxane inhibitor; an IL-1 receptor antagonist; anti-IL-1 monoclonal antibodies; anti-IL-6 monoclonal antibodies; a growth factor; an elastase inhibitor; a pyridyl-imidazole compound; antibodies or antagonists to other human cytokines or growth factors (e.g., TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF and PDGF); a cell surface molecule (e.g., CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, or CD90 or a ligand thereof); methotrexate; (ii) a cyclosporin; FK506; rapamycin; mycophenolate mofetil; leflunomide; NSAIDs (e.g., ibuprofen); corticosteroids (e.g., prednisolone); a phosphodiesterase inhibitor; an adenosine agonist; an antithrombotic agent; a complement inhibitor; (ii) an adrenergic agent; drugs that interfere with signaling by pro-inflammatory cytokines such as TNF 5 or IL-1 (e.g., NIK, IKK, or MAP kinase inhibitors); inhibitors of IL-1 convertase; (ii) a TNF invertase inhibitor; t cell signaling inhibitors such as kinase inhibitors; (ii) a metalloprotease inhibitor; sulfasalazine; azathioprine; 6-mercaptopurine; an angiotensin converting enzyme inhibitor; soluble cytokine receptors (e.g., soluble p55 or p75TNF receptor, siL-1RI, siL-1RII, siL-6R) and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13, or TGF).

For the treatment of crohn's disease, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: TNF antagonists (e.g., anti-TNF antibodies), D2E7 (adalimumab), CA2 (infliximab), CDP 571, TNFR-Ig construct, (p 75TNFRIGG (etanercept)), p55TNFRIGG (LENERCEPT) ^TM ) An inhibitor or a PDE4 inhibitor.

For the treatment of inflammatory bowel disease, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: corticosteroids (such as budesonide or dexamethasone); sulfasalazine, 5-aminosalicylic acid; oxalazine; drugs that interfere with the synthesis or action of pro-inflammatory cytokines such as IL-1 (e.g., IL-1 convertase inhibitors or IL-1 ra); t cell signaling inhibitors (e.g., tyrosine kinase inhibitors); 6-mercaptopurine; IL-11; mesalazine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate/atropine sulfate; loperamide hydrochloride; methotrexate; omeprazole; a folate; ciprofloxacin/glucose-water; hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinolone acetonide acetate; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodone hydrochloride/acetaminophen; promethazine hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphene naphthalenesulfonate; hydrocortisone; a plurality of vitamins; balsalazide disodium (balsalazide disodium); codeine phosphate/apap; colesevelam hydrochloride; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab or interferon-gamma.

For the treatment of multiple sclerosis, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: a corticosteroid; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; (ii) a cyclosporin; methotrexate; 4-aminopyridine; tizanidine; interferon-la (Biogen); interferon-lb (Chiron/Berlex); interferon-n 3 (Interferon Sciences/Fujimoto), interferon- (Alfa Wassermann/J)&J) Interferon 1A-IF (seroo/inlet Therapeutics), pegylated interferon 2b (Enzon/Schering-ploough), copolymer 1 (Cop-1;teva Pharmaceutical Industries, inc.); high pressure oxygen; intravenous immunoglobulin; cladribine; antibodies or antagonists to other human cytokines or growth factors and their receptors (e.g., TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II, GM-CSF, FGF or PDGF).

For the treatment of AIDS, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or ligands thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof may also be administered in combination with: methotrexate, cyclosporine, FK506, rapamycin, mycophenolate, leflunomide, S1P1 agonists, NSAIDs (e.g., ibuprofen), corticosteroids (e.g., prednisolone), phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic drugs, drugs that interfere with signaling by proinflammatory cytokines such as TNF or IL-1 (e.g., NIK, IKK, P38, or MAP kinase inhibitors), IL-1 convertase inhibitors, TACE inhibitors, T cell signaling inhibitors (e.g., kinase inhibitors), metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurine, angiotensin converting enzyme inhibitors, soluble cytokine receptors (e.g., soluble P55 or P75TNF receptors, siL-1RI, siL-1RII or siL-6R), or anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-13, or TGF).

The compounds of formula (I) or pharmaceutically acceptable salts thereof may also be administered in combination with: such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, zalilodene hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, immune factor NNS03, ABR-215062, anergix.MS, chemokine receptor antagonists, BBR-2778, cara Gu Lin, CPI-1189, LEM (liposome-encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE 4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neuromax, pirfenidone allotrope (allp) 8 (RDP-1258), sTNF-R1, talampanel (talampanel), teriflunomide (teriflunomide), TGF-beta 2, telithromolide (VLA), VLA 1404-4, interferon gamma-gamma antagonists, for example, ELLAMPITA-1404-interferon, or interferon gamma-4 agonists.

For the treatment of ankylosing spondylitis, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocycline, prednisone, anti-TNF antibodies, D2E7CA2 (infliximab), CDP 571, TNFR-Ig construct (p 75 TNFRigG)Or p55TNFRigG)。

For the treatment of asthma, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: salbutamol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levosalbutamol hydrochloride, salbutamol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, butbuterol acetate, prednisolone, theophylline anhydrate, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, cromolyn sodium, fexofenadine hydrochloride, flunisolide/menthol, amoxicillin/clavulanate, levofloxacin guaifenesin, dexamethasone sodium phosphate, moxifloxacin hydrochloride, doxycycline hydrochloride, guaifenesin/d-methanethiol, p-ephedrine/cod/chlorpheniramine (chlorphenir), gatifloxacin, cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin, pe/dihydrocodeinone/chlorpheniramine, cetirizine hydrochloride/pseudoephedrine, phenylephrine/cod/promethazine, codeine/promethazine, cefprozil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone, an anti-IL-13 antibody, or oxcinaline sulfate.

For the treatment of COPD, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: salbutamol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, salbutamol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrate (theophylline anhydrous), methylprednisolone sodium succinate (methylprednisolone sodium succinate), montelukast sodium (montelukast sodium), budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaiacol glyceryl ether, azithromycin, beclomethasone dipropionate, levosalbutamol hydrochloride, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorphenamine, metaproterenol sulfate (suprofate), methylprednisolone, codeine/chlorphenamine, tiamine, tiaproflavine, bromhexine/bromhexine, and bromhexine.

For the treatment of psoriasis, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: calcipotriene (calcipotriene), clobetasol propionate (clobetasol propionate), triamcinolone acetonide, halobetasol propionate (halobetasol propionate), tazarotene (tazarotene), methotrexate, fluocinonide, betamethasone dipropionate (betamethasone dipropionate), fluocinolone acetonide, acitretin (acitretin), tar shampoo (tar shampo), betamethasone valerate, mometasone furoate (mometasone furoate), ketoconazole (ketoconazole), pramoxine/fluocinonide (pramoxine/fluconazole), hydrocortisone valerate (hydrocortisone valerate), fluocinolone acetonide (flunarolide), urea, betamethasone (betamethasone), clobetasol propionate/esolvesol propionate (clobetasol propionate), fluocinolone propionate (fluocinolone propionate) azithromycin, hydrocortisone, moisturizing formula (moisturizing formula), folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept folate (etanercept folate), lactic acid, methoxsalen, hc/bismuth subgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen, citalopram hydrochloride (halcinonide), salicylic acid, anthralin, clocotrione pivalate (clocotolone pivalate), coal extract, coal tar/salicylic acid/sulfur, desoximetasone (desoximetasone), diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/na lact, mineral oil/peanut oil, isopropyl petroleum/myristate, psoralen (psoralen), salicylic acid, and soap/tribromosalen, thimerosal/boronic acid, celecoxib, infliximab, cyclosporine, alefacept (alefacept), efacizumab, tacrolimus, pimecrolimus (pimecrolimus), PUVA, UVB, sulfasalazine, ABT-874, or usekinamab.

For the treatment of psoriatic arthritis, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone dipropionate enhancement, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethyl sulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, naproxone, tolmetin sodium (tolmetin sodium), calcipotriene, cyclosporine, sodium/misoprostol, fluocinonide, glucosamine sulfate, diclofenac sodium gold thiomalate, dihydrocodeinone/apap bitartrate, ibuprofen, risedronate sodium (risperidone sodium), sulfadiazine, thioguanine, valdecoxib, alexie, D2E7 (adalimumab) or efavirenza.

For the treatment of lupus, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: NSAIDs (e.g., diclofenac, naproxen, ibuprofen, piroxicam, or indomethacin); COX2 inhibitors (e.g., celecoxib, rofecoxib, or valdecoxib); antimalarial drugs (e.g., hydroxychloroquine); steroids (e.g., prednisone, prednisolone, budesonide, or dexamethasone); cytotoxic agents (e.g., azathioprine, cyclophosphamide, mycophenolate mofetil, or methotrexate); PDE4 inhibitors or purine Synthesis inhibitors (e.g. N-acetyl-D)). For example, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: sulfasalazine, 5-aminosalicylic acid, olsalazine,Drugs or caspase inhibitors (e.g., IL-1 convertase inhibitors or IL-1 ra) that interfere with the synthesis, production or action of pro-inflammatory cytokines (e.g., IL-1).

The compound of formula (I) or a pharmaceutically acceptable salt thereof may also be administered in combination with: t cell signaling inhibitors (e.g., tyrosine kinase inhibitors) or molecules that target T cell activation (e.g., CTLA-4-IgG, anti-B7 family antibodies, or anti-PD-1 family antibodies).

The compound of formula (I) or a pharmaceutically acceptable salt thereof may also be administered in combination with: an IL-11 antibody, an anti-cytokine antibody (e.g., fonotolizumab (anti-IFNg antibody)), or an anti-receptor antibody (e.g., an anti-IL-6 receptor antibody or an antibody to a B cell surface molecule).

The compound of formula (I) or a pharmaceutically acceptable salt thereof may also be administered in combination with: LJP 394 (abelimus), a B cell depleting or inactivating drug (e.g., rituximab (anti-CD 20 antibody) or lymphostat-B (anti-BlyS antibody)), a TNF antagonist (e.g., anti-TNF antibody), D2E7 (adalimumab), CA2 (infliximab), CDP 571, a TNFR-Ig construct (p 75TNFRIGG (etanercept)), or p55TNFRIGG (LENERCEPT) ^TM )。

The compounds of formula (I) or pharmaceutically acceptable salts thereof may also be administered in combination with one or more agents useful in the prevention or treatment of AIDS: HIV reverse transcriptase inhibitors, HIV protease inhibitors, immunomodulators or other retroviral agents. Examples of reverse transcriptase inhibitors include, but are not limited to, abacavir (abacavir), adefovir (adefovir), didanosine (didanosine), dipivoxil delavirdine, efavirenz (efavirenz), emtricitabine (emtricitabine), lamivudine (lamivudine), nevirapine (nevirapine), rilpivirine (rilpivirine), stavudine (stavudine), tenofovir (tenofovir), zalcitabine (zalcitabine), and zidovudine (zidovudine). Examples of protease inhibitors include, but are not limited to, an Gena vir (amprenavir), atazanavir (atazanavir), darunavir (dauunavir), indinavir (indinavir), fosamprenavir (fosamprenavir), lopinavir (lopinavir), nelfinavir (nelfinavir), ritonavir (ritonavir), saquinavir (saquinavir), and tipranavir (tipranavir). Examples of other retroviral drugs include, but are not limited to, eltamivir (elvitegravir), enfuvirtide (enfuvirtide), maraviroc (maraviroc), and raltegravir (raltegravir).

For the treatment of type II diabetes, hepatic steatosis, insulin resistance, metabolic syndrome or related disorders, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with: insulin modified to improve duration of action in vivo; drugs that stimulate insulin secretion, such as acetohexamide (acetohexamide), chlorpropamide (chlorparamide), glyburide (glyburide), glimepiride (glimepiride), glipizide (glipizide), gliclazide (glizide), glimepiride (gliquide), glipizide (gliclazide), gliquidone (gliquidone), repaglinide (rapalogide), nateglinide (nateglinide), tolazamide (tolazamide), or tolbutamide (tolbutamide); drugs that are glucagon-like peptide agonists, such as isntadine (exantate), liraglutide (liraglutide) or tasselutamide (taspoglutide); drugs that inhibit dipeptidyl peptidase IV, such as vildagliptin (vildagliptin), sitagliptin (sitagliptin), saxagliptin (saxagliptin), linagliptin (linagliptin), alogliptin (alogliptin), or sarogliptin (septidagliptin); drugs that bind peroxisome proliferator-activated receptor γ, such as rosiglitazone (rosiglitazone) or pioglitazone (pioglitazone); drugs that reduce insulin resistance, such as metformin; or drugs that reduce glucose absorption in the small intestine, such as acarbose, miglitol or voglibose.

For the treatment of acute or chronic kidney disease, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination with dopamine, a diuretic (e.g. furosemide), bumetanide, thiazides, mannitol, calcium gluconate, sodium bicarbonate, salbutamol, paricalcitol, doxercalciferol, cinacalcet or bardoxolone methyl.

The amount of both the compound of formula (I) or salt thereof and the additional agent (in those compositions comprising additional therapeutic agents as described above) which may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In certain embodiments, the compositions of the present invention are formulated such that a dosage of 0.01 to 100mg/kg body weight/day of the present invention can be administered.

The additional therapeutic agent and the compound of formula (I) may act synergistically. Thus, the amount of additional therapeutic agent in such compositions may be less than that required in monotherapy using only the therapeutic agent, or may have fewer side effects on the patient when lower doses are used. In certain embodiments, in such compositions, a dose of 0.01 to 1,000 μ g/kg body weight/day of an additional therapeutic agent may be administered.

Provided herein are methods of increasing the duration of response to a cytotoxic agent in an individual having cancer comprising administering to the individual (a) an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and (b) an effective amount of a cytotoxic agent.

In certain embodiments of any of the methods, the cytotoxic agent is a targeted therapy. In certain embodiments, the targeted therapy is one or more of an EGFR antagonist, a RAF inhibitor, and/or a PI3K inhibitor.

In certain embodiments of any of the methods, the targeted therapy is an EGFR antagonist. In certain embodiments of any of the methods, the EGFR antagonist is N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine and/or a pharmaceutically acceptable salt thereof. In certain embodiments, the EGFR antagonist is N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine. In certain embodiments, the EGFR antagonist is N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl) furan-2-yl) quinazolin-4-amine, di-4-methylbenzenesulfonate, or a pharmaceutically acceptable salt thereof (e.g., lapatinib).

In certain embodiments of any of the methods, the targeted therapy is a RAF inhibitor. In certain embodiments, the RAF inhibitor is a BRAF inhibitor. In certain embodiments, the RAF inhibitor is a CRAF inhibitor. In certain embodiments, the BRAF inhibitor is vemurafenib. In certain embodiments, the RAF inhibitor is 3- (2-cyanoprop-2-yl) -N- (4-methyl-3- (3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino) phenyl) benzamide or a pharmaceutically acceptable salt thereof (e.g., AZ628 (CAS # 878739-06-1)).

In certain embodiments of any of the methods, the targeted therapy is a PI3K inhibitor.

In certain embodiments of any of the methods, the cytotoxic agent is chemotherapy. In certain embodiments of any of the methods, the chemotherapy is a taxane. In certain embodiments, the taxane is paclitaxel. In certain embodiments, the taxane is docetaxel.

In certain embodiments of any of the methods, the cytotoxic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments of any of the methods, the cytotoxic agent is a taxane and a platinum agent. In certain embodiments, the taxane is paclitaxel. In certain embodiments, the taxane is docetaxel. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin.

In certain embodiments of any of the methods, the cytotoxic agent is a vinca alkaloid. In certain embodiments, the vinca alkaloid is vinorelbine. In certain embodiments of any of the methods, the chemotherapy is a nucleoside analog. In certain embodiments, the nucleoside analog is gemcitabine.

In certain embodiments of any of the methods, the cytotoxic agent is radiation therapy.

In certain embodiments of any of the methods, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered concomitantly with a cytotoxic agent (e.g., targeted therapy, chemotherapy, and/or radiotherapy). In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered prior to and/or concurrently with a cytotoxic agent (e.g., targeted therapy, chemotherapy, and/or radiotherapy).

Examples of the invention

As described in the examples below, in certain exemplary embodiments, the compounds are prepared according to the following general procedures. It is to be understood that while general methods describe the synthesis of certain compounds of the invention, the following general methods and other methods known to those of ordinary skill in the art can be applied to all compounds and subclasses and classes of each of these compounds as described herein.

General scheme A

Representative compounds of formula (I) were prepared according to the scheme shown above.

Intermediate A (e.g. general Synthesis of intermediates)Prepared as described in (1) treatment with an alkylating agent and a base in a solvent such as DMF or acetonitrile at elevated temperature to provide the corresponding N-R ¹ A substituted derivative. Those products are coupled with a substituted aryl boronic acid under Pd-catalyzed conditions to form a biaryl intermediate from which the tosyl group is removed under hydrolysis conditions to provide the compound of formula (I).

General scheme B

Intermediate a (prepared as described in the general synthesis of intermediates) is treated with an alkylating agent and a base in a solvent such as DMF or acetonitrile at elevated temperature to afford the corresponding N-R ¹ A substituted derivative. Those products were coupled with 3-borono-4-methoxybenzoic acid under Pd-catalyzed conditions to form the corresponding biaryl carboxylates. Those intermediates are coupled with various amines to give compounds of formula (I).

General scheme C

Intermediate A (prepared as described in the general synthesis of intermediates) is treated with an alkylating agent and a base at elevated temperature in a solvent such as DMF or acetonitrile to provide the corresponding N-R ¹ A substituted derivative. Those products were coupled with (4- (methoxycarbonyl) phenyl) boronic acid under Pd-catalyzed conditions to form the corresponding biaryl esters. Methylmagnesium bromide is added, followed by hydrolysis to remove the tosyl group, to give the compound of formula (I).

General scheme D

Intermediate a (prepared as described in the general synthesis of intermediates) is treated with an alkylating agent and a base in a solvent such as DMF or acetonitrile at elevated temperature to afford the corresponding N-R ¹ A substituted bromide. Deprotection of those products under hydrolytic conditions followed by coupling with 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-ol (prepared from 1,4-dibromobenzene treated with butyllithium and quenched with acetone followed by boronation) forms compounds of formula (I).

General scheme E

Intermediate B (prepared as described in the general synthesis of intermediates) is treated with an alkylating agent and a base at elevated temperature in a solvent such as DMF or acetonitrile to afford the corresponding N-R ¹ A substituted derivative. Those products were coupled with (3- (dimethylcarbamoyl) phenyl) boronic acid under Pd-catalyzed conditions to give compounds of formula (I).

General procedure for the preparation of intermediate A

Step 1:

2-methoxy-4-methyl-3-nitropyridine

A solution of 2-chloro-4-methyl-3-nitropyridine (250g, 1.45mol) in methanol (1.0L) was added dropwise (2 h) to stirred and cooled (0 ℃ C.) sodium methoxide (250g, 4.63mol) in methanol (methanol: (2 h)850 mL) in a solvent. After addition, the mixture was heated to reflux for 23h, at which time TLC indicated that the reaction was complete. The mixture was concentrated under reduced pressure to a volume of about 900mL and quenched by the addition of water (1.5L). The resulting solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (250g, 100% yield) as a brown solid. ¹ H NMR(400MHz，DMSO-d6)：δ8.22(d，J＝5.2Hz，1H)，7.10(d，J＝5.6Hz，1H)，3.92(s，3H)，2.26(s，3H)。

Step 2:

5-bromo-2-methoxy-4-methyl-3-nitropyridine

Sodium acetate (365g, 5.37mol) was added to a stirred solution of 2-methoxy-4-methyl-3-nitropyridine (250g, 1.49mol) in acetic acid (1.5L) at ambient temperature, followed by dropwise addition (30 min) of Br ₂ (639g, 4.00mol). After addition, the mixture was heated at 80 ℃ for 12h, at which time TLC indicated that the reaction had been completed. The mixture was cooled (0 ℃) and quenched by the sequential addition of 10% aqueous sodium sulfate (1.5L) and saturated aqueous sodium sulfate (1.5L). The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (302g, 82.2% yield) as a light yellow solid. ¹ H NMR(400MHz，DMSO-d6)：δ8.25(s，1H)，3.94(s，3H)，2.29(s，3H)。

And step 3:

(E) -2- (5-bromo-2-methoxy-3-nitro-4-pyridinyl) -N, N-dimethyl-vinylamine

DMF-DMA (600 mL) was added slowly to a stirred and heated (80 ℃ C.) solution of 5-bromo-2-methoxy-4-methyl-3-nitropyridine (134g, 0.54mol) in DMF (1.1L). After the addition, the mixture was heated at 95 ℃ for 5h. The mixture was cooled to room temperature and poured into ice-cold water (3L). The resulting red solid was collected by filtration and washed with waterWater washed and dried under reduced pressure to give the title compound (167g, 100% yield) as a red solid. ¹ H NMR(400MHz，DMSO-d6)：δ8.24(s，1H)，7.05(d，J＝13.6Hz，1H)，7.05(d，J＝13.6Hz，1H)，4.80(d，J＝13.2Hz，1H)，3.88(s，3H)，2.90(s，6H)。

And 4, step 4:

4-bromo-7-methoxy-1H-pyrrolo [2,3-c ] pyridine

2- (5-bromo-2-methoxy-3-nitropyridin-4-yl) -N, N-dimethylvinylamine (50.0g, 165mmol), fe (50.0g, 893mmol) and NH ₄ Cl (50.0g, 943mmol) in methanol/H ₂ The mixture in O (1900/250 mL) was heated at reflux for 7h, at which time LCMS indicated that the reaction was complete. The mixture was filtered while hot and the filter cake was washed with methanol (3 × 200 mL). The combined filtrates were concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5:1) to give a crude product. The crude material was triturated with acetonitrile to give the title compound (37.4 g,99.5% yield) as a light brown solid. LCMS M/Z (M + H) 226.7, 228.7.

And 5:

4-bromo-7-methoxy-1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridine

A solution of 4-bromo-7-methoxy-1H-pyrrolo [2,3-c ] pyridine (34.3g, 0.15mol) in THF (700 mL) was added dropwise to a stirred and cooled (0 ℃ C.) solution of sodium hydride (60%, 19.2g, 0.48mol) in THF (700 mL). After the addition, the mixture was stirred at room temperature for 1h and then cooled again to 0 ℃. Tosyl chloride (38.0 g,0.20 mol) in THF (700 mL) was added dropwise and the resulting mixture was stirred at ambient temperature for 2h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (1.0L) and then extracted with ethyl acetate (3 × 600 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with acetonitrile to give the title compound (51.2g, 88.9% yield) as a brown solid. The crude material was used in the next step without further purification.

Step 6:

4-bromo-1- (p-toluenesulfonyl) -6H-pyrrolo [2,3-c ] pyridin-7-one

HBr (40% aq, 1.1L) was added to 4-bromo-7-methoxy-1- (p-toluenesulfonyl) pyrrolo [2,3-c]Pyridine (102.5g, 0.27mol) in ethanol (200 mL). After addition, the mixture was heated at 90 ℃ for 2h, at which time TLC indicated that the reaction had been completed. The mixture was cooled to 0 ℃ and the resulting white solid was collected by filtration. The solid was washed with water and dried in vacuo to give the title compound (intermediate a) (87.5g, 88.6% yield) as a light brown solid. ¹ H NMR(400MHz，DMSO-d6)：δ11.48(s，1H)，8.01(d，J＝3.6Hz，1H)，8.90(d，J＝8.0Hz，2H)，7.38(d，J＝8.0Hz，2H)，7.32(s，1H)，6.57(d，J＝3.2Hz，1H)，2.34(s，3H)。

General procedure for the preparation of intermediate B

Step 1:

5-bromo-2-methoxy-3-nitropyridine

Sodium methoxide (17.2g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (15.0 g, 64.2mmol) in methanol (125 mL). After addition, the reaction mixture was heated at reflux for 2h. The mixture was concentrated under reduced pressure and the residue was diluted with water (200 mL). Collecting the obtained precipitate by filtration, washing with water, and drying under reduced pressure to obtainThe title compound (12.0 g,81.5% yield) was a brown solid. ¹ H NMR(400MHz，CDCl ₃ )：δ8.43(d，J＝2.4Hz，1H)，8.38(d，J＝2.0Hz，1H)，4.09(s，3H)。

Step 2:

4-bromo-7-methoxy-2-methyl-1H-pyrrolo [2,3-c ] pyridine

Isopropenylmagnesium bromide (0.5M in THF, 105.0mL,55.0 mmol) was added dropwise to a stirred and cooled (-78 ℃ C.) solution of 5-bromo-2-methoxy-3-nitropyridine (4.0 g,17.1 mmol) in THF (40 mL). After addition, the resulting mixture was gradually warmed to room temperature and stirred for an additional 3h. The reaction mixture was quenched by addition of 1M aqueous ammonium chloride (150 mL) and then extracted with ethyl acetate (3 × 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10). LCMS M/Z (M + H) 240.1, 242.1.

And step 3:

4-bromo-2-methyl-1,6-dihydropyrrolo [2,3-c ] pyridin-7-one

Hydrogen bromide (40% aqueous solution, 20 mL) was added to 4-bromo-7-methoxy-2-methyl-1H-pyrrolo [2,3-c]Pyridine (1.65g, 6.8 mmol) in ethanol (10 mL). After addition, the reaction mixture was heated at 90 ℃ for 15h, at which time TLC indicated that the reaction had been completed. The mixture was cooled to 0 ℃ and the resulting solid was collected by filtration. The solid was washed with water and dried to give the title compound (intermediate B,0.9g,57.9% yield) as a brown solid. ¹ H NMR(400MHz，DMSO-d6)：δ12.06(s，1H)，11.00(s，1H)，7.03(s，1H)，5.97(s，1H)，2.29(s，3H)。LCMS M/Z(M+H)226.8，228.8

Example 1

3- (6-allyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethyl-benzamide

Step 1

6-allyl-4-bromo-1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridin-7-one

To a cooled (0 ℃) solution of 4-bromo-1- (p-toluenesulfonyl) -6H-pyrrolo [2,3-c ] pyridin-7-one (intermediate A) (300mg, 0.8mmol) in DMF (4 mL) was added sodium hydride (60% in mineral oil, 50mg, 1.0mmol). The mixture was stirred for 15min, then 3-bromoprop-1-ene (100mg, 1.0 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirring was continued for 2h. The reaction mixture was quenched with water (20 mL) and then extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine (2 × 20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (350mg, 100% yield) as a yellow solid. The crude material was used in the next step without further purification. LCMS M/Z (M + H) 409.3.

Step 2

3- [ 6-allyl-7-oxo-1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridin-4-yl ] -N, N-dimethyl-benzamide

To a mixture of 3- [ 6-allyl-7-oxo-1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridin-4-yl ] -N, N-dimethyl-benzamide (step 1, 350mg, 0.86mmol) and [3- (dimethylcarbamoyl) phenyl ] boronic acid (220mg, 1.1mmol) in 1M potassium carbonate (2 mL) in acetonitrile (2 mL) and water was added [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (ii) (63mg, 0.086 mmol). The reaction mixture was subjected to microwave irradiation at 100 ℃ for 10 minutes. The mixture was filtered through a pad of celite, rinsing with ethyl acetate (30 mL). The filtrate was washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (300mg, 70% yield) as a yellow solid. The crude material was used in the next step without further purification. LCMS M/Z (M + H) 476.4.

Step 3

3- (6-allyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethyl-benzamide

3- [ 6-allyl-7-oxo-1- (p-toluenesulfonyl) pyrrolo [2,3-c]Pyridin-4-yl]A mixture of-N, N-dimethyl-benzamide (step 2, 35mg, 0.074mmol) in methanol (1 mL) and 10M potassium hydroxide in water (0.8 mL) was stirred at 50 ℃ for 1h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (25-35% in ACN/H2O, 0.1% HeNH4OH) to give the title compound (13mg, 65% yield) as a white solid. ¹ H NMR(400MHz，DMSO-d6)δ7.66(m，J＝7.7，1.4Hz，1H)，7.58–7.49(m，2H)，7.41–7.31(m，3H)，6.44(d，J＝2.7Hz，1H)，6.02(m，J＝17.2，10.7，5.5Hz，1H)，5.21–5.08(m，2H)，4.68(m，J＝5.5，1.6Hz，2H)，2.99(m，J＝11.6Hz，6H)。LCMS M/Z(M+H)322.2。

The following compounds were prepared in a similar manner to example 1:

examples 2 to 54

Example 55

6- (but-3-en-1-yl) -4- (3- (difluoromethoxy) -5- (morpholine-4-carbonyl) phenyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Step 1:

(3-bromo-5-hydroxyphenyl) (morpholino) methanone

To a solution of 3-bromo-5-hydroxybenzoic acid (2.00g, 9.2 mmol) in DMF (20 mL) was added HATU (3.89g, 10.2 mmol), DIPEA (1.32g, 10.2 mmol) and morpholine (887 mg,10.2 mmol). The reaction mixture was stirred at rt for 10h, at which time LCMS showed the reaction was complete. The mixture was poured into water (40 mL) and extracted with ethyl acetate (50mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ethyl acetate = 1:2) to give the title compound (900mg, 31% yield) as a white solid.

Step 2:

(3-bromo-5- (difluoromethoxy) phenyl) (morpholino) methanone

To (3-bromo-5-hydroxyphenyl) (morpholino) methanone (900mg, 3.2mmol) in DMF (20 mL)/H ₂ Adding K into O (5 mL) solution ₂ CO ₃ (877mg, 6.3mmol) and 2-chloro-2,2-sodium difluoroacetate (966mg, 6.3mmol). The reaction mixture was heated at 100 ℃ for 2h, at which time LCMS showed the reaction was complete. After cooling, the mixture was poured into water (600 mL) and the resulting mixture was extracted with ethyl acetate (50mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ethyl acetate = 1:1) to give the title compound (400mg, 38% yield) as a yellow solid.

And step 3:

(3- (difluoromethoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) (morpholino) methanone

(3-bromo-5- (difluoromethoxy) phenyl) (morpholino) methanone (400mg, 1.19mmol), 4,4,4',4',5,5,5',5' -octamethyl-2,2 ' -bis (1,3,2-dioxaborole) (455mg, 1.79mmol), potassium acetate (175mg, 1.79mmol) and Pd (dppf) Cl ₂ (73mg, 0.1mmol) of a mixture in dioxane (25 mL) in N ₂ Heating at 120 deg.C for 5h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (60 mL) and washed with water (30mL × 2). The separated organic layer was concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether/ethyl acetate = 1:1) to give the title compound (300mg, 66% yield) as a yellow oil.

And 4, step 4:

The title compound was prepared in 13.8% yield from (3- (difluoromethoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) (morpholino) methanone and 4-bromobut-1-ene in a similar operation as shown in example a 06. ¹ H NMR(400MHz，DMSO-d6)δ12.18(s，1H)，7.55-7.36(m，3H)，7.18-7.15(m，1H)，6.42(s，1H)，5.87-5.80(m，1H)，5.07-4.99(m,2H)，4.11-4.08(m，2H)，3.63-3.53(m，4H)，3.36-3.26(m，4H)，2.48-2.46(m，2H)。LCMS M/Z(M+H)444。

Example 56

6-but-3-enyl-4- [7- (morpholine-4-carbonyl) -3H-benzimidazol-5-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one

Step 1

4-bromo-6- (but-3-en-1-yl) -1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

To 4-bromo-1- (p-toluenesulfonyl) -6H-pyrrolo [2,3-c]To a solution of pyridin-7-one (10.0g, 27.23mmol) (intermediate A) in DMF (150 mL) were added cesium carbonate (17.8g, 54.46mmol) and 4-bromobut-1-ene (4.8g, 35.40mmol). After addition, the mixture was stirred at ambient temperature for 16h, at which time LCMS indicated that the reaction was complete. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in H ₂ O (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were concentrated under reduced pressure and the crude product was purified by silica gel chromatography (hexane/ethyl acetate = 5:1) to give the title compound (6.0 g,52% yield) as a colorless oil. ¹ H NMR(400MHz，DMSO-d ₆ )：δ8.05-8.04(m，1H)，7.94-7.89(m，1H)，7.76(s，1H)，7.45-7.35(m，2H)，6.58-6.57(m，1H)，5.73-5.66(m，1H)，4.92-4.84(m，2H)，3.93-3.89(m，2H)，2.39(s，3H)，2.36-2.27(m，2H)。

Step 2

(2-amino-3-nitrophenyl) (morpholino) methanone

To a solution of morpholine (2.4g, 27.45mmol) in DMF (80 mL) was added 2-amino-3-nitrobenzoic acid (5.0g, 27.45mmol), HATU (12.5g, 32.94mmol) and N-ethyl-N-isopropylpropan-2-amine (10 mL). The reaction mixture was stirred at ambient temperature for 15h, at which time LCMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and washed with water (2 × 50 mL). The organic solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate = 3:1) to give the title compound (5.0 g,73% yield) as a yellow solid.

Step 3

(2-amino-5-bromo-3-nitrophenyl) (morpholino) methanone

To a solution of (2-amino-3-nitrophenyl) (morpholino) methanone (5.0 g, 19.90mmol) in acetic acid (50 mL) was added Br ₂ (3.82g, 23.88mmol). The reaction mixture was stirred at 0 ℃ for 30min, at which time LCMS indicated that the reaction was complete. The reaction mixture was poured into ice-cold water (30 mL). The resulting precipitate was collected by filtration and dried under reduced pressure to give the title compound (5.0 g,76% yield) as a yellow solid.

Step 4

(2,3-diamino-5-bromophenyl) (morpholino) methanone

To (2-amino-5-bromo-3-nitrophenyl) (morpholino) methanone (5.0 g, 15.15mmol) in EtOH/H ₂ Adding NH into O (5:1, 100 mL) solution ₄ Cl (4.1g, 75.73mmol) and Fe (4.2g, 75.73mmol). The reaction mixture was heated at reflux for 15h, at which time LCMS indicated that the reaction was complete. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with brine (2 × 40 mL). The separated organic layer was concentrated to give the crude title compound (4.2g, 92% yield) as a yellow oil.

Step 5

(6-bromo-1H-benzo [ d ] imidazol-4-yl) (morpholino) methanone

To a solution of (2-amino-5-bromo-3-nitrophenyl) (morpholino) methanone (4.2g, 12.72mmol) in DMF (40 mL) was added triethoxymethane (2.8g, 19.08mmol) and 4-methylbenzenesulfonic acid (220mg, 1.27mmol). After addition, the reaction mixture was stirred at ambient temperature for 15h, at which time LCMS indicated that the reaction was complete. The solvent was evaporated under reduced pressure and the residue diluted with water (40 mL). The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane/methanol = 10).

Step 6

(6-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-4-yl) (morpholino) methanone

To a solution of (6-bromo-1H-benzo [ d ] imidazol-4-yl) (morpholino) methanone (3.0 g, 9.67mmol) in DMF (50 mL) at 0 ℃ was slowly added sodium hydride (60%, 464mg, 11.61mmol). After the addition, the mixture was stirred at 0 ℃ for 1h, then (2- (chloromethoxy) ethyl) trimethylsilane (1.9 g, 11.61mmol) was added dropwise. The resulting mixture was stirred at ambient temperature for an additional 2h, at which time LCMS indicated that the reaction was complete. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (50 mL) and then extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were concentrated under reduced pressure. The crude product was purified by silica gel chromatography (hexane/ethyl acetate = 1:1) to give the title compound (3.0 g,70% yield) as a yellow solid.

Step 7

Morpholino (6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-4-yl) methanone

Reacting (6-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-4-yl) (morpholino) methanone (3.0 g,6.81mmol), 4,4,4',4',5,5,5',5' -octamethyl-2,2 ' -bis (1,3,2-dioxaborole) (3.6 g, 13.62mmol), potassium acetate (1.7 g, 17.64mmol), and Pd (dppf) Cl ₂ (0.5g, 0.68mmol) in dioxane (45 mL) was heated under microwave conditions at 110 ℃ for 45min at which time LCMS indicated that the reaction had been completed. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (80 mL), washed with water (2 × 50 mL) and concentrated to give the crude title compound (1.35g, 41% yield) as a brown oil.

Step 8

6- (but-3-en-1-yl) -4- (4- (morpholine-4-carbonyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) -1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Morpholino (6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-4-yl) methanone (450mg, 0.92mmol), 4-bromo-6- (but-3-en-1-yl) -1-tosyl-1H-pyrrolo [2,3-c]Pyridin-7 (6H) -one (389mg, 0.92mmol), pd (dppf) Cl ₂ (66mg, 0.09mmol) and cesium carbonate (601mg, 1.85mmol) in dioxane/H ₂ The mixture in O (10mL, 4. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water (2 × 20 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate = 2:1) to give the title compound (500mg, 77% yield) as a yellow solid.

Step 9

To 6- (but-3-en-1-yl) -4- (4- (morpholine-4-carbonyl)1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d)]Imidazol-6-yl) -1-tosyl-1H-pyrrolo [2,3-c]Dioxane/H of pyridin-7 (6H) -one (500mg, 0.71mmol) ₂ To the O (10mL, 1). The reaction mixture was heated at 80 ℃ for 3h, at which time LCMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (2 × 20 mL), and concentrated under reduced pressure to give crude 6- (but-3-en-1-yl) -4- (4- (morpholine-4-carbonyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d [ -d]Imidazol-6-yl) -1H-pyrrolo [2,3-c]Pyridin-7 (6H) -one (350mg, 90% yield).

To a solution of the above crude material in dichloromethane (15 mL) was added trifluoroacetic acid (15 mL). After addition, the reaction mixture was stirred at ambient temperature for 3h, at which time LCMS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (acetonitrile 13-33%/0.1% hcl in water) to give the title compound (11mg, 5% yield). ¹ H NMR(400MHz，CD ₃ OD)：δ9.58(s，1H)，8.16(s，1H)，7.91(s，1H)，7.48(s，2H)，6.57(s，1H)，5.97-5.88(m，1H)，5.09(t，J＝10.4Hz，2H)，4.26(t，J＝7.2Hz，2H)，4.02-3.48(m，8H)，2.65-2.57(m，2H)；LCMS M/Z(M+H)418。

Examples 57 and 58

6-but-3-enyl-4- [ 3-methyl-7- (morpholine-4-carbonyl) benzimidazol-5-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one and 6-but-3-enyl-4- [ 1-methyl-7- (morpholine-4-carbonyl) benzimidazol-5-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one

Step 1

6- (but-3-en-1-yl) -4- (4- (morpholine-4-carbonyl) -1H-benzo [ d ] imidazol-6-yl) -1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

To a solution of 6- (but-3-en-1-yl) -4- (4- (morpholine-4-carbonyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) -1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one (500mg, 0.71mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). After addition, the reaction mixture was stirred at ambient temperature for 3h, at which time LCMS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give the crude title compound (400mg, 98% yield) as a yellow oil.

Step 2

To a stirred and cooled (0 ℃) solution of (6-bromo-1H-benzo [ d ] imidazol-4-yl) (morpholino) methanone (500mg, 0.87mmol) in DMF (10 mL) was slowly added sodium hydride (60%, 42mg, 0.92mmol). After addition, the mixture was stirred at 0 ℃ for 1h, then iodomethane (149mg, 0.92mmol) was added. The resulting mixture was stirred at ambient temperature for 2h, at which time LCMS indicated that the reaction was complete. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and then extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate = 1:1) to give a mixture of methylated regioisomers (250mg, 49% yield) as a brown solid.

To dioxane/H of the above regioisomer (250mg, 0.43mmol) ₂ To a solution of O (10mL, 1), sodium hydroxide (34mg, 0.86mmol) was added. The reaction mixture was heated at 80 ℃ for 3h, at which time LCMS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane (40 mL) and water (30 mL). The separated organic layer was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (acetonitrile 18-48%/0.1% in water as NH.) ₄ OH) to yield the title compound as a white solid.

Example 57 (6.3mg, 3% yield). ¹ H NMR(400MHz，CD ₃ OD)：δ9.59(s，1H)，8.26(s，1H)，7.95(s，1H)，7.53-7.49(m，2H)，7.62(d，J＝2.8Hz，1H)，5.98-5.89(m，1H)，5.13-5.06(m，2H)，4.29-4.26(m，4H)，4.02-3.46(m，8H)，2.66-2.61(m，2H)。LCMS M/Z(M+H)432。

Example 58 (11mg, 6% yield). ¹ H NMR(400MHz，CD ₃ OD)：δ9.54(s，1H)，8.14(s，1H)，7.87(s，1H)，7.48(s，2H)，6.55(d，J＝2.8Hz，1H)，5.96-5.90(m，1H)，5.13-5.06(m，2H)，4.27-4.24(m，2H)，4.14(s，3H)，4.04-3.54(m，8H)，2.64-2.59(m，2H)。LCMS M/Z(M+H)432。

Example 59

6-but-3-enyl-4- [ 3-ethyl-7- (morpholine-4-carbonyl) benzimidazol-5-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one

The title compound was prepared in 4% yield from iodoethane in a similar operation as shown in example 02. ¹ H NMR(400MHz，CD ₃ OD)：δ8.32(s，1H)，7.87(s，1H)，7.54(s，1H)，7.40(s，1H)，7.35(s，1H)，6.58(s，1H)，5.93-5.87(m，1H)，5.10-5.02(m，2H)，4.43-4.38(m，2H)，4.21(t，J＝7.2Hz，2H)，3.88-3.81(m，4H)，3.62-3.56(m，2H)，3.42-3.35(m，2H)，2.61-2.56(m，2H)，1.55(t，J＝7.2Hz，3H)。LCMS M/Z(M+H)446。

Example 60

6-but-3-enyl-4- [6- (morpholine-4-carbonyl) -1H-benzimidazol-4-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one

Step 1

3,4-diamino-5-bromobenzoic acid methyl ester

4-amino-3-bromo-5-nitrobenzoic acid methyl ester (1.0g, 3.64mmol) and SnCl ₂ .2H ₂ A mixture of O (1.6 g, 7.27mmol) in ethyl acetate (30 mL) was heated at 90 ℃ for 18h, at which time LCMS indicated that the reaction was complete. After cooling, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were concentrated under reduced pressure to give the crude title compound (850 mg,95% yield) as a yellow solid. ¹ H NMR(400MHz，CDCl ₃ )：δ7.74(d，J＝1.6Hz，1H)，7.35(s，1H)，4.25(br.，s，2H)，3.86(s，3H)，3.50(br.，s，2H)。

Step 2

4-bromo-1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester

To a solution of 3,4-diamino-5-bromobenzoic acid methyl ester (850mg, 3.47mmol) in THF (30 mL) was added triethoxysilane (1.04g, 7.0mmol) and TsOH.H ₂ O (66mg, 0.35mmol). The resulting mixture was stirred at room temperature for 5h, at which time LCMS indicated that the reaction was complete. The solvent was evaporated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were concentrated under reduced pressure to give the crude title compound (820 mg,93% yield) as a pale white solid. ¹ H NMR(400MHz，CDCl ₃ )：δ8.40(s，1H)，8.22(s，2H)，3.97(s，3H)。

Step 3

(6- (methoxycarbonyl) -1H-benzo [ d ] imidazol-4-yl) boronic acid

Reacting 4-bromo-1H-benzo [ d]Imidazole-6-carboxylic acid methyl ester(820mg, 3.21mmol), 4,4,4',4',5,5,5',5' -octamethyl-2,2 ' -bis (1,3,2-dioxaborole) (1.15g, 4.51mmol), pd (dppf) Cl ₂ A mixture of (234mg, 0.32mmol) and potassium acetate (631mg, 6.44mmol) in dioxane (30 mL) was in N ₂ Heat at 120 ℃ for 16h under atmosphere, at which time LCMS indicated the reaction was complete. After cooling, the mixture was filtered through a pad of celite and rinsed with dioxane (20 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were concentrated under reduced pressure to give the crude product as a brown solid (650 mg,92% yield). LCMS M/Z (M + H) 220.8.

Step 4

4- (6- (but-3-en-1-yl) -7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester

4-bromo-6- (but-3-en-1-yl) -1-tosyl-1H-pyrrolo [2,3-c]Pyridin-7 (6H) -one (421mg, 1.00mmol), (6- (methoxycarbonyl) -1H-benzo [ d ]]Imidazol-4-yl) boronic acid (330mg, 1.5 mmol), cesium carbonate (652mg, 2.0mmol) and Pd (dppf) Cl ₂ (73mg, 0.10 mmol) in dioxane/H ₂ Mixture in O (5/1, 30 mL) in N ₂ Heat at 100 ℃ for 3h at which time LCMS indicated the reaction was complete. The solvent was evaporated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/methanol =99:1 to 16) to give the title compound as a white solid (400mg, 77% yield). LCMS M/Z (M + H) 516.

Step 5

4- (6- (but-3-en-1-yl) -7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -1H-benzo [ d ] imidazole-6-carboxylic acid

At the room temperature, the reaction mixture is heated,to 4- (6- (but-3-en-1-yl) -7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo [2,3-c]Pyridin-4-yl) -1H-benzo [ d]To a solution of methyl imidazole-6-carboxylate (400mg, 0.77mmol) in methanol (10 mL) was added sodium hydroxide solution (1N in water, 2.0mL,2.0 mmol). The resulting mixture was heated at 100 ℃ for 2h, at which time LCMS indicated that the reaction was complete. After cooling, the mixture was adjusted to pH =3-4 by adding 1N aqueous HCl. The resulting mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were concentrated under reduced pressure to give the crude title compound (200mg, 74% yield) as a white solid. ¹ H NMR(400MHz，DMSO-d ₆ )：δ12.94(br.s，1H)，12.16(s，1H)，8.84(s，1H)，8.19(s，1H)，8.06(s，1H)，7.67(s，1H)，7.45(d，J＝8.0Hz，0.5H)，7.34(s，1H)，7.07(d，J＝7.6Hz，0.5H)，6.24(s，1H)，5.87-5.80(m，1H)，5.08-4.97(m，2H)，4.13-4.09(m，2H)，2.50-2.48(m，1H)，2.25(s，1H)。

Step 6

6-but-3-enyl-4- [6- (morpholine-4-carbonyl) -1H-benzoimidazol-4-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one

4- (6- (but-3-en-1-yl) -7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c)]Pyridin-4-yl) -1H-benzo [ d]A mixture of imidazole-6-carboxylic acid (100mg, 0.28mmol), morpholine (73mg, 0.84mmol), HATU (141mg, 0.37mmol) and N-ethyl-N-isopropylpropan-2-amine (72mg, 0.56mmol) in DMF (10 mL) was heated at 60 ℃ for 8h when LCMS indicated that the reaction was complete. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (50 mL), washed with brine (2 × 20 mL), and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (acetonitrile 10-40%/0.1% hcl in water) to give the title compound as a white solid (25mg, 21% yield). ¹ H NMR(400MHz，CD ₃ OD)：δ9.56(s，1H)，7.97(d，J＝4.0Hz，1H)，7.78(s，1H)，7.58(s，1H)，7.45(d，J＝2.8Hz，1H)，6.28(d，J＝2.8Hz，1H)，5.94-5.88(m，1H)，5.15-5.05(m，2H)，4.27(t，J＝7.2Hz，2H)，3.93-3.47(m，8H)，2.65-2.59(m，2H)。LCMS M/Z(M+H)418。

Example 61

4- (6- (but-3-en-1-yl) -7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethyl-1H-benzo [ d ] imidazole-6-carboxamide

The title compound was prepared in 33% yield from dimethylamine hydrochloride in a similar operation as shown in example 04. ¹ H NMR(400MHz，CD ₃ OD)：δ9.54(s，1H)，7.96(d，J＝1.6Hz，1H)，7.78(d，J＝1.6Hz，1H)，7.55(s，1H)，7.44(d，J＝2.8Hz，1H)，6.29(d，J＝2.8Hz，1H)，5.95-5.88(m，1H)，5.14-5.04(m，2H)，4.26(t，J＝7.2Hz，2H)，3.20(s，3H)，3.12(s，3H)，2.65-2.59(m，2H)。LCMS M/Z(M+H)376。

Example 62

6-but-3-enyl-4- [ 1-methyl-6- (morpholine-4-carbonyl) benzimidazol-4-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one

Step 1

6- (but-3-en-1-yl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

4-bromo-6- (but-3-en-1-yl) -1-tosyl-1H-pyrrolo [2,3-c]Pyridin-7 (6H) -one (5.0g, 11.87mmol), 4,4,4',4',5,5,5',5' -octamethyl-2,2 ' -bis (1,3,2-dioxaborole) (7.5g, 29.67mmol), potassium acetate (2.3g, 23.74mmol), and Pd (dppf) Cl ₂ (870mg, 1.19mmol) in dioxane (50 mL)The mixture was heated at 120 ℃ for 1h under microwave conditions, at which time LCMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. From the residue H ₂ Diluted O (20 mL) and extracted with ethyl acetate (3X 20 mL). The combined organic layers were concentrated under reduced pressure and the crude product was purified by silica gel chromatography (hexane/ethyl acetate = 2:1) to give the title compound (3.5g, 44% yield) as a light yellow oil.

Step 2

4-bromo-1-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester

To 4-bromo-1H-benzo [ d ]]To a solution of imidazole-6-carboxylic acid methyl ester (3.8g, 14.9mmol) in DMF (80 mL) were added potassium carbonate (6.2g, 44.69mmol) and CH ₃ I (6.3g, 44.69mmol). After addition, the reaction mixture was stirred at 30 ℃ for 6h, at which time LCMS indicated that the reaction was complete. The solvent was removed by concentration under reduced pressure. The residue is substituted by H ₂ Diluted with O (30 mL) and extracted with ethyl acetate (3X 30 mL). The combined organic layers were concentrated to give the title compound (1.8g, 45% yield) as a yellow solid.

Step 3

4- (6- (but-3-en-1-yl) -7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -1-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester

Reacting 4-bromo-1-methyl-1H-benzo [ d]Imidazole-6-carboxylic acid methyl ester (500mg, 1.86mmol), 6- (but-3-en-1-yl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-c]Pyridin-7 (6H) -one (1.04g, 2.23mmol), cesium carbonate (908mg, 2.79mmol) and Pd (dppf) Cl ₂ (136mg, 0.19mmol) in dioxane/H ₂ The mixture in O (5:1, 18 mL) was heated under microwave conditions at 120 ℃ for 40min, at which time LCMS indicated that the reaction was complete. The solvent was evaporated under reduced pressure. From the residue H ₂ O (50 mL) was diluted and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate = 1:2) to give the title compound (350mg, 36% yield) as a yellow solid.

Step 4

4- (6- (but-3-en-1-yl) -7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -1-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid

To 4- (6- (but-3-en-1-yl) -7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo [2,3-c]Pyridin-4-yl) -1-methyl-1H-benzo [ d]Methyl imidazole-6-carboxylate (350mg, 0.66mmol) in methanol/H ₂ To the O (15/3 mL) solution was added sodium hydroxide (132mg, 3.30mmol). The mixture was heated at 80 ℃ for 16h, at which time LCMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure and the residue was taken up with H ₂ Dilution with O (8 mL). The solution was adjusted to pH =5-6 by adding 2N aqueous HCl. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure to give the title compound (220mg, 92% yield) as a yellow solid.

And 5:

To 4- (6- (but-3-en-1-yl) -7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c]Pyridin-4-yl) -1-methyl-1H-benzo [ d]Triethylamine (123mg, 1.21mmol), HATU (460mg, 1.21mmol) and morpholine (106mg, 1.21mmol) were added to a solution of imidazole-6-carboxylic acid (220mg, 0.61mmol) in DMF (5 mL). The resulting mixture was stirred at 30 ℃ for 16h, at which time LCMS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure and the crude product was purified by reverse phase chromatography (acetonitrile 19%/0.1% NH4OH in water) to give the title compound (86mg, 33%Yield) as a white solid. ¹ H NMR(400MHz，DMSO-d ₆ )：δ12.09(s，1H)，8.33(s，1H)，7.84(s，1H)，7.64(s，1H)，7.46(s，1H)，7.35-7.34(m，1H)，6.37(s，1H)，5.93-5.84(m，1H)，5.12-5.07(m，2H)，5.03-5.00(m，1H)，4.15-4.11(m，2H)，4.08(s，3H)，3.63-3.57(m，8H)，2.46-2.44(m，2H)。LCMS M/Z(M+H)432。

Example 63

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -N-cyclopropyl-4-methoxy-benzamide

Step 1:

4-bromo-6- [ (E) -but-2-enyl ] -1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridin-7-one

The title compound was prepared in the same manner as described in example 1, step 1.

Step 2:

3- [6- [ (E) -but-2-enyl ] -7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -4-methoxy-benzoic acid

Bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (0.05 eq, 0.24 mmol) was added to a mixture of 4-bromo-6- [ (E) -but-2-enyl ] -1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridin-7-one (4.75 mmol) and 3-borono-4-methoxy-benzoic acid (1.25 eq, 5.9 mmol) in 1,4-dioxane (14 mL) and potassium phosphate (2M in water, 3 eq, 14.24 mmol). The reaction mixture was heated at 90 ℃ for 2h. After cooling, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30-70% ethyl acetate/heptane) to afford the desired tosyl intermediate.

The intermediate was dissolved in methanol (10 mL) and 10M potassium hydroxide in water (1 mL) was added. The reaction mixture was heated to 45 ℃ and held for 2h, then methanol was removed under reduced pressure. The residue was dissolved in 10mL of water, and the aqueous layer was extracted with diethyl ether. The aqueous solution was adjusted to pH 2 using 1M hydrochloric acid and the resulting precipitate was collected by filtration. The crude product was triturated with hot isopropanol to give the desired product (1.01g, 63%) as a mixture of trans: cis diastereoisomers 9:1. LCMS M/Z (M + H) 339.

And step 3:

3- [6- [ (E) -but-2-enyl ] group]-7-oxo-1H-pyrrolo [2,3-c]Pyridin-4-yl]A mixture of-4-methoxy-benzoic acid (42mg, 0.125mmol), cyclopropylamine (14mg, 0.250mmol), triethylamine (0.053mL, 0.38mmol) and HATU (53mg, 0.14mmol) in N, N-dimethylformamide (1 mL) was heated at 45 ℃ overnight. The reaction mixture was filtered, rinsed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (5-85% ACN/H2O, 0.1% NH4OH) to give 3- [6- [ (E) -but-2-enyl]-7-oxo-1H-pyrrolo [2,3-c]Pyridin-4-yl]-N-cyclopropyl-4-methoxy-benzamide (29.9mg, 63%). ¹ H NMR(400MHz，DMSO-d ₆ )δ11.95(s，1H)，8.28(d，J＝4.2Hz，1H)，7.85(dd，J＝8.6，2.4Hz，1H)，7.79(d，J＝2.3Hz，1H)，7.30–7.21(m，1H)，7.21–7.07(m，2H)，6.07–5.94(m，1H)，5.78–5.52(m，2H)，4.57(dd，J＝4.7，1.8Hz，2H)，3.77(s，3H)，2.89–2.70(m，1H)，1.72–1.59(m，2H)，0.75–0.61(m，2H)，0.61–0.50(m，2H)。LCMS M/Z(M+H)378。

The following compounds were prepared in a similar manner to example 63:

examples 64 to 78

Example 79

6- [ (E) -but-2-enyl ] -4- [4- (1-hydroxy-1-methyl-ethyl) -2-methoxy-phenyl ] -1H-pyrrolo [2,3-c ] pyridin-7-one

Step 1:

Step 2:

4- [6- [ (E) -but-2-enyl ] -7-oxo-1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridin-4-yl ] -3-methoxy-benzoic acid methyl ester

Bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (141mg, 0.2mmol) was added to a mixture of 4-bromo-6- [ (E) -but-2-enyl ] -1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridin-7-one (step 1,1.52g,3.6 mmol) and methyl 3-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (1.56g, 5.3mmol) in 1,4-dioxane (10 mL) and 2M potassium phosphate in water (3 eq, 10.7 mmol). The reaction mixture was heated to 90 ℃ and held for 2h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The organic solution was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-35% ethyl acetate: heptane) to give the title compound (470mg, 26%). LCMS M/Z (M + H) 507.

And step 3:

Methylmagnesium bromide (3.0M in diethyl ether, 0.47mL,1.4 mmol) was added dropwise to cooled (0 ℃ C.) 4- [6- [ (E) -but-2-enyl]-7-oxo-1- (p-toluenesulfonyl) pyrrolo [2,3-c]Pyridin-4-yl]-methyl 3-methoxy-benzoate (233mg, 0.46mmol) in tetrahydrofuran (8 mL). The reaction mixture was gradually warmed to room temperature and then quenched with 1N HCl until the solution was pH 3. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (1 mL) and 10M potassium hydroxide in water (0.25 mL) was added. The reaction mixture was heated to 45 ℃ and held for 2h, then concentrated under reduced pressure. The residue was dissolved in water (50 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic extracts are dried over sodium sulfate andconcentrating under reduced pressure. The residue was purified by preparative HPLC (5-50% ACN/H2O 0.1% NH4OH) to give 6- [ (E) -but-2-enyl]-4- [4- (1-hydroxy-1-methyl-ethyl) -2-methoxy-phenyl]-1H-pyrrolo [2,3-c]Pyridin-7-one (104mg, 64%). ¹ H NMR(400MHz，DMSO-d6)δ11.91(s，1H)，7.29–7.14(m，3H)，7.10–7.02(m，2H)，6.12–5.98(m，1H)，5.77–5.53(m，2H)，5.03(s，1H)，4.55(d，J＝5.4Hz，2H)，3.73(s，3H)，1.72–1.61(m，2H)，1.47(s，5H)。LCMS M/Z(M+H)353。

The following compounds were prepared in a similar manner to example 79:

examples 80 to 81

Example 82

6-butyl-4- (4- (2-hydroxypropan-2-yl) phenyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Step 1:

2- (4-bromophenyl) propan-2-ol

N-butyllithium (2.5M in hexanes, 6.8mL, 17.0mmol) was added dropwise to a stirred and cooled (-78 ℃ C.) solution of 1,4-dibromobenzene (4.0g, 16.9mmol) in THF (50 mL). After addition, stirring was continued at-78 ℃ for 1h and acetone (3.0g, 51.7mmol) was added dropwise. The resulting mixture was warmed to 0 ℃ and stirred for an additional 3h, then quenched by the addition of saturated aqueous ammonium chloride (40 mL). The mixture was extracted with 75% ethyl acetateExtraction with petroleum ether (3X 50 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.8g, 50%) as a colorless oil. LCMS M/Z [ M-OH ⁺ ]197。

Step 2:

2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-ol

A mixture of potassium acetate (1.4g, 13.9mmol), 4,4,4',4',5,5,5',5' -octamethyl-2,2 '-bis (1,3,2-dioxaborolane) (2.2g, 8.4 mmol), 2- (4-bromophenyl) propan-2-ol (1.5g, 7.0mmol), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (ii) (0.15g, 0.2mmol) in dioxane (15 mL) was degassed for 30min and then heated at 80 ℃ for 12h under nitrogen. After cooling, the reaction mixture was filtered through a pad of celite, rinsing with ethyl acetate. The filtrate was evaporated and the residue was purified by chromatography on silica gel (petroleum ether: ethyl acetate 1:1) to give the title compound (1.1g, 69%) as a colorless oil.

And 3, step 3:

4-bromo-6-butyl-1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridin-7-one

And 4, step 4:

4-bromo-6-butyl-1H-pyrrolo [2,3-c ] pyridin-7-one

Sodium hydroxide (0.5g, 12.5mmol) in water (2 mL) was slowly added to a solution of 4-bromo-6-butyl-1H-pyrrolo [2,3-c ] pyridin-7-one (1.0g, 2.4 mmol) in methanol (20 mL) and water (2 mL). The resulting mixture was heated at 80 ℃ for 2h. After cooling, the mixture was concentrated under reduced pressure and the aqueous residue was diluted with water (30 mL). The resulting precipitate was collected by filtration, washed with water (2 × 30 mL) and concentrated under reduced pressure to give the title compound (0.5g, 78%) as a white solid. LCMS M/Z (M + 1) 270.

And 5:

Reacting 4-bromo-6-butyl-1H-pyrrolo [2,3-c]Pyridin-7 (6H) -one (190mg, 0.7 mmol), 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-ol (210mg, 0.8 mmol), cesium carbonate (456mg, 1.4 mmol) and [1,1' -bis (diphenylphosphino) ferrocene]A mixture of palladium (ii) dichloride (51mg, 0.07mmol) in dioxane (5 mL) and water (1 mL) was heated at 90 ℃ for 3h under nitrogen blanket. After cooling, the mixture was filtered through a small pad of celite (rinsing with ethyl acetate). The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (acetonitrile: water (10 nM ammonium bicarbonate), 55% -85%) to give the title compound (38mg, 17%) as a white solid. ¹ H NMR(400MHz，DMSO-d6)：δ12.07(s，1H)，7.55-7.50(m，4H)，7.34-7.33(t，J＝2.6Hz,1H)，7.30(s，1H)，6.44(t，J＝2.2Hz，1H)，5.01(d，J＝3.6Hz，1H)，4.02(t，J＝7.2Hz，2H)，1.70-1.66(m，2H)，1.46(s，6H)，1.35-1.30(m，2H)，0.93-0.90(t，J＝7.2，3H)。LCMS M/Z(M+H)329。

Example 83 was prepared in a similar manner to example 82:

example 84

7- [6- [ (E) -but-2-enyl ] group]-7-oxo-1H-pyrrolo [2,3-c]Pyridin-4-yl]-4-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepines-2-ketones

Step 1:

3- (5-bromo-2-nitro-anilino) butyric acid

A round-bottomed flask was charged with 4-bromo-2-fluoro-1-nitrobenzene (0.511g, 2.321mmol), (R) -3-aminobutyric acid, HCl (0.216g, 1.548mmol), potassium carbonate (0.428g, 3.10mmol) and DMSO (7.5 mL). The flask was heated to 100 ℃ and stirred for 18h. After cooling, the mixture was poured into 1M HCl and washed with ethyl acetate (3 ×). The combined organic layers were washed with brine and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluting with dichloromethane/methanol) to give 3- ((5-bromo-2-nitrophenyl) amino) butanoic acid, which was used in the subsequent reduction. LCMS M/Z (M + H) 303/305.

Step 2:

7-bromo-4-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepine-2-ketones

A disposable reaction tube was charged with (R) -3- (5-bromo-2-nitrophenylamino) butyric acid (0.283g, 0.934mmol), ethanol (6 mL), and acetic acid (1.069mL, 18.67mmol). Iron (0.417g, 7.47mmol) was added and the suspension stirred at 110 ℃ for 18h. After cooling, the mixture was filtered through celite and concentrated under reduced pressure to a residue, which was purified by silica gel chromatography (eluting with hexane/ethyl acetate) to give the title compound. LCMS M/Z (M + H) 255/257.

And step 3:

The disposable tube was charged with 4-bromo-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one (intermediate a) (500mg, 1.362mmol), (E) -1-chlorobut-2-ene (265 μ l,2.72 mmol), cesium carbonate (665mg, 2.042mmol), and 1,4-dioxane (10 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and the product was extracted three times with ethyl acetate, then the organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give (E) -4-bromo-6- (but-2-en-1-yl) -1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one, which was used in the subsequent step without purification.

And 4, step 4:

6- [ (E) -but-2-enyl ] -1- (p-toluenesulfonyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [2,3-c ] pyridin-7-one

A disposable reaction vial was charged with (E) -4-bromo-6- (but-2-enyl) -1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one (150mg, 0.36mmol), triethylamine (149 μ l,1.068 mmol), bis (acetonitrile) palladium (II) dichloride (9.2mg, 0.036 mmol), 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl (14.6mg, 0.036mmol), and 1,4-dioxane (2 mL). 4,4,5,5-tetramethyl-1,3,2-dioxaborolan (103. Mu.l, 0.712 mmol) was added and the mixture was stirred at room temperature while the gases escaped from the reaction mixture. After 15min, the mixture was heated to 100 ℃ and stirred for 2H, then cooled, diluted with ethyl acetate, stripped twice with 1,4-dioxane, and concentrated to give (E) -6- (but-2-en-1-yl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one as a yellow oil which was used in the next step without purification.

And 5:

7- [6- [ (E) -but-2-enyl ] group]-7-oxo-1H-pyrrolo [2,3-c]Pyridin-4-yl]-4-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepine-2-ketones

Charging a disposable reaction tube with (E) -6- (but-2-enyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-c]Pyridin-7 (6H) -one (167mg, 0.357mmol), 7-bromo-4-methyl-4,5-dihydro-1H-benzo [ b][1,4]Diaza derivatives-2 (3H) -one (76mg, 0.297mmol), tetrakis (triphenylphosphine) palladium (0) (34.3mg, 0.030mmol), potassium phosphate (82mg, 0.594mmol). 1,4-dioxane (3.8 mL)/water (0.2 mL) was added and the mixture degassed, then stirred at 100 ℃ for 2h. The reaction mixture was cooled, quenched with 2M sodium hydroxide and methanol, and stirred at room temperature for 2h. Ammonium hydroxide (saturated aqueous solution) was added, and the product was extracted 4 times with ethyl acetate. The organic layers were combined and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluting with hexane and ethyl acetate) to give the title compound as a white amorphous solid (31 mg). ¹ H NMR(400MHz，DMSO-d6)＝12.10(br.s.，1H)，9.51(s，1H)，7.35(t，J＝2.7Hz，1H)，7.17(s，1H)，7.11(s，1H)，6.92(dd，J＝8.0，13.0Hz，2H)，6.47(t，J＝2.4Hz，1H)，5.67-5.62(m，2H)，5.48(br.s.，1H)，4.58(d，J＝3.5Hz，2H)，3.92-3.78(m，1H)，2.47(d，J＝3.7Hz，1H)，2.27(dd，J＝7.5，13.5Hz，1H)，1.65(d，J＝4.4Hz，3H)，1.21(d，J＝6.2Hz，3H)。LCMS M/Z(M+H)363。

Example 85

3- (6- (2-Cyclopropylethyl) -2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N, N-dimethylbenzamide

Step 1:

4-bromo-6- (2-cyclopropylethyl) -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Sodium hydride (60% oil dispersion, 70.5mg, 1.76mmol) was added to cooled (0 ℃ C.) 4-bromo-2-methyl-1,6-dihydropyrrolo [2,3-c]Pyridin-7-one (intermediate B) (400mg, 1.76mmol) in THF (7 mL). After the addition, the reaction mixture was stirred for 0.5h, then a solution of (2-iodoethyl) cyclopropane (345mg, 1.76mmol) in THF (1 mL) was added. The mixture was warmed to room temperature and stirred for 2h, at which time LCMS indicated that the reaction was complete. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (0.5 mL) and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with water (2 × 15 mL), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether: ethyl acetate 1:1) to give the title compound (150mg, 29% yield) as a light brown solid. ¹ H NMR(400MHz，CD ₃ OD)：δ7.35(s，1H)，6.08(s，1H)，4.15-4.04(m，2H)，2.54-2.24(m，3H)，1.70-1.54(m，2H)，0.77-0.60(m，1H)，0.48-0.35(m，2H)，0.08-0.04(m，2H)。LCMS M/Z(M+H)295。

Step 2:

Reacting 4-bromo-2-methyl-1H-pyrrolo [2,3-c]Pyridin-7 (6H) -one (79 mg)0.27 mmol), (3- (dimethylcarbamoyl) phenyl) boronic acid (51.7 mg, 0.27mmol), cesium carbonate (174mg, 0.54mmol) and [1,1' -bis (diphenylphosphino) ferrocene]A mixture of palladium (ii) dichloride (10mg, 0.01mmol) in dioxane (3 mL) and water (0.5 mL) was subjected to microwave irradiation at 110 ℃ for 0.5h. After cooling, the mixture was filtered through a small pad of celite (rinsing with ethyl acetate). The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (acetonitrile: water (0.3% formic acid), 46% -76%) to give the title compound (30.5mg, 31%) as a white solid. ¹ H NMR(400MHz，CD ₃ OD)：δ7.72(d，J＝8.0Hz，1H)，7.65(s，1H)，7.57(t，J＝7.4Hz，1H)，7.42(d，J＝7.6Hz，1H)，7.33(s，1H)，6.28(s，1H)，4.23(t，J＝7.0Hz，2H)，3.15(s，3H)，3.09(s，3H)，2.45(s，3H)，1.75-1.69(m，2H)，0.79-0.77(m，1H)，0.48-0.43(m，2H)，0.09-0.05(m，2H)。LCMS M/Z(M+H)364。

The following compounds were prepared in a similar manner to example 85:

examples 86 to 103

Example 104

6- [ (E) -but-2-enyl ] -4- [ 4-chloro-5- (morpholine-4-carbonyl) -2-pyridyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one

Step 1:

(E) -6- (but-2-en-1-yl) -2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

To 4-bromo-6- [ (E) -but-2-enyl)]-2-methyl-1H-pyrrolo [2,3-c]To a mixture of pyridin-7-one (3.00g, 10.7mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborocyclopentane (6.83g, 53.3mmol) in 1,4-dioxane (50 mL) was added triethylamine (3.24g, 32.01mmol), SPhos (2.19g, 5.34mmol) and bis (acetonitrile) palladium (II) dichloride (277.0mg, 1.07mmol). The reaction mixture is then reacted with N ₂ Stirred at 80 ℃ for 16hrs under an atmosphere. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5/1) to give 6- [ (E) -but-2-enyl group]-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-c]Pyridin-7-one (4.00 g, crude) as a yellow solid.

And 2, step:

(E) -6- (6- (but-2-en-1-yl) -2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-chloronicotinic acid ethyl ester

This compound was prepared in a similar procedure to example 62, step 3.

And step 3:

(E) -6- (6- (but-2-en-1-yl) -2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-chloronicotinic acid

This compound was prepared in a similar procedure to example 60, step 5.

And 4, step 4:

(E) -6- (but-2-en-1-yl) -4- (4-chloro-5- (morpholine-4-carbonyl) pyridin-2-yl) -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one (5)

Example 103 was prepared in a similar operation to example 60, step 6. ¹ H NMR(400MHz，CD ₃ OD)δ8.69(s，1H)，8.10(s，1H)，7.88-7.80(m，1H)，5.84-5.72(m，1H)，5.71-5.61(m，1H)，4.68(d，J＝5.6Hz，2H)，3.87-3.73(m，4H)，3.71-3.63(m，2H)，3.46-3.36(m，2H)，2.45(s，3H)，1.87-1.79(m，0.8H)，1.70(d，J＝6.1Hz，2.2H)。LCMS(M+H ⁺ )m/z：427。

The following compounds were prepared in a similar manner to example 104:

examples 105 to 110

Example 111

6- [ (E) -but-2-enyl ] -4- [ 6-chloro-5- (morpholine-4-carbonyl) -2-pyridyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one

Step 1:

(2-Chloropyridin-3-yl) (morpholino) methanones

This compound was prepared in a similar procedure to example 55, step 1.

Step 2:

2-chloro-3- (morpholine-4-carbonyl) pyridine 1-oxide

In N ₂ Next, to a mixture of (2-chloro-3-pyridinyl) -morpholino-methanone (3.00g, 13.24mmol) in trifluoroacetic acid (15 mL) was added hydrogen peroxide (5.90g, 52.04mmol) in one portion. The mixture was stirred at 65 ℃ for 16hrs. The mixture was concentrated under reduced pressure and saturated NaHCO was used ₃ The solution adjusted the residue to pH 8. The mixture was extracted with DCM. The combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (2-chloro-1-oxido-pyridin-1-ium-3-yl) -morpholino-methanone (2.40 g, crude) as a yellow solid.

And 3, step 3:

(6-bromo-2-chloropyridin-3-yl) (morpholino) methanone

(2-chloro-1-oxido-pyridin-1-ylin-3-yl) -morpholino-methanone (2.00g, 8.24mmol) and POBr ₃ (9.45g, 32.96mmol) of CH ₃ CN (80 mL) solution was stirred at 70 ℃ for 16hrs. The mixture was concentrated under reduced pressure and quenched with water (20 mL). The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated sodium bicarbonate and brine (30 mL), then dried over sodium sulfate and concentratedConcentrating under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate =30/1, 20/1) to give (6-bromo-2-chloro-3-pyridinyl) -morpholino-methanone (300mg, 0.87mmol, 11%) as a yellow oil.

And 4, step 4:

(E) -6- (but-2-en-1-yl) -4- (6-chloro-5- (morpholine-4-carbonyl) pyridin-2-yl) -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 111 was prepared in a similar operation to example 85, step 2.

¹ H NMR(400MHz，CD ₃ OD)δ7.88-7.82(m，3H)，6.68(s，1H)，5.78-5.66(m，2H)，4.69-4.68(m，2H)，3.79(s，4H)，3.71-3.64(m，2H)，3.39-3.34(m，2H)，2.45(s，3H)，1.71(d，J＝6.0Hz，3H)。LCMS(M+H ⁺ )m/z：427。

Example 112

1- [4- [6- [ (E) -but-2-enyl ] -2-methyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -2-chloro-benzoyl ] piperidine-4-carboxylic acid

Step 1:

1- (4-bromo-2-chlorobenzoyl) piperidine-4-carboxylic acid methyl ester

This compound was prepared in a similar procedure to example 55, step 1.

Step 2:

1- (2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl) piperidine-4-carboxylic acid methyl ester

This compound was prepared in a similar procedure to example 55, step 3.

And step 3:

(E) -1- (4- (6- (but-2-en-1-yl) -2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -2-chlorobenzoyl) piperidine-4-carboxylic acid methyl ester

This compound was prepared in a similar procedure to example 1.

And 4, step 4:

(E) -1- (4- (6- (but-2-en-1-yl) -2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -2-chlorobenzoyl) piperidine-4-carboxylic acid

Example 112 was prepared in a similar operation to example 60, step 5.

¹ H NMR(400MHz，CD ₃ OD)δ7.69(d，J＝6.0Hz，1H)，7.65-7.61(m，1H)，7.45-7.43(m，1H)，7.28(s，1H)，6.25(s，1H)，5.77-5.67(m，2H)，4.66-4.65(m，2H)，4.54-4.51(m，1H)，3.52-3.48(m，1H)，3.19-3.01(m，2H)，2.66-2.64(m，1H)，2.43(s，3H)，2.09-2.06(m，1H)，1.92-1.89(m，1H)，1.84-1.69(m，5H)。LCMS(M+H ⁺ )m/z：468。

Example 113

(E) -1- (4- (6- (but-2-en-1-yl) -2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -2-chlorobenzoyl) piperidine-4-carboxamide

Example 113 was prepared in a similar operation to example 60, step 6.

¹ H NMR(400MHz，CD ₃ OD)δ7.71(d，J＝6.8Hz，2H)，7.67-7.63(m，1H)，7.51-7.39(m，1H)，7.30(s，1H)，6.28(s，1H)，5.80-5.66(m，2H)，4.83-4.82(m，1H)，4.73-4.68(m，3H)，3.56(s，1H)，3.24-3.14(m，1H)，3.02-2.96(m，1H)，2.59-2.56(m，2H)，2.46(s，3H)，2.00-1.98(m，1H)，1.87-1.63(m，6H)。LCMS(M+H ⁺ )m/z：467。

Example 114

6- [ (E) -but-2-enyl ] -4- [ 3-isopropoxy-4- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one

Step 1:

(4-bromo-2-methoxy-phenyl) -morpholino-methanone

This compound was prepared in a similar procedure to example 55, step 1.

Step 2:

(4-bromo-2-hydroxy-phenyl) -morpholino-methanone

In N ₂ To a mixture of (4-bromo-2-methoxy-phenyl) -morpholino-methanone (500mg, 1.67mmol) in dichloromethane (10 mL) was added BBr at 0 deg.C ₃ (835mg, 3.33mmol). The mixture was stirred at 80 ℃ for 16hrs. Pouring the mixture into H ₂ O (50 mL) and extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give (4-bromo-2-hydroxy-phenyl) -morpholino-methanone (400 mg, crude material)As a white solid.

And step 3:

(4-bromo-2-isopropoxy-phenyl) -morpholino-methanone

To a mixture of (4-bromo-2-hydroxy-phenyl) -morpholino-methanone (300mg, 1.05mmol) and 2-bromopropane (155mg, 1.26mmol) in DMF (8 mL) was added potassium carbonate (435mg, 3.15mmol). The mixture was stirred at 80 ℃ for 16hrs. TLC showed the reaction was complete. Pouring the mixture into H ₂ O (80 mL), then extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 4/1) to give (4-bromo-2-isopropoxy-phenyl) -morpholino-methanone (344mg, 1.05mmol, 100%) as a white solid.

And 4, step 4:

[ 2-isopropoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl ] -morpholino-methanone

This compound was prepared in a similar procedure to example 55, step 3.

And 5:

This compound was prepared in a similar procedure to example 85, step 3. ¹ H NMR(400MHz，CDCl ₃ )δ10.90-10.77(m，1H)，7.34(d，J＝8.0Hz，1H)，7.17-7.14(m，1H)，7.08(s，1H)，6.97(s，1H)，6.19(d，J＝1.2Hz，1H)，5.80-5.58(m，2H)，4.81(d，J＝6.8Hz，0.36H)，4.69(d，J＝4.0Hz，1.40H)，4.66-4.60(m，1H)，3.89-3.86(m，1H)，3.78-3.72(m，4H)，3.62-3.61(m，1H)，3.44-3.27(m，2H)，2.48(s，3H)，1.84-1.83(m，0.53H)，1.72(d，J＝5.2Hz，2.36H)，1.37(dd，J＝10.8，6H)。LCMS(M+H ⁺ )m/z：450。

Example 115 was prepared in a similar operation to example 114.

Example 116

(E) -6- (but-2-en-1-yl) -4- (3-chloro-4- (piperazine-1-carbonyl) phenyl) -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Step 1:

(E) -4- (4- (6- (but-2-en-1-yl) -2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -2-chlorobenzoyl) piperazine-1-carboxylic acid tert-butyl ester

This compound was prepared in a similar procedure to example 85, step 2.

Step 2:

At N ₂ Next, to 4- [4- [6- [ (E) -but-2-enyl group]-2-methyl-7-oxo-1H-pyrrolo [2,3-c]Pyridin-4-yl]-2-chloro-benzoyl]Piperazine-1-carboxylic acid tert-butyl ester (200mg, 380.9. Umol) in methanol (4 mL) mixtureA solution of HCl/methanol (4M, 1.00mL) was added in one portion. The mixture was stirred at 20 ℃ for 4hrs. The mixture was then concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: waters Xbridge C18150X 20mm X5um. Mobile phase A: with 0.5% (v/v) NH ₃ .H ₂ O, water. Mobile phase B: meOH, gradient: 40 to 70 percent. Flow rate: 25 ml/min) to give 6- [ (E) -but-2-enyl)]-4- [ 3-chloro-4- (piperazine-1-carbonyl) phenyl]-2-methyl-1H-pyrrolo [2,3-c]Pyridin-7-one (66mg, 150umol, 40%) as a white solid. ¹ H NMR(400MHz，CD ₃ OD)：δ7.70(s，1H)，7.65-7.63(m，1H)，7.44(d，J＝8.0Hz，1H)，7.28(s，1H)，6.26(s，1H)，5.78-5.68(m，2H)，4.67(d，J＝6.4Hz，2H)，3.79-3.77(m，2H)，2.94-2.76(m，5H)，2.44(s，3H)，1.72(d，J＝5.6Hz，3H)。LCMS(M+H ⁺ )m/z：425。

Example 117

(E) -4- (4- (3- (3-amino-1H-pyrazol-1-yl) azetidine-1-carbonyl) -3-chlorophenyl) -6- (but-2-en-1-yl) -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 117 was prepared in a similar operation to example 60, step 6.

¹ H NMR(400MHz，CD ₃ OD)δ7.69(s，1H)，7.64-7.62(m，1H)，7.58(d，J＝8.0Hz，1H)，7.40(d，J＝6.4Hz，1H)，7.27(s，1H)，6.24(s，1H)，5.73-5.67(m，2H)，5.63(d，J＝2.4Hz，1H)，5.10-5.09(m，1H)，4.60-4.55(m，3H)，4.49-4.48(m，1H)，4.40-4.38(m，2H)，2.43(s，3H)，1.70(d，J＝5.6Hz，3H)。LCMS(M+H ⁺ )m/z：477。

Example 118 was prepared in a similar procedure to example 117.

Examples119

(E) -6- (but-2-en-1-yl) -4- (4- (2-hydroxypropan-2-yl) -2,5-dimethoxyphenyl) -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Step 1:

2- (4-bromo-2,5-dimethoxyphenyl) propan-2-ol

To a solution of 1- (4-bromo-2,5-dimethoxy-phenyl) ethanone (500mg, 1.93mmol) in tetrahydrofuran (10 mL) was added dropwise methylmagnesium bromide (3M, 2.00mL) at-78 ℃. The mixture was stirred at-78 ℃ for 1hr, then the mixture was warmed to 0 ℃ and stirred for 1hr. Saturated NH for the mixture ₄ The Cl solution was quenched and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate =20/1, 10/1) to give 2- (4-bromo-2,5-dimethoxy-phenyl) propan-2-ol (300mg, 0.98mmol,51% yield) as a yellow oil.

And 2, step:

Example 119 was prepared in a similar procedure to example 85, step 2.

¹ H NMR(400MHz，CD ₃ OD)δ7.32(s，1H)，7.13-7.11(m，1H)，6.95(s，1H)，5.96(s，1H)，5.75-5.66(m，2H)，4.62(d，J＝5.2Hz，2H)，3.82(s，3H)，3.72(s，3H)，2.39(s，3H)，1.71(d，J＝5.6Hz，3H)，1.61(s，6H)。LCMS(M+H ⁺ )m/z：397。

Example 120

3- [6- [ (E) -but-2-enyl ] -2-methyl-7-oxo-1H-pyrrolo [2,3-c ] pyridin-4-yl ] -4-methoxy-N- (pyrimidin-5-ylmethyl) benzamide

Step 1:

5- (azidomethyl) pyrimidines

To a mixture of pyrimidin-5-ylmethanol (800mg, 7.27mmol) in DCM (30 mL) and toluene (25 mL) was added DBU (2.21g, 14.5 mmol) and DPPA (4.00g, 14.5 mmol). The mixture was stirred at 25 ℃ for 16hrs. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 4/1) to give 5- (azidomethyl) pyrimidine (1.20 g, crude) as a colorless oil.

Step 2:

pyrimidin-5-ylmethylamines

To a mixture of 5- (azidomethyl) pyrimidine (600.0 mg, 4.44mmol) in THF (15 mL) was added triphenylphosphine (2.33g, 8.88mmol) and water (160.0 mg, 8.88mmol). The mixture was stirred at 25 ℃ for 16hr. The mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. The phases were separated and the aqueous phase was adjusted to pH =8 with saturated sodium bicarbonate. The mixture was lyophilized to give pyrimidin-5-ylmethylamine (1.10 g, crude) as a white solid.

And step 3:

3-bromo-4-methoxy-N- (pyrimidin-5-ylmethyl) benzamide

This compound was prepared in a similar procedure to example 55, step 1.

And 4, step 4:

Example 120 was prepared in a similar operation to example 85, step 2.

¹ H NMR(400MHz，CDCl ₃ )δ11.99(d，J＝13.6Hz，1H)，9.12(s，1H)，8.90(s，2H)，8.28(s，1H)，8.09-8.01(m，2H)，7.35(s，1H)，7.07(d，J＝8.4Hz，1H)，5.99(s，1H)，5.86-5.81(m，1H)，5.64-5.55(m，1H)，4.79-4.62(m，4H)，3.82(s，3H)，2.30(d，J＝5.2Hz，3H)，1.78(d，J＝6.8Hz，0.6H)，1.71(d，J＝6.0Hz，2.4H)。LCMS(M+H ⁺ )m/z：444。

Example 121

6-butyl-4- [2,5-dimethoxy-4- (morpholine-4-carbonyl) phenyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one

To 6- [ (E) -but-2-enyl)]-4- [2,5-dimethoxy-4- (morpholine-4-carbonyl) phenyl]-2-methyl-1H-pyrrolo [2,3-c]To a solution of pyridin-7-one (example 108, 30.0mg, 66.4. Mu. Mol) in methanol (2 mL) was added Pd/C (7.0 mg, 6.6. Mu. Mol). The mixture was degassed under vacuum and washed with H ₂ And (5) purging. Mixing the mixture in H ₂ Stirring at 80 deg.C for 12hr under atmosphere, then filtering the mixture, and concentrating the filtrate in vacuo. The residue was purified by silica gel chromatography (dichloromethane: methanol = 20) to give the crude product. Crude product generalPerpre-HPLC (column: waters Xbridge C18 x 20mm x 5um; mobile phase A: water with 0.05% Ammonia solution; mobile phase B: CH ₃ CN; gradient: 14-44% b,10 min) to give 6-butyl-4- [2,5-dimethoxy-4- (morpholine-4-carbonyl) phenyl]-2-methyl-1H-pyrrolo [2,3-c]Pyridin-7-one (4.0mg, 8.8umol,13% yield) as a white solid. ¹ H NMR(400MHz，CDCl ₃ )δ7.05(s，1H)，6.99(s，1H)，6.95(s，1H)，5.98(s，1H)，4.09(t，J＝7.3Hz，2H)，3.60-3.96(m，11H)，3.30-3.47(m，1H)，2.45(s，3H)，1.77-1.86(m，2H)，1.44(d，J＝7.5Hz，2H)，0.97(t，J＝7.3Hz，3H)。LCMS(M+H ⁺ )m/z：454。

The following compound was prepared in a similar manner to example 121:

examples 122 to 123

Example 124

Synthesis of biotinylated Probe Compound (1000) for the following TAF assay.

Step 1:

2-methoxy-4-methyl-3-nitropyridine

A solution of 2-chloro-4-methyl-3-nitropyridine (250g, 1.45mol) in methanol (1.0L) was added dropwise (2 h) to a stirred and cooled (0 ℃ C.) solution of sodium methoxide (250g, 4.63mol) in methanol (850 mL). After addition, the mixture is heated toReflux for 23h at which time TLC indicated the reaction was complete. The mixture was concentrated under reduced pressure to a volume of about 900mL and quenched by the addition of water (1.5L). The resulting solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (250g, 100% yield) as a brown solid. ¹ H NMR(400MHz，DMSO-d6)：δ8.22(d，J＝5.2Hz，1H)，7.10(d，J＝5.6Hz，1H)，3.92(s，3H)，2.26(s，3H)。

Step 2:

5-bromo-2-methoxy-4-methyl-3-nitropyridine

Sodium acetate (365g, 5.37mol) was added to a stirred solution of 2-methoxy-4-methyl-3-nitropyridine (250g, 1.49mol) in acetic acid (1.5L) at ambient temperature, followed by dropwise addition (30 min) of Br ₂ (639g, 4.00mol). After addition, the mixture was heated at 80 ℃ for 12h, at which time TLC indicated that the reaction had been completed. Cooling the mixture (0 ℃) and reducing the content of Na by adding 10% in order ₂ SO ₃ Aqueous solution (1.5L) and saturated Na ₂ SO ₃ Aqueous solution (1.5L) was quenched. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (302g, 82.2% yield) as a light yellow solid. ¹ H NMR(400MHz，DMSO-d6)：δ8.25(s，1H)，3.94(s，3H)，2.29(s，3H)。

And step 3:

(E) -2- (5-bromo-2-methoxy-3-nitro-4-pyridinyl) -N, N-dimethyl-vinylamine

DMF-DMA (600 mL) was added slowly to a stirred and heated (80 ℃ C.) solution of 5-bromo-2-methoxy-4-methyl-3-nitropyridine (134g, 0.54mol) in DMF (1.1L). After addition, the mixture was heated at 95 ℃ for 5h, at which time TLC indicated that the reaction had been completed. The mixture was cooled to room temperature and poured into ice-cold water (3L). Through filteringThe resulting red solid was collected, washed with water, and dried under reduced pressure to give the title compound (167g, 100% yield) as a red solid. ¹ H NMR(400MHz，DMSO-d6)：δ8.24(s，1H)，7.05(d，J＝13.6Hz，1H)，7.05(d，J＝13.6Hz，1H)，4.80(d，J＝13.2Hz，1H)，3.88(s，3H)，2.90(s，6H)。

And 4, step 4:

4-bromo-7-methoxy-1H-pyrrolo [2,3-c ] pyridine

2- (5-bromo-2-methoxy-3-nitropyridin-4-yl) -N, N-dimethylvinylamine (50.0g, 165mmol), fe (50.0g, 893mmol) and NH ₄ Cl (50.0g, 943mmol) in methanol/H ₂ The mixture in O (1900/250 mL) was heated at reflux for 7h, at which time LCMS indicated that the reaction was complete. The mixture was filtered while hot and the filter cake was washed with methanol (3 × 200 mL). The combined filtrates were concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5:1) to give a crude product. This crude material was triturated with acetonitrile to give the title compound (37.4 g,99.5% yield) as a light brown solid. LCMS M/Z (M + H) 226.7, 228.7.

And 5:

4-bromo-7-methoxy-1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridine

Reacting 4-bromo-7-methoxy-1H-pyrrolo [2,3-c]A solution of pyridine (34.3 g, 0.15mol) in THF (700 mL) was added dropwise to a stirred and cooled (0 ℃ C.) solution of sodium hydride (60%, 19.2g, 0.48mol) in THF (700 mL). After the addition, the mixture was stirred at room temperature for 1h and then cooled again to 0 ℃. Tosyl chloride (38.0 g,0.20 mol) in THF (700 mL) was added dropwise and the resulting mixture was stirred at ambient temperature for 2h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (1.0L) and then extracted with ethyl acetate (3 × 600 mL). Combined organic matterSubjecting the extract to Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was triturated with acetonitrile to give the title compound (51.2g, 88.9% yield) as a brown solid. The crude material was used in the next step without further purification.

Step 6:

4-bromo-1- (p-toluenesulfonyl) -6H-pyrrolo [2,3-c ] pyridin-7-one

HBr (40% aq, 1.1L) was added to 4-bromo-7-methoxy-1- (p-tolylsulfonyl) pyrrolo [2,3-c]Pyridine (102.5g, 0.27mol) in ethanol (200 mL). After addition, the mixture was heated at 90 ℃ for 2h, at which time TLC indicated that the reaction had been completed. The mixture was cooled to 0 ℃ and the resulting white solid was collected by filtration. The solid was washed with water and dried in vacuo to give the title compound (87.5g, 88.6% yield) as a light brown solid. ¹ H NMR(400MHz，DMSO-d6)：δ11.48(s，1H)，8.01(d，J＝3.6Hz，1H)，8.90(d，J＝8.0Hz，2H)，7.38(d，J＝8.0Hz，2H)，7.32(s，1H)，6.57(d，J＝3.2Hz，1H)，2.34(s，3H)。

And 7:

4-bromo-6-methyl-1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridin-7-one

Iodomethane (24.5g, 172.8mmol) was added dropwise to a stirred 4-bromo-1-tosyl-1H-pyrrolo [2,3-c]Pyridin-7 (6H) -one (intermediate A) (16.7g, 45.5mmol) and cesium carbonate (17.8g, 54.6mmol) in dioxane (250 mL). After addition, the reaction mixture was stirred at room temperature for 18h, at which time LCMS indicated that the reaction was complete. The solvent was evaporated under reduced pressure and the residue diluted with water (200 mL). The mixture was extracted with EtOAc (3 × 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica gel (petroleum ether/acetic acid)Ethyl ester = 3:1) to give the title compound (14.0 g,81.4% yield) as a brown solid. ¹ H NMR(400MHz，DMSO-d6)：δ8.03(d，J＝3.6Hz，1H)，7.92(d，J＝8.4Hz，2H)，7.78(s，1H)，7.39(d，J＝8.4Hz，2H)，6.57(d，J＝3.6Hz，1H)，3.35(s，3H)，2.35(s，3H)。

And 8:

a50 mL vial was charged with a magnetic stir bar, 4-bromo-6-methyl-1-tosyl-1H-pyrrolo [2,3-c]Pyridin-7 (6H) -one (0.281g, 0.737mmol), 1,4-dioxane (3.69mL, 0.737mmol), water (0.5mL, 27.8mmol), K ₂ CO ₃ (0.306g, 2.211mmol), 4- (tert-butoxycarbonylamino) phenylboronic acid (0.227g, 0.958mmol) and Pd (PPh) ₃ ) ₄ (0.085g, 0.074mmol). The vial was purged, placed under nitrogen, and heated to 95 ℃ with stirring and held for 12h, then cooled to room temperature. The reaction mixture was then diluted with water (20 mL). A precipitate formed which was collected by vacuum filtration using a buchner funnel. The solid was washed with additional water (2 × 25 mL), dried and collected. This material was suspended in methanol (. About.5 mL) and treated with KOH (200 mg). After 2h, meOH was removed in vacuo, the crude material was suspended in water (-20 mL), and the resulting solid was collected by vacuum filtration using a buchner funnel. The solid was washed with additional water, collected, and dried in vacuo to give 4- (6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c]Pyridin-4-yl) phenylcarbamic acid tert-butyl ester (362mg, 0.907 mmol) as a pale yellow solid. LCMS M/Z (M + H) 494.

And step 9:

a50 mL round bottom flask was charged with a magnetic stir bar, tert-butyl 4- (6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl carbamate (350mg, 1.031mmol), meOH (2.062mL, 1.031mmol), and HCl (1.031mL, 4.12mmol) (4N in dioxane). The reaction mixture was then stirred at room temperature for 4h, then diluted with dioxane (25 mL). A precipitate formed, which was collected by vacuum filtration using a buchner funnel, washed with additional dioxane, and dried in vacuo to give 4- (4-aminophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one (188mg, 0.786mmol,76% yield) as a white solid. LCMS M/Z (M + H) 240.

Step 10:

a25 mL vial was charged with a magnetic stir bar, 4- (4-aminophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one (0.038g, 0.159mmol), anhydrous DMF (0.794mL, 0.159mmol), DIPEA (0.139mL, 0.794mmol), 17-oxo-21- ((3aS, 4S, 6aR) -2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) -4,7,10,13-tetraoxa-16-azaheneicosane-1-acid (0.078g, 0.159mmol), and HATU (0.075g, 0.199). The crude reaction mixture was directly purified by reverse phase HPLC to give N- (4- (6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl) -1- (5- ((3aS, 4S,6 aR) -2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) pentanoylamino) -3,6,9,12-tetraoxapentadec-15-amide (31mg, 0.041mmol,26.0% yield). LCMS M/Z (M + 2H)/2 357.

Example 125

Synthesis of biotinylated Probe Compound (1001) for the following CECR2 assay.

Step 1:

2-methoxy-4-methyl-3-nitropyridine

A solution of 2-chloro-4-methyl-3-nitropyridine (250g, 1.45mol) in methanol (1.0L) was added dropwise (2 h) to a stirred and cooled (0 ℃ C.) solution of sodium methoxide (250g, 4.63mol) in methanol (850 mL). After addition, the mixture was heated to reflux for 23h, at which time TLC indicated that the reaction was complete. The mixture was concentrated under reduced pressure to a volume of about 900mL and quenched by the addition of water (1.5L). The resulting solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (250g, 100% yield) as a brown solid. ¹ H NMR(400MHz，DMSO-d6)：δ8.22(d，J＝5.2Hz，1H)，7.10(d，J＝5.6Hz，1H)，3.92(s，3H)，2.26(s，3H)。

Step 2:

5-bromo-2-methoxy-4-methyl-3-nitropyridine

And step 3:

(E) -2- (5-bromo-2-methoxy-3-nitro-4-pyridinyl) -N, N-dimethyl-vinylamine

DMF-DMA (600 mL) was added slowly to a stirred and heated (80 ℃ C.) solution of 5-bromo-2-methoxy-4-methyl-3-nitropyridine (134g, 0.54mol) in DMF (1.1L). After addition, the mixture was heated at 95 ℃ for 5h, at which time TLC indicated that the reaction had been completed. The mixture was cooled to room temperature and poured into ice-cold water (3L). The resulting red solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (167g, 100% yield) as a red solid. ¹ H NMR(400MHz，DMSO-d6)：δ8.24(s，1H)，7.05(d，J＝13.6Hz，1H)，7.05(d，J＝13.6Hz，1H)，4.80(d，J＝13.2Hz，1H)，3.88(s，3H)，2.90(s，6H)。

And 4, step 4:

4-bromo-7-methoxy-1H-pyrrolo [2,3-c ] pyridine

2- (5-bromo-2-methoxy-3-nitropyridin-4-yl) -N, N-dimethylvinylamine (50.0g, 165mmol), fe (50.0g, 893mmol) and NH ₄ Cl (50.0g, 943mmol) in methanol/H ₂ The mixture in O (1900/250 mL) was heated at reflux for 7h, at which time LCMS indicated the reaction was complete. The mixture was filtered while hot and the filter cake was washed with methanol (3 × 200 mL). The combined filtrates were concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5:1) to give a crude product. This crude material was triturated with acetonitrile to give the title compound (37.4 g,99.5% yield) as a light brown solid. LCMS M/Z (M + H) 226.7, 228.7.

And 5:

4-bromo-7-methoxy-1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridine

Reacting 4-bromo-7-methoxy-1H-pyrrolo [2,3-c]A solution of pyridine (34.3 g, 0.15mol) in THF (700 mL) was added dropwise to a stirred and cooled (0 ℃ C.) solution of sodium hydride (60%, 19.2g, 0.48mol) in THF (700 mL). After the addition, the mixture was stirred at room temperature for 1h and then cooled again to 0 ℃. Tosyl chloride (38.0 g,0.20 mol) in THF (700 mL) was added dropwise and the resulting mixture was stirred at ambient temperature for 2h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (1.0L) and then extracted with ethyl acetate (3 × 600 mL). The combined organic extracts are purified over Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was triturated with acetonitrile to give the title compound (51.2g, 88.9% yield) as a brown solid. The crude material was used in the next step without further purification.

Step 6:

4-bromo-1- (p-toluenesulfonyl) -6H-pyrrolo [2,3-c ] pyridin-7-one

And 7:

4-bromo-6-methyl-1- (p-toluenesulfonyl) pyrrolo [2,3-c ] pyridin-7-one

Iodomethane (24.5g, 172.8mmol) was added dropwise to a stirred 4-bromo-1-tosyl-1H-pyrrolo [2,3-c]Pyridin-7 (6H) -one (intermediate A) (16.7g, 45.5mmol) and cesium carbonate (17.8g, 54.6mmol) in dioxane (250 mL). After addition, the reaction mixture was stirred at room temperature for 18h, at which time LCMS indicated that the reaction was complete. The solvent was evaporated under reduced pressure and the residue diluted with water (200 mL). The mixture was extracted with EtOAc (3 × 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 3:1) to give the title compound (14.0g, 81.4% yield) as a brown solid. ¹ H NMR(400MHz，DMSO-d6)：δ8.03(d，J＝3.6Hz，1H)，7.92(d，J＝8.4Hz，2H)，7.78(s，1H)，7.39(d，J＝8.4Hz，2H)，6.57(d，J＝3.6Hz，1H)，3.35(s，3H)，2.35(s，3H)。

And step 8:

a50 mL vial was charged with magnetic stirringStirring rod, 4-bromo-6-methyl-1-tosyl-1H-pyrrolo [2,3-c]Pyridin-7 (6H) -one (0.281g, 0.737mmol), 1,4-dioxane (3.69mL, 0.737mmol), water (0.5mL, 27.8mmol), K ₂ CO ₃ (0.306g, 2.211mmol), 4- (tert-butoxycarbonylamino) phenylboronic acid (0.227g, 0.958mmol) and Pd (PPh) ₃ ) ₄ (0.085g, 0.074mmol). The vial was purged, placed under nitrogen, and heated to 95 ℃ with stirring and held for 12h, then cooled to room temperature. The reaction mixture was then diluted with water (20 mL). A precipitate formed which was collected by vacuum filtration using a buchner funnel. The solid was washed with additional water (2 × 25 mL), dried and collected. This material was suspended in methanol (. About.5 mL) and treated with KOH (200 mg). After 2h, meOH was removed in vacuo, the crude material was suspended in water (-20 mL), and the resulting solid was collected by vacuum filtration using a buchner funnel. The solid was washed with additional water, collected, and dried in vacuo to give 4- (6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c]Pyridin-4-yl) phenylcarbamic acid tert-butyl ester (362mg, 0.907mmol) as a pale yellow solid. LCMS M/Z (M + H) 494.

And step 9:

Step 10:

Example 126

The inhibitory activity of representative compounds on bromodomains can be assessed using known methods or using one of the following assay protocols.

IC of inhibitors using BRD4 AlphaLisa binding assay ₅₀ Measuring

BRD4BD1 marked with His/Flag epitope _42-168 Cloning, expression and purification to homogeneity. BRD4 binding and inhibition was assessed by monitoring the binding of biotinylated H4-tetraacetylpeptide (New England Peptide, NEP 2069-1/13) to the target using the AlphaLisa technique (Perkin-Elmer). Specifically, BRD4 (BD 1) (30 nM final) was mixed with peptide (200 nM final) in 40mM HEPES (pH 7.0), 40mM NaCl, 1mM DTT, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 in 384 well ProxiPlates in the presence of DMSO (1.2% DMSO final) or serial dilutions of the compounds in DMSO. After 20 min incubation at room temperature, alpha streptavidin donor beads and AlphaLisa anti-Flag acceptor beads were added to final concentrations of 10ug/mL each. After 3 hours of equilibration, the plates were read on an Envision instrument and IC calculated using four parameter nonlinear curve fitting ₅₀ 。

IC of inhibitors using BRD9 AlphaLisa binding assay ₅₀ Measuring

BRD9 tagged with His/Flag epitope _134-239 Cloning, expression and purification to homogeneity. BRD9 binding and inhibition was assessed by monitoring the binding of biotinylated H4-tetraacetylpeptide (New England Peptide, NEP 2069-11/13) to the target using AlphaLisa technology (Perkin-Elmer). Specifically, in 384-well ProxiPlates, BRD9 (final 50 nM) and peptide (final 3 nM) were combined in the presence of DMSO (final 0.8% DMSO) or serial dilutions of the compound in DMSO at 50mM HEPES (pH 7.5), 150mM NaCl, 1mM TCEP, 0.01% (w/v) BSA and0.008% (w/v) Brij-35. After 20 min incubation at room temperature, alphaLisa streptavidin acceptor beads (Perkin-AL 125C) and AlphaLisa nickel donor beads (Perkin AS 10 ID) were added to final concentrations of 15ug/mL each. After equilibrating for ninety minutes in the dark, each plate was read on an Envision instrument and IC calculated using a four parameter non-linear curve fit ₅₀ 。

IC of inhibitors determined using TAF1-BD2TR-FRET binding ₅₀ Measuring

TAF1-BD2 tagged with His/Flag epitope _1504-1635 Cloning, expression and purification to homogeneity. TAF1-BD2 binding and inhibition was assessed by monitoring the binding of biotinylated small molecule compound 1000 (example 124) to the target using TR-FRET assay technique (Perkin-Elmer). Specifically, TAF1-BD2 (final 6 nM) was mixed with biotin-ligand (final 50 nM) in 50mM HEPES (pH 7.5), 50mM NaCl, 1mM TCEP, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 in 384 well ProxiPlates in the presence of DMSO (final 0.2% DMSO) or serial dilutions of the compounds in DMSO. After incubation for 10min at room temperature, eu-W1024 anti-6 XHis antibody (Perkin Elmer AD 0110) and SureLight were added ^TM A mixture of allophycocyanin-streptavidin (APC-SA, perkin Elmer CR 130-100) to final concentrations of 0.2nMolar antibody and 25nMolar APC-SA, respectively. After twenty minutes of equilibration, plates were read on an Envision instrument and IC calculated using a four parameter nonlinear curve fit ₅₀ . The novel compound 1000 and the above-described TAF1-BD2TR-FRET binding assay represent additional embodiments of the present invention.

IC of inhibitors using CECR2TR-FRET binding assay ₅₀ Measuring

His/Flag epitope-tagged CECR2 _424-538 Cloning, expression and purification to homogeneity. CECR2 binding and inhibition was assessed by monitoring the binding of biotinylated small molecule compound 1001 (example 125) to the target using TR-FRET assay technique (Perkin-Elmer). Specifically, CECR2 (final 1.5 nM) was combined with biotin-ligand (final 25 nM) in 384-well ProxiPlate in the presence of DMSO (final 0.2% DMSO) or serial dilutions of the compound in DMSO at 50mM HEPES (pH 7.5), 50mM NaCl, 1mM TCEP, 0.01% (w/v) BSA and 0.008% w/v Brij-35. After 15min incubation at room temperature, eu-W1024 anti-6 XHis antibody (Perkin Elmer AD 0110) and SureLight were added ^TM A mixture of allophycocyanin-streptavidin (APC-SA, perkin Elmer CR 130-100) to final concentrations of 0.2nMolar antibody and 12.5nMolar APC-SA, respectively. After forty minutes of equilibration, plates were read on an Envision instrument and IC calculated using a four parameter nonlinear curve fit ₅₀ . The novel compound 1001 and the above-described CECR2TR-FRET binding assay represent further embodiments of the present invention.

Data for representative compounds of formula (I) from the four assays described above are provided in the table below.

While a number of embodiments have been described, these examples can be varied to provide other embodiments that utilize the compounds and methods described herein. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description of the specific embodiments.

Claims

1. A compound of formula (I) or a salt thereof:

wherein:

R ¹ is butyl, 2-cyclopropylethyl, cyclopentylmethyl, 2-penten-1-yl, cyclohexylmethyl, cyclobutylmethyl, 2-cyclohexylethyl, pentyl, 2-methylpropyl, 2-buten-1-yl, 2-furalPyranylmethyl, 3-methylbut-1-yl, 2-propenyl, 3-methyl-2-buten-1-yl, 3-buten-1-yl, 2-methoxyethyl, 3-methoxypropyl, or 4-methoxybenzyl;

R ² is H, C _1–12 Alkyl radical, C _2–12 Alkenyl radical, C _2–12 Alkynyl or C _3–8 Cycloalkyl radicals in which each C is _1–12 Alkyl radical, C _2–12 Alkenyl radical, C _2–12 Alkynyl or C _3–8 Cycloalkyl is optionally substituted by one or more radicals R ^b Substitution;

q is:

each R ^b Independently selected from oxo, C _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2–6 Alkynyl, halo C _1-6 Alkyl, carbocyclyl, heterocyclyl, -F, -Cl, -Br, -I, -NO ₂ 、-N(R ^w ) ₂ 、-CN、-C(O)-N(R ^w ) ₂ 、-S(O)-N(R ^w ) ₂ 、-S(O) ₂ -N(R ^w ) ₂ 、-O-R ^w 、-S-R ^w 、-O-C(O)-R ^w 、-O-C(O)-O-R ^w 、-C(O)-R ^w 、-C(O)-O-R ^w 、-S(O)-R ^w 、-S(O) ₂ -R ^w 、-O-C(O)-N(R ^w ) ₂ 、-N(R ^w )-C(O)-OR ^w 、-N(R ^w )-C(O)-N(R ^w ) ₂ 、-N(R ^w )-C(O)-R ^w 、-N(R ^w )-S(O)-R ^w 、-N(R ^w )-S(O) ₂ -R ^w 、-N(R ^w )-S(O)-N(R ^w ) ₂ and-N (R) ^w )-S(O) ₂ -N(R ^w ) ₂ Wherein said C is _1–6 Alkyl radical, C _2–6 Alkenyl radical, C _2-6 Alkynyl, halo C _1-6 Alkyl, carbonCyclyl or heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, halo, -NO ₂ 、-N(R ^w ) ₂ 、-CN、-C(O)-N(R ^w ) ₂ 、-S(O)-N(R ^w ) ₂ 、-S(O) ₂ -N(R ^w ) ₂ 、-O-R ^w 、-S-R ^w 、-O-C(O)-R ^w 、-C(O)-R ^w 、-C(O)-O-R ^w 、-S(O)-R ^w 、-S(O) ₂ -R ^w 、-C(O)-N(R ^w ) ₂ 、-N(R ^w )-C(O)-R ^w 、-N(R ^w )-S(O)-R ^w 、-N(R ^w )-S(O) ₂ -R ^w And C _1–6 Radical substitution of alkyl, said C _1–6 Alkyl is optionally substituted with one or more groups independently selected from oxo and halogen;

each R ^wa Independently selected from hydrogen and C _1–6 An alkyl group, a carboxyl group,

with the proviso that the compound of formula (I) is not wherein R ¹ Is propyl, propyl substituted by halogen or C substituted by-OH _2–3 Alkyl compounds.

2. A compound of claim 1, wherein R is ² Is H.

3. The compound of claim 1, or a salt thereof, wherein R ² Is C _1–12 Alkyl optionally substituted by one or more radicals R ^b And (4) substitution.

4. The compound of claim 1, or a salt thereof, wherein R ² Is methyl.

5. A compound selected from:

6-but-3-enyl-4- [ 1-methyl-6- (morpholine-4-carbonyl) benzoimidazol-4-yl ] -1H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (E) -but-2-enyl ] -4- [ 4-chloro-5- (morpholine-4-carbonyl) -2-pyridyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one;

6-butyl-4- [ 3-methoxy-5- (morpholine-4-carbonyl) -2-pyridyl ] -2-methyl-1H-pyrrolo [2,3-c ] pyridin-7-one,

or a salt thereof.

6. A composition comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

7. The composition of claim 6, in combination with an additional therapeutic agent.

8. The composition of claim 7, wherein the additional therapeutic agent is a chemotherapeutic agent.

9. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a bromodomain-mediated disorder in an animal.

10. The use of claim 9, wherein the disorder is cancer, an inflammatory disorder or an autoimmune disease.

11. The use of claim 10, wherein the disorder is cancer and the cancer is selected from the group consisting of carcinoma and sarcoma.

12. The use of claim 10, wherein the disorder is cancer and the cancer is selected from solid tumors.

13. The use of claim 10, wherein the disorder is cancer and the cancer is selected from leukemia.

14. The use of claim 10, wherein the disorder is cancer and the cancer is selected from lung cancer, breast cancer, pancreatic cancer, colorectal cancer and melanoma.

15. The use according to claim 10, wherein, wherein the disorder is cancer and the cancer is selected from acoustic neuroma, acute leukemia, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, bronchial carcinoma, cervical carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, colon carcinoma, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic changes, embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor positive breast carcinoma, essential thrombocytosis, ewing's tumor, fibrosarcoma, follicular lymphoma, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, liver carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, and combinations thereof lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and wilms ' tumor.

16. The use of claim 10, wherein the disorder is cancer and the cancer is colorectal cancer.

17. The use of claim 10, wherein the disorder is cancer and the cancer is selected from germ cell testicular cancer, hepatocellular carcinoma, lymphangiosarcoma, and papillary carcinoma.

18. The use of claim 10, wherein the condition is cancer and the cancer is selected from acute lymphocytic leukemia, acute myelogenous leukemia, acute T-cell leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and lymphoblastic leukemia.

19. The use of claim 10, wherein the disorder is an inflammatory disorder or an autoimmune disease and the inflammatory disorder or autoimmune disease is selected from addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, behcet's disease, bullous skin disease, chronic obstructive pulmonary disease, crohn's disease, dermatitis, eczema, giant cell arteritis, fibrosis, glomerulonephritis, hepatic vascular occlusion, hepatitis, hypophysitis, immunodeficiency syndrome, kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, takayasu's arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and wegener's granulomatosis.

20. The use of claim 10, wherein the disorder is an inflammatory disorder or an autoimmune disease and the inflammatory disorder or autoimmune disease is an inflammatory bowel disease.

21. The use of claim 9, wherein the bromodomain is selected from the group consisting of ASH1L, ATAD, ATAD2B, BAZ A, BAZ1B, BAZ2A, BAZ B, BPTF, BRD1, BRD2, BRD3, BRD4, BRD7, BRD8, BRD9, BRDT, BRPF1, BRPF3, BRWD1, BRWD3, CECR2, CREBBP aka, CREBBP CBP, EP300, GCN5L2, KIAA2026, MLL4, PBRM, PCAF, PHIP, SMARCA2, SMARCA4, SP100, SP110, SP140, SP L, TAF, tft 1L, TRIM, TRIM28, TRIM33, TRIM66, ynd 3711.

22. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prophylactic or therapeutic treatment of a bromodomain-mediated disorder.

23. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a bromodomain-mediated disorder in an animal.

24. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for increasing the efficacy of a cancer treatment comprising a cytotoxic agent in an animal.

25. The use of claim 24, further comprising administering a cytotoxic agent to the animal.

26. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for delaying or preventing the development of cancer resistance to a cytotoxic agent in an animal.

27. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for prolonging the duration of response to a cancer treatment in an animal, wherein the duration of response to the cancer treatment when the compound, or pharmaceutically acceptable salt thereof, is administered is prolonged relative to the duration of response to the cancer treatment in the absence of administration of the compound, or pharmaceutically acceptable salt thereof.

28. (a) Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and (b) a cytotoxic agent, in the manufacture of a medicament for treating cancer in an individual.

29. The use of claim 28, wherein the cytotoxic agent is selected from the group consisting of antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-a inhibitors, fatty acid biosynthesis inhibitors, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and cancer metabolism inhibitors.

30. The use of claim 28, wherein the cytotoxic agent is an antimetabolite.

31. The use of claim 28, wherein the cytotoxic agent is a taxane.

32. The use of claim 31, wherein the taxane is paclitaxel or docetaxel.

33. The use of claim 28, wherein the cytotoxic agent is a platinum agent.

34. The use of claim 28, wherein the cytotoxic agent is an antagonist of EGFR.

35. The use of claim 34, wherein the antagonist of EGFR is N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine or a pharmaceutically acceptable salt thereof.

36. The use of claim 28, wherein the cytotoxic agent is a RAF inhibitor.

37. The use of claim 36, wherein the RAF inhibitor is a BRAF or CRAF inhibitor.

38. The use of claim 36, wherein the RAF inhibitor is vemurafenib.

39. The use of claim 28, wherein the cytotoxic agent is a PI3K inhibitor.